DE1670200A1 - New aryl-substituted piperazinylcarboxylic acid anilides and processes for their preparation - Google Patents

Description

DR. R. POSCHBNRIEDER Jl ?. ffprti.

DR E. Bt IHITNER DIPL-ING. H.-J. MÜLLER P 1 6 70 200.4

Patent attorneys

8MONCtItNBO / Sehn

rahri-Slra'Je 38 Τ 1βί η443? 55

Byk-Gulden Lomberg Chemical Factory GmbH, Constance / Lake Constance, Gottlieberstr. 25th

New aryl-substituted piperazinylcarboxylic acid anilides and processes for their preparation

The invention relates to new aryl-substituted piperazinylcarboxylic acid anilides of the formula

__ CO - A - 4

R ₂

in which R ₁ , R ₂ and R, hydrogen, a saturated or unsaturated alkyl or alkoxy radical up to 5 carbon atoms, an aralkoxy or cyanoalkyl radical with alkyl radicals up to 6 carbon atoms, where R ₁ and Rp together also denote the Can form a methylenedioxy group, A is a straight or branched, saturated one

209810/1912 - 2 -

¹ 'r / cilagen (Art · 7 ■; τ Abc · ι ι: ■? · ■ ·. -J. Ζ Jos /.-.- (..- "....». ■ ·.

or unsaturated aliphatic radical up to 7 G atoms, who also has a hydroxy, methoxy, C-I_3-alkyl, phenyl or benzyl group can carry, Y denotes hydrogen, an alkyl radical with up to 5 carbon atoms or a methoxy group or halogen-substituted phenyl radical, Z represents hydrogen, an alkyl or alkoxy radical to to 5 carbon atoms, halogen, the nitrilo- or trifluoromethyl group and X for halogen, the nitro, trifluoro methyl, nitrilo, sulfonic acid, sulfonamido, Carboxy, carbalkoxy, carboxamido, K-carbonylanilino or the 4-carbonylaminobenzenesulfonamido (i) group stands.

The process starts from halocarboxylic acid anilides of the formula

- CO - A - Hal

where R, R ₂ , R *> X and A have the meanings given and Hal is halogen, preferably chlorine and bromine. These compounds are reacted with aryl-substituted piperazines of the formula

Y Z

in which Y and Z have the meanings given. These reactions produce hydrogen halide, which is either bound by the piperazine base used, which is thus the registration

- 3 -209810/1912

appropriate reaction withdrawn and must therefore be used in excess. It is advantageous to bet the reactants to bind the hydrogen halide therefore to an auxiliary base, which with the Reaction components, in particular the specified halocarboxylic anilides, not reacted. It has been found that especially triethylamine and N-ethyldicyclohexylamine correspond to this requirement and therefore not, as could be assumed, with the halocarboxylic acid anilides react with the formation of quaternary ammonium salts and the feasibility the procedure according to the application would affect.

The process can be carried out in a temperature range of 10 to 150 G, wherein sufficient in the presence of solvents such as alcohols, acid amides, nitriles, or mixtures thereof Reaction temperatures up to about 10O ⁰ C, while in the absence of solvents, the required temperature up to 15O ⁰ C can be. By working up in a manner known per se, namely by alternately transferring the reaction products into media immiscible with water and then back into water, etc., the compounds prepared according to the process are obtained and, if necessary, obtained in pure form by recrystallization.

So much for the halocarboxylic acid anilides used as starting materials and their precursors are not known, their production is also specified, without any protection being sought for this in the context of this application.

_ 4 -209810/1912

The products obtained by the present process have valuable pharmacological properties, e.g. sedative, neuroleptic, anticonvulsive, analgesic, Ant! Histamine, ant! Serotonin and antihypertensive Effects. In addition to the toxicity information, the extent of these effects is shown in Tables 2-6 below laid down and compared to for each specified effect known substances. The following were used as such:

Chlordiazepoxide, Meprobamat, Phenobarbital, Aminophenazon, Phentolamine, Lys ergsäur eddaethylamin (LSD), Piprinhydrinat = (1-Methylpiperidyl-4) -benzhydrylether-8-Chlorortheophyllinat), triple namamines = N-Benzyl-N ¹ , N '-dimethyl -pyridylaethylenediamine.

From the tables it can be seen that the according to the application Processes produced compounds with regard to the extent of their effects compared to known substances are partially superior; In part, the superior effect of the substances according to the application is based on their lesser effect Toxicity and tolerance.

The following examples illustrate the process according to the application, the feasibility is further characterized by the bolegt compounds in Table 1. t

Examples

1. C- (1 -Ph ρ η y] ji perazi nyl-4) * - propi oiu? Üure- (2-ni tro- __ _r 4 f !> - dimeth o.y. \) -anilide (substance V β [· > 136)

In a jn ;; ung of 0.0 r AoihyJdioyc J ohexyl amine and [i, 1 r 1 - '!' Ijonylpi fiorazin i η '; () ml /' fiJancl will t-iur

/ (1H810 / 19 1 /

slowly poured a hot solution of 10 g of 4-ß-bromopropionylamino-5-nitroveratrol (the preparation of this substance and the analogous compounds and their precursors, which are required for the implementation of the registered process, is described at the end of the examples) in 50 ml of acetonitrile and the mixture 5 hours at 50 - 60 ⁰ C heated. The solvents are then drawn off in vacuo and the yellow residue is taken up in a mixture of 100 ml of water and 100 ml of benzene. After the aqueous layer has been separated off, the benzene phase is extracted twice with 50 ml of 2N hydrochloric acid each time. By alkalizing the aqueous layer with 2N NaOH, the above compound precipitates in crystalline form and is recrystallized from ethyl acetate / cyclohexane (1: 3).

Yield: 11.9 g = $ 95.3> d. Th .; Mp .: 167.5 to 168.5 ⁰ C.

2. 3- / i- (2-Methoxyphenyl) -piperazinyl-4 / -propionic acid- (2-nitro-4,5-dimethoxy) -anilide (substance B 65 140 )

A hot solution of 65 g of 3-chloropropionic acid-2-nitro-4,5-dimethoxyanilide in 500 ml of acetone is added to a solution of 48 g of 1- (2-methoxyphenyl) ~ piperazine and 25.3 g of triethylamine in 200 ml of acetone stirring poured, the mixture is kept for 12 to 14 hours at 5O ⁰ C and then diluted with 1 1 water. The above compound precipitates in crystalline form and, after washing with n-sodium carbonate solution and then with plenty of water dünnschichtohromatographisch pure.

Yield: 96.4 g = 96.4 $> d. Th.
- 146 ⁰ C.

209810/1912

M.p .: 145-146 ⁰ C.

^mm \ j "**

3. ß- (1-o-Methoxyphenylpiperazinyl-4) -propionic acid- (2-bromo-4, 5-dimeth.oxyan.ilide ( substance 66 121)

7.1 g of 4-ß-bromopropionylamino-5-bromveratrol, 4.5 g of ethyldicyclohexylamine and 6.3 g of i- (o-methoxyphenyl) piperazine are in a mixture of 25 ml of ethanol and acetonitrile for 4 1/2 hours 50 ⁰ C heated. The reaction solution is evaporated to dryness in vacuo and the colorless residue is converted into the hydrochloride by treatment with 100 ml of 2N hydrochloric acid. After washing several times with 2N hydrochloric acid and benzene, the residue is made alkaline with 2N NaOH and transferred to 60 ml of chloroform. After drying the chloroform layer over calcined K ₂ CO * and evaporating the chloroform in vacuo, the above compound is obtained, which is recrystallized from cyclohexane.

Yield: 8.0 g = 86.5. # D. Th.
M.p .: 145-146 ⁰ C.

4. ß- (1-o ~ methoxyphenylpiperazinyl-4) -propionic acid- ^ -chlor ^ .S-dimethoxyj-anilide (substance B 66 124)

5.9 g of 4-ß-bromopionylamino-5-chlorveratrol, 4.2 g of ethyldicyclohexylamine and 4.5 g of i- (o-methoxyphenyl) piperazine are in a mixture of 15 ml of ethanol and acetonitrile for 5 hours to 50-60 ⁰ C heated. After working up the reaction mixture as in Example 3 and recrystallization from cyclohexane, the compound is obtained in pure form.

Yield: 7.5 g = 94.5 # of theory
Mp .: 144-145 ⁰ C.

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5 «ß- (1 ~ o-Tolylpiperazinyl-4) -propionic acid- (2-nitro- 4,5-dimethyl) -anilia (substance B 66 130)

6.0 g of 4-ß-bromopropionylamino-5-nitro-o-xyl oil, 3 »7 g, 1- (o-tolyl) piperazine and 4.6 g of ethyldicyclohexylamine are in a mixture of 50 ml of ethanol and acetonitrile 3 heated hours at 5O ⁰ C. The reaction mixture is then diluted with 150 ml of chloroform and extracted twice with 50 ml of 2N NaOH and 50 ml of water each time. After drying the chloroform layer over KpOO, iY is evaporated to dryness and the residue is recrystallized from cyclohexane / ethyl acetate (.1: 1),

Yield: 5.8 g = 73.5 $ d.Th *
Mp. 156 to 157 ⁰ C

6. F - (1-o-methoxyphenylpiperazinyl-4) - butyric acid (2-n i tro * -4,5-dimethoxy) anilide (substance B 66 166)

60 ^ 6 g of 4-chloro-2 ~ butyric acid are nitro-4,5-dimethoxyanilide mixed well with 200 g of 1- (2-methoxyphenyl) -piperazine and 20 to 24 hours at 50 - 6O ⁰ C heated. The reaction mixture is treated with 300 ml of benzene and the 1- (2-methoxyphenyl) piperazine hydrochloride which has separated out is filtered off with suction. The filtrate is sucked out with 200 ml of 2N-b ^T alzsäure and this solution exhaustively extracted with chloroform to give the hydrochloride of the above compound changes into the chloroform phase, thesis is shaken still .2 times with j'e 50 ml of saturated NairäviinMcarbonatlÖsung that ChloroformseliioM dried over ^^^ 3 and dried iY * to dryness. The residue is umkrif-ΛηΠ i niort from ethyl acetate and provides the. oMgo connection pure Λ π ν <

- 8-. ". M ^ P fti 0/191?. ..--

Yield: 91 g = 99 1 ° of theory
Sohmp.s 155 - 156 ⁰ C.

7. 3- (1- (2-Methoxyphenyl) -piperazinyl-4) -propionic acid- (2-carbethoxy-4,5-dimethoxy) anilide (substance B 67023)

A solution of 8.94 g of 3-bromopropionic acid (2-carbethoxy-4,5-dimethoxy) anilide in 75 ml of acetonitrile is with

£ a solution of 5.4 g of 1- (2-methoxyphenyl) piperazine and 5.0 g of dicyclohexylamine combined in 75 ml of ethanol and heated for 15 hours 5O ⁰ C. Precipitated dicyclohexylamine hydrobromide is filtered off with suction and washed out well with benzene. The combined filtrates are evaporated and the oily residue is taken up in 80 ml of chloroform. By extracting the chloroform solution with 100 ml of _{2N hydrochloric acid, the hydrochlorides of =} 1- (2-methoxyphenyl) piperazine and dicyclohexylamine are transferred into the aqueous phase, while the hydrochloride of the reaction product remains completely in the chloroform phase. After the phases have separated, the chloroform layer is washed with 100 ml of 2N sodium hydroxide solution

ψ shaken, dried over potassium carbonate and evaporated. After crystallization of the residue from 50 ml of ethyl acetate, the compound is obtained in pure form, =

Yield: 7.3 g (62 fo of theory);
M.p. 126 ⁰ C.

8. 3- (i- (4-Methoxyphenyl) -piperazinyl-4) -propionic acid- (2-carbam.Yl-4,5-dlmethoxy) -anilide (Substance B 67053)

A solution of 10 g of 3-bromopropionic acid is combined (2-carbamyl-4,5-dimethoxy) anilide in 25 ml of dimethylformamide with a solution of 9.1 g of 1- (4-methoxyphenyl).

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piperazine and 3.5 g of triethylamine in 30 ml of acetone and the mixture is left to ^{stand at 50 °} C. for 8 hours * The reaction mixture is then diluted with 1 l of water and the crystal slurry is filtered off with suction. The filter cake is washed neutral with saturated sodium bicarbonate solution and plenty of water. EThen the colorless crystals have dried i. Yak. the "compound in pure lorm" is obtained by crystallization from 100 ml of ethanol.

Yield: 7.4 g ( $ 55 of theory);
Schrap .: 195 ° C

9 ♦ 3- (1-Phenylpiperazinyl-4) propionic acid (2-sulfamyl- 4,5-dimethoxy) anilide (substance B 67083)

10.7 g of 2-chloropropionic acid (2-sulfamyl-4,5-dimethoxy) ailide are reacted with 5.7 g of 1-phenylpiperazine and 3.6 g of triethylamine analogously to Example 8 and that Reaction mixture worked up. Crystallization of the crude product from 50 ml of ethyl acetate is obtained the connection in.

Yield: 7.6 g (53.4 % of DM);
M.p .; 232 ⁰ C.

The 4-ß-bromopropionylamino-5-n-nitroveratrol used in Example 1 is obtained as follows

a) In a solution of 453 g of S ^ bromopropionyl chloride in 600 ml abs. Chloroform becomes a with stirring Solution of 405 g of freshly distilled Aminoveratrol in 1 1 abs. Added dropwise chloroform. One heats up after the addition at reflux until the hydrogen chloride development stops, distilledc a.

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1200 ml of solvent at "cool 15-30 minutes to -10 ⁰ C, drained, washed with a little ethanol and dried in a vacuum. 4-ß-bromopropionylaminoveratrol is obtained in colorless needles.

Yield: 673 g = 88 $> of theory
M.p .: 143 ⁰ O.

b) To a heated to 75 ⁰ O solution of 672.8 g of 4-.beta.-Brompropionylaminoveratrol in 2500 ml of glacial acetic acid are added dropwise with stirring 500 ml of 65 $ nitric acid in 2 Stiuden, wherein the temperature at 75 - 8O ⁰ C holds. After cooling to 20 ⁰ C is sucked, Fi wäschi'faen It he RESET and with water until neutral and dried in vacuo. The result is 4-ß-bromopropionylamino-5-nitroveratrol.

Yield: 668.5 g = 85.7% of theory M.p .: 151-152 ⁰ C.

The following compounds can also be obtained analogously to procedure a):

4-ß-bromopropionylamino-1,2-methylenedioxybenzene: Yield: 65 $> d.Th.
Mp .: 150-151 ⁰ C.

4-ß-bromopropionylamino-1,2-diaethoxy-benzene: Yield: 74 # of theory

M.p .: 129-130 ⁰ C (from ethyl acetate / ethanol 1: 1)

4-ß-Brorapropionylaraino-o-xylene: yield 70 i "of theory

Melting point: 108 - 110 ⁰ C (from ethanol)

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4- ΐ - chlorobutyroylaminoveratrol:

Yield: $ 98> d.Th.

M.p .: 98 to 98.5 ⁰ C (from methanol) 4 - (/ - Chlorvaleroylaminoveratrol:

Yield: 75.7 $ of theory

Sehmp .: 84 - 86 ⁰ C (from ethanol) ß-bromopropionic acid-3,4-diisopropoxyanilide:

Yield: 59 & ά.Th,

M.p .: 101-102 ⁰ C (from cyclohexane) ß-bromopropionic acid-3,4-di-n-butoxyanilid:

Yield: 65 % of theory

Melting point: 123 - 124 ⁰ C (from ethanol) ß-bromopropionic acid-3,4-dibenzyloxyanilide:

Yield: 57% of theory

Mp .: 135 - 137 ° C (from benzene / cyclohexane 2: 1) ß-bromopropionic acid-3,4-diallyloxyanilide:

Yield: 85% of theory

M.p .: 98-100 ⁰ C (from benzene / cyclohexane 1: 1) 3-bromopropionic acid-N-ethyl-3,4-dimethoxyanilide:

Yield: $ 87> d.Th .;

Oil (after boiling with petroleum ether) 3-chlorobutyric acid-3,4-dimethoxyanilide:

Yield: 77.5 % of theory

Melting point: 117-118 ⁰ C (from ethyl acetate / cyclohexane 1: 1) 3-chloropropionic acid-3,4-dimethoxyanilide:

Yield: 85 <$> of that .

M.p .: 136.5-137 ° 0 (from ethyl acetate)

2 0 9810/1912

3-bromopropionic anilide:

Yield: 77 1 ° of theory

M.p .: 121-122 ⁰ C (from methanol)

4-chlorobutyric anilide:

Yield: 30 # of theory

M.p .: 68 - 69 ⁰ C (from ethanol #igem 50)

ß-bromopropionic acid-2-nitroanilide:

Yield: 87 "h of theory

M.p .: 92.5 - 93.5 ° C (from ethanol)

4-chlorobutyric acid-2-nitroanilide:

Yield: 81 # d.Th · m.p .: 46 - 47 ⁰ C (from ethanol)

3-bromopropionic acid-2-bromanilide:

Yield: $ 73> d.Th.

Melting point: 93 - 94 ⁰ C (from isopropanol)

4-chlorobutyric acid-2-bromanilide:

Yield: 62 ^ of theory

M.p .: 60 - 61 ⁰ C (from isopropanol)

3-bromopropionic acid-2-chloroanilide:

Yield: $ 86.5> d.Th.

Mp .: 79-80 ⁰ C (from 50 #igem ethanol)

4-chlorobutyric acid-2-chloroanilide:

Yield: 36.5 1 "theory

Sehmp .: 66 - 67 ⁰ C (from isopropanol)

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In accordance with procedure b), the compounds shown in a) are converted into the following substances obtain:

4-ß-bromopropionylamino-5-nitro-1,2-methylenedioxybenzene:

Yield: 96 # of theory

Mp .: 134-135 ⁰ C (from ethyl acetate)

4-ß-bromopropionylamino-5-nitro-1,2-diethoxybenzene:

Yield: 92 <? » d.Th.

M.p .: 130-131 ⁰ C (from methanol)

4-ß-bromopropionylamino-5-nitro ~ 1,2-dimethylbenzene:

Yield: 67 # of theory

Melting point: 112 - 115 ⁰ C (from ethanol)

4_ jf> - chlorobutyroylamino-5-nitroveratrol:

Yield: quantitative m.p .: 146-147 ⁰ C (from ethanol)

4-c / - Chlorvaleroylamino-5-nitroveratrol:

Yield: 99 _f 4 $> d.Th.

Mp .: 134-135 ⁰ C (from ethyl acetate)

ß-bromopropionic acid-2-nitr0-4 »5-diisopropoxyanilide:

Yield: $ 59> i.e.

M.p .: 91 to 93 ⁰ C (from methanol)

ß-Bromopropionic acid-2-nitro-4 _f 5-di-n-butoxyanilide: Yield: 93.5% of theory Sehmp .: 90 - 92 ⁰ C

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ß-Bromopropionic acid-2-nitro-4,5-dibenzyloxyanilide: Yield: 94 $> d.Th.
Mp .: 169 to 173 ⁰ C

ß-Bromopropionic acid-2-nitro-4, 5-diallyloxyanilide:

Yield: 76 # of theory

M.p .: 94-96 ⁰ C. (from Cycloliexan / isopropanol 10: 1)

3-chlorobutyric acid-2-nitro-4,5-dimethoxyanilide:

Yield: $ 90> d.Th.

M.p .: 124-125 ⁰ C (from ethyl acetate)

3-chloropropionic acid-2-nitro-4,5-dimethoxyanilide:

Yield: 94 # of theory

Mp .: 144-145 ⁰ C (from ethyl acetate)

3-bromopropionic acid-U-ethyl-2-nitro-4,5-dimethoxyanilide:

Yield: 34.6% of theory

Melting point: 110 - 111 ⁰ C (from ethyl acetate / cyclohexane 1: 9)

The 4-ß-bromopropionylamino-5-bromveratrole used in Example 3 is obtained as follows:

14.4 g of the 4-8-bromopropionylaminoyeratrol obtained according to a) are dissolved in 200 ml of glacial acetic acid at 50 ^° C. and a solution of 9 g of bromine in ml of glacial acetic acid is added dropwise at this temperature. The mixture is stirred for a few more minutes, poured onto 800 ml of ice water, the precipitate is filtered off with suction and washed with 40 ml of ethanol. After recrystallization of the dry crude product from methanol, the above compound is obtained in pure form. Yield: 13.4 g »74 # of theory

Mp .: 135 ⁰ C.

- 15 209810/1912

The 4-ß-bromopropionylamino-5-chlorveratrole used in Example 4 is made as follows:

To 14.4 g of the 4-ß-bromopropionylamino obtained according to a) veratrols, dissolved in 100 ml of chloroform, are 13.5 g of sulfuryl chloride at room temperature within 15 minutes added dropwise. After standing for 8 hours, the mixture is poured onto 100 ml of ice water, the chloroform layer separated and washed this neutral. After drying over magnesium sulfate, i.V. Evaporates to dryness, leaving an oily colorless residue on trituration with cyclohexane crystalline solidified. After recrystallization from cyclohexane / ithylacetat (1: 1) the above compound becomes received pure.

Yield: 12.3 g = 75 # of theory
Mp .: 121-122 ⁰ C.

The 3-bromopropionic acid (2-carbethoxy-4,5-dimethoxy) anilide used in Example 7 is obtained as follows:

a) 47.0 g of 6-Nitroveratrumsäureäthylester are in 500 ml of glacial acetic acid with the addition of 1.0 g of 10- ^ igen Palladium / carbon hydrogenated without pressure. The hydrogenated solution is filtered off with suction from the catalyst and in vacuo. evaporated. The gray residue is taken up in 170 ml of chloroform and the chloroform solution with 100 ml of saturated sodium bicarbonate solution shaken, washed with water, dried over potassium carbonate and evaporated. Of the The residue is ethyl 6-aminoverate ester in quantitative yield.

- 16 ■ 209810/1912

b) 25.7 g of ethyl 6-aminoverateate - dissolved in 100 ml of chloroform - are added dropwise to a solution of 21.4 g of 3-bromopropionyl chloride with thorough stirring and the mixture is refluxed until the evolution of hydrogen chloride has ceased. The reaction mixture is then washed with 100 ml water, 50 ml of N hydrochloric acid, 50 ml saturated sodium bicarbonate and again with 100 ml H water, dried over potassium carbonate and evaporated in vacuo. a, After crystallization of the residue from 200 ml Essigester gives the compound in pure form.

Yield: 38.6 g (92.5 $ of theory); Mp .: 132 ⁰ C.

The 3-bromopropionic acid (2-carbamyl-4,5-dimethoxy) anilide used in Example 8 is obtained as follows:

a) 69 g 6-nitro-3,4-dimethoxy-benzonitrile are dissolved in 700 ml * methanol and 100 ml of tetrahydrofuran at 60 ⁰ C, treated with 90 g of hydrazine hydrate and reduced by portionwise addition of an aqueous Raney-nickel suspension. After completion of the reduction is filtered off the catalyst and evaporated the Fl Itrat one. After chromatography on silica gel N with chloroform, the residue yields 6-amino-3,4-dimethoxybenzonitrile.

Yield 50.2 g (85% of theory);
M.p. 156 ⁰ C.

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la) 17 g of 6-amino-3,4-dimethoxybenzonitrile are with 18 g of 3-bromopropionyl chloride in the case of 3-bromopropionic acid (2-carbethoxy-4,5-dimethoxy) anilide Brought to react and worked up with each other described manner. One receives after Crystallization of the crude product from 200 ml of ethyl acetate 3-bromopropionic acid (2-carbamyl-4,5-dimethoxy) anilide.

Yield 20.75 g (75 $> theory) mp. 188 ⁰ C.

The 3-chloropropionic acid (2-sulfamyl-4,5-dimethoxy) anilide used in Example 9 is analogous to the production process for the 3-bromopropionic acid (2-carbethoxy-4 »5-dimethoxy) anilide from 6-amino 3,4-dimethoxybenzenesulfonamide and 3-chloropropionyl chloride with a yield of 66 # dG? H. receive and mp. 161 ⁰ C (from Essigester). The 6-amino-3,4-dimethoxybenzenesulfonamide is made from 6-nitro-3,4-dimethoxybenzenesulfonamide (Beilstein, Volume XI., 1st supplement, page 69) by reduction "with Raney nickel / hydrazine hydrate in a methanol-tetrahydrofuran mixture obtained 191 ⁰ C -. in a yield of 84 # of theory, and a mp of 190..

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209810/1912

Tab e TL e 1

Sub- 155 OCH ₃ R ₂ R ₃ X Y Z A. punching
No. B 158 OCH ₃ OCH ₃ H NO ₂ H o-CHj (CH ₂ J ₂ 65 159 OCH ₃ OCH ₃ H NO ₂ H o-CL (CH ₂ J ₂ 65 602 OCH ₃ OCH ₃ H NO ₂ H m-OCHj (CH ₂ J ₂ 65 601 OCHj OCH ₃ H NO ₂ H Di-CH ₃ (CH ₂ J ₂ 6th 504 OCH ₃ OCH ₃ H NO ₂ H m-CL (CH ₂ J ₂ 6th 605 OCH ₃ Supreme Court ₃ H NO ₂ H P-OCH ₃ (GH ₂ J ₂ 6 ( 603 OCH ₃ OCH ₃ H NO ₂ H P-CH ₃ (CH ₂ J ₂ 6th 122 OCH ₃ OCH ₃ H NO ₂ H p-Cl (CH ₂ J ₂ 6th 123 OCH ₃ OCH ₃ H Br H 0-CH ₃ (CH ₂ J ₂ 66 125 OCH ₃ OCH ₃ H Br H o-Cl (CH ₂ J ₂ 66 126 OCH ₃ Supreme Court ₃ H Cl H 0-GH ₃ (CH ₂ J ₂ 66 169 O - OCH ₃ H Cl H o-Eq (CH ₂ J ₂ 66 170 OG ₂ H ₅ CH ₂ - O H NO ₂ H o-CHj (CH ₂ J ₂ 66 131 CH ₃ OC ₂ H ₅ H HO ₂ H o-OCHj (CH ₂ J ₂ 66 113 OCH ₃ CH ₃ H NO ₂ H 0-OCH ₃ (CH ₂ J ₂ 66 115 OCH ₃ OCH ₃ H NO ₂ 2-CHj H (CH ₂ J ₂ 66 OCH, H Br 2-CHj H (CH ₂ J ₂ 66

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- 19 -

Table 1 (continued)

Substance no. B R

ΟΤΠ UE ₃
66 178 OCH OCH H NO ₀ H o-OCH * (CH _O )

66 287 OC ₄ H ₉ Oi) OC ₄ H ₉ Oi) H

66 288 OC ₄ H ₉ ^ i JOC ₄ H ₉ Oi) H

66 366 BzO BzO H

66 367 BzO

66 364 AO

66 365 AO

66 363 OCH ₃

66 289

BzO

AO

AO

OCH ₃

0-CH ₂ -O

66 290 OC ₂ H ₅ OC ₂ H ₅

66 370 HH

67 004 H H 67 005 H H 67 017 H H

66 379 OCH ₃ OCH ₃

66 282 OCH ₃ OCH ₃

66 380 OCH ₃ OCH ₃

67 011 H H 67 012 H H

H H H H H H H H H H H H H H H

NO ₂

NO ₂

NO ₃

NO ₂

NO ₂

NO ₂

Br

NO ₂

NO ₂

NO Cl NO

H H

H H H H H H H H H H H H H H H H

0-OCH ₃ Tn-CH ₃

O-OCH ₃ 111-CH ₃ O-OCH ₃ In-CH ₃ Tn-CP ₃ Tn-CH ₃ m-CH ₃ O-OCH ₃

0-CH ₃ Tn-CH ₃ In-CP ₃

(CH ₂ ) ₂ (CH ₂ ) ₂

(CH ₂ )

₂ ) ₂

(CH ₂ ) ₂

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- 20 -

Table 1 (continued)

Substance-
Ms. B ^R 1

67 018 HHH Br HH ( ₂ U

66 373 OGH ₃ OCH ₅ H NO ₂ H Bi-OH ₃ OH p-CH-CH

66 377 OCH ₃ OCH ₃ C ₂ H ₅ NO ₂ H B-OoH ₃

66 378 OCH ₃ OCH ₃ C ₃ H ₅ NO ₂ H m -CH ₃

66 180 OCH ₃ OCH ₃ H NO ₂ H 0-OCH ₃ (CH ₂ )

67 021 OCH ₃ OCH ₃ H Cl H p-Cl (CH ₂ ) ₂ 67 241 HHH Br H p-Br

66 336 OCH ₃ OCH ₅ H Br H p-Br

67 035 OCH ₃ OCH ₃ OCH ₃ Br H 0-OCH ₃ (CH ₂ ) ₂ 67 050 OCH ₃ OCH ₃ OCH ₃ Br H p-Br (^ 2 ^ 2

67,022 OCH ₃ OCH ₃ H NO ₂ H 0-OCH ₃ CH ₂ -CH-CH ₃

67 076 OCH ₃ OCH ₃ H NO ₂ H 0 -OC ₂ H ₅ (CH ₂ ) ₂

209810/1912

Table 1 (continued)

punching

Entry B Crystallized from P. C Yield $>

65 155 ethyl acetate 138-139 87

65 158 ethyl acetate / petroleum ether (1: 1) 143-144 78

65 159 ethyl acetate 160-161 88

6 602 Essigeeter 139 88 jf

6 601 ethyl acetate / petroleum ether (1i1) 156-157 79

6 604 cyclohexane 160 79

6,605 Cycloliexan 135-136 72

6,603 cyclohexane 131 79

66 122 Gyclonexan 131-132 75.5 66 123 Cycloliexan 144-145 71 66 125 Cyclohexane 144-145 86 66 126 Cycloliexane 154-155 88 66 169 Ethanol / Cyolohexane (#: 1) 137-138 77.5

66 170 Cyclonexane / Ethanol (7: 1) 69- 70 83 "

66 131 Cyclohexane / ethyl acetate (2: 1) 120-121 71.5

66 113 ethyl acetate 140-141 67

66 115 isopropanol / ethyl acetate (1: 1) 129-130 54

- 22 209810/1912

Table 1 (continued)

Sub-
punching
No. B 178 Crystallizes out (1: 93-95 5 the end
prey
* 66 287 Petroleum ether 2) 92-94 89 66 288 Ethyl acetate / petroleum ether 86-89 84 66 366 Ethanol 160-162 93 66 367 Ethyl acetate 133-135 5 87 66 364 Ethyl acetate 85.5-87 83 66 365 Cyclohexane 1: 1 86-89 66 66 363 Cyclohexane ) 138.5-139, 77 66 289 Ethyl acetate / cyclohexane ( 130-132 76 66 290 Ethanol 125-126 91 66 370 Ethyl acetate 98-100 91 66 004 Cyclohexane 112.5-113, 93 67 005 Methanol 69.5-70.5 84.5 67 017 Methanol 119-120 84.5 67 379 Meüi anol 1) 162-163 75.5 66 282 Ethyl acetate 107-108 63 66 380 Methanol / ethyl acetate (1: 91-92 56 66 011 Methanol 95.5-96.5 70 67 012 Ethyl acetate 90-91 50 67 Ethanol 71

- 23 -209810/1912

Table 1 (continued)

Substance-
No. B 018 Crystallizes out F. ⁰ G yield 67 373 Ethanol 92-93 48 66 377 Ethyl acetate 135-136 74 66 378 Cyclohexane / ethyl acetate (4: 1) 135-136 77 66 180
021 Ethyl acetate 118-119 74 66
67 241 Ethanol 198-200
(as Hydrochloric!)
141-142 29
74 67 336 Isopropanol 132.5-133.5 74.2 66 035 Ethyl acetate 132 63 67 050 Ethyl acetate / cyclohexane (1: 1) 118-120 75 67 022 Ethyl acetate 134.5-135.5 75 67 076 Ethanol 162-163 54.5 67 Ethyl acetate 137.5-138.5 95

BzO = benzyloxy,

AO = allyloxy,

Ethyl acetate = ethyl acetate

- 24-209810/1912

! Table .2

Lethal, sedative, neuroleptic and paralytic doses in mice

Medium > 1400 Medium ι oral Medium paralyt. dose m I.
3 ¹ P50 Red. 'PD ₅₀ Sub lethal 860 sed.neuxdL. j 38 χ • P ? ' mg «g img & g punch dose DOS. DOS. 180 15th •1 orally drum ,orally No. LD ₅₀ ILD ₅₀ 430 SD ₅₀ IND ₅₀ 30th 12th I. 28 ™ 50 1
I.
, 62 mgfcg 'mgfeg mgfcg 35 13th I.
I. 17th mgKg ¹ 40 i.p. 'orally 900 orally Χ / χ-en »tau 8th I.
■ 20th i.p. I 60 B 65 140 > 1400 38 XICDO I. I.
I.
I. 26th 28 - B 66 121 > 700 1000 33 a 38 I. 24 B 66 124 720 22nd 280 I> 1000 i ¹ 45 30th 100 B 66 166 140 17th I.
I. 20th I.
I. 10 Chlorine- I.
I. 200 250 diazep 270 8th ] I.
I. 33 oxide Mepro 659 180 1 bamat 1

50

mean lethal dose after 3 days of observation

= mean sedative dose = quotient from the sum of the following changes in behavior: inhibition spontaneous motility, sedation, muscle relaxation, loss of the ability to grip and hold

- 25 -

209810/1912

Mean neuroleptic dose = quotient from the sum of the following changes in behavior: Ptosia, Loss of whisker and ear reflexes, hypothermia and abolition of the righting reflexes

mean paralytic dose = determined with With the help of a torsion bar or a rotating wire drum.

Table 3 Anticonvulsant effect on the mouse

Sub- LD ₁ -Q a) electrical b) penta a) LD punching ? cramp methylene LD ₅₀ SS50 No. i.p. protection against
the sound.
Cramp ED ^ q
mg / kg ip tetrazole ^ ₅ O cramp > 29 B 66 121 > 700 15th protection against
the sound.
Spasm ED ₅₀ > 46 > 50 B 66 122 > 1000 9 mg / kg i.p. > 100 18th B 66 124 720 32 24 > 22 6th Pheno-
barbi-
valley 180 16 19th 11 17th Chlorine-
diazep
oxide 270 40 39 7th 32 16

26 -

209810/1912

gabile 4 Analgesic effect

(Measured on the increase in the reaction time of the mouse after placing it on a hot plate, 55 ^° C.)

Sub
punch
No. dose
mg / kg
orally Number
animals # Ve
30th »Rl. d.
.n after
60 React
L Appli
90 ion time
cation
120 B 65 140 5 30th 50 57 53 60 B 66 166 5 40 53 62 62 43 B 66 124 5 20th 53 51 53 53 Amino
phenasone 50 40 50 57 53 60

- 27 -

209810/1912

Table 5 Antinistamine and antoserotonin effects

Substance-·
No. Inhibition of the histo-
minspasm des
isol. guinea pig
chenileums
ED ₅₀ mg / 1 Inhibition of serotonin
spasm of isol.
Rat uterus
ED ₅₀ mg / 1 B 6602 0.025 0.05 B 6604 0.05 - B 6605 0.025 - B 66166 - 0.07 B 66180 0.02 - B 66282 0.0 * 5 - Piprin
hydrinate 0.015 - Triple nominal
amine 0.05 - Lyserg
acid -
dietary
amine (LSD) - 0.02
i

- 28 -

209810/1912

Table 6

Inhibition of the pressory adrenaline and boradrenaline effect in the despinalized rat and the nictitating membrane contraction of the cat in preganglionic Irritation and lowering of blood pressure in the cat.

rat 1 rat 2 3 inhibition inhibition cat cat äer the inhibition Lowering the Ä.drenal in- Norepinephrine the Blood pressure effect effect Nictitating membrane around $ 30 ED ₅₀ ED ₅₀ contr. through approx. mg / kg i.v. mg / kg i.v. ED ₅₀ mg / kg i.v. 0.075 1.0 mg / kg i.v. B 65 HO 0.065 0.9 0.35 0.05 B 66 370 0.25 ~ 1.5 0.085 0.015 B 66 124 0.05 »/ 0.8 0.2 0.04 B 66 131 0.065 0.6 0.35 0.05 B 66 166 0.075 0.7 0.080 0.02 Phentol 0.2 > 2.0 amine

T) rat despinalized

(0.01 mg / kg! -Adrenaline or noradrenaline)

2) Cat anesthetized and spinalized

3) Cat anesthetized
("Pernocton" 80 mg / kg im)

- patent claims -

- 29 -

? 09fi10 / 1912

Claims (2)

Claims 1. Aryl-substituted piperazinyloarboxylic acid anilides of the formula —A— 4 in which R ₁ , R ₂ and R, hydrogen, a saturated or unsaturated alkyl or alkoxy radical up to carbon atoms, an aralkoxy or Gyanoalkylreat with alkyl radicals up to 6 carbon atoms, where R ₁ and R ₂ together also denote Can form a methylenedioxy group, A is an unbranched or branched, saturated or unsaturated aliphatic radical with up to 7 carbon atoms, which can also carry a hydroxyl, methoxy, C ₁ -alkyl, phenyl or benzyl group, Y denotes Represents hydrogen, an alkyl radical up to 5 carbon atoms or a phenyl radical substituted by a methoxy group or halogen, Z represents hydrogen, an alkyl or alkoxy radical up to 5 carbon atoms, halogen, the nitrilo- or trifluoromethyl group and X represents halogen, the nitro, trifluoromethyl, nitrile, sulfonic acid, sulfonamido, carboxy, carbalkoxy, carboxamido, II-carbonylanilino or the 4-carbonylaminobenzosulfonamido (1) group. - 30 - 209810/1912 2. Process for the preparation of aryl-substituted piperazinylcarboxylic acid anilides of the formula CO-A-4 R ₂ in which R ₁ , Rg and R, hydrogen, a saturated or unsaturated alkyl or alkoxy radical up to carbon atoms, an aralkoxy or cyanoalkyl radical with alkyl radicals up to 6 carbon atoms, where R ₁ and Rg together also form the methylenedioxy group can, A is a straight or branched, saturated or unsaturated aliphatic radical up to 7 carbon atoms, which can also carry a hydroxy, methoxy, C ₁ , alkyl, phenyl or benzyl group, Y is hydrogen, an alkyl radical up to 5 carbon atoms or a phenyl radical substituted by a methoxy group or halogen, Z represents hydrogen, an alkyl or alkoxy radical up to 5 carbon atoms, halogen, the halo or trifluoromethyl group and X represents halogen , the nitro, trifluoromethyl, nitrile, sulfonic acid, sulfonamido, carboxy, carbalkoxy, carboxamido, N-carbonylanilino or the 4-carbonylaminobenzosulfonamido (i) group, according to claim 1, characterized in that one carboxylic acid anilides the formula - 31 209810/1912 • Ν - CO - A - Hal, in which R ₁ , R ₂ , A ^ur id A have the meanings given and Hal is halogen, m substituted piperazines of the formula ₂ , A ^ur id A the meanings given M and Hal stands for halogen, with arylsub- in which Y and Z stand for the radicals indicated, in the presence or absence of an auxiliary base which does not react with the reaction components, for example a tertiary amine, is reacted at temperatures of up to 150 ^° C. and the reaction products are isolated by working up. 209810/191?