DE1235304B - Process for the production of new phenylcyclohexylalkylamines or their salts - Google Patents

Description

, - 500

fcDESREPUBLIC OF GERMANY

L ' T SC H ES

PATENT OFFICE

EDITORIAL

Int. CL: C 07 c

German KL: 12 ο - 25

C87C

Number: 1 235 304

File number: B 70885 IVb / 12o

Filing date: February 26, 1963

Open date: March 2, 1967

87 /

The present invention relates to the preparation of new phenylcyclohexylalkylamines general formula I,

in which R _{1 is} hydrogen or a lower alkyl radical, R ₂ and R _{3 are} hydrogen, hydroxy, alkoxy, methylenedioxy or aralkoxy radicals and η is 2 or 3, or their salts.

It has been found that these compounds have coronary vasodilator effects; she should be used as medicinal products.

The new compounds are prepared by methods which are customary per se. The inventive The method is characterized in that either in a known manner a) Amines of the general formula II

Ri

(CH ₂ ) "- NH

(Π)

in which Ri and "the meaning given above have, together with phenylpropanones of the general formula III,

(III)

in what R? and Rj has the meaning given above have, catalytically hydrogenated, by means of nascent hydrogen, such as with sodium amalgam, Lithium aluminum or sodium borohydride, or electrolytically reduced or

Method of making new
Phenylcyclohexylalkylamines or their salts

Applicant:

C. F. Boehringer & Soehne G. m. B. H..

Mannheim-Waldhof

Named as inventor:

Dr. phil. Erich Haack, Heidelberg;

Tues. nat. Alfred Popelak, Mannheim;

Dr. rei. nat. Gustav Lettenbauer,

Lampertheim (Hess.);

Dr. med. Wolfgang Schaumann,

Mannheim-Waldhof;

Dr. med. Klaus Ritter, Mannheim

b) Amines of the general formula II with a halide of the general formula IV

(IV)

in which R ₂ and R _{3 have} ^{the meaning given above, reacts ode r} in the presence of hydrogen halide binding agents and common solvents
c) amines of the general formula V.

(V)

in which Ri, R ₂ and R? have the meaning given above, with a halide of the general formula VI

(CH ₂ ) " - Shark

(VI)

in which η has the meaning given above, if appropriate in the presence of agents which bind hydrogen halide, or

70S 517/569

d) Carboxamides of the general formula VII

OR ₁

(CH ₂ ), -! - C - N - CH - CH ₂ CH ₃

in which Ri, R ₂ , Ra and η have the meaning given above, reduced to the corresponding amines by means of complex metal hydrides, such as lithium aluminum hydride, in suitable solvents,

whereupon the compounds obtained - if R _{1 is} a hydrogen atom - are subsequently alkylated on nitrogen in the usual way or - if R ₂ and R _{3 are} alkoxy or aralkoxy groups - converted in the usual way into the corresponding hydroxy compounds and the compounds obtained in an converted into their salts in a known manner.

In method a), the amine of the general formula II can also be used first with the phenylpropanones of the general formula III reacted and then reduced the condensation product obtained will. The reduction is carried out in each case by catalytic hydrogenation or by means of nascent Hydrogen, e.g. B. with sodium amalgam, lithium aluminum hydride or sodium borohydride, or else effected electrolytically. The known ones are used to carry out the catalytic reduction Catalysts, e.g. B. noble metal catalysts, nickel catalysts or Raney catalysts in usual Solvents, e.g. B. alcohols or aqueous alcohols.

When the amines of the general formula II are reacted with the halides of the general formula Formula IV or the amines of the general formula V with the halides of the general formula VI it is advisable to use a second mole of the amine used to bind the hydrogen halide released applied. However, other common substances such as alkali or alkaline earth metal hydroxides can also be used or carbonates, and organic bases, e.g. B. pyridine and triethylamine can be used. the The reaction takes place in common solvents such as aromatic hydrocarbons, ethers, cyclic ones Ethers and halogenated hydrocarbons.

The reduction of the carboxamides of the general formula VII is carried out by means of complex metal hydrides (e.g. lithium aluminum hydride) in suitable solvents (ether, tetrahydrofuran) executed.

The subsequent N-alkylation of the process products of the general formula 1 (R ₁ = hydrogen) can be carried out in a customary manner, e.g. B. by catalytic hydrogenation in the presence of appropriate aldehydes, by acylation and subsequent reduction using complex metal hydrides or by reaction with the corresponding alkyl halides.

In the event that R ₂ and R _{3 are} alkoxy or aralkoxy radicals, the products of the process can subsequently be converted into the corresponding hydroxy compounds; this is done in the usual way, e.g. B. by heating with hydrobromic acid, aluminum chloride or by catalytic hydrogenation.

The basic process products can be converted into with the help of inorganic or organic acids converted into the corresponding salts in a known manner. As inorganic acids come z. Am Question hydrohalic acids, sulfuric acid, phosphoric acid and as organic acids e.g. B. acetic acid, Lactic acid, maleic acid, tartaric acid and citric acid.

The process according to the invention is explained in more detail in the following examples.

example 1

l- [3 '- (Phenylisopropylamino) propyl] -

1-phenylcyclohexane

d) 7.3 g of N- (l'-phenylisopropyl) - ^ - (l-phenylcyclohexyl) propionic acid amide (F. 91 to 93 C from n-heptane) are dissolved in a mixture of 80 ml of ether and 40 ml of tetrahydrofuran and the solution under Stirring added dropwise to a suspension of 0.8 g of lithium aluminum hydride in 200 ml of ether. Afterward the mixture is refluxed for 5 hours.

After the excess lithium aluminum hydride has been decomposed with a saturated ammonium chloride solution, the aluminum hydroxide is separated off and the ether is evaporated. The residue is distilled in a high vacuum: boiling point _O2 = 187 to 200 ^° C., viscous, almost colorless oil (6 g). The distilled base is dissolved in tetrahydrofuran together with the molar amount of maleic acid, the solution is evaporated to dryness and the residue is recrystallized from isopropanol, mp 130 to 133 ^° C.

C ₂₄ H ₃₃ N • C ₄ H ₄ O ₄ (molecular weight 451.6).

Calculated ... C 74.46, H 8.26, N 3.10 ° / ₀ ;
Found ... C 74.41, H 8.27, N 3.12%.

b) 10 g (0.05 mol)] are phenyl-2-bromopropane with 22 g (0.1 mole) of 3- (l-phenylcyclohexyl) propylamine (Kp. = _0i3 130 to 14O ⁰ C) in 100 ml of xylene heated under reflux for 6 hours. The xylene is distilled off in vacuo, the residue is mixed with ether and extracted several times with water. After drying the ethereal solution over sodium sulphate, it is evaporated to dryness. The oily residue (16.2 g) is distilled in a high vacuum analogously to Example 1, d) and, if necessary, converted into the maleate.

60

Example 2

1- [2 '- (Phenylisopropylamino) ethyl] -1-phenylcyclohexane

a) 3.5 g of 2- (l'-phenylcyclohexyl) ethylamine (bp., == 117 to 122 ° C) and 2.9 g of phenylacetone are dissolved in 100 ml of benzene and put on a water bath for 1 hour heated to reflux; this separates water

away. After drying over sodium sulfate, the benzene is distilled off in vacuo, the residue is dissolved in 50 ml of methanol and 0.7 g of sodium borohydride is added in portions. The reaction mixture remains at room temperature for 6 hours and is then concentrated in vacuo. After adding 200 ml of water, it is extracted with ether, an ether solution is washed with water and dried over sodium sulfate. The residue (6 g) obtained after the ether has been distilled off is _{purified by distillation (bp. Ol} ^ = 175 to 190 ° C.) and converted into the maleate. The recrystallized from isopropanol maleate melts at 170 to 173 ⁰ C.

C ₂₃ H ₃₁ N • C ₄ H ₄ O ₄ (molecular weight 437.6).
Calculated ... C 74.10, H 8.06, N 3.20%;
Found ... C 74.05, H 8.36, N 3.22%.

Example 3

1- [2 '- (3 ", 4" -Methylenedioxyphenylisopropylamino) ethyl] -1-phenylcyclohexane

a) 5 g of 2- (l'-phenylcyclohexyl) ethylamine (bp _a = 117 to 122 ⁰ C) and 4.45 g of 3,4-Methylenedioxyphenylacetone are dissolved in 200 ml of methanol and after standing for 30 minutes at room temperature in Catalytically hydrogenated in the presence of 200 mg PtO _2. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the methanol is distilled off in vacuo. 9.1 g of crude 1- [2 '- (3 ", 4" -Methylenedioxyphenylisopropylamino) - ethyl] -1 - phenylcyclohexane are obtained as a viscous oil. The maleate of the base melts after recrystallization from isopropanol at 157 to 159 ° C.

C ₂₄ H ₃₁ O ₂ N · C ₄ H ₄ O ₄ (molecular weight 481.6).

Calculated ... C 69.83, H 7.32, N 2.91%;
Found ... C 70.24, H 7.32, N 3.01%.

Example 4

1- [3 '- (3 ", 4" -Methylenedioxyphenylisopropylamino) propyl] -1-phenylcyclohexane

d) Analogously to Example 1, d), 7.8 g of crude N - [Γ - (3 ", 4" - methylenedioxyphenyl) - isopropyl] - /? - (1-phenylcyclohexyl) propionic acid amide reduced with 0.8 g lithium aluminum hydride in 350 ml ether. After a similar work-up, 7.7 g of crude are obtained 1 - [3 '- (3 ", 4" - methylenedioxyphenylisopropylamino) propylj-1-phenylcyclohexane obtained as a viscous oil. The solution of the oil in ether is mixed with the calculated amount of maleic acid in ether, the precipitated Sucked off crystals and recrystallized from isopropanol. M.p. 148 to 150 ° C.

C ₂₅ H ₃₃ O ₂ N ₂ • C ₄ H ₄ O ₄ (molecular weight 495.6).
Calculated ... C 70.28, H 7.52, N 2.82%;
Found ... C 69.98, H 7.59, N 2.99%.

Example 5

l- {3 '- [N-methyl-N- (3 ", 4" -methylenedioxy-

phenyl) isopropyl] aminopropyl} -l-phenyl-

cyclohexane

172 g of the base prepared according to Example 4, d) are hydrogenated together with 1 ml of 40% strength formaldehyde solution in 60 ml of methanol in the presence of 50 mg of PtO ₂ until the uptake of hydrogen has ceased. After the methanol has been distilled off, the residue is taken up in ether, washed with dilute ammonium hydroxide, the ethereal solution is dried over sodium sulphate and evaporated to dryness in vacuo. The compound (1.7 g) obtained is a viscous colorless oil. The oxalate of the base, recrystallized from isopropanol-methylene chloride, melting at 141 to 143 ⁰ C.

C ₂₆ H ₃₅ O ₂ N · C ₂ H ₂ O ₄ (molecular weight 483.6).
Calculated ... C 69.54, H 7.71, N 2.89%;
found ... C 69.48, H 7.72, N 2.94%.

Example 6

1- [3 '- (p-Benzyloxyphenylisopropylamino) propyl] -1 -phenylcyclohexane

a) Analogously to Example 2, a), 3 g of 3- (l'-phenylcyclohexyl) propylamine and 3.47 g of p-benzyloxyphenylacetone are reduced with sodium borohydride. After the reaction mixture has been worked up, the very viscous ether residue (6.25 g) is taken up in ether, the ether solution is acidified with ethereal hydrochloric acid and the precipitated hydrochloride is recrystallized from isopropanol-methylene chloride. The salt obtained in this way melts at 153 to 155 ^° C.

C ₃₁ H ₃₉ NO • HCl (molecular weight 478.1).

Calculated ... C 77.87, H 8.44, N 2.93, Cl 7.42%; Found ... C 78.09, H 8.76, N 2.96, Cl 7.84%.

Example 7

1- [2 '- (p-Benzyloxyphenylisopropylamino) ethyl] -1-phenylcyclohexane

a) Analogously to Example 2, a), 4.6 g of 2- (l'-phenylcyclohexyl) ethylamine are added and 4.6 g of p-benzyloxyphenylacetone reduced with sodium borohydride. After work-up of the reaction mixture, the very viscous ether residue (8.8 g) is dissolved in ether, with the calculated Amount of maleic acid is added and the precipitated maleate is recrystallized from isopropanol; M.p. 165 to 168 ° C.

C ₃₀ H ₃₇ NO • C ₄ H ₄ O ₄ (molecular weight 543.66).
Calculated ... C 75.10, H 7.60, N 2.58%;
found ... C 75.26, H 7.35, N 2.65%.

Examples

1- [2'- (p-Hydroxyphenylisopropylamino) ethyl] -1-phenylcyclohexane

2.2 g of the 1- [2 '- (p-benzyloxyphenylisopropylamino) -ethyl] -l-phenylcyclohexane base prepared according to Example 7, a) are dissolved in 50 ml of methanol and after addition of 2.7 ml of lN hydrochloric acid in the presence hydrogenated by 100 mg of palladium-carbon until the hydrogen uptake ceases. To The catalyst is suctioned off, the solution is mixed with 20 ml of water and the methanol in vacuo distilled off. The hydrochloride deposited (1.7 g) is filtered off with suction and recrystallized from methanol; F. 259 to 261 ° C.

C ₂₃ H ₂₉ NO • HCl (molecular weight 371.95).

Calculated ... C 74.27, H 8.13, H 3.77, Cl 9.53%; Found ... C 74.15, H 8.44, N 3.69, Cl 9.42%.

Example 9

1- {3 '- [(3 ", 4" -Dimethoxyphenyl) isopropylamino] propyl} -1-phenylcyclohexane

a) Analogously to Example 2, a), 8.5 g of 3- (l'-phenylcyclohexyl) propylamine are obtained and 8.1 g of 3,4-dimethoxyphenylacetone reduced with sodium borohydride. the The viscous crude base obtained (15.6 g) is chromatographed on 200 g of aluminum oxide with ether as the solvent cleaned; the purified base is a viscous colorless oil. The oxalate of the base melts again Recrystallization from isopropanol-methylene chloride at 180 to 182 ° C.

C ₂₆ H ₃₇ NO ₂ • C ₂ H ₂ O ₄ (molecular weight 485.6).
Calculated ... C 69.25, H 8.10, N 2.88%;
Found ... C 69.24, H 7.84, N 3.20 ° / ₀ .

Example 10

1- {3 '- [N-Ethyl-N- (3 ", 4" -methylenedioxyphenyl) isopropylamino] propyl} -1-phenylcyclohexane

9.4 g of N-acetyl-1- {3 '- [(3 ", 4" -methylenedioxyphenyl) isopropylamino] propyl} -1 -phenylcyclohexane (produced by acetylation according to Example 4, d) obtained base with acetic anhydride and pyridine) are dissolved in 100 ml of absolute ether and under Stirring added dropwise to a suspension of 0.85 g of lithium aluminum hydride in 100 ml of ether. Afterward the mixture is refluxed for 1 hour. After standing for 10 hours at room temperature If the lithium aluminum hydride is decomposed by water, the ethereal solution is separated over Dried sodium sulfate and evaporated to dryness. 8.5 g of one are obtained as residue viscous, colorless oil, which is dissolved in isopropanol and acidified with anhydrous nitric acid. After a short rub, the nitrate of the l- {3 '- [N-ethyl-N- (3 ", 4" -methylenedioxyphenyl) isopropylamino] - propyl} -1 - phenylcyclohexane. It is recrystallized from ethyl acetate and obtained colorless crystals with a melting point of 102 to 105 ° C.

C ₂₇ H ₃₇ NO ₂ • HNO ₃ (molecular weight 470.6).
Calculated ... C 68.91, H 8.13, N 5.95%;
Found ... C 68.95, H 8.17, N 6.06%.

Example 11

1- {3 '- [N-Ethyl-N- (4 "-benzyloxyphenyl) isopropyl] aminopropyl} -1-phenylcyclohexane

10.8g 1- [3 '- (4 "-Benzyloxyphenylisopropyl-amino) propyl] -1-phenylcyclohexane [s. Example 6, a)] are dissolved in 150 ml of methylene chloride, and 9.8 ml of pyridine and 11.6 ml of acetic anhydride are added. The reaction mixture remains at room temperature overnight and is then repeated several times washed with 2N hydrochloric acid and 2N soda solution. After drying the methylene chloride solution over sodium sulfate and distilling off the methylene chloride 11.8 g of the N-acetyl compound are obtained, which are dissolved in 200 ml of ether with stirring to form a suspension 1.9 g of lithium aluminum hydride are added dropwise to 100 ml of ether. The reduction is after 2 hours finished, excess lithium aluminum hydride is decomposed with water and the ether layer is separated. 10.8 g of ether residue are obtained, which, dissolved in ether, are chromatographed on 150 g of basic aluminum oxide will. 9.6 g of viscous oil can be eluted with ether, which solidifies in crystalline form on standing. Recrystallization from methanol gives 9.2 g of colorless crystals which melt at 51 to 52.5 ° C.

Q ₃ H ₄₃ NO (molecular weight 469.7).

Calculated ... C 84.39, H 9.23, N 2.98%;
found ... C 84.31, H 9.22, N 3.10%.
Equivalent weight ... 471.

Example 12

1 - [3 '- (3 "-Methoxy 1-4 -benzyloxyphenylisopropylamino) propyl] -1-phenylcyclohexane

d) 17.5 g N- (3 "-methoxy-4" -benzyloxyphenylisopropyl) - β - (1 - phenylcyclohexyl) - propionamide [prepared from 3-methoxy -A- benzyloxyphenylisopropylamin (Kp _0I2 177-180 ° C) and. / 3- (l-PhenylcyclohexyO-propionic acid chloride] dissolved in 250 ml of ether are added dropwise to a suspension of 2.75 g of lithium aluminum hydride in 100 ml of ether with stirring and then heated under reflux for 2 hours A separated ether layer gives 17 g of ether residue, which, dissolved in ether, is converted into the salt with the calculated amount of maleic acid.

C ₃₂ H ₄₁ NO ₂ • C ₄ H ₄ O ₄ (molecular weight 587.7).
Calculated ... C 73.57, H 7.72, N 2.38%;
found ... C 73.20, H 7.79, N 2.48%.

Example 13

(+) - 1- [3 '- (3 ", 4" -Methylenedioxyphenylisopropylamino) propyl] -1-phenylcyclohexane

d) 8 g of (+) - 3,4-methylenedioxyphenylisopropylamine (tartrate: [λ] *, ⁰ = + 26.8 ° in water) are dissolved in 200 ml of methylene chloride with 20 ml of pyridine and 11.3 g ^ - (l- The unpurified (+) - N- (3 ', 4'-methylenedioxyphenylisopropyl) - / 3- (l-phenylcyclohexyl) propionic acid amide (15.5 g) is converted into the amide in 200 ml of ether dissolved, added dropwise to a suspension of 3 g of lithium aluminum hydride in 70 ml of ether with stirring and heated under reflux for 3 hours The maleate (10.7 g) melts after recrystallization from ethyl acetate-methylene chloride at 155 to 157 ° C.

[«] £ = +15.2 ± 0.5 ° (in CHCl ₃ ; c ~ 1%).
C ₂₆ H ₃₃ NO ₂ • C ₄ H ₄ O ₄ (molecular weight 495.6).
Calculated ... C 70.28, H 7.52, N 2.82%;
found ... C 69.83, H 7.70, N 2.84%.

Example 14

(+) - 1- [3 '- (Phenylisopropylamino) propyl] -1 -phenylcyclohexane

d) 15 g of (+) - phenylisopropylamine are dissolved in 250 ml of methylene chloride with 27 ml of pyridine and 27.8 g

^ - (l-PhenylcyclohexyO-propionic acid chloride converted to the amide. The (+) - N- (phenylisopropyl) - β - (I - phenylcyclohexyl) - propionic acid amide (33.9 g of viscous oil) is dissolved in 400 ml of ether, added dropwise with stirring to a suspension of 7.4 g of lithium aluminum hydride in 150 ml of ether and the mixture is then refluxed for 6 hours maleic acid is converted to the salt. the maleate (35.3 g) melts after recrystallization from ethyl acetate at 158-159 ⁰ C.

[Oi] ² J = + 11.9 ± 0.5 ° (in CHCl ₃ ; c ~ 1%).
C ₂₄ H ₃₃ N • C ₄ H ₁ O ₄ (molecular weight 451.6).

Calculated ... C 74.46, H 8.26, N 3.10 ° / ₀ ;

Found ... C 74.24, H 8.17, N 3.12%.

Analogously to the maleate of (-) - l- [3 '- (Phenylisopropylaminoj-pfopylj-l-phenylcyclonexansjarblose crystals from Essigestersäureäthyl, melting at 158 ⁰ C.

[a] 2 = -11.3 ± 0.5 ° (c ~ 1% in CHCl ₃ ).
C ₂₄ H ₃₃ N • C ₄ H ₁ O ₄ (molecular weight 451.6).

Calculated ... C 74.46, H 8.26, N 3.10%;
Found ... C 74.19, H 8.29, N 3.14%.

Example 15

1- [N-ethyl-N- (phenylisopropyl) -2'-aminoethyl] -1-phenylcyclohexane

7.5 g of l- [2 '- (phenylisopropylamino) ethyl] -l-phenylcyclohexane [prepared from the maleate and alkali obtained according to Example 2, a)] are acetylated with acetic anhydride and, as in Example 10, with 1.3 g of lithium aluminum hydride in 250 ml of absolute ether reduced and worked up. 8.3 g of a colorless, oily base are obtained, which is converted into the oxalate. The oxalate (9.5 g) forms colorless crystals and, after recrystallization from ethyl acetate-methylene chloride, melts at 130 to 132 ^° C.

C ₂₅ H ₃₅ N • C ₂ H ₂ O ₁ (molecular weight 439.6).
Calculated ... C 73.77, H 8.49, N 3.18%;
found ... C 73.45, H 8.60, N 3.11%.

Example 17

1- {N-Ethyl-N - [(3 ", 4" -dimethoxyphenyl) isopropyl] -2'-aminoethyl} -1-phenylcyclohexane

8.8 g of l- [2 '- (3 ", 4" -Dimethoxyphenylisopropylamino) -äthyl] -l-phenylcyclohexane [prepared from the maleate and alkali obtained according to Example 16, a)] are acetylated and analogously to Example 10 with 1, 7 g lithium ίο aluminum hydride in 200 ml absolute ether reduced and worked up. 8.9 g of colorless, oily base, which is converted into the oxalate, are obtained. The oxalate (colorless crystals) melts after recrystallization from Essigsäureäthyl-methylene chloride at from 110 to 111.5 ⁰ C.

C ₂₇ H ₃₉ NO ₂ • C ₂ H ₂ O ₄ (molecular weight 499.6). Calculated ... C 69.71, H 8.27, H 2.80%: found ... C 69.64, H 8.22, N 3.00%.

Example 18

1- {N-Ethyl-N - [(3 ", 4" -dimethoxyphenyl) isopropyl] -3'-aminopropyl} -1-phenylcyclohexane

From 16 g of oxalate of the 1 - [3 '- (3 ", 4" - dimethoxyphenylisopropylamino) propyl] -1-phenylcyclohexane prepared according to Example 9, a) the base is prepared and acetylated in the usual way. The acetyl compound (15.6 g) is reduced analogously to Example 10 with 2.1 g of lithium aluminum hydride in 300 ml of absolute ether and worked up. The oily, colorless base is converted into the oxalate, which after recrystallization from ethyl acetate — methylene chloride colorless Forms crystals with a temperature of 165 to 167 ° C.

C ₂₈ H ₄₁ NO ₂ • C ₂ H ₂ O ₄ (molecular weight 513.6).

Calculated ... C 70.15, H 8.44, N 2.73%; Found ... C 69.66, H 8.56, N 3.02%. Equivalent weight ... found 508.

Example 16

1- [2 '- (3 ", 4" -Dimethoxyphenyl-isopropylamino) -ethyl] -l -phenylcyclohexane

a) Analogously to Example 2, a) 15 g of 2- (l'-phenylcyclohexyl) ethylamine and 14.5 g of 3,4-dimethoxyphenylacetone are reduced together with 2.8 g of sodium borohydride, and the reaction mixture is worked up. The maleate obtained in conventional manner from the base forms by recrystallization from ethyl acetate-methylene chloride as colorless crystals, melting at 128 to 130 ⁰ C.

C ₂₅ H ₃₅ NO ₂ • C ₁ H ₄ O ₄ (molecular weight 497.6).
Calculated ... C 70.00, H 7.90, N 2.81%;
Found ... C 70.17, H 8.18, N 3.09%.

Example 19

1- {N-Ethyl-N - [(4 "-benzyloxyphenylisopropyl) -2'-aminoethyl]} - 1-phenylcyclohexane

20 g of l- [N-acetyl-N- (4 "-benzyloxyphenylisopropyl) -2'-aminoethyl] -l-phenylcyclohexane [colorless oil, prepared by acetylation of the base prepared according to Example 7, a)] are in 300 ml of absolute Dissolved ether, added dropwise to a suspension of 2.5 g of lithium aluminum hydride in 200 ml of absolute ether and heated under reflux for _{3V for 2 hours with stirring} Ethyl acetate and melts at 8O ⁰ C.

C ₃₂ H ₄₁ NO • C ₂ H ₂ O ₄ (molecular weight 545.7).

Calculated ... C 74.83, H 7.94, N 2.57%; found ... C 74.27, H 8.10, N 2.58%.

Equivalent weight ... found 546. 65

The advantageous therapeutic properties of the compounds prepared according to the invention go from the following comparative tests.

709 517/569

Comparative experiments

PL 361 = PL 362 = PL 370 = PL 371 = PL 396 = PL 363 = PL 377 = PL 394 = PL 407 = PL 430 = PL 431 = PL 432 = PL 436 =

1 - [3 '- (Phenylisopropylamino) propyl] -1-phenylcyclohexane.

1- [2 '- (Phenylisopropylamino) ethyl] -1 - phenylcyclohexane.

1- [2 '- (3 ", 4" -methylenedioxyphenylisopropylamino) ethyl] -l-phenylcyclohexane. 1- [3 '- (3 ", 4" -methylenedioxyphenylisopropylamino ^ propylj-1-phenylcyclohexane.

1- {3'- [N-methyl-N- (3 ", 4" -methylenedioxyphenyl) isopropyl] aminopropyl } -l-phenyl cyclohexane.

1- [3 '- (p-Benzyloxyphenylisopropylamino) -propylj-1-phenylcyclohexane.

1- [2 '- (p-Benzyloxyphenylisopropylamino) ethyl] -1-phenylcyclohexane.

1- [2 '- (p-Hydroxyphenylisopropylamino) ethyl] -1 -phenylcyclohexane.

l- {3 '- [N-Ethyl-N- (3 ", 4" -methylenedioxyphenyl) -isopropylamino] -propyl} -l-phenyl- cyclohexane.

(+) - 1- [3 '- (3 ", 4" -Methylenedioxyphenylisopropylamino) propyl] -1-phenylcyclohexane.

(+) - 1- [3 '- (Phenylisopropylamino) propyl] -1-phenylcyclohexane.

(-) - 1- [3 '- (Phenylisopropylamino) propyl] -1 -phenylcyclohexane.

= 1- {3 '- [N-Ethyl-N- (4 "-benzyloxyphenyl) -isopropylj-aminopropylj-1-phenylcyclohexane.

40

PL 438 = 1- {3 '- [(3 "-Methoxy-4" -benzyloxyphenyl) isopropylamino] propyl } -l-phenylcyclohexane.

The above compounds were examined using the following test methods:

1. The vasodilator effect on the isolated guinea pig heart according to Langendorf f.

2. The vasodilator effect on the rabbit's hind leg through which blood flows in situ.

3. Blood pressure lowering effect in rabbits after intravenous injection.

The well-known coronary vasodilator »Segontin« (= N- [3'-phenylpropyl- (2 ')] -1, l-diphenylpropyl- (3) -amine) was used as a comparison substance. used. In all experiments, "Segontin" was used as the standard and by giving different high doses the equivalent amounts of "Segontin" and test substance are determined. In the first three columns the table shows the effectiveness of the test substance as a percentage of that of "Segontin".

Since the substances are intended to be used as coronary dilators, the ratio is the most important factor between coronary-widening effect on the one hand and general vasodilation or drop in blood pressure on the other hand. In the last two columns of the table, the coronary specificity was derived from the relation the effectiveness on the heart compared to that on the hind leg and on blood pressure.

substance
No. Gefaßerwe
heart treatment
leg Blood pressure corona
heart
leg rspecificity
heart
Blood pressure "Segontin"
PL 361 100
127 100
44 100
420 1.0
2.9 1.0
0.3 ' PL 362 170 57 70 3.0 2.4 PL 370
PL 371 154
142 49
72 68
81 3.1
2.0 1.8 PL 396 278 120 94 2.3 2.9 PL 363 209 25th 54 8.4 3.9 PL 377 102 * 63 62 1.6 1.6 PL 394 70 35 55 2.0 1.3 PL 407 201 ** 85 65 2.4 3.1 PL 430 142 72 81 2.0 1.8 PL 431 127 44 420 2.9 0.3 PL 432 125 43 400 2.9 0.3 PL 436
PL 438 284 '
305 ' - - - -

* Works three to five times longer than "Segontin".
** Works twice as long as "Segontin".
^x Due to a lack of substance, only the experiments on
Langendorff-Herz performed.

In the table above, all figures are underlined which show that the process products are superior to "Segontin". At the All new compounds (with the exception of PL 394) were significantly more effective than Langendorff hearts "Segontin"; the effect of PL 377 was roughly the same as that of "Segontin" in terms of strength, but lasted much longer, so that this substance is also superior to "Segontin".

Particularly noteworthy is the much greater coronary specificity of the new compounds in comparison to »Segontin«.

Claims (1)

Claim: Process for the production of new phenylcyclohexylalky! Amines of the general formula I, in which R _{1 is} hydrogen or a lower alkyl radical, R ₂ and R _{3 are} hydrogen, hydroxy, alkoxy, methylenedioxy or aralkoxy radicals and η is 2 or 3, or and their salts, characterized in that either in known way a) amines of the general formula II, Ri NH (Π) in which Ri and η have the meaning given above, together with phenylpropanones of the general formula III, O = C-CH ₂ - ^ J (III) CH ₃ in which R ₂ and R _{3 have} the meaning given above, catalytically hydrogenated, by means of nascent hydrogen, such as with sodium amalgam, lithium aluminum or sodium borohydride, or electrolytically reduced or b) amines of the general formula II with a halide of the general formula IV, Hal— (IV) CH ₃ Have meaning, optionally in the presence of hydrogen halide binding agents and customary solvents, or
c) amines of the general formula V, in which Ri, R ₂ and Rs have the meaning given above, with a halide of the general formula VI (CH ₂ ) ,, - Shark in which R ₂ and R ₃ the abovementioned in which η has the abovementioned meaning, if appropriate in the presence of agents which bind hydrogen halide, or d) Carboxamides of the general formula VII (CH ₂ ) ,, - 1 - C - N - CH - CH ₂ in which Ri, R ₂ , R3 and η have the meaning given above, reduced to the corresponding amines by means of complex metal hydrides, such as lithium aluminum hydride, in suitable solvents, whereupon the compounds obtained - if R _{1 is} a hydrogen atom - subsequently in the customary manner on Nitrogen is alkylated or - if R ₂ and R _{3 are} alkoxy or aralkoxy groups - converted in the customary manner into the corresponding hydroxy compounds and, if desired, the compounds obtained are converted into their salts in a manner known per se. Considered publications:
Arch. D. Pharmazie, Vol. 295, 1962, pp. 196 to 205. 70S 517/569 2. 67 © Bundesdruckerei Berlin