DE1126889B - Process for the preparation of new, modified in their effect, a simplification of the reserpine molecule, substituted amines with antihypertensive and spasmolytic effects - Google Patents

Description

Process for the production of new, modified in their effect, a simplification of the reserpine molecule, substituted amines with antihypertensive and spasmolytic action It is known that the Rauwolfia alkaloid reserpine has several important pharmacological properties, whereby this substance both as an antihypertensive agent and as a sedative has found medical application. This substance has also been found to have spasmolytic activity in pharmacological studies, but so far reserpine has not found any medical application as an antispasmodic. One of the disadvantages of this compound is that this one compound has many important pharmacological properties and, in a therapeutic application, mostly only one of these effects should be used, while the other effects must in most cases be regarded as harmful side effects. Another disadvantage of reserpine is its complex chemical structure. It was found that reserpine is a compound of the formula below, that is, it has a five-membered ring system that is difficult to produce. The object on which this invention is based was to find a structurally simplified modification of the reserpine molecule, whereby on the one hand compounds that are significantly easier to prepare are obtained and on the other hand show a less complicated pharmacological effect.

It has been found that if the indolyl group (AB) in the reserpine molecule is replaced by a phenyl group and the CDE ring system is completely or partially broken, but with a CC chain between the phenyl nucleus and the (nitrogen atom and a CC chain between the nitrogen atom and the benzoyloxy group A certain group of new compounds which have this structure in common have an antihypertensive and a spasmolytic activity in the absence of the sedative effect characteristic of reserpine. The present invention relates accordingly the production of new, modified in their effect, a simplification of the reserpine molecule representing substituted amines with antihypertensive and spasmolytic effect of the formula or of salts thereof, where in the formula R and / or R2 is a hydrogen atom, a hydroxyl group, an alkoxy group or a benzyloxy group, R3 is an amino group, a hydroxyl, an alkoxy or a benzyloxy group, R4 is a hydrogen atom or a hydroxyl group, R5 is a hydrogen atom or an alkyl group, R6 is a hydrogen atom or an alkyl group, or together with the nitrogen atom and the group R, forms a piperidine ring which is optionally substituted by an alkyl group, R is a hydrogen atom, a hydroxyl group or an alkoxy group and R $ is a hydroxyl or is an alkoxy group.

Of the compounds in which R3 denotes an amino group, should in particular those in which R ,. and R2 is a hydrogen atom describe. This amino group is preferably located in the p or o position.

If in the compounds according to the invention R5 is an alkyl group, it preferably contains 1 to 4 carbon atoms and is especially a methyl group, R6 is preferably an alkyl group having 1 to 6 carbon atoms, in particular an alkyl group having 2 or 3 carbon atoms, e.g. B. an ethyl, propyl or Isopropyl group. If Y denotes an alkylene group, it contains 1 to 8 carbon atoms, preferably 3 to 7. When the group R6 with the nitrogen atom and the group Y forms an alkyl piperidyl group, this group preferably consists of one Piperidine ring with at position 3 or 4 opposite the nitrogen atom (position 1) a methylene group. In the compounds according to the invention the latter type the benzoyloxy group is attached to the methylene group. The groups Rs, Y can with the nitrogen atom also form a piperidine ring which has no alkyl substituent wearing. In this case, the benzoyloxy group is preferably on the carbon atom of the piperidine ring, which is opposite to the nitrogen atom at position 3 or 4 lies.

The antihypertensive effects of those to be described individually below Compounds have been determined, among other things, in white rats weighing around 200 g. the Animals were raised by intraperitoneal administration of 1.2 g per kilogram of body weight Ethyl urethane (200 /, aqueous solution) anesthetized.

The blood pressure was measured using a mercury manometer in the left Carotid artery measured. A heparin solution was used to reduce blood clotting used. The substances to be tested were introduced through a cannula which was inserted into the Femoral vein was involved. Before and after the introduction of the substances to be tested equal amounts of the solvent were injected to avoid any effects to be able to assess blood pressure as a result of volume changes.

The compounds prepared according to the invention generally worked a rapid drop in blood pressure that occurs shortly after the injection, usually after just 1 to 2 minutes, it reached its maximum value, whereupon it increased or decreased less rapidly until blood pressure returned to baseline was. With various compounds there is an increase in blood pressure up to the initial value very slowly, so that the duration of the blood pressure reduction at a dose of 400 y per rat was 15 to 40 minutes.

To express the lowering of blood pressure to a certain extent and substances Comparing with each other is in the table for a number of substances the value: effective dose coefficient (W.D.K.) determined. This W.D.K. becomes thereby obtained that the product of the maximum decrease in blood pressure (as a percentage of the initial value) and the duration of the decrease in blood pressure as such (in minutes) by the size of the tested Dose (into 0.1 mg per rat of about 200 g) were divided.

The dosage was chosen so that the maximum reduction in blood pressure was usually 30 to 4011 hours from the initial value.

The spasmolytic activity of the neurotropic type of those produced according to the invention Compounds were tested in vitro against carbaminoylcholine ("Doryl") according to the Magnus method according to Pflügers Archiv, 102, p. 123 and f1 (1904), and is given in the table.

If barium chloride is used as a spasmogen, it becomes spasmolytic Measured musculo-tropic effect. Among the compounds with a low W.D.K. those compounds are understood whose W.D.K. is less than about 50. Is the W.D.K. greater than about 75, these are compounds with a high W.D.K.

Is the spasmolytic activity of the compounds against »Doryl <c measured, less than 15, these are compounds with a low, spasmolytic activity against »doryle.

Is the spasmolytic activity of the compounds against barium chloride measured greater than 1/2 times papaverine, so is of compounds with a high spasmolytic Activity against barium chloride. If it is less than 1/4 times papaverine, so it concerns compounds with a low antispasmodic activity against Barium chloride.

The adrenolytic effect of the compounds prepared according to the invention was measured on an isolated rabbit spleen exposed to adrenaline in a state was held by constant contraction. The creating effect of the compounds according to the invention forms a quantitative picture of the adrenolytic effect.

The bradycardic effect of the compounds was determined by uptake of the Measured by the electrocardiogram.

In these investigations it was found that the type and size of the substituents or groups R, to R $ and Y of the compounds prepared according to the invention Art and the magnitude of the measured pharmacological effects. Based on these Perceptions could give some general rules regarding the influence of the Groups R to R $ and Y determined on the pharmacological effect of the compounds will.

An amino group in the left benzene nucleus usually causes an increase of the W.D.K. This applies in particular to compounds in which R ,. and R2 is a hydrogen atom and R3 denote a p- or o-amino group. The presence of two hydroxy groups in the left benzene nucleus is also suitable, the W.D.K. to increase, namely in the case that R1 and R2 denote p- and m-hydroxyl groups, respectively.

Alkoxy substituents in the left benzene nucleus have an increasing influence on the spasmolytic activity of the compounds, in particular if for Rl a hydrogen atom, for R2 a hydrogen atom or an alkoxy group and R3 is an alkoxy group having 1 to 4 carbon atoms. The alkoxy group is said to be preferably a methoxy or ethoxy group, in particular in the p- or m-position.

It has also been shown that RS in the form of an alkyl group, in particular a methyl group, too an increase in spasmolytic Able to bring about activity.

It has also been found that compounds prepared according to the invention, in which Y consists of a branched or unbranched alkylene chain with 3 to 7 carbon atoms, especially an alkylene group having 4 to 6 carbon atoms, a high antihypertensive and / or spasmolytic effect.

In the case of compounds prepared according to the invention which have a group where R6 and Y form a substituted or unsubstituted piperidyl group with the nitrogen atom, an increase in the antihypertensive properties could also be observed, in particular when an alkylene group having 1 to 4 carbon atoms, e.g. B. a methylene or isopropylene group is present in the 3- or 4-position to the nitrogen atom, which is directly connected to the benzoyloyx group.

Among the compounds prepared according to the invention there is one group with a high antihypertensive effect, a low spasmolytic effect, and another group with relatively low blood pressure lowering a high spasmolytic Effect too.

The first connecting group can be divided into three separate groups subdivide. The first of these subgroups contains those compounds at where R1 and R2 are hydrogen atoms, R3 is an amino group, preferably in the o- or p-position, R4 is a hydrogen atom or a hydroxyl group, but preferably a hydrogen atom, R3 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, in particular a hydrogen atom or a methyl group, R, an alkyl group with 1 to 5 carbon atoms, in particular a methyl group, Y an alkylene group with 3 to 7 carbon atoms, preferably with 3 to 5 carbon atoms, R, a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms and R8 is an alkoxy group having 1 to 4 carbon atoms denote, where R, and Re are preferably represented by methoxy groups in the p- and m-positions of the benzene nucleus should be occupied.

The second subgroup differs from the first-mentioned in that the group R, forms a piperidine ring with the nitrogen atom and the group Y. This second subgroup can be formulated in particular as follows: R1 and R2 are both a hydrogen atom and R $ is an amino group, preferably in the o- or p-position to the other substituent of the benzene nucleus. R4 is a hydrogen atom or a hydroxyl group, preferably a hydrogen atom. R5 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, preferably a hydrogen atom or a methyl group. The group R8 forms with the nitrogen atom and the group Y a ring of the formula: A is with the group: preferably linked to carbon atom 4 of the piperidine ring. In formula B, R9 denotes an alkylene group having 1 to 4 carbon atoms, preferably a methylene group in the 4-position of the piperidine ring. R7 is a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms, and R8 is an alkoxy group having 1 to 4 carbon atoms. Preferably, R 1 and R 8 are methoxy groups in the p- or m-position, based on the carbalkoxy radical of the benzene ring.

The third subgroup with high W.D.K. and almost no spasmolytic Activity consists of compounds in which R1 is a hydrogen atom, R2 and R3 a free hydroxyl group in the p- or m-position of the benzene ring, R4 a hydrogen atom, RS is a hydrogen atom or a methyl group, R6 is an alkyl group with 2 or 3 Carbon atoms, Y is an alkylene group having 3 to 5 carbon atoms, R is a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms, preferably a methoxy or Ethoxy group, and Re an alkoxy group having 1 to 4 carbon atoms, preferably denote a methoxy or ethoxy group.

The second group of compounds, that is, with high levels of spasmolytic and low antihypertensive effect, consists of compounds of the above general formula in which R1 is a hydrogen atom, R2 is a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms; R3; an alkoxy group having 1 to 4 Carbon atoms, R4 a hydrogen atom or a hydroxyl group, R5 a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, RB an alkyl group with 1 to 5 carbon atoms, Y is an alkylene group having 3 to 7 carbon atoms, R Represent hydrogen atom or an alkoxy group and Ra represent an alkoxy group. Included can be highlighted as a preferred subgroup compounds in which R1 a hydrogen atom, R2 a hydrogen atom or a p-methoxy or ethoxy group, R3 is an m-methoxy or ethoxy group, R4 is a hydrogen atom, RS is a hydrogen atom or a methyl group, Re an alkyl group with 2 or 3 carbon atoms, Y a Alkylene group with 4 to 6 carbon atoms, R, a hydrogen atom or a p-methoxy- or -ethoxy group and R e is an m-methoxy or -ethoxy group.

The pharmacological action of a number of these compounds is can be seen from the table. In the left column denotes the Roman numeral the number of the exemplary embodiment in which the establishment of the connection is described is. In the three right columns are indicated: the W.D.K., the spasmolytic Activity against »Dorylu or BaCl, further was on the compounds I, III to V, IX to XII and XIV and XV have a bradycardic effect and on the compounds 1, 11, VI to VIII found adrenolytic activity.

The making of the still new connections is in different ways possible. These manufacturing processes are explained in the following and labeled A, B, C, D and E respectively. According to method A, a compound is left of formula 1 (see formula sheet) with one of the compounds of formula IIa, IIb or IIc respond. In these formulas and in the following formulas, R1 up to and including R $ and Y have the meanings already mentioned unless otherwise stated is. In formula IIb, R denotes a lower, aliphatic hydrocarbon radical, z. B. methyl or ethyl and Hlg in formula IIc is a chlorine or bromine atom.

According to the method B, a compound of formula XII with a Reacted compound of formula XIII, where Me is a metal atom, preferably a Alkali, e.g. B. sodium or potassium atom and Hlg is a chlorine, bromine or iodine atom.

According to the method C, a compound of formula XV with a Brought compound of formula XVI to the reaction. Referred to in the latter formula X is a chlorine, bromine or iodine atom or a keto or aldehyde oxygen atom.

According to process D, in compounds of the formula XIX, the group R6, as far as it denotes a lower alkyl group, by reaction with a Compound of the formula R, Hlg introduced, in which Hlg is a bromine or chlorine atom, or with dimethyl or diethyl sulfate when R6 represents a methyl or ethyl group.

According to method E, compounds are prepared in which R4 is a hydroxyl group by adding the keto to secondary in keto compounds of the formula XX Alcohol group is hydrogenated.

The aforementioned methods A to E are usually not readily suitable for the preparation of compounds in which R3 represents an amino group, and / or in those cases in which R6 is hydrogen.

It goes without saying that in such a case the primary amino group R3 or the secondary amino group NH z. B. by introducing a benzyl or acetyl group to protect temporarily and after the end of the reaction according to known To set methods free again. For the benzyl group, this can be done by catalytic Hydrogenation, e.g. B. with hydrogen 'and finely divided precious metal, e.g. B. platinum or Palladium. The acetyl group can be saponified, e.g. B. with diluted, aqueous alkali, in the presence or absence of a lower, aliphatic alcohol, z. B. dilute, aqueous sodium or potassium hydroxide, or with dilute, aqueous, strong acids, e.g. B. hydrochloric acid or sulfuric acid, optionally in the presence of a lower, aliphatic alcohol. There is this saponification to be carried out carefully so that the benzoyl group substituted by the groups R. and Ra is not split off at the same time.

Compounds in which R3 denotes an amino group can also are prepared by of the aforementioned starting materials I, XII, XV and XIX is assumed, where R3 does not denote an amino group but a nitro group. When R6 is not a hydrogen atom, when R3 is a nitro group, the aforementioned can be used Processes A to E can be carried out without the formation of the aforementioned by-products. After the coupling reaction has ended, the nitro group is then known per se Way to reduce to the amino group, e.g. B. using tin (or iron) and hydrochloric acid or preferably by catalytic hydrogenation. Naturally, care should be taken that no reducing agent is used in this reduction, which is the benzoyloxy group can attack. It can e.g. B. with sodium and alcohol both a transesterification as a reduction of the ester group may also occur.

The following examples serve to further illustrate the invention, whereby the production of some new starting materials to be used in them is preceded becomes: a) 5-Butylamino-hexanol- (2) A solution of 43 g (0.37 mol) 5-Ketohexanol- (2) (prepared as described in Doklady Akad. Nauk., S. S. S. R., 88, p. 845 [1953]) and 33 g (0.45 mol) of butylamine in 150m1 of alcohol was taken at room temperature hydrogenated at atmospheric pressure with platinum as a catalyst. As soon as the hydrogen uptake stopped, the reaction mixture was suction filtered and the filtrate with concentrated Acidified hydrochloric acid. The alcohol was evaporated and the residue dissolved in water. This solution was washed with ether, then made alkaline and washed three times with Ether extracted. The ethereal extracts were dried over Na, SO4, filtered, the ether evaporates and the residue is distilled in vacuo. The yield was 20 g (310 /,). Boiling point 65 to 80 ° C / 0.7 mm. Equivalent weight 178 (calculated 173).

b) 5- [N-Butyl-2 '- (4 "-methoxyphenyl) -äthylamino] -hexanol- (2) A mixture from 19 g (0.11 mol) of 5-butylaminohexanol- (2) and 8 g (0.038 mol) of 4-methoxyphenylethyl bromide (prepared as described in J. Org. Chem., 9, p. 250 [1944]) was during Heated to 105 to 110 ° C for 8 hours. After cooling, there were 25 ml of dry ether added and the mixture allowed to stand for 20 hours. This was followed by 25 ml of water added and the aqueous layer separated. The ethereal layer was still washed once with 10 ml of water. The saturated aqueous layers were washed twice extracted with 10 ml of ether. These essential extracts were made with the essential Layer combined and dried over Nag SO. In the aqueous layer were through Titration 0.37 equivalents of Br ions found. The solution in ether was filtered, the ether evaporates and the residue is distilled in vacuo. The yield was 6.5 g (57 ° / a). Boiling point 158 to 162 ° C. Equivalent weight 310 (calculated 307). c) 5-Methylamino-hexanol- (1) The preparation takes place according to that described under a) Procedure. Instead of platinum, Raney nickel was used as the catalyst. Thereafter the first distillation the equivalent weight was too high, the substance was through Purified solution of the hydrochloride in water; this solution was washed with ether, then made alkaline and then extracted with ether. The essential extracts were dried over Na, S 04, filtered, the ether evaporated and the residue distilled again in vacuo. The yield was 30%. Boiling point 80 to 83 ° C / 0.8 mm. Equivalent weight 140 (calculated 13l).

d) 5- [N-Methyl-2 '- (4 "-nitrophenyl) -äthylamino] -hexanol- (1) A solution of 7 g of 5-methylamino-hexanol- (1) (0.05 mol), 11, 5 g (0.05 mol) 2- (4'-nitrophenyl) ethyl bromide (prepared according to J. Am. Chem. Soc., 62, p. 1436 [1940]) and 7.5 g (0.05 mol) Triethanolamine in 100 ml of absolute alcohol was boiled for 10 hours. The alcohol was then evaporated, 50 ml of water and 200 ml of ether were added to the residue. The ethereal layer was washed twice more with 25 ml of water. In the aqueous layer, 0, 05 equivalents of Br ions found. The ethereal layer was then extracted twice with 20 ml of 0.15 N hydrochloric acid. The aqueous solution thus obtained was made alkaline with 5 ml of 50% sodium hydroxide solution and extracted twice with 50 ml of ether The ethereal extracts were dried over Nag S 04, filtered and the ether evaporated.The yield was 1.5 g (110 /,), equivalent weight 279 (calculated 280).

e) N, N-ethyl-1'-methyl-2 '- (4 "-methoxyphenyl) -ethyl-3-carbethoxy-propionamide A solution of 57.9 g (0.3 mol) of N-ethyl-1-methyl-2- (4'-methoxyphenyl) ethylamine in 200 ml of dry benzene was stirred and cooled for half an hour a solution of 24.7 g (0.15 mol) of 3-carbethoxypropionyl chloride in a water bath at room temperature (see for its preparation: J. Am. Chem. Soc., 60, p. 402, [1938]) dry in 150 ml Benzene added. The mixture was then boiled for 3 hours while stirring, cooled and the resulting precipitate sucked off and washed with ether. The ether and benzene were evaporated from the filtrate and the residue in vacuo distilled. The yield was 46 g (950%). Boiling point 172 to 175 ° C / 0.1 mm.

f) 4- [N-Ethyl-l'-methyl-2 '- (4 "-methoxyphenyl) -äthylamino] -butanol- (1) A solution of 46 g (0.15 mol) of N, N-Ethyll'-methyl-2 '- (4 "-methoxyphenyl) -ethyl - 3 - carbäthoxypropionamid in 200 ml of dry ether was for 30 minutes a Solution of 20 g (0.5 mol) of lithium aluminum hydride in 500 ml of dry ether was added. The mixture was then boiled for 20 hours. The reaction complex was made with water decomposed, the resulting precipitate was filtered off with suction and washed with ether. The solution in ether was dried over sodium sulphate and filtered, and the ether was evaporated and the residue is distilled in vacuo. The yield was 31 g (78%). boiling point 158 to 163'C / 0.08mm. Equivalent weight 257 (calculated 265).

g) 1- (3 ', 4'-Dimethoxyphenyl) -2- (N-ethylamino) propane. propanone- (2) (J. Am. Chem. Soc., 66, p. 26 [194.4.]) and ethylamine was catalytically hydrogenated with platinum as a catalyst. The yield was 810 / ,. Boiling point 162 to 165 ° C / 13 mm. Equivalent weight 229 (calculated 223).

h) N, N-ethyl-1'-methyl-2 '- (3 ", 4" -dimethoxyphenyl) -ethyl-3-carbethoxy-propionamide The production was carried out according to the method described under e) by using the im compound described in the previous section with 3-carbethoxypropionyl chloride was made to react. The yield was 1000 / ,. That wasn't distilled Product was used for the reaction described below.

i) 4- [N-Ethyl-1'-methyl-2 '- (3 ", 4" -dimethoxyphenyl) -äthylamino] -butanol- (1) The preparation was carried out according to the method described under f) by the in the preceding Section h) was reduced with a solution of lithium aluminum hydride in ether. The yield was 700 /. Boiling point 165 to 168 ° C / 0.08 mm. Equivalent weight 297 (calculated 295).

j) 1- (3 ', 4'-Dimethoxy-benzoyloxy) -6-bromohexane A suspension of 20.5 g (0.1 mol) of the sodium salt of 3,4-dimethoxybenzoic acid in a solution of 30 g (0.12 mol) of 1,6-dibromohexane in 250 ml of dry acetonitrite was during Cooked for 90 hours. After cooling, the precipitate was filtered off with suction; from the filtrate the acetonitrile was evaporated in vacuo and the residue was distilled in vacuo. The yield was 14.5 g (420 /,). Boiling point 202 to 205 ° C / 0.5 mm. Bromine content 25.8 ° / a (calculated 23.2 ° / a). The distillation also produced 16.5 g of 1,6-dibromohexane recovered.

k) 1-Bromo-6- [N-ethyl-1 "-methyl-2" - (4 "'- methoxyphenyl) -äthylamino] -hexane hydrobromide A solution of 19.3 g (0.1 mol) N- Ethyl 1-methyl-2- (4'-methoxphenyl) ethylamine and 24.4 g (0.1 mol) 1,6-dibromohexane in 250 ml absolute alcohol were boiled for 4 hours, after which the reaction mixture was filtered off with suction and the alcohol evaporated from the filtrate. 100 ml of acetone were added to the residue, and after storage for 1 day in the refrigerator, the precipitate was filtered off with suction and dried. The yield was 21 g (48%). Bromine content (ionic): 19.7% ( calculated 18.3%).

i) 4-Hydroxy-piperidine This compound was prepared by that Di-2-carbaäthoxyäthylamin converted into the benzoyl compound and this according to a Dieckmann condensation with Na H in 3-carbaethoxy-4-oxo-N-benzoylpiperidine was converted. The latter compound was saponified, decarboxylated, and then added converted into 4-hydroxy-N-benzoyl-piperidine by catalytic reduction. By The 4-hydroxypiperidine was obtained from this saponification. This manufacture is in J. Am. Chem. Soc., 68, p. 1051 (1946).

n) N- [2 '- (4 "-Methoxyphenyl) ethyl] -4-hydroxypiperidine A mixture of 8 g (0.08 mol) of 4-hydroxypiperidine, 6.5 g (0.03 mol) of 4-methoxyphenylethyl bromide and 25 ml of benzene was boiled and the benzene was removed by distillation. After half an hour the benzene had distilled off and the residue was heated for 8 hours in an oil bath to 110 ° C. After cooling, 50 ml of ether were added, the precipitate was suctioned off and twice washed with 30 ml of ether. The ether was evaporated from the filtrate and the residue crystallized out. The yield was 4.2 g (60%). Melting point 83 to 84 ° C. Equivalent weight 250 (calculated 235). Methoxyl content 13 , 2 % (calculated 13.2%).

o) 4-Hydroxymethylpiperidine 4-Hydroxymethylpiperidine was catalytic Hydrogenation of the corresponding pyridine compound in 80% acetic acid at 60 ° C below a pressure of 4 atmospheres. Platinum was used as the catalyst (J. für Prakt. Chem., 151, p. 74 [1938]; J. Am. Chem. Soc., 69, p. 630 [1947]).

p) N- [2 '- (4 "-Nitrophenyl) ethyl] -4-hydroxymethyl-piperidine A solution of 11.5 g (0.1 mol) 4-hydroxymethylpiperidine and 11.5 g 2- (4'- Nitrophenyl) ethyl bromide (0.05 mol) in 75 ml of dry benzene was heated for 21 1/2 hours to 65 to 70 ° C. After cooling, the precipitate was filtered off with suction and the filtrate was washed twice with 10 ml of water 20 ml of 2N hydrochloric acid were extracted, and the combined 2N hydrochloric acid extracts were washed once with 20 ml of ether, the water layer was made alkaline with 20 ml of 50% sodium hydroxide solution, and the crystals formed were filtered off with suction, washed with water and dried over phosphorus pentoxide. The yield was 5.0 g (38%), melting point 125 to 127 ° C. Equivalent weight 256 (calculated 264).

q) N- [2 '- (2 "-Nitrophenyl) ethyl] -4-hydroxymethylpiperidine The preparation was carried out according to the method described under p) by reacting 4-hydroxymethylpiperidine with 2- (2'-nitrophenyl) ethyl bromide The yield was 30 %, equivalent weight 259 (calculated 264).

r) N, N-Ethyl-2 '- (4 "-äthoxyphenyl) -äthyl-3-carbäthoxy-propionamid Die Production takes place according to the process described under e) by adding N-ethyl-2- (4'-ethoxyphenyl) ethylamine was reacted with 3-carbethoxypropionyl chloride. It was here, however not the amine itself, but triethylamine used as a hydrochloric acid binder. The crude reaction product (48 g = 100%) was used directly for the further; reaction used.

s) 4- [Ethyl-2 '- (4 "-äthoxyphenyl) -äthylamino] -butanol- (1) The production found in accordance with the procedure under f); instead, by following the steps in the previous section r) the described compound was reduced with lithium aluminum hydride. The yield was 360 / ,. Boiling point 155 to 157 ° C / 0.1 mm. Equivalent weight 270 (calculated 265).

t) N, N-ethyl-1'-methyl-2 '- (4 "-ethoxyphenyl) -ethyl-3-carbethoxy-propionamide The production took place according to the method under e). by N-ethyl-1'-methyl-2 '- (4 "-ethoxyphenyl) -ethylamine was reacted with 3-carbethoxypropionyl chloride. It was here, however not the amine itself, but triethylamine used as a hydrochloric acid binder. The yield was 69 ° / a. Boiling point 182 to 193 ° C / 0.1 mm.

u) 4- [N-Ethyl-1'-methyl-2 '- (4 "-äthoxyphenyl) -äthylamino] -butanol- (1) The preparation took place according to the method under f) by the in the previous section t) The compound described was reduced with lithium aluminum hydride, the yield was 780 ° C., boiling point 149 to 153 ° C./0.08 mm, equivalent weight 277 (calculated 279).

v) N, N-ethyl-1'-methyl-2 '- (3 ", 4", 5 "-trimethoxyphenyl) -ethyl-3-carbethoxy-propionamide The preparation took place according to the process under e) by adding N-ethyl-1'-methyl-2 '- (3 ", 4", 5 "-trimethoxyphenyl) -ethylamine was reacted with 3-carbethoxypropionyl chloride. It was here, however not the amine itself, but triethylamine used as a hydrochloric acid binder. The conversion was quantitative. The crude product was used for further reaction used.

w) 4- [N-Ethyl-1'-methyl-2 '- (3 ", 4", 5 "-trimethoxyphenyl) -äthylamino] -butanol- (1) The production was carried out according to the method described under f) by using the im previous section v) described compound with lithium aluminum hydride reduced became. The yield was 45%. Boiling point 182 to 186 ° C / 0.05 mm. Equivalent weight 318 (calculated 325).

x) 1- (4'-Benzyloxyphenyl) -2-nitroethene A solution of 75 g (0.35 Mol) 4-benzyloxybenzaldehyde (J. Chem. Soc., 1935, p. 1540), 27 g (0.44 mol) nitromethane and 20 ml of batylamine in 200 ml of dry benzene was boiled for 2 hours, whereby through Distillation, the water formed was separated off. Had cooked after 2 hours about 6.5 ml of water formed. The benzene was evaporated in vacuo, and the 150 ml of petroleum ether (40 to 60 ° C.) were added to the residue. The precipitate was Sucked off, washed with petroleum ether (40 to 60 ° C) and dried. The yield was 44 g (50%). Melting point 112-114 ° C.

y) 2- (4'-Benzyloxyphenyl) ethylamine A solution of 44 g (0.17 mol) 1- (4'-Benzyloxyphenyl) -2-nitroethene in 300 ml of dry tetrahydrofuran was under Stir for one hour a solution of 30 g (0.8 mol) of lithium aluminum hydride added in 700 ml of dry tetrahydrofuran. The mixture was then 4 hours cooked with stirring. The reaction complex was decomposed with water and the resulting one Sucked off precipitate and washed with 200 or 100 ml of ether. The common Filtrates were dried over sodium sulfate, filtered and the solvents evaporated. The residue was distilled in vacuo. The yield was 20 g (53%). boiling point 170 to 174'C / 0.2 mm. Equivalent weight 235 (calculated 227).

z) N-propionyl-2- (4'-benzyloxyphenyl) ethylamine A mixture of 20 g (0.09 mol) of 2- (4'-benzyloxyphenyl) ethylamine and 100 ml of propionic anhydride Cooked for 40 minutes. The excess prepionic anhydride was then removed in vacuo evaporated and 50 ml of ether added to the residue. The precipitation became suctioned off and washed with 25 ml of ether. The yield was 18 g (72 "). Melting point 64 to 66'C.

aa) N-propyl-2- (4'-benzyloxyphenyl) ethylamine A solution of 18 g (0.064 mol) N-propionyl-2- (4'-benzyloxyphenyl) -ethylamine in 250m1 dry tetrahydrofuran was stirred within 10 minutes of a solution of 7 g (0.18 mol) of lithium aluminum hydride added in 250 ml of dry tetrahydrofuran. The reaction mixture was then Boiled for 20 hours with stirring and then decomposed by adding 15 ml of water. The precipitate was filtered off with suction and washed twice with 250 ml of ether. The common Filtrates were dried over sodium sulfate, filtered, and the solvents were evaporated. The residue was distilled in vacuo. The yield was 10 g (580 / "). Boiling point 158 to 165" C / 0.1 mm. Equivalent weight 281 (calculated 269).

bb) N, N-propyl-2 '- (4 "-benzyloxyphenyl) -ethyl-3-carbethoxy-propynamide The production was carried out according to the method described under e) by using the im previous section aa) described compound with 3-carbethoxypropionyl chloride was made to react. However, triethylamine was used here as a hydrochloric acid binder used. The crude product (14.6 g = 102%) was used immediately for the following Reaction used.

cc) 4- [N-Propyl-2 '- (4 "-benzyloxy) -phenylethylamino] -butanol- (1) Die Manufacture took place according to the method under f) by following the steps in the preceding Section bb) described compound with lithium aluminum hydride was reduced. The yield was 70 liters. Boiling point 202 to 212 ° C / 0.5 mm. Equivalent weight 334 (calculated 341).

dd) 1- (3 ', 4'-Dibenzyloxyphenyl) -2-nitropropene- (1) A solution of 60 g (0.19 mol) 3,4-dibenzyloxybenzaldehyde, 20 g (0.27 mol) nitroethane and 5.5 ml Butylamine in 100 ml of dry toluene was boiled for 18 hours while by distillation the water formed was separated off. After 18 hours of cooking they had about 3 ml of water formed. The toluene was evaporated in vacuo and the residue was a mixture of 100 ml of petroleum ether (40 to 60 ° C) and 300 ml of alcohol was added. Of the Precipitation was suctioned off and dried. The yield was 33 g (47%). Melting point 112 to 115 ° C.

ee) 1-methyl-2- (3 ', 4'-dibenzyloxyphenyl) ethylamine A suspension of 25g (0.067 mol) 1- (3 ', 4'-dibenzyloxyphenyl) -2-nitropropene- (1) in 210 ml dry Methylal quickly became a solution of 10.5 g (0.28 moles) of lithium aluminum hydride in 70 ml of dry methylal added that the reaction mixture was still boiling. After the addition, the mixture was boiled for an additional hour, then cooled and cooked through Addition of 28 ml of water decomposes. The precipitate was filtered off, twice with 70 ml of benzene and washed twice with 50 ml of ether. The filtrate was made with sodium sulfate dried, filtered, the solvents evaporated and the residue in 200 ml of ether dissolved. This solution was extracted with 150 ml of 0.4 N hydrochloric acid, and the aqueous solution was washed with 125 or 75 ml of ether. Then the aqueous Solution made alkaline by adding 40 ml of 2N sodium hydroxide solution and extracted with 150, 150 or 100 ml of ether. The common ether extracts were dried over sodium sulfate, filtered and the solvent evaporated. The yield was 13.8 g (64 ° / 0). Equivalent weight 347 (calculated 347).

ff) N-propionyl-1-methyl-2- (3 ', 4'-dibenzyloxyphenyl) ethylamine a Mixture of 15 g (0.043 mol) of 1-methyl-2- (3 ', 4'-dibenzyloxyphenyl) ethylamine and 4.0 ml of propionic anhydride was boiled for 1 hour. The excess of propionic anhydride was evaporated in vacuo and the residue was used directly for the next Reaction stage used. The yield was 100%.

gg) N-propyl-l-methyl-2- (3 ', 4'-dibenzyloxyphenyl) ethylamine The preparation took place according to the method under ee), by adding the compound described in the previous section ff) with a solution of lithium aluminum hydride in methylal was reduced. In this case, however, the reaction mixture was boiled for 2 hours. The yield was 730 / ,. Boiling point 184 to 188 ° C / 0.01 mm. Equivalent weight 386 (calculated 389).

hh) N, N-propyl-1'-methyl-2 '- (3 ", 4" -dibenzyloxyphenyl) -ethyl-3-carbethoxy-propionamide The production was carried out according to the method described under e) by using the im previous section gg) described compound with 3-carbethoxypropionyl chloride was made to react. Here, however, triethylamine was used as a hydrochloric acid binder used. The crude product (12 g = 103%) was used immediately for the next one Reaction used.

ii) 4- [N-propyl-1'-methyl-2 '- (3 ", 4" -dibenzyloxyphenyl) -äthylamino] -butanol- (1) The preparation took place according to the method under f) by the in the preceding Section described compound with lithium aluminum hydride was reduced. The yield was 890 / ,. Boiling point 210 to 220 ° C / 0.05 mm. Equivalent weight 456 (calculated 461).

jj) 3-hydroxymethylpiperidine The preparation was carried out according to the method under o). The yield was 350 / ,. Boiling point 130 to 132'C / 14 mm. Equivalent weight 119 (calculated 115).

kk) 1- [1'-methyl-2'-oxo-2 '- (4 "-benzyloxyphenyl) ethyl] -3-hydroxymethyl-piperidine hydrochloride A solution of 9.3 g (0.03 mol) of 1- (4'-benzyloxyphenyl) -3-bromopropanone-2, 3.4 g (0.03 mol) 3-hydroxymethylpiperidine and 4.5 g (0.045 mol) triethylamine in 125 ml absolute alcohol was boiled for 3 hours. The reaction mixture was increased to 75 ml evaporated and then poured into 300 ml of water. The resulting oil was with twice 125 ml of ether extracted, and the common ether extracts over sodium sulfate dried, filtered, the ether evaporated and the residue 25 ml of dry benzene added, that was vaporized on it. The residue was dissolved in 200 ml of ether and filtered. 15 ml of 2.4 N-alcoholic hydrochloric acid were slowly added to the solution in ether. A thick oil precipitate was formed, which slowly crystallized. The precipitation was sucked off and dried. The yield was 4.5 g (40 ° / 0). Melting point 156 to 159 ° C (with decomposition). Chlorine content 9.49 ° / n (calculated 9.110 / yr.

Working Examples Example I 2- (3 ', 4'-Dimethoxybenzoyloxy) -5- [N-butyl-2 "- (4"' - methoxyphenyl) -ethylamino] -hexane A solution of 3.1 g (0.01 mol) 5- [N-Butyl-2 '- (4 "-methoxyphenyl) -äthylamino] -hexanol- (2) in 80 ml of dry benzene were added 2.1 g (0.01 mol) of 3,4-dimethoxybenzoyl chloride and the solution After evaporation of the benzene, an oil was obtained which was dissolved in 15 ml of 30% alcohol, made alkaline with 5 ml of concentrated NH4OH and, after dilution with water up to 100 ml, extracted twice with 30 ml of ether Extracts were dried over NazS 04, filtered and the ether evaporated. The oily residue had a weight of 3.3 g (= 70 ° / 0). Equivalent weight 472 (calculated 471). UV absorption spectrum: UV absorption spectrum, .imax = 262.5 mb, £ imax = 7850 2zmax = 285 m &, e2max = 5200 Example II 1- (3 ', 4'-dimethoxybenzoyloxy) -5- [N-methyl- 2 "- (4"'- aminophenyl) -ethylamino-hexane] - dihydrochloride The corresponding nitro compound was according to the method described in Example 1 thereby made that 5- [N-methyl-2 '- (4 "-nitrophenyl) -ethyl- aminoj-hexanol- (1) (see d) with 3,4-dimethoxybenzoyi- chloride was esterified. This nitro compound was with palladium as a catalyst in 400 /, alcohol hydrogenated. The yield was 77%. Chlorine content 14.7 per cent (calculated 14.6%). UV absorption spectrum 2imax = 247.5 m & t elmaz = 14 400 22max = 290 m [L E2max = 6 850 Example III 1- (3 ', 4'-dimethoxybenzoyloxy) -4- [N-ethyl- I "- methyl- 2 "- (4"'- methoxyphenyl) ethylamino] butane hydrochloride The production took place according to the in Example I procedures instead of using 4- [N-ethyl 1'-me- ethyl-2 '- (4 "-methoxyphenyl) -äthylamino] -butanol- (1) (see f) esterified with 3,4-dimethoxybenzoyl chloride became. The yield was 880%. Melting point 97 up to 102 ° C. Chlorine content 7.68 "/, (calculated 7.660 / 0). UV absorption spectrum , .imaz = 262.5 with elmax = 11700 22max = 285 mp, e2max = 6,000 After crystallization from methyl ethyl ketone the rose Melting point at 105 to 107 ° C. analysis Found . . . C 64.71 ° / o, H 7.85 ° / o, N 2.97 ° / o; calculated ... C 64.73 ° / o, H 7.83 ° / o, N 3.02 ° / o. Example IV 1- (3 ', 4'-dimethoxybenzoyloxy) -4- [N-ethyl- 1 "-methyl-2" - (3 "', 4"' - dimethoxyphenyl) -ethyl- amino] butane The production took place according to the in Example I instead of using 4- [N-ethyl-1'-me- thyl-2 '- (3 ", 4" -dimethoxyphenyl) -äthylamino] -butane ol- (1) (see i) with 3,4-dimethoxybenzoyl chloride was esterted. The hydrochloride didn't want to go out Acetone, methyl ethyl ketone, alcohol and mixtures crystallize this solvent with ether. By doing the hydrochloride dissolved in water, this solution with Ammonia made alkaline and extracted with ether the free base was isolated. The yield was 93 per cent. Equivalent weight 460 (calculated 459). UV absorption spectrum Aimax = 262 m # L elnaax = 12 000 @ .zmax = 287 m # t e2max = 7 320 Example Va 1- (3 ', 4'-Dimethoxybenzoyloxy) -6- [N-ethyl- 1 "-methyl-2" - (4 "'- methoxyphenyl) -ethylamino] - hexane hydrochloride A solution of 15.5 g (0.08 mol) of N-ethyl-1-methyl-2- (4'-methoxyphenyl) -ethylamine and 13.8 g (0.04 mol) of 1- (3 ', 4' -Dimethoxybenzoyloxy) -6-bromohexane in 100 ml of dry acetonitrile was boiled for 100 hours. The acetonitrile was evaporated in vacuo and 75 ml of dry ether was added to the residue. The precipitate was filtered off with suction and the ether was evaporated from the filtrate. The residue was dissolved in 20 ml of 2N alcoholic hydrochloric acid and the alcohol was evaporated in vacuo. The residue was crystallized from a mixture of 15 ml of methyl ethyl ketone and 30 ml of ether. The yield was 15.5 g (77%). Melting point 82 to 93'C. Chlorine content 7.8% (calculated 7.2%).

UV absorption spectrum: 2imax = 262 m & t. eimax = 12 400 22max = 285 mp. e?, max = 6,300 After crystallization from a mixture of methyl ethyl ketone and ether, the melting point rose from 95 to 98 ° C. Chlorine content 7.2l) /, (calculated 7.20 / yr. Analysis: found ... C 65.84%, II 8.20 ° / o, N 3.06 ° / o. Calculated ... C 65, 70%, H 8.17%, N 2.84%. Example Vb 1- (3 ', 4'-Dimethoxybenzoyloxy) -6- [N-ethyl-1 "-methyl-1" - (4 "'-methoxyphenyl) ethylamino] hexane hydrochloride A suspension of 12 g (0.05 mol) of the sodium salt of 3,4-dimethoxybenzoic acid and 11 g (0.025 mol) 1-bromo-6- [N-ethyl-1 "-methyl-2" - (4 "-methoxyphenyl) -äthylamino] -hexan-hydrobromid (see k) in 250 ml of dry acetonitrile was 100 hours boils, whereupon the acetonitrile evaporates in vacuo became. The residue was 100 ml of water and 200 ml of ether added; the ethereal layer was separated and the aqueous layer was once with 50 ml of ether extracted. The essential extracts were combined, washed twice with 50 ml of water, dried over sodium sulfate and filtered. To the 25 ml of 2N alcoholic hydrochloric acid were added to the filtrate sets, and the precipitate was suctioned off. Of the Precipitate was formed from a mixture of 10 ml Methyl ethyl ketone and 20 ml of ether crystallized. the The yield was 6.7 g (50%). Melting point 93 to 96'C. Chlorine content 7.4 °; o (calculated 7.20, #). Example VI N- [2 '- (4 "-methoxyphenyl) -ethyl] -4- (3"', 4 "'- di- methoxybenzoyloxy) piperidine hydrochloride The production took place according to the in Example I procedures instead by using N- [2 '- (4 "-methoxy- phenyl) ethyl] -4-hydroxypiperidine (see n) with 3,4-di- methoxybenzoyl chloride was esterified. A compli- cation in this reaction formed the deposition of the Hydrochloride of N-2 '- (4 "-Methoxyphenyl) -ethyl- 4-hydroxy-piperidine, which evaded the reaction. 43% of the starting product was returned won. The yield was 29%. Melting point 210 to 211 V C. Chlorine content 7.940 /, (calculated 8.190 /,). UV absorption spectrum 7.lmax = 263 mu elmax = 13 400 i2max = 287 mu. egntax = 6 750 analysis Found ... C 63.52 ° / o, H 7.1 ° / o, N 3.24 ° / o. C 63.79 ° / 0; H 7.02 ° / 0; calculated ... C 63.38 °,! o, H 6.89 °, 'o. N 3.2101 o. Example VIIa N- [2 '- (4 "-Nitrophenyl) ethyl] -4- (3"', 4 "'- dimethoxy- benzoyloxy) methyl piperidine hydrochloride The production took place according to the in Example I procedures instead of using N- [2 '- (4 "-nitro- phenyl) ethyl] -4-hydroxy-methyl-piperidine (see p) was esterified with 3,4-dimethoxybenzoyl chloride. The yield was 580%. Melting point 210 to 211'C. Chlorine content 7.570 / " (calculated 7.640 / y. Example VIIb N- [2 '- (4 "-aminophenyl) ethyl] -4- (3"', 4 "'- di- methoxybenzoyloxy) methyl piperidine dihydrochloride The production was carried out by catalytic reduction tion of the compound described in Example VIIa. In this case, palladium was used as a catalyst turns. The yield was 500 l, melting point 272 to 273 ° C (with decomposition). Chlorine content 14.9 (calculated 15.1% ). UV absorption spectrum Aimax = 250 mb. Eimax = 15,800 A2max = 292.5 mu. -2max = 8 150 analysis Found ... C 58.46 ° / o, H 6.87 ° / o, N 5.97 ° / o, C 58.56 ° / o; H 6.95%; N, 6.08%; calcd .... C 58.590 / 0, H 6.790 / " N 5.950 / 0. Example VIII N- [2 '- (2 "-aminophenyl) ethyl] -4- (3"', 4 "'- di- methoxybenzoyloxy) -methyl-piperidine-dihydro- chloride a) N-2 '- (2 "-nitrophenyl) -ethyl-4- (3"', 4 "'- di- methoxybenzoyloxy) methyl piperidine hydrochloride The production took place according to that in Example 1 described method instead by using N- [2 '- (2 "-nitro- phenyl) ethyl] -4-hydroxy-methyl-piperidine (see q) was esterified with 3,4-dimethoxybenzoyl chloride. The substance did not crystallize and was reduced. b) The amino compound was prepared, by the compound described under VIII, a) was catalytically reduced. In this case it was Palladium used as a catalyst. The yield was 1501, (it was based on a quantitative Yield in the preparation of the nitro compound went out). Melting point 258 to 259 ° C. Chlorine- content 15.40 /, (calculated 15.1 0 /,). UV absorption spectrum @imax = 243 m (t eimax = 25 600 @ 2max = 291 rnp. 82ynax = 7,800 Analysis: Found . . C 56.66 ° / o, H 7.10 ° / o, OC H 311.43 ° / o; calculated . . C 58.59 ° / o, H 6.79 ° / o, OC H3 13.16 ° / o. Example IX 1- (4'-methoxybenzoyloxy) -4- [N-ethyl- 2 "- (4"'- ethoxyphenyl) -äthylamino] -butane-hydro- chloride The production took place according to the in Example 1 instead of using 4- [N-ethyl- 2 '- (4 "-ethoxyphenyl) -äthylamino] -butanol- (I) (see s) was esterified with 4-methoxybenzoyl chloride. the Yield was 74 ", f. Melting point 103-104 ° C. Chlorine content 8.20 "/, (calculated 8.14 UV absorption spectrum 2. "" x = 258 mu, e, nax = 17,800 Analysis: Found ... C 66.05%, H 7.99%, N 3.19 ° / a; calculated ... C 66.19 ° / o, H 7.87 ° / o, N 3.22 ° / o. Example X 1- (4'-Methoxybenzoyloxy) -4- [N-ethyl-1 "-methyl- 2 "- (4"'- ethoxyphenyl) ethylamino] butane hydrochloride The production was carried out according to the method in Example I. described method by 4- [N-ethyl-1'-methyl- 2 '- (4 "-ethoxyphenyl) -äthylamino] -butanol- (1) (see u) was esterified with 4-methoxybenzoyl chloride. the Yield was 800 / ,. Melting point 83 to 86 ° C. Chlorine content 7.93% (calculated 7.89%). UV absorption spectrum 2max = 258 mlt. smax = 17400 analysis Found ... C 64.67 ° / o; H 8.110 / " N 3.07 ° / o; calculated ... C 66.80%, H 8.07 ° / o, N 3.11 0/0. Example XI 1-) 4'-Ethoxybenzoyloxy) -4- [N-ethyl-1 "-methyl- 2 "- (4"'- ethoxyphenyl) ethylamino] butane hydrochloride The preparation took place according to the in Example I. described method instead by 4- [N-ethyl-1'- methyl-2'- (4 "-ethoxyphenyl) -ethylamino] -butanoi- (1) (see u) was esterified with 4-ethoxybenzoyl chloride. The yield was 870%. Melting point 113 to 114 ° C. Chlorine content 7,500 / 0 (calculated 7,650 / 0). UV absorption spectrum Amax = 257 mu, smax = 17300 analysis Found ... C67.630 / " H8.470 / 0, N3.080 / ,; calculated ... C67,370 / "H8,270 /,), N3,030 / ,. Example XIIa 1- (4'-Benzyloxybenzoyloxy) -4- [N-ethyl-1 "-methyl- 2 "- (4"'- ethoxyphenyl) ethylamino] butane hydrochloride The production took place according to the in Example I instead of the 4- [N-ethyl- l '- methyl - 2'- (4 "- ethoxyphenyl) - ethylamine ino] - buta - nol- (1) was esterified with 4-benzyloxybenzoyl chloride. The yield was 86 ". Melting point 114 bis 117 ° C. Chlorine content 6.73 0/0 (calculated 6.78 0/0). Example XII b 1- (4'-Hydroxybenzoyloxy) -4- [N-ethyl-1 "-methyl- 2 "- (4"'- ethoxyphenyl) ethylamino] butane hydrochloride 5.23 g (0.01 mol) of those described in Example XIIa Compound were dissolved in 75 ml of 80 " alcohol. This solution became a pre-hydrogenated, acid-free one Palladium catalyst added, which consists of 150 mg of palladium obtained medium chloride and 750 mg of decolorizing carbon and was hydrated. After the calculated amount Hydrogen had been absorbed, became the Sucked off catalyst, and the filtrate was im Vacuum dry steamed. The residue turned off 25 ml of acetone crystallized, filtered off with suction and dried. The yield was 3.55 g (820/0). Melting point 129 up to 130'C. Chlorine content 8.14 "/, (calculated 8.180 / j. UV absorption spectrum 2max = 259 m ( t smax = l7100 analysis Found ... C66.41 "/" H8.070 / "N3.20" /, -, calculated ... C66.49 "/" H7.910 / "N3.240 / 0. Example XIII 1- (4'-Methoxybenzoyloxy) -4- [N-ethyl-1 "-methyl- 2 "- (3"', 4 "', 5"'- trimethoxyphenyl) ethylamino] butane The production was carried out according to the in Example I described procedures by using 4- [N-ethyl-I'-methyl- 2'- (3 ", 4", 5 "- trimethoxyphenyl) - ethylamino] - buta - nol- (1) (see w) with 4-methoxybenzoyl chloride was esterted. The yield was 610/0. Equivalent to- weight 470 (calculated 459). UV absorption spectrum: 2rnax = 254 to 258 m # t smax = 17300 Example XIVa 1- (3 ', 4'-diethoxybenzoyloxy) -4- [N-propyl-2 "- (4"' - benzyloxyphenyl) ethylamino] butane The preparation was carried out according to the method described in Example I, by reacting 4- [N-propyl-2 '- (4 "- benzyloxy) -phenylethylamino] -butanol- (1), with 3', 4'-diethoxybenzoyl chloride. The yield was 900 /, equivalent weight 524 (calculated 532).

Example XIVb 1- (3 ', 4'-Diethoxybenzoyloxy) -4- [N-propyl-2 "- (4"' - hydroxyphenyl) ethylamino] butane hydrochloride A solution of 2.74 g (0.0045 mol) 1- (3 ', 4'-diethoxybenzoyloxy) -4- [N-propyl-2 "- (4"' - benzyloxyphenyl) ethylamino] butane hydrochloride in 75 ml of 80 0/0 alcohol was at room temperature under atmospheric pressure with 30 mg of platinum hydrogenated as a catalyst. After the calculated amount of hydrogen Was absorbed, the reaction mixture was filtered, and alcohol and water were evaporated from the filtrate in a vacuum below 25 ° C. The residue was through Addition and evaporation of 50 and 25 ml of dry benzene, respectively, dried. The residue did not want from alcohol, acetone or mixtures of alcohol and ether, methyl ethyl ketone and ether or isopropyl alcohol and ether crystallize. The yield was 2.4 g (104 0/0). Chlorine content 7.13 0/0 (calculated 7.4.0 0/0).

UV absorption spectrum 2imax = 263 m # t Eimax = 10600 '2max = 285 mu s2max = 5200 Example XVa 1- (4'-Ethoxybenzoyloxy) -4- [N-propyl-1 "-methyl-2" - (3 "" , 4 "'- dibenzyloxyphenyl) -äthylamino] -butane hydrochloride The preparation was carried out according to the method described in Example I, adding 4- [N-propyl-l'-methyl-2' - (3", 4 "-dibenzyloxyphenyl) - ethylamino ] - buta-nol- (1) was esterified with 4-ethoxybenzoyl chloride. The yield was 970 /, equivalent weight 741 (calculated 609). This crude product was used directly for the subsequent reaction.

Example XVb 1- (4'-Ätlioxybenzoyloxy) -4- [N-propyl-1 "-methyl-2" - (3 "', 4"' - dihydroxyphenyl) -ethylamino] -butane hydrochloride A solution of 2 g (0.003 mol) of the compound described in Example XVa in 50 ml of 80 0/0 alcohol was added at room temperature under atmospheric pressure hydrogenated with an acid-free palladium catalyst. The catalyst was made by hydrogenation a solution of 100 mg palladium chloride in a suspension of 500 mg Norit and Get 10 ml of water. The palladium catalyst was then filtered off with suction and washed with water and alcohol washed until the filtrate reacted neutrally. After the calculated Amount of hydrogen had been absorbed, the reaction mixture was filtered, and from the filtrate water and alcohol were evaporated in vacuo below 30 ° C. The residue wanted not from a mixture of methyl ethyl ketone and ether or acetone and ether crystallize. The yield was 0.9 g (63%). Chlorine content 8.2% (calculated 7.63%).

UV absorption spectrum @ »iax = 257 mu, @naax = 14200 Analysis Found ... N 3.08%, O C2 H5 9.40% calculated. . . N 3.010 / "O C2 H5 9.67 Example XVIa 1- [1'-Methyl-2'-oxo-2 '- (4" -benzyloxyphenyl) -ethyl] -3- (4'-methoxybenzoyloxy) -methyl-piperidine Hydrochloride The preparation was carried out according to the method described in Example I by esterifying N-propyl-1-methyl-2 (3 ', 4'-dibenzyloxyphenyl) ethylamine with 4-methoxybenzoyl chloride. However, triethylamine was added here as a hydrochloric acid binder. The yield was 76 "/,. Melting point 189 to 194 ° C (with decomposition). Chlorine content 6.870 /, (calculated 6.7811 / 0).

Example XVlb 1- [1'-Methyl-2'-hydroxy-2 '- (4 "-hydroxyphenyl) -ethyl] -3- (4'-methoxybenzoyloxy) -methyl-piperidine hydrochloride The preparation was carried out according to the method described in Example XVb by hydrogenating the compound described in Example XVIa by means of an acid-free palladium-carbon catalyst. The yield was 33 %, melting point 201 to 207 ° C. (with decomposition). Chlorine content 8.07% (calculated 8.150%). ).

UV absorption spectrum: @max = 258.5 mix "max = 18700 Analysis Found ... C 63.42%, H 7.010 /" N 3.39%; calculated ... C 63.38 ° / o, H 6.89 ° / o, N 3.22 ° / o.

Claims (7)

PATENT CLAIMS: 1. Process for the production of new, modified in their effect, a simplification of the reserpine molecule representing, substituted amines with antihypertensive and spasmolytic effects of the general formula: or of salts thereof in which R1 and / or R2 are a hydrogen atom, a hydroxyl group, an alkoxy group or a benzyloxy group, R3 is an amino group, a hydroxyl, an alkoxy or a benzyloxy group, R4 is a hydrogen atom or a hydroxyl group, R is a hydrogen atom or an alkyl group, Re a hydrogen atom or an alkyl group, Y an alkylene group or, together with the nitrogen atom and the group R6, a piperidine ring - optionally substituted by an alkyl group, R7 a hydrogen atom, a hydroxyl group or an alkoxy group and R $ a hydroxyl or a Alkoxy group, characterized in that A. is a compound of the general formula: wherein R1, R2, R4 to Re and Y have the above meanings and R3 'is a benzylated or acylated amino group or a nitro group, with a compound of the general formula: esterified in a manner known per se, in which R is a hydroxyl or alkoxy group or a chlorine, bromine or iodine atom and R7 and R8 have the above meanings, and in the ester or ester salt obtained, the benzylated or acylated amino group which may be present in saponified in a known manner or the nitro group reduced to the amino group in a known manner or B. a compound of the general formula: wherein R1 to R, and Y have the above meanings and Hlg denotes a halogen atom, or a salt thereof with a compound of the general formula: brings to reaction in which R7 and R8 have the above meanings and Me is a metal atom, preferably an alkali atom, or C. a compound of the general formula with a compound of the general formula brings to reaction in which formulas R3 ', R4 to R $ and Y have the meanings already mentioned, with the exception of those in which the groups R6 and Y form a ring with the nitrogen atom, and X is a halogen atom or a keto or aldehyde -Oxygen-D. a compound of the formula or a salt thereof with a compound of the formula RB Hlg or with a dialkyl sulfate to react, in which formulas R3, R4 to R $ and Y have the meanings already mentioned, R, 'is an alkyl group and E. in a compound of the formula or a salt thereof, in which formula R3 can have the above meanings or the meanings of R3 and R1, R2, R4 to R8 and Y have the meanings already mentioned, the keto group is hydrogenated to the secondary alcohol group in a manner known per se and - if R3 'is a nitro group - this is reduced to an amino group. 2. The method according to claim 1, characterized in that RI is hydrogen, R2 and R3 both denote a hydroxyl, alkoxy or benzyloxy group. 3. Procedure according to Claim 1, characterized in that R1 and R ,, hydrogen and R3 is a hydroxy, Denotes alkoxy or amino group. 4. The method according to claims 1 to 3, characterized characterized in that R5 is an alkyl group having 1 to 4 carbon atoms, preferably is a methyl group. atom is, and after the end of the reaction, if necessary existing benzylated or acylated amino group or nitro group in known Way converted into the corresponding amino group or Hlg represents a halogen atom, and after the reaction has ended, any benzylated or aeylated Amino or nitro group converted into the corresponding amino group in a known manner or 5. Process according to claims 1 to 4, characterized in that R6 is a Alkyl group with 1 to 6 carbon atoms, preferably with 2 or 3 carbon atoms represents. 6. Process according to claims 1 to 5, characterized in that Y is an alkylene group having 1 to 8 carbon atoms, preferably 3 to 7 carbon atoms, is. 7. The method according to claims 1 to 5, characterized in that the groups R6 and Y form a piperidine ring with the nitrogen atom, which is optionally an the position 3 or 4 carries an alkylene group with 1 to 4 carbon atoms. B. Procedure according to claims 1 to 7, characterized in that R7 is a hydrogen atom or an alkoxy group with 1 to 4 carbon atoms, preferably a methoxy or ethoxy group, and R $ is an alkoxy group having 1 to 4 carbon atoms, preferably is a methoxy or ethoxy group.