DE1215729B - Process for the production of new bis-alkanolamine derivatives and their salts - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

German KX: 12 q- 32/21

Number: 1 215 729

File number: L45116IVb / 12q

Filing date: June 14, 1963

Opening day: May 5, 1966

It is known that bis-phenylalkylamine derivatives the formula

(OH)

(ÖH) _m

in which m is the number 2 or 3, η is a number from 1 to 6, R is hydrogen or a low molecular weight alkyl radical and W is inter alia a polymethylene radical, as described in US Pat. No. 2,653,977, a relatively long-lasting effect point to the blood pressure, partly in the hypertensive, partly in the hypotensive sense and are recommended for the treatment of abnormal blood pressure conditions in humans.

Method of making new
Bis-alkanolamine derivatives and their salts

Applicant:

Lentia limited liability company,

Buying and selling,

Munich 15, Schwanthalerstr. 39

Named as inventor:

Dr. Otto Schmid, Leonding near Linz / Danube;

Dr. Heimo Stormann-Menninger-Lerchenthal;

Dr. Gerhard Zölß,

Richard Gratz,

Karl Wismayr, Linz / Danube (Austria)

Surprisingly, it turned out that
new compounds of the general formula

ho ~ \ _ / - choh -ch ₂ -nh- (ch ₂ ) * nh - ch ₂ - choh - ^. oh / ^x oh

in which χ is an integer from 2 to 12, and 30 are seated as these known compounds. The new salts thereof with similar toxicity an essential compounds are produced by using bis-stronger pharmaceutically usable action bealkanonamine derivatives of the general formula

CO · CH ₂ · N · (CH ₂ ), -N-CH ₂ -CO - <> - OR
RR

in which R denotes hydrogen, a hydrogenolytically cleavable radical or an acyl radical, according to usual Methods catalytically hydrogenated, any acyl radicals present are split off by saponification and the bis-alkanolamines obtained are optionally converted into salts.

Palladium-carbon has proven to be the best catalyst for catalytic hydrogenation. as Solvents for the hydrogenation are low molecular weight aliphatic alcohols, optionally in a mixture with water, recommended. "

If protection of the phenolic OH groups and the two secondary amino groups is necessary appears, this is expediently done either with the help of a hydrogenolytically cleavable residue, such as of the benzyl radical, or with the aid of acyl radicals.

The compounds used as starting material can be obtained by reacting 2 moles of 3,4-dioxy-co-chloroacetophenone, in which, if necessary, both OH groups can be split off by hydrogenolysis Radical or an acyl radical are protected, with polymethylenediamines in which in the amino groups one hydrogen atom each by a hydrogenolytically cleavable radical or an acyl radical is protected. The resulting hydrogen halide is replaced by 1 mole of im Trapped excess polymethylenediamine present.

609 567/533

Protection within the scope of the invention is not claimed for the production of the starting materials.

The compounds of the formula I prepared according to the invention have a pronounced broncholytic effect, which in the case of the shorter-chain compounds, eg. B. with those of the formula I, with denon χ 4 or 6 means the same strength, with the longer-chain compounds is only slightly weaker than that of the known asthma drug isoproterenol. Konzett, Arch, exper. Path. Pharmacol., 195, 71 [1940]) with a dose of 0.25 to 0.5 y / kg of the compound N, N'-bis- [2- (3 ', 4' -dihydroxyphenyl) -2-hydroxyethyl] -tetramethylenediamine are completely inhibited. A dose of 1 to 2.5 μg / kg of the compound N, N'-bis [2- (3 ', 4 ^/ -dihydroxyphenyl) -2-hydroxyethyl] -octamethylenediamine is required for this, of isoproterenol 0.25 up to 0.5 y / kg is required to achieve the same effect. The compounds also have a pronounced effect on heart rate; they have the effect of increasing the heart rate.

The advantage of the compounds prepared according to the invention, however, lies primarily in the duration the effect, which for both the broncholytic effect and for the heart rate effect the duration of the increase in heart rate on the anesthetized dog can be demonstrated. Both Effects are determined by reaction with the so-called jS receptors according to A 1 q u i s t (Am. J. Physiol. 153, 586 [1948]) and it can therefore be the more easily measurable increase in heart rate than relative measure for the duration of action of the substances apply.

For this purpose, dogs under Nembutal anesthesia were given the substances to be tested in doses which cause an increase in the frequency of the heart that is about the same. The heart rate was then determined by means of an EKG and the time after which the maximum frequency difference on the Half of its value. The following duration of action, measured on the 50% Fall time in minutes, determined.

substance dose 50% fall time N, N'-bis- [2- (3 ', 4'-di-_ hydroxyphenyl) - 2-hydroxyethyl] - tetramethylene diamine 10 y / kg <~ 240 minutes N, N'-bis- [2- (3 ', 4'-di- hydroxyphenyl) - 2-hydroxyethyl] - hexymethylene diamine 10 y / kg ~ 240 minutes hydroxyphenyl) - 2-hydroxyethyl] - octamethylene diamine 10 y / kg 20 minutes N, N'-bis- [2- (3 ', 4'-di- hydroxyphenyl) - 2-hydroxyethyl] - decamethylenediamine 10 y / kg 25 minutes Isoproterenol 5 y / kg 2 minutes

According to the USA patent 2653 977 dose 50% fall time made connections: - ■ - substance 5 ^; -
■ -, ^j
N, N'-bis- [2- (3 ', 4'-di- , hydroxyphenyl) - 500 y / kg 60 minutes*) '2-ethyl] -tetra- ^: - _I0 methylenediamine ... N, N'-bis- [2- (3 ', 4'-di- hydroxyphenyl) - 100 y / kg 120 minutes *) 2-ethyl] -hexa- methylenediamine ... i5 N, N'-bis- [2- (3 ', 4'-di- hydroxyphenyl) - < 100 y / kg <10 minutes 2-ethyl] -octa- methylenediamine ... N, N'-bis- [2- (3 ', 4'-di- ²⁰ hydroxyphenyl) - 200 y / kg <10 minutes 2-ethyl] -deka- methylenediamine ...

*) Estimated as the frequency was only followed for 60 minutes, j- In the compounds prepared according to the invention with 4 and 6 CH2 groups, on the other hand, the experiments were extended up to 5 hours.

Those made in accordance with U.S. Patent 2,653,977 Compounds that were also tested show especially when they have 4 and 6 CH2 groups in the chain also have a long duration of action, but their effect is orders of magnitude weaker. The equally effective isoproterenol, on the other hand, is inferior in terms of duration of action.

As clinical trials show, in the case of the compounds prepared according to the invention, the dose is for achieving a sufficient broncholytic effect lower than that for achieving a clearly noticeable cardiac action, making them very good, long-acting means of combating represent spastic conditions of the airways. They are also available in higher doses as a means of combating it suitable for certain cardiac arrhythmias.

example 1

1.8 g of N, N ^/ -Bis-2- (3 ', 4'-dihydroxyphenyl) -2-oxoethyl-tetramethylenediamine dichlorohydrate are mixed with hydrogen at 42 ° C. under normal pressure in a mixture of 100 ml of methanol and 20 ml of water hydrogenated with vigorous stirring using 0.6 g of palladium carbon (10%). The substance used only dissolves completely in the course of the hydrogenation. After 3 hours, the theoretically expected amount of hydrogen has been absorbed and the hydrogenation comes to a standstill. The palladium carbon is separated off, the solution is evaporated and the residue is crystallized with absolute ether. After suctioning off, it is washed with absolute ether. 1.5 g of N, N'-bis [2 - (3 ', 4' - dihydroxyphenyl) - 2 - hydroxyethyl] - tetramethylenediamine dichlorohydrate are obtained. F. 187 to 188 ^° C., yield 82.5% of theory.

The Ν, Ν'-bis [2- (3 ^/ , 4'-dihydroxyphenyl) -2-oxoethyl] -tetramethylenediamine dichlorohydrate used as starting material can be prepared in the following way:

It is first the corresponding N, N'-dibenzyl compound by prolonged boiling (10 hours) of

2 moles of 4-chloroacetyl-pyrocatechol with 2 moles of N, N'-dibenzyltetramethylenediamine prepared in boiling acetone, approximately the theoretical amount of Ν, Ν'-dibenzyltetramethylenediamine being precipitated as dichlorohydrate from the acetone solution and separated off. The acetone solution contains the desired N, N'-dibenzyl-N, N'-bis- [2- (3 ', 4'-dihydroxyphenyl) -2-oxoethyl] -tetramethylenediamine. The benzyl residues are then split off hydrogenolytically from the crude product in hydrochloric acid methanolic solution at a pH of about 1, the N, N '- bis - [2 - (3 Ά' - dihydroxyphenyl) - 2 - oxoethyl] tetramethylenediamine dichlorohydrate by boiling with water and crystallization is obtained pure in the cold. The substance is ^{dried at 80 °} C. in a vacuum. F. from 245 ⁰ C (decomposition).

In an analogous way the following are obtained:

By hydrogenation of N, N'-bis- [2- (3 ', 4'-dihydroxyphenyl) -2-oxoethyl] -octamethylenediamine dichlorohydrate, the N, N' _: bis- [2- (3 ', 4'-dihydroxyphenyl ) -2 - hydroxyethyl] octamethylenediamine dichlorohydrate from 211 to 212 ° C.

By hydrogenation of N, N'-bis- [2- (3 ', 4'-dihydroxyphenyl) - 2-oxoethyl] - decamethylenediamine dichlorohydrate N, N'-bis [2- (3 ', 4'-dihydroxyphenyl) -2 - hydroxyethyl] - decamethylenediamine - dichlorohydrate with a temperature of 184 ° C.

Example 2

5 g of N, N'-dibenzyl-N, N'-bis- [2- (3 ', 4'-dihydroxyphenyl) -2-oxoethyl] -hexamethylenediamine-dichlorohy- drat as a monohydrate are in a mixture of 270 ml of methanol and 50 ml of water at 45 ° C under vigorous stirring by means of 2.0 g of palladium carbon (10% strength) hydrogenated at normal pressure. After around 4 hours it is the theoretical amount (4 mol of hydrogen per 1 mol of substance) of hydrogen for the splitting off of the two Benzyl radicals and the reduction of the two carbonyl groups to carbinol groups were added, and the Hydrogenation comes to a standstill. After separating the catalyst, it is evaporated to dryness, the residue was triturated with acetone, the crystals formed were filtered off with suction and washed with acetone washed. Yield of N, N'-bis- [2- (3 ', 4'-dihydroxyphenyl) -2-hydroxyethyl] -hexamethylenediamine dichlorohydrate 3.3 g, that's 92% of theory. By

HO - <^ ^ -CHOH ■ CH ₂ NH
OH

in which χ denotes an integer from 2 to 12, and its salts, thereby marked

Falling from a mixture of methanol and ether 2.8 g with a melting point of 197.5 ° to 198 ° C. are obtained.

The Ν, Ν'-dibenzyl-N, N'-bis- [2- (3 ', 4'-dihydroxyphenyl) -2-oxoethyl] - used as starting material Hexamethylenediamine dichlorohydrate monohydrate is produced as follows:

2 moles of 4-chloroacetylpyrocatechol are dissolved in 2000 ml of acetone and heated to boiling with 2 moles of N, N'-dibenzylhexamethylenediamine for 12 hours, during which almost the theoretical amount of N, N'-dibenzylhexamethylenediamine dichlorohydrate precipitates, which is filtered off with suction after cooling will. The filtrate is mixed with 1.5 times the volume of hydrochloric acid 1: 1, with about 66% of the theoretically possible amount of crude dichlorohydrate of Ν, Ν'-dibenzyl-N, N '- bis - [2 - (3', 4 ' - dihydroxyphenyl) - 2 - oxoethyl] hexamethylenediamine precipitates. The product is purified by recrystallization from water with the addition of animal charcoal. After drying at room temperature, the substance contains 1 mol of water of crystallization. F. 206 to 209.5 ⁰ C.

Example 3

3 g of N, N'-bis [2- (3 ', 4'-dihydroxyphenyl) -2-oxoäthylj-dodecamethylenediamine dichlorohydrate are in 140 ml of methanol with 1.5 g of palladium carbon (10%) until the hydrogen uptake ceases hydrogenated at normal pressure. After removing the palladium carbon, the filtrate is evaporated to dryness and triturated with absolute ether: Yield of N, N '- bis - [2 - (3', 4 '- dihydroxyphenyl) - 2 - hydroxy ethyl] - dodecamethylenediamine - dichlorohydrate 2.6 g, that's 86% of theory; M.p. 142 to 144.5 ° C. Reprecipitated from ethanol-acetone F. of the analytically pure product rises to 146 to 147.5 ⁰ C.

The Ν, Ν'-bis [2- (3 ', 4'-dihydroxyphenyl) -2-oxoethyl] -dodecamethylenediamine dichlorohydrate used as starting material is prepared in the manner described in Example 1. F. 216 to 22O ⁰ C (decomposition).

45

Claims (1)

Claim: Process for the preparation of new bis-alkanolamine derivatives the general formula NH • CH ₂ • CHOH OH OH net that one bisalkanonaminderivate in a manner known per se the general formula RO - <^ y ~ CO-CH ₂ · N ■ (CH ₂ ), -N-CH ₂ -CO - <> - OR RCK RR in which R is hydrogen, a hydrogenolytically cleavable radical or an acyl radical, catalytically hydrogenated, any acyl radicals present are split off by saponification and the The bis-alkanolamines obtained are optionally converted into salts. 609 567/533 4.66 © Bundesdruckerei Berlin