NO120685B - - Google Patents

Description

Process for the production of therapeutic

active benzhydrylaminopropanol ethers.

The present invention relates to a method for the production of therapeutically effective benzhydrylaminopropanol ethers with the general formula:

and syreaddis jonssa.i U;r thereof, where the different R symbols are the same or different and each represents a hydrogen atom or an alkyl group with 1-6 carbon atoms, or the symbols R-^ and R-^' together form a -CHg- CHg-b-ro, and Q is an alkyl group with 1-6 carbon atoms, not all the R symbols being hydrogen atoms. The term "alkyl" used means straight-chain or branched alkyl groups.

Structurally related ethers are known from Norwegian patents No. 86 547, No. 104 031, No. 106 585 and No. 107 421. The new ethers of formula I are distinguished by their anti-arrhythmic activity and such activity is not known to is demonstrated by the compounds covered by the above-mentioned patents.

The TCs of formula I have valuable therapeutic properties; they have muscleotropic-spasmolytic and local-anesthetic properties. Moreover, some of the compounds show marked antiarrhythmic properties similar to those of quinidine, while others show (3-sympatholytic activity. Preferred ethers are those in which the phenyl ring contains at least one alkyl substituent. Compounds of formula I wherein Q is an isopropyl group are of very important.

For the above-mentioned purpose, the compounds produced according to the invention can be administered orally or parenterally in the form of tablets, capsules, injectable preparations or the like by incorporating an appropriate dose of the compound together with pharmaceutically acceptable carriers. The dose for different mammalian species is up to 100 mg daily administered orally or parenterally. The preferred dose is from 5 to 25 mg, and oral administration is preferred.

For use as therapeutic agents, the prepared compounds of formula I can be used as bases or as acid addition salts containing pharmaceutically acceptable non-toxic anions, e.g. hydrohalides, sulfates, oxalates, tartrates, fumarates, acetates, citrates, maleates, succinates, lactates and pamoates.

According to the present invention, the compounds of formula I are prepared by a glycidyl ether of the formula:

where the various symbols have the same meaning as stated above, is reacted with an amine of the formula HgN-Q, where Q has the same meaning as stated above, after which the compounds obtained are, if desired, transferred to an acid addition salt. The reactants are preferably heated in a closed container (eg a Carius tube) and preferably dissolved in an inert anhydrous solvent such as benzene, toluene or xylene.

A benzhydrylaminopropanol ether obtained by means of the above-mentioned method can be converted into an acid addition salt by means of methods known per se, e.g. by the action of an acid on the base in a suitable solvent, e.g. an ether.

The starting substances of formula II can be prepared by reacting a benzhydryl halide of the general formula: where Hal is a halogen atom and where the other symbols have the same meaning as stated above, with 2,3-epoxy-propan-l-ol (glycidol):

The reaction is preferably carried out in an anhydrous inert organic medium, such as benzene, diethyl ether or tetrahydrofuran.

Another way to prepare the compounds of formula II is by condensation of a benzhydryl derivative of the formula: where M is an alkali metal atom, preferably sodium, and where the other symbols have the same meaning as indicated above, with' epichlorohydrin;

The reaction is preferably carried out by heating the reactants in an inert organic solvent such as an aromatic hydrocarbon, e.g. benzene, toluene or xylene.

The compounds of formula II can also be prepared by epoxidation of an appropriately substituted benzhydryl allyl ether of the formula:

where the different symbols have the meaning stated above. Epok siding is carried out in a manner known per se, e.g. with perbenzoic acid in benzene solution at a temperature of between 0° and 5°C.

The following examples illustrate the invention.

Example 1

In a closed container, a mixture of 5.7 ml of isopropylamine and a solution of 11.1 g of 1,2-epoxy-[(p-methyl-oc-phenylbenzyl)-ox^/propane in 25 ml of anhydrous benzene is heated in 16 hours at 80°C. After

after cooling, treat the mixture with 3 parts of water each of 20 ml. The benzene layer is separated and dried with sodium sulphate. The solvent is removed by evaporation. Using electrometric titration, it is determined how many equivalents of benzhydrylaminopropanol ether have been formed, after which an equivalent amount of hydrogen chloride in diethyl ether

is added. After crystallization from acetone, 12.9 g of 1-(isopropylamino)-3-(p-methyl-a-phenylbenzyl)oxy-7-propan-2-ol hydrochloride are obtained.

Yield 83$, melting point 146°-148°C.'

The production of the benzhydryl glycidyl ether used as starting material is described in the following example.

Example 2

A suspension is made of 11.1 g of 2,3-epoxy-propan-1-ol (glycidol) and 15.9 g of sodium carbonate in 30 ff of anhydrous benzene, and care is taken that no moisture enters the container. The mixture is heated until the solvent boils at reflux. 21.7 g of (p-methyl-o-phenylbenzyl) chloride are added dropwise with stirring to the refluxing mixture. After the addition is complete, the mixture is stirred and kept under reflux for a further 20 hours. After cooling and filtering, the solvent is removed from the filtrate by distillation. After crystallization from petroleum ether (boiling range, 80°-100°C), 13.9 g of 1,2-epoxy-3-(p-methyl-<x-phenylbenzyl)oxy/propane is obtained. Yield 56%, boiling point 109°-113°C/0.5 mm Hg.

Example 3

By following the general procedure as described in example 1, in which unsubstituted or variously substituted benzhydrylglycidyl ethers are used instead of 1,2-epoxy-3~/~ (p-methyl-cc-phenylbenzyl)oxy_7propane, the benzhydrylaminopropanol ethers of formula I indicated below are obtained in form of their hydrochlorides.

Analytical data:

Example 4

By following the general procedure described in

example 1, wherein 1,2-epoxy-3-[(10,11-dihydro-5H-dibenzo[a,d__7cyclo-hepten-5-yl)oxy]propane is used instead of 1,2-epoxy-3-Z ~(P-methyl~a~phenylbenzyl)oxx7propane, l-/~(10,11-dihydro-5H-dibenzo/α,d_7 cyclohepten-5-yl)oxx7-3-(isopropylamino)-propan-2-ol is obtained hydrochloride. Melting point 156°-157°C.

Example 5

By following the general procedure described in example 2, in which unsubstituted or variously substituted benzhydryl chlorides are used instead of (p-methyl-oc-phenylbenzyl) chloride, benzhydryl glycidyl ethers of formula II are obtained as described below;

In the following, the results obtained in trials with compounds produced according to the present invention are stated in terms of their various actual activities. Results obtained from trials with compounds covered by the previously mentioned Norwegian patents are also shown. The following compounds prepared according to the present method were investigated: A. 1-(isopropylamino)-3-(o-t.butyl-cc-phenylbenzyl)oxy/propan-2-ol hydrochloride

B. 1-(di-2,6-xylylmethoxy)-3-(isopropylamino)propanol-2-hydrochloride C. 1-(isopropylamino)-3-(p-methyl-oc-phenylbenzyl)oxy_7propane-2- ol hydrochloride

D. (10,11-dihydro-5H-dibenzoZ~a,d_i_/cyclohepten-5-yl)ofxy[-3-(isopropylamino)-propan-2-ol hydrochloride

E. 1-(2,6-Dimethyl-α-o-tolylbenzyl)oxy-3-(isopropylamino)propanol-2-hydrochloride.

a) Activity against aconitine arrhythmia.

Compounds B and E were administered orally to rats. The animals were anesthetized and after a certain time interval aconitine was given i.v. in a dose of 20 /kg. An FCG examination was carried out before and 5, 10, 15, 20, 25 and 30 minutes after administration of aconitine. Doses of 52-5 and 105 mg/kg of compound B and 60.3 mg/kg of compound E provided complete or nearly complete protection against acortin-induced arrhythmia.

b) Extension of the resistant period.

The experimental object was the isolated left auricle of a guinea pig. The

the smallest time interval was determined between two electrical stimuli that be-

seemed a heart-stopping reaction.

c) Effect against arrhythmia in dogs with underligated coronary arteries Compound B is more active than quinidine sulfate both intravenously

and orally.

d) Effect against "ouabaine"-induced arrhythmia in dogs

Compound B is clearly active in the same doses as quinidine sulfate.

e) Effect against electrical stimulation of the cat's heart

Effect of compound B on

1. Heart rate: stronger than for quinidine sulfate.

2. Ven.trikel-threshold value: approx. 4 times that of quinidine sulph at. 3. Auricle threshold value: approx. 4 times that of quinidine sulfate.

f) Toxicity

Oral LD^q in mice

A: 440 mg/kg

B: 210 mg/kg

C: 350 mg/kg

1. Norwegian patent no. 86 547: 2-(di-2,6-xylylmethoxy)-N,N-dimethyl-ethylamine hydrochloride.

When administered to experimental animals, this compound caused bradycardia, which makes it unsuitable for use in the treatment of cardiac disorders.

2. Norwegian patent no. 104 031:

No data are available here regarding anti-arrhythmic activity. 3. Norwegian patent no. 106 5^5: N-methyl-2-(o-methyl-a-phenylbenzyloxy) ethylamine hydrochloride.

Aconitine-induced arrhythmia in rats is not antagonized by oral doses up to 145 mg/kg.

Norwegian patent no. 107 421: 2-/"(10,11-dihydro-5H-dibenzo/~a,dJ

cyclohepten-5-yl)oxy-N,N-dimethylethylamine hydrogen maleate.

The compound was administered intravenously to anesthetized cats. At a dose of 8 mg/kg, a strong reduction in heart rate followed by a residual mild bradycardia was observed. Administration of 4 and 8 mg/kg produced changes in FCG: a short, strong PQ prolongation and a short, moderate prolongation of the QRS duration. The corresponding hydrochloride also caused anomalies in the ECG. The compound was administered intravenously in unanesthetized dogs. 16 mg/kg caused disappearance of the P peak. The other "golf" complexes became irregular after a cumulative dose of 32 mg/kg. Heart rate increased and remained increased after doses of 2-32 mg/kg.

It can thus be summarized that little is known regarding the effect of the previously known compounds and cardiac arrhythmia. The data available indicate an absence of activity or a deleterious effect on the heart. In addition to the data relating to the effect on the heart, the following therapeutic properties were investigated for compounds prepared according to the present method with the achievement of the given results:

I. ( 3- sympatholytic activity

The contractions in isolated organs induced by 3 x 10" M methacholine are reduced by the use of isoprenaline. Some compounds reduced the activity of isoprenaline. The activity was expressed as pA2, i.e. the negative logarithm of the molar concentration of the antagonist (the test compound). which causes a change by a factor of 2 in the doses of antagonist (isoprenaline in this case) needed for a particular effect.

II. Musculotropic-spasmolytic activity

The activity against barium chloride-induced spasms in isolated guinea pig intestines was determined and compared with the activity of papaverine.

(F=1-(isopropylamino)-3-(o-methyl-α-phenylbenzyl)ox3[7propan-2-ol hydrochloride).

Claims (1)

Process for the production of therapeutically effective benzhydrylaminopropanol ethers with the general formula: and acid addition salts thereof, where the different R symbols are the same or different and each represents a hydrogen atom or an alkyl group with 1-6 carbon atoms, or the symbols R-^ and R-^' together form a -CHg-CHg bridge, and Q is an alkyl group with 1-6 carbon atoms, in that not all the R symbols are hydrogen atoms, characterized in that a glycidyl ether with the formula: where the various symbols have the same meaning as stated above, is reacted with an amine of the formula HgN-Q, where Q has the same meaning as stated above, after which the compounds obtained are, if desired, transferred to an acid addition salt.