NO141753B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW PROPANOLAMINES WITH BETA-RECEPTOR BLOCKING AND ALFA-RECEPTOR BLOCK EFFECT - Google Patents

Description

The invention relates to analog methods for the production of new propionolamines with B-receptor blocking and α-receptor blocking effects.

The new compounds have the general formula I

wherein R is selected from the group consisting of hydrogen and methyl, R p is selected from the group consisting of hydrogen, methyl, ethyl, propyl, allyl, cyano, methoxy, propargyloxy,

R is selected from the group consisting of

of hydrogen, and methyl and R is selected from the group consisting of

2 4

of hydrogen, and methyl provided that R and R are not both hydrogen.

The new compounds have valuable pharmacological properties

properties.

Thus they block cardiac g-receptors, as shown by determination of antagonism of tachycardia after an intravenous injection of 0.5 µg/kg of d/l-isoproterenol sulfate in anesthetized cat at an intravenous dose of 0.002' to 2 mg/kg .. They also block the vascular B-receptors shown by determination of antagonism of vasodilatation after an intravenous injection of 0.5/Ug/kg of d/l-isoproterenol sulfate on anesthetized

cat at an intravenous dose of 0.002 to 2 mg/kg or more.

These compounds also have stimulating properties

receptors, i.e. they show intrinsic activity. This self-

cabinet is particularly pronounced with regard to vascular ^-receptors which effect dilatation of the peripheral blood vessels.

The new compounds can be used in treatment

of arrhythmia, angina pectoris and hypertension. The peripheral vasodilatation is particularly valuable in the latter two to-

traps. It can also be used as intermediate products for

position of other valuable pharmaceutical compounds.

Compounds according to the invention are:

3-[2-(4-hydroxyphenyl)-1-methylethylamino7-1-o-methylphenoxy-

propanol-2,

3-[2-(4-hydroxyphenyl)-1-methylethylamino7-1-o-ethylphenoxy-

propanol-2,

3~/_ 2-(4-Hydroxyphenyl)-1-methylethylamino7-1-o-propylphenoxy-

propanol-2,

3-/2-(4-hydroxyphenyl)-1-methylethylamino7-1-o-allylphenoxy-propanol-2, 3-/~2-(4-hydroxyphenyl)-1-methylethylamino7-1-o-propargyloxy-phenoxy-propanol-2,

3-/.~2-(4-Hydroxyphenyl)-1-methylethylamino7-1-o-cyanophenoxy-

propanol-2,

3~/~2-(4-hydroxyphenyl)-1,1-dimethylethylamino-7-1-o-methyl-phenoxy-propanol-2,

3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino-7-1-o-ethylphenoxy-propanol-2,

3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino-7-1-o-propyl-phenoxy-propanol-2,

3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino-7-1-o-allylphenoxy-propanol-2,

3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino-7-1-o-propargyl-oxyphenoxy-propanol-2,

3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino-7-1-o-cyano-phenoxy-propanol-2,

3-ethyl-3-[2-(4-hydroxyphenyl)-1-methylethylamino-7-1-o-allylphenoxy-propanol-2,

3-/_ 2-(4-Hydroxyphenyl)-1-methylethylamino7-1-o,in-dimethyl-vphenoxy-propanol-2,

3-[2-(4-hydroxyphenyl)-1-methylethylamino-7-1-o-methoxyphenoxy-propanol-2,

3-methyl-3-/<->2-(4-hydroxyphenyl)-1-methylethylamino/-1-o-ethyl-phenoxy-propanol-2, 3-methyl-3-/~2-(4-hydroxyphenyl)-1 -methylethylamino7-1-o-cyano-phenoxy-propanol-2,

3-methyl-3-[._2-(4-hydroxyphenyl-1,1-dimethylethylamino]-1-o-methylphenoxy-propanol-2,

3-methyl-3-_/~~2-(4-hydroxyphenyl)-1,1-dimethylethylamino-7-1-o-allylfenoxy-propanol-2 and

3- /<.> 2-(4-hydroxy<y>phen<y>l)-1-meth<y>let<y>lamin<o>7-1-m-methylphenoxy-propanol-2.

Salt-forming acids can be used in manufacturing

of therapeutically tolerable salts of the compounds and these are: • hydrohalic acids, sulfuric acidj phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid , ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulfanilic acid, methionine, tryptophan , lysine or arginine.

The substances must be administered intravenously or parenterally for acute or chronic treatment of the above-mentioned cardiovascular disorders.

The biological effect of the new compounds has been investigated and the various tests carried out will be shown and explained below.

The new compounds are obtained according to those known per se

methods.

A compound of formula II

2 3 4 1 in which R , R and R have the above meaning, X means the hydroxy group, Z is a reactive esterified hydroxy group, or X<1> and Z together form an epoxy group and are reacted with an amine of formula

in which R^ has the above meaning.

A reactive, esterified hydroxy group is special

a hydroxy group esterified with a strong, inorganic or organic acid, preferably a hydrohalic acid, a hydrochloric acid, hydrobromic acid or hydroiodic acid, further sulfuric acid or a strong organic sulphonic acid, e.g. benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid. Z is preferably chlorine, bromine or iodine.

This reaction is carried out in the usual way. When using

of a reactive ester as starting material, the reaction preferably takes place in the presence of a basic condensing agent and/or with an excess of an amine. Suitable basic condensation agents are e.g. alkali metal hydroxides such as sodium and potassium hydroxide, alkali metal carbonates and potassium carbonate and alkali metal alcohols such as sodium methylate, potassium ethylate and potassium tert.-butylate.

A compound of formula III

2 3 M in which R , R and R have the above meaning is reacted with a compound of formula

wherein R<1> and Z have the above meaning.

This reaction is carried out in the usual way, preferably in the presence of a basic condensing agent and/or an excess of an amine. Suitable basic condensation agents are e.g. alkali alcoholates, especially sodium or potassium alcoholate, or also alkali carbonates such as sodium or potassium carbonate.

A compound of formula IV

2 4 in which R and R have the above meaning are reacted with a compound of formula V

wherein Z, X"1" and R and R^ have the above meaning.

The reaction is carried out in the usual way. In those cases where reactive esters are used as starting material, the compound of formula IV can conveniently be used in the form of the metal phenolate as an alkali metal phenolate, preferably sodium phenolate, or one works in the presence of an acid-binding agent, preferably a condensing agent, which can form a salt with the compound of formula IV as an alkali metal alcoholate.

A compound of formula IV

in which R 2 and R 4 have the above meaning, is reacted with a compound of formula VI

in which R<1> and R-5 have the above meaning.

This reaction is carried out in the usual way. Thus, the reaction is carried out under alkaline conditions in a suitable solvent such as benzyl alcohol by boiling the reaction mixture for a few hours. Thereby, the phenol is primarily transferred to the metal phenolate as alkali metal phenolate before it is added to the acetidinol of formula VI.

Furthermore, a residue can be cleaved from a compound of formula I, in which the nitrogen atom of the amino group and/or the hydroxyl group is connected to cleaveable residues.

Such cleavable residues are especially those which are cleavable by solvolysis, reduction, pyrolysis or fermentation.

Residues that can be cleaved by solvolysis are particularly residues that can be cleaved by hydrolysis or ammonolysis.

Residues that can be split off by means of hydrolysis are e.g. an acyl residue which, when present, is functionally varied carboxy groups, e.g. oxycarbonyl radicals such as alkoxycarbonyl radicals, e.g. tert.-butoxycarbonyl residue, or ethoxycarbonyl residue, aralkyloxycarbonyl residue such as phenyl lower oxycarbonyl residue, e.g. a carbobenzyloxy acid residue halocarbonyl residue, e.g. a chlorocarbon residue, further arylsulfonyl residues such as toluenesulfonyl or bromobenzenesulfonyl residues and optionally as halogenated or fluorinated lower alkanoyl residues such as formyl, acetyl or trifluoroacetyl residues or a benzyl residue or cyano groups or silyl residues, such as trimethylsilyl residues.

Of the above-mentioned residues present at the hydroxyl groups, which residues can be split off by hydrolysis, oxycarbonyl residues and lower alkanoyl residues or benzoyl residues are preferably used.

In addition to the above, double bond residues are also used, which can be split off at the amino group by hydrolysis, e.g. alkylidene or benzylidene residues or a phosphorylidene group such as a triphenylphosphorylidene group, the nitrogen atom then having a positive charge.

Residues which can be split off at the hydroxy group and the amino group by hydrolysis are further divalent residues which, where appropriate, have substituted methylene. As substituents on the methylene residue, any organic residue can be used, as it does not play any role during the hydrolysis, which component is a substituent on the methylene residue. As methylene substituents, e.g. aliphatic or aromatic residues such as alkyl as mentioned above, aryl e.g. phenyl or pyridyl can be used. The hydrolysis can be carried out in any usual way, preferably in a basic or preferably acidic medium.

Compounds which are residues which can be split off by hydrolysis are also compounds of formula VII

12 3 4

in which R , R , Fr and R have the above meaning and Y means a carbonyl or thiocarbonyl residue.

The hydrolysis is carried out in an analogous way, e.g. in the presence of a hydrolysing substance, e.g. in the presence of an acidic substance, e.g. dilute mineral acid, such as sulfuric or hydrohalic acid or in the presence of a basic substance, such as alkali metal hydroxides, such as sodium hydroxide. Oxycarbonyl residues, arylsulfonyl residues or cyano groups can be cleaved in a suitable manner with the aid of acidic agents such as with the aid of hydrohalic acid, preferably hydrobromic acid. Preferably, the separation takes place, using diluted hydrobromic acid, possibly in a mixture with acetic acid. Cyano groups are preferably split off using hydrobromic acid at an elevated temperature such as in boiling hydrobromic acid according to the "bromocyano method" (von Braun). Furthermore, e.g. a tert.-butoxycarbonyl residue is cleaved off under anhydrous conditions by means of a treatment with an own* acid such as trifluoroacetic acid. Acidic substances are preferably used by hydrolysis of the compounds of formula VI.

Residues that can be split off by ammonolysis are especially halogenocarbonyl residues such as the chlorocarbonyl residue. The ammonolysis can be carried out in the usual way, e.g. by means of an amine, containing at least one hydrogen atom, bound to the nitrogen atom, such as a mono- or dilaverealkylaitiine, e.g. methylamine or dimethylamine, or especially ammonia, preferably at an elevated temperature. Instead of ammonia, a substance that gives ammonia such as hexamethylenetetramine can be used.

Residues that can be split off by means of a reduction are e.g. an α-arylalkyl residue, such as a benzyl residue or an α-araloxycarbonyl residue such as a benzyloxycarbonyl residue, which can be cleaved in the usual way by means of a hydrogenolysis, in particular by catalytically activated hydrogen, such as by means of hydrogen in the presence of a hydrogenation catalyst, e.g. Raney nickel. Further residues cleavable by means of hydrogenolysis are 2-halogenoalkoxycarbonyl residues such as 2,2,2-trichloroethoxycarbonyl residues or 2-iodoethoxy or 2,2,2-tribromethoxycarbonyl residues, which can be cleaved off in the usual way, suitably by means of a metallic reduction (so-called nascent hydrogen). Nascent hydrogen can be obtained by the action of metal or metal alloys, such as amalgam, on a compound that gives hydrogen such as carboxylic acid, alcohols or water, in particular zinc or zinc alloys together with acetic acid can be used. Furthermore, hydrogenolysis of 2-halogen alkoxycarbonyl residues can take place, using chromium or chromium (II) compounds such as chromium (II) chloride or chromium (II) acetate.

A residue that can be cleaved by reduction can also be an arylsulfonyl group such as the toluenesulfonyl group, which can be cleaved in the usual way by reduction using nascent hydrogen, e.g. by means of an alkali metal such as lithium or sodium in liquid ammonia and suitably cleaved from a nitrogen atom. When carrying out the reduction, care must be taken that other reducing groups are not affected.

Residues cleavable by pyrolysis, in particular residues cleavable from the nitrogen atom are in some cases substituted, preferably unsubstituted carbamoyl groups. Suitable substituents are e.g. lower alkyl or aryl lower alkyl such as methyl or benzyl or aryl, such as phenyl, the pyrolysis is carried out in the usual way, taking care of other thermally active groups.

Residues which are cleavable by fermentation, in particular residues cleavable from the nitrogen atom, are substituted, however suitably unsubstituted carbamoyl groups. Suitable substituents are e.g. lower alkyl or aryl lower alkyl, such as methyl or benzyl, or aryl such as phenyl. The fermentation is carried out in the usual way, e.g. with the help of enzyme urease or soybean extract at approx. 20°C or slightly elevated temperature.

Furthermore, a Ship base with formula VIII

or IX

or a cyclic tautomer corresponding to formula IX with formula X

1 2 ~*> 4

is reduced, in which R , R , Fr and R have the above-mentioned meaning, as R"<*>" is not methyl and where the compounds of formula IX and X can also exist at the same time. This reduction is carried out in the usual way, e.g. using a di-light metal hydride, such as sodium borohydride, lithium aluminum hydride, by using a

hydride such as borane with formic acid or by means of a catalytic hydrogenation, such as with hydrogen in the presence of Raney nickel.

During the reduction, it must be ensured that other groups are not affected.

Furthermore, the oxo group in connection with formula XI

.12 3 H in which R , R , R and R have the above meaning, is reduced to a hydroxy group. This reduction is carried out in the usual way, in particular using a dilett metal hydride, as mentioned above, or according to the "Meerwein-Pondorf-Verley method" or a modification thereof, using an alkanol as a reaction component and as a solvent, such as isopropanol, and using a metal alkanolate such as methyl isopropanolate, e.g. aluminum isopropanolate. Furthermore, in a compound of formula XII

13 4 2

wherein R , R , and R have the above meanings and wherein X is one

2 2 2

residue that can be transferred to a residue R is transferred X to R .

In the usual way, the substituents can be varied from the compounds obtained within the framework of the end products, as well as compounds that are formed can be introduced cleaved off or transferred into other end products in another way.

Depending on the process conditions and the starting material, the end product is obtained either in free form or in the form of the acid addition salt, which is covered by the scope of the invention. Thus, for example, basic, neutral or mixed salts can be obtained as well as hemiamino, sesqui- or polyhydrates. The acid addition salts of the new compounds can be transferred to free compounds in a manner known per se, using e.g. basic agents such as alkali or ion exchangers. On the other hand, free bases obtained can form salts with inorganic or organic acids. In the preparation of the acid addition salts, such acids are preferably used which form suitable therapeutically acceptable salts. Such acids are e.g. hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, maleic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid, phenylacetic acid , benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acids, halobenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulfanilic acid; methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds such as e.g. the picrates can serve as a cleaning agent for the free bases formed when the free bases are transferred to salts, these are separated and the bases are released again from the salt. According to the close relationship between the new compounds in free form and in the form of their salts, it is to be understood from the above and the following that, if possible, the corresponding salts are included in the free compounds.

The starting materials are in and of themselves known and can,

if they are new, they are obtained by methods known per se.

In clinical use, the compounds prepared according to the invention are usually administered orally, rectally or by injection.

tion in the form of a pharmaceutical preparation containing an active compound, either as free base or as pharmaceutically acceptable, non-toxic acid addition salts, e.g. hydro-

chlorides, lactates, acetates, sulfamates or the like in combination with a pharmaceutical carrier.

Consequently, the mention of the new compounds produced according to the invention includes either the free amine base or acid addition

the salts of the free base, even if the compound is referred to gene-

generally or specifically, provided that where such expressions describe

is used, e.g. in the examples, would not agree with this broad meaning. The carrier may be a solid, semi-solid or liquid diluent or a capsule. These pharmaceutical preparations are a further object of the invention. Generally, the amount of active substance is between 0.1 and 95% by weight

the preparation, suitably between 0.5 and 20% by weight in the preparation for injection and between 2 and 50% by weight for preparations for oral administration.

When manufacturing pharmaceutical preparations containing

in the case of a compound produced according to the invention in the form of a dose unit for oral administration, the selected compound can be mixed with a solid, powdered carrier, such as e.g. with lactose,

sucrose, sorbitol, mannitol, starch, such as potato starch, corn starch amylopectin, cellulose derivatives or gelatin,

as well as with a lubricant such as magnesium stearate, calcium

stearate, polyethylene glycol wax or the like, and pressed

pills. If it is desired with coated tablets, it can

core prepared above is coated with concentrated sugar solutions. The solution may contain e.g. gum arabic,

gelatin, talc, titanium dioxide or the like. Furthermore, tab-

the lights are coated with a varnish dissolved in a slightly volatile organic solvent or mixture of solvents. A dye can be added to this coating to easily distinguish between tablets with different active compounds or with different amounts of active compounds.

The tablets are usually packed by machines that have

an electronic counting device. The different types of packaging consist of glass or plastic containers, but also cans, tubes and special packaging adapted to the dose.

The daily dose of the active substance varies and

depends on the type of administration, but as a general rule it is 100 to h00 mg/day of active substance as peroral administration and 5 to 20 mg/day as intravenous administration.

The invention shall be explained in more detail by means of some non-limiting examples.

Example 1.

Preparation of 3-[2-(4-hydroxyphenyl)-1-methylethylamino7-yl2lU}2£v.l£222ksY_-p_r^£anol-2

2.5 g of 1,2-epoxy-3-o-methylphenoxy-propane are mixed

with 1.5 g of 1-(4-hydroxyphenyl)-2-amino-propane and 25 ml of isopropanol and the entire solution is refluxed for 1 hour. The solution was then evaporated in vacuo. The thus form-

lower base was dissolved in acetone and the hydrochloride was precipitated,

using HCl in ether. The hydrochloride was filtered off and washed with acetonitrile. The yield of 3-β-2-(β-hydroxyphenyD-1-methylethylaminoT-1-o-methylphenoxy-propanol-2) was 1, h g. Melting point 112°C.

The structure was determined by NMR.

Example 2.

3-/~2-(4-hydroxyphenyl)-1-methylethylamino7-1-o-ethylphenoxypropanol-2 was prepared according to example 1, using 1,2-epoxy-3~(o-ethyl)phenoxy-propane and l- (4-hydroxyphenyl)-2-amino-propane as starting material. The melting point of the hydrochloride is 143°C and the structure was determined by NMR and equivalent weight.

Example 3-

3-/~2-(4-hydroxyphenyl)-1-methylethylamino7-1-o-allylphenoxy-propanol-2 was prepared according to example 1, using 1,2-epoxy-3~o-allylphenoxy-propane and l-( 4-hydroxyphenyl)-2-amino-propane as starting material. The melting point of the tartrate is 71°C. The structure was determined by NMR and equivalent weight.

Example 4.

3-/_ 2-(4-hydroxyphenyl)-1-methylethylamino7-1-o-propargyloxy-phenoxy-propanol-2 was prepared according to example 1, using 1,2-epoxy-3~o-propargyloxyphenoxy-propane and 1 -(4-hydroxyphenyl)-2-amino-propane as starting material. The p-hydroxybenzoate was prepd.

Example 5.

3~/ 2-(4-hydroxyphenyl)-1-methylethylamino7-1-o-cyanophenoxy-propanol-2 was prepared according to example 1,

using 1,2-epoxy-3-o-cyanophenoxy-propane and 2-(4-hydroxyphenyl)-1-methylethylamine as starting material. The hydrochloride was formed as a water-soluble oil and the structure was determined by NMR.

Example 6.

3-/~2-(4-hydroxyphenyl)-1,1-dimethylethylamino7-1-o-methyl-phenoxy-propanol-2 was prepared according to example 1, using 1,2-epoxy-3-o-methylphenoxypropane and 2 -(1J-hydroxyphenyl)-1,1-dimethylethylamine as starting material. The hydrochloride was obtained as a water-soluble oil and the structure was determined by NMR.

Example 7.

3-[2-(4-Hydroxyphenyl)-1,1-dimethylethylamino-7-1-o-ethyl-phenoxy-propanol-2 was prepared according to Example 1,

using 1,2-epoxy-3-o-ethylphenoxypropane and 2-(4-hydroxyphenyl)-1,1-dimethylethylamine as starting material. The melting point of the hydrochloride is 15<2>t°C.

Example 8.

3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino-7-1-o-allylphenoxy-propanol-2 was prepared according to example 1, using 1,2-epoxy-3-o-allylphenoxy-propane and 2 -(4-hydroxyphenyl)-1,1-dimethylethylamine as starting material. The melting point of the hydrochloride is litO°C.

Example 9.

3-[2-(4-Hydroxyphenyl)-1,1-dimethylethylamim^Z^-o-propargyloxy-phenoxypropanol-2 was prepared according to Example 1, using 1,2-epoxy-3-o-propargyloxy -phenoxypropane and 2-(4-hydroxyphenyl)-1,1-dimethylethylamine as starting material.

Example 10.

3-/~2-(4-hydroxyphenyl)-1,1-dimethylethylaminoZ-1-o-cyanophenoxy-propanol-2 was prepared according to example 1, using 1,2-epoxy-3~o-cyanophenoxypropane and 2- (4-Hydroxyphenyl)-1,1-dimethylethylamine as starting material.

Melting point 144°C (HC1).

Example 11.

3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o,m-dimethylphenoxy-propanol-2 was prepared according to Example 1,

using 1,2-epoxy-3-o,m-dimethylphenoxypropane and 2-(4-hydroxyphenyl)-1-methylethylamine as starting material. Melting point 125°C (HC1).

Example 12.

3-[2-(4-hydroxyphenyl)-1-methylethylamino-1-o-methoxyphenoxypropanol-2 was prepared according to Example 1,

using 1,2-epoxy-3-o-methoxyphenoxy-propane and 2-(4-hydroxyphenyl)-1-methylethylamine as starting material. Melting point ll4°C (HC1).

Example 13.

3-methyl-3-[2-(4-hydroxyphenyl)-1-methylethylamino-1-o-ethylphenoxy-propanol-2 was prepared according to Example 1,

in that 1,2-epoxy-1-methyl-3-o-ethylphenoxy-

propane and 2-(4-hydroxyphenyl)-1-methylethylamine as starting material

laugh. The hydrochloride was obtained as a water-soluble oil and the structure was determined by NMR.

Example 14.

3-methyl-3-[2-(4-hydroxyphenyl)-1-methylethylamino-7-1-o-cyanophenoxy-propanol-2 was prepared according to Example 1,

using 1,2-epoxy-1-methyl-3-o-cyanophenoxy-

propane and 2-(4-hydroxyphenyl)-1-methylethylamine as starting material

laugh. The hydrochloride was obtained as a water-soluble oil and the structure was determined by NMR.

Example 15.

3-ethyl-3~/. 2-(4-Hydroxyphenyl)-1-methylethylamino-1-o-allyl-phenoxy-propanol-2 was prepared according to Example 1,

using 1,2-epoxy-1-ethyl-3-o-allylphenoxy-

propane and 2-(4-hydroxyphenyl)-1-methylethylamine as starting material

laugh. The hydrochloride was obtained as a water-soluble oil and the structure was determined by NMR.

Example 16.

3-methyl-3-[2-(4-hydroxyphenyl)-1,1-dimethylethyl-amino-7-1-o-methylphenoxy-propanol-2- was prepared according to example 1, using 1,2-epoxy-1- methyl-3-o-methylphenoxy-propane and 2-(4-hydroxyphenyl)-1,1-dimethylethylamine as starting material. The hydrochloride was formed as a water-soluble oil and the structure was determined using NMR. Example 17.

3-methyl-3-[2-(4-hydroxyphenyl)-1,1-dimethylethyl-amino-7-1-o-allylphenoxy-propanol-2 was prepared according to example 1, using 1,2-epoxy-1-methyl -3-o-allylphenoxy-propane and 2-(4-hydroxyphenyl)-1,1-dimethylethylamine as starting material. Melting point 172°C (HC1).

Example 18.

3-[2-(4-Hydroxyphenyl)-1-methylethylamino-7-1-m-methylphenoxypropanol-2 was prepared according to Example 1,

using 1,2-epoxy-3-m-methylphenoxypropane and 2-(4-hydroxyphenyl)-1-methylethylamine as starting material. Melting point 150°C (HC1).

Example 18a.

Preparation of 3__/—1-methyl 1-2-(4-hydroxyphenyl)ethylamino7-1-o-åiiY.2£§G21£§Y.-butanol-2

2.5 g of 2,3-epoxy-1-o-allylphenoxybutane was mixed with 1.5 g of 1-methyl-2-(4-hydroxyphenyl)ethylamine and 25 ml of isopropanol and the whole mixture was refluxed for 100 hours. The solution was then evaporated in vacuo. The base thus formed was dissolved in trichloroethylene and the hydrochloride was precipitated, using HCl in ether. Water was added and the mixture was titrated with 1 molar HCl. The pH was determined with a glass electrode and the value was adjusted against ml of HC1. At a band in the basket, the water phase was separated, new water was added and the procedure was repeated until the next band in the basket. This water phase was separated, made alkaline with NH 3 OH and extracted with methylene chloride. The organic phase was washed with water, dried and evaporated. The hydrochloride was precipitated with ether x HCl. The ether was decanted and the product solidified by evaporation in high vacuum. The yield of 3-[1-methyl-2-(4-hydroxyphenyl)ethylamino-7-1-o-allylphenoxy-butanol-2.HCl was 1.6 g. Melting point 70°C. The structure was determined by NMR.

Example 19 (variant b+e)

10 g of 1,2-epoxy-1-o-allylphenoxypropane in 100 ml

ethanol is saturated with gaseous ammonia, and the mixture is heated in an autoclave on a boiling water bath for 4 hours. The solvent is then evaporated, and the residue is dissolved in ethyl acetate and HCl gas is introduced. Thereby, hydrochlorides are crystallized which are filtered off and dissolved in 60 ml of ethanol, and mixed with 20 g of 2-(4-methoxy-simethoxy-phenyl-1,1-dimethyl iodide and 15 g of I^CO^. The mixture is heated in an autoclave at 120°C for 2 hours, after which it is evaporated and the residue is treated with 100 ml of 2N HC1 for one hour at room temperature. The aqueous phase is alkalized from ammonia and extracted with ethyl acetate. The ethyl acetate phase is dried with MgSO^, after which the hydrochloride is precipitated with gaseous HC1. In this way, 3-/ 1,1-dimethyl-2-(4-hydroxyphenyl)-ethylamine Q7-1-(o-allyl-phenoxy-7-propanol-2) as hydrochloride, mp 141°C.

Example 20 (variant c+e)

Na (2.4 g) is dissolved in 100 ml of alcohol, after which 13.4 g of o-methoxyphenol and then 35 g of -3-[l-methyl-2-(4-methoxymethoxy-phenyl)-ethylamino7-l-chloro are added -propanol-2. The mixture is heated in an autoclave on a boiling water bath for 5 hours. It is then filtered and the filtrate is evaporated to dryness. The residue is treated with 2N HCl for one hour at room temperature and extracted with ether, after which it is alkalized with ammonia and extracted with ether. After drying the ether phase with MgSO4, the hydrochloride is precipitated with gaseous HC1. Thus 3-[1-methyl-2-(4-hydroxyphenyl)-ethylamino]-1-(b-methoxyphenoxy)-2-propanol-2 is obtained. Temp. 114°C (HC1.)

Example 21 (variant d)

0.116 mol o-methoxyphenol is mixed with 0.080 mol l-(4-methoxymethoxyphenyl)ethyl7-3-acetidinol, 0.5 mol benzyl alcohol and 0.003 mol KOH. The mixture is heated under reflux and stirring for 6 hours at 140°C and then cooled and extracted with 2N HCl. The water phase is left for one hour at room temperature, then made alkaline and finally extracted with chloroform. After drying and evaporation, the residue is dissolved in ether and the solution is mixed with HCl in ether. The hydrochloride is filtered off and washed with acetone. The hydrochloride of 3-/l-methyl-

-2-(4-Hydroxyphenyl)ethylamino^-1-(o-methoxyphenoxy)propanol-2.

Temp. 114°C.

Example 22 (variant f)

According to the above Ex. 6, 1-amino-3-(o,m-dimethyl)-phenoxypropanol-2 is prepared. Dissolve 5 g of this compound in 50 ml of methanol and add 15 g of 4-hydroxybenzylmethylketone, obtaining 3-[1-methyl-2-(4-hydroxyphenyl)-ethylimine]-1-o,m-dimethyl-phenoxypropanol-2. The solution is cooled to 0°C and at this temperature 5 g of sodium borohydride are added in portions, the imino compound formed being reduced. The temperature is then increased to room temperature and after 1 hour 150 ml H20 is added

and extracted with ether. The ether phase is dried over MgSO^ and evaporated. The residue is transferred to hydrochloride. In this way, 3-(1-methyl-2-(4-hydroxyphenyl)-ethylamino7-1-(b,m-dimethyl-phenoxy-7-propanol-2-hydrochloride) with a melting point of 125°C is obtained.

Example 23 (variant g)

1.0 g of 3-o,m-dimethyl-phenoxy-1-(1-methyl-2-(4-hydroxyphenyl)ethylamino-7-propanone-2) is dissolved in 25 ml of methanol and the solution is cooled to 0°C in an ice bath. 0.25 g of NaBH^ is added in portions while stirring, first at 0°C over the course of one hour and then at room temperature for % hour. The formed solution is evaporated, after which 50 ml of water is added. The water phase is extracted 3 times with 50 ml of chloroform, after which the combined chloroform phases are dried and evaporated. The hydrochloride was precipitated from an ether solution by addition of HCL-containing ether. The recrystallization took place from acetone. The hydrochloride of 3-(1-methyl-2-(4-hydroxyphenyl)ethylamino)-1-(b,m-dimethyl-phenoxy-7-propanol-2) melts at 125°C.

Example 24 (variant h)

That in Ex. 1 experiment carried out is repeated, replacing 1,2-epoxy-1-o-allyl-phenoxypropanol-2 with an equivalent amount of 1,2-epoxy-1-o-(2-propynyl)-phenoxy-propanol-2. Thereby, hydrochloride of 3-/1,1-dimethyl-2-(4-hydroxyphenyl)ethylamineq7-1-o-(2-propynyl)phenoxy-propanol-2 is obtained, which is dissolved in alcohol, mixed with Pd/C catalyst and hydrogenated until occupied calculated amount of H2 - After filtration, evaporate to dryness and the residue is recrystallized from ethyl acetate. In this way is obtained the hydrochloride of 3-/1,1-dimethyl-2-(4-hydroxyphenyl)ethylamineq7-1-^b-allyl-phenoxy_/-propa-

nol-2 with melting point 140°C.

Example 25

3-/2-(4-Hydroxyphenyl)-1-methyl-ethylamino7-1-o-allylphenoxy-butanol-2 is prepared from 2,3-epoxy-1-o-allyl-phenoxy-

butane and 2-(4-hydroxyphenyl)-1-methylethylamine according to Ex. 1

above. Melting point 70°C as hydrochloride.

Biological effect

The B-receptor-blocking substances according to the invention

were then tested for their biological properties. All compounds were thereby tested on anesthetized cats (male and female cats weighing 2.5-3.5 kg), pretreated with reserpine (5 mg/kg body weight administered intramuscularly) approximately 16 hours before the experiment. The animals were treated with reserpine to eliminate the endogenous sympathetic control of cardiac activity and vascular smooth muscle action. The cats were anesthetized with pentobarbital (30 mg/kg body weight administered i.p.) and artificially ventilated at room temperature. A bilateral vagotomy was per-

formed in the neck. Blood pressure was measured from a cannulated carotid artery and heart activity was recorded from a cardiotacho-

meters, by electrocardiogram (ECG). Intrinsic beta mimetic activity on the heart appeared as increased cardiac activity after drug administration. The test compounds were given intravenously in logarithmically increasing doses. The obtained values were recorded on dose-referenced curves, from which the affinity value (ED^q) was determined

voted. At the end of each experiment, high doses of iso-

prenaline given to achieve maximum cardiac activity response.

The compounds were also examined in conscious dogs. Beagle dogs were trained to lie still and lifted to an up-

erect position by placing the front legs on a away for 2 minutes. Arterial blood pressure was recorded via a blood pressure transmitter for

tied with the dog at heart level. Heart activity was measured by ECG. All dogs were pre-treated with methylscopolamine to prevent vagal effects. Recordings were made before, and 15 and 75 minutes after administration of the test compound, first in the supine position for 2 minutes and then in the upright position for

2 minutes. The test compounds were given in increasing doses with

2 hour intervals.

Table 1 below shows the affinity value of intrinsic-g-mimetic activity in reserpinized cats and the effect on blood pressure in conscious dogs of the compound according to the invention. Similar values were shown for comparison for propanolol, (l-isopropylamino-3-(1-naphthoxy)-propanol-2 and metoprolol, (l-isopropylamino-3-/4-(2-methoxyethyl)phenoxy/-propanol-2) .

Table 1 also shows pA2 measured in rats. pA2 is

- the logarithm of the concentration of the antagonist which leads to the fact that the dose of noradrenaline must be doubled to achieve the same effect as noradrenaline that is achieved without the antagonist or

and all concentrations are given in mol/l. pA2 is thus a measure of the α-receptor effect, where higher pA2 = higher α-effect.

The experiments show that they investigated compounds

are potent 3-receptor antagonists with or without intrinsic B-mimetic activity. The compounds also lower blood pressure in

conscious dogs more clearly than for propanolol and metoprolol. The clear hypotensive effect in conscious dogs of the new compounds

ser depends on a vasodilatory effect in combination with radial 6-receptor blockade.

Claims (5)

1. Analogous method for the production of new propanolamines with g-receptor blocking and a-receptor blocking effects, and with formula: where R is selected from the group consisting of hydrogen and methyl and R^ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, allyl, cyano, methoxy, propargyloxy, R is selected from the group consisting of hydrogen and methyl, R^ is selected from the group consisting of hydrogen and methyl, 2 4 provided that R and R are not both hydrogen, characterized by a) a compound of formula II 2 3 4 - 1 in which R , R and R have the above meaning, X means a hydroxy group and Z means a reactive, esterified hydroxy group or X and Z forms together an epoxy group is reacted with an amine of formula: wherein R^" has the above meaning, or b) a compound of formula III in which R , R and R <4> have the above meaning is reacted with -a compound of formula: 'in which R^" and Z have the above meaning, or c) a compound of formula IV in which R and R have the above-mentioned meaning is reacted with a compound of formula V: > 11 3 in which Z, X , R and R have the above-mentioned meaning, or d) a compound of formula IV in which x R^ and R^ have the above-mentioned meaning is reacted with a compound of formula VI: <r>' i • ! '-"■i :"T i r!" 1 3 in which R and R have the above meaning, or e) from a compound of formula I, in which R, R 2 and R<3 >have the above meaning, and which compound has a cleavable residue at the nitrogen atom in the amino group and/or has a cleavable residue at the hydroxy group, cleaves off this residue, or f) a Schiff base of formula VIII or IX or a cyclic tautomer of formula X of the compound of formula IX: 12 3 4 wherex R , R , R and R- have the above meaning except for the case when R<1> is methyl, and as compounds IX and X may be present at the same time, is reduced or g) in a compound of formula XI: in which R 1 , R 2 , R 3 and R 4 have the above meaning, the oxo group is reduced to a hydroxy group, or h) in a compound of formula XII: 13 4 2 in which R , R and R have the above meaning and in which X is a residue transferable in R 2 ; with the above meaning, X 2 is transferred to R<2>/ and free bases formed are transferred in their therapeutically acceptable salts or salts formed are transferred in their free bases. 2. Process for the production of 3-/2-(4-hydroxyphenyl)-1-methylethylamineq7-1-o-methyl-phenoxy-propanol-2 according to claim 1, characterized in that 1,2-epoxy-3-o-methyl-phenoxypropane is reacted with 2-(4-hydroxyphenyl)-1-methylethylamine. 3. Process for the production of 3-/2-(4-hydroxyphenyl)-1-methylethylamineq7-1-o-cyano-phenoxy-propanol-2 according to claim 1, characterized in that 1,2-epoxy-3-o-cyano-phenoxy -propane is reacted with 2-(4-hydroxyphenyl)-1-methylethylamine. 4. Process for the production of 3-/2-(4-hydroxyphenyl)-1,1-dimethylethylamineq7-1-o-allyl-phenoxy-propanol-2 according to claim 1, characterized in that 1,2-epoxy-3-o-allylphenoxypropane is reacted with 2-(4-hydroxyphenyl)-1,1-dimethylethylamine. 5. Process for the production of 3-(2-(4-hydroxyphenyl)-1,1-dimethylethylamino7-1-o-cyano-phenoxy-pronanol-2 according to claim 1, characterized in that 1,2-epoxy-3-o-cyano-phenoxy-propane is reacted with 2-(4-hydroxyphenyl)-1,1-di- methylethylamine.