CH618419A5 - Process for the preparation of novel hydroxyamines - Google Patents

Abstract

For the preparation of novel hydroxyamines of the formula <IMAGE> with R<1> to R<4> as in the patent claim, and the acid addition salts of these compounds, a starting compound of the formula <IMAGE> is used. The latter is reacted with a compound of the formula <IMAGE> In this formula, X stands for hydrogen or for a removable group. The resulting isomeric mixtures can be separated into the pure isomers and the resulting racemates into the optical antipodes. The resulting free bases can be converted into a therapeutically acceptable salt thereof or the resulting salts converted into the corresponding free bases. The novel hydroxyamines block cardiac beta -receptors. They are used for the treatment of arrhythmias, of angina pectoris and of hypertension.

Description

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PATENT CLAIMS 1. Process for the preparation of new hydroxyamines of the formula (I)

r3 r1

1 i och2chohchnhc-ch2- - (

-oh ch,

(I)

wherein R1 is hydrogen or methyl, R2 is hydrogen, methyl, ethyl, propyl, allyl, cyano, methoxy or propargyloxy, R3 is hydrogen or methyl and R4 is hydrogen or methyl, where R2 and R4 are not simultaneously hydrogen, and the acid addition salts of these compounds, thereby characterized in that a compound of formula (IV)

(iv)

wherein R2 and R4 have the meanings given above, with a compound of the formula (V)

xv z-ch2chchnhcch2 ch_

(v)

The present invention relates to a process for the preparation of new hydroxyamines which are active / 3-receptor-blocking compounds.

When administered to mammals, especially humans, these compounds block the ß-receptors of the heart and are therefore valuable remedies for the treatment of the symptoms and features of cardiovascular diseases.

io The new compounds obtainable according to the invention have the formula (I)

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] ch2chühchnhc-ch ^ -

R

4h,

(I),

wherein R1 is hydrogen or methyl, R2 is hydrogen, methyl, ethyl, propyl, allyl, cyano, methoxy or propargyloxy, R3 is hydrogen or methyl and R4 is hydrogen or methyl, where R2 and R4 are not simultaneously hydrogen.

The state of the art can be demonstrated using the following publications:

U.S. Patent No. 3,328,424 - Schenker et al. - describes the compound l-isopropylamino-3- (o-isopropoxy-phenoxy) -propanol-2, which, however, has no clinically valuable a-receptor activity. However, the compounds made according to this invention show both α-receptor activity and β-receptor blocking activity.

U.S. Patent No. 3,852,468 - Howe et al. - Compounds of the formula in which R1 and R3 have the meanings given above and in which Z is a reactive, esterified hydroxyl group and X1 is -OH or Z and X1 together are an epoxy group, is reacted and isomeric mixtures obtained are separated into the pure isomers and Free bases obtained are converted into their therapeutically acceptable salt.

2. A process for the preparation of the new hydroxyamines of the formula (I) as defined in claim 1, characterized in that the compounds of the formula (IV), which are also defined in claim 1, with a compound of the formula (V ')

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xv r1

z-ch2chchnhcch2

-or (v)

ch.

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60

in which R1 and R3 have the meanings given above and Z represents a reactive, esterified hydroxyl group and in which R represents a cleavable group, is reacted, R is cleaved off and isomeric mixtures obtained are separated into the pure isomers and free bases obtained in their therapeutically permissible Salt are transferred.

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3 2 r r n och2chohch2nhr

In the above formula, R1 stands for an unsubstituted alkyl of 1 to 10 carbon atoms, for unsubstituted cycloalkyl with 3 to 8 carbon atoms or for alkyl with 1 to 6 carbon atoms, that with hydroxy, phenyl, halophenyl or alkoxyphenyl can be substituted; R2 stands for hydrogen or alkyl with 1 to 4 C atoms, R3 stands for acyl with 1 to 10 C atoms and R4 finally stands for hydrogen, halogen, —OH, nitro, cyano, acetamide, trifluoromethyl, alkyl, alkoxyalkyl, phenylalkyl , Phenylalkoxy, aryl or aryloxy, where all the radicals mentioned can have 1 to 10 C atoms or for cycloalkyl with 3 to 8 C atoms or hydroxyalkyl, alkoxy, alkenyloxy, alkynyloxy, alkenyl, alkylthio, alkanoyl or alkoxycarbonyl each with 1 to 5 carbon atoms. The esters of the abovementioned compounds with aliphatic carboxylic acids or aromatic carboxylic acids or other condensation products thereof are also possible. However, these compounds also do not show any of the important a-receptor activities.

GB Patent No. 1,344,976 describes compounds of the formula

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O-

och

0ch2ch0hch2nhch2ch2

In the formula, Z represents chlorine, alkoxy, cyano, hydroxymethyl, acetyl, alkyl in the meta position or alkyl in the ortho position.

However, none of the meta-substituted compounds mentioned shows any a-receptor activity. The ortho-substituted compounds of the aforementioned British patent show side activities in combination with their βx-receptor blocking selectivity, which are not desired.

The new compounds obtainable according to the invention have valuable pharmacological properties. B. the cardial / 3 receptors, which can be shown by determining the antagonism of tachycardia after intravenous injection of 0.5 fim / kg of d / l-isoproterenol sulfate in an anesthetized cat after intravenous injection of 0.002 to 2 mg / kg . The compounds obtainable according to the invention also block the vascular β-receptors, which can be determined by determining the antagonism of the vasodilation after intravenous injection of 0.5 wg / kg of d / l-isoproterenol sulfate in an anesthetized cat by intravenous administration of 0.002 to 2 mg / kg or more is shown. The compounds obtainable according to the invention also have stimulating properties on β-receptors, i.e. H. they show a specific effectiveness (intrinsic activity). This characteristic is particularly pronounced with regard to the vascular ß -receptors which cause dilation of the peripheral blood vessels.

The new compounds obtainable according to the invention can be used for the treatment of arrhythmias, angina pectoris and hypertension. Peripheral vasodilation is particularly valuable for the latter two indications. The compounds can also be used as intermediates for the preparation of other valuable compounds with pharmacological properties.

The process according to the invention for the preparation of new hydroxyamines of the formula (I) is defined in patent claims 1 and 2.

Preferred compounds are the following: 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-methyl-

phenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-ethyl-

phenoxypropanol- (2),

3 - [2- (4-hydroxyphenyl) -1-methylethylamino] -1-o-propyl-

phenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-allyl-

phenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-pro-

pargyloxyphenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-cyano-

phenoxypropanol- (2),

3 - [2- (4-Hydroxypheny 1) -1,1 -dimethylethylamino] -1 -o-

methylphenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l, l-dimethylethylamino] -l-o-

ethylphenoxypropanol- (2),

3 - [2- (4-Hydroxypheny 1) -1,1 -dimethylethylamino] -1 -o-

propylphenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l, l-dimethylethylaminol-l-o-

allylphenoxypropanol- (2),

3 - [2- (4-hydroxyphenyl) -1,1 -dimethylethylamino] -1 -o-

propargyloxyphenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l, 1 -dimethylethylamino] -l-o-cyanophenoxypropanol- (2),

3-ethyl-3 - [2- (4-hydroxyphenyl) -1-methylethylamino] -1-o-allylphenoxypropanol- (2), io 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -lo, m -dimethylphenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -lo-meth-

oxyphenoxypropanol- (2),

3-methyl-3 - [2- (4-hydroxyphenyl) -1-methylethylamino 1-15 l-o-ethylphenoxypropanol- (2),

3-methyl-3- [2- (4-hydroxyphenyl) -l-methylethylamino] -

1-o-cyanophenoxypropanol- (2), 3-methyl-3- [2- (4-hydroxyphenyl-l, l-dimethylethylamino] -lo-methylphenoxypropanol- (2), 20 3-methyl-3- [2 - (4-hydroxyphenyl) -l, l-dimethylethylamino j -1 -o-allylphenoxypropanol- (2) and 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -lm-methyl-phenoxypropanol- (2 ).

Salt-forming acids can be used to prepare therapeutically permissible salts of the compounds obtainable according to the invention, for example hydrohalic acids, sulfuric, phosphoric, nitric or perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, for example formic acid, vinegar -, 30 propion-, amber-, glycol-, milk-, apple-, wine-, citro-nen-, ascorbin-, maleic-, hydroxymalein-, pyruvate-, phenylacetic acid-, benzoe-, p-aminobenzoe-, anthranil -, p-Hy-droxybenzoic, salicylic, p-aminosalicyl, embon, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylene sulfonic, Ha-35 benzene sulfonic, toluenesulfonic, naphthylsulfonic or sulfanic acid, Methionine, tryptophan, lysine or arginine.

The compounds obtainable according to the invention can be used orally or parenterally for acute and chronic treatment of the above-mentioned cardiovascular diseases. The biological effects of the new compounds obtainable according to the invention were tested and the various tests carried out with the compounds mentioned are indicated and explained below.

Depending on the process conditions and the starting materials used, the end product is obtained either in free form or in the form of its acid addition salt, which is included in the scope of the invention. For example, basic, neutral or mixed salts can be obtained, as can hemiamino, sesqui or polyhydrates. so The acid addition salts of the new compounds can be converted into the free compounds in a manner known per se, using basic agents, such as alkalis, or ion exchangers. On the other hand, the free bases obtained can form 55 salts with organic or inorganic acids. In the production of acid addition salts, preference is given to using those acids which form suitable therapeutically permissible salts. Such acids are, for example, hydrohalic acids, sulfuric, phosphoric, nitric or perchloric acid, aliphatic, alicyclic, aromatic-60 table or heterocyclic carboxylic or sulfonic acids, such as, for example, formic, acetic, propionic, amber, glycolic , Milk, apple, wine, lemon, ascorbic, maleic, hydroxymalein, amber, phenylacetic, benzoic, p-amino-benzoic, anthranil, p-hydroxybenzoic, salicyl, p -Amino-65 salicylic or embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic or ethylenesulfonic acids, halobenzenesulfonic, toluenesulfonic or naphthylsulfonic acids or sulfanilic acid; Methionine, tryptophan, lysine or arginine.

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These or other salts of the new compounds, for example the picrates, can serve to purify the free bases obtained by converting the bases into salts, by separating them and by releasing the bases from the salts. Because of the close relationship between the new compounds in free form and in the form of their salts, it is understood from the foregoing and the following that, if possible, the corresponding salts can also be used * if the free compounds are mentioned.

Depending on the choice of starting materials and the process, the new compounds can be present as optical antipodes or racemates, or if they contain at least two asymmetric carbon atoms, they can be present in the form of an isomeric mixture (racemate mixture).

The isomeric mixtures obtained (racemate mixtures) can be separated into the two stereoisomeric (diastereomeric) pure racemates, for example by means of chromatography and / or by fractional crystallization, depending on the physico-chemical differences between the components.

The racemates obtained can be separated by methods known per se, for. B. by recrystallization from an optically active solvent, by means of microorganisms or by reaction with optically active acids, salts of the compounds being formed, which are then separated, for example because of their different solubility, into the diastereomeric forms from which the antipodes are then separated by suitable means Freedom. Suitable optically active acids are, for example, the L and D forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphor sulfonic acid or quinic acid. The more active part of the two antipodes is preferably isolated.

In clinical use, the compounds obtainable according to the invention can normally be administered orally, rectally or by injection in the form of a pharmaceutical preparation which contains an active component either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, e.g. B. which contains hydrochloride, lactate, acetate, sulfamate or the like, in combination with a pharmaceutical carrier.

The mention of the new compounds obtainable according to the invention relates either to the free amine base or to the acid addition salts of the free base, even if the compounds are generally or specifically described, provided that the context in which such terms are used, e.g. B. in the examples, does not agree with the broad meaning. The carrier can be a solid, semi-solid or liquid diluent or a capsule. The amount of active compound is usually between 0.1 and 95% by weight of the preparation, preferably between 0.5 and 20% by weight for preparations for injection and between 2 and 50% by weight for preparations for oral administration.

In the manufacture of pharmaceutical preparations for oral administration, the compound obtainable according to the invention can be mixed with a solid, powdery carrier, for example with lactose, sucrose, sorbitol, mannitol, starch, for example potato starch, corn starch or amylopectin, cellulose derivatives or gelatin, or together with a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like; the mass can then be compressed into tablets. If dragées are to be produced, the cores prepared as above can be coated with concentrated solutions of sugar. These solutions can also contain, for example, gum arabic, gelatin, talc, titanium dioxide or the like. In addition, the dragées can be coated with a lacquer dissolved in a volatile organic solvent or mixture of solvents. A dye can be added to these coatings to enable easy distinction between tablets with different active compounds or with different amounts of active compound.

In the production of soft gelatin capsules (pearl-shaped, closed capsules) consisting of gelatin and, for example, glycerol, or in the production of similar closed capsules, the active compound can be mixed with a vegetable oil. Hard gelatin capsules can contain granules of the active compound in combination with a solid, powdery carrier, for example with lactose, sucrose, sorbitol, mannitol, starch (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Unit dosage forms for rectal administration can be prepared in the form of suppositories containing the active substance in admixture with a neutral fat base, or in the form of gelatin rectal capsules containing the active substance in admixture with a vegetable oil or paraffin oil.

Liquid preparations for oral administration can be in the form of syrups or suspensions, e.g. B. solutions containing about 0.2 to about 20 wt.% Of active substance, the remainder consisting of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations can contain colorants, flavorings, saccharin and / or carboxymethyl cellulose as thickeners.

Solutions for parenteral administration by injection can be prepared in the form of an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active compound, preferably in a concentration of about 0.5 to about 10.0% by weight. These solutions can also contain stabilizing agents and / or buffer substances and can be obtained in ampoules with different doses.

A preferred embodiment of the method according to the invention is explained in more detail below using an example. The temperatures are given in ° C.

example

2.4 g of sodium were dissolved in 100 ml of ethanol, whereupon 13.4 g of o-methoxyphenol and then 35 g of 3- [l-methyl-2- (4-benzyloxyphenyl) ethylamino] -l-chlorine were added to the above solution. propanol-2 were given. The reaction mixture was then heated in an autoclave over boiling water for 5 hours. The precipitated solid was then filtered off and the filtrate was evaporated to dryness. The residue was taken up in water and acidified by adding 2N HCl. The mixture was then extracted with ether, then made alkaline with ammonia and extracted again with ether. The second ether phase was dried over magnesium sulfate, and the hydrochloride of the product could be precipitated by passing gaseous HCl through it. This was 3- [l-methyl-2- (4-benzyloxyphenyl) ethylamino] -l- (o-methoxyphenoxy) propanol-2 • HCl. The melting point of the compound was 114 ° C.

The intermediate product is then subjected to a catalytic hydrogenation, in the form of a solution in ethanol. The benzyl group is replaced by hydrogen.

The β-receptor blocking agents obtainable according to the invention were tested with regard to their biological properties. All compounds were tested on anesthetized cats (male and female weighing 2.5 to 3.5 kg) approximately 16 hours prior to reserpine trials

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(5 mg / kg body weight, administered intramuscularly) had been tested. The animals were pretreated with Reser-pin to eliminate endogenous sympathetic heartbeat control and vascular smooth muscle tone. The cats were anesthetized with pentobarbital (30 mg / kg 5 body weight, administered intraperitoneally) and artificially ventilated with room air. A bilateral vagotomy was performed on the neck. Blood pressure was measured with a cannula in the carotid artery and the heartbeat was recorded with a cardiotachometer triggered by the 10 electrocardiogram (ECG). The actual beta-mimetic effectiveness on the heart was indicated by an increased heartbeat after the administration of the agent. The test compounds were administered intravenously in logarithmically increased doses. The values obtained were recorded as dose-effect curves, from which the effectiveness values (ED50) (affinity values) were determined. At the end of each trial, high doses of iso-prenaline were given to get the maximum heartbeat effect. 20th

The compounds were also tested on conscious dogs. Beagles were trained to lie still and to stand upright for 2 minutes by placing their front paws on a table. Arterial blood pressure was recorded using a blood pressure transmitter attached to the heart. The heartbeat was determined by the EKG. All dogs were pretreated with methylscopolamine to eliminate vagus effects. Recordings were made before and 15 and 75 minutes after test compound administration, first with the dogs on their backs for 2 minutes and in an upright position for 2 minutes. The test compounds were administered at 2 hour intervals in increasing doses.

The experiments prove that the investigated compounds are effective β-receptor antagonists, with or without real β-mimetic activity. The compounds also lower blood pressure in conscious dogs significantly more than propranolol and metoprolol. The pronounced hypotensive effect of the compounds obtainable according to the invention on dogs that are conscious is based on a vasodilatory effect in combination with cardiac /? - receptor blocking.

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