CS247552B1 - 1-(2,4-dichlorophenoxy)-3-(3,4-dimethoxy-beta-phenethylamino)-2-propanol and its additional salts with acids - Google Patents

Abstract

1. 1-(2,4-Dichlorophenoxy)-3- (3,4-dimethoxy-beta-phenethylamino)-2-propanol of formula I see diagramm : EP0086256,P7,F1 as racemate or in optically active form.

Description

The invention relates to racemic and optically active 1- (2,4-dichlorophenoxy) -3- (3,4-dimethoxy-β-phenethylamino) -2-propanol of the formula I and its acid addition salts as well as processes for its preparation.

The compound of the invention is represented by Formula I

Cl

Cl

OH

OCH ₃

This compound selectively blocks the adrenergic / s -receptors while stimulating ^_ ^ 2 receptor, an anti-hypertensive, antiarrhythmic, and exhibit cardioprotective effects on the central nervous system. It can therefore advantageously be used for the treatment and prophylaxis of angina, myocardial infarction, hypertonia, cardiac arrhythmias, hyperkinetic heart syndrome, hyperthyroidism, migraine, parkinsonism and the like.

The area of ingestion is the pharmaceutical industry.

1-phenoxy-3-alkylamino-2-proelnols have been described several times (German Patent No. 2,259,489 1, No. 2,213,044, DDR Patent No. 45,360, Belgian Patent No. 783,086, Dutch Patent Specification). No. 6,813,616, British Patent No. 1,148,563, Dutch Patent No. 7,307,821, DDR Patent No. 93,349, British Patent No. 1,078,852, Belgian Patent No. 746,107. 1- (2,5-dichlorophenoxy) -3- (3,4-dimethoxy-D-phenylethylamino) -propan-2-ol is known (Japanese Patent Specification No. 52,053,829); however, its activity differs from that of the 2,4-dichloro derivative according to the invention in that it lacks significant stimulatory effects on the β 3 -receptors of the blood vessels, which are of great importance for therapeutic use.

It is an object of the present invention to provide a pharmaceutical industrial-adrenolytic active substance of the frnoxyerone-amine type which combines a number of advantageous pharmacological properties in previously unknown combinations.

SUMMARY OF THE INVENTION The present invention is based on the preparation of a process for the preparation of compounds of formula (I) which have not been described yet, which have shown their particular pharmacological properties which differ significantly from those of the present invention. known blockers.

A compound of the invention may be prepared.

(a) reaction of 1- (2,4-Sichlorophenyl) -3-chloro-propl-2-yl with 3,4-Simtoxy-1-phenylbenzene. In order to achieve the most effective disappearance, the reaction is carried out in a basic manner, preferably in the presence of an excess of 3,4-Simethoxy-2-methyl-1-min, used as reaction reaction. Some examples of suitable bases include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, alkali metal carbonates such as potassium carbonate 1 sodium carbonate, and tertiary amines such as trp ^poxy amine.

The reaction is conveniently carried out in an organic solvent. Examples of suitable solvents are canols such as ethanol and isopropyl alcohol, ethers such as dioxane, ketones such as acetone 1-berylethyl keto, hydrocarbons such as benzene, toluene 1 xylene, 1 chlorinated hydrocarbons such as chloroform ^] ^^ <^) 11сггьг ^ 1п i trtrlchaorrtln. Reaction times of 1 temperature can be broadly varied. The reaction is generally carried out at temperatures between 20 and 200 ° C for 1 to 48 hours.

The reaction product is isolated directly as the free base or, after treatment with an acid, as the addition salt with O 2. Preferably, the halohydride is dissolved in twice the equimolar mmol of 3,4-Sibetoxy- [beta] -phenylacrine in propanol, and the mixture is heated under reflux for 16 hours under reduced pressure.

The resulting product is extracted with an organic solvent, preferably one in which the 3,4-dimethoxy-.beta.-phenethylamine hydrochloride formed does not dissolve. Examples of suitable solvents are acetone and ethyl acetate. The reaction can also be carried out in a water-immiscible organic solvent, or only to a minor extent, such as chloroform, and the 3,4-dimethoxyniphenethylamine lydrochloride can be removed from the reaction mixture by extraction with water.

The end product is isolated from the reaction mixture as is by treating the reaction mixture with isopropanoic or ethereal hydrogen chloride solution or by introducing dry hydrogen chloride gas;

b) reacting 1- (2,4-diillophenoxy) -2,3-epoxypropane with 3,4-dimethoxy-5-phenethylamine. The reaction is optionally carried out in a solvent environment and at an elevated temperature. Generally, the reaction is carried out at a temperature of 15 to 150 ° C for 15 minutes to 48 hours. Examples of suitable solvents are alkanols such as methanol, ethanol and iso-opanol, ethers such as dioxane, ketones such as acetone and methylethylktton, hydrocarbons such as benzene, toluene and xylene, and chlorinated hydrocarbons such as chloroform, tttrachOormttln and tttrlillorttln. Typically, the reactants are used in <RTIgt; 1 </RTI> moieties, although a slight excess may be employed;

c) hydrolysis of 3- (3,4-dimethoxy-β-phthyl) -5- (2,4-di-chloro-oxyl) -oxazolid-2-one . The hydrolysis of said oxazolidone is conveniently carried out with an alkaline lye, for example an aqueous solution of sodium hydroxide or potassium hydroxide. Alternatively, an organic solvent may be used in this reaction. Suitable solvents are, for example, alkanols such as ethanol and

d) reaction of 2,4-diillorphenol with 1,2-eroxy-3- (3,4-dimethoxy-1H-phenethyl) propane or 11-llogen-3- (3,4-dimethoxy- [3-phenethyl] amino) propao-2-ol, preferably 1-chloro or 1-chloro; 1-bromo-3- (3,4-dimethoxy- [3-phenethylamino) propan-4-ol. The reaction may conveniently be carried out in the presence of an acid binder such as potassium hydroxide or sodium hydroxide. On the other hand, it is possible. use alkali metal phenolate as starting material. The reaction may optionally be carried out in a solvent medium and at an elevated temperature, for example at the boiling point of the solvent. Examples of suitable solvents are alkano, such as ethanol. and nitro, hydrocarbons such as benzene, toluene and xylene, and chlorinated hydrocarbons such as chloroform, tetrachloromethane and tetrachloroethane;

e) reaction of 1- (2,4-dicrrphenoxy) -3-aminrrrpan-2-ol with 3,4-dimethyloxy-1H-ethyl-chloride. The reaction is conveniently carried out in the presence of an acid binding agent, such as sodium hydroxide or sodium bicarbonate. The reaction may optionally be carried out at elevated temperature and in a solvent environment, for example an alkane such as ethanol, n-propanol; a ^^ propano !;

, /

f) reaction of 2,4-diillrophenil with 1- (3,4-trimethoxyl-1-fetyl) -1-pyridin-3-yl. Suitably, the reaction is carried out in the absence of water and oxygen and in the presence of a basic or acidic catalyst, such as sodium or potassium hydroxide, triethylamine and triflic acid. The reaction may optionally be carried out at elevated temperature, preferably in the range of from 120 to 250 ° C and in a solvent environment. Suitable solvents are, for example, alkanols, such as benzyl, and chlorinated hydrocarbons, such as chlorobenzene; ‘

g) cleavage of the protecting group R on the alcoholic hydroxyl group of the side chain of the compound of formula II

_O-CH2 - CH - CH ₂ - NH -CH ₂ - CI _<2

OH /

in which

R represents a protecting group, for example an acyl radical, in particular an acetyl, benzoyl or hexanoyl radical, or an acetal group such as a tetrahydro-propyranyl group, by heating at room temperature to 150 ° C with an aqueous or alcoholic alkali hydroxide solution or acid, preferably hydrochloric acid.

The starting materials required for carrying out processes (a) to (g) are in part already known and in part can be prepared by conventional methods. The compound of the invention has an asymmetric carbon atom in the -CH (OH) group and therefore comes as a racemate or even as optical antipodes. In addition to the use of optically active starting materials, these antipodes can also be obtained by resolution of the racemate with conventional auxiliary acids, such as the (+) or (-) form of tartaric acid, dibenzoyltartaric acid, mandelic acid, 3-bromocapro-8-suioo- 8-new and camphor-10-sulfonic acid.

The compound of the invention may be converted into its physiologically tolerable acid addition salts and its esters in the usual manner. Examples of suitable acids for preparing acid addition salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, methanesulfonic acid, lactic acid, tartaric acid, malic acid and maleic acid. Conversion of a compound of the invention into its esters may be achieved, for example, by reaction with acyl halides or acyl anhydrides, for example acetyl chloride, acetic anhydride and butyryl chloride.

The compound of the invention in animal experiments surprisingly distinguished over known okátoůtai ^ / ^ i -receptor opranoloj.u (Oíeí of ^R ^) ^ IÍooIoí-u (num Cor ^ ^R) ^ u Practol 775 Cl superior pharmacological properties. For example, the compound of formula (I) combines two anti-anginal active principles in combination, and hitherto unknown, with the eeepts-r:

- blocking cardiac β-eepeptors decreases heart oxygen consumption,

Stimulation of the 2 2 'receptors leads to vascular dHαi, decreases the peripheral resistance of the blood vessels and thus less stress on the heart.

In a rat myocardial infarction model (oral administration of 3, 6 and 12 mm / kg of compound of formula I for 28 days prior to A. ligon and sinLstra ligature evaluation criteria: CPK, GOT, ECG changes, relative infarct severity) Even after prophylactic administration, approximately two-fold of the curative effect of Propranoool. Vveikost blocking Д --eeepto _L-R compound of the formula I depends on the type (antagonism of isoproterenol, propranolol = 100):

Mooel test Compound of Formula I TTlinolol rat heart rate (whole animal) 340 60 kosOr-lttlitl (isolated hallway) 24 21 lipolysis (epidermal fat) 220 96 guinea pig kosOr-lttiitl (isolated hallway) 76 80 rabbit peeistaltika gut 100 ALIGN! 35

On cat and dog β-receptors (heart rate and co-trachability in the whole animal), the compound of formula I was half as effective as Proprandol. While Propranolol in cats and dogs abolishes the blood pressure lowering effect of Isoproterenol by blocking the vascular receptors, the effect of Isoproterenol is potentiated by the application of a compound of formula (I) by adrenergic stimulation. Valation due to the β 2 -adrenergic action of the compound of the invention results in an antihypertensive effect, unusually sinus in the known X-receptor blockers, which is approximately 10 times more potent than Propranolol (a spontaneously hypertensive rat). Of great therapeutic importance is the stimulation of adrenergic receptors of bronchial muscle, which can be demonstrated both in isolated tracheal muscle and in whole animal experiments.

Thus, administration of 0.1 mg / kg of a compound of the invention to a dog can lead to an increase in the volume of breath time similar to the administration of Isoproterenol, while Propranolol reduces this by its brotchocaotrictor effect. In non-clogged urine, administration of 0.76 mg / kg causes a doubling of the time of otivantivoot versus histamine-inducing asthma (Isoproterenol: ED _5q = 0.04 mm / кд), while administration of 9.1 mg / kg has passed this time due to bnchoconntrictoric shortens the effect.

The reason of this is ^d at ^p desert neseletoivně ůsobícíc ^h ator ^{of the} blo ^ -receptor in patients with obstructive airway diseases contraindicated. However, the use of so-called cardioselective? -Receptor blockers, such as Practolol, Talinolol and Cl 775, is considered to be a concern in these patients, as shown by clinical experience, since these drugs lead to dyspnea or cause asthmatic preferably seizures.

attack. Since the compounds of formula I exhibit 1 ^ 2 '^ ^{а п гепег} 9! effects, the risk of increased airway resistance or asthma induction may be applied

In addition, the compounds of formula I are characterized by significant therapeutically significant antiarrhythmic effects that outstrip the effects of Propanolol, TTainolol, Practolol and the known antiarrhythmic tachymain (EIR), an increase in urinary vibration threshold: compound of formula I 0.22 mg / kg, Propanolol 1 Tlinolol 0.31 mggkg, Tachnmain 0.71 µg / kg). The central effects of the compound of formula I are therapeutically significant; thus, the compound of formula I exhibits approximately the same antiparkinic effect on tricotin-induced tremor in urine as triD hexylphetyl (Parkopan). The toxicity of the compound of formula (I) is lower than that of Propanolul and Talinolol (the LDAP of the compound of formula (I) is 141 mg / kg, for propanolol, 107 mg / kg, for Talcolol 96 mg / kg). .

The compound of the invention has the same indication areas as the already known R-receptor blockers, but exhibits stronger attiatgitous, cardioprotective and antihkpertetic effects due to the novel combination of R-receptor blockers, while at the same time enhancing cardioprotective and anti-hypertensive effects. Respiratory tract. It can therefore be conveniently administered for the treatment of angina, myocardial infarction, hypertonia, and for the treatment of central nervous disorders such as, for example, episodes, migraine, drug susceptibility and psychosis.

The single-dose therapeutic dose of a compound of the invention is between 1 and 20 mg for oral administration and between 10 and 100 mg for oral administration.

The compounds of the present invention may be formulated in conventional galenic forms such as tablets, capsules, dragees, powders, solutions, emulsions and depot forms using conventional pharmaceutical excipients as well as conventional manufacturing techniques. The compounds of the present invention may be advantageously used in combination with other pharmacodepressants. Examples of substances suitable for combination with the compound of formula I are attiatgitootic drugs such as propaanriol tri-triflate, peetiaeathrirll trichloride and dipyridamole, cardiac glycosides such as Digitoxin and Digoxin, antihypertensives such as Clonidine and Dihhaziraazit. diuretics such as Feaooeii and Hykiroelolithiazia, and centrally active drugs such as Diazepam and Lepinal.

The invention is illustrated by the following examples.

Example 1

5.1 g of 1- (2,4-dichlorophenoxy) -3-chloro-propan-2-ol and 7.2 g of 3,4-dimethoxy-.beta.-phenylamine are dissolved in 15 ml of ethyl acetate and refluxed for 20 hours. cooler. The precipitated 3,4-dimethoxy-β-phenethylamine cydrochoride is filtered off with suction, the reaction mixture is extracted with water and the organic phase is dried over sodium sulfate. The evaporation residue was swollen in an excess of the propanol-HCl solution. The reaction mixture was evaporated, the residue was washed with ether and recrystallized from ethyl acetate-ethanol to give 6.5 g (74% yield) of 1- (2,4-dichlorophenoxy) -3- (3,4-dimethoxy) hydrochloride. p-Phenethylamino) propan-4-ol as colorless crystals, m.p. 151-152 ° C.

Example 2

Dissolve 21.9 g of 1- (2,4-dichlorophenyl) -2,3-epoylpropanoate in 50 ml of itnarnaanol, and add a solution of 18.1 g of 3,4-dimetoyl-1-phenethylamine in 50 ml of arnsarnarnol, and the mixture was heated under reflux for 10 hours. Then iso ^ opano! After distilling off under reduced pressure, the residue was dissolved in ether and the ether solution was washed with water, dried over sodium sulfate, filtered and orippaged. As a residue, 1- (2,4-dichlnrfennyy) -3- (3,4-dimetoxχ-Д-phenethylamino) -prnaan-2-AD in the form of colorless crystals which are ^on the ARE r ^y ticular are installing from ethyl acetate-ethanol . This gives a colorless fine crystalline powder with a melting point of 120 to 121 ° C. Yield: 38 g (95% of theory).

Example 3 g of 3- (3,4-dimethoxy- N -phenyl) -5- (2,4-dichloro-methyl) -oxazolidin-4-one is dissolved in 20 ml of methanol and the solution is heated under reflux for 3 hours. condenser with 20 ml

50% sodium hydroxide solution. Then the ethanol is added, the residue is acidified with hydrochloric acid, extracted with ether and the aqueous phase is made alkaline with sodium hydroxide solution. The precipitated 1- (2,4 'dichlnrrennxy) -3- (3,4-dimetoyy · - / зf netslamino _e) -propan-ol is filtered off and recrystallized from ethyl acetate-ethanol. 2.8 g (yield 60% of theory) of a colorless fine crystalline powder of melting point 120 DEG-121 DEG C. are obtained.

Example 4

16.3 g of 2,4-dichlorophenol and 4.0 g of sodium hydroxide are dissolved in 300 ml of ethanol, and 28.5 g of 1,2-epoyl-3- (3,4-dimethynyl-renetslamino) propane are added. and the reaction mixture was then heated to reflux for 4 hours. The reaction mixture is then evaporated to dryness under reduced pressure, the residue is dissolved in 80 ml of chloroform, the solution is extracted with water and the organic phase is dried over sodium sulphate. After filming. to the solution was added twice the amount of ether and dry hydrogen chloride gas was added to the mixture.

The precipitate formed is filtered off with suction, washed with ether and recrystallized from dilute ethanol. 9.7 g of 1- (2,4-dichlorophenoxy) -3- (3,4-dimethoxy-6-phenethylamino) -propan-2-ol hydrochloride are obtained as a colorless fine crystalline powder, m.p. 151-152. Deň: 32 ° C. Yield ^{9.7 g of} obstructions by ^{dp i} D o ^{and 22%} of theory.

Example 5

16.3 g ^2, 4-dichlorophenol and 8.0 g of sodium hydroxide was dissolved in 100 ml of ethanol for ^{2 y} 0 ml of water and ^the mites are ^added with ^{32.9 g hydroxylamine} roc ^h lori ^d l ^- chloro-3- ^{(3, 4-di-methoxy - t} 0 ^-f ene ^yl amino) -propan-2-ol. The reaction mixture was then heated at reflux for 4 hours and then evaporated to dryness under reduced pressure. The residue was treated similarly as in Example 2, ^C M ^{F s} ská of ¹¹ (2 ^{g, of} howling that ^{for 28% of} theory) of 1- ^(2,4 -dich ^l or ^{phenoxy yl) -3} - ^{(3, 4} -d ^{i -X-} methoxy bitches ^- * ethylamino) -propan-2-ol.

Example б

A mixture of 27.3 g of 1- (2,4-dichlorophenoxy) -3-aminopropan-2-ol, 16.8 g of sodium bicarbonate,

20.1 g of 3,4-dimethoxy-4-phenethyl chloride and 300 ml of n-propanol are heated under reflux for 18 hours, the reaction mixture is evaporated to dryness under reduced pressure and the residue is worked up as described in Example 2. The yield is: 24.3 g (56% of theory).

Example 7

A mixture of 13.4 g of 2,4-dichlorophenol, 23.7 g of 1- (3,4-dimethoxy-4-phenethyl) azetidin-3-ol and 0.5 g of potassium hydroxide in 50 ml of benzyl alcohol is heated with stirring. hours at 140 ° C under a stream of nitrogen. After cooling, 150 ml of ethyl acetate are added, the mixture is shaken three times with 100 ml of Zn hydrochloric acid each time and the aqueous phase is washed with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and dry hydrogen chloride gas is introduced. The precipitated 1- (2,4-dichlorophenoxy) -3- (3,4-dimethoxy-4-phenethylamino) propan-2-ol hydrochloride is filtered off with suction and recrystallized from a mixture of ethyl acetate and ethanol. 12.4 g (yield 36% of theory) of a colorless fine-crystalline powder of melting point 151 DEG-152 DEG C. are obtained.

EXAMPLE 8 g 1- (2,4-Dichlorophenoxy) -3- (3,4-dimethoxy-4-phenethyl) aminopropanetetrahydro-pyranyl ether are dissolved in 25 ml of 2N hydrochloric acid and the resulting solution is heated under reflux for 15 minutes. The reaction mixture was extracted with ether and the aqueous phase was made basic with sodium hydroxide solution. The oily liquid obtained is taken up in ether, the ether solution is washed with water, dried over sodium sulphate, filtered and evaporated to about half the volume. The evaporated solution is treated with dry hydrogen chloride gas to form a precipitate which is filtered off with suction, washed with ether and recrystallized from water. There was thus obtained 1- (2,4-dichlorophenoxy) -3- (3,4-dimethoxy-4-phenethylamino) -propan-2-ol hydrochloride (1.7 g, 62% yield) as a colorless fine crystalline powder. mp 151-152 ° C.

Claims (14)

1- (2,4-Dichlorophenoxy) -3- (3,4-dimethoxy-4-phenethylamino) -2-propanol of formula I and its acid addition salts. 2 ^ -di ^ lo ^ eno! ovata rea ^g of ¹ - (3,4-d ⁱ methoxy ^{/ З} з phenethyl) ^- azetidin ^- 3-o ^e em and the resulting S ^ u ^ Nina formula I is optionally converted in adičaí its salts by treating with an acid. 2. A process for the preparation of a compound of the formula I according to claim 1 and its acid addition salts, characterized in that 1- (2,4-dichlorophenoxy) -3-chloro-2-propanol is reacted with 3,4-dimethoxy. -phenethylamine, whereupon the resulting product is optionally converted into its addition salt by reaction with an acid. 3. The process of claim 2 wherein the reaction of 1- (2,4-dichlorophenoxy) -3-chloro-2-propanol with 3,4-dimethoxy- [beta] -phenethylamine is carried out in organic solvents such as alkanols. , ethers, ketones, hydrocarbons or chlorinated hydrocarbons, and in the presence of bases such as alkali metal hydroxides or carbonates or tertiary amines, at the reflux temperature of the solvents. 4. A process for the preparation of a compound of formula I according to claim 1, characterized in that 1- (2,4-dichlorophenoxy) -2,3-epoxypropane is reacted with 3,4-dimethoxy-J-pheneyylamine and the resulting compound of formula I is optionally converting in its addition salt by reaction with an acid. 5. A process according to claim 4, wherein the reaction is carried out under reflux at 15 to 150 [deg.] C. in the presence of an organic solvent, preferably an alcohol such as methanol or ethanol, an ether such as dioxane or a ketone. such as acetone, or aromatic hydrocarbons such as benzene or toluene, or chlorinated hydrocarbons such as chloroform. 6. A process for the preparation of a compound of formula (I) according to claim 1, wherein the hydrolysis is 3- (3,4-dimethoxyphenylphenyl) -5- (2,4-dichlorophenoxymethyl) oxazolid-2-oa and the resulting the compound of formula I is optionally converted into its editing salt by treatment with an acid. 7. Process according to claim 6, characterized in that the hydrolysis is carried out with dilute solutions of alkali in an alcohol, preferably aqueous solutions of potassium hydroxide or sodium hydroxide with the addition of an alcohol such as ethanol and / or methanol. 8. A process for the preparation of a compound of formula (I) according to claim 1, which process comprises reacting 2,4-dichloropheaol with 1,2-epoxy-3- (3,4-dimethoxy- [4-phenethylamino) propane and the resulting the compound of formula (I) is optionally converted into its addition salt by treatment with an acid. 9. A process for the preparation of a compound of formula (I) according to claim 1, which process comprises reacting 2,4-dichloro-dichlorofrefearl with 1-halogen --- (3,4-dimethoxy-3-phenethylamino) propan-4-ol. and optionally forming the compound of formula (I) in its addition salt by reaction with an acid. 10. Process according to claim 8 or 9, characterized in that the reaction is carried out in the presence of an acid-binding agent, such as potassium or sodium hydroxide, optionally using an alkali metal pheaolate as the starting compound and alkanols such as ethanol or isopropanol; hydrocarbons such as benzene, xylene or toluene; chlorinated hydrocarbons such as chloroform, carbon tetrachloride or tetrachloroethane, preferably at the boiling point of the solvent used. 11. A process for the preparation of a compound of formula I according to claim 1, characterized in that it is left 12. The process of claim 11, wherein the reaction is carried out at a temperature of 120 to 150 ° C in an atmosphere of water and oxygen and in the presence of a catalyst such as sodium hydroxide or hydroxide. Potassium, triethylamine or acid. 13. A process for the preparation of a compound of formula (I) according to claim 1, which comprises: from a compound of formula II Cl R (II) wherein R represents a protecting group, in particular an acyl radical, for example an acetyl, benzoyl or hexanoyl radical, or an acetal radical, for example a tetrachloroethyl group, which is cleaved off and the resulting compound of formula I is optionally converted into its acid addition salt by reaction with an acid. 14. A process according to claim 14, wherein the deprotection is carried out at a temperature of 15 to 150 [deg.] C. in an aqueous or alcoholic solution of an alkali metal hydroxide or, when R is an acetyl group, using an acid such as hydrochloric acid.