NO142666B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-ARYLOXY-4-AMINO-2-BUTANOLS - Google Patents

Description

The present invention relates to analogous methods for the production of certain therapeutically active, organic compounds which can be described as disubstituted 2-butanols and relates more particularly to the production of 1-aryloxy-4-amino-2-butanols.

The invention thus relates to the production of compounds

with the formula:

and pharmaceutically acceptable salts thereof, wherein Ar is 1-naphthyl,

R 1 is ethyl or 2-hydroxymethyl-prop-2-yl, and R 2 is hydrogen,

1 2

or Ar is 2-methoxyphenyl, R is cyclohexyl, and R is hydrogen or methyl.

The process compounds of formula I are generally characterized by important and considerable pharmacological activity, which indicates their use in counteracting certain physiological abnormalities in an animal body. The compounds are local anesthetics, α-adrenergic blocking agents, 3-adrenergic blocking agents and antiarrhythmic agents.

There are previously known various l-aryloxy-3-amino-2-propanols which are stated to have (3-adrenergic-blocking, anticonvulsant, sedative and psychosedative activity. Among US patents which re-

speaking of the above-mentioned 1,3-disubstituted-2-propanols and their pharmacological activities, are US patents 3,337,628, 3,415,873, 3,432,545 and 3,520,919. In particular, US patent 3,337,628 mentions l-isopropylamino-3-( 1-naphthyloxy)-2-propanol which is a strong (3-adrenergic blocking agent.

The new 1-aryloxy-4-amino-2-butanols produced according to the invention were investigated for pharmacological activity and proved to have antiarrhythmic use against experimentally induced cardiac arrhythmia in dogs. The previously known homologous 1,3-disubstituted-2-propanols also have antiarrhythmic activity. However, in contrast to the previously known 2-propanols, the new 2-butanols produced according to the invention have minimal [3-adrenergic blocking activity, which enables their use in the regulation of moderate to severe arrhythmia without the dangers of heart failure and respiratory difficulties, which dangers exist when the previously known 1,3-disubstituted-2-propanols with strong β-adrenergic blocking activity are used to combat cardiac arrhythmia.

The process compounds are of particular interest because of their antiarrhythmic activity.

The process compounds are most conveniently used in the form of pharmaceutically acceptable acid addition salts. Such salts have improved water solubility compared to the free bases. Suitable acid addition salts are those derived from mineral acids such as hydrochloric acid, hydrogen bromide, sulfuric acid and phosphoric acid, and from organic acids such as acetic acid, citric acid, lactic acid, maleic acid, oxalic acid, fumaric acid and tartaric acid. The preferred acid addition salt is the hydrochloride. The acid addition salts are conveniently prepared by reacting the basic compounds with the selected acid, one or both of which may be in the form of ether, alcohol or acetone solutions.

The process compounds of formula I are prepared according to the invention by mixing, heating and reacting a compound of the formula: where Ar is as stated above, with a compound of the formula:

1 2

where R and R are as above,

and that a thus obtained base of formula I is optionally transferred to an acid addition salt thereof.

The starting materials with formula IV can be prepared by the method shown schematically in process diagram I, where Ar is as stated above.

Process core I - Production of starting 1-aryloxy-4-chloro-2-butanols (IV)

The 1-aryloxy-4-chloro-2-butanols (IV) are generally prepared by treating an aqueous basic solution or an aqueous-alcoholic-basic solution of a phenol, a substituted phenol or an aryl compound having an acidic hydroxyl group of formula II with 1,4-dichloro-2-butanol III. The addition is carried out at or below 70°C, preferably at from 30°C to 65°C during from 3 hours to 8 hours. After the addition, the reaction mixture is heated at from 50°C to 75°C, preferably at

60 - 70°C for from 6 hours to 48 hours, usually from

12 hours to 18 hours. The 1-aryloxy-4-chloro-2-butanol is isolated from the reaction mixture by extraction using a suitable organic solvent such as e.g. ether, isopropyl ether or chloroform, evaporation of the solvent after drying to obtain the 2-butanol which is isolated by suitable means such as by distillation or crystallization. Alternatively, the 1-aryloxy-4-chloro-2-butanol can be prepared by adding an aqueous basic solution to a mixture of the phenol or compound with an acidic hydroxyl group and the 1,4-dichloro-2-butanol at a rate such that the reaction mixture is maintained at a pH of from 9.0 to 10.5, preferably at a pH of 9.5 to 10.0. The product is isolated as described above.

The following methods are given to illustrate the preparation of the starting materials.

Method 1

4-chloro-1-(1-naphthyloxy)-2-butanol

To a mixture of 1 mol (147 g) of 1-naphthol, 350 ml of water and 2 mol (112 g) of potassium hydroxide was added at 54°C 1 mol (143 g) of 1,4-dichloro-2-butanol. The temperature of the reaction mixture was maintained below 60°C during the addition of the chlorobutanol. The reaction mixture was heated at 65°C for 12 hours, then mixed with 500 ml of water and 350 ml of chloroform. The chloroform layer was separated, washed with water, dried over sodium sulfate, evaporated, and the remaining oil was distilled under reduced pressure to give 128 g of a crystalline solid which distilled at 162-165°C/0.01 mm. The solid was recrystallized with ether and petroleum ether (30 - 60°C), whereby a material was obtained which melted at 75 - 77°C.

Analysis: Calculated for C14H15<0>2C1: C 67.07; H 6.03

Found : C 67.19; H 6.19

Method 2

4-chloro-1-(2-methoxyphenoxy)-2-butanol

To a mixture of 2 moles (248.26 g) of 2-methoxyphenol, 4 moles (160 g) of sodium hydroxide, 250 ml of water and 1 liter of isopropanol was added with stirring 2.2 moles (314.64 g) of 1,4-dichloro -2-butanol. The mixture was boiled under gentle reflux overnight. The reaction mixture was extracted with 1 liter of isopropyl ether, dried over sodium sulfate and distilled under reduced pressure. The distillate collected at 136-138°C/0.015 mm (396.8 g) solidified to a white crystalline solid melting at 48-50°C.

Analysis: Calculated for C^H^O^1: C 57.52; H 6.14

Found: C 57.49; H 6.54

The production of the new 1-aryloxy-4-amino-2-butanols I according to the invention is indicated by the following process scheme:

Process diagram 2 - Production of ' 1- aryloxy- 4- amino- 2- butanols

where the symbols are as above.

In the process scheme, the l-aryloxy-4-chloro-2-butanol (IV) is reacted with an amine (V) to obtain the new l-aryloxy-4-amino-2-butanols (I). The preceding reaction may be carried out by (A) heating a mixture of the chlorine compound and the amine with a solvent in a steel bomb, (B) heating a mixture of the chlorine compound and the amine without a solvent in a steel bomb, (C) refluxing a mixture of the chlorine compound, the amine and a solvent at atmospheric pressure or (D) heating a mixture of the chlorine compound and the amine without a solvent at atmospheric pressure and at a suitable temperature. The method chosen is somewhat dependent on the nature of the amine reactant. Thus, when the amine is a low molecular weight volatile amine, method A or B is preferred, and the bomb contents are heated at from 100°C to 150°C for from 12 hours to 24 hours. When the amine is a high molecular weight, non-volatile amine or an amine of low volatility, method C or D is preferred, and the reaction mixture is refluxed at the temperature of the solvent used or the mixture is heated at from 100°C to 150°C. The reaction time can be varied, as the reaction times are somewhat shorter when the chlorine compound and the amine are reacted together in the absence of a solvent and a higher reaction temperature is used. The reaction product in each case is isolated by conventional acid-base extraction methods, and the free base is optionally transferred to a pharmaceutically acceptable acid addition salt which is further purified by crystallization from a suitable solvent or solvent system. 1-aryloxy-4-amino-2-butanols which do not form well-defined salts can be purified by vacuum distillation.

Examples 1-4 illustrate the preparation of the new 1-aryloxy-4-amino-2-butanol compounds according to the invention by one of the four optional methods.

Example 1

4-( cyclohexylamino)- 1-( 2- methoxyphenoxy)- 2- butanol- monohydrate

A mixture of 11.5 g (0.05 mol) 4-chloro-1-(2-methoxy-phenoxy)-2-butanol, 9.9 g (0.1 mol) cyclohexylamine and 250 ml 2-propanol was boiled under reflux for 32 hours. The resulting reaction mixture was stored in a refrigerator overnight and then filtered. The filtrate was evaporated to dryness under reduced pressure, and the residue was extracted with 200 ml of 3N hydrochloric acid. The acidic aqueous solution was washed with ether and made alkaline. The crystalline solid was recrystallized with methanol and water, yielding 8.4 g of product, m.p. 55-57°C. NMR, IR and MS analyzes were consistent with the assumed structure. Analysis: Calculated for C17H2gN04: C 65.57? H 9.38; N 4.50

Found: C 65.53; H 8.86; N 4.46

Example 2

4-[( 2- hydroxymethyl- prop- 2- yl)-amino]- 1-( 1- naphthalenyloxy)- 2-butanol

A mixture containing 13.5 g (0.05 mol) 4-chloro-1-(1-naphthoxy)-2-butanol, 8.9 g (0.1 mol) 2-amino-2-methylpropanol and 100 ml 2 -propanol was boiled under reflux for 8 hours. The resulting reaction mixture was filtered after standing at room temperature and cooled to 5°C. The filtrate was treated with ethereal hydrochloric acid to obtain a crystalline precipitate. The crystalline solid was transferred to the free base by dissolving in water and adjusting the pH to 8. Recrystallization of the free base with hot water gave 6.8 g of the product as a white crystalline solid, mp 98-100 °C. Analysis: Calculated for ClgH25N03: C 71.26; H 8.30; N 4.62

Found: C 71.34; H 8.33; N 4.46

Example 3

4-( N- cyclohexyl- N- methyl- amino)- 1-( 2- methoxyphenoxy)- 2- butanol maleate

A mixture containing 5.76 g (0.025 mol) of 1-(3-methoxyphenyl)-4-chloro-2-butanol and 5.6 g (0.05 mol) of N-methyl-N-cyclohexylamine was heated at 120°C for 15 minutes, and the resulting reaction mixture was extracted with 300 ml of 3N hydrochloric acid. The acidic solution was extracted with 150 ml of ether and made alkaline with sodium hydroxide. The oily precipitate was extracted with 200 ml of isopropyl ether and washed to neutrality with water and dried over sodium sulfate. The dried isopropyl ether mixture was evaporated to dryness. Yield was 3.85 g of an oily material which was identified by NMR, IR and MS as the free base of the title compound.

3.07 g (0.01 mol) of the free base of the title compound was mixed with 1.16 g (0.01 mol) of maleic acid in 35 ml of 2-propanol and heated to boiling. The white, crystalline precipitate obtained at room temperature from 2-propanol was recrystallized with 2-propanol. A yield of 2.95 g of the maleate salt of the title compound (69.7%) with melting point 109-111°C was obtained.

Analysis: Calculated for C22H33<N>O7: C 62.39; H 7.85; N 3.31

Found: C 62.15; H 7.68; N 3.15

Example 4

4-ethylamino-1-(1-naphthyloxy)-2-butanol hydrochloride

A mixture of 12.5 g (0.05 mol) 4-chloro-1-(1-naphthoxy)-2-butanol, 25 ml ethylamine and 50 ml butanol was introduced into a steel bomb and heated at 120°C for 24 hours . The volatile materials were removed from the reaction mixture under reduced pressure, and the residue was extracted with 400 ml of 3N hydrochloric acid. The aqueous acid extract was washed twice with 100 ml of ether, made alkaline with caustic soda, and gave an oily precipitate. The oily precipitate was extracted into ether and dried over sodium sulfate and then treated with ethereal hydrogen chloride. The crystalline solid was filtered off and recrystallized with 2-propanol and isopropyl ether. The yield was 8.5 g with a melting point of 153-155°C, and was soluble in water. Analysis by NMR, IR and MS agreed with the assumed formula.

Analysis: Calculated for C16H22C1N02: C 64.97; H 7.50; N 4.74

Found: C 63.97; H 7.52; N 4.51

(a):

The ability to antagonize the isoproteronol-induced increase

in heart rate in intact open-breasted anesthetized dogs was used as a measure of (3-adrenergic receptor blocking activity. Doses of isoproteronol were administered at geometric intervals until a maximal increase in heart rate was achieved. After i.v. administration of the test compound or the reference standard, isoproteronol- the series repeated and the dose further increased to the point of maximal response. Dose-response curves for isoproteronol in the presence of the antagonist were plotted, and the maximal dose^ (MD^) of isoproteronol was determined for each level of antagonist. The potency of the compounds was determined in relation to propanolol when comparing the ratios of MDcjq per dose of antagonist.

The method of connecting dolsono can be processed into pharmaceutical preparations for administration to live animals, which preparations contain as active ingredient at least one of the process compounds together with a pharmaceutical carrier or excipient. The compounds are thus transferred to a form suitable for oral, rectal, parenteral or intracardiac administration. Thus, e.g. preparations for oral administration are preferably solid and can be taken in the form of capsules, tablets or coated tablets containing carriers that are usually used in pharmacy.

Advantageously, the preparations are produced as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage unit forms according to the invention. Each dosage unit adapted for oral administration may conveniently contain 10 - 40 mg of active ingredient, each dosage unit adapted for intracardiac or intravenous administration may conveniently contain 1-2 mg/ml of active ingredient, while each dosage unit adapted for intramuscular administration may conveniently contain 5-10 mg /ml active ingredient.

Claims (1)

Analogous method for the preparation of therapeutically active l-aryloxy-4-amino-2-butanols with the formula: and pharmaceutically acceptable salts thereof, where Ar is 1-naphthyl, R 1 is ethyl or 2-hydroxymethyl-prop-2-yl, and R 2 is hydrogen, or Ar is 2-methoxyphenyl, R is cyclohexyl, and R <2> is hydrogen or methyl, characterized in that a compound with the formula: where Ar is as indicated above, is mixed, heated and reacted with a compound of the formula: 1 2 where R and R are as above, and that a thus obtained base of formula I is optionally transferred to an acid addition salt thereof.