DE2357748C3 - 3,4-Dipivaloxy-alpha square bracket to (isopropylamino) -methyl square bracket to - benzyl alcohol, its acid addition salts and the medicinal product containing them - Google Patents

Description

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3,4 - Dihydroxy - α - [(isopropylamino) methyl] benzyl alcohol called Isoproterenol is a well-known sympathomimetic amine that is almost exclusively on the ^ -receptors of the postganglionic adrenergic nerves acts in the sympathetic nervous system and therefore, among other things, a Heart stimulation causes tachycardia, palpitations and an increase in the strength of the contraction of the heart muscle, an enlargement of the vascular layers supplying the skeletal muscles and a Expresses relaxation of the bronchial muscles. Therefore, isoproterenol is clinically important as a brochure extender for diseases of the respiratory tract, such as bronchial asthma, and as a cardiac stimulant for heart blockages. However, there are a number of disadvantages associated with this known compound, the widespread use of isoproterenol in its main area of use as a bronchodilator Means essentially excluded.

The object on which the invention is based is thus to find new bronchiolytically effective Get compounds that are free from the unwanted side effects of 3,4 - Dihydroxya - [(isopropyl) methyl] benzyl alcohol are and have particularly increased stability and lipoid solubility and thus resorbability.

The invention relates to 3,4-dipivaloxyti - [(isopropylamino) - methyl] - benzyl alcohol, its pharmaceutically acceptable acid addition salts and medicaments containing these compounds. These new compounds are extremely valuable for the treatment of bronchial asthma and for use as a general sympathomimetic agent because they act on the postganglionic adrenergic nerve endings and structures stimulated by them and because they also have an increased rate of absorption.

The 3,4 - dipivaloxy - α - [(isopropylamino) methyl] benzyl alcohol is prepared in the way that you first of all a -halo-3,4-dihydroxyacetophenone with stoichiometric amounts, usually with an excess of the alkylammine, for example with about 3 to 4 or more molar equivalents of the alkylamine per reactive halogen atom in the α-halo-3,4-dihydroxyacetophenone treated and implemented. The reaction takes place in the presence of a suitable solvent at a temperature of about 10 to about 75 ° C and at atmospheric pressure or higher pressures from 1 to about 10 at and the like. The reaction partners begin to react when they touch each other, however, it is generally preferred to carry out the reaction for about 10 minutes to about 1 hour, to obtain the corresponding product α - isopropylamino - 3,4 - dihydroxyacetophenone from the starting materials to win.

Then the hydroxyl groups of the product a-isopropylamino-S ^ dihydroxyacetophenone in esterified in positions C-3 and C-4 of the aryl ring, by reacting an acylating agent with the hydroxyl groups in an organic medium. Examples of acylating agents suitable for esterifying the hydroxyl groups are for example anhydrides, mixed anhydrides, the chloride of the corresponding alkanoic acid and the like takes place by treating and reacting the hydroxyl groups with, for example, an acid chloride, Pivalyl chloride, in the presence of a solvent at a temperature of about 5 to 100 ° C, usually at reflux temperature, and at a pressure of 1 atm or higher for about 2 to 24 hours or an even longer time. Generally, the reactants are in equivalent amounts or present in excess, for example 2 to 10 moles of acid chloride per mole of hydroxyl groups. The acylated product is obtained by precipitation with an organic acid, followed by a conventional one Organic extraction and reprecipitation with an aqueous medium follows to give the product to give α-isopropylamino-3,4-dipivaloxyacetophenone.

The keto function of the aliphatic side chain becomes the corresponding alcohol group in a conventional manner very smooth and in good yield by catalytic hydrogenation of <x -isopropylamino-3,4-dipivaloxyacetophenone reduced. In general, the hydrogenation takes place in the presence of a metal catalyst, such as platinum, palladium, rhodium, platinum oxide or the like. The reduction of the ketone in a hydrogen environment usually occurs at about 1 to 3 atm and at room temperature or with heating about 20 to 75 ° C. The catalytic hydrogenation is usually carried out in a Parr standard apparatus or the like. The carbonyl group can also by standard methods, such as by reduction with metal hydride or the like. Be reduced. See H. O. House, Modem Synthetic Reactions, pp. 1 to 22, 1965, edited by W. A. Benjamin, Inc., New York.

The separation of the racemate can be carried out according to conventional standard separation methods that the Are known to those skilled in the art and, for example, from Fieser and Fieser in Organic Chemistry, p. 270 to 281, 1944, published by D. C. Heath and Company, Boston, and by Morrison and B ο y d in Organic Chemistry, pp. 231-233, 1969 published by Allyn and Boston, Inc., Boston are. The invention includes both the racemate and the isolated optical isomers.

The pharmaceutically acceptable acid addition salts can be prepared by conventional chemical methods can be synthesized.

The new compounds can be used in pharmacy and veterinary medicine to treat bronchial asthma including hay fever and allergic rhinitis in various pharmaceutical preparations to be used. They are thus in the form of injectable solutions, suppositories, ointments, emulsions, Jellies, plasters, oral inhalants, nasal inhalants, Aerosols and administrable in other suitable forms. The pharmaceutical or Veterinary preparations preferably contain 0.1 μg to LO g of the compounds according to the Invention mixed with a pharmaceutically acceptable organic or inorganic carrier

germaterial as a dosage unit. Typical pharmaceutically acceptable carrier materials are, for example Water, mixtures of water and water-miscible solvents such as low molecular weight Alkanols or aralkanols, vegetable oils, polyalkylene glycols, Petroleum-based jellies, ethyl cellulose, ethyl oleate, carboxymethyl cellulose, polyvinylpyrrolidone, Isopropyl myristate and other commonly used pharmaceutically acceptable carrier materials. The pharmaceutical preparation can also contain non-toxic auxiliary substances, such as emulsifiers, Protective agents, wetting agents, thickeners and the like, such as polyethylene glycols 200, 300, 400 and 600, carbon waxes 1000, 1500, 4000 and 10 000, antibacterial components such as qnaternary Ammonium compounds, phenyl mercury salts, which are known to have cold sterilizing properties own and are not harmful when used, thimerosal, propylparaben, buffer substances, such as Sodium chloride, sodium borate, sodium acetate, gluconate buffer and other conventional ingredients, such as sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monopalmitylate, Dioctyl sodium sulfosuccinate, monothioglycerin, thiosorbitol, ethylenediaminetetraacetic acid etc. In addition, suitable vehicles such as conventional ones can be used as carrier media for the present purpose Phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic Sodium borate vehicle.

For example, a typical method of making a solution for use with common Atomizing and containing 3,4-dipivaloxy - α - [(isopropylamino) - methyl] - benzyl alcohol salt, Sodium chloride, chlorobutanol, oxime sulfate and distilled water in the following measures : First, a measured amount of chlorobutanol is poured into 500 ml of distilled water while stirring and optionally dissolved with mild heating to form a solution. Then sodium chloride, Oxime sulfate and 3,4-dipivaloxy-a - [(isopropylamino) methyl] benzyl alcohol hydrochloride added and the solution stirred until clear. Then distilled water is added up to the liter mark, and the solution is now through a conventional filter with a pore size of 0.2 to 0.4 μ filtered. The solution then has a shelf life of 3 years at 4 ° C and its composition is the following:

Components g.1

3,4-Dipivaloxy-a - [(isopropylamino) -2.0
methyl] benzyl alcohol bitartrate

Sodium chloride 8.0

Chlorobutanol 5.0

Oxime sulfate 0.1

Distilled water on 11

A second pharmaceutical preparation similar to that prepared above is followed obtained this process, but with the exception that the amount of 3,4-dipivaloxy - «- [(isopropylamino) methyl] benzyl alcohol hydrochloride is increased to 10 g and 2% phenylethyl alcohol is used as a protective agent.

A new lyophilized pharmaceutical preparation for later reprocessing immediately before therapeutic administration is prepared as follows: First, 4 g of 3,4-dipival

5 oxy -α- [(isopropylamino) methyl] benzyl alcohol hydrochloride and 8 g mannitol USP are mixed with 1 liter of distilled water with stirring, and the resulting solution is filtered through a sterile filter. Then 5 to 12 ecm of this solution are transferred into amber-colored bottles and lyophilized by conventional methods until the freshly formed cake is dry. The lyophilized dry cake is then reconstituted with 10 ecm of a thinning agent of the following composition: 2 g sodium chloride, 5 g chlorobutanol, 0.1 g oxime sulfate, mixed with distilled water to the volume line in a 100 ml volumetric flask.

The lyophilized cake can optionally be so

ίο can be produced that the mannitol can be replaced by buffer substances, such as a mixture of sodium chloride and sodium dihydrogen phosphate and a mixture replaced by potassium chloride and potassium acetate and sodium acetate.

Examples of preparations which are suitable for inhalation therapy are, for example, those compositions that of atomizers with a pressing device, a container, a Venturi effect device and pressurized dispenser for using chlorofluorocarbon Can be administered as propellants, pre-micronized powders in liquid propellants, liquid-vapor phase aerosols and the like, Typically, a preparation that Tür is conventional Atomizer is suitable, optionally from 0.4 to 0.8% solution of 3,4-dipivaloxy - «- [(isopropylamino) methyl] benzyl alcohol hydrochloride in a buffered carrier material made of sodium chloride, sodium citrate, Glycerine and a trace of a protective

by means of. In one embodiment, the air in the manifold can be replaced with nitrogen gas will. A typical pressurized manifold may optionally be 0.20 to 0.50 weight percent 3,4 - Dipivaloxy - α - [(isopropylamino) -

methyl] benzyl alcohol in a mixture of dichlorodifluoromeihan and dichlorotetrafluoroethane with a sodium lactate-lactic acid buffer, about 30 to 40 percent by weight (weight per weight) of an alkanol and containing aromatic flavors. Other compositions containing the compound suspended in chlorofluorocarbons according to the Invention and sorbitan trioleate or the like. Containing, can also be used for administration of the compound be used.

The dose administered, either a single dose or a daily dose, will of course vary according to the route of administration selected and the size of the patient. For the dose administered there are no defined limits, but it is usually an effective amount or on a molar basis Basis is the equivalent of the pharmacologically active form that is used in the metabolic release of the active Drug is formed to get the desired pharmacological and physiological effect.

The medicinal dose for warm-blooded acid animals, such as humans and primates (monkeys and monkeys) for intramuscular and subcutaneous administration is about 100 μg to 5 mg, administered in 0.1 to

1.5 ml of a 0.1 to 0.5% oil suspension with the usual intramuscular dose of 200 to 750 μg in 0.2 to 0.75 ml of a 0.1 to 0.5% solution. at Medicinal products for oral inhalation, the concentration of the compounds according to the invention is preferably at about 0.01 to 2.0% when administered as a fine mist. For typical administration in surgical procedures of the nose and throat, solutions of 0.002 to 0.975% can be used. In general, the dosage form for a typical non-toxic salt, such as the hydrochloride, is in a solution for inhalation at a concentration of about 0.025 to 4% or the like. The dosage for agricultural animals is generally about 4 to 10 ml on subcutaneous or intramuscular Paths for horses and cattle and at about 0.2 to 0.6 ml or the like for dogs.

example

Synthesis of 3,4-Dipivaloxy-a - [(isopropylamino) -methyl] -benzyl alcohol

First, in alignment with the method of Corrigan et al. in J. Am. Chem. Soc, 71, p. 530 and 531 (1949), a mixture of 0.20 moles of α-chloro-3,4-dihydroxyacetophenone, Compound 1, 0.66 mol of isopropylamine and 125 ml of isopropanol heated to 75 ° C. with stirring, at this temperature for 5 minutes held and then cooled to room temperature uniler stirring. The crude product separates during the Implementation and is made by adding the smallest amount of concentrated hydrochloric acid to an acidic Solution converted to the hydrochloride salt, compound 2.. Overnight cooling leads to a precipitate of the product salt, which is recovered by adding 500 ml of acetone and filtration. The resulting crystalline product has a

The reaction goes as follows:
O

Melting point m.p. = 239 to 242 ° C and is used without further purification

Then 0.125 mol of compound 2 in 250 ml of ethyl acetate are dissolved, and 0.125 moles of perchloric acid are slowly added as a 70% aqueous solution added with continuous stirring. Then an excess of civilyl chloride, compound 3, added in an amount of 280 ml and the mixture is slowly warmed to the reboot temperature. The reaction mixture is refluxed for about 5 hours and then under continuous Cooled stirring to room temperature. The product is called the perchlorate salt by adding 500 ml Ether failed. The product, compound 4, is isolated and dissolved in the smallest amount boiling acetone, addition of hexane until the onset of cloudiness and precipitation by cooling cleaned overnight.

Then add 20 g of compound 4 dissolved in 200 ml of 95% ethanol in a Parr reaction kettle, 1.5 g of Adams catalyst, platinum oxide, was added and the mixture was stirred under hydrogen at 3.4 at Shaken (50 psi) for 1 hour at ambient temperature. The mixture is then filtered and the Ethanol removed on a standard rotary evaporator. The resulting oil is in 200 ml of water dissolved, the solution is neutralized with ammonium hydroxide and extracted exhaustively with chloroform. The combined chloroform extracts are dried over calcium chloride, filtered and evaporated. The residue is dissolved in 200 ml of ether and the product, compound 5, as the hydrochloride salt precipitated by the introduction of excess gaseous hydrochloric acid. The product is purified by dissolving boiling acetone in the smallest amount, hexane up to added cloudiness and cool overnight in the refrigerator. The crystalline material thus obtained has a melting point F. = 153 to 155 ° C.

HO

CH ₂ Cl + (CHj) ₂ CHNH ₂
Connection 1

HCl HO

HO

O (CH ₃ ) ₃ CC -

Il HClO ₄
(CHj) ₃ CCCl- »O

(CH ₃ ) ₃ CC -O

Connection 3

O j CH ₂ NHCH (CH ₃ J ₂ • HCl
Connection 2

CH ₂ NHCH (CH ₃ ) ₂ • HClO ₄
Connection 4.

H ₂ / Pt

HCl

CH ₂ NHCH (CH ₃ I ₂ • HCl

connection

Claims (2)

Patent claims: 1. 3,4 - Dipivaloxy - α - [(isopropylamino) methyl] benzyl alcohol and its pharmaceutically acceptable acid addition salts. 2. Medicament containing a compound according to claim 1.