Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
  • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
  • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
  • C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds

Definitions

• R stands for hydrogen or for an alkyl radical
• R stands for an alkyl, hydroxyalkyl or cycloalkyl radical
• R stands for an alkyl radical of 2 or more carbon atoms, or for a haloalkyl, cycloalkyl or alkenyl radical, and the aldehyde condensation products and the esters thereof, and the salts thereof.
• This invention relates to new alkanolamine derivatives which possess [i-adrenergic blocking activity, for example such activity in cats, and which are therefore likely to be useful in the treatment or prophylaxis of coronary artery diseases, for example angina pectoris and cardiac arrhythmias, and in the treatment of hypertension and phaeochromocytoma, in man.
• R stands for hydrogen or for an alkyl radical, wherein R stands for an alkyl, hydroxyalkyl or cycloalkyl radical, and wherein R stands for an alkyl radical of 2 or more carbon atoms, or for a haloalkyl, cycloalkyl or alkenyl radical, and the aldehyde condensation products and the esters thereof, and the salts thereof.
• alkanolamine derivatives encompasses all possible stereoisomers thereof, and mixtures thereof.
• R when it stands for an alkyl radical there may be mentioned, for example, an alkyl radical of not more than 6 carbon atoms, for example the methyl, ethyl or isopropyl radical.
• R when it stands for an alkyl or hydroxyalkyl radical there may be mentioned, for example an alkyl or hydroxyalkyl radical of not more than 10 carbon atoms, for example the methyl, ethyl, n-propyl, isopropyl, s-buty1, t-butyl, l-methyloctyl or 2- hydroxy-1,1-dimethylethyl radical.
• an alkyl or hydroxyalkyl radical of not more than 10 carbon atoms for example the methyl, ethyl, n-propyl, isopropyl, s-buty1, t-butyl, l-methyloctyl or 2- hydroxy-1,1-dimethylethyl radical.
• R or R when it stands for a cycloalkyl radical there may be mentioned, for example, a cycloalkyl radical of not more than 6 carbon atoms, for example the cyclopentyl radical.
• R when it stands for an alkyl radical of 2 or more carbon atoms there may be mentioned, for example, an alkyl radical of at least 2 and not more than 10 carbon atoms, for example the ethyl, isobutyl or n-heptyl radical.
• R when it stands for a haloalkyl radical there may be mentioned, for example, an
• R when it stands for an alkenyl radical there may be mentioned, for example, an alkenyl radical of not more than 6 carbon atoms, for example the allyl radical.
• aldehyde condensation products of the alkanolamine derivatives We mean the oxazolidine derivatives of the formula:
• R and R have the meanings stated above, and wherein R stands for hydrogen or for an alkyl or aryl radical, and the salts thereof, which are derived from the alkanolamine derivatives of the invention of the stated formula wherein R stands for hydrogen.
• R when it stands for an alkyl or aryl radical there may be mentioned, for example, an alkyl or aryl radical of not more than 10 carbon atoms, for example the isopropyl or phenyl radical.
• esters of the alkanolamine derivatives there may be mentioned, for example, O-esters derived from a saturated or unsaturated aliphatic carboxylic acid, for example such an acid of not more than 20 carbon atoms, for example acetic, palmitic, stearic or oleic acid, or O-esters derived from an aromatic carboxylic acid, for example such an acid of not more than 10 carbon atoms, for example benzoic acid.
• a saturated or unsaturated aliphatic carboxylic acid for example such an acid of not more than 20 carbon atoms, for example acetic, palmitic, stearic or oleic acid
• O-esters derived from an aromatic carboxylic acid for example such an acid of not more than 10 carbon atoms, for example benzoic acid.
• acid-addition salts for example salts derived from inorganic acids, for example hydrochlorides, hydrobromides, phosphates or sulphates, or salts derived from organic acids, for example oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, ,8-naphthoates, adipates or l,1-methylene-bis(Z-hydroxy- 3-naphthoates), or salts derived from acidic synthetic resins, for example sulphonated polystyrene resins, for example Zeo-Karb 225 (Zeo-Kar'b is a trademark).
• Relatively insoluble salts for example the 1,1'-methylenebis-(2-hydroxy-3-naphthoates), have the advantage that they afford prolonged blood levels of the salt when it
• Particular new alkanolamine derivatives of the invention are, for example,
• Z there may be mentioned, for example, a chlorine or bromine atom.
• the interaction may conveniently be accelerated or completed by the application of heat, and it may be carried out in an inert diluent or solvent, for example methanol.
• the interaction involving an epoxide may conveniently be accelerated or completed by the application of heat, and it may be carried out in an inert diluent or solvent, for example methanol or ethanol.
• the last-named interaction may conveniently be carried out in the presence of an acid-binding agent, for example sodium hydroxide.
• an alkali metal derivative of the phenol reactant for example the sodium or potassium derivative, may be used as starting material.
• the interaction may be carried out in a diluent or solvent, for example ethanol, and it may be accelerated or completed by the application of heat.
• the hydrogenolysis may be effected, for example, by catalytic hydrogenation, for example hydrogenation in the presence of a palladiumon-charcoal catalyst, in an inert diluent or solvent, for example ethanol.
• the hydrogenolysis is preferably effected in the presence of an acidic catalyst, for example hydrochloric acid.
• Suitable reducing conditions are those provided by the presence of hydrogen and a hydrogenation catalyst, for example platinum, in an inert diluent or solvent, for example ethanol, and/or, in the case where, in the said carbonyl compound used as starting material, R stands for an alkyl radical, in an excess of the carbonyl compound used as starting material; or by the presence of an alkali metal borohydride, for example sodium borohydride, in an inert diluent or solvent, for example ethanol or aqueous methanol, and/or in an excess of the carbonyl compound used as starting material.
• a hydrogenation catalyst for example platinum
• an inert diluent or solvent for example ethanol
• R stands for an alkyl radical, in an excess of the carbonyl compound used as starting material
• an alkali metal borohydride for example sodium borohydride
• the said amino derivative may be generated in situ by, for example, reduction of the corresponding a-diazoketone, a-azidoketone, a-hydroxyiminoketone, a-nitroketone, a-nitro-alcohol, cyanhydrin or acyl cyanide.
• R and R have the meanings stated above, or an ester thereof, or a salt thereof, with a compound of the formula R Y, wherein R Y stands for a reactive ester derived from an alcohol of the formula R OH, wherein R has the meaning stated above.
• Y there may be mentioned, for example, the chlorine, bromine, or iodine atom, the toluene-p-sulphonyloxy radical or a radical of the formula: --OSO OR wherein R has the meaning stated above.
• R Y is isopropyl bromide.
• the interaction may conveniently be carried out in the presence of a base, for example an inorganic base, for example sodium carbonate, and in the presence of a diluent or solvent, for example ethanol.
• a base for example an inorganic base, for example sodium carbonate
• a diluent or solvent for example ethanol.
• the interaction may conveniently be carried out at an elevated tem perature, for example at a temperature of between C. and 200 C., for example at about C.
• R and R have the meanings stated above, or a salt thereof, with an aldehyde of the formula R CHO, wherein R has the meaning stated above.
• the said interaction may be carried out in a diluent or solvent, for example ethanol, benzene, toluene or xylene, optionally in the presence of a catalyst, for example hydrochloric acid, acetic acid or iodine, and it may be accelerated or completed by the application of heat.
• a catalyst for example hydrochloric acid, acetic acid or iodine
• the water formed during the reaction may be removed by azeotropic distillation using a suitable solvent, for example benzene, toluene or xylene as entraining agent, or it may be removed by means of a dehydrating agent, for example anhydrous potassium carbonate.
• alkanolamine esters of the invention which comprises the interaction of the corresponding alkanolamine derivative or a salt thereof with an acylating agent.
• acylating agents there may be mentioned acid halides or anhydrides derived from saturated or unsaturated aliphatic carboxylic acids of from aromatic carboxylic acids, for example acetyl chloride, acetic anhydride or benzoyl chloride.
• the acylation may be carried out in a diluent or solvent, which, in the case where an acid anhydride is used as acylating agent, may conveniently be the acid from which the anhydride is derived.
• R stands for hydrogen
• the alkanolamine derivative must be present as a salt thereof, in order that acylation of the nitrogen atom may be prevented.
• the 2-(2,2-dichloro-1,1-difluoroethoxy)phenol is prepared in the following manner:
• Example 3 A mixture of 10 parts of o-ethoxyphenol, 17 parts of epichlorohydrin and 0.01 part of piperidine is heated at EXAMPLE 3
• the process described in Example 2 is repeated except that 42 parts of t-butylamine and 42 parts of methanol are used in place of the 14 parts of isopropylamine.
• the product is isolated as described in Example 2 except that the residual basic oil is dissolved in 100 parts of dry ether. Excess of an ethereal oxalic acid solution is added and the mixture is filtered. The solid residue is crystallised from xylene and there is thus obtained 1-(2-ethoxyphenoxy)-3-t-butylamino-2-propanol hydrogen oxalate,M.P.
• EXAMPLE 4 The process described in Example 2 is repeated except that 45 parts of n-propylamine and 60 parts of methanol are used in place of the 14 parts of isopropylamine.
• the product is isolated as described in Example 2 and the residue is crystallised from petroleum ether (B.P. 100 C.). There is thus obtained 1-(2-ethoxyphenoxy)-3-npropylamino-Z-propanol, M.P. 86.5-87.5 C.
• EXAMPLE 5 The process described in Example 2 is repeated except that 45 parts of cyclopentylamine and 60 parts of methanol are used in place of the 14 parts of isopropylamine.
• the product is isolated as described in Example 2 and the residue is crystallised from petroleum ether (B.P. 60-80 C.). There is thus obtained 3-cyclopentylamino-1-(2- ethoxyphenoxy)-2-propanol, M.P. 87..5-88 C.
• EXAMPLE 6 Amixture of 1 part of 2,3-epoxy-1-(2-ethoxyphenoxy) propane, 1 part of 2-amino-2-methylpropan-1-ol and 6 parts of methanol is heated under reflux for 16 hours. The excess amine and the solvent are removed by evaporation and the residue is shaken with a mixture of aqueous 2 N hydrochloric acid and ethyl acetate. The aqueous phase is separated and made alkaline and the mixture is extracted three times with 6 parts of ethyl acetate each time. The combined extracts are dried and evaporated to dryness,
• the 2,3-epoxy-1-(2-ethoxyphenoxy) propane used as starting material may be obtained as follows:
• EXAMPLE 7 The process described in Example 6 is repeated except that the 1 part of 2-amino-2-methylpropan-1-ol is replaced by 5 parts of a solution of methylamine in methanol. The product is isolated as described in Example 6 except that the residual oil is crystallised from petroleum ether (B.P. 80l00 C.). There is thus obtained 1-(2-ethoxyphenoxy)-3-methylamino-2-propanol, M.P. 91-92.5 C.
• EXAMPLE 8 A mixture of 4 parts of 3-(2-allyloxyphenoxy)-l-chloro- Z-propanol, 10 parts of isopropylamine and parts of methanol is heated in a sealed tube at 110 C. for 10 hours.
• EXAMPLE 9 A mixture of 2 parts of 1-(2-allyloxyphenoxy)-2,3- epoxypropane, 10 parts of t-butylamine and parts of methanol is heated under reflux for 4 hours. The excess amine and methanol are removed by evaporation and the residue is shaken with ether and aqueous 2 N hydrochloric acid. The aqueous phase is separated, made alkaline and extracted three times with 50 parts of ether each time. The combined ethereal extracts are dried and evaporated to one tenth of their original volume. Ethereal oxalic acid solution is added and the mixture is filtered. The solid residue is crystallised from ethyl acetate and there is thus obtained 1 (2 allyloxyphenoxy) 3 t butylamino-Z- propanol hydrogen oxalate, M.P. 105106 C.
• the 1-(2-allyloxyphenoxy)-2,3-epoxypropane used as starting material may be obtained as follows:
• EXAMPLE 10 The process described in Example 9 is repeated except that 10 parts of diethylamine are used in place of the 10 parts of t-butylamine. The product is isolated as described in Example 9 and there is thus obtained 1- (2-allyloxyphenoxy)-3-diethylamino 2-propanol hydrogen oxalate, M.P. 83-85 C.
• EXAMPLE 1 l A mixture of 2 parts of 1-chloro-3-(Z-n-heptyloxyphenoxy)-2-propanol, 10 parts of isopropylamine and 20 parts of methanol is heated in a sealed tube at 110 C. for 12 hours. The excess amine and methanol are removed by evaporation and the residue is shaken with 30 parts of aqueous 2 N sodium hydroxide solution and 150 parts of ethyl acetate. The organic phase is separated, dried and evaporated to dryness. The residue is crystallised from petroleum ether (B.P. l00 C.) and there is thus obtained 3-isopropylamino-l-(2 n-heptyloxyphenoxy) 2- propanol, M.P. 77 C.
• the l-chloro-3-(2 nheptyloxyphenoxy 2-propanol used as starting material may be prepared as follows:
• EXAMPLE 12 The process described in Example 11 is repeated except that 10 parts of n-propylamine are used in place of the 10 parts of isopropylamine. The residue is recrystallised from the petroleum ether (B.P. 80-100 C.) and there is thus obtained l-(2-n-heptyloxyphenoxy)-3-n-propylamino-2-propanol, M.P. 83 C.
• EXAMPLE 13 The process described in Example 11 is repeated except that 10 parts of t-butylamine are used in place of the 10 parts of isopropylamine.
• the product is isolated as described in Example 11 except that the residual, basic oil is dissolved in 40 parts of anhydrous ether and ethereal oxalic solution is added. The mixture is filtered and the solid residue crystallised from Water. There is thus obtained l-(2-n-heptyloxyphenoxy 3-t-butylamino 2-propanol hydrogen oxalate, M.P. 126 C.
• EXAMPLE 14 A mixture of 2.35 parts of o-isobutoxyphenol, 12 parts of epichlorohydrin and 0.01 part of piperidine is heated at 90l00 C. for 18 hours. Excess of epichlorohydrin is removed by distillation under reduced pressure and the residual oil is dissolved in 50 parts of chloroform. The chloroform solution is washed successfully with 20 parts of aqueous 11 N-hydrochloric acid, 20 parts of water, 20 parts of aqueous sodium bicarbonate solution and 20 parts of water, and is then dried over anhydrous magnesium sulphate. The chloroform is removed by distillation under reduced pressure and there is thus obtained 1-chloro-3- 2-isobutoxyphenoxy) -2-propanol.
• EXAMPLE 15 A mixture of 11 parts of l-chloro-3-(2-cyclopentyloxyphenoxy)-2-propanol, 100 parts of isopropylamine and 200 parts of methanol is heated in a sealed tube at 110 C. for 12 hours. The excess amine and methanol are removed by evaporation and the residue is shaken with 100 parts of aqueous 2 N sodium hydroxide solution and 100 parts of ethyl acetate. The organic phase is separated, dried and evaporated to dryness, and the residual oil is dissolved in ether. An ethereal solution of oxalic acid is added and the mixture is filtered. The solid residue is crystallised from n-butyl acetate and there is thus obtained 1-(2-cyclopentyloxyphenol 3-isopropylamino 2-propanol hydrogen oxalate, M.P. 189-191 C.
• the 1-chloro-3-(2-cyclopentyloxyphenoxy 2-propanol used as starting material may be obtained as follows:
• Example 16 The process described in Example 15 is repeated except that 100 parts of t-butylamine are used in place of 100 parts of isopropylamine. The resulting oxalate is crystallised from n-butyl acetate and there is thus obtained l-(2-cyclopentyloxyphenoxy) 3-t-butylamino-2- propanol oxalate, M.P. 166 l70 C.
• Example 17 The process described in Example 15 is repeated except that 10 parts of cyclopentylamine are used in place of 10 parts of isopropylamine. The resulting oxalate is crystallised from ethanol and there is thus obtained 3- cyclopentylamino 1 (2-cyclopentyloxyphenoxy)-2-propanol hydrogen oxalate, M.P. 186-187 C.
• EXAMPLE 1 8 A mixture of 20 parts of 1-(2-ethoxyphenoxy)-3-isopropylamino-Z-propanol, 7 parts of 35% aqueous formalin solution and 600 parts of xylene is heated under reflux for 6 hours, the water formed in the reaction being removed by means of a Dean and Stark water-collecting apparatus. The xylene is removed by evaporation and the residual oil is distilled. There is thus obtained -(2- ethoxyphenoxymethyl) 1 isopropyloxazolidine, B.P. 135 C./0.2 mm.
• EXAMPLE 19 A mixture of 5 parts of 1-(2-ethoxyphenoxy)-3-isopropylamino-Z-propanol hydrochloride and 50 parts of acetyl chloride is heated under reflux for 6 hours. The excess acetyl chloride is removed by evaporation and the residue is shaken with 50 parts of aqueous 2 N sodium bicarbonate solution and 100 parts of ether. The organic phase is separated, dried and evaporated to dryness. The residual oil is purified by preparative thin-layer chromatography on 1 mm.
• the 3-amino-1-(2-ethoxyphenoxy)-2-propanol used as starting material may be prepared as follows:
• EXAMPLE 21 A mixture of 3 parts of 3-amino-1-(2-ethoxyphenoxy)- 2-propanol, 1 part of sodium borohydride, 2 parts of acetone and 20 parts of ethanol is heated under reflux for 4 hours. The ethanol is removed by evaporation and the residue is shaken with 30 parts of aqueous 2 N hydrochloric acid and 100 parts of ether. The aqueous phase is separated, made alkaline and extracted three times with 100 parts of ether each time. The ethereal extracts are combined, dried and evaporated to dryness and the residue is crystallised from petroleum ether (B.P. 6080 C.). There is thus obtained 1-(Z-ethoxyphenoxy)-3-isopropylamino-2-propanol, M.P. 87-88 C.
• EXAMPLE 22 14 parts of o-ethoxyphenol are added to a solution of 4 parts of sodium hydroxide in 2,000 parts of anhydrous ethanol. To this solution is added a solution of 20 parts of 1-(N-benzyl-N-isopropylamino)-2,3 epoxypropane in 200 parts of anhydrous ethanol, and the mixture is heated under reflux for 4 hours. The solution is cooled and evaporated to dryness under reduced pressure and the residue is shaken with 500 parts of water and 1,000 parts of ethyl acetate. The organic phase is separated, dried and evaporated to dryness. The residual oil is 3-(N- benzyl-N-isopropylarnino) 1 ((2 ethoxyphenoxy) 2- propanol.
• a mixture of 30 parts of 3--(N-benzyl-N-isopropylamino)-1-(2-ethoxyphenoxy)-2 propanol, 3 parts of a 10% palladium-on-charcoal catalyst, 30 parts of concentrated hydrochloric acid and 1,000 parts of ethanol is shaken in an atmosphere of hydrogen at ambient temperature and atmospheric pressure. The mixture is then filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is shaken With 300 parts of aqueous 2 N hydrochloric acid and 1000 parts of ether. The aqueous phase is separated, made alkaline and extracted three times with 1,000 parts of other each time.
• R is selected from isopropyl and t-butyl.
• a compound according to claim 1 selected from 1- (Z-cyclopentyloxyphenoxy) 3 isopropylamino-Z-propanol and the acid-addition salts thereof.
• a compound according to claim 1 selected from 1 20 (Z-cyclopentyloxyphenoxy) 3 cyclopentylamino-Z-propanol and the acid-addition salts thereof.

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Citations (3)

• 1965
  • 1965-06-08 GB GB24189/65A patent/GB1128052A/en not_active Expired
• 1966
  • 1966-05-18 US US550951A patent/US3538150A/en not_active Expired - Lifetime
  • 1966-05-25 DE DE19661543693 patent/DE1543693A1/de active Pending
  • 1966-05-31 FI FI1432/66A patent/FI45183B/fi active
  • 1966-06-06 AT AT535466A patent/AT282585B/de active
  • 1966-06-07 NO NO163339A patent/NO118172B/no unknown
  • 1966-06-08 BE BE682273D patent/BE682273A/xx unknown
  • 1966-06-08 ES ES0327698A patent/ES327698A2/es not_active Expired
  • 1966-06-08 BR BR180266/66A patent/BR6680266D0/pt unknown

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