CA1065894A - Phenoxypropanolamines - Google Patents
PhenoxypropanolaminesInfo
- Publication number
- CA1065894A CA1065894A CA238,765A CA238765A CA1065894A CA 1065894 A CA1065894 A CA 1065894A CA 238765 A CA238765 A CA 238765A CA 1065894 A CA1065894 A CA 1065894A
- Authority
- CA
- Canada
- Prior art keywords
- hydroxyphenyl
- propanol
- methylethylamino
- hydrochloride
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
Abstract
Abstract of the Disclosure This invention relates to compounds of the formula I
Description
~9~ .
Heart Active Compounds The present invention relates to new potent ~-receptor blocking compounds as well as their preparation and a method for treat-ing symptoms and signs of cardiovascular disorders by blocking the ~-receptors of the heart by administering to mammals, including man, these new compounds.
The new compounds of the invention are those of the general formula R3 Rl OCH2CHOHCH~HC-CH2- ~ OH
~ R~ .
wherein Rl is selected from the group consisting o~ hydrogen and methyl, ~ :
R is selected rom the group consisting o~ hydrogen, methyl, ethyl, propyl, allyl, methoxy, propargyloxy, cyano, R3 is selected from the group consisting of hydrogen, methyl and ethyl, and R~ is selected Çrom the group .: :
consisting o hydrogen and methyl, provided that R2 and R~ are not both hydrogen. .. ::
The new compo~mds have valuable pharmacological properties.
? - 1 -6589~ :
,: ' Thus they block cardiac ~-receptors, which is shown at the determination of the antagonism of tachycardia after an intravenous injection of 0.5 ~g/kg of d/l-isoproterenol sulphate on an anesthetized cat a~ an intravenous dose of 0.002 to 2 mg/kg. They also block the vascular ~-receptors which is shown at the determination of the antagonism of vasodilation after an intravenous injection of 0.5 ~g/kg of d/l-isoproterenol sulphate on an anesthetized cat at an intravenous dose of 0.002 to 2 mg/kg or more. The compounds have also ~-stimulating properties on ~-receptors, i.e. they show intrinisic activity.
This property is especially pronounced concerning vascular ~-receptors causing dilatation of pheripheral blood vessels.
The ne~ compounds can be used at the treatment of arrythmias, angina pectoris and hypertension. The peripheral vasodilatation is especially valuable for the two last mentioned indications. One may also use them as intermediates at the preparation of other valuable pharmaceutical compounds.
Compounds according to the present invention are:
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-methylphenoxy-propanol-2;
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-ethylphenoxy-propanol-2;
3-C2-~4-hydroxyphenyl)-1-methylethylamino~-1-o-propylphelloxy-propanol-2;
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-allylphenoxy-propanol-2;
3-~2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-propargyloxyphenoxy-propanol-2;
3~r2~4-hydroxyphenyl)_l-methylethylamino]-1-o-cyanophenoxy-propanol-2;
3~[2-~4-hydroxyphenyl)-1,1-dimethylamino]-1-o-methylphenoxy-propanol-2;
3-C2-~4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-ethylphenoxy-propanol-2;
3-C2-(4-hydroxyphenyl)-1,1-dimethylethylamino~-1-o-propylphenoxy-propanol-2;
3-12-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-allylphenoxy-propanol-2;
3 ~2-C4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-propargyloxyphenoxy-propanol-2;
3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-cyanophenoxy-propanol-2;
3-ethyl-3~r2-(4-hydroxyphenyl)~l-methylethylamino]-1-o-allylphenoxy-propanol-2;
;
Heart Active Compounds The present invention relates to new potent ~-receptor blocking compounds as well as their preparation and a method for treat-ing symptoms and signs of cardiovascular disorders by blocking the ~-receptors of the heart by administering to mammals, including man, these new compounds.
The new compounds of the invention are those of the general formula R3 Rl OCH2CHOHCH~HC-CH2- ~ OH
~ R~ .
wherein Rl is selected from the group consisting o~ hydrogen and methyl, ~ :
R is selected rom the group consisting o~ hydrogen, methyl, ethyl, propyl, allyl, methoxy, propargyloxy, cyano, R3 is selected from the group consisting of hydrogen, methyl and ethyl, and R~ is selected Çrom the group .: :
consisting o hydrogen and methyl, provided that R2 and R~ are not both hydrogen. .. ::
The new compo~mds have valuable pharmacological properties.
? - 1 -6589~ :
,: ' Thus they block cardiac ~-receptors, which is shown at the determination of the antagonism of tachycardia after an intravenous injection of 0.5 ~g/kg of d/l-isoproterenol sulphate on an anesthetized cat a~ an intravenous dose of 0.002 to 2 mg/kg. They also block the vascular ~-receptors which is shown at the determination of the antagonism of vasodilation after an intravenous injection of 0.5 ~g/kg of d/l-isoproterenol sulphate on an anesthetized cat at an intravenous dose of 0.002 to 2 mg/kg or more. The compounds have also ~-stimulating properties on ~-receptors, i.e. they show intrinisic activity.
This property is especially pronounced concerning vascular ~-receptors causing dilatation of pheripheral blood vessels.
The ne~ compounds can be used at the treatment of arrythmias, angina pectoris and hypertension. The peripheral vasodilatation is especially valuable for the two last mentioned indications. One may also use them as intermediates at the preparation of other valuable pharmaceutical compounds.
Compounds according to the present invention are:
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-methylphenoxy-propanol-2;
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-ethylphenoxy-propanol-2;
3-C2-~4-hydroxyphenyl)-1-methylethylamino~-1-o-propylphelloxy-propanol-2;
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-allylphenoxy-propanol-2;
3-~2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-propargyloxyphenoxy-propanol-2;
3~r2~4-hydroxyphenyl)_l-methylethylamino]-1-o-cyanophenoxy-propanol-2;
3~[2-~4-hydroxyphenyl)-1,1-dimethylamino]-1-o-methylphenoxy-propanol-2;
3-C2-~4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-ethylphenoxy-propanol-2;
3-C2-(4-hydroxyphenyl)-1,1-dimethylethylamino~-1-o-propylphenoxy-propanol-2;
3-12-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-allylphenoxy-propanol-2;
3 ~2-C4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-propargyloxyphenoxy-propanol-2;
3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-cyanophenoxy-propanol-2;
3-ethyl-3~r2-(4-hydroxyphenyl)~l-methylethylamino]-1-o-allylphenoxy-propanol-2;
;
- 2 -.. ... .:: : :
~L06~i~94
~L06~i~94
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-l~o,m-dimethyl-phenoxy-propanol-2, 3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-methoxy-phenoxy-propan-2, 3-methyl-3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-cthyl-phenoxy-propanol-2, 3-methyl-3-[2-(~-hydroxyphenyl)-1-methylethylamino]-1-o-cyano-phenoxy-propanol-Z, 3-methyl-3-[2-(4-hydroxyphenyl-l,l-dimethylethylamino]-1-o-methylphenoxy-propanol-2, 3-methyl-3-~2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-allylphenoxy-propanol-2, and 3-[2-(4-hydroxyphenyl)-1-methylethylamino~-1-m-methylphenoxy-propanol-2.
Salt forming acids may be used in preparing therapeutically acceptable salts of the compounds these are: hydrohalogen acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxy or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, or pyrovic acid, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicyclic or p-aminosalicyclic acid, em-bonic acid, methanesulfonic, ethanesulfonic, hydroxyethane sulfonic, ethyl-enesulfonic, halogbenzenesulfonic, toluenesulfonic, naphthylsulfonic, or sulfanilic acid, methionine, tryptophane, lysine or arginine.
The substances are intended to be administered orally or parent-erally for acute and chronic treatment of above mentioned cardiovascular disorders.
The biological effects of the new compounds have been tested, and ;;
the different tests carried out will be shown and explained below.
The new compounds are obtained according to methods known E~ se (see, e.g. Canadian Patents 982,140 and 1,017,755; United States Patent ~:
Salt forming acids may be used in preparing therapeutically acceptable salts of the compounds these are: hydrohalogen acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxy or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, or pyrovic acid, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicyclic or p-aminosalicyclic acid, em-bonic acid, methanesulfonic, ethanesulfonic, hydroxyethane sulfonic, ethyl-enesulfonic, halogbenzenesulfonic, toluenesulfonic, naphthylsulfonic, or sulfanilic acid, methionine, tryptophane, lysine or arginine.
The substances are intended to be administered orally or parent-erally for acute and chronic treatment of above mentioned cardiovascular disorders.
The biological effects of the new compounds have been tested, and ;;
the different tests carried out will be shown and explained below.
The new compounds are obtained according to methods known E~ se (see, e.g. Canadian Patents 982,140 and 1,017,755; United States Patent ~:
4,000,313 and Belgian Patent 825,515),and the following processes based on these methods constitute embodiments of the invention. Thus, a compound of formula II
~C~65~4 xl ~ OCH2CHCIIZ II
R4 ~2 R
wherein R2, R3 and R4 have the meaning given above, Xl is a hydroxy group, Z
is a reactive, esterified hydroxy group and is chloro, bromo, iodo, sulfate, benzenesulfonyl residue, 4-bromobenzenesulfonyl residue, 4-toluenesulfonyl residue, or Xl and Z together form an epoxy group is reac~ed with an amine of the formula Rl H2N-C-CH ~ OH
wherein Rl has the same meaning as given above.
A reactive, esterified hydroxy group is partîcularly a hydroxy group esterified with a strong, inorganic or organic acid, preferably a hydro-halogen acid, as hydrochloric acid, hydrobromic acid, or hydroiodic acid, further sulfuric acid or a strong organic sulfonic acid, e.g. benzenesulfonic acid, 4-bromobenzenesulfonic acid, or 4-toluenesulfonic acid~ Thus, Z is preferably chloro- bromo or iodo.
This reaction is carried out in a common way. At the use of a reactive ester as a starting material the preparation takes place preferably in the presence of a basic condensating agent and/or with an excess of an amine. Suitable basic condensating agents are e.g. alkalimetal hydroxides as sodium or potassium hyclroxide, alkalimetal carbonates as potassium carbonate and alkalimetal alcoholates as sodium methylate, potassium ethylate and potas-sium tert.-butylate.
~urther, a compound of formula III
~ QCH2C'}10HCHNH2 tIII) ~O .,.
. . .
~06~394~ :
w herein R2, R3 and R4 have the meanings given above is reacted with a compound of the formula Rl OH
wherein Rl and Z have the same meanings as given above. Intermediates of formula III have been disclosed in the U.K Patent 1,069,345 and in U.S. ~-~
Patents 3,852,291; 3,501,769; and 3,538,150.
This reaction is carried out in a common way~ preferably in the presence of a basic condensating agent and/or an excess of an amine. Suitable basic condensating agents are e.g. alkaline alcoholates, preferably sodium or potassium alcoholate, or also alkaline carbonates as sodium or potassium car-bonate.
Further a compound of formula IV ~ ;
OH (~V) R2 ~ ;
wherein R2 and R4 have the same meanings as given above is reacted with a . ,:
compound of formula V
xl ~,1 ' .
Z-CH2CHCH-NH-CCH2 ~ 01( wherein Z, Xl and Rl and R3 have the same meanings as given above and R is a `
splitable, protecting group. Intermediates of formula V are disclosed in Belgium Patent 825,515. ;
This reaction is carried out in a common way. In those cases where reactive esters are used as starting material, the compound of formula IV may suitably be used in the form of its metalphenolate as alkalimetalphenolate, preferably sodiumphenolate, or one works in the presence of an acid binding ;~ '. .' -,' ', .
~ _5_ , ~696~ii899~ ~:
':
agent, preferably a condensating agent, which can form a salt of the compound of formwla IV as an alkalimetal alcoholate.
Further, a compound of formula IV
~ OH (IV) wherein R2 and R4 have the same meanings as given above, is reacted with a compound of formula VI Rl R - CH - N - CCH - ~ OH
CH CH CH
1 2 3 (VI) 0~1 wherein Rl and R3 have the same meanings as given above. Intermediates of formula VI are disclosed in Belgium Patent 825,515.
This reaction is carried out in a common way. Thus, the reaction is carried out under alkaline conditions in a suitable solvent, as benzyl-alcohol by boiling the reaction mixture for some hours. Thereby the phenol is primarily converted to its metalphenolate as alkalimetalphenolate before it is added to the acetidinol of formula VI.
Further, one may split off a residue from a compound of formula I
àbove, in which the nitrogen atom of the amino group and/or the hydroxy groups have attached thereto a splitable residue.
Such spl:itable residues are especially those which are splitable by solvolysis, reduction, pyrolysis or fermentation.
Residues splitable by solvolysis are preferabl~ residues splitable by hydrolysis or ammonolysis.
Residues splitable br means of hydrolysis are e.g. an acyl residue, which, when present, are functionally varied carboxy groups, e.g. oxycarbonyl residues, as alkoxycarbonyl residues, e.g. tert.-butoxycarbonyl residue, or ethoxycarbonyl residue, aralkoxycarbonyl residues as phenylloweralkoxycarbon~l residues, e.g. a - 5a -' - ' ~65i~9~ .
carbobenzyloxy residue halogencarbonyl residue, e.g. a chlorocarbon residue further arylsulphonyl residues as toluenesulfonyl or bromobenzenesulfonyl re-sidues and possibly as halogenated, as fluorinate loweralkanoyl residues as formyl-, acetyl- or trifluoroacetyl residue or a ben~yl residue or cyano groups or silyl residues, as trimethylsilyl residue.
Of the above mentioned residues present at the hydroxy groups which residues are splittable by~hydrolysis pre~erabl~ the oxycarbonyl residues and the loweralkanoyl residues or the benzoyl residues are used.
Besides the above mentioned also double-bound residues, which are splittable atthe amino group by hydrolysis are used, e.g. alkylidene or benzyl-idene residue or a phosphorylidene group as a triphenylphosphorylidene group, whereby the nitrogen atom then obtains a positive charge.
Residues splittable atthe hydroxy group and the amino group by ;
hydrolysis are furthermore divalent residues as in occurring cases substituent methylene. As substituents on the methylene residues any organic residue may be used, whereby it does not matter at the hydrolysis which compound is the substituent to the methylene residue. As methylene substituents e.g. aliphatic . . .
or aromatic residues as alkyl as mentioned above, aryl e.g. phenyl or pyridyl may be used. The hydrolysis may be carried out in any common way, suitably in a basic or preferably in an acid medium.
Compounds having residues being splittable ~ hydrolysis are also the compounds according to formula VII
~ C}l2lc~L - C~
R R Y~ CH3 ~ OH
~herein Rl, R2, R3 and R4 have the same meanings as given above and Y is a carbonyl or thiocarbonyl residue.
The hydrolysis is carried out in an analogous way, e.g. in the pre-sence of a hydrolysing agent, e.g. in the presence of an acidic agent as e.g.
diluted mineral acids, as sulfuric acid or hydrohalogen acid, or in the pre-sence o~ basic agents as e.g. alkalimetal hydroxides, as sodium hydroxide.
Oxycarbonyl residues, aryl sul~onyl residues and cyano groups may in a suitable ~ ~65~3~4 :
way be split off by means of acidic agen~s as by means of a hydrohalogen acid, suitably hydrobromic acid. Preferably the splitting may take place using diluted hydrobromic acid, possibly in a mixture with acetic acid~ Cyano groups are preferably split off by means of hydrobromic acid at an elevated tempera-ture, as in boiling hydrobromic acid, according to the "bromocyano method"
Cv. Braun)- Purther, e.g~ a tert~-butoxycarbonyl residue may be split o~f under anhydrous conditions by means of a treatment with a suitable acid, as trifluoroacetic acid~ Acidic agents are preferably used at an hydrolysis of compounds of formula ~I.
; Residues splittable b~ammonolysis are especially the halogencarbonyl residues, as the chlorocarbonyl residue~ The ammonolysis may be carried out in a common way, e.g. by means of an amine containing at least one hydrogen ~-atom bounded to the nitrogen atom, as a mono- or diloweralkylamine e.g. methyl-amine or dimethylamine, or especially ammonia, preferably at an elevated tem-perature. Instead of ammonia one may use an agent which gives ammonia as hexa-methylene tetraamine.
Residues splittable ~ means of a reduction are e.g. an ~-arylalkyl residue, as a benzyl residue or an ~-aralkoxycarbonyl residue as a benzyloxy- ~;carbonyl residue, which in a common way may be split off by means of a hydro-genolysis, especially by catalytically activated hydrogen, as by hydrogen in the presence of hydrogenating catalysts, e.g. Raney-nickel. Purther residues split~a~le b~means of hydrogenolysis are 2-halogenalkoxycarbonyl residues as 2,2,2-tri-chloroethoxycarbonyl residues or 2-iodoethoxy- or 2,2,2-tri-bromo-ethoxycarbonyl residues, which may be split off in a common way, suitably by `
means of a metallic reduction (so called nascerating hydrogen). Nascerating ~ydrogen may be obtained by the influence of metal or metal alloys, as amalgam on compounds which give hydrogen as carboxy acids, alcohols or water, whereby especially zink or zinkalloys together with acetic acid may be used. Hydro- ~;
genolysis of 2-halogenalkox~carbonyl residues may further take place using chromium or chromium ~IT) compounds as chromium (II) chloride OT chromium (II) acetate.
A residue splittable by~reduction may also be an arylsulfonyl group as a toluenesulfonyl group, which in a common way may be split .
~C~65~4 xl ~ OCH2CHCIIZ II
R4 ~2 R
wherein R2, R3 and R4 have the meaning given above, Xl is a hydroxy group, Z
is a reactive, esterified hydroxy group and is chloro, bromo, iodo, sulfate, benzenesulfonyl residue, 4-bromobenzenesulfonyl residue, 4-toluenesulfonyl residue, or Xl and Z together form an epoxy group is reac~ed with an amine of the formula Rl H2N-C-CH ~ OH
wherein Rl has the same meaning as given above.
A reactive, esterified hydroxy group is partîcularly a hydroxy group esterified with a strong, inorganic or organic acid, preferably a hydro-halogen acid, as hydrochloric acid, hydrobromic acid, or hydroiodic acid, further sulfuric acid or a strong organic sulfonic acid, e.g. benzenesulfonic acid, 4-bromobenzenesulfonic acid, or 4-toluenesulfonic acid~ Thus, Z is preferably chloro- bromo or iodo.
This reaction is carried out in a common way. At the use of a reactive ester as a starting material the preparation takes place preferably in the presence of a basic condensating agent and/or with an excess of an amine. Suitable basic condensating agents are e.g. alkalimetal hydroxides as sodium or potassium hyclroxide, alkalimetal carbonates as potassium carbonate and alkalimetal alcoholates as sodium methylate, potassium ethylate and potas-sium tert.-butylate.
~urther, a compound of formula III
~ QCH2C'}10HCHNH2 tIII) ~O .,.
. . .
~06~394~ :
w herein R2, R3 and R4 have the meanings given above is reacted with a compound of the formula Rl OH
wherein Rl and Z have the same meanings as given above. Intermediates of formula III have been disclosed in the U.K Patent 1,069,345 and in U.S. ~-~
Patents 3,852,291; 3,501,769; and 3,538,150.
This reaction is carried out in a common way~ preferably in the presence of a basic condensating agent and/or an excess of an amine. Suitable basic condensating agents are e.g. alkaline alcoholates, preferably sodium or potassium alcoholate, or also alkaline carbonates as sodium or potassium car-bonate.
Further a compound of formula IV ~ ;
OH (~V) R2 ~ ;
wherein R2 and R4 have the same meanings as given above is reacted with a . ,:
compound of formula V
xl ~,1 ' .
Z-CH2CHCH-NH-CCH2 ~ 01( wherein Z, Xl and Rl and R3 have the same meanings as given above and R is a `
splitable, protecting group. Intermediates of formula V are disclosed in Belgium Patent 825,515. ;
This reaction is carried out in a common way. In those cases where reactive esters are used as starting material, the compound of formula IV may suitably be used in the form of its metalphenolate as alkalimetalphenolate, preferably sodiumphenolate, or one works in the presence of an acid binding ;~ '. .' -,' ', .
~ _5_ , ~696~ii899~ ~:
':
agent, preferably a condensating agent, which can form a salt of the compound of formwla IV as an alkalimetal alcoholate.
Further, a compound of formula IV
~ OH (IV) wherein R2 and R4 have the same meanings as given above, is reacted with a compound of formula VI Rl R - CH - N - CCH - ~ OH
CH CH CH
1 2 3 (VI) 0~1 wherein Rl and R3 have the same meanings as given above. Intermediates of formula VI are disclosed in Belgium Patent 825,515.
This reaction is carried out in a common way. Thus, the reaction is carried out under alkaline conditions in a suitable solvent, as benzyl-alcohol by boiling the reaction mixture for some hours. Thereby the phenol is primarily converted to its metalphenolate as alkalimetalphenolate before it is added to the acetidinol of formula VI.
Further, one may split off a residue from a compound of formula I
àbove, in which the nitrogen atom of the amino group and/or the hydroxy groups have attached thereto a splitable residue.
Such spl:itable residues are especially those which are splitable by solvolysis, reduction, pyrolysis or fermentation.
Residues splitable by solvolysis are preferabl~ residues splitable by hydrolysis or ammonolysis.
Residues splitable br means of hydrolysis are e.g. an acyl residue, which, when present, are functionally varied carboxy groups, e.g. oxycarbonyl residues, as alkoxycarbonyl residues, e.g. tert.-butoxycarbonyl residue, or ethoxycarbonyl residue, aralkoxycarbonyl residues as phenylloweralkoxycarbon~l residues, e.g. a - 5a -' - ' ~65i~9~ .
carbobenzyloxy residue halogencarbonyl residue, e.g. a chlorocarbon residue further arylsulphonyl residues as toluenesulfonyl or bromobenzenesulfonyl re-sidues and possibly as halogenated, as fluorinate loweralkanoyl residues as formyl-, acetyl- or trifluoroacetyl residue or a ben~yl residue or cyano groups or silyl residues, as trimethylsilyl residue.
Of the above mentioned residues present at the hydroxy groups which residues are splittable by~hydrolysis pre~erabl~ the oxycarbonyl residues and the loweralkanoyl residues or the benzoyl residues are used.
Besides the above mentioned also double-bound residues, which are splittable atthe amino group by hydrolysis are used, e.g. alkylidene or benzyl-idene residue or a phosphorylidene group as a triphenylphosphorylidene group, whereby the nitrogen atom then obtains a positive charge.
Residues splittable atthe hydroxy group and the amino group by ;
hydrolysis are furthermore divalent residues as in occurring cases substituent methylene. As substituents on the methylene residues any organic residue may be used, whereby it does not matter at the hydrolysis which compound is the substituent to the methylene residue. As methylene substituents e.g. aliphatic . . .
or aromatic residues as alkyl as mentioned above, aryl e.g. phenyl or pyridyl may be used. The hydrolysis may be carried out in any common way, suitably in a basic or preferably in an acid medium.
Compounds having residues being splittable ~ hydrolysis are also the compounds according to formula VII
~ C}l2lc~L - C~
R R Y~ CH3 ~ OH
~herein Rl, R2, R3 and R4 have the same meanings as given above and Y is a carbonyl or thiocarbonyl residue.
The hydrolysis is carried out in an analogous way, e.g. in the pre-sence of a hydrolysing agent, e.g. in the presence of an acidic agent as e.g.
diluted mineral acids, as sulfuric acid or hydrohalogen acid, or in the pre-sence o~ basic agents as e.g. alkalimetal hydroxides, as sodium hydroxide.
Oxycarbonyl residues, aryl sul~onyl residues and cyano groups may in a suitable ~ ~65~3~4 :
way be split off by means of acidic agen~s as by means of a hydrohalogen acid, suitably hydrobromic acid. Preferably the splitting may take place using diluted hydrobromic acid, possibly in a mixture with acetic acid~ Cyano groups are preferably split off by means of hydrobromic acid at an elevated tempera-ture, as in boiling hydrobromic acid, according to the "bromocyano method"
Cv. Braun)- Purther, e.g~ a tert~-butoxycarbonyl residue may be split o~f under anhydrous conditions by means of a treatment with a suitable acid, as trifluoroacetic acid~ Acidic agents are preferably used at an hydrolysis of compounds of formula ~I.
; Residues splittable b~ammonolysis are especially the halogencarbonyl residues, as the chlorocarbonyl residue~ The ammonolysis may be carried out in a common way, e.g. by means of an amine containing at least one hydrogen ~-atom bounded to the nitrogen atom, as a mono- or diloweralkylamine e.g. methyl-amine or dimethylamine, or especially ammonia, preferably at an elevated tem-perature. Instead of ammonia one may use an agent which gives ammonia as hexa-methylene tetraamine.
Residues splittable ~ means of a reduction are e.g. an ~-arylalkyl residue, as a benzyl residue or an ~-aralkoxycarbonyl residue as a benzyloxy- ~;carbonyl residue, which in a common way may be split off by means of a hydro-genolysis, especially by catalytically activated hydrogen, as by hydrogen in the presence of hydrogenating catalysts, e.g. Raney-nickel. Purther residues split~a~le b~means of hydrogenolysis are 2-halogenalkoxycarbonyl residues as 2,2,2-tri-chloroethoxycarbonyl residues or 2-iodoethoxy- or 2,2,2-tri-bromo-ethoxycarbonyl residues, which may be split off in a common way, suitably by `
means of a metallic reduction (so called nascerating hydrogen). Nascerating ~ydrogen may be obtained by the influence of metal or metal alloys, as amalgam on compounds which give hydrogen as carboxy acids, alcohols or water, whereby especially zink or zinkalloys together with acetic acid may be used. Hydro- ~;
genolysis of 2-halogenalkox~carbonyl residues may further take place using chromium or chromium ~IT) compounds as chromium (II) chloride OT chromium (II) acetate.
A residue splittable by~reduction may also be an arylsulfonyl group as a toluenesulfonyl group, which in a common way may be split .
5~39~
off by reduction using nascerating hydrogen, e.g. by means of an alkalimetal, as lithium or sodium in liquid ammonia, and suitably may be split off from a nitrogen atom. At the carrying out of the reduction one has to take care of ~ ;
the fact that other reducing groups are not influenced.
Residues splitable by means of pyrolysis~ especially residues split-able from the nitrogen atom, are in occurring cases substituted suitably un-substituted carbamoyl groups. Suitable substituents are e.g. loweralkyl or arylloweralkyl as methyl or benzyl or aryl, as phenyl, the pyrolysis is carried out in a common way, whereby one may have to take care of other thermicallr susceptible groups.
Residues splitable by means of fermentation, especially residues splitable from the nitrogen atom are in occurring cases substituted, however suitably unsubstituted carbamoyl groups. Suitable substituents are e.g.
loweralkyl or arylloweralkyl~ as methyl or benzyl, or aryl as phenyl. The fermentation is carried out in a common way, e.g. by means of the enzyme urease or soy bean extract at about 20C or slightly elevated temperature.
Further, a cyclic tautomer of formula X
~ OCH2fH CH
4 2 Q ~ H ~X) H3C C~12 ~ 0~1 can be reduced, wherein Rl, R ~ R3 and R4 have the same meanlngs as given above, Rl not being methyl. This reduction is carried out in a common way, e.g. using a di-lightmetalhydride, as sodiumborohydride, lithiumaluminium-hydride~ using a hydride as Boran with formic acid, or by means of a catalytic hydrogenation, as with hydrogen in th0 presence of Raney^nickel~ At the reduction one has to take care of the fact that other groups are not affected~
Further, the oxo group in a compound corresponding to these of ~" '' '' '' .
.
~65~394L
formula I and ~hich carries an oxo group at a carbon atom bound to a nitrogen atom may be reduced to two hydrogen atoms. ;
Said compounds are e.g. such of the formula XIII
O Rl ~ OCH2CHOHCNH-C-CH2 ~ OH (XIII) R R C~3 . ~
wherein Rl, R2 and R4 have the meaning as given above, and R3 is hydrogen. ~
_ 9~ _ ~S89~
The reduction can be carried out according to the abo~e described manner using complex metalhydrides, e.g. lithiumaluminiumhydride or di-iso-butylaluminiumhydride. Suitably the reaction takes place in an inert solvent as an ether, e.g. diethylether or tetrahydrofuran.
In a common way the substituents may be varied from the compounds obtained within the end product as well as the compounds obtained may be in-troduced, split off or transformed into otherend ~rod~cts i~s a common way.
...: ~
Depending on the process conditions and ~he starting material the end product is obtained either in free form or in the form of its acid addi-:. . . .
tion salt, which is included in the scope of the invention. Thus, for example, -basic, neutral or mixed salts may be obtained as well as hemiaminoJ sesqui- or polyhydrates. The acid addition salts of the new compounds may in a manner known per se be transformed in~o free compounds using e.g. basic agents as alkali or ion exchanger. On the other hand, the free bases obtained may form salts with organic or inorganic acids. In the preparation of acid addition . .
salts preferably such acids are used which form suitable therapeutically ac-ceptable salts. Such acids are e.g. hydrohalogen acids, sulfuric acids, phos-phoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxy or sulfonic acids, as formic, acetic, propionic, succinic, ~ glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid, phenylacetic, benzoic, p-aminobenzoic, antranilic, p-hydroxy-~enzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic ethylenesulonic acids, halogenbenzene- -sulfonic, toluenesulfonicJnaphthylsulphonic acids, or sulanillc acid;
methionine, tryptophane, lysine or arginine.
These or other salts of the new compounds as e.g. picrates may serve .. . .
as purifying agents of the free bases obtained as the free bases are trans-formed into salts, these are separated and the bases are then set free from the salts again. According to the close relationship between the new compounds in free form and in the form of their salts it will be understood from the above and the below that, if possible, the corresponding salts are included in the ~ree compound.
The inventlon also relates to any embodiment of the process of which - lQ -one starts ~rom any compound obtained as an intermediate in an~ process step and one carries out the lacking process step, or one breaks off the process at any step, or at which one forms a starting material under the reaction condi-tions, or at which a reaction component possibly in the form of its salt is presen~.
Thus, one may react an aldehyde of the formula XIX
~ OCH2CHOHCHO CXIX) ~herein R2 and R4 have the same meaning as given above, and R3 is hydrogen with an amine of the formula ~12~ C~I~ ~0 wherein Rl has the same meanings as given above, in the presence of a suitable reducing agent, as one of the above mentioned. Thereby a compound of formula VII is obtained as an intermediate, which then is reduced according to the invention.
~urther, one may in a manner known per se react an amine of the for-mula III with an aldehyde or a keton of the formula ~ -O=CI-CH2 ~ OH
in the presence of a suitable reducing agent, as one oE the above mentioned to produce compounds wherein Rl is hydrogen. Thereby, a compound oE Eormula IX
or X is obtained as an intermediate, which then is reduced according to the invention.
The new compounds may, depending on the choice of starting materials and process, be present as optical antipodes or racemate, or, if they contain at least two asymmetric carbon atoms, be present as an isomer mixture ~racemate mixture).
The isomer mixtures ~racemate mixtures) obtained may, depending on physical~chemical diferences of the component9 be separated into the both stereoisomeric (diastereomeric) pure racemate e.g. by means of chromotography . .
~L~D65894 ~-and/or fractionated cr~stallisation.
The racemates obtained can ~e separated according ~o known methods, e.g. by means of recrystallisation from an optical active solvent, by means of microorganisms, or by a reaction with optically active acids forming salts of the compound and separating the salts thus obtained, e.g. by means of their different solubility in the diastereomeres, from which the antipodes by the influence of a suitable agent may be set free. Suitably useable optically ac-tive acids are e.g. the L- and D-forms of tartaric acid, di-o-tolyl-tartaric acid, malic acid, mandelic acid, camphersulfonic acid or china acid. Prefer-ably the more active part of the two an~ipodes is isolated.
Suitably such starting materials are used for carrying out the reac-tions o~ the invention, which material leads to groups of end products primari-ly especially desired and especially to the specifically described and prefer-red end products.
The starting materials are known or may, if they should be new, be obtained according to processes known ~ se.
In clinical use the compounds of the invention are administered nor-mally orally, rectally or by injection in the form of a pharmaceutical prepara- ;
tion, which contains an active c~mponent either as free base or as pharmaceu-2Q tically acceptable, non-toxic acid addition salts, e.g. the hydrochloride lactate, acetate, sulphamate or the like in combination with a pharmaceutical-ly carrier.
Thereby the men~ioning of the new compounds of the invention is here related to either the free amine base or the acid addition salts of the free ~ase, even if the compounds are generally or specifically described, provided that the context in which such expressions are used, e.g. in the examples, with this broad meaning should not correspond. The carrier may be a solid, semisolid or liquid diluent or a capsule. These pharmaceutical preparations are a further object o~ the invention. Usually the amount of active compound is between 0.1 to 95% by weight of the preparation, suitably between 0.5 to 20% by weight in preparations for in~ction and between 2 to 50% by weight in preparations for oral adminlstration.
In the preparation of pharmaceutical preparations containing a com-~ ~5~4 ~
pound of the present invention in the form o~ dosage units for oral administra-tion the compound elected may be mixed with a solid, pulverulent carrier, as e.g. with lactose, saccharose, sorbitol, mannitol, starch, as potatoe starch, corn starch amylopectin, cellulose derivatives or gelatine, as well as with an intrifriction agent as magnesium stearate, calcium stearate, polyethyleneglycol waxes or the like, and be pressed into tablets. If coated tablets are wanted, the above prepared core may be coated with concentrated solution of sugar~
which solution may contain e.g. gum arabicum, gelatine, talc, titandioxide or the like. Furthermore, the tablets may be coated with a lacquer dissolved in an easily volatile organic solvent or mixture of solvents. To this coating a dye may be added in order to easily distinguish between tablets with different active compounds or with diffPrent amounts of the active compound present.
In the preparation of soft gelatine capsules (pearl-shaped, closed capsules), which consist of gelatine and e.g. glycerine or in the preparation ;~
of similar closed capsules the active compound is mixed with a vegetable oil.
Hard gelatine capsules may contain granules of the active compound in combina-tion with a solid, pulverulent carrier as lactose, saccharose, sorbitol, man-nitol, starch ~as e.g. potatoe starch, corn starch or amylopectin), cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared in the form of suppositories, which contain the active substance in a mixture with a neu-tral at base, or they may be prepared in the form of gelatine-rectal capsules which contain the active substance in a mixture with a vegetable oil or paraf-fin oil.
Liquid preparations for oral adminlstration may be present in the ~orm of syrups or suspensions, e.g. solutions containing from about 0.2% by ~eight of about 20% by weight of the active substance described, whereby the residue consists of sugar and a mixture of ethanol, water, glycerol and propy-lene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents saccharine and carboxyme~hylcellul~se as a thickening agent.
Solutions for parenteral administratlon ~y injection may be prepared as an aqueous solutlon of a watersoluble pharmaceutically acceptable salt of S~39 ' the active compound, preferably in a concentration from about 0.5% by weight to about 0.10% by weight. These solutions may also contain stabilizing agents ;
and/or buffering agents and may suitably be available in different dosage unit ampoules.
The preparation of pharmaceutically tablets for peroral use is car-ried out in accordance with the following method:
The solid substances included are ground or sieved to a certain par-ticle size. The binding agent is homogenized and suspended in a certain amount of solvent. The therapeutic compound and necessary auxiliary agents are mixed during a continuous and constantly mixing with the binding agent solution and are moistened so that the solution is uniformly divided in the mass without overmoistening any parts. The amount of solvent is usually so adapted that the mass obtains a consistency reminding of wet snow. The moistening of the pulverulent mixture with the binding agent solution causes the particles to gather together slightly to aggregates and the real granulating process is carried out in such a way that the mass is pressed through a sieve in the form of a net of stainless steel having a mesh size of about 1 mm. The mass is then placed in thin layers on a tray to be dried in a drying cabinet. This drying takes place during 10 hours and has to be standardized carefully as the damp degree of the granulate is of utmost importance for the following process and for the feature of the tablets. Drying in a fluid bed may possibly be used. In this case the mass is not put on a tray but is poured into a con-tainer having a net bottom.
After the drying step the granules are sieved so that the particle size wanted is obtained. Under certain circumstances powder has to be removed.
To the so called final mixture, disintegrating, antifriction agents and antiadhesive agents are added. After this mixture the mass shall have its right composition for the tabletting step.
The cleaned tablet punching machine is provided with a certain set of punches and dies, whereupon the suitable adjustment for the weight of the tablets and the degree of compression is tested out. The weight of the tablet is decisive for the size of the dose in each tablet and is calculated starting .'' ' '-`` 3L~065~3g9L
from the amount of therapeutic agent in the granules. The degree of compres-sion affects the size of the tablet, its strength and its ability to disin-tegrate in water. Especially as regards the two later properties the choice of compression pressure (0.5 to 5 ton) means something of a balance-step.
~hen the right adjustment is set the preparation of tablets ls started which is carried out with a rate of 20.000 to 200.000 tablets per hour. The pres-sing of the tablets requires different times and depends on the size of the batch.
The tablets are freed from adhering pulver in a specific apparatus and are then stored in closed packages until they are delivered.
Many table~s, especially these which are rough or bitter, are coated with a coating. This means that these are coated with a layer of sugar or some other suita~le coating.
The tablets are usually packed by machines having an electronic counting device. The different types of packages consist of glass or plastic gallipots but also boxes, tubes and specific dosage adapted packages.
The daily dose of the active substance varies and is depending on the type of administration, but as a general rule it is 100 to 400 mg/day of acti~e substance at peroral administration and 5 to 20 mg/day at intravenous administration.
The following illustrates the principle and the adaptation of inven-tion, however, without being limited thereto. Temperature is given in degree Celsius.
Preparation or 3-[2-(~-hydroxyphenyl)-1-methylethylamino]-l-o-methylphenoxy-propanol-2 2.5 g or 1,2-epoxy-3-o-meth~lphenoxy propane were mixed with 1.5 g of 1-(4-hydroxyphenyl)-~-amino-propane and 25 ml of isopropanol and the total solution was refluxed for 1.5 hours. The solution was thereupon evaporated in vacuo. The base thus obtained was dissolved in acetone and the hydrochlo-ride was precipitated using HCl in ether. The hydrochloride was filtered off and washed ~ith acetonitril. The yield o~ 3-[2~ hydroxyphenyl)-1-methyl-~ 15 _ 65~9~L
ethylamino]-l-o-methylphenox~-propanol-2 was 1.4 g. ~elting point 112C.
The structure was determined uslng NMR.
Example 2 ; - .
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-ethylphenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-(o-ethyl) phenoxy-propane and 1-~4-hydroxyphenyl)-2-amino-propane as starting materials. -Melting point of its hydrochloride is 143C its structure was determined by MMR and equi~alent weight.
Example 3 :'-'. . .' ' 4-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-allylphenoxy-propanol-2 was prepared according to Example 1 using lJ2-epoxy-3-o-allyl-phenoxy-propane and 1-(4-hydroxyphenyl)-2-amino-propane as starting material.
Melting point of tartrate is 71C. Its structure was determined by NMR and equi~alent weight.
3-[2-~4-hydroxyphenyl)-1-methylethylamino]-1-o-propargyloxy phenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-propargyl- ;~
oxyphenoxy-propane and 1-~4-hydroxyphenyIL2-amino-propane as starting material.
The p-hydroxyben~oate was prepared.
Example 5 . .
3-[2-~4-hydroxyphenyl)-1-methylethylamino]-1-o-cyanophenoxy-propanol-2 was prepared according to Example 1 using lJ2-epoxy-3-o-cyanophenoxy-propane and 2-~4-hydroxyphenyl)-1-methylethylamine as starting materials.
The hydrochloride was obtained as a water soluble oil and its structure was determined using MM~.
Example 6 3-[2-~4-hydroxyphenyl)-1 J l-dimeth~lamino]-l-o-meth~l~phenoxy~ :
propanol-2 was prepared according to Example 1J using lJ2-epoxy-3-o-methyl-phenoxypropane and 2-t4-hydroxyphen~l)-lJl-dimethylethyl amine as s~arting ;
materlals. The hydrochloride was obtained as a water soluble oil and its structure was determined using MMR. , ~ 16 l: .
~5~
Fxam~le 7 3-[Z-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-eth~lphenoxy-propanol-2 was prepared according to Example I using 1,2-epoxy-3-o-ethyl-phenoxypropane and 2-(4-hydroxyphenyl)-l,l-dimethylethylamine as starting materials. The melting point of the hydrochloride is 154C.
Example 8 3-r2-(4_hydroxyphenyl)-1,1-dimethylethylamino]-1-o-all~lphenoxy-propanol-2 was prepared according to Example 1, using 1,2-epoxy-3-o-allyl-phenoxy propane and 2-~4-hydroxyphenyl)-1,1-dimethylethyl amine as starting materials. The melting point of the hydrochloride is 140C.
Example 9 3-[2-~4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-propargyloxy phenoxypropanol-2 was prepared according to Example 1, using 1,2-epoxy-3-o-propargyloxyphenoxypropane and 2-(4-hydroxyphenyl)-1,1-dimethylethylamine as starting materials.
Example 10 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-cyanophenoxy-propanol-2 was prepared according to Example 1, using 1,2-epoxy-3-o-cyano-phenox~propane and 2-~4-hydroxyphenyl)-1,1-dimethylethylamine as starting -materials. Melting point 144C ~HCl).
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o,m-dlmethylphenoxy-propanol-2 was prepar~d in accordance with Example 1 using 1,2-epoxy-3-o,m-dimethylphenoxypropane and 2-(4-hydroxyphenyl)-1-methylethylamine, as starting materials. Melting point 125C ~HCl).
3-[2-(4-hydroxyphenyl)~l-methylethylamino_l-o-methoxyphenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-methoxyphenoxy-propane and 2-~4-hydroxyphenyl)-1-methyleth~lamine as starting 3Q materials. Melting point 114C ~HCl) Example 13 3~meth~1~3~[2~4~hydroxyphenyl)_1-methylethylamino_l-o-ethyl-~ ~ 17 ~
`` 3L 0165~394 ~ :
phenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-l-meth~1-3-o-eth~lphenox~~propane and 2-(4-hydroxyphen~l)-1-methyleth~lamine) as startlng materials. The hydrochloride was obtained as a water soluble oil and its structure was determined using MMR.
Example 14 3-methyl-3-[2-~4-hydroxyphenyl)-1-methylethylaminol-1-o-cyanophenoxy-propanol 2 was prepared in accordance with Example 1 above using 1,2-epoxy-1-.~ . .
meth~l~3-o-cyanophenoxy-propane and 2-(4-hydroxyphenyl)-1-methylethylamine as starting materials. The hydrochloride was obtained as a water soluble oil and 1~ its structure was de~ermined using MMR.
Example 15 3-ethyl-3-[2-~4-hydroxyphenyl)-1-methylethylamino-1-o-allylphenoxy-propanol-2 was prepared in accordance with Example 1 above using 1,2-epoxy-1-ethyl-3-o-allylphenoxy-propane and 2-~4-hydroxyphenyl)-1-methylethylamine as starting materials. The hydrochloride was obtained as a water soluble oil and its structure was determined using NMR.
Example 16 `~
3-methyl-3-[2-~4-hydroxyphenyl)-1,1-dimethy]ethylamino]-1-o-methyl-phenoxy-propanol-2 was prepared in accordance with Example 1 above using 1,2-epox~-1-methyl-3-o-methylphenoxy-propane and 2-~4-hydroxyphenyl~-1,1-dimethyl-ethylamine as starting materials. The hydrochloride was obtained as a water ~`soluble oil and its structure was determined using MMR.
..
~ 17~ ~
.
,.
~065~94 Example 17 3-methyl-3-~2-~4-hydroxyphenyl)-1,1-dimethylethylamino~-1-o-allyl-phenoxy-propanol-2 was prepared in accordance with Example 1 above using 1,2-epoxy-l-methyl-3-o-allylphenoxy-propane and 2-C4-hydroxyphenyl)-1,1-dimethyl-ethylamine as starting materials. Melting point 172C ~HCl).
Example 18 3-[2-(4-hydroxyphenyl)-1-methylethylamino~-1-m-methylphenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-m-methylphenoxypropane and 2-C4-hydroxyphenyl)-1-methylethylamine as starting materials. Melting point 150C (HCl).
Example 00 Preparation of 3-[1-methyl-2-(4-hydroxyphenyl)ethylamino]-1-o-allylphenoxy butanol-2 .
2.5 g of 2,3-epoxy-l~o~allylphenoxy butane were mixed with 1.5 g of l~methyl~2~(4~hydroxyphenyl)ethylamine and 25 ml of isopropanol and the total solution was refluxed for 100 hours. The solution was thereupon evaporat-ed in vacuo. The base thus obtai.ned was dissolved in trichloroethylene and the hydrochloride was precipitated using LICl in ether. ~ater was added and the mixture was titrated with 1 M HCl. The pH was determined with a glass elec-trode and the values were plotted against ml HCl. At a band in the curve the water phase was separated, fresh water was added and the procedure was repea-ted until the next band in the curve. This water phase was separated, made alka-line with NH40H and extracted with methylene chloride. The organic phase was washed with water, dried and evaporated. The hydrochloride was precipi-tated with ether x HCl. The ether was decanted and the product solidifies upon evaporation in high vacuum. The yield of 3-[1-methyl-2-(4-hydroxyphenyl)ethyl-amino~ o-allylphenoxy butanol-2HCl was 1.6 g. Melting point 70C. The structure was determined using NMR.
~ - 18 -. .: - . . , ~589~L ;
Table :
Compound Reserpinized cat Conscious dog ~`
Block of isopren. Intrinsic BP in mm Hg --ED50 mg/kgactivity after 1.5 mg/kg i v HR PRbe~ts/min Supine Erect .
Propranolol 0.1 0.10 + 5 0 ~
Metoprolol 0.2 4.70 - 5 - 3 -Example 00 0.5 0.6+28 -33 -45 Example 19 ~- -A syrup containing 2% ~weight per volume of active substance was pre-pared from the following ingredients:
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-l-o-methylphenoxy-propanol-2 ~ICl 2.0 g ~ .
Saccharine 0.6 g ~ -Sugar 30.0 g Glycerine 5.0 g Flavouring agent 0.1 g Ethanol 96% 10.0 g `
Destilled water ad100.0 ml SugarJ saccharine and the ethersalt were dissolved in 60 g of warm water. A~ter cooling glycer~e and solution of flavouring agents dissolved in ethanol were added. To the mixture water was then added to 100 ml. ~`
The above given active substance may be replaced with other pharma-.; . .. .
ceutically acceptable acid addition salts.
Example 20 3-[2-~4-hydroxyphenyl)-1~1-dimethylethylamino-1-o-allylphenoxy~-pro- ' ~' panol-2 hydrochloride ~250 g) was mixed with lactose C175.8 g) potatoe starch (169.7 g) and colloidal silicic acid (32 g). The mixture was moistened with a 10% solution of gelatine and was granulated through a 12-mesh sieve. A~ter ;~
drying potatoe starch ~160 g), talc ~50 g) and magnesium stearate (5 g) were admixed and the mixture thus obtained was pressed into tablets ~10.000) which contain 25 mg of substance. The tablets are sold on ~he market provided with a breaking score to give another dose than 25 mg or to give multiples thereof when broken.
- 18a -:' ,,, . ~
8~
~xample 21 Granules were prepared from 3-[2-~4-hydroxyphenyl)-1-methylethyl-amino]-l-o-propargyloxyphenoxy-propanol-2-p-hydroxybenzoate (250 g), lactose ~175.9 g~ and an alcoholic solution of polyvinylpyrrolidone (25 g). After the drying step the granules were mixed with talc (25 g) potatoe starch (~0 g) and magnesium stearate (2.50 g) and was pressed into 10.000 tablets being biconvex.
These tablets are primarily coated with a 10% alcoholic solution of shellac and thereupon with an aqueous solution containing saccharose (45%), gum arabi-cum (5%), gelatine (4%) and dyestuff ~0.2%). Talc and powder sugar were used for powdering after the first five coatings. The coating was then coated with a 66% sugar syrup and polished with a 10% carnauba wax solution in carbon tetrachloride.
Example 22 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-3-o-ethylphenoxy-propanol-2-hydrochloride ~1 g), sodiumchloride ~0.8 g) and ascorbic acid ~0.1 g) were dissolved in sufficient amount of distilled water to give 100 ml of solution. This solution, which contains 10 mg of active substance on each ml was used in filling a~poules, which were sterilized by heating at 120C for 20 minutes.
Biological effects The ~-receptor blocking agents of the present invention were tested as regards their biological properties. All compo~mds were thereby tested in anaesthetized cats~males and ~emales weighing 2.5-3.5 kg) pretxoated with reserpine ~5 mg/kg bodyweight administered intra musculary) about 16 hours be-fore the experiments. The animals were pretreated with reserpine in order to eliminate the endogenous sympathetic control of heart rate and vascular smooth muscle tone. The cats were anaesthetized with pentabarbital ~30mg/kg body-weight administered i.p.) and artificially ventilated with room air. A bi-lateral vagotomy was performed in the neck. Blood pressure was obtained from a cannulated carotid artery and heart rate was registered from a cardio-tachometer, triggered by the electrocardiogram ~ECG~. Intrinsic beta mimetic activity on the heart was seen as increased heart rate after drug administra-- 19 - : ~ .
tion. The test compounds were given intraveneously in logarithmically in- :
creasing doses. The values obtained were plotted on dose-response curves, from which affinity values (ED50) were estimated. At the end of each experi-ment high doses of isoprenaline were given in order to obtain the maximal heart rate response.
The compounds were also tested on conscious dogs. Beagle dogs were :~
trained to be lying quietly and to be lifted to an erect position by placing ~ ' their forelegs on a table for 2 minutes. Arterial blood pressure was register-ed via a blood pressure transducer attached to the dog at the heart level.
Heart rate was triggered from the ECG. All dogs were pretreated with methyl-scopolamine to avoid vagal influences. Recordings were taken before and 15 and 75 min after administration of the test compound, first in supine position for 2 min and then in the erect position for 2 minutes. The test compounds were given in increasing doses with 2 hours intervals.
Table 1 below shGws affinity values and intrinsic ~-mimetic activity `
in reserpinized cats and effects on blood pressure in conscious dogs of compound of the present invention. Corresponding values for propanolol, ~l-isopropylamino-3-(1-naphthoxy)-propanol-2, and metoprolol, tl-isopropyl-amino-3-~4-~2-methoxyethyl)phenoxy]-propanol-2), are shown for comparison. ;`~
Table 1 also shows PA2 measured on rats. pA2 is -log of the concen-tration of an antagonist which leads to the fact that the dose of noradren-aline has to be doubled in order to obtain the same effect of noradrenaline as one obtains without the antagonist or pA2~ log ~dr-l)-log ~antagonist) . . ED of noradrenaline (antoganist) whereln dr is dose ratlo = 50 ED50 of noradrenaline ~control) and all concentrations are given in mol/l. pA2 is thus a measure of ~-receptor-effect where higher PA2 -~ higher ~-effect.
.. ,. . :
.,.... . . :
~ ;5~39L .
N cn N N 1~ c~ co ~ t~l N O tD N ~
r~1: I I (Dr~r~ tDLn~D ~DtD I I ~
. .
> t~ ~r~
,~t~ o ~ ol n tJ~ Ln O
h ~ ,~ tr) ~,~ N I N
3~LLI l l l l l c~O ~ c~ .
OI- . .~
O Ctl~
, ~ ,c Ln ~n N O O 0 0 L ~ I N ~ I ~,~ I ~
t~ I I ~ I I .
c~ m ~D tn .
. .
.
t~ C
, ~, .
.,~ ~ ~ O O Cl:7 N ~ ~ N ct~ ol N ~D O co O N tn ~ C~2 ,_1 ~ ~r-( ~ r-l tl-) tr) trl tD t~l trl ~ ~ ~ r-l ~t t + ~ r-l ~ + + + + 'I' + + ~ +
tl) ~ G. O ~ .
t~ H ~ ~ ~ .
ID ~ .
~ .
~ C . .
t ~ ~ ~ O r~ r~l r--l ttl O O O N U~l LD O t~ tD ~ ~
t~ O Q O ~ O O r-l O O O O O O O O r~l tr~ ~0 0 0 0 U~
.r~ ~0 . ' . ~0 ~10 . .
E Il~
O O ~ r~l ~CO Ul r--I N ~ d N
O 111 ~-1 N O r~l 1~ 0 0 0 r--I O N O r- l ~ r--I ~r) 11-1 N Ir~
r I O O O U~l r-l N O
.
~. ~ .
r~ . .~
r rO ~, ' "
c- tti L i .
tl tl O r~l N tr) Ln U~ Ct~ rO! r~ ~N~ ~ r--l r--I r-1 r~l r~ o ~:
O ~ lV X "
o n. ~ LL
~1065~
The experlments demonstate that the compounds tested are potent B-receptor antagonists with or without intrinsic B-mimetic activit~. The com-pounds also decrease blood pressure in conscious dogs significantly more than propranolol and metroprolol. The pronounced h~potensive effect in conscious dogs of the ne~ compounds depends on a ~asodilating effect in combination with -cardiac beta-receptor blockade.
off by reduction using nascerating hydrogen, e.g. by means of an alkalimetal, as lithium or sodium in liquid ammonia, and suitably may be split off from a nitrogen atom. At the carrying out of the reduction one has to take care of ~ ;
the fact that other reducing groups are not influenced.
Residues splitable by means of pyrolysis~ especially residues split-able from the nitrogen atom, are in occurring cases substituted suitably un-substituted carbamoyl groups. Suitable substituents are e.g. loweralkyl or arylloweralkyl as methyl or benzyl or aryl, as phenyl, the pyrolysis is carried out in a common way, whereby one may have to take care of other thermicallr susceptible groups.
Residues splitable by means of fermentation, especially residues splitable from the nitrogen atom are in occurring cases substituted, however suitably unsubstituted carbamoyl groups. Suitable substituents are e.g.
loweralkyl or arylloweralkyl~ as methyl or benzyl, or aryl as phenyl. The fermentation is carried out in a common way, e.g. by means of the enzyme urease or soy bean extract at about 20C or slightly elevated temperature.
Further, a cyclic tautomer of formula X
~ OCH2fH CH
4 2 Q ~ H ~X) H3C C~12 ~ 0~1 can be reduced, wherein Rl, R ~ R3 and R4 have the same meanlngs as given above, Rl not being methyl. This reduction is carried out in a common way, e.g. using a di-lightmetalhydride, as sodiumborohydride, lithiumaluminium-hydride~ using a hydride as Boran with formic acid, or by means of a catalytic hydrogenation, as with hydrogen in th0 presence of Raney^nickel~ At the reduction one has to take care of the fact that other groups are not affected~
Further, the oxo group in a compound corresponding to these of ~" '' '' '' .
.
~65~394L
formula I and ~hich carries an oxo group at a carbon atom bound to a nitrogen atom may be reduced to two hydrogen atoms. ;
Said compounds are e.g. such of the formula XIII
O Rl ~ OCH2CHOHCNH-C-CH2 ~ OH (XIII) R R C~3 . ~
wherein Rl, R2 and R4 have the meaning as given above, and R3 is hydrogen. ~
_ 9~ _ ~S89~
The reduction can be carried out according to the abo~e described manner using complex metalhydrides, e.g. lithiumaluminiumhydride or di-iso-butylaluminiumhydride. Suitably the reaction takes place in an inert solvent as an ether, e.g. diethylether or tetrahydrofuran.
In a common way the substituents may be varied from the compounds obtained within the end product as well as the compounds obtained may be in-troduced, split off or transformed into otherend ~rod~cts i~s a common way.
...: ~
Depending on the process conditions and ~he starting material the end product is obtained either in free form or in the form of its acid addi-:. . . .
tion salt, which is included in the scope of the invention. Thus, for example, -basic, neutral or mixed salts may be obtained as well as hemiaminoJ sesqui- or polyhydrates. The acid addition salts of the new compounds may in a manner known per se be transformed in~o free compounds using e.g. basic agents as alkali or ion exchanger. On the other hand, the free bases obtained may form salts with organic or inorganic acids. In the preparation of acid addition . .
salts preferably such acids are used which form suitable therapeutically ac-ceptable salts. Such acids are e.g. hydrohalogen acids, sulfuric acids, phos-phoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxy or sulfonic acids, as formic, acetic, propionic, succinic, ~ glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid, phenylacetic, benzoic, p-aminobenzoic, antranilic, p-hydroxy-~enzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic ethylenesulonic acids, halogenbenzene- -sulfonic, toluenesulfonicJnaphthylsulphonic acids, or sulanillc acid;
methionine, tryptophane, lysine or arginine.
These or other salts of the new compounds as e.g. picrates may serve .. . .
as purifying agents of the free bases obtained as the free bases are trans-formed into salts, these are separated and the bases are then set free from the salts again. According to the close relationship between the new compounds in free form and in the form of their salts it will be understood from the above and the below that, if possible, the corresponding salts are included in the ~ree compound.
The inventlon also relates to any embodiment of the process of which - lQ -one starts ~rom any compound obtained as an intermediate in an~ process step and one carries out the lacking process step, or one breaks off the process at any step, or at which one forms a starting material under the reaction condi-tions, or at which a reaction component possibly in the form of its salt is presen~.
Thus, one may react an aldehyde of the formula XIX
~ OCH2CHOHCHO CXIX) ~herein R2 and R4 have the same meaning as given above, and R3 is hydrogen with an amine of the formula ~12~ C~I~ ~0 wherein Rl has the same meanings as given above, in the presence of a suitable reducing agent, as one of the above mentioned. Thereby a compound of formula VII is obtained as an intermediate, which then is reduced according to the invention.
~urther, one may in a manner known per se react an amine of the for-mula III with an aldehyde or a keton of the formula ~ -O=CI-CH2 ~ OH
in the presence of a suitable reducing agent, as one oE the above mentioned to produce compounds wherein Rl is hydrogen. Thereby, a compound oE Eormula IX
or X is obtained as an intermediate, which then is reduced according to the invention.
The new compounds may, depending on the choice of starting materials and process, be present as optical antipodes or racemate, or, if they contain at least two asymmetric carbon atoms, be present as an isomer mixture ~racemate mixture).
The isomer mixtures ~racemate mixtures) obtained may, depending on physical~chemical diferences of the component9 be separated into the both stereoisomeric (diastereomeric) pure racemate e.g. by means of chromotography . .
~L~D65894 ~-and/or fractionated cr~stallisation.
The racemates obtained can ~e separated according ~o known methods, e.g. by means of recrystallisation from an optical active solvent, by means of microorganisms, or by a reaction with optically active acids forming salts of the compound and separating the salts thus obtained, e.g. by means of their different solubility in the diastereomeres, from which the antipodes by the influence of a suitable agent may be set free. Suitably useable optically ac-tive acids are e.g. the L- and D-forms of tartaric acid, di-o-tolyl-tartaric acid, malic acid, mandelic acid, camphersulfonic acid or china acid. Prefer-ably the more active part of the two an~ipodes is isolated.
Suitably such starting materials are used for carrying out the reac-tions o~ the invention, which material leads to groups of end products primari-ly especially desired and especially to the specifically described and prefer-red end products.
The starting materials are known or may, if they should be new, be obtained according to processes known ~ se.
In clinical use the compounds of the invention are administered nor-mally orally, rectally or by injection in the form of a pharmaceutical prepara- ;
tion, which contains an active c~mponent either as free base or as pharmaceu-2Q tically acceptable, non-toxic acid addition salts, e.g. the hydrochloride lactate, acetate, sulphamate or the like in combination with a pharmaceutical-ly carrier.
Thereby the men~ioning of the new compounds of the invention is here related to either the free amine base or the acid addition salts of the free ~ase, even if the compounds are generally or specifically described, provided that the context in which such expressions are used, e.g. in the examples, with this broad meaning should not correspond. The carrier may be a solid, semisolid or liquid diluent or a capsule. These pharmaceutical preparations are a further object o~ the invention. Usually the amount of active compound is between 0.1 to 95% by weight of the preparation, suitably between 0.5 to 20% by weight in preparations for in~ction and between 2 to 50% by weight in preparations for oral adminlstration.
In the preparation of pharmaceutical preparations containing a com-~ ~5~4 ~
pound of the present invention in the form o~ dosage units for oral administra-tion the compound elected may be mixed with a solid, pulverulent carrier, as e.g. with lactose, saccharose, sorbitol, mannitol, starch, as potatoe starch, corn starch amylopectin, cellulose derivatives or gelatine, as well as with an intrifriction agent as magnesium stearate, calcium stearate, polyethyleneglycol waxes or the like, and be pressed into tablets. If coated tablets are wanted, the above prepared core may be coated with concentrated solution of sugar~
which solution may contain e.g. gum arabicum, gelatine, talc, titandioxide or the like. Furthermore, the tablets may be coated with a lacquer dissolved in an easily volatile organic solvent or mixture of solvents. To this coating a dye may be added in order to easily distinguish between tablets with different active compounds or with diffPrent amounts of the active compound present.
In the preparation of soft gelatine capsules (pearl-shaped, closed capsules), which consist of gelatine and e.g. glycerine or in the preparation ;~
of similar closed capsules the active compound is mixed with a vegetable oil.
Hard gelatine capsules may contain granules of the active compound in combina-tion with a solid, pulverulent carrier as lactose, saccharose, sorbitol, man-nitol, starch ~as e.g. potatoe starch, corn starch or amylopectin), cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared in the form of suppositories, which contain the active substance in a mixture with a neu-tral at base, or they may be prepared in the form of gelatine-rectal capsules which contain the active substance in a mixture with a vegetable oil or paraf-fin oil.
Liquid preparations for oral adminlstration may be present in the ~orm of syrups or suspensions, e.g. solutions containing from about 0.2% by ~eight of about 20% by weight of the active substance described, whereby the residue consists of sugar and a mixture of ethanol, water, glycerol and propy-lene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents saccharine and carboxyme~hylcellul~se as a thickening agent.
Solutions for parenteral administratlon ~y injection may be prepared as an aqueous solutlon of a watersoluble pharmaceutically acceptable salt of S~39 ' the active compound, preferably in a concentration from about 0.5% by weight to about 0.10% by weight. These solutions may also contain stabilizing agents ;
and/or buffering agents and may suitably be available in different dosage unit ampoules.
The preparation of pharmaceutically tablets for peroral use is car-ried out in accordance with the following method:
The solid substances included are ground or sieved to a certain par-ticle size. The binding agent is homogenized and suspended in a certain amount of solvent. The therapeutic compound and necessary auxiliary agents are mixed during a continuous and constantly mixing with the binding agent solution and are moistened so that the solution is uniformly divided in the mass without overmoistening any parts. The amount of solvent is usually so adapted that the mass obtains a consistency reminding of wet snow. The moistening of the pulverulent mixture with the binding agent solution causes the particles to gather together slightly to aggregates and the real granulating process is carried out in such a way that the mass is pressed through a sieve in the form of a net of stainless steel having a mesh size of about 1 mm. The mass is then placed in thin layers on a tray to be dried in a drying cabinet. This drying takes place during 10 hours and has to be standardized carefully as the damp degree of the granulate is of utmost importance for the following process and for the feature of the tablets. Drying in a fluid bed may possibly be used. In this case the mass is not put on a tray but is poured into a con-tainer having a net bottom.
After the drying step the granules are sieved so that the particle size wanted is obtained. Under certain circumstances powder has to be removed.
To the so called final mixture, disintegrating, antifriction agents and antiadhesive agents are added. After this mixture the mass shall have its right composition for the tabletting step.
The cleaned tablet punching machine is provided with a certain set of punches and dies, whereupon the suitable adjustment for the weight of the tablets and the degree of compression is tested out. The weight of the tablet is decisive for the size of the dose in each tablet and is calculated starting .'' ' '-`` 3L~065~3g9L
from the amount of therapeutic agent in the granules. The degree of compres-sion affects the size of the tablet, its strength and its ability to disin-tegrate in water. Especially as regards the two later properties the choice of compression pressure (0.5 to 5 ton) means something of a balance-step.
~hen the right adjustment is set the preparation of tablets ls started which is carried out with a rate of 20.000 to 200.000 tablets per hour. The pres-sing of the tablets requires different times and depends on the size of the batch.
The tablets are freed from adhering pulver in a specific apparatus and are then stored in closed packages until they are delivered.
Many table~s, especially these which are rough or bitter, are coated with a coating. This means that these are coated with a layer of sugar or some other suita~le coating.
The tablets are usually packed by machines having an electronic counting device. The different types of packages consist of glass or plastic gallipots but also boxes, tubes and specific dosage adapted packages.
The daily dose of the active substance varies and is depending on the type of administration, but as a general rule it is 100 to 400 mg/day of acti~e substance at peroral administration and 5 to 20 mg/day at intravenous administration.
The following illustrates the principle and the adaptation of inven-tion, however, without being limited thereto. Temperature is given in degree Celsius.
Preparation or 3-[2-(~-hydroxyphenyl)-1-methylethylamino]-l-o-methylphenoxy-propanol-2 2.5 g or 1,2-epoxy-3-o-meth~lphenoxy propane were mixed with 1.5 g of 1-(4-hydroxyphenyl)-~-amino-propane and 25 ml of isopropanol and the total solution was refluxed for 1.5 hours. The solution was thereupon evaporated in vacuo. The base thus obtained was dissolved in acetone and the hydrochlo-ride was precipitated using HCl in ether. The hydrochloride was filtered off and washed ~ith acetonitril. The yield o~ 3-[2~ hydroxyphenyl)-1-methyl-~ 15 _ 65~9~L
ethylamino]-l-o-methylphenox~-propanol-2 was 1.4 g. ~elting point 112C.
The structure was determined uslng NMR.
Example 2 ; - .
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-ethylphenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-(o-ethyl) phenoxy-propane and 1-~4-hydroxyphenyl)-2-amino-propane as starting materials. -Melting point of its hydrochloride is 143C its structure was determined by MMR and equi~alent weight.
Example 3 :'-'. . .' ' 4-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-allylphenoxy-propanol-2 was prepared according to Example 1 using lJ2-epoxy-3-o-allyl-phenoxy-propane and 1-(4-hydroxyphenyl)-2-amino-propane as starting material.
Melting point of tartrate is 71C. Its structure was determined by NMR and equi~alent weight.
3-[2-~4-hydroxyphenyl)-1-methylethylamino]-1-o-propargyloxy phenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-propargyl- ;~
oxyphenoxy-propane and 1-~4-hydroxyphenyIL2-amino-propane as starting material.
The p-hydroxyben~oate was prepared.
Example 5 . .
3-[2-~4-hydroxyphenyl)-1-methylethylamino]-1-o-cyanophenoxy-propanol-2 was prepared according to Example 1 using lJ2-epoxy-3-o-cyanophenoxy-propane and 2-~4-hydroxyphenyl)-1-methylethylamine as starting materials.
The hydrochloride was obtained as a water soluble oil and its structure was determined using MM~.
Example 6 3-[2-~4-hydroxyphenyl)-1 J l-dimeth~lamino]-l-o-meth~l~phenoxy~ :
propanol-2 was prepared according to Example 1J using lJ2-epoxy-3-o-methyl-phenoxypropane and 2-t4-hydroxyphen~l)-lJl-dimethylethyl amine as s~arting ;
materlals. The hydrochloride was obtained as a water soluble oil and its structure was determined using MMR. , ~ 16 l: .
~5~
Fxam~le 7 3-[Z-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-eth~lphenoxy-propanol-2 was prepared according to Example I using 1,2-epoxy-3-o-ethyl-phenoxypropane and 2-(4-hydroxyphenyl)-l,l-dimethylethylamine as starting materials. The melting point of the hydrochloride is 154C.
Example 8 3-r2-(4_hydroxyphenyl)-1,1-dimethylethylamino]-1-o-all~lphenoxy-propanol-2 was prepared according to Example 1, using 1,2-epoxy-3-o-allyl-phenoxy propane and 2-~4-hydroxyphenyl)-1,1-dimethylethyl amine as starting materials. The melting point of the hydrochloride is 140C.
Example 9 3-[2-~4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-propargyloxy phenoxypropanol-2 was prepared according to Example 1, using 1,2-epoxy-3-o-propargyloxyphenoxypropane and 2-(4-hydroxyphenyl)-1,1-dimethylethylamine as starting materials.
Example 10 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-cyanophenoxy-propanol-2 was prepared according to Example 1, using 1,2-epoxy-3-o-cyano-phenox~propane and 2-~4-hydroxyphenyl)-1,1-dimethylethylamine as starting -materials. Melting point 144C ~HCl).
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o,m-dlmethylphenoxy-propanol-2 was prepar~d in accordance with Example 1 using 1,2-epoxy-3-o,m-dimethylphenoxypropane and 2-(4-hydroxyphenyl)-1-methylethylamine, as starting materials. Melting point 125C ~HCl).
3-[2-(4-hydroxyphenyl)~l-methylethylamino_l-o-methoxyphenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-methoxyphenoxy-propane and 2-~4-hydroxyphenyl)-1-methyleth~lamine as starting 3Q materials. Melting point 114C ~HCl) Example 13 3~meth~1~3~[2~4~hydroxyphenyl)_1-methylethylamino_l-o-ethyl-~ ~ 17 ~
`` 3L 0165~394 ~ :
phenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-l-meth~1-3-o-eth~lphenox~~propane and 2-(4-hydroxyphen~l)-1-methyleth~lamine) as startlng materials. The hydrochloride was obtained as a water soluble oil and its structure was determined using MMR.
Example 14 3-methyl-3-[2-~4-hydroxyphenyl)-1-methylethylaminol-1-o-cyanophenoxy-propanol 2 was prepared in accordance with Example 1 above using 1,2-epoxy-1-.~ . .
meth~l~3-o-cyanophenoxy-propane and 2-(4-hydroxyphenyl)-1-methylethylamine as starting materials. The hydrochloride was obtained as a water soluble oil and 1~ its structure was de~ermined using MMR.
Example 15 3-ethyl-3-[2-~4-hydroxyphenyl)-1-methylethylamino-1-o-allylphenoxy-propanol-2 was prepared in accordance with Example 1 above using 1,2-epoxy-1-ethyl-3-o-allylphenoxy-propane and 2-~4-hydroxyphenyl)-1-methylethylamine as starting materials. The hydrochloride was obtained as a water soluble oil and its structure was determined using NMR.
Example 16 `~
3-methyl-3-[2-~4-hydroxyphenyl)-1,1-dimethy]ethylamino]-1-o-methyl-phenoxy-propanol-2 was prepared in accordance with Example 1 above using 1,2-epox~-1-methyl-3-o-methylphenoxy-propane and 2-~4-hydroxyphenyl~-1,1-dimethyl-ethylamine as starting materials. The hydrochloride was obtained as a water ~`soluble oil and its structure was determined using MMR.
..
~ 17~ ~
.
,.
~065~94 Example 17 3-methyl-3-~2-~4-hydroxyphenyl)-1,1-dimethylethylamino~-1-o-allyl-phenoxy-propanol-2 was prepared in accordance with Example 1 above using 1,2-epoxy-l-methyl-3-o-allylphenoxy-propane and 2-C4-hydroxyphenyl)-1,1-dimethyl-ethylamine as starting materials. Melting point 172C ~HCl).
Example 18 3-[2-(4-hydroxyphenyl)-1-methylethylamino~-1-m-methylphenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-m-methylphenoxypropane and 2-C4-hydroxyphenyl)-1-methylethylamine as starting materials. Melting point 150C (HCl).
Example 00 Preparation of 3-[1-methyl-2-(4-hydroxyphenyl)ethylamino]-1-o-allylphenoxy butanol-2 .
2.5 g of 2,3-epoxy-l~o~allylphenoxy butane were mixed with 1.5 g of l~methyl~2~(4~hydroxyphenyl)ethylamine and 25 ml of isopropanol and the total solution was refluxed for 100 hours. The solution was thereupon evaporat-ed in vacuo. The base thus obtai.ned was dissolved in trichloroethylene and the hydrochloride was precipitated using LICl in ether. ~ater was added and the mixture was titrated with 1 M HCl. The pH was determined with a glass elec-trode and the values were plotted against ml HCl. At a band in the curve the water phase was separated, fresh water was added and the procedure was repea-ted until the next band in the curve. This water phase was separated, made alka-line with NH40H and extracted with methylene chloride. The organic phase was washed with water, dried and evaporated. The hydrochloride was precipi-tated with ether x HCl. The ether was decanted and the product solidifies upon evaporation in high vacuum. The yield of 3-[1-methyl-2-(4-hydroxyphenyl)ethyl-amino~ o-allylphenoxy butanol-2HCl was 1.6 g. Melting point 70C. The structure was determined using NMR.
~ - 18 -. .: - . . , ~589~L ;
Table :
Compound Reserpinized cat Conscious dog ~`
Block of isopren. Intrinsic BP in mm Hg --ED50 mg/kgactivity after 1.5 mg/kg i v HR PRbe~ts/min Supine Erect .
Propranolol 0.1 0.10 + 5 0 ~
Metoprolol 0.2 4.70 - 5 - 3 -Example 00 0.5 0.6+28 -33 -45 Example 19 ~- -A syrup containing 2% ~weight per volume of active substance was pre-pared from the following ingredients:
3-[2-(4-hydroxyphenyl)-1-methylethylamino]-l-o-methylphenoxy-propanol-2 ~ICl 2.0 g ~ .
Saccharine 0.6 g ~ -Sugar 30.0 g Glycerine 5.0 g Flavouring agent 0.1 g Ethanol 96% 10.0 g `
Destilled water ad100.0 ml SugarJ saccharine and the ethersalt were dissolved in 60 g of warm water. A~ter cooling glycer~e and solution of flavouring agents dissolved in ethanol were added. To the mixture water was then added to 100 ml. ~`
The above given active substance may be replaced with other pharma-.; . .. .
ceutically acceptable acid addition salts.
Example 20 3-[2-~4-hydroxyphenyl)-1~1-dimethylethylamino-1-o-allylphenoxy~-pro- ' ~' panol-2 hydrochloride ~250 g) was mixed with lactose C175.8 g) potatoe starch (169.7 g) and colloidal silicic acid (32 g). The mixture was moistened with a 10% solution of gelatine and was granulated through a 12-mesh sieve. A~ter ;~
drying potatoe starch ~160 g), talc ~50 g) and magnesium stearate (5 g) were admixed and the mixture thus obtained was pressed into tablets ~10.000) which contain 25 mg of substance. The tablets are sold on ~he market provided with a breaking score to give another dose than 25 mg or to give multiples thereof when broken.
- 18a -:' ,,, . ~
8~
~xample 21 Granules were prepared from 3-[2-~4-hydroxyphenyl)-1-methylethyl-amino]-l-o-propargyloxyphenoxy-propanol-2-p-hydroxybenzoate (250 g), lactose ~175.9 g~ and an alcoholic solution of polyvinylpyrrolidone (25 g). After the drying step the granules were mixed with talc (25 g) potatoe starch (~0 g) and magnesium stearate (2.50 g) and was pressed into 10.000 tablets being biconvex.
These tablets are primarily coated with a 10% alcoholic solution of shellac and thereupon with an aqueous solution containing saccharose (45%), gum arabi-cum (5%), gelatine (4%) and dyestuff ~0.2%). Talc and powder sugar were used for powdering after the first five coatings. The coating was then coated with a 66% sugar syrup and polished with a 10% carnauba wax solution in carbon tetrachloride.
Example 22 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-3-o-ethylphenoxy-propanol-2-hydrochloride ~1 g), sodiumchloride ~0.8 g) and ascorbic acid ~0.1 g) were dissolved in sufficient amount of distilled water to give 100 ml of solution. This solution, which contains 10 mg of active substance on each ml was used in filling a~poules, which were sterilized by heating at 120C for 20 minutes.
Biological effects The ~-receptor blocking agents of the present invention were tested as regards their biological properties. All compo~mds were thereby tested in anaesthetized cats~males and ~emales weighing 2.5-3.5 kg) pretxoated with reserpine ~5 mg/kg bodyweight administered intra musculary) about 16 hours be-fore the experiments. The animals were pretreated with reserpine in order to eliminate the endogenous sympathetic control of heart rate and vascular smooth muscle tone. The cats were anaesthetized with pentabarbital ~30mg/kg body-weight administered i.p.) and artificially ventilated with room air. A bi-lateral vagotomy was performed in the neck. Blood pressure was obtained from a cannulated carotid artery and heart rate was registered from a cardio-tachometer, triggered by the electrocardiogram ~ECG~. Intrinsic beta mimetic activity on the heart was seen as increased heart rate after drug administra-- 19 - : ~ .
tion. The test compounds were given intraveneously in logarithmically in- :
creasing doses. The values obtained were plotted on dose-response curves, from which affinity values (ED50) were estimated. At the end of each experi-ment high doses of isoprenaline were given in order to obtain the maximal heart rate response.
The compounds were also tested on conscious dogs. Beagle dogs were :~
trained to be lying quietly and to be lifted to an erect position by placing ~ ' their forelegs on a table for 2 minutes. Arterial blood pressure was register-ed via a blood pressure transducer attached to the dog at the heart level.
Heart rate was triggered from the ECG. All dogs were pretreated with methyl-scopolamine to avoid vagal influences. Recordings were taken before and 15 and 75 min after administration of the test compound, first in supine position for 2 min and then in the erect position for 2 minutes. The test compounds were given in increasing doses with 2 hours intervals.
Table 1 below shGws affinity values and intrinsic ~-mimetic activity `
in reserpinized cats and effects on blood pressure in conscious dogs of compound of the present invention. Corresponding values for propanolol, ~l-isopropylamino-3-(1-naphthoxy)-propanol-2, and metoprolol, tl-isopropyl-amino-3-~4-~2-methoxyethyl)phenoxy]-propanol-2), are shown for comparison. ;`~
Table 1 also shows PA2 measured on rats. pA2 is -log of the concen-tration of an antagonist which leads to the fact that the dose of noradren-aline has to be doubled in order to obtain the same effect of noradrenaline as one obtains without the antagonist or pA2~ log ~dr-l)-log ~antagonist) . . ED of noradrenaline (antoganist) whereln dr is dose ratlo = 50 ED50 of noradrenaline ~control) and all concentrations are given in mol/l. pA2 is thus a measure of ~-receptor-effect where higher PA2 -~ higher ~-effect.
.. ,. . :
.,.... . . :
~ ;5~39L .
N cn N N 1~ c~ co ~ t~l N O tD N ~
r~1: I I (Dr~r~ tDLn~D ~DtD I I ~
. .
> t~ ~r~
,~t~ o ~ ol n tJ~ Ln O
h ~ ,~ tr) ~,~ N I N
3~LLI l l l l l c~O ~ c~ .
OI- . .~
O Ctl~
, ~ ,c Ln ~n N O O 0 0 L ~ I N ~ I ~,~ I ~
t~ I I ~ I I .
c~ m ~D tn .
. .
.
t~ C
, ~, .
.,~ ~ ~ O O Cl:7 N ~ ~ N ct~ ol N ~D O co O N tn ~ C~2 ,_1 ~ ~r-( ~ r-l tl-) tr) trl tD t~l trl ~ ~ ~ r-l ~t t + ~ r-l ~ + + + + 'I' + + ~ +
tl) ~ G. O ~ .
t~ H ~ ~ ~ .
ID ~ .
~ .
~ C . .
t ~ ~ ~ O r~ r~l r--l ttl O O O N U~l LD O t~ tD ~ ~
t~ O Q O ~ O O r-l O O O O O O O O r~l tr~ ~0 0 0 0 U~
.r~ ~0 . ' . ~0 ~10 . .
E Il~
O O ~ r~l ~CO Ul r--I N ~ d N
O 111 ~-1 N O r~l 1~ 0 0 0 r--I O N O r- l ~ r--I ~r) 11-1 N Ir~
r I O O O U~l r-l N O
.
~. ~ .
r~ . .~
r rO ~, ' "
c- tti L i .
tl tl O r~l N tr) Ln U~ Ct~ rO! r~ ~N~ ~ r--l r--I r-1 r~l r~ o ~:
O ~ lV X "
o n. ~ LL
~1065~
The experlments demonstate that the compounds tested are potent B-receptor antagonists with or without intrinsic B-mimetic activit~. The com-pounds also decrease blood pressure in conscious dogs significantly more than propranolol and metroprolol. The pronounced h~potensive effect in conscious dogs of the ne~ compounds depends on a ~asodilating effect in combination with -cardiac beta-receptor blockade.
Claims (44)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a new amine of the formula I
[I]
or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen and methyl, and R2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, allyl, cyano, methoxy, propargyloxy, and R3 is selected from the group consisting of hydrogen, methyl and ethyl, and R4 is selected from the group consisting of hydrogen and methyl, provided that R2 and R4 are not both hydrogen, character-ized in that a) a compound of the formula II
[II]
wherein R2, R3 and R4 have the same meanings as given above, X1 is a hydroxy group and Z is a reactive, esterified hydroxy group and is chloro, bromo, iodo, sulfate, benzenesulfonyl residue, 4-bromobenzenesulfonyl residue or 4-toluene-sulfonyl residue, or X1 and Z together form an epoxy group, is reacted with an amine of the formula wherein R1 has the same meanings as given above, or b) a compound of the formula III
[III]
wherein R2, R3 and R4 have the same meanings as given above is reacted with a compound of the formula wherein R and Z have the same meanings as given above, or c) a compound of the formula IV
[IV]
wherein R2 and R4 have the same meanings as given above is reacted with a compound of formula V
[v]
wherein Z, X1, R1 and R3 have the same meanings as given above, or d) a compound of the formula IV
[IV]
wherein R2 and R4 have the same meanings as given above is reacted with a compound of the formula VI
[VI]
wherein R1 and R have the same meanings as given above, or e) from a compound of the formula I wherein R, R2 and R3 have the same meanings as above, and which compound has a splitable residue at the nitrogen atom of the amino group or has a splitable residue at the hydroxy groups or both, this residue is split off, or f) a cyclic tautomer of formula X
[X]
wherein R1, R2, R3 and R4 have the same meanings as above except for the case when R1 is methyl, is reduced, or g) in a compound corresponding to the one of formula I having an oxo group at a C-atom close to the N-atom, this oxo group is reduced to two hydrogen atoms and isomer mixtures obtained are separated into pure isomers, and/or racemates obtained are separated into optical antipodes and/or free bases obtained are transformed into their therapeutically acceptable salt or salts obtained are transformed into their free bases.
[I]
or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen and methyl, and R2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, allyl, cyano, methoxy, propargyloxy, and R3 is selected from the group consisting of hydrogen, methyl and ethyl, and R4 is selected from the group consisting of hydrogen and methyl, provided that R2 and R4 are not both hydrogen, character-ized in that a) a compound of the formula II
[II]
wherein R2, R3 and R4 have the same meanings as given above, X1 is a hydroxy group and Z is a reactive, esterified hydroxy group and is chloro, bromo, iodo, sulfate, benzenesulfonyl residue, 4-bromobenzenesulfonyl residue or 4-toluene-sulfonyl residue, or X1 and Z together form an epoxy group, is reacted with an amine of the formula wherein R1 has the same meanings as given above, or b) a compound of the formula III
[III]
wherein R2, R3 and R4 have the same meanings as given above is reacted with a compound of the formula wherein R and Z have the same meanings as given above, or c) a compound of the formula IV
[IV]
wherein R2 and R4 have the same meanings as given above is reacted with a compound of formula V
[v]
wherein Z, X1, R1 and R3 have the same meanings as given above, or d) a compound of the formula IV
[IV]
wherein R2 and R4 have the same meanings as given above is reacted with a compound of the formula VI
[VI]
wherein R1 and R have the same meanings as given above, or e) from a compound of the formula I wherein R, R2 and R3 have the same meanings as above, and which compound has a splitable residue at the nitrogen atom of the amino group or has a splitable residue at the hydroxy groups or both, this residue is split off, or f) a cyclic tautomer of formula X
[X]
wherein R1, R2, R3 and R4 have the same meanings as above except for the case when R1 is methyl, is reduced, or g) in a compound corresponding to the one of formula I having an oxo group at a C-atom close to the N-atom, this oxo group is reduced to two hydrogen atoms and isomer mixtures obtained are separated into pure isomers, and/or racemates obtained are separated into optical antipodes and/or free bases obtained are transformed into their therapeutically acceptable salt or salts obtained are transformed into their free bases.
2. A compound of the formula I defined in claim 1 or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.
3. A process which comprises reacting 1,2-epoxy-3-o-methylphenoxy propane with 1-(4-hydroxyphenyl)-2-amino-propane to yield 3-[2-(4-hydroxy-phenyl)-1-methylethylamino]-1-o-methylphenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
4. 3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-methylphenoxy-propanol-2 and its hydrochloride salt whenever prepared by a process accord-int to claim 3, or by an obvious chemical equivalent thereof.
5. A process which comprises reacting 1,2-epoxy-3-o-ethylphenoxy-propane with 1-(4-hydroxyphenyl)-2-amino-propane to yield 3-[2-(4-hydroxy-phenyl)-1-methylethylamino]-1-o-ethylphenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
6. 3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-ethylphenoxy-propan-ol-2 and its hydrochloride salt whenever prepared by a process according to claim 5, or by an obvious chemical equivalent thereof.
7. A process which comprises reacting 1,2-epoxy-3-o-allylphenoxy-propane with 1-(4-hydroxyphenyl)-2-amino-propane to yield 3-[2-(4-hydroxy-phenyl)-1-methylethylamino]-1-o-allylphenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
8. 3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-allylphenoxy-propanol-2 and its hydrochloride salt whenever prepared by a process accord-ing to claim 7, or by an obvious chemical equivalent thereof.
9. A process which comprises reacting 1,2-epoxy-3-o-propargyloxy-phenoxy-propane with 1-(4-hydroxyphenyl-2-amino-propane to yield 3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-propargyloxyphenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chlor-ide.
10. 3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-propargyloxyphenoxy-propanol-2 and its hydrochloride salt whenever prepared by a process accord-ing to claim 9, or by an obvious chemical equivalent thereof.
11. A process which comprises reacting 1,2-epoxy-3-o-cyanophenoxy-propane with 2-(4-hydroxyphenyl)-1-mekhylethylamine to yield 3-[2-(4-hydroxy-phenyl)-1-methylethylamino]-1-o-cyanophenoxy-propanol-2, and when the hydro-chloride is required, reacting the product with hydrogen chloride.
12. 3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-cyanophenoxy-propanol-2, and its hydrochloride salt whenever prepared by a process accord-ing to claim 11, or by an obvious chemical equivalent thereof.
13. A process which comprises reacting 1,2-epoxy-3-o-methylphenoxy-propane with 2-(4-hydroxyphenyl)-1,1-dimethylethylamine to yield 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-methylphenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
14. 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamlno]-1-o-mekhylphenoxy-propanol-2 and its hydrochlorlde salt whenever prepared by a process accord-ing to claim 13, or by an obvious chemical equivalent thereof.
15. A process which comprises reacting 1,2-epoxy-3-o-ethylphenoxypropane with 2-(4-hydroxyphenyl)-1,1-dimethylethylamine to yield 3-[2-(4-hydroxy-phenyl)-1,1-dimethylethylamino]-1-o-ethylphenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
16. 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-ethylphenoxy-propanol-2 and its hydrochloride salt whenever prepared by a process accord-ing to claim 15, or by an obvious chemical equivalent thereof.
17. A process which comprises reacting 1,2-epoxy-3-o-allylphenoxy propane with 2-(4-hydroxyphenyl)-1,1-dimethylethylamine to yield 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamLno]-1-o-allylphenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chlor-ide.
18. 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-allylphenoxy-propanol-2 and its hydrochloride salt whenever prepared by a process accord-ing to claim 17, or by an obvious chemical equivalent thereof.
19. A process which comprises reacting 1,2-epoxy-3-o-propargyloxyphen-oxypropane with 2-(4-hydroxyphenyl)-1,1-dimethylethylamine to yield 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino] -1-o-propargyloxyphenoxypropanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
20. 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-propargyloxy-phenoxypropanol-2 and its hydrochloride salt whenever prepared by a process according to claim 19, or by an obvious chemical equivalent thereof.
21. A process which comprises reacting 1,2-epoxy-3-o-cyanophenoxy-propane with 2-(4-hydroxyphenyl)-1,1-dimethylethylamine to yield 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-cyanophenoxypropanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
22. 3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-cyanophenoxy propanol-2 and its hydrochloride salt whenever prepared by a process accord-ing to claim 21, or by an obvious chemical equivalent thereof.
23. A process which comprises reacting 1,2-epoxy-3-o,m-dimethylphenoxy-propane wlth 2-(4-hydroxyphenyl)-1-methylethylcumine to yield 3-[2-(4-hydroxy-phenyl)-1-methylethylamino)-1-o,m-dimethyl-phenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
24. 3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o,m-dimethyl-phenoxy-propanol-2 and its hydrochloride salt whenever prepared by a process accord-ing to claim 23, or by an obvious chemical equivalent thereof.
25. A process which comprises reacting 1,2-epoxy-3-o-methoxyphenoxy-propane with 2-(4-hydroxyphenyl)-1-methylethylamine to yield 3-[2-(4-hydroxy-phenyl)-1-methylethylamino-1-o-methoxyphenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
26. 3-[2-(4-hydroxyphenyl)-1-methylethylamino-1-o-methoxyphenoxy-prop-anol-2 and its hydrochloride salt whenever prepared by a process according to claim 25, or by an obvious chemical equivalent thereof.
27. A process which comprises reacting 1,2-epoxy-l-methyl-3-o-ethyl-phenoxy-propane with 2-(4-hydroxyphenyl)-1-methylethylamine to yield 3-methyl -3-[2-(4-hydroxyphenyl)-1-methylethylamino-1-o-ethyl-phenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chlor-ide.
.
.
28. 3-methyl-3-[2-(4-hydroxyphenyl)-1-methylethylamino-1-o-ethyl-phenoxy-propanol-2 and its hydrochloride salt whenever prepared by a process according to claim 27, or by an obvious chemical equivalent thereof.
29. A process which comprises reacting 1,2-epoxy-1-methyl-3 o-cyano-phenoxy-propane with 2-(4-hydroxyphenyl)-1-methylethylamine to yield 3-methyl -3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-cyanophenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chlor-ide.
30. 3-methyl-3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o-cyano-phenoxy-propanol-2 and its hydrochloride salt whenever prepared by a process according to clalm 29, or by an obvious chemical equivalent thereof.
31. A process which comprises reacting 1,2-epoxy-1-ethyl-3-o-allyl-phenoxy-propane with 2-(4-hydroxyphenyl)-1-methylethylamine to yield 3-ethyl -3-[2-(4-hydroxyphenyl)-1-methylethylamino-1-o-allylphenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chlor-ide.
32. 3-ethyl-3-[2-(4-hydroxyphenyl)-1-methylethylamino-1-o-allylphenoxy-propanol-2 and its hydrochloride salt whenever prepared by a process accord-ing to claim 31, or by an obvious chemical equivalent thereof.
33. A process which comprises reacting 1,2-epoxy-1-methyl-3-o-methyl-phenoxy-propane with 2-(4-hydroxyphenyl)-1,1-dimethylethylamine to yield 3-methyl-3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-methylphenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
34. 3-methyl-3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-methyl-phenoxy-propanol-2 and its hydroehloride salt whenever prepared by a process aecording to claim 33, or by an obvious chemical equivalent thereof.
35. A process which comprises reacting 1,2-epoxy-1-methyl-3-o-allyl-phenoxy-propane with 2-(4-hydroxyphenyl)-1,1-dimethylethylamine to yield 3-methyl-3-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-1-o-allyl-phenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
36. 3-methyl-3-[2-(4 hydroxyphenyl)-1,1-dimethylethylamino]-1-o-allyl-phenoxy-propanol-2 and its hydrochloride salt whenever prepared by a process according to claim 35, or by an obvious chemical equivalent thereof.
37. A process which comprises reacting 1,2-epoxy-3-m-methylphenoxy-propane with 2-(4-hydroxyphenyl)-1-methylethylamine to yield 3-[2-(4-hydroxy-phenyl)-1-methylethylamino]-1-m-methylphenoxy-propanol-2, and, when the hydroehloride is required, reaeting the product with hydrogen chloride.
38. 3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-m-methylphenoxy-propanol-2 and its hydroehloride salt whenever prepared by a proeess aeeord-lng to elalm 37, or by an obvious chemical equivalent thereof.
39. A process which comprises reacting 2,3-epoxy-1-o-allylphenoxy butane with 1-methyl-2-(4-hydroxyphenyl)ethylamine to yield 3-[1-methyl-2-(4-hydroxy-phenyl)ethylamino]-1-o-allylphenoxy-butanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
40. 3-[1-methyl-2-(4-hydroxyphenyl)ethylamino]-1-o-allylphenoxy-butanol-2 and its hydrochloride salt whenever prepared by a process according to claim 39, or by an obvious chemical equivalent thereof.
41. A process which comprises reacting 1,2-epoxy-3-o,m-dimethylphenoxy-propane with 2-(4-hydroxyphenyl)-1-methylethylamine to yield 3-[2-(4-hydroxy-phenyl)-1-methylethylamino]-1-o,m-dimethylphenoxy-propanol-2, and, when the hydrochloride is required, reacting the product with hydrogen chloride.
42. 3-[2-(4-hydroxyphenyl)-1-methylethylamino]-1-o,m-dimethylphenoxy-propanol-2 and its hydrochloride salt whenever prepared by a process accord-ing to claim 41, or by an obvious chemical equivalent thereof.
43. A process according to claim 1 whereby the product is isolated in the form of a dextro-rotating optical antipode.
44. A process according to claim 1 whereby the product is isolated in the form of a levo-rotating optical antipode.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE7413789A SE422052B (en) | 1974-11-01 | 1974-11-01 | PROCEDURE FOR PREPARING CERTAIN STATED 1-PHENOXY-2-HYDROXY-3-AMINOPHENYL PROPYL DERIVATIVES |
| SE7506348A SE402764B (en) | 1975-06-04 | 1975-06-04 | PROCEDURE FOR PRODUCING NEW HEART ACTIVE ASSOCIATIONS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1065894A true CA1065894A (en) | 1979-11-06 |
Family
ID=26656538
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA238,765A Expired CA1065894A (en) | 1974-11-01 | 1975-10-31 | Phenoxypropanolamines |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS51131841A (en) |
| AT (1) | AT340898B (en) |
| CA (1) | CA1065894A (en) |
| CH (1) | CH618416A5 (en) |
| CS (1) | CS189725B2 (en) |
| DD (1) | DD122073A5 (en) |
| DE (1) | DE2530613A1 (en) |
| DK (1) | DK444375A (en) |
| FI (1) | FI752312A (en) |
| FR (1) | FR2289173A1 (en) |
| GB (1) | GB1518689A (en) |
| HK (1) | HK35981A (en) |
| HU (1) | HU172651B (en) |
| IE (1) | IE42131B1 (en) |
| IT (1) | IT7950876A0 (en) |
| LU (1) | LU73704A1 (en) |
| MY (1) | MY8200084A (en) |
| NL (1) | NL7509549A (en) |
| NO (1) | NO141753C (en) |
| SU (3) | SU591137A3 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6022894A (en) * | 1996-04-09 | 2000-02-08 | Nps Pharmaceuticals, Inc. | Method of using calcilytic compounds |
| US6818660B2 (en) | 1996-04-09 | 2004-11-16 | Nps Pharmaceuticals, Inc. | Calcilytic compounds |
| US7202261B2 (en) | 1996-12-03 | 2007-04-10 | Nps Pharmaceuticals, Inc. | Calcilytic compounds |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW483881B (en) | 1996-12-03 | 2002-04-21 | Nps Pharma Inc | Calcilytic compounds |
| MY159417A (en) * | 2000-01-24 | 2017-01-13 | Smithkline Beecham Corp | Calcilytic compounds |
-
1975
- 1975-07-09 DE DE19752530613 patent/DE2530613A1/en not_active Ceased
- 1975-07-31 AT AT593075A patent/AT340898B/en not_active IP Right Cessation
- 1975-08-06 NO NO752766A patent/NO141753C/en unknown
- 1975-08-08 SU SU752163124A patent/SU591137A3/en active
- 1975-08-08 DD DD187767A patent/DD122073A5/xx unknown
- 1975-08-11 NL NL7509549A patent/NL7509549A/en not_active Application Discontinuation
- 1975-08-14 FI FI752312A patent/FI752312A/fi not_active Application Discontinuation
- 1975-09-09 GB GB37072/75A patent/GB1518689A/en not_active Expired
- 1975-09-16 CH CH1196675A patent/CH618416A5/en not_active IP Right Cessation
- 1975-10-02 IE IE2155/75A patent/IE42131B1/en unknown
- 1975-10-02 DK DK444375A patent/DK444375A/en not_active Application Discontinuation
- 1975-10-21 FR FR7532205A patent/FR2289173A1/en active Granted
- 1975-10-30 CS CS757327A patent/CS189725B2/en unknown
- 1975-10-30 HU HU75HE00000693A patent/HU172651B/en unknown
- 1975-10-31 CA CA238,765A patent/CA1065894A/en not_active Expired
- 1975-10-31 JP JP50131346A patent/JPS51131841A/en active Pending
- 1975-10-31 LU LU73704A patent/LU73704A1/xx unknown
-
1976
- 1976-11-01 SU SU762415408A patent/SU617007A3/en active
- 1976-11-01 SU SU762415407A patent/SU624570A3/en active
-
1979
- 1979-11-21 IT IT7950876A patent/IT7950876A0/en unknown
-
1981
- 1981-07-23 HK HK359/81A patent/HK35981A/en unknown
-
1982
- 1982-12-30 MY MY84/82A patent/MY8200084A/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6022894A (en) * | 1996-04-09 | 2000-02-08 | Nps Pharmaceuticals, Inc. | Method of using calcilytic compounds |
| US6521667B1 (en) | 1996-04-09 | 2003-02-18 | Nps Pharmaceuticals, Inc. | Calcilytic compounds |
| US6818660B2 (en) | 1996-04-09 | 2004-11-16 | Nps Pharmaceuticals, Inc. | Calcilytic compounds |
| US7202261B2 (en) | 1996-12-03 | 2007-04-10 | Nps Pharmaceuticals, Inc. | Calcilytic compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| AT340898B (en) | 1978-01-10 |
| SU624570A3 (en) | 1978-09-15 |
| SU591137A3 (en) | 1978-01-30 |
| NL7509549A (en) | 1976-05-04 |
| FR2289173B1 (en) | 1980-11-21 |
| JPS51131841A (en) | 1976-11-16 |
| AU8363875A (en) | 1977-02-10 |
| IE42131B1 (en) | 1980-06-04 |
| NO752766L (en) | 1976-05-04 |
| GB1518689A (en) | 1978-07-19 |
| HK35981A (en) | 1981-07-31 |
| LU73704A1 (en) | 1976-08-13 |
| IT7950876A0 (en) | 1979-11-21 |
| DK444375A (en) | 1976-05-02 |
| ATA593075A (en) | 1977-05-15 |
| IE42131L (en) | 1976-05-01 |
| DD122073A5 (en) | 1976-09-12 |
| NO141753C (en) | 1980-05-07 |
| CH618416A5 (en) | 1980-07-31 |
| NO141753B (en) | 1980-01-28 |
| FI752312A (en) | 1976-05-02 |
| CS189725B2 (en) | 1979-04-30 |
| HU172651B (en) | 1978-11-28 |
| SU617007A3 (en) | 1978-07-25 |
| DE2530613A1 (en) | 1976-05-06 |
| FR2289173A1 (en) | 1976-05-28 |
| MY8200084A (en) | 1982-12-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6143769A (en) | Phenylacetic acid benzylamides | |
| US4234595A (en) | 3-Indolyl-tertiary butylaminopropanols | |
| CA1052387A (en) | Heart active compounds | |
| US4165384A (en) | Amide substituted phenoxy propanol amines | |
| US3996382A (en) | Phenoxy-hydroxypropylamines, their preparation, and method and pharmaceutical preparations for treating cardiovascular diseases | |
| US4391821A (en) | 7-Substituted benzopyranes and process for the preparation thereof | |
| FI63745C (en) | FRAMEWORK FOR THE FRAMEWORK OF THERAPEUTIC MEDICINAL PRODUCTS | |
| CA1065894A (en) | Phenoxypropanolamines | |
| CA1093095A (en) | Amines | |
| US3949088A (en) | Substituted phenoxy propanol amines used for treating cardiovascular diseases | |
| US4263325A (en) | β-Receptor blocking compounds and treatment of cardiovascular disorders therewith | |
| EP0007294A2 (en) | Membrane stabilizing compounds having beta-receptor blocking activity, their preparation, method for treatment of arrhythmic conditions, and pharmaceutical preparations containing same | |
| CA1178588A (en) | PARA-SUBSTITUTED 3-PHENOXY-1-CARBONYLAMINOALKYLAMINO- PROPANOL-2-S HAVING .beta. RECEPTOR BLOCKING PROPERTIES | |
| CA1093096A (en) | Heart active derivatives of 1-amino-2,3-dihydroxy propane | |
| US4263323A (en) | β-Receptor blocking compounds and treatment of cardiovascular disorders therewith | |
| US4161542A (en) | Heart active compounds | |
| CA1246083A (en) | Ethanolamines | |
| SE446980B (en) | ALKYLTIOPHENOXIAL CYLAMINES AND PROCEDURES FOR PREPARING THEREOF | |
| EP0139921B1 (en) | 2-phenylethylamine derivatives | |
| US4000313A (en) | 1-Isopropylamino-3[4'-(2-methoxy- or ethoxy-carbonylaminoethoxy)-phenoxy]propanol-2 and cardioselective antagonism use | |
| US4035420A (en) | Substituted ureido alkylene phenoxy propanolamines | |
| CA1331005C (en) | Pyridylethanolamines, pharmaceutical compositions containing them and processes for their preparation | |
| AU592358B2 (en) | Derivatives of diphenoxyethylamine, a process for their production and the pharmaceutical compositions containing the same | |
| SK1052001A3 (en) | Substituted phenylamidines with antithrombotic action | |
| CA1048526A (en) | 1-isopropylamino-3-(4'-(2-alkoxycarbonyl-aminoethoxy)-phenoxy)-propan-2-01 |