GB1589838A - 1-phenoxy-3-amino-propan-2-ols - Google Patents
1-phenoxy-3-amino-propan-2-ols Download PDFInfo
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- GB1589838A GB1589838A GB41699/77A GB4169977A GB1589838A GB 1589838 A GB1589838 A GB 1589838A GB 41699/77 A GB41699/77 A GB 41699/77A GB 4169977 A GB4169977 A GB 4169977A GB 1589838 A GB1589838 A GB 1589838A
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- ethylamino
- hydroxyphenoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
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- 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
Abstract
The process is used for preparing the novel amines of the formula (I) <IMAGE> R<1>, R<2> and R<3> are defined in Patent Claim 1. The reactions for preparing the said compounds always take place between primary amines and compounds having a reactive, esterified hydroxyl group or an epoxy group. The novel compounds effectively block beta receptors.
Description
(54)1 -PHENOXY-3-AMINO-PROPAN-2- OLS (71) We, AKTIBOLAGET HASSLE, a Swedish Company, of Karragatan S, S-431 20 MGlnda!, Sweden, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to new potent,ss-receptor blocking compounds, to their preparation and to their use in treating symptoms and signs of cardiovascular disorders by blocking the p-receptors of the heart.
The new compounds are those of the general formula
wherein Rl is methyl, ethyl, propyl, methoxy, cyano, cyanomethyl, hydroxymethyl or CH,OCH2CH2NHCOCH2O-, R2 and R3 are the same or different and each is hydrogen, hydroxy, methoxy or hydroxymethyl provided that R2 and R3 are not both hydrogen, n is 2, and X is -0- or -S-.
X is oxygen or sulphur, preferably oxygen.
R2 and R3 are preferably bound in the 2, 3 or 4 position, particularly in the 3- and 4-position to the alkylene side chain on the phenoxy or phenylthio group, whereby preferably R2 is hydrogen and R3 is hydroxy, or R2 and R3 are 3,4-dimethoxy.
The new compounds have valuable pharmacological properties. Thus they block cardiac p-receptors, which is shown at the determination of the antagonism of tachycardia after an intravenous injection of 0.5 ,ug/kg of d/l-isoproterenol sulphate on an anaesthetized cat at an intravenous dose of 0.002 to 2 mg/kg. They also block the vascular p-receptors which is shown at the determination of the antagonism of vasodilation after an intravenous injection of 0.5 ug/kg of d/l-isoproterenol sulphate on an anaesthetized cat at an intravenous dose of 0.002 to 2 mg/kg or more. The compounds have also stimulating properties on p-receptors, i.e. they show intrinsic activity.
This property is especially pronounced concerning vascular p-receptors causing dilation of peripheral blood vessels.
The new 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.
Preferred compounds according to the present invention are: 3- [2- (4-hydroxyphenoxy) -ethylamino] -1-o-methylphenoxy-propanol-2; 3- [2- (4-hydroxyphenoxy) -ethylamino] - 1 -o-ethylphenoxy-propanol-2; 3- [2- (4-hydroxyphenoxy) -ethylamino] -1-o-propylphenoxy-propanol-2; 3-[2-(4-hydroxyphenoxy)-ethylamino] -1-o-cyanophenoxy-propanol-2; 3- [2- (4-hydroxyphenoxy) -ethylamino ] - 1 -o-cyanomethylphenoxy-propanol-2; 3- [2- (4-hydroxyphenoxy) -ethylamino] -1-o-hydroxymethyloxyphenoxy-propanol-2; 3- [2- (4-hydroxyphenylthio ) -ethylamino] - 1 -o-cyanophenoxy-propanol-2; 3- [2- (4-hydroxyphenylthio) -ethylamino] -1-o-methylphenoxy-propanol-2; 3- [2- ( 3-methoxy-4-methoxyphenoxy) -ethylamino] - 1 -o-methylphenoxy-propanol-2; 3 - [2- (3 -hydroxymethyl-4-hydroxyphenoxy) -ethylamino] - 1 -o-cyanophenoxy
propanol-2; 3- [2- (3,4-dihydroxyphenylthio) -ethylamino] - 1 o-cyanophenoxy-propanol-2; 3- [2- (4-methoxyphenoxy) -ethylamino] - 1 -o-cyanophenoxy-propanol-2; 3- [2-(2-hydroxyphenoxy) -ethylamino] - 1 -cyanophenoxy-prnpanol-2; 3-[2-(4-hydroxy-3-methoxyphenoxy)ethylamino]-1-o-cyanophenoxy-propanol-2; 3- [2-( 3,S-dimethoxyphenoxy) ethylamino] - 1-o-cyanophenoxy-propanol-2; 3- [2- (4-hydroxyphenoxy) ethylamino] -1-o (2-methoxyethyl)aminocarbonylmethoxy- phenoxy-propanol-2.
Salt forming acids may be used in preparing pharmaceutically acceptable salts of the compounds. These are for example: hydrohadogen 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, paminobenzoic, anthranilic, p-hydroxybenzoic, salicyclic or p-aminosalicyclic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethane sulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthylsulfonic, or sulfanilic acid, methionine, tryptophan, lysine or arginine.
The substances are normally intended to be administered orally or parenterally 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 compounds of the invention can be obtained according to merhods known per se. Thus, a compound of formula II
wherein R1 has the meaning given above, X1 is a hydroxy group, Z is a reactive, esterified hydroxy group, or X' and Z together form an epoxy group, can be reacted with an amine of the formula
wherein R2, R9, n and X have the meanings given above.
A reactive, esterified hydroxy group is particularly a hydroxy group esterified with a strong, inorganic or organic acid, preferably a hydrohalogen acid, such 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. Z is preferably chloro, bromo or iodo.
This reaction is carried out in a usual way. With 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. alkali metal hydroxides, such as sodium or potassium hydroxide, alkali metal carbonates such as potassium carbonate and alkali metal alcoholates such as sodium methylate, potassium ethylate or potassium tert.-butylate.
The reaction is preferably carried out in an alkanol having 1 to 4 carbon atoms by refluxing the reactants in said solvent for a time long enough to give the compound of formula I, generally 1 to 12 hrs.
Further, a compound of formula III
wherein Rl has the meaning given above, can be reacted with a compound of the formula
wherein R2, RS, n, X, and Z have the meanings given above.
This reaction is carried out in a usual 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 such as sodium or potassium carbonate.
This reaction is preferably carried out in an alkanol having 1 to 3 carbon atoms in an autoclave being heated to 100 to 1300C for 5 to 15 hrs.
Further, a compound of formula IV
wherein R1 has the meaning given above can be reacted with a compound of the formula V
wherein Z, X1, R2, Rg, n and X have the meanings given above.
This reaction is carried out in a usual 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 metal phenolate, such as alkali metal phenolate, preferably sodium phenolate, or one works in the presence of an acid binding agent, preferably a condensating agent, which can form a salt of the compound of formula IV as an alkali metal alcoholate.
This reaction is preferably carried out in an alkanol having 1 to 3 carbon atoms in an autoclave being heated to 80 to 1000C for 5 to 15 hrs.
Further, a compound of formula Va
wherein R1, Z and n have the meanings given above, can be reacted with a compound of formula IVa
wherein R2, R3 and X have the meanings given above.
This reaction is preferably carried out in the same way as the reaction between compounds of formula IV and V above.
Further, a compound of formula IV
wherein R1 has the meaning given above, can be reacted with a compound of formula
VI
wherein R2, RS, n and X have the meanings given above.
This reaction is carried out in a novel way. Thus, the reaction may be carried out under alkaline conditions in a suitable solvent, such as benzylalcohol, by boiling the reaction mixture for some hours. Thereby the phenol is primarily converted to its metal phenolate as alkali metal phenolate before it is added to the acetidinol of formula VI.
Further, one may split off a residue from a compound of formula I above, in which the nitrogen atom of the amino group and/or the hydroxy groups have attached thereto a splitable residue.
Such splitable residues are especially those which are splitable by solvolysis, reduction, pyrolysis or fermentation.
Residues splitabe by solvolysis are preferably residues splitable by hydrolysis or ammonolysis.
Residues splitable by means of hydrolysis are e.g. acyl residues, which, when present, are functionally varied carboxy groups, e.g. oxycarbonyl residues, such as alkoxycarbonyl residues, e.g. the tert.-butoxycarbonyl or ethoxycarbonyl residue, aralkoxycarbonyl residues such as phenylloweralkoxycarbonyl residues, e.g. a carbo benzyloxy residue; halogencarbenyl residues, e.g. a chlorocarbon residue; arylsulphonyl residues such as toluenesulfonyl or bromobenzenesultonyl residues; possibly halogenated, such as fluorinated loweralkanoyl residues such as formyl-, acetyl- or trifluoroacetyl residues; a benzyl residue; cyano; or silyl residues, such as the trimethylsilyl residue.
Of the above mentioned residues present at the hydroxy groups, which residues are splitable by hydrolysis, preferably the oxycarbonyl residues, the loweralkanoyl residues or the benzoyl residues are used.
Besides tbe above mentioned, also double-bound residues, which are splitable at the amino group by hydrolysis are used, e.g. an alkylidene or benzylidene residue or a phosphorylidene group such as a triphenylphosphorylidene group, whereby the nitrogen atom then obtains a positive charge.
Residues splitable at the hydroxy group and the amino group by hydrolysis may furthermore be divalent residues such as substituted methylene. Any organic residue may be used as a substituent on the methylene residue, since it does not matter at the hydrolysis which compound is the substituent to the methylene residue. Possible methylene substituents are, for example, aliphatic or aromatic residues such as alkyl as mentioned above, aryl e.g. phenyl or pyridyl. The hydrolysis may be carried out in any usual way, suitably in a basic or preferably in an acid medium.
Compounds having residues splitable by hydrolysis are also compounds according to formula VII
wherein Rl, R2, R3, n and X have the meanings given above and Y is a carbonyl or thiocarbonyl residue.
The hydrolysis can be carried out in an analogous way, for example, in the presence of a hydrolysing agent, e.g. in the presence of an acidic agent such as a diluted mineral acid, e.g. sulfuric acid or hydrohalogen acid, or in the presence of a basic agent such as an alkali metal hydroxide, e.g. sodium hydroxide. Oxycarbonyl residues, aryl sulfonyl residues and cyano groups may in a suitable way be split off by means of acidic agents such as a hydrohalogen acid, suitably hydrobromic acid. Preferably the splitting takes 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 temperature, such as in boiling hydrobromic acid, according to the "bromocyano method" (v. Braun). Further, a tert.-butoxycarbonyl residue, for example, may be split off under anhydrous conditions by means of a treatment with a suitable acid, such as trifluoracetic acid. Acidic agents are preferably used for the hydrolysis of compounds of formula VI.
Residues splitable by ammonolysis are especially the halogencarbonyl residues, such as the chlorocarbonyl residue. The ammonolysis may be carried out in a usual way, e.g. by means of an amine containing at least one hydrogen atom bounded to the nitrogen atom, such as a mono- or diloweralkylamine e.g. methylamine or dimethylamine, or especially ammonia, preferably at an elevated temperature. Instead of ammonia one may use an agent which provides ammonia such as hexamethylene tetramine.
Residues splitable by means of a reduction are e.g. a-arylalkyl residues, such as a benzyl residue or a-aralkoxycarbonyl residues such as a benzyloxycarbonyl residue, whicn m a usual way may be split off by means of a hydrogenolysis, especially by catalytically activated hydrogen, such as by hydrogen in the presence of hydrogenating catalysts, e.g. Raney-nickel. Further resides splitable by means of hydrogenolysis are 2-halogenalkoxycarbonyl residues such as 2,2,2-trichloroethoxycarbonyl residues or 2iodoethoxy- or 2,2,2-tri-bromoethoxycarbonyl residues, which may be split off in a usual way, suitably by means of a metallic reduction (so called nascent hydrogen).
Nascent hydrogen may be obtained by the influence of metal or metal alloys, such as amalgam, on compounds which give hydrogen, such as carboxy acids, alcohols or water, whereby especially zinc or zinc alloys together with acetic acid may be used.
Hydrogenolysis of 2-halogenalkoxycarbonyl residues may further take place using chromium or chromium (II) compounds such as chromium (II) chloride or chromium (II) acetate.
A residue splitable by reduction may also be an arylsulfonyl group as a toluenesulfonvl group, which in a common way may be split off by reduction using nascent hydrogen, e.g. by means of an alkali metal, such as lithium or sodium in liquid ammonia, and suitably may be split off from a nitrogen atom. For carrying out the reduction, it should be ensured that other reducible groups are not influenced.
Residues splitable by means of pyrolysis, especially residues splitable from the nitrogen atom, may be substituted, but preferably unsubstituted carbamoyl groups.
Suitable substituents are e.g. lower alkyl or aryl lower alkyl such as methyl or benzyl, or aryl, such as phenyl. The pyrolysis can be carried out in a usual way, whereby one may have to take care of other thermically susceptible groups.
Residues splitable by means of fermentation, especially residues splitable from the nitrogen atom, may be substituted, but are preferably unsubstituted carbamoyl groups. Suitable substituents are e.g. lower alkyl or aryl lower alkyl, such as methyl or benzyl, or aryl such as phenyl. The fermentation may be carried out in a usual way, e.g. by means of the enzyme urease or soy bean extract at about 200C or slightly elevated temperature.
Further, a Schiff's base of formula VIII or IX
and/or a cyclic tautomer corresponding to formula IX of formula X
can be reduced, wherein R', R2, R3, n and X have the meanings given above. One or a combination of compounds of formulae IX and X may be reduced. This reduction may be carried out in a usual way, e.g. using a di-lightmetal hydride, such as sodiumborohydride or lithiumaluminiumhydride, using a hydride such as borane with formic acid, or by means of a catalytic hydrogenation, such as with hydrogen in the presence of Raney-nickel. For the reduction, it should be ensured that other groups are not affected.
Further, the oxo group in the compound of formula XI
wherein R', R2, R3, n and X have the meanings given above, can be reduced to a hydroxy group. This reduction can be carried out in a usual way, especially using a di-lightmetal hydride, as mentioned above, or according to the "Meerwein-Pendorf
Verley method" or a modification thereof, suitably using an alkanol as a reaction component and as solvent, such as isopropanol, and using a metal alkanolate, such as a metal isopropanolate, e.g. aluminium isopropanolate.
Further, in a compound of formula XII
wherein R2, R9, n and X have the meanings given above, and wherein X2 is a residue transformable to a residue Rl, the residue X2 can be transformed to Rl.
Further, the oxo group in a compound corresponding to formula I which carries an oxo group at a carbon atom bound to the nitrogen atom of the amino group may be reduced by two hydrogen atoms.
Said compounds are e.g. of the formula XIII
wherein Rl, R2, R3, n and X have the meanings given above.
The reduction can be carried out according to the above described manner using complex metal hydrides, e.g. lithiumaluminium hydride or di-isobutylaluminium hydride. Suitably the reaction takes place in an inert solvent such as an ether, e.g. diethylether or tetrahydrofuran.
In a usual way, the substituents may be varied from those in the compounds obtained within the end product; substituents may be introduced or split off or the compounds obtained transformed into other end products in a usual way.
Depending on the process conditions and the starting material, the end product is obtained either in free from or in the form of its acid addition salt, which is included in the scope of the invention. Thus, for example, basic, neutral or mixed salts may be obtained as well as hemiamino, sesqui- or polyhydrates. The acid addition salts of the new compounds may in a manner known per se be transformed into free compounds using e.g. basic agents such as alkali or ion exchangers. 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 pharmaceutically acceptable salts. Such acids are e.g. 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 pyruvic acid, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acids, halogenbenzenesulfonic, toluenesulfonic, naphthylsulphonic acids, or sulfanilic acid; methionine, tryptophane, lysine or arginine.
These or other salts of the new compounds as, e.g. picrates, may serve as purifying agents or the compounds, obtained as the free bases, are transformed 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 in the specification that, where appropriate, the corresponding salts are included in references to the free compound.
The invention also relates to any embodiment of a preparative process in which one starts from any compound obtained as an intermediate in any process step and carries out the lacking process step(s) to produce the compound of formula (I); or in which one first forms the starting material under the reaction conditions; or in which a reaction component possibly in the form of its salt is present.
Thus, one may react an aldehyde of the formula XIX
wherein R1 has the meaning given above, with an amine of the formula
wherein R2, RS, n and X have the meaning given above, in the presence of a suitable reducing agent, such as one of the above-mentioned. Thereby a compound of formula
VII can be obtained as an intermediate, which then is reduced according to the invention.
Further, one may in a manner known per se react an amine of the formula III with an aldehyde or a ketone of the formula
in the presence of a suitable reducing agent, such as one of the above mentioned to produce a compound of formula IX or X as an intermediate, which then is reduced according to the invention.
The compounds of the invention may, depending on the choice of starting materials and process, be present as optical antipodes or racemates, 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 physicalchemical differences of the component, be separated into the both stereoisomeric (diastereomeric) pure racemate e.g. by means of chromatography and/or fractionated crystallization.
The racemates obtained can be separated according to known methods, e.g. by means of recrystallization from an optically 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 diastereomers, from which the antipodes by use of a suitable agent may be set free.
Suitably usable optically active 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.
Preferably the more active part of the two antipodes is isolated.
Suitably such starting materials are used for carrying out the reactions of the invention, since these materials lead to preferred end-products, especially to the specifically described end products.
The starting materials are either known or may, if they should be new, be obtained according to processes known per se.
In clinical use, the compounds of the invention are administered normally orally, rectally or by injection in the form of a pharmaceutical preparation, which contains an active component either as free base or as pharmaceutically acceptable, non-toxic acid addition salts, e.g. the hydrochloride, lactate, acetate or sulphamate, in combination with a pharmaceutical carrier.
This discusslon of the compounds of the invention is intended to cover both the free amine base and the acid addition salts of the free base, except where the context in which such expressions are used, e.g. in the Examples, makes this inappropriate.
The carrier may be, for example, a solid, semi-solid or liquid diluent or a capsule.
These pharmaceutical preparations are a further subject of the invention. Usually the amount of active compound is from 0.1 to 99% by weight of the preparation, suitably from 0.5% to 20% by weight in preparation for injection and from 2% to 50% in preparations for oral administration.
In the preparation of pharmaceutical preparations containing a compound of the present invention in the form of dosage units for oral administration, the compound elected may be mixed with a solid, pulverulent carrier, e.g. with lactose, saccharose, sorbitol, mannitol, starch (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatine, as well as with an antifriction agent such as magnesium stearate, calcium stearate or polyethyleneglycol waxes, 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 or titanium dioxide. Furthermore, the tablets may be coated with a laquer dissolved in an easily volatile organic solvent or mixture of solvents. To this coating, a dye may be added in order easily to distinguish between tablets with different active compounds or with different 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 may be mixed with a vegetable oil. Hard gelatine
capsules may contain granules of the active compound in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, starch (e.g. potato
starch, corn starch or amylopectin), cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared in the torm of supposi
tories, which contain the active substance in a mixture with a neutral fat 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 paraffin oil.
Liquid preparations for oral administration may be in the form of syrups or
suspensions, e.g. solutions containing from 0.2% to 20% by weight of the active
substance described, whereby the residue consists of sugar and a mixture of ethanol,
water, glycerol and propylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thicken
ing agent.
Solutions for parenteral administration by injection may be prepared as an aqueous solution of a water soluble pharmaceutically acceptable salt of the active compound, preferably in a concentration from 0.5% to 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 may be carried out in accordance with the following method:
The solid substances included are ground or sieved to a certain particle 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 constant 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 reminiscent of wet snow. The moistening of the pulverulent mixture with the binding agent solution causes the particles to gather together slightly to form 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 degree of dampness of the granulate is of utmost importance for the following process and for the character 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 container having a net bottom.
After the drying step, the granules are sieved so that the required particle size wanted is obtained. Under certain circumstances powder has to be removed.
To the so-called final mixture, disintegrating, anti-friction agents and anti-adhesive agents are added. After this mixture the mass should have the right constitution 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 from the amount of active agent
in the granules. The degree of compression affects the size of the tablet, its strength
and its ability of disintegrate in water. Especially as regards the two latter properties
the choice of compression pressure (0.5 to 5 ton) must be carefully balanced. When
the right adjustment is set, the preparation of tablets is started and carried out with a rate of 20,000 to 200,000 tablets per hour. The pressing of the tablets requires different times and depends on the size of the batch.
The tablets are freed from adhering pulver and are then stored in closed packages until they are delivered.
Many tablets, especially those which are rough or bitter, are coated with a coating.
This means that these are coated with a layer of sugar or some other suitable coating.
The tablets are usually packed by machines having an electronic counting device.
Different types of packages used are glass and plastic gallipots, but boxes, tubes and specific dosage adapted packages may also be used.
The daily dose of the active substance varies and depends on the type of administration, but as a general rule it is 100 to 400 mg/day of active substa 2- (3,4-dimethoxyphenoxy) -ethylamine as starting materials. The hydrochloride melted at 1600C.
Example 6.
3- [ 2- ( 4-hydroxyphenoxy) -ethylamino] -3-o-cyanophenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropene and 2-(4-hydroxyphenoxy)-ethylamine as starting materials. The tartrate melted at 520C.
Example 7.
2(2- ( 4-hydroxyphenoxy) -ethylamino-1-o-methoxyphenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-methoxyphenoxy-propane and 2- ( 4-hydroxyphenoxy) -ethylamine as starting materials.
Example 8.
3- j ( 4-hydroxyphenoxy) -ethylamino-1 o-ethylphenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-ethylphenoxy-propane and 2-(4 hydroxypbenoxy)-ethylamine as starting materials.
Example 9.
3- [2- (4-hydroxyphenylthio) -ethylamino-1 -o-cyanophenoxy-propanol-2 was prepared in accordance with Example 1 above using 1,2-epoxy-3-o-cyanophenoxy-propane and 2-(4-hydroxyphenylthio) -ethylamine as starting materials.
Example 10.
3-[2-(4-methoxyphenoxy)-ethylamino-1-o-cyanophenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-cyanophenoxy-propane and 2-(4methoxyphenoxy)-ethylamine as starting materials. Mp. 1340C as hydrochloride.
Example 11.
3- [2- (2-hydroxyphenoxv )ethylaminoj -1-o-cyanophenoxy-propanol-2 was prepared in accordance with Example 1 using 12-epoxy-3-o-cyanophenoxypropane and 2-( 2-hydroxyphenoxy)ethylamine as starting materials. Mp 1810C as hydrochloride.
Example 12.
3 - [2 - (4 - hydroxy - 3 - methoxyphenoxy)ethylamino] - 1 - 0 - cyano- phenoxy - propanol - 2 was prepared in accordance with Example 1 using 1,2-epoxy3-o-cyanophenoxypropane and 2- (4-hydroxy-3 -methoxyphenoxy) ethylamine as starting materials. Mp. 78 C as hydrochloride.
Example 13.
3- (2- ( 3,5-dimethoxyphenoxy) ethylamino] -1-o-cyanophenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2-(3,5-dimethoxyphenoxy)ethylamine as starting materials. Mp. 1590C as hydrochloride.
Example 14.
A syrup containing 2% (weight per volume) of active substance was prepared from the following ingredients:
A compound according to the invention in the form of a
pharmaceutically acceptable acid addition salt. 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
Distilled water ad 100.0 ml
Sugar, saccharine and the ether salt were dissolved in 60 g of warm water. After cooling, glycerine and solution of flavouring agents dissolved in ethanol were added.
The mixture water was then made up to 100 ml.
Example 15.
A compound according to the invention in the form of a pharmaceutically accept
able acid addition salt (1 g), sodium chloride (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 ampoules, which were sterilized by heating at 1200C for 20 minutes.
Example 16.
10 g of o-methylphenylglycidylether in 100 ml of ethanol were saturated with gaseous ammonia and the mixture was heated in an autoclave on a boiling waterbath for 4 hours. The solvent was evaporated and the residue was dissolved in ethylacetate and HC1-gas was introduced. The hydrochloride then precipitated and it was filtered off and dissolved in 50 ml of ethanol to which 2-(4-methoxy-methoxy)-phenoxyethylchloride and 15 g of K2CG, had been added. The mixture was heated in an autoclave at 1300C for 10 hours whereupon the solvent was evaporated and the residue was treated with 100 ml of 2N HC1 for 1 h at ambient temperature. The aqueous phase was made alkaline with ammonia and extracted with ethyl acetate. The solvent phase was dried over K2CO3, whereupon 1-[2-(4-hydroxy)-phenoxy-ethylamino)-3-(o- methylphenoxy)-propanol-2- was obtained. The base obtained was converted to its hydrochloride, 1 - [2- (4-hydroxy-phenoxy-ethylamino-3- (o-methylphenoxy) -propanol-2 hydrochloride. Melting point 1500C.
Example 17.
2.4 g of Na were dissolved in 100 ml of ethanol, whereupon 10.8 g of o-methyl- phenol and then 22.9 g of 1[2-(4-methoxymethoxy)-phenoxy-ethylaminol-3-chloro- propanol-2 were added. The mixture was heated in an autoclave on a boiling water
bath for 10 hours. Thereupon it was filtered and the filtrate was evaportaed to
dryness. The residue was treated with 2N HCI for 1 h at ambient temperature and extracted with ether, whereupon the aqueous phase was made alkaline with ammonia and extracted with ether. The ether phase was dried over MgSO4 and 1-[2-(4 hydroxy) -phenoxy-ethylaminoj -3 - ( o-methylphenoxy) -propanol-2- was obtained and was converted to its hydrochloride and isolated. Melting point 1500C.
Example 18.
0.116 moles of o-methylphenol were mixed with 0.080 moles of 1-[2-(4 methoxymethoxyphenoxy)ethyl]-3-acetidinol, 0.500 moles of benzylalcohol and 0.003 moles of KOH. The mixture was refluxed while stirring for 6 hrs at 1400C and was then cooled and extracted with 2N HCI. The aqueous phase was allowed to stand for 1 h at ambient temperature, was then made alkaline, and was finally extracted with chloroform. After drying and evaporation the residue was dissolved in ether and to the solution HCI in ether was added. The hydrochloride was filtered off and was washed with acetone. The hydrochloride of 3-[2-(4-hydroxyphenoxy)ethylamino]- 1-(o-methylphenoxy)-propanol]-2 melted at 150 C.
Example 19.
In accordance with Example 16 above 1-amino-3-(o-methylphenoxy)-propanol-2 was prepared. 5 g of this compound were dissolved in 50 ml of methanol and 15 g of 4-hydroxyphenoxy-acetaldehyde were added, whereby 3-f2-(4-hydroxyphenoxy)- ethylimino] -1-o-methylphenoxy-propanol-2 was obtained. The solution was cooled
to 0 C and at this temperature 5 g of sodium borohydride were added little by little,
whereby the imino compound was reduced. The temperature was then allowed to rise
to ambient temperature and after 1 h 150 ml of H2O were added and the total
mixture was extracted with ether. The ether phase was dried over MgS04 and was
evaporated. The residue was transformed into its hydrochloride. In this way 3-[2- (4-hydroxyphenoxy)-ethylamino] 1 (o-methylphenoxy)-propanol-2 . HCI was ob- tained. Melting point 1500C.
Example 20.
1.0 g of 3-o-methylphenoxy-1-[2-(4-hydroxyphenoxy)-ethylaminol-propanone-2 was dissolved in 25 mls of methanol and the solution was cooled to 0 C on an ice
bath. 0.25 g of NaBH4 were added little by little while stirring first at 0 C for 1 h
and then at ambient temperature for 0.5 h. The solution thus obtained was evaporated
whereupon 50 ml of HSO were added. The aqueous phase was extracted 3 times with
50 ml chloroform, the collected chloroform phase was dried and evaporated. The
hydrochloride was precipitated from an ether solution of the residue by adding ether
containing HCl. Recrystallization was made from acetone. The hydrochloride of
3- F2- (4-hydroxyphenoxy) -ethylamino] -1 - ( o-methylphenoxy) propanol-2 melted at 1500C.
Biological Effects.
The ,ss-receptor blocking agents of the present invention were tested as regards their biological properties. All compounds were thereby tested in anaesthetized cats (males and females weighing 2.5-3.5 kg) pretreated with reserpine (5 mg/kg bodyweight administered intramuscularly) about 16 hours before 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 nentobarbitol (30 mg/kg bodyweight administered i.p.) and artificially ventilated with room air. A bilateral vagotomy was performed in the neck. Blood pressure was obtained from a cannulated carotid artery and heart rate was registered from a cardiotachometer, triggered by the electrocardiogram (ECG). Intrinsic beta mimetic activity on the heart was seen as increased heart rate after drug administration. The test compounds were given intravenously in logarithmically increasing doses. The values obtained were plotted on dose-response curves, from which affinity values (ED50) were estimated. At the end of each experiment 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 lie quietly and to remain quiet when lifted to an erect position by placing their forelegs on a table for 2 minutes. Arterial blood pressure was registered via a blood oressure transducer attached to the dog at the heart level. Heart rate was triggered from the ECG. All dogs were pretreated with methylscopolamine 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 witb 2 hours intervals. pA2 was also measured on rats. pA2 is -log of the concentration of an antagonist which leads to the fact that the dose of noradrenaline has to be doubled in order to obtain the same effect of noradrenaline as one obtains without the antagonist or pA2 = log (dr-1)-log (antagonist) ED=o of noradrenaline (antagonist)
wherein dr is dose ratio = ED50 of noradrenaline (control) and all concentrations are given in mol/l. pA2 is thus a measure of a-receptor effect where higher pA2 higher a-effect.
The experiments demonstrate that the compounds tested are potent s-receptor antagonists being cardioselective and with or without intrinsic ,ss-mimetic activity. The compounds also decrease blood pressure in conscious dogs significantly. The pronounced hypotensive effect in conscious dogs of the new compounds depends on a vasodilating effect in combination with cardiac beta-receptor blockade. Results obtained in above given tests are given in Table I below.
TABLE I
Reserpinized Cat ss-blockade of ss-blockade of isoprenaline isoprenaline Intrinsic activity heart rate peripheral resistance
R1 R2/R3 ED50 mol/kg ED50 mol/kg # beats/min % of isoprenaline pA2 -CN 4-OCH3 0.22 2.7 7 7 6.4 -OCH2CONHCH2CH2OCH3 4-OH 0.05 1.8 0 0 5.5 -CN 2-OH 1.7 17 35 39 6.5 -CN 3-OCH3, 4-OH 0.3 3.4 17 27 6.8 -CN 3,5-diOCH3 2.9 11 15 17 6.5 -CH3 3,4-diOCH3 1.5 5.8 8 11 6.0 -CH3 2-OCH3 4.5 11 8 8 7.0 -CH3 4-OCH3 0.5 8.2 17 22 5.8 -CN 4-OH 0.08 5.5 13 15 6.3 -CH3 2-OH 0.6 17 30 29 6.0
Claims (47)
- WHAT WE CLAIM IS:1. A compound of the formulawherein R' is methyl, ethyl, propyl, methoxy, cyano, cyanomethyl, hydroxymethyl or CH,0CH2CH2NHCOCH2O-, R2 and R3 are the same or different and each is hydrogen, hydroxy, methoxy or hydroxymethyl provided that R2 and R3 are not both hydrogen, n is 2, and X is -0- or -S-.
- 2. A compound according to claim 1 wherein Rl is methyl, ethyl, propyl, methoxy or hydroxymethyl.
- 3. A compound according to claim 1 wherein R1 is cyano or cyanomethyl.
- 4. 3 - [2 - (4 - Hydroxyphenoxy) - ethylamino] - 1 - o - methylphenoxy- propanol - 2.
- 5. 3 - [2 - (4 - Hydroxyphenoxy) - ethylamino] - 1 - o ethylphenoxy - propanol2.
- 6. 3 - [2 - (4 - Hydroxyphenoxy) - ethylamino] - 1 - o - propylphenoxypropanol - 2.
- 7. 3 - [2 - (4 - Hydroxyphenoxy) - ethylamino] - 1 - o - cyanophenoxypropanol - 2.
- 8. 3 - [2 - (4 - Hydroxyphenoxy) - ethylamino - 1- o - cyanomethyiphenoxy- propanol - 2.
- 9. 3 - [2 (4 - Hydroxyphenoxy) - ethylamino] - 1 - o - hydroxymethylphenoxypropanol - 2.
- 10. 3 - [2 - (4 - Hydroxyphenylthio) - ethylamino] - 1 - o - cyanophenoxypropanol - 2.
- 11. 3 - [2 - 4 - Hydroxyphenylthio) - ethylamino] - 1 - o - methylphenoxypropanol - 2.
- 12. 3 - [2 - (3 - Methoxy - 4 - hydroxyphenoxy) - ethylamino] - 1 - o- methylphenoxy - propanol - 2.
- 13. 3 - [2 - (3 - Hydroxymethyl - 4 - hydroxyphenoxy) - ethylamino] - 1 - ocyanophenoxy- propanol - 2.
- 14. 3 - [2 - (3,4 - Dihydroxyphenylthio) - ethylamino] - 1 - o - cyanophenoxy- propanol - 2.
- 15. 3 - [2 - (4 - Methoxyphenoxy) - ethylamino] - 1 - o - cyanophenoxypropanol- 2.
- 16. 3 - [2 - (2 Hydroxyphenoxy) - ethylamino] - 1 - o - cyanophenoxypropanol - 2.
- 17. 3 - [2 - (4 - Hydroxy - 3 - methoxyphenoxy) - ethylamino] - 1 - o - cyanophenoxy - propanol - 2.
- 18. 3 - [2 - (3,5 - Dimethoxyphenoxy) - ethylamino] - 1 - o - cyanophenoxypropanol - 2.
- 19. 3 - [2 -(4 - Hydroxyphenoxy) - ethylamino] - 1 - o - (2 - methoxyethyl)aminocarbonylmethoxvphenoxy - propanol - 2.
- 20. A compound according to any one of claims 1 to 19 in the form of a dextrorotating optical antipode.
- 21. A compound according to any one of claims 1 to 19 in the form of a levorotating optical antipode.
- 22. A compound according to any one of claims 1 to 21 in the form of the free base.
- 23. A compound according to any one of claims 1 to 21 in the form of a salt.
- 24. A compound according to any one of claims 1 to 21 in the form of a pharmaceutically acceptable salt.
- 25. A process for preparing a compound as defined in claim 1 wherein a compound of formula IIwherein R' is as defined in claim 1, Xl is a hydroxy roup and Z is a reactive, esterified hydroxy group, or X' and Z together form an epoxy group, is reacted with an amine of the formulawherein R2, Rt, n and X are as defined in claim 1.
- 26. A process for preparing a compound as defined in claim 1 wherein a compound of formula IIIwherein R' is as defined in claim 1, is reacted with a compound of the formulawherein R2, RS, n and X are as defined in claim 1 and Z is as defined in claim 25.
- 27. A process for preparing a compound as defined in claim 1 wherein a compound of formula IVwherein Rl is as defined in claim 1, is reacted with a compound of formula Vwherein R2, RS, n and X are as defined in claim 1 and Z and Xl are as defined in claim 25.
- 28. A process for preparing a compound as defined in claim 1 wherein a compound of the formula IVwherein Rl is as defined in claim 1, is reacted with a compound of formula VIwherein R2, RS, n and X are as defined in claim 1.
- 29. A process for preparing a compound as defined in claim 1 which comprises removing the protecting groups from a reactant which is a protected derivative of a compound of formula I in which the nitrogen atom of the amino group and/or the hydroxy group is protected.
- 30. A process for preparing a compound as defined in claim 1 which comprises reducing a Schiff's base of formula VIII or IXand/or a cyclic tautomer thereof of formula Xwherein R2, R2, Rs, n and X are as defined in claim 1.
- 31. A process for preparing a compound as defined in claim 1 wherein the oxo group is reduced to a hydroxy group in a compound of formula XIwherein R', R2, RS, n and X are as defined in claim 1.
- 32. A process for preparing a compound as defined in claim 1 which comprises reacting a compound of formula XIIwherein R2, RS, n and X are as defined in claim 1 and X2 is a residue transformable into R1 as defined in claim 1 to transform X2 into R'.
- 33. A process for preparing a compound as defined in claim 1 which comprises reacting a compound of formula Vawherein R1 and n are as defined in claim 1 and 2 is as defined in claim 25 with a compound of formula IVawherein R2, Rs and X are as defined in claim 1.
- 34. A process for preparing a compound as defined in claim 1, which comprises reducing to a methylene group the oxo group in a derivative of a compound of formula I having an oxo group at a carbon atom bound to the nitrogen atom of the amino group.
- 35. A process according to any one of claims 25 to 34, wherein the compound is obtained in the form of a free base and the free base is converted into a pharmaceutically acceptable acid addition salt by reaction with a pharmaceutically acceptable acid.
- 36. A process according to any one of claims 25 to 34, wherein the compound is obtained in the form of an acid addition salt and this salt is converted to the free base.
- 37. A process according to any one of claims 25 to 36, wherein the compound is obtained in the form of an isomer mixture and the mixture is resolved to isolate an optical antipode.
- 38. A process according to any one of claims 25 to 37 wherein a compound according to any one of claims 2 to 24 is prepared.
- 39. A process according to any one of claims 25 to 38 substantially as hereinbefore described with reference to any one of Examples 1 to 13 and 16 to 20.
- 40. A compound as claimed in any one of claims 1 to 24 obtained by a process according to any one of claims 25 to 39.
- 41. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 24 or 40 together with a pharmaceutically acceptable carrier.
- 42. A preparation according to claim 41 wherein the compound comprises 0.1 to 95% by weight of the preparation.
- 43. A preparation according to claim 41 in a form suitable for administration by injection wherein the compound comprises 0.5% to 20% by weight of the preparation.
- 44. A preparation according to claim 43, for parenteral application which comprises an aqueous solution of a water soluble salt of the compound in an amount of 0.5% to 10% by weight of the preparation.
- 45. A preparation according to claim 41 in a form suitable for oral adminis tration wherein the compound comprises 2% to 50% by weight of the preparation.
- 46. A preparation according to claim 41 substantially as hereinbefore described with reference to Example 14 or 15.
- 47. A method of blocking the ,ss-receptors of the heart of a mammal excluding man which comprises administering to the mammal a compound according to any one of claims 1 to 24 or 40 or a preparation according to any one of claims 41 to 46.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE7611125A SE416545B (en) | 1976-10-07 | 1976-10-07 | PROCEDURE FOR THE PREPARATION OF NEW HEART-ACTIVE 1-FRNOXI-3-AMINOPROPAN-2-OL-DERIVATIVES |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1589838A true GB1589838A (en) | 1981-05-20 |
Family
ID=20329066
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB41699/77A Expired GB1589838A (en) | 1976-10-07 | 1977-10-06 | 1-phenoxy-3-amino-propan-2-ols |
Country Status (22)
Country | Link |
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JP (1) | JPS5346928A (en) |
AT (1) | AT351509B (en) |
AU (1) | AU516727B2 (en) |
BE (1) | BE859474A (en) |
CA (1) | CA1093096A (en) |
CH (1) | CH636337A5 (en) |
CS (5) | CS208732B2 (en) |
DD (1) | DD132195A5 (en) |
DE (1) | DE2743493A1 (en) |
DK (1) | DK145375C (en) |
FI (1) | FI772936A (en) |
FR (1) | FR2367054A1 (en) |
GB (1) | GB1589838A (en) |
HU (1) | HU177638B (en) |
IE (1) | IE45938B1 (en) |
LU (1) | LU78263A1 (en) |
NL (1) | NL7710941A (en) |
NO (1) | NO145436C (en) |
NZ (1) | NZ185318A (en) |
SE (1) | SE416545B (en) |
SU (3) | SU735166A3 (en) |
ZA (1) | ZA775603B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0210849A1 (en) * | 1985-07-30 | 1987-02-04 | Imperial Chemical Industries Plc | 2-Hydroxy-3-phenoxypropyl amines |
US5187190A (en) * | 1989-11-06 | 1993-02-16 | Imperial Chemical Industries Plc | Phenoxypropanolamine compounds |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DD150456A5 (en) * | 1979-03-01 | 1981-09-02 | Ciba Geigy Ag | PROCESS FOR THE PREPARATION OF DERIVATIVES OF 3-AMINO-1,2-PROPANDIOL |
JPH0627370B2 (en) * | 1985-08-23 | 1994-04-13 | 日本エステル株式会社 | Polyester irregular cross-section thick and thin yarn |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE590054A (en) * | 1959-04-22 | 1960-10-24 | Pfizer | Alkylamines and their preparation. |
GB1264128A (en) * | 1968-06-29 | 1972-02-16 | ||
GB1433920A (en) * | 1973-10-01 | 1976-04-28 | Ici Ltd | Alkanolamine derivatives |
-
1976
- 1976-10-07 SE SE7611125A patent/SE416545B/en unknown
-
1977
- 1977-09-19 ZA ZA00775603A patent/ZA775603B/en unknown
- 1977-09-28 DE DE19772743493 patent/DE2743493A1/en not_active Withdrawn
- 1977-10-03 AT AT702177A patent/AT351509B/en not_active IP Right Cessation
- 1977-10-03 NZ NZ185318A patent/NZ185318A/en unknown
- 1977-10-04 AU AU29300/77A patent/AU516727B2/en not_active Expired
- 1977-10-05 FI FI772936A patent/FI772936A/en not_active Application Discontinuation
- 1977-10-05 DD DD7700201371A patent/DD132195A5/en unknown
- 1977-10-05 HU HU77HE752A patent/HU177638B/en unknown
- 1977-10-05 NL NL7710941A patent/NL7710941A/en not_active Application Discontinuation
- 1977-10-06 CS CS776486A patent/CS208732B2/en unknown
- 1977-10-06 CS CS776486A patent/CS208733B2/en unknown
- 1977-10-06 DK DK443177A patent/DK145375C/en active
- 1977-10-06 GB GB41699/77A patent/GB1589838A/en not_active Expired
- 1977-10-06 CA CA288,290A patent/CA1093096A/en not_active Expired
- 1977-10-06 CS CS776486A patent/CS208730B2/en unknown
- 1977-10-06 FR FR7730156A patent/FR2367054A1/en active Granted
- 1977-10-06 CS CS776486A patent/CS208731B2/en unknown
- 1977-10-06 NO NO773406A patent/NO145436C/en unknown
- 1977-10-06 IE IE2046/77A patent/IE45938B1/en unknown
- 1977-10-06 CS CS776486A patent/CS208734B2/en unknown
- 1977-10-06 SU SU772528198A patent/SU735166A3/en active
- 1977-10-06 LU LU78263A patent/LU78263A1/xx unknown
- 1977-10-07 BE BE181531A patent/BE859474A/en unknown
- 1977-10-07 JP JP12133477A patent/JPS5346928A/en active Pending
- 1977-10-07 CH CH1230577A patent/CH636337A5/en not_active IP Right Cessation
-
1978
- 1978-07-28 SU SU782640402A patent/SU784760A3/en active
- 1978-07-28 SU SU782641105A patent/SU959623A3/en active
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0210849A1 (en) * | 1985-07-30 | 1987-02-04 | Imperial Chemical Industries Plc | 2-Hydroxy-3-phenoxypropyl amines |
US4772631A (en) * | 1985-07-30 | 1988-09-20 | Imperial Chemical Industries Plc | Phenyl ethers |
US5187190A (en) * | 1989-11-06 | 1993-02-16 | Imperial Chemical Industries Plc | Phenoxypropanolamine compounds |
Also Published As
Publication number | Publication date |
---|---|
CS208731B2 (en) | 1981-09-15 |
LU78263A1 (en) | 1978-06-09 |
IE45938L (en) | 1978-04-07 |
FR2367054B1 (en) | 1981-11-06 |
SE7611125L (en) | 1978-04-08 |
SU735166A3 (en) | 1980-05-15 |
CS208733B2 (en) | 1981-09-15 |
HU177638B (en) | 1981-11-28 |
AT351509B (en) | 1979-07-25 |
DD132195A5 (en) | 1978-09-06 |
CS208732B2 (en) | 1981-09-15 |
NL7710941A (en) | 1978-04-11 |
SU784760A3 (en) | 1980-11-30 |
NO773406L (en) | 1978-04-10 |
DK443177A (en) | 1978-04-08 |
DK145375B (en) | 1982-11-08 |
CH636337A5 (en) | 1983-05-31 |
CA1093096A (en) | 1981-01-06 |
DK145375C (en) | 1983-04-11 |
CS208730B2 (en) | 1981-09-15 |
NO145436C (en) | 1982-03-24 |
CS208734B2 (en) | 1981-09-15 |
BE859474A (en) | 1978-04-07 |
ATA702177A (en) | 1979-01-15 |
IE45938B1 (en) | 1983-01-12 |
AU2930077A (en) | 1979-04-12 |
ZA775603B (en) | 1978-06-28 |
SE416545B (en) | 1981-01-19 |
JPS5346928A (en) | 1978-04-27 |
FR2367054A1 (en) | 1978-05-05 |
NZ185318A (en) | 1980-02-21 |
DE2743493A1 (en) | 1978-04-13 |
NO145436B (en) | 1981-12-14 |
FI772936A (en) | 1978-04-08 |
SU959623A3 (en) | 1982-09-15 |
AU516727B2 (en) | 1981-06-18 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed [section 19, patents act 1949] | ||
PCNP | Patent ceased through non-payment of renewal fee |