Polar-substituted Propanolamines As Anti-angina And Anti-hypertensive Agents

Abstract

Novel propanolamine derivatives, especially 3-phenoxy-1-phenoxyalkylamino-2-propanols, useful in the treatment of hypertension and cardiac conditions, such as angina pectoris and cardiac arrhythmias.

Parent Case Text

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. Ser. Number 877,006, filed on Nov. 14, 1969 under Group 126, and now abandoned.

Description

BACKGROUND OF THE INVENTION

This invention relates to novel propanolamine derivatives, which have useful therapeutic properties in the field of medicinal chemistry, and is particularly concerned with 3-phenoxy-1-phenoxyalkylamino-2-propanols, in which the phenyl group of the 1-substituent carries an electron-withdrawing polar substituent, and analagous compounds in which one or other of the phenyl groups is replaced by a naphthyl group. More particularly the compounds of the invention are useful in the curative or prophylactic treatment of cardiac conditions, such as angina pectoris and cardiac arrhythmias, and in the treatment of hypertension. Angina pectoris and cardiac arrhythmias (irregular heart beat) are due to interference with the blood supply to the heart muscle. In the past, drugs have been sought which would improve the blood supply and most work has concentrated on attempts to dilate the coronary arteries. More recently, efforts have been made to find drugs which will block the .beta.-adrenergic receptors in heart muscle and thus prevent over stimulation of the heart.

The heart muscle is directly influenced by nervous system stimuli substances or catecholamines (e.g. adrenaline, non-adrenaline, and isoprenaline) which affect body organs such as the heart by attaching themselves to "receptors" which are specialized areas of the cell membranes. Particularly, the .beta.-adrenergic receptors are concerned in the stimulation of heart muscle, and the compounds of this invention exhibit a tendency to block .beta.-adrenergic receptors and reduce the effect of the nervous system catecholamines on the heart.

SUMMARY OF THE INVENTION

The compounds of the invention are those having the general formula:

where:

R.sup.1 represents hydrogen, halogen or a lower alkyl, lower alkoxy, phenyl, or phenyl-substituted lower alkyl group;

R.sup.2 and R.sup.7 each represent hydrogen, halogen or a lower alkyl or alkoxy group;

R.sup.3 represents carboxy, lower alkoxycarbonyl, formyl, lower alkanoyl, sulfo, sulfino, lower alkoxysulfonyl, lower alkoxysulfinyl, cyano, azido, nitro, trifluoromethyl, CONR.sup.9 R.sup.10, SO.sub.2 NR.sup.9 R.sup.10, CONHNR.sup.9 R.sup.10, and SO.sub.2 NHNR.sup.9 R.sup.10, where R.sup.9 and R.sup.10 are each hydrogen, lower alkyl, or phenyl, or taken together with the nitrogen atom to which they are attached complete a heterocyclic group, e.g. a pyrrolidino, piperidino, piperazino, or morpholino group;

R.sup.4 and R.sup.5 each represent hydrogen or a lower alkyl group;

R.sup.6 represents hydrogen or a lower alkyl, lower alkanoyl or benzyl group;

rings A and B may each be phenyl or naphthyl;

X represents oxygen or sulfur;

Y represents oxygen, sulfur, or a sulfinyl, sulfonyl, or N(R.sup.11) wherein R.sup.11 represents hydrogen or lower alkyl;

m is 0 or 1;

n is 1, 2, or 3 when m is 1; n is 0, 1, 2, 3, or 4 when m is 0;

and K is 0, 1, or 2;

the carboxylic acid esters and aldehyde condensation products of such compounds, and their pharmaceutically acceptable acid addition salts.

The novel compounds of the invention are useful as anti-angina and anti-hypertensive agents in mammals. Particularly effective compounds are those belonging to the class of 3-phenoxy-1-phenoxyalkylamino-2-propanols. Even more particularly effective are the compounds of the class previously mentioned in which the polar substituent is a carbamoyl group.

DETAILED DESCRIPTION OF THE INVENTION

In this specification "halogen" comprises fluorine, chlorine, bromine and iodine; and the term "lower," used to qualify an alkyl (R), alkoxy (OR), or alkanoyl (RCO) group, indicates that within such group R contains up to 4 carbon atoms.

The aldehyde condensation products of the compounds of the invention are oxazolidines, having the formula: ##SPC1##

which are formed by condensation of compounds of the invention in which R.sup.6 is hydrogen with an aldehyde of the formula R.sup.8 CHO, where R.sup.8 is hydrogen or a lower alkyl group.

The compounds of the invention, which includes optically-active isomers, have the property of blocking the .beta.-adrenergic receptors and are useful in the curative or prophylactic treatment of cardiac conditions, such as angina pectoris and cardiac arrhythmias, and in the treatment of hypertension. Particularly effective compounds of the invention are those of the class of 3-phenoxy-1-phenoxyalkylamino-2-propanols. More particularly are those in which the polar substituent is a carbamoyl group such as, 1-[2-(4-carbamoylphenoxy)ethylamino]-3-(2-methylphenoxy)propan-2-ol; 1-[2-(4-carbamoylphenoxy)ethylamino]-3-(2-methoxyphenoxy)propan-2-ol; 1-[2-(2-carbamoyl-4-methylphenoxy)ethylamino]-3-(2-methylphenoxy) propan-2-ol; 1-[2-(2-carbamoyl-4-methylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy )propan-2-ol; 1-[2-(2-carbamoyl-4-methoxyphenoxy)-1-methyl-ethylamino]-3-(2-methylphenox y)propan-2-ol; 1-[2-(2-carbamoyl-6-methylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy )propan-2-ol; 1-[2-(4-carbamoylphenoxy)-1-methylethylamino]-3-(2-phenylphenoxy)propan-2- ol; and 1-[2-(4-methoxycarbonyl-2,6-dimethylphenoxy)-1-methyl-ethylamino]-3-(2-met hylphenoxy)propan-2-ol.

Electron-withdrawing polar substituents are those which contain a polar group with its electropositive atom either adjacent to the phenyl or naphthyl ring or separated from the phenyl or naphthyl ring by a methylene or ethylene group. Such polar groups include carbonyl, sulfonyl, sulfinyl, cyano, azido, nitro, trihalomethyl groups.

Thus R.sup.3 in the above formula may be carboxy, lower alkoxycarbonyl, formyl, lower alkanoyl, substituted carbamoyl, N-amino-carbamoyl, sulfo, sulfino, alkoxysulfonyl, alkoxysulfinyl, substituted sulfamoyl, N-amino-sulfamoyl, cyano, azido, nitro, or trifluoromethyl group. This, of course, does not exclude other electron-withdrawing polar substituents which are contemplated by this invention.

Substituted carbamoyl and sulfamoyl groups and their N-amino derivatives are those having the formulas --CO. NR.sup.9 R.sup.10, --SO.sub.2. NR.sup.9 R.sup.10, --CO.NHNR.sup.9 R.sup.10, and --SO.sub.2 NHNR.sup.9 R.sup.10, respectively, where R.sup.9 and R.sup.10 are each hydrogen or a lower alkyl or a phenyl group, or together with the nitrogen atom to which they are attached complete a hetero-cyclic group, e.g. a pyrrolidino, piperidino, piperazino or morpholino group.

The compounds of the invention may be prepared in a number of ways: (1) A compound of the formula

where Z is halogen or any other suitable "leaving" group, e.g. a sulfonyloxy group such as C.sub.6 H.sub.5.SO.sub.2.O-- or p--CH.sub.3.C.sub.6 H.sub.4.SO.sub.2.0-, may be reacted with an amine of the formula

where R.sup.6 is hydrogen, lower alkyl, or benzyl, by heating, either in the presence of excess amine and a suitable solvent, e.g. methanol, or in equimolar proportions in the presence of an alkali such as sodium bicarbonate. After filtration and evaporation to dryness the product is recovered by distillation in vacuo or by dissolving in a suitable solvent and precipitating as a suitable salt, e.g. the hydrochloride, maleate, fumarate or oxalate, by addition of the appropriate acid. (2) An amine of the formula

where R.sup.6 is hydrogen, lower alkyl, or benzyl, may be reacted with a compound of the formula

and the product recovered, the conditions for reaction and recovery being similar to those given for method (1). (3) An epoxy compound of the formula

may be reacted with an amine of the formula

where R.sup.6 is hydrogen, lower alkyl, or benzyl, in equimolar proportions at ambient temperature, and the product recovered as in methods (1) and (2). (4) An amine of the formula

may be reacted with an aldehyde or ketone of the formula

to give the corresponding Schiff's base, which is reduced in the presence of a catalyst, e.g. platinum, to a compound of the invention in which R.sup.5 and R.sup.6 are each hydrogen. This method is preferred where R.sup.4 is lower alkyl.

The aldehyde condensation products of the compounds of the invention may be prepared by reacting a compound of the invention in which R.sup.6 is hydrogen with an aldehyde of the formula R.sup.8 CHO, where R.sup.8 is lower alkyl, in a diluent or solvent, e.g. ethanol, preferably in the presence of an acid catalyst, e.g. hydrochloric or acetic acid, and preferably at an elevated temperature. The water formed in the reaction may be removed by azeotropic distillation by means of an entraining solvent, e.g. benzene, or by a dehydrating agent such as anhydrous potassium carbonate.

Esters of compounds of the invention, and compounds in which R.sup.6 is lower alkanoyl, may be formed by acylation of the free hydroxyl group or the secondary amino group, respectively, in a conventional manner with a carboxylic acid chloride or anhydride derived from a saturated or unsaturated aliphatic acid or from an aromatic acid (e.g. acetic anhydride or benzoyl chloride) for the esters, or with a lower alkanoic acid chloride or anhydride for introduction of R.sup.6.

The compounds of the invention exist in D- and L-opticallyactive isomeric forms and the invention includes these forms as well as the racemic mixtures. Methods of preparation (1), (2) and (4) described previously may be used to prepare opticallyactive isomers by using the appropriate substituted 2-propanol enantiomer as starting material, whereas method (3) will result in the production of racemic mixtures. Alternatively, the racemic product of any of the above methods may be resolved by well known techniques, e.g. by fractional crystallization of an addition salt formed with an optically active acid.

Compounds of the invention in which R.sup.4 is not the same as R.sup.5 have two asymmetric centers and exist as two racemic pairs of diastereoisomers. In general, the products of each of the methods (1) to (4) described above, when R.sup.4 is not the same as R.sup.5, will be a mixture of the two pairs of steroisomers, and these pairs may usually be separated from each other by physical methods, e.g. by fractional crystallization or chromatography of the free bases or suitable salts, as shown in Examples XIII and XLVII . The invention includes the separated pairs, as well as mixtures thereof, as racemic mixtures or as separated D- and L- forms.

Acids from which pharmaceutically acceptable addition salts of the compounds of the invention can be prepared are those which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate and p-toluene sulfonate salts.

The compounds of the invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally, preferentially in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally, for example, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic.

The starting materials necessary for the above reaction methods leading to the desired compounds are either all known compounds or else they can easily be prepared by those skilled in the art in accordance with standard organic procedures.

Among these compounds, a preferred class of compounds has been found to be those in which R.sup.4 is hydrogen or a methyl group, R.sup.5 is hydrogen, Y is oxygen and n is 1. More particularly, there are preferred those compounds in which R.sup.2 is hydrogen, methyl, methoxy (R.sup.7 being hydrogen or methoxy when R.sup.2 is methoxy) or chloro, R.sup.3 is an unsubstituted carbamoyl group, and K is 0 or 1. Preferably, the unsubstituted carbamoyl group is attached to a phenyl ring in the 2-position or the 4-position, and when it is in the 2-position then preferably R.sup.2 is methyl or methoxy in the 4-, 5-, or 6-position.

Compounds of the invention may be prepared in a number of ways as described previously, but the preferred method for preparation of compounds in which R.sup.4 is lower alkyl and R.sup.5 is hydrogen is that in which an amine of the formula

is reacted with a ketone of the formula

to give the corresponding Schiff's base, which is reduced with hydrogen in the presence of a catalyst, e.g. platinum, or with sodium borohydride, to a compound of the invention in which R.sup.5 and R.sup.6 are each hydrogen.

The invention is illustrated by the following Examples in which temperatures are given as .degree.C.

EXAMPLE I

2-(2-Bromoethoxy)benzamide (12.2g.), DL-1-amino-3-(2-methylphenoxy)propan-2-ol (9 g.), sodium bicarbonate (4.2 g.) and ethanol (100 ml.) were refluxed together for 16 hr. The mixture was cooled, filtered and evaporated in vacuo to give a semi-solid residue. The residue was stirred with benzene (60 ml.) and the insoluble material was removed by filtration. Evaporation of the benzene liquors gave a gum which was redissolved in ethanol and converted to an oxalate by treatment with ethereal oxalic acid solution. The oxalate was recrystallized from aqueous ethanol as white needles m.p. 121.degree.C. Basification of the oxalate gave the free base of DL-1-[2-(2-carbamoylphenoxy)ethylamino]-3-(2-methylphenoxy)propan-2-ol (2 g.) as a white solid, m.p. 105.5.degree.-106.degree.C.

Analysis found: C, 66.4; H, 6.9; N, 8.0%

Calc'd for: C.sub.19 H.sub.24 N.sub.2 O.sub.4 : C, 66.25; H, 7.0; N, 8.1%

EXAMPLE II

2-(3-Chloropropoxy)benzamide (19.4 g.), DL-1-amino-3-(2-methylphenoxy)propan-2-ol (16.4 g.), sodium bicarbonate (11.4 g.) and ethanol (200 ml.) were refluxed together for 16 hr. The mixture was cooled and filtered to remove inorganic material. The ethanolic liquors were evaporated in vacuo to give the crude product as a sticky solid (35.5 g.). Recrystallization from ethanol gave two crops which differed in physical properties. The second crop (10.3 g.) was recrystallized from isopropanol to give DL-1-[3-(2-carbamoyl-phenoxy)propylamino]-3-(2-methylphenoxy)propan-2-ol as a white crystalline solid (8 g.) m.p. 117.degree.-118.degree.C.

Analysis - found: C, 66.95; H, 7.5; N, 7.7%

Calc'd for C.sub.20 H.sub.26 N.sub.2 O.sub.4 : C, 67.0; H, 7.3; N, 7.8%

EXAMPLE III

A mixture of 2-carbamoyl-phenoxy-acetone (19 g.) DL-1-amino-3-(2-methylphenoxy)propan-2-ol (18.1g.) and ethanol (250 ml.) was treated with platinum oxide (100 mg.) and hydrogenated at a pressure of 60 p.s.i. and 50.degree.C. for 12 hours. The catalyst was removed by filtration followed by evaporation to dryness in vacuo. The oily residue was converted to the oxalate and dissolved in a boiling mixture of ethanol and water. On cooling, the oxalate of unchanged starting material was deposited and removed by filtration. The ethanolic liquors were evaporated to dryness and basified with sodium carbonate to give DL-1-[2-(2-carbamoylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)propa n2-ol as the free base, which after extraction into chloroform, followed by drying and evaporation, was obtained as an oily solid. Recrystallization from ethyl acetate gave the product as a white solid (2 g.) m.p. 131.degree.-4.degree.C.

Analysis - found: C, 67.4; H, 7.55; N, 7.6%

Calc'd for C.sub.20 H.sub.26 N.sub.2 O.sub.4 : C, 67.0; H, 7.3; N, 7.8%

EXAMPLE IV

1-(2-Methylphenoxy)-2:3 -epoxypropane (6 g.) and N-(4-ethoxycarbonylphenyl)ethylene diamine (5 g.) were heated together in ethanol (20 ml.) for 2 hrs., followed by standing at room temperature for 16 hours. The ethanol was evaporated in vacuo and the residue was dissolved in ether. The oxalate was precipitated by the addition of ethereal oxalic acid and after two recrystallizations (ethanolwater) DL-N-(4-ethoxycarbonylphenyl)-N'-[3-(2-methylphenoxy)-2-hydroxypropyl] ethylenediamine oxalate was obtained as a white crystalline solid (2.2 g.) m.p. 161.5.degree.-162.5.degree.C.

Analysis - found: C, 59.9; H, 6.5; N, 6.0

Calc'd for C.sub.23 H.sub.30 N.sub.2 O.sub.8 : C, 59.7; H, 6.5; N, 6.1%

EXAMPLE V

1-(4-Dimethylsulfamoylphenoxy)-2-bromethane (6 g.), DL-3-(2-methylphenoxy)-1-aminopropan-2-ol (5 g.) and sodium bicarbonate (1.6 g.) were refluxed together in absolute ethanol (100 ml.) for 16 hours. After cooling the mixture was filtered and evaporated to dryness in vacuo. The residue was dissolved in ether and converted to the oxalate by treatment with ethereal oxalic acid solution. The oxalate was recrystallized from water and DL-1-[2-(4-dimethylsulfamoylphenoxy)ethylamino]-3-(2-methylphenoxy)propan- 2-ol oxalate was obtained as a white crystalline solid (1.6 g.) m.p. 182.degree.-183.5.degree.C.

Analysis - found: C, 52.3; H, 5.9; N, 5.75; S, 6.5%

Calc'd for C.sub.22 H.sub.30 N.sub.2 O.sub.9 S: C, 53.0; H, 6.1; N, 5.6; S, 6.4%

The following compounds were prepared by the methods of Examples I or II, from the appropriate (halo-alkoxy) benzene derivative and DL-1-amino-3-phenoxy-propan-2-ol derivative, as indicated: ##SPC2##

The products, isolated as the free base in each case unless otherwise stated, were characterized as follows, calculated analytical figures being given in brackets below the found values in each case:

Analysis % Example m.pt. C H N __________________________________________________________________________ VI 100-102.degree. 62.38 6.35 7.92 (62.41 6.46 8.09) 157-159.degree. 66.2 7.0 7.8 (66.25 7.0 8.1) VIII 103-104.degree. 66.7 7.3 7.8 (67.0 7.3 7.8) IX 187-190.degree. 57.1 6.3 6.2 (oxalate) (56.9 6.1 6.0) X(A) 178-181.degree. 58.9 6.6 6.5 (oxalate) (58.9 6.3 6.3) X(B) 129-130.degree. 66.7 7.4 7.7 (67.0 7.3 7.8) X(C) 108-110.degree. 64.0 6.6 7.4 (64.2 7.0 7.5) X(D) 115-118.degree. 66.9 7.1 7.9 (67.0 7.3 7.8) X(E) 234-238.degree. 54.2 5.6 7.1 (hydrochloride) (53.9 5.5 7.0) X(F) 138-9.degree. 71.1 6.7 6.5 (71.4 6.7 6.7) X(G) 118-119.degree. 66.7 7.2 7.6 (67.0 7.3 7.8) X(H) 191-195.degree. 59.8 6.4 6.9 (hydrochloride) (59.9 6.6 7.4) X(I) 155-156.degree. 62.0 6.9 6.6 (62.4 7.0 6.9) X(J) 96-98.degree. 67.1 7.4 7.7 67.0 7.3 7.8) X(K) 124-127.degree. 59.9 6.7 5.8 (oxalate) (59.7 6.5 6.1) X(L) 181-184.degree. 58.3 6.4 6.1 (oxalate) (58.9 6.3 6.3) __________________________________________________________________________

EXAMPLE XI

1-[2-(2-carbamoyl-4-methylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy) propan-2-ol

2-Carbamoyl-4-methylphenoxyacetone (5 g.) and DL-1-amino-3-(2-methylphenoxy)propan-2-ol (4 g.) were refluxed in ethanol for 1 hour. The ethanol was removed in vacuo and replaced with methanol (50 ml.) followed by the slow addition of sodium borohydride (2 g.) at 25.degree.-30.degree.. The mixture was stirred for 30 minutes and then poured onto ice and acidified with acetic acid. Rebasification with sodium carbonate was followed by extraction with chloroform. The extract was dried over magnesium sulfate and evaporated in vacuo to give an oil which solidified on standing. Recrystallization from a mixture of ethanol and water gave the pure free base (3.5 g.) m.p. 110.5.degree.-113.degree..

Analysis: Found - C, 67.23; H, 7.36; N, 6.99% C, 66.65; H, 7.16; N, 7.21%

Calc'd for: C.sub.21 H.sub.28 N.sub.2 O.sub.4 - C, 67.72; H, 7.58; N, 7.52%

The following compounds were prepared by the method of Example XI , from DL-1-amino-3-(2-methylphenoxy)propan-2-ol and the appropriate ketone, as indicated:

Example R.sup.2 R.sup.3 R.sup.4 ketone __________________________________________________________________________ XII 5-CH.sub.3 3-CONH.sub.2 CH.sub.3 3-carbamoyl-5-methylphenoxyacetone XIII 4-Cl 2-CONH.sub.2 CH.sub.3 2-carbamoyl-4-chlorophenoxyacetone XIV H 4-CONH.sub.2 CH.sub.3 4-carbamoylphenoxyacetone XV 5-CH.sub.3 2-CONH.sub.2 CH.sub.3 2-carbamoyl-5-methylphenoxyacetone XVI H 3-CONH.sub.2 CH.sub.3 3-carbamoylphenoxyacetone XVII H 3-CON(CH.sub.3).sub.2 CH.sub.3 3-dimethylcarbamoylphenoxyacetone XVIII H 2-CONH.sub.2 C.sub.2 H.sub.5 1-(2-carbamoylphenoxy)butan-2-one XIX H 4-NO.sub.2 CH.sub.3 4-nitrophenoxyacetone XX H 4-COOCH.sub.3 CH.sub.3 4-methoxycarbonylphenoxyacetone XXI H 4-CN CH.sub.3 4-cyanophenoxyacetone XXII H 3-CF.sub.3 CH.sub.3 3-trifluoromethylphenoxyacetone XXIII H 4-CH.sub.2 CONH.sub.2 CH.sub.3 4-carbamoylmethylphenoxyacetone XXIV H 2-CH.sub.2 CONH.sub.2 CH.sub.3 2-carbamoylmethylphenoxyacetone XXV H 2-CONHC.sub.6 H.sub.5 CH.sub.3 2-(N-phenylcarbamoyl)phenoxyaceton e XXVI 2-OCH.sub.3 5-CONH.sub.2 CH.sub.3 5-carbamoyl-2-methoxyphenoxyaceton e XXVIII 4-CH.sub.3 2-CON(CH.sub.3).sub.2 CH.sub.3 2-(N,N-dimethylcarbamoyl)-4-methyl phenoxyacetone XXIX 3-CH.sub.3 4-CONH.sub.2 CH.sub.3 4-carbamoyl-3-methylphenoxyacetone XXX H 4-SO.sub.2 NH.sub.2 CH.sub.3 4-sulfamoyl-phenoxyacetone XXXI 2-OCH.sub.3 4-CONH.sub.2 CH.sub.3 4-carbamoyl-2-methoxyphenoxyaceton e XXXII 4-OCH.sub.3 2-CONH.sub.2 CH.sub.3 2-carbamoyl-4-methoxyphenoxyaceton e XXXIII 2-CH.sub.3 4-CONH.sub.2 CH.sub.3 4-carbamoyl-2-methylphenoxyacetone XXXIV 3-CH.sub.3 4-NO.sub.2 CH.sub.3 3-methyl-4-nitrophenoxyacetone XXXVI 2-CH.sub.3 5-CONH.sub.2 CH.sub.3 5-carbamoyl-2-methylphenoxyacetone XXXVII 6-CH.sub.3 2-CONH.sub.2 CH.sub.3 2-carbamoyl-6-methylphenoxyacetone *XXXVIII 2,6-di-CH.sub.3 4-COOCH.sub.3 CH.sub.3 4-methoxycarbonyl-2,6 -dimethylphenoxyacetone XXXIX 3-OCH.sub.3 4-CONH.sub.2 CH.sub.3 4-carbamoyl-3-methoxyphenoxyaceton e *XL 2,6-di-OCH.sub.3 4-CONH.sub.2 CH.sub.3 4-carbamoyl-2,6-dimethoxyphenoxyac etone __________________________________________________________________________ *NOTE: For Example XXXVIII, R.sup.2 and R.sup.7 are 2-CH.sub.3 and 6-CH.sub.3 respectively.

For Example XL, R.sup.2 and R.sup.7 are 2-OCH.sub.3 and 6-OCH.sub.3 respectively.

The products, isolated as the free base in each case, unless otherwise stated, were characterized as follows.

EXAMPLE XII

1-[2-(3-carbamoyl-5-methylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy) propan-2-ol

Oil, identified by spectroscopic evidence.

EXAMPLE XIII

1-[2-(2-carbamoyl-4-chlorophenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy) -propan-2-ol

Isolated as two racemic pairs of diastereoisomers, m.p. 132.degree.-134.degree. (1) and 119.degree.-121.degree. (2), respectively

Analysis:

isomer (1) - found: C, 61.21; H, 6.50; N, 6.84; Cl, 9.82%

isomer (2) - found: C, 61.05; H, 6.33; N, 6.85; Cl, 9.23%

Calc'd for C.sub.20 H.sub.25 N.sub.2 O.sub.4 Cl: C, 61.15; H, 6.41; N, 7.13; Cl, 9.03%

EXAMPLE XIV

1-[2-(4-carbamoylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)propan-2- ol

m.p. 113.degree.-114.5.degree.

Analysis: Found - C, 66.44; H, 7.11; N, 7.49%

Calc'd for C.sub.20 H.sub.26 N.sub.2 O.sub.4 - C, 67.02; H, 7.31; N, 7.82%

EXAMPLE XV

1-[2-(2-carbamoyl-5-methylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy) propan-2-ol

m.p. 138.degree.

Analysis: Found - C, 67.88; H, 7.08; N, 6.80%

Calc'd for C.sub.21 H.sub.28 N.sub.2 O.sub.4 - C, 67.72; H, 7.58; N, 7.52%

EXAMPLE XVI

1-[2-(3-carbamoylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)propan-2- ol

m.p. 116.degree.-117.degree.

Analysis: Found - C, 65.74; H, 7.52; N, 7.22%

Calc'd for C.sub.20 H.sub.26 N.sub.2 O.sub.4 - C, 65.74; H, 7.54; N, 7.48% + 1/2 CH.sub.3 OH

(the product contained one half mole of occluded methanol.)

EXAMPLE XVII

1-[2-(2-dimethylcarbamoylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy) propan-2-ol

m.p. 73.degree.-75.degree.

Analysis: Found - C, 67.97; H, 7.57; N, 7.01%

Calc'd for C.sub.22 H.sub.30 N.sub.2 O.sub.4 - C, 68.36; H, 7.82; N, 7.25%

EXAMPLE XVIII

1-[1-(2-carbamoylphenoxymethyl)propylamino]-3-(2-methylphenoxy)propan-2-ol

m.p. 128.degree.-129.degree.

Analysis: Found - C, 67.35; H, 7.18; N, 7.19%

Calc'd for C.sub.21 H.sub.28 N.sub.2 O.sub.4 - C, 67.72; H, 7.58; N, 7.52%

EXAMPLE XIX

1-[2-(4-nitrophenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)propan-2-ol

m.p. 89.5.degree.

Analysis: Found - C, 62.99; H, 6.80; N, 7.44%

Calc'd for C.sub.19 H.sub.24 N.sub.2 O.sub.5 - C, 63.32; H, 6.71; N, 7.77%

EXAMPLE XX

1-[2-(4-methoxycarbonylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)pro pan-2-ol

m.p. 75.degree.-76.degree.

Analysis: Found - C, 67.39; H, 7.48; N, 3.93%

Calc'd for C.sub.21 H.sub.27 NO.sub.5 - C, 67.54; H, 7.29; N, 3.75%

EXAMPLE XXI

1-[2-(4-cyanophenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)propan-2-ol.

m.p. 74.degree.75.degree.

Analysis: Found - C, 70.29; H, 6.80; N, 8.17%

Calc'd for C.sub.20 H.sub.24 N.sub.2 O.sub.3 - C, 70.56; H, 7.11; N, 8.23%

EXAMPLE XXII

1-[2-(3-trifluoromethylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)pro pan-2-ol

m.p. 75.degree.-76.degree.

Analysis: Found - C, 62.94; H, 6.19; N, 3.28%

Calc'd for C.sub.20 H.sub.24 F.sub.3 NO.sub.3 - C, 62.61; H, 6.3; N, 3.65%

EXAMPLE XXIII

1-[2-(4-carbamoylmethylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)pro pan-2-ol

m.p. 145.degree.-6.degree.

Analysis: Found - C, 68.0; H, 7.40; N, 7.26%

Calc'd for C.sub.21 H.sub.28 N.sub.2 O.sub.4 - C, 67.7; H, 7.58; N, 7.52%

EXAMPLE XXIV

1-[2-(2-carbamoylmethylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)pro pan-2-ol

m.p. 136.degree.-138.degree.

Analysis: Found - C, 67.5; H, 7.3; N, 7.3%

Calc'd for C.sub.21 H.sub.28 N.sub.2 O.sub.4 - C, 67.7; H, 7.6; N, 7.5%

EXAMPLE XXV

1-[2-(2-n-phenylcarbamoylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy) propan-2-ol

isolated as the hemi-fumarate, m.p. 176.degree.-178.degree.

Analysis: Found - C, 68.3; H, 6.7; N, 5.6%

Calc'd for C.sub.28 H.sub.32 N.sub.2 O.sub.6 - C, 68.3; H, 6.6; N, 5.7%

EXAMPLE XXVI

1-[2-(5-carbamoyl-2-methoxyphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy ) propan-2-ol

m.p. 100.degree.-105.degree.

Analysis: Found - C, 64.5; H, 7.4; N, 6.9%

Calc'd for C.sub.21 H.sub.28 N.sub.2 O.sub.5 - C, 64.9; H, 7.3; N, 7.2%

EXAMPLE XXVII

1-[2-(4-carbamoylphenoxy)-1-methyl-ethylamino]-3-(2-phenylphenoxy)propan-2- ol

This compound was prepared by the method of Example XII from 4-carbamoylphenoxyacetone and DL-1-amino-3-(2-phenylphenoxy)propan-2-ol and isolated as the free base. m.p. 158.degree.-160.degree.

Analysis: Found - C, 70.9; H, 6.9; N, 6.2%

Calc'd for C.sub.25 H.sub.28 N.sub.2 O.sub.4 - C, 71.4; H, 6.7; N, 6.7%

EXAMPLE XXVIII

1-[2-(2-n,n-dimethylcarbamoyl-4-methylphenoxy)-1-methyl-ethylamino]-3-(2-me thylphenoxy)propan-2-ol)

Oil

Analysis: Found - C, 69.1; H, 8.0; N, 6.5%

Calc'd for C.sub.23 H.sub.32 N.sub.2 O.sub.4 - C, 69.0; H, 8.1; N, 7.0%

EXAMPLE XXIX

1-[2-(4-carbamoyl-3-methylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy) propan-2-ol

m.p. 126.degree.-129.degree.

Analysis: Found - C, 67.3; H, 7.4; N, 7.1%

Calc'd for C.sub.21 H.sub.28 N.sub.2 O.sub.4 - C, 67.7; H, 7.6; N, 7.5%

EXAMPLE XXX

1-[2-(4-sulfamoyl-phenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)propan-2 -ol

isolated as the hemi-fumarate, m.p. 185.degree.-186.degree.

Analysis: Found - C, 55.6; H, 6.2; N, 5.9%

Calc'd for C.sub.21 H.sub.28 N.sub.2 O.sub.7 S - C, 55.8; H, 6.2; N, 6.2%

EXAMPLE XXXI

1-[2-(4-carbamoyl-2-methoxyphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy ) propan-2-ol

m.p. 132.degree.-142.degree.

Analysis: Found - C, 65.0; H, 7.1; N, 7.0%

Calc'd for C.sub.21 H.sub.28 N.sub.2 O.sub.5 - C, 64.9; H, 7.3; N, 7.2%

EXAMPLE XXXII

1-[2-(2-carbamoyl-4-methoxyphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy ) propan-2-ol

m.p. 109.degree.-110.degree.

Analysis: Found - C, 64.7; H, 7.1; N, 7.0%

Calc'd for C.sub.21 H.sub.28 N.sub.2 O.sub.5 - C, 64.9; H, 7.3; N, 7.2%

EXAMPLE XXXIII

1-[2-(4-carbamoyl-2-methylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy) propan-2-ol

m.p. 110.degree.-113.degree.

Analysis: Found - C, 67.7; H, 7.6; N, 7.3%

Calc'd for C.sub.21 H.sub.28 N.sub.2 O.sub.4 - C, 67.7; H, 7.6; H, 7.5%

EXAMPLE XXXIV

1-[2-(3-methyl-4-nitrophenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)prop an-2-ol

m.p. 76.degree.-77.degree.

Analysis: Found - C, 64.4; H, 7.1; N, 7.5%

Calc'd for C.sub.20 H.sub.26 N.sub.2 O.sub.5 - C, 64.2; H, 7.0; N, 7.5%

EXAMPLE XXXV

1-[2-(4-n-aminocarbamoyl-phenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy) propan-2-ol

This compound was prepared from the product of Example XX by heating with hydrazine hydrate in ethanol.

m.p. 129.degree.

Analysis: Found - C, 64.2; H, 7.1; N, 11.2%

Calc'd for C.sub.20 H.sub.27 N.sub.3 O.sub.4 - C, 64.3; H, 7.3N, 11.3%

EXAMPLE XXXVI

1-[2-(5-carbamoyl-2-methylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy) propan-2-ol

m.p. 122.degree.-123.degree.

Analysis: Found - C, 67.2; H, 7.1; N, 7.1%

Calc'd for C.sub.21 H.sub.28 N.sub.2 O.sub.4 - C, 67.7; H, 7.6; N, 7.5%

EXAMPLE XXXVII

1-[2-(2-carbamoyl-6-methylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy) propan-2-ol

isolated as the oxalate, m.p. 170.degree.-171.5.degree.

Analysis: Found - C, 63.3; H, 7.0; N, 7.0%

Calc'd for C.sub.23 H.sub.30 N.sub.2 O.sub.8 - C, 63.3; H, 7.0; N, 6.7%

EXAMPLE XXXVIII

1-[2-(4-methoxycarbonyl-2,6-dimethylphenoxy)-1-methyl-ethylamino]-3-(2-meth ylphenoxy)propan-2-ol

isolated as the hydrochloride, m.p. 128.degree.-130.degree.

Analysis: Found - C, 63.3; H, 7.6; N, 3.2%

Calc'd for C.sub.22 H.sub.32 NO.sub.5 Cl - C, 63.1; H, 7.4; N, 3.2%

EXAMPLE XXXIX

1-[2-(4-carbamoyl-3-methoxyphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy )propan-2-ol

hydrochloride, identified by spectroscopic evidence.

m.p. 134.degree.-143.degree.

EXAMPLE XL

1-[2-(4-carbamoyl-2,6-dimethoxyphenoxy-1-methyl-ethylamino]-3-(2-methylphen oxy)propan-2-ol

hydrochloride, identified by spectroscopic evidence.

m.p. 114.degree.-126.degree.

EXAMPLE XLI

1-[2-(4-carbamoyl-phenoxy)-1-methyl-ethylamino]-3-(1-naphthoxy) propan-2-ol.

This compound was prepared by the method of Example XI from 4-carbamoylphenoxyacetone and DL-1-amino-3-(1-naphthoxy) propan-2-ol and isolated as the free base, m.p. 143.degree.-144.degree..

Analysis: Found - C, 69.8; H, 6.7; N, 6.8%

Calc'd for C.sub.23 H.sub.26 N.sub.2 O.sub.4 - C, 70.0; H, 6.6; N, 7.1%

EXAMPLE XLII

1-[2-(3-carbamoyl-2-naphthoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)prop an-2-ol

This compound was prepared by the method of Example XI from 3-carbamoyl-2-naphthoxyacetone and DL-1-amino-3-(2-methylphenoxy)propan-2-ol and isolated as the free base, m.p. 106.degree.-108.degree.

Analysis: Found - C, 70.21; H, 7.0; N, 6.6%

calc'd for C.sub.24 H.sub.28 N.sub.2 O.sub.4 - C, 70.56; H, 6.9; N, 6.7%

The following compounds were prepared by the method of Example IV, from the appropriately substituted 1-phenoxy-2:3-epoxypropane and 2-(4-carbamoylphenoxy)-ethylamine, and isolated as the free base in each case.

Analysis % Example R.sup.1 m.p. C H N __________________________________________________________________________ XLIII 2-C.sub.6 H.sub.5 124-125.degree. 70.7 6.6 7.0 (2-phenyl) (70.9 6.5 6.9) XLIV 3-CH.sub.3 124-126.degree. 66.1 7.2 8.4 (66.3 7.0 8.1) XLV 2-OCH.sub.3 108-112.degree. 63.2 6.9 7.9 (63.3 6.7 7.8) __________________________________________________________________________

example xlvi

1-[2-(4-carbamoylphenoxy)ethylamino]-3-(1-naphthoxy)propan-2-ol

This compound was prepared by the method of Example IV, from 1(1-naphthoxy)-2:3-epoxypropane and 4-(2-aminoethoxy) benzamide, and isolated as the free base, m.p. 122.degree.-123.degree..

Analysis: Found - C, 69.2; H, 6.3; N, 7.4%

calc'd for C.sub.22 H.sub.24 N.sub.2 O.sub.4 - C, 69.5; H, 6.4; N, 7.4%

EXAMPLE XLVII

1-[n-benzyl-2-(2-carbamoyl-4-methylphenoxy)-1-methyl-ethylamino]-3-(2-methy lphenoxy)propan-2-ol

1-(2-Methylphenoxy)-2,3-epoxypropane (13.8g.), 1-(2-carbamoyl-4-methylphenoxy)-2-(benzylamino)-propane (25 g.), ethanol (250 ml.) and water (50 ml.) were heated together under reflux for 6 hours. The reaction mixture was evaporated and dried in vacuo to give the free base of the desired product as a clear oil (39g.). This oil was then dissolved in the minimum quantity of chloroform and chromatographed on a column (80.times.3cm) packed with silicagel, using chloroform as the eluting solvent. The first 500 ml. of eluate was collected and the solvent removed in vacuo to give an oil which solidified after standing for two weeks. Repeated fractional recrystallization of the solid from ethyl acetate, gave solid products A and B, m.p. 115.degree. and 132.degree., respectively, which were the two racemic pairs of diastereoisomers of the product.

Analysis:

Found for Product A: C, 72.29; H, 7.35; N, 6.20%.

for Product B: C, 72.31; H, 7.21; N, 6.06%

Calc'd for C.sub.28 H.sub.34 N.sub.2 O.sub.4 : C, 72.70; H, 7.41; N, 6.06%

Hydrogenation of each of the products A and B of this example, using a palladium-on-carbon catalyst, removes the N-benzyl group and yields one of the racemic pairs of diastereoisomers of the product of Example XI.

EXAMPLE XLVIII

The following propanolamine derivatives are prepared according to the procedures described in Examples I, IV, V, and XI from the appropriate starting compounds, those in which R.sub.6 is lower alkanoyl being prepared by conventional acylation procedures from corresponding compounds in which R.sub.6 is H:

rings A and B are both phenyl in the following table: ##SPC3##

Ring A is naphthyl and ring B is phenyl in the following table: ##SPC4##

Ring A is phenyl and ring B is naphthyl in the following table: ##SPC5##

Rings A and B are each 1-naphthyl in the following table: ##SPC6##

The activity of compounds of the invention as .beta.-adrenergic blocking agents has been shown by their effectiveness in one or more of the following tests: (a) blocking the action of injected catecholamines on the isolated, perfused guinea-pig heart; (b) suppressing the tachycardia induced by isoprenaline in the anaesthetized rat or cat; (c) blocking the stimulating action of isoprenaline on the adenyl cyclase enzyme present in rate heart muscle.

In test (a), force and rate of contraction, and flow rate through the coronary vessels, are measured. The response to standard doses of one or more catecholamines are obtained, and the test compound is then administered. The catecholamines and test compounds are in all cases injected directly into the perfusing fluid immediately before entering the coronary vessels. The catecholamine doses are repeated and the extent of inhibition of the responses by the test compound is measured.

In test (b), groups of five urethane-anaesthetized rats are dosed with the test compound (2 mg./kg.) subcutaneously. Heart rates are recorded before dosing and for thirty minutes after and the rats are then given a subcutaneous challenge of isoprenaline (0.1 ,g/kg.). The degree of isoprenaline-induced tachycardia is recorded at fifteen minute intervals. Similarly, chloralosed cats are dosed with the test compound (0.1 to 1.0 mg./kg.) intravenously, and the effect of an isoprenaline challenge on heart rate is measured.

In test (c), homogenized rat heart in a standardized medium is incubated with adenosine-5'-triphosphoric acid (ATP) labelled with tritium, with and without isoprenaline, and the test compound is added at various concentrations to the homogenate with the isoprenaline. After incubation at 30.degree. C., cyclic-3', 5'-adenosinemonophosphoric acid (cyclic-AMP), containing a known proportion of carbon-14 labelled material, is added and synthesis of cyclic-AMP by the adenyl cyclase enzyme is stopped by raising the temperature. Cyclic-AMP is separated and purified, and the amount synthesized in each case by the enzyme is measured as its tritium to carbon-14 ratio. The concentration of test compound which gives a 50 percent inhibition of the stimulating effect of isoprenaline on cyclic-AMP synthesis is taken as a measure of its activity.

By these criteria, the more active compounds have been found to be those in which R.sup.3 is a carbamoyl (including N-substituted-and N-amino-carbamoyl, as hereinbefore described), carbamoyl-methyl (K is 1 for (CH.sub.2).sub.K R.sup.3 -substituent), methoxycarbonyl or cyano group in the 2- or 4-position on a phenyl group, R.sup.4 is hydrogen or a methyl group, R.sup.5 and R.sup.6 are each hydrogen, Y is oxygen and n is 1.

Further evaluation of these more active compounds has been carried out by assessing their activity in suppressing isoprenaline-induced tachycardia in dogs, the compound being administered intraveneously and orally to conscious dogs at dose levels of 0.125 and 0.25 mg/Kg (intravenous) and 0.5 to 4mg/Kg (orally). These tests have shown that, of these compounds, the most active when administered orally are those in which R.sup.1 is a methyl, methoxy or phenyl group in the 2-position on a phenyl group and R.sup.3 is an unsubstituted carbamoyl group or a methoxycarbonyl group, provided that, when R.sup.3 is in the 2-position on the phenyl group, then R.sup.2 is a methyl or methoxy group in the 4-, 5- or 6-position. Intravenous test results in dogs confirmed relative activities found in test (b) in rats or cats, in or test (c).

The activity of compounds of the invention as antihypertensive agents has been shown by their effectiveness in lowering the blood pressure of conscious hypertensive rats or dogs, using a subcutaneous dose of 10 mg./Kg. in the rat and an oral dose of 20 mg/Kg. in the dog. Compounds having most activity in these tests are those in which R.sup.3 is a carbamoyl or nitro group, R.sup.4 is hydrogen or a methyl group, R.sup.5 and R.sup.6 are each hydrogen and n is 1 or 2.

The following example shows the therapeutic activity of many of the compounds whose preparations are illustrated in the previous examples.

EXAMPLE XLIX ##SPC7##

EXAMPLE L

The hydrochloride salt of each of the compounds of Examples I-XLVIII is prepared by dissolving the compound as a free base in an aqueous solution containing an equivalent amount of hydrochloric acid and evaporating the resultant solution.

Similarly, other acid addition salts are prepared by this same procedure corresponding to hydrobromide, hydroiodide, sulfate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate, and p-toluene sulfonate by employing the appropriate acid.

EXAMPLE LI

The aldehyde condensation product of each of the compounds of Examples I-XLVIII is prepared by reacting the compound as a free base, in which R.sup.6 is hydrogen, with formaldehyde in ethanol and an acid catalyst such as hydrochloric or acetic, at an elevated temperature, and the product is then recovered after removal of the excess water by azeotropic distillation or by means of an entraining solvent such as benzene.

Similarly, the other aldehyde condensation products are prepared by this same procedure corresponding to acetaldehyde, propionaldehyde, butyraldehyde, and isobutyraldehyde.

EXAMPLE LII

The carboxylic acid ester of each of the compounds of Examples I-XLVIII is prepared by acylating in the conventional manner the compound as the free base with acetyl chloride and recovering the ester.

Similarly, other carboxylic acid esters are prepared by this same procedure corresponding to formyl chloride, propionyl chloride, butyrylchloride, iso-butyrylchloride, benzoyl chloride, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, benzoic anhydride, crotonic chloride and crotonic anhydride.

The dosage levels at which compounds of the invention should be administered will depend on the purpose for which they are administered, i.e. the treatment of the cardiac conditions already mentioned or the treatment of hypertension, and also on the route of administration, i.e. oral or parenteral, e.g. intravenous. They will also depend on the age, body-weight and idiosyncrasies of the individual patient, the physician in any event determining the appropriate dosage which is most suitable for a patient. Broadly, however, oral dosage levels for the treatment of cardiac conditions will be in the range from 0.5 to 4 mg/Kg/day, and for the treatment of hypertension will be in the range from 2 to 10 mg/Kg/day, these amounts being given in up to 4 divided doses per day. Dosage levels for intravenous administration will be about one-tenth of these in a single dose. Thus, for an average (70Kg) adult patient, individual oral doses in tablet or capsule form will be in the range from 10 to 50 mg. of active compound, and intravenous doses will be in the range from 1 to 20 mg. of active compound.

Claims

What is claimed is:

1. A compound selected from the group of propanolamines consisting of those of the formula:

the pharmaceutically-acceptable acid addition salts thereof; the carboxylic acid esters of the formula:

wherein R.sup.12 is selected from the group consisting of formyl, lower alkanoyl, lower alkenoyl, and benzoyl; and the aldehyde condensation products of the formula:

wherein R.sup.8 is selected from the group consisting of hydrogen and lower alkyl; R.sup.1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, phenyl, and phenyl-substituted lower alkyl; R.sup.2 and R.sup.7 are each selected from the group consisting of hydrogen, halogen, lower alkyl, and lower alkoxy; R.sup.3 is an electron-withdrawing polar substituent selected from the group consisting of CONR.sup.9 R.sup.10 and CONHNR.sup.9 R.sup.10, where R.sup.9 and R.sup.10 are each hydrogen or lower alkyl;

R.sup.4, r.sup.5, and R.sup.6 are each selected from the group consisting of hydrogen and lower alkyl;

and n is 1, 2, or 3.

2. A compound as claimed in claim 1 in which R.sup.4 is hydrogen or a methyl group, R.sup.5 is hydrogen, and n is 1.

3. A compound as claimed in claim 2 in which R.sup.2 is hydrogen, chlorine, methyl, or methoxy.

4. A compound as claimed in claim 2, in which R.sup.3 is in the 2- or 4-ring position.

5. A compound as claimed in claim 4, in which R.sup.1 is methyl, methoxy, or phenyl on the 2-ring position, and R.sup.3 is CONH.sub.2 in the 2- or 4-ring position, provided that when R.sup.3 is in the 2-position then R.sup.2 is methyl or methoxy in the 4-, 5- or 6-ring position.

6. 1-[2-(4-carbamoylphenoxy)ethylamino]-3-(2-methyl-phenoxy)propan-2-ol.

7. 1-[2-(4-carbamoylphenoxy)ethylamino]-3-(2-methoxy-phenoxy)propan-2-ol.

8. 1-[2-(2-carbamoyl-4-methylphenoxy)ethylamino]-3-(2-methylphenoxy)propan- 2-ol.

9. 1- [2-(2-carbamoyl-4-methylphenoxy)-1-methyl-ethylamino]-3-(2-methylphenoxy)pr opan-2-ol.

10. 1[2-(2 -carbamoyl-4-methoxyphenoxy)-1-methyl-ethyl-amino]-3-(2-methylphenoxy)propa n-2-ol.

11. 1-[ 2-(2-carbamoyl-6-methylphenoxy)-1-methyl-ethyl-amino]-3-(2-methylphenoxy)pr opan-2-ol.

12. 1-[2-( 4-carbamoylphenoxy)-1-methyl-ethylamino]-3-(2-phenylphenoxy)propan-2-ol.