Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3755413 A
Publication typeGrant
Publication dateAug 28, 1973
Filing dateJul 22, 1970
Priority dateJul 23, 1969
Also published asDE1937477A1, DE1937477B2, DE1937477C3
Publication numberUS 3755413 A, US 3755413A, US-A-3755413, US3755413 A, US3755413A
InventorsA Engelhardt, H Koppe, W Kummer, H Stahle, W Traunecker, K Zeile
Original AssigneeBoehringer Sohn Ingelheim
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
1-cyanophenoxy-2-hydroxy-3-(cycloalkyl-amino)-propanes
US 3755413 A
Abstract  available in
Images(9)
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

United States Patent U.s. Cl. 260-465 E 6 Claims ABSTRACT OF THE DISCLOSURE Racemic mixtures of a compound of the formula R is alkyl of 1 to carbon atoms, I

R is cyano, carboxyl, hydroxyl, amino, nitro, trifluoromethyl, alkyl of up to 5 carbon atoms, alkenyl of up to 5 carbon atoms, alkinyl of up to 5 carbon atoms, alkoxy of up to 5 carbon atoms, alkenyloxy of up to 5 carbon atoms, alkinyloxy of up to 5 carbon atoms, hydroxyalkyl of up to 5 carbon atoms, alkoxyalkyl of up to 5 carbon atoms, aminoalkyl of "up to 5 carbon atoms, alkylaminoalkyl of up. to 5 carbon "atoms, dialkylaminoalkyl of up to 5 carbon atoms, alkylamino of up to 5 carbon atoms, cyano(alkyl of up to 5 carbon atoms), alkoxy of up to 5 carbon atoms)carbonyl, alkyl of up to 5 carbon atoms)amino-carbonyl, alkyltbio of up to 5 carbon atoms, acyloxy of up to 5 carbon atoms, acylamino of up to 5 carbon at0ms,'aryl of up to carbon atoms, aralkyl of up to 10 carbon atoms, aryloxy of up to 10 carbon atoms, aralkoxy-of up to 10 carbon atoms, arylamino of up to 10 carbon atoms or halogen,

R is hydrogen, halogen, cyano, alkyl of up to 5 carbon atoms, alkoxy of up to 5 carbon atoms or alkenyl of up to 5 carbon atoms,

R and R together with each other, are 3,4-methyIenedioxy,

R is hydrogen, halogen, alkyl of up to 5 carbon atoms or alkoxy of up to 5 carbon atoms, and n is an integer from 2 to 7, inclusive,

optically active components thereof, and non-toxic, pharmacologically acceptable acid addition salts.:of said racemic and optically active compounds, useful;,-.as.

B-adrenergic receptor blocking agents in warmblooded animals.

This invention relates to novel l-phenoxy-lZ-hydroxy- 3-(cycloalkyl-amino)-propanes and their non-toxic acid addition salts, as well as to various methods of preparing these compounds.

wherein R is alkyl of 1 to 5 carbon atoms,

R is cyano, carboxyl, hydroxyl, amino, nitro, trifluoromethyl, alkyl of up to 5 carbon atoms, alkenyl of up to 5 carbon atoms, alkinyl of up to 5 carbon atoms, alkoxy of up to 5 carbon atoms, alkenyloxy of up to 5 carbon atoms, alkinyloxy of up to 5 carbon atoms, hydroxyalkyl of up to 5 carbon atoms, alkoxyalkyl of up to 5 carbon atoms, aminoalkyl of up to 5 carbon atoms, alkylaminoalkyl of up to 5 carbon atoms, dialkylaminoalkyl of up to 5 carbon atoms, alkylamino of up to 5 carbon atoms, cyano(alkyl of up to 5 carbon atoms), (alkoxy of up to 5 carbon atoms) carbonyl, (alkyl of up to 5 carbon atoms)amino-carbonyl, alkylthio of up to 5 carbon atoms, acyloxy of up to 5 carbon atoms acylamino of up to 5 carbon atoms, aryl of up to 10 carbon atoms, aralkyl of up to 10 carbon atoms, aryloxy of up to 10 carbon atoms, aralkoxy of up to 10 carbon atoms, arylamino of up to 10 carbon atoms or halogen,

R is hydrogen, halogen, cyano, alkyl of up to 5 carbon atoms, alkoxy of up to 5 carbon atoms or alkenyl of up to 5 carbon atoms, 7

R and R together with each other, are 3,4-methylenedioxy,

R is hydrogen, halogen, alkyl of up to 5 carbon atoms or alkoxy of up to 5 carbon atoms, and

n is an integer from 2 to 7, inclusive,

optically active components thereof, or non-toxic, pharmacologically acceptable acid addition salts of said racemic or optically active compounds.

The compounds according to the present invention may be prepared by a number of methods involving well known chemical principles, among which the following have proved to be particularly convenient and efiicient.

Method A By reacting a compound of the formula wherein R R and R have the same meanings as in Formula I and Z is GHCH;

or sCHOH-CH HaI, where Hal is halogen, with a cycloalkylamine of the formula E-mm) R (III) wherein R and n have the same meanings as in Formula I.

Method B By reacting a compound of the Formula II with' an N,'N-dicycloalkylurea of the formula wherein R and n have the same meanings as in Formula I. The reaction is preferably performed in a water-immiscible, high-boiling-point solvent, such as Tetralin, Decalin, benzonitrile or the like, or without a solvent in the molten state, at temperatures between and 220 C., preferabl'y at 180200 C. Thus, this reaction is not practicable or can only be performed with difliculty, in those cases where heat-sensitive groups (such as unsaturated groups, hydroxyl or amino groups) are present in the starting material.

Method C By splitting oif an easily removable protective group from a compound of the formula wherein R, R R R and n have the same meanings as in Formula I and G is a hydrolytically easily removable group (for instance, an acyl or an acetal group).

Method D By splitting oif a protective group from a tertiary amine of the formula Sch / o om-onon-cmJr-oijonm wherein R, R R R and n have the same meanings as in Formula I and Sch represents a hydrogenolytically or hydrolytically easily removable protective group, such as benzyl or acetyl.

Method B By hydrolysis of an oxazolidinone of the formula Q cm-oH-cn, R, I I- $112).

wherein R, R R R and n have the same meanings as in Formula I, for example with a strong alkali in an aqueous or aqueous/ alcoholic medium.

Method F By hydrolysis or pyrolysis of a urea derivative of the formula wherein R, R R R and n have the same meanings as in Formula I, and R and R (which may be identical to or different from each other) are each hydrogen or alkyl (preferably lower alkyl), aralkyl (preferably benzyl), or aryl (preferably phenyl), in conventional fashion. The hydrolysis is carried out, for instance, with a strong base, such as aqueous KOH; on the other hand, the pyrolysis only be performed with good yields if there are no heatsensitive groups present in the starting material.

Further possibilities for the production of the compounds of the Formula I are provided if the starting material wherein the 1-phenoxy-2-hydroxy-3-cycloalkylamino structure is already present, but wherein one of the substituents R to R is still missing or is only present in the form of a precursor, is converted by the introduction of the missing phenyl substituent or by conversion of the precursor of the phenyl substituent into the desired 'substituent R R or R into the end product of the Formula I. Thus, for example:

4 Method G Compounds of the formula A g g 0CH;GH0HCH2NHC@3H:% R: i

R; R (IX) wherein R, R R and n have the same meanings as in Formula I and A is a group convertible by conventional methods into R such as the aldehyde-(CHO)-group (converts by reduction into -CH OH or CH the CONH or --CH=NOH group (converts by dehydration into the cyano group), a halo-alkyl group (converts by reaction with ammonia or amines, water or aliphatic alcohols into an aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl or alkoxyaryl group), a hydroxyl group (converts by etherification into an alkoxy group), a halogen atom (converts by reaction with Cu(I)CN and pyridine at elevated temperatures into a cyano group), a nitro group (converts by reduction into the amino group), an alkoxycarbonyl group (converts by saponification into a carboxyl group) or an amino group (converts by diazotization and heating with copper(I)- cyanide or copper(I)-halide into the cyano group or a halogen atom), may be converted into compounds of the Formula I, by using the conventional methods required for each case (dehydration, exchange reaction or condensation, alkylation, reduction, diazotization and heating with a copper-I-salt, etc.).

Method H Likewise, compounds of the formula OCHg-CHOHCH NH-H;) B

wherein R, R and R and n have the same meanings as in Formula I and B represents a group convertible into R; in conventional manner, such as the hydroxyl or aldehyde (CHO) group or an amino group, or compounds of the formula wherein R, R R and n have the same meanings as in Formula I and D represents a group convertible into R, in conventional manner (such as the aldehyde, hydroxyl or amino group), may be converted into compounds of the Formula I by using the conventional method required for each case (alkylation, reduction, diazotization and heating with a copper-I-salt, etc.).

wherein R and n have the same meanings as in Formula land Aris or Q where R, and R or R and R have the same meanings as in Formula I. his process may be carried out, for ex ample, by reaction with a mixture of concentrated bydrogen peroxide and the corresponding hydrohalic acid at elevated temperatures.

Some of the starting materials required for methods A through I are known, while the others may be obtained according to the conventional processes. Thus, the epoxides of the Formula II may easily be prepared by reacting a corresponding phenol or phenolate of the formula OKt (XIII) wherein R R and R have the same meaning as in Formula I and Kt represents hydrogen or a cation (for example, an alkali metal cation). The epoxides, in turn, may be used for the preparation of further starting materials; for example, the halohydrins of the Formula 11 may be prepared by reaction of the epoxides with the corresponding hydrohalic acid.

- The ureas of the Formula IV may be prepared, for example, by reaction of phosgene with amines of the Formula III. The latter, in turn, may be prepared starting from the corresponding carbinols according to the socalled Ritter reaction [see .I.A.C.S. 70 (1948), 4048] by reaction with KCN in glacial acetic acid and cleavage of the formamide thus formed with KOH. Compounds of the Formula V may be obtained by reacting a halohydrin of the Formula II with a compound which forms the protective group G, such as vinyl ether or dihydropyran, and subsequently reacting the obtained compound of the formula R3 (XIV) wherein R R R Hal and G have the meanings previously defined, with an amine of the Formula III. The tertiary amines of the Formula VI are obtained by reacting a compound of the Formula XIII with a compound of the formula Sch wherein R and n have the same meanings as in Formula I. A urea derivative of the Formula V may, for instance, be obtained according to the method described in Chem. Abstr. 58, page 3337c, by reacting an epoxide of the Formula II with the corresponding urea derivative (for instance, with a compound of the Formula IV). The compounds of the Formulas IX to XII already comprise the 1-phenoxy-2-hydroxy-3-cycloalkylaminopropane structure and may, therefore, be prepared analogous to method A described above, starting from the corresponding phenol, via the corresponding l-phenoxy2,3-epoxypropane (producible therefrom by reaction with epichlorohydrin) by reaction with a cycloalkylamine of the Formula III.

The compounds according to the present invention comprise an asymmetric carbon atom in the CHOH-group and therefore occur as racemates as well as in the form of optical antipodes. The latter may be obtained not only by means of separation of racemates with the usual auxiliary acids, such as dibenzoyl-D-tartaric acid or D-3- bromocamphor-8-sulfouic acid, but also by using the corresponding optically active starting material.

The 1-phenoxy-3-cycloalkylamino-propanols of the Formula I according to the invention may be converted into non-toxic pharmaceutically acceptable acid addition salts in conventional fashion. Examples of such salts are, for instance, those formed with hydrochloric acid, hydro bromic acid, sulfuric acid, methane-sulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid, 8- chlorotheophylline or the like.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE 1 l- 2'-cyano-phenoxy) -2-hydroxy-3- 1"-methylcyclohexylamino)-propane hydrochloride 8.75 gm. (0.05 mol) of 1-(2'-cyanophenoxy)-2,3-propane-epoxide were dissolved in 100 ml. of ethanol, and 25 ml. of a 2 M solution of l-mcthylcyclohexylamine were added. After two hours of refluxing the solvent was distilled off, and the residue was treated with 200 ml. of water. The aqueous mixture was acidified with HCl, heated to C. and separated from insoluble matter. The cooled aqueous phase was made alkaline with NaOH after extraction with ether, and the precipitated base was extracted with ether. The organic phase was Washed with water and dried over MgSO After distilling off the ether, the remaining crystalline base was recrystallized from ethylacetate by addition of petroleum ether. The dry substance was dissolved in a little acetonitrile, ethereal HCl was added, and the crystalline hydrochloride was collected by vacuum filtration. Yield: 5.8 gm., M.P. 163- 165 C.

EXAMPLE 2 1- (2'-cyanophenoxy) -2-hydroxy-3-( 1-methylcyclopentylamino)-propane hydrochloride 7.8 gm. (0.045 mol) of 1-(2'-cyanophenoxy)-2,3-propaneepoxide were dissolved in 100 ml. of methanol, 5.5 gm. (0.055 mol) of l-methylcyclopentylamine were added, and the mixture was refluxed for three hours. After distilling off the solvent, the residue was treated with 1 N, HCl, and insoluble matter was filtered off. After extracting the aqueous phase with ether, the former was made alkaline with NaOH and the precipitated base was taken up in ether. The organic phase was washed with water and dried over MgSO After distilling oft the ether, the crystalline base was dissolved in ethanol, ethereal HCl was added, and the precipitated hydrochloride was collected by vacuum filtration and recrystallized from ethanol by addition of ether. Yield: 4.5 gm., M.P. 132- 134 C.

EXAMPLE 3 1-(2-bromophenoxy) -2-hydroxy-3-( 1 "-methyl-cyclopentylamino)-propane hydrochloride 5 gm. (0.05 mol) of l-methylcyclopentylamine were added to a solution of 7.5 gm. (0.033 mol) of 1-(2- bromophenoxy-2,3-propaneepoxide in ml. of ethanol, and the mixture was refluxed for two hours. After distilling off the ethanol in vacuo, the residue was dissolved in a little ethanol, and ethereal HCl was added. The crystalline substance precipitated thereby was recrystallized from ethanol by addition of ether. Yield: 8.2 gm., M.P. 156-157 C.

7 EXAMPLE 4 1- (2'-chloro-5'-methylphenoxy) -2-hydroxy-3-( 1"-methylcyclopentylamino -prop ane hydrochloride 1- (2-bromophenoxy -2-hydroxy-3- 1 "-methylcyclohexylamino)-propane hydrochloride 4.5 gm. (0.04 mol) of l-methyl-cyclohexylamine were added to a solution of 6.9 gm. (0.03 mol) of 1-(2- bromophenoxy-Z,3-propaneepoxide in 80 ml. of ethanol, and the mixture was refluxed for two hours. The residue remaining after distilling off the solvent in vacuo was dis solved in ethanol, and ethereal HCl was added. The precipitated hydrochloride was recrystallized from ethanol/ ether. Yield: 5.2 gm., M.P. 157-158 C.

EXAMPLE 6 1- 2'-prop argyloxyphenoxy -2-hydroxy-3 l"-methylcyclohexylamino) -propane hydrochloride 6.1 gm. (0.03 mol) of 1-(2-propargyloxyphenoxy)- 2,3-propaneepoxide were dissolved in 75 ml. of ethanol, 4.5 gm. (0.04 mol) of l-methylcyclohexylamine were added, and the mixture was boiled for two hours. Then, the solvent was distilled off, the residue was dissolved in ethanol, and the solution was acidified with ethereal HCl. The crystalline hydrochloride was collected and recrystallized from ethanol by addition of ether. Yield: 6.2 gm., M.P. 137138 C.

EXAMPLE 7 1- (2'-a1lyloxyphenoxy) -2-hydroxy-3- 1 -methylcyclohexylamino)-propane oxalate 6.2 gm. (0.03 mol) of 1-(2'-allyloxyphenoxy)-2,3-propaneepoxide were dissolved in 60 ml. of ethanol, 4.5 gm. (0.04 mol) of 1-methylcyclohexylamine were added, and the mixture was refluxed for two hours. After distilling off the solvent, the residue was dissolved in ether, and an ethereal solution of oxalic acid was added. The crystalline oxalate was recrystallized from ethanol by addition of ether. Yield: 5.9 gm., M.P. 141-143" C.

EXAMPLE 8 1- (2-ethinylphenoxy) -2-hydroxy-3-( 1"-methylcyclopentylamino) -propane hydro chloride 7.5 gm. (0.04 mol) of 1-(2'-ethinylphenoxy)-2,3- epoxypropane were dissolved in 80 ml. of ethanol, gm. (0.05 mol) of l-methylcyclopentylamine were added, and the mixture was refluxed for 2.5 hours. The residue remaining after distilling ofi the solvent was dissolved in ethanol, and ethereal HCl was added. The colorless crystalline precipitate was recrystallized from ethanol/ether. Yield: 6.7 gm., M.P. 171-173 C.

EXAMPLE 9 t1- 2'-bromophenoxy -2-hydroxy-3-( 1"-methylcycloheptylamino) -propane hydrochloride 6.9 gm. (0.03 mol) of 1-(2'-bromophenoxy)-2,3-propaneepoxide were dissolved in 75 ml. of ethanol, 5 gm. (0.04 mol) of l-methylcycloheptylamine were added, and the mixture was refluxed for two hours. The residue remaining after distilling off the solvent in vacuo was dissolved in ethanol, and the solution was acidified with ethereal HCl. The solid hydrochloride precipitated thereby was recrystallized from ethanol by addition of ether. Yield: 6.4 gm., M.P. 167-168 C.

EXAMPLE 10 Analogous to Example 4, 1-(2-chloro-5'-methylphenoxy) 2 hydroxy 3 (1"-methylcyclohexyl)-amino)- propane hydrochloride was prepared from l-(2'-chloro-5'- methyl-phenoxy 2,3 epoxypropane and l-methyl-cyclohexylamine. The HCl addition salt was obtained by dissolution of the base in ethanol and acidifying the solution with ethereal HCl. M.P. 174177 C.

EXAMPLE 11 Analogous to Example 4, 1-(2'-chloro-5'-methylphenoxy) 2 hydroxy 3 (1"-ethylcyclohexylamino)-propane hydrochloride was prepared by reacting 1-(2-chlor0 5' methylphenoxy)-2,3-epoxypropane with l-ethylcyclohexylamine. M.P. of the HCl addition salt (obtained from the base as in Example 4): 179-180" C.

EXAMPLE 12 Analogous to Example 1, 1-(2'-cyanophenoxy)-2-hydroxy 3 (1" ethylcyclohexylarnino)-propane hydrochloride was obtained from 1-(2-cyanophenoxy)-2,3- epoxypropane and l-ethylcyclohexylamine. The HCl addition salt, obtained as in Example 1, melted at 157- 158 C.

EXAMPLE 13 Analogous to Example 6, 1-(2-propargyloxyphenoxy)- 2 hydroxy 3 (1 methylcyclopentylamino)-propane hydrochloride was obtained from 1-(2'-propargyloxyphenoxy) 2,3 epoxypropane and l-methylcyclopentylamine. M.P. of the HCl salt: 167-l68 C.

EXAMPLE 14 Analogous to Example 7, 1-(2-allylphenoxy)-2-hydroxy 3 (1 methylcyclohexylamino)-propane hydrochloride was prepared from 1-(2'-a1lylphenoxy)-2,3- epoxypropane and l-methylcyclopentylamine. M.P. of the HCl addition salt: l10111 C.

EXAMPLE 15 Analogous to Example 8, 1-(2'-ethinyl-phenoxy)-2-hydroxy 3 (1" methylcyclohexylamino) propane hydrochloride was prepared from 1-(2'-ethinylphenoxy) -2,3- epoxypropane and l-methylcyclohexylamine. M.P. of the HCl addition salt: 184-185 C.

EXAMPLE 16 Analogous to Example 1, 1 (2' methyl-4'-cyanophenoxy) 2 hydroxy 3 (1" methylcyclohexylamino)- propane hydrochloride was prepared from 1- (2'-methyl- 4' cyanophenoxy) 2,3 epoxypropane and l-methylgycllslgxylamine. M.P. of the HCl addition salt: 206- EXAMPLE 17 Analogous to Example 1, 1-(2-cyanophenoxy)-2-hydroxy 3 (1" isopropylcyclohexylamino)-propane hydrochloride was prepared by reacting 1-(2'-cyanophenoxy) -2,3-epoxypropane with 1-isopropylcyclohexylamine. The hydrochloride, obtained by dissolution of the base in ethanol and acidifying the solution with ethereal HCl, melted at ZOO-201 C.

EXAMPLE 18 Analogous to Example 4, 1-(2'-chloro-5'-methylphenoxy) 2 hydroxy 3 (1"-methylcycloheptylamino)- propane hydrochloride was prepared from 1-(2'-ch1oro- 5' methylphenoxy) 2,3 epoxypropane and l-methylcycloheptylamine. The hydrochloride was obtained from tha base by acidification with ethereal HCl. M.P. 191- 19 9 EXAMPLE 19 Analogous to Example 1, 1-(2'-hydroxymethylphedroxy 3 (1" methylcycloheptylamino)-propane hydrochloride was prepared from 1-(2-cyanophenoxy)-2,3- epoxypropane and l-methylcycloheptylamine. The hydrochloride had a melting point of l60 l61 C.

EXAMPLE 20 l (2' propargyloxyphenoxy) 2 hydroxy-3-(1"- methylcycloheptylamino)-propane hydrochloride was prepared from 1 (2' propargyloxyphenoxy):2,3-propaneepoxide and 1-methylcycloheptylamine. Dissolution of the base in ethanol and acidification of the solutlon with ethereal HCl yielded the HCl addition salt, M.P. 110- 111 C.

EXAMPLE 21 1 (2' allylphenoxy) 2 hydroxy-3-(1"-methylcycloheptylamino)-propane hydrochloride was prepared from 1 (2 allylphenoxy) 2,3 epoxypropane and 1- methylcycloheptylamine, analogous to Example 7. The hydrochloride had a melting point of l24-126 C.

EXAMPLE 22 Analogous to Example 7, 1-(2-allyloxyphenoxy)-2-hydroxy 3 (1" methylcycloheptylamino)-propane hydrochloride was prepared from 1-(2-allyloxyphenoxy)-2, 3-epoxypropane and l-methylcyclohexylamine. M.P. of the hydrochloride: 9799 C.

EXAMPLE 23 Analogous to Example 7, 1-(2'-allyloxyphenoxy)-2-hydroxy 3 (1" methylcyclopentylamino)-propane oxalate was prepared from 1-(2'-allyloxyphenoxy)-2,3-epoxypropane and l-methylcyclopentylamine. The free base was dissolved in ethanol, and the solution was acidified with an ethereal solution of oxalic acid, yielding the oxalate, M.P. 100-101 C.

EXAMPLE 24 Analogous to Example 1, 1-(2'-hydroxymethylphenoxy) 2 hydroxy 3 (l"-methylcyclohexyl)-amino propane oxalate was prepared from l-(2'-hydroxymethylphenoxy) 2,3 epoxypropane and l-methylcyclohexylamine. The oxalate melted at 211-212 C.

EXAMPLE 25 1-(2'-cyano-4'-chlorophenoxy)-2-hydroxy-3-(1"- methylcyclohexylamino -propane HCl 2.2 gm. (0.0066 mol) of 1-(2-cyanophenoxy)-2-hydroxy-3-( l"-methylcyclohexylamino)-propane hydrochloride (prepared according to Example 1) were dissolved in 15 ml. of concentrated HCl, and the solution was heated to 45 C., whereupon 0.75 gm. (0.066 mol) of 30% hydrogen peroxide was added dropwise to the solution over a period of five minutes; the temperature rose to 65 C. The reaction mixture was then stirred for /2 hour at 65 C. and then cooled. The product crystallized out. Yield: 1.6 gm.; M.P. (hydrochloride): l94-196 C EXAMPLE 26 1- 2'-cyanophenoxy) -2-hydroxy-3- l "-rnethylcyclohexylamino -propane HCl 19.5 gm. (0.1 mol) of 1-(2'-cyanophenoxy)-2,3-epoxypropane were dissolved in 100 ml. of alcohol, and the solution was admixed with 13.5 gm. (0.12 mol) of l-methylcyclohexylamine. The mixture was refluxed for two hours, and subsequently the solvent was distilled oflf. The residue was recrystallized twice from ethylacetate by addition of petroleum ether having a boiling point of 40 C. Yield: 20.4 gm. gm. of the base were converted with ethereal hydrochloric acid into the hydrochloride. Yield (after recrystallization from alcohol/ether): 4.6 gm.; M.P. (hydrochloride): 166168 C.

10 EXAMPLE 27 1- (2'-aminophenoxy -2-hydroxy-3- I "-methylcyclohexylamino -prop ane 2 HCl EXAMPLE 28 1-(2'-bromophenoxy)-2-hydroxy-3-(1"-methylcyclohexylamino) -propane hydrochloride 1.16 gm. (0.00375 mol) of l-(2'-bromophenoxy)-2-hydroxy-3-bromopropane were heated in Tetralin with 1.8 gm. (0.0075 mol) of N,N'-bis-(1-methy1cyc1ohexyl)urea for two hours at l220 C. After cooling, 50 ml. of ether were added, and by extraction with 1 N HCl the basic components were extracted. The aqueous phase was extracted with ether and made alkaline with NaOH. The precipitated basic components were taken up in ether, and the ether phase was washed with water and dried over MgSO After distilling off the ether, a residue remained which was dissolved in a little ethanol, and the solution was admixed with ethereal HCl. The precipitated crystals were separated and dried. Yield: 300 mgm.; M.P. 154-156 C.

EXAMPLE 29 1- (2'-bromophenoxy) -2-hydroxy-3-( 1"-methyl-cyclohexylamino)-propane hydrochloride The tetrahydropyranyl ether obtained from 7.25 gm. (0.025 mol) of 1-(2-bromophenoxy)-2-hydroxy-3- bromopropane, 2.52 gm. (0.03 mol) of dihydropyran and 10 gm. of p-toluenesulfonic acid at 50 C. was dissolved in50 ml. of ethanol, 8.5 gm. (0.075 mol) of l-methylcyclohexylamine were added to the solution, and the mixture was refluxed for six hours. After distilling 01f the solvent, the residue was dissolved in a little acetone, and upon addition of maleic acid to the solution, the maleate was obtained. 2 gm. of the maleate were heated in 25 ml. of 2 N HCl on a water bath for ten minutes. After cooling, the solution was extracted with ether. The aqueous phase was made alkaline with NaOH, and the precipitated base was taken up in ether. The ether solution was washed, dried, and the ether was distilled 01f. The hydrochloride was obtained by dissolving the residue in a little ethanol and adding ethereal HCl to the solution. Yield: mgm.; M.P. 153-157 C EXAMPLE 30 l- (2'-methyl-4'-cyanophenoxy) -2-hydroxy-3-(1"- rnethylcyclohexylamino)-propane hydrochloride 0.75 gm. of 1-(2-methyl-4'-cyanophenoxy)-2-hydroxy- 3- [N-acetyl-( l-methylcyclohexylamino) propane was refluxed in 20 ml. of ethanol with 0.3 gm. of KOH for two hours. After distilling 01f the solvent, water was added, and the aqueous mixture was extracted with ether. The organic phase was washed with water and dried over MgSO After evaporation of the ether, the residue Was dissolved in a little ethanol, ethereal I-ICl was added, and the crystalline hydrochloride was collected by vacuum filtration. Yield: 0.3 gm.; M.P. 204-206 C EXAMPLE 31 1 (2-methyl-4'-cyanophenoxy -2-hydroxy-3- 1"- methylcyclohexylamino)-propane hydrochloride 1.1 gm. of 3-(1"-methylcyclohexyl)-5-(2'-methyl-4'- cyanophenoxyrnethyl)-oxazolidinone were refluxed in 20 ml. of ethanol and 4 ml. of water with 0.6 gm. of KOH for 90 minutes. After distilling off the solvent, water was added, and the aqueous mixture was extracted with ether. The ether phase was washed with water and dried over MgSO After distilling off the ether, the residue was dissolved in a little ethanol, ethereal HCl was added, and the precipitated hydrochloride was collected. Yield: 0.28 gm.; M.P. 202206 C.

EXAMPLE 32 1- (2'-cyanophenoxy) -2-hydroxy-3 1 "-methylcyclohexylamino) -propane hydrochloride A diazonium salt solution, prepared from 3.52 gm. (0.01 mol) of 1-(2'-aminophenoxy)-2-hydroxy-3-(1"- methylcyclohexylamino)-propane-2HCl, 4 ml. of concentrated HCl, 20 ml. of water and an aqueous solution of 1.4 gm. (0.02 mol) of NaNO was slowly added dropwise to a hot solution of gm. of copper sulfate, 5.8 gm. of copper cyanide in 30 ml. of water. After stirring the mixture for 30 minutes at 90 C., it was cooled and made alkaline with NaOH. After addition of chloroform, the insoluble components were separated. The organic phase was isolated, washed with water and dried over MgSO After distilling oif the CHCl the residue was dissolved in ethanol, and ethereal HCl was added. The crystals precipitated thereby were recrystallized once more from ethanol by addition of ether. Yield: 950 mgm.; M.P. 16l-164 C.

EXAMPLE 33 Analogous to Example 1, l-(2'-cyano-5-methylphenoxy)-2-hydroxy 3 (l"-methylcyclohexylamino)-propane was prepared from 1-(2-cyano-5'-methylphenoxy)- 2,3-propaneepoxide and l-methylcyclohexylamine in ethanol. M.P. (hydrochloride): 173-476 C.

EXAMPLE 34 Analogous to Example 1, I-(Z-cyano-S-methylphenoxy)-2-hydroxy 3 (l-methylcycloheptylamino)- propane was prepared from l-(2-cyano-5-methylphenoxy) -2,3-propaneepoxide and l-methylcycloheptylamine in ethanol while refluxing. M.P. (hydrochloride): 192 194 C.

EXAMPLE 35 Analogous to Example 1, 1-(2-cyano-5-methylphenoxy)-2-hydroxy 3 (1"-methylcyclopentylamino)- propane was prepared from 1-(2-cyano-5-methylphenoxy)-2,3-propaneepoxide and l-methylcyclopentylamine. M.P. (hydrochloride): 143-l46 C.

EXAMPLE 36 1-(2'-chloro-5-methylphenoxy) -2-hydroxy-3- 1"- methylcyclopentyl amino) -propane hydrochloride 1.9 gm. (0.005 mol) of N-isopropyl-N-(1'-methylcyclopentyl)-N'-{2-hydroxy-3"-(2.'-chloro 5" methylphenoxy)-propyl]-urea, 15 ml. of Tetralin and 100 mgm. of LiCl were combined, and the mixture was heated at 200 C. for one hour. Thereafter, the reaction mixture was diluted with ether and extracted twice with ml. of 1 N HCl each. The combined HCl phases were washed once with a little ether and made alkaline with NaOH. The precipitated oil was taken up in ether. After washing with water and drying with MgSO the ether was distilled off, the remaining oil was dissolved in ethanol, and the solution was acidified with ethanolic HCl. After addition of ether the product crystallized out. M.P. 170- 172 0.; yield: 600 mgm.

EXAMPLE 37 1- (2'-cyanophenoxy) -2-hydroxy-3-( 1 "-methylcyclohexylamino)-propane hydrochloride 3.52 gm. (0.01 mol) of 1-(2'aminophenoxy) 2 hydroxy-3-(1" methylcyclohexylamino) propane hydrochloride were dissolved in a mixture of 20 ml. of water and 4 ml. of concentrated HCl, and then a solution of 1.4 gm. (0.02 mol) of NaNO in 5 ml. of water was slowly added dropwise to the solution. By exterior cooling with ice the temperature was kept between 9 and +5 C. After the addition was finished, the temperature of the combined solution was kept at about 0 C. for 15 minutes more. 5 gm. of CuSO -5H O (0.02 mol), 5.8 gm. of KCN (0.04 mol) and 30 ml. of water were combined and, while stirring, the mixture was heated to C. The diazonium solution was stirred into the hot Cu(I)CN- solution, and the batch was kept for 30 minutes at 90 C. After cooling and adding aqueous 10% NaOH, the reaction mixture was extracted with chloroform. The chloroform extract was Washed with water, dried with MgSO and evaporated. The residue was dissolved in ethanol, and the solution was acidified with ethanolic HCl. After addition of ether, the product crystallized out. After recrystallization from alcohol-ether, 950 mgm, of the product were obtained. M.P. 161-163" '0.

EXAMPLE 3 8 1- (2'-cyano-5-methylphenoxy) -2-hydroxy-3-( 1"-methylcyclohexylamino) -propane hydrochloride 2.92 gm. (0.0111101) of 1-(2-amino-5'-methylphenoxy)- 2-hydroxy-3-(1"-methylcyclohexylamino) propane were dissolved in a mixture of 20 ml. of water and 6 ml. of HCl. Thereafter, a solution of 1.4 gm. (0.02 mol) of NaNO in 5 ml. of water was slowly added dropwise to the amine solution, while stirring. By exterior cooling with ice the temperature was kept between 0 and +5 C. After the addition was finished the mixed solution was kept at about 0 C. for 15 minutes more. 5 gm. of

CuSOy SH O (0.02 mol), 5.8 gm. of KCN (0.09 mol) and 30 ml. of H 0 were combined and heated to 90 C. while stirring. The diazonium solution was added dropwise to the hot Cu(I)CN-solution while stirring, and the batch was allowed to react for 30 minutes at 90 C. After cooling and adding aqueous 10% NaOH, the reaction mixture was extracted with chloroform. The chloroform extract was washed with-water, dried with MgSO; and evaporated. The residue was dissolved in acetonitrile, and the solution was acidified with ethanolic HCl. The hydrochloride which crystallized out was recrystallized once more acetonitrile. M.P. 173 C.; yield: 500 mgm.

The compounds according to the present invention, that is, those embraced by Formula I above and their nontoxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, the compounds of the instant invention exhibit very effective fi-adrenergic receptor blocking activities in warmblooded animals, such as guinea pigs, and are therefore useful therapeutics for the treatment and prophylaxis of diseases of the coronaries and for the treatment of cardiac arrythmia, especially tachycardia. The compounds also exhibit effective hypotensive activities.

Particularly effective as B-adrenergic receptor blocking agents are those compounds of the Formula I wherein R is methyl; R and R are hydrogen or also alkyl; R is an unsaturated group, such as ethinyl, cyano, allyl or allyloxy (especially in 2-position with respect to the proposed chain), or hydroxy-methyl; and n is 4, 5 or 6; and their non-toxic acid addition salts. In addition, compounds of the Formula I wherein R is methyl, R is halogen, R is hydrogen or methyl, R is hydrogen and n is 4, 5 or 6, and their non-toxic acid addition salts are also very strong B-adrenergic receptor blocking agents. Among these, the following specific compounds and their nontoxic acid addition salts are of special interest:

1-(2'-ethinylphenoxy)-2-hydroxy-3-( l"-methylcyclopentylamino)-propane;

1-(2-cyanophenoxy-2-hydroxy-3-( l "-methylcyclopentyamino)-propane;

1- (2-cyanophenoxy) -2-hydroxy-3- 1"-methylcyclohexyl-amino) -propane;

1- (2-chloro-5'-methylphenoxy -2-hydroxy-3-( 1-methylcyclopentyl-amino -propane;

l- (2'-hydroxymethylphenoxy -2-hydroxy-3-( 1"-methylcyclohexyl-amino -propane; and

1- (2-bromophenoxy) -2-hydroxy-3-( 1' '-methylcycloheptyl-amino -propane.

1-(2' cyanophenoxy) 2 hydroxy-3-(l"-methylcyclopentyl-amino)-propane is especially interesting due to its pronounced isoproterenol-antagonistic action with virtually complete absence of direct brady-cardiac action. Compounds of the Formula I wherein the phenyl group is substituted with a cyano group in 2-position and simultaneously with a lower alkyl (preferably methyl) group in 5-position are also especially effective; for instance,

1- 2'-cyano-5'-methylphenoxy) -2-hydroxy-3-( 1"-methylcyclope ntyl amino )-prop ane,

1- (2-cyano-5'-methylphenoxy) -2-hydroxy-3- 1"-methylcyclohexylamino) -propane, and

1- (2'-cyano-5'-methylphenoxy) -2-hydroxy-3-( 1"- methylcycloheptylamino) -propane and the non-toxic, pharmaceutically acceptable acid addition salts thereof.

For pharmaceutical purposes the compounds according to the present invention are administered to warm-blooded animals perorally or parenterally as active ingredients in customary dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, Wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. Such dosage unit compositions may, in addition to a compound of the present invention, also comprise an eifective dosage unit of one or more compounds having a diflerent pharmacodynamic property, such as a coronary dilator, a sympathomimetic, a cardiac glycoside and/or a tranquilizer. One effective dosage unit of the compounds according to the present invention is from 0.0166 to 5.0 mgm./ kg. body weight, preferably 0.083 to 1.67 mgm./kg. (perorally) and 0.0166 to 0.34 mgm./kg. (parenterally).

The following examples illustrate a few dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 39 Tablets The tablets composition was compounded from the following ingredients:

Parts 1-(2'-cyanophenoxy) 2 hydroxy 3 (l"-methyl cyclopentylamino)-propane-HCl 40.0 Corn starch 164.0 Secondary calcium phosphate 240.0 Magnesium stearate 1.0

Total 445.0

Preparation: The individual components were intimately admixed with each other, the mixture was granulated in customary fashion, and the granulate was compressed into 445 mgm.-tablets with a conventional tablet making machine. Each tablet contained 40 mgm. of the propanol salt and, when administered perorally to a warm-blooded animal of about 60 kg. body weight in need of such treat- 14 ment, produced a very effective fi-adrenergic receptor blocking action.

EXAMPLE 40 Gelatin capsules The capsule filler composition was compounded from the following ingredients:

Parts 1-( 2'-cyanophenoxy) 2 hydroxy 3 (1-methylcyclohexylamino) -propane -HCl 25.0 Corn starch 175.0

Total 200.0

EXAMPLE 41 Hypodermic solution Parts 1-(2-chloro 5' methylphenoxy) 2 hydroxy-3- (1"-methylcyclopentylamino)-propane-HCl 2.5

Sodium salt of EDTA (ethylenediaminetetraacetic acid) 0.2 Distilled water, q.s. ad 100.0 parts.

Preparation: The propanol salt and the EDTA salt were dissolved in a sufficient amount of distilled water, and the solution was diluted to the desired volume with distilled water. Thev solution was filtered until free from suspended particles and filled into 1 cc. ampules under aseptic conditions. Finally, the ampules were sterilized and sealed. Each ampule contained 25 mgm. of the propanol salt, and when the contents thereof were intravenously administered to a warm-blooded animal of about 60 kg. body weight in need of such treatment, a very gffecgive fi-adrenergic receptor blocking action was prouce EXAMPLE 42 Coated sustained release tablets The tablet core composition was compounded from the following ingredients:

Parts 1-(2-ethinylphenoxy) 2 hydroxy 3 (1"-methylcyclopentylamino)-propane-HCl 25.0

Preparation: The propanol salt, the CMC and the stearic acid were intimately admixed with each other, and the mixture was granulated in customary fashion, using a solution of the CAP in 200 ml. of a mixture of ethanol and ethylacetate as the moistening agent. The granulate was then compressed into 380 mgm.-cores, which were coated in the usual way with an aqueous 5% solution of polyvinylpyrrolidone containing sugar. Each coated tablet contained 25 mgm. of the propanol salt and, when administered perorally to a warm-blooded animal of about 60 kg. body weight in need of such treatment, produced a very etfective fi-adrenergic receptor blocking action over an extended period of time.

1 5 EXAMPLE 43 Tablets with combination of active ingredients The tablet composition was compounded from the following ingredients:

Preparation: The propanol salt, the lactose, the corn starch, the colloidal silicic acid and the polyvinylpyrrolidone were intimately admixed with each other, and the mixture was granulated in the usual way, using an aqueous solution of the soluble starch as the moistening agent. The granulate was admixed with magnesium stearate, and the composition was compressed into 500 mgm.-tablets. Each tablet contained 35 mgm. of the propanol salt and 75 mgm. of the pyrimidopyrimidine compound and, when perorally administered to a warm-blooded animal of about 60 kg. body weight in need of such treatment, produced very etfective ,B-adrenergic receptor blocking and coronary dilating actions.

Analogous results were obtained when any one of the other compounds embraced by Formula I or a non-toxic acid addition salt thereof was substituted for the particular salt in Examples 39 through 43. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

16 We claim: 1. A compound of the formula CH: wherein R is cyano, R is hydrogen or methyl, and n is 4, 5 or 6,

or a non-toxic, pharmacologically acceptable acid addition salt thereof.

2. A compound according to claim 1, which is 1-(2'- cyanophenoxy)-2-hydroxy 3 (1" methylcyclopentylamino)-propane or a non-toxic pharmaceutically acceptable acid addition salt thereof.

3. A compound according to claim 1, which is 1-(2- cyanophenoxy)-2-hydroxy 3 (1" methylcyclohexylamino)-propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

4. A compound according to claim 1, which is 1-(2'- cyano-S'-methylphenoxy)-2-hydroxy-3-(1" methylcyc1o pentylamino)-propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

5. A compound according to claim 1, which is 1-(2'- cyano-5-methylphenoxy)-2-hydroxy-3-( 1" methylcyclohexylamino)-propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

6. A compound according to claim 1, which is 1-(2'- cyano-5-methylphenoxy)-2-hydroxy-3-(1" methylcycloheptylamino)-propane or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

References Cited UNITED STATES PATENTS 3,459,782 8/1969 Hoppe et a1 260-465 LEWIS GOTTS, Primary Examiner- D. H. TORRENCE, Assistant Examiner US. Cl. X.R.

260307 F, 340.5, 465 D, 468 C, 471 R, 488 CD, 519, 553 A, 559 A, 562 A, 566 A, 570.7; 424282, 304, 309, 311, 319, 324

m1; 9, line .2 "hydroXymethy lphe should read ULIILU OlzilLC) frilbiii Ulflbl;

CERTIFICATE OF CORRECTION Patent no. 3,755, H3 Dated August 28, 1973 HERBERT KOITE, WERNER KUMMFIR H a. n ALBRECHT ENGELHARDT and WERNER 'TRAUNECKER .TTIE

Inventofls It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

, line 16 L1 ,"alkoxyar'yl" should Feud --a1 oX a1k 1--.-

Col 8; line 38 "methylcyclohexyleminoi' should read methy-lcyclopentylamino-- u cyanoph enox yhy 001." l2 line H6 insert --fror nafter "more" Signed and sealed this 29th day of October 197A.

( E I Y r L Attest: 5 3 I I M oYM. GIBSON JR, 0.. MARSHALL DANN" Arresting Officer I Commissioner of Patents

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3937706 *Nov 29, 1972Feb 10, 1976Boehringer Ingelheim GmbhB-adrenergic receptor blocking agents
US3998790 *Jan 15, 1974Dec 21, 1976Aktiebolaget HasslePhenoxy-hydroxypropylamines, their preparation, and method and pharmaceutical preparations for treating cardiovascular diseases
US4021576 *Dec 10, 1975May 3, 1977Boehringer Ingelheim GmbhBeta-adrenergic receptor blockers
US4035420 *Oct 2, 1975Jul 12, 1977Aktiebolaget HassleSubstituted ureido alkylene phenoxy propanolamines
US4038313 *Dec 11, 1975Jul 26, 1977Ciba-Geigy CorporationCycloalkylureido phenoxy propanolamines
US4038414 *Dec 19, 1975Jul 26, 1977Ciba-Geigy CorporationAntiarrhythmia agents
US4120978 *Apr 4, 1977Oct 17, 1978Ciba-Geigy CorporationPharmaceutical composition for inhibiting and blocking cardioselective beta-receptors
US4145442 *Aug 31, 1976Mar 20, 1979Aktiebolaget HasslePhenoxy-hydroxypropylamines, their preparation, and method and pharmaceutical preparations for treating cardiovascular diseases
US4165384 *Jan 19, 1977Aug 21, 1979Aktiebolaget HassleAdrenergic blocking agents, cardiovascular disorders
US4220659 *Jul 14, 1978Sep 2, 1980Boehringer Ingelheim Gmbh1-Phenoxy-2-hydroxy-3-alkynylamino-propanes and salts thereof
US4471127 *Aug 26, 1982Sep 11, 1984Ciba-Geigy Corporation1-5-Bis-(1,4-benzodioxin-2-yl)-3-azapentane-1,5-diols
US5039801 *Aug 28, 1987Aug 13, 1991The United States Of America As Represented By The Department Of Health & Human ServicesThermal fragmentation of methylbenzylurea disastereomers or secondary amines and preparation of optically active secondary amines
WO1982001869A1 *Nov 16, 1981Jun 10, 1982American Hospital Supply CorpMethod for treatment or prophylaxis of cardiac disorders
Classifications
U.S. Classification558/422, 564/346, 558/414, 560/42, 564/56, 562/451, 548/232, 560/142, 549/437, 564/48, 558/415, 558/419, 560/252
International ClassificationC07C213/00, E04H13/00, C07C253/00, A61P9/12, A61P9/06, A61K31/275, A61P9/08, C07C255/54, C07C217/32, C07C233/00, A61P9/10, A61P25/02, A61K31/135, C07D263/24, C07C217/34, C07C217/84, C07C67/00, A61K31/13, C07C255/53
Cooperative ClassificationE04H13/00, C07C255/53, A61K31/13, C07C233/00, A61K31/275, A61K31/135
European ClassificationC07C233/00, E04H13/00, C07C255/53, A61K31/13, A61K31/275, A61K31/135