US3925446A

US3925446A - 1-Aryloxy-2-hydroxy-3-alkynylamino-propanes

Info

Publication number: US3925446A
Application number: US444713A
Authority: US
Inventors: Herbert Koppe; Werner Kummer; Helmut Stahle; Gojko Muacevic
Original assignee: CH Boehringer Sohn AG and Co KG
Current assignee: CH Boehringer Sohn AG and Co KG; Boehringer Ingelheim GmbH
Priority date: 1973-02-28
Filing date: 1974-02-22
Publication date: 1975-12-09
Anticipated expiration: 1992-12-09
Also published as: BG21208A3; MX4592E; DK143128B; NO740670L; CH605691A5; CH605637A5; CH605636A5; BG21394A3; IE39482B1; CS186263B2; BG20564A3; NL7402704A; AU6606574A; ES436316A1; CH605690A5; NL169733B; ES436311A1; FR2218900B1; YU50074A; HU168598B

Abstract

wherein R1, R2, R3, R4 and R5 are hydrogen or various substituents, and their physiologically compatible acid addition salts, as well as the process for producing the compounds, therapeutic compositions and methods. The 1-aryloxy-2-hydroxy-3alkynylamino-propanes have andrenolytic properties and bloodpressure reducing properties.

Racemic and optically active compounds of the formula

Description

United States Patent 1191 Kiippe et al.

[ Dec. 9, 1975 3,459,782 8/1969 Koppe et al. 3,541,130 1 1/1970 Koppe et al. t.

1-ARYLOXY-2-HYDROXY-3- ALKYNYLAMINO-PROPAN ES lnve'ntors: Herbert Kiippe; Werner Kummer;

Helmut Stahle; Gojko Muacevic, all of Ingelheim am Rhein, Germany Assignee: Boehringer Ingelheim GmbH,

lngelheim am Rhein, Germany Filed: Feb. 22, 1974 Appl. No.: 444,713

Foreign Application Priority Data Feb, 28, 1973 Germany 2309887 Jan. 26, 1974 Germany 2403809 References Cited UNITED STATES PATENTS 3,712,927 1/1973 Howe et al 260/465 X Primary Examiner-Lewis Gotts Assistant Examiner-Dolph H. Torrence Attorney, Agent, or FirmHammond & Littell [57] ABSTRACT Racemic and optically active compounds of the formula wherein R R R R and R are hydrogen or various substituents, and their physiologically compatible acid addition salts, as well as the process for producing the compounds, therapeutic compositions and methods. The l 1aryloxy-2-hydroxy-3-alkynylamino-propanes have andrenolytic properties and blood-pressure reducing properties.

6 Claims, No Drawings o at:

l-ARYLOXY-Z-HYDROXY-3-ALKYNYLAMINO- PROPANES OBJECTS OF THE INVENTION wherein R is a member selected from the group consisting of hydrogen; halogen; nitro; alkyl having from 1 to carbon atoms; alkoxy having from 1 to 4 carbon atoms; alkenyl having from 2 to 5 carbon atoms; alkynyl having from 2 to 5 carbon atoms; alkylamino having from 1 to 5 carbon atoms; dialkylamino having from 1 to 5 carbon atoms in each alkyl; alkoxyalkyl having from 2 to 6 carbon atoms; alkylaminoalkyl having from 2 to 6 carbon atoms; dialkylaminoalkyl having from 3 to 12 carbon atoms; --(CH ),,CN, (CH ),,NH -(CI-I ,OH, all where x is an integer from O to 3; COOH; -COOR wherein R is an alkyl having from 1 to 4 carbon atoms; alkynyloxy having from 3 to 6 carbon atoms, alkenyloxy having from 3 to 6 carbon atoms; -CO-R OCO-R NI-I-CO--R all where R is a member selected from the group consisting of alkyl having 1 to 6 carbon atoms, phenylalkyl having 7 to carbon atoms and phenyl; cycloalkyl having from 3 to 7 carbon atoms; QCO--NR R where Q is a member selected from the group consisting of a single bond, oxygen, NI-I-, CH and CH --NH- and R and R are members selected from the group consisting of hydrogen, lower alkyl and taken together with the nitrogen, pyrrolidino, piperidino and morpholino; phenyl; phenyl substituted with a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro, cyano, and carboxyl; phenoxy; and phenoxy substituted with a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro, cyano, and carboxyl;

R is a member selected from the group consisting of hydrogen, halogen, alkyl having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, alkanoyl having from 1 to 4 carbon atoms, alkenyl having from 2 to 4 carbon atoms, cyano, amino, nitro, and, together with R 3,4-methylenedioxy;

R is a member selected from the group consisting of hydrogen, halogen, alkyl having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, and, tobether with R in the ortho position, CI-I=)\ CI-ICI-I=CH and -(CH where n is an integer from 3 to 5;

R is a member selected from the group consisting of hydrogen and alkyl having from 1 to 3 carbon atoms;

R is a member selected from the group consisting of alkyl having from 1 to 3 carbon atoms and, together with R -(CH where p is an integer from 4 to 6; and its physiologically compatible acid addition salt.

Another object of the invention is the development of methods to produce the above l-aryloxy-Z-hydroxy- 3-alkynylamino-propanes.

A yet further object of the invention is the development of therapeutic compositions and methods with the above l-aryloxy-2-hydroxy-3-alkynylamino-propanes. I

These and other objects of the present invention will become more apparent as the description thereof proceeds.

DESCRIPTION OF THE INVENTION The invention is concerned with novel substituted racemic or optically active l-aryloxy-2-hydroxy-3- alkynylamino-propanes and the acid addition salts thereof, the use of these novel compounds as active ingredients in pharmaceuticals and processes for production thereof.

The novel compounds correspond to general formula wherein, in the formula R is a hydrogen or halogen atom, a nitro group, an alkyl group with l to 5 carbon atoms, an alkoxy group with l to 4 carbon atoms, an alkenyl or alkynyl group with 2 to 5 carbon atoms, a lower alkyl (or di-lower alkyl) amino group, a lower alkoxyalkyl group or a lower alkyl (or di-lower alkyl) amino-lower alkyl group, a group of the partial formula (CI-I --CN, -(CH NI-I or -(CII OI-I, whereby x is zero or an integer from 1 to 3, COOI-I, COOR where R, means an alkyl group of 1 to 4 carbon atoms, an alkenyloxy or alkynyloxy group with 3 to 6 carbon atoms, a lower aliphatic, araliphatic or aromatic acyl-, acyloxy or acylamino group, a cycloalkyl group with 3 to 7 carbon atoms, the group Q-- CONR R (where Q is a single bond, an oxygen atom, a -NH--, CH or -CH -NH group, and R and R are hydrogen, lower alkyl or together with the nitrogen atom a heterocycle, such as the pyrrolidino, piperidino or morpholino group, or an aryl or aryloxy (preferably phenyl or phenoxy) group optionally substituted by halogen, alkyl, alkoxy, a nitro, cyano or carboxyl group;

R is a hydrogen or halogen atom, an alkyl or alkoxy group with l to 4 carbon atoms, an acyl or alkenyl group with 2 to 4 carbon atoms, a cyano, amino or nitro group or together with R the 3,4-methylenedioxy group;

R is a hydrogen or halogen atom, an alkyl or alkoxy group with l to 4 carbon atoms or, together with R the group CI-I=CHCH=CH- or (CH (n an integer from 3 to 5) with a bond of the free valencies in o-position towards each other;

R is hydrogen or an alkyl group with 1 to 3 carbon atoms, and

R is an alkyl group with l to 3 carbon atoms or, to-

gether with R the group (CI-I where p means one of the integers 4 to 6 If R represents a lower aliphatic acyl group, lower alkanoyl, such as the acetyl, propionyl, butyryl or isobutyryl group, may, for example, be considered here. As araliphatic acyl group R may represent phenylalkanoyl, such as the phenacetyl group, which is optionally substituted at the phenyl with one or several halogen atoms, alkyl groups, nitro, cyano or carboxyl groups. If R represents aromatic acyl, it may be, for example, a benzoyl group optionally substituted once or several times by halogen, lower alkyl, nitro, cyano or carboxyl.

If R represents an acyloxy or acylamino group, the acyl group therein may as well be represented by the acyl groups individually listed in the above paragraph.

The novel compounds may be produced in a number of ways, in which the following are representative:

a. Reacting a compound of general formula II g-Z II where R, to R are defined as in formula I and Z is or CHOHCH Hal (Hal halogen), with an amine of general formula Nlh-C-CECH lIl where R, to R are defined as in formula I and G is an easily hydrogenolytically removable group, for example, an acyl or an acetal group.

0. Cleavin g a protective group of general formula V where R to R are defined as in formula I and Sch is an easily removable protective group, for example, an acyl group or the carbobenzoxy group;

d. I-Iydrolyzing an oxazolidine derivative of general formula VI -OCH -CH- H R N] ICECH VI R R X R where R to R are defined as in formula 1, and X represents CO, CH or a --Cl-I-lower alkyl group, for example, with sodium hydroxide or potassium hydroxide solution in water or in an alcohol/water mixture.

In addition, other processes for the production of compounds of formula I are possible, such as converting a compound having already the 3-alkynylaminopropanol-Z side chain, but not having one of the substituents R R or R on the phenyl ring and in place thereof another substituent convertible to the desired substituent, to the desired substituent R R or R by conventional methods.

e. Converting compounds of formula VIIa where R and R are defined as in formula I, and Ar is a group of the partial formula (where R R and R have the above meanings), for example, with a mixture of hydrogen halide and hydrogen peroxide at elevated temperature.

Furthermore, the following process is suitable for producing compounds of general formula I, where R and/or R represent a CN:

g. Introducing a CN group into compound of general formula IXa C CH where R, and R are defined as in formula I, and M represents a group of the partial formula (where R, R and R are defined as in formula I) and C is an amino group or halogen.

This may be effected, in case C is an amino group, by means of diazotizing and boiling in the presence of cya- 6 nides such as KCN and in case C is halogen by reaction with Cu(I)CN in a high boiling solvent.

The starting compounds required for carrying outthe processes (a) to (g) have already been partly known. The remainder can be obtained by known processes. Thus, the epoxides of formula II may be produced easily by reaction with a corresponding phenol or phenolate of formula X where R, to R have the meanings mentioned above and Kt is hydrogen or a cation (e.g., an alkali metal cation). The epoxides may be used for production of further starting materials; for instance, the halogen hydrins of formula II may be produced by reacting the epoxides with the corresponding hydrogen halide.

Amines of formula III have been known and represent mostly commercial products. Compounds of formula IV may be obtained by reacting a halohydrin of formula II with a compound (such as vinyl ether or dihydropyran) to give the protective group G and, subsequently, reacting the obtained compound of formula with a compound of general formula III.

The tertiary amines of formula V are obtained by re acting a compound of general formula X with a compound of general formula where R R and Sch have the above-mentioned mean- XIII where R and R have the meanings mentioned above.

The compounds of formulas VIIa, VIlb, VIII, IXa and IXb already contain the complete l-phenoxy-2- hydroxy-3-alkynylamino-propane structure and may, therefore, be produced analogously to the process (2.) described above, starting from the corresponding phenol, via the corresponding l-phenoxy-2,3-epoxypropane (producible by reaction with epichlorohydrin) by reaction with an alkynylamine of formula III.

The compounds according to the invention possess an asymmetric carbon atom at the CI-IOH group and can occur, therefore, as racemates as well as in the form of optical antipodes. The latter may be obtained by separation of racemates with the conventional optically active acids, such as dibenzoyl- (or di-p-toluyI-)D- tartaric acid or D-3-bromocamphor-8-sulfonic acid or by using optically active starting materials as well.

The l-aryloxy-2-hydroxy-3-alkynylamino-propanes of general formula I according to the invention may be converted into the physiologically compatible acid addition salts thereof in the conventional way. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methane-sulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid or 8- chlorotheophylline.

The compounds of general formula I or the physiologically compatible acid addition salts thereof have shown valuable therapeutic properties, in particular, adrenolytic properties as demonstrated by animal tests in guinea pigs and may, therefore, be used for treatment or prophylaxis of diseases of the coronaries and for treatment of cardiac arrhythmia, especially of tachycardia, in human medicine. The blood-pressure decreasing properties of the compounds are therapeutically interesting too. Compared to the known ,B-receptor blockers, for example, the commercial product 1- 1-naphthyloxy)-2-hydroxy-3-isopropylaminopropane (Propranolol), the compounds have the advantage of a considerably decreased toxicity combined with a superior action.

The invention, therefore, also relates to a process for the treatment of coronary diseases, cardiac arrhythmia and high blood pressure in warm-blooded animals comprising administering a safe but effective amount of the l-aryIoxy-2-hydroxy-3-alkynylamino-propane compounds of formula I.

Here compounds of general formula I have proved to be valuable, in particular, where R and R represent each a methyl group and one of R R and R is other than hydrogen (substituted l-phenoxy-3-(2-methylbutynyl-3-amino-2)-2-propanols).

Among the preferred meanings for R are to be stressed the unsaturated substituents such as alkenyl (e.g., allyl), alkynyl (e. g., ethynyl, propynyl), alkenyloxy (e.g., allyloxy), alkynyloxy (e.g., propargyloxy) or cyano, in particular, if they stand in the 2- position to the propanolamine side-chain.

R may represent in this case preferably hydrogen, but furthermore, lower alkyl (e.g., methyl), preferably in the 5-position to the propanolamine side-chain, while R is hydrogen as a rule. R and R are again preferably methyl.

A further preferred sub-group is formed by such substances of general formula I, where R represents a hydroxyalkyl, in particular, the hydroxymethyl group; or

an amino or acylamino, especially acetylamino group; whereby R and R may represent in the first case hydrogen, in the second case hydrogen or else halogen or lower alkyl. R, and R are again preferably methyl.

Important individual compounds are, in particular: l-(2-cyano-phenoxy)-3-(Z-methylbutynyl-3-amino-2)- 2-propanol and l-(2-ethynylphenoxy)-3-(2-methylbutynyl-3-amino-2)-2-propanol, l-(2-allylphenoxy)-3-(2- methylbutynyl-3-amino-2)-2-propanol, furthermore, 1-( 3 ,5-dibromo-4-aminophenoxy)-3-( Z-methylbutynyl-3-amino-2 )-2-propanol l-( 2-hydroxymeth ylphenoxy)-2-(Z-methylbutynyl-3-amino-2)-2-propanol, the l-( 3-chlorophenoxy )-3-( 2-methylbutynyl-3-amino- 2)-2-propanol and the l-(4-acetamidophenoxy)-3-(2- methylbutynyl-3-amino-2)-2-propanol or the physiologically compatible acid addition salts thereof.

The single dose of the compounds according to the invention lies at l to 300 mg, preferably 5 to mg (orally) or 1 to 20 mg (parenterally). When adminis tered to warm-blooded animals, the single dosage is from 0.015 mg to 5 mg/kg.

The active ingredients according to the invention may be incorporated into the conventional galenic forms of administration, such as tablets, coated tablets, solutions, emulsions, powders, capsules or forms of sustained release. For the production of the above, the usual pharmaceutical excipients as well as the conventional methods of production may be applied.

Corresponding tablets may be obtained by mixing the active ingredients with known excipients, for example, with inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc and/or agents for obtaining sustained release, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate/phthalate or polyvinylacetate.

The tablets may also be composed of several layers. There may be produced correspondingly coated tablets by mans of coating cores, prepared analogous to the tablets, with agents usually applied for tablet-coats, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. For obtaining sustained release or in order to avoid incompatibilities, the core may consist of several layers as well. Thus, the tablet coat for obtaining sustained release may also consist of several layers, whereby the excipients mentioned above for tablets may be used.

Drinks of the active ingredients or active ingredient combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerin or sugar, as well as an agent improving the taste, for example, a flavor, such as vanilla or orange extract. Besides they may comprise suspension auxiliaries or thickeners, such as sodium carboxymethylcellulose, wetting agents, such as condensation products of fatty alcohols with ethylene oxide, or protective substances, such as p-hydroxybenzoates.

Injectable solutions are produced in the conventional way, such as under addition of preservation agents, such as p-hydroxybenzoates, or stabilizers, such as Komplexonen (the sodium salt of ethylene diaminetetraacetic acid), and filled into injection vials or ampoules.

Capsules containing the active ingredients or active ingredient combinations may be produced, for example, by admixing the active ingredients with inert carri- EXAMPLE 1 l-a-Naphthoxy-3-( 3-ethylpentynyl-4-amino-3 )-2- propanol HCl (according to process [a]) (I, R H,

10 Grams (0.05 mol) of l-a-naphthoxy-2,3-epoxypropane were dissolved in 80 ml of ethanol. 5.55 Grams (0.05 mol) of 3-ethyl-3-amine-pentyne-4 were added and the mixture was refluxed for two hours at boiling temperature. After having cooled off, the solvent was distilled off. The residue was dissolved in ether and acidified with alcoholic HQ. The crystallizable compound was isolated and recrystallized from a mixture of acetonitrile and ethanol.

Yield: 9.5 gm, m.p. 195 to 196C.

EXAMPLE 2 1-m-To1yloxy-3-(2-methy1butynyl-3-amino-2)-2- propanol HCl (according to process [a]) (1, R 3-CH R and R H, R, and R CH 8.2 Grams (0.05 mol) of l-m-tolyloxy-2,3-epoxypropane were dissolved in 90 ml of ethanol, and after addition of 6.25 gm (0.075 mol) of 2-methyl-2- aminebutyne-3, the mixture was refluxed for two hours. After distilling off the solvent, the residue was recrystallized from ethyl acetate under addition of petroleum ether. The crystalline base was dissolved in acetonitrile; alcoholic HCl was added and crystallization was started under addition of ether. 6.5 Grams of colorless crystals were obtained, which are chromatographically pure. M.p. 139 to 141C.

EXAMPLE 3 1-(2-Allylphenoxy)-3-(2-methylbutynyl-3-amino2)-2- propanol.oxalate (according to process [a]) (I, R

Z-allyl, R2 and R3 H, R4 and R5 9.5 Grams (0.05 mol) of l-(2-allylphenoxy)-2,3- epoxypropane were dissolved in 60 ml of methanol. 8.3 gm (0.1 mol) of 2-methyl-2-amine-butyne-3 were added and the mixture was refluxed for three hours.

10 After having distilled off the solvent, the basic residue was dissolved in acetone and a solution of 6 gm of oxalic acid was added. The precipitating crystalline oxalate was recrystallized from acetone once more. Yield: 4.7 gm, m.p. 144 to 146C.

EXAMPLE 4 l-(2-Cyanophenoxy)-3-(2-methylbutynyl-3-amino-2)- 2-propanol HCl (according to process [a]) (I, R

2 CN, R3 and R3 H, R4 and R3: CH3) 17.5 Grams (0.1 mol) of l-(2-cyanophenoxy)-2,3- epoxypropane were dissolved in 130 ml of ethanol. After addition of 16.6 gm (0.2 mol) of 2-methyl-2- amine-butyne-3, the mixture was refluxed for 2 hours. The solvent was distilled off. The remaining residue was acidified with HCl and shaken. After vacuum filtering the insoluble particles, the filtrate was adjusted alkaline by NaOH. The precipitating base was dissolved in chloroform and the organic phase, after separation, was dried over Na SO After filtration the chloroform was distilled off and the residue wass recrystallized from ethyl acetate under addition of petroleum ether. The base was dissolved in acetonitrile and acidified with alcoholic HCl. The hydrochloride crystallized colorlessly.

Yield: 13.9 gm (uniform substance, in the thin-layer. chromatogram). M.p. 169 to 171C. 1

EXAMPLE 5 1-( 2-Cyanophenoxy)-3 l-ethynylcyclohexylamino Z-propanol HCl (according to process [a]) (1, R

2CN, R and R R and R together= 9 Grams (0.05 mol) of l-ethynylcyclohexylamine were dissolved together with 8.7 gm (0.05 mol) of l-(2- cyanophenoxy)-2,3-epoxypropane in ml of ethanol and refluxed for 2 hours. After having distilled off the solvent, the residue was dissolved in ethyl acetate and shaken with diluted HCl. The aqueous phase was separated and adjusted alkaline with NaOH. The precipitated base was extracted with ethyl acetate. The organic phase was washed, dried over MgSO filtered and the solvent was distilled off. The remaining residue was recrystallized from ethyl acetate under addition of ligroin. The colorless crystalline base was dissolved in alcohol. Alcoholic HCl was added and the hydrochloride was brought to crystallization by dropping in ether. After separation, the salt was recrystallized once more from ethanol under addition of ether.

Yield: 6.5 gm, m.p. 176 to 177C.

Analogous to the Examples 1 to 5, the following compounds of formula 1 are produced in line with process (a), e.g. by reacting the correspondingly substituted 1- phenoxy-2,3-epoxypropane according to formula II with the corresponding amine according to formula [11 in ethanol.

TABLE-continued M.P. of HC1- Salt in Case Nothing Else Indicated R, R, R, R. R c

3CH; H H (CH 159-160 2CH -CH=CH H H (CH 120-122 Z-Br H H CH CH 138-139 4-CN H H CH CH 194-196 4NO H H CH CH 183-184 4CH OH H H CH CH 108-1 (Base) 2-OCH; H H CH CH 161-163 4 co0cH H H CH CH 127-129 H 3,4(CH,);,- CH, (:H 139-140 4Tert. c.H H H CH. ci-l 146-147 2iso C H H H CH CH 157-158 Z-C CH H H CH CH 165-167 4-NHCONHCH H H CH CH 107-109 (Base) 4NHCON(C H H H CH CH 125-127 4NHCONHC H2CN H CH CH 161-164 (Base) 4NH-CO-NHCH 2CN H CH CH 155-157 (Base) 4NHCONHiC;,l-ECN H CH CH 12.7-130 (Base) 4CH -CO NH H H CH CH 107-110 (Base) 3(C H ),N- H H CH CH 134-137 (dihydrochloride) 4COOH H H CH CH 159-162 4NH-COCH: H H CH CH 137-138 (Base) 2-CH OH H H CH CH 150-152 (Oxalate) 2C H H H CH CH 150-152 2-Cl 4Cl H CH CH 170-1 71 3C1 H H CH CH 142-144 2CONH H H CH CH 230-233 2CN 4Cl H CH CH 176-177 3-Br 4Nl-1 5-Br CH CH 183-185 (dihydrochloride) 2C C-CH; H H CH CH 164-166 H 3,4O-(CH )O CH CH 175-176 4-COC H H H CH CH 149-151 4-OH H H CH CH 136-1375 (Base) 2-C H H H CH CH 157-158 2-C1 H H CH CH 150-151 EXAMPLE 6 50 l-( 2-Allyloxyphenoxy )-3- 2-methylbutynyl )-3-amin0- 2) 2 propanol HC1 (according to process [b]) (1, R EXAMPLE 7 2-OCH CH=CH R and R H, R., and R CH 2.4 Grams (0.025 mol) of tetrahydropyran were dropped slowly into 6.42 gm (0.025 mol) of l-(2- allyloxyphenoxy)-3-bromo-2-propanol and a catalytical quantity of p-toluenesulfonic acid at to C. Then the mixture was heated for minutes to C, dissolved in 40 ml of benzene, and 5 gm (0.06 mol) of 2-methyl-2-amine-butyne-3 were added to it. The mixture was refluxed for 2 hours; then the solvent was distilled off and the residue was heated for 15 minutes with diluted hydrochloric acid to 80C. After cooling off, it was extracted from ether and the aqueous phase was adjusted alkaline by NaOH. The precipitating basic portions were taken up in ether. The organic phase was dried with M gSO and after filtering the ether was distilled off. The residue was dissolved in little ethanol. Etheric HC1 was added and the crystalline hydrochloride recrystallized twice. M.p. 99 to 102C.

l- 4-Nitrophenoxy )-3- Z-methylbutynyl-3-amino-2 2-propanol .l-lCl (according to process [c]) (1, R 4-NO R and R H, R, and R CH 2.7 Grams (approximately 0.008 mol) of l-(4-nitr0- phenoxy)-3-(N-acetyl-2-methylbutynyl-3-amino-2)-2- propanol were refluxed in 25 ml of ethanol with 1 gm of KOH for 2 hours. After having distilled off the solvent, a viscous residue remained, which was treated with diluted HC1. After shaking out with chloroform, the aqueous phase was adjusted alkaline with NaOH and the precipitating amine was taken up in chloroform. After drying over NaSO the solvent was distilled off and the residue was recrystallized from ethyl acetate under addition of petroleum ether.

Yield: 1.5 gm, m.p. to 127C (base). Mixed melt ing point with substance obtained according to process (a): 126 to 127C.

EXAMPLE 8 l-( 2-Cyanophenoxy )-3-( Z-methylbutyn e-3-amino-2 2-propanol HCl (according to process [d]) (I, R, 2-CN, R and R H, R; and R CH 2.84 Grams (0.01 mol) of 3-(2-methylbutyne-3-yl- 2)-5-(2-cyanophenoxymethyl)-oxazolidine-2-one were refluxed in 20 ml of ethanol, after addition of 3 gm of KOH in 6 ml of water, for three hours. After having distilled off the solvent, the residue was treated with water and extracted with chloroform. Then the chloroform solution was shaken with diluted HCl and the separated aqueous phase was adjusted alkaline with NaOH. The precipitating base was taken up in chloroform. The organic phase was washed with water and dried over Na After filtration, CHCl was distilled off and the residue was recrystallized from ethyl acetate under addition of petroleum ether.

Yield: 1.3 gm, m.p. 84 to 86C (base). Mixed melting point with identical substance: 83 to 85C.

EXAMPLE 9 1-( 4-Amino phenoxy )-3-( 2-methylbutynyl-3-amino-2 2-propanol HCl (according to process [e]) (1, R 4-NH R and R H, R and R CH A mixture of 8.1 gm of tin-I1 chloride in 20 ml of conc. HCl was heated to 60C and 2.62 gm (0.01 mol) of l-( 4-nitrophenoxy 3 2-methylbutynyl-3-amino- 2)-2-propanol were added in portions, so that the temperature did not exceed 65C. After the addition had been finished, the mixture was stirredfor 30 minutes and after cooling off it was adjusted alkaline with NaOH. The precipitating basic portions were shaken with chloroform. The chloroform solution was washed with water and dried over Na SO After distilling off the CHCl a solid residue remained, which was recrystallized from ethyl acetate under addition of petroleum ether.

Yield: 1.4 gm, m.p. 122 to 123C (base).

According to process (e), the compound 1-(4- hydroxyphenoxy)-3(2-methylbutynyl-3-amino-2)-2- propanol was made by heating the compound l-(4-diethylaminocarbonyloxyphenoxy)-3-(2-methylbutynyl-3- amino-2)-2-propanol (m.p. of hydrochloride: 126C) in the presence of concentrated aqueous HCl. M.p. of the end product (base) is 136 to 137.5C.

EXAMPLE 1-( 2-Cyano-4-chlorophenoxy)-3-(2-methylbutynyl-3- amino-2)-2-propanol HCl (according to process [f]) (I, R, =2-CN. R2=4c1, R..= H, R r and R1,: C Ha) 3.87 Grams (0.015 mol) of l-(2-cyanophenoxy)-3- (2-methylbutynyl-3-amino-2)-2-propanol were admixed with 25 ml of conc. HCl and heated to 45C. While cooling 1.7 gm (0.015 mol) of 30% H 0 were dropped in in such a way that the temperature did not rise above 65C. After the batch had been stirred for a further 30 minutes, the crystal mass was vacuumed off and washed with water. The hydrochloride was recrystallized from ethanol.

Yield: 1.95 gm. m.p. 176 to 177C.

EXAMPLE 1 l l-( 2-Cyanophenoxy)-3 2-methylbutynyl-3-amino-2 Z-propanol HCl (according to process [g]) (1, R

2- CN, R3 and R3: H, R4 and R7,:

PLE. 12

1-( 4-Hydroxycarbonylphenoxy)-3-( Z-methylbutyn yl- 3-amino-2)-2-propanol HCl (according to process [e]) (1, R RCOOH, R and R H, R., and R CH 5 Grams of 1-(4-ethoxycarbonylphenoxy)-3-(2- methylbutynyl-3-amino-2)-2-propanol hydrochloride were refluxed in 30 ml of conc. HCl for two hours. After cooling, the crystalline mass that originated by hydrolysis was vacuum filtered and recrystallized twice from ethanol under addition of ether. Yield: 3.1 gm, m.p. 159 to 162C.

EXAMPLE l3 1-( 3,5-Dibromo-4-aminophenoxy)-3-( 2-methylbutynyl-3-amino-2)-2-propanol 2 RC1 (according to R and R CH 4.96 Grams (0.02 mol) of l-(4-aminophenoxy)-3-(2- methylbutynyl-3-amino-2)-2-propano1 were added into a mixture of 30 ml of HBr (65%) and 10 ml of water and heated to 45C. While stirring and cooling, 4.54 gm (0.04 mol) of H 0 30%, were dropped into the mixture in such a way that the temperature did not rise over 65C. After it had been kept at approximately 65C for a further 30 minutes, the crystalline substance was vacuum filtered after cooling. It was then recrystallized from ethanol under addition of ether. Then the hydrochloride was dissolved in water. NaOH was added. The base was extracted with CHClg and, after evaporation of the solvent, recrystallized from ethyl acetate under addition of petroleum ether. The chromatographically pure base was dissolved in ethanol; alcoholic HCl was added and the dihydrochloride was brought to crystallization under addition of ether. Yield: 3.8 gm, m.p. 183 to 185C.

EXAMPLES OF FORMULATIONS 1. Tablets l-( 2-cyanophenoxy)-3-(2-methyl- PRODUCTION The individual components were admixed well and the mixture was granulated in the usual way. The granulate was pressed into tablets of 445 mg by weight, of which each contains 40 mg of active ingredient.

Instead of the active ingredients mentioned in this example, the substances l-( 2-cyanophenoxy)-3-( lethynylcyclohexylamino)-2-propanol. HCl and 1-(2- cyano-4-chlorophenoxy)-3-( 2-methylbutynyl-3-amino- 2)-2-propanol may be used in the same quantity.

2. Gelatin Capsules The content of the capsules was composed as follows:

butynyl-3-amino-2)2-propanol I-ICl 25.0 mg Corn starch 175.0 mg 200.0 mg

PRODUCTION The active ingredients of the content of capsule were mixed well and 200 mg portions of the mixture were filled into gelatin capsules of suitable size. Each capsule contains 25 mg of the active ingredient.

3. Injection Solution The solution was produced of the following ingredients:

1-( 2-cyano-5 -m ethylphenoxy )-3- (Z-methylbutynyl-3-amino-2 )-2- propanol HCl 2.5 parts Sodium salt of EDTA (ethylenediaminetetraacetic acid) 0.2 parts Distilled water ad 100.0 parts PRODUCTION same quantity may be used as well.

4. Coated Tablets with Sustained Release Core:

propanol HCl 25.0 gm Carboxymethyl cellulose (CMC) 295.0 gm Stearic acid 20.0 gm Cellulose acetate/phthalate (CAP) 40.0 gm

PRODUCTION Active ingredient, CMC and stearic acid were mixed well and the mixture was granulated in the usual way, using a solution of the CAP in 200 ml of a mixture of ethanol/ethyl acetate. Then the granulate was pressed to 380 mg cores, coated in the conventional way with a sugary 5% solution of polyvinylpyrrolidone in water. Each coated tablet contains 25 mg of active ingredient.

16 5. Tablets la-Naphthoxy-3-( 3-ethylpentynyl- Instead of the B-adrenolytically active substances mentioned in this example, the substances l-( 2-allyloxyphenoxy)-3-(2-methylbutynyl 3-amino-2)-2- propanol. HCl and l-(2-propargyloxyphenoxy)-3-(2- rnethylbutynyl-3-amino-2)-2-propanol. HCl may be used as well in the same quantity.

PRODUCTION The active ingredient together with the lactose, corn starch, colloidal silicic acid and polyvinyl pyrrolidone was granulated after thorough mixing in the usual way, using an aqueous solution of the soluble starch. The granulate was admixed with the magnesium stearate and pressed into 1000 tablets each of 500 mg of weight, containing each 35 mg of the first and mg of the second active ingredient.

The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood, however, that other expedients known to those skilled in the art or disclosed herein may be employed without departing from the spirit of the invention and the scope of the appended claims.

We claim:

1. A racemic or optically active compound of the formula wherein R is (CH CN, where X is 0, l, 2 or 3, R is hydrogen, halogen or NHCONI-IR, where R is lower alkyl, R, is alkyl of 1 to 3 carbon atoms, and R is alkyl of 1 to 3 carbon atoms or, together with R (CH where p is 4, 5 or 6, or a physiologically compatible acid addition salt thereof.

2. A compound of claim 1, wherein R is (CH -CN, where X is O, 1, 2 or 3, R is hydrogen, halogen or NHCONI-IR, where R is lower alkyl, and R and R are methyl, or a physiologically compatible acid addition salt thereof.

3. A compound of claim 1, which is of the formula 18 R is hydrogen, chlorine or NHCONHR,

where R is alkyl of l to 3 carbon atoms, and R and R are methyl. or a physiologically compatible acid addition salt 5 thereof.

5. A compound of claim 3, which is of the formula wherein R is hydrogen, chlorine or NH-CONHR, CHZ 2 H where R is alkyl of l to 3 carbon atoms, and H3 R and R are methyl, ethyl or together pentamethylene or a h slolo icall com atible acid addition salt or a physiologically compatible acid addition salt thereog y g y p thereofi 6. A compound of claim 1, wherein R is 2-cyano, R

4. A compound of claim 3, is hydrogen and R and R are methyl. wherein Patent No.

UNITED STATES PATENT OFFICE Dated December 9. 1975 l flwjerbert Kippe et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 1,

Col. 8,

Col. 9,

Col. 10,

Cole 10,

Col. 11,

Line

this

gigned and first Day 0? June1976 A Nest:

RUTH C. MASON Arresting Officer c. MARSHALL DANN Commissioner vj'larenls and Trademarks

Claims

1. A REACEMIC OR OPTICALLY ACTIVE COMPOUND OF THE FORMULA

2. A compound of claim 1, wherein R1 is -(CH2)X-CN, where X is 0, 1, 2 or 3, R2 is hydrogen, halogen or -NH-CO-NHR, where R is lower alkyl, and R4 and R5 are methyl, or a physiologically compatible acid addition salt thereof.

3. A compound of claim 1, which is of the formula

4. A compound of claim 3, wherein R2 is hydrogen, chlorine or -NH-CO-NHR, where R is alkyl of 1 to 3 carbon atoms, and R4 and R5 are methyl, or a physiologically compatible acid addition salt thereof.

5. A compound of claim 3, which is of the formula

6. A compound of claim 1, wherein R1 is 2-cyano, R2 is hydrogen and R4 and R5 are methyl.