IL44301A

IL44301A - 1-aryloxy-2-hydroxy-3-alkynyl-amino-propanes and their salts their production and pharmaceutical compositions containing them

Info

Publication number: IL44301A
Application number: IL44301A
Authority: IL
Original assignee: Boehringer Sohn Ingelheim
Priority date: 1973-02-28
Filing date: 1974-02-27
Publication date: 1977-03-31
Also published as: IE39482L; DK143128C; ES423466A1; ES436316A1; HU168598B; GB1450287A; CA1062717A; ES436311A1; IE39482B1; MX4588E; YU50074A; JPS594417B2; NL169733B; FI62054B; NO740670L; CH605639A5; AT330150B; BG20566A3; NO138062C; CH605691A5

Description

'οκ * 3 » ρ κ-3- * ο ρ 1 κ π *π-2- "» ο ρ ι κ1* * η -1 mnp i »-) o3rn o"ns»* ,ο·»σ·τπ η'ΐβ ο Novel l-aryloKy-2-hydroxy-3~a kynylamino- propanes and their salta, their production and pharmaceutical compoeltions containing them C.H. BOEHRINGER SOHN G. 42366 The present invention relates to novel substituted racemic and optically active l-aryloxy-2-hydroxy-3-alkyny_L-amino-propanes , the acid addition salts thereof, and to processes for their production.

Some of the compounds according to the invention, i.e. those in which R2 = R3 = hydrogen, and = cycloalkyl, fall within the scope of the generic formula disclosed in Israel patent specification No. 31121. However, none of the propane derivatives according to the invention, which are characterized by a 3-alkynylamino group, are specifically described or even mentioned in Israel patent specification No. 31121.

According to one feature of the present invention there are provided compounds of the general formula :- [wherein R^ represents a hydrogen or halogen atom, a nitro group, an alkyl group with 1 to 5 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkenyl or alkynyl gropwith 2 to 5 carbon atoms, a lower alkoxyalkyl group or a group of the formula: -(CH2)x-CN, -(CH2)x-NH2 or -(CH^-OH, (in which x is zero or an integer from 1 to 3) , the group -C00H or -C00R , (in which R, represents an alkyl group with 1 b o to 4 carbon atoms) , an alkenyloxy or alkynyloxy group with 3 to 6 carbon atoms, lower alkanbyl, alkanoyloxy o^c. alkanoylamino, phenacetyl optionally substituted in the phenyl moiety by at least one. halo, alkyl, nitro, cyano or carboxyl group, benzoyl optionally substituted by at least one halo, alkyl, nitro, cyano or carboxyl group, a cycloalkyl group with.3 to 7 carbon atoms, the group: , (in which Q represents a single bond, an oxygen atom, a NH- , CH,,- or Cl^- H group and R7 and R_ , which may be the same or different, each represents' a o hydrogen atom, or a lower alkyl group or ^ and Rg together with the nitrogen atom therebetween represent a pyrrolidino, piperidino or morpholino, or phenyl or phenoxy, -optionally substituted by at least one halogen atom, alkyl, alkoxy, nitro, cyano or carboxyl group); I¾2 represents a hydrogen or halogen atom, an alkyl or alkoxy group with 1 to 4 carbon atoms, lower alkanoyl or alkenyl group with 2 to 4 carbon atoms, or a cyano, amino or nitro group; or and together represent a 3 , 4-methylenedioxy group; R a hydrogen or halogen atom, or an alkyl or alkoxy 3 ' group with 1 to 4 carbon atoms; or and R^,being bonded to adjacent carbon atoms in the phenyl moiety, together represent the group :- -CH=CH-CH=CH- or "^CH2')n" (in which n is an integer from 3 to 5); represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; and R,. represents an alkyl group with 1 to 3 carbon atoms; or and R,. together represent the group ~ CH ^- (in which p represents an integer from 4 to 6)] and acid addition salts thereof.

The compounds according to the invention as hereinbefore defined contain an asymmetric carbon atom and thus may exist not only in racemic form but also in the form of optically active isomers. It will be appreciated that all such forms of the compounds of formula I (and acid addition salts thereof) are within the scope of the present invention.

The acid addition salts useful for incorporation in pharmaceutical compositions are physiologically compatible acid addition salts, other acid addition salts may however be useful in the preparation of compounds of formula I and physiologically compatible acid addition salts thereof.

The compounds of general formula I and their physiologically compatible acid addition salts have shown interesting pharmacological activity in animal tests on guinea pigs, particularly adrenolytic activity. The compounds of formula I may thus be useful in human medicine for the treatment or prophylaxis of diseases of coronary vessels and for the treatment of cardiac arrythmia, especially of tachycardia. The blood pressure decreasing properties of the compounds are also therapeutically interesting.

Compounds of formula I have thus been tested and found to have a greater activity coupled with a substantially less toxic effect than known β-receptor blockers such, as, for example, the commerical product 1- ( 1-napthyloxy)- 2-hydroxy-3-isopropylaminopropane (propanolol) .

Where a compound of formula I contains the group Rg , the said group preferably represents a pyrrolidino, piperidino, morpholino, phenyl or phenoxy group.

Where represents lower alkanoyl, alkanoyloxy or alkanoylamino the said alkanoyl group is preferably an acetyl, propionyl, butyryl or isobutyryl group.

Preferred compounds according to the present invention by virtue of their especially favourable physiological properties include compounds of formula I (wherein represents an alkenyl, alkynyl, alkenyloxy, alkynyloxy or cyano group especially the allyl, ethynyl, propynyl, allyloxy oir- propargyloxy group) and- acid addition salts thereof. Compounds according to the present invention wherein the group R-^ is in the 2-position of the phenoxy group are particularly preferred.

Other preferred compounds according to the present invention include compounds of formula I. [wherein R^ represents a hydrogen atom or a lower alkyl (e.g. methyl) group] and acid addition salts thereof. The substituent is preferably in the 5-position of the phenoxy group and R^ preferably represents a hydrogen atom.

Preferred compounds according to the invention, by virtue of their interesting physiological properties also include compounds of formula I [wherein ^ represents a hydroxyalkyl group (especially the hydroxysthy1 group) and ¾2 and both represent hydrogen atoms] and acid N addition salts thereof.

Other preferred compounds according to the invention, by virtue of their interesting physiological properties, include compounds of formula I [wherein R^ represents an amino or alkanoylanvino group (especially the acetylamino group) and and R.. , which may be the same or different, each represent a hydrogen or halogen atom or an alkyl group] and acid addition salts thereof.

Compounds of formula I. (wherein R^ and R^ both represent a methyl group) and acid addition salts thereof are also preferred compounds of the invention.

Especially preferred compounds of the invention include the following compounds :- 1- ( 2-Cyanophenoxy) -3- ( 2-amino- 2-methylbut-3-ynyl) - 2- propanol and acid addition salts thereof; 1- ( 2-Ethynylphenoxy) -3- ( 2-amino-2-methylbut-3-ynyl.) - 2- propanol and acid addition salts thereof; compound of claim 17. l-(3,5-Dibromo-4-aminophenoxy)-3-(2-amino-2-methylbut-3- yryl.)-2-propanol and acid addition salts thereof; 1-!( 2-Hydroxy thylphenoxy) -3- (2-amino- 2-methylbut-3-yiyl) 2-propanol and acid addition salts thereof; 1- ( 3-Chlorophenoxy) -3- ( 2-amino- 2-methylbut- 3-ynyl) - 2- propanol and acid addition jsalts thereof ; and ύ 1- ( 4-Acetamidophenoxy) -3- ( 2-amino- 2-methylbut- 3-ynyl) - 2- propanol and acid addition salts thereof.

The compounds of formula I may, for example, be prepared by one of the following processes (a) to (h) which processes constitute a further feature of the present invention: - a) Reacting a compound of formula R3 [wherein R^ , and R^ are as hereinbefore defined and Z represents the group:- -CH — Cl^ or -CHOH-Cl^-Hal (wherein Hal represents a halogen atom)] with a compound of the formula NH -CR/RC-C = CH III h D wherein R. and Rr are as hereinbefore defined, b) Hydrolysing or hydrogenating a compound of the wherein R^, R^ , R^ > and R,_ are as hereinbefore defined and G represents a hydrolytically or hydrogenolytically removable group such, as for example an acyl or acetal group . c) Reacting a compound of the formula (wherein R^, ^, ^ , ^ and R<. are as hereinbefore defined and Sch represents a removable protecting group) whereby a compound of formula I is obtained. The reaction is preferably effected by hydrolysis or hydrogenation.

Where the reaction is effected by hydrogenation the hydrogenation is such that the -C Ξ CH group in the compound of formula V is not reduced. A compound of with water into a hydroxymethyl group) , a halogen atom (converts by reaction with Cu(l)CN and pyridine at i elevated temperatures into a cyano group) , a nitro group (converts by reduction into !an amino group) , an alkoxy- I carbonyl group (converts by saponification into a carboxyl group) or an amino group (converts by diazoti- zatjion and heating with copper (1) cyanide).

Thus the group A may be converted into the group R^ byIap lying such measures (e.g. dehydration, exchange reaction or reduction, diazotization and heating with a ! copper- (1)- salt etc.) as may be necessary, f) I the reaction of a compound of the formula (wherein R. , R0 , RA and R.. are as hereinbefore defined and represent such groups as a halogen atom or the group -C0NH2 or -CH=N0H or the aldehyde (-CH0) group (converts i by reduction into a methyl group) or an amino group (converts by diazotization and treatment with a copper (I) salt into a cyano group or a chlorine atom). g) For the preparation of compounds of foirmula I as I hereinbefore defined (wherein or represents a halogen atom) the halogenation of a compound of the formula R.

Ar-OCH -CHOH-CH -NH—C—C= CH VIII j wherein R. and Rr are as hereinbefore defined and 4 5 represents the group (wherein R^, and R^ are as hereinbefore defined).

! The halogenation is preferably effected by the use of a hydrogen halide/hydrogen peroxide mixture and advantageously at an elevated temperature. h) for the preparation of compounds of formula I as hereinbefore defined (in which or represents a cyano group) , the reaction of a compound of the formula:- R.

M-0-CH -CH0H-CH -NH—C—C ≡ CH IXa R5 (wherein R^ and R^ are as hereinbefore defined and M represents the rou : (wherein R^, and R^ are as hereinbefore defined and C represents an amino group or halogen atom) to convert the compound of formula IXa into a compound of formula I Where C represents an amino group, the reaction is preferably effected by diazotization and subsequent boiling in the presence of a cyanide such as KCN.

Where C represents a halogen atom the reaction is preferably effected with Cu(I)CN conveniently in the presence of a high boiling solvent.

Certain of the starting materials required for carrying out processes (a) to (h) are already known, but in any case may be obtained according to known processes. Thus, the epoxides of formula II may, for example, be produced by ,reaction with a corresponding phenol or phenolate of formula R 3 wherein R^, and R^ are as hereinbefore defined and Kt means hydrogen or a cation (e.g. an alkali metal cation). The epoxides may conveniently be used for the production of further starting materials, e.g. the halohydrins of formula II which may, for example, be produced by reacting the epoxide with a corresponding hydrogen halide.

The amines of formula III are known and, in general, represent commercial products. Compounds of formula IV may, for example, be obtained by reacting a halohydrin of formula II with a compound (such as vinyl ether or dihydropyran) capable of introducing the protecting group G and, subsequently, reacting the compound thus obtained of formula: - -r XI with a compound of general formula III.

The tertiary amines of formula V may, for example, be obtained by reacting a compound of general formula X with a compound of general formula Sch R Z-CH -N C-C = CH XII R5 wherein R. , Rc and Sch are as hereinbefore defined. 4 5 The oxazolidinones of formula VII (e.g. compounds where X = CO) may be produced, for example, starting from an epoxide of formula II, by reacting the latter with a urethane (producible from chloroethyl formate and an amine of formula II) of formula HC=C-C-HN-C-OC H XIII 0 wherein R, and Rr are as hereinbefore defined. 4 5 The compounds of formulae Vila, Vllb, VIII, IXa and IXb already contain the (complete l-phenoxy-2-hydroxy- 3-alkynylaminopropane structure and may therefore be produced in a similar manner to process (a) described above, starting from the corresponding phenol , which gives the corresponding l-phenoxy-2 ,3-epoxypropane on reaction with epichlorohydrin. The product is then reacted with an alkynylamine of formula III in order to give the desired starting compound.

Compounds of general formula I contain an asymmetric carbon atom at the -CHOH- grouping and therefore occur in the form of racemates and optically active isomers. Any racemates present may be resolved into their optically active forms by methods known per se e.g. by means of optically active acids, such as for example dibenzoyl or di-p_-toluyl-D-tartaric acid or D-3-bromocamphor-8-sulphonic acid. The optically active isomers may be prepared either by starting from optically active starting compounds or by resolving the racemates obtained into their optical isomers in conventional manner.

The l-phenoxy-2-hydroxy-3-hydroxyalkylamino-propanes according to the invention may if desired be converted into their physiologically compatible acid addition salts in the conventional way. Acids suitable for the formulation of physiologically compatible acid addition salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid, and 8-chlorotheophylline.

According to a yet still further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I as hereinbefore defined or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient. The compositions according to the invention may also include, if desired, other physiologically active compounds, for example coronary dilators, sympathicomimetics , cardiac glycosides or tranquilizers.

The compositions according to the invention may be presented, for example, in a form suitable for oral, parenteral or rectal administration.

The compounds according to the invention may be presented in the conventional pharmacological forms of adminis ration, such as tablets, coated tablets, solutions, emulsions, powders, capsules or sustained release forms. Conventional pharmaceutical excipients as well as the usual methods of production may be employed for the preparation of these forms. Tablets may be produced, for example, by mixing the active ingredient or ingredients with known excipients, such as for example with diluants, 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 talcum, and/or agents for obtaining sustained release, such as carboxypolymethylene , carboxmethyl cellulose, cellulose acetate phthalate, or polyvinylacetate.

The tablets may if desired consist of several layers. Coated tablets may be produced by coating cores, obtained in a similar manner to the tablets,with I agents commonly used for tablet coatings for example polyvinyl pyrrolidone or shellac, gum arabic, talcum, titanium dioxide or sugar. In order to obtain sustained release or to avoid incompatibilities, the core may consist of several layers too. The tablet-coat may also consist of several layers in order to obtain sustained release, in which case the excipients mentioned above for tablets may be used.

Syrups of the active ingredient according to the invention or combinations of active ingredients may additionally contain a sweetener, such as saccharin, cyclamate, glycerin or sugar, and/or taste improving agents such as flavourings e.g. vanillin or orange extract. They may also contain suspension agents or thickeners, such as sodium carboxymethyl cellulose, wetting agents, such as for example condensation products of fatty alcohols with ethylene oxide, or preservatives, such as £-hydroxybenzoates .

Injection solutions may, for example, be produced in the conventional manner, such as by the addition of preservation agents, such as p_-hydroxybenzoates , or stabilizers, such as Co plexons. The solutions are then filled into injection vials or ampoules.

Capsules containing one or several active ingredients may be produced for example by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and filling the mixture into gelatin capsules .

Suitable suppositories may, for example be produced by mixing the active ingredient or active ingredient combinations with the conventional carriers envisaged for this purpose, such as neutral fats or polyethyleneglycol or derivatives thereof.

Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, suppositories and ampoules are examples of suitable dosage unit forms. Each dosage unit preferably contains 1 to 300 mg. of the said active ingredient and especially 5 to 100 mg of the said active ingredient for oral administration and 1 to 20 mg for parenteral administration.

The following examples illustrate the preparation of compounds according to the invention, and also pharmaceutical compositions containing such compounds as active ingredients : - Example 1 1- α-Naphthoxy-3- (3-amino-3-ethylpett-4-yny1)-2-propanol .

HC1 (according to process a) 10 g (0.05 mol) of l-oc-naphthoxy-2 ,3-epoxypropane are dissolved in 80 ml of ethanol and 5.55 g (0.05 mol) of 3-amino-3-ethylpent-4-yne are added. The mixture is refluxed for 2 hours at the boiling temperature of the reaction mixture. After cooling the mixture, the solvent is distilled off, the residue dissolved in ether and acidified with alcoholic HC1. The compound which crystallises out is isolated and recrystallized from a mixture of acetonitrile and ethanol.

Yield: 9.5 g, m.p. 195 - 196°C.

Example 2 l-m-Tolyloxy-3-(2-amino-2-methylbut-3-ynyl)-2-propanol .

HCl (according to process a) 8.2 g (0.05 mol) of l-m-tolyloxy-2 ,3-epoxypropane are dissolved in 90 ml of ethanol and after the addition of 6.25 g (0.075 mol) of 2-amino-2-methylbut-3-yne are refluxed for 2 hours. After distilling off the solvent, the residue is recrystallized from ethyl acetate on the addition of petroleum ether. The crystalline base is dissolved in acetonitrile , alcoholic HC1 is added and crystallization is started on the addition of ether. 6.5 g of colourless crystals are obtained, which are chromatographically pure. M.p. 139 - 141°C.

Example 3 1- (2-Allylphenox ) -3- (2-amino-2-methylbut-3-yny1)-2-propanol oxalate (according to process a) 9.5 g (0.05 mol) of l-(2-allylphenoxy)-2 ,3-epoxy-propane are dissolved in 60 ml of methanol, 8.3 g (0.1 mol) of 2-amino-2-methylbut-3-yne are added and the mixture is refluxed for 3 hours. After distilling off the solvent, the basic residue is dissolved in acetone and a solution of 6 g of oxalic acid is added. The precipitating crystalline oxalate is once more recrystallized from acetone. Yield: 4.7 g, m.p. 144 - 146°C.

Example 4 1- (2-Cyanophenox )-3- (2-amino-2-methylbut-3-yny1)-2-propanol. HC1 (according to process a) . 17.5 g (0.1 mol) of 1- (2-cyanophenoxy)-2 ,3-epoxy-propane are dissolved in 130 ml of ethanol and after the addition of 16.6 g (0.2 mol) of 2-amino-2-methylbut-3-yne the mixture is refluxed for 2 hours. The solvent is distilled off, the remaining residue acidified with HC1 and shaken. After filtering off the insoluble particles with suction, the filtrate is made alkaline with NaOH, the precipitating base is dissolved in chloroform and the organic phase, after separation, dried over After filtration the chloroform is distilled off and the residue fecrystallized from ethyl acetate on the addition of petroleum ether. The base is dissolved in acetonitrile and acidified with alcoholic HC1. The hydrochloride crystallizes out in the form of colourless crystals.

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

Example 5 1- (2-Cyanophenoxy) -3- ( 1-ethynyIcyc1ohexylamino) -2-propano1.

HCl (according to process a) 9 g (0.05 mol) of 1-ethynylcyc1ohexylamine are dissolved together with 8.7 g (0.05 mol) of l-(2-cyano-phenoxy)-2 ,3-epoxypropane in 100 ml of ethanol and refluxed for 2 hours. After distilling off the solvent, the residue is dissolved in ethyl acetate and shaken with dilute HCl. The aqueous phase is made alkaline with NaOH, and the precipitated base extracted with ethyl acetate. The organic phase is washed, dried over MgSO^, filtered and the solvent is distilled off. The remaining residue is recrystallized from ethyl acetate in the presence of ligroine. The colourless crystalline base is dissolved in alcohol, alcoholic HC1 is added and the hydrochloride is crystallized out by adding ether dropwise to the mixture. After separation, the salt is once more recrystallized from ethanol in the presence of ether.

Yield: 6.4 g, m.p. 176 - 177°C.

The following compounds of formula I are produced according to 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 III in ethanol. The reactions are effected in a similar manner to that set out in Examples 1 to 5. m.p. of HC1- salt (unle Rl R2 R3 R5 otherwise stated) 2-CN H H C2H5 C2H5 170-171° 3-CH3 H H C2H5 C2H5 143-145° -0-CH2-CH=CH2 H H C2H5 C2H5 112-113° -CH2-CH=CH2 H H C2H5 C2H5 128-129° ,3-CH=CH-CH=CH- H CH3 CH3 159-161° -0-CH2-CH=CH2 H H CH3 CH3 100-103° 3-CH3 H H -(CH2) 5* 159-160° 2-Br H H CH3 CH3 138-139° 4-N02 H H CH3 CH3 183-184° -CH20H H H CH CH3 108-110° (Base) -OCH3 H H CH3 161-163° CH3 -C00CH3 H H CH3 CH3 127-129° ,4-(CH2)3- H CH3 CH3 139-140° -isoC3H7 H H CH3 CH3 157-158° -CsCH H H CH3 CH3 165-167° -NH-C0-NHCH3 H H CH3 CH3 107-109° (Base) m.p. of HC1- Rl R2 R3 R4 R5 salt Cmless otherwise stated ) -NH-C0-N(C2H5)2 H H CH3 CH3 125-127° -NH-C0-NHC2H5 2-CN H CH3 CH3 161-164° (Base) -NH-C0-NHCH3 2-CN H CH3 155-157° CH3 (Base) -NH-CO-NHiC3H7 2-CN H CH CH3 127-130° (Base) -CH2-C0-NH2 H H CH3 CH3 107-110° (Base) -(C2H5)2N- H H CH3 134-137° CH3 (dihydro- chloride) -C00H H H CH3 CH3 159-162° -NH-C0CH3 H H CH3 137-138° CH3 (Base) -CH2OH H H CH3 150-152° CH3 (Oxalate) -C6Hn H H CH3 CH3 150-152° 2-Cl 4-Cl H CH3 CH3 170-171° 3-Cl H H CH3 CH3 142-144° -CONH2 H H CH3 CH3 230-233° 2-CN 4-Cl H CH3 CH3 176-177° m.p; of HC1- R2 salt (unless R3 R4 R5 ^_y~ otherwise stated) 3-Br 4-NH2 5-Br CH3 CH3 183-185° (Dihydro- chloride) 2-CEC-CH3 ■ H H CH3 CH3 164-166° 3,4-0-(CH2)-0- H CH3 CH3 175-176° 4-C0-C2H5 H H CH3 CH3 149-151° 4-0H . H H CH3 136-137.5° CH3 2-C6H5 H H CH3 CH3 157-158° 2-Cl H H CH3 CH3 150-151° -NH-C0003H7 H H 0H3 0H3 129-130° (BeΘΘ) 4- H-C00C-H,. 6-C0CH- H CH5 CH3 5 7 175-177° 2-C0CH5 4-UH2 H CH5 CH3 118-119°(Base) H H CH3 CH3 140-141° 2-C2H5 H H CH5 149-151° 4-NH-CO-O^ 6-CN H CH5 OH, 137-138°(Base) 2-CN 4-NH2 H CH3 CH_ 56-_59°(Base) 5 Example 6 l-(2-Allyloxyphenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2 propanol. riCl (according to process b) 2.4 g (0.025 mol) of tetrahydropyran are slowly added dropwise at 20 to 25°C to 6.42 g (0.025 mol) of 1- (2-allyloxyphenoxy)-3-bromo-2-propanol and a catalytic r quantity of p-toluenesulfonic acid. The mixture is then heated for 30 minutes to 40°C, dissolved in 40 ml of benzene and 5 g (0.06 mol) of 2-amino-2-methylbut-3-yne are added thereto. The mixture is refluzed for 2 hours, then the ' minutes, with dilute hydrochloric acid, to 80°C. After cooling the mixture is extracted with ether and the aqueous phase made alkaline with NaOH. The precipitating basic portions are taken up in ether, the organic phase dried with MgSO^ and after filtering the ether is distilled off. The residue is dissolved in a little ethanol, ethereal HC1 is added and the crystalline hydrochloride is recrystallized twice.

M.p. 99 - 102°C.

Example 7 1- (4-Nitrophenoxy)-3- (2-amino-2-methylbut-3-ynyl)-propanol.

HCl (according to process c) 2.7 g (approximately 0.008 mol) of 1- (4-nitrophenoxy) -3-(N-acetyl-2-amino-2-methylbut-3-ynyi)-2-propanol are refluxed in 25 ml of ethanol with 1 g of KOH for 2 hours. After distilling off the solvent, a viscous residue remains, which is treated with dilute HCl. After shaking with chloroform, the aqueous phase is made alkaline with NaOH and the precipitating amine is taken up in chloroform.

After drying over NaSO^, the solvent is distilled off and the residue recrystallized, with the addition of petroleum ether, from ethyl acetate.

Yield: 1.5 g, m.p. 125 - 127°C (base). Mixed melting point with substance obtained according to process (a): 126 - 127°C.

Example 8 1- (2-Cyanophenoxy)-3- (2-amino-2-methylbut-3-yne)-2-propanol .

HCl (according to process d) 2.84 g (0.01 mol) of 3- (2-methylbutyne-3-yl-2)-5-(2-cyanophenoxymethyl)-oxazolidine-2-one are refluxed in 20 ml of ethanol , following the addition of 3 g of KOH in 6 ml of water, for 3 hours. After distilling off the solvent, the residue is treated with water and extracted with chloroform. The chloroform solution is then shaken with dilute HCl and the separated aqueous phase is made alkaline with NaOH. The precipitating base is taken up in chloroform, the organic phase washed with water and dried over is distilled off and the residue recrystallized from ethyl acetate in the presence of petroleum ether.

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

Example 9 1- ( -Aminophenox )-3- (2-amino-2-methylbut-3-yny1)-2-propanol. HCl (according to process e) A mixture of 8.1 g of tin-II-chloride in 20 ml of conccentrated HCl is heated to 60°C and 2.62 g (0.01 mol) of l-(4-nitrophenoxy)-3- (2-amino-2-methylbut-3-ynyl)-2-propanol are added in portions , so that the temperature does not exceed 65°C. After the addition has been completed, the mixture is stirred for 30 minutes and after cooling is made alkaline with NaOH. The precipitating basic portions are shaken with chloroform, the chloroform solution is washed with water and dried over After distilling off the CHCl^ a solid residue remains, which is recrystall-ized from ethyl acetate in the presence of petroleum ether.

Yield: 1.4 g, m.p. 122 - 123°C (base).

According to process (e) the compound 1- (4-hydroxy-phenoxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol was made by heating the compound 1- (4-diethylaminocarbonyloxy-phenoxy)-3- (2-amino-2-methylbut-3-yny1)-2-propano1 (m.p. of hydrochloride: 126°C) in the presence of concentrated aqueous HC1.

M.p. of the end product (base) is 136 - 137.5°C.

Example 10 1- (2-Cyano-4-chlorophenoxy)-3-(2-amino-2-methylbut-3-ynyl)- 2-propanol. HCl (according to process f) 3.87 g (0.015 mol) of 1- (2-cyanophenoxy)-3- (2-amino-2-methylbut-3-ynyl )-2-propanol are mixed with 25 ml of concentrated HCl and heated to 45°C. While cooling 1.7 g (0.015 mol) of 307c ^2^2 are added dropwise in such a way that the temperature does not rise above 65°C. After the batch has been stirred for a further 30 minutes , the crystal mass is filtered off with suction and washed with water. The hydrochloride is recrystallized from ethanol. Yield: 1.95 g. m.p. 176 - 177°C.

Example 11 l-(2-Cyanophenbxy)-3-(2-amino-2-methylbut-3-ynyl)-2-propanol .

HCl (according to process g) 0.697 g (0.002 mol) of 1- (2-bromophenoxy)-3- (2-amino-2-methylbut-3-ynyl)-2-propanol hydrochloride are mixed with 0.376 g (0.0042 mol) of Cu(l)CN and 0.4 g of dimethylformamide and heated for 2 hours to 190°C. After cooling, the mixture is treated with water and made alkaline with NaOH. The basic portions are taken up in CHCl^ and washed with water. The chloroform is distilled off and the residue purified over a silica gel column. The pure base thus obtained is dissolved in acetonitrile and acidified with alcoholic HC1. The hydrochloride crystallizes out in colourless crystals.

M.p. 168 - 171°C.

Example 12 1- (4-Hydroxycarbonylphenoxy)-3- (2-amino-2-methylbut-3-yny1) -2-propanol. HC1 (according to process e) 5 g of 1- (4-ethoxycarbonylphenoxy)-3- (2-amino-2-methylbut-3-yny1)-2-propanol hydrochloride are refluxed in 30 ml of concentrated HC1 for two hours. After cooling, the crystalline mass which is formed by hydrolysis is filtered off with suction and recrystallized twice from ethanol in the presence of ether.

Yield: 3.1 g m.p. 159 - 162°C.

Example 13 1- (3 ,5-Dibromo- -aminophenoxy)-3- (2-amino-2-meth lbut-3-ynyl)-2-propanol. 2 HC1 (according to process f) 4.96 g (0.02 mol) of l-(4-aminophenoxy)-3-(2-amino- 2-methylbut-3-ynyl)-2-propanol are added to a mixture of 30 ml of HBr (65%) and 10 ml of water and heated to 45°C. While stirring and cooling 4.54 g (0.04 mol) of 30% are added dropwise thereto, in such a way that the temperature does not rise above 65°C. After the mixture has been maintained at approximately 65°C for a further 30 minutes the crystalline substance is filtered off with suction after cooling and is recrystallized from ethanol in the presence of ether. The hydrochloride is then dissolved in water, NaOH is added, the base extracted with CHCl^ and after evaporation of the solvent, recrystallized from ethyl acetate in the presence of petroleum ether.

The chromatographically pure base is dissolved in ethanol, alcoholic HC1 is added and the di-hydrochloride is then recrystallized on the addition of ether.

Yield: 3.8 g, m.p. 183 - 185°C.

Pharmaceutical Composition Examples A. Tablets 1- ( 2-cyanophenoxy) -3- ( 2-amino-2-methy1- but-3-ynyl)-2-propanol. HC1 40.0 mg corn starch 164.0 mg sec. calcium phosphate 240.0 mg magnesium stearate 1.0 mg 445.0 mg Production; The individual components are well mixed and the mixture is granulated in the usual way. The granulate is pressed into tablets each weighing 445 mg and each containing 40 mg of active ingredient.

Instead of the active ingredient mentioned in this example, l-(2-cyanophenoxy)-3-(l-ethynyl-cyclohexyl-amino)-2-propanol. HC1 and 1- ( 2-cyano-4-chlorophenoxy) -3-(2-amino-2-methylbut-3-ynyl)-2-propanol may be used in the same quantity.

B. One capsule contains 1- ( 2-ethyn lphenoxy) -3- ( 2-amino-2-methylbut-3- ynyl)-2-propanol. HC1 25.0 mg corn starch 175.0 mg 200.0 mg Production: The active ingredient and the corn starch are mixed well and 200 mg portions of the mixture are filled ί into gelatin capsules of suitable size. Each capsule contains 25 mg of the active ingredient.

C. Injection Solution The solution contains the following ingredients: 1- ( 2-cyano- 5-methylphenoxy) -3- ( 2-amino- 2-methylbut-3-ynyl)-2-propanol. HC1 2.5 parts sodium salt of EDTA (ethylenediamine- tetra acetic acid) 0.2 parts distilled water ad 100.0 parts Production: The active ingredient and EDTA-salt are dissolved in sufficient water and then made up to the desired volume with more water. The solution is filtered free of suspended particles and filled into ampoules under aseptic conditions. Finally, the ampoules are sterilized and sealed. Each ampoule contains- 25 mg of active ingred¬ ient.

Instead of the active ingredient mentioned in Example 1 l-(2-hydroxymeth lphenoxy)-3-(2-amino-2- methylbut-3-ynyl)-2-propanol. HC1 or l-(2-allylphenoxy)- 3-(2-amino-2-methylbut-3-ynyl)-2-propanol. HC1 may be used in the same quantity.

D. Coated Tablets with Sustained Release Core: (-)-l-(2-cyanophenoxy)-3- (2-amino-2- methylbut-3-ynyl)-2-propanol . HC1 25.0 g carboxymethyl cellulose (CMC) 295.0 g stearic acid 20.0 g cellulose acetate phthalate (CAP) 40.0 g 380.0 g Production: The active ingredient , CMC and stearic acid are mixed well and the mixture is granulated in the usual way, using a solution of the CAP in 200 ml of a mixture of ethanol/ethyl acetate. The granulate is then pressed into 380 mg-cores , and coated in the conventional way with a sugary 5% solution of polyvinylpyrrolidone in water.

Each coated tablet contains 25 mg of active ingredient.

E. Tablets 1-a-naphthoxy-3- (3-amino-3- ethyl- pent-4-ynyl)-2-propanol . HC1 2 ,6-bis- (diethanolamino)- ,8- dipiperidino-pyrimido- [5 ,4-d]- pyrimidine lactose corn starch colloidal silicic acid polyvinylpyrrolidone magnesium stearate soluble starch 500.0 g Instead of the β-adrenolytically active substances mentioned in this Example 1- (2-allyloxyphenoxy)-3- (2-amino-2-methylbut-3-ynyl)-2-propanol . HC1 and l-(2-propargy1oxyphenoxy)-3- (2-amino-2-methylbut-3-yny1-2 propanol. HC1 may also be used in the same quantity.

Production; The active ingredient together with the lactose, corn starch, collodial silicic acid and polyvinylpyrrolidone is granulated after thorough mixing in the usual way, using an aqueous solution of the soluble starch. The granulate is mixed with the magnesium stearate and pressed into 1000 tablets each weighing 500 mg and each containing 35 mg of the first and 75 mg of the second active ingredient, Pharmacological Test data Compound Isoproterenol (in the form of HCl salt) antagonistic activity 1- (2-Cyanophenox )-3-(2-amino-2-methy1-but-3-ynyl)-2-propano1 170 X DCI 1-( 2-Ethynylphenoxy) -3- (2-amino-2-methyl but-3-yny1)-2-propano1 78 X DCI 1- ( 2-Allylphenoxy)-3-(2-amino-2-methy1 but-3-ynyl)-2-propanol 25 X DCI 1- (3-Chlorophenoxy) -3- (2-amino-2-methyl but-3-ynyl)-2-propanol 35 X DCI The determination of the isoproterenol anatagonistic activity is effected using guinea pigs and comparing the results obtained with the standard substance DCI (3 ,4-dichloroisoproterenol) . The activity of the standard substance is equivalent to 1 sedation unit.

The method is described in French Patent 8162M.

The toxicity of the test compounds is determined by subcutaneous administration of a 1-2% solution of the test compound to white mice. (Period of observation = 2 weeks). The evaluation of the results is carried out according to J. T. Litchfield jun. and F. Wilcoxon 1949 J. Pharmacol. Exptl. Therap. 96/S 99-113.

Claims

1. Compounds of the general formula [wherein R, represents a hydrogen or halogen atom, a nitro group, an alk 1" group with 1 to 5 carbon atoms, an alkoxy group with 1 to carbon atoms, an alkenyl or alkynyl group with 2 to 5 carbon atoms, a lower alkoxyalkyl group or a group of the formula -(CH2)x-CN, -(CH2)x- H2 or -(CH^-OH, (in which x is zero or an integer from 1 to 3) , the group -C00H or -COOR^, (in which represents an alkyl group with 1 to A carbon atoms) , an alkenyloxy or alkynyloxy group with 3 to 6 carbon atoms, lower alkanoyl, alkanoyloxy or alkanoylamino , phenacetyl optionally substituted in the phenyl moiety by at least one halo, alkyl, nitro, cyano or carboxyl group, benzoyl optionally substituted by at least one halo, alkyl, nitro, cyano or carboxyl group, a cycloalkyl group with 3 to 7 carbon atoms, the group :- Q-CO-NHR-R, which Q represents a single bond, an oxygen atom, a NH- , CH^- or Cl^-NH group and and Rg , which may be the same or different, each represents a hydrogen atom or a lower alkyl group or R^ and g together with. the nitrogen atom therebetween represent pyrrolidino, pxperidino or morpholino, or phenyl or phenoxy optionally substituted by at least one halogen atom, alkyl, alkoxy, nitro, cyano or carboxyl group) ; R2 represents a hydrogen or halogen atom, an alkyl or alkoxy group with 1 to 4 carbon atoms, lower alkanoyl or alkenyl group with 2 to 4 carbon atoms, or a cyano, amino or nitro group; or R^ and together represent a 3 , ^-methylenedioxy group; R^ represents a hydrogen or halogen atom, or an alkyl or alkoxy group with 1 to 4 carbon atoms; or and R^ , being bonded to adjacent carbon atoms in the phenyl moiety, together represent the group :- -CH=CH-CH=CH- or. ~^ U2) ' (in which n is an integer from 3 to 5); R^ represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms ; and R^ represents an alkyl group with 1 to 3 carbon atoms; or and R,. together represent the group - CI^^ (in which p represents an integer from 4 to 6)] and acid addition salts thereof.

2. Compounds as claimed in claim 1 wherein represents lower alkanoyl, alkanoyloxy or alkanoylamino in which alkanoyl is an acetyl, propionyl, butyryl or iso-butyryl group, or a phenacetyl group optionally substituted on the phenyl moiety by at least one halogen atom or alkyl, nitro , cyano, or carboxyl group, or a benzoyl group optionally substituted by at least one halogen atom or lower alkyl, nitro, cyano or carboxyl group.

3. Compounds as claimed in claim 1 wherein represents an alkenyl, alkynyl, alkenyloxy, alkynyloxy or cyano group.

4. Compounds as claimed in claim 3 wherein R^ represents an allyl, ethynyl, propynyl, allyloxy or propargyloxy group.

5. Compounds as claimed in any of claims 1 to 4 wherein R^ is present in the 2-position of the phenoxy group.

6. Compounds as claimed in any of the preceding claims wherein represents a hydrogen atom or an alkyl group.

7. Compounds as claimed in claim 6 wherein represents a methyl group.

8. Compounds as claimed in any of the preceding claims wherein is present in the 5-position of the phenoxy group .

9. Compounds as claimed in any of the preceding claims wherein represents a hydrogen atom.

10. Compounds as claimed in claim 1 wherein represents a hydroxyalkyl group and and R^ both represent a hydrogen atom.

11. Compounds as claimed in claim 10 wherein R^ represents a hydroxymethyl group.

12. Compounds as claimed in claim 1 wherein R^ represents an amino or alkanoylamino group and R and R_ f which may be the same or different, each represents a hydrogen or halogen atom or an alkyl group.

13. Compounds as claimed in claim 12 wherein R^ represents an acetylamino group.

14. Compounds as claimed in any of the preceding claims wherein both and R,- represent a methyl group.

15. l-( 2-Cyanophenoxy) -3- ( 2-amino-2-meth lbut-3-ynyl) -2-propanol and acid addition salts thereof.

16. l-(2-Ethynylphenoxy) -3-(2-amino-2-methylbut-3-ynyl) -2-propanol and acid addition salts thereof.

17. 1- ( 2-Allylphenoxy) -3- ( 2-amino-2-methylbut-3-yny1) - 2-propanol and acid addition salts thereof.

18. l-(3 , 5-Dibromo-4-aminophenoxy)-3- ( 2-amino-2-methylbut- 3-ynyl)-2-propanol and acid addition salts thereof.

19. 1- ( 2-Hydroxymethylphenoxy) -3- ( 2-amino-2-methylbut-3-ynyl)-2-propanol and acid addition salts thereof.

20. 1- (3-Chlorophenoxy) -3-( 2-amino-2-methylbut-3-ynyl) -2-propanol and acid addition salts thereof.

21. 1- ( A-Acetamidophenoxy) -3- ( 2-amino-2-methylbut-3-ynyl)-2-propanol and acid addition salts thereof.

22. Compounds of the general formula:- 44301/2 [wherein R^ represents a hydrogen or halogen atom, an alkyl group with 1 to 5 carbon atoms, an alkoxy group with 1 to A carbon atoms, an alkenyl or alkynyl group with 2 to 5 carbon atoms, a group of the formula :- -(CH2>-xCN , -(CH2^NH2 or -fCH^OH (in which x is 0 or an integer from 1 to 3), the group -C00H or -COOR^ (in which represents an alkyl group with 1 to i carbon atoms) , an alkenyloxy or alkynyloxy group with 3 to 6 carbon atoms, lower alkanoyl, alkanoyloxy, or alkanoylamino, phenacetyl optionally substituted in the phenyl moiety by at least one halo, alkyl, nitro, cyano or carboxyl group, benzoyl optionally substituted by at least one halo, alkyl, nitro, cyano or carboxyl group, a group of the formula :- -NH-C0-NHR?R8 (in which R^ and Rg , which may be the same or different, each represents a hydrogen atom or a lower alkyl group; or R-, and RQ together with the nitrogen atom therebetween / . ■ . o . .. represents pyrrolidino, piperidino or morpholino, or a phenyl or phenoxy group optionally substituted by a halogen atom or an alkyl, nitro, cyano or carboxyl group? and R2 , R3, R4 and R5 are as defined in claim 1 with the proviso that R2 may not represent an alkanoyl group with 2 to 4 carbon atoms] and acid addition salts thereof.

23. Compounds as claimed in claim 1 in the form of physiologically compatible acid addition salts.

24. Compounds as claimed in claim 22 in the form of physiologically compatible acid addition salts.

25. Compounds as claimed in claim 1, other than as claimed in any of claims 15 to 21, as herein specifically disclosed.

26. Compounds as claimed in claim 22, other than as claimed in any of claims 15 to 20, as herein specifically disclosed.

27. A process for the preparation of compounds of formula I as defined in claim 1 which comprises reacting a compound of formula: - [wherein R^, R2 and R^ are as defined in claim 1 and Z represents the group: -C ;HH -—-CH2 or -CHOH-CH2~Hal \ 0 (wherein Hal represents a halogen atom)] with a compound of the formula; - Nl^-CR^-C SCH III (wherein and R.. are as defined in claim 1) ,

28. A process as claimed in claim 27 for the preparation of compounds of formula I as defined in claim 22 which comprises reacting a compound of formula II (in which R^, and R^ are as defined in claim 22) with a compound of formula III.

29. A process for the preparation of compounds of formula I as defined in claim 1 which comprises hydrolysing or hydrogenating a compound of the formula:- (wherein R^, R2> R^ , R^ and R.. are as defined in claim 1 and G represents a hydrolytically or hydrogenolytically removable group) .

30. A process as claimed in claim 29 wherein a compound of formula IV is used in which G represents an acyl or acetal group.

31. A process as claimed in claim 29 or claim 30 for the preparation of compounds of formula I as defined in I V claim 22 which comprises hydrolysing or hydrogenating a compound of formula IV (in which and are as defined in claim 22 and R0, R, and Rc are -as defined 3 4 J in claim 1) . 1

32. A process for the preparation of compounds of formula I as defined in claim 1 which comprises reacting a compound of the formula:- (wherein R^ , R^* R3 > an<^ are as defined in claim 1 and Sch represents a removable protecting group) whereby a compound of formula I is obtained.

33. A process as claimed in claim 32 wherein the reaction is effected by hydrolysis or hydrogenation.

34. A process as claimed in claim 32 or claim 33 wherein a compound of formula V is used in which Sch represents an acyl or carbobenzoxy group.

35. A process as claimed in any of claims 32 to 34 for the preparation of compounds of formula I (as defined in claim 22) which comprises reacting a compound of formula V (in which and are as defined in claim 22 and R^, R^ and R,. are as defined in claim 1) whereby a compound of formula I is obtained.

36. A process for the preparation of compounds of formula I as defined in claim 1 which comprises wherein R.. , R , R„, R. and Rc are as defined in claim 1 1 ' I 3 A j and X represents the group:- -CO-, or -C^- > or a -CH- lower alkyl group.

37. A process as claimed in claim 36 wherein the hydrolysis is effected by the use of an aqueous sodium hydroxide or potassium hydroxide solution or by the use of an alcohol/water mixture.

38. A process as claimed in claim 36 or claim 37 for the preparation of compounds of formula I as defined in claim 22 which comprises the hydrolysis of a compound of formula VI in which R^ and R are as defined in claim 22 and R~, R. and R.. are as defined in claim 1.

39. A process for the preparation of compounds of formula I as defined in claim 1 which comprises reacting a compound of the formula: - C SCH Vila (wherein » ^3» ^ anc* ^5 are as defined in claim 1 and A represents an atom or group which may be converted into R^) to convert the compound of formula Vila into a compound of formula I as defined in claim 1.

40. A process as claimed in claim 39 wherein A represents a -CONH2 > -COOR^ (wherein R^ is as defined in claim 1), alkoxy, 0-acyl or nitro group.

41. A process as claimed in claim 39 or claim 40 for the preparation of compounds of formula I as defined in claim 22 which comprises reacting a compound of formula Vila (in which R^ is as defined in claim 22) to convert the compound of formula Vila (in which R^ is as defined in claim 22) into a compound of formula I as defined in claim 22.

42. A process for the preparation of compounds of I formula I as defined in claim 1 which comprises reacting R3 (wherein R^ , , R^ and R,. are as defined in claim 1 and B represents an atom or group which may be converted into R2) to convert the compound of formula VIlb into a compound of formula I as defined in claim 1.

43. A process as claimed in claim 42 wherein a compound of formula Vllbi is used in which B represents a halogen atom or a nitro or amino group or the group -CONH^ or -CH=NOH.

44. A process as claimed in claim 42 or claim 43 for the preparation of compounds of formula I as defined in claim 22 which comprises reacting a compound of formula VII b (in which R^ is as defined in claim 22) to convert the compound of formula Vllb (in which ^ is as defined in claim 22) into a compound of formula I as defined in claim 22.

45. A process for the preparation of compounds of formula I as defined in claim 1 (wherein or ^3 represents a halogen atom) which comprises halogenating a compound of the formula Ar-0-CH2-CHOH-CH2-NH-C-C = CH VIII *5 [wherein and R,. are as defined in claim 1 and Ar (wherein , and R^ are as defined in claim 1).

46. A process as claimed in claim 45 wherein the halogenation is effected by the use of a hydrogen halide/ hydrogen peroxide mixture.

47. A process as claimed in claim 45 or claim 46 wherein the halogenation is effected at an elevated temperature.

48. A process as claimed in any of claims 45 to 47 for the preparation of compounds of formula I as defined in claim 22 which comprises halogenating a compound of formula VIII (in which and are as defined in claim 22). ;

49. A process for the preparation of compounds of formula I as defined in claim 1( in which or represents a cyano group) which comprises reacting a compound of the formula:- M-0-CH»-CH0H-CH -NH-C-C=rCH IXa R5 (wherein R. and Rr are as defined in claim 1 and M 4 5 represents the group :- in which laim 1 and C represents an amino group or a halogen atom) to convert the compound of formula IXa into a compound of formula I as defined in claim 1 wherein R^ or represents a cyano group.

50. A process as claimed in claim 49 wherein a compound of formula IXa is used in which C represents an amino group and the reaction is effected by diazotisation and subsequent boiling in the presence of a cyanide.

51. A process as claimed in: claim 50 wherein the cyanide is potassium cyanide.

52. A process as claimed in claim 49 wherein a compound of formula IXa is used in which C represents a halogen atom and the reaction is effected by the use of Cu(l)CN in the presence of a high boiling solvent.

53. A process as claimed in any of claims 49 to 52 for the preparation of a compound of formula I as defined in claim 22 (in which or represents a cyano group) which comprises reacting a compound of formula IXa to convert the compound of formula IXa into a compound of formula I as defined in claim 22 wherein or represents a cyano group.

54. A process as claimed in any of claims 27, 29, 32, 36, 39, 42, 45 and 49 wherein the compound of formula I obtained is subsequently converted into an acid addition salt thereof.

55. A process as claimed in any of claims 28, 31, 35, 38, 41, 44, 48 and 53 wherein the compound of formula I obtained is subsequently converted into an acid addition salt thereof. I

56. A process as claimed in any of claims 27, 29, 32, 36, 39, 42, 45, 49 and 54 wherein a racemate as claimed in claim 1 is obtained and is subsequently separated into its optically active isomers.

57. A process as claimed in any of claims 28, 31, 35, 38, 41, 44, 48, 53, and 55 wherein a racemate as claimed in claim 22 is obtained and is subsequently separated into its optically active isomers.

58. A process for the preparation of compounds as claimed in claim 1 in the form of optically active isomers in which a compound of formula I as defined in claim 1 in the form of a racemic mixture is resolved into its optically active isomers.

59. A process for the preparation of compounds as claimed in claim 22 in the form of optically active isomers in which a compound of formula I as defined in claim 22 in the form of a racemic mixture is resolved into its optically active isomers.

60. A process as claimed in any of claims 27, 29, 32, 36, 39, 42, 45, 49, 54, 56 and 58 substantially as herein described. |

61. A process as claimed in any of claims 28, 31, 35, 38, 41, 44, 48, 53, 55, 57 and 59 substantially as herein described.

62. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any of Examples 1 to 13.

63. Compounds, as claimed in claim 1 when prepared by a process as claimed in any of claims 27, 29, 32, 36, 39, 42, 45, 49, 54, 56, 58, 60 and 62.

64. Compounds as claimed in claim 22 when prepared by a process as claimed in any of claims 28, 31, 35, 38, 41, 44, 48, 53, 55, 57, 59 and 61.

65. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I as claimed in claim 1 or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.

66. Compositions as claimed in claim 65 in a form suitable for oral, parenteral , or rectal administration.

67. Compositions as claimed in claim 65 or claim 66 in the form of granules, tablets, coated tablets, capsules, pills, syrups, emulsions, suspensions, powders, drops, suppositories, or injection solutions.

68. Compositions as claimed in claim 65 in the form of dosage units.

69. Compositions as claimed in claim 68 wherein each dosage unit contains .1 to 300 mg. of the said active ingredient.

70. Compositions as claimed in claim 71, for oral administration, wherein each dosage unit contains from 5 to 100 mg. of the said active ingredient.

71. Compositions as claimed in claim 69, for parenteral administration, wherein each dosage unit contains from 1 to 20 mg. of the said active ingredient.

72. Compositions as claimed in any of claims 65 to 71 which contain a further physiologically active ingredient.

73. Composition as claimed in claim 72 wherein the further physiologically active ingredient is a coronary dilator, sympathicomimetic , cardiac glycoside or tranquilizer 44301/2

74. Pharmaceutical compositions as claimed in any of*"-claims 65 to 73 comprising as active ingredient a compound of formula I as defined in claim 22 or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.

75. Compositions as claimed in claim 65 substantially as herein described.

76. Compositions as claimed in claim 7 substantially as herein described.

77. Pharmaceutical compositions substantially as herein described in any of Examples A to E.