IE52166B1 - 3-aminopropoxyphenyl derivatives,their preparation and pharmaceutical compositions containing them - Google Patents

Description

R is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, 53166 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, halogen of atomic number of from 9 to 53, trifluoromethyi, 1-pyrrolyl, cyano, carbamoyl, alkenyl of 2 to 5 carbon atoms, alkenyloxy of 3 to 5 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to the oxygen atom,or alkancyl of 1 to 5 carbon atoms, R2 is alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety, phenyl, phenylalkyl of 7 to 10 carbon atoms, or phenyl or phenylalkyl of 7 to 10 carbon atoms monosubstituted or independently disubstituted or independently trisubstituted. in the phenyl ring by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, A is alkylene of 2 to 5 carbon atoms, X is a bond, an oxygen or a sulfur atom, Y is an oxygen or a sulfur atom, and either Z is an oxygen atom and n is 2 or 3 or Z is a bond and n is 1, 2 or 3, with the provisos, that a) when I?2 is alkyl, then Z is an oxygen atom and the group -NH-A-X-R is other than the moiety of formula -NH-CH (CHj) CHjCHj-^O^ -NH-CH (CH3) CH2CH2-0-(/Q -NH-CH(CH,)CH2CH2CH2-O-(O or -nh-ch(ch3>ch2ch(ch3)-o-(O) ' b) when R2 is alkyl and X is a bond or an oxygen atom, then Y is an oxygen atom, and c) when R2 is unsubstituted or monosubstituted phenyl, X is a bond and Z is an oxygen atom, or when R2 is cycloalkyl or cycloalkylalkyl and 15 X is a bond, then R^ is other than hydrogen^ and physiologically acceptable hydrolyzable derivatives thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form.

Physiologically hydrolyzable derivatives are those derivatives which under physiological conditions are split to the corresponding compounds having a hydroxy group in the 2 position·of the 3-aminopropoxy side chain.

A group of derivatives in esterified form of the compounds of formula X is e.g. the compounds of formula E, wherein r, R^, R2, A, X, Y, Z and n are as defined above and Rg is alkyl of 1 to 12 carbon atoms, cycloalkyl of to 7 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms, or phenyl or phenylalkyl of 7 to 12 carbon atoms monosubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, or mono- or independently disubstituted in the phenyl ring by halogen of atomic number of from 9 to 35, or monoor independently di- or independently trisubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms.

Any trisubstituted phenyl ring preferably is substituted by alkoxy) preferably the substituents are identical.

Preferred are the compounds wherein the hydroxy group in the 2 position of the 3-aminopropoxy side chain is in unesterified form.

S2166 Alkylene only - ---— — — — —--— comprises radicals having a carbon chain of at least 2 carbon atoms separating X from the nitrogen atom of the 3-aminopropoxy side chain.

Alkyl and/or alkoxy and/or alkylthio preferably are of 1 or 2 carbon atoms, especially of 1 carbon atom. Halogen preferably is chlorine or bromine, espe·? cially bromine. Cycloalkyl preferably is of 3, 5 or especially is allyl. Alkenyloxy preferably is of 3 or 4 carbon atoms, it especially is allyloxy. Cyclalkylalkyl is especially of 3, 5 or 6 carbon atoms- in the cycloalkyl moiety and especially of 1 or 2 carbon atoms in the alkyl moiety, it preferably is cyclopropylmethyl. Phenvlalkyl preferably is of 7 or 8 carbon atoms, it especially is benzyl.

A preferably is ethylene. When A is of more than carbon atoms, then it preferably is trimethylene or a moiety branched in the a position, such as when R2 is alkyl, A preferably is unbranched.

X preferably is a bond or an oxygen atom, especially an oxygen atom. R preferably is substituted phenyl, preferably mono- or disubstituted, especially monosubstituted. It preferably is substituted by alkoxy. When it is monosubstituted, it preferably is substituted in the para position. When it is disubstituted, it preferably is substituted in the meta and para positions. When it is trisubstituted, it preferably is substituted in the meta ,meta tad para positions. When R^ is alkanoyl it is preferably acetyl.

R^ preferably is hydrogen, cycloalkyl, alkenyl, halogen or cyano, especially hydrogen or cyano. R^ preferably is alkyl, cycloalkylalkyl or phenylalkyl, especially cycloalkylalkyl or phenylalkyl. When is phenyl or phenylalkyl, it preferably is substituted, preferably mono- or disubstituted, especially monosubstituted.

It preferably is substituted by alkoxy. When it is monosubstituted phenyl or phenylalkyl, it preferably is substituted in the para position. When it is disubstituted phenyl or phenylalkyl, it preferably is substituted in the meta - and para positions. When it is trisubstituted phenyl or phenylalkyl, it preferably is substituted in the meta, meta and para positions.

Y preferably is an oxygen atom, n preferably is 2. Z preferably is an oxygen atom.

When a phenyl ring is polysubstituted, the substituents preferably are identical.

A group of compounds of the invention is the compounds of formula la, wherein R, Rj, n and Z are as defined above 216 6 R3 with the exception of alkyl of 1 to 4 carbon atoms has the significance indicated above for R2, A3 is alkylene of 2 to 5 carbon atoms and Xa is an oxygen or a sulfur atom, and physiologically acceptable hydrolyzable derivatives thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form.

In a sub-group E^ in formula la is ether than hydrogen.

Another group of compounds of the invention is the compounds of formula lb, wherein R and R^ are as defined above, R2 is alkyl of 1 to 4 carbon atoms, A*5 is ethylene or trimethylene, X*1 is a bond or an oxygen atom and nb is 2 or 3 and physiologically acceptable hydrolyzable derivatives thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form.

In a subgroup R^ in formula lb is other than 5 hydrogen. In another subgroup is an oxygen atom.

Another group of compounds of the the compounds of formula Ipa, invention is wherein R^ is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkoxy of 1 to 4 carbon atoms, R^a is hydrogen or halogen of atomic number of from 9 to 35, rP3 is alkyl of 1 to 4 carbon atoms, A^a is alkylene of 2 to 5 carbon atoms and np is 2 or 3, with the proviso that -NH-A^a-O-RP is other than the moiety of formula -NH-CK -NH-CK(CH3)CH2CH2CH2 or -NH-CH(CH3)CH2CH.(CH3)-O-< (J - 9 Another group of compounds of the invention is the compounds of formula Ipb, wherein Rf and np are as defined above, 3 „Pb R^b is alkyl of 1 to 4 carbon atoms and is alkylene of 2 to 5 carbon atoms, with the proviso that -NIl-APb-RR is other than the moiety of formula -NH-CH (CH,) CH,CH -/O Another group cf compounds of the invention is 10 the compounds of formula Ipc, wherein rP and np are as defined above, PC Y is an oxygen or a sulfur atom, RRC is 1-pyrrolyl, cyano or carbamoyl, - 10 Rpc is alkyl of 1 to 4 carbon atoms or cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety, 7iPC is alkylene of 2 to 5 carbon atoms and XP is an oxygen or sulfur atom, with the provisos that, a) when RPC is alkyl, then -NH-Apc-xp-RP is other than the moiety of formula -NH-CH(CH3)CH2CH2-O-<(J -NH-CH(CHj)CH2CH2CH2-O-( O -NH-CH(CH3)CH2CH(CH3)-0-/Q b) when Rpc is alkyl and XP is an oxygen atom, then YPC is an oxygen atom.

Another group of compounds of the invention is wherein Ipd Rr ^Pd opd and np are as defined above, is an oxygen or a sulfur atom, and Rpd have the significance indicated above for Rpc and Rpc, respectively, and - 11 Apd is alkylene of 2 to 5 carbon atoms, with the provisos that, a) when Rpd is alkyl, then -NH-Apd-RP is other than the moiety of formula -NH-CH (CH3) C^CH.^ b) when Rpd is alkyl, . then is an oxygen atom. and Another group of compounds of the invention is the compounds of formula Ipe, wherein RP and np are as defined above, ppe is hydrogen, halogen of atomic number of from 9 to 35 or cyano, Rpe is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkoxy of 1 to 4 carbon atoms and Ape is alkylene of 2 to 5 carbon atoms.

Conveniently RP in formulae Ipa to Ipe is substituted phenyl.

Another group of compounds of the invention is the compounds of formula Is, 62166 wherein Rs is phenyl or phenyl monosubstituted or independently disubstituted by alkoxy of 1 to 4 carbon atoms, rS is hydrogen, halogen of atomic number of from 9 to 35, cyano, carbamoyl,alkenyl of 2 to 5 carbon atoms or cycloalkyl of 5 or 6 carbon atoms R2 is alkyl of 1 to 4 carbon atoms, cyclcpropylmethyl, phenylalkyl of 7 or 8 carbon atoms or phenylalkyl of 7 or 8 carbon atoms mnnosubstituted or independently disubstituted in the phenyl ring yby alkoxy of 1 to 4 carbon atoms, g A is ethylene or trimethylene, Xs and ZS independently are a bond or an oxygen atom and ns is 2 or 3, with the provisos that, £ a) when Rj is alkyl, then Zs is an oxygen atom and - 13 g b) when R^ is cyclopropylmethyl and g X is a bond f then is other than hydrogen, and physiologically acceptable hydrolyzable deri5 vatives thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form. g In a subgroup R^ in formula Is is other than hydrogen. In another subgroup r| is other than alkyl.

In accordance with the invention, a compound of the invention may be obtained by a process comprising reacting a corresponding compound of formula II, wherein R^, Rj, Y, Z and n are as defined above 15 and R is a group capable of reacting with a primary amine to give a 2-amino-l-hydroxyethyl group, with an appropriate compound of formula III, H2N-A-X-R III wherein A, X and R are as defined above, and, where required, appropriately esterifying the 2 position of the 3-aminopropoxy side chain in the resulting compound of formula I. - 14 10 The amination process may be effected in conventional manner for the production of analogous 3amino-2-hydroxypropoxyaryl compands. For example, R* may be a group of formula -CH-CH2 or a derivative of this group, e.g. a group of formula -CH(0K)-CI’2L, wherein L is chlorine, bromine or a group P. r-S0 -0-, y — wherein R^ is phenyl, tolyl or lower alkyl. L is especially chlorine. The reaction is preferably effected in ethanol or in an appropriate ether such as dioxane. Optionally an excess of the amine may be used as solvent. Alternatively, the reaction may be effected in a fusion melt. Suitable reaction temperatures may be from about 20 to about 200°C, conveniently the reflux temperature of the reaction mixture when a solvent is present.

The optional esterification of the 2 hydroxy group in the side chain may be effected in manner known for the production cf analogous esters of 3-amino-2-hydroxypropoxyaryl compounds, if necesio sary using selective reactions when other reactive groups are present. 216 6 - 15 Free base forms of the compounds of the invention may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for acid addition salt formation include hydro5 chloric, malonic and fumaric acids.

In the compounds of the invention, the carbon atom in e.g. the 2 position of the 3-aminopropoxy side chain is asymmetrically substituted. The compounds may thus exist in the racemic form or in individual optical isomer form. The preferred optical isomer has the S configuration at this asymmetrically substituted carbon atom of the 3-aminopropoxy side chain. Individual optical isomer forras may be obtained in conventional manner, for example by using optically active starting materials or by fractional crystallisation of racemate salts using optically active acids.

A compound used as a starting material may be obtained in conventional manner.

In particular, a compound of formula II may be obtained by introducing by O-alkylation a group -OCH2-Rx into a compound of formula IV, OH Z-(CH2)n-Y-R2 - 16 wherein R^, R2, Y, Z and n are as defined above. A compound of formula IV preferably is reacted in anionic form.

A compound of formula IVa IVa wherein R* is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, halogen of atomic number of from 9 to 53, 1-pyrrolyl, cyano, carbamoyl, alkenyl of 2 to 5 carbon atoms, alkenyloxy of 3 to 5 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to the oxygen atom, or alkanoyl of 1 to 5 carbon atoms, n' is 2 or 3 and Y and R2 are as defined above, may e.g. be obtained by deprotecting a corresponding °(cH2)n'-Y-R2 V - 17 η' wherein R|, R^and Y are as defined above and Bz is a protecting group, e.g. benzyl or tetrahydropyranyl, under appropriate -conditions, e.g. with palladium on charcoal or by acidic hydrolysis.

A compound of formula IVb, OH wherein R^, Y and n' are as defined above and I I , · · ' t R^ is alkylthio of 1 to 4 carbon atoms or trifluoromethyl, may e.g. be obtained by selectively etherifying a corresponding 1,4-dihydroxy .derivative at the hydroxy group in the meta position with respect to R|* , e.g. by reaction with a molar equivalent of a compound of formula Hal-(CK2) .-Y-R^ wherein R2,Y and n' are as defined above and Hal is halogen, preferably in an inert solvent such as acetone and in the presence of a base such as potassium carbonate.

A compound of formula Va wherein Bz, Y, R2 and n*are as defined above, may e.g. be obtained by appropriately etherifying 4-benzyloxyphenol, e.g. with an appropriate bromine derivative, conveniently in more than 1 step, e.g. by first forming the moiety -O(CH2) i-Y-H and then alkylating to' introduce the moiety R2 The compounds of formula Vb, OBz rof7' OCCH^.-Y-R, wherein R2, Y, n' and Bz are as defined above, and R^’1 with the exception of hydrogen has the significance indicated above for R^ , may e.g. be obtained by mono-chlorinating, -brominating or -iodinating a r compound of formula IVa, wherein R^ is hydrogen, in the position ortho to the hydroxy moiety, subsequently, if desired, appropriately protecting the hydroxy group in a resultant compound of·formula IVa, wherein P.J. is bromine, to obtain a compound of formula Vc, 53166 - 19 wherein Rj, Y, n' and Bz are as defined above and subsequently, if desired, converting a compound of formula Vc, in a Grignard-type reaction, e.g. with lithium, to a corresponding compound of formula Vb, wherein R|11 is alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms or alkenyl of 2 to 5 carbon atoms. Alternatively, a compound of formula Vc may be converted to a corresponding cyano compound, e.g. with cuprous cyanide in dimethyl formair.ide and subsequently, if desired, the cyano group hydrolyzed to a corresponding compound of formula Vb, v/herein R|'' is carbamoyl. Subsequently, if desired, this carbamoyl compound may be converted in a Hofman type degradation into a corresponding amino derivative and this amino derivative converted e.g. with 2,5dimethoxyfurane to a corresponding compound of formula Vb, wherein R£*' is 1-pyrrolyl. Alternatively, if desired, the amino derivative may be converted into a corresponding diazonium salt, e.g. with nitrous acid, and this diazonium salt further reacted with e.g. potassium fluoride in water to a corresponding compound of formula Vb, v/herein R|'' is fluorine. Alternatively, the diazonium salt may be converted by reaction with aqueous acid to a corres25 ponding hydroxy compound and this hydroxy compound converted by etherification into a corresponding compound of formula Vb, wherein Rj1' is alkoxy of 1 to 4 carbon atoms or alkenyloxy of 3 to 5 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to the oxygen atom. - 20 The R|'' = alkanoyl derivative may be made by Friedel-Crafts acylation. If desired, the diazonium group may be converted into many other moieties, e.g. alkylthio by reaction with an alkali metal mercaptide. if required, the trifluoromethyl group may be obtained by fluorinating a corresponding carboxylic group which is in turn obtained from hydrolyzing a cyano group.

Instead of protected compounds of formula Vb it may be alternatively possible to use directly the corresponding unprotected compounds. For example, the group R^ = β,y-alkenyl may be introduced into the ortho position by subjecting the corresponding β,'ί'alkenyl ether to a Claisen rearrangement. If desired, the cyclopentyl group may be introduced by subjec15 ting the corresponding cyclopent-2-enyl.ether to a Claisen rearrangement to form the ortho cyclopent-2enyl phenol which is then hydrogenated.

A compound of formula IVc, wherein R^ and Y are as defined above, R2 has the significance indicated above for R2 and n'' is 1, 2 or 3, - 21 may e.g. be obtained essentially in analogous manner to that described above for the production of compounds of formula IVa from the corresponding protected compounds. If desired, the protecting group may be methyl instead of benzyl or tetrahydropyranyl. The deprotecting reaction may be carried out in the presence of an alkali metal alkyl mercaptide. The protected compounds wherein R^ is other than hydrogen, alkylthio or trifluoromethyl may be produced in analogous manner to that desdribed above for the production of compounds of formula Vb. It may alternatively be possible to convert one substituent R^ into another substituent R^ when the compound is in unprotected form, e.g. ortho-bromo derivatives may be formed simply from the corresponding phenol. The protected compounds wherein R^ is hydrogen may be produced by building up the ether moiety -(CI’2) ,,-Y-R^ in conventional manner, e.g. by a Williamson synthesis.

The compounds of formula IVd, OH IVd Z(CH)-Y-R'' i η ι wherein R^, Z, n and Y are as defined above and - 22 R?' with the exception of cycloalkylalkyl has the significance indicated above for and the protected compounds corresponding thereto, e.g. the compounds wherein the hydroxy group is methoxy protected in the form of a benzyloxy.^or tetrahydropyranyloxy group, are believed to be new.

Insofar as the preparation of any particular starting material is not particularly described, this may be effected in conventional manner.

In the following Examples all temperatures are in degrees Centigrade and are uncorrected. 521G6 - 23 Example 1: 2-{2-hydroxy-3-[2-(4-methoxyphenoxy)ethylamino] -propoxy}-5-(2-methoxyethoxy)benzonitrile 2.4 g of 2-(2,3-epoxypropoxy)-5-(2-methoxy5 ethoxy)-benzonitrile and 8.35 g of 2-(4-methoxyphenoxy) ethylamine are dissolved in 30 ml of ethanol, the solvent is then evaporated and the resulting mixture stirred for 1 hour at 70°. The reaction melt is then dissolved in ether and allowed to crystallize under cooling. Purification is effected by recrystallization in benzene. The title compound is obtained (M.P. 95-97°).

The starting material is obtained as follows: Bromine dissolved in chloroform is added at o° to a solution of 4-(2-methoxyethoxy)phenol (M.P. 98-99° ) [prepared by reacting 4-benzyloxyphenol with 2-chloroethyl methyl ether and debenzylating the resultant i-benzyloxy-4-(2-methoxyethoxy) benzene (M.P. 41 - 43° ) by hydrogenation with palla20 dium on charcoal] in methanol and the mixture stirred for 2 hours. After chromatography over silicagel, the resultant 2-bromo-4-(2-methoxyethoxy)phenol (oil) is reacted for 60 hours with a mixture of potassium carbonate, acetone and benzyl bromide. After chromatography over silicagel, the resultant 1-benzyl oxy-2-bromo-4-(2-methoxyethoxy)benzene (oil) is reacted in dimethylformamide for 5 hours with cuprous cyanide. After purification by partition between aqueous hydrochloric acid solution and ethyl acetate, the -24resultant 2-benzyloxy-5-(2-methoxyethoxy)benzonitrile (M.P. 50-51°) is debenzylated over 10 % palladium on charcoal in methanol. The resultant 2-hydroxy-5-(2-methoxyethoxy)benzonitrile(oil) is reacted at 100° with epichlorhydrin and a catalytic amount of piperidine,and 2-(2,3-epoxyprcpoxy)-5(2-methoxyethoxy)benzonitrile (oil) is obtained.

From the agpropriate compounds of formula II, wherein R is --CH-fcl^ , and the appropriate compounds of formula III the following compounds of formula I may be obtained in analogous manner to Example 1: - 27 [2-(4-Mathoxybenzyloxy)ethyl]phenol .(oil) used as a starting material is Φ 0) •P «3 q ι—1 0 rC O ϋ >1 ip ι—1 Λ 0 Λ q r—J τί 0 >1 Φ ϋ N q «Ρ q •Ρ cf φ (0 tp λ •Ρ >1 Λ N x Ο q φ o λ ω .c jj •Ρ >4 X φ e ιΡ 0 <0 •Ρ •μ Φ Ip k Φ £ 0 •Ρ 1 e q q β &> 0 Φ q •P •P •Ρ rP +) o W Λ q •P k φ •Ρ W 4J •P Φ ω -P q H q ip *ύ O >5 φ q .c ω Φ •P q & ft Φ e φ rP Ό rp >1 •Ρ >1 IX β Λ 0 q +J k Ν Φ Cu q 0 0 φ £ ip λ 0 ϋ <-* k >1 >1 43 ϋ κ 1 CM £ Ο Λ —’ q 44 1 •rl Φ Ό· '0 >1 0 V) κ ο q • •P q +> •P q q Φ ϋ k *rl β rtf q ω | Φ *H q CM k 0 k | r>1 ntf ΙΟ Λ >1 Π 1 »0 q k >1 X Φ k Φ 0 q •P Ό k •rl Φ q Ό 4-) q >1 •P rQ q ω Κ 1 0 •P < CM ιη hydrolyzing 2-benzyloxy-5-(2-methoxyethoxy)benzonitrile with KOH in tert-butanol and debenzylating the resultant . 2-benzyloxy-5-(2-methoxyethoxy)benzamide (M.P. 113-115° ) by hydrogenation with palladium on charcoal. - 28 The compounds of the invention (except the compounds of Formule IVd and the protected compounds corresponding thereto) possess pharmacological activity.

In particular, the compounds possess β-adrenoceptor blocking activity, as indicated by standard tests. For example, in the spontaneously beating guinea pig atrium (A. Bertholdtet al., Postgrad.Med. 57, Suppl. 1 [1981] 9-18) they inhibit the positive chronotropic isoprenaline effect at bath concentra«6 tions of from about 10 M to about 10 M.

Some of the compounds, e.g. the compounds of Examples 12, 14 and 15 also exhibit σ-blocking activity as indicated in standard tests. For example the activity is observed in the everted rat aorta (according to the principles of K.K.F.Ng, S. Duffy, W.J. Louis and A.E. Doyle, Proceedings of the Australian Physiological and Pharmacological Society, j>, [1975] 158P). The activity is also confirmed in binding studies, e.g. basically as described by R.J. Summers, B. Jarrott and W.J. Louis, Neuroscience Letters 20 (1980) 347-350.

The compounds are therefore indicated for use as β- and also α-adrenoceptor blocking agents, e.g. for the prophylaxis and therapy of coronary diseases, such as angina pectoris, conditions which are associated with sympathetic over-stimulation, e.g. nervous heart complaints, myocardial infarction, hypertension, for the intermediate treatment of - 29 migraine and for the treatment of glaucoma and thyrotoxicosis. In view of their antiarrhythmic effect, they are useful as antiarrhythmics for the treatment of disturbances in the heart rhythm, such as supraventricular tachycardia.

An indicated daily dose is from about 10 about t0/500mg, suitable administered, e.g. orally, in divided dosages of from about 2.5 mg to about 250 mg of the compounds two to four times daily, or in retard form.

The compounds have more marked and wider spread beneficial pharmacological properties than could be expected for compounds having this type of structure. In particular their activity is more car15 dioselective than could be expected from similar known compounds. This cardioselectivity can be demonstrated in vitro by the use of isolated tissues of the guinea-pig, in accordance with standard procedures. Thus, left ventricular and lung membranes of a guinea-pig can be prepared according to standard pharmacological procedures (G. Engel et al., Triangle [1980] 69-76) and made to react with an exogenous125 ly added radioactive β-ligand such as I — 2-cyanopindolol (I-CYP) to determine affinity of the test compound to p^ and p^ adrenoceptors. - 30 For the compound of Example 1, the cardioselectivity amounts to about 80 times, for the compound of Example 2, to about 410 times, for the compound of Example 3, to about 170 times and for the compound of Example 7, to about 640 times.

Guinea pig lung and left ventricular membranes may e.g. be prepared as follows: Adult guinea pigs (35O-5OOg) are killed by decapitation. The heart and lung are perfused with Tris saline buffer (Tris-HCl 10 mM, pH = 7.5, NaCl 0.154 1^ 37°C), removed and freed from connective tissues and trachea. The lung membranes are prepared as described by Kleinstein, J. and Glossmann H., Kaunyn — Schmiedeberg's Arch.Pharmacol. 305 [1978] 191-200 with the modification that medium A contains only 20 mM KaKCO^. The final pellet is suspended in 10 ml 20 mM NaHC03 and stores in liquid nitrogen. The preparation of the left ventricle membranes follows the procedure published by McNamara, D.B. et al., J.Biochem. 75 [1974] 795-803 until the step where the 'membrane fraction' is received. These membranes are stored in liquid nitrogen and immediately before use further diluted to the appropriate concentrations as indicated in the text. - 31 The compounds of Examples 1 to Ιή exhibit effective β-adrenoceptor blocking activity in the above in vitro tests at concentrations of 10~9 m to 10_SM.

The high selectivity of blockade for the 5 compounds —---— - —---- — is of major importance in the treatment of hypertension where exacerbation of an existing asthmatic condition may be precipitated by currently commercially available compounds.

The compounds also possess a degree of intrin10 sic sympathomimetic activity, a property which is useful in preventing undue bradycardia and helps reduce the incidence of heart failure in subjects with heart muscle disease.

Of the compounds in optically active form, those in which the carbon atom in the 2-position of the 3-aminopropoxy side chain has the (S)-configuration are pharmacologically more active than the corresponding (R)-enantiomers.

The preferred uses of the compounds are the use against coronary diseases and hypertension.

Preferred are the compounds of Examples 1,2, and 11, especially of Examples 1 and 3. - 32 10 The compounds may be administered in pharmaceutically acceptable acid addition salt form. Such salt forms exhibit the same order of activity as the free forms and are readily prepared in conventional 5 manner. The present invention also provides a pharmaceutical composition comprising a compound of the invention in free form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet. 1.

A process for the production of a compound of formula I wherein OCH2CHCIi NH-A-X-R R is phenyl of phenyl monosubstituted or independently disubstituted or independently trisuhstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, R^ is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, halogen of atomic number of from 9 to 53, trifluoromethyl, 1-pyrrolyl, cyano, carbamoyl, alkenyl of 2 to 5 carbon atoms, alkenyloxy of 3 to 5 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to the oxygen atom, or alkanoyl of 1 to 5 carbon atoms? R2 is alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety, phenyl, - 34 10 phenylalkyl of 7 to 10 carbon atoms, or phenyl or phenylalkyl of 7 to 10 carbon atoms monosubstitutefi or independently disubstituted or independently trisubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, A is alkylene of 2 to 5 carbon atoms, X is a bond, an oxygen or a sulfur atom, Y is an oxygen or a sulfur atom, and either Z is an oxygen atom and n is 2 or 3 or Z is a bond and n is 1, 2 or 3, with the provisos, that a) when R2 is alkyl, then Z is an oxygen atom and the group -NH-A-X-R is other than the moiety of formula -NH-CH(CK^)CH2CH2-(O b) when R2 X then Y -NH-CH (CH3) CH2CH2~0-3) CH2CH2CH2-O-^0^> or -NH-CH (Ch'3) CH2CH (Clip -0-ZO\ ; is alkyl and is a bond or an oxygen atom, is an oxygen atom, and c) when R2 is cycloalkyl or cycloalkylalkyl and X is a bond, or when R2 is unsubstituted or rconosubstitutea phenyl, X is a bond and Z is an oxygen atom, then R^ is other than hydrogen, - 35 or a physiologically acceptable hydrolyzable derivative thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esteri· fied form, which comprises reacting a corresponding compound of formula II,

Claims (15)

1. wherein R , K 2 , Y, Z and n are as defined in claim 1 and R r is a group capable of reacting with a primary amine to give a 2-amino-l-hydroxyethvl group, with an appropriate compound of formula III, h 2 n-a-x-r III wherein A, X and R are as defined above, and,where required, appropriately esterifying the

2. Position of the 3-aminopropoxy side chain in the 15 resulting compound of formula I, - 36 2. A process for the production of a compound as defined in claim 1, substantially as hereinbefore described with reference to any one of the Examples.

3. A compound as defined in claim 1, whenever 5 produced by a process according to claim 1.

4. A compound of formula X, as defined in claim 1 or a physiologically acceptable hydrolyzable derivative thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esteri10 fied form.

5. A compound of formula I, as defined in claim 1.

6. A compound of claim 4 of formula E, wherein 13 R, R^, R^, A, X, Y, Z and n are as defined in , Claim 1 and R g is alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to

7. Carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms, or phenyl or phenylalkyl of 7 to 12 carbon atoms monosubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, or monoor independently disubstitufced in the phenyl ring - 37 by halogen of atomic number of from 9 to 35, or mono- or independently di- or independently trisubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms. 57. A compound of claim 4, wherein R^ is hydrogen, cycloalkyl, halogen or cyano.

8. A compound of claim 4, wherein R^ I s alkyl, cycloalkylalkyl or phenylalkyl,

9. A compound of claim 4, wherein A is ethylene

10. A compound of claim 4, bond or an oxygen atom.

11. A compound of claim 4, or disubstituted phenyl. wherein X is wherein R is mono

12. A compound of claim 4, wherein Y is an 15 oxygen atom.

13. A compound of claim 4, wherein n is 2.

14. A compound of claim 4, wherein Z is an oxygen atom. - 38 15. A compound cf claim 4 of formula Xa, wherein R, E^, n and Z are as defined in claim 1, R a with the exception of alkyl of 1 to 4 carbon 5 atoms has the significance indicated in claim 1 for R 2 , A a is alkylene of 2 to 5 carbon atoms and X a is an oxygen or a sulfur atom, Ci* a physiologically acceptable hydrolyzable 10 derivative thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form. 16. A compound of claim 15, wherein R^ is other than hydrogen.

15. 17. A compound of claim 4 of formula lb,