DK163994B - 1-Phenoxy-2-hydroxy-3-aminopropane derivatives, pharmaceutical preparation which comprises the derivatives, and the use of the derivatives - Google Patents

Description

in

DK 163994 B

The present invention relates to novel 1-phenoxy-2-hydroxy-3-aminopropane derivatives.

GB 1,509,527, EP 52,072 and EP 85,286 disclose various 1-phenoxy-2-hydroxy-3-aminopropane derivatives with β-adrenoceptor blocking action. Compared to the known 1-phenoxy-2-hydroxy-3-aminopropane derivatives having β-adrenoceptor blocking effect, the compounds described in this specification and claims exhibit an unexpectedly high β-1 blocking selectivity and an unexpectedly high degree. of oral bioavailability.

The invention relates to 1-phenoxy-2-hydroxy-3-aminopropane derivatives of the general formula I

OH

and yes? nh-a-nhco-x f '

R

where X represents 3- or 4-tetrahydropyranyl, A represents alkylene with 2 or 3 carbon atoms, hydrogen, alkyl of 1-4 carbon atoms, halogen having an atomic number of 9-53 or cyano, and R represents hydroxy or a group -Z - (012) 2-0-¾. represents hydrogen, alkyl of 1-5 carbon atoms, cycloalkyl 20 of 5-7 carbon atoms, cycloalkylalkyl of 3-7 carbon atoms in the cycloalkyl moiety and 1-4 carbon atoms of the alkyl moiety, or phenyl or phenylalkyl of 7-10 carbon atoms, wherein the phenyl ring optionally, mono- or same or different di- or identical or different trisubstituted with halogen having an atomic number of 9-35, and Z represents oxygen or a single bond, and acid addition salts thereof.

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These compounds are hereinafter referred to as "the compounds of the invention".

A monosubstituted phenyl ring is preferably substituted at the para position. A disubstituted phenyl ring is preferably substituted in the meta and para position. A trisubstituted phenyl ring is preferably substituted at the meta, meta and para position. A phenyl ring is preferably unsubstituted, monosubstituted or disubstituted. A polysubstituted phenyl ring is preferably substituted with identical substituents.

Preferably, alkyl of 1-4 carbon atoms has 1 or 2, especially 1 carbon, empty. Preferably, alkyl of 1-5 carbon atoms has 3 or 4, especially 3 carbon atoms; the term preferably denotes propyl. Halogen having an atomic number of 9-35 or 9-53 preferably represents chlorine or bromine, especially bromine. Cycloalkyl of 3-7 carbon atoms preferably has 3, 5 or 15, especially 5 or 6 carbon atoms. Cycloalkyl of 5-7 carbon atoms preferably has 5 or 6, especially 6 carbon atoms. Cycloalkylalkyl having 3-7 carbon atoms in the cycloalkyl moiety and 1-4 carbon atoms in the alkyl moiety preferably has 3, 5 or 6 carbon atoms in the cycloalkyl moiety and preferably 1 or 2 carbon atoms in the alkyl moiety; the term preferably represents cyclopropylmethyl. Phenylalkyl having 7-10 carbon atoms preferably has 7 or 8 carbon atoms; the term especially refers to benzyl.

The alkyl of 2 or 3 carbon atoms preferably represents ethylene. When the group contains more than 2 carbon atoms, it preferably represents trimethylene or an α-position to -NH- in the 3-aminopropoxy residue branched group such as -CH (CH3) CH2-, αR preferably represents a group -Z- (CH2) 2_0_R2 *

Rj ^ sits in the ortho position of the 3-aminopropoxy chain of ideas.

It preferably represents hydrogen, cyano or halogen, especially hydrogen or halogen, especially hydrogen.

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When R2 is optionally substituted phenyl or phenylalkyl, it is preferably unsubstituted or monosubstituted.

X is preferably tetrahydropyran-4-yl.

Z preferably represents oxygen.

A preferred group of compounds of the invention consists of compounds of the general formula 1 '

OH

OQLCHCH.NH-A-NHCO-X z- (CH2) 2-O-R2 where A, X, Z, and R2 have the meaning given above, as well as acid addition salts thereof.

In a subgroup, R £ represents hydrogen, alkyl of 1-4 carbon atoms, cycloalkyl of 5-7 carbon atoms or cycloalkylalkyl of 3-7 carbon atoms in the cycloalkyl moiety and 1-4 carbon atoms of the alkyl moiety.

A further group of compounds of the invention consists of 15 compounds of general formula I

? H

also9chch.nh-a-nhco-x βξτ '

OH

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4 where A, R 1 and X have the meaning given above, and acid addition salts thereof.

A further group of compounds of the invention consists of compounds of the general formula

OH

!

0CH2CHCH2NH-A -NHCO-X

(Eras

K

wherein X and A are as defined above, R 2 represents hydrogen, halogen having an atomic number of 9-53 or cyano, and 8LS fl 5¾10 R represents hydroxy or a group -Z- (CH 2) 2 -O-R 2 where Z is as defined above and R 2 represents alkyl of 1-5 carbon atoms, cycloalkyl of 5-7 carbon atoms or cycloalkylalkyl of 3-7 carbon atoms in the cycloalkyl moiety and 1-4 carbon atoms of the alkyl moiety.

SS gg 15 In a subgroup, R has the meaning given above and R

SS SS

draws a group -Z- (CH2 ^ -O "^ · 2" ^ our Z and R2 have it above

SS

significance. In another subgroup, R j represents hydrogen and

SS

R hydroxy.

A further group of compounds of the invention consists of 20 compounds of general formula Ipb

OH

0CH2CHCH2NH-A-nhco-x (o) ^

OH

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5 where A and X have the meaning given above.

The compounds of the invention are prepared by 3-amino-2-oxypropylation of the corresponding compounds of general formula IV

OH

é "iv

R

5 wherein R and are as defined above, or starting materials therefor.

The process steps of the invention can be carried out using the reaction conditions known from the preparation of analogous 3-amino-2-oxypropoxyaryl compounds.

The selection of the most suitable variants must, of course, be made taking into account the reactivity of the substituents present.

If R represents a group -2 - ((¾) 2 * ° · Ε · 2>, the compounds of general formula IV are preferably used rather than their starting materials.

Starting materials for compounds of general formula IV are compounds which can be converted to a compound of general formula IV, for example by corresponding etherification, aromatic substitution and / or protecting group decomposition.

For example, if Z represents oxygen, starting materials constitute corresponding linkages in which the group -O- (O ^) 2-O-¾ is replaced by a hydroxy group, if desired in protected form. For compounds where R 2 does not represent hydrogen, starting materials, for example, constitute similar compounds in which the -O-R 2 group is replaced by hydroxy, if desired in protected form. For compounds where R 2 represents hydrogen, for example, 25 starting materials constitute similar compounds wherein the group -O-H is in protected form.

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The process steps can therefore be performed in more than one workflow.

For example, one may react with a compound of general formula IV in protected form or introduce a 3-amino-2-oxypropylres t in protected form and after the 3-amino-2-oxypropylation has been effected, the protecting group (s) may be deprotected.

Examples of protecting groups for, for example, a hydroxy-substituted phenyl ring are benzyl, methyl or tetrahydropyran-2-yl, preferably benzyl.

According to one embodiment, 3-amino-2-oxypropylene is not performed in two 10 operations.

In a first workflow, a group -0112-¾ is introduced. wherein ϋχ represents a group which, when reacted with a primary amine, yields a 2-amino-1-hydroxyethyl group at 0-alkylation at the 1-position of compounds of general formula IV to give the corresponding compounds of general formula II

PcVRx iqt

R

where Εχ, R ^ and R have the meaning given above.

In another process, the compounds are reacted with the general formula

II having similar compounds of general formula III

H2N-A-NHCO-X III

wherein A and X are as defined above and at least one hydroxy group in the compounds thus obtained of the general formula I is optionally esterified as desired.

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The step of O-alkylation at the 1-position can be carried out using known conditions for the preparation of analog ethers. The compounds of general formula IV are preferably used in anionic form.

Compounds of general formula IV are suitably used in which all optional hydroxy groups except the hydroxy group at the 1-position are in protected form.

The step of amination can be carried out using known conditions for the preparation of analogous 3-amino-2-hydroxypropoxyaryl compounds. As the group is used, for example, the group 10 / O / -CH-CH 2 or a derivative thereof, for example a group of the general formula -CH (OH) CH 2 -L, where L represents chloro, bromo or a group Ky-SO2-0- wherein R 1 is phenyl, tolyl or lower alkyl. In particular, L represents 15 chlorine. Preferably, ethanol or an appropriate ether such as dioxane is used. Optionally, an excess of the amine is used as a solvent. The reaction is conveniently carried out in the melt. Appropriate temperatures are from approx. 20 to approx. 200 ° C; it is conveniently worked at reflux temperature if a solvent is present.

The optional esterification of the compounds thus obtained of the general formula I may be carried out analogously to known methods for the preparation of analog esters, and if necessary under selective conditions, if other reactive groups exist, for example amino or hydroxy residues.

The compounds of the invention may be in free form, i.e. usually as a base, or in salt form. From the compounds in free form, acid addition salts can be prepared in known manner, for example with hydrochloric acid, malonic acid, succinic acid or fumaric acid, and vice versa.

In the compounds of the invention, the carbon atom at, for example, the 2-position of the 3-aminopropoxy side chain is asymmetric; the compounds may therefore occur in the form of racemates or the corresponding enantiomers. The one-

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8 antiomers whose S configuration is contingent on the asymmetrically substituted carbon atom of the 3-aminopropoxy side chain are preferred. The enantiomers of the compounds of the invention can be obtained in known manner, for example, by using the corresponding enantiomers of the starting compounds or by fractional crystallization of salts of the racemates with optically active acids. Any diastereomeric mixtures, for example, if X represents tetrahydropyran-3-yl, may also be separated by known methods, for example, by fractional crystallization.

If the preparation of the necessary starting materials is not described, these are known or can be prepared by methods known per se or analogous to the methods described herein or known per se.

The invention is further illustrated by the following examples, in which all temperature indications are uncorrected.

EXAMPLE 1 1- [4- (2-Methoxyethyl) phenoxy] -3- [2- (tetrahydropyran-3-yl-carbonylamino) ethylamino] -2-propanol 5 g of 1- (2,3-Epoxypropoxy) -4- (2-methoxyethoxy) benzene and 6 g of N- (2-aminoethyl) tetrahydropyran-3-carboxamide are heated for 30 minutes at 130 ° C, cooled and taken up in ethyl acetate. The solution is worked up in the usual way. There is thus obtained the title compound (mp 107-108 ° C of methanol / ethyl acetate).

The starting material is obtained by reaction of 4- (2-methoxyethyl) phenol with epichlorohydrin in the presence of catalytic amounts of piperidine.

Analogously to Example 1 is obtained from the corresponding compounds of the general formula II wherein R

A

-CH-CH2

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9 (unless otherwise indicated in the table) and the corresponding compounds of general formula III the following compounds of general formula I:

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Ex.

No. R ^ a) X R A Mp. eC

2 H Tetrahydro-O (CH 2) 20 Me - (CH 2) 2- sc 118-120 pyran-3-yl 3 H Tetrahydro- (CH 2) 20 Me - (CH 2) 2- b 128-129 pyran-4 yl 4b) o-Br Tetrahydro- (CH2) 20 Me - (CH2) 2- b 118-127 pyran-4-yl 5 o-Br Tetrahydro-O (CH2) 20CH2x ^ - (CH2) 2- b 105-107 pyran-3-yl 6 H Tetrahydro-O (CH 2) 20 Me - (CH 2) 2- b 107-108,5 pyran-4-yl 7c) o-CN Tetrahydro- (CH 2) 20 Me - (CH 2) 2- b 128-130 pyran-4-yl 8 o-Br Tetrahydro- (CH 2) 20 Me - (CH 2) 2- b 104-107 pyran-3-yl 9 o-CN Tetrahydro- - (CH 2) 20 Me - (CH2) 2- b 118-122 pyran-3-yl 10 H Tetrahydro--0 (CH2) 20CH2 - <J - (CH2) 2- b 121-123 pyran-3-yl 11 H Tetrahydro - -0 (CH2) 20CH2-] - (CH2) 2- b 106-108 pyran-4-yl 12 H Tetrahydro--0 (CH2) 20CH2- <3- (CH2) 3- b 96-97 4-yl 13 H H Tetrahydro-OH - (CH 2) 2- b 122-125 pyran-3-yl

Ex.

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No. a) X R A Mp. ° C

14® * H Tetrahydro-OH - (CH2) 2- b 122-125 Pyran-3-yl 15d) H Tetrahydro-OH - (CH2) 2- b 124-126 Pyran-4-yl 16e) H Tetrahydro-OH - (CH2) 2- b 124-126 pyran-4-yl 17 H Tetrahydro--0 (CH2) 20CH2CH3 - <CH2) 2- 105-107 pyran-4-yl 18 oF Tetrahydro--0 (CH2) 20CH2 - <Q - (CH2) 2- 100-101 pyran-4-yl 19 oF Tetrahydro--0 (CH2) 20CH2CH2 ~ 5) -F - (CH2) 2- 107-109 pyran-4-yl 20 H Tetrahydro--0 (CH2) 20CH2CH3 CH3 pyran-4-yl -CHCH2-21 o-CH3 Tetrahydro--0 (CH2) 20CH3 - (CH2) 2- 20 pyran-4-yl 22H Tetrahydro--0 (CH2) 20CH2 - ^^ - F - (CH2) 2- 115-117 pyran-4-yl 23 H Tetrahydro--0 (CH2) 24 H Tetrahydro-O (CH 2) 20-O} - (CH 2) 2- 106-108 pyran-4-yl

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12 b = in free base form sc = in bis (base) succinate salt form

Me - methyl o- = in ortho position for the 3-aminopropoxyside chain.

The intermediate 2-bromo-4- (2-methoxyethyl) phenol (oil) is obtained by bromination of 4- (2-methoxyethyl) phenol.

C ·)

The intermediate 2-hydroxy-5- (2-methoxyethyl) benzonitrile (m.p. 94-96eC) is obtained by starting from 2-bromo-4- (2-methoxyethyl) phenol (see below b) by reaction with benzyl bromide, cyaniding it thus obtained 10 derivatives with copper cyanide and subsequent debenzylation of the thus obtained 2-benzyloxy-5- (2-methoxyethyl) benzonitrile (oil) with palladium-on-charcoal.

d)

The amination step is carried out in an inert atmosphere with the hydroxy group in protected form such as benzyloxy and the protected compound thus obtained is then subjected to protecting group decomposition by hydrogenation with palladium-on-carbon.

e)

By starting from the corresponding compound of the general formula II, where Rjj represents -CH (OH) CH2 Cl.

The compounds of the invention in free form or in the form of physiologically acceptable salts thereof are characterized by interesting pharmacodynamic properties. They can be used as medicines.

In particular, they have an β-adrenoreceptor blocking effect. This is evident from standard tests. Thus, they inhibit the positive-chronotropic isoprene line effect on the isolated, spontaneously knocking guinea pig heart chamber 25 (A. Bertholet et al., Postgrad-Med. 57, Appendix 1, 1981, pp. 9-17) at a bath concentration of about 10 to approx. 10M.

The effect of the compounds of the invention compared to known compounds

To investigate the selectivity and bioavailability of compounds of the present invention compared to known β-adrenoceptor blocking compounds with similar structures, the following experiments were performed.

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selectivity

methods

Isolated tissue preparations

Studies were performed on isolated atrium and tracheal rings from 5 guinea pigs. All tissue was equilibrated for 60 minutes with Krebs-Ringer physiological saline solution, which in mmol / l consisted of NaCl, 120; KCl 5.6; MgSO4> 1.2: CaCl2, 2.5; KH 2 PO 4, 1.4; NaHCO3, 25; glucose, 11.2; EGTA, 0.0025.

Cumulative concentration-response curves were made for each preparation 10 as described by Van Rossum (Archiv. Int. Pharmacodyn. 143, pp. 299-329, 1963), and curves were adapted by computer analyzes according to Zaborowsky et al., (J. Phamnacol. Meth., 4, pp. 165-178, 1980).

To measure antagonist activity, the agent used was added to the organ bath at least 45 minutes after the first control concentration-15 response curve was established, and the bath was equilibrated for 20 minutes before the next concentration-response curve was established. The shift to the right of this curve was calculated as a pA2 value (MacKay, J.

Pharm. Pharmacol., 30, pp. 312-313, 1978).

Isolated spontaneously striking atria from guinea pigs 20 Guinea pig hearts were removed from adult animals (500-700 g) and placed in Krebs-Ringer solution (pH 7.4) aerated with 5% CO 2 in 02. The atria were dissected free from the ventricles and overlying tissues. placed in a 30 ml bath maintained at 37 ° C and connected to an isotonic transducer. A tension of 2 g was applied. Chronotropic activity was amplified and recorded on a Grass-poly graph.

Guinea pig trachea slices

Trachea was excised from adult guinea pigs (500-700 g), removed from overlying tissue and cut transversely for ca. 3 mm wide washers. A slice was placed in a 30 ml bath maintained at 37 ° C. Relaxation of the 30 disc with isoprenaline was recorded by an isotonic transducer

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14 connected to a Grass polygraph, after the tone had been established by administration of 1 μπαοΐ / ΐ carbachol (15 minutes before concentration-response curves). The tension of each tissue was 1 g.

Fixed rat preparation 5 Rats weighing approx. 200-250 g were anesthetized with halo than, the left artery carotis and left vein jugularis were cannulated, and trachea was exposed and cannulated. The animal was artificially respected and eventually fixed. Blood pressure and heart rate were measured from the left artery carotid, while drugs were administered in 10 normal heparinized saline via the left venous jugular vein.

Under these conditions, the fixed rat preparation was stable for at least 4 hours (Lun et al., J. Auton. Pharmac. 2, p. 217, 1982).

To measure β -adrenoceptor activity, isoprenaline 0.1 / µg / kg was initially given three times at 5-min intervals to establish control heart rate responses. When these were reproducible, the first dose of test substance (antagonist) was given followed by a standard dose of isoprenaline 5 minutes later. The protocol was repeated at 15 minute intervals using successively higher antagonist doses. The dose range was based on a logarithmic series, 0.1, 0.3, 1.0, 3.0, 10, 30, 100 and 300 µg / kg and in some cases 1000 µg / kg.

The following results were obtained:

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Strength on Strength on guinea pig heart guinea pig trachea Selective β-adrenoceptor-adrenoceptor (ID50, receptors (ID50, (atrium / 5 Compound molar wife. Molar wife) trachea)

Commercially available β-adrenoceptor antagonists ** (a) Non-selective

Fropanolol 5 x 10 * 9 5 x 10'9 1.0 10 Pindolol 2 x 10'9 2 x 10'9 1.0 (b) "Relatively" selective

Metoprolol 1 x 10'® 5x10'® 5

Betaxolol 4 x 10'® 1 x 10'® 29

Atenolol 1.6 x 10- 20 15 Bevantolol 8 x 10'® - 5 MICI 89,406 "3 x 10'® - 19

Compounds of the present invention according to Example 10 1 x 10 “^> 1 x 10 '^ absolute *> 800 # 20 Forb. according to Example 11 2 x 10 '? > 1 x 10 'absolute *> 500 #

Conn. according to Example 13 7 x 10 '^> 1 x 10' ^ absolute *> 200 #

Conn. according to Example 17 2 x 10 '^> 1 x 10' ^ absolute * 25> 500

Conn. according to Example 18 3 x 10'8 8 x 10 "5 2042 #

Conn. according to Example 19 7 x 10'9 4 x 10 '^ 4800

Conn. according to Example 20 1 x 10> 1 x 10- ^ absolute *> 1000 # 30 Forb. according to Example 21 2 x 10 '^> 1 χ 10 "^ absolute *> 500 #

Conn. according to Example 22 2 x 10-8 6 χ 10-5 2200

Conn. according to Ex. 23 2 x 10'® 3 χ 10'5 1500

Conn. according to Example 24 2 x 10 '^> 1 x 10' ^ absolute * 35> 500 #

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16 ID50 represents the antagonist concentration that doubles the isoprenaline concentration required to give a response of 50% of the maximum in a given tissue. The pA2 value is the negative logarithm of Π> 50> ie. a pA 2 of 4.0 represents an ID 50 of 1 x 10

5 * absolute = / S-1 specific, i.e. pA2 for trachea <4.0 # This value represents selectivity calculated assuming that pA2 for trachea is 4.0. It therefore represents a minimum selectivity for these examples which can rightly be described as β-1-specific adrenoceptor antagonists

Compounds of the formula OH

R-OCH2CHCH2-NH.R 'wherein R and R' have the following meanings: R R '

Propanolol -CH (CH3) 2 15

Pindolol -CH (CH3) 2

H

Metaprolol -CH (CH3) 2 ch2ch2och3

Betaxolol -ΟΗ (ΟΗ3) 2

20 CH2CH20CH2- <J

Atenolol Φ -CH (CH3) 2 ch2conh2

Bevantolol iOl _ / OHC3 CH3 ^ -CH2CH2 - / ^ V-OCH3 ICI 89.406 CN 1 [O) -ch2ch2nhconh ^ 5 ^

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BiotilgængelLghed

The bioavailability of 2 compounds of the present invention (compounds of Examples 10 and 11) was compared to 3 compounds of the type described in EP 52,072. The only 5 difference between the formulas of the five compounds tested is in group X.

The compounds were administered at an oral dose of 5 mg / kg in a gelatin capsule for male and female gray dogs (weight 15-27 kg). At selected times (for up to 5 hours), blood samples were taken from a vein from the leg using a cannula. Plasma drug levels were measured by HPLC using a modification of the method of propanolol described by Drummer et al. (J. Phara. Sci., 70, p. 1030, 1981), wherein the column conditions were individualized to allow separation of the test compound. All compounds were measured using UV detection at 214 nm.

15 Oral area under curve (AUC) was plotted as a graph of plasma drug-level versus time. The AUC of all compounds was obtained from the curve by the trapezoidal method (Wagner, in Biopharma ceutics and relevant pharmacokinetics, Drug Intelligence Publication, Hamilton, Illinois, USA, p. 183, 1973).

The bioavailability of the compounds was determined using standard procedures from an equivalent drug dose of ice administered intravenously to the same dog over the same time period.

The following results were obtained where bioavailability is indicated as AUCorai divided by AUCiv multiplied by 100:

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18 X AUC (0-5 h) Bioavailability

Compounds of the Invention: according to Example 10 0 170.450 62%

Conn. according to Example 11 O 219.457 81%

Compounds of EP 52,072: - <Q) 40,200 24% 10 ru <5,000 <2% / tr \ 14,535 8% -CH2 - (O / -0C3

The above results show that the compounds of the present invention have an unexpectedly high bioavailability, up to 15 times the bioavailability of compounds of EP 52,072.

The compounds can therefore be used as β-adrenoreceptor blockers, among other things, for the prevention and treatment of coronary diseases such as angina pectoris, conditions arising from sympathetic overstimulation such as nervous heart disease, myocardial infarction, hypertension, migraine treatment and glaucoma treatment -toksikose. Because of their antiarrhythmic effect, they are suitable for the treatment of cardiac arrhythmias, such as the supraventricular learning tachycardia.

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Of course, for the above applications, the dose to be used will vary depending on the substance used, the mode of administration and the treatment desired. Generally, however, satisfactory results are obtained with a daily dose of approx. 0.1-10 mg per kg of body weight 5; if necessary, administration may be in 2-4 sub-doses or as a retard form. The daily dose is in the range of approx. 10 mg to approx. 500 mg; suitable dosage forms for, for example, oral administration generally contain approx. 2.5-250 mg in addition to solid or liquid carriers.

10 Examples of daily doses range from approx. 20 mg to approx. 200 mg, preferably approx. 50 mg to approx. 100 mg.

The compounds have more pronounced and varying pharmacological effects than would be expected for compounds of this type of structure. In particular, their effect is more cardioselective than might be expected from similar known compounds.

This can be detected in vitro on guinea pig trachea by known methods.

Trachea is allowed to relax under the influence of isoproterenol and in the presence of known concentrations of the substance to be tested.

In these experiments, the potency of the compounds described in Examples 1-13 and 15 is inferior to the trachea than the potency demonstrated on the cardiac chamber according to the method described above. For the compounds described in Examples 6, 10 and 11, no effect on trachea up to a concentration of 1 x 10 7 M is detected and for the compound described in Example 1 up to 2 x 10 7 M. For comparison, propranolol already blocks at a concentration of 1 x 10'® M in the same experiment.

In rats whose spinal cord has been cut, the compounds may cause a 100% inhibition of the effect of 0.1 pg / kg i.v. isoproterenol at heart rate, but, on the other hand, usually has no effect on the blood pressure change caused by isoproterenol. The ED ^ for the isoproterenol tachycardia varies from ca. 3 pg / kg to approx. 300 pg / kg i.v.

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On awake dogs, the maximum inhibitory effect of the compounds of Examples 6 and 11 for isoproterenol tachycardia (0.1 / tg / kg i.v.) is about 50-60% of the maximum achievable effect with non-selective agents such as propranolol. The incompleteness of the block in dogs reflects the significant number of β-cardiac receptors in this preparation which are not blocked by highly β-selective compounds.

The high selectivity of the blockade for these compounds is of great importance in the treatment of hypertension, in which, with the interconnections currently in the market, an aggravation of a latent asthmatic condition may occur.

The compounds also have some inherent sympathomimetic activity. This property is useful in preventing unwanted bradycardia and therefore contributes to reducing the incidence of heart failure 15 in patients affected by heart muscle disease. The compounds usually also have a better oral absorption than would be expected for compounds of this type of structure.

The compounds of the invention in free form or in the form of physiologically acceptable salts thereof which, in para position to the 3-aminopropoxy side chain have a hydroxy group, have a significant stimulatory effect on the cardiac /} receptors in addition to a / 3-adrenoreceptor blocking effect. . This is evident from standard tests. Thus, after an intravenous administration of about anesthetized vagotonized cats spinalized in the region of the second cervical vertebra, 20-25 approx. 2500 µg / kg an increase in heart contraction strength measured by a "strain gauge arch" located on the left ventricle. This effect is also evidenced by a concentration-dependent stimulation of the isolated, spontaneously knocking guinea pig heart chamber. The size of the stimulation is approx. 40-50% of the stimulation obtained with 30 standard / 9 stimulants such as isoproterenol.

Thus, these compounds possess both β-agonistic and β-antagonistic properties. They can be used as cardiotonics, for example for the treatment of heart failure, especially in cases where a positive-inotropic effect without appreciable simultaneous influence of blood pressure is recommended.

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21 les. The relationship between the agonistic and antagonistic effects is particularly favorable in these compounds: the agonist component produces the cardiotonic effect, whereas the antagonist component protects against disproportionate contraction strength increase which could lead to arrhythmia.

Of course, for the above cardiotone use, the dose to be used will vary depending on the substance used, the mode of administration and the treatment desired. However, usually satisfactory results are obtained with a daily dose of approx.

0.01-0.5 mg / kg body weight; if necessary, administration may be given in 2-4 sub-doses or as a retard form. For larger mammals, the daily dose in the range is approx. 1-50 mg; suitable dosage forms for, for example, oral administration usually contain approx. 0.25-25 mg of the compounds of the invention in addition to solid or liquid carriers.

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

Use of the compounds against coronary disease and hypertension is preferred.

The compounds of Examples 6 and 11, especially Example 11, are preferred.

The compounds of the invention in free form or in the form of pharmacologically acceptable salts thereof can be administered as such or in an appropriate dosage form. The invention also relates to pharmaceutical compositions containing the compounds of the invention in free form or in the form of physiologically acceptable salts thereof, for example acid addition salts, together with pharmaceutical carriers or diluents. Pharmaceutical forms, e.g., a solution or tablet, can be prepared analogously to known methods.

Claims (3)

Pharmaceutical composition, characterized in that it contains a compound according to claim 1 as an active component together with a pharmaceutical carrier or diluent. DK 163994 B 23 Chemical compound for use as a medicament, characterized in that it has the formula I as claimed in claim 1. Use of a compound of formula I as claimed in claim 15 for the preparation of a pharmaceutical composition having / J adrenoreceptor blocking effect.