JPH0318607B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a 3-aminopropoxyphenyl derivative, a method for producing the same, and a pharmaceutical composition containing the same. According to the invention there is provided a compound of the formula: (wherein R is phenyl or phenyl monosubstituted or independently disubstituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and R ₁ is hydrogen, alkyl, halogen of atomic number 9 to 53, cyano or carbamoyl, R ₂ is alkyl of 1 to 4 carbon atoms, 3 carbon atoms
~7 cycloalkyl, cycloalkyl part has 3 to 7 carbon atoms and alkyl part has 1 to 1 carbon atoms
4 cycloalkylalkyl, 7 to carbon atoms
10 phenylalkyl, or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is substituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and A is alkylene of 2 to 3 carbon atoms; and X is a bond or oxygen, Y is oxygen, Z is oxygen and n is 2 or 3, or Z is a bond and n is 1, 2 or 3, provided that a R ₂ When alkyl, Z is oxygen and the group -NH-A-X-R has the formula or (b when R ₂ is cycloalkyl or cycloalkylalkyl and X is a bond, R ₁ is other than hydrogen) or an acid addition salt thereof. According to the invention, the formula (In the formula, R ₁ , R ₂ , Y, Z and n are as described above, and R _X reacts with a primary amine to form a 2-amino-
is a group capable of giving 1-hydroxyethyl) is reacted with a compound of formula H ₂ N-A-X-R in which A, X and R are as above, and the reaction product is By recovering the compound in free form or in the form of an acid addition salt, the object compound of the formula can be obtained. The amination step can be carried out by a conventional method for producing similar 3-amino-2-hydroxypropoxyaryl compounds. For example, R _x is the formula

A group of the formula or a derivative thereof such as a group of the formula -CH(OH)-CH ₂ L, where L is chlorine,
Bromine or the group R _y -SO ₂ -O-, where R _y is phenyl, tolyl or lower alkyl. L is especially chlorine. The reaction is preferably carried out in ethanol or a suitable ether such as dioxane. If desired, excess amine is used as a solvent. Alternatively, the reaction is carried out in the melt. Suitable reaction temperatures are from about 20°C to about 200°C, with the reflux temperature of the reaction mixture being convenient if a solvent is present. Esterification of the 2-hydroxy group in the side chain, if desired, can be carried out by known methods for preparing esters of analogous 3-amino-2-hydroxypropoxyaryl compounds, when other reactive groups are present. If necessary, selective reaction methods are used. Compounds according to the invention in free base form can be converted into acid addition salts and vice versa in conventional manner. Suitable acids for acid addition salt formation include hydrochloric acid, malonic acid and fumaric acid. In the compound of the present invention, for example, the carbon atom at position 2 of the 3-aminopropoxy side chain is asymmetrically substituted. The compounds thus exist in laminate form or in the form of respective optical isomers. A preferred optical isomer has an S-configuration at the asymmetrically substituted carbon atom of the 3-aminopropoxy side chain. Each optical isomer can be obtained by a conventional method, for example, by fractional crystallization of a racemic salt using an optically active starting material or using an optically active acid. The compounds used as starting materials can be obtained by conventional methods. In particular, a compound of formula (wherein R ₁ , R ₂ , Y, Z and n are as above) by O-alkylation into the compound -OCH ₂ -
It can be obtained by introducing R _x . The compounds of formula are preferably reacted in anionic form. Formula α (In the formula, R' ₁ is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, 1 carbon atom
~4 alkylthio, cycloalkyl with 3 to 7 carbon atoms, halogen with atomic number 9 to 53, 1-pyrrolyl, cyano, carbamoyl, 2 to 7 carbon atoms
5 alkenyl, alkenyloxy of 3 to 5 carbon atoms in which the double bond is not bonded to the carbon atom adjacent to the oxygen atom, or alkanoyl of 1 to 5 carbon atoms, n' is 2 or 3, Y and R ₂ are as above), for example, the corresponding formula (wherein R' ₁ , R ₂ , n' and Y are as above and Bz is a protecting group, e.g. benzyl or tetrahydropyranyl) under suitable conditions, e.g. palladium on charcoal. or by acid hydrolysis. formula b (In the formula, R ₂ , Y and n' are as above,
R″ ₁ is alkylthio or trifluoromethyl of 1 to 4 carbon atoms) can be prepared by selectively etherifying the corresponding 1,4-dihydroxy derivative at the hydroxy group in the meta position with respect to R″ ₁ . , for example the expression Hal
-(CH ₂ ) _o '-Y-R ₂ (where R, Y and n' are as above and Hal is a halogen), preferably in an inert solvent such as acetone. It can be obtained by reacting it in the presence of a base such as potassium carbonate. Formula α (where B _z , Y, R ₂ and n' are as above) can be prepared by suitably etherifying the 4-benzyloxyphenol, for example using a suitable bromine derivative, conveniently in one step. It can be obtained in more steps, for example by first forming the -O( _CH2 ) _o' -Y-H moiety and then alkylating to introduce the _R2 moiety. formula b (wherein R ₂ , Y, n' and Bz are as described above, and R ₁ has the meanings given above for R' ₁ except for hydrogen), for example, a compound with R at the ortho position to the hydroxy moiety mono-chlorinating, -brominating or iodinating a compound of formula a in which R' ₁ is hydrogen, and then optionally suitably protecting the hydroxy group in the product compound of formula a in which R' ₁ is bromine; formula c (wherein R ₂ , Y, n' and Bz are as above) and then, if desired, a compound of formula c is subjected to a Grignard-type reaction using, for example, lithium to obtain the corresponding compound of formula b (where R ₁ is 1-4 carbon atoms
alkyl, cycloalkyl of 3 to 7 carbon atoms, or alkenyl of 2 to 5 carbon atoms). Alternatively, a compound of formula c can be converted to the corresponding cyano compound using, for example, cuprous cyanide in dimethylformamide, and then optionally the cyano group can be hydrolyzed to form the corresponding compound of formula b, where R ₁ is carbamoyl. convert into a compound. If desired, the carbamoyl compound can then be converted to the corresponding amino derivative by Hoffmann-type reduction, and the amino derivative can be converted into the corresponding amino derivative, for example by 2,5-dimethoxyfuran, in which R ₁ is 1-
Switching to the corresponding compound of formula b which is pyrrolyl. Alternatively, if desired, the amino derivative can be converted into the corresponding diazonium salt, for example using nitrous acid, and this diazonium salt can be further reacted with potassium fluoride, for example in water, to form the corresponding formula b, where RA is fluorine. Alternatively, the diazonium salt can be converted into the corresponding hydroxy compound by reaction with an aqueous acid solution, and this hydroxy compound can be converted to the corresponding formula b (where R ₁ is a carbon atom of 1 to 4 carbon atoms) by etherification. Alkoxy or alkenyloxy having 3 to 6 carbon atoms, the double bond of which is not attached to the carbon atom adjacent to the oxygen atom). Derivatives in which R ₁ is alkanoyl can be made by Friedel-Crafts acylation. If desired, the diazonium group can be converted to alkylthio by reaction with many other groups, such as alkali metal mercaptides. If necessary, the trifluoromethyl group can be obtained by fluorination of the corresponding carboxyl group obtained by hydrolysis of the cyano group. Instead of compounds of formula b protected with protective groups, it is also possible to directly use the corresponding unprotected compounds. For example, the corresponding β, γ−
Alkenyl ethers are subjected to Claisen rearrangement to form radicals.
R ₁ =β,γ-alkenyl can be introduced in the ortho position. If desired, a cyclopentyl group can be introduced by subjecting the corresponding cyclopent-2-enyl ether to Claisen rearrangement to form orthocyclopent-2-enylphenol, which is then hydrogenated. formula c (wherein R ₁ and Y are as above, R′ ₂ has the meaning above for R ₂ , and n″ is 1, 2 or 3) corresponds to the compound of formula a. Optionally, the protecting group can be methyl instead of benzyl or tetrahydropyranyl.Deprotecting group reaction may be carried out in the presence of an alkali metal alkyl mercaptide. Protected compounds in which R ₁ is other than hydrogen, alkylthio or trifluoromethyl may be prepared in a manner analogous to the preparation of compounds of formula b described above. It is also possible to change one substituent R ₁ to another substituent R ₁ when the compound is in the unprotected form, for example ortho-bromo derivatives can be converted to the corresponding phenol. It can be easily formed from
Protected compounds in which R ₁ is hydrogen can be prepared by converting the ether moiety -(CH ₂ ) by conventional methods, e.g. Williamson synthesis.
It can be produced by constructing _o ″-Y-R′ _2.Formula d (wherein R ₁ , Z, n and Y are as above, and R″ ₂ has the meaning given above for R ₂ except for cycloalkylalkyl) and corresponding protected compounds such as those in which the hydroxy group is Compounds protected in the form of benzyloxy, methoxy or tetrahydropyranyloxy groups are believed to be new and are also part of the present invention. Any starting materials whose preparation is not specifically described can be prepared by conventional methods. It should be noted that even if the compound of the present invention of the formula has been subjected to an appropriate chemical transformation (for example, a derivative in which the hydroxyl group at the 2-position of the aminopropoxy side chain is esterified), it may be It should be understood that it falls within the technical scope of the present invention as long as it liberates the compound of the present invention of the formula and exhibits substantially the same pharmacological action as it when taken into the body. All are uncorrected values in °C. Example 1 2-{2-hydroxy-3-[2-(4-methoxyphenoxy)ethylamino]-propoxy}-5
-(2-methoxyethoxy)benzonitrile 2-(2,3-epoxypropoxy)-5-(2
-methoxyethoxy)-benzonitrile 2.4g and 2-(4-methoxyphenoxy)ethylamine
8.35 g are dissolved in 30 ml of ethanol, then the solvent is evaporated and the resulting mixture is stirred for 1 hour at 70°. The reaction melt is then dissolved in ether,
Crystallize under cooling. Purification is carried out by recrystallization in benzene. The title compound is obtained (melting point 95~
97°). The starting material is obtained as follows: 4-(2-methoxyethoxy)phenol (melting point 98-99°) [4-benzyloxyphenol
-Produced by reacting with chloroethyl methyl ether and debenzylating the produced 1-benzyloxy-4-(2-methoxyethoxy)benzene (melting point 41-43°) by hydrogenation using palladium on carbon] Bromine dissolved in chloroform is added to the methanol solution of at 0° and the mixture is stirred for 2 hours. After chromatography on silica gel, the obtained 2-bromo-4-(2-
methoxyethoxy)-phenol (oil) is reacted with a mixture of potassium carbonate, acetone and benzyl bromide for 60 hours. Chromatographed on silica gel to obtain 1-benzyloxy-
2-Bromo-4-(2-methoxyethoxy)benzene (oil) is reacted with cuprous cyanide in dimethylformamide for 5 hours. 2- obtained after purification by partitioning between aqueous hydrochloric acid and ethyl acetate.
Benzyloxy-5-(2-methoxyethoxy)
Benzonitrile (melting point 50-51°) in methanol
Debenzylate using 10% palladium on carbon. The resulting 2-hydroxy-5-(2-methoxyethoxy)benzonitrile (oil) was reacted with epichlorohydrin and a catalytic amount of piperidine at 100° to give 2-(2,3-epoxypropoxy)-5-(2 -methoxyethoxy)benzonitrile (oil) is obtained. Rx

A compound of the following formula is obtained in the same manner as in Example 1 from a suitable compound of the formula and a suitable compound of the formula:

【table】

TABLE The compounds of the invention (excluding compounds of formula d and corresponding protected compounds) have pharmacological activity. In particular, these compounds have beta-adrenergic receptor blocking activity, as shown by standard tests. For example, the spontaneous beat of the guinea pig's atrium (A,
Bertholet et al., Postgrad.Med. 57 , Suppl.1 [1981]
9-18), these compounds have a bath concentration of approximately
Prevents positive chronotropic isoprenaline effects at 10 ^-8 M to about 10 ^-6 M. Certain compounds, such as those of Examples 12, 14 and 15, also exhibit alpha-blocking activity, as demonstrated by standard tests. For example, its activity has been demonstrated in the rat inverted aorta (KKFNg, WJ according to S. Duffy's principle).
Louis and AEDoyl, Proceedings of the Aust
−ralian physiological and, Phar−
Macological Society, 6 , [1975] 158P). Activity can also be evaluated in binding studies (e.g.
R. J. Summers, B. Jarrott and W. J. Louis,
Neuroscience Letters, 20 (1980) 347-350). These compounds are therefore useful as beta- and alpha-adrenergic receptor blockers, for example in coronary artery diseases such as angina pectoris, in conditions associated with overstimulation of the sympathetic nervous system, such as neurological heart disease, myocardial infarction, hypertension. It is indicated for use as a prophylactic and therapeutic agent, an intermediate treatment for migraine, and a treatment for glaucoma and thyrotoxicosis. In view of their antiarrhythmic effects, these compounds are useful as antiarrhythmic agents for treating heart rhythm disturbances such as upper ventricular tachycardia. The indicated dosage per day is about 10 mg of compound to about 500
mg, administered orally in divided doses of about 2.5 mg to about 250 mg two to four times a day, or in slow-release form, as appropriate. The compounds of the present invention have beneficial pharmacological properties that are far more marked and far-reaching than could be expected for compounds with this type of structure. In particular, their activity is more selectively cardioactive than would be expected for similar known compounds. This selective cardioactivity can be demonstrated in vitro tests using isolated tissues of guinea pigs according to standard methods. That is, membranes of the left ventricle and lungs of guinea pigs were prepared using standard pharmacological methods (G. Engel et al., Triangle 19 ).
[1980] 69-76), and a radioactive β such as I ¹²⁵ -2-cyanopindolol (I-CYP)
- Ligands can be added exogenously to assay the affinity of test compounds for β ₁ and β ₂ adrenergic receptors. The selective cardioactivity was about 80 times greater for the compound of Example 1, about 410 times greater for the compound of Example 2,
The compound of Example 3 reaches about 170 times, and the compound of Example 7 reaches about 640 times. Guinea pig lung and left ventricular membranes can be prepared as follows: Adult guinea pigs (350-500 g) are killed by decapitation. . The heart and lungs were soaked in Tris saline buffer (Tris-HCl 10mM, PH=7.5, NaCl 0.154M, 37
Perfuse at 50°C and remove connective tissue and trachea. The membranes of the lungs, Kleinstein, J. and Glossmann H.,
Naunyn−Schmiedeberg′s Arch.Pharmacol. 305
[1978] 191-200, with the modification that medium A contained only 20 mM _NaHCO3 . 20mM of finished pellets,
Suspend in 10 ml of NaHCO ₃ and store in liquid nitrogen. Preparation of left ventricular membranes was performed by McNamara, DB et al.
J.Biochem. 75 [1974] 795-803 was followed up to the stage where "membrane pieces" were obtained. These membranes were stored in liquid nitrogen and further diluted to the appropriate concentration as per manufacturer's instructions immediately before use. The compounds of Examples 1 to 18 exhibit the above-mentioned effective β-adrenergic receptor blocking activity in vitro tests at concentrations of 10 ^-9 M to ^{10 -5} M. The highly selective blocking properties of the compounds of the invention are of paramount importance in the treatment of hypertension, where asthma flare-ups may be promoted by compounds currently available on the market. These compounds also have endogenous sympathetic nervous system activity, a property that prevents undue bradycardia and helps reduce the extent of cardiac defects belonging to cardiac myopathies. The testing methods and results for the pharmacological activity of the compounds of the present invention described above are shown in more detail as follows. Pharmacology (a) Effects on intraocular pressure (glaucoma) A 0.25% w/v solution of the compound is administered to both eyes of awake rabbits. Body fluid concentrations after topical administration were compared to other β-blockers including propranol, timolol and atenolol 2 hours after topical administration, and the area under the curve (AUC, (0-2 hours) μg· ml ⁻¹ /min) is clearly highly advantageous over other drugs commonly used for this condition, such as betaxolol and timolol.

[Table] All solutions are 1% hypromelose (methpt)
(PH7.0) 0.25w/v%. Another group of rabbits weighing 2-4 Kg are simultaneously and rapidly injected with 20 ml/Kg of 5% dextrose into the peripheral vein of each ear to raise the intraocular pressure. Elevated intraocular pressure is measured in the eyes of rabbits using a Daisilab pneumatic tonometer (model 30RT). Baseline intraocular pressure was measured by creating a constant resting pressure state for 15 minutes;
When IOP is stable, drugs and excipients are administered by topical administration. In all experiments, the drug solution (usually 100μ) is administered to one eye and the same amount of vehicle to the other eye. Treatment eyes are randomized in different experiments so that both left and right eyes are effectively treated. Measurement of IOP is 0.5,
Perform after 1, 1.5, 2 and 5 hours. Crude data obtained from specific experiments are shown in Table 2.

[Table] Rabbit IOP after administration of 0.3 ml of 4% compound aqueous solution to the right eye (RE) and 0.3 ml of saline to the left eye (LE)
It is. Time points of drug (or excipient) administration and dextrose injection are shown. The effect on intraocular pressure is approximately equivalent to that of the beta-blocker timolol. (b) Beta-1 specificity Specificity for beta-1 adrenergic receptors increases safety. That is, the relative lack of beta-2 effects reduces the risk of beta-2 side effects such as asthma, increased peripheral resistance, and various metabolic side effects that are disadvantageous effects of non-selective beta blockers. This beta 1 specificity is demonstrated in in vitro rat and guinea pig and receptor binding experiments described above and in vivo in cerebrospinal puncture rats and guinea pigs. Beta-1 specificity experiments in cut tissue preparations used cut atria and tracheal rings from both rats and guinea pigs. The cumulative concentration-response curves of each specimen were determined as reported by Juan Lotsum
Archiv.In.Pharmacodyn. No.
143, pp. 299-329 (1963)), and the curves were subjected to computer analysis by Zabarowski et al. (Journal of Pharmacological Methods).
Volume 4, pp. 165-178 (1980)). For determination of antagonism, add the appropriate reagent to the organ bath at least 45 minutes after the first control concentration-response curve and allow it to equilibrate for 20 minutes before obtaining the next concentration-response curve. keep. The slope of this curve to the right was measured as the _pA2 value (Matsukei, Journal of Pharmacy and Pharmacology (J.Pharm.
Pharmacol.) Vol. 30, pp. 312-313 (1978)).
The tissues examined using this method were a spontaneously beating atrium isolated from a rat, a spontaneously beating atrium isolated from a guinea pig, a tracheal chain isolated from a rat, and a guinea pig tracheal tissue. The antagonism of responses to cumulative concentrations of isoproterenol on isolated heartbeat (spontaneous) atria and isolated tracheal chains or slices of rats and guinea pigs was measured and subjected to computer analysis by Zabarowski et al. (1980). Accurate analysis of the effects of the compounds of the present invention using tracheal chain (beta-2) preparations is difficult because their effects are very small and high concentrations must be used to be effective; The beta-1 specificity of these compounds is confirmed. Their beta 1 specificity was compared to various reference beta adrenergic antagonists and is shown in Table 3.

【table】

【table】

[Table] * Substitutions at position 2 Table 3 - In guinea pig atrium and trachea,
In vitro efficacy and selectivity of control and claim compounds

【table】

[Table] The numbers in the box represent the selectivity calculated assuming that the tracheal pA ₂ is 4.5. This clearly represents the minimum selectivity ratio and indicates the absolute selectivity of the compound. Similar results were obtained in experiments with tissues isolated from guinea pigs and are shown in Table 3. (c) In-vivo experiment of beta-1 selectivity (i) Spinal puncture rat specimen A rat weighing approximately 200-250 g was anesthetized with halothane, a cannula was inserted into the left carotid artery and left jugular vein, the trachea was exposed, and the cannula was inserted. do.
The animal is artificially ventilated and the spinal cord is punctured. Blood pressure and heart rate were measured from the left carotid artery;
Administer the drug in normal heparinized saline through the left jugular vein. Under these conditions, spinal tap rat preparations remain stable for at least 4 hours. For the measurement of beta-adrenergic receptor action,
Isoproterenol 0.2 μg/Kg is initially administered 3 times intravenously at 5 minute intervals and the control response to heart rate is determined. If these are reproducible, the first dose of the test compound (antagonist) is given 5 minutes after the standard isoproterenol dose. Repeat this protocol at successively higher concentrations of antagonist at 15 min intervals. The dosage range is expressed as a logarithm series of 0.1,
0.3, 1.0, 3.0, 10, 30, 100, 300, 1000, 3000 and 10000 μg/Kg. These experiments confirmed the high beta-1 selectivity of these compounds in in vitro preparations when compared to propranolol, betaxolol, atenolol and timolol. In a separate experiment, we investigated the effects of compounds on airway resistance in anesthetized guinea pigs. (ii) Guinea pigs Guinea pigs are anesthetized using 5 mg/Kg (ip) of 25% urethane. Blood pressure is measured from the left normal carotid artery. The drug is injected intravenously through a cannula inserted into the left jugular vein. The animal is ventilated through the airway cannula using a constant volume breathing pump. The heart rate is 56 beats/min, and the heart rate is 1 mg/min/body weight.
It is 100g. The airway pressure is measured by connecting the T-connection of the airway cannula to a Statham transducer, and its outlet to the instrumentation system and indicated on the Glass polygraph. Histamine (3 μg/Kg) was initially administered every 10 minutes;
Control responses to increases in airway pressure are measured. If these are constant, the first dose of drug is given 5 minutes after the standard dose of histamine. 1, 3, 10,
This operation is repeated with successive increases of 30, 100, 300, 1000 and sometimes 3000 μg/Kg. Vehicles administered intravenously to guinea pigs do not affect the histamine-induced increase in tracheal airway pressure;
Both propranolol and atenolol enhance histamine responses with this dosing regimen (1-1000 μg/Kg). Both propranolol and atenolol at 1 mg/Kg compared to the control.
Increases to 300%. Only Example 5 has a slight effect on histamine response. 2 mg/Kg promotes approximately 50% of the control response. These results confirm the specificity of D-140b for cardiac beta-adrenoceptors and suggest that this type of specific beta-1 adrenoceptor may be used in patients with glaucoma or chronic obstructive pulmonary disease associated with cardiovascular disease or asthma. This shows that the antagonist is effective and can be used safely. (d) Partial Agonist Activity As mentioned above, many of these compounds also have significant endogenous sympathomimetic activity, which is probably effective in preventing inappropriate bradycardia. , reduce the incidence of heart failure due to cardiomyopathy and hypertension. This partial agonist activity was demonstrated in the cerebrospinal puncture rat preparations described above, in which
Exemplary cumulative doses ranging from 0.1 to 1000 mg/Kg were injected into this preparation with beta-blocking drugs (propranolol and atenolol) known to have no partial agonist activity and endogenous sympathomimetic activity. The drug increased heart rate compared to pindolol. This partial agonist has also been studied in acute hemodynamic studies in conscious sheep. A dose range of 0.03-3 mg/Kg was partially administered to desensitized sheep with long-term implants of an aortic electromagnetic flow probe to measure cardiac blood output and a blood pressure transducer to measure blood pressure. Selected example compounds with agonist activity were injected intravenously. Each administration was separated by a minimum of 20 minutes. Heart rate (HR), mean arterial blood pressure (MAP) and cardiac blood output (CO) were continuously monitored. Total peripheral resistance (CTPR) was calculated by dividing mean arterial blood pressure by cardiac blood output. In these studies, the example compounds of the invention produced a dose-dependent increase in cardiac blood output;
This increase is similar to the effect of the partial agonist xamoterol, which lacks partial agonist activity and
This was in contrast to atenolol, which showed no change or decrease in cardiac blood output in the dose range of 0.03-3 mg/Kg. (e) Arrhythmias Other experiments with these compounds have shown the ability to eliminate reperfusion arrhythmias in models of cardiac activity. In these studies, Wistar rats (body weight 200−
(300 g) was anesthetized with urethane, the heart was removed and placed in ice-cold Krebs-Henseleit solution. The heart is then placed in a Langendorff aortic retrograde perfusion system. A cannula is then inserted into the left atrium and perfused. Aortic effluent is sent directly to the lever sir, 100 cm above the heart. Surround the heart in a glass jacket at 37.0°C. The perfusate was Krebs-Henseleit solution ([K ⁺ ] = 4.5 mmol/l, glucose 11.1 mmol/l) bubbled with 95% O ₂ and 5% CO ₂ at 37.0°C.
It is l. Atrial electrograms were obtained by recording between a metal left atrial inflow cannula and a clip placed in the left atrium. Ventricular electrograms were obtained by recording between a thin stainless steel needle placed on the surface of the left ventricular wall and an aortic outflow cannula. (i) Hemodynamic monitoring Aortic effluent was collected in a lever sirer 100 cm above the heart, and coronary venous flow was collected in drops through a funnel at the base of the water jacket. left ventricular pressure and
dP/dt was measured through a small catheter placed lateral to the left atrial cannula when the specimen's heart was elevated. The hemodynamic parameters were a disseminated cardiac rhythm between the left atrium and the aortic cannula, 300 B/1/
Measured by minutes of electrical pacing. (ii) Creation of ischemia Place a 5/0 nylon suture behind the left coronary artery.
A 2 mm suture was placed so that it appeared next to the left atrium. To create ischemia, the thread was tied tightly over the length of the polyvinyl tubing. Successful ligation was assessed by observing coronary sinus flow, total cardiac blood output, and cardiac systolic blood pressure. Reperfusion was achieved by cutting the threads with a blade directly down onto the tubing to avoid damaging the myocardium or coronary arteries. After an initial 10 minute stabilization period, perfusion is changed from a reservoir containing Glebsu-Henseleit solution to a reservoir containing a similar solution and a predetermined concentration of drug. After 5 minutes, ischemia begins. After 15 minutes, reperfusion occurs and the heart is monitored for an additional 10 minutes. At the end of this time, hemodynamic variables were measured again to complete the experiment. In another set of experiments, the drug-containing solution was not used until 5 minutes before reperfusion, but an otherwise similar sequence was performed. Ventricular tachycardia was diagnosed when three or more consecutive morphologically similar premature ventricular contractions caused a dissociation between the atrial and ventricular electrograms or a 1:1 V-A lead. Ventricular fibrillation was diagnosed when six or more consecutive ventricular syndromes showed gross morphological abnormalities. No toxicity was observed when the compound of the present invention was administered within the indicated dose range. More detailed studies were carried out using preferred compounds such as the compound of Example 5 and other compounds with different substituents on R ₂ . The results obtained revealed that these compounds did not exhibit acute toxicity. Experiments were conducted in rats for oral administration, mutagenic testing and 4 week chronic toxicity. The compound of Example 5 is
The LD ₅₀ value was approximately 60 mg/Kg, and the onset dose was 30 mg/Kg.
On the other hand, Beta Brodsker's betaxolol, which is considered to be highly safe, has no effect on rats.
_LD50 value is 30-34 mg/Kg. When 500 mg/Kg of the compound of Example 5 was administered once by gavage, none of the animals showed any symptoms and remained healthy until 7 days later. As a bacterial mutation test, no mutagenicity was observed in standard AM Salmonella plate experiments. No toxicity was observed in an experiment in which the drug was administered as a methylcellulose suspension to rats for 4 weeks at a dose of 10-100 mg/Kg. Among optically active compounds, those in which the carbon atom at position 2 of the 3-aminopropoxy side chain has an (S)-structure are more pharmacologically active than the corresponding (R)-enantiomers. A preferred use of these compounds is against coronary artery disease and hypertension. Preferred compounds are those of Examples 1, 2, 3 and 11, especially those of Examples 1 and 3. These compounds can be taken in the form of pharmaceutically acceptable acid addition salts. Such salt forms exhibit activity comparable to that of the free form;
And it can be easily produced by conventional methods. The invention also provides pharmaceutical compositions comprising a compound of the invention in free form or in the form of a pharmaceutically acceptable acid addition salt, together with a pharmaceutical carrier or diluent. Such compositions can be in the form of solutions or tablets, for example.

Claims (1)

[Claims] 1 formula (wherein R is phenyl, or 1 to 4 carbon atoms
phenyl mono- or independently di-substituted with alkyl or alkoxy of 1 to 4 carbon atoms, R ₁ is hydrogen, alkyl of 1 to 4 carbon atoms, halogen of 9 to 53 atoms, cyano or carbamoyl; Yes, R ₂ is alkyl of 1 to 4 carbon atoms, 3 carbon atoms
~7 cycloalkyl, cycloalkyl part has 3 to 7 carbon atoms and alkyl part has 1 to 1 carbon atoms
4 cycloalkylalkyl, 7 to carbon atoms
10 phenylalkyl, or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is substituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and A is alkylene of 2 to 3 carbon atoms; and X is a bond or oxygen, Y is oxygen, Z is oxygen and n is 2 or 3, or Z is a bond and n is 1, 2 or 3, provided that a R ₂ When alkyl, Z is oxygen and the group -NH-A-X-R has the formula or (b when R ₂ is cycloalkyl or cycloalkylalkyl and X is a bond, R ₁ is other than hydrogen) or an acid addition salt thereof. 2 formulas (In the formula, R ₁ , R ₂ , Y, Z and n are as described below, and R _X reacts with a primary amine to form a 2-amino-
is a group capable of giving 1-hydroxyethyl) is reacted with a compound of formula H ₂ N-A-X-R (wherein A, X and R are as below), and the reaction product is consisting of recovering the compound in free form or in the form of an acid addition salt. (wherein R is phenyl or phenyl monosubstituted or independently disubstituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and R ₁ is hydrogen, alkyl, halogen of atomic number 9 to 53, cyano or carbamoyl, R ₂ is alkyl of 1 to 4 carbon atoms, 3 to 53 carbon atoms;
7 cycloalkyl, the cycloalkyl part has 3 to 7 carbon atoms and the alkyl part has 1 to 4 carbon atoms
cycloalkylalkyl, from 7 to 10 carbon atoms
or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is substituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and A is alkylene of 2 to 3 carbon atoms; , X is a bond or oxygen, Y is oxygen, Z is oxygen and n is 2 or 3, or Z is a bond and n is 1, 2 or 3, provided that a R ₂ is alkyl , Z is oxygen and the group -NH-A-X-R has the formula or (when bR ₂ is cycloalkyl or cycloalkylalkyl and X is a bond, R ₁ is other than hydrogen) or an acid addition salt thereof. 3 formulas (wherein R is phenyl or phenyl monosubstituted or independently disubstituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and R ₁ is hydrogen, alkyl, halogen of atomic number 9 to 53, cyano or carbamoyl, R ₂ is alkyl of 1 to 4 carbon atoms, 3 to 53 carbon atoms;
7 cycloalkyl, the cycloalkyl part has 3 to 7 carbon atoms and the alkyl part has 1 to 4 carbon atoms
cycloalkylalkyl, from 7 to 10 carbon atoms
or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is substituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and A is alkylene of 2 to 3 carbon atoms; , X is a bond or oxygen, Y is oxygen, Z is oxygen and n is 2 or 3, or Z is a bond and n is 1, 2 or 3, provided that a R ₂ is alkyl , Z is oxygen and the group -NH-A-X-R has the formula or ( _{b is a group other than cycloalkyl or cycloalkylalkyl and X is a bond, R 1 is} other than hydrogen) or an acid addition salt thereof and a pharmaceutical carrier or diluent. A human or veterinary pharmaceutical composition for the treatment of coronary artery disease, diseases resulting from sympathetic nervous system overstimulation, myocardial infarction, hypertension, migraine, glaucoma, thyrotoxicosis, angina pectoris, heart failure or heartbeat disorders, consisting of: thing. 4 formula (wherein R is phenyl or phenyl monosubstituted or independently disubstituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and R ₁ is hydrogen, alkyl, halogen of atomic number 9 to 53, cyano or carbamoyl, R ₂ is alkyl of 1 to 4 carbon atoms, 3 to 53 carbon atoms;
7 cycloalkyl, the cycloalkyl part has 3 to 7 carbon atoms and the alkyl part has 1 to 4 carbon atoms
cycloalkylalkyl, from 7 to 10 carbon atoms
or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is substituted with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and A is alkylene of 2 to 3 carbon atoms; , X is a bond or oxygen, Y is oxygen, Z is oxygen and n is 2 or 3, or Z is a bond and n is 1, 2 or 3, provided that a R ₂ is alkyl , Z is oxygen and the group -NH-A-X-R has the formula or , b R ₂ is cycloalkyl or cycloalkylalkyl, X is a bond, R ₁ is other than hydrogen) or its acid addition salt as an active ingredient;
Beta-adrenergic receptor blocker for humans or animals.