DE2062055B2 - Propanolamine derivatives, process for their preparation and pharmaceuticals containing them - Google Patents

Description

The invention relates to propanolamine derivatives with good therapeutic properties. It is particularly affecting new derivatives of l-phenoxy-3-ethylaminopropan-2-ols, which are effective as blocking agents for O-adrenergic receptors and which are stronger inhibitory effect on myocardial 0 receptors, d. H. those that affect the heart tissue than on peripheral / 3 receptors, e.g. B. those that affect the tracheal, bronchial or vascular tissue have. They are therefore used to treat heart conditions such as angina and cardiac arrhythmias suitable and are particularly favorable because they can be used for such purposes without them adversely affect the condition of the lungs or blood pressure in sensitive patients.

The compounds of the present invention have the general formula

0-CH ₂ -CH-Ch ₂ -NH-CH ₂ -CH ₂ -O

OH R ¹⁶

R ⁴

in the

R ¹ denotes an acetamido, propionamido, ethoxycarbonylamino, carbamoyl or N-methyl-carbamoyl group, which is optionally separated from the benzene ring by a methylene or ethylene group,

R "is a formamido, acetamido or carbamoyl group and

R ¹⁶ denotes a hydrogen atom, a methyl or allyl group, with the proviso that R ^{16 is} not H when R ⁴ = carbamoyl,

and their pharmaceutically acceptable acid addition salts.

As acids for the preparation of the pharmacologically acceptable acid addition salts of the invention Compounds can be used those that have non-toxic addition salts with pharmacologically compatible anions, such as hydrochlorides, hydrobromides, hydroiodides, sulfates or bisulfates, phosphates or acid phosphates, acetates, maleates, fumarates, lactates, tartrates, citrates, gluconates, saccharates and p-toluenesulfonates.

A preferred group of compounds according to the invention are those in which R ¹ and R ^{4 are} each an acetamido group which is bonded directly to the phenyl ring, in particular the 1- [4-acetamido-2-methylphenoxy] -3- [2- (4 acetamidophenoxy) ethylamino] propan-2-ol.

The compounds of the invention can be administered alone. But they are generally in Mixture with a pharmaceutical carrier, which in relation to the mode of administration and the standard pharmaceutical practice selected. For example, they can be taken orally in the form of Tablets are administered which contain such excipients, such as starch or lactose, or in Capsules, either alone or in admixture with excipients, or in the form of elixirs or Suspensions containing flavorings or coloring agents. You can do it parenterally, ζ. Β. intramuscular or subcutaneously. For parenteral administration, they are best served in a sterile form aqueous solution used, the other dissolved components, e.g. B. sufficient salts or glucose may contain to make the solution isotonic.

The compounds according to the invention can be prepared in various ways in a manner known per se will.

1. A compound of the general formula
P-CH ₂ -CH-CH ₂ -Z

OH

in which Z is a halogen atom or any suitable "leaving" group, e.g. B. a sulfonyloxy group, such as a benzenesulfonyloxy or p-toluenesulfonyloxy group, means, can with an amine of the general formula

Q-CH ₂ -CH ₂ -NH ₂

by heating either in the presence of excess amine and a suitable solvent, e.g. B. Methanol or ethanol, or in equimolar amounts in the absence of a solvent or in the presence of alkali, e.g. B. sodium bicarbonate, and a suitable solvent, as mentioned above, for the reaction to be brought. The crude product is obtained either by filtering or evaporating the filtrate Dry or by suspending the solid in a suitable medium, ζ. Β. an aqueous one Sodium carbonate solution, and collecting the precipitate. The product is through Purified vacuum distillation and / or recrystallization from a suitable solvent, whereby one the free base is obtained, or by dissolving in a solvent and precipitating as a salt, ζ. B. as hydrochloride, Fumarate, maleate or oxalate, by adding the appropriate acid.

2. An amine of the general formula

0-CH ₂ -CH-CH ₂ -NH ₂

OH

can with a compound of the general formula 0-CH ₂ -CH ₂ -Z

under the conditions specified in procedure 1

are reacted, and the product can be recovered and purified according to method 1.
3. An epoxy compound of the general formula

0-CH ₂ -CHCH ₂

10

can be reacted with the same amine as used in Process 1 in equimolar amounts at ambient temperature or by heating in a suitable solvent such as methanol, and the product can also be recovered and purified as in Process 1.
4. An amine of the general formula

0-CH ₂ CH-CH ₂ -NH ₂

25th

can with an aldehyde of the general formula

Q-CH ₂ -CHO

30th

35

be implemented, whereby the corresponding Schiff base is formed, which is then in the presence of a catalyst, ζ. B. platinum, hydrogenated or reduced with sodium borohydride. The product will be after the Filter to remove catalyst or solid reaction products by evaporating the filtrate in the Vacuum gained and cleaned according to procedure 1.

5. The compounds according to the invention in which R ^{1 is} an acetamido or propionamido group can be prepared from the corresponding l- (nitrophenoxy) -3-ethylaminopropan-2-ols by reducing the nitro group to an amino group and acylating this amino group using a suitable derivative (e.g. the anhydride or chloride) of the acid. The starting material can be obtained by any one of Processes 1 to 4 except that R ^{1 is} replaced with a nitro group.

For example, an epoxy compound of the general formula

Q-CH ₂ -CH

CH ₂

NO ₂

R ¹ "

used in equimolar amounts at ambient temperature or by heating in one suitable solvent, e.g. B. methanol, reacted and the product according to method 1 recovered and purified.

The product is then dissolved in a suitable solvent, e.g. B. methanol, dissolved and in the presence a catalyst, e.g. B. platinum oxide, hydrogenated at ambient temperature and elevated pressure. The emerging The mixture is filtered and the filtrate is evaporated. The correspondingly substituted 1- (aminophenoxy) -3-ethylaminopropan-2-ol is obtained, that can, but does not have to be, cleaned before the next step.

The final step involves adding the amino compound dilute to water and adjust the pH to 4 to 5 by adding a suitable amount Hydrochloric acid. Then the acid anhydride or chloride is added and the pH of the solution is increased possible addition of a base, e.g. B. a sodium hydroxide solution, held at 4 to 5. The mixture will made alkaline and the crude product filtered off. The product is then crystallized from a Purified suitable solvent, which gives the free base, or it is converted into an acid addition salt converted which can then be purified by recrystallization from a suitable solvent.

The invention is illustrated in more detail by the following examples.

example 1

5.3 g of l- (4-acetamidophenoxy) -3-amino-propan-2-ol and 2 g of l-bromo-2- (4-acetamidophenoxy) -ethane were heated together at 140 ⁰ C for 3 hours. The resulting solid was suspended in aqueous sodium carbonate solution and filtered. The precipitate was recrystallized first from water and then from ethanol. 0.25 g of 1 - (4-acetamidophenoxy) -3- [2- (4-acetamidophenoxy) ethylamino] propan-2-ol were obtained. Mp. 193 to 194 ° C.

Analysis I.

Calculated: C 62.82, H 6.78, N 10.47%;
found: C 62.33, H 6.76, N 10.32%.

Example 2

5.6 g of l- (4-acetamido-phenoxy) 2,3-epoxy-propane and 4.9 g of 2- (4-carbamoyl-phenoxy) -ethylamine were in Dissolve 100 ml of ethanol and let the solution stand for 3 days at room temperature. The emerging Precipitate was filtered off and recrystallized from aqueous ethanol. 5.4 g of 1 - [4-acetamido-phenoxy] -3- [2- (4-carbamoylphenoxy) -äthyIamino] - were obtained propan-2-ol as a white crystalline solid. Fp. 175 to 177 ° C.

Analysis for C ₂₀ H ₂₅ N ₃ O ₅ :
Calculated: C 62.00, H 6.50, N 10.85%;
Found: C 61.83, H 6.39, N 11.18%.

b0

b5

with the same amine as in Method 1, Examples 3-21

The following compounds were prepared according to the procedure described in Example 2 from the corresponding substituted 1-phenoxy-2,3-epoxy-propane and 2-phenoxy-ethylamine produced. The products were in each case, unless otherwise stated, isolated as the free base.

at R ¹⁶ R ¹ R ⁴ Fp. C- analysis % H % N game 6.59 11.08 (6.78) (10.47) 3 H 4-NH • CO • CHj 4-NH CO CH ₃ 198-200 (theoretical value in brackets) 6.72 10.32 % C (6.78) (10.47) 4th H 4-NH ■ CO ■ CH ₃ CH., 4-CONH, 187-9 62.51 6.78 9.90 (62.82) (7.04) (10.11) 5 H 4-NH • CO • CH ₂ CH ₃ 4-NH • CO • CH ₃ 203 63.08 7.21 9.98 (62.82) (7.04) (10.11) 6th 2-CH ₃ 4-NH • CO • CH ₃ 4-NH • CO • CH ₃ 178-80 63.74 7.01 10.06 (63.59) (7.04) (10.11) 7th H 4-CH ₂ NH CO CII, 4-NH CO CH ₃ 176-7 63.59 6.93 10.19 (63.59) (6.78) (10.47) 8th H 4-CH ₂ • CO • NH ₂ 4-NH CO CH ₃ 190-2 63.68 6.93 10.60 (63.59) (6.78) (10.47) 9 2-CH ₃ 4-NH • CO • CH ₃ 4-CONH, 181-2 62.67 6.96 9.71 (62.82) (6.77) (9.74) IO H 4-NHCOOCH ₂ CII ₃ 4-NH CO CH ₃ 166-8 63.07 6.89 10.22 (62.82) (7.04) (10.11) 11 H 4-CH ₃ CH ₂ NH CO CH ₃ 4-CONH ₂ 170-3 61.24 6.46 9.87 (61.24) (6.52) (10.07) 12th H 4-NH • CO 0 • CH ₂ CH ₃ 4-CONH, 176-8 63.77 6.51 10.04 (63.59) (6.97) (10.02) 13th Il 4-CO NH-CH ₃ 4-NH CO CH ₃ 196-8 60.69 (Mono- (60.42) 7.23 9.84 hydrate) 60.30 (7.28) (9.78) 14th II 4-CH ₃ CH ₂ • NH • CO • CH ₃ 4-NH CO CH, 174-5 (60.13) 6.88 10.24 (6.78) (10.47) 15th H 4-CH ₂ • NH • CO • CH ₃ 4-CONH ₂ 177 64.06 6.58 10.57 (64.31) (6.50) (10.85) 16 H 4-CH ₂ • CO • NH ₂ 4-CONH ₃ 194-6 63.05 6.37 10.55 (62.82) (6.50) (10.85) 17th H 4-CO • NH • CH ₃ 4-CONH ₂ 176-7 62.43 7.36 9.61 (62.00) (7.28) (9.78) 18th H 4-CH ₂ NH CO CH ₂ CH ₃ 4-NH CO CH ₃ 171-3 61.84 7.35 9.45 (62.05) (7.43) (9.39) 19th 2-CH, 4-CH ₂ • NH • CO • CII ₃ 4-NH CO CH ₃ 104-6 64.38 (Mono- (64.31) 7.06 9.33 hydrate) 61.87 (7.08) (9.52) 20th 2-CH ₃ -CII = CH ₃ 4-NH CO CH ₃ 4-NH CO CH ₃ 147-9 (61.72) 6.67 10.77 (6.50) (10.85) 21 II 4-NI-CO-CH ₃ 4-NH CHO 154-6 64.69 (65.28) 62.15 (62.00)

The compounds according to the invention can exist in the form of the optically active D- and L-isomers. The invention relates both to these two forms and to the racemic mixtures. After the above Processes 1, 2 and 4 described, the optically active isomers can be prepared if the appropriately substituted 2-propanol cnantiomers used as starting materials, while the Process 3 and 5 result in racemic mixtures. The racemic product named after any of the above given methods can also be obtained by known techniques, e.g. B. by fractional crystallization an acid addition salt, with an optically active acid.

The activity of the crfindungsgcmiii.tcn compounds uls / J-adrcncrcgcnc Blockicrungsmittcl in drugs

and the degree of selectivity of their inhibitory effect on myocardial jJ receptors, ie those that affect cardiac tissue, compared to their effect on peripheral β- receptors, e.g. B. those that affect tracheal, bronchial or vascular tissue has been detected by one or more of the following examination methods:

a) Measurement and comparison of the inhibition of the changes induced by catecholamine in isolated Auricles of the heart and trachea of guinea pigs;

b) Measurement and comparison of the suppression of isoprene in anesthetized guinea pigs. lin induced tachycardic and relaxation of the trachea;

c) Measurement of the suppression of isoprenaline in anesthetized cats or dogs Tachycardia and

d) Measurement and comparison of the suppression of the stimulating effect of isoprenaline on the im> Adenyl cyclase enzyme present in rat heart and lung tissues.

In experiment a) the isolated guinea pig atria are removed and trachea electrically stimulated in a regulated fluid physiological environment and those evoked by increasing amounts of adrenaline added to the fluid Effects on the speed and force of contraction of the auricles, as well as the effect of Isoprenaline on the degree of relaxation of the trachea are measured. Then the test compound will be in different concentrations are added to the liquid and the effect of the addition of adrenaline or isoprenaline measured again. The concentrations of the test compound that inhibited 50% of the Effects of adrenaline and isoprenaline are then calculated and used as a measure of the effect in Relationship to the myocardial or peripheral / 3 receptors assumed.

In experiment b) blood pressure, heart rate and pressure are in a section of the Trachea of a guinea pig anesthetized with enough sodium pentobarbitone to measure to prevent spontaneous breathing while doing artificial breathing directly into the lungs with a constant speed is maintained. It is isoprenaline in a standard dose of 0.5 μg Injected intravenously to induce tachycardia, relaxation of the trachea and lowering of blood pressure. The ability of the test compound to suppress tachycardia and / or to relax the trachea and / or to counteract the drop in blood pressure by the isoprenaline, is then measured, by injecting the test compound before the isoprenaline.

In experiment c) cats anesthetized with chloral are given the test compound (0.1 to 1.0 mg / kg) intravenously is injected and the effect of isoprenaline on heart rate is measured. The heart rates are measured prior to administration of the test compound and for 30 minutes thereafter and then the cats are given a dose of isoprenaline subcutaneously. The degree of isoprenaline tachycardia caused is recorded at 15 minute intervals.

Dogs are also used as test animals, with the compound not being administered intravenously or orally administered to anesthetized dogs at doses of 0.125-0.25 mg / kg (intravenous) and 0.5-4 mg / kg (oral) will.

In experiment d), the rat heart is homogenized in a standardized medium with adenosine-5'-triphosphoric acid (ATP) labeled with tritium incubated with and without isoprenaline, and the test compound is added in various concentrations to the homogeneous mixture with the isoprenaline. After incubation at 30 ° C, cyclic 3 ', 5'-adenosine monophosphoric acid (cyclic AMP), which is a known amount of a carbon-14 labeled material is added, and the synthesis of cyclic AMP by the adenyl cyclase enzyme is terminated by increasing the temperature. the cyclic AMP is separated and purified, and the amount synthesized by the enzyme in each case is measured as the ratio of tritium to carbon-14. The concentration of the test compound that results in a 50% inhibition of the stimulatory effect of isoprenaline on cyclo-AMP synthesis, is seen as a measure of their activity. To determine the degree of tissue selectivity of the agent, will the procedure is repeated with homogenized rat lung, and the results are compared with those for homogenized rat heart were compared.

The results of experiments a), b) and d) have shown that compounds with a high selectivity for heart tissue compared to lung tissue, ie, which have a much stronger inhibitory effect on myocardial than on peripheral ^ receptors, are those where R ^{4 is} an acetamido group. A high selectivity for heart tissue, combined with a high effectiveness in the case of oral administration to non-anesthetized dogs in test c), are in particular those compounds in which R ¹ and R ⁴ each represent an acetamido group.

It is believed that for administration to humans in the treatment of heart disease, such as angina pectoris, oral doses of the most active compounds of the invention are in the range of 0.5 up to 4 mg / kg per day in 3 or 4 single doses per day and that doses for intravenous administration are approximately V10 of the above doses as a single dose per day. So can for a typical adult patients (70 kg) single tablets or capsules contain 10 to 50 mg of the active compound and intravenous doses of 1 to 20 mg in a suitable vehicle.

A representative number of compounds according to the invention was determined according to method c) and d) examined for their effectiveness and compared with that of the known compound Practolol. The following results were obtained:

example R ¹ R " R ⁴ effect on adenyl cyclase Rats activity ') Selectivity ² ) Oral Activity ³ ) (Dogs) 1 + 3 Acetamido H Acetamido 26th 50 57 ⁴ ) 5 Propionamido H Acetamido 34 47 22nd 6th Acetamido CH ₃ Acetamido 17th 160 49 7th Acetamidomethyl H Acetamido 9 40 43 8th Carbamoylmethyl H Acetamido 23 40 37

continuation

12th

Example R ¹

Effect on adenyl cyclase in rats

activity

Selectivity ² )

Oral

Activity ³ )

(Dogs)

Acetamido CH ₃ Carbamoyl 21 Ethoxycarbonylamino H Acetamido 21 N-methylcarbamoyl H Acetamido 46 Acetamidoethyl H Acetamido 30th Acetamidomethyl CH ₃ Acetamido 9 Acetamido C ₃ H ₆ *) Acetamido 5 Acetamido H Formamido 13th

Practolol

20 24 44 22 22 28 48

15th

30th

20th

(NT)

37

19th

33

(NT)

64 ⁵ )

*) Allyl.

') Concentration in ppm that is necessary for a 50% inhibition of the stimulating effect of isoprenaline on the Adenyl cyclase enzyme in heart tissue in rats (experiment d), column ltt

² ) Heart / lung ratio in experiment d).

³ ) Percentage inhibition of isoprenaline-induced tachycardia in dogs, 2 hours after administration of 2 mg / kg unless otherwise stated (experiment c), column IQ

⁴ ) 4 mg / kg.

⁵ ) 16 mg / kg.

(NT) Not investigated.

LD50 when administered orally to mice:

Connection according to the example LD50

6 9 Practolol

> 2500> 2500> 1600

Claims (4)

Claims: Propanolamine derivatives of the general formula O-CH ₂ -CH-CH ₂ -NH-CH _{2 -Ch 2} -O R ¹ R ¹⁶ in the R ¹ denotes an acetamido, propionamido, ethoxycarbonylamino, carbamoyl or N-methyl-carbamoyl group, which is optionally separated from the benzene ring by a methylene or ethylene group; R ⁴ group is a formamido, acetamido or Carbamoyi- 20 and R ¹⁶ denotes a hydrogen atom, a methyl or AlIyI group, with the proviso that R ^{16 is} not H when R ⁴ = carbamoyl, 25th and their pharmaceutically acceptable acid addition salts. 2. 1 - [4-Acetamido-2-methylphenoxy] -3- [2- (4-acetamidophenoxy) ethylamino] propan-2-ol. 3. Process for the preparation of the compounds 30 according to claim 1, characterized in that one in a manner known per se a) a compound of the general formula R ¹ or R ¹ O-CH ₂ CH CH ₂ R ¹⁶ Q-CH ₂ CHCH OH _R 16 with an amine of the general formula Q-CH ₂ -CH ₂ -NH ₂ implements or
b) an amine of the general formula 0-CH ₂ CHCH ₂ NH ₂ OH
R ¹ R ¹⁶ 40 45 50 55 60 b5 R ⁴ with a compound of the general formula 0-CH ₂ -CH ₂ Z or with an aldehyde of the formula 0-CH ₂ -CH = O reacted, where Z is a halogen atom or any other suitable "leaving" group, and when reacted with an aldehyde, the resulting Schiff base is hydrogenated or
c) a compound of the general formula O-CH-.CHCH ₂ NO ₂ R " 0-CH ₂ CHCH ₂ Z OH NO ₂ R ¹⁶ or an amine of the general formula 0-CH ₂ CHCH ₂ NH ₂ OH NO ₂ R ^lh implements according to a) or b), the nitro group of the resulting product is reduced to an amino group and, for the preparation of compounds in which R ^{1 is} an acetamido or propionamido group, the amino group is acylated with an acetic acid or propionic acid derivative. 4. Medicament containing a compound according to claim 1 or 2, optionally together with a pharmacologically acceptable carrier.