DE2004354B2 - Phenethanolamine ethers, processes for their preparation and pharmaceuticals containing these compounds - Google Patents

Description

f V-CH-CH ₃ -N ^

CH-CH ₂ -N

and their physiologically acceptable acid addition salts, in which R ^{1 is} an alkyl group with 1 to 4 carbon atoms, optionally substituted by a methoxy group, the allyl or benzyl group, R ^{2 is} a hydrogen atom, an alkyl group with 1 to 4 carbon atoms ao or the 1- Represents methyl or the l, l-dimethyl-3-phenylpropyl group.

2. Process for the preparation of the compounds according to claim 1, characterized in that a ketone of the general formula is used in a manner known per se

OH

R ¹ O-

COCH ₂ shark

or an alcohol of the general formula X

R ¹ O- ^ f Y-CH-CH

35

40

in which X is the - CONH ₂ group or a radical which can be converted into this group, R ^{1 has} the meaning given in claim 1 and Hal is a halogen atom, with an amine of the general formula

NH ₂ R ²

where R ^{2 has} the meaning given in claim 1, optionally reacts in the presence of a solvent and, if the starting material is a ketone, then reducing the keto group and optionally converting X into the - CONHjs group.

3. Medicament containing a compound according to claim 1.

The present invention relates to new derivatives; s phenylethanolamine, which is a valuable biological Processes for their preparation in the form of medicaments containing these compounds are effective according to the preceding claims.

and their physiologically acceptable acid addition salts in which R ^{1 is} an alkyl group with 1 to 4 carbon atoms, optionally substituted by a methoxy group, the allyl or benzyl group, R ^{3 is} a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or the 1-methyl - or the!, l-DimethyW-phenyl-propyl group.

The above-mentioned alkyl groups have 1 to 4 carbon atoms and are straight-chain or branched carbon chains.

Since the compounds of general formula I have at least one asymmetric carbon atom, The present invention also encompasses all possible optically active forms and racemic mixtures of these connections. Racemic compounds can be prepared by conventional methods, for example through salt formation with optically active acids and subsequent fractional crystallization, separate.

Diastereoisomeric mixtures can be obtained by fractional crystallization on the basis of their acidic Separate salts.

The compounds of the present invention have a strong blocking effect / S adrenergic receptors; besides, they are antagonists of Λ-adrenergic receptors. They can be used as hypotonic agents and used to treat and Prophylaxis of cardiovascular diseases, for example angina pectoris or Raynaud's disease, can be used with extremely few side effects and can also be used advantageously for Protecting the heart against drug-induced or overexertion-induced tachycardia.

Salicylamides are known from ZA-PS 67 05 591, but they only have a blocking effect have, while the compounds according to the invention have both a λ- and a / 3-blocking Have an effect. This is a significant advantage as you only have one connection instead of two different ones Needs to administer substances. In addition, those proposed according to the invention are capable of Compounds that lower blood pressure to a greater extent - so they own one stronger / 3-blocking effect - than the known Salicylamides.

In the anesthetized dog, for example, the intravenous injection of 1 mg / kg of 5- [l-hydroxy-2- (l-methyl-3-phenylpropyl) -aminoethyl] -o-anisamide increases the tachycardia caused by intravenous injection of isoprenaline completely and enforces it Injection of norepinephrine decreased response by 62%. In in vitro tests for antagonism of isoprenaline-induced increase in the force of contraction of electrically excited

In the atria of guinea pigs, the compound had a pA ₂ value of 8.1 compared to 7.9 for the ^ -blocking propranolol. When controlling norepinephrine-induced contractions of the vas deferens in the rat, the compound had a pA ₂ of 6.0. Phentolamine, known as the standard £ 3 blocker, had a pA ₂ value of 6.9 in this preparation. In the conscious dog with increased blood pressure due to the release of adrenaline, the compound caused a drop in blood pressure of 25 to 30 mm Hg after oral doses of 1 to 2 mg / kg. Although, in contrast, the corresponding allyl ether [I; R ₁ = CH ₂ = CHCH ₂ - R ₂ = -CH (CH ₃ ) -CH. · CH ₂ (C ₆ H ₅ )] when administered intravenously at 1 mg / kg to the anesthetized dog completely blocked the / J-adrenergic response of isoprenaline, the α-response induced by injection of noradrenaline was reduced by only about 20%.

These results are together with those obtained with the tested compounds of Examples 6 and 7 were compared with the results of commercially available compounds been. First of all, it is the / ^ blocker known compound "Propanoio!", which is described in the Merck Index, 8th edition, p. 875, and around the "-blocker" phentolamine, which can be found on p. 814 of the above-mentioned standard work.

The compounds of the invention exhibit both λ and / 5 blocking effects. The relationship between the two activities is given in the last column of the table below. This table also contains the expression "DR ₁₀ ". It means the dose which is necessary to induce a 10-fold phase shift to the right in the dose-stimulus curve of the agonist. The agonists used in these studies are isoprenaline for a / 3-S receptor and phenylephrine for an α receptor. The ratio given in the last column of the table indicates that z. B. in the compound of Example 6, the α-blocking effect is 19 times less than that of the ^ -blocking effect. This ratio is obtained by dividing the DRi ₀ -a value by the DR ₁₀ - /? Value (heart rate).

link / J-blocking effect DR ₁₀ value
(diastolic
Blood pressure) α-blocking effect Ratio β: α of the example Irritation caused by isoprenaline (mg / kg) Stimulus through DR ₁₀ value (heart
speed) 1.9 Phenylephrine ver
causes DR ₁₀ value
(diastolic
Blood pressure (mg / kg) 0.18 (mg / kg) 1:19 6th 0.57 0.18 10.8 1:62 7th 0.1 6.2 1: 8 8th 0.45 3.5 Comparison 0.03 link - - Propanol 0.14 - - Phentolamine - 1.1

The results obtained show the excellent action of the compounds according to the invention both as α and / S blockers.

The compounds are used in human or veterinary medicine for therapeutic or prophylactic Purposes used. The invention therefore also includes pharmaceutical agents which are used as active ingredients Compounds of the general formula I or their physiologically acceptable acid addition salts contain. Preferred salts are, for example, the hydrochlorides sulfates, maleates, acetates, fumarates, Lactates or citrates of these compounds. Such means can be used in a customary manner with the help of carrier materials or auxiliaries and optionally formulation agents with or without additional drugs. These means include, for example, fixed or liquid preparations for oral use, suppositories and injections. For oral administration Tablets represent the most suitable form, which can be prepared by conventional methods and if desired can be wrapped. Injections can be done with the help of physiologically acceptable Carrier materials and agents as solutions, suspensions or as dry products for their production form before application. The usable dosages of the active ingredient can widely Scope vary. Suitable dosages are generally within the range of 5 to 1000 mg, preferably 20 to 200 mg.

The compounds of the present invention can be used in various ways known per se Build ways.

According to a production process, the compounds of the invention are prepared by reacting the ketones of the general formula II with an amine NH ₂ R ² in a solvent, for example benzene or ethyl methyl ketone, with formation of the amino

ketones of the general formula III prepared from which then the compounds of the present invention by reducing the keto group by conventional methods, for example with hydrogen and a Noble metal catalyst or with a complex metal hydride such as sodium borohydride will.

In a modification of this process, the carbonyl group is reduced to the —CHOH group before the condensation with the amine NHR ₂ .

R ¹ O

R ¹ O

COCH ₂ Ha :!

(H)

COCH ₂ NHR ₂ (III)

in formulas II to V, R ¹ and R ^{2 have} the same meaning as in formula I; X denotes the - CONH ₂ group or a radical which can be converted into this group; Hai stands for a halogen atom.

The compounds according to the invention in which R ^{2 represents} a hydrogen atom can be obtained from compounds of the general formulas I or III in which R ^{2 is} the benzyl radical by reduction with hydrogen and a noble metal catalyst.

The compounds of the invention can also be prepared by reacting a halide of the formula R ¹ Hal with a phenol derivative of the general formula IV and subsequent reduction of the carbonyl group. In a modification of this process, the phenol (IV) is first converted to an alkali metal salt in order to facilitate ^{the reaction with the halide R 1 Hal.}

HO

HO

CO -CH ₂ -N (IV)

CH ₂ (C ₆ H ₅ )
H

CH • CH ₂ • N

OH

CH ₂ (C ₆ H ₅ )

If necessary, the phenol IV can be reduced to the alcohol V, for example with sodium borohydride, before it is ^{condensed with the halide R 1} Hal.

The compounds according to the invention in which R ^{2 is} not a hydrogen atom can also be obtained by alkylating the compounds in which R ^{2 is} a hydrogen atom but by condensation with a carbonyl compound and subsequent reduction of the azomethine thus formed with, for example, a complex metal hydride such as sodium borohydride, or with hydrogen and a noble metal catalyst.

The abovementioned processes can also be carried out when X is, for example, an alkoxycarbonyl group represents, which is then converted into the acid amide group by treatment with ammonia can be. This conversion can be carried out at a suitable stage, for example in the case of intermediates like (II) or (III), in which X is an alkoxycarbonyl group is to perform.

The following examples serve to illustrate the invention.

example 1

5- (2-tert-Butylamino-1-hydroxyethyl) -o-anisamide hydrochloride

λ) A solution of 5.74 g of 5-bromoacetylo-anisic acid methyl ester is left and 6.4 g of N-benzyl-tert-butylamine in 100 ml of methyl ethyl ketone for 5 hours To reflux. The N-benzyl-tert-butylamine-hydrobromine is nitrated and the filtrate evaporates to dryness. The residue is triturated with ether and separates another small amount of the amine hydrobromide (4.65 g). The essential solution treats one with an ethereal solution of hydrogen chloride, crystallizes the gummy precipitate from a few drops of methanol containing

Ethyl acetate, thus obtaining 8.0 g of 5- (N-benzyl-N-tert-butylglycyO-o-anissäuremethylester hydrochloride of melting point 178-179 ⁰ C. After recrystallization from ethyl acetate / methanol to obtain 4.4 g of melting point 181 to 183 ^C C (with decomposition).

b) 4.05 g of 5- (N-benzyl-N-tert-butylglycyl) -o-anisic acid methyl ester hydrochloride in 60 ml of ethanol are added to a prereduced suspension of 1.0 g of 10% palladium-on-carbon in 15 ml of ethanol and hydrogenated until the hydrogen uptake ceases (the hydrogen uptake was 441 cm ³ ). The catalyst is filtered off, the filtrate is evaporated to dryness and obtained 2.9 g of 5- (2-tert-butylamino-l-hydroxyethyl) -o-anissäuremethylester hydrochloride as a white crystalline solid of melting point 189-194 ⁰ C.

c) 2.39 g of 5- (2-tert-butylamino-1-hydroxyethyl) -o-anisic acid methyl ester hydrochloride are dissolved in water, make the solution alkaline with sodium bicarbonate solution and extracted it with chloroform. The chloroform extracts are washed with saline solution and dried it over sodium sulfate, it evaporates to dryness and receives 2.1 g of free base as a colorless gum, which crystallizes when standing. Melting point (from benzene) 195 to 197 ° C.

This amine is dissolved in 10 ml of ethanol and 20 ml of ammonia (density 0.88) and the solution is left in Stand room temperature. After 2 days there is no longer any starting material. The solution will be then evaporated to dryness and benzene was added to the residue. 1.45 g of a colorless one are obtained Solid with a melting point of 151 to 155 ° C. 1.3 g of this base are dissolved in chloroform / ethano! (9; 1), treats the solution with ethereal hydrochloric acid receives 1.2 g of 5- (2-tert-butylamino-1-hydroxyethyl) -o-anisamide hydrochloride with a melting point 241 to 242'C.

Example 2

2-benzyloxy-5- [1-hydroxy-2- (isopropylaminoethyl] benzamide

a) A solution of 2 g of 2-benzyloxy-5-bromoacctyl beii7.ocsäurcmethyIcstcr is cooled in 50 ml of methanol and 100 ml of tetrahydrofuran to 0 to 10 C and

treats the solution with 0.75 g of sodium borohydride with stirring. The resulting solution is stirred for 90 minutes at room temperature, then evaporated to a small volume and kept at or below 15 ° C. The solution is then treated with 15 ml of 2N hydrochloric acid and ice to give a white suspension which extracted with ether and dried. After the ether has evaporated, the residue is dissolved in 25 ml of ethanol, 2.5 ml of isopropylamine are added and the solution is refluxed overnight. The solvent and the excess isopropylamine are then evaporated off, the residue is treated with dilute sodium hydroxide solution and extracted with ether. After drying and evaporation of the ethereal solution, an oily residue is obtained which is dissolved in ether dried over sodium and treated with ethereal hydrogen chloride. An oily precipitate is obtained which solidifies when a little acetone is added and after scratching with a glass rod. The solid (0.75 g) has an unsharp melting point of about 150 ° C. After recrystallization from acetone, 0.3 g of white microcrystals of 2-benzyloxy-5- [1-hydroxy-2- (isopropylamino) ethyl are obtained ] methyl benzoate hydrochloride with a melting point of 169 to 170 ^° C.

b) The compound obtained according to a) is made alkaline and gives a white crystalline solid with a melting point of 112 to 150.degree. 0.5 g of this solid is dissolved in 10 ml of ethanol and the solution is treated with 5 ml of ammonia (density 0.88). The resulting solution is allowed to stand at room temperature for 1 week. The solution is then evaporated to dryness, ether is added to the residue and 0.42 g of 2-benzyloxy-5- [1-hydroxy-2- (isopropylamino) ethyl] benzamide is obtained as a white solid with a melting point of 135 to 138 ° C. After recrystallization from ethyl acetate, the melting point increases to 142 to 144 ^C C.

40

Example 3

5- [1-Hydroxy-2- (1-methyl-3-phenylpropyl) -aminoethyl] -o-anisamide

a) A solution of 3.88 g of 5- (N ₁ N-dibenzylglycyl) -o-anisamide in 25 ml of tetrahydrofuran and 125 ml of ethanol is added to a prereduced suspension of 1.0 g of 10% palladium-on-carbon in

25 ml of ethanol. The uptake of hydrogen ceases within 14 hours on. The catalyst is filtered off and the solvent is evaporated off under reduced pressure Pressure and receives 5- (2-amino-1-hydroxyethyl) -o-anisamide as a colorless gum.

b) To a solution of the amide obtained according to a)

1.5 g of benzyl acetone are added to 70 ml of ethanol and the mixture is allowed to boil gently under reflux for 1 hour. 0.4 g of a suspension of prereduced 5% platinum on carbon in 10 ml of ethanol is then added to the cooled solution and the mixture is hydrogenated until the uptake of hydrogen has ceased. The uptake of hydrogen is complete within 14 hours. The catalyst and the solvent are removed and 2.36 g of 5- [l-hydroxy-2- (l-methyl-3-phenylpropyl) aminoethyl] o-anisamide are obtained as an oil which slowly crystallizes on trituration with ether. Melting point of the crystals 110 to 148 ⁰ C.

The compound obtained above is recrystallized from tetrahydrofuran and benzene and obtained Compound as a white solid with a melting point of 110 to 132 ° C.

5.3 g of this diastereoisomeric mixture crystallized one three times from 74% ethanol to obtain 1.9 g of a pure diastereoisomer of Melting point 152 to 154 ° C. This compound gives a hydrochloride with a melting point of 180 ° C.

It is evaporated, the obtained from the first crystallization of the base ^ mother liquors, the residue is crystallized from ethanol, thus obtaining 900 mg of the other diastereoisomer of the base of melting point 120 to 122 ⁰ C. The treatment with ethanolic hydrogen chloride yields the hydrochloride of melting point 190-192 ° C.

Example 4

2- (Benzyloxy) -5- (2-tert-butylamino-1-hydroxyethyl) benzamide

2.0 g of 5- (2-tert-butylamino-1-hydroxyethyl) salicylamide hydrochloride in 50 ml of ethyl methyl ketone and 1.5 g of anhydrous potassium carbonate are heated together under reflux for 30 minutes. 1.75 g of benzyl chloride in 5 ml of ethylmethyl ketone are added dropwise with stirring and the mixture is refluxed for 17 hours. The potassium salts are filtered off, the filtrate is evaporated to dryness in vacuo and a cream-colored solid is obtained, which is recrystallized from ethyl acetate. This gives 1.4 g of 2- (benzyloxy) - 5 - (2 - tert -. Butylamino -1 - hy droxy ethyl) - benzamide as colorless needles melting at 12O ⁰ C.

Example 5

5- (2-Amino-1-hydroxyethyl) -o-anisamide hydrochloride

a) Add 515 g of 5-bromoacetyl-salicylamide to one stirred solution of 750 g of dibenzylamine in 3.01 Ethyl methyl ketone. The mixture is refluxed for 1 hour and the dibenzylamine hydrobromide is filtered off off and dry the solution. The filtrate is allowed to cool when the crude product crystallizes. The latter is filtered off, dried and recrystallized from ethyl acetate. 336 g are obtained 5- (N, N-dibenzylglycyl) -salicylamide as an off-white solid with a melting point of 168 ° C.

b) 37.4 g of 5- (N, N-dibenzylglycyl) salicylamide are refluxed with 10 ml of methyl iodide and 20 g of anhydrous potassium carbonate in 350 ml of ethyl methyl ketone for 2 hours. The inorganic salts are filtered off and the solvent is evaporated off in vacuo. The residue is dissolved in ethyl acetate, the solution is washed with water and again evaporated. The oily residue is crystallized from isopropanol and 14 g of 5- (N, N-Dibenzylglycyl) -o-anisamide as a white Festkörpei of melting point 113-114 ⁰ C.

c) A solution of 13.0 g of 5- (N, N-dibenzylglycyl> o-anisamide in 800 ml of ethanol is added with an excess treated by solid sodium borohydride (about 2 g) and allowed to stand overnight at room temperature calmly. Then the ethanol is evaporated under reduced pressure and the residue is distributed between ethyl acetate and water. The ethyl acetate layer is separated off and washed with brine dry them over magnesium sulphate and evaporate them. The residue crystallizes easily on trituration with ether and yields 11.1 g of 5- (2-dibenzylamine

509 544/42

10

l-hydroxyethyl) -o-anisamide as a white solid with a melting point of 120 to 123 ° C.

d) Dissolve the dibenzylamino alcohol in 50ml Ethanol and gives a pre-reduced suspension of Ig 10% palladium-on-carbon in 20 ml of ethanol added. The mixture is hydrogenated until hydrogen uptake is finished. After removing the catalyst and the solvent, 2.1 g are obtained 5- (2-Amino-1-hydroxyathyl) -o-anisamide as a colorless one Rubber that solidifies slowly, with a melting point of 114.4 ° C

One lost 2 g of this base in ethanol, the solution treated with ethereal hydrogen chloride and 13 g of the hydrochloride as a yellow brown solids of melting point 219.7 ⁰ C.

Example 6

5- {1-Hydroxy-2 - [(1-methyl-3-phenylpropyl) -amino] -ethyl} -2- (methoxymethoxy) -benzamide

a) 37.4 g of S-iN.N-dibenzylglycyO-salicylamide are dissolved with heating in 500 ml of methyl ethyl ketone. The solution is cooled and stirred while one

₁₅ solid bodies formed are removed and give 2 0 g of hydrochloride with a melting point of 168 to 169 ° C

b) 5- {2 - [(1,1-Dimethyl-3-phenylpropyl) -amino] -l-hydroxyethyl} -o-anisamide

1.7 g of the above-mentioned hydrochloride in 50 ml of ethanol are reduced by means of hydrogen at room temperature in the presence of 0.5 g of a 10% palladium-on-carbon catalyst. After the reduction has ended (about 2 hours) the catalyst is removed and washed with hot methanol. The _{solvents are removed from the solution and the washing water} by evaporation and the residue is treated in 100 ml of methanol with 100 ml of ammonia solution (density 0.880). After 44 hours the solution is cingedampft under reduced pressure to yield after recrystallisation from ethanol, the amide hydrochloride of melting point 163-165 ⁰ C.

Example 8

² - y ^lox y ^A11-5- {l-hydroxy-2 - [(l-rnethyl-3-phenyl-P ^ro Pyl) amino] -äthyI} -benzamide hydrochloride

8.0 g of 5- {

JI T ^y - T ^y ^ T ^^ P ^ PyOaminol-äthylVsaUcylamid.dasinSOml

Ä V ρ J ^a _t ^s mixture for another hour a ₅ ethanol and a solution of 0.6 g sodium in

and the solid is filtered off, washed with methylethyl- 30 ml of ethanol was suspended, with 2 ml of allyl bromide.

uTerSΤοοΐΐ, nT · T ' ^ "I Sm ^ ^{After 4 hours} g <™ heating under Rüdefluß" steams

and if you get 30.0 g of the sodium salt of 5- (N, N-Dimene, the mixture is dissolved, the residue is dissolved in ether

benzy glycy O-sahcylamide. 3.96 g are suspended in water and the ethereal layer is extracted

^M f ^ y ₁ ketone and 30 three times with 50 ml ^ Siu ^ jSS ^^

ethoxymethoxy) benzamide as one white crystalline solid with a melting point of 127.5 ° C.

b) 4.18 g of methoxymethyl ether are suspended in 250 ml of methanol and 1.7 g of benzyl acetone are added along with a slurry of 0.5 g of 10% palladium oxide on carbon and 1.0 g of 5% Add platinum-on-charcoal in 10ml ethanol. The GE-

hydrochloride with a melting point of 158 Ws 160 ° C auimejzpunict os to it> u c.

B e i s ρ i e 1 9

To the

»4

Solid of melting point 102 ⁰ C. The compound is recrystallized from isopropyl acetate and now has a melting point of 106 ° C.

Example 7

5- {2 - [(l, l-Dimethyl-3-phenylpropyl) -amino] -l-hydroxyethyl} -o-anisamide

a) 5- [N-benzyl-N- (U-dimeth _{y l-3-P} hen _y lprop _y l) -glycyll-o-anissäuremethvlester-tydrochlorid.

A solution of 2.0 g of methyl S-bromoacetyl-o-anisate and SJgN-benzyl-ia-dimeth ^ -phenirlpropylamine in 30 ml of ethyl methyl ketone Under reflux for 20 hours, it is evaporated and the residue is treated with ether. One interrupts 2.25 g of precipitated amine hydrobromide from and be the ethereal filtrate acts with an excess of ethanolic hydrogen chloride. The one here

_S5

_{6o sä}

6 ₅

One can: "si, r \" r · "

of whichTede S ™ AU ^ w W "JS ' ^{J g Aktlvbes} constituent contains.

Tablets

. ^To produce 5000 tablets, each of which contains 100 mg of active ingredients, the mixture is mixed

m P ^ '^ ⁸ Mw * ™ ⁰ **** ¹ * ^{and 5} S Steann- K

S Klet? f

bleed JC.Z ^^^ ^{Manufacture of Ta} :

learn G ^ fat vl ^ Ä ^ m ^ ¹¹ ^ '"""™

τΖ Ί £? Γη ¹¹¹¹ S ^ 200 mg. JL Al? 5000 tablets, of which

"~ 7" ™ "- * ^{iW" e} rttiivucsianaieii, 500 g of lactose ■ -> Λ ^Maisstä strength and a sufficient amount .n _P r -> /, "" _sn _ ".": - Lös _U n _g of Natriumhydroxy-

emer
one

ethyl cellulose for the production of a moist, coherent mass. The moist mass is driven through a No. 14 sieve (BSS) and dried in a fluidized bed dryer at 60 ^° C. The dry granules are then driven through a No. 22 sieve (BSS) and mixed with 60 g of dry corn starch and 15 grams of magnesium stearate. The lubricated granules are compressed on a suitable tablet press using a 9.525 mm deep concave punch to produce tablets each weighing approximately 350 mg.

These tablets can be coated with a suitable film-forming material such as methyl cellulose, hydroxypropylmethyl cellulose, Coating ethyl cellulose or mixtures of these substances using normal techniques.

The tablets can also be coated with sugar using normal sugar coating techniques.

Injection solutions

For the preparation of injection solutions, each ampoule containing 10 mg of active ingredient per milliliter contains, dissolve 10 g active ingredient and 7.5 g sodium chloride in 950 ml suitable for injection purposes Water. When everything is resolved, you fill

ίο with water suitable for injections except for 11. The solution is divided into suitable ampoule sizes, 1, 5 or 10 ml, melted and sterilized by heating in an autoclave.
The "active ingredient" used in these agents is the compound 5- [1-hydroxy-2- (1-methyl-3-phenylpropyl) -aminoethyl] -o-anisamide, the preparation of which is described in Example 3, according to the invention.

Claims (1)

Claims: 1. Compounds of the general formula The present invention accordingly relates to compounds of the general formula I. Il C-NH ₂