DE2804625A1 - 4-Acylamino-phenyl-ethanolamine derivs. - with analgesic, spasmolytic, beta-mimetic and/or beta-blocking activity - Google Patents

Abstract

Phenyl-ethanolamine derivs. of formula (I) and their salts are new. In (I), R1 is h, halogen or CN; R2 is F, CN, CF3, NO2 or 1-3 C alkyl; R3 is opt. branched 1-5C alkoxy, 2-5C alkenyloxy, 6-10C aryloxy, 7-11C aralkoxy or NH2 opt. mono- or di-substd. by opt. branched 1-5C alkyl, 2-5C alkenyl, 6-10C aryl and/or 7-11c aralkyl; R4 is 3-5C cycloalkyl or 3-5C alkyl. (I) have analgesic uterine spasmolytic, striated muscle spasmolytic and esp. beta-mimetic (bronchospasmolytic) and/or beta-blocking activities. They can be used for tocology, reducing blood pressure by peripheral vasodilation and mobilising body fat, and for treating allergies (e.g. allergic asthma or inflammatory allergies), spastic respiratory tract disorders and arrhythmia.

Description

Case 5/699 A
Dr. Bottle / bottle

DR. KARL THOMAE GMBH, BIBERACH AN DER RISS

New 4-acylamino-phenyl-ethanolamine

The present invention relates to new II-acylaminophenylethanolamines the general formula

^R 4

and their physiologically compatible acid addition salts with inorganic ones and organic acids, which have valuable pharmacological properties, in addition to an analgesic, uterine spasmolytic and an antispastic effect on the striated muscles, in particular ß2-mimetic and / or ß., - blocking Effects, as well as processes for their production.

In the above general formula I means

R ^ a hydrogen or halogen atom or the cyano group,

R _{2 is} a fluorine atom, the cyano, trifluoromethyl or nitro group or an alkyl group with 1 - ^ carbon atoms,

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2T

R, a straight-chain or branched alkoxy group with 1 to 5 Carbon atoms, an alkenyloxy group with 2 to 5 carbon atoms, an aryloxy group having 6 to 10 carbon atoms or an aralkoxy group having 7 to 11 carbon atoms or an amino group replaced by a straight or branched chain alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an aryl group having 6 to 10 carbon atoms and / or an aralkyl group having 7 to 11 Carbon atoms can be mono- or disubstituted, and

R ₁ , a cycloalkyl or alkyl group each having 3 to 5 carbon atoms.

Among the meanings mentioned in the definition of the radicals R ^ - Rj
R. that of the hydrogen, fluorine, chlorine, bromine or iodine atom or the cyano group, for

Rg those of the fluorine atom, the cyano, trifluoromethyl, nitro, methyl, Ethyl, n-propyl, isopropyl, η-butyl, sec-butyl, isobutyl or tert. Butyl group, for

R, which is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert.Pentyloxy-, phenoxy-, naphthyloxy-, benzyloxy-, Phenylethyloxy, allyloxy, butenyloxy, pentenyloxy, amino, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, n-pentylamino, dimethylamine, diethylamino, di-n-propylamino, Diisopropylamino, di-n-butylamino, di-sec.butylamino, Diisobutylamino, di-tert-butylamino, di-n-pentylamino, phenylamino, Naphthylamine, benzylamino, phenylethylamino, methylethylamino, methylbenzylamino, methyl-n-propylamino, Methylisopropylamino-, methyl-n-butylamino-, ethyl-propylamino-, Xthyl-isopropylamino-, diphenylamino-, methyl-phenylamino-, Ethyl phenylamino, isopropyl phenylamino, allylamino, Diallylamino, n-butenylamino or n-pentenylamino group and for

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R ^ those of the isopropyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, Cyclobutyl or cyclopentyl group into consideration.

Preferred compounds of the above general formula I, however, are those in the

R ₁ , Rp and R ^ are as defined at the outset and R is a straight-chain or branched alkoxy group with 1 to 5 carbon atoms, an alkenyloxy group with 2 to 5 carbon atoms, an aralkoxy group with 7 to 11 carbon atoms or, when R _{1 is} a hydrogen or halogen atom and Rp represents a fluorine atom, the trifluoromethyl or nitro group, also an optionally substituted by a straight-chain or branched alkyl group with 1 to 5 carbon atoms, an alkenyl group with 2 to 5 carbon atoms, an aryl group with 6 to 10 carbon atoms or an aralkyl group with 7 to 11 carbon atoms means substituted amino group.

However, particularly preferred compounds of the above general formula I are those in which

R ₁ and Rp are as defined at the beginning,

R, an alkoxy group having 1 to 1 carbon atoms or, if R _{1 is} a hydrogen or halogen atom and Rp is a fluorine atom, the trifluoromethyl group or nitro group, an amino group optionally substituted by an alkyl group having 1 to 4 carbon atoms and

R ^ mean the isopropyl or tert-butyl group.

The new compounds of the above general formula I can be produce according to the invention by the following process:

a) Reduction of an acetophenone of the general formula

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-M-

, (II)

in the

R. to R. are as defined at the outset.

The reduction is carried out in a suitable solvent such as methanol, Methanol / water, ethanol, isopropanol, butanol, diethyl ether, tetrahydrofuran or dioxane expediently with a complex metal hydride, with aluminum isopropylate in the presence of a primary or secondary alcohol, with catalytically activated Hydrogen or with nascent hydrogen at temperatures between -2O ° C and the boiling point of the used Solvent carried out.

For example, the reduction with a complex metal hydride such as sodium borohydride or lithium aluminum hydride is expedient in a suitable solvent such as methanol, methanol / water, diethyl ether or tetrahydrofuran at temperatures between -20 ° and 50 ° C, the reduction with aluminum isopropylate in isopropanol at the boiling point of Ieopropanol and while distilling off the acetone formed, the reduction with catalytically activated hydrogen with hydrogen in the presence of a catalyst such as platinum, palladium, Raney nickel or Raney cobalt at room temperature and at one Hydrogen pressure of 1-5 at, and the reduction with nascent hydrogen, e.g. with activated metallic aluminum; and water or with zinc and hydrochloric acid, at temperatures up to the boiling point of the solvent used.

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- se -

b) reduction of an aldehyde of the general formula

, Uli)

in the

FL to R_ are as defined at the outset, or its hydrate in Presence of an amine of the general formula

N - R _1,, (IV)

in the

R ₁ J is as defined at the outset.

The reduction is carried out in a solvent such as methanol, ethanol, butanol, diethyl ether, tetrahydrofuran or dioxane a complex metal hydride or with catalytically excited hydrogen at temperatures between -20 ° C and the boiling point of the solvent used.

Conveniently, for example, the reduction with a complex metal hydride such as sodium borohydride or lithium aluminum hydride in a suitable solvent such as methanol, methanol / water, Diäthylather or tetrahydrofuran at temperatures between -20 ° C and the boiling point of the solvent used, for example at temperatures between 0 and 50 ⁰ C. , and the reduction with catalytically excited hydrogen with hydrogen in the presence of a catalyst such as platinum, palladium, Raney nickel or Raney cobalt at temperatures

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between 0 and 100 C, but preferably at room temperature, and carried out at a hydrogen pressure of 1-5 at.

The reaction is expediently carried out here in the manner that the in situ formed compound of the general formula

C-CH-N-R

in the

R ₁ to R |. as defined at the outset, is not isolated, but this can of course be isolated and reduced in accordance with the method described above.

The new compounds of the general formula I obtained can, if desired, be converted into theirs with inorganic or organic acids Physiologically acceptable acid addition salts are converted with one equivalent of the acid in question. As have acids For example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid proved to be suitable.

The compounds of the general formulas II and III used as starting materials can be prepared by processes which are known per se produce. For example, a compound of the general formula II is obtained by reacting a corresponding one 2-halo-acetophenons with a corresponding amine and a Compound of the general formula III by oxidation of a corresponding acetophenone with selenium dioxide (see examples), here it is not necessary to isolate the required output connections.

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- Y-

As already mentioned at the outset, the new compounds of the present application and their physiologically acceptable salts with inorganic and organic acids with good oral absorption on valuable pharmacological properties, besides an analgesic, uterine spasmolytic and an antispastic effect on the striated muscles in particular ß "-mimetic (broncholytic) and / or ß ^ -blocking effects, they are characterized in particular by a rapid onset of action after oral administration.

For example, the substances were

A = l-Cl-Ä'thoxycarbonylamino-3-chloro-5-fluorophenyl) -2-tert-butylamino-ethanol hydrochloride,

B = l- ( ⁱ l-Ä "thoxycarbonylamino-3-cyano-5-fluorophenyl) -2-tert-butylamino-ethanol hydrochloride,

C = 1- ( ⁱ 4-ethoxycarbonylamino-3-cyano-phenyl) -2-tert-butylaminoethanol hydrochloride and

D = 1- (4-Ä "thoxycarbonylamino-3-cyano-phenyl) -2-isopropylaminoethanol hydrochloride

examined for their broncholytic effect as follows:

The broncholytic effect was tested on anesthetized guinea pigs in the test arrangement according to KONZETT and RÖSSLER (Arch. Exp. Path. Pharmak. 195, 71 (19 ^{1 IO)).} From the averaged percentage attenuation of the acetylcholine iv by 20 μg / kg acetylcholine achieved with the various intravenous or intraduodenal doses. _{induced bronchospasm, an ED 50 was} calculated using linear regression analysis according to LINDER (Statistical Methods, 4th ed. pp. 148-162, Birkhäuser, Basel 1964):

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- V-

Ak-

substance after IV application t / 2 min after i.d. application A.
B.
C.
D. ED ₅₀ , µg / kg 60
70
^ 50
> 50 ED ₅₀ ^ ug / kg 30.7
5.6
23.5
64.0 32.2
7.0
8.7

Substance B was also tested for an anti-asthmatic effect after oral administration in the test arrangement according to KALLOS and PAGEL (Acta med. Scand. 9_1, 292 (1937)). The guinea pigs were exposed to a stream of acetylcholine aerosol which was generated with the aid of a nozzle at 1.5 atmospheres from a 0.4 solution of acetylcholine in 0.9 NaCl solution. The extension of the time until the onset of the asthma attack to more than three times that determined in the pre-test was rated as absolute protection. _{From the percentage of animals protected after the various doses, an ED 50 was} calculated according to LITCHPIELD and WILCOXON (J. Pharmacol, exp. Ther. £ 6, 99 (1949)):

substance after per os application Maximum effect after
Minutes t / 2 min B. ED ₅₀ jig / kg 15-30 150

The acute toxicity was determined in mice of both sexes with a mean weight of 20 g after iv administration. From the percentage of animals which died after different doses within I ¹ I days, and according to Litchfield Wilcoxon (J. Pharmacol, Exp Ther 96, 99 (1949)..) Counting the LD.:

50

loading

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- g-

45.

substance ^LD 50 mg / kg iv A.
B.
C.
D. 70.2
97.5
67.2
61.9

The compounds of general formula I prepared according to the invention and their physiologically acceptable salts with inorganic or organic acids are therefore suitable for tocolysis, for lowering blood pressure through peripheral vasodilation, for mobilizing body fat or for treating allergic conditions such as allergic asthma or allergic inflammatory conditions, spastic respiratory diseases of different origins or cardiac arrhythmias, and for this purpose, optionally in combination with other active substances, can be incorporated into the usual pharmaceutical preparation forms such as tablets, coated tablets, solutions, sprays, ampoules or suppositories. The single dose is human 5-100 yug two to * \ χ daily.

The following examples are intended to explain the invention in more detail:

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example 1

1- (4-Ethoxycarbonylamino-3-chloro-5-fluoro-phenyl) -2-tert -butylamino-ethanol hydrochloride

Be at 6O ° C in a solution of 3.7 g of selenium dioxide in 30 ml of dioxane and 1 ml of water with stirring 8.7 g of 4'-Äthoxycarbonylamino-3'-chloro-5-fluoro-acetophenone ^t portionwise added. The mixture is then refluxed for 4 hours. 4.1 ml of tert-butylamine are added dropwise to the solution of 4'-ethoxycarbonylamino-3 ^f -chloro-5'-fluoro-phenylglyoxal, after cooling and with external cooling with ice. When the addition is complete, it is diluted with 350 ml of ethanol and the undissolved material is filtered off. The solution containing the crude 4 ¹ -ethoxycarbonylamino-3'-chloro-5'-fluoro-phenyl-glyoxylidene-tert.butylamine is admixed in portions with 5 g of sodium borohydride while stirring and cooling with ice and left to stand overnight at room temperature. Excess sodium borohydride is then destroyed with acetone, water is added and the mixture is extracted with chloroform. The chloroform solution is washed with water / water, dried with sodium sulfate, briefly boiled after adding activated charcoal and evaporated to dryness in vacuo. The solid residue of 1- (4-ethoxycarbonylamino-3-chloro-5-fluorophenyl) -2-tert-butylamino-ethanol is taken up in isopropanol and acidified to pH 4 with ethereal hydrochloric acid. After the addition of ether, crystallization occurs. The crystals are suctioned off and washed with ether. Melting point: 192-193 ° C

The following connections are established analogously to Example 1:

1- (4-Ethoxycarbonylamino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol
Melting point: 168 - 170 ⁰ C (decomp.)

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- γί-

l- (i | -ethoxycarbonylamino-3-broin-5-fluoro-phenyl) -2-isopropylaminoethanol hydrochloride Melting point: 180-182 ° C

1- ( ¹ * -ethoxycarbonylamino-3-bromo-5-i * luoro-phenyl) -2-tert-butylaminoethanol hydrochloride Melting point: 197 - 198 ° C (decomp.)

1- ( ¹ -Xthoxycarbonylamino-3-i'luorophenyl) -2-tert-butylamino-sthanol hydrochloride. Melting point: 235-236 ° C

1- ( ¹ IA thoxycarbonylamino-3-cyano-5-fluorophenyl) -2-tert-butylaminoethanol hydrochloride Melting point: 198 - 200 ° C (decomp.)

l - (^ - Ethoxycarbonylamino-3-nitro-phenyl) -2-tert-butylaminoethanol hydrochloride Melting point: 189-19O ° C (decomp.)

1- (M-ethoxycarbonylamino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamine ethanol

Melting point: 127-130 ° C

1- / J-FlUOr- 5- j od-M- (3-methyl-ureido) -pheny17-2-tert-butylaminoethanol hydrochloride Melting point: sintering from 115 ° C (amorphous substance) mass spectrum (C ₁ IjH ₁₇ N ^ OpPJ):

Molecular peak of the base: Found: 409 Calc .: M09 ^ 5

1- / J-Fluor-5-iodo-4- (3-methyl-ureido) -phenyl / -2-cyclopropylaminoethanol hydrochloride Melting point: I67-170 ° C

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- μ.

1- (3-cyano-5 ^-fluoro-1 -isobutyloxycarbonylamino-phenyl) -2-tert-butylamino-ethanol hydrochloride

(The excess sodium borohydride was washed with dilute hydrochloric acid destroyed)

Melting point: 189-191 ° C

1- (4-Benzyloxycarbonylamino-3-fluoro-5-iodo-phenyl) - ^ - cyclopropy1-amino-ethanol

(The excess sodium borohydride was washed with dilute hydrochloric acid destroyed)

Melting point: 135-137 ° C

l- (l ^{1-allyloxycarbonylamino-3} ~ i'luor-5-iodo-phenyl) -2-cyclopropylamino-ethanol

(The excess sodium borohydride was washed with dilute hydrochloric acid destroyed)

Melting point: 122-123 ° C

I-Is obutyloxycarbonylamino-5-iodo-phenyl) -2-cycloproopy 1-amino-ethanol

(The excess sodium borohydride was destroyed with dilute hydrochloric acid)
Melting point: 126-128 ° C

1- (4-sthoxycarbonylamino-3-cyano-phenyl) -2-isopropylamino-ethanol Melting point: 112-115 ° C

1- (4-Xthoxycarbonylamino-3-cyano-phenyl) -2-tert-butylamino-ethanol Melting point: 78-82 ° C

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Example 2

1- (iJ-Ethoxycarbonylamino-S-bromo-i-methyl-phenyl) -2-tert-butylamino -ethanol

12 g ^{i »l} -Ä'thoxycarbonylamino ^{t-5-bromo-3'-methyl-acetophenone} are dissolved in 200 ml of chloroform and heated to boiling. 6.5 g of bromine, which is quickly consumed with evolution of hydrogen bromide, are added dropwise to the boiling solution. The 4'-ethoxycarbonylamino-5 ', 2-dibromo-3'-methyl-acetophenone now present in the solution is then removed by adding 14.6 g of tert-butylamine and boiling for 30 minutes in 4 ^l -Xthoxycarbonylamino-5'- bromo-3'-methyl-2-tert-butylamino-acetophenone is transferred .. The mixture is concentrated to dryness in vacuo, the residue is taken up in 50 ml of methanol and 20 ml of water and the keto group is reduced by adding a solution of 3.8 g Sodium borohydride in 20 ml of water, the pH of the reaction mixture being kept between 6 and 8 by adding dilute hydrochloric acid. After the reduction is complete, the methanol is distilled off in vacuo, the residue is diluted with water, made clearly alkaline with ammonia and extracted with chloroform. The organic phase is separated off, dried and concentrated to dryness. The residue is purified on a silica gel column (eluent: chloroform / methanol 2: 1), the eluate is concentrated, the residue is dissolved in ethanol and ethereal hydrochloric acid is added. 1- (4-Ethoxycarbonylamino-5-bromo-3-methyl-phenyl) -2-tert-butylamino-ethanol hydrochloride is obtained.
Melting point: 212-21H ° C (decomp.).

The following compounds were produced analogously to Example 2:

1- (1-Kthoxycarbonylamino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol
Melting point: 168 - 170 ⁰ C (decomp.)

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1- (4-Ethoxycarbonylamino-3-bromo-5-fluoro-phenyl) -2-isopropylaminoethanol hydrochloride Melting point: 180-182 ° C

1- ( ¹ JX thoxycarb ony lamino- 3-brom- 5- fluoropheny 1) - 2-1 ert. Buty laminoethanol hydrochloride Melting point: 197 - 198 ° C (dec.)

1- (Jl-Äthoxycarb ony lamino-3-f luor-pheny 1) -2-tert.b uty lamino-ethanol hydrochloride Melting point: 235-236 ⁰ C.

! .- (Jj-Äthoxycarbony lamino- 3-cyano-5-fluorophenyl) -2-tert-butylaminoethanol hydrochloride Melting point: 198 - 200 ⁰ C (decomp.)

1- (4-Ethoxycarbonylamino-3-nitro-phenyl) -2-tert-butylaminoethanol hydrochloride Melting point: 189 - 190 ° C (decomp.)

1- ( ¹ -ethoxycarbonylamino-3-fluoro-5-iodo-phenyl) -2-cyclopropylamine ethanol

Melting point: 127 to 130 ⁰ C

-iod-M- (3-methyl-ureido) -phenyl / -2-tert-butylaminoethanol hydrochloride Melting point: sintering from 115 ⁰ C (amorphous substance) mass spectrum (C ₁ ^ H ^ N, O ₂ FJ):

Molecular peak of the base: found: H09 calc .: 409.25

-S-j od-4- (3-methyl-ureido) -phenyl / -2-cyclopropylamino Ethanol hydrochloride melting point: 167 - 170 ° C

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- Vi

1- (3-cyano-5-fluoro-4-isobutyloxycarbonylamino-phenyl) -2-tert-butylamino-ethanol hydrochloride Melting point: 189-191 ° C

1- (4-Benzyloxycarbonylamino-3-i "luoro-5-iodo-phenyl) -2-cyclopropylamino-ethanol

Melting point: 135-137 ° C

1- (3-PlUOr- ¹ I-ISOb uty Io xy carbony lamino-5-j od-phenyl) -2-cy c lopropylamino-ethanol

Melting point: 126-128 ° C

1- (4-Ethoxycarbonylamino-3-cyano-phenyl) -2-isopropylamino-ethanol Melting point: 112-115 ° C

l- (4-Sthoxycarbonylamino-3-cyano-phenyl) -2-tert-butylamino-ethanol Melting point: 78-82 ⁰ C

1- / 3-cyano- ¹ l- (3-tert-butyl-ureido) -phenyl7-2-tert-butylaminoethanol

Melting point: 105 - 110 ⁰ C (dec.) Mass spectrum (CqH ₀ ONi ₁ O ₀ )

Molecular peak of the base: Found: 332 Calcd .: 332.45

The 4 '- (3-tert-butyl-ureido) -2-bromo-3'-cyano-acetophenone required as a starting product was obtained by reacting 4'-phenoxycarbony1-amino-2-bromo-3 ^l -cyanoacetophenone and tert .Butylamine produced at room temperature.

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Example A.

Tablets with 10 ^ f lO-ethoxycarbonylamino-S-cyano-S -fluorophenyl) - 2-tert.butylamino-ethanol-hydro chloride

Composition:
1 tablet contains:

Active ingredient 0.01 mg

Milk sugar 82.49 mg

Potato starch 33.00 mg

Polyvinylpyrrolidone ¹ J ₁ OO mg

Magnesium stearate 0.50 mg

120.00 mg

Production method:

The active substance and PVP are dissolved in ethanol. The mixture of milk sugar and potato starch is moistened evenly with the active ingredient / granulating solution. Moisture sieving is carried out with a 1.5 mm mesh size. It is then ^{dried at 50 °} C. and dry sieving is carried out with a mesh size of 1.0 mm. The granules obtained in this way are mixed with magnesium stearate and compressed into tablets.

Tablet weight: 120 mg Stamp: 7 well, flat

Example B.

Dragees with 5 ¥ * l-Cl-ethoxycarbonylamino ^ -cyan-S-fluorophenyl) 2-tert-butylamino-ethanol hydrochloride

Composition:

1 dragee contains:

Active substance 0.005 mg

Milk sugar 82,495 mg

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Potato starch 33,000 mg

Polyvinylpyrrolidone 4.000 mg magnesium stearate 0.500 mg

120,000 mg

Production method:

Dragee cores analogous to tablets in Example A. Core weight: 120 mg
Stamp: 7 mm, domed

The cores are covered with a shell using a known method, which consists essentially of sugar and talc. The finished coated tablets are polished with beeswax. Dragee weight: 200.0 mg

Example C

Gelatin push-fit capsules with 10 f ! - (^ - Äthoxycarbonylamino ^ -cyan- 5-fluorophenyl) -2-tert-butylamino-ethanol hydrochloride

Composition:
1 capsule contains:

Active ingredient 0.01 mg

Milk sugar 59.99 mg

Corn starch 60.00 mg

120.00 mg

Production method:

The active ingredient is mixed intensively with milk sugar and corn starch and filled into gelatine capsules of a suitable size. Capsule filling: 120.0 mg

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Example D

Ampoules with £ 10! - (! L-Ethoxycarbonylamino ^ -cyan-S-fluorophenyl) -2-tert-butylamino-ethanol hydrochloride

Composition:
1 ampoule contains:

, Active ingredient 0.01 mg

Citric acid 2.5 mg

Sodium hydrogen phosphate 7.5 mg

Table salt 4.6 mg

Ampoule water to 2.0 ml

Production method:

The active substance, Buffersübstanzeη and table salt are in ampoule water dissolved and then filtered germ-free.

Filling: in brown ampoules of 2 ml under protective gassing (Np)

Sterilization: 20 minutes at 120 ^° C

Example E.

Suppositories with £ 10! - (^ phenyl) -2-tert-butylamino-ethanol hydrochloride

Composition:

1 suppository contains:

Active ingredient 0.01 mg

Suppository mass (e.g. Witepsol W ^ 5) ad 1,700.00 mg

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Production method:

The finely powdered active substance is stirred into the melted ^{suppository mass, which has been cooled to ^ 0 0} C, using an immersion homogenizer, and the mass is poured into slightly pre-cooled molds at 37 ° C.

Suppository weight: 1.7 g

Example F

Syrup with 10 tf ! - (ll-EthoxycarbonylaminoO-cyano-S -fluorophenyl) 2-tert-butylamino-ethanol hydrochloride per 10 ml

Composition: 0.0001 G 100 ml of syrup contain: 0.1 G Active ingredient 1.0 G Benzoic acid 50.0 G Tartaric acid 1.0 G sugar 0.05 G Orange flavor 100.0 ml Food red Dist. Water ad Production method:

Approx. 60 g dist. Water are heated to 80 ° C and then successively Benzoic acid, tartaric acid, the active ingredient, the color and sugar dissolved. After cooling to room temperature, the Aroma added and made up to the given volume. The syrup is filtered.

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Example G

Dragees with 25 ^ l - ^ - ethoxycarbonylamino - ^ - cyano-S -fluorophenyl) - 2-tert-butylamino-ethanol hydrochloride

SUMMARY: 1 coated tablet contains:

Active ingredient 0.025 mg

Milk sugar 82,475 mg

Potato starch 33,000 mg

Polyvinylpyrrolidone 4,000 mg

Magnesium stearate 0.500 mg

120,000 mg

Manufacturing process: Analogous to example A.

Example H

Ampoules with 20] f l-Ci-Athoxycarbonylamino ^ -cyan-S-fluorophenyl) · 2-tert-butylamino-ethanol hydrochloride

Composition: 1 ampoule contains:

Active substance 0.02 mg

Citric acid 2.5 mg

Sodium hydrogen phosphate 7.5 mg

Table salt 4.6 mg

Ampoule water to 2.0 ml

Manufacturing process: Analogous to example D.

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Claims (1)

Claims 1. New ^ -Acylamino-phenyl-ethanolamine of the general formula in the R _{1 is} a hydrogen or halogen atom or the cyano group, Rp is a fluorine atom, the cyano, trifluoromethyl or nitro group or an alkyl group with 1 to Ί carbon atoms, R, a straight-chain or branched alkoxy group with 1 to carbon atoms, an alkenyloxy group with 2 to 5 carbon atoms, an aryloxy group having 6 to 10 carbon atoms or an aralkoxy group having 7 to 11 carbon atoms or an amino group represented by a straight or branched chain alkyl group having 1 to 5 carbon atoms an alkenyl group having 2 to 5 carbon atoms, an aryl group with 6 to 10 carbon atoms and / or an aralkyl group with 7 to 11 carbon atoms mono- or disubstituted can be, and R | j is a cycloalkyl or alkyl group, each with 3 to 5 carbons Substance atoms mean, and their physiologically compatible acid addition salts with inorganic or organic Acids. 90983? / 0180 2. New compounds of the general formula I according to claim 1, in the R, Rp and R ₁ . are as defined at the outset and R, a straight-chain or branched alkoxy group with 1 to 5 carbon atoms, an alkenyloxy group with 2 to 5 carbon atoms, an aralkoxy group with 7 to 11 carbon atoms or, when R _{1 is} a hydrogen or halogen atom and R "is a fluorine atom, the Trifluoromethyl or nitro group, also an amino group optionally substituted by a straight-chain or branched alkyl group with 1 to 5 carbon atoms, an alkenyl group with 2 to 5 carbon atoms, an aryl group with 6 to 10 carbon atoms or an aralkyl group with 7 to 11 carbon atoms, and their physiologically compatible acid addition salts with inorganic or organic acids. 3. New compounds of general formula I according to claim 1, in which R ₁ and R_ are as defined at the beginning, R, an alkoxy group having 1 to ^ carbon atoms, or when R ₁ represent a hydrogen or halogen atom and Rp represents a fluorine atom, the trifluoromethyl or nitro group, and an optionally substituted by an alkyl group having 1 to ¹ J carbon atoms amino group, and Rh is the isopropyl or tert-butyl group, and their physiologically compatible acid addition salts with inorganic or organic acids. ¹ J. New compounds of the general formula I according to claim 1, in which R _{1 11} represent a hydrogen or halogen atom or the cyano group, R ₂ is a fluorine atom, the cyano, trifluoromethyl or nitro group, R, an alkoxy group having 1 to ¹ carbon atoms, J and R are isopropyl or tert-butyl, and their physiologically compatible acid addition salts with inorganic or organic acids. 909832/0180 280A62B 5. l-CJ-ethoxycarbonylamino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol and its acid addition salts. 6. l- ( ⁱ l-Ethoxycarbonylainino-3-cyano-5-i'luorophenyl) -2-tert-butylamino-ethanol and its acid addition salts. 7. 1- (4-Kthoxycarbonylamino-3-cyano-phenyl) -2-tert-butylamino-ethanol and its acid addition salts. 8. ^{1- (1} <-ethoxycarbonylainino-3-cyano-phenyl) -2-isopropyllainino-ethanol and its acid addition salts. 9. Medicaments containing a compound of the general formula I according to claim 1 in addition to one or more inert carriers or diluents. 10. Process for the preparation of new ¹ I-ACylamino-phenyl-ethanolamines of the general formula in the R is a hydrogen or halogen atom or the cyano group, R_ is a fluorine atom, the cyano, trifluoromethyl or nitro group, or an alkyl group with 1 to ^ carbon atoms, R_ is a straight-chain or branched alkoxy group with 1 to 5 carbon atoms, an alkenyloxy group with 2 to 5 Carbon atoms, an aryloxy group with 6 to 10 carbon atoms, an aralkoxy group with 7 to 11 carbon atoms 909832/0180 atoms or an amino group replaced by a straight-chain or branched alkyl group with 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an aryl group having 6 to 10 carbon atoms and / or a Aralkyl group having 7 to 11 carbon atoms can be mono- or disubstituted, and mean a cycloalkyl or alkyl group each having 3 to 5 carbon atoms, as well as their physiological Compatible acid addition salts with inorganic or organic acids, characterized in that a) an acetophenone of the general formula , (II) in the R ₁ to Ru are as defined at the outset, is reduced in a suitable solvent or b) an aldehyde of the general formula , (III) 909832/0180 - 35 - in the R ₁ to R _{5 are} as defined at the outset, or its hydrate with an amine of the general formula ^ N - Rj,. (IV) in the R _{11 is} as defined at the outset, reacted and the compound of the general formula formed as an intermediate C-CH-NR ₄ in the R ₁ to R ₁ J are as defined at the outset, which does not need to be isolated, is reduced in a suitable solvent and a compound of the general formula I thus obtained is then, if desired, converted into its physiologically acceptable salts with inorganic or organic acids. 11. The method according to claim 10a, characterized in that the reduction is carried out with a complex metal hydride, with aluminum isopropoxide in the presence of a primary or secondary alcohol, with catalytically excited hydrogen or with nascent hydrogen at temperatures between -20 ⁰ C and the boiling point of the solvent used will. 909832/0180 12. The method according to claim 10b, characterized in that the reduction with a complex metal hydride or with catalytic excited hydrogen at temperatures between -20 ° C and the boiling point of the solvent used will. 909832/0180