DE1643296A1 - Means for the treatment of bronchospastic symptoms - Google Patents

Description

Priority ν. 19 * October 19 66 in Sweden registration number: lh 182/66

The present invention relates to compounds that are effective for the treatment of bronchospastic manifestations of various Are created, especially for the treatment of asthmatic phenomena. The invention also relates to the production such compounds as well as agents containing themyand the use of these agents for therapeutic purposes. Specifically, the present invention is concerned with bronchospasmolytic active 1- (3,5-dihydroxyphenyl) -2-alkylaminoethanols.

A large number of l- (3 _t h -dihydroxyphenyl) -2-aminoethanols with bronchospasmolytic activity are known, but compounds of this type with the two hydroxyl groups in 3 reduction of the benzene ring are attacked in the organism by certain enzymes, ie _o by catechol O-methyltransferase ,

1098A0 / 1733 - 2 -

COMT, which can be found in the liver, among other things. By this attack inactivates the compounds and therefore substances of this type have only a short durability. Compounds with "the two hydroxyl groups in the 3» 5-position of the benzene ring, however, are not attacked by COMT. Only a few compounds of this last-mentioned type are known, and these can be summarized by the general formula X. will:

-CH - CH - NHR ²

OH R ¹

A compound of the formula I wherein R is a water st off atom

and R is a methyl group is in the German patent 865 315. Compounds of formula I in which

1 2

R is a hydrogen atom and R is 2-hexyl-j 2-heptyl-, 2-octyl- or n-butyl group, are described in Belgian patent 635 889, compounds in which R is a water

2 atom and R the group

3
- is OH, where R is a hydrogen

atom or a methyl group are in Irish Patent Application No. J1167 / 63 discloses and compounds wherein

109840/1733 - 3 -

_3 _ 1843296

1 2

R is a hydrogen atom or a methyl group and R is a Means isopropyl group are in British patent specification 920 623. These known compounds of the formula I are bronchospasmolytically active compounds of relatively long duration, but have been found to increase the heart rate, and this effect diminishes the therapeutic usefulness of these substances is essential.

According to the present invention, new l- (3, 5 - ' Dihydroxyphenyl) -2-alkylaminoethanols of the general formula

HC

- CH - CH ₂ - NH - R II

OH

OH ₃ ^ in which, an ede group η - C—— CH, - C —- CH_, -

CH, C
CH ₃

C ₂ H ₅

means in which η is an integer from 0 to 3 and R is Hydrogen atom, a methyl or ethyl group means / These Connections have a long durability and cause Surprisingly, very little effect on the heart. This means that these substances have a different affinity on the ß-receptors in the heart and in the brochial muscles show what probably depends on the fact that the ß-receptors in these two organs are not identical.

10984071733

These advantages are achieved according to the present invention, by using compounds of the above formula II and physiologically acceptable acid addition salts thereof according to known methods Methods.

A. Reduction of a diketo compound of the formula III in the presence of an amine of formula IV according to the following reaction scheme

H ₂ NO

IV Red.

CH - CH ₂ -NH-R ί> Η

III

whereupon R is replaced with hydrogen if necessary.

B. Implementation of compounds of the formula VI and VII according to the following reaction scheme

-NO

VI

VII

VIII

3 k whereupon R and R, if necessary, replaced by hydrogen

w «rd« n.

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1043296

C. Reduction of a compound of Formula IX according to the following Reaction scheme

OH

IX

GH ₂ -F- R (3) R

VIII

3 h
, whereupon R and R, if necessary, are replaced by pulp * In these formulas, R is a group of the type mentioned above,

3 "

R is a hydrogen atom or one which can be easily replaced by hydrogen Group such as an alkyl or acyl group of no more than five carbon atoms or a mono- or bicyclic aralkyl group of no more than eleven carbon atoms, such as the benzyl or naphthyl line thy l group, and R is a hydrogen atom or a mono- or bicyclic one Aralkyl group of not more than eleven carbon atoms.

-GH-CH ^ -N-

XXV

XXVI

where R and η have the above meaning,

Always "

Ee is not necessary to create the protective group R- by hydrogen

1096 4071731

set. Accordingly, when R is an acyl group, compounds are obtained which is as effective as that in pharmacological terms

3 are corresponding compounds in which R is hydrogen.

It should be noted that the compounds according to the invention in the form of optically active Isoruei ⁱ 'n. are present which can be isolated in any manner known per se for the separation of an amine, and the concept of the invention is to be understood to mean that such a procedure is also intended to fall within the scope of the present invention.

The preferred method of making compounds of the Formula II is Method C. The starting materials of Formula IX can be obtained in any desired manner. Some of the possible ways are shown in the following reaction schemes, where the numbers and letters under the arrows indicate the example and the subsection where the specific reactions are listed.

C ₂ H ₅ OH

OH

-C- OCJK-IJ ² 5,
0

CH ₂ Cl

Ib

XI

1Ö98Ä0 / 173t

-7 -

2) hydrolysis
Tb

C ₆ H ₅ CH ₂ O

-C-OH

SOCL,

lc

CH ₂ = N

XII XIII

ld

C ₆ H ₅ CH ₂ O

-C-CH = N ⁺ = N "

I!

HBr

C ₆ H ₅ CH ₂ O

H ₂ N C-CH ₂ Br

XIV ti?

' XV

-C-CH ₂ -O

-R reduction _ _ *

-CH-CH ₀ -NO

XVI II

F.
C ₆ H ₅ CH ₂ O

C ₆ H ₅ CH ₂ O

-St

-OC ₂ H ₅ stage I. Xthylacetate + NaH stage II. Decarboxylation

XIjI

Bromination

-C-CH, Ii copper (il) bromide Ij bromine Ik bromine

XVII1Ö9U0 / 1733

Ii Ij Ik

- CH ₂ Br

XV

This connection is also treated as indicated under E.

step

C ₆ H ₅ CH ₂ O

\ / A.

COO Bt

- Cl

COO Et

Stage II decarboxylation Ig

XIII

ig

C ₆ H ₅ CH ₂ O

C ₆ H ₅ CH ₂ O

- CH,

XVII '

This connection is also treated as indicated under F.

109840/1733

H.

CH COO

CH COO

H-NF

- C, CH ₂ Br O

XVIII

CH COO

CH COO

CH ₂ -

^C 6 ^H 5

Stage I Reduction Stage II Removal of protective groups

2 e

XIX

e

HO

- CH OH

- R

II

I.

- CH ₂ Br

d

XV

1 7 - 10 -

1643290

d

0, H-CH ₀ O 5 2

- CH ₂ . _N

XXl

'6H ₅ CH ₂ O

C ₆ H ₅ CH ₂ O

- CH - CH ₂ -

OH

CH ₂ C ₆ H ₅

reduction

2 d

XXII

HO

HO

-CH- CH ₂ - N - R OH H

II

J. This scheme also illustrates method A.

C ₆ H ₅ CH ₂ O

C ₆ H ₅ CH ₂ O

CP-Hj H ₂ O

Il Il

ο Level IH ₂ N - R Level II _reduction

2 a

XXIII - 11 -

109840/1730

HO

HO

OH

- PH - CH ₂ ■ - N - R

II

K. This reaction scheme also illustrates method B.

- CH CH,

\ y '

Level IH ₂ N - R Level II reduction

2b j 6

XXIV

- CH - CH ₂ OK

II

This is another explanation of Method Di.

CH COO

CH_COO

CH ₃ COO

-C-Cl

CuCN

■>.

109840/17

CH ₃ COo

eduction stage II hydrolysis

-C-CN

- 12 -

-IJ-

CH

SXIX

This manufacturing process is only for the manufacture of Cycloalkyl compounds can be used where R ° denotes hydrogen.

The reduction of the compound of the formula IX can, for example are executed

a) by catalytic reduction, such as with Raney nickel or with palladium-activated carbon or platinum oxide, or

b) chemical reduction, such as with lithium aluminum

3 hydride or sodium borohydride, in which case R is a hydroxy protecting group is, or

c) chemical reduction of the carbonyl group, such as with Lithium aluminum hydride or sodium borohydride, whereupon the hydroxy

3 k

Protecting groups R and R by catalytic reduction, for example can be removed with palladium carbon or platinum oxide.

3
If R is an alkyl group in formula VIII, this can be replaced by hydrogen with ether-splitting agents,

109840/1733 - 13 -

for example using to η boron tribromide, at lower Temperature or by heating with halogen ■ ** passer st open «In in this case, the alcoholic hydroxyl group is advantageously protected by acetylation and splitting takes place using hydrobromic acid in anhydrous glacial acetic acid or glacial acetic acid / acetic anhydride, which is then hydrolyzed

3
will. If R in formula VIII is an acyl radical, this can

can be split off by treatment with acids. If in the

3 k
Formula VIII R and R denote aralkyl, this can be removed by hydrogenolysis.

The new l- (3 »5 -dihydroxyphenyl) -2-alkylamino-ethanols of the. present binding are very good bronchodilators and. have only a very slight heart-accelerating effect. The compound l- (3, 5 -dihydroxyphenyl) -2- (tertbutylamino) -ethanol proved to be a more effective bronchodilator than l- (3. »5 -dihydroxyphenyl) -2- (isopropylamino) - both in vitro and in vivo. ethanol, and the duration of the activity is longer than that of this known compound, and in an experiment on the isolated rabbit heart the cardiac accelerating effect is only 1/1 of that of the isopropylamino compound. The relationship between the cardiac stimulating effect and the bronchodilator effect was also ^{demonstrated in spontaneously beating i} :, ■ guinea pig | <er2i atrial preparations and spiral-shaped tracheal preparations when both preparations were placed in the same bath. When the compound of the present invention was slowly poured into the bath solution, bronchodilation was obtained without any effect on the heart.

1 0 98 40/1 733 - ι * -

16Λ3296

-Ik-

muscle preparation. The weak, heart-accelerating effect of the tert-butylamino compound according to the present invention also observed in periodic studies of the compound in anesthetized cats.

The weakening of the heart-accelerating effect is obtained so by replacing a secondary open-chain carbon atom by a tertiary carbon atom or by making the secondary carbon atom part of a cycloalkyl group power. Although the compound of formula II specifically described herein is one in which the group R is the is tert-butyl radical, the concept of the invention also includes such Compounds in which the group R of the tert-pantyl or Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or a derivative thereof substituted by lower alkyl groups Is cycloalkyl. The essential feature is that the tertiary carbon atom or the cycloalkyl group directly with connected to the nitrogen atom.

The new compounds according to the invention can be administered in the form of salts according to physiologically acceptable acids will. Suitable acids that can be used are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, Fumaric acid, citric acid, tartaric acid, maleic acid or succinic acid.

The invention also provides pharmaceutical compositions which contain at least one of the compounds as the active ingredient

109840/1733 - ¹⁵ -

of the invention in combination with a pharmaceutical carrier. Such funds can be used for oral, bronchial, rectal or parenteral administration.

For the manufacture of pharmaceutical agents in the form of dosage Units for oral administration containing a compound of the invention in the form of a free base or one pharmaceutically acceptable "salts thereof, the active ingredient may be mixed with a solid, powdered carrier be, such as with lactose, sucrose, sorbitol, mannitol, a starch such as potato starch, corn starch, corn starch or amylopectin, a cellulose derivative or gelatin, and this carrier can also contain lubricants such as magnesium

or calcium stearate or a carbowax or other polyethylene glycol waxes, and the composition is then compressed to form tablets or dragee cores. W _e nn dragees are required, the cores may be coated, for example with concentrated sugar solutions which may contain gum arabic, talc and / or titanium dioxide, or alternatively they may be coated with a lacquer, the organic in readily volatile solvents or mixtures of organic solvents is dissolved, dyes can be added to these coatings. To produce soft gelatine capsules (pearl-shaped closed capsules), which consist of gelatine and, for example, glycerine, or to produce similar closed capsules, kandi's active substance is mixed with a Carbowax ^. Hard gelatin capsules can contain granules of the active substance with solid, powdered carrier substances such as lactose, sucrose, sebitol, mannitol,

109840/1733 " ^l6 ""

1643298

Starch, (for example potato starch, corn starch, or amylopectin) , Cellulose derivatives or gelatin and also contain.

t
Contain magnesium stearate or stearic acid. Dosage units for rectal administration can be in the form of suppositories which contain the active substance mixed with a neutral fatty base, or they can be gelatin rectal capsules which contain the active substance in a mixture with a Carbowax ^ or other polyethylene glycol waxes. Each dosage unit preferably contains 0.5 to 50 mg of the active ingredient.

Liquid preparations for oral administration can be in the form of syrups, suspensions or emulsions and contain them for example about 0.1 to 20 wt .- ^ active substance and, if desired, additional additives, such as the stabilizing agents, suspending agents, dispersing agents, Food enhancers and / or sweeteners.

Liquid preparations for rectal administration can be obtained in the form of aqueous solutions containing about 0.1 to 2 wt .- ^ contain active substance and also, if desired, contain stabilizers and / or buffer substances.

For parenteral administration by injection, the carrier can be a sterile, parenterally acceptable liquid, such as distilled water for injections (free from temperature-increasing substances) or an aqueous solution of polyvinylpyrrolidone or a parenterally compatible oil, such as for example arachis oil, possibly together with stabilizing

109840/1733

agents and / or buffer substances. Dosage units of the Solutions can advantageously be enclosed in capsules, each dosage unit preferably 0.05 to 5 mg contains active ingredient.

The preparations are preferably suitable for administration into the bronchial tubes in the form of a drip or spray solution. The solution advantageously contains 0.1 to 10 wt .- ^ active Component.

The invention is further explained below using the example «

example 1

Preparation of 3 »5-dibenzylody- C ^ - (tert-butylamino) acetophenone as starting material.

a) ethyl 3 »5-dihydroxybenzoate

308 g of A-resorcylic acid were dissolved in 1100 mm of absolute ethanol, and 25 ml of concentrated sulfuric acid were added * The reaction mixture was refluxed for 20 hours. The ethanol was evaporated and the residue was poured into water and extracted with ether. The ether phase was washed with sodium bicarbonate solution and water and dried with magnesium sulfate. After evaporation of the ether · erhislt m & n · a crystallizing resin · The ester was prepared from water toakristalli eierti F. 128 bi · 130 ° C.

- 18 -1öi $ 4ö / i7 $ i ORIGINAL

b) 3> 5-dibenzyloxybenzoic acid

In a 2 liter three-necked flask with a stirrer and eiran Reflux condenser were 221 g of ethyl 3,5-dihydroxybenzoate, 750 ml of absolute ethanol, 36O ml of benzyl chloride and 210 g of potassium carbonate are given. The reaction mixture was refluxed boiled, stirred for 20 hours and filtered hot. The ethanol was evaporated and the residue was added to water and sodium hydroxide added until alkaline reaction. The aqueous phase was extracted with ether and the ether phase was extracted with Dried magnesium sulfate. The ether was evaporated and the remaining benzyl chloride was removed under reduced pressure distilled off. The remaining oil was 3 hours on one Water bath with 150 g of potassium hydroxide in 750 ml of ethanol and 50 ml Refluxed water. The ethanol was evaporated, UtI 250 ml of water was added *. When acidifying the solution 5N hydrochloric acid crystallized 3 »5-dibenzyloxybenzoic acid. This was recrystallized from ethyl acetate 1 F. 2l4 to 216 C.

c) 3 »5-dibenzyloxy-benzoyl-chloro-oil

I67 g of 3,5-dibenzyloxybenzoic acid and 400 ml of redistilled Thionyl chloride was refluxed on an oil bath for 1 hour. Excess thionyl chloride was reduced The pressure was distilled off, and a crystalline Hasse remained. This was recrystallized from petroleum ether (K.ρ * 6θ to 85 ° C.) s F. 73 °

d) 3 »5-dibenzyloxy-diazo-aoatophanone

No known methods were produced. 86 g

108840/1713. i

N-nitroso-p-toluolsulphomethylamid in ether was slowly added to a solution of potassium hydroxide 2h g in 40 ml of water and 100 ml of diethylene glycol monoethyl ether in 40 ml ether. The reaction flask was heated to 55 to 65 ° C on a water bath, and the diazomethane formed was distilled with JÖier into the receiving vessel, which contained 71 g of 3t5-di-benzyloxybenzoyl chloride in 250 ml of absolute ether at -25 ° C. The reaction mixture was allowed to slowly come to room temperature. The ether solution was used directly in the next reaction.

e) 3 ι5-dibenzyloxy-W_bromacetophenon

To the ethereal solution from the previous reaction stage were 300 ml benzene uiti with ether saturated with hydrogen bromide added, until the nitrogen evolution ceased. If the solution evaporated, the residue crystallized. The crystals were soluble in xylene and could be washed with petroleum ether (b.p. 40-60 ° C) precipitated * They were washed with absolute ether: F. 82 to 84 ° C. In a similar way, 3,5-dibenzyloxy-W-chloroacetophenone was produced prepares. F. 78 to 80 C.

f) 3,5-dibenzyloxy-CO- (tert-butylamino) acetophenone

1 »5 g of tert-butylamine and .85 ml of absolute ethanol were in into a 250 ml flask with a reflux condenser and the mixture was heated to reflux conditions. The implementation was carried out under nitrogen. At reflux temperature, 4.1 g of 3 »5-dibenzyloxy-W-bromoacetophenone in 15 oil Benzene added. The mixture was refluxed for 20 hours

109840/1733

heated and after evaporation a yellow oil was obtained. This oil was shaken with absolute ether and white crystals formed (tert-butylamine hydrobromide). The crystals were filtered off and washed with ether. To the combined ether phases were added 10 $ hydrobromic acid to give a white precipitate formed _o This precipitate was filtered off and washed thoroughly with water and ether. It was recrystallized from ethanol: mp 196-198 ° C.

The steps according to d) and e) can be replaced by the following steps:

g) 3 »5-dibenzyloxyacetophenone

70 g of 3,5-dibenzyloxy-benzoyl chloride in dry benzene were slowly added to a solution of diethyl ethoxy magnesium malonate, which had been obtained in a known manner. The reaction mixture was refluxed overnight, and after cooling, 300 ml of benzene and 200 ml of 5N sulfuric acid were added to hydrolyze the mixture. The benzene phase was washed 3 times with water and then dried with magnesium sulfate. The benzene was evaporated and the excess diethyl malonate was distilled off under reduced pressure. 400 ml of dioxane, 80 ml of water and kO ml of concentrated hydrochloric acid were added to the residue. The reaction mixture was heated on an oil bath at 130 ^° C. for 2k hours. After evaporation, a brown oil remained which crystallized on standing. It was recrystallized from ethanol. P. 60 to 61 ° C.

1 0 9 8 h 07 1 7 % 3

h) 3 »5-dibenzyloxy-acetophenone

5 »0 g of 50% sodium hydride suspension and a few ml of benzene were placed in a 500 ml three-necked flask with a stirrer, a reflux condenser and a dropping funnel. Then 18.1 g of ethyl 3 »5-dibenzyloxybenzoate in 150 ml of dry benzene were added. The reaction mixture was stirred and heated on an oil bath (90-100 ° C) and 4.5 g of ethyl acetate in 25 ml of dry benzene was slowly added. The mixture was then heated and stirred for 7 hours. The reaction mixture was then cooled and a few ml of ethanol was added and the whole was then poured into 150 ml of a 50% acetic acid solution. The acidic water phase was extracted with ether. The ether phase was washed with water, sodium bicarbonate solution and lasser and then dried with magnesium sulphate. After evaporation, an oil was obtained. This oil was treated with 80 ml of dioxane, 16 ml of water and 8 ml of concentrated hydrochloric acid and the mixture was heated on an oil bath at 130-140 ° C for 15 hours. After evaporation, ether was added and the ether phase was washed with water, 2N sodium hydroxide solution and water. The ether phase was then evaporated and the residue dissolved in hot ethanol, and 200 ml of 1N sodium hydroxide solution was added. The mixture was refluxed for 5 hours to hydrolyze residual ethyl 3,5-dibenzyloxybenzoate. The ethanol was evaporated and the water phase extracted with ether. The ether phase was washed with water, dried with magnesium sulphate and evaporated. The remaining oil crystallized from petroleum ether (boiling point 80 to 110 ° C.).

F. 61.5 to 62.0 ° C.

- 22 -

109640/1733

i) 3 »5-dibenzyloxy-üÄ-bromoacetophenone

11.2 g of copper (II) bromide were placed in a three-necked flask given a stirrer and a reflux condenser. 25 ml of ethyl acetate were added and the mixture was heated to reflux with stirring. 10 g of 3 »5-dibenzyloxyacetophenone in 30 ml of hot chloroform were added, and that Refluxing was continued until the black-green color changed to light brown. The copper (E) bromide formed became filtered off, and after evaporation of the filtrate, a brown oil which soon crystallized was obtained. This was out Recrystallized ethanol: F. 82 to 8 * 1- C. Alternatively, can this stage i) can be replaced by stage j) or k).

j) 3,5-dibenzyloxy- ^ -Bromoacetophenone

In a 250 ml three-necked flask equipped with a stirrer, a reflux condenser and a dropping funnel, 5 »0 g of 3,5-dibenzyloxyacetophenone in 90 ml of chloroform were placed. Then 15 drops of glacial acetic acid saturated with hydrobromic acid were added to the solution at 0 C. H ml of a solution which had been prepared from 2.4 g of bromine and 25 ml of chloroform were then added. The mixture was heated to reflux conditions and then rapidly cooled to ⁰ ° C. The remaining bromine solution was slowly added with stirring and cooling, and then stirring was continued for a further hour at room temperature and finally the mixture was refluxed for 1/2 hour. After cooling to room temperature, nitrogen was introduced in order to remove residual hydrobromic acid

109840/1733 - ² ^ -

cold sodium bicarbonate solution and saturated with sodium chloride Water washed. The organic phase was dried with magnesium sulfate and evaporated. The leftover Oil crystallized on standing. It turned out Recrystallized ethanol: mp 82 to 84 ° C.

k) 3,5-dibercyloxy-Ct) -bromoacetophenone

20.0 β 3 5-dibenzyloxyacetopheion were dissolved in 460 ml dry etching agent and cooled to 0 ° C. 9.7 g of bromine dissolved in 30 ml of dry, ethanol-free chloroform were slowly added. The temperature was kept at 0 ° C. during the addition. The temperature of the reaction mixture was then allowed to rise to room temperature and held there for 2.5 hours with stirring. The ether was then evaporated at room temperature, and an oil was obtained, which soon crystallized. The product is identical to that obtained according to Example 1 (j).

Example 2

Production of 1- (3 »5-dihydroxyphenyl) -2- (tert-butylamino) ethanol and its_salts _ _ _ _

a) To a solution of 6.8 g of the hydrate of 1 —glyoxyloyl— 3,5-dibeiizyloxybenzene in 50 ml of methanol was 7t ° S tert-butylamine and 30 ml of benzene are added. The reaction mixture. was refluxed for 3 hours and evaporated «The residual oil crystallized when ethanol was added. M.p. 78.5 to 79 »5 ° C. 2.5 g of this compound in 75 ml absolute ethanol were used under Äionnalbedingungen with Raney nickel

- Zk ~

109840/1733 bad original

hydrogenated. After filtering from the catalyst and the The remaining oil was evaporated with ethanol / penzene dried. The base in ethanol was made with hydrogen bromide treated in ethanol and evaporated. The residue can be recrystallized from glacial acetic acid / chloroform.

The IR «* spectrum of this product is identical« - with that of the Product in 2c «

b) 2.7 g of tert-butylamine in 20 ml of ethanol were added to a solution of 3.5 g of 3 »5 -dibenzyloxyphenylepoxyethane in 100 ml of ethanol. The reaction mixture was refluxed for k hours and then evaporated. The crystalline residue can be recrystallized from absolute ether. The melting point of 1- (3 »5 -dihydroxyphenyl) -2- (tert-butylamino) ethanol is 119 to 122 ° C. The salt preparation and the reduction can be carried out in the same way as described under 2a).

: ■) 2.4 g of 3,5-dibenzyloxy-4r = - (tert-butylamino) acetophenone hydrobromide in 200 ml of glacial acetic acid were hydrogenated in the presence of 0.3 g of Lü ^ oiger palladium carbon at room temperature and normal pressure. Ethanol was added to dissolve the precipitated reaction product. The catalyst was filtered and the residue evaporated to dryness, 50 ml of absolute ethanol were added and the solution was in the presence of 0.3 lO ^ cent palladium on carbon at 35 ⁰ C and hydrogenated atm. 5 The catalyst was filtered off and the residue evaporated to dryness. Then it was recrystallized from glacial acetic acid / chloroform: P. 93 to 97 ° C for the monohydrate. The non-hydrogenated compound

109840/1733 - 25 -

BATH ORIGINAL

had a melting point of 205 to 206 ° C (decomposition),

d) To a solution of 32 g of benzyl-tert-butylamine in 300 ml of absolute ethanol at reflux temperature, 32 g of 3 »5 ~ dibenzyloxy - & - bromoacetophenone in 100 ml of dry benzene were added. The mixture was refluxed for 20 hours and then evaporated . Winch added Werm absolute ether to the residue was Benzyl-tert-butylaminhydrobromid from C The precipitated compound was filtered off, and the _# Piltrat an excess of 2 N sulfuric acid was added "With this addition, the hydrogen sulfate of 3 ', 5-dibenzyloxy-d ) - (Benzyl-tert-butylamino) -acetophenone precipitated «fts was recrystallized from acetone / ether» Since the product crystallizes with different organic solvents, the melting point varies with the type and amount of the crystal solvate, but the product can be used directly for the hydrogenation werder,

15 g of 3,5-dibenzyloxy-U- (benzyl-tert-butylamino) -acetophenone hydrogen sulfate in 200 ml of glacial acetic acid were 'in a Parr print' reaction apparatus in the presence of 1.5 g of 10% palladium coal hydrogenated at 50 C and 5 atm. The response time was 5 hours · The catalyst was filtered off, the piltrate became evaporated to dryness, giving the hydrogen sulfate of 1 «(3, 5 -dihydroxyphenyl) -2- (tert-butylamino)« ethanol. This compound is hygroscopic, but it can be converted to the non-hygroscopic sulfate in the following manner will"

1 098 AO / 1 733 bad «™ *» - - ²⁶ -

. ■■■ « Λ Ο

The hydrogen sulfate was dissolved in water and the pH of the solution was adjusted to 5 »6 (pH meter) with 0.1 η sodium hydroxide solution. The water solution was dried to dryness, and the residue was dried with absolute: ethanol / benzene and again evaporated to dryness. The remaining crystal mixture was extracted with absolute methanol in a Soxhlot extraction apparatus The sulfate of 1- (3> 5 -dihydroxyphenyl) -2- (tert-butylamino) ethanol crystallized in the methanol phase. F ₀ 2 ^ 6 to 2 '* 8 ° C.

The sulfate can also be prepared in the following manner After hydrogenation with palladium carbon in glacial acetic acid, the Catalyst filtered off. At an elevated temperature, the theoretical amount of anhydrous i.atmimacetat was added, the solution was stirred for 5 minutes when the sodium sulfate precipitated, and then this was filtered off from the hot solution, The sulfate of 1- (3> 5 -dihydroxyphenyl) -2- (tert-butylamino) ethanol was obtained from the filtrate isolated.

e) To 6.1 g of 3 »5-diacetoxy-ίύ-bromoacetophenone, dissolved in 100 ml dry benzene, 7 | 0 g of benzyl-tert-butylamine in 50 ml added to dry enzene. The mixture was refluxed for 3 hours and then evaporated. If absolute ether to the residue was added benzyl-tert-butylanine hydrobromide fell off and was filtered off »The etheric phase was treated with hydrogen bromide in ether until the solution was easy was pissed off.

The precipitated salt mixture was treated with water; j .- ·.;. B »nzyl" $ ®rt «buiylaminb.ydrobromid to dissolve * Die- Eyis · i & -, /: · .. · ι:?»>

109840/1733 " ₂₇

BAD ORlGtNAl.

j3 e

• 3fm filtered off, washed with water and recrystallized by dissolving in ethanol and precipitating with absolute ether 17I to Iv; ~ -

1.1 δ of this salt was dissolved in warm absolute ethanol, before 0.1 β IQ'foi #e Palladdum carbon was added. The fluid was then hydrogenated via sewing at 50 ° C. and 5 atm. The catalyst was filtered off and the volume of the solution was reduced by evaporation. The hydrobromide of l- (3 »5 -Diaceto>::>. Pheiiyl) -2- (tert-butylamino) ethanol with 1 mole Kristallwassi was iv upon the addition of ether precipitated 108 F. to 11I ^C C ,, The Protective acetyl groups can be removed by boiling the 1- (3 * 5 diacetoxyphenyl) -2- (tert-butA ^ lamino) -ethanol hydrobromide with hydrobromic acid for 3 hours: * After evaporation and drying, the product was recrystallized as described under 2c .

Example 3

Production of 1- (3 t 5 -dibenzylox3Thenyl) -2- (benzyl-ttr; «butylamino) -atiianol _

2 g of sodium borohydride were added to 18.3 g of 3 t 5 -diber> zyloxy - <«i - (benzyl-tert-butylamino)» acetophenone in ethanol. The reaction mixture was left to stand overnight. Some methanol was added and the solution was evaporated. Water and 2N sodium hydroxide solution were added to the residue, and the water phase was extracted with ether. The ether phase was dried with magnesium sulfate. The ether was evaporated , m> be ±

103840/1733 bad original

an oil was obtained which crystallized on standing, F, 78 to 79 ° C. The recrystallized product can through Replacement of the pheuyl group by hydrogen 3, n known Way into the corresponding 2-butylaniinoderivat · converted ve rderu-

Example k '

1 * 1

Preparation of 1- (3 »5 ~ dihydroxyphenyl) -2 ~ (tert.-pe; ntylamino ) —Ethanol hydroxyl bromide »_ _

Zk, 5 g of dibenzyloxy-4? ~ Bromoacctophenone in 100 ml of dry benzene were added to a refluxing solution of 18 ml of tert-pentylamine dissolved in 200 ml of absolute ethanol. The refluxing was continued for about 20 hours. The reaction mixture was evaporated and ether was added to the remaining oil. When this was added, the hydrobromide of tert-pentylamine precipitated. The precipitate was filtered off and an excess of 10% hydrobromic acid was added to the piltrate. The 3 _t 5- '· - «! *)« - (tert-pentylamino) ~ acetopbeiion hydrobromide

crystallized. and had a melting point of 172 to 176 C.

This compound then became catalytic in the same way as Described under 2c! ' hydrogenated to give 1- (3> 5 -dihydroxyphenyl ) «- 2- (tert-pentylamine) -ethanol hydrobromide with a content half a molecule of crystal water. M.p. 95 to 110 ° C.

example

11
Production of -1- (3 t 5 -dihydroxypbenyl) -2- (cyclobutylamino)

_Q ^ ₇₃₃ . ^

BATH ORIGINAL

~ 29 ~

5) 5 g of benzylcyclobutylamine were dissolved in 100 ml of absolute ethanol and 7.0 g of 3,5 * -dibeuzyloxy-> bromoacetophoion in 30 ml of trodaaem benzene were added to this solution Wakes up boiled under reflux -and immersed in it. When absolute ether was added to the residue, the benzylcyclobutylaffline hydrobromide precipitated and was filtered off. When 10% hydrobromic acid was added to the filtrate, the 3,5-dibenzyloxy-iJ ~ ( _in iizylcyclobutyl-amino) -acetophenone hydrobromide was added the end. This was recrystallized from acetone / ether ο F „8 5 to 88 ⁰ O ₀

4.2 g of the recrystallized product were dissolved in ethanol, and 0.5 g of 10% palladium-on-carbon was added. The hydrogenation was carried out in a Parr pressure ^{reaction apparatus at about 50 ° C.} and 5 atmospheres. The reaction time was about 15 hours. The catalyst was filtered off and the product crystallized on evaporation. This was recrystallized from ethanol / ether. The melting point of 1- (3, 5 - dihydroxy · «phenyl) -2- (eyelobutylarino) -äthanolhydrobromid is 227-228 ^O C

Example 6

Preparation of 1 "(3, 5 -dihydroxypheinyl ) <~ 2 <" ( cyclopropylamino) "ätlianolhydrobromid

®ine solution of 3.5 g of 3,5 "öiben _Z yioxyphenyl" epoxyäthan in 100 ml ethanol was mixed and ι 2.5 g Cyclopropylamln in 20 ml of ethanol, boiled for 15 hours under reflux "The LJJsUJig was then evaporated until a yellow oil remained, the oil crystallized

109840 / mS

.- "*> .- 1643298

with the addition of ether »the melting point of 1 ~ (3» 5 dibenzyloxyphenyl ) -2- (cyclopropylamino) ethanol is; II3 up to 116 ° C.

2.5 g of this compound was dissolved in ethanol and the solution was made slightly acidic by adding ethanol saturated with hydrogen bromide. The hydrogenation was then carried out in the same _manner} as described in example. 1 The product was ₌ dissolved in acetone and upon addition of petroleum ether (4O'bis 6O C) and ether an oil separated from which quickly crystallized in Kühlschrark "" This compound held acetone, which by drying in a drying pistol under reflux ( boiling ethanol, about 48 hours). The melting point of 1- (3> 5 -dihydroxyphenyl) ■ 2- (cyclopropylaniino) -ethanol hydrobromide is IhO to 1 ^ 5 C »

Example 7

Production of the sulphate of 1- (3, 5 «dihydroxyphenyl) -2- (cyclopentylamina) ~ ethanol»

13 »0 g of benzylcyclpentylamine were dissolved in 100 ml of absolute ethanol and heated under reflux. Then 12. » 3 g of 3-s5 "l>ibenzyloxy" O "bromoacetophenone in 35 ml of benzene were added, the mixture was refluxed for 7 hours. The mixture was then left to stand for 9 hours at room temperature. dry Äth @ r became sugesetst «- With this encore you got a white Ni ed. Tea Beiri« ■ zyleyQ'i & pen. ty laminliydrobroinidj which filtered off the Filts-sit would be an excess of 10%
sug © s @ tste "It a © hi®d an oil off ^ weloii © a

to984 0/1 7-33 '

BAD original

The crystals were filtered off and washed with water and with ether and dried. The crude product of 3 "5" dibonz-yloxy-ίύ - (benzylcyclopentylamino) -acetopbe _: nonhydro- bromide was used directly in the following experiment.

The base of the above-mentioned salt was dissolved in ethanol / dioxane and the solution was cooled with ice water. "Now an excess of sodium borohydride, dissolved in ethanol" and water would be added. The reaction mixture was allowed to slowly come to room temperature overnight Sodium hydroxide solution was added, the water phase was extracted with ether, which was then dried with magnesium sulfate and evaporated. An oil was obtained which was hydrogenated directly with palladium carbon, as described in Example 1, but with a reaction time of four hours. adjusted with 1N sodium hydroxide solution. After evaporation to dryness and drying with absolute ethanol / benzene , the residue was extracted with absolute methanol in a Soxhlet extraction apparatus. A crystalline product was obtained on evaporation of the phase

Example 8

Preparation of the sulfate of 1 - (- 3, 5 -dihydroxyphenyl) -2- (cycloper.tylamino ) —Ethanoi «

26 ₉ 2 g of 3> 5-diacetoxybenzoyl chloride were added to an oil bath

109 8 40/1733 bad ORIGINAL

C heated until the substance was melted. At this moment, Q g CuCN (for 3 hours at 110 ⁰ C dried) 11 were added and the mixture was stirred for 3 hours on an oil bath at 18O ° C. The reaction product was distilled under high vacuum and the distillate quickly crystallized. The melting point of the 3,5-diacetoxybenzoyl cyanide was 16 to 118 ° C.

Then 5-0 g of 3,5-diacetoxybenzoyl cyanide and 0.7 g of platinum oxide were hydrogenated in glacial acetic acid for 3 hours in a Parr pressure reaction apparatus. The catalyst was filtered off and then another 0.7 g of platinum dioxide was added, whereupon 16.2 g of cyclopentanone were slowly added. The hydrogenation was carried out at atmospheric pressure and room temperature. The reaction mixture was allowed to stand overnight. The catalyst was filtered off and the solution was evaporated. To the residue was added water and 100 ml of 5% strength sulfuric acid solution ^he added, and the mixture was heated for 2 hours under reflux to remove the protective groups. After evaporation, the residue was dissolved in water and the pH was adjusted to 5.5 (pH meter) with 1N sodium hydroxide solution. After evaporation to dryness and after drying with absolute ethanol / benzene, the residue was extracted with absolute methanol in a Soxhlet extraction apparatus. The methanol phase was evaporated and the residue was dissolved in a small amount of absolute ethanol. On standing, a crystalline product was formed which was found to be identical to the product described in Example 7 (iR spectrum and melting point).

- 33 -

109840/1733

Example 9

Pharmacology marriage trials

a) Bronchial spasmolytic effect! The bronchial spasmolytic reduction of lr (3 »5 -dihydroxyphenyl) -. 2- (tert-bxitylamino) -ethanol was with that of the known compounds adrenaline and l- (3t5 -dihydroxyphenyl) -2- (iso-propylamino)» - Ethanol on spirally cut guinea pig trachea according to a method originally described by Castillo & Beer / j, Pharmacol. Explt. Therap. 9.0. (Ι9Λ7.), Page LOH / described and later by Const adamantine J_ J. Pharm Pharmacol ο ο 17 (1965), page 384 / has been modified. In this experiment the compound of the present invention was found to be about twice as active as the isopropyl compound and about half as powerful as adrenaline.

In an in vivo experiment according to Konzett & Rößler fÄ.v <3a. ₀ Exp. Päth.Pharmak. 195 (19 ^ 0), page 71.7, the bronchial spasmolytic effect after intravenous administration was also twice as strong as that of the isopropyl compound

The duration of the effect turned out to be longer than that of the known Isopropyl derivatives (Fig. 15 DTE = 1- (3, 5 -dihydroxyphenyl) -2- (tert-butylamino) ethanol; DIE = 1- (3, 5 -dihydroxypheTiyl) -2- (isopropylamino) ethanol).

Similar results were obtained »if the cycloalkyl compounds, were examined. The bronchospasmic effect of e.g. 1- (3, 5-dihydroxyphenyl) -2- (cyclobutylamino) ethiol was in the determination described above about 1.2 times the

109840/1? F % _ _3h

Activity of the known isopropyl compound and about O, k- "times the activity of adrenaline»

b) Effect on the heart: the relationship between the; The heart-stimulating effect and the bronchodilator effect have been studied in vitro by the atrial air tube preparations from the Hé rschice inchen. To compare the effect on the heart and the effect on bronchial muscles under identical experimental conditions, both the spntaii beating atrium as well as the spiral cut trachea into the ^one same bath in Cancer "has been given s solution" Both preparations were of the same animal removed «The compound to be examined was now allowed to flow slowly into the bath solution. In this way the concentration of the compound was slowly increased and it was easy to observe which muscle the compound acted most on. Adrenaline was used as a comparative substance. This agent causes bronchodilation and cardiac muscle stimulation in the same concentration range. The infusion was carried out for 10 minutes. After washing and recovery, the test solution was run in in the same manner as described for adrenaline, and the effect on the two preparations for this agent could easily be compared with that of adrenaline.

In the drawing means:

Figure 1 shows the duration of the effect of DTE and DIE against Bronchxo— constrict ion induced by histamine (guinea pigs 0.95 kg). The bronchial spasmolytic

0 98 4 0/1733 ^ΒΑΰ

The effect was determined using the Konzett & Rössler method »

explains the effects of adrenaline (ADR) and DTE trachea cut to a spiral and the right one Auricle of the guinea pig. Both preparations were taken from the same animal and examined under the same experimental conditions ·

Figure 3 shows the effect of adrenaline (ADR), noradrenaline (NA) and isoprenaiine (IPR) on spiral cut Trachea and right auricle of the heart from the xteerschweinclien Both specimens were taken from the same lier been uriu were under identical experimental Conditions examined

Figure ^ f shows the effects of adrenaline (ADR) and DIE spiral cut trachea and right atrium from the guinea pig “Both preparations were taken from the same animal and were taken from identical experimental bediiBingen investigated.

Figure 5 illustrates the effects of adrenaline (ADR) and DTE on the speed and power of isolated rabbit hearts. .

Figure 6 illustrates the effect of adrenaline (ADR.) «DIS AND DTE on speed and power of isolated »rabbit heart ·

- 36 BAD OHiQlNAl.

109840/1733

As can be seen from Figure 2.! It was found that 1- (3 »5 dihydroxyphenyl) -2- (tert-butylaniino) ethanol (DTE) provides bronchodilation without cardiac stimulation. For comparison, the effect of noradrenaline (NA), isoprenaline (! PR) and T- (3,5-dihydroxyphenyl) -2 ~ (isopropylamino) ethanol (DIE) on this preparation is shown in FIGS. 3 and k. Norepinephrine, which is a weak bronchodilator, stimulates the heart muscle without affecting the bronchial muscles. As can be seen from Fig. K , isoprenaline and DIE are strong heart-stimulating substances against their bronchodilator action.

The heart-stimulating effect was also demonstrated on isolated rabbit hearts (Langendorff preparation) studied »As in Figure 5 one can see the heart accelerating effect of the compound according to the invention low and only about 1/50 that of Adrenaline. The effect of DIE on such a preparation is shown in fig. The heart accelerating effect of this agent was determined to be about a quarter of that of adrenaline in this experiment. The heart-stimulating effect of the Cycloalkyl-substituted compounds according to the present invention Invention was of the same magnitude as observed for the alkyl substituted compounds. Accordingly, had 1— (3 ι 5 ~ dihydroxyphenyl) -2- (cyclobutylamino) -ethanol a heart- stimulating effects that are less than the Ö, 1 times that of those of adrenaline scam.

Example 10

Toxicity determinations

The toxicity of 1- (3, 5 -dihydroxyphenyl) -2- (tert-butylamino) -

109840/1733 - 37 -

1643298

Ethanol (DTE) for mice after intravenous (i.v.), subcutaneous (s.c.) and oral administration is listed in Table I. For comparison, the corresponding LD ,, «for l- (3 > 5 -

Dihydroxyphenyl) -2-isopropylian ( _{O) ethanol (DIE) listed o}

TABLE Γ ;

Acute toxicity in mice

Compound administration ^ LDj. (mg / kg), number of animals

_ Mice_ (Base) _ / __ ~ -L *

DIE - i.v. 47 25

DJS i.v. SO .25

orally 3200 i.v. SO s.c. 295 orally 4800

'■ According to Engelhardt et al, Arzneimittelforschung 11, (1961), Pages 521 to 525 »

The toxicity determinations of the cycloalkyl compounds according to the present invention were also carried out and showed that these compounds, also in this respect, are comparable to open-chain alkyl derivatives. LB., (± * v ») for 1 -» (3 ¹ 1 5 ¹ -Oiliydroxyphenyl) -. 2- (eyclobutylaitiiho) -ethanol in mice is 54 mg / kg

The compounds of the present invention have a favorable ratio of cardiac stimulation to bronchospasmolytic Activity «This unexpected property makes it particularly suitable for the treatment of bronchial paatiasis

Symptoms such as asthma and other related ailments, that act on the respiratory system

The following examples explain how the compounds of present invention can be incorporated into pharmaceutical preparations.

Example 11

Aerosol for Inhalation Active Substance "

Frigen® 11/12/113/114

1.00 g

0.20 g

to 100.0 g

Example 12

Tablets

Each tablet contains: active substance corn starch P lactose gelatin talc
Magnesium stearate

20.0 mg

25.0 mg

190 _r 0 mg.

l _r 5 I ¹¹ S 12.0 mg

1.5

250.0 mg

Example 33

Suppo sitort υπ

Each suppository contains!

Active substance

20.0 mg

- 39 -

Ascorbyl palmitate Suppository base (irahausen Η) 1.0 mg 2000.0 mg

example Ik

Syrup

Active substance liquid glucose sucrose

A s c ο rb i η acid e sodium pyrosulphite Disodium edetate orange essence allowed color purified water 0.200 g 30.0 © 50.0 g

0.1 g * 0.01 g

0.01 g

0.025 g

0.015 g to 100.0 g

Example 15

In.j ection solution Active substance Sodium pyrosulphite Disodium edetate Sodium chloride Sterile water for injection 0.500 mg 0.500 mg 0.100 mg 8, 500 mg at 1.00 mn

Example 16 Inhalation solution Active sub st an ζ sodium pyr ο sulfite disodium edetate sodium chloride

5.00 g 0.10 g

0.10 g 0.85 g

1098 40/1733 - ko -

purified water to 100.0 ml

Example 17 Solution for rectal administration (rectal ampoule)

Active substance 20.0 mg

Sodium pyrosulfite 1.5 mg

Disodium edetate 0.3 mg

sterile tapping water to 3.0 ml

Example 18 Sublingual tablets

Each tablet contains «

Active substance lactose

Agar

talc

5.0 mg 85.0 mg 5.0 mg 5.0 100.0 mg

Example 19 plug

Active substance 2.00 g

Ascorbic acid 1.00 g

Sodium pyrosulfite 0.10 g

Disodium edetate 0.10 g

liquid glucose 50.00 g

absolute alcohol 10.00 g purified water to 100.0 al

1 09840 / -VT13

Claims (1)

P at β η ta η SP r ii che 1 ») Compound of the general formula CH - CH2 - N« R OH H and physiologically acceptable acid addition salts thereof, * in which R is one of the groups in which η is an integer from 0 to 3 and R is a "hydrogen atom, methyl or ethyl group, and R is a hydrogen atom or an aliphatic alkyl group with up to 5ί carbon atoms" means "2"). tert-toutylamino) ethanol or i- (3, 5 -Dihydroxyphenyl-a-icyclQbutylaminoJöthanol, 3.) Process for the preparation of a compound of the general formula 109840/171 ^ / OH - CH2 - N - RH in which R is one of the groups, CHr / CH3 1 - CIr, - Ct- * CH ", - means in which η is an integer from 0 to 3 and R is a hydrogen atom or a methyl or ethyl group, and R is a hydrogen atom or an easily replaceable by hydrogen ( jruppe means, or of their physiologically acceptable acid addition salts, dadu rch marked that one 1.) a diketo compound of the general formula in the presence of an amine of the general formula H ₂ H - B 109840/1733 reduced by methods known per se and then optionally R " exchanged for hydrogen ^ or 2,) a compound of the general formula R ³ O R ³ O - CH - CH, with a compound of the general formula HN-R to form a compound of the general formula R ³ O R ³ O OH - CH ₂ - N - R 3 . L · converts and then if necessary «the groups R and R against water Substance exchanges or 3,) a compound of the general formula R ³ O ^ K -ι - ^m z - N - R > 0 R ^Z R ³ O- 10S840 / 1733 with formation of a compound of the general formula OH - CH ₂ - N - R I * nadi methods known per se reduced and then optionally R 4th and R exchanges for hydrogen, where in the above formulas R is a hydrogen atom or a mono- or bicyclic aralkal group means having no more than 11 carbon atoms. 4.) The method according to claim 3 »characterized in that one 3 compounds used in which the group R is an alkyl or Acyl group with no more than 5 carbon atoms, a mono- or a bicyclic aralkyl group having not more than 11 carbon atoms, a benzyl or naphthylmethyl group. 5 ·) Process for the preparation of a compound of the general formula -CH- CH ₂ - OH PH,) 2'n where η is an integer from 0 to 3, characterized in that that one is a compound of the general formula 109840/1733 after hydrogenation with a cyclic ketone of the general formula O = C-JCH ₂ ) _n 'CH ₂ reacted, whereupon the resulting reaction mixture is subjected to further hydrogenation, afterwards the groups R if necessary through 3
Hydrogen can be replaced, where R is a hydrogen atom or a group that can easily be replaced by hydrogen, namely an alk, Si or acyl group with no more than 5 carbon atoms, a mono- or bicyclic aralkyl group with no more than 11 carbon atoms, a benzyl or naphthylmethyl group, means. 6.) Means for the treatment of bronchospasm, marked by a content of at least one compound of the general formula - CH - CH ₂ -N- R OH H wherein R is one of the groups CHn R 3 ( , - C-CH ₃ , - CH C ₂ H ₅ 1 0 9 8 Λ 0/17 33 originally inspected is, where R ° is a hydrogen atom, a methyl or ethyl 3 is a group and η is an integer from 0 to 3, and R is a Hydrogen atom or an aliphatic ^ acyl group with not is more than 5 carbon atoms, or a pharmaceutically acceptable acid addition salt of such a compound in Combination with a pharmaceutical carrier. 7o) means according to claim 6, characterized in that it is in the form a suspension, emulsion, syrup, powder, tablet, capsule, coated tablet, spray liquid, inhalation liquid, a suppository or injectable solution. 8.) Composition according to claim 6 and 7 »characterized in that it is in the form of dosage units. 9 ·) means according to claim 6 to 8, characterized in that the pharmaceutical carriers in addition to tableting auxiliaries, Taste-improving agents, suspending or dispersing agents, stabilizing agents, sterile water which is free from temperature enhancing substances is, oil or oily emulsions or suppository bases receives. 1 098A0 / 1733 L e r s e i t e