DE2013256B - - Google Patents

Description

CH ₂ CH ₂ gates in the bronchial muscles, which is probably due to the fact that the / S receptors in these two otganes are not identical.

The compounds of the above general formula and their therapeutic. receives compatible salts one in a manner known per se by reducing a compound of the general formula II

wherein R is a hydrogen atom or an aliphatic Acyl group with 2 to 5 carbon atoms and their therapeutically acceptable salts.

to R ¹ O

OC ₂ H ₅ CH ₂ -CH ₂

C-CH-N-CH

R ² CH ₂ -CH ₂

The present invention relates to AniinobulaKol derivatives, those in the treatment of bronchospastic diseases of various origins, in particular Asthma, which are effective, which is the general formula

RO

RO

- CH-N-OH H

/
CH

CH ₃ -CH,

(I)

wherein R is a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms means, and their therapeutically acceptable salts, bs is a large number of N-substituted 1- (3,4-dihydroxyphenyl) -2-aminopropane-cene and butanols with bronchospasmolytic activity are known, but compounds of this type are used with the two Hydroxyl groups of the benzene ring in the 3,4-position im Organism attacked by certain enzymes, for example catechol-O-methyltransferase ("COMT"), which is found in the liver, among other things. This attack will disable the connection. Therefore, substances of this type only have a short duration of action. Connections with the two hydroxyl groups in the 3,5-position of the beiizole ring are not attacked by »COMT«. Some compounds of this latter type are known. Among the known compounds is

wherein R ^{1 is} a hydrogen atom or a protecting group such as an alkyl group having not more than 5 carbon atoms such as methyl and ethyl, an acyl group

with 2 to 5 carbon atoms or a mono- or bicyclic araliphatic «: group with not more than 11 carbon atoms, such as benzyl or naphthylmethyl, and R ² denotes a hydrogen atom or a mono- or bicyclic aralkyl group with not

25 means more than 11 carbon atoms, whereupon, rails required, the substituent R ^{1 is converted} in the usual way into the substituent R and R ^{2 is} replaced by hydrogen. The reduction of the compound of general formula II may Example-CH ₂ -CH ₂ 30 as

a) by catalytic reduction, for example with Raney-NicVel or with palladium-carbon or Platinum oxide, or

b) by chemical reduction, such as with lithium aluminum hydride or sodium borohydride, in which case R ¹ must be a group protecting the hydroxyl group, or

c) be carried out by chemical reduction of the carbonyl group, such as with lithium aluminum hydride or sodium borohydride, whereupon the groups R ¹ and R ² protecting the hydroxyl group are removed by catalytic reduction, for example with palladium-carbon or platinum oxide.

HO

HO

CH ₃
CH-CH-NH-CH

I I \

OH CH ₃ CH ₃

to mention.

A compound of the above formula is described in British Patent Specification 920,623.

The compounds according to the invention now show a long duration of action and only a very weak one Effect on the heart. This valuable and surprising property coii; b'nation means that the Compounds according to the present invention have a different affinity for the / ^ receptors in the Heart muscle versus the affinity to the /? - recipe

If in the general formula II R ^{1 is} an alkyl group, this can be achieved by ether-splitting agents, for example with boron tribromide, at low temperature or by heating with hydrogen halide

acid can be exchanged for hydrogen. ^{If R 1} in the general formula II is an acyl radical, this can be split off by treatment with acids. ^{If R 1} and R ^{2 are} aralkyl groups in the general formula II, these can be removed by hydrogenation.

If R ^{1 is} an araliphatic protecting group, such as benzyl, it can be split off by catalytic hydrogenation at the same time as the reduction of the carbonyl group. One obtains in analogy to

other syntheses in this field use the erythro or threo form or a mixture thereof. the Erythroform is the active form in the treatment of bronchospastic diseases.

When R is an aliphatic acyl group with 2 to 5 carbon atoms, compounds are obtained which are practically as effective in pharmacological terms as the corresponding compounds in which R represents a hydrogen atom.

The compounds of the invention have two asymmetric carbon atoms and are therefore in two diastereoisomeric forms exist, each of which in principle for the separation of an amine known manner can be isolated and separated, and therefore the invention is intended to include this.

The racemate obtained in the above reactions can be separated into the enantiomers by the free base is converted into a salt or an amide of an optically active acid, and from this the amine after the customary separation of the diastereoisomeric mixture thus obtained in a manner known per se releases again. The compounds in their optically pure form.

The compounds according to the present invention can also be used as a purified mixture of stereoisomers, how it z. B. obtained in the reaction sequence described above, can be used.

Starting materials of the general formula II can be obtained in any way. Some of the Possible ways are shown by the following reaction schemes:

Z ¹ O

HO

CH ₃ CH ₃

In the above formulas, Z ¹ preferably denotes an alkyl radical.

Z ² O

Z ² O

Z ² O

Z ² O

OC ₂ H ₅
C-CH-NH

/
-CH

CH ₂ -CH ₂

CH ₂ CH ₂

Z ² O

In the above formulas, Z ² preferably denotes an aralkyl radical.

The novel compounds of the present invention are good bronchodilator agents and only have a very weak heart-accelerating effect. The compound 1- (3,5-di-

hydroxyphenyl) -2-cyclopentylamino) butanol as a effective bronchodilator with a long duration of action, and when tested on the isolated Rabbit hearts, the heart accelerating effect is less than 0.001 that of adrenaline. The Ver-

The relationship between the heart-stimulating effect and the bronchodilating effect was also found on left atrium in the guinea pig that was electrically stimulated and in a spiral cut Tracheal specimen of the guinea pig demonstrated when both specimens are in the same bath were immersed. When the compound according to the invention was slowly introduced into the bath solution, bronchodilatation was obtained without any effect on the cardiac muscle preparation.

The new compounds according to the invention can be in the form of salts with physiologically compatible Acids are administered. Suitable acids that can be used are, for example Hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, tartaric acid, maleic acid or succinic acid.

The compounds according to the invention can be processed into pharmaceutical preparations, with they as an active ingredient at least one of the compounds according to the invention together with one pharmaceutical carrier material included. Such preparations can be used for oral, bronchial, rectal, parental

teral or topical administration may be provided.

For oral administration, a compound of the invention is in the form of the free base or a pharmacologically acceptable salt with a solid, powdered carrier material, such as lactose, sucrose, Sorbitol, mannitol, a starch like potato starch .. grain starch, corn starch or amylopectin, a cellulose derivative or gelatin mixed. Lubricants such as magnesium or calcium stearate can also be used or a polyethylene glycol wax, can be added, whereupon the mixtures become tablets or Dragee cores are pressed. When coated tablets

are necessary, the kernels can be coated with concentrated sugar solutions, for example, which contain gum arabic, talc and / or titanium dioxide, or they can instead with a varnish

be coated in a volatile organic solvent or mixture of organic Solvent is dissolved. Dyes can also be added to these coatings.

To produce soft gelatine capsules (pearly, closed capsules) made of gelatine and, for example, glycerine, or to produce similar closed capsules, the active substance can be mixed with a polyethylene glycol wax. Hard gelatine capsules can contain granules of the active substance with solid, powdered carrier materials such as lactose, sucrose, sorbitol, mannitol, starch (for example potato starch, corn starch or amylopectin), cellulose derivatives or gelatine, and also magnesium stearate or stearic acid. For rectal administration, the compounds may also eriindungsgemäßen gelatine rectal capsules are used which contain the active substance in admixture with a Polyäthylenglykolwachs in the form of suppositories which you active substance in admixture with a neutral fatty base, or. Each dosage form preferably contains 0.5 to 50 mg of the active ingredients.

Liquid preparations for oral administration can be in the form of solutions, suspensions or Emulsions are present which contain, for example, about 0.1 to 20 percent by weight of active substance and also, if desired, additives such as stabilizers, taste-improving agents and / or sweeteners.

Liquid preparations for rectal administration can be used in the form of aqueous solutions be that about 0.1 to 2 percent by weight of active substance and optionally also stabilizers and / or contain buffer substances.

For parenteral administration by injection, the carrier material can be a stable, parenterally compatible Liquid of polyvinylpyrrolidone or a parenterally compatible oil, such as arachis oil, be and optionally contain stabilizers and / or buffer substances. Dosage units of the solution may advantageously be enclosed in capsules, each dosage unit being preferred Contains 0.05 to 5 mg of active ingredient.

For the immediate treatment of the bronchial tubes, the preparations are advantageously in the form of a Spray solution or suspension. Appropriately, these contain 0.1 to 10 percent by weight of active substance.

The invention is further illustrated by the following examples.

example 1

1- (3,5-dihydroxyphenyl) -2-cyclopentylaminobutanol sulfate

55

The 1- (3,5-dibenzyloxyphenyl) -2-cyclopentylamino-butanol sulfate required as starting material was made as follows:

a) 21.9 g of 3 ', 5'-dibenzyloxy-2-bromobutyrophenone were dissolved in 50 ml of dry benzene and 9.4 g of cyclopentylamine were added. The reaction mixture was refluxed and stirred for 15 hours. The formed cyclopentylamine hydrobromide was filtered off (7.8 g). The benzene phase was evaporated and the remaining oil was dissolved in ether. The stirred ether solution was treated with 100 ml of 20% hydrobromic acid for 1 hour. The crystalline product formed was filtered off and washed with water and ether.
Yield 21.4 g, F. = 90 to 100 ^° C.

Analysis:

Calculated ... Br 15.2%;

found .... Br 15.4%.

b) 21.4 g of 3 ', 5' - dibenzyloxy - 2 - cyclopentylamino - butyrophenone hydrobromide were with Made alkaline with 10% aqueous sodium carbonate and the base extracted with ether. the Ether phase was washed with water and dried over magnesium sulfate and then evaporated. The remaining oil was dissolved in 50 ml of ethanol and 6.0 g of sodium borohydride was added. The stirred reaction mixture was heated on a water bath for 2 hours and then evaporated. After adding 50 ml of 5N sodium hydroxide solution, the base was extracted with ether. The ether phase became evaporated and the residue dried with ethanol / benzene.

Yield 16.6g.

10.0 g of this base was dissolved in ether and 100 ml of 2η-sulfuric acid was added, then was stirred for 2 hours. The crystalline product formed was filtered off and washed with water and ether washed.

F. = 91 to 92 ° C.

The product obtained above was then dissolved in 150 ml of glacial acetic acid and placed in a Parr hydrogenation apparatus hydrogenated at 50 ° C. and 5 atm pressure overnight. The catalyst was filtered off and that Evaporated filtrate. The residue was dissolved in water and evaporated once more to remove traces of Remove acetic acid.

Yield: 4.0 g.

This product was dissolved in water. After filtering, the pH was adjusted to 5.6 (pH meter) adjusted by adding 0.1 η sodium hydroxide solution. The aqueous phase was evaporated to dryness and the residue dried several times with ethanol / benzene. Absolute methanol became the residue given and the hardly soluble sodium sulfate filtered off. The methanol was evaporated and the Recrystallized residue from ethanol.

Yield 2.0 g; F. = 173 to 174 ° C.

The following examples explain the preparation of the acyl compounds.

Example 2

1- (3,5-Diacetoxyphenyl) -2-cyclopentylaminobutanol hydrochloride

The 3,5-diacetoxy-2-cyclopentylamino-butyrophenone hydrochloride required as starting material was made as follows:

3.0 g of 3,5 - dihydroxy - 2 - cyclopentylamino butyrophenone hydrochloride were suspended in 150 ml of acetonitrile, 3.1 g of acetyl chloride were added, and the mixture was refluxed for 18 hours. After evaporation of the reaction mixture the residue was dissolved in ethanol and crystallized with ether.

Yield 1.5 g (39% of theory); F. = 140 ° C (Kofler's heating bench).

0.5 g of the 3,5-diacetoxy-2-cyclopentylamino - butyrophenone hydrochloride obtained in this way were in

Dissolved 50 ml of ethanol and 0.2 g of 10% palladium carbon were added. The mixture was left in a Parr hydrogenation apparatus for 6 hours at 4 atmospheres Pressure hydrogenated. The catalyst was then filtered off and the filtrate was evaporated. The residue crystallized overnight and was washed with ether.

Yield 0.4 g (80% of theory), m.p. = 210 ⁰ C (Kofiersche Heizbank).

Example 3

1- (3,5-Diisobutyroxyphenyl) -2-cyclopentylaminobutanol hydrochloride

The 3,5-diisobutyroxy-2-cyclopentylamino-butyrophenone hydrochloride required as starting material was prepared as follows: 3.5 g of 3,5-dihydroxy-2-cyclopentylamino-butyrophenone hydrochloride were suspended in 150 ml of acetonitrile. 7.0 g of isobutyryl chloride was added and that The reaction mixture was refluxed for 6 days. The reaction mixture was then evaporated and the residue dissolved in ethanol. 1 liter of ether was added to this solution, and the mixture was left stand in a refrigerator overnight. This gave crystals.

Yield 2.7 g (46% of theory), m.p. = 170 ⁰ C (Kofiersche Heizbank).

2.0 g of the 3,5-diisobutyroxy-2-cyclopentylamino-butyrophenone hydrochloride thus obtained were dissolved in 100 ml of ethanol, and 0.3 g of lOVoige palladium carbon were added. The mixture was left in a Parr hydrogenation apparatus for 6 hours at 4 atmospheres Pressure hydrogenated. The catalyst was filtered off and the filtrate was evaporated. The residue crystallized overnight and was washed with ether.

Yield 1.7 g (85% of theory), melting point = 160 ° C (Kofler's heating bench).

The following examples illustrate application forms of the compounds according to the invention.

Example 4

Aerosol for inhalation

Active substance 1.00 g

Triglyceride mixture on the basis
saturated vegetable fatty acids of

Chain lengths C ₈ -C ₁₂ 0.20 g

Mixture of monofluorotrichloromethane, difluorodichloromethane,
1 ^ 2-trifluorotrichloroethane and
1,1,2 ^ -Tetrafluorodichloro ... 100.0g

Example 5

Tablets
Each tablet contains

Active substance 20.0 mg

Corn starch 25.0 mg

Lactose 190.0 mg

Gelatin 1.5 mg

Talc 12.0 mg

Magnesium stearate 1.5 mg

250.0 mg

Example 6 Suppositories Each suppository contains

Active substance 20.0 mg

Ascorbyl palmitate 1.0 mg

Suppository base to 2000.0 mg

Example 7 syrup

Active substance 0.200 g

Liquid glucose 30.0 g

Sucrose 50.0 g

Ascorbic acid 0.1 g

Sodium pyrosulfite 0.01 g

Disodium edetate 0.01 g

Orange essence 0.025 g

Acceptable dye 0.015 g

Purified water to 100.0 g

Example 8 Solution for injection

Active substance 0.500 mg

Sodium Pyrosulfite 0.500 mg

Disodium edetate 0.100 mg

Sodium chloride 8,500 mg

Sterile water for injections to 1.00 ml

Example 9 Inhalation solution

Active substance 5.00 g

Sodium pyrosulfite 0.10 g

Disodium edetate 0.10 g

Purified water to 100.0 ml.

Example 10

Solution for rectal administration (rectal ampoules)

Active substance 20.0 mg

Sodium pyrosulfite 1.5 mg

■ Edetate disodium 0.3 mg

Sterile water to 3.0 ml

Example 11 sublingual tablets Each tablet contains:

Active substance 5.0 mg

Lactose 85, T) mg

Agar 5.0 mg

Talc 5.0 mg

100.0 mg Example 12

drops

Active substance 2.00 g

Sodium pyrosulfite 0.10 g

Ascorbic acid 1.00 g

Disodium edetate 0.10 g

Liquid glucose 50.00 g

Absolute alcohol 10.00 g

Purified water to 100.0 ml

Pharmacological experiments
a) Bronchospasmolytic effect

The bronchospasmolytic effect of 1- (3,5-dihydroxyphenyl) - 2 - (cyclopentylamino) - butanol 5 was compared with that of the known compounds adrenaline, 1 - (3,4 - dihydroxyphenyl) - 2 - isopropylamino - Ethanol ("isoprenaline") (see British patent specification 920 623) and 1 - (3,5-dihydroxyphenyl) -2-isopropylamino - Propanol (see British patent specification 920 623) with a spiral cut windpipe of the Compared to guinea pigs according to the method originally described by Castillo and B e r (J. Pharmacol. Exptl. Therap., Vol. 90 [1947], p. 104) and later by Constantine (J. Pharm. Pharmacol, Vol. 17 [1965], p. 384). In this experiment the effect was 1 - (3,5 - dihydroxyphenyl) - 2 - (eydopentylamino) butanol about 0.6 times as strong as that of adrenaline. "Isoprenaline" was about 13 times in this attempt more effective than adrenaline. The erythroform of l- (3,5-dihydroxyphenyl) - 2 - isopropylamino - propanol was 0.040 times and its threoform 0.016 times as effective like adrenaline.

The in vivo effect of 1- (3,5-dihydroxyphenyl) -2 - (cyclopentylamino) butanol in protecting guinea pigs against bronchospasm was also tested when the guinea pigs were placed in a histamine aerosol. The compounds were injected intraperitoneally 15 minutes prior to aerosol treatment. Animals unaffected after being in the aerosol for 4 minutes were considered to be protected. The dose that protected 50% of the animals within 4 minutes in the aerosol was designated as ED _50. The effect of 1 - (3,5 - dihydroxyphenyl) - 2 - (cyclopentylamino) - butanol when administered orally was also examined. The results are compiled in Table I. "Isoprenaline" was used as the reference substance

Table I. connection

1- (3,5-Dihydroxyphenyl) -2- (cyclopentylamino) butanol
(according to the invention)

desgL

"Isoprenaline" (known)

administration

po
Lp.

1.9
1.8
0, Q7

The electrically stimulated auricle and the spirally cut trachea placed in the same bath in Krebs solution. Both preparations were from removed from the same animal. The compound to be examined was allowed to slowly run 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 was most effective on. Adrenaline, "isoprenaline" and 1- (3,5-Dihydroxyphenyl) -2-isopropylaminopropanol were used as reference substances adrenaline causes bronchodilation and heart muscle stimulation in the same concentration range. the Infusion was carried out for 10 minutes. After washing and recovering, the test solution was left in the same way as described above for adrenaline and for "isoprenaline", and the Effect of this agent on the two preparations could easily be compared with that of the three known comparison compounds. The results are listed in tables below. The effect of adrenaline on the heart muscle is given as 1.0.

Table II

40

ED ₅₀

mg / kg

Body weight

60

When tested in vivo according to Konzert Λ PJossler (Arch. Exp. Pharmao, vol. 195, p. 71 [1940 ·]) faridman the bronchospasmolytic effect after intravenous administration as about 0.07 times as great as that of "isoprenaline" when the The experiment was done on cats, and about 0.04 times that of "isoprenaline" when the experiment was done on dogs.

? i b) Effect on the, heart *; - ■>.

The relationship between the cardiac stimulating effect and the bronchodilator. Effect was studied in vitro on the left heart fortiof ^{r of} the guinea pig. To determine the effect on the heart and the effect on the bronchial muscles under identical

connection

1- (3,5-Dihydroxyphenyl) -2- (cyclopentylamino) butanol (according to the invention)

Erythroform of 1- (3,5-dihydroxyphenyl) -2-isopropylamino-propanol
(known)

Threoform of 1- (3,5-dihydroxyphenyl) -2-isopropylamino-propanol
(known)

"Isoprenaline" (known)

Adrenaline (known)

effect opposite to adrenaline

<0.001
0.0015

0.0016
12.9
1.0

The compound of the present invention had no effect on the dosed heart preparation up to 0.4 mg / ml.

The heart-stimulating effect was also demonstrated on the isolated rabbit heart (Langendorff preparation) examined. The heart accelerating effect of the compound according to the invention was very weak, less than 0.001 times that of adrenaline.

As the biological tests clearly show, the compound H has 3,5-dihydroxyphenyl) -2- (cyclopentylamino) butanol a very favorable ratio of cardiac stimulation to bronchospasmolytic activity This valuable and surprising property makes the compounds according to the invention special suitable for the treatment of bronchospastic diseases such as asthma and other similar ones! Conditions affecting the respiratory system.

c) toxicity test

(30 animals) were DieToxmtät of l- (3,5-dihydroxyphenyl) -2- (cyclo pentylamino) -butjmol in mice NaCl LD _S0 De subcutaneous administration determined value was 400 ± 30 mg / kg. In comparison, the LD ₅₀ for "isoprenaline sulfate" is intravenously 131 mg / kg and for adrenaline intravenously 2.5 mg / kg.

Claims (1)

Claim: Aminobutanol derivatives of the general formula RO RO OH C ₂ H ₅ CH ₂ -CH ₂ CH-CH-NH-CH