NO129626B - - Google Patents

Description

Analogy method for the preparation of bronchospasmolytically active cyclopentylaminobutanol derivatives.

The present invention relates to an analogical process

way to produce compounds that are effective for be-

action of bronchospastic conditions of various origins, especially asthmatic conditions. According to the invention, bronchospasmolytically active compounds are thus produced with the formula:

and therapeutically acceptable salts thereof, where R is hydrogen' or alkanoyl groups containing 2-5 carbon atoms.. V.-!') A large number of N-substituted 1*-( 3 1 . -, *t 1) are known -dihydroxyphenyl)-2-aminopropanols and butanols with bronchospasmolytic activity, but compounds of this type with the two hydroxyl groups in the 3,4 position in the benz ring are attacked in the organism by certain enzymes, e.g. catechol-O-methyitransferase (COMT).which . among other things is found in the liver. The compound will be inactivated due to such an attack and therefore substances of this type have a short duration. However, compounds with the two hydroxyl groups in the 3,5-position of the benzene ring are not attacked by COMT. Some compounds of this latter type are known. Among the known compounds are

which is described in British patent no.' 920,623.

It is surprisingly found that the compounds with

formula I combines long duration with a very weak effect on the heart. This valuable and unexpected combination of properties means that the compounds produced according to the invention show a different affinity to the γ-receptors in the heart muscle compared to the affinity of the 3-receptors in the bronchial muscles, and is probably due to the fact that the 6-receptors in these two organs are not identical.

According to the invention, the compounds with the above formula I are obtained by a compound with the formula:

where R is hydrogen, alkyl groups with at most 5 carbon atoms, acyl groups with at most 5 carbon atoms or mono- or bicyclic

2 aralkyl groups with a maximum of 11 carbon atoms, and where R is hydrogen or mono- or bicyclic aralkyl groups with a maximum of 11 carbon atoms

atoms, is reduced to form a compound with

the formula

1 2

where R and R have the meanings given above, after which,

if necessary, the compound of formula III, if R is an alkyl group, is reacted with an ether-cleaving agent; if R"*"

is an acyl group, treated with, an acid; and if R and/or R are aralkyl groups, subject to hydrogenolysis, - for replacement

of these groups with hydrogen, after which, if desired, the resulting compound of formula I is resolved into its optical isomers, and/or converted into therapeutically acceptable salts thereof.

The reduction of the compounds of formula II can

is carried e.g.

a.) by catalytic reduction, e.g. with Raney nickel, palladium charcoal or platinum oxide, or b) by chemical reduction, e.g. with lithium aluminum hydride or sodium borohydride, R<1> then being a hydroxy-protecting group, or

c) by chemical reduction of the carbonyl group, e.g.

with lithium aluminum hydride or sodium borohydride, after which the •12.. hydroxy protecting groups R and R are removed by catalytic reduction, e.g. with palladium charcoal or platinum oxide.

If R"<*>" in formula II is an alkyl group, . this can be replaced with hydrogen by ether-releasing agents, e.g. by using boron tribromide, at low temperature or by heating with hydrogen halides. If R1 in formula II is an acyl residue, this can be cleaved off by treatment with acids. If R and/or R 2 i . formula II is aralkyl, these groups can be removed by hydrogenolysis.

When R 1 is an araliphatic group such as benzyl, the

it is split off by - catalytic hydrogenation at the same time as reducing

tion of the carbonyl group. The erythro or threo form or a mixture of these is thereby obtained in an analogous manner to other syntheses in this area. The erythroform is the active form in the treatment

of bronchospastic conditions.

When R is an alkanoyl group containing 2-5 carbon atoms, compounds are obtained which in pharmacological terms are practically as effective as the corresponding compounds where R is hydrogen.

The compounds produced according to the invention have two asymmetric carbon atoms and exist in two diastereoisomeric forms, each of which can be isolated and cleaved using any method known per se for cleaving an amine.

The racemate obtained by the above reactions can be easily resolved into their enantiomeric compounds by converting the free base into a salt or amide of an optically active acid and regenerating the amine after the usual separation of the diastereoisomeric mixture thus obtained.

The starting materials of formula II can be obtained in any desired manner. Some of the possible methods appear from the following reactions: ,

In the above formulas, Z₂" is preferably a protecting aliphatic group.

In the formulas given above, Z 2 is preferably a protecting araliphatic group.

The new compounds produced according to the invention are good bronchodilators and have only a very weak cardioaccelerating effect. The compound 1-(3<1>, 5^-dihydroxy-phenyl)-2-(cyclopentylamino)-butanol has thus been shown to be a powerful bronchodilator with a long-lasting effect and when tested on an isolated rabbit heart, the cardioaccelerating effect is less than 1 /1000 of it to adrenaline. The relationship between the cardiac stimulating effect and the bronchodilatory effect has also been demonstrated on electrically stimulated heart chambers from guinea pigs and spirally cut tracheal preparations when both preparations were added to the same bath. When the compound of formula I was slowly infused into the bath solution, bronchodilation was achieved without any effect on the heart muscle preparation.

The new compounds can be administered in the form of salts with physiologically acceptable acids. Suitable acids that can be used are e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, furmaric acid, citric acid, tartaric acid, maleic acid or succinic acid.

The prepared compounds can be used in preparations intended for oral, bronchial, rectal, parenteral or topical administration.

For the production of pharmacological preparations in the form of dosage units for oral use containing a compound of formula I in the form of the free base, or a pharmacologically acceptable salt thereof, the active ingredient can be mixed with solid powdered carrier, e.g. lactose, sucrose, sorbitol, mannitol, starch such as potato starch, corn starch or amylopectin, a cellulose derivative or gelatin, and may also include lubricants such as magnesium or calcium stearate or a "Carbowax or other polyethylene glycol waxes and compressed into tablets or cores for dragees. If dragees are to be produced, the cores can be coated with, for example, concentrated sugar solutions which may contain gum arabic, talc and/or titanium dioxide, or they;''can alternatively be coated with a ,1-ak dissolved in volatile '■ /" organic solvents or mixtures of such solvents. Dyes can be added to these coatings.

In the production of soft gelatin capsules (pearl-shaped closed ''■' capsules) consisting of gelatin and e.g. glycerol',''éTlér<:>'like closed -capsules, > can '-the active-'f brbihdelse- be mixed with a "Carbowax'^"...Hard gelatin capsules can•contain granules of '• the - active compound together :with solid powdered carriers such as -lactose, sucrose, sorbitol, mannitol, starch (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin, and may also contain -magnesium stearate or stearic acid. Dosage units for rectal use can be in the form of suppositories comprising the active compound in admixture with a neutral fatty base, or rectal capsules of gelatin comprising the active compound in admixture with a Carbowax ® or other polyethylene glycol waxes. Each dosage unit preferably contains 0.5-50 mg of the active compound.

Liquid preparations for oral use can be in the form of solutions, suspensions or emulsions, e.g. containing from approx. 0.1 to 20' weight-5? of the active compound and also, if desired, such auxiliaries as stabilizers, flavors and/or sweeteners.

Liquid preparations for rectal administration can be 1 form of aqueous solutions containing from approx. 0.1 to 2% by weight of the active compound and also, if desired, stabilizers and/or buffer substances.

For parenteral application by injection, the carrier can be a sterile, parenterally acceptable liquid, e.g. pyrogen-free water or an aqueous solution of polyvinylpyrrolidone, or a parenterally acceptable oil, e.g. arachis oil and possibly stabilizing agents and/or buffer substances. Dosage units in the solution can advantageously be enclosed in ampoules where each dosage unit preferably contains from 0.05 to 5 mg of active ingredient.

For administration to the bronchi is preferred

a spray solution or suspension. This contains

preferably from 'G:, 1 to '10 weight-% active' component.' ""

Discover innéTsén; illustrated by the following examples. Example :.T'." ' Forward tilling of' 1'-'( 3^5^-dihydrbxyph enyl) - 2 - ( cyclb-

pentylamino).-. butanol sulfate;...

: 21,, 4 g of ,3.^,5^-dibenzyl oxy- 2-cyclopentylami>no-butyro-•:>> phenone hydrobromide.- was^.made alkaline - with 10% mand sodium carbonate and the base was 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. ethanol pg- 6.0 g of sodium borohydride was added. The stirred reaction mixture was heated on a water bath for tp hours and then evaporated. After addition-; of 50 ml of 5 N sodium hydroxide solution, the base was extracted .. with ether.. The ether phase was evaporated and the residue - dried with ethanol/.. benzene, yield 16.6 g.

10.0 g of this base was dissolved, in. ether- and. 100 ml. - ■ 2 N sulfuric acid was added and stirring was carried out for two hours.

The crystalline product obtained was filtered off and washed with water and ether. Melting point 91°-92°C.

1-(31»51-dibenzyloxyphenyl)-2-cyclopentylaminobutanol-: sulfate was dissolved in 150 ml of glacial acetic acid and hydrogenated in a Parr-. pressure reaction apparatus at 50°C. and a pressure of 5 atmospheres above . the night. The catalyst was filtered off and the filtrate evaporated. The residue was dissolved in water and re-evaporated to remove traces of glacial acetic acid. Yield 4.0 g. This product was dissolved in water. After filtration, the pH value was adjusted to 5.6 (pH meter) with the addition of 0.1 N sodium hydroxide solution. The water phase was evaporated to dryness and the residue dried several times with ethanol/benzene. Absolute methanol was added to the residue and partially soluble sodium sulfate was filtered off. The methanol was. evaporated and. the residue crystallized from ethanol. Yield 2.0 g, melting point 173°-174°C.

The starting material used was obtained as follows: Preparation of 3<1>,5"'"-dibenzyloxy-2-cyclopentylaminobutyrophenone hydrobromide

21.9 g of 3"'"J5"''-dibenzyloxy-2-bromobutyrophenone was dissolved in 50 ml of dry benzene and 954 g of cyclopentylamine was added. The reaction mixture was refluxed and stirred for 15 hours. The cyclopentylamine hydrobromide formed at react

The reaction was filtered off, yield 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 one hour. The crystalline product obtained was filtered off and washed with water and ether. Yield 21.4 g, melting point 90°-100°C. Br" (calculated) = 15.2%, Br" (found) =15.4$.

Example 2. Preparation of 1-(3<1>,5^-diacetoxyphenyl)-2-cyclopentylamino)butanol hydrochloride

°>5 g of 3<1>»5<1_>diacetoxy-2-cyclopentylamino-butyro-phenone hydrochloride was dissolved in 50 ml of ethanol and 0.2 g of 10%

Pd/C was added. The mixture was hydrogenated in a Parr pressure reactor for 6 hours at 4 atmospheres. The catalyst was filtered off and the filtrate evaporated. The residue crystallized overnight and was washed with ether. This gave a yield of 0.4 g (80%), m.p. 210°C (Kofler heating bench).

The starting compound used was obtained as follows: 3.0 g of 3^,5^-dihydroxy-2-cyclopentylamino-butyro-phenone hydrochloride was suspended in 150 ml of acetonitrile, 3.1 g of acetyl chloride was added and the mixture was refluxed for 18 hours. After evaporation, the residue was dissolved in ethanol and crystallized with ether. Yield: 1.5 g (39%), m.p. 140°C (Kofler heating bench).

Example 3. Preparation of 1-(3<1>,5<1->diisobutyroxyphenyl)-2-(cyclopentylamino)-butanol hydrochloride

2.0 g of 3"^,5<1>"-diisobutyroxy-2-cyclopentylamino-butyrophenone hydrochloride was dissolved in 100 ml of ethanol and 0.3 g of 10% Pd/C was added. The mixture was hydrogenated in a Parr pressure reactor for 6 hours at 4 atmospheres. The catalyst was filtered off and the filtrate evaporated. The residue crystallized overnight and was washed with ether. This gave the desired compound in a yield of 1.7 g (85%), m.p. l60°C (Kofler heating bench).

The starting compound used was obtained as follows: 3.5 g of 3<1>,5<1_>dihydroxy-2-cyclopentylamino-butyrophenone hydrochloride was suspended in 150 ml of acetonitrile, 7.0 g of isobutyryl chloride was added and reflux was carried out for 6 days. The mixture was evaporated and the residue dissolved in ethanol and 1 liter of ether was added, after which the whole was placed in a refrigerator overnight. This resulted in the precipitation of crystals. Yield: 2.7 g (46%), m.p. 170°C (Kofler heating bench). Pharmacological trials

a) Bronchospasmolytic effect

The bronchospasmolytic effect of 1-(31,5-dihydroxy-phenyl)-2-(cyclopentylamino)-butanol was compared with that of the known compounds adrenaline and 1-(3<1>,5<1_>dihydroxypheny1)-2- (i-propylamino)-ethanol (isoprenaline) on spirally cut guinea-pig trachea according to the method originally described by Castillo and Bey (J.Pharmacol.Ezptl.Therap. 90 (1947), 104) .and later modified by Constantine ( J. Pharm. Pharmacol. 17 (1965) 384). In this experiment, the effect of 1-(3<1>,5<1->dihydroxyphenyl)-2-(cyclopentylamino)-butanol was about 0.6 times the effect of epinephrine - Isoprenaline was in this experiment about 13 times more effective than epinephrine . The in vivo effect of 1-(3<1>,5<1->dihydroxyphenyl)-2-(cyclopentylamino)-butanol was studied for the protection of guinea pigs against bronchospasm when the compound was placed in a histamine aerosol. The compounds were injected i.p. 15 minutes before the aerosol treatment. Animals that were not affected after 4 minutes of exposure to the aerosol were considered protected. The dose that protected 50% of the animals after a 4-minute stay in the aerosol was designated ED 50. The effect of 1-(31,5^-dihydroxy-phenyl)-cyclopentylamino-butanol given per os was also studied. The results are given in Table I. Isoprenaline was used as a reference compound.

When testing in vivo, according to Konzett. & Rossler, (Arch. .. Exp. Path, Pharmak. 1.95 71 (1940)) it was found that the bronchospasmolytic. effect after i.v. administration was approx. 0.07 times that of isoprenaline, when tested on cats and approx. 0.04 times that of isoprenaline when tested on dogs.

b) Effect on the heart

The relationship between the pacemaker effect.and'

the bronchodilator effect, was studied in vitro on the left. heart chambers for guinea pigs. To compare the effect on heart and the effect on bronchial muscles under identical experimental conditions, both the anterior chamber, electrically stimulated, and the helical trachea were placed in the same bath in Kreb's solution. Both preparations were taken from the same animal. The compound to be investigated was slowly infused into the bath solution. In this way, the concentration of the compound was slowly raised and that. was easy to observe on which muscle the compound was most effective. Adrenaline and isoprenaline were used as reference substances. Adrenaline causes bronchodilation and cardiac muscle stimulation in the same concentration range. Infusion was made during. 10, minutes... After washing and recovery, the test solution was infused in the same manner as described for. adrenaline•and isoprenaline and the effect on the two preparations of this agent could easily be compared with that of adrenaline and isoprenaline. The results are set out in Table II below. The impact. of adrenaline on the heart muscle is given the value 1.0.

It was found that the compound prepared according to the invention did not give. any effect on the cardiac preparation in doses up to 0.4 mg/ml.

The cardiac stimulating effect was also studied on isolated rabbit heart (Langendorff preparation). The cardiac-accelerating action of the compound of formula I was found to be very high

weak, less than 0.001 times that of adrenaline.

This means that the main compound according to the invention has a much weaker heart-accelerating effect than e.g. the compounds described in Norwegian patent 124,723, dys. compounds with the formula:

where R is hydrogen or alkanoyl with no more than 5 carbon atoms. The compound with the above formula where R is hydrogen has

a heart-accelerating effect which is 1/50 of the effect of adrenaline (cf. page 17? line 11 of Norwegian patent 124,723) and this compound thus produces more than 20 times stronger side effects on the heart than the main compound obtained according to the present invention .

Corresponding comparison with regard to the desired bronchospasmolytic effect shows that the above-mentioned compound according to Norwegian patent 124,723 is at most three times more effective than the main compound obtained according to the present invention, which combined with the above data means that the latter compound has a better bronchoselective effect.

This valuable and unexpected property makes the compounds prepared according to the present invention particularly suitable: for the treatment of bronchospastic conditions, such as asthma and other related diseases affecting the respiratory system.

c) Toxic test

The toxicity of 1-(3<1>,5<1->dihydroxyphenyl)-2-(cyclopentylamino)-butanol to mice (30 animals) after subcutaneous administration was determined, and the LDj-q value was found to be 400 -•30 mg/kg.

Claims (1)

Analogous method for the preparation of bronchospasmolytically active compounds with the formula: where R is hydrogen or alkanoyl groups with 2-5 carbon atoms, and therapeutically acceptable salts thereof, characterized in that a compound with the formula: where R"*" is hydrogen, alkyl groups with up to 5 carbon atoms, acyl groups with up to 5 carbon atoms or mono- or bicyclic aralkyl groups with up to 11 carbon atoms, and where R 2 is hydrogen or mono- or bicyclic aralkyl groups with up to 11 carbon atoms, is reduced to form a compound with the formula: 12 .. where R and R have the meanings given above, after which, if necessary, the compound of formula III, if R<1> is an alkyl group, is reacted with an ether-cleaving agent; if R<1> is an acyl group, treated with an acid; and if R 1 and/or R 2 are aralkyl groups, subject to hydrogenolysis, to replace these groups with hydrogen, after which, if desired, the obtained compound of formula I is resolved into its optical isomers, and/or converted into therapeutically acceptable salts thereof.