DE2013256A1 - Aminobutanol derivatives and processes for their preparation - Google Patents

Description

Dr. Hans-Heinrich Willrath Dr. Dieter Weber

PATENT LAWYERS Telegram address: WILLPATENT Postal check: Frankfurt / Main 6763 Bank: Dresdner Bank AG. Wiesbaden

Account No. 276 807

D - 62 WIESBADEN March 16, 1970 P.O. Box 1327 Ιΐ / βρ

Gustav-Freytag-StrsSe Φ (06121) 87 27

Astra AEL 197 -

Aktiebolaget Draco, Dag Hammarskjölds väg 7, 223 6k Lund / Sweden

Amlnobutanol derivatives and processes for their preparation

Priority t April 1, 1969 in Sweden Note No. i 4675/69

The present invention relates to compounds useful in the treatment of bronchospastic conditions of various origins, particularly asthmatic conditions, are effective di · making these compounds as well their use for therapeutic purposes. In particular, the present invention relates to bronchospasmolytic active compounds of the general formula

H-CH-K.-CH H

, CH ₀ ·· »CH»

CH ₂ -CH ₂

0Ö98U / 19S5

and therapeutically acceptable salts thereof, wherein R represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms.

There is a large number of N-substituted 1- (3, 4-dihydroxyphenyl) -2-am ± nopropanols and -butanols with bronchospaemolytic activity known, but compounds of this type with the two hydroxyl groups in the 3,4-position of the benzene ring in the organism attacked by certain enzymes, such as catechol-O-methyltransferase, COMT, which is found in the liver, among other things. Because of this attack the compound is inactivated and therefore substances of this type have only a short duration of action. Compounds with the two hydroxyl groups in the 3.5 position of the benzene ring, however, are not used by COMT attacked. Some compounds of this latter type are known. Among the known connections is

H-CH-HH OH CH.

A compound of the above formula is known Patent 920,623 described.

0098U / 19S5

According to the present invention has now surprisingly found that a compound of the general formula

CH ₂ - GH ₂

CH ₂ - GH ₂

and their therapeutically acceptable salts, in which R has the above meaning, have a long duration of action a very weak effect on the heart. This valuable and surprising combination of properties means that the compound according to the present invention has a different affinity for the has ß-receptors in the heart muscle compared to the affinity for the ß-receptors in the bronchial muscles,

which probably depends on the fact that the m

ß-receptors in these two organs are not identical are.

These advantages are obtained in accordance with the present invention by preparing a compound of Formula I above and therapeutically acceptable salts thereof by reducing a compound of the general formula

-009844 / -195S

where R. is a hydrogen atom or a protective group, such as an alkyl group with not more than 5 carbon atoms, such as methyl and ethyl, an acyl group with not more than 5 carbon atoms or a mono- or bicyclic araliphatic group with no more than 11 Carbon atoms, such as benzyl or naphthylmethyl,

2
and R denotes a hydrogen atom or a mono- or bicyclic aralkyl group having not more than 11 carbon atoms, whereupon, if necessary,

1 2

R is replaced by R and R is replaced by hydrogen. The reduction of the compound according to formula II can, for example

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

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

c) by chemical reduction of the carbonyl group, as in

009844/1955

-J-

For example, be carried out with Llthlumalumlnlumhydrld or sodium borohydride, whereupon the hydroxyl group

1 2

protecting groups R and R by catalytic reduction, such as with palladium carbon or Platinum oxide.

If Inder formula II R is an alkyl group, this can -

by, ether-splitting agents, for example Bortri bromide, at low temperature or by heating

exchanged for hydrogen with hydrohalic acid " will. If in the formula II R is an acyl radical, can this can be split off by treatment with acids.

12th If in formula II R and R are aralkyl groups, these can be removed by hydrogenolysis.

When R is an araliphatic protecting group, such as benzyl, is, it can be split off by catalytic hydrogenation at the same time as the reduction of the carbonyl group. In analogy to other syntheses, one obtains this area the erythro- or threo-form or a mixture the same. The erythrocyte form is the most active form in the treatment of bronchospaetic conditions.

If 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 compound · «, where R« is in hydrogen atoin means.

0098U / 19SS

The compounds according to the invention have two asymmetric carbon atoms and are therefore in two diastereoisomeric forms, each of which are known in principle for the resolution of an amine Manner can be isolated and separated, and therefore the invention is intended to encompass this too.

The racemate obtained in the above reactions can be separated into the enantiomers by the converts the free base into a salt or an amide of an optically active acid and the amine according to the usual Separation of the resulting diastereoisomeric mixture regenerated.

The compounds of the present invention can either be obtained as a purified mixture of the Stereoisomers, as it is obtained in the reaction sequence described above, or as products of any another reaction sequence for the preparation of the compounds, which also leads to a stereoisomeric mixture, which contains the or di «biologically active isomer can be used.

Starting materials of Formula II can be obtained in any desired manner. Some of the possible Paths are shown by the following reaction schemes!

- 7 0098U / 195S

Z ¹ O. —C - CH ..! U: Z ¹ O " f T

- CHBr

■ /.

Z ¹ O.

- CH - NH- *

(f yC - CH - NH

Hey

CH ₂ - CH ₂

In the above formulas, Z preferably denotes an aliphatic protecting group.

• r ^ -i

¹ C

CH - KH - CH

Z ² O '

-CH

IH ₂ - CH ₂

00984A / 19S5

2
Xn in the above formulas, Z preferably denotes a

araliphatic protecting group.

The new compounds of the present invention are good agents for bronchodilation and only have a very weak heart-accelerating effect. Proved so
the compound 1- (3 »5-dihydroxyphenyl) -2- (cyclopentylamino) -butanol proved to be an effective bronchodilator with a long duration of action, and in the trial
on the isolated rabbit heart the cardiac accelerating effect is less than O ₁ OOl that of adrenaline. The relationship between the cardiac stimulating effect and the bronchodilating effect was also demonstrated in the left atrium in the guinea pig which was electrically stimulated and in a spirally cut tracheal specimen from the guinea pig when both specimens were immersed in the same bath. If the compound according to the invention slowly in the
Bath solution was introduced, bronchodilatation was obtained without any effect on the cardiac muscle preparation.

The new compounds according to the invention can in the Administered in the form of salts with physiologically acceptable acids. Appropriate acids to be used are, for example, hydrochloric acid, hydrobromic acid, Sulfuric acid, fumaric acid, citric acid, tartaric acid, Maleic acid or succinic acid.

00984A / 19SS

The invention continues to provide pharmaceutical preparations, the active ingredient at least one of the compounds according to the invention together with a pharmaceutical Support material included. Such preparations can be used for oral, bronchial, rectal, parenteral or local administration.

For the production of pharmaceutical preparations in the form of dosage units for oral administration with

'■■■■ I

a content of a statement according to the invention in the ^

Form of the free base or a pharmaceutically acceptable one Salt of the same can be the active ingredient with a solid, powdered carrier material such as for example lactose, sucrose, sorbitol, mannitol, a starch such as potato starch, corn starch, corn starch or amylopectin, a cellulose derivative or gelatin, and it can also lubricants such as magnesium or calcium stearate or a. ~ ^ ~ ^ "~ V. ^" Or other polyethylene glycol waxes to-, Ij be set, whereupon the mixtures become tablets or Dragee cores are pressed. When coated tablets are required are, the kernels can be coated with concentrated sugar solutions, for example, the rubber larabcum, Contain talc and / or titanium oxide, or they can instead be coated with a varnish that works in one lives volatile organic solvent or a mixture organic solvent is dissolved. Dyes can also be added to these coatings.

- - Io -

009844/1065

- Io -

For the production of soft gelatine capsules (pearl-shaped, closed capsules), which consist of gelatin and, for example, glycerine, or for the production of similar ones closed capsules, the active substance can be mixed with a Carbowax ^. Hard gelatin capsules can contain granules of the active substance with solid, powdered carrier materials such as lactose, sucrose, sorbitol, mannitol, starch (such as potato starch, Grain starch or amylopectin), cellulose derivatives or gelatin and also magnesium stearate or stearic acid. Dosage units for rectal administration can be obtained in the form of suppositories containing the active substance in admixture with a neutral fatty base, or for rectal administration Gelatin rectal capsules can also be produced, which contain the active substance in a mixture with a Carbowax W or other polyethylene glycol waxes. Each dosage unit preferably contains 0.5 to 50 mg of the active ingredients.

Liquid preparations for oral administration may be in the form of solutions, suspensions or emulsions containing, for example, about 0.1 to 20% by weight active Contain substance and also, if desired, additives such as stabilizers, taste-improving Agents and / or sweeteners.

Flüadge preparations for rectal administration can be used in

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0098U / 19S5

in the form of aqueous solutions, which are about 0.1 to 2 wt .- ^ active substance and possibly also stabilizing agent and / or contain buffer substances.

For parenteral V _e rabreichung by injection, the carrier material is a stable, parenterally acceptable liquid such as pyrogen-free water, or an aqueous solution of polyvinylpyrrolidone, or a parenterally acceptable oil, such as arachis oil, and optionally be Stabilization | contain agents and / or buffer substances. Dosage units of the solution can advantageously be enclosed in capsules, each dosage unit preferably containing 0.05 to 5 now active ingredient.

For administration to the bronchi, the preparations are advantageously in the form of a spray solution or Suspension before * These contain 0.1 to 10 % Active substance by weight. Using the following examples

the invention is further explained. ^ ~

example 1

Production of 1- (3 »5 -dibenzyloxyphenyl) -2-cyclopentylaminobutanol sulfate as starting material

a) Preparation of 3'j5'-dibenzyloxy-2-cyclopentylaminobutyrophenone hydrobromide

21.9 g of 3 ', 5'-dibenzyloxy-2-bromobutyrophenone was dissolved in 50 ml of dry benzene and 9 kg of cyclopentylamine was added

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009844 / 19SS

added. The reaction mixture was refluxed and stirred for 15 hours. That formed in the reaction Cyclopentylamine hydrobromide was filtered off. (Yield 7 * 8 g). The benzene phase was evaporated, and that remaining oil was dissolved in ether. The stirred ether solution was mixed with 100 ml of 20% hydrobromic acid Treated for 1 hour. The crystalline product formed was filtered off and washed with water and ether. Yield 21.4 g, m.p. = 90 to 100 ° C,

Br "(calc.) = 15.2 #; Br" (found) = 15.4 $>.

b ) Production of 1- (3 ', 5 * -dibenzyloxyphenyl) -2-cyclopentylamino-butanol sulfate

21.4 g of 3 ', 5'-dibenzyloxy-2-cyclopentylamino-butyrophenone hydrobromide were made alkaline with 10 # aqueous 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 leftover 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 5 η sodium hydroxide solution the base was extracted with ether. The ether phase was evaporated and the residue was dried with ethanol / benzene. Yield 16.6g.

- 13 -

0098U / 19BS.

10.0 g of this base were dissolved in ether, and 100 ml 2 η sulfuric acid was added, followed by stirring for 2 hours. The crystalline product formed was filtered off and washed with water and ether. F. = 91 to 92 ° C.

Example 2

Production of l- (3 '* 5'-dihydroxyphenyl) -2-cyqlopenty1-

amino) butanol sulfate

The product obtained according to Example 1b was dissolved in 150 ml of glacial acetic acid and hydrogenated in a Parr pressure reaction apparatus at 50 ° C. and 5 atmospheres pressure overnight. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in water and evaporated again to remove traces of acetic acid. Yield 4.0g. This product was dissolved in water. After filtering, the pH was adjusted to 5 »6 (pH meter) by adding 0.1 η sodium hydroxide solution. The water phase was evaporated to dryness and the residue was dried several times with ethanol / benzene. Absolute methanol was added to the residue and the hardly soluble sodium sulfate was filtered off. The methanol was evaporated and the residue was recrystallized from ethanol. Yield 2.0g, m.p.-173 to ⁰

The following examples illustrate how the compounds can be incorporated into pharmaceutical preparations according to the present invention)

0098U / 19S5 ~ ^lk -

- Ik -

Example 3

Aerosol for inhalation

Active substance 1, OO g

Miglyol Φ 0.20 g

Prigen® 11/12/113 / H ^ to 100.0 g

Example k

Tablets

Each tablet contains:

Active substance 20.0 ng

Corn starch 25.0 mg

Lactose 190.0 mg

Gelatin 1.5 ng

Talc 12.0 mg

Magnesium stearate 1.5 mg

250.0 mg Example 5

Suppositories

Each suppository contains;

Active substance 20.0 mg

Ascorbyl palmitate 1.0 mg

Suppository base

(imhausen H) to 2000.0 mg

- 15 -

009844 / 19SS

Example 6

Active substance 0.200 g

Liquid glycose 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 7

Solution for injection

Active substance 0.500 mg

Sodium Pyrosulfide fc 0.500 mg

Disodium edetate 0.100 mg

Sodium chloride 8.500 mg sterile water for injection to 1.00 ml

Example 8

Xnhalaton solution

Active substance 5.00 g

Sodium pyrosulfite 0.10g

Disodium edetate 0.10 g

Purified water to 100.0 ml

- 16 -

009844 / 19SS

Example 9

Solution for rectal administration (rectal ampoules)

Active substance 20.0 mg

Sodium pyrosulfite 1.5 mg

Disodium edetate 0.3 mg

Sterile water to 3.0 ml

Example 10

Sublingual tablets

Each tablet contains:

Active substance

Lactose

talc

Example 11

drops

5.0 mg 85.0 mg 5.0 mg 5.0 mg 100.0 mg

Active substance 2.00 g

Sodium pyrosulf ± k '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

009844/1955

Pharmacology marriage trials

a) bronchospasmolytic effect

The bronchospasmolytic effect of 1- (3 »5 -dihydroxyphenyl) -2- (cyclopentylamino) -butanol was compared with that of the known compounds adrenaline and 1- (3, 4 -dihydroxyphenyl) -2- (isopylamino) ethanol ( is opr enalin) compared to the spirally cut guinea pig trachea according to the method originally proposed by Castillo and Beer / J. Pharmacol. Exptl. Therap. 90 (1947) "Page"

loV7be8ohrieben and later by Constanine /j.Pharm. Pharmacol, 17 (1965), page 384-7. at In this experiment, the effect of 1- (3,5-dihydroxyphenyl) -2- (cyclopentylamino) butanol was about 0.6 times as strong like that of adrenaline. Isoprenaline was about 13 times more effective than adrenaline in this attempt.

1 ^X

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 protected. The dose, which protected 50 pounds of the animals in the aerosol for 4 minutes, was designated as ED « ₀

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009844/1955

also examined. The results are in Table I. compiled. Xsoprenaline was used as the reference substance.

Table I. Compound administration

■ g / kg body weight

1- (3 ¹ , 5 ¹ -dihydroxy-

phenyl) -2-cyclo-

pentylaminobutanol i.p. 1.9

- "- p.o. 1.8

Xsoprenaline i.p. 0.07

When testing in vivo according to Konzett & Rössler, /Arch.Exp. Pharmac. 195, page 71i (19 ** OJ [7 found the bronchospasmolytic effect after intravenous administration as about 0.07 "al as large as that of isoprenaline if the experiment was carried out on cats, and as about 0.04 times as large as that of isoprenaline, if the experiment was carried out with dogs.

b) Effect on Her as

The relationship between the cardiac stimulating effect and the bronchodilating effect was determined in vitro on studied left atrium of the guinea pig. To the effect on the heart and the effect on the · bronchial muscles under identical experimental conditions

009844/1955

would compare the electrically stimulated atrium and the spirally cut trachea into the same Bath in Kreb's solution. Both preparations were made taken 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 on which muscle the compound was most effective. Adrenaline and isoprenaline were used as reference substances turns. Adrenaline causes bronchodilation and heart muscle stimulation in the same concentration range. The infusion was carried out for 10 minutes. To the what the η and win one let the experimental solution in same way as above for adrenaline and for isoprenaline described, shrinkage, and the effect of this agent on the two preparations could easily be compared with that of adrenaline and isoprenaline can be compared. The results are shown in Table II below. the Effect of adrenaline on the heart muscle is with the ™

Value given as 1.0.

Table II

Compound effect versus

adrenaline

1- (3 ¹ , S ^ dihydroxyphenyl) -2-cyclopentylaminobutanol <£. 0.001

Isoprenaline 12.9

Adrenaline 1.0

- 2o -

009844/1955

The compound of the present invention gave no effect on the cardiac preparation in doses up to 0.4 mg / ml.

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

As the biological tests clearly show, the compound has 1- (3 »5-dihydroxyphenyl) -2-cyclopentylaminobutanol a very favorable ratio of cardiac stimulation to bronchospasmolytic activity. This valuable and surprising property makes the compounds according to the invention particularly suitable for the treatment bronchospastic conditions, such as asthma and other similar conditions that affect the airways.

c) toxicity test

The toxicity of 1- (3 .5 -Dihydroxyphenyl) -2- (cyclopentylamino) -butanol in mice (30 animals) after subcutaneous administration was decided. The LD __ value was 400 - 30 mg / kg.

009844/1955

Claims (1)

Pat θ η t a η proverbs 1.) Compound of the general formula C R ^ , CH ₉ - CH ₅ - CH -NH- and their therapeutically acceptable salts, in which II is a Hydrogen atom or an aliphatic acyl group with Means 2 to 5 carbon atoms. 2.) Compound of the formula H -CH - NH-CH CH ₂ - CH- CH ₂ -CH ₂ and their pharmaceutically contractual «salts. 3.) Compound according to claim 1 and 2 in their optically relmr Shape. k.) Compound according to claim 1 and 2 in the form of an Oe- '-2Z- 0098 44/1955 misohes of the stereoisomers obtained in the preparation. 5 ·) Compound according to claim 1 and 2 in the threo form. 6.) Process for the preparation of "toη aminobutanol derivatives general formula # τ CH - M - CH wherein R represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms, and from their therapeutically acceptable salts, characterized in that a compound of the general formula ' R ^X O ■ J- ¹ wherein R is a hydrogen atom, an alkyl protecting group having not more than 5 carbon atoms, an acyl protecting group with no more than 5 carbon atoms or a mono- or bicyclic aralkyl protecting group with no more than 009844/1955 11 denotes carbon atoms and R denotes a Vasseratoffatom or a mono- or bicyclic aralkyl group with not means more than 11 carbon atoms, forming., a compound of the formula ν '■ · ■:. ■' . ** ■■■ '■ ··': XZI * ■ 1 · ■ 2 ' ^: where R and R have the above meaning: reduced and, 1 2 ^{i ::} ■ ' if necessary, R against R and R against hydrogen exchanges ·. _ - ■ "■" · - «.., 'Λ .'- '. '-: y. 7 ·) Method according to claim 6, characterized in that « the compound II is catalytically hydrogenated, ¹ ■ - ""^;: ■ "■%;' ■ '■' ... ''"" 8.) Process according to claim 6, characterized in that the compound II is reduced with the aid of a · complex metal «hydride. ·"'...^; 9 *) Method according to claim 6, characterized in that - · '■ 1 a starting compound is used in which R is an aromatic protective group, and this is the same • Removed early through reduction of the carbonyl group. 10.) Method according to claim 6 to 7 and 9t daduroh marked zoföhnot that one uses oino AuscEuicsvorliiiKfflung in the R eino -Dpassylgrupp-o Ijodoutot. . 009844/1955