CS199644B2 - Method of producing new derivatives of phenylaminoethanol - Google Patents

Description

The invention relates to the production of novel pharmacologically active compounds. Novel compounds produced by the process of the invention. in particular they have anti-allergic and anti-anaphylactic activity and are particularly valuable as anti-asthma agents and can also be used in the treatment and prophylactic treatment of other allergic diseases.

By "allergy" is meant. Darland's “Illustrated Medical Dictionary”, 24th edition, 1967, a hypersensitivity condition obtained by exposure. (exposure) to a particular allergen, wherein re-exposure leads to an altered reaction ability. Examples of various allergies include allergic rhinitis, hay fever and urticaria. A common feature of many types of allergic reactions in humans is the antigen response. - an antibody that results in the release of pharmacologically active substances (= mediators), inter alia histamine and SRS-A (a slow-reacting anaphylactic agent). The mediators released in this way cause bronchoconstriction, oedemas, increased mucus formation, itching, etc. The sequence of allergic attack reactions can be explained schematically as follows:

Stage 1

The organism enters allergen (antigen) i

Grade · 2

Ant-igen enters. reaction with antibodies, which. leads. to

Stage 3 release of mediators i

Stage 4

199844 released substances, in particular histamine and SRS-A, cause symptoms of an allergic reaction:

bronchoconstriction, oedema, increased mucus production, etc.

199B44

This kind of increased reaction of the organism, explained above, to allergens (antigens), which may be foreign protein or other substances, is called anaphylactic reaction.

The mechanisms involved in the anaphylactic reaction are discussed, among others, by Assem in Cllnical Allergy, 1974, vol. 4,. . pp. 185-194, and Assem and Schild in Int. Sheet. Allergy, 40, 576-589 (1971).

Although the following description emphasizes exogenous type bronchial asthma, which is only one. It is clear that the results obtained by the method of the invention can also be applied to other forms of allergy.

The usual treatment of asthma treats symptoms occurring in grade 4. In particular, bronchial constriction is alleviated by the administration of agents that alleviate bronchial spasms and augment bronchi. However, this treatment is usually started only when the asthma attack is on the way or is already fully developed. It would be desirable to make available a prophylactic method that could be used to prevent a true outbreak of allergic attacks. This could be achieved by inhibiting the release of the mediators appearing in step 3 of the above scheme. It is known that some sympathomimetic amines, among which those used in the treatment of asthma - adrenaline, isoprenaline, terbutaline - also inhibit the release of mediators induced by antigen.

These substances have anti - anaphylactic activity in the same dose range,. as required to achieve bronchodilation. This means, among other things, that unwanted side effects, sometimes occurring after these sympathomimetic amines, such as palpitations and tremors, could limit their use as anti-anaphylactic agents.

It is an object of the present invention to provide compounds that inhibit antigen-induced release of histamine and other spasmogenic agents in a dose range that do not produce "classical" sympathomimetic effects, such as vaspdilatation, heart stimulation and tremor. Compounds with a specific inhibitory effect on the release of spasmogenic agents are effective as prophylatic and anti-anaphylactic agents in the treatment of various types of allergies including bronchial asthma, without the side effects observed with sympathomimetic amines commonly used as bronchospasmolytic agents.

According to the invention, it has been found that the compounds of formula (I)

R ^ O

CJCCH-CH 2 NH-A-aR ¹

OH

R <

(П in which

R ¹ and R ' ² are the same or different and are hydrogen, an aliphatic acyl group having 1 to 5 carbon atoms, a benzoyl or phenylacetyl group, and

A denotes a straight or branched chain alkylene group having 3 to 6 carbon atoms or a cycloalkylene group having 4 to 6 carbon atoms, and their physiologically acceptable salts have a pronounced anti-anaphylactic. efficacy over a dose range at which their heart-stimulating and bronchospasmolytic effects are negligible. This one. an unexpected and favorable combination of properties makes the compounds of the invention valuable anti-anaphylactic agents that can be used. use in the prophylaxis of various forms of allergy, such as allergic rhinitis,. hay fever, urticaria, asthma, etc. with a reduced risk of side effects commonly observed with sympathomimetic amines.

Illustrative examples of R 1 and R ² include

H—

CH3CO—

CH3CH2CO—

CH3CH2CH2CO— (CHsbCHCO—

CH 3 (CH 2) 3 CO-CH 3

AND

H — C — CH2CO—

AND

CH3

CH3

AND

CH3 — c — what—

AND

CH3

Illustrative examples of groups A include: —CH2CH2CH2— —CH — CH2—

CH3 —CH2 — CH—

AND

CH3

CH2CH2CH2CH2 - z

199844

CHs

I.

—C — CH2—

CH3

CHs

I —CH2CH2CH— —CH2CH — CH2—.

CH3 —CHCH2CH2— ·

AND·

CH3 ->

C2H5 —CH2CH—,

CH3 CH3

II.

—CH — CH— ζΟΗ

HIM

СН-СНхИН-СН ^ Н ^ НОН

HO ^Oh

—CHCHž—

AND

C2H5

/ СЦс-СН-ch I x _c ^ _cw _t

CH — CH »X <, ^c

- ^C · ^

The group R @ ¹ is preferably hydrogen.

Group A is preferably straight or branched chain alkylene groups having 3 to 4 carbon atoms.

Illustrative examples of the compounds of the invention are

CH <

I 3

CH-CHNH-CHCHCH-OH

OH

№

XCH- CHgNH- CHgHCH6 OH OH.

HIM

CH.

I 3

CH-CH, NH- CHCH.CH & OH

HIM

CH-CHr NH-CH-CH-OH 1. , * I · i

OH CH3 CH3

C H-CH 1 -NH-CHCH 1 H 1 · * I κ

OH CjHs

HIM

-CH · CH 2 NH-C 1 H 2 O 2 CH 2 CH 2 Cl 2 · OH OH

CHt

3 CH.-HH-C-CH.OH t ₍ b

CH5

CHI OH

ГУ-СОО._ 'CWj ^{4 = 7} £ \ -СН'СН; ИН-С-СН ^ Н

O-C00 ^{RUN СНз}

О-С ^ ОСХ_.

ZV CW-CW ^ NH- с- CWjOW Z \ ОН Cl ·)} ^ У-сн ^ оо сн, о

CH-CHgNH-C- CHgCCH *

₃

О-соо cw ₃ О // II I II \ / CW-CUg-АШ-с-щрсс ^ е 'он ^ н.

^ У ^СОО Ч ^сн 1 θ / ^ CW-CAfcNW-C-СЦрС (СНр ^ СН ^

Q-cOO ^Í ζ--с _{5 5} W W W W W W W W W W

199844

/ СИ _К СН-ОН

СН-СНгЫН-СН I

/

CH-CH-CHrNH l * · \ ен cis-CH ^ OH ^ с -сн / си ₃ соо

CH _AND COO

_CH-R-NH-C CUpH i A | ΧΟΗ сн _ь снрнро

CH-CH2-NH-CCH-OH <4

AND.

снрн ^ соо OH

Ch

I НС-СОО

cw ₃

W-CfyNN-C-ChOH нс-соо I ^с ”з _H} cc- £ oo ch _s

CH cM_CH _ZX-R-NH-C CW OW ru \ = s / ^λ * I ^С, Ъ г OH CH.

WC-C-COO's, cw ₄ ро с с-соо ch ch HC-C-COO i

cw ₃

CH-CHNH-CHChpH

OH ^CW 3

199844

A preferred group of compounds are those in which R @ ¹ is hydrogen and A is straight or branched chain alkyl. of from 3 to 4 carbon atoms.

Preferred compounds of the invention are

CH-CH 2 NH-C-HOH | ^A I * OHCH (Example 1)

HIM

K— I

CH-CH ₁ NH-CH CH 5 OH z '- °) H

HO (Example 2)

CH,. I ³

CH-CH-NH-CHJCH-OH * ^X (Example 4)

A particularly preferred compound of the invention is

(Example 1)

Since the compounds of the formula I according to the invention have at least one asymmetric hydrocarbon atom, the invention also encompasses all possible optically active and racemic forms. mixtures of compounds. Racemic mixtures can be resolved by conventional means, for example by salt formation with an optically active compound followed by fractional crystallization.

The compounds of the invention may be formulated for use in human and veterinary medicine for therapeutic and prophylactic uses. In general, they can be used in the form of physiologically acceptable salts, for example hydrochloride, sulfate, maleate, tartrate, etc.

In clinical practice, the compounds of the invention are usually administered orally, by injection or by inhalation in the form of pharmaceutical compositions containing the active ingredient in the form of the parent compound or optionally in the form of a physiologically acceptable salt thereof, together with a physiologically acceptable carrier. or a digestible capsule, such formulations are another purpose of the invention. The active compound is usually 0.1 to 99% by weight of the preparation, for example 0.5 to 20% by weight for preparations intended for injection purposes and between 0.1 and 50 why, for preparations intended for oral administration.

For the preparation of pharmaceutical preparations in the form of - dosage units (dosage units) for oral administration containing a compound of the invention, the active ingredient can be admixed with a solid - powdered carrier, e.g. lactose, sucrose, sorbitol, mannitol, starch, e.g. amylopectin, lamina powder or lemon pulp powder, cellulose derivative or gelatin, and glidants such as magnesium or calcium stearate, or polyethylene glycol (Carbowax) or other polyethylene glycol waxes, and may be compressed to form tablets or cores -For dragees. If dragees are required, the cores may be coated, for example with concentrated sugar solutions, which may contain - acacia, talc and / or titanium dioxide or a film-forming substance, dissolved in slightly volatile organic solvents or organic solvent mixtures. .

Dyestuffs may be added to these coatings, for example to distinguish different contents of the active ingredient. For the preparation of soft gelatin capsules - (bead-like capsules) consisting of gelatin - and for example - glycerol as a plasticizer, or similar closed capsules) - the active compound can be mixed with polyethylene glycol (Carbowax) or a suitable oil, e.g. oil, non-olive oil or groundnut oil. Hard gelatine capsules may contain granules of the active ingredient with solid powdered carriers such as lactose, sucrose, mannitol, starches (for example, potato or corn starch or amylopectin), cellulose derivatives -or gelatin, and as - glidants - may - also contain magnesium stearate or stearic acid.

By using several layers of active drug, separated by slowly dissolving coatings, slow release tablets are obtained. Another method of making slow release tablets is by distributing the dosage of active compound into granules into tablets together with a carrier. The active compound can also be incorporated into slow-dissolving tablets made, for example, from fatty and waxy compounds, or evenly distributed in a tablet from an insoluble substance, for example from a physiologically inert plastic.

Effervescent powders are prepared by mixing the active ingredient with non-toxic carbonates or bicarbonates, e.g. sodium, potassium or calcium, e.g.

Liquid preparations for oral administration can. be in the form of elixirs, syrups or suspensions, for example solutions containing from 0.1 to 20% by weight of the active ingredient, sugar and a mixture of ethanol, water, glycerol, propylene glycol and optionally flavoring, saccharin and / or carboxymethylcellulose as a dispersing agent.

Injectable preparations for parenteral administration may contain an aqueous solution of the water-soluble physiological harmless salts of the active compound according to the invention, at a desired concentration of 0.5 to 10% by weight, and optionally also a stabilizing agent and / or buffers in the aqueous solution. Dosage units of solution. they may preferably be enclosed in ampoules.

The dose at which the active compound is administered can vary within wide limits and depends on various factors, for example, the individual requirements of each patient. A suitable oral dosage range is from 10 to 20 mg per day. A suitable parenteral dosage range is from about 1 to about 50 mg / day.

Pharmaceutical compositions containing the active ingredients may be formulated appropriately so as to provide dosages within these ranges either as single dosage units or as multiple dosage units.

The invention therefore provides a process for the preparation of the novel phenylaminoethano derivatives of the formula I

OC 1 -Cy-CH ₂ HH-A-oR

Oo ™ (I) in which.

R 1, R ² and A are as defined above, and their physiologically acceptable salts thereof, the object of the invention is to reduce the compound of formula II

R - is hydrogen or a hydroxyl protecting group such as an alkyl or aliphatic acyl group of up to 5 carbon atoms, a mono- or bicyclic-aralkyl group of up to 11 carbon atoms such as benzyl or - naphthylmethyl, or benzoyl - or phenylacetyl ,

A has the meaning given above and

B represents a group of formulas —CH = N — or —CH2 — N—, R ³ wherein

R 5 is hydrogen or an N-protecting group such as benzyl, whereupon the protecting groups R and R ^{3 are} removed, if necessary; then, if necessary, the compound of formula I thus obtained is converted into its physiologically acceptable salt and / or resolved into its optical isomers.

A particularly preferred compound of the invention, 1a

СН-СМтЫН-С ^ СН _а ОН

I Λ | Л,

0H ^c h _IA> is produced so that the -compound of formula II

RO

where

R is as defined above, A is CH 2

I —CH2 — C—

AND

CH3

B has the same meaning as given above, and then, if necessary, deprotects R and R ³ from the obtained compound.

The starting materials mentioned above are new compounds. These compounds of formulas (V) and (VI) are another purpose of the present invention.

Starting materials can be prepared, for example, as illustrated in the reactions below, wherein R, R 3, -X and A are as defined above:

RO / 0 Xi

RO

RO

(VD

JastUíA.R * 'jtH

CC-H + HN-A-OR-li if ^A

O O in * if. IR is L-> Asylum. group.

RO from ° -f = CH = N OH

RO

RO

CH ₃

CH-NC-CH ^f OR ^Z * ^CH 3

The following examples illustrate the invention.

Example 1

Preparation of 1- (3,5-dihydroxyphenyl) -2 - [(1,1-dimethyl-2-hydroxyethyl) amino] ethanol sulfate

a) Preparation of 1- (3,5-dibenzyloxyphenyl) -2 - [(1,1-dimethyl-2-hydroxyethyl) amino] ethanol sulfate

To a solution of 7.8 g of 3,5-dibenzyloxyphenylglyoxal monoethylacetal in 150 ml of diethyl ether is added a solution of 1.8 g of 2-amino-2-methylpropanol (1) in 50 ml of dry ether. The title compound begins to crystallize soon and the reaction mixture is allowed to stand for 20 hours at room temperature, then the crystals are filtered off. Yield 6 g, The structure of the compound was confirmed by NMR.

Reaction scheme

b) Preparation of 1-bis (5-dibenzyloxyphenyl) - [- (1,1-diniethyl-2-hydroxyethyl) amino] ethanol

To the suspension 6 - g 3,3 (dimethyl (6 (hydroxy (

-6- (3,5-dibenzyloxyphenyl) -4,5-dihydromorpholine in ethanol was added in portions. small portions, 0.6 g of sodium borohydride. Obtained, clear. the solution was stirred at room temperature for 4 hours, then the solvent was evaporated. The residue is taken up in ether and washed with water until the pH is neutral.

199044 i

The ether phase was dried over magnesium sulfate and concentrated in vacuo to give 4 g of the title compound as a white solid. This compound was identified using NMR and IC and was identical in all respects to the compound obtained according to Example 1a.

Reaction scheme

c] Production of the title compound

Catalytic hydrogenation. The 3,3-dimethyl-6-hydroxy-6- (3,5-benzyloxyphenyl) -4,5-dihydromorpholine obtained in step b) at room temperature and a positive pressure of 379.5%. kPa in the presence of 5% palladium on carbon in sulfuric acid-containing ethanol gives 1- (3,5-dihydroxyphenyl) - [(1,1-dimethyl-2-hydroxyethyl) amino] ethanesulfate. identified by thin layer chromatography analysis.

Same. The method can be used to prepare the following compounds.

Example 2

1- (3,5-Dihydroxyphenyl) -2 - [(1-methyl-2-hydroxyethyl) amino] ethanesulfate

SO4 ² ': 97.4%, mp 1S4 ° C. The structure of the compound was confirmed by NMR.

Example 3

1 <(3,5-Dihydroxyphenyl) -2 - [(4-hydroxycyclohexyl) amino) ethanol hydrochloride calculated: 11.7% Br found: 11.5% Br.

Melting point 234 ^o C.

The structure of the compound was confirmed by NMR.

Example 4

1- (3,5-Dihydroxyphenyl) -2 - [(2-hydroxypropyl) amino] ethanol hydrochloride

Oil:

calculated: 13.4 ° C; The structure of the compound was confirmed by NMR.

Example 5 1- (3,5-Dihydroxyphenyl-2 - [(1-ethyl-2-hydroxyethyl) amino]] ethanol hydride

Oil:

calculated: 12.8% Cl found: 11.6% Cl The structure of the compound was confirmed. by NMR. ,

Example 6

II (3,5-dihydroxyphenyl) -2 - [[3-hydroxypropyl) amino] ethanol sulfate% SO42 -.

The structure of the compound was confirmed by NMR.

Example 7

11 (3,5-Dihydroxyphenyl) -2- [• (2 ₁ 2-dimethyl-2-hydroxyethyl) amino] ethanol hydrochloride calculated: 12.8 Cl - found: 12.5% Cl -

The structure of the compound was confirmed by NMR.

For example

1,1- [3,5lbSl (2-methylpropioyloxy) phenyl] -2 - [(1,1-dimethyl-2-hydroxyethyl) amino] ethanol hydrobromide calculated: 17.3% Br found: 17.4% Br

The structure of the compound was confirmed by NMR.

199844

Example 9

1- [3,5'-bis (2,2-dimethylpropionyloxy) phenyl] -2 - [(1,1-dimethyl-2-hydroxyethyl) amino] ethanol hydrochloride calculated: 16.3% Br ~ found: 16 , 4% Br ~

The structure of the compound was confirmed by NMR.

Example 10

Production of 1- (3,5-dihydroxyphenyl-2 - [(1,1-dimethyl-2-hydroxyethyl) amino] ethanol sulfate

a) Production of 1- (3,5-benzyloxyphenyl) -2- (1,1-dimethyl-2-hydroxyethylamino) ethanol

3,5-Dibenzyloxyphenylglyoxal monoethylacetal and 2-amino-2-methylpropan-1-ol are reacted in ethanol and the intermediate

3,5-Dibynyl-oxy- 1- (1,1-11-methyl-2-hydroxyethyl) aminoacetophenone is reduced in situ with sodium borohydride without isolation of 1- (3,5-benzyloxyphenyl) -2- (1,1- dimethyl-2-hydroxyethylamino) ethanol.

Reaction scheme:

On В fy

------>

CfyO Za

CH,

I ³

C-CfNH-C-CH, OH I

OH

I '*

Cfy

(b) Preparation of 1- (3,5-dihydroxyphenyl-2 - [(1,1-dlmethyl-2-hydroxyethyl) amino] ethanol

The reaction product obtained in step a] is catalytically reduced in the presence of 5% palladium on carbon in ethanol as described in Example 1c to give the title compound 1- (3,5-dihydroxyphenyl-2- [i (1, 2, 2, 2, 2, 3, 1-dimethylamino-2-hydroxyethyl) amino] ethanol.

The following examples illustrate how the compounds of the invention can be incorporated into pharmaceutical formulations:

Example 11

Aerosol for inhalation:

1- (3,5-dihydroxyphenyl-2- [· (1,1-dimethylamino-2-hydroxyethyl) amino] ethanol sulfate 100) g solvent (Miglyol) 020 g _p lanlant (Frlgen 11/12/113/114) to · 100,00 g

Example 12

Tablets

Each tablet contains: 1- (3,5-dihydroxyphenyl) -2 - [(1,1-dimethylamino-2-hydroxyethyl) amino] ethanol 20, (0) mg corn starch 25, (0) mg lactose 199,00mg gelatin 1.55 mg talc 11, 0mg magnesium stearate 1150mg

250,00 mg

Example · 13

Cípky

Each cone contains:

1- (3,5-dihydroxyphenyl) -2- [i (1-methyl-2-hydroxyethyl) amino] ethanol sulfate 20103 mg ascorbyl palmitate 0.0mg suppository base · · (Imhausen H) to 2000.0 mg

199844

Example 14

Syrup

1- (3,5-dihydroxy-) hydrochloride phenyl] -2 - [. (2-hydroxypropyl) - amino) ethanol 0,200 g liquid glucose 30,0 g sucrose 50,0 g ascorbic acid 0.1 g sodium pyrosulfite 0.01 g disodium acid salt edetově 0.01 g orange essence 0.025 g harmless dye 0.015 g cleaned water up to 1000.0 g Example 15 Injection solution 1- (3,5-dlhydroxy-) hydrochloride phenyl) -2 - ((2-hydroxypropyl) - aminoethanol- 0.500 mg sodium pyrosulfite 0.500 mg disodium acid salt edetové 0.100 mg sodium chloride 0.500 mg sterile water for Injection to 1.00 mg Example 16 Inhalation solution

1- (3,5-Dihydroxyphonyl) -2 - [, (1,1-dimethylmethyl-2-hydroxy-) sulphate

ethyl) amino] ethanol 5,00 g sodium pyrosulfite 0,10 g disodium acid salt edetové 0,10 g sodium chloride 0.85 g cleaned water to 100.0 ml

Example 17

Solution for rectal administration (rectal vials) Sulfate 1- (3,5-dihydroxyphenyl) -2 - [(1-methyl-2-hydroxy-

ethyl) amino] ethanol sodium pyrosulfite disodium edetate sterile water 20.0 mg 1.5 mg 0.3 mg to 3.0 ml Example 18 Sublingual tablets 1- (3,5-dihydroxyphenyl) -2- [12-hydroxypropyl) amino] ethanol hydrochloride lactose agar talc 85.0 mg 5.0 mg 5.0 mg

100.0 mg

Example 19

Drops

1- (3,5-dihydroxyphenyl) -2 - ((2-hydroxypropylamino) ethanol hydrochloride ascorbic acid sodium pyrosulfite disodium salt odorous liquid glucose absolute ethanol purified water

Pharmacological tests

A. Antianaphylactic effect

The anti-anaphylactic effect was tested on activity and passively sensitized laboratory animals.

Active sensitization of animals is achieved by injection of ovalbumin protein. This application renders the animals hypersensitive to subsequent ovalbumin challenge. The anti-anaphylactic effect of the test substances was tested in vitro by exposing the lungs from actively sensitized animals to ovalbumin and assessing the effect of the test compound on the amount of histamine released from the lung preparation.

1. Inhibition of Histamine Release from Actively Sensitized Guinea Pig Lungs

Methods:

Guinea pigs of both sexes weighing 300-400 g receive a single 50 mg intraperitoneal injection of ovalbumin emulsified in complete Freund's adjuvant. Animals are used 2-5 weeks later in the challenge experiment described below.

The sensitized animals are dead and bled. The lungs are removed and pulverized. Lungs from 2-4 animals are used in each series of experiments. After several washes with Krebs solution, the tissue is divided into Krebs solution tubes (0.1 g of tissue per ml) and placed in a 37 ° C water bath. After 5 minutes of pre-incubation, ovalbumin (= antigen) is added. The test compound was added 2 minutes before ovalbumin addition. Incubation is usually continued for a further 15 minutes, occasionally shaking the tubes occasionally. The histamine release phase is stopped by placing the tubes in an ice bath. The incubation fluids are decanted and replaced with sodium chloride solution acidified with hydrochloric acid to pH 3.5. The lung tissue with sodium chloride solution is boiled for 8 minutes in a water bath. The incubation fluids and tissue extracts are kept in an ice bath prior to testing.

The histamine content of incubation fluids and boiled extracts is determined

2,00 g

1,00 g

0,10 g

0,10 g 50,00 g 10,00 g to 100,00 ml guinea pig intestine test. Parts of the terminal ileum, 2 cm long, of the guinea pigs weighing 0.2 to 0.3 kg are placed longitudinally - _20:. ml baths (37 ° C) containing Krebs solution, continuously. aerated with small bubbles of carbogen. Atropine in an amount of 10-7 is added to the bath. mol - propranolol 10 - ^e mol. The contractions are recorded using a force-displacement transmitter (Grass, FT03) and a recorder (Grass, Model-7),

About 1 hour after several washes, the susceptibility of the preparations to repeated doses of histamine is examined. Segments with - low sensitivity and considerable variability and unstable base are discarded. High-level preparations are also excluded. spontaneous efficacy. The preparations are standardized to correspond to 2, 4, 8 and 12 mg histamine base per ml. These doses are administered repeatedly in random order until consistent responses are obtained. The extent of the bowel condition within this range corresponds to the logarithm of the dose of histamine. The test solutions are added in an amount of 0.1 to 1.0 ml, which is chosen to induce the same amount of contractions as is obtained with an interventional dose of histamine.

By maintaining this intervention standard histamine. dosage at a constant level facilitates monitoring changes in intestinal sensitivity that have been in contact with histamine or test solution for 15 seconds. During this time, the largest number of contractions was recorded. After washing, allow two minutes to elapse before administration of the next dose. - Add all solutions by pipette. The contractile power of the test solutions on the isolated guinea pig ileum is expressed as the histamine base. Spontaneous lung-induced histamine release is derived from the values reported in the text. The results are expressed as histamine released relative to gram-weight of wet lung tissue or percent-inhibition-histamine release. Terbutaline or isoprenaline is used as a reference. Terbutaline (bricanyl) is a sympathomimetic amine used in the treatment of bronchial asthma. Two equally performed samples are used in each series of experiments. All samples in the same series are tested against the same histamine standard. The test results for the preferred compound of the invention are given in Table 1 below. A summary of the test results is summarized in Table IV, in which the effect of each substance is to the efficacy of terbutaline. Comparisons are made between doses causing 50% inhibition of histamine release. Table I

Inhibition (%) of histamine release from guinea pig sensitized lungs. Control release without inhibition is 15 to 30% of hisInhibitor tissue inhibition - (%)

10-8 taminu. They are reported. mean values + standard deviation · - average, - the number of preparations tested - - is - in parentheses.

at different concentrations - (molarity)

10-7 10-® 10-5 compound of Example 1 Terbutaline

20 + 5 (2)

30: +5-. (10)

24 + 5 ^: (4)

42; +3 (10) 51 + 3 (9)

43: +5 (8) - 58 + 3 -

Remarks on the results of Table

The ovalbumin-WC-histamine release from the actively sensitized guinea pig lungs represents 10-30% of the tissue amount determined by the boiling tissue. Spontaneous histamine release from lung tissue did not exceed 2%. When the test compound of Example 1 is added to the lung tissue for 2 minutes before the antigen, histamine release is inhibited by a dose-dependent mechanism. The potency of the test compound is about the same as that of terbutaline. The maximal inhibition of histamine release by the test compound of Example 1 is approximately the same as that of isoprenaline. The inhibitory effect is completely blocked by propranolol in a dose of 10 ⁶ mol. The inhibitory effect of terbutaline on histamine release is achieved with the same concentrations that release pilocarpine-induced tracheal trachea.

2. Inhibition of the release of non-histamine - - slow contracting agent -SRS-A

The non-histamine, acting-slow contraction, was tested on the same ileum preparation as above but with 0.04 µg / ml brompheniramine added. This concentration completely blocks the histamine response. In order to obtain a contraction equilibrium, the test fluid is used for 1 minute. The contractility of this non-histamine fraction is expressed by SRS-A units, wherein the response of one SRS-A unit is equivalent to a maximum tension of 5 mg of histamine obtained on the same non-blocked guinea pig ileum preparation. The results are given in Table II below.

199844

82

Table II

Inhibitory effect on the release of slowly becoming sensitized guinea-pig lungs (SBS-Aj \

Experiment No. Inhibition Control (%) obtained with the compound of Example 1 (molarity)

unit release / g lung ΙΟ » ΙΟ ⁷ ΙΟ ⁶ 10-5 1 108 and 51 50 57 not given 2 33 55 57 61 79 3 27 Mar: 57 52 66 83

Remarks on the results of the tests in Table II

From Table II it is apparent that in the presence of the test substance (from Example 1) in a concentration of 10-8 mol to 1 O ⁵ in the three experiments with different samples of pulmonary tissues inhibited 50-75% nehlstamlnových spasmogen.

3. Inhibition of passive cutaneous anaphylacticidal reaction in rats

Method:

Male rats weighing 150-300 g (Sprague Dawley) are anesthetized with pentobarbital (30 ^L mg / kg intravenously). Evans blue (10 mg / kg) and test substance are injected intravenously into the femoral vein. Six intracutaneous punctures are then performed in two rows on each side of the midline of the abdomen with dextran of 70,000 molecular weight. The amount of dextran to be injected is 60 µg in 0.1 ml of sodium chloride solution. Dextran induces an anaphylactoid reaction. After 30 minutes, the animals are sacrificed and the abdominal skin is excised. Using the values 1 to 4, the color intensity is visually determined. The experiments with the control animals were always carried out without the action of the drug of the compound of Example 1 with teributaline. The other compounds were tested in two animals, each at the 3-4 dose level. Comparison with terbutaline is made at the ED 50 level, which is an effective dose for 50% inhibition of the color intensity of the blue stains.

The results are shown in Table III below:

Table III

Inhibitory action on dextran-induced spike reactions in rats with the compound of Example 1 and terbulin.

Test compound Dose mg / kg i.v. the compound of Example 1 0.01 the compound of Example 1 0.10 the compound of Example 1 1.00 Terbutalin OjOl Terbutalin 0.10 Terbutalin 1.00

Remarks on the results of the tests in Table III.

Injections of dextran induce papillary reactions with a diameter of 15 to 20 mm. The compound of Example 1 and terbutaline inhibit bud development to the same extent. There is no significant difference between the efficacy of the two substances. The inhibitory effect is completely blocked by propranolol (0.5 mg / kg) administered intravenously 5 minutes before agonists.

Table IV shows the efficacy values of all test substances relative to terbutaline (ED 50 = 0.08 mg / kg).

B. Bronchospasmolytic effect

In order to study the relative effectiveness of anti-blue, ее is determined visually using values of 1 to 4. PCA · = passive cutaneous anaphylactoid reactions.

Inhibition of PCA (%) Number of experiments

16 + 2

42 + 65

78 + 25

18 + 35

56 + 65

81 + 45 of the anaphylactic effect of bronchospasmolytic effect, the bronchospasmolytic effect of the compounds of the invention is monitored.

Isolated guinea pig trachea relaxation

Method:

Guinea pigs weighing 0.15-0.30 kg are removed from the trachea. Its spiral sections are placed in a 25 ml organ bath in Krebs solution with a continuous air mixture of 95% oxygen and 5% carbon dioxide. Pilocarpine is added in an amount of 1 µg / ml. The initial tension is about 2 g. Relaxations are recorded isothermally. The test solutions are added to the liquids in the bath either as a single dose or cumulatively. Responses are expressed as a percentage of the maximum possible response of each preparation obtained by adding a supermaximal concentration of isoprenaline. 'For each specimen. individual EC 50 values (concentrations eliciting 50% of the maximal response) are counted.

Maximum response is achieved with isoprenaline. Table IV gives comparisons of efficacy with terbutaline at this level. The efficacy values reported are mean values of 2 to 4 experiments.

Results

Compound of. Example 1 relaxes the isolated guinea pig trachea as well as isoprenaline. In cumulative experiments, the EC 50 for the compound of Example 1 is 0.2 + 40), 54 µg / ml (Mol. Weight + Standard Deviation, 8 experiments). The potency of the compound is 0.03 times that of adrenaline and 0.04 times that of terbutallin.

The tracheal relaxation activities of all test compounds are given in Table IV.

C. Heart-stimulating effect

Compounds of the invention. are also tested in relation to their cardiac stimulating effect. The prominent cardiac stimulating effect is one of the serious undesirable side effects of the substances that are considered for. use to treat allergies, including bronchial asthma.

Stimulation of guinea pig ventricular contractility

Method

The guinea pig left atrium is excised from animals of both sexes 0.5 to 0.9 kg and immediately suspended in a 100 ml tissue bath with Krebs flow 24 at 31 ° C, an air mixture of 95 why, oxygen and 5% carbon dioxide . The preparation is stimulated with pulses (from Model 55 Grass Stimulator, frequency: 1 s, duration: 1 to 5 ms, voltage 1 to 5 'V). Isomeric tension is registered. The increase in contractile force is expressed as a percentage of control tension. Test compounds are added in unit dose form with occasional washing. Individual EC 50 values (concentrations causing a residual tension increase of '50%') are calculated and a comparison of efficacy with terbutaline is performed at this level.

The efficacy data in Table IV represents the average of two. attempts.

Results

The compound of Example 1 increases the contractility of the electrically stimulated auricles of the guinea pig left atrium. The EC 50 value is 2.70 ± 0.10 (tU / ml (molar mass + + standard deviation of the average, 5 trials) and for terbuitalin 0.11 ± 0.02 µg / ml. The cardiac stimulating effect of the compound is blocked by propranolol in an amount of 1 µg / ml.

Stimulating effect of all test compounds in relation to terbutaline. - is given in Table IV.

Compilation of pharmacological test results

Table 'IV' below summarizes the pharmacological test results for the 'anti-anaphylactic, bronchospasmolytic and cardiac stimulating effects. All values are given as relative efficacy, using the appropriate terbutaline effect as unit (1.0).

Ta.bulka IV

Compilation of data from pharmacological tests. The effect of the terbutaline comparator is taken as 1.0 and the effect of the test compounds is related to this terbutaline effect

Tested Structure Inhibition Inhibition Relaxation Stimula- substance from OF relax- passive vent- ce srdeč- ex. C. vání his- cutaneous nlce her auri- taminu z anafy- guinea pigs kuly actively laktoid- guinea pigs honestly- financial reaction of the lungs ce in rats guinea pigs

НО

Isoprénalln

HIM

Q) -CH-CH ₃ NH-CH (CH ₃ ) ₂

OH

2,0

ΙΟ18

1000

Terbutaline (reference substance)

HIM

ЮУ-СН-СНгИН-С- CH.

CH,

1.0

1.0

1.0

О, О

He did

HO HO

AND

OH

HO (CH.KCH-C-0 * 11'o,

OY-CH-CH 2 N-C-sulfur * | I A OH H CH, он

Example 8

O (СН & СН-С-0

Ю ^ -СН-СН _г Н-С-СЦрН 'OH

H CH,

1.0

1.0

0.04

0.03

0.1

1.0

Example 2

HIM

1.0

1.0

0.1

0.3

Example 4

Example 5

Example 3

HO h снрн

0.003

0.01

0.03

1.0

HIM

H OH

CH; N-CH

I i

H CH.OH

Remarks on the results of the tests in Table IV

The efficacy data given in column 4 of Table IV represent the average values of 2 to 3 sawmill tissue samples at the 3 to 4 dose level. The number of studies for the compound of Example 1 and for terbutaline is given in Table I.

It can be seen from Table IV that the compounds of the invention inhibit antigen-induced histamine release from guinea pig cuts and the development of anaphylactoid skin reactions in rats. The concentrations of terbutaline required for trachea release and inhibition of histamine release are approximately the same. The same relationship between trachea relaxation and inhibition of histamine release was found with isoprenaline. However, terbutaline shows a much more favorable relationship between antiallergic effects and cardiac muscle stimulation than isoprenaline (quotient 1 for terbutaline and 0.2 for isoprenaline).

Preferred compounds of the invention, i.e., 1- (3,5-dihydroxyphenyl) -2 - ((1,1-dimethyl-3-hydroxyethyl) jamino Jetanol sulfate and related compounds, have a different activity profile than terbutaline and isoprenaline, i.e. have anti-allergic effects The compound of Example 1 inhibits anaphylactic histamine release from guinea pig lungs and anaphylactoid skin reaction in rats at the same concentration as terbutaline, whereas the effect on guinea pig trachea is only 0.04 times that of terbutaline that is, the quotient between antiallergic effects and trachea relaxation is 25. The effect of the compound of Example 1 on the atrial auricular preparation is 0.03 times the effect of terbuitalin, i.e. it has the same favorable ratio between tracheal relaxation and atrial auricular stimulation as terbutaline Propranolol blocks this effect, indicating that it is iS- As seen in Table II, the compound of Example 1 also inhibited a non-histamine muscle contraction agent that is released from the lungs upon anaphylaxis.

Thus, the compounds of the present invention exhibit selective antiallergic effects over a dose range whose effect on bronchi and heart is negligible.

C. Toxicity

The acute toxicity (LD 50 of 1- (3,5-dihydroxyphenyl) sulphate) - [(1,1-dimethyl-2-hydroxyethyl) amino] ethanol was determined by a standard mouse test (

NMRI, 25 g). Intravenous toxicity is 110 ± 58 mg / kg body weight and the LD 50 after subcutaneous administration is 400 ± 18 mg / kg body weight.

Claims (2)

A process for the preparation of novel phenylaminoethanol derivatives of the general formula I in which R ¹ and R ² are the same or different and are hydrogen, an aliphatic acyl group having 1 to 5 carbon atoms, benzoyl or phenylacetyl, A represents a straight or branched alkylene group having from 3 to 6 carbon atoms or a cycloalkylene group having from 4 to 6 carbon atoms, as well as their physiologically acceptable salts, characterized in that the compound of the formula II is reduced RO in which R is hydrogen or a hydroxyl protecting group such as an alkyl or aliphatic acyl group of up to 5 carbon atoms, a mono- or bicyclic aralkyl group of up to 11 carbon atoms such as benzyl or naphthylmeithyl, or a benzoyl or phenylacetyl group, A has the meaning given above and В means Group of formula —CH = N— 199844 or —СНг-NR5 where R ³ is hydrogen or an N-protecting group such as benzyl, whereupon R ³ and R ³ protecting groups are removed and, if necessary, the compound of formula I obtained is converted into its physiologically acceptable salt and / or or resolves into their optical isomers. 2. The process of item 1 for producing a compound of formula Ia, wherein the compound of formula II wherein R has the same meaning as given in point 1 And denotes a group СНз —CH ₂ —οΙ СНз V has the same meaning as given in 1 above and is then reduced, if necessary, by removing the protecting groups R and R ³ from the obtained compound.