CS199643B2 - Method of producing novel derivatives of phenylaminoethanol - Google Patents

Description

The invention relates to a process for the preparation of novel pharmacologically active phenylaminoethanol derivatives. Their therapeutic use is also disclosed, and pharmaceutical compositions containing the compounds are also described. The novel compounds of the present invention are particularly antiallergic. and anti-anaphylactic efficacy and are particularly valuable as anti-asthma agents and can also be used in the treatment and prophylactic treatment of other allergic diseases.

The term "allergy" refers to Dorland's "Illustrated Medical Dictionary",

24th Edition, 1967 ", a hypersensitivity state obtained by exposure (exposure) to a particular allergen, and re-exposure leads to a change in 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-antibody response, which leads to the release of pharmacologically active substances (= mediators), among others histamine and SRS-A (= slow-reacting anaphylactic agent). The mediators released in this way cause bronchoconstriction, oedemas, increased mucus formation, itching, etc. The sequence of reactions can be explained schematically as follows:

Stage 1

The organism enters allergen (antigen) i. .

Stage 2

Antigen - enters the reaction with antibodies, resulting in

L.

Stage 3 insertion of medlators l

Stage 4.

the released substances, especially histamine and SRS-A, induce symptoms of an allergic reaction: brhohoostriction, edema, increased mucus production and the like.

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

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

While the following description emphasizes exogenous bronchial asthma, which is only one form of allergy, 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 has already started or is 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 mediators appearing in step 3 of the above scheme. Some sympathomimetic amines, including those used in the treatment of asthma - adrenaline, isoprenaline, terbutaline - are also known to inhibit the release of antigen-induced mediators.

These substances have anti-anaphylactic activity in the same dose range as is 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, for example by vasodilation, cardiac stimulation and tremor. Compounds with a specific inhibitory effect on the release of spasmogenic agents are effective as prophylactic and antianaphylactic agents in the treatment of various types of allergies, including bronchial asthma, without the side effects observed with sympathomimetic amines commonly used as brochospasmolytic agents.

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

R ¹ 0 ⁰ ()>

in which

R ¹ and R ² are the same or different and denote hydrogen, an aliphatic acyl group having 1 to carbon atoms, benzoyl or phenaylacetyl and

And depicting a straight or branched chain of 3 to 6 carbon atoms or a cycloalkylene group of 4 to 6 carbon atoms, and their physiologically acceptable salts, exhibit marked anti-anaphylactic activity over a dose range at which their heart-stimulating and bronchospasmolytic effects are negligible. This unexpected and beneficial combination of properties makes the compounds of the invention valuable anti-anaphylactic agents that can be used in the prophylaxis of various forms of allergy, such as allergic rhinitis, hay fever, urticaria, asthma and the like with reduced risk of side effects commonly observed with sympathomimetic amines.

Illustrative examples are H— СНзСО— СНзСНгСО— CH3CH2CH2CO— (СНз) гСНСО— examples of groups R ¹ and θ-CAi-CСНз (СН2) зСО—

СНз

AND

H — С — СНгСО -

AND

СНз

СНз

AND

СНз — с — со—

СНз

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

AND

СНз —CH2 — CH—

AND

СНз —CH2CH2CH2CH2—

СНз

-C-CH2I

СНЗ

СНз

I —CHzCHžCH—

-CH2CH-CH2-

CI-I3 —CHCH2CH2—

AND

CH3

C2H5 —CH2CH— β

CH3 СНз —CH — CH— —CHCH2—

AND

C2H5

/ СЦ-СН ^-CH I and \ CH — CHa

. ČH3

CH - CH - NH - CHCH - H - OH OH

-CH CH2 R @ ^{1 is} preferably hydrogen.

A is preferably straight or branched chain alkylene groups containing 3 or 4 carbon atoms.

Illustrative examples of the compounds of the invention are

CH,

I 3

CHCH CHCH-NH _{£ £} OH

OH

CH,

I 5

CH-CH 3 NH-CHCHCHOH OH

CH »

I '

CH-CH 2 NH-CHCH 2 CH OH

OH

HIM

CH-CHNH-CH-CHCH 2 OH

OH CH _S CH 3

HIM

HIM

NO-CH-NH-, CH _£ Cty OH OH C & но

ζ ^ -coo

O

CH-CH 2 NH-C-CH 2 Cl 2 CH 3 CC 3

CHt 1 ^{3 CH} ₃

cn ₃

CH-CH _£ NW-C-CH; OH ii *

OH _{CH3 (у} СО о & ΟΗ £ Οθ '0 ^μ

С00. ^С н _ъ

СУ CH-CH; NH-C- CH.OH 1 * I * OH CH (^ -ΟΗ, ΟΟΟ, (У ^ соо)

4__ CH ₃

1-CH-CH-NH-C-CH ₂ H ₁ - / 1 * I ** / OH CH ₂

Q-coo ° ^μ

CH ₉ o

3II

CH-C 1 -NH-C-CH.OCCH 3. i ⁴ I * · °

CH ₃ (у _С оо,

CH I _t 'FACH -CH _£ ± NH

ОН СН. ^{4 = 7} ω-CH-CHgNH-CH ω ^-ч ч С ^ ^ ^ ^ ^ с

CH-CH-CHrNH I _H0 and _H

HIM

V - ^CH - (CH - CH 2 NH - CH CH - OH

I-CH-CH

OH но ^ СНСН ^ Н-С-СН ^

Q-coo ^ ^IH У

CH ₅ COO CH ₃

C ^CH-CHjNH-C-CHgH

CH.COO ^{OH CH} $ w

CH.

I ³

CH-NH-C-CH / OH is ₅ to ₃ with

AND

CH 2 CH 2 CO 2 ^ομ

CW. I ³ СН-СН ^ -НН-ССНгОН / -% СР ₅

HC-COO 1 \ _____ cw ₃

^{€ μ} ι N-CH-CH3-NH-C-CKOH ОН CH, нс-соо

CH, сн, цр-с-соо

Уу сн,> / М.С-С-СОО «- I сн _л

CH-CH3 NH-CHCH3 OH

A preferred group of compounds are those compounds wherein R ¹ represents a hydrogen atom and A represents a straight- or branched chain of 3 or 4 carbon atoms.

Preferred compounds of the invention are

HO (JJ-CW-CH-CH _£ WC- OH ^но он Д tp ^ i-klídl)

OH

CH, CH-CH 2 NH-CHCH 2 OH (example. λ)

chemical mixtures of compounds. Racemic mixtures can be resolved by conventional methods, for example by salt formation with an optically active acid followed by a crystallization fraction.

The compounds of the invention may be formulated for use in human and veterinary medicine for therapeutic and prophylactic uses. They can generally be used in the form of physiologically acceptable salts, for example, hydrochloride, sulfate, maleicate, tartrate and the like.

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, a physiologically acceptable salt thereof, together with a physiologically harmless carrier which may be a solid, semi-solid or liquid diluent. or a digestible capsule. 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% by weight for preparations intended for oral administration.

For the preparation of pharmaceutical compositions in the form of dosage units for oral administration containing a compound of the invention, the active ingredient may be admixed with a solid powder carrier such as lactose, sucrose, sorbitol, mannitol, starch such as potato starch, corn starch, amylopectin, laminar powder or powder. lemon pulp, cellulose derivative or gelatin, and glidants such as magnesium or calcium stearate or polyethylene glycol waxes (e.g. Carbowax (g) J) may also be included and may be compressed to form tablets or dragee cores. coated, for example with concentrated

A particularly preferred compound of the invention is the above compound of Example 1.

Since the compounds of the formula I according to the invention have at least one asymmetric carbon atom, the invention also includes all possible optically active forms and radicals.

Sugar solutions, which may contain gum arabic, talc and / or titanium dioxide or a film-forming agent, dissolved in slightly volatile organic. solvents or mixtures of organic solvents. Dyestuffs can be added to these coatings, for example to distinguish different contents of the active ingredient. For the preparation of soft gelatine capsules (bead-like capsule capsules) consisting of gelatin and, for example, glycerol as a plasticizer or similar capsule, the active compound can be admixed with polyethlyenglycolam (Carbowax (§)) or a suitable oil, for example sesame. oil, olive oil or peanut oil.

Hard gelatine capsules may contain granules of the active ingredient with solid powdered carriers such as lactose, sucrose, mannitol, starches (e.g. potato or corn starch or amylopectin), cellulose derivatives or gelatin, and may also contain magnesium stearate or stearic acid as glidants. . By using several layers of active drug, separated by slow dissolving coatings, slow release tablets are obtained. Another method for producing slow release tablets is by dividing the dose of the active compound into granules having different thickness coatings and compressing the granules into tablets together with the carrier. The active compound may also be incorporated into slow-dissolving tablets made, for example, from fatty and waxy compounds, or evenly dispersed in a tablet from an insoluble material, for example 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 may be in the form of elixirs, syrups or suspensions, for example solutions containing from about 0.1 to 20% by weight of active ingredient sugar and a mixture of ethanol, water, glycerol, propylene glycol and optionally a flavoring, saccharin and / or or carboxymethylcellulose as a dispersing agent.

Injectable preparations for parenteral administration may contain an aqueous solution of the water-soluble physiologically acceptable salts of the active compound according to the invention, a desirable concentration of 0.5 to 10% by weight and optionally also a stabilizing agent and / or a buffer in the aqueous solution. Dosage units of the solution 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 200 mg per day. A suitable parenteral dosage range is from about 1 to about 50 mg per 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 compounds of the invention are prepared by known methods, for example by reacting a compound of formula II

/ \ ch-cha (in which

R denotes hydrogen or a protecting group for a hydroxyl group, for example an alkyl or aliphatic acyl group, at most. 5. a carbon atom, a mono- or bicyclic aralkyl group of not more than 11 carbon atoms, for example a benzyl or naphthylmethyl group, or a benzoyl group or a phenylacetyl group, with a compound of the general formula III

HN — A — OR ²

Ø ³ (III).

in which

R2 denotes hydrogen, aliphatic. an acyl group having 1 to 5 carbon atoms or a benzoyl group or a phenylacetyl group, x

R3 represents a hydrogen atom or an N-protecting group, for example benzyl and

A denotes a straight-chain or branched alkylene group having 3 to 6 carbon atoms or a cyclolylene group having 4 to 6 carbon atoms, to form a compound of formula IV

RO

in which

R, R ' ² , R ^{3 and} -A have the meaning given above, whereupon if it is. optionally, deprotecting the groups R and R ³ , and optionally converting the final product into a physiologically acceptable salt.

The starting materials used in the above reaction are known compounds which can be prepared in a known manner.

Starting materials can be prepared, for example, as is. illustrated in the reactions below, wherein R, R 3, X and A are as described in this description:

The following examples illustrate the invention.

Example · 1

Preparation of 1- (3,5-dihydroxyphenyl) -2 - ((1,1-dlmethyl-2-hydroxyethyl Jamino) ethanol sulfate

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

To a solution of 6.6 g of 3,5-benzyloxystyrene oxide in 100 ml of n-propanol is added 4.5 g of 2-amino-2-methyl-1-propanol. After refluxing for 20 hours, the mixture was evaporated to dryness and the residue was extracted with diethyl ether. The ether phase is washed with water and. dried with magnesium sulfate. Concentration of the ether solution leads to crystallization of the base of the above compound. Yield 3.7 g.

Analyzes of the reaction product were performed using IC, NMR and mass equivalent. The crystalline base was dissolved in a mixture of ethanol and diethyl ether and a calculated amount of 5N sulfuric acid was added to precipitate the sulfate of the title compound.

Yield 4.7 g.

Analysis: IC, NMR, SCh ² : 99.4%.

(b) 2.0 g of 1- (3,5-benzyloxxphenyl) -2- (1,1-dimethyl-2-hydroxyethyl) amino] ethanol sulfate are suspended in 200 ml of methanol and hydrogenated at room temperature and atmospheric pressure for 1 hour. hours in the presence of 0.2 g. 20% palladium on coal. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue was recrystallized from isopropyl alcohol.

Yield 0.7 g.

Analyzes: IR, NMR, SOC (99.0%) + traces of residual solvent. ·

Same way. was used ' . for the preparation of the following compounds:

Example 2,

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

SO42 ·: 97.4%, mp 194 ° G. The structure of the compound was confirmed by NMR.

Example 1 a d 3

1- (3,5-Dihydrophenyl) -2 - ((4-hydroxycyclohexyl) amino] ethanol hydrochloride

Calculated: 11.7% Br, found 11.5%

Br-.

Temperature. mp 234 ° C.

The structure of the compound was confirmed by NMR.

Example '4

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

Oil, calculated: 13.4% С. found:

12.4% C1-.

The structure of the compound was confirmed by NMR.

Example 1 a d 5

1- (3,5-Dihydroxyphenyl) -2 - ((1-ethyl-2-hydroxyethyl) amino) ethyl alcohol hydrochloride

Oil, calculated: 12.8% Cl, found: 11.6% target.

The structure of the compound was confirmed by NMR.

Example 1 'and d 6

1- (3,5-111117111'0X710071) -2 - (, (3-hydroxypropyl) amino] ethanol sulfate

SO42-: 92%.

The structure of the compound was confirmed by NMR.

Example 1 a d 7

1- (3,5-Dihydroxyphenyl) -2 - ((2,2-dimethyl-2-hydroxyethyl) amino] ethanol hydrochloride

Calculated:. 12.8% Cl ~, found 12.5% Cl.

212 ° C.

The structure of the compound was confirmed by NMR.

The following .compounds. are produced in the same way:

Example 13

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Example 8

1- [3,5-bis (2-Methylpropionyloxy) phenyl] -2 - [(1,1-dimethyl-2-hydroxyethyl) amino] ethanol hydrobromide

Calculated: 17.3 Br, found: 17.4% Br-.

The structure was confirmed by NMR.

Example 9

1- [3,5-bis (2,2-Dimethylpropionyloxy) phenyl] -2 - [(1,1-dimethyl-2-hydroxyethyl) amino] ethanol hydrobromide

Calculated: 16.3% Br, found: 16.4 Br.

The structure of the compound was confirmed by NMR.

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

Example 10

Aerosol for inhalation:

1- (3,5-dlhydroxyphenyl-2 - [(1,1-dimethyl-2-hydroxyethyl) amino] ethanesulfate 1.00 g solvent (Miglyol) 0.20 g propellant (Frigen ®

11/12/113/114) up to 100,00 g

Example 11

Tablets

Each tablet contains:

1- (3,5-dihydroxyphenyl) -2 - [(1,1-dimethyl-2-hydroxy-

ethyl) amino] ethanolsulfate 20.0 mg cornstarch 25.0 mg lactose 190.0 mg gelatine 1.5 mg talc 12.0 mg magnesium stearate 1.5 mg

250.0 mg

Example 12

Cípky

Each cone contains:

1- (3,5-dihydroxyphenyl) -2 - [(1-methyl-2-hydroxyethyl) amino] Jethanol sulphate 20.0 mg ascorbyl palmitate 1.0 mg suppository base (Imhausen H) to 2000.0 mg

Syrup

1- (3,5-dihydroxyphenyl) -2 - [(2-hydroxypropyl) JaminoJethanol Hydrochloride 0.200 g

liquid glucose 30.0 8 sucrose 5.0 G ascorbic acid 0.1 8 sodium pyrosulphite 0.01 G edetic acid disodium salt 0.01 G orange essence 0.025 g harmless dye 0.015 8 purified water to 1000.0 8

Example 14

Solution for injection.

1- (3,5-dlhydroxyphenyl) -2- [11-hydroxy-propyl] amino] ethanol hydrochloride 0.500mg sodium pyrosulphite 0.500mg disodium edetate 0.100'mg sodium chloride 8.500mg sterile water for injections up to 1.00mg

Example 15

Inhalation solution

1- (3,5-dihydroxyphenyl) -2- [(1,1-dimethyl-2-hydroxyethyl) amino] Jethanesulfate 5.00 g sodium pyrosulphite 0.1 g g disodium edetate Os, 10 g sodium chloride 0.85 g purified water to 100.0 ml

Example 16

Solution for rectal use (rectal vials) 1- (3,5-dihydroxyphenyl) -2 - [(1-methyl-2-hydroxyethyl) amino] Jethanol sulphate 20.0mg sodium pyrosulphite 1.5mg disodium edetate 0.3mg sterile water to 3.0 ml

Example 1 a d 1 7

Sublingual tablets

1- (3,5-dihydroxyphenyl) -2 - [(2-hydroxypropyl) amino] ethanol hydrochloride 5.0 mg lactose 65.0 mg agar 5.0 mg talc 5.0 mg

100.0 mg

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Example '15

Drops

1- (3,5-dihydroxyphenyl) -2 - [(2-hydroxypropyl) amino] ethanol hydrochloride 2,00'g ascorbic acid 1, (00: g sodium pyrosulphite 0,10'g edetic acid disodium 0,1-0 · G liquid glucose 50,00 g absolute ethanol 10,00 g purified water up to 100,00 ml

Pharmacological tests

A. Anti-Anaphylactic effect

The anti-anaphylactic effect was tested in actively and passively sensitized laboratory animals.

Active sensitization of animals is achieved by injection of ovalbumin protein. This application renders the animals hypersensitive to the following 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 evaluating the effect of the test compound on the amount of histamine released as such from the lung preparation.

1. Irhiibic release of histamine from actively sensitized guinea pig lungs

Methods:

Guinea pigs of both sexes weighing 300 to 40 g, are given a single 50 mg mg of intraperitoneal injection of ovalbumin emulsified in complete Freund's adjuvant. Animals are used 2 to 5 weeks later in challenge. I'll try below.

Sensitized animals are sacrificed and bled. The lungs are removed and pulverized. Lungs from 2 to 4 animals are used in each test sari. After washing several times with Krebs solution, the tissue is divided into tubes with Krebs solution (0.1 g of tissue per 1 ml) and placed in a 37 ° C water bath. compound is added 2 minutes before ovalbumin addition Incubation is usually continued for a further 15 minutes while the tubes are occasionally shaken manually Occasionally the histamine release phase is stopped by placing the tubes in an ice bath The incubation fluids are decanted and replaced with acidified sodium chloride solution Hydrochloride to pH 3.5 Boil tissue with sodium chloride solution for 5 min on water bath Incubation fluids and tissue extracts are kept in an ice bath prior to testing.

The histamine content of incubation fluids and cooked extracts is determined by a guinea pig intestine test. Portions of the terminal ileum, 2 cm long, from guinea pigs weighing 0.2 to 0.3 kg are placed in 20 ml baths at 37 ° C containing Krebs solution continuously aerated with small bubbles of carbogen. Atropine in an amount of 10-7 mol and propanolol in an amount of 10-mol were added to the bath. The contractions were recorded using a force transducer (Grass, FT03) and a recorder (Grass, Model 7).

After about 1 hour after several washes, the sensitivity of 1 preparations to repeated doses of ⁷ histamine is tested. Segments with low sensitivity and considerable variability and unstable base are discarded. Preparations with high spontaneous activity are also excluded. The preparations are standardized to correspond to 2, 4, 5 and 12 ng of histamine base in 1 ml. These doses are administered repeatedly in a random sequence until constant responses are obtained. The extent of bowel contraction within this range corresponds to the logarithm of the histamine dose. The test solutions are added in an amount of 0.1 to 1.0 ml, chosen to induce the same amount of contractions as is obtained with an interventional dose of histamine. Keeping this standard standard histamine dose at a constant level facilitates the monitoring of changes in bowel sensitivity that have been in contact with histamine for 15 seconds. or • with the test solution. During this time, the largest number of contractions was recorded. After washing, allow 2 min. · Before the next dose. All solutions are added by pipette. The contractility of the test solutions on the isolated guinea pig ileum is expressed as the histamine base. The spontaneous lung-induced histamine release is derived from the values reported. The results are expressed as released histamine per gram of wet lung weight or percent inhibition of histamine release.

Terbutaline or isoprenaline. is used as a reference. Terbutaline (Bricanyl (R)) is a sympathomimetic amine used in the treatment of bronchial asthma Two identical samples are used in each test series All samples in the same sera are tested against the same histamine standard. The compound of the invention is given in Table I below. A summary of the test results is summarized in Table IV, in which the effect of each substance in relation to the efficacy of terbutaline is compared.

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Table I

Inhibition (%) of hlstamine release from sensitized guinea pig lungs. Control release without inhibition is 15 'to 30% of tissue Inhibitor Inhibition (%)

Ho »ho -histamine. The mean values + standard deviation of the mean are given and the number of specimens tested is in parentheses.

in various concentrations (molarity)

Ю-7 10-8 io ~ ⁵

Compound of Example 1 Terbutaline

20 ± 5 -

30 mm (1)

30 + 5 (9)

24 + 5. (7)

42 + 3 (9)

443 ± 8)

51 + .3 (9)

58 + 3 (7)

Remarks on the results of Table

Ovalbumin-indicated histamine release from actively sensitized guinea pig lungs represents 10 to 30% of the tissue amount determined by boiling tissue. Spontaneous release of histamine from lung tissue did not exceed 2%. When the test compound of Example 1 was added to the lung tissue for 2 min. prior to antigen, hisitamine release is inhibited by a dose-dependent mechanism. The potency of the test compound is approximately the same as that of terbutaline. Maximum 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 at a dose of 10-6 mol. The inhibitory effect of terbutaline on histamine release is achieved with the same concentrations that release pilocarpine-induced guinea pig traps.

2. Inhibition of the release of the non-ancient, slow withdrawal principle - SRB-A

The non-histamine, slowly contracting principle is tested on the same ileum preparation as above, but after addition. 0.04 µl / ml brompheniramine. This concentration completely blocks the hlstamine response. - To obtain a contraction equilibrium - it is used for the test fluid - time 1.5 min. Contactivity of this non-histamine fraction is expressed by SRS-A units, the response of one SRS-A unit being equivalent to a maximum of 5 μξ histamine obtained on the same non-blocked guinea pig ileum preparation. Results These are given in Table II below.

T and b u 1 k and II

Inhibitory effect on the release of slow contracting non-histamine principle (SRS-A) from sensitized lungs - guinea pig ч

Experiment no. Control U- Inhibition (%) obtained with the compound of Example 1 (molarity) release rate, ^_ 10 8 10/10 "10 'units / g lung

10851

3355

2757

Remarks on the test results from Table II

It can be seen from Table II that in the presence of the test substance (from Example 1) at a concentration of 10-8 to 10 ^-5 mol.l in three experiments with different samples, lung tissue inhibits 50-75% by non-histamine spasmogens.

3. Inhibition of passive cutaneous anaphylactoid reaction in rats

Method:

Male Sprague Dawley rats weighing 150-300 g are anesthetized with pentobarbital (30 mg / kg intravenously). Evans blue (10 mg / kg) - and test substance - are injected intravenously into the femoral vein. Six intracutaneous punctures are then performed at

57 not given

81 79

86 83 two rows on each side of the midline of the abdomen with dextran - 70,000 molecular weight. The amount of - dextran - applied to each puncture is 60 µg in 0.1 ml ml sodium chloride solution. Dextran induces - anaphylactoid reaction. After 30 min. the animals are sacrificed and the abdominal skin is excised. - Using points 1 to 4, - the color intensity is visually determined. Experiments with non-control animals - always take place without the action of the drug with the compound of the example - las terbutaline. The other compounds were tested on two animals at each - at a dose level of 3-4 doses. Comparison with terbutaline is made at the ED50 level, which means an effective dose of 50% inhibition of the color intensity of the blue stains.

The results are shown in Table III below.

Γ

Table III

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

Blues, lesions are determined visually using points 1 to 4. (PCA = passive cutaneous anaphylactoid reaction.)

Test compound Dose mg / kg 1st v.

Compound from Example 1 0.01 Compound from Example 1 0.10 Compound from example 1 1.00 Terbutalin 0.01 0.10 Terbutalin Terbutalin 1.00

PCA Inhibition (%)

Number of attempts

16 + 25

42 + 65

78 + 25 .18 + 35

56 ± 65

81: +45

Remarks on the results of the tests in Table III.

Dextran injections 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) given intravenously for 5 minutes. before agonists.

Table IV gives 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 potency of the anti-anaphylactic effect of the bronchospasmolytic effect, the bronchospasmolytic effect of the compounds of the invention is monitored.

Relaxation of the isolated guinea pig trachea

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 ' s solution continuously aerated with 95 mixture ^! % oxygen and 5 ·% carbon dioxide. Pilocarpine is added in an amount of · 1 · / zg / ml. The initial tension is about 2 g. Relaxations are recorded isometrically. 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 isoprenaline concentration. Individual EC 50 values (concentrations eliciting 50 ° / o maximum response) are calculated for each preparation.

With isoprenaline the maximal response is achieved. Table IV gives comparisons of efficacy with terbutallne performed at this level. The efficacy values reported are mean values of 2 to 4 experiments.

Results

The compound of Example 1 relaxes the isolated guinea pig trachea as well as isoprenaline. In cumulative experiments, the ED 50 value for the compound. from Example · 1'0.2 + '+0), 54 µmol / ml (molecular weight + + and standard deviation of mean, · 8 experiments). The potency of the compound is 0.03 times that of adrenaline · and 0.04 times that of terbutaline.

The tracheal relaxation efficacy of all test compounds is given in the table

IV.

C. Heart-stimulating effect

The compounds of the invention are also tested in relation to. their cardiac stimulating effect. The significant cardiac-stimulating effect is one of the serious undesirable side effects of substances that are considered for use in the treatment of allergy, including bronchial asthma.

Stimulation of guinea pig cardiac contractility

Method

The guinea pig left atrium is excised from animals of both sexes of 0.5 to 0.9 kg and immediately _; is suspended in a 100 ml tissue bath with Krebs solution at 31 ° C, an air mixture of 95% oxygen and 5 ·% carbon dioxide. The preparation is stimulated with pulses · [from Grass Stimulator model 55 (frequency: 1 s, duration: 1 to 5 ms, voltage 1 to 5 V)]. Registers ·. with isomeric tension. 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 an increase in residual tension by 50%) are calculated and a comparison of efficacy with terbutaline is performed at this level.

Efficacy data in Table IV. represent the average of two experiments.

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Results

The compound of Example 1 increases the contractility of the electrically stimulated auricle of the left atrium of the guinea pig atrium. The EC 50 value is 2.70 + 0.10 (g / ml. (Molecular weight + standard deviations of the average, 5 experiments) and for terbutaline 0.11 + 0.02 µg / ml. The potency of the compound is 0.04 times the potency. The heart-stimulatory effect of the compound is blocked by propranolol in an amount of 1 µl / ml.

The stimulatory effect of all test compounds relative to terbutaline is given in Table IV.

Compilation of pharmacological test results

Table IV below summarizes the results of the pharmacological / anti-anaphylactic, bronchospasmolytic and cardiac stimulating effects. All values are given as relative efficiencies,. where appropriate. effect of terbutaline as a unit of <(1.0).

Table IV

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

Tested Structure Inhibition Inhibition Relaxation Stimula- substance from relax- passive. vent- ce srdeč- example vání his- cutaneous nice her auri- C. taminuz actively sensitizediplic 'guinea pigs anaphylactoid reactions. in rats guinea pigs guinea pigs

HIM

Isoprenalin

CH-CH ₂ NH-CH (CH _{3 12}

OH

2,0

Terbutaline (reference substance)

HIM

1.0

Example 1 ho CH _S ? OV cw-сад-с- ch / oh hT OH η CH,

1.0 (сн & сн-с-о сн _ъ

Example 8 O (ОУсН-CHrN-C-CkOH

Q> - / I * I * (CH & CH - CO ^{ομ μ ср} з

0.1

Example - 2

Example 4

1.0

1.0

10 18 1000 1.0 1.0 1.0 1.0 0.04 0.03 1.0 1.0 0.1 0.3 0.03 0.003 0.01

Test structure Example compound

C.

²⁴

Inhibition of passive Relaxation Stimulo-loosening skin bronchitis of the anaphylaxis of auritamine z. guinea pig lactoid actively guinea pig responses - in guinea pig rat lungs

Example 5

CH-CK-N-CH II '

OH. , H сири

0.07 0.1 0.001 0.001

Example 3

HIM

0.07 0.01 0.001 0.000

Remarks on results - tests from Table IV

The efficacy data reported in column 4 of Table IV represents the average of 2 to 3 different lung 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 is evident from Table IV that the compounds of the invention inhibit antigen-induced histamine release from guinea pig lung sections 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-2-hydroxyethyl] amino-ethanesulfate of Example 1, and related compounds have a different activity profile than terbutaline and isoprenaline, that is, they have antiallergic effects at concentrations at which they have a very weak relaxing effect on the trachea. The compound of Example 1 inhibitor is anaphylactic histamine release from guinea pig lungs and anaphylactoid skin reaction in rats at the same concentration as terbutaline, while the effect on guinea pig trachea is only 0.04 times that of terbutaline. which means that -. the quotient between antiallergic effects and trachea relaxation is 25. The effect of the compound of Example 1 on the auricle preparation. atrial atria is 0.03 times the effect of terbutaline, ie it has the same favorable ratio between trachea relaxation and cardiac atrial auricular stimulation as terbutaline. Proprenolol. blocks this effect, indicating that it is a β-stimulant. As can be seen from Table II, the compound of Example 1 also inhibits a non-histamine muscle contracting agent that is released from the lungs upon anaphylaxis.

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

C. Toxicity

The acute toxicity (LD50) of 1- (3,5-dihydroxyphenyl) -2- [1 (1,1-dimethyl-2-hydroxyethyl) amino] ethanol sulfate was determined by a standard mouse test - (male, NMRI, weight 25 g) ). Intravenous toxicity is 110 + 58 mg / kg body weight - and the LD 50 after succinate administration is 400 + 18 mg / kg body weight.

Claims (2)

OBJECT OF INVENTION 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 denote hydrogen, an aliphatic acyl group having 1 to 5 carbon atoms, benzoyl or phenylacetyl; and A denotes a straight-chain or branched alkylene group having 3 to 6 carbon atoms or a cycloalkylene group having 4 to 6 carbon atoms, as well as their physiologically acceptable salts, characterized in that a compound of the formula II is reacted HN — A — OR ² AND R ³ in which R ² is hydrogen, an aliphatic acyl group having 1-5 carbon atoms or benzoyl or phenylacetyl, R ³ is hydrogen or an N-protecting group such as benzyl, and A denotes a straight-chain or branched alkylene group having 3 to 6 carbon atoms or a cycloalkylene group having 4 to 6 carbon atoms, to form a compound of formula IV RO / ° \. CH — CH _k (ID in which R is hydrogen or a hydroxyl-protecting group, for example an alkyl or aliphatic acyl group of up to 5 carbon atoms, a mono- or bicyclic aralkyl group of up to 11 carbon atoms, for example benzyl or naphthylmethyl, or a benzoyl or phenylacetyl group, of the formula III in which the above-mentioned general symbols have the meanings given above, then, if necessary, removing the protecting groups R and R ³ , and optionally converting the final product into a physiologically acceptable salt, 2. Method of claim 1 к manufacture of compounds of formula Ia n <r ™, characterized in that the starting compounds of formula III are used those compounds in which R ³ is as defined in clause 1 and R ² are hydrogen.