CS228126B2 - Production method of new 1-/4-hydroxyphenyl 1/-2-aminoethanole derivative - Google Patents

Description

The present invention relates to a process for the production of novel compounds which are effective in the treatment of reversible obstructive pulmonary conditions of various origins, in particular asthmatic conditions, but which have reduced cardiostimulation and have a tremorogenic effect.

Sympathomimetic amines are generally used as bronchodilators in the treatment of reversible obstructive pulmonary conditions, such as asthma. However, sympathomimetic amines, such as adrenaline and isoadrenaline, have an undesirable cardiostimulatory effect. Available bronchodilators, such as terbutaline, are bronchoselective, which means that they have less cardiostimulatory effect relative to their bronchodilate effect, but often still have an undesirable tremorogenic side effect, which can naturally greatly harm the patient.

The tremorogenic effects of β-stimulants are discussed, for example, by Marsden et al., Clin. Sci. 1967, 33, 53-65 and Marsden and Medows, J. Physiol. 1970, 207, 429-448.

Thus, there is a need for bronchospasmolytic agents with a pronounced bronchodilator effect, particularly when administered orally, while having a low cardiostimulatory effect and a low tremorogenic effect.

The invention relates to a process for the production of novel compounds having a pronounced bronchodilator activity while having a low cardiostimulatory activity and a low tremorogenic effect. The compounds of the invention have also been shown to have a β-receptor blocking effect and the invention also relates to their use as β-receptor blocking agents in mammals, including humans. Drugs combining the α-adrenoreceptor and α-adrenoreceptor blocking properties may be useful in the treatment of specific diseases such as asthma [Aggerbeck et al. Br. J. Pharma. (1979) 65, 155-159, Nousiainen. et al., Pharmacology (1977) 15, 469-477]. Another feature of the compounds produced according to the invention is that they are effective to induce relaxation of the human uterus.

The present invention provides a process for the preparation of the novel 1- (4-hydroxyphenyl) -2-aminoethanol derivatives of formula (I)

228128

OH

CH, r'o-γ-CH-CH 2 NH-C-CH 2 CH, and therapeutically useful salts thereof; in the above general formula I n denotes the numbers 1, 2 or 3,

R ¹ is hydrogen, an aliphatic acyl group containing 2-5 carbon atoms and unsubstituted or substituted benzoyl of the formula

O

Λ-COB.

where

Zntačí ^R3 is hydrogen or methyl, and

R 2 is hydrogen, C 1 -C 4 aliphatic alkyl, benzyl, C 2 -C 5 aliphatic acyl and unsubstituted or substituted benzoyl of formula (cw).

where

Alkyl groups (R ^{2 only} ):

_-CH3, -C2H5, C3H7-11, 1-C3H7, n-C 4 H _7, sec-C4H7, i-C4H7.

Illustrative examples of compounds of the invention are:

R ⁴ represents a hydrogen atom or a methyl group.

The radicals R @ ³ and R ^{@ 4} can be substituted at any of the positions 2, 3 and 4 on the phenyl ring.

Illustrative examples of R ¹ and R ² are:

hydrogen, acyl groups ^(R1 and ^R2)

H, CH ₃ CO 2, CH ₃ CH ₂ JO ₂ , CH ₃ CH ₂ CH ₂ CO -, HC (CH ₃ ) a CO-, CH ₃ (CH ₂ ) a CO-, ch ₃

CH ₃ C — CO _{3 3} ch ₃

HC-CH ₂ -CO-

ch ₃

OH CH, i ³

CH-CH-NH-CH ₃ CC

ch ₃

H ₃ C — CH — CH ₂ CO228126 ' ^0H z— \

HO-O-CH-CH2-H-C-C1-O

X ^CHi <£ & *

OH

CH. i 3

HO - (-) - CH - CH3 NH - C - (-) -

CH, / ^{7 3} O (CH? CH _5! Χ »£ Ύ> χίχ · · · .χ ;.

OH r ~,

HO-CH-CH-NH-C-CH 2 Cl 2

CH, H

OOCCH,

OH CH,

OH-CH-HH-C-r

CH, = ⁷

OQCCJlf

OH

CH,

H 0 C H - C H 3 - Ν H - C - C ^CH 5 oc oocch _of ch ₃

OH

CH, i 3

H ^O '^ Q ^^ CH _s-NH-C ~ CH ^

M, ³ OOCCH3 CHICH3

OH fH ₃

HO-C ^-CH-CH-NH-C-CH ^Hi ^ y ^CH * ΓΓ

OH

CH, i > 5

H 0- <f ^ CH - <^ HH-C-CH _of CH _F / ~ ^

CH,

OCH · '

OH

CH,

OC.Hff

OH i

CH.

H O - ^^ CH-CH-C-NH-CH _Z CH _Z - ^ ~ ^ i

CH,

OKH ^ CH ^

OH

CH, ^H CH 3 i-CH-N-CH-HC ^ CH ^^

CH, pW CH3

HO ^^ - CH-CH-N HC- CH _Z CH ^ ~~ \ ^CH \ / O

OQCCH,

HIM

OH

CH, i ³

-ζ-CH-CH ^NH-C-CHjCH ^-yOOCCHg;

CH,

OH

AND

CH ³ I f-fo ^ QhCH-CH-NH-C-CH = ^CH-7 \\

CH,

OOCCH 2 CH 2 CH 2

OH CH _b

HO - (-) - CH - CH ₂ NH - C - CH ₂ CH 2 -

CH,

OOCCH3 CHICH3

OH

AND

CH O l ⁱ ^ - ^^ - ^ CH-NH-C-CH-CH ^ H ^

CH,

OH

228ΐ2θ θΗ Z · Λ _H0 _ £ yl H -CH £ NH-C-C-CH _of CH /

CH

OCH,

OH i

CH, and _H · q_ / A-CH-NH-C _{£-ch £} c ^ ch _of

CH,

OC, H,

CH,

OH, 3 _HO ptoVi _H -CH 2 NH-C-CH ₂ CH _and CH ₂ CH _and /

OCH 2 CH 3 flow

CH 1 = ⁷ CH, CH ² CH _{3 4} -pto, 'T'

OH i ^h 3 / Γλ '-..... • -C-CH _I CH _I CH _I - <^ y

- 3h ₃ ηο-Γ ^ η-οη ^ η oocch ₃ oh / w ho ^ J ^ ch-ch-nh-c-ch ^ chAJ

X ^CH * QOCCH _S

OH 0H ₃ r ~ x _ΗΟ - ^^ ΟΗ <Η; ΗΗ-Ο-ΟΗ ^ Η ^ 0Η _λ - (/

CHa jTZu

OOCCH2H3

OH CH _b

HO- / - CH-CHrN H- C-CH 2 CH 2 CH CH,

OOCCH2CH3CH3

OH ι

CK

CH-CH-NH-C-CH ₂ CH ₂ CH 2

CH,

CH ^ COO-T

OH I

CH, I ^{3 c} H _{d and} CH COO OCH-CH-NH-C-CH = ^CH-χλ

CH,

OCH,

WITH

CK

Examples of preferred groups for compounds of Formula I are given below:

1. Compounds wherein! R ¹ represents a hydrogen atom.

2. Compounds wherein R ² represents an aliphatic acyl group containing 2-5 carbon atoms.

Compounds wherein n is 2 (two).

4. Compounds wherein n is 1 (one).

5. Compounds wherein R ² represents an alkyl group containing 1 to 4 carbon atoms.

Compounds where n is 2 (two), R ¹ is hydrogen and R ² is C 1 -C 4 alkyl.

7. Compounds wherein n is 2, R ¹ represents alifaťckou acyl group having 2-5 carbon atoms or benzoyl or substituted nesubatituovanou formula

in which

Douses ^R3 is hydrogen or methyl and

R ² represents an alkyl group containing 1 to 4 carbon atoms.

Compounds wherein n is 1 (one), R ¹ is hydrogen and R ² is C 1 -C 4 alkyl.

Compounds wherein n is 1, R ¹ is an aliphatic acyl group containing 2 to 5 carbon atoms or an unsubstituted or substituted benzoyl group of the general formula

O

in which

R ³ represents a hydrogen atom or a methyl group and R ² represents an alkyl group having 1 to 4 carbon atoms.

A preferred compound of the invention is

Since the compounds of the formula I according to the invention contain at least one asymmetric carbon atom, the invention also includes all possible optically active forms and racemic mixtures of the compounds. The raremic mixture can be resolved by conventional means, for example by salt formation with an optically active acid, followed by traction crystallization.

In clinical practice, the compounds will usually be administered orally, by injection or by inhalation in the form of a pharmaceutical composition comprising the active ingredient in the form of the parent compound, or optionally in the form of a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier which may be a solid, semi-solid or such formulations are a further feature of the invention.

The compound can also be used without a carrier material, examples of pharmaceutical formulations are tablets, drops, aerosol for inhalation, etc. The active ingredient is usually contained between 0.03 and 99 or between 0.1 and 99% by weight in the formulation, for example between 0 and 99%. , 5 and 20% by weight for preparations for injectable use, and between 0.1 and 50% by weight for preparations for oral administration.

The novel compounds produced according to the invention can be administered in the form of salts with physiologically acceptable acids. Suitable acids which can be used are, for example, hydrochloric, hydrobromic, sulfuric, fumaric, citric, tartaric, maleic or succinic acids.

Pharmaceutical compositions containing as active ingredient at least one compound produced according to the invention together with a pharmaceutical carrier may be intended for oral, bronchial, rectal or paremferal administration.

For the manufacture of pharmaceutical compositions in the form of dosage units for oral administration comprising a compound of the invention in the form of the free base or a pharmaceutically acceptable salt thereof, the active ingredient may be admixed with a solid, powdered carrier, e.g. lactose, sucrose, sorbiitol, mannitol, starch, e.g. , corn, starch or amylopectin, cellulose derivative or gelatin, and may also contain glidants such as magnesium or calcium stearate or Carbowax or other polyethylene glycol waxes, and may be compressed into tablets or dragee cores. If dragees are required, the cores may be coated, for example with concentrated sugar solutions, which may contain gum arabic, talc and / or titanium dioxide or, optionally, a lacquer dissolved in readily volatile organic solvents or organic solvent mixtures. Dyestuffs can be added to these coatings. In the manufacture of soft gelatin capsules (pearl-shaped closed capsules) consisting of gelatin and, for example, glycerol, or similar closed capsules, the active ingredient can be mixed with Carbowax. Hard gelatin capsules may contain granules of the active ingredient with solid powders! carriers such as lactose, sucrose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin and may also contain magnesium stearate or stearic acid.

Dosage units for rectal administration may be in the form of suppositories containing the active ingredient in admixture with a neutral fat base or gelatin rectal capsules containing the active ingredient in admixture with Carbowax or other polyethylene glycol waxes. A single dosage unit preferably contains 0.5 to 50 mg of active ingredient.

Liquid preparations for oral administration may be in the form of syrups, suspensions or emulsions containing, for example, from about 0.1 to 20% by weight of the active ingredient and, if desired, excipients such as stabilizing agents, suspending agents, dispersing agents. flavoring and / or sweetening agents.

Liquid preparations for rectal administration may be in the form of aqueous solutions containing from about 0.1 to 2 percent by weight of the active ingredient as well as, if desired, stabilizing agents and / or buffering agents.

The carrier for parenteral injection may be a sterile parenterally acceptable liquid, for example pyrogen-free water or an aqueous solution of polyvinylpyrrolidone, or a parenterally acceptable oil, for example arachis oil and optionally stabilizing agents and / or buffers. Dosage units of the solution may advantageously be enclosed in ampoules, with the individual dosage unit preferably containing from 0.05 to 5 mg of active ingredient.

For administration to the bronchi, the compositions are preferably formulated in the form of sprayed solutions of the suspension. The solution or suspension preferably contains from 0.1 to 10 weight percent of the active ingredient.

The dose at which the active ingredients may be administered may vary within wide limits and will depend on various factors, for example, the individual requirements of the individual patient. A suitable oral dose may range from 0.5 to 10 mg per day.

For aerosol dosing, a suitable dosage unit may contain from 0.05 to 0.5 mg of active ingredient. One or two such dosage units may be administered at each treatment.

Pharmaceutical formulations containing the active ingredients may be suitably formulated so that doses within the indicated ranges are available as single or multiple doses.

Compounds of formula I wherein R ¹ and R ^{2 are} aliphatic acyl groups or unsubstituted or substituted benzyl groups exhibit the same rapid onset as the corresponding compounds in which R ¹ and / or R ^{2 are} hydrogen but have a prolonged pharmacological effect. This is probably due to better absorption followed by hydrolysis of the ester bond in the body. Compounds in which R ¹ and R ² denote aliphatic acyl groups or unsubstituted or substituted benzoyl groups act as essential prodrugs for the respective compounds in which R ¹ and / or R ² denote a hydrogen atom .

The novel compounds of the invention are prepared by known methods, for example by the following methods B or A (this is not the subject of the present invention):

B. reduction of an iminoketone derivative of general formula VI

in which

R represents hydrogen, an aliphatic acyl group of 2 to 5 carbon atoms, an unsubstituted or substituted benzoyl group of the general formula

22812B

Β where

R @ ³ denotes hydrogen or a methyl group or denotes a hydroxyl group, for example an alkyl of 1 to 5 carbon atoms or a mono- or bicyclic aralkyl group having at most 11 carbon atoms, for example benzyl or naphthylmethyl, n denotes 1, 2 or 3,

R ² is hydrogen, an aliphatic alkyl group of 1 to 4 carbon atoms, benzyl, aliphatic acyl group having 2 to 5 carbon atoms or unsubstituted or substituted benzoyl of the formula

where

R ⁴ represents a hydrogen atom or a methyl group to give a 1- (4-hydroxyphenyl) -2-aminoethanol derivative of the general formula V

in which

R @ ² and R @ ² have the meanings given above, where appropriate, the protective group R is removed, or

A. reacting a compound of formula III

R O ~ - - - - CH - N - C - (C (V) in which

CH - CH, ^W \ _O Z ² (III) in which

R is as defined above, with a compound of formula IV

(IV) wherein

R and n are as defined above, and R ⁵ is hydrogen or an N-protecting group, such as a benzyl group, to give a 1- (4-hydroxyphenyl) -2-aminoethanol derivative of formula V

R, R ² and R ⁵ have the meanings given above, then, if desired, the R and R ⁵ protecting groups are removed; thereafter, if desired, the compound of formula (I) thus obtained is converted into a pharmaceutically acceptable salt and / or resolved into its optical isomers.

The starting materials used in processes B and A above are known compounds which can be produced in a known manner.

The following examples illustrate the invention. Examples

Example 1

Method A:

Preparation of 1- (4-hydroxyphenyl) -2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol hydrochloride as well as Preparation of 1- (4-benzyloxyphenyl) -2- (1,1-dimethoxyphenylpropylamino) ethanol sulfate 8: 128

A solution of 3.5 g (0.018 mol) of 1,1-dimethyl-3- (2-methoxyphenyl) propylamine and 3.8 g (0.017 mol) of 4-beinzyloxystyrene oxide in 150 ml of n-propanol was heated to reflux for two hours. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in ethanol, neutralized with concentrated sulfuric acid in ethanol to give a crystalline precipitate, after two recrystallizations from isopropyl alcohol and finally from ethanol, 0.9 g of the title compound was obtained.

Sulfate (calculated: 100%

Sulfate (found): 101%

NMR data: COCl ₃ <5 (ppm):

1.15 (6H, s);

1.60 (2 H, m),

2.60 (2H, 2H, m);

3.75 (3 H, s),

4.55 (1 H, q),

5.07 (2 H, s),

7.10 (4 H + 4 H + 5 H, m).

This compound was hydrogenated as described below: b).

b) Preparation of 1- (4-hydroxyphenyl) -2- [1,1-: dimethyl-3- (2-methoxyphenyl) propylamino] ethanol hydrochloride

³ ί / Λ ch ₃ och $

HCl

· A solution of 3.1 g 1- (4-benzyloxyphenyl) -2 _T [l ld.imethyl-3- (2-methoxyphenyl) propylamino} -ethanol in 40 ml of isopropanol was hydrogenated in the presence of 0.05. g 10% Pd / C at atmospheric pressure and at room temperature. When the calculated amount of hydrogen was consumed, 1 g of benzyl chloride was added along with fresh catalyst. The hydrogenation was continued until hydrogen consumption ceased. The catalyst was filtered off and the filtrate was concentrated in vacuo. After addition of ethyl ether, the hydrochloride of the title compound crystallized.

Yield: 2.5 g

Cl (calculated): 9.7%

Cl (found): 9.7%

NMR data: δ (ppm):

1.55 (6H, s);

1.90 (2 H, m),

2.77 (2 H, m),

3.20 (2H, m);

3.85 (3H, 9);

4.85 (DOH),

5.05 (1 H, m),

7.32 (8 H, m).

Mass spectrum: (M-18) m / e = 311 di-TMS derivative M ⁺ m / e = 473 (M-15) = = 458

Example 2 Method A:

Preparation of 1- (4-hydroxyphenyl) -2- (1,1-dimethyl-2- (2-methaxylphenyl) ethylamino) ethanol

a) Preparation of 1- (4-benzyloxyphenyl) -2- [1,1-dlmethyl-2- (2-methoxyphenyl) ethylamino] -ethanol sulfate

1 / Z H 2 SO 4

A solution of 7.2 g (0.04 mol) of 1,1-dimethyl-2- (2-methOKyphenyl) ethylamine and 9.1 g (0.04 mol) of 4-benzyloxystyrene oxide in 120 ml of ethanol was heated to reflux. cooler for 20 hours. After evaporation to dryness, the residue was dissolved in ether and neutralized with 2 N sulfuric acid. The resulting precipitate was filtered off and washed with water and ether, recrystallized from ethanol.

Yield: 4.4 g.

The product obtained was used directly in step b).

b) Preparation of 1- (4-hydroxyphenyl) -2- [1,1-dimethyl-2- (2-methoxyphenyl) ethylamino] ethanol sulfate

OH CH 2

HS ^ ΟΗ „<^ ν ₂ HSO _t

A solution of 2 g of 1- (4-benzyloxyphenyl) -2- [1,1-dimethyl-2- (2-methoxyphenyl) ethylamino] ethanol in 50 ml of methanol was hydrogenated in the presence of 0.5 g of 10% Pd / C with at atmospheric pressure and at room temperature. When the calculated amount of hydrogen was consumed, the catalyst was filtered off and the filtrate was evaporated. The residue was recrystallized from ethanol.

Yield: 1.5 g, SO ₄ ² - 100.5%

NMR data: (DMSO-d ₆₎ § (ppm):

0.65 (6 H, s),

1.92 (DMSO),

2.42 (4 H, m),

3.10 (3 H, s),

O O z - \ II O δ z O - ^ _ y-C 'CH + ty

4.25 (1 H, m),

6.50 (8 H, m).

Mass spectrum:

TMS der .: M ⁺ m / e = 460 (M-15) m / e = 445;

Example 3

Method B:

Preparation of 1- (4-hydroxyphenyl) -2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol

a) Preparation of 1- (4-benzyloxyphenyl) -2- (1,1-dimithyl-3- (2-methoxyphenyl) propylamino] ethanol

BtO-C ^ CH-N-C-Ctytyl-CH3. nru.

reduction

->

CH,

Bi.0

CH-CH 2 -C-C 4 C 4 OH W CH.

A solution of 3.0 g (0.0155 mol) of 1,1-dimethyl-3- (2-methoxyphenyl) propylamine and 4.0 g (0.0155 mol) of 4-benzyloxyphenylglyaxal in 40.0 ml of ethanol is heated to boiling The intermediate, iminoketone, was then directly reduced by the addition of 1.5 g of sodium borohydride, and the solution was stirred for an additional hour after evaporation of the reaction mixture to dryness in vacuo. The residue was partitioned between ether and water, the ether phase was washed with water, dried over magnesium sulphate and evaporated and the crystalline residue was recrystallized from ethanol.

Yield: 3.1 g.

NMR data for imine intermediate iminoketone: (CDCl 3) δ (ppm):

1.25 (6H, s),

1.82 (2 H, m),

2.60 (2 H, m),

3.75 (3 H, s),

5.10 (2 H, s),

7.18 (weight, m),

8.10 (2 H, d),

8.35 (1 H, S).

b) Preparation of 1- (4-Hydroxyphenyl) -2- (1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol

The compound obtained in step a) was hydrogenated in the same manner as in Example 1b) to give the title compound.

Example 4

Method B:

Preparation of 1- [4-piloyloxyphenyl] -2- (1,1-dimethyl-3- (2-methoxyphenyl) propylamino) ethanol

CH, ¹⁴

CK-.CCO ^J o

OH 1

CH 1 - CH - CH 2 N - C - CH 2 CH 4 H CH.

OCH,

A solution of 2-gl, 1-dimethyl-3- (2-methoxyphenyl) propylamine and 2.9 g of 4-pivaloyloxyphenylglyoxal monoethylacetal in 100 ml of ethanol is heated at reflux for 2 hours and then allowed to stand at temperature. room for 20 hours.

Dibdran (B ₂ H ₈ ) prepared from 23 ml of boron trifluoride etherate and 3.4 g of sodium borohydride in 110 ml of diglyne is introduced into this solution using a nitrogen stream. When the reaction is complete, water is added carefully and the reaction mixture is evaporated to dryness. The residue was extracted with ether, then washed with water, dried and evaporated. The residue was dissolved in ethanol and neutralized with an ethainolic sulfuric acid solution. The crystalline residue obtained after evaporation is recrystallized from ethanol.

Yield: 1.6 g; 100% neutral sulfate

NMR data: (CDCl ₃ , CF 6 COOH) δ (ppm):

1.40 (9 H, s),

1.52 (6H, 9);

2.00 (2 H, m),

2.90 (2 H, m),

3.25 (2 H, m),

3: 90 (3H, a),

5.25 (1 H, m),

7.18 (8 H, m).

Example 5 • Method B:

Preparation of T- (4-methylbenzoyloxy) phenyl-2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol

OH

-frNí i

H CH.

CH ^ / - \

C ~ ^CH 2 ^CH £ \ ^1/2 / ^1/2

OCH,

The title compound was prepared as described in Example 4 for 1- (4-pivaloyloxyphenyl) -2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol sulfate from 6.0 g 1. 1-dimethyl-3- (2-methoxyphenyl) propylamine and 9.8 g of 4- (4-methylbenzyloxy) phenylglyoxal moinoethylaceital in 200 ml of ethanol.

Recrystallized from isopropyl alcohol. Yield: 1.3 g 99.4% neutral sulfate

NMR data: (CDCl ₃ + CF ₃ COOH) δ (ppm):

1.52 (6H, s);

OH

2.02 (2 H, m),

2.50 (3H, s),

2.75 (2 H, m),.

3.15 (2H, mj,

3.85 (3 H, s),

5.25 (1G, mj,

7.20 (12 H, m).

Example 6

Preparation of 1- (4-Hydroxyphenyl) -2- [1,1-dimethyl-3- (2-ethoxyphenyl) propylamino] ethanol hydrochloride

CH, ^ho - <^ _ 2 ~ chloro ~ N- C- CH ^ CHCH _from

H CH,

i HCl

OCH2CH3

The title compound a was prepared from 1- (4-benzyloxyphenyl) -2- [1,1-dimethyl-3- (2-ethoxyphenyl) propylamino] ethanol in the same manner as described in Example 1b).

Yield: 15 ° / o,

Cl (calculated): 9.0%,

Cl (found): 9.0 ° / o ^! .

NMR _(DMSO-dg) δ (in ppm::

1.1 (3 H, t),

1.15 (6H, s);

1.7 (2H, m);

2.2 (DMSO 3,

2.9 (2H, mj,

3.9 (2 H, q),

4.8 (1H, m); 7.0 (8H, m).

Example 7

Preparation of 1- (4-hydroxyphemyl) -2- [1,1-dimethyl-4- (2-methoxyphenyl) butylamino] ethanol sulfate

HIM

OH

CH,

CH - CH - NH - C - CH - CH - CH.

& three,

CH,

OCH,

1/2 HSO ^

The title compound was prepared from 2.6 g of 1- (4-benzyloixyphenyl) -2- (1,1-dimetyl-4- (2-methoxyphenyl) butylamino] ethanol sulfate as described in Example 1b).

Yield: 1.7 g sulfate (calculated): 100% sulfate (found): 100%

CIMS (NH 3 NH 3 + 344

HPLC: 98.6%.

Example 8

Preparation of 1- (4-hydroxyphenyl) -2- [1,1-dimethyl-3- (2-hydroxyphenyl) propylamino] ethanol sulfate

1/2 H 2 SO 4

The title compound was prepared from 1.9 g of 1- (4-benzyloxyphenyl) -2- [1,1-dimethyl-3- (2-hydroxyphenyl) propylamino] ethanol sulfate in the same manner as in Example 1bj. Yield: 1.4 g.

HPLC analysis 96.8% sulphate (calculated): 100% sulphate (found): 100%

CIMS (NH3) MH ^& _lt ; + ^&gt; : 316

NMR: (CD ₃ OD + CH ₃ COOH) i (ppm):

1.0 (6H, s);

1.5 (2H, m);

2.3 (2H, m);

2.8 (2H, mj,

2.95 (CD ₃ OD)

4.5 (1 H, n),

6.8 (8H, et al.).

Preparation of starting materials

a) Preparation of 1,1-dimethyl-3- (2-methoxyphenyl) propylamine used in Methods A and B.

Step 1: 2-methoxybenzalacetophenone

To a solution of 68 g (0.5 mol) of o-methoxybenzaldehyde in 100 ml of acetone was added dropwise 12.5 ml of 10% sodium hydroxide solution with stirring. The temperature was kept below 30 ° C and the reaction mixture was stirred for three hours at room temperature, then 2 N hydrocarbon acid was added and the solution was heated to reflux for 1 hour. The solution is then extracted with ether, the ether phase is washed with water, dried and evaporated in vacuo. The residue was distilled.

Yield: 32.4 g m.p .: 124-6 ° C / 2 mm Hg

NMR (CDCl 3) δ (ppmj):

2.20 (3H, s,

3.90 (3H, sj,

6.75 (1 H, d),

7.15 (4 H, m),

7.95 (1 H, d).

Step 2: 4- (2-Methoxyphenyl) butan-2-ol

O.CH3

ch _£ ch-c.

A solution of 32.4 g of 2-methoxybenzalacetone in ethanol was hydrogenated in the presence of Raney nickel at atmospheric pressure and at room temperature. The catalyst was filtered off and the filtrate was evaporated to give the title compound as an oil.

Yield: 28.9 g.

NMR (CDCl 3) δ (ppmj:

2.10 (3 H, s),

2.90 (4 H, m),

3.90 (3 H, s),

7.00 (4 H, m).

Step 3: 1,1-dimethyl-3- (2-methoxyphenyl) propanol

OCH \ ⁿ 2>

(Of ch,

A solution of methylmagnesium soda (0.21 mol) in 50 ml dry ether was added dropwise with stirring and cooling to a solution of 28.9 g (0.16 mol) of 4- (2-methoxyphenyl) butan-2-one in 30 ml of dry ether. After the addition was complete, the mixture was stirred for 2 hours at room temperature, then added at 0 ° C in water. After extraction with ether, the title compound is obtained after evaporation of the dried ether phase.

Yield: 28.6 g.

NMR (CDCl 3) δ (ppm):

1.25 (6H, s);

1.75 (2 H, m),

7.70 (2 H, m),

3.90 (3 H, s),

7.00 (4H, et al.).

Step 4: 1,1-dimethyl-3- (2-methoxyphenyl) propylamta

To a solution prepared by adding 22.4 ml of concentrated sulfuric acid in 20.6 ml of acetic acid to 8.6 g of sodium cyanide dissolved in 20.6 ml of acetic acid, was added 28.6 g, 1-dimethyl-3- (2- The mixture was then stirred at 70 ° C for 0.5 hour The reaction flask was sealed and left at room temperature for 2 hours, after which the mixture was poured into 500 ml of water and After ether extraction, 29.4 g of the intermediate formamide were isolated, hydrolyzed to the title compound without further purification by boiling with 200 ml of 5 N sodium hydroxide for three hours. ether which, after evaporation, gave the title compound as an oil.

Yield: 14.4 g.

NMR (CDCl3) <5 (ppm):

1.15 (6H, s);

1.52 (2 H, m),

2.66 (2 H, m),

3.85 (3 H, s),

7.08 (4 H, m).

b) Preparation of 4-benzyloxystyrene oxide using Method A

Step 1: 4-Benzyloxy-2'-bromoacetoifenoin

Step 2: 4-Benzyloxystyrene oxide

A solution of 40 g of 4-benzyloxy-2'-bromoacetophenoate in 400 ml of dioxane was added dropwise to a solution of 5 g of sodium borohydride in 40 ml of water and 400 ml of dioxane at 0 ° C. The mixture was stirred for 20 hours at room temperature, then a solution of 9 g of sodium hydroxide in 60 ml of water was added and the solution was heated to reflux and then cooled and evaporated to dryness in vacuo. The residue was partitioned between water and ether. The ether phase was dried and evaporated to give a crystalline residue: 27.3 g.

NMR (CDCl 3) δ (ppm):

3.00 (2 H, m),

3.85 (1 H, m),

5.15 (2 H, s),

7.15 (9 H, m).

c) Preparation of the 4-benzyloxyphenylglyoxal used in Method B

To a solution of 32 g (0.14 mol) p-benzyloxyacetophenone in 200 ml dioxane was added 18 g (0.16 mol) selenium dioxide in 25 ml water. The mixture was stirred for 20 hours at 90 ° C, then filtered and evaporated to dryness in vacuo. The crystalline residue was suspended in ether and filtered.

Yield: 26.5 g.

NMR (CDCl ₃ ) δ (ppm):

5.20 (2 H, s),

7.10 (2 H, m),

7.40 (5 H, s),

8.20 (2 H, m), a

9.65 (ΙΗ, β).

O ^B10 C-CH3 Br

A solution of 15.7 ml of bromine in 400 ml of dioxane was added dropwise with stirring to a solution of 70.5 g (0.31 mol) of 4-benzyloxy-naphtheinone in 500 ml of dioxane. The mixture was stirred at room temperature for 2 hours, then activated carbon was added and the solution was filtered. The filtrate was evaporated to dryness and the solid residue was recrystallized from ethanol.

Yield: 73.2 g.

NMR (CDCl ₃ ) δ (ppm):

4.45 (2 H, s),

5.15 (2 H, s),

7.10 (1 H, m),

7.50 (5 H, s),

8.07 (1 H, m).

d) Preparation of 4-monoethylacetal-4-pivaloyloxyphenylglyoxal used in Method C

Step 4: 4-pivaloyloxyacetofenon <x ₀ • LU CHRC-C ~ ⁰ O 1 CH

O

O

C-CH $

To a solution of 20 g (0.15 mol) of p-hydroxyacetophenone in 200 ml of pyridine was added 30 g (0.25 mol) of pivalic acid chloride while cooling and stirring. The reaction mixture was then allowed to stand at room temperature for 20 hours. After evaporation to dryness, the residue was partitioned between ether and water. The ethereal phase was washed with 2N hydrochloric acid and then with water.

After evaporation of the ether phase, the residue is recrystallized from petroleum ether (b.p. 40-60 ° C).

Yield: 28 g.

NMR (CDCl3) (ppm):

1.40 (911, sj,

2.65 (3 H, s),

7.25 (2 H, dj,

8.10 (2 H, d).

Step 2: Monoethylacetal-4-pivaloyloxyphenylglyoxal

CH, (J q ^{1 11} / 7Λ uz ^ / 3 CC-0 —C-CH ch ₅

OC ^ g

OH

To a solution of 28 g (0.13 mol) of 4-pivaloyloxyacetophenoinium in 200 ml of dioxane was added a solution of 16.7 g (0.15 mol) of selenium dioxide in 25 ml of water. The mixture was stirred for 20 hours at 90 ° C, after which the solution was filtered and evaporated. The remainder of the pollen was refluxed with ethanol, which was then evaporated. A reddish oil was obtained.

Yield: 10 g.

NMR (CDCl 3) f f (ppm):

1.25 (3 H, It),

1.40 (9H, s);

4.00 (3 H, m),

5.70 (1 H, s),

7.15 (1 H, d),

8.18 (1 H, d).

c) Preparation of 4- (4-methylbenzoyloxy) diphenylglyoxal monoethylacetal

Step 1: 4- (4-methylbenzoyloxy) acetophenone

was prepared as described for 4-pivaloyloxyacetophenone.

Yield: 71%.

NMR (CDCl 3 I δ (ppm):

2.45 (6H, s);

7.35 (4 H, m),

8.10 (4 H, m).

Column 2: 4- (4-Meithylbenzoyloxy) phenylglyoxal monoethylacetal

It was prepared as well as monoethylacetal-4-pivialoyloxyphenylglyoxal.

Yield: 30%.

NMR (CDCl ₃ )? (Ppm):

1.25 (3 H, t),

2.45 (3 H, s),

3.80 (2 H + 1 H, m),

7.80 (8 H, m).

II / C-CH

OC ^ ₅

OH f j Preparation of 1- (4-benzyloxyphenyl) -2- [1,1-dimethyl-3- (2-ethoxyphenyl) propylamino] ethanol used in Example 6

Step 1: 2-ethoxybenzalacetophenone

The title compound was prepared from 2-ethoxybenzaldehyde and acetone as described above for 2-methoxybenzalacetone.

Yield: 76%.

NMR (CDCl 3) δ (ppm):

1.4 (3 H, t),

2.2 (3H, s,

4.0 (2H, q);

6.7 (1 H, d),

7.2 (4H, m).

7.9 (1 H, d).

Step 2: 4- (2-ethoxyphenyl) butan-2-one

The title compound was prepared from 2-ethoxybenzalacetone as described above for 4- (2-methoxyphenyl) tan-2-one.

Yield: 68%. Boiling point 83 to 86 ° Ό / / 0.07 mm Hg.

NMR (CDCl 3) δ (ppmj:

1.15 (3H, i.e.

2.0 (3H, s);

2.7 (4 H, m),

3.9 (2 H, q),

6.9 (4H, et al.).

Step 3: 1,1-Dimethyl-3- (2-ethoxyphenyl) propanol

The title compound was prepared from 4- (2-ethoxyphenyl) butan-2-one as well as

No. 28126 described above for 1,1-dimethyl-3- (2-methoxyphenyl) propanol.

Yield: 85%.

NMR (CDCl 3)? (Ppm):

1.2 (6H, s,

1.3 (3H, t)

1.7 (2H, m);

2.7 (2H, m);

4.0 (2H, q);

7.0 (4 H, m).

Step 4: 1,1-Dimethyl-3- (2-ethoxyphemyl) propylamine

The title compound was prepared from 1,1-dimethyl-3- (2-ethoxyphenyl) propanol as described above for 1,1-dimethyl-3- (2-methoxyphenyl) propylamine.

Yield: 15%.

NMR (CDCl3) <5 (ppm):

1.0 (6H, s);

1.2 (3H, t);

1.5 (2H, m);

2.6 (2H, m);

3.9 (2 H, q),

6.9 (4 H, m).

Step 5: 1- (4-Benzyloxyphenyl) -2- [1,1-dimethyl-3- (2-ethoxyphenyl) propylamino] ethainol

The title compound was prepared from 4-benzyloxyphenylglyoxal and 1,1-dimethyl-3- (2-ethoxyphenyl) propylamine as described in Example 3a).

Yield: 15%.

NMR (CDCl 3) δ (ppm):

1.2 (6H, s);

1.5 (3H, t);

1.7 (2H, m);

2.8 (2H, m);

3.8 (2H, m).

4.1 (2 H, qj,

4.8 (1 H, m),

5.1 (2 H, s),

7.2 (13H, et al.

g) Preparation of 1- (4-benzyloxyphenyl) -2- (1,1-dimethyl-4- (2-melthoxyphenyl) butylamino) ethanol used in Example 7

Step 1: o-Methoxyphenylpropionic acid

A mixture of 68 g of o-methoxybenzaldehyde, 75 g of acetic anhydride and 30 g of sodium acetate was heated with stirring at 150 ° C for 1 hour and then at 170-180 ° C for 15 hours. The mixture was then cooled to 90 ° C and poured into 400 ml of water. The resulting mixture was neutralized with sodium carbonate and then distilled with water vapor until a clear liquid was obtained, which was then filtered hot. The filtrate was then acidified with concentrated hydrochloric acid and the precipitate (51.2 g) was aspirated and washed with water. The precipitate was dissolved in 300 mL of methanol and hydrogenated at room temperature and atmospheric pressure in the presence of 0.4 g Pd / C. When the calculated amount of hydrogen was consumed, the mixture was filtered and evaporated to give 50.2 g of the title compound.

NMR (CDCl ₃ ) δ (ppm):

2.8 (4H, m)

3.8 (3H, s)

7.1 (4H, m).

11.4 (1 H, s).

Step 2: o-methoxyphenylpropauol

A solution of 50 g of o-methoxyphenylpropionic acid in 500 ml of dry ether was added dropwise to a cooled and stirred suspension of 10 g of lithium hydride in dry ether. The temperature of the reaction mixture was then allowed to rise to room temperature, then the mixture was neutralized with a 20% solution of sodium potassium sulfate at 0 ° C. The ether phase was discarded and the residue was washed with ether. The combined ether phases were washed with water, dried over magnesium sulfate and evaporated to give the title compound. Yield: 38.2 g.

NMR (CDCl 3) δ (ppm):

1.8 (2 H, t),

2.1 (1H, s,

2.7 (2 H, t),

3.6 (2 H, t),

3.6 (2 H, t),

3.8 (3H, s)

7.0 (4 H, m).

Step 3: o-methoxyphenylpropyl chloride

To a solution of 38 g of o-methoxyphenylpropanol in 100 ml of trichlorethylene was added dropwise 60 ml of ithionyl chloride. The solution was refluxed for three hours, then evaporated. The residue was distilled and the fraction boiling at 122-126 ° C / mmHg was collected.

Yield: 21.6 g.

NMR (CDCl 3) δ (ppm):

2.2 (2H, m).

2.8 (2H, mj,

3.5 (2H, m);

3.8 (3H, s)

7.1 (4 H, m).

Step 4: 1,1d ^: methyl-4- (2-methoxyphenyl) butanol

A solution of 21.8 g of o-methoxyphenylpropyl chloride in 10 ml of dry ethyl ether was added dropwise to a mixture of 3.0 g of magnesium in 10 ml of dry ether. When the Grigmard reagent formation was complete, 7 g of acetone were added. The reaction was allowed to proceed for 2 hours at room temperature, then the mixture was cooled and water was added.

The ether phase was separated, washed with water, dried over magnesium sulfate and evaporated to give 20.6 g of the title compound.

NMR (CDCl ₃ ) δ (ppm):

1.1 (6H, s);

1.4 (4H, m)

2.5 (2H, m);

3.8 (3 H, s),

7.0 (411, m).

Step 5: 1,1-dimethyl-4- (2-methoxyphenyl) butylamine

The title compound was prepared from 20.5 g of 1,1-dimethyl-4- (2-methoxyphenyl) butanol as described above for 1,1-dimethyl-3- (2-methoxyphenyl) propylamine. g base.

Yield: 2.8 g of sulfate of the title compound.

NMR (CDCl3):

1.1 (6H, s);

1.5 (4H, ia,

2.7 (2H, m);

3.8 (3H, s)

7.0 (4 H, s).

Step 6: 1- (4-Benzoyloxyphenyl) -2- (1,1-dimethyl-4- (2-methoxyphenyl) butylamino) ethanol sulphate

The title compound was prepared from 2.4 g of 1,1-dimethyl-4- (2-methoxyphenyl) butylamine and 3.0 g of 4-benzyloxyphenylglyoxal, as described in Example 3a).

Yield: 2.6 g.

NMR (GDCl 3 + CF 3 COOH) δ (ppm):

1.1 (8H, s,

1.5 (4H, m)

2.5 (2H, m);

2.9 (2H, mj,

3.7 (3H, s,

5.0 (2H, sj,

5.1 (1H, m / e,

7.0 (13 H, m).

b) Preparation of 1- (4-benzyioxyphenyl) -2- (1,1-dimethyl-3- (2-hydroxyphenyl) propylamino] ethanol used in Example 8

Step 1: 1,1-Dimethyl-3- (2-hydroxyphenyl) propylamine 1,1-Dimethyl-3- (2-methoxyphenyl) propylamine, 3.0 g, was dissolved in 100 mL of 48% hydrobromic acid and The mixture was refluxed for 1 hour, then 50 ml of hydrobromic acid was added, the mixture was boiled for 15 hours, the hydrobromic acid was evaporated in vacuo, the residue was dissolved in water and taken up with activated carbon. The ether phase was evaporated to give an oily residue.

Yield: 2.1 g.

NMR (D, O) .delta. (Ppm):

1.15 (6H, s),

1.8 (2H, m).

2.6 (2H, mj, (DOHj,

7.1 (4H, m).

Step 2: 1- (4-Benzyloxyphenethyl) -2- (1,1-dimethyl-3- (2-hydroxyphenyl) propylamino) ethanol

The title compound was prepared from 1.33 grams of 1 H -dimethyl-3- (2-hydroxyphenyl) -propylamine and 2.2 g of 4-benzyloxyphenylglyoxal as described in Example 3a). Yield: 1.9 g.

NMR (CD ₃ OD) δ (ppm):

1.2 (6H, s)

1.6 (2H, m);

2.4 (2H, m);

2.9 (2 H, m),

3.1 (CD5OD)

4.7 (1 H, m),

4.8 (2H, s,

6.8 (13 H, m).

The starting materials for Method B can be prepared by the following reaction scheme: i

RO o o 11 11 C-CH in which

R is as described above for Process A, with a compound of formula

in which

Example 10 n, R ² and R ⁵ are as described in Method A above to give a compound of formula

Tablets

Each tablet contains:

1- (4-Hydroxyphenyl) -2- [1,1-dimethyl-3- (2-melthoxyphenyl) propylamino] sulfate -

b) reaction of a compound of the formula ethanol 2.0 mg wheat starch 25.0 mg lactose 210.0 mg gelatin 1.5 mg lobe 10.0 mg magnesium stearate 1.5 mg

250.0 mg

RO o OR ⁶ I ¹ i OCH

OH

Example 11 wherein

R is as defined in A above and wherein

R ⁶ represents a hydrogen atom or a C 1 -C 5 alkyl group with a compound of the formula

Suppositories

The single cone contains:

1- (4-Hydroxyphenyl) -2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol sulphate 2.0 mg ascorbyl palmitate 1.0 mg suppository base (Imhausen H) up to 2000, 0 mg

Example 12

CH,

C.H,

H, N-C-CH3

wherein R ² is as defined in Method A above to give a compound of formula

Syrup

1- (4-Hydroxyphenyl) -2- [1,1-dimethyl-2- (2-methoxyphenyl) ethylamino] -

ethanol 0.020 g glucose syrup 30,0 g sugar 50,0 g ascorbic acid 0.1 g sodium pyrosulfite 0.01 g disodium adetate 0.01 g orange essence 0.025 g dye 0.015 g purified water to 100.0 ml

Example 13

O ch ₃

RO ~ f ~ V ^CH NN C-fCH ^ X

CH,

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

Solution for injection

1- (4-Hydroxyphenyl) -2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol hydrochloride 0.200 mg sodium pyrosulfite 0.500 mg disodium adetate 0.100 mg sodium chloride 8.500 mg sterile water for injections 00 ml

Example 14

Example 9

Inhalation solution

Aerosol for inhalation

1- (4-Hydroxyphenyl) -2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol sulfate 0.25 g

Myglyol 0.20 g

Fringen 11/12/113/114 up to 100 g

1- (4-Hydroxyphenyl) -2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol sulphate 0.25 g sodium pyrosulphite 0.10 g disodium adetate 0.10 g sodium chloride 0.85 g purified water to 100.0 ml

Example 15

Solution for rectal administration (rectal ampoules)

1- (4-Hydroxyphenyl) -2- (1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol sulphate 2.0 mg sodium pyrosulfite 1.5 mg disodium adetate 0.3 mg sterile water to 3.0 ml

Example 16

Sublingual tablets

1- (4-Hydroxyphenyl) -2- [1,1-dimethyl-3- (2-methoxyphenyl} propylamino] -ethanol] hydrochloride 1.0 mg lacosose 85.0 agar 5.0 mg violet 5.0 mg

100.0 mg

Example 17

Drops

1- (4-Hydroxyphenyl) -2- (1,1-dimethyl-3- (2-methoxyphenyl) propylamino) ethanol sulphate 0.20 g ascorbic acid 1.00 g sodium pyrosulfite 0.10 g disodium adetate 0 , 10 g glucose syrup 50,00 g absolute ethanol 10,00 g purified water to 100,0 ml

Pharmacological tests

A. Simultaneous recording of bronchospasmolytic effect, tremorogenic effect and cardiostimulatory effect

The bronchospasmolytic effect and the tremorogenic effect were measured simultaneously in anesthetized cats.

Method:

The method used is described in detail by O. A. T. Olsson, Acta pharmacol, et. toxicol. 34, 103-114 (1974).

Cats weighing 2.5 to 3.5 kg were anesthetized with patobarbital (mebumalum NPN) first by intraperiitoneal injection (30 mg / kg) and then by continuous intravenous infusion to maintain a constant level of anesthesia throughout the experiment.

Arterial blood pressure is measured by a Statham transducer from a cannulated carotid artery. Heart rate is measured using a tachometer monitoring the R-wave frequency of the electrocardiotgnam.

M. soleus hind limbs consisting predominantly of slow contraction fibers are prepared essentially according to Bo.women and Seimls,

J. Physiol. 144, 92-107 (1958). The muscle is enclosed in a “curler” rubber-coated plastic chamber. The entire limb is wrapped with a metal foil covered with plastic to keep it steady (temperatures of 35 to 36 degrees Celsius (controlled by a thermocouple on the limb).

The cat is placed on the back on a thermostatically controlled operating table and the right hind limb is fixed, with special attention being paid to ensuring that blood flow is not inhibited. The tendon is cut and connected to a Grass strain gauge (PT 10C). The isometric muscle tension is calibrated to 50 grams (resting tension) and 500 g (maximum tension). A bipolar plexiglas shielded bipolar electrode is placed on the itibialis nerve, near the m. Imperfect tetanus muscle contractions are induced by rectangular pulses by stimulating the nerve using Grass S48 with timullar. The pulse duration is 0.05 seconds with a frequency selected between 8 and 12 Hz and a voltage between 5 and 8 volts. Stimulation occurs for 1.8 seconds every 20 seconds.

The trachea is cannulated and artificial air breathing is performed using a constant volume Braun respirator. The frequency is 15 to 20 per minute and a residual volume of 8 to 10 ml per kilogram, or sufficient to suppress spontaneous respiratory movements and provide about 150 ml / kg / min. The change in residual volume after administration of the contracting agents is measured as the excess air from the constant volume loss with constant breathing. The voltage is determined using a water column threshold (60 to 70 mm) and excess breathing using a Grass Voltage Voltage Sensor ΡΓ 5A.

Bronchial tone is increased by inhalation of a histamine aerosol developed in a Rooth-Petersen nebulizer from a solution containing 0.1 to 0.3 mg / ml histamine and supplemented to 5% glycerol. When bronchospasm is induced, the nebulizer is connected to the respirator entrance. When the excess respiration has reached a uniform level, the compound tested for thromchorelaxation activity is injected into the brachial vein.

Test results

The test results are given in the table

1. The bronchospasmolytic effect is measured by the dose, calculated in moles per kg of body weight of the test animal, which causes a 30% reduction in hiitamln-induced bronchospasm. The tremorogenic effect is measured by the dose also calculated in moles per kilogram (animal body weight, which causes a 30% reduction in electrically induced soleus contractions). frequency.

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Remarks on the results

From Table 1 it can be seen that the test substances have a relatively higher bronchospasmolytic effect than itoremorogemic compared to terbutaline. This is prolonged in particular for D 2343 and D 2331. Compound D 2343 having a bronchospasmolytic effect in excess of 3x the bromchosipasmolytic effect of terbutaline, the tremorogenic effect being only 0.5 'of the tremorogenic effect of terbutaline and the cardiostimulatory effect not exceeding the cardiostimulatory effect of terbutaline a preferred compound.

B. Bronchospasmolytic efficacy following oral and subcutaneous administration

The bronchospasmolytic activity of the compound of the invention for oral administration was tested in guinea pigs. The compound of Example 1, designated D 2343, was tested. Terbutaline was used as a reference.

Way:

The bronchospasmolytic effect was tested as an inhibitory effect on histamio-induced bronchoconstriction in non-anesthetized guinea pigs.

The test animals were exposed to a Roth36 hisitamin aerosol

-Pelterson Nebuligator from a solution of 0.3 mg / ml histarnine hydrochloride.

Guinea pigs of both sexes, weighing 190-250 g, of the Dunkin-Hertley strain were used. Control animals premedicated with sodium chloride solution begin to breathe intensely and irregularly after less than four minutes of aerosol exposure. Animals pre-treated with the test substance, resistant to breathing for 4 minutes with a histamine aerosol, are considered protected. In the oral study, animals were fasted for 15 hours and ad libitum given water prior to gavage with D 2343 or terbutaline.

In the study with subcutaneous administration, were administered three to four different doses of D 2343 and terbutaline were administered 15 minutes before treatment histarninu to determine the _ED50 which is the dose protecting 50% of animals for more 4 minutes in the histamine aerosol. Each compound was administered to 30 to 40 animals.

In the oral study, the time from administration of the substance to the exposure of the animals to histarnine was 30 minutes.

Results

The results of the tests are given in Table 2. The ED ₅₀ doses are calculated on a molecular basis in moles per kg body weight of the test animal.

Table 2

Bromchospasmolytic effect of 1- (4-hydroxyphenyl) -2- [1,1-dimethyl-3- (2-methoxyphenyl) propyl] ethanol after oral and subcutaneous administration

Test substance Dose protecting 50% of animals against hisitamin aerosol for more than 4 minutes (ED ₅₀ µmoles / kg subcutaneous use oral use

Notes on test results

From Table 2 it can be seen that the test compound of the invention (D 2343) was po. by subcutaneous administration 2.7 times more potent than terbutaline and after oral administration 2.1 times more potent than terbutaline.

0.34 + 0.06 2.51 + 0.39

0.93 + 0.14 5.28 + 0.86

C. Onset and duration of bronchospasmolytic activity after oral administration

The onset and duration of the brochospasmolytic effect of the compounds of Example 1 and Example 4 were tested. These compounds have structural formulas

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Way

Bronchoispasmolytic efficacy was evaluated as inhibition of hisitamin-induced bronchoconstriction in non-aesthetized migraines.

The test animals were exposed to a histamine aerosol generated by a Roth-Peltersob nebulizer from a solution of 0.3 mg / m &lt; -1 &gt; hydrochloride hydrochloride.

Guinea pigs of both sexes weighing 160 to 230 g, a Dunkin-Hartley strain, were used. The animal pre-treated with sodium chloride solution had intensive and irregular breathing after aerosol exposure for less than 4 minutes. Animals pretreated with a substance of the invention resistant to a histamine aerosol for 4 minutes without affecting respiration are considered protected. The animals were fasted for 15 hours, receiving water ad libitum prior to gavage administration of the test substance. Each test substance was administered in an amount of 4.10 ^-6 mol / kg body weight. Groups of 8 to 10 animals were aerosol tested for 7, 15, 30, 60 and 120 minutes after administration of the test substance. The percentage of animals that resist aerosol for 4 minutes and 10 minutes was determined. The results are given in Table 3.

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The duration of action of the compound of Example 4 was noticeably prolonged compared to that of the compound of Example

1.

D. Testing for α-receptor blocking action

The effect of α-receptor blocking compounds of the invention was investigated. This effect is relevant in the treatment of asthma. It has been shown, for example, by Nousiainen et al., Pharmacology 15: 469-477 (1977), that some compounds having a blocking effect may potentiate the effects of β-receptor stimulating agents, for example terbutaline.

Thymoxamine, an α-receptor blocking agent, was used as a reference.

Way:

Albino rabbits of both sexes (2-3 kg) were used. About 5 cm of the aorta near the arch of the aorta were removed, transferred to a Krebs solution dish and cut spirally. Usually, 3 slides are obtained from the extracted vessel. Each strip was placed in an isolated organ bath in Krebs solution at 37 ° C and aerated with carbogein. The loading of the specimen was 2 g and the pressure changes were evaluated isometrically on a Graiss PRO 3 and P5 polygraph.

Noradrenaline, a powerful α-receptor stimulator, exerts a contracting effect on the aortic strips when added to the bath. The α-receptor blocking effect of the test substance is evaluated by adding the test substance to the organ bath before adding norepinephrine.

Noradrenaline solution was used at a concentration of 70-80% of the maximum draw (0.03-0.06 µg / ml). The test substance was added to the organ bath 10 minutes prior to the addition of norepinephrine.

Results are measured as the concentration of test substance that inhibits nor-adrenaline-induced contraction by 50% (ED 50). Results

The test results are given in Table 4 below.

Table 4

Α-Receptor Blocking Activity of the Compounds of the Invention

Test substance Concentration inhibiting 50% of noradrenaline-induced contractions μΜ

Thymoxamine

ED 50 values are based on tests with 6 preparations obtained from 3 animals. Remarks on the test results

It can be seen from Table 4 that compound D 2343 according to the invention has an α-receptor blocking activity that is greater than the α-blocking activity of thymaxamine.

It has also been shown that the α-blocking effect of D 2343 is achieved by the same dose range as its β-stimulating effect. As mentioned previously, a combination of α-adrenoreceptor blocking properties and β-adrenoceptor stimulating properties may be beneficial in the treatment of asthma.

E. Inhibitory effect on uterine contractions of rats in

0.6 + 0.2

0.5 + 0.2

1.5 + 0.4 vitro induced by oxytocin and carbochol

The relaxation effect of the compounds of the invention on the uterus was tested. Te was used as reference. butalin.

Way:

Female Spragus-Dawley rats weighing 150-200 g were used. The estrogenic steroid (Est radurin, Leo), 0.25 mg / 100 g, was administered subcutaneously 4-6 days prior to the experiments to induce eistrus in animals.

The horn of the uterus was opened lengthwise by incision, placed in an isolated organ bath in Locke's solution at 33 ° C and aerated with carbogen. The contraction of the preparation was induced by oxyitocin (Pertocon, Ferringj or carbochol added to the bath 3 minutes after administration of the test substance, at a dose inducing 70 to 80% of the maximum contraction or 0.005 to 0.02 IU / ml oxytocin and 0.2 to 0.6 pg) The inhibitory effect induced by the test substance was eliminated by prioprainolium (1 µg / ml or 0.4 x 10 ^-5 M, added to the bath 15 minutes before the test substance).

Tension changes were recorded isometrically (FPO 3 sensor and Grass polygraph)

P3).

Results

The results are given in Table 5. The results are given as the concentration of test substance that reduces contraction induced by exotocin or carbochol by 50% (EC 50).

Table 5

Inhalation effect on contractions induced in rat uterus

Test substance inhibition of contractions - Inhibition of contractions induced by oxytocim called carbochoEC 50 (M) hem EC 50 (M)

OH

CH,

CH-CH-HH-C-CH 2 CH 2

CH,

OCH,

0.18 ± 0.06 x 10 ^81> 0.32 + 0.08 x 1082)

Terbutalin.

2.10 + 0.70 x 10 ~ ⁸¹⁾ 2.61 + 0.51 x 10

-82) ¹¹ p = 0,01 Oxytocin series: 10 preparations per 6 animals ²⁾ p = 0,001 Carbachol series: 9 preparations from 5 animals

Notes on test results

Table 4 shows that compound D 2343 of the invention is more potent as an uterine relaxation agent than terbutaline. Terbufiarn has been tested as an uterine relaxation agent to inhibit premature labor, as described, for example, by Andersson et al. Acta Obsitelt. Gynac. Soand. 1974. The results of the tests in Table 5 show that compound D 2343 of the invention is at least as effective as terbutaline when used as a uterine-relaxing agent.

When using an agent with a relaxing effect on the uterus, it is particularly important that a compound having reduced tremorogenic activity is available, since treatment of such cases is only performed for a certain period of time. In treatment with terbutallne, it has been found that the tremorogenic effect at the start of treatment is subsequently reduced if treatment is continued for a certain period of time. Such suppression of the tremorogenic effect does not occur in the effect on uterine relaxation due to the short duration of medication in such cases. Thus, the compounds of the invention represent an important improvement in the uterine relaxation action in this regard.

E. Acute toxicity in mice

The acute toxicity of compound D 2343 according to the invention was monitored.

Male mice (NMRI 0 0 'weighing 20-25 g) were used. Test substances were administered intravenously (into the tail vein), subcutaneously, iintraperitoneally and orally (by gavage to fasted animals) in 6 doses in log, row with 10 or more animals tested. per dose to determine 1.1).

Toxic doses were followed by death within the first hour after intravenous, subcutaneous and initraperitoneal administration and within the first three hours after oral administration. No mortality of other animals was observed over the next 5 days. The results are shown in Table 6.

Table 6

Acute toxicity of compound D 2343 according to the invention

Method of administration LDgo D2343 (M = 378.5) mig / kg M / kg (X 10 intravenous 12 (+1) 3.5 subcutaneous 50 13 intraperiitoneal 45 (+2) 12 oral 170 (+9) 45

F. Use as α-receptor blocking agents, the compounds can be used to treat Rayitory naud's disease. Raynaud's disease is a pairoxysmal disorder of the arteries of the fingers and toes

Α-blocking properties characterized by seizures of ceptor pain are known in the compounds of the invention, whilst the fingers turn white and blue.

Claims (1)

I will invent the object A process for the preparation of the novel 1- (4-hydroxyphenyl) -2-aminoethanol derivatives of the general formula I H ^RI OH ° CH-NH-qHCH _{£ t) h} OŘ ^2- (a) in which n stands for 1, 2 or 3, R @ ¹ denotes hydrogen, an aliphatic acyl group having 2 to 5 carbon atoms or unsubstituted or substituted benzoyl groups of the formula R ⁴ is hydrogen or methyl and iterapeutícky usable salts of these compounds, characterized in that the reduction is carried out iminoketone derivative of formula VI About where R ³ denotes hydrogen or methyl and R ² is hydrogen, an aliphatic alkyl group having 1 to 4 carbon atoms, benzyl, aliphatic acyl group having 2 to 5 carbon atoms or unsubstituted or substituted benzoyl obeoného formula wherein for R ² have the same meanings as described above for formula I, and R is hydrogen, an aliphatic acyl group having 2 to 5 altoms of carbon, an unsubstituted or substituted benzoyl group of the formula: R ³ denotes hydrogen or a methyl group or a hydroxyl-protecting group, for example an alkyl group having 1 to 5 carbon atoms, or a mono- or bi46-cyclic arylalkyl group having at most 11 carbon atoms, for example a benzyl or naphthylmethyl group, to give a 1- (4) the hydroxydiophenyl J-2-aminoethanol of formula V (V) in which, and thereafter, if desired, the compound of formula I thus obtained for R and R ² is as defined above, whereupon it is found to be pharmaceutically acceptable; salt If desired, the R group may be separated from and / or resolved into its optical isomers.