DE2640972A1 - AMINOAETHANOL DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THE MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

The present invention relates to new pharmacologically active compounds, processes for their preparation and their therapeutic use. The invention also relates to pharmaceutical preparations which contain these compounds. More specifically, the novel compounds of the invention have antiallergic and anti-anaphylactic activity and are special
valuable as an antiasthmatic agent and can also be used in the
therapeutic and prophylactic treatment of other allergic diseases.

709815/1195

Postsdiedc: Frankfurt / Main 67 63-602 Bank: Dresdner Bank AG. Wiesbaden. Account no. 276807

The term "allergy" means "hypersensitive" according to Borland's Illustrated Medical Dictionary, 24th Edition, 1967 Condition as a result of being brought together with a special one Allergen, which brings to light an altered ability to react. "As examples of various allergies Asthma, allergic rhinitis, hay fever and hives can be mentioned. A common characteristic of many types of allergic Reactions in humans is an antigen-antibody reaction that leads to the release of pharmacologically active substances (= Intermediate), i.e. from histamine and SRS-A (= slowly reacting substance from anaphylaxis) leads. The mediators thus released cause bronchial constriction, edema, increased mucus production, itching, etc. The result of the reaction in an allergic Attack can be explained schematically as follows:

Stage 1 allergen (antigen) enters the organism

Stage 2 The antigen reacts with antibodies, this leads to

Stage 3 release of intermediaries

Level 4 The substances released, especially histamine and SRS-A, give rise to the symptoms of the allergic reaction: Bronchial constriction, edema, increased mucus production, etc.

The type of exaggerated reaction of the organism explained above to allergens (antigens), which may be foreign proteins or other substances, is called an anaphylactic reaction designated.

The mechanisms associated with the anaphylactic reaction were by Assem in "Clinical Allergy", 1974, Volume 4, pages to 194 and by Assem and Schild in "Int. Arch. Allergy", 40, Pp. 576-589 (1971).

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Although special emphasis is placed on in the following description
Bronchial asthma is of the exogenous type, which is only one form of allergy, it goes without saying that the advantages achieved according to the invention are also obtained in other forms of allergy.

In the conventional treatment of asthma, the symptoms appearing in stage 4 are treated. The constriction of the bronchi in particular is relieved by the administration of substances that reduce the bronchial spasm and thus widen the bronchi. However, this treatment is usually only started when the asthma attack is approaching or already full
is available. It would be desirable to have access to a prophylactic method of treatment that could thus be used to prevent the onset of allergic attacks. This could be done by inhibiting the release of the mediators occurring in stage 3 in the above scheme. It
it is known that some sympathomimetic amines also use the
Inhibit antigen-induced release of mediators, and under
Of these amines, there can be mentioned those that are usually used in
used in the treatment of asthma, such as adrenaline, isoprenaline, and terbutaline. In contrast to the task
According to the invention, these substances bring out the anti-anaphylactic effect in the same dosage range as is required to achieve bronchodilatation. This means that the undesirable side effects obtained with these sympathomimetic amines, such as palpitations and
Tremors, sometimes severely restricting their use as effective anti-anaphylactic agents.

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The aim on which the invention is based now consisted in obtaining compounds which would release the antigen-induced release inhibit histamine and other spasmogenic substances in a dosage range in which they do not have "classic" produce sympathomimetic effects such as vasodilation, cardiac stimulation and tremor. Connections with such specific inhibitory effects on the release of spasmogenic substances are effective as prophylactic antianaphylactic Means in treating various types of allergies, such as bronchial asthma, without giving the side effects, which are associated with sympathomimetic amines, which were commonly used as bronchospasmolytic agents, notices.

According to the present invention it has been found that compounds the general formula

₂ - NH - A - OR

and their physiologically compatible salts have a strong anti-anaphylactic Have an effect in dosage ranges where their cardiac stimulating and bronchiospasmolytic effects are negligible are. In this general formula, R and R are identical or different and denote hydrogen atoms, aliphatic Acy groups with 1 to 5 carbon atoms, benzoyl groups or phenylacetyl radicals, and A represents a straight-chain or branched-chain alkylene group having 3 to 6 carbon atoms or a cycloalkylene group with 4 to 6 carbon

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material atoms. The found surprising and beneficial Combination of properties makes these compounds according to the invention to valuable anti-anaphylactic agents that contribute the prophylactic treatment of various forms of allergy, such as allergic rhinitis, hay fever, hives, Asthma, etc., with a reduced risk of side effects, commonly observed with sympathomimetic amines can be used.

1 2

Illustrative examples of groups R and R are as follows:

H-

CH ₃ CO-CH ₃ CH ₂ CO- CH ₃ CH ₂ CH ₉ CO- (CH ₃ ) ₂ CHC0-

CH ₀ CCH ^) ₀ CO- </ ^x > CH ₀ C -

3 -

I.
HC-CH ₂ CO-

CH ₃ -C-CO-

^CH 3

Illustrative examples of group A include the following:

-CH ₂ CH ₂ CH ₂ -

-CH-CH ₂ -CHo

-CH ₂ -

CH ₃

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CH,

L> Π ry

-CH ₂ CH ₂ CH-

^ L.n— Uno

CH.

-CHCH ₂ CH ₂ - ^CH

-CH ₂ CH-

XH.

-CH-CH-

-CHCH ₂ -C ₂ H ₅

-CH

-CH

CH-

-CH ₂ CH-

-CH

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-CH

. Sl (D-

CH>

-CH ₂ CH ₂ "

,1 ,

The preferred meaning for the group R is hydrogen atom.

The preferred meanings for group A are straight-chain or branched-chain alkylene groups having 3 to 4 carbon atoms .

Illustrative examples of compounds according to the invention are as follows:

HO

OH

ι " ³

H - CH ₂ - NH - CHCH ₂ - OH

HO.

/ ^ CH - CH ₂ - NH - CH ₂ CH ₂ CH ₂ - OH

HO

HO

OH

(/ V- CH -

"'OH

-NH- CHCH ₂ - OH CH ₀

HO

/ "Vch -

HO

OH

CH ₂ - NH - CH ₂ - CH - OH

CH,

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- NH - CH ₂ CH ₂ CH ₂ CH ₂ - OH

Oh

CH-

t-CH - CH ₂ - NH - CH ₂ CH ₂ CH - OH

OH

CH,

• f - CH - CH ₂ - NH - CH ₂ CHCH ₂ - OH OH

Or

/ OH

CH ₂ - NH - CHCH ₂ CH ₂ - OH

HO

Ϊ V

Υ—

CH OH

- CH ₉ - NH - CH - CH - OH

• ² :!

CH ₃ CH ₃

HO '

-CH - CH ₂ - NH - CHCH ₂ - OH

OH

C ₂ H ₅

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CH,

CH -. CH ₂ - | \ f H-C-CH ₂ OH

OH CH,

P% —coo CH,

<( y-CH-CH ₂ -NH-C-CH ₂ OH

-CO

OH CH,

-CH ₀ COC CH,

/ V- y- CH-CH ₀ -NH-C-CH ₀ OH OH

■ _O IMI IC - Ol IqI

CH ₂ COO '

( V

f \

-COO '

CH - CH ₂ - NH - C - CH ₂ OCCH ₃

> —CO CH ₃

V-CH-CH ₂ -NH-C-CH ₂ OCC ₂ H ₅

CH,

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ft *.

(/ V — COQ-I CH "

V-CH - CH ₂ - NH - C - CH ₂ OC (CH ₂ CH _{3 4} J

, FX

OH

-COO '

// V

^{y /} V- CH ₂ COO-. CH

OH - CH ₂ - NH r C - CH ₂ O - C - CH ₀

-CH ₂ COO '

.CH,

-CH - CHo -NH-

CH

CH - OH

OH

ch;

HO '

HO,

ru _ pu _ nu

HO '

OH

- NH - CH - CH

-CH ₂ CH

HO

CH - CH ₂ - NH - CH OH CH - OH

CH ₃ CO

CH ^ CO

CH.

CH _{- CH 2} - NH - C - CH ₂ OH

OH ■ CH-

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CH ₃ CH ₂ COO ..

CH ₃ CH ₂ CO

2540972

f »3

- CH - NH - CCH, - CH

CH,

Γ ³

- CH ₂ - NH - C - CH ₂ OH CH "

H ^ C-C-COO I.

- CH

CH _Q

I ³

₂ - NH - C - CH ₂ OH ^! 3

CH,

H ₃ CC-COO ^ / -CH - CH ₂ r- NH CH ₃ CH ₃ . X = OH I.
- CHCH CH ₃ H C-C-COO Λ = /

CH,

- OH

The preferred group of compounds consists of those wherein R is hydrogen and A is straight or branched chain Denotes an alkyl group having 3 to 4 carbon atoms. Among the preferred compounds according to the invention are the following:

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OH

CH,

- NH-C-

CH.

- OH

(Example 1)

CH,

CH ₂ - NH - CHCH ₂ - OH

(Example 2)

CH,

■ /

--CH- CH ₂ . .-NH - CH ₂ CH - OH ■ OH '

(Example 4)

The preferred connection after the invention is

CH.

- NH - C - CH ₀ - OH

CH,

(Example 1)

Since the compounds according to the invention with the above formula I have at least one asymmetric carbon atom, the invention also includes all possible optically active Forms and racemic mixtures of the compounds. The racemisehen Mixtures can be separated by conventional methods such as salt formation with a

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optically active acid and subsequent fractional crystallization.

The compounds according to the invention can be used in human medicine and veterinary medicine for therapeutic and prophylactic use can be processed into preparations. Generally they are in the form of a physiologically acceptable one Salt such as hydrochloride, sulfate, maleate, tartrate, etc., is used.

In clinical practice the compounds according to the present invention are used Invention normally orally, by injection or by inhalation in the form of a pharmaceutical preparation administered containing the active ingredient in the form of the original compound or optionally in the form of a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier, which the latter can be a solid, semi-solid, or liquid diluent or an ingestible capsule, and such preparations constitute a further aspect of the invention. Usually the active substance makes up 0.1 to 99% by weight of the preparation such as 0.5 to 20% by weight for preparations for injection or 0.1 to 50% by weight for preparations for oral administration.

To pharmaceutical preparations in the form of dosage units for oral administration containing a compound To produce according to the invention, the active ingredient can be provided with a solid, powdery carrier, such as, for example Lactose, sucrose, sorbitol, mannitol, a starch such as potato starch, corn starch or amylopectin, laminar

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powder or citrus pulp powder, a cellulose derivative or gelatin, are mixed and can also be lubricants, such as

Magnesium or calcium stearate or a Carbowax ^ - ^ or other polyethylene glycol waxes and are pressed to form tablets or dragee cores. If coated tablets are required, the cores can, for example, be coated with concentrated sugar solutions, which may contain gum arabic, talc and / or titanium dioxide, or instead they can be coated with a film-forming agent that is dissolved in highly volatile organic solvents or in mixtures of organic solvents is present. Dyes can be added to these coatings, for example in order to distinguish between different contents of the active substance. For the production of soft gelatine capsules (perfo-shaped closed capsules), which consist of gelatine and, for example, glycerine as a plasticizer, or for the production of similar closed capsules, the active substance can be mixed with a Carbowax ^v> - 'or a suitable oil such as sesame oil, olive oil or peanut oil to be mixed. Hard gelatin capsules can contain granules of the active substance with solid, powdery carriers such as lactose, sucrose, sorbitol, mannitol, starches (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatin, and they can also contain magnesium stearate or stearic acid as lubricants.

When using several layers of the active substance, which are separated from each other by slowly dissolving coatings, you get tablets with delayed drug release. Another Way to manufacture tablets with delayed action

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Substance delivery is to distribute the dose of the active substance on granules with coatings of different thicknesses and compressing the granules together with the carrier substance to form tablets. The active substance can also dissolve in slowly Tablets, such as those made from fat and wax substances, can be incorporated or evenly in a tablet an insoluble substance such as a physiologically inert plastic substance.

Effervescent powders are made by mixing the active ingredient with non-toxic carbonates or hydrogen carbonates, such as sodium, Potassium or calcium carbonate or hydrogen carbonate produced, such as using calcium carbonate, potassium carbonate and potassium hydrogen carbonate, being non-toxic acids such as tartaric acid, ascorbic acid and citric acid, and for example Flavorings can be added.

Liquid preparations for oral administration may be in the form of elixirs, syrups or suspensions, or for example be prepared in the form of solutions containing about 0.1 to 20% by weight of active substance, sugar and a mixture of ethanol, Water, glycerine, propylene glycol and optionally flavorings, saccharine and / or carboxymethyl cellulose as dispersants contain.

Preparations can be used for parenteral administration by injection an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substances according to the invention, optionally in a concentration of 0.5 to 10% by weight, and optionally also contain a stabilizing agent and / or buffer substances in aqueous solution. Dosing

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This solution can advantageously be packed in ampoules be included.

The dosage with which the active ingredients are administered can vary within wide limits and depends on various factors, such as the individual Needs of every patient. A suitable oral dosage range is 10 to 200 mg per day. A suitable one The dosage range for parenteral administration is about 1 to 50 mg per day.

The pharmaceutical compositions containing the active ingredients may be conveniently compiled to contain doses in these areas either as individual Dosage units or as several dosage units result.

The compounds according to the invention are prepared by methods known per se by A) a compound of the general formula

(/ \) _ CH - CH ₂ υ

wherein R is a hydrogen atom or a hydroxyl protecting group, such as an alkyl or aliphatic acyl group having not more than 5 carbon atoms, a mono- or bicyclic aralkyl group having no more than 11 carbon atoms, such as a benzyl group or naphthylmethyl group, or a benzoyl group or a phenylacetyl group, with a Compound of the general formula

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HN-A- OR ² R ³

wherein R is a hydrogen atom, an aliphatic acyl group with 1 to 5 carbon atoms or a benzoyl or Phe-

3
Nylacetyl group, R is a hydrogen atom or an N-protecting group such as a benzy group and A is an alkylene group having 3 to 6 carbon atoms or a cycloalkylene group having 4 to 6 carbon atoms, to form a compound of the general formula

RO '

\ - CH

OH

CH ₇ - N

² \, R-

A - OR '

converts and then optionally the protective groups R and

R removed or

B) a compound of the general formula

• 3

wherein R, R and A have the meaning given for method A. have, forming a compound of the general formula

RO-.

-CH-CH ₂ -N-A-OH

OH

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. 34.

reduced and then optionally the protective groups R and R removed or

C) a compound of the general formula

VI

CH = N

wherein R and A have the meaning given for method A, with formation of a compound of the general formula

- "NH - A - OH

IVb

OH

reduced and then optionally the hydroxyl protective Groups R removed or

D) a compound of the general formula

VII

wherein R has the meaning given in method A and X is a halogen atom, such as Cl, Br or I, means ^ with a Compound of the general formula

, 2

NH-A- OR R ³ '

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III

-η.

2 3

wherein A, R and R are as defined above, forming a compound of the general formula

RO ._

/ V-CH-CH ₂ -N-A-OR ² iv

_R0 / "oh R ³

converts and then optionally the protective groups R and R removed or

E) a compound of the general formula

V VC -CH ₀ -N - "- A • - OR ² - VIII

IR ³

2 3

wherein R, R, R and A are as defined above, forming a compound of the general formula

RO

ft V-CH - CH ₂ - N - A - OR ^{2 IV}

ί U

J ΧΔ

OH ^Κ

reduced and then optionally the protective groups R and R removed or

F) for the preparation of compounds of the formula I in which A is connected to the nitrogen atom via a methylene group, a compound of the general formula

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264097 ^

RO 3}

3
worxn R and R have the above meaning, A ^{1 is} a straight-chain or branched-chain alkylene group having 2 to 5 carbon atoms and R is a mono- or bicyclic aralkyl group having not more than 11 carbon atoms, such as a benzyl group or naphthylmethyl group, to form a compound of general formula

RO

RO

-CH - CH ₂ - N - A '- CH ₂ OH IA

I I -a

OH R ^J

reduced and then optionally the protective groups R

and R removed.

The starting materials used in Reactions A, D, E and F above are known compounds that can be prepared in a known manner. Those in Reactions B and C above The starting materials used are new compounds. These compounds of the formulas V and VI represent a further aspect of the invention.

The starting materials can be, for example, according to the following methods explained by reaction equations, where in these reaction equations R, R, X and A have the above meanings.

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Method a

RO

RO

C - CH,

Ii 0

Reduktxon \ X with NaBH ₄

-CH - CH.

RO

Method B.

RO

RO

.0 A

/ V

RO '

C - CH ₂ - X + HN - A - OH-O R ³

RO

-C.

OH ^CH 2

Method c

, 0-

when R ² = H

CCH + H ₂ N -A- OR ^!

-A

OH

CH.

-C - CH = N - C -

when R ^ = an acyl group

Method F.

RO

RO

Vc - C - H * H ₇ N - A '- C - 0 - R ² - ^ V

0

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CH - CH ^ -NH -A '-C-Q-R

The following examples serve to further illustrate the invention.

example 1

Production of 1- (3,5-dihydroxyphenyl) -2 - / '(1,1-dimethy 1-2-hydroxyethyl) -amino7-ethanol sulfate according to method A.

To a solution of 6.6 g of 3,5-dibenzyloxystyrene oxide in 100 ml n-propyl alcohol were 4.5 g of 2-amino-2-methylpropanol- (1) added. After refluxing for 20 hours, the mixture was evaporated to dryness and the residue became extracted with diethyl ether. The ether phase was with water washed and dried over MgSO. Concentration of the ether solution in vacuo resulted in crystallization of the base from the above designated connection. Yield 3.7g.

Analyzes were carried out on the reaction product by IR spectroscopy, NMR spectroscopy and determination of the equivalent weight carried out. The crystalline base was in ethanol / diethyl ether dissolved, and a calculated amount of 5N

^H 2 ^SO 4 was added to precipitate the sulfate salt of the above identified compound. Yield 4.7g. Analyzes: IR, NMR, SO ₄ ² ": 99.4%. ·

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b) 1- (3,5-Dibenzyloxyphenyl) -2- / 71 , 1-dimethyl-2-hydroxyäthy1) -amino_7-ethanol sulfate (2.0 g) was suspended in 200 ml of methanol and at room temperature and atmospheric pressure for 1 hour in Hydrogenated in the presence of 0.2 g of 20% palladium carbon. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue turned off

Isopropyl alcohol recrystallized. Yield 0.7g.

2 analyzes: IR, NMR, SO. (99.0%) + traces of remaining

Solvent.

The same procedure was used to make the following compounds:

Example 2

1- (3, 4-dihydroxyphenyl) -2- / 7i-methyl-2-hydroxyethyl) amino7-ethanol sulfate

SO ₄ ": 97.4%. Mp. = 194 ° C. The identity of the compound was confirmed by NMR spectroscopy.

Example 3

1- (3,5-dihydroxyphenyl) -2- / 74-hydroxycyclohexyl) -amino / - ethanol hydrochloride

Br ~ _ber : 11.7%. Br " _f : 11.5%. Mp. = 234 ° C. The identity

the compound was confirmed by NMR spectroscopy.

Example 4

1- (3,5-Dihydroxyphenyl) -2- / T2-hydroxypropyl) -amino7-ethanol hydrochloride

oil: Cl ~ _ber : 13.4%. Cl " _f : 12.4%. The identity of the compound was confirmed by NMR spectroscopy.

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Example 5

1- (3,5-Dihydroxyphenyl) -2 - / (1-ethyl-2-hydroxyethyl) -aminoj-ethanol hydrochloride

Oil: Cl ~ _ber ^: 12/8% · Cl " _f : 11.6%. The identity of the compound was confirmed by NMR spectroscopy.

Example 6

1- (3,5-Dihydroxyphenyl) -2 ~ / T3-hydroxypropyl) amino? - ethanol sulfate 92% SO ₄ ² ", NMR.

Example 7

1- (3,5-dihydroxyphenyl) -2- / Jl , 2-dimethyl-2-hydroxyethyl) - amine o / - ät h ano lhy dr ο ch lor i d

Cl ~ _ber : 12.8%. Cl " _f : 12.5%. Mp. = 212 ° C. The identity
the compound was confirmed by NMR spectroscopy.

Example 8

Production of; 1- / 3,5-bis- (2-methylpropionyloxy) -phenyl7-2- / Ti / 1-dimethy1-2-hydroxyäthy1) -amino7-ethanol hydrobromide

a) SiS-Bis- ^ g-

To 3,5-dihydroxyacetophenone (30.4 g) dissolved in 350 ml
Acetonitrole, 63 ml of 2-methylpropionyl chloride were added. The mixture was stirred and refluxed for 20 hours after which it was evaporated to dryness. The residue was dissolved in ether and treated with Norit.
After filtration and evaporation, a dark oil was obtained. Yield 56 g / NMR. The oil was dissolved in 400 ml of dry diethyl ether and 0.7 ml of Br "in 75 ml of chloroform

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were added at 0 ° C. The mixture was stirred at room temperature for 1 hour. The solution was treated with Norit, filtered and evaporated to dryness. The residue was taken up in 75 ml of isopropyl alcohol and 75 ml of petroleum ether (boiling point = 40 to 60 ° C.), after which the precipitate was filtered off and washed with petroleum ether. Yield 39.2 g, Br _calc : 21.5%. Br _f : 21.4%.

b) li / I ^ S-Bis - ^^^ me ^ ylgrogionyloxY ^ lEhenyJ ^ -g-broinethanol To a solution of 4.8 g of 3,5-bis- (2-methylpropionyloxy) -CO-bromoacetophenone in 100 ml of dioxane and a solution of 0.5 g of NaBH ₄ in 20 ml of water was added to 25 ml of water. The reaction mixture was kept neutral by adding 2N HCl during the addition of the NaBH. Solution. After stirring for one hour at room temperature, the mixture was evaporated to dryness and the residue was extracted with ether. The ether phase was washed with water over MgSO. dried and evaporated to give an oil as a residue. Yield 3.7 g, NMR.

c) 1- / 3 _Λ 5-bis -_ (2-methYlprgpignyloxy) _- phenyIZr ^2- Zl 1 jl \ zdime-

A solution of 1- (3,5-bis- / _ 2-methylpropionyloxv_7-phenyl) -2-bromoethanol (3.7 g) and 2-amino-2-methylpropanol- (1) (2.7 g) in 100 ml of acetonitrile was refluxed for 20 hours and then evaporated to dryness. The residue was dissolved in diethyl ether, causing precipitation of the hydrobromide caused by 2-amino-2-methylpropanol- (1) (1.4 g). The filtrate was washed with water, dried over MgSO ^ and with methanolic hydrobromic acid solution

70981S / 119S

acidified, after which crystals were obtained. Yield 0.3g. ^Br "ber ^{.: 17} ' ^3% ' ^Br " found. ^{: 17} ' ^{4 =} ' ^NMR '

Example 9

1- / 3,5-Bis- (2,2-dimethylpropionyloxy) -phenyl7 ~ 2- / Ti, 1-dimethyl-2-hydroxyethyl) -amino7-ethanol hydrobromide . Br " _ber : 16.3%. Br" _ef : 16.4%. The identity of the compound was confirmed by NMR spectroscopy.

Example 1O

Production of 1- (3,5-dihydroxyphenyl) -2- / Ti, 1-dimethy1-2-hydroxyethyl) -amino7-ethano-sulfate according to method C

To a solution of 7.8 g of 3,5-dibenzyloxyphenylglyoxalmonoethylacetal in 150 ml of dry diethyl ether became a solution of 1.8 g of 2-amino-2-methylpropanol- (1) in 50 ml of dry ether added. The above connection soon started to crystallize and the mixture was allowed to stand at room temperature for 20 hours, after which the crystals were filtered off became. Yield 6g, NMR.

Reaction scheme:

ChL

I ³

C-CH + H ₂ N-C-CH ₂ OH

0 0 CH ₃

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.CH,

CH,

CH = N

0.6 g of NaBH were added to a suspension of 6 g of S ^ -dimethyl-e-hydroxy-G- (3,5-dibenzyloxypheny1) -4 _{f 5-dehydromorpholine in ethanol.} added in small portions. The resulting clear solution was stirred at room temperature for 4 hours, after which the solvent was evaporated. The residue
was taken up in ether and washed with water until
the wash water had a neutral pH. The ether phase was over MgSO. dried and concentrated in vacuo to give 4 g of the above identified compound as a white solid. This compound was analyzed using NMR and IR spectroscopy and was identical in all respects to the compound obtained in Example 1a.

Reaction chema:

/ V,

.0 CH

-CH,

NaBH

4 ν

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• τ / 7.

CH - CH ₀ - NH - C - CH ₉ OH

I ² I

^CH 3

c) Production_der_ober_bezeichen_Verbinäun2 Catalytic hydrogenation at room temperature and 3.74 atm (55 psig) of S ^ -dimethyl-e-hydroxy-ö- (3,5-dibenzyloxyphenyl) -4,5-dehydromorpholine, which was obtained in step b) was, in the presence of 5% palladium carbon in ethanol, which contained H ₂ SO ^, gave 1- (3,5D! hydroxyphenyl) - / Tl, 1-dimethyl-2-hydroxyethyl) -amino7 ~ ethanol sulfate, as by thin layer chromatography has been analyzed.

Example 11

Preparation of 1 - (3,5-dihydroxypheny 1-2- / 71 ., 1 -dimethy'l-2-hydroxyethyl) -amino7-ethanol sulfate according to method C

3,5-Dibenzyloxyphenylglyoxalmonoäthylacetal and 2-Amino-2-methylpropanol- (1) were reacted with each other in ethanol, and the intermediate product 3,5-dibenzyloxy- (Gi) - (1,1-dimethyl-2-hydroxyethyl) -iminoacetophenone was reduced with NaBH «in situ without isolation and gave 1- (3,5-dibenzyloxyphenyl) -2- / Ϊ, 1-dimethyl ^ -hydroxyethylaminoZ-ethanol.

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■ η.

\\ - CH ₂ O

/ Γ \

ch;

/ —CL - C - H + H ₀ N - C - CH ₀ OH H 2 ι 2

0 0

CH,

/ V-

C11 _o C / OH ■ ^ CH - == N

NaBH

CH.

C-CH ₂ -NH-C-CH ₂ OH

CH.

The reaction product obtained in stage a) was catalytically reduced in the presence of 5% palladium carbon in ethanol, as described in Example 10c, using the compound 1- (3,5-dihydroxyphenyl-2- / 7i, i-dimethyl-2-hydroxyethyl) amino? ethanol received.

Example 12

Production of 1- (3,5-dihydroxypheny1-2- / 71,1-dimethy1-2-hydroxyethyl) -amino / -ethanol according to method F

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A mixture of 6.6 g of benzyl 2-amino-2-methylpropionate and 9.8 g of 3,5-dibenzyloxyphenyl glyoxal monoethyl acetal in 150 ml Ethanol was stirred at room temperature for 20 hours. Then 1.9 g of NaBH. added and the mixture was left for 3 hours stirred at room temperature and then evaporated to dryness. The residue was taken up in ether / water, and the ether phase was washed with water, over MgSO. dried and filtered. Acidification of the ethereal solution with ethanolic Sulfuric acid caused the sulphate of the above-mentioned compound to precipitate. Yield 6g. the Identity of the product was confirmed by NMR spectroscopy.

Reaction chema:

C. ~ C - H + H ₂ N -

I υ

0 0

-C-C-O-CH 3

NaBH

CHo 0

I f -CH ₂ -NH-CC

CH ₀

-D-CH

, -rs

A solution of 3 g of 1- (3,5-dibenzyloxyphenyl) -2- (1-benzyloxycarbony1-1-methylathy1) -aminoethanol sulfate in 75 ml of methanol

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was at room temperature and 3.74 atmospheres (55 psig) during Hydrogenated for 20 hours in the presence of 0.5 g of 10% palladium carbon. The catalyst was filtered off and the filtrate evaporated to dryness. The residue was extracted with boiling isopropyl alcohol, which was then taken to dryness was evaporated. The residue was recrystallized from ethanol / acetonitrile. Yield 0.5 g, the IR and NMR spectra were identical to those of an authentic sample of the compound identified above.

Reaction chema:

⁽ W / ² \ CH, O

I 7Ä

-CH - CH, - NH - C - C - 0 - CH., - / ^v < ² IA

OH

-CH- [T \ / 2

- CH ₂ - NH CH _q
I. CH -C-
I. OH I.
CH ₃

The following examples illustrate how the compounds according to the invention are incorporated into pharmaceutical preparations can.

Example 13 Aerosol for inhalation

1- (3,5-Dihydroxyphenyl-2- / 7i, 1-dimethyl-2-hydroxyethyl) -amino7-ethanol sulfate 1.00 g

709815/1135 ° ^'20

Frigen ^R 11/12/113/114 to 100.0 g

Example 14

Tablets 20.0 mg Each tablet contained 25.0 mg 1- (3,5-dihydroxyphenyl) -2- / 71,1-dimethy1- 190.0 mg 2-hydroxyethyl) amino7-ethanol sulfate 1r5 mg Cornstarch 12.0 mg Lactose 1.5 mg gelatin Talc Magnesium stearate

250.0 mg

Example 15 Suppositories

Each suppository contained

1- (3,5-Dihydroxyphenyl) -2- / 71-methyl-2-hydroxyethyl) amino7-ethanol sulfate

Ascorbyl palmitate Suppository base (Imhausen H)

Example 16 syrup

1 - (3,5-Dihydroxyphenyl) -2- / 72-hydroxypropyl) -amino7-ethanol hydrochloride

liquid glucose cane sugar ascorbic acid sodium pyrosulfite Disodium edetate

Orange food _{, 709 815/1}

20th rO mg 1 , 0 mg on 2000 , 0 mg

0.200 g

30.0 g

50.0 g

0.1 g

0.01 g

0.01 g

0.025 g

Dye 0.015 g

purified water to 100.0 g

Example 17 Injection solution

1 - (3, 5-dihydroxyphenyl) -2- / 72-hydroxypropyl) -amino7-ethanol hydrochloride 0.500 mg

Sodium Pyrosulfite 0.500 mg

Disodium edetate 0.100 mg

Sodium chloride 8,500 mg

Sterile water for injection to 1.00 mg

Example 18 Inhalation solution

1- (3,5-dihydroxyphenyl) -2- / 71,1-dimethy1-2-hydroxyethyl) amino / ethanol sulfate

Sodium Pyrosulfite Disodium Edetate N atrium Chloride Purified water

Example 19 Solution for rectal administration (rectal ampoules)

1- (3,5-Dihydroxyphenyl) -2- / 71-methy1-2-hydroxyethyl) -amino7-ethanol sulfate

Sodium Pyrosulfite Disodium Edetate Sterile Water

5 , 00 G 0 , 10 G 0 , 10 G 0 , 85 G to 100 , 0 ml

20.0 mg 1.5 mg 0.3 mg to 3.0 ml

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Example 20 '*'

Sublingual tablets

1- (3,5-dihydroxyphenyl) -2- / T2-hydroxypropyl) amino / ethanol hydrochloride 5.0 mg

Lactose 85.0 mg

Agar 5.0 mg

Talc 5.0 mg

100.0 mg

Example 21

drops

1- (3,5-Dihydroxyphenyl) -2 - / (2-hydroxypropyl) -amino_ / - ethanol hydrochloride As corbic acid sodium pyrosulfite disodium edetate Liquid glucose. Absolute alcohol. Purified water

Pharmacological experiments

A. Anti-anaphylactic effect

The anti-anaphylactic effect was sensitized to actively and passively Laboratory animals tested.

Active sensitization of the animals was achieved by injecting ovalbumin, a protein. This administration makes the animals hypersensitive to subsequent exposure of ovalbumin. The antianaphylactic activity of the test compounds was tested in vitro by removing lungs from ac-

70981S / 1198

2.00 G 1, 00 G 0.10 G 0.10 G 50.00 G 10.00 G to 100.0 ml

tively sensitized animals were exposed to ovalbumin and the effect of the test substance on the amount of histamine released by the lung preparation was measured.

Hemmun2_der_Histaminfreisetzun2_a.us_Lungen

METHODS: Guinea pigs of both sexes, 300 to 400 g, received single intraperitoneal injections of ovalbumin, 50 mg, emulsified in Freund's complete excipient for ^{1 s.} The animals were used 2 to 5 weeks later in the experiment described below.

The sensitized animals were sacrificed and bled. The lungs were excised and carefully minced. Lungs from 2 to 4 animals were used in each set of experiments. After several washes in Krebs solution, the Tissue was distributed in tubes with Krebs solution (0.1 g tissue / ml) and placed on a water bath (37 C). Ovalbumin (= the antigen) was added after 5 minutes of pre-incubation. The test connection was added 2 minutes before the ovalbumin addition. The incubation was usually carried out for an additional 15 minutes, the tubes being hand-shaken at intervals. The histamine release phase was canceled by the Tubes were placed on an ice bath. The incubation fluids were decanted and replaced with saline acidified to pH 3.5 'with hydrochloric acid. The lung tissue with the Saline was boiled on a water bath for 8 minutes. The incubation fluids and tissue extracts were up to Examination kept on an ice bath.

7 09815/1195

The histamine content of the incubation liquids and boiled Extracts were determined from the guinea pig intestinal sample. Pieces of the ileum end, 2 cm long, from guinea pigs with weighing 0.2 to 0.3 kg, were lengthways in 20 ml baths (37 C) with Krebs solution and this was continuously aerated with small bubbles. Atropine, 10 M, and propranolol, 10 M were added to the bath. Contractions were measured using a force displacement transducer (Grass, FTO3) and a polygraph (Grass, Model 7). After about 1 hour of washing several times, the sensitivity became the preparation tested against repeated doses of histamine. Segments of low sensitivity, high variability and unstable baseline were discarded. Preparations with high spontaneous activity were also excluded. The preparations were standardized so that they were 2, 4, 8 and 12 ng Histamine base / ml responded. These doses were repeated in given in an arbitrary order until a stable response was obtained. The extent of the contraction of the intestine in this Range was proportional to the log of the histamine dose. The test solutions were added in 0.1 to 1.0 ml, which is about gave the same amount of contraction as that obtained with an intermediate dose of histamine. By this intervening Standard histamine dose was kept constant, it was easy to see changes in intestinal sensitivity determine who was in contact with the histamine or the test solution for 15 minutes. During this time it was the maximum contraction registered. After a wash, 2 minutes were allowed to elapse before the next dose was administered became. All solutions were added with a pipette.

70981 5/1195

The strength of the contracting action of the test solutions on the isolated guinea pig ileum was called the histamine base expressed. The spontaneous release of histamine caused by treatment of the lungs was from the induced values given in the text. The results are as histamine release per gram of lung tissue (wet weight) or expressed as a percentage of inhibition of histamine release. The reference substance was terbutaline or isoprenaline

Cr)

used. Terbutaline (Bricanyl ^ - ^/ ) is a sympathomimetic amine used in the treatment of bronchial asthma. Two identically treated samples were run in each series of experiments. All samples in the same row were tested against the same histamine standard. The test results for the preferred compound of the invention are shown in Table I below. The entirety of the test results is shown in Table IV, where the effect of each substance is shown in relation to the effect of terbutaline. Doses that caused 50% inhibition of histamine release were compared between doses.

Table I.

Inhibition (%) of histamine release in sensitized guinea pig lungs. The control release without inhibition was 15 to 30% of tissue histamine. They are mean values with the j ^ "deviations and in brackets the numbers of those tested Lung preparations indicated.

70981 B / 1195

S / 1.

Inhibitor inhibition (%] different more Concentration ΙΟ ' ⁵ (9) tion (molarity) ± ³ (8th) 10 " ⁸ 10 " ⁷ 10" ⁶ + 3 link
after Bei
game 1 20 + 5 (4) 5 (10) 42 + 3 (10) 51 Terbutaline 30th (1) 5 (7) 43 + 5 (8) 58 Comment on the test erg" see Table I. ) at 30+ 24 + sbnis

The release of histamine induced by ovalbumin actively sensitized guinea pig lungs corresponded to 10 to 30% of the amount of tissue estimated by boiling the tissue became. The spontaneous release of histamine from the lung tissue did not exceed 2%. When the test compound of Example 1 to the lung tissue 2 minutes before the antigen was added, the release of histamine was inhibited in a dose-dependent manner. The strength of the test compound was about the same as that of terbutaline. The maximum inhibition of histamine release through the test compound of Example 1 was approximately equal to that of isoprenaline. The inhibitory effect was with propranolol, 10 6 M, completely blocked. The inhibitory effect of terbutaline on histamine release was obtained with the same concentrations as the pilocarpine contracted guinea pig trachea relaxed.

2. Inhibition of the release of SRS-A _{x of a} nonhista3

A non-histaminic, slowly contracting principle was used with the same ileum preparations as above, but after addition of brompheniramine (0.04, u <j./ml) tested. This concentration completely blocks the histamine response. A consortium

709815/1195

cycle time of 1.5 minutes was used for the test liquid det to get a contract balance. The ability to contract with this non-histaminic fraction is expressed as SRS-A units, the response being a Unit SRS-A equivalent to the maximum tension effect of

5 ng of histamine in the same unblocked guinea pig

ileum preparation. The results are in the following Ta belle II compiled.

Table II

Inhibitory effect on the release of a slowly contracting, non-histaminic principle (SRS-A) in sensitized

Guinea pig lungs

Experi
ment no. Control
release
Units/
Grams of lungs inhibition
ίο " ⁸ ' (%) with
example
10 " ⁷ the connection
1 (molarity)
ΙΟ " ⁶ according to
10 " ⁵ 79 1 108 51 50 57 not
determined 83 2 33 55 57 61 3 27 57 52 66 Comments to the tests] results of Table II

It can be seen from Table II that in the three experiments with different starting materials of lung tissue 50 to 75% of the nonhistaminic spasmogens were inhibited, 'if the investigated compound according to the invention (Example 1) was present in a concentration of 10 to 10 M.

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Method: Male rats (150 to 300 g) of the Sprague Dawley strain were anesthetized with pentobarbital (30 mg / kg ip). Evans blue (10 mg / kg) and the test substance were given intravenously into the femoral vein. Then, with dextran (molecular weight = 70,000), 6 intracutaneous welts were created in two rows on either side of the midline of the abdomen. The amount of dextran administered in each welt was 60 µg in 0.1 ml saline. The dextran causes an anaphylactoid reaction. Thirty minutes later the animals were sacrificed and the abdominal skin was excised. Color intensity was determined visually using a 1 to 4 point scale. Control animals without agent treatment were each tested with the compound of Example 1 and terbutaline. 5 animals were tested at each dose. 2 animals were tested with 3 to 4 doses each with the other compounds. The comparison with terbutaline is made at the ED _5Q value, ie the effective dose for a 50% inhibition of the color intensity of the blue-turning injuries.

The results are shown in Table III below.

Table III

Inhibitory effect of the compound according to Example 1 and of terbutaline on the reactions in welts produced with dextran in the Rat. The bluing of the injuries was assessed visually using a 1 to 4 point scale. PCA = passive anaphylactoid skin reaction

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dose
mg / kg IV inhibition
the PCA (%) 2640972 III Test connection number of
Experiments Connection of the 0.01 16 + 2 example 1 0.10 42 + 6 5 η 1.00 78 + 2 5 Il 0.01 18 + 3 5 Terbutaline 0.10 56 + 6 5 Il 1.00 81 + 4 5 II Test result sen the table 5 Comments on the

The dextran injections caused welt reactions with Diameters from 15 to 20 mm. The compound of Example 1 and terbutaline inhibited the development of welts in the same Dimensions. There was no significant difference in effectiveness between these two agents. The inhibitory effect was with propranolol (0.5 kg / kg), intravenously 5 minutes before the antagonist administered, completely blocked.

The activity values of all tested compounds in comparison with terbutaline (ED _5Q values = 0.08 mg / kg) are summarized in Table IV.

B. Bronchial spasmolytic effect

To study the relative anti-anaphylactic efficacy, the bronchial spasmolytic effect of the compounds was after investigated the invention.

Entgannun2 _- der_isolierte_Meerschweinchenluftröhre method: The trachea was cut out of guinea pigs (0.15 to 0.30 kg). It was cut spirally and fixed in a bath (25 ml) of Krebs solution, which con-

709816/1195

was continuously aerated with O ₂ (95%) and CO ₂ (5%). 1. µg / ml pilocarpine was added. The initial tension was about 2 g. Relaxations were recorded isometrically. The test solutions were added to the bath liquid either as a single dose or together. The response was expressed as the percentage of the maximum possible response of each preparation that was obtained when an above-maximum concentration of isoprenaline was added. The individual EC ₁ . Values (the concentration that gave 50% of maximal response) were calculated for each preparation. The maximum response was obtained with isoprenaline. The comparisons of efficacy with terbutaline made on this basis are summarized in Table IV. The efficacy values are the mean values of 2 to 4 experiments.

Results

The compound according to Example 1 relaxed the isolated guinea pig trachea to the same extent as isoprenaline. The EC ₁ - value for the compound of Example 1 was 2.04 + 0.54 .ug / ml (mean + deviation, 8 experiments) in the cumulative experiments. The potency of the compound was 0.03 times that of adrenaline and 0.04 times that of terbutaline.

The tubal relaxing potencies of all compounds tested are listed in Table IV.

C. Herstimulatory effect

The compounds according to the invention have also been investigated for their cardiac stimulating effect. A strong cardiac stimulator Effect is a serious undesirable side effect

70981 5/1195.

substances for use in the treatment of allergies such as bronchial asthma.

Method: The left atrium of the guinea pig heart was excised from animals of both sexes (0.5 to 0.9 kg) and immediately suspended in a 100 ml tissue bath containing Krebs solution at 31 ° C. and containing 95% O ₂ and 5% CO _ ventilated. The preparation was stimulated by strokes with a Grass stimulator, model 55 (frequency: once per second, duration: 1 to 5 milliseconds, voltage: 1 to 5 volts). Isometric tension was recorded. Increases in contraction force were expressed as a percentage of the control tension. The test solutions were added as single doses with washing in between. The individual EC _n . Values (concentration giving a 50% increase in residual voltage x) were calculated, and comparisons of efficacy with terbutaline were made on this basis. The total values in Table IV are the mean values of 2 experiments each.

Results

The compound according to Example 1 increased the contractility of the electrically stimulated left guinea pig atrium. The EC _5Q value was 2.70 + 0.10 µg / ml (mean + deviation, 5 experiments) and for terbutaline 0.11 + 0.2 µg / ml. The potency of the compound was only 0.04 times that of terbutaline. The herζstimulierenden effect of the compound was blocked with 1. ug / ml propranolol.

709815/1 195

The stimulating effect of all compounds tested in comparison with terbutaline is listed in Table IV.

Summary of the 2 pharmacological test results The following Table IV shows the pharmacological test results of the anti-anaphylactic effect, the bronchial spasmolytic Effect and the heart-stimulating effect summarized. All values are compared as a relative effect indicated with the respective effect of terbutaline, the respective terbutaline effect assumed by the value 1.0 will.

7 09815/1 195

Table IV

Test connection according to example no .

structure

Isoprenaline

Terbutaline (reference substance

- CH

₂ - NH - CH (CH ₃ J ₂

CHo

I ³

- CH ₂ - NH - C - CH ₃ OH CH _n

Inhibition of histamine

release
off active

more sensitized

Guinea pig
chenlunge

inhibition
the passive anaphylactoid skin reaction
in rats

Relaxation of the

Guinea pig
chenluft

tube

2.0

1.0

10

1.0

18th

1.0

Stimulating the

Guinea pig atrium

1000

1.0

example 1

HO

HG

'· * .. CH "

CH - CH ₉ - N - C - CH ^ OH

OH

H CH. 1.0

1.0

0.04

0.03

Example 8

(CH _q ) ₉ CH-C-0

^{J Δ} (I 0

)) ~ CH - CH ₉ - N

i I

□ Η Η

CH,

C - CH ₉ OH

0.1

1.0

Continuation from Table IV

Example 2

cn At - "** · game 4

Example 5

Example 3

HQ

HO

HOHO.

HO HO

^ ^H 3 - CH ₂ - N - CH

H CH ₂ OH

CH - CH ₂ - N - CH ₂ - CH

OH'

CH - CH. I '

OH OH

N ι

■ H

- CH

CH ₂ OH

1/0

1.0

0.07

0, o7

1.0 0.1

0.3

0.03 0.003 0.01

0.001 0.001

0.01 0.001 0.000

Koirarientare_to_the_Tester2 results_of_Table_IV The activity values given in the second column of Table IV are mean values of 2 to 3 different lung tissue sources with 3 to 4 different dosages. The number of tests for the compound according to Example 1 and for Terbutaline is given in Table I.

From Table IV it can be seen that the tested compounds of the invention inhibited antigen-induced histamine release from the minced guinea pig lung and inhibited the development of anaphylactoid skin reactions in the rat. Those for tracheal relaxation and inhibition of histamine release required terbutalin concentrations were about the same. The same relationship between tracheal relaxation and inhibition of histamen release was also found for isoprenaline. However, terbutaline showed a much cheaper one Relationship between antiallergic effects and hermus stimulation as isoprenaline (for terbutaline the Quotient 1, for isoprenaline 0.2).

The preferred compound of the invention, i.e. 1- (3,5-dihydroxyphenyl) -2- / 71, i-dimethyl-2-hydroxyethyl) amincy-ethanol sulfate of Example 1, and related compounds have a different profile of activity than terbutaline and isoprenaline, i.e. they show antiallergic effects in concentrations where they only have very little tubal relaxing effect. The compound of Example 1 inhibits anaphylactic histamine release from the guinea pig lung and the anaphylactoid skin reaction of the rat in the same concentrations as terbutaline, while their effect on the guinea pig trachea

709815/1195

is only 0.04 times that of terbutaline, which means that the quotient between antiallergic effects and tracheal relaxation is 25. The effect of the connection of the example 1 on the atrial prep was only 0.03 times as large like that of terbutaline, i.e. it has the same favorable relationship between tracheal relaxation and atrial stimulation like terbutaline. The effect was blocked with propranolol, indicating that it is a β-stimulating agent acts. As can be seen in Table II, the compound of Example 1 also inhibited the non-thistinic muscle contractors Agents that are released from the lungs in anaphylaxis.

Thus, the compounds according to the invention show selective antiallergic effects in dosage ranges where their effect on the bronchi and on the heart is negligible.

C. Toxicity

The acute toxicity (LD, - _O ) of 1- (3,5-dihydroxyphenyl) -2- / 71 r 1-dimethyl-2-hydroxyethyl) -amine _: 7-ethanolsulfaf was determined according to the standard test with mice (0 *, NMRI , 25 g). With intravenous administration an LD ₅₀ of 110 + 5 mg / kg body weight and with subcutaneous administration an LD of 400 + 18 mg / kg body weight was found.

709815/1195

Claims (36)

Claims 1 2
and their physiologically acceptable salts, in which R and R are identical or different and denote hydrogen atoms, aliphatic acyl groups with 1 to 5 carbon atoms, benzoyl groups or phenylacetyl groups and A denotes a straight-chain or branched-chain alkylene group with 3 to 6 carbon atoms
or represents a cycloalkylene group having 4 to 6 carbon atoms. 2. Aminoethanol derivatives and their physiologically compatible saI- 1
Ze according to claim 1, wherein R represents a hydrogen atom. 3. Aminoethanol derivatives and their physiologically acceptable salts according to claim 1 and 2, wherein A is a straight-chain or branched-chain alkylene group having 3 to 4 carbon atoms. 4. Aminoethanol derivatives and their physiologically compatible saI- Ze according to claims 1 and 3, wherein R is an aliphatic acyl group means having 1 to 5 carbon atoms. 5. Aminoethanol derivatives and their physiologically acceptable salts according to claim 1 to 3, wherein R is a hydrogen atom, a 709815/1195 Benzoyl group or phenylacetyl group and A is a straight chain or branched chain alkylene group having 3 to 4 carbon atoms. 6. Aminoethanol derivatives and their physiologically acceptable salts according to claim 5, wherein R is hydrogen and A is denotes straight-chain or branched-chain alkylene group having 3 to carbon atoms. 7. Aminoethano derivative of the formula CH ₃ CH - CH ₂ - NH - CHCH ₂ - OH and its physiologically acceptable salts. 8. Aminoethanol derivative of the formula HO ^ V-CH - CH ₇ - NH - CH ₂ CH ₂ CH ₂ - OH and its physiologically acceptable salts. 9. Aminoethanol derivative of the formula CH - CH ₀ - NH - CHCH and its physiologically acceptable salts. 7 0 9 8 1 G / 1 1 9 5 10. Aminoethano derivative of the formula Court CH - CH ₂ - NH - CH ₂ - CH - OH OH - CH ^ and its physiologically acceptable salts. 11. Aminoethano derivative of the formula HO CH - CH ₂ - NH - CH ₂ CH ₂ CH ₂ CH ₂ - OH HO and its physiologically acceptable salts. 12. Aminoethanol derivative of the formula HO CH. CH ₂ - NH - CH ₂ CH ₂ CH - OH HO OH and its physiologically acceptable salts. 13. Aminoethanol derivative of the formula HO CH, HO -CH - CH ₂ - NH - CH ₂ CHCH ₂ - OH OH and its physiologically acceptable salts. 709815/1195 ' 14. Aminoethanol derivative of the formula HO CH, HO -CH - CH ₂ - NH - CHCH ₂ CH ₂ - OH OH and its physiologically acceptable salts. 15. Aminoethano derivative of the formula HO. CH - CH ₂ - NH - CH - CH - OH HO ' OH CH ₃ CH ₃ and its physiologically acceptable salts. 16. Aminoethanol derivative of the formula CH - CH ₂ - NH - CHCH ₂ - OH and its physiologically acceptable salts. 17. Aminoethanol derivative of the formula HO HO CH. V-CH-CH ₂ -NH-If-CH ₂ OH OH CH, and its physiologically acceptable salts. 7 0 9 8 15/1195 18. Aminoethanol derivative of the formula HO. -, - CH - CH- - NH - CH OH .CH. "CH, CH - OH and its physiologically acceptable salts. 19. Aminoethanol derivative of the formula CH - CH ₂ - NH - CH .CH-. - CH r OH - CH and its physiologically acceptable salts. 20. Aminoethanol derivative of the formula PLJ Ln CH - CH ₂ - NH - CH OH CH - OH and its physiologically acceptable salts. 21. Aminoethanol derivative of the formula CH ₃ CO CH CO CH-CH ₂ -NH-C-OH 'CH ₀ and its physiologically acceptable salts. 709815/1195 22. Amino ethanol derivative of the formula CH ₃ CH ₂ COO CH ₃ CH ₂ COO CH. CH - CH ₂ - NH - CCH ₂ - OH CH, and its physiologically acceptable salts. 23. Aminoethano / derivative of the formula -CH - CH ₉ -NH -C- CH ₉ OH OH CH ₀ and its physiologically acceptable salts. 24. Amino ethanol derivative of the formula H _q CC-COO ³ I. CH, H-C-C-COO ³ I. CH, CH - CH ₂ - NH - C - CH ₂ OH and its physiologically acceptable salts. 25. Amino ethanol derivative of the formula CH ₃ COO CH ₃ COO ^ V-CH-CH ₂ -NH OH 709815/1195 - CH ₂ CH ₂ CH ₂ - OH and its physiologically acceptable salts. 26. Ethiinoethanol derivative of the formula CH ₃
H ₃ CC-COO CH ₃ H-C-C-COO CH-, 7 W- CH OH CH ₃ CH ₂ - NH - CHCH ₂ - OH and its physiologically acceptable salts. 27. Aitiinoethanol derivative of the formula -COO ) —Coo CH. H - CH ₂ - NH - C - CH ₂ OH OH CH. and its physiologically acceptable salts 28. Aminoathane gold derivative of the formula ζ ^ -CH ₂ COO CH. -CH - CH ₂ -NH-C-CH ₂ OH CH. and its physiologically acceptable salts. 29. Aminoethanol derivative of the formula i — COO CH. - NH - C - CH ₀ OCCHo ι 2 / \ v COO OH 709816 / 11-95 and its physiologically acceptable salts. 30. Aminoethanol derivative of the formula i ' M -COO- ^ CH ₃ -CH - CH ₉ - NH - C - CH ₉ OCC ₉ H ₁ -OH CH ₃ and its physiologically acceptable salts. 31. Aminoethanol derivative of the formula V-coo ^ _CH (/ V-CH - CH "-NH-C- > = / I ² [^ x ^ OH CH // V-COO ³ and its physiologically acceptable salts. 32. Aminoethanol derivative of the formula CH _Q Π F \ I ³ Ii // C J-CH - CH ₂ - NH - C - CH ₂ O - Γ - 0 ^ '" OH' CH. and its physiologically acceptable salts. 33. Aminoethanol derivatives and their physiologically compatible Salts according to claims 1 to 32 in the form of a racemic mixture. 34. Aminoethanol derivatives and their physiologically acceptable salts according to claims 1 to 32 in the form of a substantially pure stereoisomer. 709815/1195 35. Process for the preparation of aminoethano! Derivatives und.deren physiologically compatible salts according to claims 1 to 34, characterized in that one
A) a compound of the general formula II -CH 'CH ₀ wherein R is a hydrogen atom or a hydroxyl protecting one Group such as an alkyl group or aliphatic acyl group having not more than 5 carbon atoms, a mono- or bicyclic aralkyl group with no more than 11 carbon atoms, like a benzyl group or naphthylmethyl group, or a benzoyl group or a phenylacetyl group means with a compound of the general formula HN-A- OR ² III R ³ 2
wherein R represents a hydrogen atom, an aliphatic acyl group having 1 to 5 carbon atoms or a benzoyl group or 3
Phenylacetal group means, R a hydrogen atom or is an N-protecting group such as a benzyl group, and A is a straight-chain or branched-chain alkylene group having 3 to 6 carbon atoms or a cycloalkylene group having 4 to 6 carbon atoms, to a compound of the general formula
RO -CH - CH ₀ - N - A - OR ² II ₃ EAR 709815/1195 40, reacted and then optionally the protective groups R and R removed or
B) a compound of the general formula wherein R, R and A have the above meaning to a compound of the general formula CH - CH ₂ - N - A - OH reduced and optionally the hydroxyl protecting groups R removed or
C) a compound of the general formula —C. OH --LJ A -CH = N wherein R and A have the above meaning to a compound of the general formula CH - CH ₂ - NH - A - OH 709815/1195 reduced and, if necessary, the hydroxyl protecting groups pen R removed or
D) a compound of the general formula -CH - CH ₂ - X VII OH RO " wherein R has the above meaning and X is a halogen atom, such as Cl, Br or I, with a compound of the general formula HN-A- OR ² III 2 3 wherein A, R and R have the above meaning to a compound of the general formula
RO (/ \ S-CH -'TH -MAT OR ^{2. IV} OH RO. converts and optionally removing the protective groups R and R, or E) a compound of the general formula RO C-CH ₂ -NA-DR ^{2 VI11} 2 3
wherein R, R, R and A have the above meaning to a compound of the general formula 709815/1195 CH - CH ₂ - N - A - OR IV reduced and optionally the protective groups R and R removed, or F) for the preparation of compounds of the formula I in which A is connected to the nitrogen atom via a methylene group, a compound of the general formula CH - CH ₂ - N - A '- C - 0 - R ⁴ ΐχ R ³ ö wherein R and R have the above meanings, A ^{1 is} a straight or branched chain alkylene group having 2 to 5 carbon atoms and R is a mono- or bicyclic aralkyl group having not more than 11 carbon atoms, such as a benzyl or naphthylmethyl group, to a compound of the general formula IA V-CH-CH ₂ -N-A '-CH ₂ OH reduced and optionally the protective groups R and removed, and, if appropriate, the compound of the formula I obtained by methods A to F in a manner known per se 70981 5/1195 converts physiologically acceptable salts and / or into their separating optical isomers. 36. Medicaments containing at least one aminoethanol derivative according to claim 1 to 34, preferably in a pharmaceutically acceptable carrier. 709815/1195