DE2062055A1 - Propanolamine derivatives - Google Patents

Description

The invention relates to propanolamine derivatives with good therapeutic properties. It particularly relates to new derivatives of 1-phenoxy- (or 1-phenylthio-) 3-alkylaminopropan-2-ols, which are effective as blocking agents for β- adrenergic receptors and which have a stronger inhibitory effect on myocardial β receptors, ie those that affect the heart tissue than peripheral / 3 receptors, for example those that affect the tracheal, bronchial or vascular tissue. They are therefore suitable for the treatment of heart diseases such as angina pectoris and cardiac arrhythmias, and are particularly advantageous because they can be used for such purposes without adversely affecting the condition of the lungs or the blood pressure in sensitive patients.

The compounds of the present invention have

-2

10

6/1941

the general formula

X-CH ₀ -CH-CH ₉ -NC- (CH ₉ -) "Y OH R ¹ V

I 1

in which R is a carboxyamido, lower alkoxy-carbonylamino- or carbamoyl group, which is separated from the phenyl ring by a methyl

2 3 len or ethylene group can be separated, R and R ^ each

4 is a hydrogen atom or a lower alkyl group, R is a Carboxyamido, sulfonamido, lower alkoxy-carbonylamino, Carbamoyl or sulfamoyl group derived from the phenyl ring cmrch a methylene or ethylene group can be separated, R a Hydrogen atom, a lower alkyl or alkanoyl group or a benzyl group, X an oxygen or sulfur atom, Y a Oxygen or sulfur atom or a sulfinyl, sulfonyl or imino group or a direct bond, n if Y is not a direct bond, 1, 2 or 3, and if Y is a direct bond Bond is 0 to 4, and in which each of the phenyl groups bonded to X and Y is further marked with an or several lialogenatomen or lower alkyl, alkenyl, alkoxy or alkenoxy groups can be substituted.

The invention also relates to the aldehyde condensation products of those compounds of the formula I in which R is Hydrogen atom is the esters of compounds of formula I in which the 2-hydroxy group with a lower alkanoic acid is esterified, as well as the pharmaceutically acceptable acid addition salts of compounds of the formula I and those mentioned Esters and aldehyde condensation products.

In this description the term "carboxy-

amido group "a group -NR R ⁷ , in which R ^{6 is} a carboxylic acid-

7th
rest and R ^{1 is} a hydrogen atom or a lower alkyl group,

6 7
or R and R 'together with the nitrogen atom are cyclic

- 3-

109826/1941

Mean imido group. The carboxylic acid residue can be, for example Formyl, acetyl, propionyl, acryloyl, cyclohexane-carbonyl, Benzoyl, furoyl or pbenylacetyl radical or a substituted one Derivative, such as a chloroacetyl, trifluoraeetyl, glycolyl, Phenoxyacetyl, ioluoyl, nitrobenzoyl or chlorobenzoyl radical) A cyclic imido group can be from an aliphatic or aromatic dicarboxylic acid and can therefore be, for example, a succinimido, maleimido or phthalimido group.

Similarly, the term "sulfonamido group" means one Group -UR R, in which R is a sulfonic acid residue and R is a hydrogen atom or represents a lower alkyl group. The sulfonic acid residue can, for example, be methanesulfonyl or benzenesulfonyl or a substituted derivative such as a toluenesulfonyl radical.

The term "carbamoyl group" embraces substituted or unsubstituted carbamoyl groups of the formula -COUR R and "Sülfamoyl" means substituted or unsubstituted

ip 115 in 11 1? Sulfamoyl groups of the formula -SO ₀ NR ¹ ^ R ^p , where R, R ¹ , W ^ and R ^J each mean a Yi / 'water atom or a lower alkyl or an aryl or an aryl-lower alkyl group.

The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, and the term "lower" in connection with an alkyl, alkenyl, alkoxy, alkenoxy or alkanoyl group means that this group does not exceed 4 Contains carbon atoms. The term "imino group" means a group )> NR, in de]
whose alkyl group is

Group ^ N-R, in which R is a hydrogen atom or a non-

The aldehyde condensation products of the compounds of the formula I are oxazolidines of the general formula

X-CH ₀ -CH-CH ₀ R ²

1 1 I "

Ο / - C- (CH ₀ - ^ - T

Oh

- 4 - 109826/194

in which R ^ is a hydrogen atom or a lower alkyl group means. These aldehyde condensation products arise .by

5 condensation of compounds of formula I in which R is a Is hydrogen atom, with formaldehyde or an aliphatic Aldehyde with up to 5 carbon atoms.

As acids for the preparation of the pharmacologically acceptable acid addition salts of the compounds according to the invention those can be used that contain non-toxic addition salts with pharmacologically acceptable anions such as hydrochloride, Hydrobromides, hydroiodides, sulfates or bisulfates, phosphates or acid phosphates, acetates, maleates, fumarates, Lactates, tartrates, citrates, gluconates, saccharates and p-toluenesulfonates form.

In a particular group of compounds according to the invention, R and R are each a carboxyamido group and especially a lower alkanoylamino, e.g., an acetamido group, attached directly to the phenyl ring.

A preferred group of compounds according to the invention are those in which R is in the 4-position on the phenyl ring, which can also be further substituted in the 2-position. In another preferred group, R is an acetamido group in the 4-position on the phenyl ring. In a particularly preferred group of compounds, R is an acetamido or acetamidumethyl group in the 4-position on the phenyl ring, which can be substituted in the 2-position with a lower alkyl or alkenyl group, u;
4-position on the phenyl ring.

4th
may be substituted, and R is an acetamido group in

The compounds of the invention can be administered alone. But they are generally mixed with a pharmaceutical carrier selected in relation to the mode of administration and common pharmaceutical practice is administered. For example, they can be administered orally in the form of tablets containing such excipients

109826/1941

- ⁵ - 2062Q55

such as starch or lactose, or in capsules, either alone or in admixture with excipients, or in the form of Elixirs or suspensions containing flavorings or coloring agents. They can be performed parenterally, e.g. intramuscularly or administered subcutaneously. For parenteral administration, they are best presented in the form of a sterile aqueous solution which may contain other dissolved components, e.g. sufficient salts or glucose, to make the solution isotonic close.

The compounds according to the invention can be prepared in various ways

ι
1.I A compound of the formula

X-CH ₂ -CH-CH ₂ -Z

OH

in dei * Z is a halogen atom or any suitable "leaving" group, for example a sulfonyloxy group, such as a benzenesulfonyloxy or p-toluenesulfonyloxy group, can be mixed with an amine of the formula Jl

in which Ir does not mean a lower alkanoyl group, by heating either in the presence of excess amine and a suitable solvent, e.g. methanol or ethanol, or in equimolar amounts in the absence of a solvent or in the presence of alkali, e.g. sodium carbonate and a suitable solvents, as mentioned above, are reacted. The crude product is obtained either by filtration and evaporating the filtrate to dryness or by suspending the solid in a suitable medium, e.g.

■ - 6 109826/1941

aqueous sodium carbonate solution, and collecting the precipitate, be won. The product is obtained by vacuum distillation and / or recrystallization from a suitable solvent purified to obtain the free base, or by dissolving in a solvent and precipitating as a salt, e.g. as the hydrochloride, Pumarate, maleate or oxalate, by adding the appropriate acid.

2.

An amine of the formula

X-CH ₂ -CH-CH ₂ -NH

OH

in which R is not an alkanoyl group, with a Yer-

2 bond of the formula R

R-

implemented under the conditions specified in process 1) and the product can be obtained according to procedure 1) and cleaned.

3. An epoxy compound of the formula

X-CH ₀ -CHCH ₀

² Y ²

can with the same amine as used in process 1) in equimolar amounts at ambient temperature or by Heating in a suitable solvent, e.g., methanol, can be reacted and the product can also be used as in Process 1) recovered and purified.

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109826/1941

4. For the preparation of a compound of the formula I in which Ir and E ^ are each hydrogen atoms, an amine can formula

X-CH ₂ -CH-CH ₂ -IiH ₂

OH
with an aldehyde or ketone of the formula

.Y (-CH ₂ ) _n -co \

be implemented, with the appropriate Schiff base which are then hydrogenated in the presence of a catalyst, e.g. platinum, or reduced with sodium borohydride can · The product is filtered to remove catalyst or solid reaction products by evaporation of the filtrate obtained in vacuo and according to procedure 1) cleaned. This process is used for the production of

"5 5 bonds of the formula I, in which E and E are each water

are material atoms, and E is a lower alkyl group, preferably

5. The compounds according to the invention in which R is a carboxyamido group of the formula E M- can be prepared from the corresponding i- (nitrophenoxy) - or 1-t-nitrophenylthio) -3-alkylaminopropan-2-ols by reducing the iaitro group to an amino group and acylating them üminogruppe can be produced with the help of a suitable derivative (eg the anhydride or chloride) of the acid K OH. The starting material can be obtained by any one of Processes 1 to 4 except that R is replaced with a nitro group.

For example, a Bpoxy compound of the formula

X-CH ₂ -CH-CH ₂

109826/1941

each of which the nitro group is in the 2-, 3- or 4-position, with the same amine as used in Method 1 in equimolar amounts at ambient temperature or by heating in a suitable solvent, e.g. methanol, reacted and the product according to the method 1 can be recovered and purified.

The product is then in a suitable solvent, e.g., methanol, dissolved and in the presence of a catalyst, e.g., platinum oxide, at ambient temperature and elevated pressure hydrogenated. The resulting mixture is filtered and the filtrate is evaporated. The correspondingly substituted one is obtained i- (aminophenoxy) - or 1- (aminophenylthio) -3-alkylamino-propan-2-ol, that can, but does not have to be, cleaned before the next step.

The final step involves adding the amino compound to the water and adjusting the pH to 4-5 by adding a suitable amount of dilute hydrochloric acid. Then an acid anhydride or chloride is added and the The pH of the solution is kept at 4 to 5 by adding a base, e.g. a sodium hydroxide solution, if necessary. The mixture is made alkaline and the crude product filtered off. The product is then purified by recrystallization from an appropriate Purified solvent, whereby the free .Base is obtained, or it is converted to an acid addition salt which is then recrystallized from a suitable solvent can be cleaned.

The aldehyde condensation products of the compounds

of formula i in which Ir is a hydrogen atom

15 by reaction with the corresponding aldehyde R * XHO in

a diluent or solvent such as ethanol, preferably in the presence of an acidic catalyst such as hydrochloric acid or acetic acid, and preferably at elevated temperature. The water formed during the reaction

109826/1941

can by azeotropic distillation using a suitable Solvent, e.g. benzene, or by treatment with a dehydrating agent, e.g. anhydrous potassium carbonate, removed. ■

In each of the processes described above, the phenyl groups of the starting substances, as previously described,

to be further substituted »

; The esters of the compounds of formula I and the compounds of formula I in which K is a lower alkanoyl group means, can by acylation of the free hydroxyl group or the secondary amino group with the corresponding Acid chloride or anhydride can be prepared in the usual way.

The invention is further illustrated by the following examples explained.

example 1

13 g of 1- (4-acetamidophenoxy) -5-aminopropan-2-ol, 10 g of 2-acetamidophenoxy-acetone and 75 ml of ethanol were refluxed together for k hours. Then, 0.3 g of platinum oxide were added and the mixture hydrogenated at 2O ⁰ C and 77 "3 kg / cm (1 100 psi). After the hydrogen uptake had ended, the catalyst was filtered off and the filtrate was evaporated in vacuo. A yellow semi-solid product was obtained. This product was dissolved in chloroform and extracted with aqueous hydrochloric acid. The aqueous layer was made alkaline and extracted with chloroform. After evaporation in vacuo, 15 g of a yellow solid were obtained. This solid was converted into the fumarate and this was recrystallized from methanol / diethyl ether and then from isopropanol / diethyl ether. 3 »9 g of 1- (4-acetamidophenoxy) -3-L 2- (2-acetamidophenoxy) -1-methyl-ethylamino / propane-2-oljbemi-fumarate-heini hydrate were obtained. M.p. 104 ° 0.

109826/1941

Analysis;

Calculated for C ₂₂ H ₂₉ N ^ O ₅ * 1/2 [C ₄ H ₄ O ₄ ] · 1/2 H ₃ O:

■ C 59.70 H 6.68 N 8.71 * fi

Found: C 59.45 H 6.58 N 8.46 %

Examples 2 to 4

The following compounds were prepared by the method described in Example 1 from the appropriately substituted 1-phenoxy-3-aminopropan-2-ol and phenoxy-acetone k. The product was in each case, unless otherwise stated, as free Acid isolated.

Tabel

109826/1941

Tabel

OCH ₂ CHCh ₂ NHCHCH ₂ O OH CH,

cn

CD

example -NH. R ¹ R ⁴ Pp analysis (theoret • value i.Klamme: 2 -NH. CO. CH 4-CONIL 142 °
(Oxalate) % C . % H % N 3 -NH. CO. CH 4-NH.CO.CH 165-7 ° 56.32
(56.30 6.24
5.94 8.50
8.56) 4th CO. CH 2-C0NH_ 97-99 °
furaarat
Hemi-
hydrate) 63.88
(63.59 6.91
7.04 10.31
ία, ii). 59.16
(58.80 6.52
6, .45 8.95
9.05)
1

ro ι

CD CD NJ CD cn cn

■ Example 5

5.3 g of 1- (4-acetamidophenoxy) -3-aminopropan-2-ol and 2 g of 1-bromo-2- (4-acetamidophenoxy) -ethane were together for 3 hours heated to 140 ° G. The resulting solid was suspended in aqueous sodium carbonate solution and filtered. The precipitate was first made up of water and then out

Recrystallized ethanol. 0.25 g of 1- (4-acetamidophenoxy) -3- [2- (4-acetamidophenoxy) ethylamino / propan-2-ol were obtained. Pp. 193-194 ⁰ C.

Analysis;

Calculated for C ₂₁ H ₂₇ N ₅ O ₅ : C 62.82 H 6.78 N 10.47 #

Found: C 62.33 H 6.76 N 10.32 $

Example 6

The following compound was prepared from the appropriately substituted according to the procedure described in Example 5 1-pbenoxy-3-aminopropan-2-ol and 1-bromo-2-phenoxyethane manufactured. The product was isolated as a hemifumarate:

OCH ₀ CHCH ₀ ME ₀ Ch ₀ O

Cl C CC

OH

example

Fp.

Analysis (theoretical value in brackets)

-NH.CO.CH, -CONH,

123 ° (Hemifuma rat)

59.01 6.06 9.45 (59.31 6.12 9.43)

- 13 -

109826/1941

• Example 7

5.6 g of 1- (4-acetamido-pheno.xy) 2,3-epoxy-propane and 4.9 g of 2- (4-carbamoyl-phenoxy) -ethylamine were dissolved in 100 ml of ethanol and the solution for 3 days "Left to stand at room temperature. The resulting precipitate was filtered off and recrystallized from aqueous ethanol. 5.4 g of 1- [4- acetamido-phenoxy] -3- [2- (4-car" bamoylphenoxy) -ethylaminoJ-propane 2-ol as a white crystalline solid. Pp. 175-177 ⁰ C

Analysis;

Calculated for C ₂₀ H ₂₅ W ₅ O ₅ JG 62.00 H 6.50 N 10.85 1 »

Found J C 61.83 H 6.39 N 11.18 ^

Examples 8 to 50

The following compounds were substituted according to the procedure described in Example 7 from the 1-phenoxy-2,3-epoxy-propane and 2-phenoxy-ethylamine produced. In each case, unless otherwise stated, the products were isolated as the free base.

Tables

-H-

109826/1941

OCH CHCH ₀ NHCH ₀ CH ₀ O OH

Tab hurry

example H 4-NH. R ¹ H R ⁴ CH ₃ Pp analysis
(theor.toert i % H .Brackets 8th H 4-NH. CO. CH H 4-NH.CO. 198-200 ° % C 6.59 ·
6.78 % N 9 H 4-NH. CO.CH CH, H 4-CONH ₂ CH ₃ 187-9 ° 62.51 '
(62.82 6.72
6.78 11.08
10.47) 10 2-CH ₃ 4-NH. CO.CH CH H 4-NH.CO. CH ₃ 203 ° 63.08
(62.82 6.78
7.04 10.32
10.47) 11 H 4-CH CO. CH H 4-NH.CO. CH ₃ 178-80 ° 63.74
(63.59 7.21
7.04 9.90
10.11) 12th H 4-NH. .NH.CO.CH H 4-NH.CO. CH ₃ 176-7 ° 63.59
(63.59 7.01
7.04 9.98
10.11) 4-NH. CO.CH ₀ .CH ₀ .CH,
<i Δ J H 4-NH.CO. CH ₃ 206-7 ° 63.68
(63.59 7.32
7.28 10.06
10.11) 14th CO. CH 4-NH.CO. 144-6 ° 64.18
(64.31 7.02
7.04 9.74
9.78) 63.24
(63.59 9.8i
10.11)

CD CD K)

ta +> φ co

-d * co O tv- fv »fs. OJ TH fv> rv O ON fv. fv. - * ci Z TH <f < IA tv- VO - ^ • ν. Iv Cl TH 88 <f vD co 0 0 0 «Ν rv V- ffv * "» #V rv «v (V-CO rv * v r »» v ON CN O O
TH TH vD I ^s * 8.8 ON ON ON O
TH 88 τ-Ι CO ίΛ CO ON <f VO VD Jv, r ^ VO Cl TH fs. a on Cv. Cl Cl co O ^ Cl VD Ol <f IA IA ON <& VD VO tv- fv. VD νο VO fv « ONCO VO tv- VD VO VD VD tv- ol VD Ή tv- ol O] M fv. ON tv * s ON Cl O c-> O VD CO O co • ν · ν tv- IA Cl Cl rH ON VD -S * rv Cv ^ * rv r <ri (V Cv * VO VD rv · ν rv rs • v rv. iR OJ CI <f -Cf CN. OJ VO VD CN, 0Λ O
r-t rl O O O O O VO VO VD VO VO VO O VO VO VO VD VD VO VO VO O O *
O O CO O ri O +> O O +> OI Cl Cl I. 0Λ I. 0 1 a CO CO I CS I. I. I. VO I. CO CO O l I. νο C "3 O ON T-f VD O VO
TH I CTJ VD O ^ O t >> Ή CO IV- TH Cl τΗ TH TH CA vf vf C ' ■ δ 01 vf 9 0
0 Ϊ2 9 8th d
υ d
ο Oil • οι
a O 8th JM • • "2" Z υ • 25th a τ * O 0 j. a 0 Z ζ υ ■ * 0 - 0 J- I. ι I. a I. I. I. B. a a a " K a * ^
0 ν Cl
a d C. 1" 0 0
e
B. S. .CH d Z φ O υ S. ² y a
ο δ - 9 JM O
υ O
1 d O 8th t C. U 8th 0
υ υ § a 8th fl JN * Z Oil I. 0 C. O
O O a
ζ i I. S. a
Z I. J ₄ ι I. I. if a S. CM co
I. a t
ΙΛ
t-i VO
t-l TH H
Cl CM
01

109826/1941

- 16 -

Table (continued)

24 "

CD (O OO KJ

31

4-CH_CH _o .NH.C0.CH, H

4-NH.C0.CH "

174-5

4-NH.C0.O.CH "

4-NH.C0.CH "

195-7

2-OCH, 4-CH .NH.CO.CH

j * · j

4-COML

162-4 '

4-CH-.NH.C0.CH,

4-CONH,

177 ^BC

3-CH .NH.CO.CH.

4-CONH,

142-4 ¹ -

-CH ₂ .CO.

4-CONH,

194-6 ^c

4-NH.C0.CH "

4-NH.C0.CH_.CH. 204-5

4-CO.NH.CH.

4-CONH,

176-7

4-NH.C0.CH "

4-NH.CO.CH,

143-4 ^C

% C

64.06

(64.31

% H 7 _? 23 V "

7 * 28

6O _T O5 (6o _T 42

6.10 6

6l _T 55 (61.24

6.77

63.05 (62.82

6.88 6.78

62.45 (62.82

6.82 6.78

62.43 (62.00

6.58 6.50

63 _T 27 (63 * 59

% N

9.84

9.78)

10.07 10.07)

9 _r 35 9.74)

10.24 1O ₇ 47)

10.26 10.47)

10.57 10.85)

7.10

10.41

7.04 10.11)

61.84 (62.05

6.37 6.50

10.55 10.85)

63.22 (63.59

7.14 V

7.04

10.06 10.11)

ro

CD CD

CD

cn. cn

Table (port setting)

33 H 4-CH-.NH.C0.CH-.CH- H · 4-NH »CO.CH- 171-3 ° % C
• 64.30
(64.31 % H
7.36
7.28 % N
9.61
9.78) 34 H 4-NH.CHO H 4-NH.CO.CH 153-5 ° ' 6l, 93
(62.00 6.53
6.50 10.43
10.85) Q ■ 35 H 2-CO.NH H 4-CONH-
G* 178-80 ° 61.08
(61.11 6.30
6.21 10.93
11.25) 9 82 6 36 H 4-CH .NH.C0.CH_ H 4-CH ₂ .CONH ₂ 190-1 ° 63.16
(63.59 6.82
7 ₇ o4 10.52
10.11) / 194 37 H 2-NH.CO.CH- H 4-NH.CO.CH- 159-60 ° 62.78
(62.82 7.17
6.78 10.50
10.47) 38 H 4-CH ₂ .NH.CKO H 4-NH.CO.CH 158-60 ° 62.4o
(62.82 6.76
6.78 10.42
10.47) 39 H 4-CH ₂ .NH.C0.CH- H 2-NH.CO.CH 165-6 ° 63.63
(63.59 7.30
7.04 9.75
10.11) 40 2-CH ₃ 4-CH-.NH.C0.CH, H ' 4-NH.CO.CH 104-6 °
(Mono-
hydra t) 61.87
(61.72 7.35 9.45
9.39 41 H 4-NH.CO.CH H 4-CH ₂ .CONH ₂ 196-7 ° ■ 63.06
(62.82 6.95
6.78 9.94
10.47)

O CD hO

Q approx
Z -ϊ - #
Γ · e ·
^ R σν er O r <
· »R ·
OO
Ti TI CO CO
IA I ^s -
Ov Ov 9.33
9.52) OCO
co r-
Ov OV Ov IA
IACO
OO
TH TH 9.79
9.64) OV- #
ocTcT
TH h »IA
r-.co
cTcT
TH tH I. O
δ
*
I. I. "I. X CO O O O tH CO
ία approx VD CO
O O -ί ¹ CO IA O
- * IA Ov O IACO tv- O
VO IA M. cvTrT t ^ rT IvTrT VO VD IAvO VD VO VD VO OO
O CA O CO Ov
VD IA
# * V * VO T-I
rl CA CVCO
VO Ci (N. T-I
O CA Ov O
fv- O CO O
VD Ov - # approx
O CO IA O S " VD VD approx CA
VD VO vo vb VO VO VD VO Ti CJ
VO VD IA IA CA CJ
VO VO oTof
VD VO 4-NH.CO. O
(M O
CA O
OO O
• O O O
CO O
• J · O O
IA
τ-ι -XZX I.
co
τ-Ι I.
Ti Ti CO
CA
-rl 186- t
CM
IA
tH IA CA
δ C. 4-NH.CO.CH ₃ 8th
K
Z
f 8th
•
X
Z
υ 4-NH.CO.CH δ
d
O
X
3 4-NH.CO.CH. 4-NH.CO.OL €
O
O
a
X
CM X K X S. δ s " [.CO. δ " [.CO, [.CO. δ υ 2
ί 4-NH.CO. §
X ™
O 4-NH.CO. ί Z
§
CA 4-NH.CO. 4-NH.CO. 2-OCH S. « δ S. 2-Cl ' K CM 3 ³ S.

109826/19 ^ 1

- 19 -

Example 51

12 g of 1- £ 3-nitrophenoxy] -3- [2- (4-carbainoylplienoxy) -ätiiyl- amine] propan-2-ol, which is obtained according to Example 7 from 1- (3-lN-nitrophenoxy-2,3-epoxypropane and 2- (4-CarbamQylphenoxy) -äthylamin had been obtained, were dissolved in 1 l of methanol and the solution was hydrogenated with the aid of 0.3 g of platinum oxide at low temperature and 3.52 kg / cm (r> 0 psi) was filtered and the piltrate was evaporated to a waved solid.Recrystallization from methanol gave 1 ~ r3-aminophenoxy] -3- £ 2- (4-carbamoyl-phenpxy) -ethylamino] prbpan-2-ol as a white pesticide. 149 - 151 ⁰ C.

10 g of the amino compound were added to 150 ml of water and the mixture was brought to a pH of 4 to 5 with dilute hydrochloric acid. Then 3 g of acetic anhydride were added dropwise and the pH of the solution was kept at 4 to 5 by adding dilute sodium hydroxide solution. After one hour, the mixture was made alkaline with dilute sodium hydroxide solution and the pesticide was filtered off. 1- [3-Acetamidophenoxy -3 - '[2- (4-eai ⁱ bainoylphenoxy) ethylamino] propan-2-ol was obtained as white pest. Mp 164-165 ° C. The product was then recrystallized from aqueous ethanol.

Analysis;

Bereolünet for C ₂₀ H ₂₅ N ₅ O ₅ SC 62.00 H 6.50 N 10.85 ^ Found. : C 61.82 H 6.44 N 10.74 ° J>

Examples 52 to 53 .

The following connections were made according to the in Example 51 prepared method, the last step for Example 53 instead of acetic anhydride Acryloyl chloride was used.

' Table

- 20 -

109826/1941

Tabel

example R ¹ R ⁴ M. Pt. (theor analysis
.Value in brackets) % N % Cl 52 3-NHiCO.CH 4-NH.CO.CH 237-9 °
(Hydro
chloride) Jv V ^ % H 9.33
9.60 8.19
8.08) 53 4-nh.co.ch:ch ₂ 4-NH.CO.CH 241-3 °
(Hydro
chloride) 57.33
(57.57 6.77
6.64 9.17
9.43) - 58 _? 62
(58.73 6.09
6.27

ro

cn cn

The inventive S-sn compounds can be in the form of optically active D and L = isomers are present. The invention affects both these forms and the racemic mixtures. Do procedures 1, 2 and 4 above

inside the optically active isomers are produced when

mm the appropriately substituted 2-propanol enantiomers used as starting materials, while in the process 3 ^! and 5 racemic mixtures arise. The racemic product obtained by any of the methods given above can also be separated by known techniques, for example by fractional crystallization of an acid addition salt with an optically active acid.

2 ^ 5 The compounds according to the invention in which R- and Ir

are unequal, have two asymmetric centers and can exist in two racemic pairs of diastereoisomers.

In general, according to each of the processes 1 to 5 are

2 3 baltenen products in which E and R ^ are not the same are a mixture of the two stereo-isomer pairs, and these pairs can normally be separated by physical methods, e.g. by fractional crystallization, or chromatography of the free base or suitable salts. The invention encompasses both the separate pairs and their mixtures in the form of racemic mixtures or the separate D- and 1-forms.

The activity of the compounds according to the invention as / 3-adrenergic blocking agents and the degree of selectivity their inhibitory effect on myocardial / 3 receptors, i.e. those that affect the heart tissue compared to their effect on peripheral / J receptors, e.g., those that Tracheal · »bronehial or vascular tissue affect was proven by one or more of the following examination methods:

a) Measurement and comparison of the inhibition by catecholamine induced changes in isolated auricles and

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. 109826/1941

Guinea pig trachea

b) Measurement and comparison of the suppression caused by isoprenaline in anesthetized guinea pigs Tachycardia and relaxation of the trachea

c) Measurement of the suppression of the anesthetized by isoprenaline Cats or dogs provoked tachycardia and

d) Measurement and comparison of the suppression of the stimulatory Effect of isoprenaline on the adenyl cyclase enzyme present in the heart and lung tissue of rats

In experiment a) the isolated guinea pig auricles and tracheae are electrically stimulated in a regulated liquid physiological environment and the effects on the speed and force of the contraction of the auricles as well as the effect of isoprenaline caused by increasing amounts of adrenaline added to the liquid the degree of relaxation of the trachea is measured. The test compound is then added to the liquid in various concentrations, and the effect of adding adrenaline and isoprenaline, respectively, is measured again. The concentrations of the test compound which result in a 50% inhibition of the effects of adrenaline and isaprenaline are then calculated and used as Measure of the effect in relation to the myocardial or peripheral β- receptors assumed.

In experiment b), blood pressure, heart rate and pressure are measured in a section of the trachea of a guinea pig measured that with sufficient sodium pentobarbitone is anesthetized to prevent spontaneous breathing, while artificial breathing is done directly into the lungs with a constant speed is maintained. Isoprenaline is given intravenously in a standard dose of 0.5 / fg injected to induce tachycardia, relaxation of the trachea and lowering of blood pressure. The ability of Test compound to suppress tachycardia and / or

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109826/1 941

the relaxation of the trachea and / or the drop in blood pressure Counteracting by the isoprenaline is then measured by injecting a test compound prior to the isoprenaline.

In experiment c) cats anesthetized with chloral are used the test compound (0.1 to 1.0 mg / kg) is injected intravenously and the effect of. Isoprenaline on ore velocity is measured. The heart rates are measured prior to the administration the test compound and measured for 30 minutes thereafter, and then the cats are given a dose of isoprenaline subcutaneously. The degree of isoprenaline caused Tachycardia is recorded at 15 minute intervals.

Dogs are also used as experimental animals, with the compound intravenously and orally in non-anesthetized dogs at doses of 0.125-0.25 mg / kg (intravenous) and 0.5-4 mg / kg (orally) is administered.

In experiment d), homogenized rat heart is incubated in a standardized medium with adenosine-5 * triphosphoric acid (ATP), which is marked with tritium, with and without isoprenaline, and the test compound is added in various concentrations to the homogeneous mixture with the isoprenaline . After incubation at 30 ⁰ O -cyclic 3 *, 5 * -adenosine-monophosphoric acid (cyclic AMP), which contains a known amount of a material labeled with carbon-14, is added, and the synthesis of cyclic AMP by the adenyl-eyclase -Enzyme is canceled by increasing the temperature. The cyclic AMP is separated and purified and the amount synthesized by the enzyme in each case is measured as the ratio of tritium to carbon-14. The concentration of the test compound which results in a 50% inhibition of the stimulatory effect of isoprenaline on the cyclo-AMP synthesis is regarded as a measure of its activity. To determine the degree of tissue selectivity of the agent, the procedure is repeated with homogenized rat lung, and the results are compared with - 24 -

109826/194 1

those who inherited for homogenized rat heart have been compared.

The results of tests a), b) and d) have shown that compounds with a high selectivity for heart tissue compared to lung tissue, i.e., which are a much stronger one have an inhibitory effect on myocardial than on peripheral ß-receptors, those are those in which R is in the 4-position R is hydrogen or a substituent in the 2-position, R is an acetamido group in the 4-position and R 'is Mean hydrogen atom. In addition, those who have high selectivity for heart tissue are associated with one have high efficacy when administered orally to non-anesthetized dogs in test c), those in which R is an acetamido or acetamidomethyl group in the 4-position, R is a hydrogen atom or a methyl or allyl group

4 17

in the 2-position, R is an acetamido group in the 4-position and R '

are a hydrogen atom.

It is believed that for administration to humans in the treatment of heart diseases such as angina pectoris the oral doses of the most active compounds according to the invention in the range of 0.5 to 4 mg / kg per day in 3 or 4 single doses per day and that doses for intravenous administration are approximately 1/10 of the doses given above as a single dose per day are. Thus, for a typical adult patient (70 kg), individual tablets or capsules 10 to Contain 50 mg of the active compound and intravenous doses 1 to 20 mg in a suitable vehicle.

Claims

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109826/1941

Claims (18)

Claims ι
in the E a Garboxyamido- lower alkoxycarbonylamino- or carbamoyl group, derived from the phenyl ring by a 2 3 methylene or ethylene group can be separated, E and E are each a hydrogen atom or a lower alkyl group , E a carboxyamido, sulfonamido, lower alkoxycarbonylamino, carbamoyl or sulfamoyl group, which is separated from the phenyl ring by a methylene or A ' ethylene group can be separated, E a hydrogen atom, a lower alkyl or alkanoyl group or a benzyl group, X an oxygen or sulfur atom, Y an oxygen or sulfur atom or a sulfinyl, sulfonyl or imino group or a direct bond, N, if Y denotes no direct bond, 1, 2 or 3, and, when Y is a direct bond, denotes 0 to 4, and in which each of the phenyl rings bonded to X or Y is lower with one or more further halogen atoms. Alkyl, alkenyl, alkoxy or alkenoxy groups can be substituted; the aldehyde condensation products of those 109826/1941 5
Compounds in which B is a hydrogen atom, the esters of compounds in which the 2-hydroxy group with a. lower alkanoic acid is esterified, as well as the pharmacologically acceptable acid addition salts of these compounds. 2. Compounds according to claim 1, characterized in that X and Y are each oxygen atoms and 3 5 E and E each denote hydrogen atoms 3. Compounds according to claim 1 or 2, characterized in that g e k e η η indicates that B is a hydrogen atom or a methyl group means. 4. Compounds according to claim 1 to 3> thereby g e k e η η - 1 4
indicates that H and E each represent a carboxyamido group which is bonded directly to the phenyl ring. 5. Compounds according to claim "4, characterized in that dai amino group mean, 1 4
draws that E and E each have a lower alkanoyl 6. Compounds according to claim 5 »thereby g e k e η η drawing mean. indicates that E and E each represent an acetamido group 7. Compounds according to claim 1 to 6, characterized in that E is in the 4-position on the phenyl ring which is only further substituted in the 2-position can be. 109826/1941 8. Compounds according to claim 1 to 7, characterized geke η η ζ ei chnet that j
is on the phenyl ring. ζ e i chnet that E is an acetamido group in the 4-position 9. Compounds according to claim 8, characterized in that g e k e η η - · indicates that R is an acetamido or an ethamidomethyl group is in the 4-position on the phenyl ring which is substituted with a lower alkyl or alkenyl group in the 2-position can be. 10. 1- [4-Acetamido-2-methylphenoxy] -3- [2- (4-acetamido-phenoxy) -ethylamino] propan-2-ol. · ' 11. 1- ^ -Acetamido-phenoxyJ ^ - [2- (4-acetamido-phenoxy) -ethylamino] -propan-2-ol. 12. 1- [4-Ethamidomethyl-phenoxy] -3- [2- (4-acetamido-phenoxy) ethylamino]] propan-2-ol. 13. 1- ^ -Acetamidomethyl ^ -methylphenoxy] -3- [2- (4-acetamidophenoxy) -ethylamino-propan-2-ol. 14. 1- [4-Acetamido-2-allylphenoxy] -3- [2- (4-acetamido-phenoxy) " ethylamino-propan-2-ol. 15. Pharmacologically acceptable acid addition salts of the compounds according to claim 8 to 12. 16. Honor for the production of compounds according to claim 1, . - 28 - ■ ι 109826/1941 gektnnttichnet _f characterized in that a compound d "r Fora"! X-CH ₀ CH-CH ₀ \ / ⁰ or with an amine of the formula E ² Y (-CH ₉ VC-HHR ^{5 l} 2'n or an amine of the formula X-CH ₉ CHCHMHR- ² I. OH X-CH ₂ CHCH ₂ Z OH with a compound of the formula , 2 wherein Z is halogen or any other suitable "leaving" group and each hienyl ring is optionally, as indicated in claim 1, may be further substituted. 17. A method for the preparation of compounds according to claims 1, - 29 - 109826/1941 ■ 2 C in which R and R represent a hydrogen atom, thereby characterized in that an amine of the formula _{2 |} 2 2 OH with an aldehyde or ketone of the formula ) _n -C = 0 reacts, each phenyl ring according to claim 1 can be further substituted, and see the resulting ship * Base hydrogenated. 18. A method for the preparation of compounds according to claim 1, 1 6 in which R is a carboxyamido group of the formula "R HH-, in which R is a carboxylic acid residue, characterized in that a compound of the formula X-CH ₉ CHCH ₉ ² V ² or NO X-CHoOHCHoZ OH with an amine of the formula R ⁱ - 30 - 109826/1941 or an amine of the formula XCH ₉ CHCH ₀ NHR- C. \ C. OH with a compound of the formula wherein Z is halogen or any other suitable "leaving" group, and each phenyl ring correspondingly Claim 1 can be further substituted, converts, reduces the nitro group of the resulting product to an amino group and acylating the amino group with a suitable derivative of an acid of the formula R OH. 19 · Use of the compounds according to claims 1 to 15, if appropriate together with a pharmacologically acceptable carrier, as a medicament. 109826/1941