DE2302027C2 - 3,4-Dihydrocarbostyril derivatives substituted in the 5- or 8-position and their salts, processes for their preparation and pharmaceuticals - Google Patents

Description

Tabel

U-CH ₁ CHCH ₂ N

Acid e.g. salt
education jö-sympathological
Min. 5 effect opposite to Isoprenaline (% Inhibition) 90 120 LDjo values to
CO 100
100 10 :O 30th 60 93.5
93.5 90.4
85.3 (mg / kg) O
to HCl BP
MR 100
100 100
100 100
100 100
98.5 95.6
95.0 100
100 100
100 78.5 O
to HCl BP
MR 100
88.5 100
100 100
100 100
100 100
100 89.0
55.8 84.3
50.2 54.5 HCl BP
MR 94.4
53.2 93.5
88.5 100
71.4 100
65.2 98.4
62.9 91.3
90.3 88.9
87.1 58.7 Maleins. BP
MR 75.6
55.6 89.9
62.9 91.7
85.5 92.5
90.3 94.4
90.3 85.3
91.1 76.3
88.9 60.1 HCl BP
MR 65.9
67.5 82.4
80.0 88.2
88.9 88.2
91.1 87.5
93.3 80.3
92.3 81.5
90.0 55.8 Maleins. BP
MR 94.6
82.6 77.6
85.0 81.8
92.5 81.8
92.5 81.5
92.3 82.1
73.9 85.7
05.2 63.3 Oxals. BP
MR 80.2
70.6 94.6
82.6 92.9
80.4 92.9
73.9 94.6
73.9 43.5 Maleins. BP
MR 84.2
70.8 88 ,:
80.5 84.1
85.7 88.0
82.0 44.3
25.6 40.5 BP
MR 92.6
82.9 80.1
75.3 63.7
57.1 57.9
42.6 37.0
46.3 • 14.4
36.3 37.5 Maleins. BP
MR 91.9
73.4 81.5
61.0 74.1
53.7 77.8
46.3 70.3

Me

Et

Allyl H

Acetyl

3,4,5-trimethoxy
benzene

i-prop.

tert.Bu

tert.Bu

tert.Bu

tert.Bu

tert.Bu

i-prop.

i-prop.

Comparative substance propranolol

ethyl

O -

-O OO

The in experiments No. I to 15 in amounts of Compounds administered in each case 10 mol / kg body weight correspond to those given below iibsolulcn values:

from n ve Γ- * ο «■

O * vo -

* t r— </ - * t— r- vo oo oo examined connection

Dose (Hg / kg)

ONfN ΓΛ f ^ CJO Tf i- m

r * i oo 'O - * i> * r ~' τ} · '00 * »Fin oorvi vovo oooo

oo (N no Ov oo in ■ "" · vo Ov rvi »n in oo oo

1-

OO

■ ο '-

OO OO

rt ο rs * rf

VO OO

5> O V

C ^ * ~ * Ov Ov ^ D

oo "- * ^" f> * O * oo »n r ^ i oo oo

OO vO OO OO

2
3
4th
5
6th
7th

9
IO

t 1

I.

12th 13th 14th 15th

35.7 47.9 47.1 32.9 42.2 41.9 43.4 42.4 60.2 40.8 32.9 32 ^ 9 35.7 44.8 44.5

IN*
I ^ ON

f ~ - _e oo_ Ov ^ rf r ^

"Γ-" vo * O *

(N for ~ r ~

OO 9C

(N vo in ο

OO Tt (N VO

r- α

vO Γ--

a. it ο, oi a.

OQ U-. CQ X CQ

CQ

β. O:

OQ X

si do

OQ

ro 'E OQ <

as

308 111/36

ίο

The new 3,4-dihydrocarbostyril derivatives of the general formula I can be prepared according to the following reaction scheme getting produced:

(VIII)

(VI)

(IX) CH ₂ CHCH ₂ -Y OH OH

OCH ₂ Z

XCH ₂ -CH-CH ₂ O

= 0 (II)

(VII)

HN

(IV)

OH H

I /

OCH ₂ CHCH ₂ N

\ R '

OH

OCH ₂ CHCH ₂ N

R '

R ₂ COCI (V)

OR ₂ H

I /

OCH ₂ CHCH ₂ N

R '

The intermediate products have the general formula II

OCH ₂ Z

in which R has the above meaning and Z is a radical of the formula

-CH-CH ₂ or
\ /
O

-CH-CH ₂ Y

OH

represents in which Y is a halogen atom.

never aaize uer Yciuinuungcn uci angi-iiK-inCu iOrrnc. I can be derived from inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and ascorbic acid. These salts are prepared in a manner known per se, for. B. by dissolving the free base and the corresponding acid in an organic solvent such as acetone, and combining the solutions in stoichiometric proportions. Compared to the free base, the salts have a greater solubility in water and a higher stability towards heat and light.

The alkyl radicals for Ri and R 'are unbranched or branched alkyl radicals with 1 to 4 carbon atoms, such as the methyl, ethyl, n-propyl, isopropyl, η-butyl, sec-butyl and tert-butyl groups.

The compounds of general formula I in which Rj represents a hydrogen atom can be prepared by two different methods. In which The first method is an S-hydroxy-i ^ -dihydrocarbosiyril derivative of the general formula II with an amine of the general formula IV

HN

(IV)

R '

in which R 'has the preceding meaning. implemented. This reaction can be carried out in the absence of a solvent be performed. However, the reaction is preferably carried out in the presence of an inert organic Solvent carried out. Examples of suitable solvents are lower alkyl ethers. how Diethyl ether, methyl ethyl ether, dipropyl ether. Dioxane and tetrahydrofuran, hydrocarbons such as benzene, Toluene and xylene, lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol and butanol. Water, dialkylformamides such as dimethylformamide and diethylformamide. Preferred solvents are Methanol, ethanol, tetrahydrofuran, dioxane, benzene, toluene and dimethylformamide are used Particularly preferred solvents are polar solvents such as methanol and ethanol. The amine is generally used in at least a stoichiometric amount. Preferably it will be in one Quantity ratio of 6 to 8 mol per 1 mol of the 3,4-dihydrocarbostyril derivative of the general formula Il used. The reaction temperature is not particularly critical. The implementation runs smoothly at temperatures from room temperature to the boiling point of the solvent used. The preferred temperature range is between 40 and 60 ° C, regardless of whether a solvent is used. The reaction time depends on the reaction temperature. The implementation is within 3 to 8 hours, generally within 4 to 5 hours. The reaction product can be used in a conventional manner be isolated, e.g. B. by filtration or separating the solvent from the reaction mixture Distillation. The cleaning can be carried out by customary methods, e.g. B. by recrystallization from a suitable solvent.

The second process for the preparation of the compounds of the general formula I in which R _{2 is} a hydrogen atom consists in the reduction of a compound of the general formula III

(III)

or its salt, in which Ri and R 'have the preceding meaning. The reduction is carried out with hydrogen in the presence of a nickel, palladium or platinum catalyst such as Raney nickel, palladium black, platinum oxide and platinum black. The hydrogenation is carried out in an organic solvent at temperatures from 0 to 150 ⁰ C, preferably 50 to 70 ° C, under normal pressure or pressures from 1 to 200 atm, preferably 10 to 50 at, performed. The pressure depends somewhat on the type of catalyst used.

When using palladium-on-carbon lies the pressure is preferably in the range of 2 to 10 at Nickel preferably between 50 and 150 at. Examples of suitable solvents are halogenated hydrocarbons and mixtures of halogenated hydrocarbons and lower aliphatic alcohols, such as chloroform, carbon tetrachloride, dichloroethane and a mixture of methanol and chloroform or Ethanol and carbon tetrachloride. Particularly preferred solvents are chloroform and carbon tetrachloride. Any organic solvent can be used for the hydrogenation, which is opposite to the Reactants and the reaction product is inert. Examples of such solvents are lower ones aliphatic alcohols such as methanol, ethanol, glacial acetic acid and ethyl acetate

The compounds of general formula III are new and show the same physiological properties as the compounds of general formula I. These compounds can easily be made using the following reaction scheme:

XCIl ₂ CH - CH ₂

HN

(HI)

(A)

OCH ₂ CH - CHj

Y \ ip.d P / have the vorstehc ⁿⁱ i anpfPfhene

Meaning. The starting compound (A) is in). Org. Chem., BJ. 36 (23). Pages 3490 to 3493 (1971). described.

The compounds of the general formula I in which R _{3 represents} the acetyl radical or the trimethoxybenzoyl radical can be prepared from the corresponding compounds of the general formula I in which R2 represents a hydrogen atom by acylation with an acyl chloride of the general formula V

R ₃ -COCI

are produced, in the R3 —CO acetyl or 3,4,5-trimethoxy is preferred. The acylation is preferably carried out in the presence of an inert organic Solvent carried out. The acylation is preferably carried out in the presence of an acid acceptor obtain. The acyl chloride of the general formula V is used in at least a stoichiometric amount. In general, it is used in a proportion of 3 to 5 moles per mole of the (2-hydroxy-3-amino) propoxy-3,4-dihydrocarbostyril derivative used. The acylation can be carried out at temperatures from room temperature to the boiling point of the solvent used be performed. In general, very good results are obtained when the acylation is in the presence a suitable solvent and at the boiling point of this solvent. The implementation is generally completed within 3 to 6 hours, preferably 4 to 5 hours.

The intermediates of the general formula II can be obtained by reacting the corresponding 5- or e-hydroxy-S ^ -dihydrocarbostyril derivative of the general Formula VI

OH

X - CH, -

CH - CH ₂
O

(Viii

in which X is a halogen atom, in the presence of a base. In general, 1 to 10 moles, preferably 1 to 3 moles of epihalohydrin are used per mole of the compound of the general formula VI. the Compounds of the general formula VI are known and disclosed in Japanese Patent Publication No. 39 694/1971 and 38 789/1971. The preparation of 3-hydroxy compounds of the general Formula Vl is also in reports of the German chem. Ges., Vol. 60 (1927), pages 858 to 862.

Examples of suitable epihalohydrins are epibromohydrin, F.pichlorohydrin and epijodohydrin. Examples suitable bases are alkali metals, alkali hydroxides, alkali carbonates and organic bases. Preferred Bases are sodium, potassium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, Piperidine, piperazine, pyridine and lower alkylamines such as diethylamine, triethylamine and methylamine. the Implementation of the compounds of the general formula VI with the compounds of the general formula VII is preferably carried out in the presence of a suitable solvent.

the reaction temperature is in the range from 0 to 120 ^° C., preferably 80 to 120 ^° C., and the reaction time is 4 to 6, preferably 5 to 6 hours. The reaction is usually carried out at atmospheric pressure. In this reaction, 5- or 8- (2,3-epoxy) -propoxy-3,4-dihydrocarbostyril derivatives and 5- or 8- (2-hydroxy-3-halogen) -propoxy-3, 4-dihydrocarbostyril derivatives of the general formula II, in which Y is the remainder

CH-CH,
\ /
O

and -CH-CH ₂ Y

OH

in which R _{1 has} the above meaning, with an epihalohydrin of the general form! VII

means The quantitative ratio of the compounds of general formula I and II depends on the nature of the used base. The compounds of the general formula I are formed in a predominant amount, if the implementation in the presence of strongly basic

Compounds such as alkali metals and alkali metal hydroxides. The connections of the general formula II are formed in predominant amount when the reaction is weak in the presence basic compounds, such as organic bases, in particular piperidine, and the epihalohydrin is used in excess. These compounds can be separated from one another by conventional methods be separated, e.g. B. by fractional crystallization, preferably by column chromatography z. B. active alumina or silica gel.

The intermediates of the general formula II, in which Z is the remainder

- CH-CH,

OH

represents, in which Y is a halogen aiom, can also by reacting a 5-hydroxy-3,4-dihydrocarbostyril derivative of the general formula VIII

(VIII)

Example 1 (No. 2)

5- (2-Hydroxy-3-tert-biitylamino) propoxy-3,4-dihydrocarbostyril hydrochloride

2.0 g of 5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril and 5 g of tert-butylamine are introduced into 30 ml of dioxane, and the resulting mixture is 3 hours heated under reflux and stirred. After the reaction has ended, the reaction mixture is reduced under reduced pressure Pressure evaporated and the residue with a solution of hydrogen chloride in methanol and then mixed with acetone The crystals formed are filtered off and from a mixture of methanol and Acetone recrystallizes Yield 13 g of colorless 5- (2-hydroxy-S-tert-butylaminoJ-propoxy-S ^ -dihydrocarbostyril hydrochloride from m.p. 277 to 278 ° C (dec.).

The starting compound was prepared as follows: 1.53 g of S-hydroxy-S / 1-dihydrocarbostyril and 3.5 g Epichlorohydrin are in 30 ml of a solution of Entered 0.216 g of sodium metal in methanol. The resulting solution is heated to 55 to 60 "C for 4 hours stirred. After cooling, the sodium chloride which has crystallized out is filtered off and the Fikrat under reduced pressure Pressure evaporated to dryness. The residue is digested with acetone. The crystals are filtered off and recrystallized from ethanol. Yield 0.8 g of colorless 5- (23-epoxy) propoxy-3,4-dihydrocarbostyril from F. 172 to 173 ° C The filtrate of the acetone solution is evaporated to dryness and the The residue was recrystallized from ethyl acetate. Yield 0.05 g of colorless 5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril from 157 to 158 ° C.

in which R, as defined above, with a 3-halo-1,2-propanediol of the general formula IX

CH ₂ -CH-CH ₂ Y

I I

OH OH

(ix)

in which Y is a halogen atom. Preferably 1 to 5 mol. In particular 1 to 3 Mol of the compound of the general formula IX with I mol of the compound of the general formula VII This reaction is carried out for 3 to 6 hours, preferably 4 to 5 hours, at atmospheric pressure in an inert solvent such as carbon tetrachloride at temperatures around room temperature up to the boiling point of the solvent used, preferably at or near the boiling point of the solvent. Examples of suitable solvents are halogenated hydrocarbons and mixtures of halogenated hydrocarbons and lower aliphatic alcohols such as Chloroform, carbon tetrachloride, dichloroethane Mixture of methanol and chloroform or of ethanol and carbon tetrachloride. Particularly preferred Solvents are chloroform and carbon tetrachloride. The compounds of the general formula VII are known from Tetrahedron Letters, 1965, p. 2441. Preferably I bi.'i 3 mol, in particular I bis !,. "» Moles of brominating agent per mole of the compound of general formula VIII used.

The following examples explain the preparation of the compounds of the invention.

Example 2 (No. 1)

Preparation of 5- (2-hydroxy-3-isopropylamino) propoxy-S ^ -dihydrocarbostyril hydrochloride

1.5 g of 5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril and 23 g of isopropylamine are added to 25 ml of methanol, and the resulting mixture is Heated and stirred under reflux for 3 hours. After the reaction has ended, the reaction mixture is under evaporated under reduced pressure. The residue will dissolved in acetone and treated with a solution of hydrogen chloride in isopropanol. The crystals formed are filtered off and recrystallized from a mixture of methanol and acetone. Yield 1.1 g colorless 5- (2-Hydroxy-3-isopropylamino) propoxy-3,4-dihydfocarbostyril hydrochloride from 224 to 225 ° C.

Example 3 (No.4)

Preparation of l-methyl-5- (2hydroxy-3-tertbutylamino) -propoxy-3,4-dihydrocarbostyril-

maleate

1.5 g of 1-methyl-5- (2J-epoxy) -propoxy-3,4-dihydrocarbostyril and 2.0 g of tert-butylamine are in 30 ml

* » Benzene entered, and the mixture obtained is stirred at 55 to 60 ° C for 4 hours. When the reaction has ended, the reaction mixture is evaporated under reduced pressure, the residue is dissolved in acetone and a solution of maleic acid in acetone

■ staggered. The crystals formed are filtered off and recrystallized from ethanol. Yield 1.3 g colorless

methyl-5- (2-hydroxy-3-tert-butylaniino) -propoxy-3,4-dihydrocarbostyril-nialcat from F. 160 to lh3 "C.

308 IU / 36

IH

Example 4 Production of l-ethyl-5- (2-hydroxy-3-isopropyl-

amino) -propoxy-3,4 ~ dihydrocarbostyril-

hydrochloride

1.0 g of 1-ethyl-5- (23-epoxy) -propoxy-3,4-dihydrocarbostyril and 2 g of isopropylamine are introduced into 20 ml of toluene, and the resulting mixture is stirred for 5 hours at 50 to 55 ° C Reaction, the reaction mixture is evaporated under reduced pressure, the residue is dissolved in acetone, and a solution of hydrogen chloride and isopropanol is added. The crystals formed are filtered off and recrystallized from ethanol. Yield 0.85 g of colorless 1-ethyl-5- (2-hydroxy-3-isopropylamino) propoxy-3 _I 4-dihydrocarbostyril hydrochloride with a melting point of 1543 to 1563 ° C

The starting compound was prepared as follows: 3.8 g of epibromohydrin and 3 drops of piperidine to 3.0 g of l-ethyl-S-hydroxy-S / t-dihydrocarbostyril was added and the mixture for 5 hours at 95 to 00 ⁰ C! Then the reaction mixture is evaporated to dryness and the residue is dissolved in 10 ml of acetone.After adding 10 ml of ether and 20 ml of benzene, the solution is applied to a chromatography column filled with silica gel and the column with a solvent mixture of acetone, ether and benzene in a volume ratio 1: 1: 2 developed. The first eluate is evaporated to dryness and the residue is recrystallized from η-hexane. Yield 03 g of colorless 1-ethyl-5- (23-epoxy) -propoxy-3,4-dihydrocarbostyril with a melting point of 50 to 523 ° C The following eluate contains 1 ethyl 5- (2-hydroxy-3-bromo) propoxy-3,4-dihydrocarbostyril. It is evaporated to dryness and the residue is recrystallized from carbon tetrachloride. Yield 15 g of colorless product with a melting point of 115 to 117.5 ° C.

Example5 (No. 6) Production of 1-allyl-5- (2-hydroxy-3-tert-

butylamino) propoxy-3,4-dihydrocarbostyril-

fumarate

13 g of l-allyl-5- (23-epoxy) -propoxy-3,4-dihydrocarbostyril and 13 g of tert-butylamine are dissolved in 30 ml of ethanol entered, and the reaction mixture obtained is stirred at 60 to 65 ° C for 4 hours. After finished Reaction, the reaction mixture is evaporated under reduced pressure, the residue in acetone dissolved and treated with a solution of fumaric acid in methanol. The crystals formed will be filtered off and recrystallized from ethanol. yield 1.0 g colorless l-allyl-5- (2-hydroxy-3lcrt.-butylamino) propoxy-S ^ -dihydrocafbostyril fumarate from F. 209 to 2tO ° C.

Example 6 Production of 1-methyl-5- (2-hydroxy-

3-isopropyiamino) -propo! Iy-J, 4-dihydro-

carbostyril hydrochloride

1.5 g of methyl-5- (2-hydroxy-3-chloro) propoxy-3.4-di hydrocarbostyril and 3.0 g of isopropylamine are introduced into 20 ml of ethanol, and the mixture obtained is refluxed for 4 hours. Thereafter, the reaction mixture is evaporated under reduced pressure and the residue with a solution of Hydrogen chloride in methanol and acetone are added. The crystals formed are filtered off and removed from a Mixture of methanol and acetone recrystallized Yield 1.4 g of colorless needles of l-methyl-5- (2-hydroxy-3-isopropylamino) -propoxy-3,4-dihydrocarbosty- ril-hydrochlorids from 157 to 159 ° C.

Example 7 (No.5) Production of l-ethyl-5- (2-hydroxy-3-tert-

butylamino) propoxy-3,4-dihydrocarbostyril-

hydrochloride

2.0 g of l-ethyl-5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril and 4.0 g of tert-butylamine are in 20 ml Added methanol, and the resulting mixture is refluxed for 6 hours Reaction mixture evaporated under reduced pressure and the residue with a solution of Hydrogen chloride in methanol and acetone are added. The crystals formed are filtered off and Recrystallized from ethanol. Yield 13 g colorless 1-Ethyl-5- (2-hydroxy-3-tert-butyiamino) -propoxy-3,4-dihydrocarbostyril hydrochloride with a temperature of 181 to 183 ° C.

Example 8 Production of 1-benzyl-5- (2-hydroxy-

3-isopropylamino) propoxy-3,4-dihydrocarbostyril-

hydrochloride

23 g of l-benzyl-5- (23-epoxy) -propoxy-3,4-dihydrocarbostyril and 2 g of isopropylamine are introduced into 40 ml of ethanol, and the mixture obtained is ^{stirred at 60 to 65 °} C. for 4 hours. The reaction mixture is then stirred evaporated under reduced pressure, the residue dissolved in acetone and treated with a solution of hydrogen chloride in ethanol. The crystals formed are filtered off and recrystallized from ethanol. Yield 1.8 g of colorless l-benzyl-5- (2-hydroxy-3-

isopropylaminoJ-propoxy-S ^ -dihydrocarbostyril hydrochloride with a melting point of 192 to 194 ° C.

Example 9

Preparation of 1-allyl-5- (2-hydroxy-3-sec-butylamino) -propoxy-3,4-dihydrocarbostyril fumarate

13 g of l-allyl-5- (23-epoxy) -propoxy-3,4-dihydroc: arboslyril and 2.0 g of sec-butylamine are introduced into 30 ml of benzene, and the mixture is reacted and worked up according to Example 22. The free base is converted into the fumarate with a loering of fumaric acid in methanol. After recrystallization from ethanol 1.1 g of colorless 1-allyl-5- (2-hydroxy-3-sec-butylamino ^ ^ propoxyO -dihydrocarbostyril fumarate are obtained, melting at 183 to 184.5 ⁰ C.

Examples 10 to 18

In the same way as in rlcn previous Examples are the following compounds.

19th

Tabel

OCH ₃ CHCH ₁ N

R ¹

10 11

12 13

18th

H H

- CHj

, j 14 - C Ha

11 -CHCH ₃ (C ₂ Hs) HCl

-CH ₂ CH (CHj) ₂ CHCOOH

CHCOOH - (CH ₂ ) JCH ₃ HCl

-CHCH ₃ (C ₂ H ₅ ) CHCOOH

CHCOOH 13 -

II 15 -CH ₂ CH = CH ₂

16 H.

20th

Ex. P ¹ Connect- R ' A. recrystalline properties application no. lized the end Crystal m.p., ° C shape

Ethanol amorphous 228-31 Ethanol amorphous 194-6

Aihanol-amorphous 203-5 methanol

Acetone colored 152-5 needles

10 -

C (CHj) ₃ HCl Me
ethanol color.
Dandruff 192-3 CH (CHj) ₂ HOOCCH
Il
HCCOOH Ethanol color.
amorphous 192-4 C (CH ₃ J ₃ CHCOOH
Il
CHCOOH Ethanol color.
amorphous 206-7 C ₂ H ₅ CHCOOH
Il
CHCOOH Iso-
propanoi color.
amorphous 168-9 CHCH ₃ (C ₂ H ₅ ) CHCOOH
Il
CHCOOH Ethanol color.
Needles 142-4

example

Preparation of 5- (2-Hydroxy-3-isopropylamino) -prQpQXy-3,4-dihydrocarbostyril

0.5 g of 5- (2-hydroxy-3-isopropylamino) propoxycarbostyril are dissolved in 100 ml of ethanol. The solution is combined with 0.5 g of Raney nickel in an autoclave and shaken for 5 hours at 40 to 5O ⁰ C and a hydrogen pressure of 50 al. After the reaction has ended, the catalyst is filtered off and the filtrate is evaporated. After recrystallization of the residue from isopropanol, 0.48 g of colorless 5- (2-hydroxy-S-isopropylaminoJ-propoxy-S / t-dihydrocarbosiy-Hl with a melting point of 144 ° to 145.5 ° C. are obtained.

Example 20

Preparation of 5- (2-hydroxy-3-lert.-butylamino) propoxy-3,4-dihydrocarbostyril hydrochloride

0.5 g 5- (2-Hydroxy-3-tert.-butylaniino) -propoxycar-

bostyril-hydroeh-and are dissolved in 500 ml of ethanol, and the solution together with 0.5 g of Raney nickel placed in an autoclave. The mixture is hydrogenated according to Example 19. There are 0.47 g colorless 5- (2-Hydroxy-3-tert-butylamino) propoxy-3,4-dihydrocarbostyril hydrochloride obtained with a mp of 278 ° C (dec .; ethanol).

Example 21

Preparation of 5- (2-Hydroxy-3-isopropylamino) -propoxy-3,4-dihydrocarbostyriI

• 9.5 g of 5- (2-hydroxy-3-isopropy! Amino) -propoxycarbostyril 0.01 g of palladium black and 10 ml of glacial acetic acid are added. The mixture is 5 hours at Shaken room temperature under a hydrogen pressure of 10 at. After the reaction has ended, de ' The catalyst was filtered off, the filtrate was evaporated, water was added to the residue and the aqueous solution was added made alkaline with ammonia. The precipitated crystals are filtered off and extracted from isopropanol recrystallized yield 0.47 g of 5- (2-hydroxy-3-isopropylamino) propoxy-3,4-dihydrocarbostyri ;. obtain. After recrystallization from a mixture of ethanol and isopropyl ether, 1.1 g are colorless 1-methyl-5- (2-acetoxy-3-isopropylamino) propoxy-3,4-dihydiocarbostyril hydrochloride obtained from F. 194 to! 96 "C (decomp.).

B e i s ρ i e 1 22

Preparation of 5- (2-acetoxy-3-tert-butylamino) -propoxy-S ^ -dihydrocarbostyril hydrochloride

2.0 g of 5- (2-hydroxy-3-tert-butylamino) propoxy-3,4-dihydrocarbostyril and 10 g of acetyl chloride are refluxed in 30 ml of acetone for 2 hours. After standing for 15 to 18 hours, the precipitated crystals are filtered off, washed with acetone and recrystallized from a mixture of methanol and acetone. Yield 1.7 g of light yellow 5- (2-acetoxy-3-tert.-butylamino) propoxy-3,4-dihydrocarbostyriI hydrochloride mp 231 ⁰ C (dec.).

Example 23 (No. 7)

Preparation of 5- (2-acetoxy-3-isopropylamino) -propoxy-S ^ -dihydrocarbostyril-hydrochloride

1.5 g of 5- (2-hydroxy-3-isopropylamino) propoxy-3,4-dihydrocarbostyril and I g of acetyl chloride in 30 ml of acetone will.! Boiled under reflux for 2 hours. After cooling, the mixture is evaporated to dryness and the residue is dissolved in water. the The solution is made alkaline with ammonia and extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate and evaporated. The residue is dissolved in acetone and with a solution mixed with oxalic acid in ether. The precipitated crystals are filtered off:;. Yield 0.9 g colorless 5- (2-acetoxy-3-isopropylamino) propoxy-3,4-dihydrocarbostyril hydrochloride from mp 196 to 198 ° C (decomp.).

Example 24

Preparation of 1 -Methyl-5- (2-acetoxy-

3-isopropylamino) propoxy-3,4-dihydrocarbostyril-

hydroehlorid

According to Example 23. but using 1.5 g of 1-methyl-5- (2-hydroxy-3-isopropylamino) -3.4-dihydrocarbostyril. wVj the corresponding acetyl derivative

Example 25

Preparation of l-benzyl-5- (2-acetoxy-3-tert.-butylamino) -propoxy-3,4-dinydrocarbostyril-

maleate

According to Example 23, but using 2.0 g of l-benzyl-5- (2-hydroxy-3-tert.-butylamino) propoxy-3,4-dihydrocarbostyril, the acetoxy derivative is obtained. After recrystallization of the crude product from a mixture of ethanol and acetone, 1.4 g are obtained l-Benzyl-S - ^ - acetoxy-S-tert-butylaminoJ-propoxy-S ^ - dihydrocarbostyril maleate from 191 to 193 ° C obtain.

B e i s ρ i e I 26

Production of 5- [3-tert-butylamino-

2- (3,4,5-trimethoxy) -benzoyloxy] -propoxy-

3,4-dihydrocarbostyril maleate

3.0 g of 5- (2-hydroxy-3-tert-butylamino) propoxy-3,4-dihydrocarbostyril and 0.1 g of sodium hydride in 60 ml of xylene are refluxed for 1 hour and touched. A solution of 2.8 g of 3,4,5-trimethoxybenzoyl chloride is then added to the reaction mixture over the course of 1 hour dripped into 40 ml of xylene. The resulting mixture is refluxed for 4 hours and stirred and then evaporated under reduced pressure. The residue is dissolved in chloroform, washed with water and extracted with 3 η hydrochloric acid.

■ »ο The hydrochloric acid solution is separated off with caustic soda made alkaline and then extracted with chloroform. The chloroform extract is evaporated. Of the The residue is dissolved in 60 ml of acetone, and maleic acid is added. The precipitated crystals will be

<5 filtered off and recrystallized from methanol. yield 2.1 g of colorless 5- [3-tert-butylam: no-2- (3.4,5-trimeth-

oxy) benzoyloxy] propoxy-3,4-dihydrocarbostyril maleate from m.p. 224 to 226 ° C (dec.).

B e i s ρ i e I 27 (No. 8)

Preparation of 5- [3-isopropylamino-2- (3,4,5-trimethoxy) -benzoyloxy] -propoxy-

3,4-dihydrocarbostyru maleate

According to Example 26, but using 3.0 g of 5- (2-hydroxy-3-isopropylamino) propoxy-3,4-dihydrocarbostyril, 1.5 g of colorless 5- [3-isopropylamino-2- (3,4,5 trimethoxy) benzoyloxy] propoxy-3,4-dihydrocarbostyril maleate are obtained obtained from mp 186 to 188 ° C (dec .; ethanol).

Example 28

In the same manner as in Example 22, the following compounds are made:

Table 3

OCH ₂ CHCH ₂ N

OR ₂ R '

R '

Recrystallized from properties

Crystal form F., ° C

CH (CHj); CHjCU

ti U I

CHj CH (CHj) ₂ 3,4,5-trimethoxy-HCl

phenyl

LJiainy jairici

Methanol

amorphous.

color amorphous.

216-218

Example 29

Preparation of 5- (2-hydroxy-3-isopropylamino) propoxyO ^ -dihycirocarbostyril maleate

1.5 g of isopropylamine in 30 ml of methanol to 1.0 g of 5- (2 _r 3-epoxy) -propo: where <y-3,4-dihydrocarbostyril, and the mixture is stirred for 4 hours at 45 to 5O ⁰ C and then evaporated. The residue is dissolved in acetone and a solution of maleic acid in acetone is added. The precipitated crystals are filtered off and recrystallized from isopropanol. Yield 2.1 g of colorless 5- (2-hydroxy-3-isopropylamino) propoxy-3,4-dihydrocarbostyril maleate, melting at 218-220 ⁰ C (ethanol).

The maleate obtained is then treated with sodium hydroxide solution or potassium hydroxide solution. Colorless 5- (2-hydroxy-S-isopropylaminoJ-propoxy-S / l-dihydrocarbostyril with a melting point of 145 to 145.5 ° C. is obtained.

Example 30

Preparation of 5- (2-hydroxy-3-isopropylamino) propoxy-S ^ -dihydrocarbostyril hydrochloride

Example 29 is repeated except that hydrochloric acid is used instead of meleinic acid. Man receives colorless 5- (2-hydroxy-3-isopropylamino) propoxy-3,4-dihydrocarbostyril] hydrochloride from 224 to 225 ° C

Example 31

Preparation of 5- (2-hydroxy-3-tert-butylamino) propoxy-3,4-dihydrocarbostyril maleate

A mixture of 0.75 g .'i- (23-F.poxy) -propoxy-3,4-dihydrocarbostyril, 1.0 g of tert-butylamine and 25 ml of ethanol is stirred at 50 to 55 ° C for 4 hours. Thereafter, the reaction mixture is under reduced pressure evaporated and the residue dissolved in acetone. 0.5 g of maleic acid is added to the acetone solution. the Precipitated crystals are filtered off and uTikristallisiert from Äthanoi. Yield 1.05 g of colorless 5- (2-hydro-

45

60

65 xy-S-tert-butylaminoJ-propoxy-S ^ -dihydrocarbostyril maleate, mp 206-207 ° C.

Example 32 (No. 12)

1.8 g of 8 (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril and 3.5 g of hopropylamine are introduced into 30 ml of isopropanol and 5 nozzles under reflux cooked. The reaction mixture is then evaporated under reduced pressure, the residue in Dissolved acetone and mixed with a solution of hydrogen chloride in isopropanol. The crystals formed are filtered off and recrystallized from ethanol. Yield 0.7 g of colorless 8- (2-hydroxy-3-isopropylaminoJ-propoxy-S ^ -dihydrocarbostvril-hydrochloride from 230 to 232 ° C. The free base melts at 157 to 159 ° C (acetone).

Example 33 (No. 3)

The following compound was prepared analogously to Example 32: 8- (2-Hydroxy-3-tert-butylamino) propoxy-3,4-dihydrocarbostyril hydrochloride, mp 236-238 ° C. (ethanol); the free base melts at 158-16I ⁰ C (acetone).

Example 34

The following connections are made in the same way:

5- [3-tert-Butylamino-2- (3,4 _r 5-trimethoxy) -benzoyloxy] -propoxy-i-methyl-S / 1-dihydrocarbostyril- '. Iydrochloride, mp 216-218 ° C (dec .; Methanol).

l-Benzyl-5- [3-terL-butylamino-2- (3,4p-trimeth-

oxyj-benzoyloxyj-propoxy ^^ - dihydrocarbostyril hydrochloride, M.p. 192-194 ° C (dec .; acetone) and

1-AlIyl-5- [3-isopropylamino-2- (3,4,5-trimethoxy) -benzoy! oxy] -propoxy-3,4-dihydrocarbostyriI-fumarate, 185-187 ° C (dec .; methanol).

l-Allyl-5- [3-terL-butyIamino-2- (3,4,5-trimethoxy) -benzoyl] -propoxy-3,4-ijihydrocarbostyril maleate, F.

186-188 ° C (decomp.; Methanol) (No. 14)! -A !! y! -5- (3-tert-buty! Amino-2-acetyIoxy) -propoxy-3,4-dihydrocarbostyril oxalate, M.p. 192-194 ° C (dec .; methanol) (No. 15).

308111/36

25 26

The ones used for the previous examples are:

Starting products were made as follows: A mixture of 1.63 g of 5-Hydroxy-3,4-dihydrocarbo-

....... -. ^ j-IJ ι. ι stvril, 2.5 g of F.pibromohydrin and 2 drops of piperidine will

5- (2,3-TPOX _y) - _P ropoxy-3.4-d.hydrocarbos.ynl _{4 Slunc} | _{en; lllf q5 to 100} o _{C e,. holds lln (} , _{added then}

1.53 g of S-hydroxy-S ^ -dihydrocarbostyril and 3.5 g 'is the reaction mixture under reduced pressure

Epichlorohydrin are evaporated to 30 ml of a solution of to dryness and the residue is removed

0.216 g of sodium was added in methanol, and the acetone obtained was recrystallized. Yield 1.2 g of colorless 5 (2,3-

The solution is stirred at 55 to 60 ^° C. for 4 hours. According to epoxy) propoxy-3,4-dihydrocarbostyril from I · '. 172 to

After cooling down, the sodium chloro-173 "C crystallizes out.

Ride filtered off and the filtrate under reduced pressure i "F. A further production method is the following:

evaporated. The residue is still warm with a solution of 0.6 g of sodium hydroxide in 40 ml

Ethyl acetate extracted. The Ethylace.jtextrakt is water with 2.45 g S-Hydroxy-S / l-dihydrocarbosly-

evaporated and the residue from a mixture of ril and 3.5 g of epichlorohydrin and added 4 hours

Recrystallized acetone and diethyl ether. Yield 1.0 g heated and stirred from 30 to 40 ° C. After cooling down

colorless 5- (2,3-epoxy) -propoxy-3,4-dihydrocarbostyril ^ the precipitated crystals are filtered off and removed

from F ". 172 to 173 ° C. Acetone recrystallized in the IR absorption spectrum. Yield 1.75 g colorless

characteristic absorption bands appear in the case of 5- (2,3-epoxy) -propoxy-3,4-dihydrocarbostyril from F.

3020, 1665 and 1590 cm '. 172 to 173 ⁰ C.

The same product can be made as follows

Claims (3)

Patent claims: I. 3,4-Dihydrocarbostyril derivatives of the general formula I substituted in the 5- or 3-position 0-CHjCKCH ₂ N (I) 10 15th wherein Ri is a hydrogen atom, an alkyl radical having 1 to 4 carbon atoms, a benzyl radical or an allyl radical; R _{2 represents} a hydrogen atom, an acetyl group or a 3,4,5-trimethoxybenzoyl group, R 'represents an alkyl radical having 1 to 4 carbon atoms, and their salts with pharmaceutically acceptable acids. 2. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se for the preparation of the 3,4-dihydrocarbostyril derivatives of the general Formula Il jo O -CH ₂ Z 35 40 45 in Z a radical of the formula CH \ CH ₂ represents, and R _{1 has} the meaning given above, initially (A) the corresponding 5- or 8-hydroxy-3,4-dihydrocarbostyril of the general formula Vl (VO 55 in which R, which has the meaning given in claim 1, with an epihalohydrin of the general formula VI X-CH ₂ -CH CII; (VII) war reacts a base at temperatures from 0 to 120 ⁰ C, or (b) for the preparation of the compounds of the general formula O —CHjZ in which R has the meaning given in claim 1 and Z is a group of the general formula - CH-CHjY OH represents in which Y is a halogen atom, a Compound of the general formula VIII (VHD in which R _{1 has} the above meaning with a 3-halo-1,2-propanediol of the general formula IX CH ₂ -CH-OH OH -CH ₂ Y (IX) in which Y represents a halogen atom, in an inert solvent at temperatures of Reacts room temperature to the boiling point of the solvent used, and then (c) a 3,4-dihydrocarbostyril derivative of the general formula II OCH ₂ Z (in in which R _{1 has} the meaning given in claim 1 and Z is a radical of the formula CH-CH ₂ or in which X represents a III halogen atom, in contrast -CH-CH ₂ -Y OH represents, wherein Y is a halogen atom, with an amine of the general formula IV
H 3. Medicament, consisting of a compound according to claim 1 and pharmaceutically usual Auxiliary and carrier materials. HN (IV) R ' in which R 'has the meaning given in claim 1, converts or
(d) a carbostyrene derivative of the general formula III O-CH ₂ CH-CH ₂ N (HD wherein R ₍ and R 'have the meaning given in claim 1, or its salt is hydrogenated in the presence of a nickel, palladium or platinum catalyst and in an organic solvent, and where appropriate, the above-mentioned compounds of the general formula 1, ir »derR ₂ denotes a hydrogen atom, with an acylating agent of the general formula V R ₃ -COCI (V) in which R ₃ -CO denotes the acetyl or 3,4,5-trimethoxybenzoyl group, is reacted and, if appropriate, the compounds obtained according to (c), (d) and (e) are converted into a salt with an acid. The invention relates to the object of the spray. The compounds according to the invention are very good f-receptor blockers. They have p-sympatholytic effects and can therefore be used to treat heart conditions, such as arrhythmias. Angina pectoris, coronary insufficiency and also used against high pressure ·. «. The new compounds are used as drugs together with customary carriers or diluents for oral or parenteral administration prepared. The testing of the compounds of the invention for blockade of the ^ receptors against isopropyl noradrenaline (isoprenaline) was carried out according to the method of CE Powell, LH. Slater, J. Pharmac, Vol. 122 (1958), p. 480. In this method, the /? - receptor-blocking effect is determined on the blood pressure of the anesthetized dog. One first examines the blood pressure-lowering and frequency-increasing effects of isoprenaline and then examines the percentage by which the blood pressure lowering and frequency increase is reduced if a / 3-receptor blocker is given beforehand. For this experiment, male dogs with a body weight of 13 to 20 kg are anesthetized with 30 mg / kg body weight of pentobarbital sodium, which is administered intravenously. Thereafter, the compound to be examined is administered to the anesthetized dog at a dose of 10 ~ ⁷ mol / kg body weight through the femoral vein. After 5 minutes, the dog is given isoprenaline through the femoral vein 03y / kg body weight. The results are shown in Table 2. Propranolol was used as a comparison substance. Toxicity was assessed i.v. on mice according to Regulation in "Journal of Medical Chemistry". Volume 17, No. 5, pages 529 to 530, checked.