CH635569A5 - Process for preparing novel 1-(2-phenyl-2-hydroxyethylamino)-3-phenoxypropan-2-ols and their acid addition salts - Google Patents

Abstract

Novel 1-(2-phenyl-2-hydroxyethylamino)-3-phenoxypropan-2-ols of the formula I are prepared by hydrolysis from an oxazolidinone or oxazolidine of the formulae IIa or IIb. The symbols in the formulae I, IIa and IIb have the meanings given in Patent Claim 1. The compounds of the formula I have a cardiovascular effect and in addition possess vasodilatory, antihypertensive and antiarrhythmic activity. <IMAGE>

Description

The invention relates to a process for the preparation of new 1- (2-phenyl-2-hydroxyethylamino) -3-phenoxypropan-2-ols of the formula I.

CH-CH-NH-CH 0-CH-CH o-0 II ^ I 2

oh r,

OH

R5 «6

(X)

3rd

635 569

and their acid addition salts, which are suitable for use in drugs and as intermediates for the manufacture of drugs. The bases of the formula I can be present as racemates, as mixtures of racemates or in the form of individual optical antipodes or can be present in the salts.

The radicals Rj to R6 in formula I have the following meaning:

Rj is hydrogen, halogen, hydroxy, amino, alkyl, alkoxy, alkanoylamino or alkylsulfonylamino;

R2 is hydrogen, hydroxy, alkyl, alkoxy or amino-carbonyl;

R3 is hydrogen or halogen, alkyl or alkoxy;

R4 is hydrogen, methyl or ethyl;

R5 and Re are hydrogen, halogen, alkyl, alkoxy, hydroxy, amino, cyano, carboxy, carbalkoxy, aminocarbonyl, alkyleneaminocarbonyl, alkanoylamino or alkylsulfonylamino;

with the proviso that if

Rj is hydrogen, 4-hydroxy or 4-chlorine,

R2 hydrogen,

R3 is hydrogen,

R4 is methyl and

R5 represents hydrogen or 2-halogen,

R6 does not represent 4-hydroxy.

Insofar as alkyl or alkoxy groups are mentioned in the above definitions or other groups which contain alkyl or ceo'h-chr4-n-

or IIb

10th

Containing alkoxy groups are meant those alkyl or alkoxy groups which have 1 to 4 carbon atoms and can be straight-chain or branched. The acyl radicals in the alkanoylamino or alkylsulfonylamino groups are derived from lower aliphatic carboxylic acids or lower alkanesulfonic acids, and the alkylene aminocarbonyl groups contain lower alkylene groups.

The following substituent meanings should be emphasized:

Rj is hydrogen, chlorine or bromine, hydroxyl group, Cj- or C2-alkyl, especially methyl, Cx- or C2-alkoxy, especially methoxy, acetylamido, propionylamido or methanesulfonamido;

15 R2 hydrogen, hydroxy group, methoxy;

R3 is hydrogen, chlorine or bromine, hydroxyl group, methyl or methoxy;

R4 is hydrogen or methyl group;

R5 is hydrogen, fluorine, chlorine or bromine, methoxy, a

20 hydroxyl, cyano, carboxy, aminocarbonyl or amino group, a carbalkoxy, alkylene aminocarbonyl or acylamido group, each containing up to 3 carbon atoms.

The compounds excluded by the disclaimer are the subject of DE-OS 2 502 993.

25th

The process is characterized in that an oxazolidinone or oxazolidine of the formula IIa ch,

i ch-ch2 ~ 0

I *

(IIa)

chr,

n-ch2-choh-ch2-o

(IIb),

wherein R is CO or CHR 'and R' C1-C3 alkyl or solvent, e.g. B. methanol, ethanol, dioxane, in counter

Represents aryl, hydrolyzed. So was a base, preferably an alkali base.

The hydrolysis can be carried out in an alkaline environment, and optionally also oxazolidinones of the formulas IIa and IIb, in an acidic environment. for example according to the reaction scheme below

It is advisable to work at an elevated temperature in

a mixture of water and one that is miscible with water

1

ckch-ckr4-nk-co-oc2h5

R-

CH,

(V)

-ch-ch2-0

(VI)

635 569

.ch0h-chr4-n-

-ch0

i 2

0 = c ch-cko-o-

■ o / 2

(lia)

chr,

(vin) + c2h5o ~ co-nh-ch2-choh-ch2o

(IX)

^ n-ch2-choh-ch2-q

(IIb)

Optically active precursors can also be used for the process according to the invention and, if appropriate, pure optical isomers can be obtained directly. Racemates obtained in the process can be separated into the optically active compounds by customary methods.

The bases of the formula I are optionally converted into salts by customary methods or, if they are present as salts, into salts of other acids or into free bases.

All starting materials can be obtained by known methods.

The compounds of formula I have cardiovascular effects and are also vasodilator, antihypertensive and antiarrhythmic. For example, they can be used as active ingredients in selectively active cardiac agents, since they combine a positive inotropic effect with only a slight frequency-increasing effect.

This can be seen, for example, in the results of the test on the isolated guinea pig atrium. The values of the amplitude change (A) and the frequency change (F) obtained in the usual test with 1 (ig active ingredient / ml) for l- [2- (4-hydroxyphenyl) -2-hydroxyethylamino] -4-cyano-

phenoxy) propanol- (2) A: + 37%, F: + 7% and for l- [2- (3,5-dihydroxyphenyl) -2-hydroxyethylamino] -3- (4-tolyloxy) propanol-2 A: + 36%, F: -3%.

For use, the new compounds can be processed with the auxiliaries customary in pharmaceutical pharmacy to form common pharmaceutical forms, e.g.

to tablets, dragees, capsules, tinctures, solutions for injection, suppositories.

The single dose is generally between about 1 and 100 mg, preferably 5 to 50 mg, depending on the form of administration, active ingredient and body weight of the person to be treated.

45 The ingredients can be processed into tablets weighing 600 mg in the usual way. If desired, the active substance content can be increased or decreased and the amount of glucose reduced or increased accordingly.

50

55

60

65

Suppositories

Composition:

Active ingredient according to the invention 50 parts by weight

Lactose, powdered 45 parts by weight

Cocoa butter 1605 parts by weight The ingredients are processed in the usual way into suppositories weighing 1.7 g.

Capsules

Composition:

1- [2- (3,5-Dihydroxyphenyl) -2-hydroxyethylamino] -3- (4-tolyloxy) propanol-2 10 parts by weight of lactose 490 parts by weight

Corn starch 400 parts by weight

Each 1000 mg of the finely powdered mixture is filled into hard gelatin capsules.

The following example is intended to explain the manufacturing processes of the active ingredients in more detail.

635 569

1- [2- (3,4-dichlorophenyl) -2-hydroxyethylamino] -3-phenoxypropanol-2-formate A solution of 6 g of 3- [2- (3,4-dichlorophenyl) -2-hydroxyethyl ethyl ] -5-phenoxymethyloxazolidinone in 50 ml of ethanol, to which 10 g of potassium hydroxide and 20 ml of water are added, is heated under reflux for 90 minutes. After cooling, the alcohol is distilled off in vacuo. The aqueous phase is extracted twice with ether, the ethereal phase washed with water and dried over magnesium sulfate. After the ether has cooled, the residue is dissolved in a little ethanol, formic acid and slowly ether added. The formate crystallizes colorless.

The compounds listed in the table are also prepared in accordance with the example above:

Table compounds of the formula

CH0H-CIIRa-NH-CH2-CH0H-CH2-0

R,

No.

Ri r2

R3

r4

R s

R6

Salt * / Mp. [° C]

1

H

H

H

CH3 (erythro)

2-CN

H

Cl / 169 to 170

2nd

H

H

H

CH3 (threo)

"2-CN

H

FU / 177 to 179

3rd

4-OH

3-OH

2-CH3

H

4-CH3

H

Cl / 244 (dec.)

4th

4-OH

H

H

H

3-CN

H

Cl / 154 to 156

5

4-OH

H

H

H

2-CH3

H

FU / 123 to 125

6

4-OH

H

H

H

2-CN

H

Cl / 135 to 136

7

4-OH

H

H

H

4-CN

H

Cl / 157 to 159

8th

3-OH

H

H

H

2-CH3

H

FU / 122

9

3-OH

5-OH

H

H

4-CN

H

FU / 152 to 155

10th

4-OH

H

H

H

4-OCH3

H

Cl / 142 to 143

11

4-OH

H

H

H

3-OCH3

4-OCH3

Cl / 177 to 179

12

3-C1

4-C1

H

H

H

H

FO / 189 to 190

13

4-OH

3-NH2

H

H

2-CH3

H

Cl / 210 (dec.)

14

4-OH

3-NH-CO-

prr

H

H

2-CH3

H

Cl / 158 to 159

15

4-OH

CrÌ3

H

H

H

4-CH, -CO-H

FU / 171 to 172

nh2

16

4-OH

3-OCH3

H

H

4-CH3

3-CH3

Cl / 148 to 149

17th

4-OH

3-CONH2

H

H

4-CH3

H

Cl / 195 to 196

18th

4-OH

H

H

CH3 (erythro)

4-CN

H

Cl / 161 to 164

19th

4-OH

H

H

CH3 (threo)

4-CN

H

Cl / 169 to 171

♦ CI: hydrochloride FU: fumarate FO: formate s

Claims (3)

635 569 1. Process for the preparation of new 1- (2-phenyl-2-hydroxyethylamino) -3-phenoxypropan-2-ols of the formula I. ch-ch-NH-cho-çh-cho-0 2. The method according to claim 1, characterized in that that you convert an obtained acid addition salt into another acid addition salt. 2- <rH- Oh (I), in the Rj is hydrogen, halogen, hydroxy, amino, alkyl, alkoxy, alkanoylamino or alkylsulfonylamino; R2 is hydrogen, hydroxy, alkyl, alkoxy or amino-carbonyl; R3 is hydrogen or halogen, alkyl or alkoxy; R4 is hydrogen, methyl or ethyl and Rs and R6 are hydrogen, halogen, alkyl, alkoxy, hydroxy, amino, cyano, carboxy, carbalkoxy, aminocarbonyl, alkyleneaminocarbonyl, alkanoylamino or alkylsulfonylamino ch0h-chr4-n. with the proviso that if Ri is hydrogen, 4-hydroxy or 4-chlorine, R2 is hydrogen, R3 is hydrogen, R4 is methyl and Rs is hydrogen or 2-halogen, 20 R6 is not 4-hydroxy, in the form of racemates, racemate mixtures and individual optical antipodes, and their salts, characterized in that an oxazolidinone or oxazolidine of the formula IIa ck, ch-ch2-o chr, n-ch2-ch0h-ch2-0 (IIa) R, (IIb) » wherein R is CO or CHR 'and R' is Ci-Ca-alkyl or aryl, hydrolyzed and optionally converting a base obtained into an acid addition salt or releasing the base from a salt obtained. 2nd PATENT CLAIMS 3. The method according to claim 1 or 2, characterized in that one separates a racemate obtained into the optically active antipodes.