NO143345B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-PHENYL-2-HYDROXYETHYLAMINE DERIVATIVES - Google Patents

Description

This invention relates to the preparation of new 2-phenyl-2-hydroxyethylamine derivatives with the formula

and salts thereof which can be used in pharmaceuticals and as intermediates

products for the manufacture of pharmaceutical compounds. The bases of formula I can exist as racemates, as mixtures of racemates or in the form of individual optical antipodes or can be contained in the salts0

The residues of Rg in formula I have the following meaning:

R^: hydrogen atom, halogen atom, hydroxy-, amino-, lower alkyl-,

lower alkoxy or lower alkanoylamido group;

R2: hydrogen atom, hydroxy-, lower alkyl-, lower alkoxy-

or carboxamido group;

R3: hydrogen or halogen atom, lower alkyl or lower

alkoxy group;

R 1 : hydrogen, methyl or ethyl group;

R,, and Rg: hydrogen atom, lower alkyl-, lower alkoxy-, cyano-,

carboxamido or lower alkylenecarboxamido group.

To the extent that alkyl or alkoxy groups or other groups containing alkyl or alkoxy groups are mentioned in the above definitions, such alkyl or alkoxy groups are to be understood as containing 1-4 carbon atoms and may be linear or branched. The acyl residues in the acylamido groups are derived from lower aliphatic carboxylic acids or lower alkane sulfonic acids, and the alkylenecarboxamido groups contain lower alkylene groups„

The following substituent meanings must be highlighted in particular:

R^: hydrogen, chlorine or bromine atom, hydroxy group,

C 1 -C 2 alkyl, especially methyl, C 1 -C 2 alkoxy, especially methoxy, acetylamido or propionylamido;

R2: hydrogen atom, hydroxy group, C1-C2 alkyl, especially methyl,

or C 1 -C 2 alkoxy, especially methoxy;

R^: hydrogen, chlorine or bromine atom, hydroxy group,

C1-C2-alkyl, especially methyl, or C1-C2- alkoxy, especially methoxy;

R 1 : hydrogen atom or methyl group;

R5: hydrogen atom, C1-C2-alkyl, especially methyl, C1-C2-alkoxy,

in particular methoxy, a cyano or carboxamido group or an alkylene carboxamido group which may contain up to 3 C atoms.

According to the invention, the new compounds can be produced by the following methods:

1„ Removal of the protecting group(s) from a compound of the formula

where

R-,, R., R- and R, have the meaning indicated above, and

■i 4 d o

R^ means hydrogen or an arylmethyl radical,

Rg means R^ or a hydroxy or amino group which is substituted with a hydrogenolytically or hydrolytically cleavable protecting group,

Rg means R» or a hydroxy group which is substituted with a hydrogenolytically or hydrolytically cleavable protecting group,

wherein at least one of the residues R^ to Rg means or contains a protecting group.

As protective groups, in particular arylmethyl, alkanoyl and aroyl groups, tetrahydropyranyl and for OH groups in the neighboring position bifunctional groups, e.g. a diarylmethylene group. Examples of the different types of protecting groups include a benzyl residue and substituted benzyl residues, lower aliphatic acyl residues, benzoyl residues and a diphenyl-methylene residue

Arylmethyl groups on nitrogen are removed by catalytic hydrogenation in the presence of common hydrogenation catalysts, e.g. platinum, palladium or Raney nickel. Arylmethyl groups or diarylmethylene groups on oxygen are removed by catalytic hydrogenation or by hydrolysis with acids. Alkanoyl, aroyl or tetrahydropyranyl residues are split off by hydrolysis.

If the starting material contains substituents which must also be present in the final product, but which can also be changed under the conditions for removal of the protective groups, care must be taken to choose sufficiently mild reaction conditions as will be known to a person skilled in the art. However, it is also possible to e.g. proceed from starting materials where R^ or Rg mean carbolic or carboxamido groups, and to convert these groups simultaneously during the hydrolytic protection group removal so that the corresponding end products with a free carboxy group are obtained. Correspondingly, this also applies to the other methods according to the invention.

The starting substances with formula II can be prepared by usual methods, e.g. by reacting an amine with the formula where R1Q and means R5 resp. Rg or a hydroxy or amino group substituted with a hydrogenolytically or hydrolytically cleavable protecting group, with a compound of the formula

(X: halogen, e.g. chlorine)

in a manner known per se.

The compounds of formula II can also be prepared analogously to the method 2 described below. In this way, depending on the reducing agents, the erythro or threo form can be obtained.

2. Reduction of the carbonyl group in a compound of the formula

where R1-R6 have the meaning given above, and one of the residues Y and Y' means the group -CO-, while the other means -CHOH-.

The reduction of the carbonyl group occurs

a) with complex hydrides, e.g. lithium aluminum hydride, sodium or potassium borohydride, sodium bis-(2-methoxyethoxy)-aluminum hydride (SDMA), or b) with hydrogen in the presence of a hydrogenation catalyst, e.g. platinum, palladium or Raney nickel.

If one starts from a compound of formula V where Y means a carbonyl group and R 1 is an alkyl group, the end products can be formed in both threo and erythro form. With those below

a) specified reducing agents, the compounds of formula I are obtained in threo form, while the use of the agents specified under b)

leading to the erythro form.

The starting materials can be prepared in the usual way, e.g. in that a connection with the formula

is reacted with a compound of the formula 3. Reaction of a compound of the formula where R^-R^ has the meaning given above, with a compound of the formula

where R5 and Rg have the meaning indicated above

Instead of the compound with formula VIII, one can also start from the chlorohydrin with formula

from which the compound VIII is formed under the reaction conditions.

4. Reduction of Schiffske bases with the formula

respectively

where R^-Rg has the meaning given above,

with hydrogen and common hydrogenation catalysts or with complex hydrides, and removal of any protective groups.

5. Reduction of acid amides with the formulas

where R^-Rg has the meaning given above,

with complex hydrides, e.g. lithium aluminum hydride, SDMA or diborane.

6. Hydrolysis of oxazolidinones resp. oxazolidines with the formula

(R: CO, CHR', where R' is C^C^alkyl or aryl)

respectively

where R-j^-Rg has the meaning indicated above.

The hydrolysis is carried out in an alkaline, possibly also acidic environment. It is appropriate to work at an elevated temperature in a mixture of water and a water-miscible solvent, e.g. methanol, ethanol, dioxane, in the presence of a base, preferably an alkali base.

The method is particularly suitable for the production of such end products which do not contain phenolic OH groups. It can also be used for the production of such starting materials for Method 1, which contain hydrolysis-resistant protective groups.

The oxazolidinones with the formulas XHIa and Xlllb can be e.g. prepare according to the following reaction core: 7. Reaction of azetidinols with the formula

where R-^-*^ has the above meaning,

with phenols with the formula

where R,- and Rg have the meaning indicated above.

The turnover is carried out at an elevated temperature, appropriate i

a high-boiling, anhydrous solvent or solvent mixture, e.g. benzyl alcohol, in the presence of an alkali hydroxide, preferably under a nitrogen atmosphere. The process usually serves to prepare such compounds of formula I

which do not contain any phenolic hydroxy groups.

One possibility for the production of the starting materials is

indicated in the following reaction core:

For the methods according to the invention, optically active precursors can also be used and optionally obtain immediately pure optical isomers. Racemates formed by the process can be separated in the usual way into the optically active compounds.

If an antipode separation is desired, e.g. in Method 2 starting from compounds of formula V in R or S form, i.e. with a uniform configuration in the CHOH group. During the reduction of the carbonyl group, depending on the starting material, the RS and RR forms resp. The SS or SR form.

The bases of formula I are optionally transferred by usual methods to salts, or, if they exist as salts, to salts of other acids or to free bases.

All starting materials can be produced by methods known per se.

The compounds of formula I have cardiovascular effects and, in addition, they have vasodilatory, antihypertensive and antiarrhythmic effects. They can e.g. are used as active substances in selectively active cardiac agents, as they combine a positive inotropic effect with only a small frequency-increasing effect.

This shows, for example, by the results obtained by examination of isolated guinea pig cardiac atria. The values for amplitude change (A) and frequency change (F) that are obtained for a normal sample with 1 µg of active substance/ml amount to 1-[2-(4-hydroxyphenyl)-2-hydroxyethylamino]-3-(4-cyanophenoxy )-propanol-(2) A: + 37%, F: + 7%,

and for

1-[2-(3,5-dihydroxyphenyl)-2-hydroxyethylamino]-3-(4-tolyloxy)-propanol-2 A: + 36%, F: - 3%.

For use, the active substances are worked up together with usual excipients in galenic pharmacy into suitable medicinal forms, e.g. for tablets, dragées, capsules, tinctures, injection solutions or suppositories.

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

The following examples shall serve to further illustrate the invention:

Example 1 1-[2-(4-Hydroxyferryl)-2-hydroxy-ethylamino]-3-(4-tolyloxy)-propanol-2-hydrochloride 12 g of α-aminomethyl-4-benzyloxy-benzyl alcohol and 9 g of 2- ( 4-tolyloxymethyl)-oxirane is dissolved in 60 ml of alcohol and boiled for 8 hours under reflux. The whole thing is allowed to cool overnight, filtered off with suction and dried." is catalytically debenzylated after the addition of 10% palladium/charcoal at room temperature and normal pressure. After absorption of the calculated amount of hydrogen, the catalyst is suctioned off, and the solvent is distilled off on a so-called Rotavapor. The residue is dissolved in acetonitrile and the calculated amount of ethereal hydrochloric acid is added. The crystallized hydrochloride of 1-[2-(4-hydroxyphenyl)-2-hydroxy-ethylamino]-3-(4-tolyloxy)-propanol-2 is filtered off with suction and dried. The compound melts at 146°C. Example 2 1-[2-(4-hydroxyphenyl)-2-hydroxy-ethylamino]-3-(3-tolyloxy)-propanol-2-hydrochloride a) 15 g of 4'-benzyloxy-2-bromo-acetophenone are dissolved in 150 ml of acetonitrile. While stirring, 13.5 g of 1-benzylamino-3-(3-tolyloxy)-2-propanol (m.p. 76-77°) and 6.9 g of anhydrous potassium carbonate are added. Boil for 3 hours under reflux, cool and extract. The calculated amount of ethereal hydrochloric acid is added to the organic phase. The hydrochloride of 4'-benzyloxy-N-benzyl-N-[2-hydroxy-3-(3-tolyloxy)-propyl]-2-amino-acetophenone (m.p. 147°C) is allowed to crystallize overnight, suction and dries.

b) Dissolve 21 g of the above-mentioned HCl salt in water to a weak alkaline reaction, add ammonia and extract with

ether. After evaporation of the ether in vacuo, the residue is dissolved in 200 ml of alcohol and reduced by adding 1.5 g of sodium borohydride to 1-[2-(4-benzyloxyphenyl)-2-hydroxy-N-benzyl-ethylamino]-3-(3- tolyloxy)-propanol-2. For processing, the mixture is first slightly acidified with dilute acetic acid, the alcohol is distilled off in a vacuum, the residue is dissolved in water and extracted with ether after adding ammonia. The solvent is distilled off in vacuo, the residue is taken up in acetonitrile and acidified

with ethereal hydrochloric acid. The hydrochloride formed is filtered off and dried (m.p. 128°C).

c) To remove both benzyl groups, it is dissolved below

b) obtained hydrochloride in the 10-fold amount of methanol.

After adding palladium/coal, hydrogenation is carried out under normal conditions until the calculated amount of hydrogen is taken up. The catalyst is sucked off and evaporated to dryness in a vacuum. The residue is dissolved while warm in acetonitrile. On cooling

the crystalline 1-[2-(4-hydroxyphenyl)-2-hydroxy-ethylamino]-3-(3-tolyloxy)-propanol-2-hydrochloride with melting point 149-150°C is obtained.

Example 3

1-[ 2-( 3- hydroxyphenyl)- 2- hydroxy- ethylamino]- 3-( 4- tolyloxy)- propanol- 2- hydrochloride

15.4 g of 3'-benzyloxy-α-bromomethyl-benzyl alcohol are boiled together with 13.5 g of N-benzyl-2-hydroxy-3-(4-tolyloxy)-propylamine and 6.9 g of anhydrous potassium carbonate in 100 ml of acetonitrile in 5 hours under reflux cooling. One extracts and adds ethereal hydrochloric acid to a slightly acidic reaction. The precipitated hydrochloride is dissolved without further purification immediately in methanol and catalytically debenzylated after addition of palladium/charcoal. The catalyst is sucked off, evaporated to dryness in a vacuum, the residue is dissolved in acetonitrile and the solution is allowed to cool slowly. The next day, the hydrochloride of 1-[2-(3-hydroxyphenyl)-2-hydroxy-ethylamino]-3-(4-tolyloxy)-propanol-2 is filtered off and dried, m.p. 138-140°C.

Example 4

1-[ 2-( 3- hydroxyphenyl)- 2- hydroxy- ethylamino]- 3-( 2- cyanophenoxy)-propanol- 2- fumarate

a) o 11.3 g of 2-(3-benzyloxyphenyl)-ethylene oxide (b.p.Q ', 152-

155 C) and 16.8 g of 1-benzylamino-3-(2-cyanophenoxy)propanol-2

(m.p. 181-182°C) in 50 ml of alcohol is boiled for 8 hours under reflux cooling. The alcohol is then distilled off in a vacuum, the residue is taken up in ethyl acetate and ethereal hydrochloric acid is added to a slightly acidic reaction. You let it all stand overnight, vacuum and dry. The hydrochloride of 1-[2-(3-benzyloxyphenyl)-2-hydroxy-N-benzyl-ethylamino]-3-(2-cyanophenoxy)-propanol-2 melts at 151-152°C.

b) For debenzylation, the compound obtained under a) is dissolved in methanol and shaken at room temperature after addition

of palladium/coal until the calculated amount of hydrogen is taken up. The catalyst is then suctioned off, the residue is dissolved while warm in alcohol and the calculated amount of fumaric acid is added.

The whole thing is allowed to cool slowly, vacuumed and dried. The fumarate of 1-[2-(3-hydroxyphenyl)-2-hydroxyethylamino]-3-(2-cyano-phenoxy)-propanol-2 melts at 165-167°C.

Example 5

1-[ 2-( 3, 5- dihydroxyphenyl)- 2- hydroxy- ethylamino]- 3-( 4- tolyloxy)-propanol- 2- hydrochloride

5.4 g of p-cresol are dissolved in 50 ml of acetonitrile. To this is added 13.8 g of anhydrous potassium carbonate and 2 3.4 g of 3,5-dibenzyl-oxy-a-N-(3-chloro-2-hydroxy-propyl)-aminomethyl-benzyl alcohol hydrochloride. The mixture is boiled for 5 hours under reflux, filtered off with suction and then evaporated to dryness. The residue is dissolved in methanol and catalytically debenzylated under normal conditions. One filters and distills off, dissolves the residue while hot in acetonitrile, adds the calculated amount of ethereal hydrochloric acid and allows the whole to cool slowly. The formed crystals of 1-[2-(3,5-dihydroxyphenyl)-2-hydroxyethylamino]-3-[4-tolyloxy]-propanol-2-hydrochloride are filtered off with suction and dried, m.p. 169-170°C.

Example 6

1-[ 2-( 4- hydroxyphenyl)- 2- hydroxy- ethylamino]- 3-[ 2- methoxy-phenoxy]- propanol- 2- sulfate

19.9 g of 1-amino-3-(2-methoxyphenoxy)-propanol-2 are dissolved together with 2 8.6 g of 4-benzyloxy-phenylglyoxal-hemiacetal

(m.p. 77-80°C) in 500 ml of methanol by heating to 40°C. The whole thing is left to stand overnight at room temperature, whereby the Schiff base of the two compounds is formed. Next day of-

cooled to -10°C, and 7.4 g of sodium borohydride are added portionwise. The temperature must not rise above 0°C hereunder and during the subsequent reaction for 5 hours. The whole is left overnight in a refrigerator and the formed crystals of 1-[2-(4-benzyloxy-phenyl)-2-hydroxy-ethylamino]-3-[2-methoxyphenoxy]-propanol-2 are suctioned off.

These crystals are dissolved in the 20-fold amount of methanol, palladium/charcoal is added and the benzyl protecting group is removed by catalytic hydrogenation. After suctioning off the catalyst, the solvent is distilled off in a vacuum, the residue is dissolved hot in a little alcohol, and the calculated amount of concentrated sulfuric acid is added. The sulphate of 1-[2-(4-hydroxyphenyl)-2-hydroxy-ethylamino]-3-[2-methoxyphenoxy]-propanol-2 crystallizes out slowly, filtered off with suction and dried, m.p. 187-188°C.

Example 7

1-[ 2-( 4- hydroxyphenyl)- 2- hydroxy- ethylamino]- 3-[ 4- carboxamido-phenoxy]- propanol- 2- hydrochloride

a) 14.9 g of 1-benzylamino-3-(4-carboxamido-phenoxy)-propanone-2 and 11.3 g of 4-(benzyloxyphenyl)-ethylene oxide in 100 ml of alcohol are boiled

for 8 hours under reflux. The whole is allowed to react further overnight at room temperature and then 2 g of sodium borohydride are added. The mixture is first stirred for 2 hours at room temperature and then for 2 hours at 70°C. The alcohol is distilled off in a vacuum, water is added to the residue and acidified with acetic acid. The mixture is then made alkaline with ammonia and decanted several times with ethyl acetate. The solvent is distilled off in a vacuum, the residue is dissolved in isopropanol while boiling and cooled slowly. The formed crystals of 1-[2-(4-benzyloxy-phenyl)-2-hydroxy-N-benzyl-ethylamino]-3-[4-carboxamidophenoxy]-propanol-2 are filtered off after a certain time and dried, m.p. . 111-112°C.

b) The dibenzyl compound obtained under a) is dissolved in the 10-fold amount of methanol and catalytically debenzylated after

addition of palladium/charcoal. After absorption of the calculated amount of hydrogen, the catalyst is suctioned off, the solvent is distilled off in a vacuum, the residue is dissolved in alcohol, and the calculated amount of ethereal hydrochloric acid is added. The hydrochloride of 1-[2-(4-hydroxyphenyl)-2-hydroxy-ethylamino]-3-(4-carbamido-phenoxy)-propanol-2 crystallizes out. Extraction and drying are carried out in a drying cabinet with forced air circulation. Melting point 179-180°C.

Example 8

1-[ 2-( 4- hydroxyphenyl)- 2- hydroxy- ethylamino]- 3- phenoxy-propanol- 2- fumarate

10.2 g of 4-benzyloxy-N-[(2-hydroxy-3-phenoxy)-propyl]-N-benzyl-mandelic acid amide are dissolved in 200 ml of absolute tetrahydrofuran. While stirring and simultaneously introducing nitrogen, 10 g are added

lithium aluminum hydride. Boil for 5 hours under reflux cooling, cool and split excess lithium aluminum hydride by slow addition of water. Decant off and evaporate to dryness. The residue is taken up in methanol and catalytically debenzylated after addition of palladium/charcoal. After absorption of the calculated amount of hydrogen, the catalyst is sucked off, evaporated in a vacuum, the residue is taken up in a little alcohol and a hot alcoholic solution with the calculated amount of fumaric acid is added. On cooling, the fumarate of 1-[2-(4-hydroxyphenyl)-2-hydroxy-ethylamino]-3-phenoxy-propanol-2 (m.p. 186°C) is obtained.

Example 9

1- [ 2- ( 3, 4- dichlorophenyl)- 2- hydroxy- ethylamino]- 3- phenoxy- propanol-2- formate

A solution of 6 g of 3-[2-(3,4-dichlorophenyl)-2-hydroxy-ethyl]-5-phenoxymethyloxazolidinone in 50 ml of ethanol, which to-

add 10 g of potassium hydroxide and 20 ml of water, heat for 30 minutes under reflux. After cooling, the alcohol is distilled off in a vacuum. The aqueous phase is extracted twice with ether, the ether phase is washed with water and dried over magnesium sulphate. After cooling the ether, the residue is taken up in a little ethanol and formic acid and ether are slowly added. The formate crystallizes out colourlessly.

Example 10

1-( 2- phenyl- 2- hydroxy- ethylamino)- 3-( 2- cyanophenoxy)- propanol- 2-hydrochloride

Dissolve 2 g of 1-(2-phenyl-2-hydroxyethyl)-azetidinol-3 in

15 ml of benzyl alcohol and 1.25 g of 2-cyanophenol and 0.1 g of potassium hydroxide are added. While stirring, heat for 5 hours to approx. 140°C. After cooling, ether is added, and shaking is carried out three times with 15 ml of 2N hydrochloric acid each time. The aqueous phase is washed with ether and made alkaline with sodium hydroxide. The basic components are taken up in ether and washed with water. The organic phase is dried over magnesium sulphate, and then the ether is distilled off. The remaining basic residue is dissolved in ethyl acetate and ethereal hydrochloric acid is added to a slightly acidic reaction. The hydrochloride is recovered as a colorless crystal.

Claims (1)

Analogy method for the preparation of therapeutic active 2-phenyl-2-hydroxyethylamine derivatives with the formula where R^ means hydrogen, halogen, hydroxy, amino, lower alkyl, lower alkoxy or lower alkanoylamido, R 2 means hydrogen, hydroxy, lower alkyl, lower alkoxy or carboxamido, R^ means hydrogen or halogen, lower alkyl or lower alkoxy, R^ means hydrogen, methyl or ethyl, and R,, and Rg mean hydrogen, lower alkyl, lower alkoxy, cyano, carboxamido or lower alkylenecarboxamido, in the form of racemates, racemate mixtures and salts thereof, characterized in that one a) from a compound with the formula where R^, R4, R^ and Rg have the above meaning, and R^ means hydrogen or an arylmethyl residue, Rg means R1 or a hydroxy or amino group which is substituted with a hydrogenolytically or hydrolytically cleavable protecting group, Rg means R2 or a hydroxy group which is substituted with a hydrogenolytically or hydrolytically cleavable protecting group, in that at least one of the residues R_ to RQ means or contains a protecting group, cleaves off the protecting group resp. the protecting groups hydrogenolytically or hydrolytically, or b) in a compound of the formula where R^-Rg has the meaning given above, and where one of the radicals Y and Y<*> means the group -CO-, and the other means -CHOH-, reduces the carbonyl group, or c) reacts a compound with the formula where R 1 -R 4 have the meaning given above, with a compound of the formula where R5 and Rg have the meaning indicated above, or d) reduces a Schiff base with the formula respectively KJ where R-j-Rg has the above meaning, with hydrogen and common hydrogenation catalysts or with complex hydrides, and cleaves off any protective groups, or e) reduces acid amides with the formula respectively where R,-R, have the meanings given above, 1 6 with complex hydrides, or f) hydrolyzes an oxazolidinone or oxazolidine with the formula respectively where R-,-R^ have the meanings indicated above, and 1 6 where R is CO or CHR' where R' is C^C-j-alkyl or aryl, or g) reacts an azetidinol with the formula where R^-R^ have the meanings given above, with a phenol of the formula where Rj. and Rg has the above meaning, in the presence of an alkali hydroxide, and optionally transfer the first formed bases of formula I by usual methods to salts or convert compounds of formula I obtained as salts to salts of other acids or to free bases.