HRP920925A2 - Aminopropanol derivatives of 3-(3-hydroxyphenyl)-1-propanone compounds, process for the preparation thereof; pharmaceutical compositions containing them - Google Patents

Description

The field of technology

The invention is from the field of synthesis of organic compounds. The designation of the invention according to the International Classification of Patents is C07C 93/06; C07D 295/08; A61K 31/13; A61K 31/395.

Technical problem

The invention solves the technical problem of the procedure for obtaining new aminopropanol derivatives of 3-(3-hydroxyphenyl)-1-propanone compounds and their physiologically acceptable salts. The compounds of the invention are useful anti-arrhythmic agents which, compared to the compounds of the prior art, have better activity with reduced toxicity.

State of the art

German patent No. 2 001 431 describes the preparation of 2-2'-hydroxy-3'-alkyl-aminopropoxy)-β-phenyl-propiophenone of the general formula:

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and their addition salts with acids. Although these compounds and their salts are pharmaceutical substances, only the n-propylamino compound (propafenone) has an anti-arrhythmic effect.

European application EP-A-0 074 014 describes the preparation of 2-2'-hydroxy-3'-(1,1-dimethylpropylamino)-propoxy-β-phenyl propiophenone (dipraphenone) and its addition salts with acids. Diprafenone is an anti-arrhythmic agent.

European patent application EP-A-0 075 207 describes aminopropanol derivatives of the general formula:

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and their physiologically acceptable addition salts with acids. Typical examples of R 1 -R 4 include hydrogen atoms or alkyl groups, and n has a value of 1, 2 or 3. These compounds are pharmaceutical substances.

Description of the solution

This invention relates to a process for obtaining new aminopropanol derivatives of 3-(3-hydroxyphenyl)-1-propanone compounds of general formula I:

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and their physiologically acceptable addition salts with acids. The invention also includes pharmaceutical preparations containing compounds of the general formula (I) or their addition salts with acids and a process for their preparation.

In the general formula (I), R1 and R2 are the same or different and represent hydrogen atoms, alkyl, cycloalkyl, alkenyl, or hydroxyalkyl groups with up to 6 carbon atoms, alkoxyalkyl, alkylthioalkyl or dialkylaminoalkyl groups with up to 9 carbon atoms, or phenylalkyl or phenoxyalkyl groups with a maximum of 6 carbon atoms in the alkyl part, whereby the phenyl group can be substituted if necessary with an alkyl or alkoxy group with a maximum of 3 carbon atoms, or R1 and R2 can, together with the nitrogen atom to which they are attached, form a saturated heterocyclic ring with 5 to 7 atoms which may be substituted with one or two phenyl and/or hydroxy groups if necessary and which may contain, as an additional heteroatom in the ring, an oxygen atom or a nitrogen atom which may if necessary be substituted with an alkyl group from 1 to 3 carbon atoms or a phenyl group. R3 represents a hydrogen atom, an alkyl group with a maximum of 3 carbon atoms, a fluorine, chlorine or chromium atom, a hydroxyl group or an alkoxy group with a maximum of 6 carbon atoms. R4 represents a hydrogen atom, an alkyl group with a maximum of 6 carbon atoms, or R4 together with a phenyl group attached to it can represent part of a condensed ring system with a maximum of 18 carbon atoms, n is an integer with values from 1 to 5.

The procedure for obtaining these compounds of the general formula (I) and their addition salts with acids consists in the reaction of the phenol ether of the general formula II:

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with an amine of the general formula:

HNR1R2 (III)

wherein R1, R2, R3, R4 and n have the above meanings.

If necessary, the obtained compound of the general formula (I) can be converted into an acid addition salt by reaction with an acid. The reaction can, for example, take place according to the method described in European patent 0 074 014.

The reaction is carried out at temperatures ranging from 10 to 120°C, at atmospheric pressure or in a closed container at elevated pressure.

The starting materials of formulas (II) and (III) can react without a diluent or solvent. The reaction is, however, preferably carried out in the presence of an inert diluent or solvent, such as a lower alcohol with 1 to 4 carbon atoms, for example methanol, ethanol or propanol, preferably isopropanol or ethanol, lower saturated dialkyl ethers, dialkylglycol ethers or cyclic ethers, such as which diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, benzene hydrocarbons, such as benzene itself or an alkylbenzene, especially toluene or xyol, or an aliphatic hydrocarbon such as hexane, heptane or octane, dimethylsulfoxide, or in the presence of water or mixture of water with the mentioned solvents.

When used in excess, the amine of formula (III) itself may constitute a suitable diluent or solvent.

Completion of the reaction depends on the reaction temperature and is generally achieved in 2 to 15 hours. The reaction product can be obtained in the usual way, for example by filtering the diluent from the reaction mixture. The obtained compound is purified in the usual way, for example by recrystallization from a solvent, by conversion into an acid addition salt or by column chromatography.

Phenyl ether of the general formula (II) can be obtained by alkylating 3-hydroxy-β-phenylpropiophenone of the general formula:

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with epihalohydrin. R 3 and R 4 have the meanings as defined above. Examples of epihalohydrins are epichlorohydrin, epibromhydrin and epiiodohydrin.

The reaction of the compound of formula (IV) in which the starting material of formula (II) is obtained is effectively carried out at a temperature of 0 to 120°C and at normal pressure, or in a closed vessel at elevated pressure. Suitable solvents or diluents are lower aliphatic ketones such as acetone, methylethyl ketone or methylisobutyl ketone, lower alcohols with 1 to 4 carbon atoms such as methanol, ethanol, propanol or butanol, lower aliphatic or cyclic ethers such as diethyl ether, tetrahydrofuran or dioxane, dialkylformamides such as dimethylformamide or diethylformamide, or dimethylsulfoxide or hexamethylphosphoric acid triamide or an excess of alkylating agent.

The reaction is preferably carried out in the presence of a base as an acid binding agent. Suitable bases are alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides or alkali metal alcoholates, especially sodium and potassium compounds, basic oxides such as aluminum oxide or calcium oxide, organic tertiary bases such as pyridine, lower trialkyl amines such as trimethyl amine or triethyl amine, or piperidine. The bases can be used in catalytic or stoichiometric amounts or in a small excess compared to the alkylating agent used.

3-Hydroxy-O-phenylpropiophenone preferably reacts with epichlorohydrin or epibromohydrin in a polar, aprotic solvent, especially in dimethylsulfoxide, at temperatures in the range of 0 to 50°C and in the presence of at least one molar equivalent of a base, especially sodium hydride, relative to the agent for alkylation.

The starting compound of the general formula (IV), i.e. 3-hydroxy-β-phenylpropiophenone, is known, as is the procedure for its preparation.

The compound of formula (I), obtained by the process according to the invention, can, if necessary, be converted into its addition salt with an acid, preferably into a salt with a physiologically acceptable acid. Common physiologically acceptable inorganic and organic acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other suitable acids are described, for example, in Fortschritte der Arzneimittelforsohung, vol. 10, p. 224-225, Birkhaeuser publishers, Basel und Stuttgart, 1966 and in Journal of Pharmaceutical Sciences, vol. 66, p. 1-5 (1977). The preferred acid is hydrochloric acid.

Addition salts with acids are usually prepared in a conventional manner by mixing the free base or a solution thereof with the appropriate acid or solutions thereof in an organic solvent, for example in a lower alcohol such as methanol, ethanol, n-propanol or isopropanol, in a lower ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or in an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the mentioned solvents can also be used to achieve better crystal formation. moreover, pharmaceutically acceptable aqueous solvents of acid addition salts of compounds of formula (I) can be obtained in aqueous acid solution.

Addition salts of compounds of formula (I) with acids can be converted to the free base in a manner known per se, for example with alkalis or with ion exchangers. Furthermore, salts can be obtained from the free base by reaction with inorganic or organic acids, especially with those suitable for the formation of therapeutically useful salts. These, as well as other salts of the new compound, such as the picrate, can also be used as a way to purify the free base, in which case the free base is first converted into a salt, then separated, and the base is released from the salt again.

Those compounds in which NR1R2 represents a tert.-pentylamino, n-propylamino, isopropylamino, tert.-butylamino, piperidino or cyclohexylamino group, R3 is hydrogen or a methoxy group in position 4. R4 is a methyl or methoxy group or together with the phenyl group to which it is attached represents a 2-naphthyl group, and n has a value of 1, 2 or 3.

The most preferred compounds are:

1-(3,4,5,-Trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert-butylamino-propoxy)-phenyl]-1-propanone hydrochloride (Example 8);

1-(2,4,6,-Trimethylphenyl)-3-[3'-(2-hydroxy-3-tert-butylamino-propoxy)-phenyl]-1-propanone hydrochloride (Example 17);

1-(3,4-Dimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopropylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride (Example 23);

1-(3,4,5,-Trimethoxyphenyl)-3-[3'-(2-hydroxy-3-cyclohexylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride (Example 32);

1-(2-Naphthyl)-3-[3'-(2-hydroxy-3-n-propylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride (Example 48).

The present invention also includes pharmaceutical preparations for oral, rectal, intravenous or intramuscular administration, which, apart from the usual carriers or diluents, contain as an active ingredient the compound of formula (I) or its acid addition salt. The invention also includes the use of new compounds and their physiologically active salts in the treatment of heart rhythm disorders.

Pharmaceutical preparations from the invention are obtained in the usual way, with conventional solid or liquid carriers or diluents and with conventional pharmaceutical adjuvants, in suitable dosage forms in accordance with the desired method of administration. Preferred preparations are unit dosage forms for oral administration. Such pharmaceutical forms are, for example, tablets, coated tablets, dragees, capsules, pills, powders, solvents or suspensions or depot preparations.

Parenteral preparations, such as injectable solvents, are also suitable. For example, one more pharmaceutical form should be mentioned - suppositories.

Suitable tablets can, for example, be obtained by mixing the active ingredient with known excipients, for example with inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, with tablet disintegrating agents such as corn starch or alginic acid, with with binders such as starch or gelatin, wetting agents such as magnesium stearate or talc and/or with means for achieving a depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets can have several layers.

Dragees are made appropriately by coating cores made in a manner analogous to tablets with preparations commonly used for coating dragees, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The coating of the dragee can also consist of several layers, in which case the auxiliary means described for tablets will be used.

Solvents or suspensions containing the active ingredient of the invention may, in addition to it, also contain flavoring agents such as saccharin, cyclamate or sugar and, for example, flavoring agents such as vanilla or orange extract. Moreover, these preparations may contain auxiliary suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxy-benzoates. Capsules containing the active ingredient can, for example, be obtained by mixing the active ingredient with an inert carrier such as lactose or sorbitol, and filling the mixture into gelatin capsules.

Suitable suppositories can, for example, be obtained by mixing the active ingredient with suitable carriers, such as neutral fats or polyethylene glycol, or their derivatives.

For human administration, the unit dose will be:

- from 0.5 to 5 mg/kg for oral administration

- from 0.05 to 2 mg/kg for intravenous administration

- from 0.1 to 3 mg/kg for intramuscular administration

- from 0.5 to 10 mg/kg for rectal administration.

In particular, the antiarrhythmic and β-sympatholytic properties of the compounds of the invention and their physiologically acceptable addition salts with acids make them particularly suitable for the pharmacotherapy of heart rhythm disorders, the treatment of coronary heart diseases and for the prophylaxis of sudden death due to heart disease. The antiarrhythmic efficiency of the compound from the invention was determined both by electrophysiological study on the Purkinje fibers of the dog's heart, and by the ventricular tachycardia in dogs induced by ouabain.

In the following tables (I and II), the compounds of the invention are compared with 3 propafenone (A).

The effect on the contractile strength of the heart was tested on the papillary muscle of guinea pigs. Hemodynamic studies were performed both on healthy dogs and on dogs with acute infarction. One of the important criteria in the following table (I) is the safety factor (S.F.), which is calculated from the ratio of antiarrhythmic efficiency, negative inotropy and specifically greater efficiency at higher frequencies, according to the formula: ratio factor Vmax × (C20 CF/C20 Vmax ). In comparison, the current leading antiarrhythmic agents, propafenone and flecainide, were noted to have S.F. 1.5 and 1.7 respectively.

As an additional criterion, the prematurity factor was established. It characterizes the desired efficacy of the compound of the invention in premature extrasystoles.

The high antiarrhythmic effect was not accompanied by any significant increase in toxicity compared to propafenone (A), as can be seen from the comparison of LD50 values in rats and mice, summarized in Table II.

Table I

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C20 CF: Concentration that reduces papillary muscle contractions by 20%.

C20 Vmax: Concentration that reduces Vmax by 20% at a base cycle length of 1000 milliseconds.

Ratio factor (% of control Vmax at base cycle length of 2000 msec)

Vmax: / (% of control Vmax at 500 msec base cycle length) at C20 Vmax.

Prematurity factor Vmax: (% of control Vmax at premature extrasystoles) / (% of control Vmax at normal heart rate) at Vmax.

S.F.: Safety factor calculated as Ratio Factor Vmax x (C20 CF/C20 Vmax).

Table II

[image] The invention is illustrated by examples.

A) Obtaining starting materials:

Examples

1-(3,4-Dimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone

100 g (0.35 mol) of 3,4-dimethoxy-β-3'-hydroxyphenyl-propiophenone is heated under reflux for 23 hours with 300 ml of epichlorohydrin and 24.2 g (0.175 mol) of potassium carbonate, with stirring. The resulting salt is filtered off, and the remaining solution is evaporated under reduced pressure. The residue is recrystallized from isopropanol. Yield: 109.8 g (91.9%) of the title compound, m.p. 81-84°C.

The following compounds were obtained in the same way:

1-(4-Methoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone,

1-(3,4,5-Trimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone,

1-(2,4,6-Trimethylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone,

1-Phenyl-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-phenyl]-1-propanone,

1-(3,4-Dimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-phenyl]-1-propanone,

1-(3,4,5-Trimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-phenyl]-1-propanone,

1-(2-Methoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-phenyl]-1-propanone,

1-(4-Methylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-phenyl]-1-propanone,

1-(2,4,6-Trimethylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-phenyl]-1-propanone.

Example II

1-(2-Naphthyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-phenyl]-1-propanone

13.1 g (0.04 mol) of 1-(2-naphthyl)-3-(3'-hydroxy-4'-methoxyphenyl)-1-propanone is heated for 5 hours under reflux with 26.3 ml of epichlorohydrin, 90 ml of isopropanol and 1.6 g ( 0.04 moles) of sodium hydroxide. The resulting salt is filtered off, and the remaining solution is evaporated under reduced pressure. The oily residue is used in the next step without purification. Yield: 16.4 g (≈ 100%).

Example III

1-(3-Phenanthrenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone

61.6 g (0.18 mol) of i-(3-phenanthrenyl)-3-(3'-hydroxy-phenyl)-1-propanone is heated for 12 hours under reflux with 105.6 ml of epichlorohydrin, 66 ml of methanol and 7.2 g (0.18 mol) of sodium hydroxide. The resulting salt is filtered off and the remaining solution is evaporated under reduced pressure. The residue is used in the next stage without purification. Yield: 65.2 g (≈ 85.3%).

B) Obtaining the compound according to the invention:

Example 1

1-(3,4-Dirnetoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylaminopropoxy)-phenyl]-1-propanone hydrochloride

27.4 g (0.08 mol) of 1-(3,4-Dimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-propanone and 20.9 g (0.24 mol) of tert.- pentylamine are dissolved in 300 ml of methanol and heated for 4 hours under reflux. The solvent and excess amine are removed under reduced pressure. The oily residue is taken up in methanol and concentrated hydrochloric acid is added to it. After heating and cooling, crystals are obtained which are recrystallized from acetone. Yield: 22.8 g (61.2%) of the title compound, m.p. 117-119°C.

The following compounds were obtained in a similar way (Examples 2 to 51):

2. 1(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 146-147°C.

3. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-morpholinopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 148-149°C.

4. 1-(3,4-dimethoxyphenyl)-3-(3'-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-1-propanone hydrochloride, mp 175-177°C.

5. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert-butylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 179-181°C.

6. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-piperidinopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 141-142°C.

7. 1-(4-Methoxyphenyl)-3-[3'-(2-hydroxy-3-n-propylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 128.5-129.5°C.

8. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 160-161°C.

9. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 119.5-120.5°C.

10. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert-butylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 158-159°C.

11. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 103-105°C.

12. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-piperidino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 158-159.5°C.

13. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-morpholino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 170-171°C.

14. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-butylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 129-131°C.

15. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-isopropylaminopropoxy)-phenyl]-1-propanone semi-oxalate, m.p. 146-148ºC.

16. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-2-n-propylaminopropoxy)-phenyl]-1-propanone hydrochloride, m.p. 84-85°C.

17. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-butylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 123.5-125.5°C.

18. 1-phenyl-3-[3'-(2-hydroxy-3-tert.-pentylaminopropoxy)-4'-methoxyphenyl]-1-propanone semi-oxalate, m.p. 162-164ºC.

19. 1-phenyl-3-[3'-(2-hydroxy-3-isopropylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 157-158°C.

20. 1-phenyl-3-[3'-(2-hydroxy-3-tert.-butylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 158-159°C.

21. 1-phenyl-3-[3'-(2-hydroxy-3-piperidinopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 115-117°C.

22. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 115-116.5°C.

23. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopropylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 128-131°C.

24. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-morpholinopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 158-161°C.

25. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-butylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 168-170°C.

26. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-cyclohexylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 117.5-120.5°C.

27. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 147-148°C.

28. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 126-129°C.

29. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 103.5-106°C.

30. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-n-isopropylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 115-116°C.

31. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-butylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 150.5-152°C.

32. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-cyclohexylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 136.5-138.5°C.

33. 1-(2-Methoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylamino-propoxy)-4'-methoxyphenyl]-1-propanone acetate, m.p. 119-120ºC.

34. 1-(2-rethoxyphenyl)-3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 141.5-143°C.

35. 1-(2-rethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-butylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 166.5-167°C.

36. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylamino-propoxy)-4'-methylphenyl]-1-propanone hydrochloride, m.p. 107.5-109.5°C.

37. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 108-110°C.

38. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-morpholinopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 117-119.5°C.

39. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-tert.-butylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 117-119°C.

40. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-piperidinopropoxy)-methoxyphenyl]-1-propanone hydrochloride, m.p. 138.5-140°C.

41. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-cyclohexylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 134-136°C.

42. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-pentylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 117-118°C.

43. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-piperidino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 119-120°C.

44. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-4'-methoxyphenyl]-1-propanone oxalate, m.p. 121-122°C.

45. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-isopropylarino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 110-111°C.

46. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-morpholino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 154-155°C.

47. 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-tert.-pentylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 130-132°C.

48. 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 142-143°C.

49. 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-isopropylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, m.p. 133-135°C.

50. 1-(3-phenanthrenyl)-3-[3'-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 140-142°C.

51. 1-(3-phenanthrenyl)-3-[3'-(2-hydroxy-3-n-propylamino-propoxy)-phenyl]-1-propanone hydrochloride, m.p. 149-152°C.

Example 52

Procedure for making tablets

a) Ingredients

Compound from Example 1 75.00 g

Microcrystalline cellulose (powder, 50 μm) 15.75 g

Poly-(1-vinyl-2-pyrrolidone) 5.00 g

Hydroxypropylmethyl cellulose 2910 3.75 g

Magnesium stearate 0.50 g

100.00 g

b) Mixing and granulation

The compound from example 1 is diluted if necessary. All substances except magnesium stearate are then mixed in a mixer, in which they are moistened with the required amount of liquid for granulation (for example, water or a mixture of isopropanol-dichloromethane 1:1). The wet mixture is then passed through a suitable sieve, dried in a dryer and sieved again. The dried granulate is then mixed with magnesium stearate in a mixer.

c) Pressing tablets

The mixture prepared under a) is pressed in a tableting press, so that tablets weighing 40 to 400 mg are obtained. The pressing force and the diameter of the tablet are adjusted so that the disintegration time, in a test vessel in accordance with Eur. Pharm., is less than 15 minutes, which provides sufficient mechanical strength of the tablet.

Example 53

Process for making film-coated tablets

A. Ingredients

a) Tablets

(see procedure for making tablets. Example 52)

b) Mixture for coating with firm

The total amount which. is applied from 5 to 20 wt.% of the tablet weight and consists of:

Hydroxypropylmethylcellulose 2910 77%, i

plasticizer Macrogol® 6000 23%.

B. Making tablets

(see procedure for making tablets, Example 52)

C. Production of film-coated tablets

The ingredients of the film coating mixture are dissolved in a suitable solvent (for example in water or a mixture of ethanol/water 70:30). The solution is sprayed in a film coating device over the tablets, which are then dried in a stream of hot air. The film-coated tablets are finally dried in an oven.

Example 54

The process of making dragees

A. Ingredients

a) Dragee core

(see procedure for making tablets)

b) Dragee coating

The total amount applied is 25-100% in relation to the mass of the core, and the composition is:

Sucrose 51.4 %

Talc 24.0 %

Calcium sulfate hemihydrate 10.3%

Starch syrup 5.0 %

Gum arabic 3.9 %

Macrogol® 6000 2.9 %

Titanium(IV) oxide 1.6 %

Finely dispersed silica gel 0.8 %

Sodium dodecyl sulfate 0.1 %

100.0%

B. Production of dragee cores

(see procedure for making tablets)

C. Making dragees

a) solution for coating dragees

Sucrose 47.6 %

Starch syrup 19.1 %

Gum arabic 3.8 %

Distilled water 29.5 %

100.0%

b) composition of the pre-coating mixture

Talc 70.0 %

Calcium sulfate hernihydrate 26.7 %

Finely dispersed silica gel 3.3 %

100.0%

c) Dragee coating - suspension composition

Sucrose 47.8 %

Talc 9.6 %

Calcium sulfate hernihydrate 4.8 %

Gum arabic 3.6 %

starch syrup 3.2 %

Macrogol® 6000 2.9 %

Titanium(IV) oxide 1.6 %

Sodium dodecyl sulfate 0.1 %

Distilled water 26.4 %

100.0 %

Coating of dragee cores

The dragee cores are first moistened in a rotating container with the dragee coating solvent and then dusted with a sufficient amount of pre-coating mixture until they roll freely again. After drying the cores, this procedure is repeated. After that, the cores are dried in a drying oven and coated in layers with a dragee coating suspension until the desired weight of the dragee is reached. The cores must be dried after applying each layer.

Example 55

Procedure for making capsules

A. For a dose of the active ingredient of 75 mg or more:

1. Ingredients

Compound from Example 2 75.00 g

Microcrystalline cellulose (powder, 50 μm) 16.25 g

Poly-(1-vinyl-2-pyrrolidone) 5.00 g

Hydroxypropylmethyl cellulose 2910 3.75 g

100.00 g

2. Mixing and granulation according to Example 52 under b).

3. Filling granules into capsules

The granulate is filled, using an encapsulating machine, into hard gelatin capsules of size 3, 2, 1 or 0, whereby the amount filled into each capsule depends on the desired dose of the active ingredient.

B. For a dose of the active ingredient of 30 to 75 mg:

1. Ingredients

Compound from Example 3 30.00 - 75.00 g

Microcrystalline cellulose (powder, 50 μm) 61.25 - 16.25 g

Poly-(1-vinyl-2-pyrrolidone) 5.00 g

Hydroxypropylmethyl cellulose 2910 3.75 g

100.00 g

The sum of the amounts of the active ingredient and microcrystalline cellulose should always be 91.25 g. The amount of the active ingredient is a thousand times the amount of the unit dose.

2. Mixing and granulation according to Example 52 under b).

3. Filling granules into capsules

Each of the size 3 or 2 hard gelatin capsules is filled with 100 mg of granulate using an encapsulation machine.

Example 56

Procedure for making ampoules

1. Ingredients

Compound from Example 6 1.5 g

Water for injections up to 100.0 ml

2. Solvent preparation

90% of the required amount of water is placed in the container, so the active compound dissolves with heating. The final volume is achieved by adding the necessary residual water to the solvent after cooling.

3. Filling the solvent into ampoules

The finished solvent is filled into glass ampoules, where the amount depends on the desired individual dose. The ampoules are then sealed by fusing.

4. Sterilization

Ampoules are sterilized by exposure to steam at a temperature of 120°C for 20 minutes.

Example 57

Procedure for making suppositories

a) Ingredients

Compound from Example 50 30-200 mg

Hard fat (melting point 35-36.5°C) up to 2000 mg

b) Preparation of the solution containing the active ingredient

The amount of solid fat required for a certain number of suppositories is melted in a water bath at 40°C. The active ingredient is passed through a 0.8 mm sieve and mixed with the solution to obtain a suspension.

c) Making suppositories

The solution is left to cool to 37-38°C and, with constant stirring, is filled into suppository molds in such quantities that the mass of one suppository is 2000 mg. The mold is sealed after the suppository has hardened.

Claims (2)

1. Procedure for obtaining aminopropanol derivatives of 3-(3-hydroxyphenyl)-1-propanone compounds of the formula: [image] in which R1 and R2 are the same or different and represent hydrogen atoms, C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl or hydroxy-C1-6alkyl, alkoxyalkyl, alkylthioalkyl or dialkylaminoalkyl groups with a maximum of 9 carbon atoms each, or phenyl-C1-6alkyl or phenoxy-C1-6alkyl, whereby the phenyl group can be substituted with a C1-3alkyl or C1-3 alkoxy group if necessary, or R1 and R2, together with the nitrogen atom to which they are attached, form a saturated heterocycle with 5 -7 members which is optionally substituted with one or two phenyl and/or hydroxy groups and which may also, if necessary, contain an additional hetero atom such as oxygen or nitrogen, whereby nitrogen may be optionally substituted by C1-3 alkyl or phenyl group; R 4 is hydrogen, C 1-3 alkyl, fluorine, chlorine, bromine, hydroxy or C 1-6 alkoxy; R4 is hydrogen, C1-3 alkyl, fluorine, chlorine, bromine, hydroxy or C1-6 alkoxy, or R4, together with the phenyl group to which it is attached, represents part of a condensed aromatic system with a maximum of 18 carbon atoms; n has a value from 1 to 5; and their addition salts with acids, characterized by the fact that the phenol ether of the general formula: [image] in which R3, R4 and n are as defined above, reacts with an amine of the general formula: HNR1R2 (III) wherein R1 and R2 are as defined above, wherein the reaction is carried out at temperatures from 10 to 120°C, preferably at temperatures from 50 to 120°C at atmospheric pressure or in a closed vessel at increased pressure, the reaction is carried out without diluents or solvents, however preferably carried out in the presence of internal diluents or solvents, such as lower alcohols with 1 to 4 carbon atoms, such as methanol, ethanol or propanol, preferably ethanol or isopropanol, lower saturated dialkyl ether, dialkyl glycol ether or cyclic ether, such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, benzene hydrocarbons, such as benzene itself or an alkyl benzene, especially toluene or xylene, or aliphatic hydrocarbons, such as hexane, heptane or octane, dimethylsulfoxide or in the presence of water or mixtures of the mentioned solvents, the amine of formula III when used in the tip can also be a suitable diluent or solvent, during 2 to 15 hours, after which the obtained p if necessary, the product is converted into its addition salt by reaction with acid. 2. The method according to claim 1, characterized in that NR1R2 represents tert-pentylamino, n-propylarino, 1,1-dimethylpropylamino, morpholino, isopropylamino, tert-butylamino, pyrrolidino or cyclohexylamino; and R 4 , together with the phenyl group to which it is attached, represents a naphthyl or phenanthrenyl group.