HU206868B - Process for producing 3,4-dihydroxy-phenetyl-amine derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to novel 3,4-dihydroxyphenethylamine compounds of formula (I) and their physiologically acceptable acid addition salts and solvates, and to pharmaceutical compositions containing them. In which R 1 is halogen or methyl, ethyl, n-propyl or n-butyl, R 2 ', R 3, R 4 and R 5 are hydrogen or one or two of them are methyl or ethyl, R 6 is halogen or 1- C 1 -C 4 alkyl, (I) X is C 5 -C 7 alkylene optionally substituted with C 1-4 alkyl or hydroxy, optionally containing one or two double bonds, or optionally interrupted by an oxygen or sulfur atom or sulfonyl group. The compounds of the present invention reduce total peripheral vascular resistance, increase cardiac output, and reduce blood pressure. They are suitable for the prevention or treatment of renal failure and cardiovascular irregularities. EN 206 868 B Scope of the description: 14 pages (including 2 sheets)

Description

The present invention relates to 3,4-dihydroxyphenethylamine derivatives of the formula (I) and their physiologically acceptable acid addition salts and solvates, and to pharmaceutical compositions containing them.

In the general formula (I)

R 'is halogen, methyl, ethyl, n-propyl or n-butyl,

R ² , R ³ , R ⁴ and R ⁵ are hydrogen or one or two of these are methyl or ethyl,

R ⁶ is halogen or C 1-4 alkyl,

X is a C 5 -C 7 alkylene chain optionally substituted with C 1 -C 4 alkyl or hydroxy, which may be optionally substituted with one or two double bonds, or optionally interrupted by oxygen or sulfur or by a parent phenyl group.

Where optical isomers exist, the formula (I) includes all enantiomers, diastereomers, mixtures thereof, including racemates. Compounds in which the alkylene chain X contains a double bond may exist in the cis or trans configuration.

Alkyl groups may be linear or branched. The halogen atom may be fluorine, chlorine, bromine or iodine. X can be - (CH ₂ ) ₅ -, - (CH ₂ ) ₆ -, - (CH ₂ ) ₇ -, - (CH ₂ ) ₃ O (CH ₂ ) ₃ -,

- (CH ₂ ) ₄ O (CH ₂ ) ₂ -, - (CH ₂ ) ₃ CHOH (CH ₂ ) ₃ -, - (CH ₂ ) ₂ CH Me (CH ₂ ) ₃ -, (CH ₂ ) ₃ S (CH ₂ ) ₃ -, - (CH ₂ ) ₃ SO ₂ (CH ₂ ) ₃ -, -CH ₂ CH = CH (CH ₂ ) ₃ -, - (CH ₂ ) ₂ CH = CH (CH ₂ ) ₂ - and - CH ₂ CH = CHCH = CHCH ₂ -.

Preferred compounds of the present invention are those wherein R ¹ is chloro or more preferably C 1-2 alkyl. especially ethyl.

R ² and R ³ , which may be the same or different, preferably represent hydrogen or methyl, or more preferably R ² , R ³ , R ⁴ and R ⁵ are each hydrogen.

Preferably X is a C 6 or C 7 alkylene chain, most preferably - (CH 2 - g). Also preferred are compounds in which X is - (CH ₂ ) ₃ S (CH ₂ ) ₃ - or - (CH ₂ ) ₃ SO ₂ (CH ₂ ) ₃ -.

R ⁶ is preferably a chlorine atom or a methyl or ethyl. Particularly preferred are those compounds wherein ^R6 is methyl or ethyl, most preferably methyl.

The physiologically acceptable acid addition salts of the compounds of formula (I) according to the invention are salts with organic or inorganic acids. Examples of such salts are the hydrochlorides, hydrobromides, sulfates, phosphates, benzoates, p-toluenesulfonates, methanesulfonates, sultanates, ascorbates, tartrates, citrates, maleates, salicylates, fumarates, stearates, stearates, stearates.

Preferred acid addition salts are the hydrochlorides and the hydrobromides.

The invention also includes solvates, in particular hydrates of the compounds of formula (I).

Animal studies have shown that the compounds of the present invention reduce, at low doses, total peripheral vascular resistance, increase cardiac output and lower blood pressure. The compounds of the invention have a long duration of action and are active after oral administration.

It has been found that the compounds of the present invention stimulate vascular dopamine receptors rather than neuronal dopamine receptors.

The compounds of the present invention also stimulate β-adrenoceptors.

Of particular interest in the compounds of this invention are 4- [2- {6- [2- (3,4-dihydroxy-2-methyl-phenyl) -ethylamino] -hexylamino} -ethyl] -3-ethyl- 1,2-dihydroxybenzene and its physiologically acceptable salts, i.e., its hydrobromide and its hydrochloride.

The compounds of the present invention are useful in the treatment and prevention of renal failure and cardiovascular disorders such as hypertension, ischemic heart disease or heart failure such as acute or hypertensive heart failure.

The compounds of formula (I) and their physiologically acceptable acid addition salts and solvates of the present invention may be formulated for administration in conventional manner. The invention therefore also relates to a process for the preparation of a medicament for human or veterinary use comprising as active ingredient a compound of formula I or a physiologically acceptable salt or solvate thereof. These pharmaceutical compositions are formulated in conventional manner by admixing the active ingredient with one or more physiologically acceptable carriers or other excipients.

The pharmaceutical compositions of the present invention may be formulated for oral, buccal, parenteral or rectal administration or for inhalation or inhalation. Oral administration is preferred.

The daily dosage of the pharmaceutical compositions of the present invention for treatment of an adult human is preferably from 5 mg to 3 g, more preferably from 25 mg to 1 g, which may be administered in 1 to 4 doses, depending on the mode of administration and the condition of the subject.

The compounds of formula (I) and their physiologically acceptable acid addition salts prepared by the process of the present invention may also be administered in combination with other therapeutic agents, such as beta-blockers, diuretics, angiotensin converting enzyme inhibitors, inotropic agents and antiemetic agents.

In accordance with the present invention, the compounds of formula I, wherein R ² -R ⁶ and X are as defined above, unless otherwise indicated, may be prepared by a variety of methods. It should be noted that some of the processes described below are starting materials from other groups2

They may also be affected as desired in the final product, such as, for example, reduction processes, in particular hydrogen and a metal catalyst, for the reduction of compounds containing an ethylene or acetylene bond. Care should therefore be taken to use, as is customary in the art, reagents that do not affect such groups, or to carry out the reaction steps in the order in which they are eliminated when present in the starting material.

Compounds of formula I wherein R ² -R ⁶ and

X is as defined above - they can be prepared by: a) reduction of compounds of formula II. In the general formula (II)

Ar ¹ Ar ¹ is a group of formulas (a) and (b) wherein R ¹ and R ⁶ are as defined for formula (I) and R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are hydrogen or a protecting group,

R ⁷ and R ⁸ are hydrogen

X 1 is a ^C 3 -C 5 alkylene chain which may be optionally substituted by C 1 -C 4 alkyl or hydroxy, or may optionally contain one or two double bonds or optionally interrupted by an oxygen or sulfur atom or a sulfonyl group,

^{Two of} Z ¹ , Z ² , Z ³ and Z ⁴ are oxygen, two together with the carbon atom are -CH ₂ -, with the proviso that either Z ¹ and Z ⁴ or Z ² and Z ³ are oxygen.

After the reduction, the protecting groups are optionally removed.

Suitable reducing agents are those commonly used for reducing amides. Suitable reducing agents are, for example, hydrides, such as lithium aluminum hydride, alanes or diboranes. Suitable solvents are ethers such as tetrahydrofuran or dioxane or a mixture of hydrocarbons (e.g. benzene) and ethers (e.g. diethyl ether). The reduction is generally carried out at a temperature of from -20 ° C to + 100 ° C, preferably from 0 ° C to 70 ° C.

The compounds of formula (I) may also be prepared by (b) carrying out an alkylation reaction with a compound of formula (III) and (IV) and an alkylating agent capable of introducing X and deprotecting. In the formulas, Ar and Ar * are as defined above, R ⁷ , R ⁸ , R ² , R ³ , R ⁴ and R '' are hydrogen, R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are protecting groups.

Thus, in a preferred embodiment of the process of the invention, the compounds of formula (III) and (IV) are reacted with an alkylating agent of formula L-X-L, wherein L is an easily removable atom or group.

This reaction is preferably carried out in a solvent in the presence of a base such as potassium carbonate or sodium hydride at temperatures between -20 ° C and + 100 ° C. Suitable solvents are, for example, ethers, e.g. tetrahydrofuran or dioxane; alcohols, e.g. ethanol; acetonitrile; substituted amines, e.g. N, N-dimethylformamide and hydrocarbons, e.g. benzene.

In the alkylating agent L-X-L, for example, L can be a halogen atom, e.g. chlorine, bromine or iodine; or an alkylsulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy.

In another preferred embodiment of the process of the invention, the compounds of formula (III) and (IV) wherein R ⁷ and R ⁸ are hydrogen may also be alkylated under reducing conditions with a compound of formula OHC-X'-CHO, wherein X ¹ has the meaning given above.

Suitable reducing agents are alkali metal or alkaline earth metal borohydrides or cyanoborohydrides such as sodium borohydride or cyanoborohydride. These reactions are carried out in a solvent such as an alcohol, e.g. ethanol or propanol. The reduction may also be carried out using hydrogen in the presence of a metal catalyst such as platinum, platinum oxide, palladium or radium in an alcohol, e.g. ethanol, one ether, e.g. dioxane or an ester, e.g. ethyl acetate. The catalyst used may be on a support, e.g. a carbon supported catalyst or a homogeneous catalyst, e.g. tris-triphenylphosphine rhodium chloride. The reduction is generally carried out at a temperature between -20 ° C and + 100 ° C, preferably between 0 ° C and 50 ° C. Under certain circumstances, any intermediate imine compound which may be formed may be isolated. Under the above conditions, the imine is reduced and then deprotected to give the compound of formula (I).

The compounds of formula (I) may also be prepared by: (c) protecting at least one of the compounds of formula (V) wherein R ⁷ , R ⁸ , are hydrogen or a protecting group, R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , and R ^2, R ^3, R ⁴ and R ⁵ is hydrogen, is deprotected.

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² may be any conventional protecting group, for example those described in "Protective Groups in Organic Chemistry", Ed. J.E. W. McOmie (Plenum). Press 1975). Suitable hydroxyl protecting groups represented by R ⁹ , R ¹⁰ , R ¹¹ and R ¹² include, for example, alkyl groups such as methyl or methoxymethyl, arylmethyl groups such as benzyl, diphenylmethyl or triphenylmethyl. or heterocyclic groups such as tetrahydropyranyl or acyl groups such as acetyl. The substituents R ⁹ and R ¹⁰ and / or R ¹¹ and R ¹² may also be taken together to form a hydroxyl protecting group, for example an alkylene chain, e.g. methylene chain. Examples of amine protecting groups represented by R ⁷ and R ⁸ include trifluoroacetyl, tert-butoxycarbonyl, trifluoroethoxycarbonyl, benzyl, benzyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl. -groups.

The protecting groups R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² may be removed by conventional means. For example, an arylmethyl group such as a benzyl group may be cleaved by hydrogenolysis in the presence of a noble metal catalyst (e.g. palladium on carbon); one hydroxy-protecting alkyl group and two hydroxy-protecting alkylenedioxy groups can be cleaved under acidic conditions, for example, with hydrogen bromide or boron tribromide,

The acyl group of HU 206 868 B can be removed by hydrolysis under basic conditions.

If desired, the compound of formula (I) obtained by any of the above methods may be converted into a physiologically acceptable salt by treatment of the free base with a suitable acid by conventional methods.

Physiologically acceptable salts may also be prepared from other salts of the compounds of formula (I), including other physiologically acceptable salts.

The enantiomers of the compounds of the invention may be prepared by resolution of the corresponding racemic compounds by conventional means, for example, by optically active resolving acid, e.g.

S. H. Wilen.

The methods described herein for the preparation of compounds of formula I can be used as the last major step in a production sequence. The same general methods can be used to prepare the desired compound to introduce the desired moiety in an intermediate step, and it is obvious that these general methods can be combined in different ways in such multi-step processes.

The compound of formula (II) may be formed by one or more acylation reactions which include the reaction of a suitable amine with a suitable acylating agent. In the following, Z ¹ , Z ² , Z ³ , Z ⁴ and X * have the same meaning as given in formula II, unless otherwise stated.

For example, compounds of formula II wherein Z ¹ is oxygen may be prepared by reacting a compound of formula IV or a reactive derivative thereof with a compound of formula VII wherein X ² is a C 4 -C 6 alkylene chain which is it may be substituted by an alkyl or hydroxy group, or may optionally contain one or two double bonds, or optionally interrupted by an oxygen or carbon atom or a sulfone group.

Compounds of formula (II) wherein Z ² is oxygen may be prepared by reacting a compound (III) with a compound of formula (VIII) or a reactive derivative thereof.

Compounds of formula (II) wherein Z ³ is oxygen may be prepared by reacting a compound of formula (IV) with a compound of formula (IX) or a reactive derivative thereof.

Compounds of formula (II) wherein Z ⁴ is oxygen may be prepared by reacting a compound (X) with a compound of formula (XI) or a reactive derivative thereof.

Compounds of formula (II) wherein Z ² and Z ³ are oxygen may be prepared by reacting a compound of formula (XII) or a reactive derivative thereof with a compound of formula (III) or (IV).

Compounds of formula (II) wherein Z ¹ and Z ⁴ are oxygen may be prepared by reacting a compound of formula (VI) and (IX), or a reactive derivative thereof, with a compound of formula (XIII).

Suitable reactive derivatives of the carboxylic acids used in the acylation reactions described above are e.g. acid halides, e.g. acid chlorides or bromides or anhydrides or active esters. Acylation with an acid halide is an acid acceptor such as an organic base, e.g. tertiary amine, e.g. triethylamine or an inorganic base, e.g. in the presence of potassium carbonate. Acylation using a free acid is preferably a coupling agent, e.g. carbodiimide such as N, N'-dicyclohexylcarbodiimide, a carbonyl compound such as. N, N'carbonyldiimidazole or azide such as. in the presence of diphenylphosphoryl azide. The reaction is preferably carried out in an anhydrous medium, e.g. in a halogenated hydrocarbon, e.g. dichloromethane or an amide, e.g. in dimethylformamide. The acylation is carried out at a temperature of -20 to +50 ° C.

Many of the compounds of formula VI are known and can be prepared by conventional methods. Other compounds of formula (VI) may be prepared by hydrolyzing a compound of formula (XIV) under conventional reaction conditions, for example, under basic conditions.

Compounds of formula (VII) wherein Z ⁴ is oxygen may be prepared by reacting a compound of formula (XI) or a reactive derivative thereof with a compound of formula (XIII), e.g. In the presence of?,? - carbonyldiimidazole as described above.

Compounds of formulas (III), (IV), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV), as well as LXL and OHC-X'- Alkylating agents of the formula CHO are either known compounds or may be prepared in a manner analogous to that described for the preparation of known compounds. Some suitable methods are described in the examples.

Compounds of formula (V) may be prepared by methods (A) and (B).

The following examples illustrate the process of the invention. In the examples, the temperature is given in ° C. The solvents were dried over magnesium sulfate or sodium sulfate. Thin layer chromatography (t.l.c.) was performed on silica sheets. Flash column chromatography (FCC) was performed on silica (Merck 9385).

Abbreviations used: THF - tetrahydrofuran; Pd-C - palladium on carbon; PdO-C - palladium oxide on carbon.

/. Intermediate (2-Ethyl-3,4-dinethoxy-phenyl) -acetonitrile

2. Intermedier

2- (2-Ethyl-3,4-dimethoxy-phenyl.) - ethane-am.in liÍdroklorid

3. Intermedier

2- [2-Ethyl-3,4-bis (phenyl-ethoxy) -phenyl] -ethanamine hydrochloride: Intermediate 7 (10g) in anhydrous THF (84 ml) was added over 5 minutes at 0 ° C. bo4

RH-THF complex and heated at reflux for 6 hours under nitrogen. The mixture was cooled, methanol (25 mL) was added and the mixture was refluxed for 30 minutes, cooled, acidified with 2N hydrochloric acid and kept at 60 ° C for 1 hour. Ethyl acetate (250 mL) was added and the organic layer was extracted with water. The aqueous extract was made basic and extracted with ethyl acetate. The extracts were dried, filtered and evaporated to give 6 g of an oil, which was dissolved in ethereal methanol and treated with ethereal hydrochloric acid to give the title compound as a white needle, m.p. 155-165 ° C.

4. Intermedier

2,2,2-Trifluoro-N- [2- (2-ethyl-3,4-dimethoxyphenyl) ethyl] acetamide

Triethylamine (22.3 mL) was added under nitrogen atmosphere (17.0 g) in anhydrous dichloromethane (120 mL).

Intermediate 2. The solution was cooled in an ice bath and 22.6 ml of trifluoroacetic anhydride in 80 ml of anhydrous dichloromethane was added dropwise over 1 hour. The solution was stirred for 2 hours, then washed successively with 2N hydrochloric acid, 8% sodium bicarbonate and brine, dried and evaporated in vacuo. The residual oil was purified by FCC eluting with a 1: 1 mixture of ether and hexane to give 18.1 g of the title compound as a white solid, m.p. 80-81 ° C.

5. Intermediate (2-Ethyl-3,4-dimethoxyphenyl) acetic acid

A solution of 0.93 g of Intermediate 1 and 6 g of sodium hydroxide in 40 ml of methanol and 20 ml of water is heated under reflux for 24 hours. The solution was concentrated in vacuo, acidified with 2N hydrochloric acid and extracted with ether. The extracts were washed with water, dried and evaporated. The residue was purified by FCC eluting with a 1: 1 mixture of ether and hexane to give 0.75 g of the title compound as white crystals, m.p. 8990 ° C.

6. Intermediate (2-Methyl-3,4-dimethoxy-phenyl) -acetic acid

By the method of Intermediate 5, 16.6 g of 2- (2-methyl-3,4-dimethoxyphenyl) -acetonitrile (16 g) were obtained, m.p. 102-104 ° C.

7. Intermediate (2-Ethyl-3,4-bis (phenylmethoxy) -phenyl) -acetonitrile (i) (2-Ethyl-3,4-dihydroxyphenyl) -acetonitrile in ml of boron tribromide in dichloromethane. of a solution of Intermediate 1 (2.05 g) in anhydrous dichloromethane (2.05 g). The resulting solution was allowed to stand at room temperature for 2.5 hours and then cooled in ice. After 15 minutes, the mixture was diluted with ether, the organic phase was separated, washed with brine, dried and evaporated. The resulting oil was diluted with ether / cyclohexane (1: 2, 250 mL) and filtered. The filtrate is concentrated to 100 ml in vacuo, the liquid phase is decanted off from the solid phase and the resulting solid is dried to give 1.68 g of the title compound, m.p. 101-103 ° C.

(ii) [2-Ethyl-3,4-bis (phenylmethoxy) phenyl] acetonitrile

Solid potassium carbonate (1.94 g) was added at room temperature to a solution of the solid product of step (i) in anhydrous dimethylformamide. 2.41 g of benzyl bromide are added and the mixture is stirred overnight, then ice water is added and the mixture is extracted with ether. The extracts were washed with water, dried and evaporated. The resulting oil was purified by FCC eluting with a 1: 1 mixture of ether and hexane to give 1.82 g of the title product as a yellow oil which slowly crystallized, m.p. 44-47.5 ° C.

8. Intermedier

3,3'-thio-bis {N- [2- (2-ethyl-3,4-dimethoxyphenyl) ethyl] propane} -amide

A solution of 2.09 g of the free base intermediate 2 and 0.89 g of 3,3'-thiodio-dipropionic acid in 120 ml of anhydrous dichloromethane was treated with 5.5 g of diphenylphosphoryl azide at 0 ° C followed by 2.02 g of triethyl treated with amine. The solution was stirred at 21 ° C under nitrogen for 5 hours. Ethyl acetate (200 mL) was added and the mixture was stirred for ca. It is concentrated to 100 ml, washed with 2N hydrochloric acid, 8% sodium bicarbonate and saturated brine, dried and evaporated to give a viscous oil. The oil was crystallized from ethyl acetate-hexane to give 2.17 g of the title compound as white needles, m.p. 115-117 ° C.

9-12. intermediates.

9. Intermedier

3,3'-Oxybis [N - {- 2- [2-ethyl-3,4-bis (phenylmethoxy) phenyl] ethyl} propane] amide

18.3 g of intermediate 3 and 4.05 g of 3,3'-oxydipropionic acid give 9.31 g of product, m.p. 159-160 ° C.

10. Intermedier

N, N '-bis {2- [2-ethyl-3,4-bis (phenylmethoxy) phenyl] ethyl} -4-oxo-heptane diamide

From 9.39 g of intermediate 3 and 2.26 g of 4-oxo-heptanedioic acid, 6.93 g of product are obtained, m.p. 188-192 ° C.

11. Intermedier

N, N'-Bis [2- (2-ethyl-3,4-dimethoxyphenyl) ethyl] -3-methylhexanediamide from Intermediate 2 and 0.38 g of 3-methylhexanedioic acid m.p. 152-153 ° C.

72. Intermedier

3,3'-Sulfonylbis {N- [2- (2-ethyl-3,4-dimethoxyphenyl) ethyl]} propanamide from Intermediate 2 and 0.5 g of 3,3'- 1.2 g of sulfonyl dipropionic acid are obtained, m.p. 164-166 ° C.

13. Intermediate [N- (6-Amino-hexyl) -2-ethyl-3,4-dimethoxyphenyl] acetamide g carbonyldiimidazole was added at 0 ° C to a solution of Intermediate 5 (20 g) in anhydrous dichloromethane. . After stirring at room temperature for 2 hours, a solution of 50 g of 1,6-hexanediamine in 500 ml of dichloromethane was added dropwise at 0 ° C. The resulting solution was stirred at room temperature for 24 hours and then concentrated in vacuo. The residue was acidified with 2N hydrochloric acid and washed with ether. The aqueous phase was stirred for 2 n

It is diluted with sodium hydroxide and extracted with dichloromethane. The extracts were washed with water, dried and concentrated in vacuo to give a white waxy solid which was recrystallized from methanol / ethyl acetate to give 26 g of the title product as a white powder, mp 136-138 ° C.

14. Intermedier

N, N '- (1,6-Hexanediyl) bis [(3,4-dimethoxy-2-methylphenyl) acetamide]

Intermediate 13 was prepared as described in Preparation of Intermediate 13 from 6.5 g of Intermediate 6 and 1.74 g of 1,6-hexanediamine in a 1: 1 mixture of dichloromethane and dimethylformamide, m.p. 176 -178 ° C.

15. Intermedier

4-Ethyl-1,3-benzodioxole-5-carboxaldehyde 1.6 M in n-butyllithium hexane

A mixture of 320 ml under nitrogen was added with stirring at -78 ° C to a solution of 100 g of N- (1,3-benzodioxol-5-ylmethylene) cyclohexanamine in 500 ml of anhydrous THF. After 15 minutes, diethyl iodide (50 mL) was added and the mixture was allowed to slowly warm to -50 ° C. Water was added and the mixture was extracted with ether. The extracts were evaporated in vacuo and the residue was heated with 250 ml of 2N hydrochloric acid on a steam bath for 20 minutes. The resulting solution was diluted with water and extracted with ether, and the extracts were dried and evaporated to give the title product as a pale yellow oil (38 g). Mass spec Rf = 0.3, eluent: ether / hexane = 1: 9 (v / v).

16. Intermediate bi- [6 - {(3,4-dimethoxy-2-methyl-phenyl) -acetylamino} hexyl] - [(2-ethyl-3,4-dimethoxy) -phenyl] -acetamide

0.54 g of carbonyldiimidazole is added portionwise to a cooled solution of 0.68 g of intermediate 6 in 20 ml of dichloromethane. The mixture was stirred at room temperature for 15 hours while nitrogen was bubbled through. To the cooled solution was added dropwise a solution of 1 g of intermediate 13 in 25 ml of anhydrous dichloromethane. The mixture was stirred at room temperature for 24 hours. The solution was concentrated in vacuo and the resulting solid was recrystallized from methanol to give 1 g of the title compound as a white solid, mp 164-166 ° C.

17. Intermedier

N, N '- (1,7-Heptanediyl) bis {N- [2- (2-ethyl-3,4-dimethoxyphenyl] ethyl] -2,2,2-trifluoroacetamide}

A 50% dispersion of 0.43 g of sodium hydrate in 25 ml of hexane was stirred for 30 minutes under a nilogen atmosphere. The hexane was decanted and replaced with dimethylformamide (25 mL) and a solution of intermediate 4 (3 g) in anhydrous dimethylformamide (3 g) was added to the sodium hydride suspension. The reaction mixture was stirred at 21 ° C for 45 minutes. Then, 1.16 g of 1,7-dibromo-heptane was added to the reaction mixture, which was cooled to 0 ° C, and then refluxed for 7 hours. After 2 days at 21 ° C, the reaction mixture was acidified with 2N hydrochloric acid and extracted with ether. The combined extracts were dried and evaporated in vacuo to give 3.5 g of the title compound as a yellow oil. Purification by FCC eluting with ether / hexane (1: 1) gave 2.3 g of product as a colorless oil. Mass spec Rf = 0.3, 1: 1 by volume ether: hexane.

18. Intermedier

Ν, Ν '- (1,6-ethanediyl) bis [(2-ethyl-3,4-dimethoxy-phenyl) -amide]

A mixture of Intermediate 5 (8.6 g), thionyl chloride (18 ml) and dichloromethane (480 ml) was heated at reflux for 2 hours, evaporated in vacuo to give a solid. A suspension of 15 g of the solid product, 3.6 g of 1,6-diaminohexane and 8 g of anhydrous potassium carbonate in 400 ml of anhydrous dichloromethane is refluxed for 24 hours. The solvent was evaporated, water was added and the mixture was extracted with chloroform. The extract was dried and evaporated to give a solid which was triturated with ether / hexane to give 5.5 g of the title product as a cream solid, m.p. 169-172 ° C.

19. Intermedier

4-Ethyl-α, α-dimethyl-1,3-benzodioxol-5-ethane-amine hydrochloride

Starting from Intermediate 15 according to conventional methods which include condensation of the malonic acid in the presence of a base, catalytic hydrogenation, alkylation with methyl iodide and n-butyllithium, Curtius rearrangement using sodium azide, and solvolysis with benzyl alcohol followed by 300 DEG C., m.p. Rf = 0.52, eluent: toluene / ethanol / ammonia (78: 20: 2 by volume).

20. Intermedier

6 - {[2- (2-Ethyl-3,4-dimethoxyphenyl) ethyl] amino} -6-oxo-hexanoic acid (i) Methyl 6 - {[2- (2-ethyl-3,4-dimethoxy) -phenyl) -ethyl] -amino} -6-oxo-hexanoate A solution of 6-chloro-6-oxo-hexanoic acid methyl ester in 100 ml of anhydrous dichloromethane was added dropwise with stirring to 10.4 g of intermediate 2 and 5.65 g of triethylamine in 100 ml of dichloromethane. After stirring at room temperature for 1 hour, the solvent was evaporated in vacuo and the residue was purified by FCC eluting with ether to give 15 g of the title compound as a white solid, m.p. 37-39 ° C.

(ii) 6 - {[2- (2-Ethyl-3,4-dimethoxyphenyl) ethyl] amino} 6-oxo-hexanoic acid, g, product of step (i), 200 ml of 2N sodium hydroxide. of ethanol and 300 ml of ethanol was heated under reflux for 1 hour. The solution was cooled and poured into 1000 ml of water. The mixture was washed with ether, acidified with 2N hydrochloric acid and extracted with ether. The extracts were washed with water, dried and evaporated to give 8.4 g of the title compound as a white solid, m.p. 92-94 ° C.

HU 206 868 B

27. Intermedier

N- [2- (4-Ethyl-3-benzodioxol-5-yl) -N-dimethyl-ethyl] -N- [2- (2-ethyl-1,3-di-methoxy-phenyl) ) ethyl] hexane-diamide

Ethyl chloroformate (0.74 g) was added to a stirred solution of Intermediate 20 (2.17 g) and triethylamine (1.01 g) in anhydrous dichloromethane (80 mL) at 0-5. The reaction mixture was stirred for 10 minutes and then added dropwise over 10 minutes

A solution of 1.5 g of intermediate 19 in 20 ml of anhydrous dichloromethane. After a further 20 minutes, the solution was washed with 8% sodium bicarbonate solution and then with 2N hydrochloric acid. The solution was dried and evaporated to dryness. The residue was purified by FCC eluting with ethyl acetate to give 1.4 g of the title compound as a white solid, m.p.

104.5 ° C.

22. Intermedier

N, N'-Bis [2- (2-chloro-3,4-dimethoxyphenyl) ethyl] hexanediamide g (2-chloro-3,4-dimethoxyphenyl) ethanamine, 0, A mixture of adipoyl chloride (85 g) and triethylamine (1.3 ml) in acetonitrile (40 ml) was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the resulting residue, which was a white solid, was stirred in water for 30 minutes and dried at 90 ° C in vacuo to give 2 g of the title compound, mp 159-161 ° C.

23. Intermedier

N- [2- (3,4-Dimetoxi.-2-methylphenyl) ethyl] -N '- [2- (2-ethyl-3,4-dimethoxyphenyl) ethyl] hexane-diamide

A solution of 23.3 g of diphenylphosphoryl azide in 100 ml of anhydrous dichloromethane is added with stirring to 14.3 g of intermediate 20 (ii) and 9.81 g of (2-methyl-3,4-dimethoxyphenyl) ethane. amine hydrochloride at 0 ° C in 500 ml of anhydrous dichloromethane under a nitrogen atmosphere. 8.58 g of triethylamine are added to the suspension, and the solution is stirred at 21 ° C for 6 hours. The solution was diluted with dichloromethane (300 ml), washed with 2N hydrochloric acid (2 x 500 ml), water and aqueous sodium carbonate, dried and evaporated, triturated with ether to give 13.4 g of the title compound as a white solid, m.p. Mp: 165-168 ° C.

Example 1

4,4 '- {Thiobis [(3,1-propanediylimino) -2,1-ethanediyl]} bis (3-ethyl-1,2-dihydroxybenzene)] dihydrobromide dihydrate (i) N, N '- [Thio-bis (3,4-propanediyl)] - bis [(2-ethyl-1,3-dimethoxyphenyl) ethanamine] dihydrochloride in ml borane-THF complex (1M) In THF) at 21 ° C under nitrogen atmosphere, to a solution of 2.11 g of intermediate 8 in 150 ml of anhydrous THF. The mixture was stirred at reflux under nitrogen for 21 hours, cooled and evaporated. 2N Hydrochloric acid was added to the residue and the mixture was stirred at 100 ° C for 3.5 hours. It is then cooled and made basic with 2N sodium hydroxide. The mixture was extracted with dichloromethane and ethyl acetate. The combined extracts were washed with saturated brine, dried and evaporated to give a viscous oil which was dissolved in methanol. To this is added ethereal hydrochloric acid. The solution was evaporated and the resulting solid was recrystallized from methanol / ethyl acetate / hexane to give 0.97 g of the title product as a white powder, m.p. 184186 ° C.

(ii) 4,4 '- {Thio-bis [(3,1-propanediylimino) -2,1-ethanediyl]} bis (3-ethyl-1,2-dihydroxybenzene] dihydrobromide dihydrate

A solution of the product of step (i) (400 mg) in methanol (5 mL) and water (5 mL) was basified with 2N sodium carbonate. The mixture was extracted with ethyl acetate and the extracts were evaporated to give an oil which was dissolved in dichloromethane (50 mL). 5 ml (1 M) of boron tribromide in dichloromethane is added dropwise with vigorous stirring. The resulting mixture was stirred at 21 ° C for 18 hours under nitrogen and then cooled to 0 ° C. Methanol was added and the resulting solution was refluxed for 0.75 hours, cooled and evaporated. The resulting solid product was dissolved in absolute ethanol and hexane was added dropwise with vigorous stirring until a gummy precipitate was obtained. The solvents were decanted and the residue dried in vacuo to give 344 mg of the title product as a white foam.

Elemental analysis according to the formula C ₂₆ H ₄₀ N ₂ O ₄ Sx2 HBix2 H ₂ O:

Calculated: C (%) = 46.1; H (%) = 6.3; N (%) = 3.9;

Found: C (%) = 46.3; H (%) = 6.8; N (%) = 4.2. .

Example 2

4,4 '- {Sulfonyl bis [(3,1-propanediylimino) -2, letandiyl]} bis [3-ethyl-1,2-dihydroxybenzene] dihydrobromide sesquihydrate (i) N, N '- [Sulfonyl-bis (3,1-propanediyl)] - bis [(2-ethyl-3,4-dimethoxyphenyl) ethylamine] dihydrochloride ml borane-THF complex (1 M) was added 0.6 g A solution of intermediate 12 in 50 ml of anhydrous THF at 0 ° C under a nitrogen atmosphere. The solution was heated under reflux for 18 hours with stirring, cooled and concentrated in vacuo. 2N Hydrochloric acid was added to the residue and the mixture was heated at 100 ° C for 1 hour with stirring. Upon cooling, a white solid precipitated which was collected and dried in vacuo to give 0.4 g of the title product as a white powder, m.p. 212-215 ° C. .

(ii) 4,4 '- {Sulfonylbis [(3,1-propanediylimino) -2, letandyl]} bis (3-ethyl-1,2-dihydroxybenzene) dihydrobromide sesquihydrate 1 M boron tribromide (1 ml) was added to a stirred suspension of 0.6 g of the product of step (i) in 90 ml of anhydrous dichloromethane with stirring. The mixture was stirred for 24 hours under nitrogen at 21 ° C. The cloudy mixture was cooled to 0 ° C and stirred well with methanol. The resulting solution was refluxed for 1 hour, cooled and evaporated in vacuo to give 0.6 g of the title compound.

EN 206 868 B as a pale pink solid, m.p. 130-133 ° C, softening point 90 EC.

Elemental analysis based on the formula C ₂ 6 H ₄₀ N ₂ O ₆ Sx ₂ H Brxl, 5 H ₂ O:

Calculated C (%) = 44.5 H (%) = 6.1 H (%) = 3.8; Found; C (%) 44.8 H (%) = 6.4 N (%) = 4.0.

Example 3

4 - [[2- {6- [2- (3,4-Dihydroxy-2-diethyl-phenyl) -cylamino] -hexan-amino} -ethyl)] - 3-ethyl-1,2-dihydroxy- benzaldehyde hydrobminide (i) N- [2- (3,4-dimethoxy-2-methyl-phenyl) -ethyl] -N '- [2- (2-ethyl-3,4-dimethoxyphenyl) -ethyl] -1,6 hexane-diainine dihydrochloride is added dropwise to a solution of 500 g of Intermediate 16 in 30 ml of anhydrous THF under stirring under a nitrogen atmosphere of 1 M borane-THF complex in ice-bath. The mixture was refluxed for 20 hours, methanol was added to the cooled solution and evaporated in vacuo. The residue was refluxed in 2N hydrochloric acid for 4 hours. The solution was cooled and the precipitate was collected and dried to give 300 mg of the title product as a white powder, m.p. 263 ° C (dec.) (Ii) 4 - [[2- {6- [2- (3,4- Dihydroxy-2-methyl-phenyl) -ethylamino] -hexyl-1-amino} -ethyl] -3-ethyl-1,2-dihydroxybenzene dihydrobromide

A solution of boron tribromide (1.2 ml) in dichloromethane (10 ml) was added dropwise, under nitrogen, to a solution of the product of step (i) in dry dichloromethane (100 ml) at 0 ° C. After stirring for 5 hours at room temperature, methanol was added. The mixture was concentrated in vacuo and the solid residue was recrystallized from methanol / ethyl acetate to give the title product as a white powder (1 g), m.p. 178-180 ° C.

Elemental Analysis for C ₂₅ H ₃₈ N ₂ O ₄ x 2 HBr Calculated: C (%) = 50.5 H (%) = 6.6 N (%) = 4.4;

Found: C, 50.7; H, 6.8; N, 4.7.

Example 4

4,4 '- [J, 6-Hexanediyl-bis (hmno-2,] - ethanediyl)] bis [3-ethyl-1,2-dihydroxybenzene] dihydrobronide (i) N, N'-Bis [2 - (2-ethyl-3,4-dini.eloxí-phenyl) ethyl-l, 6hexán diamine dihydrochloride

A suspension of 5.2 g of intermediate 18 in 220 ml of anhydrous THF is cooled to 0 ° C and 65 ml of a 1M borane-THF complex are added under a nitrogen atmosphere. After refluxing for 5 hours, the solution was cooled, treated with methanol and concentrated in vacuo. The residue was refluxed in 2N hydrochloric acid for 20 hours and then cooled. The precipitated white product was collected and dried to give 2.78 g of the title compound, m.p. 223-225 ° C.

(ii) 4,4 '[1,6-Hexanediyl-bis (imino-2, J-ethanediyl)] bis [3-ethyl-1,2-dihydroxybenzene] dihydrobromide 0.87 g of boron tribromide at 0 ° C is added dropwise at 1 ° C to a solution of the product of step (i) in 70 ml of anhydrous dichloromethane under a nitrogen atmosphere. The mixture was stirred at room temperature for 18 hours, cooled to 5 ° C and treated dropwise with methanol. The solution was refluxed for 1 hour, concentrated in vacuo and the resulting solid recrystallized from methanol / ethyl acetate to give 0.75 g of the title compound as a white solid, m.p. 205-207 ° C.

Elemental Analysis for: C ₂₆ H ₄₀ N ₂ O ₄ · 2HBr Calculated: C (%) = 52.0 H (%) = 7.1 N (%) = 4.4; Found; C (%) = 51.5 H (%) = 7.0 N (%) = 4.6.

Example 5 (i) N, N'-Bis [2- (2-ethyl-3,4-dimethoxyphenyl) ethyl] -3-methylhexane-J, 6-diamine dihydrochloride

In the same manner as in Example 5, step (i), 0.90 g of Intermediate 11 is obtained in a yield of 0.90 g, m.p.

(ii) 4,4 '- [(3-Methyl-1,6-hexanediyl) bis (itinino-2J-ethanediyl)] bis [3-ethyl-1,2-dihydroxybenzene] dihydrobromide hydrate

0.81 g of product of step (i) is obtained, m.p. 135-138 ° C.

Elemental analysis for C ₂₇ H ₄₂ N ₂ O ₄ x 2HBrxH ₂ O

Based on; C (%) H (%) N (%) Br (%) calculated 50.4 7.0 4.2 25.2; Found: 50.7 7.2 4.3 25.5.

Example 6

4,4 '- [1,6-Hexanethyl-bis (linino-2,1-ethanediyl)] bis [3-ethyl-1,2-dihydroxybenzene] dihydrobromide hydrate

A suspension of 400 mg of the product of Example 4, Step (i) in 10 ml of 48% deoxygenated hydrobromic acid is heated at reflux for 24 hours. Nitrogen gas is slowly passed through the mixture. The resulting solution was cooled and concentrated in vacuo. The resulting solid was recrystallized from methanol-ethyl acetate to give 300 mg of the title compound as a tan solid, m.p. 200-202 ° C.

Elemental analysis for C ₂₆ H ₄₀ N ₂ O ₄ x 2 HBrxH ₂ 0xl / 3 EtOAc:

Calculated: C (%) = 49.7; H (%) = 6.9; N (%) = 4.5; Found: C (%) = 50.2 H (%) = 6.8 N (%) = 4.3.

In Examples 7 and 8, the first step is as in Example 4, step (i), and the second step is as in Example 6.

Example 7 (i) N, N'-Bis [2- (2-dodo-3,4-dimethoxyphenyl) ethyl] 1,6-hexanediamine dihydrochloride

1.5 g of intermediate 22 give 1.18 g of product, m.p. 254-256 ° C (dec.).

(ii) 4,4 '- [1,6-Hexanediyl bis (imino-2,1-ethanediyl)] bis [3-chloro-1,2-dihydroxybenzene] dihydrobromide 0.6 g. Yield 0.56 g, m.p. 194-197 ° C.

HU 206 868 Β

Calcd for ₂ ^ Η ₃₀ Ο1 ₂ Ν ₂ Ο ₄ χ2 HBr O: C (%) H = 42.4 (%) = 5.2 F (%) = 4.3; Found: C, 42.7; H, 5.2; N, 4.5; 4.5.

Example 8 (i) N, N'-Bis [2- (3,4-dimethoxy-2-methylphenyl) ethyl]], 6-hexanediamine dihydrochloride, from Intermediate 14, 3.57 g. 270-272 ° C.

(ii) 4,4 '- [1,6-Hexanediyl-1-bis (imino-2,1-ethanediyl)] bis [3-methyl-1,2-dihydroxybenzene] dihydrobromide anhydrate

4.4 g of the product of Example 8 (i) are obtained, 3.02 g of product, m.p. 248-250 ° C.

Elemental analysis according to the formula C ₂₄ H ₃₆ N ₂ O ₄ x 2 HBr 1/2 H ₂ O, 1/2 MeOH:

Calculated: C (%) = 48.2; H (%) = 6.6; N (%) = 4.5; Found: C (%) = 48.7 H (%) = 6.2 N (%) = 4.6.

Example 9

Oxy-4,4'-bis [1,3-propanyl] -1-bnino-1,2-ethanedyl- (3-ethyl-1,2-dihydroxy-benzene)] dihydrochloride hydrate (i) Oxybis (J, 3- propanethyl) -N, N'-bis (2-ethyl-3,4-di- (benzyloxyl) phenyl) -ethanamine dihydrochloride (1 ml) was added in 1M borane-THF complex (8.3 g) in intermediate (500 ml) in anhydrous THF. in a nitrogen atmosphere at 21 ° C

The mixture was refluxed under nitrogen for 5.5 hours, cooled and evaporated. To the residue was added 2N hydrochloric acid and THF and the mixture was refluxed for half an hour and then cooled. The THF was evaporated and the mixture was filtered and the solid residue was washed with water and recrystallized from methanol / ethyl acetate / hexane to give 5.14 g of the title product as a white powder, m.p. 192-193 ° C.

(ii) Oxy-4,4'-bis-1,3-propanediylimino-1,2-ethanediyl- (3-ethyl-1,2-dihydroxy-benzene)] dihydrochloride

A solution of 0.66 g of the product of step (i) in 130 ml of methanol is hydrogenated at room temperature and atmospheric pressure in the presence of a pre-reduced 10% PdO-C catalyst (150 mg 50% wt) until hydrogen uptake is maintained. The mixture was filtered and the filtrate was evaporated to give a gum which was recrystallized from methanol / ethyl acetate to give 287 mg of the title product as gray crystals, m.p. 203-206 ° C (dec.).

Elemental analysis according to the formula C ₂₆ H ₄₀ N ₂ O ₅ x 2 HCl x H ₂ O:

Calculated: C (%) = 56.3; H (%) = 7.6; N (%) = 4.95; Found: C (%) = 56.6; H (%) = 7.6; N (%) = 5.1.

Example 10

4-Hydroxy-1,7-heptanediyl bis (amino-2,1-ethanedyl) 4,4'-bis [3-yl], 2-dihydroxy-benzene] dihydrochloride (i) 1,7-Bis {2- [2-etil.-3,4-di (phenylmethoxy) phenyl] ethylamino} -4-heptanol, dihydrochloride

Starting from 6.09 g of Intermediate 10 according to Example 4 (i), except that the crude product is triturated with hot ether to give 6.42 g of product, m.p. 168-183 ° C.

(ii) 4-Hydroxy-1,7-heptanediyl bis (imino-1,2-ethanediyl) -4,4'-bis (3-ethyl-1,2-dihydroxybenzene) dihydrochloride

Starting from 4.00 g of the product of Step (i), following the procedure of Example 9, Step (ii), 2.43 g of product are obtained.

Elemental analysis according to the formula C ₂₇ H ₄₂ N ₂ O ₅ x 2 HCl:

C (%) H (%) N (%) Cl (%) calculated: 58.9 8.3 4.9 12.7; Found: 59.2 8.1 5.1 13.0.

Example 11

3-Ethyl-4 - [[2- {6- [2- (2-ethyl-3,4-dihydroxyphenyl) -1,1-dimethyl-ethylamino] -hexylamino} -ethyl]] - 1 , 2-Dihydroxybenzene dihydrobromide (i) N- [2- (4-ethyl-1,3-benzodioxol-5-yl) -N, 1-dimethylethyl] -N '- [2- (2- ethyl-3,4-dimethoxyphenyl) ethyl] -, 6-hexane-diamine dihydrochloride

A suspension of 1.2 g of intermediate 21 in 60 ml of anhydrous benzene is added dropwise at 0-5 ° C to a suspension of 0.4 g of lithium aluminum hydride in 60 ml of anhydrous ether under stirring. The resulting mixture was refluxed for 20 hours. The mixture was cooled, treated with 2N sodium hydroxide solution and extracted with ether. The extracts were washed with water, dried and evaporated to give a pale bama oil. 0.2 g of this oil is mixed with 25 ml of anhydrous ether and treated with ethereal hydrochloric acid to give a white solid which is crystallized from a mixture of methanol and ethyl acetate to give 0.18 g of the title product as white sheets, m.p. 223-225. ° C.

0 \\} 3-Ethyl-4- [2- {6- [2- (2-ethyl-3,4-dihydroxyphenyl) l, l-dimethyl-ethyl] -amino} ethyl] -], 2-hydroxy-benzene

Starting from 0.54 g of the product of step (i), following the procedure of Example 3, step (ii), gives 0.29 g of product, m.p. 233-235 ° C.

Elemental Analysis for C ₂₈ H 44 N ₂ O ₄ × ₂ HBr Calculated: C (%) = 52.8 H (%) = 7.4 N (%) = 4.3; Found: C (%) = 53.0 H (%) = 7.3 N (%) = 4.4.

Example 12 (E, E) - [2,4-Hexanediol-1,6-dlyl-bis (lmino-2,1-ethanediyl)] - 4,4'-bis [3-ethyl-1,2-dhydroxy] benzene] dihydrobromide (i) (E, E) -N, N'-Bis [2- (2-ethyl-3,4-dimethoxyphenyl) ethyl] -2,4-hexadiene-1,6-diamine dihydrochloride A mixture of 4.19 g of Intermediate 2 and 1.1 g of (E, E) -2,4-hexadiene diazole is refluxed in 250 ml of anhydrous benzene for 1 hour. The solution is concentrated in vacuo and the residue is treated with 1.51 g of sodium borohydride in 150 ml of absolute ethanol. The reaction mixture was stirred at room temperature for 1.5 hours, diluted with water, stirred for a further 0.5 hours, diluted with additional water and extracted with dichloromethane. The extracts were dried and concentrated in vacuo. The resulting oil was dissolved in methanol and fed with ether

HU 206 868 és Slight excess of hydrochloric acid. The resulting solution was evaporated in vacuo to give a solid which was crystallized from methanol / ethyl acetate to give 3.03 g of the title product as a white solid, m.p. 247-250 ° C.

(ü) (E, E) - [2,4-Hexadiene-6,6-di-bis (imino-2,1-ethanediyl) -4,4'-bis [3-ethyl-1,2-dihydroxy] benzene] dihydrobromide

Using 1.0 g of the product of step (i), m.p.

Example 1 (i), except that 2N sodium hydroxide is used instead of 2N sodium carbonate, gives 456 mg of product, m.p. 240244 ° C (dec.).

Elemental Analysis for C ₂₆ H ₃₆ N ₂ O ₄ × 2 HBr Calculated: C (%) = 51.3 H (%) = 6.1 N (%) = 4.5; Found: C (%) = 51.8 H (%) = 6.4 N (%) = 4.7.

Example 13

1,7-Heptanediyl bis (imino-1,2-ethanediyl) -4,4'-bis (3-ethyl-1,2-dihydroxybenzene) hexibromide hydrate (2: 5: 2) (i) N, N '-Blsz [2- (2-Elyl-3,4-dimethoxyphenyl) ethyl] -1,7-heptanediamine dihydrochloride g Intermediate 17 in 300 mL methanol and 50 mL 2N sodium hydroxide Heat on a steam bath for 1 hour. The reaction mixture was allowed to stand at 21 ° C for 18 hours, then concentrated in vacuo and the residue extracted with ether. The extract was dried, concentrated in vacuo to give an oily product. To a solution of the oil in the dry food is added dropwise ethereal hydrochloric acid. The precipitated white solid was collected and dried, crystallized from methanol-ethyl acetate to give 0.31 g of the title product as a white solid, m.p. 233-235 ° C.

(ii) / 7,7-Heptanediyl bis(bn.ino- 1,2,2-ethanediyl) -4,4'bis (3-ethyl-1,2,2-dihydroxybenzene) hydrobromide (2: 5) : 2)

Starting from 0.45 g of the product obtained in step (i), 0.5 g of the product is obtained in the same manner as in Example 3 (ii), m.p. 182-185 ° C.

Elemental analysis for C ₂₇ H ₄₂ N ₂ O ₄ x 2.5 HBrH ₂ O

Based on: C (%) H (%) N (%) Cl (%) calculated: 47.4 6.5 4 l 29.3; Found: 47.7 6.5 4.1 29.5.

Example 14

N- [2- (2-ethyl-3,4-hydroxyphenyl.) - ethyl] -N- [2- (2-methyl-3,4-dihydroxy-phenyl) -ethyl] -I, 6-hexanediamine dihydrochloride

180 ml of a 1 M borane-THF complex are added dropwise at 0 ° C to a suspension of 14.5 g of intermediate 23 in 500 ml of anhydrous THF under cooling. The reaction mixture was refluxed for 5 hours, the solution was cooled, and methanol (200 mL) was added dropwise. The mixture was concentrated in vacuo and the residue refluxed with 2N hydrochloric acid (500 mL) for 2 h.

The resulting solution was cooled and the precipitated solid was collected and dried to give 12.6 g of the title product as a white solid, m.p. 268 ° C (dec.).

Biological tests

The selective stimulatory effects of the compounds of the present invention on vascular dopamine receptors were investigated in comparison with their stimulatory effects on neuronal dopamine receptors in canine mesenteric vascular beds (vascular dopamine receptors) and feline heart (neuronal dopamine receptors). In these assays, the compounds of the invention exhibit less than 10-fold (dopamine-equivalent unit activity) and more than 300-fold dopamine (unit equivalent) activity at vascular dopamine receptors.

The compounds of the invention are non-toxic at therapeutically effective doses and show no adverse side effects in conscious dogs at oral doses up to 10 mg / kg.

Claims (7)

A process for the preparation of compounds of formula I and their physiologically acceptable acid addition salts and solvates thereof R ¹ is halogen or methyl, ethyl, n-propyl or n-butyl; R ² , R ³ , R ⁴ and R 1 'are hydrogen or one or two of R ² and R ³ are methyl or ethyl, R ⁶ is halogen or C 1 -C 4 alkyl, X is a C 5 -C 7 alkylene chain optionally substituted with C 1 -C 4 alkyl or hydroxy, optionally having one or two double bonds or optionally interrupted by an oxygen, sulfur or sulfonyl group, characterized in that a) reducing a compound of formula II wherein R ⁷ and R ⁸ are hydrogen, Ar and Ar ¹ are groups of formula (a) and (b) wherein R ¹ and R ⁶ are as defined above, R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are hydrogen or a protecting group, X ¹ is a C 3 -C 5 alkylene chain which may be optionally substituted with C 1 -C 4 alkyl or hydroxy, or may optionally contain one or two double bonds or optionally one interrupted by oxygen or sulfur or by a sulfonyl group, two of Z ¹ , Z ² , Z ³ and Z ⁴ are oxygen, two together with the carbon atom are -CH ₂ - with the proviso that either Z ¹ and Z ⁴ or Z ² and Z ³ is O and optionally deprotected, or b) compounds of the formulas III and IV - wherein HU 206 868 Β Ar and Ar ^{1 are} as defined above, R ⁷ , R ⁸ , R ² , R ³ , R ⁴ and R ⁵ are hydrogen, R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are protecting groups - are reacted with an alkylating agent capable of introducing X and then deprotecting, or c) a compound of formula V wherein R ⁷ , R ⁸ are hydrogen or protecting group, R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are hydrogen or protecting group, but at least one of them represents a protecting group and R ² , R ³ , R ⁴ and R ⁵ are hydrogen - the protecting groups are removed and, if desired, the resulting compound of formula I is converted into a physiologically acceptable acid addition salt or solvate. 2. The method of claim 1, wherein ^R1 is a methyl starting from a compound having an ethyl group or a chlorine atom, or. Process according to claim 1 or 2, characterized in that compounds containing R ² , R ³ , R ⁴ and R ^{5 are} hydrogen. 4. A process according to any one of claims 1 to 3, characterized in that X is a compound having an alkylene chain having 6 or 7 carbon atoms. 5. A process according to any one of claims 1 to 3, wherein R ⁶ is a compound having a halogen atom or a methyl or ethyl group. The process of claim 1, 4- [2- {6- [2- (2-methyl-3,4-dihydroxyphenyl) ethylamino] hexylamino} ethyl] -3-ethyl-1,2 -dihydroxybenzene or its physiologically acceptable acid addition salts, characterized in that the appropriately substituted starting materials are used. 7. A process for the preparation of a pharmaceutical composition, characterized in that a compound of the formula I obtained according to the process of claim ¹ , wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X are as defined in claim 1. or a physiologically acceptable acid addition salt or solvate thereof, in admixture with conventional excipients and / or other excipients, to form a pharmaceutical composition.