NO165235B - ANALOGUE PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICAL ACTIVE 2-SUBSTITUTED-3,4-DIHYDROXYPHENYLETYLAMINO DERIVATIVES. - Google Patents

Description

The present invention relates to a method for the production of 2-substituted-3,4-dihydroxyphenethylamino derivatives with pharmacological activity.

According to the invention, a method for producing compounds with the following general formula is provided

and physiologically acceptable acid addition salts, wherein

R<1> represents a halogen atom or a methyl, ethyl, n-propyl or n-butyl group;

R<2>, R<3>, R<4> and R<5> each represent hydrogen atoms or one or two of the groups R<2>, R<3>, R<4> and R<5> represent a methyl or ethyl group;

R<6> represents a hydrogen or halogen atom or a C2-4 alkyl group; and

X represents a C5_7 alkylene chain optionally substituted with a C-±-4 alkyl (e.g. methyl) or hydroxy group, or optionally may contain one or two double bonds or optionally interrupted by an oxygen or sulfur atom or by a sulfone (- S02-) group.

When optical isomers can exist with formula (I), this is understood to include all enantiomers, diastereoisomers and mixtures thereof, and here racemates are included. Compounds containing one or two double bonds in the alkylene chain X can exist in cis or trans configuration.

The term "alkyl" means a group which is straight or branched. Halogen means a fluorine, bromine, chlorine or iodine atom.

Examples of the group X include -(CH2)5_, -(CH2)6-, -

(CH2)7-, -(CH2)30(CH2)3-, -(CH2)40(CH2)2, -(CH2)3CHOH(CH2)3-, -

(CH2)2CHMe(CH2)3-, -(CH2)3S(CH2)3-, -(CH2)3S02(CH2)3-, - CH2CH=CH(C<H>2)3-, -(CH2) 2CH=CH(CH2)2-, -CH2CH=CHCH=CHCH2-.

Preferred compounds produced according to the present invention are those where the group R<1> is a chlorine atom, or more preferably a C1-2 alkyl group, then especially an ethyl group.

R<2> and R<3> which may be the same or different, preferably represent a hydrogen atom or a methyl group, or more preferably R2, R<3>, R<4> and R5 each represent a hydrogen atom.

X is preferably a C 8 or C 7 alkylene chain, most preferably -(CH 2 ) 6 -, Further preferred compounds are those where X represents -(CH 2 ) 3 S(CH 2 ) 3 or -(CH 2 ) 3 SO 2 (CH 2 ) 3 -.

R<6> preferably represents a hydrogen or chlorine atom or a methyl or ethyl group. Particularly preferred compounds are those where R<6> is a methyl or ethyl group, preferably methyl.

Tests in animals have shown that compounds prepared by the present method in low doses lower the total peripheral vascular resistance, increase the capacity of the heart and produce a drop in blood pressure. Compounds according to the present invention have a long duration of action and are active after oral administration.

It has been found that compounds prepared by the present method are more effective stimulators of vascular dopamine receptors than neuronal dopamine receptors.

Compounds produced by fijjeip atv present invention

will also stimulate P-adxenoceptors.

A particularly preferred compound prepared by means of the present invention is: ]cyl]-amino]ethyl]-3-ethyl-1,2-benzenediol and its physiologically acceptable salts, e.g. its hydrobromide and hydrochloride.

Compounds prepared by means of the present invention can be used in the treatment or prophylaxis of kidney failure or cardiovascular diseases or disorders such as hypertension, in chemical heart disorders or heart failure, e.g. acute heart failure or, heart failure due to high blood pressure.

Connections with. formula (I) and their physiologically acceptable acid addition salts may be formulated for administration or delivery by any convenient means.

Compounds produced by means of the present method can thus be prepared for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred.

The daily dose that can be used for adult patients will preferably be in the range from 5mg to 3mg, most preferably from 25mg to lg which can be administered from 1 to 4 doses, e.g. depending on the delivery route chosen and the patient's general condition.

Compounds of formula (I) and their physiologically acceptable acid addition salts can be administered in combination with other therapeutic agents such as beta-blockers, diuretics, angiotensin-forming enzyme inhibitors, inotropic agents and anti-drugs.

Compounds of formula (I) can be prepared by various methods described below, where R<2->R<6 >and X are as defined above if nothing else is indicated, and where R<7> and R<8 > each represents a hydrogen atom or a protecting group, and Ar and Ar<1> represent the groups

where respectively R<1> and R<6> are as defined for formula (I), while R9, R10, R1<1> and R1<2> are each a hydrogen atom or a protecting group. It is understood that some of the reactions described in the following can affect other groups in the starting compounds that are desirable in the final product, this particularly concerns the reduction processes which are special, and especially when hydrogen and a metal catalyst are used to produce compounds containing an ethylene or

acetylene bond. One must therefore take these reactions into account and either use reactants that do not affect such groups, or carry out the reaction as part of a sequence where their use is avoided when such groups are present in the starting compound.

According to a general method (1), compounds of formula (I) can be prepared by reducing a compound of formula (II)

where X<1> is a C3_5 alkylene chain optionally substituted with an alkyl or hydroxyl group, or which may optionally contain one or two double or triple bonds or a carbonyl group, and which may optionally be interrupted by an oxygen or sulfur atom or a sulfone (-SO2 -) group, and where Z<1>, Z<2>, Z<3> and Z<4> each represent oxygen, or the groups C=Z<1>, C=Z<2> and C=Z<3 > each is the group CH2 and C=Z4 may be the group CR<2>R<3>, provided that at least one, but not more than two of the groups Z1, Z<2>,

Z<3> and Z<4> are O and Z<1> is O, then C=Z2 is the group CH2 and when Z3 is 0, C=Z<4> is the group CR<2>R<3>, and where the reduction is followed by a removal of any protecting groups.

The reducing agents which can be used are those which are generally known for the reduction of amides. Suitable reducing agents for this reaction are hydrides such as lithium, aluminum hydride, alane or diborane. Suitable solvents include ethers such as tetrahydrofuran or dioxane or a mixture of a hydrocarbon (eg benzene) and an ether (eg diethyl ether). The reduction can conveniently be carried out at any temperature from -20 to +100°, preferably between 0° and 70°.

According to another general method (2), compounds of formula (I) can be prepared by an alkylation reaction involving the compounds of formulas (III) and (IV)

and an alkylating agent of formula L-X-L where L is an easily replaceable atom or group, after which protective groups are optionally removed.

In the method, compounds of the formulas (III) and (IV) are thus reacted with an alkylating agent of the formula L-X-L whereby compounds of the formula I are produced. The reaction is preferably carried out in the presence of a base such as potassium carbonate or sodium hydride and in a solution at temperatures from -20 to +100°. Suitable reaction solvents include ethers, e.g. tetrahydrofurans or dioxanes; alcohols such as ethanol; acetonitrile, substituted amides, e.g. N,N-dimethylformamides and hydrocarbons, e.g. benzene.

L can e.g. be a halogen atom such as chlorine, bromine or iodine, or a hydroxycarbylsulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy.

The compound of formula (I) can be prepared by removing protecting groups from compounds of formula (V)

where at least one of the groups is R<7>, R8, R9, R10, R11 or R<12> is a protecting group.

When R<7>, R8, R9, R10, R<11> or R<12> is a protecting group, it can be any commonly known protecting group, e.g. of the type described in "Protective Groups in Organic Chemistry", editor J.F.W. McOmie (Plenum Press 1975). Examples of suitable hydroxyl protecting groups represented by R<7>, R8, R9, R10, R1<1> or R12 are alkyl groups such as methyl or methoxymethyl, arylmethyl groups such as benzyl, diphenylmethyl or triphenylmethyl, and heterocyclic groups such as tetrahydropyranyl or acyl groups such as acetyl. It is understood that R<9> and R10 and/or R11 and R12 can together form one or more protecting groups for both hydroxyl groups, e.g. an alkylene group such as a methylene group. Examples of suitable amine protecting groups represented by R<7> and R<8> are trifluoroacetyl, t-butoxycarbonyl, trifluoroethoxycarbonyl, benzyl, benzyloxycarbonyl and 2,2,2-trichloroethoxycarbonyl groups.

The protective groups R<7>, R8, R9, R10, R11 or R<12> can be removed using commonly known techniques, whereby a compound of formula (I) is produced. Thus, an arylmethyl group such as benzyl can be cleaved by hydrogenolysis in the presence of a noble metal catalyst (eg palladium on charcoal); an alkyl group protecting a hydroxyl group or an alkylenedioxy group protecting two hydroxyl groups can be cleaved under such conditions, e.g. with hydrogen bromide or boron tribromide, and an acyl group can be removed by hydrolysis under basic conditions.

When it is desired to prepare a physiologically acceptable salt of a compound of formula (I), the product from any of the above methods can be converted into a salt by treating the free base with a suitable acid using commonly known methods.

Physiologically acceptable salts can also. is prepared from other salts, and this includes other physiologically acceptable salts, of the compounds of formula (I) using commonly known methods.

Enantiomers of compounds according to the present invention can be prepared by dissolving the corresponding racemic mixtures using commonly known methods, e.g. an optically active dissolving acid, see e.g. "Stereochemistry of Carbon Compounds." at E.L. Eliel (McGraw Hill 1962) and "Tables of Resolving Agents" by S.H. Wilen.

The methods described for the preparation of compounds of formula (I) can each be used as a final step in a long synthesis if this is desired. The same general methods can be used for introducing the desired groups at an intermediate step in a step-by-step preparation of the desired compound, and it is understood that these general methods can be combined in different ways in a multi-step process.

Compounds of formula (II) can be built up by one or more acylation reactions which involve reacting a suitable amine with a suitable acylating agent. In the following description and discussion, Z1, Z<2>, Z<3>, Z<4> and X<1> are as defined in connection with formula (II), if nothing else is indicated.

Thus, e.g. compounds of formula (II) where Z<1> is oxygen, are prepared by reacting a compound of formula (VI) or a reactive derivative thereof, with a compound of formula (VII)

(where X<2> represents a C4_6 alkylene chain, optionally substituted with one or more alkyl or hydroxy groups, or optionally containing one or two double or triple bonds, or optionally interrupted by an oxygen atom or sulfur atom or a sulfone (-SO2-) group. Compounds of formula (II) where Z<2> is oxygen can be prepared by reacting a compound of formula (III) with a compound of formula (VIII)

or a reactive derivative thereof.

Compounds of formula (II) where Z<3> is oxygen can be prepared by reacting a compound of formula (IV) with a compound of formula (IX)

or a reactive derivative of this compound.

Compounds of formula (II) where Z<4> is oxygen can be prepared by reacting a compound of formula (X) with a compound of formula (XI) or a reactive derivative thereof

Compounds of formula (II) where Z<2> and Z<3> are oxygen can be prepared by reacting a compound of formula H2C-X<1->CO2H (XII) or a reactive derivative thereof, with compounds of formula (III) and (IV).

Compounds of formula (II) where Z<1> and Z<4> are oxygen can be prepared by reacting the compounds of formulas (VI) and (XI) or their reactive derivatives with a compound of formula HR<7>N-X-NHR <8> (XIII).

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

A number of compounds of formula (VI) are known and can be prepared in a conventional manner. Other compounds of formula (VI) can be prepared by hydrolysis of compounds of formula ArCH2CN (XIV) using usual reaction conditions, e.g. basic hydrolysis.

Compounds of formula (VII) where Z<4> is oxygen can be prepared by reacting a compound of formula (XI) or a reactive derivative thereof, with a compound of formula (XIII) in the presence of a coupling agent such as N ,N'-carbonyldiimidazole as described above.

The compounds of formulas (III), (IV), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) and the alkylating agents LXL

are either known compounds or can be prepared by analogous known methods to those described for the preparation of known compounds. Suitable methods are described in the following examples.

Compounds of formula (V) can be prepared using methods (1) and (2).

The following examples illustrate the invention. All temperatures given in °C. Solutions were dried using magnesium sulfate or sodium sulfate. Thin layer chromatography (t.l.c.) was performed on silica plates. FCC flash column chromatography was performed on silica (Merck 9385).

The following abbreviations are used: THF - tetrahydrofuran; Pd-C - palladium on carbon, PdO-C - palladium oxide on carbon.

Intermediate 1 is 2- etvl- 3. 4- dimethoxysvbenzeneacetonitrile Intermediate 2 is 2- ethyl- 3. 4- dimethoxysvbenzenetanamine hydrochloride

Intermediate product 3

2- ethyl- 3. 4- bis(phenylmethoxy)benzenethanamine hydrochloride Intermediate ((10 g) in (56 mL) dry THF was added borane-THF complex (1M in THF, 84 mL) over 5 minutes at 0°, then refluxed for 6 h under nitrogen.The mixture was cooled, added (25 mL) methanol and then refluxed for 30 min., cooled, acidified with 2N hydrochloric acid and again held at 60° for 1 hr. The mixture was treated with (250 mL) ethyl acetate, 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 6 g of an oil which was dissolved in ethereal methanol and then treated with ethereal hydrogen chloride to give the title compound as white needles, mp 155-165°.

Intermediate 4 2.2.2-trifluoro-N-f2-(2-ethyl-3.4-dimethoxyphenyl)ethyl-acetamide (22.3 ml) triethylamine (17.0 g) of intermediate 2 was added to (120 ml) dry dichloromethanenitroene. The solution was then cooled in an ice bath. (22.6 mL) of trifluoroacetic anhydride in 80 mL of dry dichloromethane was added dropwise over 1 hour. The solution was stirred for 2 hours, washed successively with 2N hydrochloric acid, 8% sodium bicarbonate and then with brine, then dried and concentrated in vacuo. The resulting oil was purified by FCC using ether/hexane (1:1) as eluent to give the title compound as a white solid (18.1 g), m.p. 80-81°.

Intermediate 5

2- etvl- 3. 4- dimethoxybenzeneacetic acid

A solution of (0.93 g) of intermediate: I and; ((6. g)) sodium hydroxide in (40 ml) ethanol. and, (2© m'l)> vaironi b>le boiled. below: reflux for 2 4 hours. UpHøsmimgen! isle evaporated, in. vaikuumi,, acidified with 2N hydrochloric acid and extracted: with ether.. The extract, bile washed with water, dried and evaporated.. ResildiuBeft: He purified by FCC using ether/hexane (1:1) as eluent , and this gave (0.75 g) of the title compound as white crystals, m.p. 89-90°.

Intermediate 6

2-methyl-3,,4-dimethoxybenzeneacetic acid (6.6 g) m.p. 102-104° was prepared from 2-methyl-3,4-dimethoxybenzeneacetonitrile (16 g) using the procedure from intermediate 5.

Intermediate product 7

2-ethyl-3.4-bis(phenylmethoxy)benzeneacetonitrile

(i) 2-ethyl-3.4-dihydroxybenzeneacetonitrile

A solution of boron tribromide in (30 mL 1M) dichloromethane was carefully added-under water bath cooling to a solution of (2.05 g) of intermediate 11 in (15 mL) dry dichloromethane. The resulting solution was stored at room temperature for 2.5 hours and then ice was added. After a further 15 minutes, the mixture was diluted with ether. The organic phase was separated, washed with brine, dried and evaporated. The produced oil was dissolved in ether/cyclohexane (1:2, 250 ml) and filtered through hyflo. The filtrate was concentrated in vacuo to 100 ml and the supernatant was decanted from a solid which was then dried to give (1.68 g) the title compound, m.p. 101-103°. (ii) 2-ethyl-3,4-bis(phenylmethoxy)benzeneacetonitrile (1.94 g) solid potassium carbonate was added at room temperature to a solution of (1 g) from step (i) in dry dimethylformamide. (2.41 g) of benzyl bromide was added. The mixture was stirred overnight and ice and water were added. The mixture was extracted with ether and the extracts were washed with water, dried and evaporated. The produced oil was purified by FCC using ether/hexane (1:1) as eluent, this gave (1.82 g) of the title compound as a yellow oil which slowly crystallized, m.p. 44-47.5°. Intermediate 8 3. 3' thiobisfN- f2-(2-ethyl-3,4-dimethoxyphenyl)ethyl1propanamide A solution of (2.09 g) of intermediate 2 in the form of its free base and (0.89 g) 3.3 '-thiodipropionic acid in (120 ml) dry dichloromethane at 0° was treated with (5.5 g) diphenylphosphoryl azide followed by (2.02 g) triethylamine. The solution was stirred at 21° under nitrogen for 5 hours. (200 mL) of ethyl acetate was added, the mixture was concentrated to ca. 100 ml, washed with 2N hydrochloric acid, 8% sodium bicarbonate and saturated brine, dried and evaporated to give a viscous oil. The oil crystallized from a mixture of ethyl acetate and hexane to give (2.17 g) of the title compound as white needles, m.p. 115-117°.

Intermediates 9-12 were prepared in a similar manner.

Intermediate 9 3. 3'-oxybis[N-f2-\2-ethyl-3,4-bis(phenylmethoxy)phenyl1ethyl1propane-amide (9.31 g), m.p. 159-160° from intermediate 3 (18.1 g) and 3,3'-oxydipropanoic acid (4.05 g).

Intermediate 10

N. N'- bis f 2- r 2- etvl- 3. 4- bis(phenvlmethoxy) phenvl] etvl1- 4- oxoheptane diamide (6.93 g), m.p. 188-192° from intermediate 3 (9.39 g) and 4-oxoheptanedioic acid. (2.26g).

Intermediate 11

N. N'-bis-f 2-(2-ethyl-3,4-dimethoxyphenyl)ethyl1-3-methylhexanediamide (1,1g), m.p. 152-153° from intermediate 2 (1g) and 3-methylhexanedioic acid (0.38g).

Intermediate 12 3. 3'-sulfonylbis TN- r 2- ( 2- ethyl- 3: . . 4'- dimethoxy)' phenv/ 11 ethylpropanaamM (1.2g), m.p. 164-166° from intermediate 2: (lg); and 3,3'-sulfonic, γ/1-dipropionic acid (0.5g)".

Intermediate 13

N-(6-aminohexyl)-2-ethyl-3. 4-dimethoxybenzena Getamide

(15g) of carbonyldiimidazole was added to a solution of (20g) of intermediate 5 in dry dichloromethane at 0° under nitrogen. The mixture was stirred at room temperature for 2 hours and then a solution of (50g) 1,6-hexanediamine in (500ml) dichloromethane was added dropwise at 0°. The solution was stirred at room temperature for 1 day and then concentrated in vacuo. The residue was acidified with (2N hydrochloric acid) and then washed with ether. The aqueous layer was basified with (2N sodium hydroxide) and extracted with dichloromethane. The extracts were washed with water, dried, concentrated in vacuo to give a white waxy solid. Recrystallization from methane/ethyl acetate gave the title compound. as (26g) white powder, m.p. 136-138°.

Intermediate 14

N. N/ - ( 1. 6- hexanediyl- l) bisT3 . 4- d^ methoxy- 2- methylbenzeneacetamidl (5g) m.p. 176-178° was prepared from intermediate 6 (6.5g) and 1,6-hexanediamine. (1.74g) in a mixture of dichloromethane and dimethylformamide (1:1), using the method from intermediate product 13.

Intermediate 15

4- etvul- l. 3- benzodioxol- 5- carboxyl aldehyde

(320 ml, 1.6M) n-butyl lithium in hexate was added under nitrogen to a stirred solution of (100g) N-(1,3-benzodioxol-5-ylmethylene)-cyclohexaneamine (100g) in (500ml) dry THF at -78°. After 15 minutes, ethyl iodide (50 ml) was added and the mixture was slowly heated to -50°• Water was added and the mixture was extracted with ether. The extracts were concentrated in vacuo and the concentrate heated to (250ml) 2N hydrochloric acid on a steam bath for 20 minutes. The resulting solution was diluted with water and extracted with ether. The extracts were concentrated in vacuo and the concentrate heated to 250 ml of 2N hydrochloric acid on a steam bath for 20 minutes. The resulting solution was diluted with water and extracted with ether. The extracts were dried and evaporated to give (38g) of the title compound as a pale yellow oil. T.l.c. (ether:hexane, 1:9) Rf 0.3.

Intermediate 16

N- T6- r r( 3. 4- dimethoxy- 2- methylphenyl) acetvnaroino1hexyl1( 2- ethyl-3. 4- dimethoxysv) benzeneacetamide

(0.54g) of carbonyldiimidazole was added portionwise to a stirred cooled solution of (0.68g) of intermediate 6 in (20ml) of dichloromethane. Nitrogen was bubbled through the mixture which was stirred at room temperature for 15 hours. (lg) of intermediate 13 in (25ml) dry dichloromethane was added dropwise to a cooled solution. The mixture was stirred at room temperature for 24 hours. The solution was then concentrated in vacuo and the solid recrystallized from methanol to give (1g) of the title compound as a white solid, m.p. 164-166°.

Intermediate 17

N,N'-(1.7-heptanedivl) bis TN-f 2-(2-ethyl-3.4- dimethoxyphenyl)ethyl]-2. 2, 2- trifluoroacetamidl

A suspension of (0.43g, 50% dispersion) of sodium hydride in (25ml) was stirred for 30 minutes under nitrogen. Hexane was poured off and replaced with (25ml) dry dimethylformamide and a solution of (3g) of intermediate 4 in (10ml) dry dimethylformamide to which was added sodium hydride suspension. The reaction mixture was stirred at 21° for 45 minutes. (1.16g) of 1,7-dibromoheptane was added and the reaction mixture was cooled at 0° and then heated under reflux for 7 hours. After 2 days at 21°, the solution was acidified with 2N hydrochloric acid and extracted with ether. The combined extracts were dried and concentrated in vacuo to give (3.5g) of a yellow oil. Purification by FCC using ether/hexane (1:1) as eluent gave (2.3g) of the title compound as a colorless oil. T.l.c. ether-hexane (1:1) Rf 0.3.

Intermediate 18

N. N' - ( 1. 6- hexanedivl) bis r 2- etvl- 3 . 4- dimethoxy. ybearzenacefcamidl;

A mixture of (8.6g) of intermediate 5>, (18ml.); thionyl chloride and (480ml) dichloromethane were refluxed for 2 hours and. evaporated in vacuo to a solid. Era touched. sraspension'. to row

(15g) of this product, (3.6g) 1,6-diaminohexane and (8g) anhydrous potassium carbonate in (400ml) dichloromethane were refluxed for 1 day. The solvent was evaporated, water was added and the mixture was extracted with chloroform. The extract was dried and evaporated to a solid which was treated with a mixture of ether and hexane to give (5.5g) of the title compound as a pale yellow solid, m.p. 169-172°.

Intermediate 19

4- etvl- g. Q- dimethyl- 1. 3- benzodioxol- 5- ethanamine hydrochloride m.p. >3 00°, t.l.c. (toluene:ethanol:ammonia 78:20:2) Rf 0.52 was prepared from intermediate 15 by a sequence of conventional reactions involving condensation with malonic acid in the presence of a base, catalytic hydrogenation, alkylation with methyl iodide and n-butyl lithium, a Curtius rearrangement using sodium azide followed by a solvolysis with benzyl alcohol„ and removal of the benzyl protecting group.

Intermediate 20

6- r r 2-( 2- ethyl- 3. 4- dimethoxyphenyl) ethyl 1aminol- 6- oxohexanoic acid (i) methyl 6- f r 2-( 2- ethyl- 3, 4- dimethoxyphenyl) ethylamino]- 6-oxohexanoate

A solution of (10g) 6-chloro-6-oxohexanoic acid methyl ester in (100ml) dry dichloromethane was added dropwise to a stirred and cooled

solution of (10.4g) of intermediate 2 and (5.65g) triethylamine

in (100ml) dichloromethane. The reaction mixture was stirred for 1 hour at room temperature, the solvent was removed in vacuo and the residue was purified by FCC using ether as eluent to give (15g) of the title compound as a white solid, m.p. 37-39°.

(ii) 6- f f2-(ethyl-3.4-dimethoxyphenyl)ethyl]aminol-6- oxohexano-insvre

A mixture of (11g) of the product from step (i) (200ml) of a 2N sodium hydroxide solution and (300ml) ethanol was refluxed for 1 hour. The solution was cooled and poured into 1 liter of water. The mixture was washed with ether, acidified with 2N hydrochloric acid and then extracted with ether. The extracts were washed with water, dried and evaporated to give (8.4g) the title compound as a white solid, m.p. 92-94°.

Intermediate 21 N- r 2-( 4- ethyl1- 1. 3- benzodioxol- 5- y1V- 1. 1- dimethylethyl1- N'- r 2- f 2-etvl- 3. 4- dimethoxyphenyl) ethyl 1 hexanediamide

(.0.74g) ethyl chloroformate was added to a stirred solution of (2.17g) of intermediate 20 and (1.01g) in (80ml) dry dichloromethane at 0-5°. The reaction mixture was stirred for 10 minutes, after which a solution of (1.15 g) of intermediate 19 in (20 ml) of dry dichloromethane was added dropwise over 10 minutes. After another 20 minutes, the solution was washed with 8% sodium bicarbonate solution followed by 2N hydrochloric acid. The solution was dried and evaporated to dryness. The residue was purified by FCC using ethyl acetate as eluent to give (1.4g) of the title compound as a white solid, m.p. 103-104°C.

Intermediate 22

N, N/- bis- f 2- f 2- chloro- 3. 4- dimethoxyphenyl) ethyl] hexanediamide

A mixture of (2g) 2-chloro-3,4-dimethoxybenzenetanamine, (0.85g) adipoyl chloride and (1.3ml) triethylamine was stirred in (40ml) dry acetonitrile at room temperature for 1 hour. The solvent was removed in vacuo and the remaining white solid was stirred with water for 30 minutes, filtered off and dried in vacuo at 90° to give (2g) of the title compound, m.p. 159-161°.

Intermediate 23

N- r 2-(3. 4- dimethoxy-2- methylphenyl) etYl1N,- r2-( 2- etvl- 3. 4- dimethoxy envl)-etvllhexanediamide

(23.3g) diphenylphosphoryl azide in (100ml) dry dichloromethane was added to a stirred cooled (0o) suspension of (14.3g) of intermediate 20(ii) and (9.81g) 2-methyl-3,4-dimethoxybenzenetanamine hydrochloride in (500ml) dry dichloromethane under nitrogen. (8.58g) of triethylamine was added to the suspension and this was then stirred at 21° for 6 hours. The solution was then diluted with (300ml) dichloromethane and washed with (2x500ml) 2N hydrochloric acid, water and aqueous sodium carbonate, then dried and evaporated to a semi-solid. Treatment with ether gave (13.4g) of the title compound as a white solid, m.p. 165-168°.

Example 1

4. 4' - ftiobisf( 3. 1- propanedivlimino)- 2. 1- ethanediyl] Ibis r 3- ethyl- 1. 2-benzenediol]. dihydrobromide dihydrogen

(i) N. N^ ftiobisO . 1- propane divl) ] bisr2- ethyl- 3 . 4- dimethoxy-benzenetanamine]. dihydrochloride

Borane - THF complex (1M in THF; 30ml) was added to a solution of (2.1g) of intermediate 8 in (150ml) dry THF at 21° under nitrogen. The mixture was stirred and refluxed under nitrogen for 21 hours, then cooled and evaporated. 2N hydrochloric acid was added to the residue, and the mixture was stirred and held at 100° for 3.5 hours. It was then cooled and basified 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 a viscous oil which was dissolved in methanol. Ethereal hydrogen chloride was then added, the solvent was evaporated, and the remaining solid was recrystallized from a mixture of methanol, ethyl acetate and hexane to give (0.97g) of the title compound as a white powder, m.p. 184-186°.

(ii) 4 . 4'-rthiobisr (3.1-propanediylimino) - 2. 1-ethanediyl 1bisf3-etvl-1. 2- benzenediol]. dihydrobromide dihydrogen

A solution of (400mg) of the product from step (i) in (5ml) ethanol and (5ml) water was basified with 2N sodium carbonate. The mixture was extracted with ethyl acetate, and the extracts were evaporated to an oil which was dissolved in (50ml) dichloromethane. A solution of boron tribromide in (5.0ml, 1M) dichloromethane was added dropwise to the vigorously stirred solution. The resulting mixture was stirred at 21° under nitrogen for 18 hours and then cooled: to 0°. Methanol was added and the solution was refluxed for 45 minutes, cooled and evaporated. The solid was dissolved in absolute ethanol and hexane was added dropwise to the vigorously stirred solution until a gummy precipitate was obtained. The solvent was poured off and the residue Me dried in vacuo to give (344mg) of the title compound as a white foam.

Analysis found: C,46,1;H,6,3;N,3,9 c26H40N2°4s-2HBr-2H2° requires: C,46,3;H,6,8;N,4,2.

Example 2' 4 . 4 ' - f sul f onylbis IT ( 3 . 1- propanedivlimino) - 2 . 1- ethanediyl " 11 bis [ 3- ethyl-1, 2- benzenediol]. dihydrobromide sesquihydrate

(i) N.N'- fsulfonbis(3.1-propanediyl)lbisr2-ethyl-3.4-dimethoxy-benzenetanamine]. dihydrochloride

Borane-THF complex (1M; 6ml) was added to a solution of (0.6g) of intermediate 12 in (50ml) THF at 0° under nitrogen. The solution was stirred and refluxed for 18 hours, cooled and concentrated in vacuo. 2N hydrochloric acid was added to the residue, and the mixture was stirred and held at 100° for 1 hour. On cooling, a white solid precipitated which was collected and dried in vacuo, giving (0.4g) of the title compound as a white powder, m.p. 212-215°.

(ii) 4. 4^ rtiobisf( 3. 1- propanedivlimino)- 2. 1- ethanedivll1bis r3-ethyl- 1. 2- benzenediol]. dihydrobromide di<y>drate

(9ml; 1M) boron tribromide was added to a stirred suspension of (0.6g) of the product from step (i) in (90ml) dry dichloromethane. The mixture was stirred at 21° for 1 day under nitrogen. The unclear mixture

was cooled to 0° and carefully treated with methanol. The solution was then refluxed for 1 hour, cooled and concentrated in vacuo to give (0.6g) of the title compound as a pale pink solid, m.p. 130-133°, soften at 90o.

Analysis found: C,44.5;H,6,1;N,3,8.

<c>26<H>4°6s-2HBr 1'5H2° requires: C,44.8;H,6.4;N,4.0%.

Example 3

4- r 2- f f 6- ff 2-( 3 . 4- dihydroxy- 2- methylphenyl betvil aminolhexyl"!-amino] - ethyl") - 3- ethyl- 1. 2- benzenediol dihydrobromide (i ) N- r 2 - ( 3 . 4 - dimethoxy v- 2 - methyl phenyl) ethyl "|- N/-[ 2-( 2 - ethyl - 3. 4-dimethoxyphenyl) ethyl 1- 1. 6- hexanediamine dihydrochloride ( 6ml, 1M) borane-THF complex was added dropwise to a stirred solution of (500mg) of intermediate 16 in (30ml) dry THF at ice bath temperature and under nitrogen.The mixture was refluxed for 20h and methanol was added to a cooled -solution, which was then evaporated in vacuo. The residue was heated in 2N hydrochloric acid and refluxed for 4 hours. Solution was cooled, and the precipitated solid was collected and dried to give (300ml) of the title compound which a white powder, m.p. 263° (decomposition). (ii) 4— f 2 f r 6— ff2-( 3. 4- dihydroxy- 2- methylphenyl) ethyl1amino1-hexvl1amino] ethyl1- 3- ethyl- l. 2 - benzenediol dihydrobromide A solution of (l.2ml) boron tribromide in (lOml) dichloromethane n was added dropwise under nitrogen to a stirred cooled solution of (1.2g) of the product from step (i) in (100ml) dry dichloromethane at 0°. The mixture was stirred at room temperature for 5 hours, after which methanol was added. The mixture was evaporated in vacuo to give a solid which was recrystallized from methanol/ethyl acetate to give (1g) of the title compound as a white powder,

sm.p. 178-180°.

Analysis found: C,50,5H,6,6;N,4,4;

<c>25<H>38<N>2°4-2HBr requires: C50.7;h;6.8;N,4.7%

Example 4

4. 4/- ride. 6- hexanediylbis( imino-2. 1- ethanedivl) Ibis r3- ethyl- l. 2-benzenediol] dihydrobromide

(i) N. N/- bis r 2-( 2- ethyl- 3. 4- dimethoxyphenyl) ethyl 1- 1. 6- hexanediamine dihydrochloride

A suspension of (5.2gj of intermediate 18 in (220ml) dry THF was cooled to 0°, and under nitrogen (65ml) 1M borane-THF complex was added. The mixture was refluxed for 5 hours. The solution was cooled, treated with methanol and evaporated in vacuo. The residue in 2N hydrochloric acid was heated for 20 hours and then cooled. The white precipitate that had collected was filtered off and dried to give (2.78g) of the title compound, mp 223-225 °.

(ii) . 4. 4'-[ 1. 6- hexanediylbis( imino-2... 1- ethanedivl) bis\ 3- ethyl- 1. 2-benzenediol lldtihydthyrobromide

two ,,87</>gi)) bortribiromdid! was added dropwise to a solution of (lg) of the product. (1) in (70 mL) dry dichloromethane at 0° under n-i.trogerø.. The mixture' was then stirred at room temperature for 18 hours, cooled to 5<®1> agj then drapev/ice! treated with methanol. Solution-a' bflie boiled under reflux for 1 hour and then evaporated in vacuo, somewhat. which gave a solid which was recrystallized from methanol and ethyl acetate to give (0.75g) of the title compound as a white solid, m.p. 205-207°.

Analysis found: C,52.0;H,7.1;N,4.4

<c>26H40N2°4-2HBr requires: C,51.5;H,7.0;N,4.6%

Example 5 was prepared in a similar way:

Example 5

(i) N,N'-bis r 2-(2-ethyl-3.4-dimethoxyphenyl)ethyl 3-methylhexane-1. 6-diamine dihydrochloride (0.90g), m.p. 198-200°.

From intermediate 11 (0.9g).

(ii) 4. 4'-{(3- methyl- l. 6- hexanediyl) bis( imino-2. 1- ethanedivl) Ibis-C3- ethyl- l. 2- benzenediol dihydrobromide hydrate (0.81g), sm. p. 135-138°.

Analysis found: C,50.4;H,7.0;N,4.2;Br,25.2

<c>27H42N2°4'2HBr'H2° requires: C,50.7;H,7,2;N,4,3;Br,25.5%.

From Example 5(i) (0.8g).

Example 6

4. 4'- r 1. 6- hexanediylbis(imino- 2. 1- ethanedivl) Ibis f3- ethyl- 1. 2-benzenediol] dihydrobromide hydrate

A suspension of (400mg) of the product from Example 4(i) in deoxygenated 48% hydrobromic acid (10ml) was heated and refluxed for 24 hours. A slow stream of nitrogen was passed through the mixture. The resulting solution was cooled and evaporated in vacuo. The solid was recrystallized from methanol/ethyl acetate to give (300ml) of the title compound as a pale brown solid, m.p. 200-202°.

Analysis found: C, 49.7; H, 6.9; N , 4, 5. <c>26H40N2°4-2HBr-H20O-1/3EtOAc requires: C,50.2;H,6.8;N,4.3%

Examples 7-8 were prepared in two steps; first step using the method from example 4(i), while the second step was carried out using the method from example 6.

Example 7

(i) N.N' bis-r 2-(2-chloro-3.4-dimethoxyphenyl)ethyl-1.6-hexanediamine. dihydrochloride (1.18g), m.p. 254-256° (decomposition). From intermediate 22 (1.5g). (ii) 4, 4'- fl. 6-hexanediylbis(imino-2,1-ethanediyl)]bisf3-chloro-1,2-benzenediol]dihydrobromide (0.56g), m.p. 194-197°.

Analysis found: C,42,4;H,5,2;N,4,3

<c>22<H>30c<l>2<N>2°4-2HBr requires: C,42,7;H,5,2;N,4,5%

From Example.7(i) (0.6g).

Example 8

(i) N. N'- bis r 2- f 3. 4- dimethoxys- 2- methylphenyl) ethyl 1- 1. 6- hexanediamine dihydrochloride (3.57g), m.p. 270-272°.

From intermediate 14 (5g).

(ii) 4. 4'- Tl. 6- hexanedivlbis( imino-2. 1- ethanedivl) Ibisr3- methyl-1. 2- benzenediol 1 dihydrobromide hemihydrate (3.02g), m.p. 248-250°. Analysis found: C,48.2;H,6.6;N,4.5. <c>24<H>36N2°4-2HBrV4<H>2°- ^MeOH requires: C,48.7;H,6.2;N,4.6%

From Example 8(i) (4.4g).

Example 9

4 ^'- oxvbisf 3 . 1- propane diyl ( imino) - 2 . 1- ethanediyll 1bisr3- etvl- l . 2-benzenediol 1dihydrochloride hydrates

(i) N. ET- roksvbisn . 1- propanediyl) Ibis f 2- ethyl- 3, 4- bis(phenylmethoxy) benzenetanaminl dihydrochloride

(83ml; 1M in THF) borane-THF complex was added to a solution of (8.30g) of intermediate 9 in (500ml) dry THF at 21° under nitrogen. The mixture was stirred and refluxed under nitrogen for 5.5 hours, then cooled and evaporated. 2N hydrochloric acid and

THF was added to the residue, and the mixture was refluxed for 1 hour. and then cooled. The THF was then evaporated and the mixture was filtered. The solid residue was washed with water and then recrystallized from methanol/ethyl acetate/hexane to give (5.14g) of the title compound as a white powder, m.p. 192-193°. (ii) 4 . 4'- roxvbisr( 3. 1- propanedivlimino)- 2. l- ethanedivl] Tbisf3-etvl- 1. 2- benzenediol1 dihydrochloride acetate.

A solution of (0.66g) of the product from step (i) in (130ml) methanol was hydrogenated at room temperature and atmospheric pressure, using a pre-reduced 10% PdO-C catalyst (150ml wet 50 w/w material) until uptake of hydrogen was complete. The mixture was filtered and the filtrate evaporated. The resulting gum was crystallized from methanol/ethyl acetate to give (287mg) of the title compound as gray crystals, m.p. 203-06° (decomposition).

Analysis found: C,56.3;H,7.6;N,4.95. <C>26<H>40N2°5'2HC1-H2° requires: C,56.6;H,7.6;N,5.1%

Example 10

4. 4/- r4- hvdroksv- l. 7- heptanediylbisf imino- 2. 1- ethanedivl) Ibis[ 3-etvl- 1. 2- benzenediol1dihydrochloride (i) 1. 7- bis T2- r2- ethyl- 3 . 4-bis(phenylmethoxy)phenyl"|ethyl 1amino]-4-he<p>tanol dihydrochloride (6.42g), m.p. 168-183° was prepared from intermediate 10 (6.42g) using of the procedure from Example 4(1) except that the crude product was treated with boiling ether. (ii) 4.4'-f 4-hydroxy-l.7-heptanediylbis(imino-2,1-ethanediyl)]-bis r 3 - ethyl-1.2-benzenediol1dihydrochloride (2.43g)

Analysis found: C,58.9;H,8,3;N,4,9;C1,12,7. <C>27<H>42N2°5-2HC1 requires: C,59.2;H,8.1;N,5.1;Cl,13.0%

was prepared from the product of step (i) (4.00g) using the procedure of Example 9(ii).

Example 11

3- ethyl- 4- r2- f f 6— ff2-( 2- ethyl- 3. 4- dihydroxyphenyl)- 1. 1- dimethyl-ethyl1amino1hexyl1amino1 ethyl1- 1. 2- benzenediol dihydrobromide (i) N-[ 2-( 4 - etvl- l. 3- benzodioxol-5-yl)- 1. 1- dimethylethyl1- N'-r2-( 2- ethyl- 3. 4- dimethoxyphenyl) ethyl1- 1. 6- hexanediamine dihydrochloride

A suspension of (1.2g) of intermediate 21 in (60ml) dry benzene was added dropwise to a stirred suspension of (0.4g) lithium aluminum hydride in (60ml) ether at 0-5° under nitrogen. The resulting mixture was then refluxed for 20 hours. The mixture was cooled, treated with a 2N sodium hydroxide solution and then extracted with ether. The extracts were washed with water, dried and evaporated to give a pale brown oil.

(0.2g) of this oil in (25ml) dry ether was treated with ethereal hydrogen chloride to give a white solid which was crystallized from methanol/ethyl acetate, and this gave the title compound as white plates (0.18g), sm .p. 223-225°. (ii) 3- ethyl- 4- r2- r r6- fr2-( 2- ethyl- 3, 4- dihydroxyphenyl)- 1. 1-dimethylethyl")- aminolhexyl 1 amino] ethyl 1 - 1. 2- benzenediol dihydrobromide ( 0.29g), mp 233-235°.

Analysis found: C,52.8;H,7.4;N,4.3.

<c>28N44N2°4-2HBr requires: C,53.0;H,7.3;N,4.4%

was prepared from (0.54g) of the product from Example 11(i) by the method of Example 3(ii).

Example 12

( E. E)- 4 . 4'- T2 , 4- hexadiene-1, 6- diyIbis( imino-2. 1- ethanediyl) ~| bisf 3-ethyl- 1. 2- benzenediol] dihydrobromide

(i) fE. E)- N, N,-bisr2-(2-ethyl-3.4-dimethoxyphenyl)ethyl1-2,4-hexadiene-1. 6- diamine dihydrochloride

A mixture of (4.19g) of intermediate 2 and (1,1g) (E,E)-2,4-hexadiendial was refluxed in (250ml) dry benzene for 1 hour. The solution was then concentrated in vacuo. The residue in (150ml) absolute ethanol was treated with (1.51g) sodium borohydride. The reaction mixture was stirred at room temperature for 1.5 hours, diluted with water, stirred for 0.5 hour, diluted with more water and then extracted with dichloromethane. The extracts were dried and concentrated in vacuo. The oil obtained was dissolved in methanol and treated with an excess of ethereal hydrogen chloride. The resulting solution was concentrated in vacuo to give a solid which was crystallized from methanol/ethyl acetate to give (3.03g) of the title compound as a white solid, m.p. 247-250°.

(ii) ( E. E)- 4. 4/- r2. 4-hexadiene-l. 6-divlbis(imino-2.1- ethanediyl) 1-bis[ 3-etvl-l. 2- benzenediol 1 dihydrobromide (456mg), m.p. 240-244°

(decomposition).

Analysis found: C,51,3;H,6,1;N,4,5.

c26H36N2°4-2HBr requires: C,51.8;N;6.4;N,4.7%

was prepared from (1.0g) of the product from step (i) by the method of example 1(ii), but replacing 2N sodium carbonate with 2N sodium hydroxide.

Example 13

4. 4'- fl. 7-heptanediylbis(imino-2.1-ethanedivl)1bisr3-etvl-1.2-benzenediol hydrobromide hydrate (2:5:2)

(i) N,N'-bis[2-(2-ethyl-3.4-dimethoxyphenyl)ethyl1-1.7-heptane-diamine dihydrochloride

A solution of (1g) of intermediate 17 in (300ml) methanol and (50ml) 2N sodium hydroxide was heated on a steam bath for 1 hour. After a further 18 hours at 21°, the solution was concentrated in vacuo and the residue was extracted with ether. The extracts were dried and concentrated in vacuo to an oil. Etheric hydrogen chloride was added dropwise to a solution of oil in dry ether. The white precipitate was filtered off and dried. Crystallized from ethanol/ethyl acetate gave (0.31g) of the title compound as a white solid, m.p. 233-235°.

(ii) 4 . 4' - fl. 7-heptanediylbis(imino-2.1-ethanediyl) ~| bis f 3- ethyl- l. 2-benzenediol hydrobromide hydrate ( 2:5:2) (0.5g), m.p. 182-185°. Analysis found: C,47,4;H,6,5;N,4,1;Br,29,3 <c>27H42N2°42-5HBrH2° requires: C,47,7;H,6,5;N ,4.1;Br,29.5%

was prepared from (0.45g) of the product of Example 13(i) using the procedure of Example 3(ii).

Example 14

N- f 2 — f 3. 4- dimethoxy- 2- ethyl1phenyl) ethyl]- N- f 2- f 3. 4- dimethoxy- 2-metvl- phenyl) ethyl1- 1. 6- hexanediamine. dihydrochloride (180ml, 1M) borane-THF was added dropwise to a stirred and cooled suspension of (1.45g) of intermediate 23 in (500ml) dry THF at 0°. The mixture was then refluxed for 5 hours. It was then cooled and added dropwise (200ml) methanol. The mixture was evaporated in vacuo and the residue heated together with (500ml) 2N hydrochloric acid at reflux for 2 hours. The resulting solution was cooled and the precipitate was filtered off and dried to give (12.6g) of the title compound as a white solid, m.p. 268° decomposition.

Claims (2)

1. Analogous method for the preparation of therapeutically active compounds of the general formula (I) and their physiologically acceptable acid addition salts, where R<1> is a halogen atom or a methyl, ethyl, n-propyl or n-butyl group, R<2>, R<3>, R<4> and R<5> are each hydrogen atoms or one or two of the groups R<2>, R<3>, R<4> and R<5> are a methyl or ethyl group; R<6> is a hydrogen or halogen atom, or a C1-4 alkyl group; and X is a C5-7 alkylene chain optionally substituted with a C1-4 alkyl or hydroxy group, or optionally containing one or two double bonds, or optionally interrupted by an oxygen or sulfur atom, or by a sulfone (-SO2-) group; characterized by (1) reducing a compound of formula (II) where R<7> and R<8> are each hydrogen and/or a protecting group Ar and Ar<1> represent the groups where R<9>, R10, R11 and R1<2> are each a hydrogen atom or a protective group; X<1> is a C2-5 alkylene chain optionally substituted with an alkyl or hydroxy group or optionally containing one or two double bonds or triple bonds or a carbonyl group, or optionally interrupted by an oxygen or sulfur atom or a sulfone (-SO2-) group; Z1, Z2, Z<3> and Z<4> are each 0, or the group C=Z<1>, C=Z2 and C=Z<3> are each the group CH2 and C=Z<4> can be the group CR<2>R<3>, provided that at least one but not more than two of the groups Z<1>, Z<2>, Z<3> and Z<4> is 0 and when Z<1> is 0 , then C=Z<2> is the group CH2, and when Z<3> is 0, then C=Z4 is the group CR<2>R<3>; and, if necessary, after the reduction removes any protecting groups that may be present; or (2) reacts the compound of formula (III) and (IV) where Ar, Ar<1>, R7, R8, R<9> and R1<0> are as defined in method (I) above, with an alkylating agent of formula L-X-L where L is a readily replaceable atom or group and, if necessary , removes any protecting groups that may be present; and optionally removes protective groups from compounds of formula (V) where R<7>, R8, R9, R10, R11 and R12 are as defined in method (1), except that at least one of the groups R<7>, R<8>, R<9>, R10, R11 or R<12> represents a protecting group; and optionally converts a compound of formula (I) or a salt thereof into a physiologically acceptable acid addition salt. 2. Process according to claim 1, for the preparation of the compound 4-[2-[6-[2-(3,4-dihydroxy-2-methylphenyl)ethylamino]-hexylamino]amino ethyl]-3-ethyl-1,2- benzenediol or physiologically acceptable salts of this compound, characterized in that corresponding starting materials are used.