NO173013B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ETHANOLAMINE DERIVATIVES - Google Patents

Description

This invention relates to methods for the production of new ethanolamine derivatives which have a stimulating effect on /32-adrenoreceptors.

Ethanolamine derivatives have previously been described as bronchodilators which have a stimulating effect on /3-adrenoreceptors.

Thus, for example, UK Patent Specification No. 2140800A describes phenethanolamine compounds of general structure

wherein R<1> and R<2> both represent hydrogen or C 1-6 alkyl;

m is an integer from 2 to 8;

n is an integer from 1 to 7; and

Ar is an optionally substituted phenyl group.

UK Patent Specification No. 2162842A and European Patent Specification No. 0178919A describe aminophenol compounds of general structure

wherein R<1> and R<2> both represent hydrogen or C 1-4 alkyl;

X denotes a C 1-7 alkylene, C 2-7 alkenylene or C 2-7 alkynylene chain;

Y denotes a C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene chain;

Ar denotes a phenyl group optionally substituted with one or more of a number of specific substituents; and Q denotes a group R<3>CO-, R<3>NHCO-, R<3>R<*>NS02-, R<5>SG2- where R<3> and R* both denote a hydrogen atom or a C1-4 alkyl group and R<5 >denotes a C1-4 alkyl group.

UK Patent Specification 2165542A describes dichloroaniline derivatives of general structure

wherein R<1> and R<2> both represent hydrogen or C 1-6 alkyl, X represents a C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene chain; Y denotes a C 1-4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene chain; and Ar denotes a phenyl group substituted with one or more of a number of specific substituents.

We have now found a new group of compounds that differ structurally from those in UK Patent Description No. 214 0800A, 2162842A and 2165542A and European Patent Description No. 0178919A and which have a desirable and useful activity profile.

Thus, the present invention provides compounds of general formula (I)

or a physiologically acceptable salt or solvate thereof, wherein Ar denotes where R<3> is a straight or branched C1-3 alkylene group,

where R<9> is a C 1-4 alkyl group,

X denotes a C 1-7 alkylene chain, Y denotes a C 1-7 alkylene chain, with the proviso that the total sum of carbon atoms in X and Y is 2 to 10;

Q denotes one

group; there

Z denotes an oxygen or sulfur atom.

It must be clear that the compounds of the general formula (I) have one or more asymmetric carbon atoms. The compounds produced according to the invention thus include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds produced according to the invention in which the carbon atom in the -CH group is i

OH

R configuration preferred.

Preferred compounds prepared according to the invention include 1-hydroxy-2-hydroxymethyl-4-[1-hydroxy-2-[[6-[2-(2-benz o[b]thienyl)ethoxy]hexyl]amino]ethyl]benzene; 5-[1-hydroxy-2-[[6-[[4-(2-thienyl)butoxy]hexyl]amino]ethyl]-1,3-benzenediol; N-[5-[2-[[6-[4-(2-benzo[b]furanyl)butoxy]hexyl]amino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;

and their physiologically acceptable salts and solvates.

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulfates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxybenzoates, 2- or 4- hydroxybenzoates, 4-chlorobenzoates, p-toluenesulfonates, naphthalenesulfonates, methanesulfonates, sulfamates, ascorbates, salicylates, acetates, diphenylacetates, triphenylacetates, fumarates, succinates, lactates, glutarate, gluconates, tricarballylates, hydroxynaphthalene carboxylates, for example 1-hydroxy- or 3-hydroxy -2-naphthalene carboxylates, or oleates. The compounds can also form salts with suitable bases. Examples of such salts are alkali metal (for example sodium and potassium), alkaline earth metal (for example calcium or magnesium) salts, and salts with organic bases (for example triethylamine).

Salts which have very little solubility in water are particularly suitable where the compounds are to be administered by inhalation or insufflation. Such salts include diphenyl acetates, 4,4'-methylenebis-3-hydroxy-2-naphthalene carboxylates and 1-hydroxy- and 3-hydroxy-2-naphthalene carboxylates.

The compounds produced according to the invention have a selective stimulating effect on /32-adrenoceptors, which furthermore have a particularly advantageous profile. The stimulatory action was demonstrated on isolated trachea from guinea pigs, where the compounds were shown to relax contractions induced by PGF2a or electrical stimulation. The compounds produced according to the invention have shown a particularly long duration of action in these tests.

The compounds produced according to the invention can be used in the treatment of diseases associated with reversible airway obstruction, such as asthma and chronic bronchitis.

The compounds produced according to the invention can also be used for the treatment of premature labour, depression and congestive heart failure and are also suggested to be useful for the treatment of. inflammatory and allergic skin diseases, glaucoma and for the treatment of conditions where it is beneficial to lower gastric acidity, particularly in the case of gastric and peptic ulcer formation.

Accordingly, the invention further provides compounds of formula (I) and their physiologically acceptable salts and solvates for use in the therapy or prophylaxis of diseases associated with reversible airway obstruction in humans or animals.

A suggested daily dose of active compounds for the treatment of a human is 0.005 mg to 100 mg which may conveniently be administered in one or two doses. The exact dose used will of course depend on the patient's age and condition and the route of administration. Thus, a suitable administration dose for inhalation would be 0.005 mg to 20 mg, for oral administration 0.02 mg to 100 mg and for parenteral administration 0.01 mg to 2 mg for administration by "bolus" injection and 0.01 mg to 25 mg when administered by infusion.

Hydroxy and/or amino groups present in the starting materials may need to be in protected form and the final step may be removal of a protecting group. Suitable protective groups and methods for their removal are, for example, those described in "Protective Groups in Organic Chemistry", Ed. J. F. W. McOmie (Plenum Press, 1973), and "Protective Groups in Organic Synthesis" by Theodora Greene (John Wiley and Sons, Inc., 1981). Thus, for example, hydroxyl groups can be protected by arylalkyl groups such as benzyl, diphenylmethyl or triphenylmethyl or as tetrahydropyranyl derivatives. Suitable amino-protecting groups include arylalkyl groups such as benzyl, α-methylbenzyl, diphenylmethyl or triphenylmethyl and acyl groups such as acetyl, trichloroacetyl and trifluoroacetyl. Common procedures for removing the protection can be used. Thus, for example, arylalkyl groups can be removed by hydrogenolysis in the presence of a metal catalyst (for example, palladium on carbon). Tetrahydropyranyl groups can be split off by hydrolysis under acidic conditions. Acyl groups can be removed by hydrolysis with a base, such as sodium hydroxide or potassium carbonate, or a group such as trichloroacetyl can be removed by reduction with, for example, zinc and acetic acid.

A compound of general formula (I) is prepared by alkylation using conventional methods of alkylation.

Thus, a compound of general formula (I) in which R<1> is a hydrogen atom is prepared by alkylating an amine of general formula (II)

followed where necessary by removal of any protecting groups.

The alkylation can be carried out using an alkylating agent of general formula (III):

(where L denotes a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy).

The alkylation is preferably carried out in the presence of a suitable acid scavenger, for example inorganic bases such as sodium or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine or pyridine, or alkylene oxides such as ethylene oxide or propylene oxide. The reaction is conveniently carried out in a solvent such as acetonitrile or an ether, for example tetrahydrofuran or dioxane, a ketone, for example butanone or methyl isobutyl ketone, a substituted amide, for example dimethylformamide or a chlorinated hydrocarbon, for example chloroform, at a temperature between ambient and the solvent reflux temperature.

In the general reactions described above, a compound of formula (I) obtained may be in the form of a salt, suitably in the form of a physiologically acceptable salt. Where desired, such salts can be converted to the corresponding free acids using conventional methods.

Physiologically acceptable salts of the compounds of general formula (I) can be prepared by reacting a compound of general formula (I) with a suitable acid or base in the presence of a suitable solvent, such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, for example methanol, ethanol or isopropanol.

Physiologically acceptable salts can also be prepared from other salts, including other physiologically acceptable salts of the compounds of general formula (I) using conventional methods.

When a specific enantiomer of a compound of general formula (I) is desired, this can be obtained by dissolving a corresponding racemate of a compound of general formula (I) using usual methods.

Thus, in one example, a suitable optically active acid can be used to form salts with the racemate of a compound of general formula (I). The resulting mixture of isomeric salts can be separated, for example by fractional crystallization into the diastereoisomeric salts from which the desired enantiomer of a compound of general formula (I) can be isolated by transfer to the desired free base.

Alternatively, enantiomers of a compound of general formula (I) can be synthesized from the appropriate optically active starting compounds using any of the general methods described herein.

Specific diastereoisomers of a compound of formula (I) can be obtained by conventional methods, for example by synthesis from a suitable asymmetric starting material using any of the methods described herein or by transfer of a mixture of isomers of a compound of general formula (I) to suitable diastereoisomeric derivatives, for example salts, which can then be separated by usual methods, for example by fractional crystallization.

The amines of formula (II) are either known compounds or can be prepared by methods analogous to those used for the preparation of the known compounds.

The following examples illustrate the invention. Temperatures are in °C. "Dried" refers to drying using magnesium sulfate or sodium sulfate unless otherwise noted. Thin layer chromatography (T.L.C.) was performed over SiO 2 . "Flash" column chromatography (FCC) was performed on silica (Merck 9385) using, unless otherwise indicated, one of the following solvent systems: A

- toluene:ethanol:0.88 ammonia,

B - ethyl acetate:methanol:triethylamine. The following abbreviations are used: DMF - dimethylformamide; DEA - N,N-diisopropylethylamine; TAB - tetra-n-butylammonium bisulphate. The starting compound 1 referred to below is α1-(aminomethyl)-4-hydroxy-1,3-benzenedimethanol.

Output connection 2

2- r f 4- f 6- bromohexyl) oxylbutylthiophene

A mixture of 1,6-dibromohexane (9.5 g), 2-thiophenebutanol (2.0 g), TAB (0.25 g) and 50% aqueous NaOH (8 mL) was stirred vigorously at 23° for 18 h . The mixture was diluted with water (50 mL), extracted with diethyl ether (2 x 50 mL) and the extracts were washed with water (50 mL) and brine (50 mL), dried and evaporated in vacuo to give a yellow oil (11 g ). Purification by FCC on silica and eluting with cyclohexane and then cyclohexane-ethyl acetate (4:1) gave a product (5.2 g) which was distilled in vacuo to give the title compound as a colorless oil (3.6 g), bp 185 -195°/0.8 torr. T.L.C. (ethyl acetate-cyclohexane 1:4) Rf 0.73.

Output connection 3

2- r 2- f( 6- bromohexyl) oxy1 ethyl1benzo fb] thiophene

2-benzo[b]thiophenethanol (2.20 g), 1,6-dibromohexane

(2.59 mL), TAB (0.25 g), aqueous 12.5 M sodium hydroxide (9 mL) and ether (20 mL) were stirred overnight at room temperature. The mixture was diluted with water (50 ml), extracted with ether (3 x 50 ml) and the combined dried extracts were evaporated. The residual oil was purified by FCC eluting with cyclohexane-diethyl ether (100:0->98:2) to give the title compound as a colorless oil (2.73 g).

Analysis Found: C, 56.55; H, 6.3; Br, 23.8; S, 9.4.

C16H2iBrOS requires

C, 56.3; H, 6.2; Br, 23.4; S, 9.4%

Example 1

N- r5- r2- lT6- r4-( 2 - benzo or b I furanvl) butoxy 1 hexvl 1 amino 1- 1-hydroxyethyl1- 2- hydroxypheny11methanesulfonamide- benzoate ( salt)

A solution of 2-[4-[(6-bromohexyl)oxy]butyl]benzo[b]-furan (790 mg) [5-[2-amino-1-hydroxyethyl)-2-hydroxyphenyl]methanesulfonamide (1.07 g) and DEA (1.2 g) in DMF (20 ml) were stirred at 100° for 3 h. The solvent was evaporated in vacuo leaving a light brown residue (2.2 g) which was purified by FCC and eluting with System A (90:10:1-^80:20:1) to give the base as a pale yellow oil (45 mg). A solution of this in methanol (10 mL) was treated with benzoic acid (11 mg), the solvent evaporated and the residue triturated under ether (10 mL) to give the title compound as a light brown solid (55 mg), mp 79- 80°.

Analysis Found C, 62.3; H, 7.1; N, 4.5; S, 5.0.

C27H38N206S.C7H6020.85 H20 requires

C, 62.2; H, 7.0;, N, 4.3; S, 4.9%

Example 2

N- r5- f2- rr6- f4-( 2- benzo r b1 furanyl) butoxy1hexyl1amino]- 1-hydroxyethyl1- 2- hydroxyvf enyl ~| methanesulfonamide 4, 4'- methylene bis-[ 3- hydroxyz- 2- naphthalene-carboxylate] salt ( 2:1)

A solution of 2-[4-[(6-bromohexyl)oxy]butyl]benzo[b]-furan (2.0 g) N-[5-(2-amino-1-hydroxyethyl)-2-hydroxyphenyl]- methanesulfonamide (3.48 g) and DEA (1.0 mL) in DMF (25 mL) were heated to 80° under nitrogen for 4 h, and the solvent was evaporated in vacuo to leave a dark brown oil. Purification by FCC and elution with System A (90:10:1) gave the free base as an immobile yellow oil (1.2 g). A portion of the base (341 mg) in methanol (20 mL) was refluxed under pamoic acid (170 mg) in methanol (5 mL) for 0.5 h. The clear solution was evaporated to give the title compound as a yellow foam (521 mg), mp 99-101°.

Analysis Found: C, 63.9; H, 6.5; N, 3.7; S, 4.25 C27H38N206S .1/2 C23H1606. 0.5H20 requires

C, 64.1; H, 6.6; N, 3.9; S, 4.4%.

Example 3

l- hydroxy- 2- hydroxymethyl- 4- rl- hydroxy- 2- f\ 6-\ 2-( 2 - benzo f b"] tieny 1) ethoxy 1 hexy 11 amino Vetvl 1 benzene

Starting compound 3 (1.55 g), starting compound 1 (1.00 g), DEA (1.2 mL) and DMF (14 mL) were stirred at 95-100° under nitrogen for 1 hour. The cooled mixture was evaporated (1 torr), treated with aqueous saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 x 540 mL). The combined dried organic extracts were evaporated onto silica gel (Merck 7734, 5 g) and the resulting silica gel plug was applied to an FCC column. Elution with System B (94:5:1-^89:10:1) gave, after trituration with ether, the title compound as a white solid (414 mg), mp 111-114.5°. T.L.C. (NEt 3 deactivated SiO 2 , System B 89:10:1) Rf 0.06.

Example 4

5- rl- hydroxy- 2- r f 6-[ 4-( 2- thienyl) butoxy1hexyl] amino1 ethyl1-1. 3- benzenediol. ( E)- 2- butenedioate ( 2:1) ( salt)

A solution of starting compound 2 (800 mg) in dry DMF (1 mL) was added to a stirred solution of 5-(2-amino-1-hydroxyethyl)-1,3-benzenediol (700 mg) and DEA (1.29 g) in dry DMF (15 ml) at 100° and stirred at 100° for 2 hours. The solvent was evaporated and the residue was purified by FCC and eluting with System A (80:20:1) to give a straw colored oil (550 mg). The oil in methanol (5 ml) was added to a solution of fumaric acid (100 mg) in methanol (5 ml), the methanol was evaporated and the remaining oil was triturated with dry ether to give the title compound as an off-white powder (550 mg), melting point 123-124°. T.L.C. (System A 80:20:1) Rf 0.25.

Example 5

l- hydroxy- 2- hydroxymethyl- 4- rl- hydroxy- 2- rf 6- r 2-( 2- benzo rblthienyl) ethoxy1hexyl1amino1ethvllbenzene, 4, 4'- methylene bis( 3- hydroxyv- 2- naphthalene- carboxylate) salt ( 2 :1)

A solution of 1-hydroxy-2-hydroxymethyl-4-[1-hydroxy-2-[[6-[2-(2-benzo[b]thienyl)ethoxy]hexyl]amino]-ethyl]benzene (0.378 g) in methanol (20 mL) was treated with 4,4'-methylenebis(3-hydroxy-2-naphthalene carboxylic acid) (165 mg) and heated at reflux for 1 hour. The mixture was cooled to room temperature, filtered and evaporated in vacuo. Trituration with dry ether gave the title compound as a yellow foam (380 mg), mp 86-93°.

Analysis Found: C, 67.9; H, 6.8; N, 2.15; S, 4.9.

C25H38NOAS. 0.5C23H1606. 0.4H20 requires

C, 68.0; H, 6.5; N, 2.2; S, 5.0%

Claims (2)

1. Analogous process for the preparation of a therapeutically active compound of formula (I) or a physiologically acceptable salt or solvate thereof, wherein Ar denotes where R 3 is a straight or branched C 1-4 alkylene group, where R<9> is a C 1-4 alkyl group, X denotes a C 1-7 alkylene chain, Y denotes a C 1-7 alkylene chain, with the proviso that the total sum of carbon atoms in X and Y is 2 to 10; Q denotes one group; there Z represents an oxygen or sulfur atom; characterized by: alkylation of an amine of formula (II) wherein Ar is as defined for formula (I); followed, if desired, by transferring the resulting compound of formula (I) or a salt thereof to a physiologically acceptable salt or solvate thereof. 2. Process according to claim 1, for the preparation of a compound of formula (I) selected from 1-hydroxy-2-hydroxymethyl-4-[1-hydroxy-2-[[6-[2-(2-benzo[ b]thienyl)ethoxy]hexyl]amino]ethyl]benzene» 5-[1-hydroxy-2-[[6-[[4-(2-thienyl)butoxy]hexyl]amino]ethyl]-1,3-benzenediol ; N-[5-[2-[[6-[4-(2-benzo[b]furanyl)butoxy]hexyl]amino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide; and their physiologically acceptable salts and solvates, characterized in that corresponding starting materials are used.