NO171451B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PHENETANOLAMINE DERIVATIVES - Google Patents

Description

This invention relates to methods for the production of phenethanolamine derivatives which have a stimulating effect on )S2-adrenoreceptors.

Phenethanolamine derivatives of general formula

in which Ar denotes groupings of the type described here later and R denotes, among other things, an alkyl, arylalkyl, aryloxyalkyl or an optionally substituted phenylalkyloxyalkyl group, have previously been described as bronchodilators which have a stimulating effect on /3-adrenoreceptors . Thus, for example, British Patent Specification No. 1200886 describes phenethanolamine compounds of general structure

wherein X denotes, inter alia, a hydroxyC1-6 alkyl group; R x denotes a hydrogen atom or an optionally branched C 1 -alkyl group; R 2 denotes, among other things, a hydrogen atom; and R 3 denotes a hydrogen atom or an optionally branched C 1-6 alkyl group, optionally substituted with hydroxyl or amino groups or heterocyclic rings, or R 3 denotes a cycloalkyl, arylalkyl or aryloxyalkyl group, optionally substituted with one or more alkoxy or hydroxyl groups.

UK Patent Description No. 2140800 describes phenethanolamine compounds of general structure in which R<1> and R<2> both denote hydrogen or C 1-4 alkyl; m is an integer from 2 to 8; n is an integer from 1 to 7; and Ar denotes an optionally substituted phenyl ring.

We have now found a new group of phenethanolamine derivatives which differ in structure from those previously described (for example British Patent Descriptions No. 1200886 and 2140800) and have a desirable and potentially useful activity profile.

Thus, according to the present invention, compounds of general formula (I) are prepared

and physiologically acceptable salts and solvates thereof, wherein

Ar denotes the group

wherein Q<1> denotes a straight or branched C 1-6 alkylene group, or

k denotes an integer from 1 to 8;

m denotes zero or an integer from 2 to 7;

with the proviso that the total sum of k and m is 4 to 12; and Q represents a naphthalenyl group.

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 in which the carbon atom i

The -CH(OH) group is in the R configuration preferred.

In the general formula (I), the chain -(CH2)k- can be, for example, a bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2 )5-, -(CH2)6- or -(CH2)7-. The chain -(CH2)m- can, for example, be -(CH2)2-, -(CH2)3-, -(CH2)A-, -(CH2)5- or

-(CH2)6- or it can be a bond.

Preferably, the total number of carbon atoms in the chains ~(CH2)k~°9~(CH2)m~ is from 0<3 with 6 tii °<3 with 12. The compounds in which the total sum of carbon atoms in the chains -(CH2)k- and - (CH2)m's 6, 7, 8, 9, 10 or 11 are particularly preferred.

In the compounds of formula (I), Q<1> can be for example -CH2-, -CH(CH3)-, -(CH2)2- or -(CH2)3-. A preferred group of compounds are those in which Q<1> denotes -CH2-.

The group Q is attached to the rest of the molecule at some available position on the naphthalenyl unit.

In a preferred group of compounds of general formula (I), Ar denotes the group (a) in which Q<1> denotes -CH2-, or group (b) and k is 5, and m is an integer from 1 to 4. Preferred compounds produced according to the invention is 4-hydroxy-α1-[ [ [6-[2-(2-naphthalenyl)ethoxy]hexyl]amino]-methyl]-1,3-benzenedimethanol, 5-[1-hydroxy-2[[6 -[(2-naphthalenyl)ethoxy]hexyl]amino]ethyl]-1,3-benzenediol, 4-hydroxy-a<1->[[[6-[2-(1-naphthalenyl)ethoxy]hexyl]amino] methyl]-1,3-benzenedimethanol, 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, benzenesulfonates, p-toluenesulfonates, naphthalenesulfonates, methanesulfonates, sulfamates, ascorbates, salicylates, acetates, diphenylacetates, triphenylacetates, adipates, fumarates, succinates, lactates, glutarates, 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 where appropriate. Examples of such salts are alkali metal (for example sodium and potassium) and alkaline earth metal (for example calcium or magnesium) salts and salts with organic bases (for example triethylamine).

The compounds produced according to the invention have a stimulating effect on /32-adrenoreceptors, 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. An extended duration of action has also been observed.

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 are also indicated as useful for the treatment of inflammatory and allergic skin diseases, congestive heart failure, depression, premature labour, glaucoma and the treatment of conditions where it is advantageous to lower gastric acidity, particularly in the case of gastric and peptic ulcer formation.

A suggested daily dose of active compounds for the treatment of a human is 0.005 mg to 100 mg which is conveniently administered in one or two doses. The exact dose used will of course depend on the age and condition of the patient and the route of administration. Thus, a suitable dose for administration by 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.

In the preparation of both starting compounds and final products, the final step in the reaction may be the removal of a protecting group. Suitable protecting groups and their removal are described below.

In a general method (1), a compound of general formula (I) can be prepared by alkylation. Common alkylation reactions can be used.

The compounds of general formula (I) are prepared according to the invention by alkylation of an amine of general formula

(II)

(wherein R6 is a hydrogen atom or a protecting group and R<7 >is a hydrogen atom) followed by removal of any protecting group where present.

The alkylation is carried out using an alkylation reagent of general formula (III):

(where Q is as above and may optionally contain a protecting group, and L is 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 conveniently takes place 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.

The protecting group may be any conventional protecting group as described, for example, in "Protective Groups in Organic Synthesis" by Theodora Greene (John Wiley and Sons Inc., 1981). Thus, for example, hydroxyl groups can be protected by arylmethyl groups such as benzyl, diphenylmethyl or triphenylmethyl, by acyl groups such as acetyl, or as tetrahydropyranyl derivatives. Examples of suitable amino-protecting groups include arylmethyl groups such as benzyl, α-methylbenzyl, diphenylmethyl or triphenylmethyl and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl.

The deprotection to form a compound of general formula (I) can be accomplished using conventional techniques. Thus, for example, arylmethyl groups can be removed by hydrogenolysis in the presence of a metal catalyst (for example, palladium on carbon). Tetrahydropyranyl groups can be cleaved by hydrolysis under acidic conditions. Acyl groups can be removed by hydrolysis with an acid such as a mineral acid, for example hydrochloric acid, or a base such as sodium hydroxide or potassium carbonate, and a group such as trichloroacetyl can be removed by reduction with, for example, zinc and acetic acid.

Amines of formula (II) are either known compounds or they can be prepared by methods analogous to those described for the preparation of known compounds. Starting compounds of formula (III) can be prepared from the corresponding alcohols of formula (X) using methods which can effect the transfer

For example, compounds of formula (III) where L represents a halogen atom can be prepared by reacting the compounds of formula (X) with a halogenating agent such as a triphenylphosphine-tetrahalomethane addition compound (conveniently formed in situ, for example by reacting triphenylphosphine and carbon tetrabromide ). The reaction can take place in the presence of a solvent such as a chlorinated hydrocarbon (for example dichloromethane) within a temperature range of 0 to 30°.

Alcohols of formula (X) can be prepared by reacting a compound of formula (XI):

(where L is as defined above) with a compound of formula

(XII):

The reaction can optionally take place in a solvent such as an ether (for example tetrahydrofuran or 1,2-dimethoxyethane), an alcohol (for example methanol) or an amide (for example dimethylformamide) at a temperature up to the boiling point of the solvent. The reaction can be carried out by first forming the anion of the compound of general formula (XII) by adding, for example, sodium, sodium hydride, potassium hydroxide or sodium hydroxide.

Compounds of formula (XI) can be prepared from the corresponding compounds of formula (XIII):

by the use of methods that may effect the transfer. For example, when L in general formula (XI) represents a hydrocarbylsulfonyloxy group (eg

methanesulfonyloxy), such compounds can be prepared by reacting the compounds of formula (XIII) with methanesulfonyl chloride in the presence of a base (for example triethylamine). The reaction suitably takes place in the presence of a solvent such as a halogenated hydrocarbon (for example dichloromethane) in a temperature range from 0 to 25°.

Compounds of formula (XIII) can be prepared by reacting a compound of formula (XIV) with a compound of formula (XV):

under conditions as described for the preparation of compounds of formula (X) above.

Compounds of formula (XIV) are either known compounds or they can be prepared from corresponding alcohols as described for the preparation of compounds of formula (III) above.

Compounds with the formulas (XII) and (XV) are either known compounds or they can be prepared by methods analogous to those used for the preparation of known compounds.

In addition, suitable methods for the preparation of starting compounds of formulas (III), (IV), (XI), (XIII) and (XIV) are described in UK Patent Specifications Nos. 2140800A and 215915IA and in the examples included herein below.

In the general reactions described above, the compound of formula (I) which is formed may be in the form of a salt, conveniently in the form of a physiologically acceptable salt. Where desired, such salts can be transferred to the corresponding free bases using vanlicre» ■Fr#»iricfarirrc;Tnå+-<=-r.

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 procedures.

The following examples illustrate the invention. Temperatures are in °C. "Dried" refers to drying using magnesium sulfate or sodium sulfate. "Flash" column chromatography (FCC) was performed on silica (Merck 9385) using one of the following systems of solvents: A - ethyl acetate:methanol:triethylamine,

B - toluene:ethanol:0.88 ammonia. The following abbreviations are used: DMF - dimethylformamide, DEA - N,N-diisopropylethylamine.

Example 1

4- hydroxyz- o:1- r f f 6- [ 2- ( 2- naphthalenyl) ethoxvl hexyl 1 aminol methyl 1 - 1. 3- benzenedimethanol

α-aminomethyl)-4-hydroxy-1,3-benzenedimethanol (1.31 g), 2-[2-[(6-bromohexyl)oxy]ethyl]naphthalene (2 g) and DEA (0.83 ml)

in DMF (dried over type 4Å sieves, 20 mL) was stirred at 100° under nitrogen for 2 h. The cooled mixture was poured into aqueous saturated sodium bicarbonate (80 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed (water, 100 mL), dried and evaporated to give a yellow sticky solid (3.5 g). This solid was adsorbed onto silica (Merck 7734, 2 g) from methanol and the resulting silica gel plug was applied to an FCC column. Elution with System A (89:10:1) gave a white solid

(0.95 g) which was crystallized from ethyl acetate (20 ml) to give the title compound (0.32 g) as a white solid, mp 112-114°.

Analysis Found: C, 73.3; H, 8.2; N, 3.1.

C27H35NOA. 0.2H20 requires

C, 73.5; H, 8.1; N, 3.2%. Water analysis, 0.2 mol water.

Example 2

5- hydroxy-2-|" f 6- f (2- naphthalenyl) ethoxy] hexvl1aminolethyl]-1. 3- benzenediol, 4. 4*- methylenbis f 3- hydroxy- 2-naphthalenecarboxvlatl ( 2:1) salt .

A mixture of 5-(2-amino-1-hydroxyethyl)-1,3-benzenediol (1.02 g), 2-[3-[(6-bromohexyl)oxy]ethyl]naphthalene (1.34 g) and

DEA (1.74 mL) in DMF (25 mL) was heated at 100° for 3 h under nitrogen. The solvent was removed in vacuo and the residue was purified by FCC and eluting with System B (80:20:1) to give the base as a pink glass solid (0.8 g).

A mixture of the base (0.4 g) and 4,4'-methylenebis[3-hydroxy-2-naphthalenecarboxylic acid] (0.18 g) in methanol (30 ml) was heated at reflux for 30 minutes. The methanol was removed in vacuo and the residue triturated with ether (20 mL) to give the title compound as an off-white solid (0.52 g), mp 105-110° (softens 100°).

Analysis Found: C, 70.2; H, 6.9; N, 2.1.

(C26H33N04)2 C2H1606.2.5H2O requires

C, 70.35; H, 6.85; N, 2.2%

Claims (3)

1. Analogous method for the preparation of therapeutically active compounds of the general formula (I) and physiologically acceptable salts and solvates thereof, wherein Ar denotes the group wherein Q<1> denotes a straight or branched C1.3 alkylene group, or k denotes an integer from 1 to 8; m denotes zero or an integer from 2 to 7; with the proviso that the total sum of k and m is 4 to 12; and Q denotes a naphthalenyl group, characterized by: alkylation of an amine of general formula (II) in which Ar is as above, in that one or both of the hydroxy groups may be protected, R<6> is a hydrogen atom or a protecting group and R <7> is a hydrogen atom, with an alkylating agent of formula (III) wherein Q is as above and may optionally contain a protecting group, and L is a leaving group, followed if necessary by removal of any protecting groups present; and/or if desired, transferring the resulting compounds of general formula (I) or a salt thereof, to a physiologically acceptable salt or solvate thereof. 2. Method according to claim 1, for the production of 4-hydroxy-α1-[[[6-[2-(2-naphthalenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol, and physiologically acceptable salts and solvates thereof, characterized in that corresponding starting materials are used. 3. Process according to claim 1, for the production of 5-[l-hydroxy-2-[[6-[(2-naphthalenyl)ethoxy]hexyl]amino]ethyl]-1,3-benzenediol; and physiologically acceptable salts and solvates thereof, characterized in that corresponding starting materials are used.