GB2165835A - Alkanolamine derivatives - Google Patents

Abstract

Alkanolamine derivatives of the formula:- <IMAGE> wherein either R<1> is hydroxy and R<2>, R<3>, R<4>, R<5> and R<6> are all hydrogen; or R<3> is hydroxy and R<1>, R<2>, R<4>, R<5> and R<6> are all hydrogen; or R<5> is hydroxy and R<1>, R<2>, R<3>, R<4> and R<6> are all hydrogen; or R<1> and R<2> form oxo and R<3>, R<4>, R<5> and R<6> are all hydrogen; or R<3> and R<4> form oxo and R<1>, R<2>, R<5>, and R<6> are all hydrogen; or R<5> and R<6> form oxo and R<1>, R<2>, R<3> and R<4> are all hydrogen; or any two of R<1>, R<3> and R<5> are hydroxy, the other one of R<1>, R<3> and R<5>, and R<2>, R<4> and R<6>, all being hydrogen; wherein R<7> is hydrogen or halogen, or alkyl or hydroxyalkyl each of up to 3 carbon atoms; and wherein R<8> is alky of up to 3 carbon atoms; acid-addition salts thereof, processes for their manufacture and pharmaceutical compositions containing them. The compounds possess peripherally-selective beta-adrenergic blocking activity.

Description

SPECIFICATION Alkanolamine derivatives This invention relates to new alkanolamine derivatives which possess peripherally-selective beta-adrenergic blocking activity.

In European Patent Specification No. 3664 there are described certain peripherally-selective beta-adrenergic blocking agents, and the background to the pharmacology of this kind of agent is also described therein. The preferred compound described therein is erythry- 1-(7-methylindan-4-yloxy)-3-isopropylam- ino-butan-2-ol, which is now known as ICI 118551.

Until now no other compound has been discovered which possesses comparable activity and selectivity. We have now discovered that certain oxygenated derivatives of ICI 118551 also possess a high level of peripherally-selective beta-adrenergic blocking activity.

Other oxygenated derivatives of indanyloxy and tetrahydronapthyloxy- alkanolamines are known, for example bunolol [1 -(5-oxo-5,6,7,8-tetrahydronaphth-1 -yloxy-3-t-butylaminopropan-2-ol], nadolol [1-(6,7 dihydroxy-5,6,7,8-tetrahydronaphth-1 -yloxy)-3-t-butylaminopropan-2-ol] and spirendolol [4'-(3-t-butylam ino-2-hydroxypropoxy)spiro(cyclohexane-i ,2'-indan)-1 '-one, but these are all t-butylamino-derivatives rather than isopropylamino-derivatives, and it is our experience that t-butylamino-derivatives are less peripherally-selective than isopropylamino-derivatives. Furthermore, the stated known compounds are all oxypropanolamines, not oxybutanolamines.

According to the present invention there is provided an alkanolamine of the formula:

wherein either R1 is hydroxy and R2, R3, R4, R5 and R6 are all hydrogen; or R3is hydroxy and R', R2, R4, R5 and R6 are all hydrogen; or R5is hydroxy and R', R2, R3, R4 and R6 are all hydrogen; or R' and R2 form oxo and R3, B, R5 and R6 are all hydrogen; or R3 and R4 form oxo and R', R2, R5 and R6 are all hydrogen; or R5 and R6 form oxo and R', R, R3 and R4 are all hydrogen; or any two of R', R3 and R5 are hydroxy, the other one of R', R3 and R5, and R2, R4 and R6, all being hydrogen; wherein R7is hydrogen or halogen, or alkyl or hydroxy-alkyl each of up to 3 carbon atoms; and wherein Rs is alkyl of up to 3 carbon atoms; or an acid-addition salt thereof.

R7 may be, for example, hydrogen, chlorine, bromine, methyl, ethyl or hydroxymethyl, especially methyl.

Rs may be, for example, methyl or ethyl, especially methyl.

It will be observed that an alkanolamine derivative of the invention possesses at least two asymmetric carbon atoms, namely those of the -CHOH- group and the adjacent -CHRs group, and that it can therefore exist in at least two racemic diastereoisomeric forms, the threo and erythro forms, and at least four optically-active forms, these being the (+) and (-) isomers of each of the racemic forms. It is to be understood that this invention encompasses any one of these isomeric forms which possesses peripherallyselective beta-adrenergic blocking activity as defined below, it being a matter of common general knowledge how any particular isomer may be isolated and how any peripherally-selective beta-adrenergic blocking activity it may possess may be measured.

It is to be understood that in general an optical isomer which has the (S)- absolute configuration of the said -CHOH- group is more active as a beta-adrenergic blocking agent than the corresponding isomer which has the (R)- absolute configuration. We have also found that in general the erythro-isomer is more peripherally-selective than the corresponding threo-isomer, but that both threo- and erythro-isomers of the compounds of the present invention possess the required selectivity.

A suitable acid-addition salt of an alkanolamine derivative of the invention is, for example, a salt derived from an inorganic acid, for example a hydrochloride, hydrobromide, phosphate or sulphate, or a salt derived from an organic acid, for example an oxalate, lactate, tartrate, acetate, salicylate, beta-naphthoate, adipate or 1,1-methylene-bis(2-hydroxy-3-naphthoate), or a salt derived from an acidic synthetic resin, for exmaple a sulphonated polystyrene resin.

Specific alkanolamine derivatives of the invention are hereinafter described in the Examples.

Of these, a preferred compound is erythro-1 -(3-hydroxy-7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol or an acid-addition salt thereof.

The alkanolamine derivative of the invention may be manufactured by any process known to be useful for the manufacture of chemically-analogous compounds.

A preferred process for the manufacture of an alkanolamine derivative of the invention comprises the reaction of a compound of the formula:

wherein RI, R2, R3, R4, R5, R6 and R7 have the meanings stated above and wherein X stands for the group:

or -CHOH.CHB"Z wherein R8 has the meaning stated above and wherein Z stands for a displaceable radical, with isopropylamine.

Z may be, for example, a halogen atom, for example a chlorine or bromine atom, or it may be a sulphonyloxy radical, for example the methane-sulphonyloxy or p-toluenesulphonyloxy radical. The reaction may be carried out in a diluent or solvent, for example water, an alcohol, for example methanol or ethanol, or an excess of isopropylamine, and it may be carried out at a temperature up to the boiling point of the diluent or solvent.

The starting material may be obtained by the reaction of a compound of the formula:

wherein Ri, R, B, B, Rs, R6 and R7 have the meanings stated above, with an epoxide of the formula:

wherein Rs and Z have the meanings stated above. It may alternatively be obtained by the reaction of a compound of the formula:

wherein R1, R2, B, R4 R5, R5, R7 and Rs have the meanings stated above, with a peroxide, for example mchloroperbenzoic acid or hydrogen peroxide.

A compound which has the threo-configuration of the -CHOH- and -CHRs- groups may be converted into the corresponding compound which has the erythro-configuration of said groups by successive protection of the isopropylamino function by acetylation with acetyl chloride, replacement of the hydroxy function by chlorine by reaction with thionyl chloride (this replacement causing no inversion of the stereo-chemistry at the carbon atom of the original -CHOH- group), and then replacement of the chlorine by hydroxy by reaction with an alkali metal hydroxide (this replacement causing inversion of the stereochemistry at the said carbon atom), the alkali metal hydroxide simultaneously removing the amino-acetyl protecting group by hydrolysis.

A compound wherein either Ra and R2, or R3 and Bt or R5 and R5 form oxo may be reduced by conventional means, for example with sodium borohydride, to the corresponding compound wherein, respectively, R1 is hydroxy and R2, B, R4, R5 and Rs are all hydrogen, or R3 is hydroxy and R', R, R4, R5 and R6 are all hydrogen; or R5 is hydroxy and RI, R3, R3, R4 and RB are ail hydrogen.

Conversely, a compound wherein either R1, R3 or R5 is hydroxy may be oxidised by conventional means, for example with manganese dioxide, to the corresponding compound wherein, respectively, R and R2, or R3 and R4, or R5 or R6 form oxo. This oxidation is more easily carried out if the -CHOH- group and the isopropylamino group of the alkanolamine side-chain are protected by formation of an oxazolidone by reaction with phosgene. A milder reducing agent, for example chromium trioxide-pyridine in methylene chloride (Collins reagent), may then be used, the carbonyl protecting group then being removed by hydrolysis with a strong base.

Optically-active enantiomorphs of the alkanolamine derivative of the invention may be obtained by the resolution by conventional means of the corresponding racemic alkanolamine derivative of the invention.

The said resolution may be carried out by reacting the racemic alkanolamine derivative with an optically-active acid, followed by fractional crystallisation of the diastereoisomeric mixture of salts thus obtained from a diluent or solvent, for example ethanol, whereafter the optically-active alkanolamine derivative is liberated from the salt by treatment with a base. A suitable optically-active acid is, for example (+)- or (-)-O,O-di-p-toluoyltartaric acid or (-)-2,3:4,5-di-O-isopropylidene-2-keto-L-gulonic acid.

The resolution process may be facilitated by treating the partially resolved akanolamine derivative in free base form obtained after a single fractional crystallisation of the diastereoisomeric mixture of salts with a solubilising agent, for example a primary amine, for example allylamine, in a relatively non-polar diluent or solvent, for example petroleum ether.

The alkanolamine derivative of the invention in free base form may be converted into an acid-addition salt thereof by reaction with an acid by conventional means.

As stated above, an alkanolamine derivative of the invention possesses peripherally-selective beta-adrenergic blocking activity. This may be demonstrated by its ability to antagonise the effect of a catecholamine such as isoprenaline in lowering the blood pressure of a perfused denervated hind limb of a dog at a dose which does not antagonise the effect of the same catecholamine in increasing the heart rate of the dog. Because of this selective activity a dose may be selected for the administration of such an alkanolamine derivative to a warm-blooded mammal such that beta-adrenergic blockage of the peripheral blood vessels may be produced without unwanted effects on the heart. At a dose of an alkanolamine derivative of the invention which produces effective peripheral beta-adrenergic blockade in the dog, no symptom of toxicity is apparent.

The alkanolamine derivative of the invention may be administered to warm-blooded animals, including man, in the form of a pharmaceutical composition comprising as active ingredient at least one alkanolamine derivative of the invention, or an acid-addition salt thereof, in association with a pharmaceuticallyacceptable diluent or carrier therefor.

A suitable composition is, for example, a tablet, capsule, aqueous or oily solution or suspension, emulsion, injectable aqueous or oily solution or suspension, dispersible powder, spray or aerosol formulation.

The pharmaceutical composition may contain, in addition to the alkanolamine derivative of the invention, one or more drugs selected from sedatives, for example phenobarbitone, meprobamate, chlorpromazine and the benzodiazepine sedative drugs, for example chlordiazepoxide and diazepam; analgesic agents, for example acetylsalicylic acid, codeine and paracetamol; hypotensive agents, for example reserpine, bethanidine and guanethidine; and agents used in the treatment of Parkinson's disease and other tremors, for example benzhexol.

When used for the treatment of tremor, migraine, anxiety, schizophrenia, glaucoma or hypertension in man, it is expected that the alkanolamine derivative would be given to man at a total oral dose of between 2 mg. and 100 mg. daily, at doses spaced at 6-8 hourly intervals, or at an intravenous dose of between 0.2 mg. and 5 mg.

Preferred oral dosage forms are tablets or capsules containing between 1 and 100 mg., and preferably 1 mg. or 10 mg. of active ingredient. Preferred intravenous dosage forms are sterile aqueous solutions of the alkanolamine derivative or of a non-toxic acid-addition salt thereof, containing between 0.05% and 1% w/v of active ingredient, and more particularly containing 0.1% w/v of active ingredient.

The invention is illustrated but not limited by the following Examples: Example 1 A stirred mixture of 7-(2,3-epoxybutoxy)-4-methylindan-1-ol (0.848 g.), isopropylamine (8.6 ml.) and methanol (8.6 ml.) was heated under reflux for 16 hours and then evaporated to dryness. The residue was purified by preparative thin-layer chromatography on twelve silica gel plates (area 20 cm. x 40 cm.) using a 6:4:2:1: v/v/v/v mixture of toluene, ethanol, ethyl acetate and concentrated aqueous ammonium hydroxide solution as developing solvent.The product was isolated from the appropriate bands on the plates by extraction with methanol, and there was thus obtained as an oil erythro-1-(3-hydroxy-7-methy- lindan-4-yloxy)-3-isopropyl- aminobutan-2-ol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.

The 7-(2,3-epoxybutoxy)-4-methylindan-1-ol used as starting material was obtained as follows: 3-Chioropropionyl chloride (5.82 ml.) was added dropwise during 15 minutes to stirred molten p-cresol (3.24 g.) which was maintained at 90-950C., and the mixture was stirred at that temperature for 90 minutes, cooled to laboratory temperature and poured into ice-water (75 ml.). The mixture was stirred for 1 hour and then extracted four times with diethyl ether (25 ml. each time), and the combined extracts were washed three times with aqueous 2N-sodium hydroxide solution. (25 ml. each time) and then four times with water (25 ml. each time), dried and evaporated to dryness.

A stirred mixture of the p-tolyl 3-chloropropionate thus obtained (5.82 g.) and anhydrous aluminium chloride (7.5 g.) was heated at 165-170"C. for 5 hours, cooled to laboratory temperature and sufficient icewater was added to break up the solid mass. The mixture was stirred for 1 hour and then extracted five times with chloroform (30 ml. each time), and the combined extracts were washed five times with water (20 ml. each time), dried and evaporated to dryness. The residue was purified by preparative thin layer chromatography on eighteen silica gel plates (area 20 cm. x 40 cm.) using chloroform as developing solvent, the product being isolated from the appropriate bands on the plates by extraction with chloroform.

A mixture of the 7-hydroxy-4-methylindan-1-one thus obtained (3.39 g.), potassium carbonate (14.2 g.), potassium iodide (1.7 g.), trans-crotyl chloride (3.8 g., containing 15% by weight of cis-isomer as impurity) and acetone (120 ml.) was stirred at laboratory temperature for 3 days, filtered and the filtrate was evaporated to dryness. The residue was purified by preparative thin-layer chromatography on eighteen silica gel plates (area 20 cm. x 40 cm.) using a 1:1 v/v mixture of diethyl ether and petroleum ether (b.p.

60-80 C) as developing solvent, the product being isolated from the appropriate bands on the plates by extraction with acetone.

A solution of m-chloroperbenzoic acid (3.0 g.) in dichloromethane (40 ml.) was added to a stirred solution of the 7-(but-trans-2-enyloxy)-4-methylindan-1-one thus obtained (2.54 g.) in dichloromethane (40 ml.) and the mixture was stirred at laboratory temperature for 5 days. Aqueous 10% w/v sodium sulphite solution (25 ml.) was added to destroy the excess of per-acid and the layers were separated. The aqueous layer was extracted three times with dichloromethane (20 ml. each time) and the combined dichloromethane solutions were washed four times with aqueous 5% w/v sodium bicarbonate solution (20 ml. each time) and four times with saturated aqueous sodium chloride solution (20 ml. each time), dried and evaporated to dryness.The residue was purified by preparative thin-layer chromatography on twelve silica gel plates (area 20 cm. x 40 cm.) using chloroform as developing solvent, the product being isolated from the appropriate bands on the plates by extraction with methanol.

Sodium borohydride (0.22 g.) and then methanol (6.2 ml.) were added to a stirred solution of the 7 (2,3-epoxybutoxy)-4-methylindan-1-one thus obtained (1.2 g.) in isopropanol (15.5 ml.) which was maintained at 0 C. and the mixture was stirred at 0-10"C. for 4 hours and then poured into saturated aqueous sodium chloride solution (100 ml.). The mixture was extracted five times with diethyl ether (30 ml. each time) and the combined extracts were washed three times with saturated aqueous sodium chloride solution (50 ml. each time), dried and evaporated to dryness. The residue was purified by preparative thinlayer chromatography on twelve silica gel plates (area 20 cm. x 40 cm.) using chloroform as developing solvent, the product being isolated from the appropriate bands on the plates by extraction with methanol.There was thus obtained 7-(2,3-epoxybutoxy)-4-methylindan-1-ol, the structure of which was confirmed by mass spectroscopy.

Example 2 Solid sodium hydroxide (40 g.) was added during 1 hour in 6 equal portions to a stirred mixture of 4hydroxy-7-methylindan-1-one (81 g.), dimethylformamide (150 ml.) and trans-crotyl chloride (100 ml; containing 15% by weight of cis-isomer as impurity) which was heated at 32"C., and the mixture was stirred at 32"C. for a further 1 hour until the exothermic reaction subsided. Water (60 ml.) and petroleum ether (b.p. 60-80"C., 500 ml.) were added and (50 ml. each time) and evaporated to dryness under reduced pressure, finally at 500C.

Aqueous 5% wiw hydrogen peroxide solution was added in 15 portions (each of 5.4 ml.) at 15-minute intervals to a stirred mixture of the 4-(but-trans-2-enyloxy)-7-methylindan-1-one thus obtained, methanol (400 ml.), benzonitrile (105 ml.) and potassium bicarbonate (30 g.) which was heated at 38"C., and the mixture was stirred at 38"C. for 18 hours, at 49"C. for 8 hours and at 22"C. for 3 days. Saturated aqueous sodium sulphite solution (125 ml.), water (125 ml.) and then isopropylamine (500 ml.) were successively added at 22"C., and the mixture was then stirred and heated under reflux for 9 hours.The methanol and excess of isopropylamine were removed by distillation at atmospheric pressure at 100"C., and water (400 ml.) and butyl acetate (750 ml.) were added. The organic layer was separated at 60"C., washed with water (230 mi.), and then water (300 ml.) and concentrated aqueous hydrochloric acid (32 ml.) were added at 30-40"C. until the pH of the mixture was 2. The mixture was stirred at 25"C. for 10 minutes, at 5"C. for 2 hours and was then filtered to remove solid benzamide. The filtrate was further acidified with concentrated aqueous hydrochloric acid to pH 0.5, stirred at 5-20"C. for 18 hours and then filtered. There was thus obtained as solid product 4-(erythro-2-hydroxy-3-isopropylaminobutoxy)-7-methyl-indan-1-one hydrochloride, m.p. greater than 230"C.

Example 3 Sodium borohydride (2.0 g.) was added during 5 minutes to a stirred suspension of 4-(erythro-2-hy droxy-3-isopropylaminobutoxy)-7-methylindan-1 -one hydrochloride (Example 2; 20.0 g.) in methanol (400 ml.) and aqueous 47% w/w sodium hydroxide solution (6.4 ml.), and the mixture was stirred at 40"C. for 2 hours, at laboratory temperature for 18 hours and was then evaporated to dryness. The residue was shaken with water (200 ml.) and ethyl acetate (200 ml.) and the organic layer was washed with water (150 ml.), filtered through phase-separating paper and evaporated to dryness. The residue was stirred with acetone (40 ml.) and the mixture was filtered. There was thus obtained as solid residue erythro-1-(1-hydroxy-7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol, m.p 98-102"C.

Example 4 The process described in the first paragraph of Example 1 was repeated using 7-(2,3-epoxybutoxy)-4methylindan-1-one (prepared as described in the penultimate paragraph of Example 1) as starting material in place of the corresponding indan-1-ol. There was thus obtained as an oil rythro-1-(7-methyi-3-ox- oindan-4-yloxy)-3-isopropylaminobutan-1-ol, which was converted into its hydrochloride, m.p. 225-226"C., by reaction with hydrogen chloride.

Claims (10)

1. An alkanolamine of the formula:

wherein either Tri is hydroxy and R2, R3, B, R5 and R5 are all hydrogen; or R3is hydroxy and R', R2, R4, Ras and R6 are all hydrogen; or R5 is hydroxy and R', R2, R3, R4 and R5 are all hydrogen; or B1 and RZ form oxo and R3, R4, R5 and R5 are all hydrogen; or R3 and R4 form oxo and R', R2, R5 and R6 are all hydrogen; or R5 and RB form oxo and R', R2, R3 and R4 are all hydrogen; or any two of R', R3 and R5 are hydroxy, the other one of R', R3 and R5, and R2, R4 and R6, all being hydrogen; wherein R7is hydrogen or halogen, or alkyl or hydroxy-alkyl each of up to 3 carbon atoms; and wherein R6 is alkyl of up to 3 carbon atoms; or an acid-addition salt thereof.

2. An alkanolamine as claimed in claim 1 wherein R7is hydrogen, chlorine, bromine, methyl, ethyl or hydroxymethyl and R6 is methyl or ethyl.

3. An alkanolamine as claimed in claim 2 wherein R7 and RB are both methyl and which is in the erythro-form.

4. The compound erythro-1 -(3-hydroxy-7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol or an acidaddition salt thereof.

5. The compound erythro-1 -(1 -hydroxy-7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol or an acidaddition salt thereof.

6. The compound erythro-1 -(7-methyl-3-oxoindan-4-yloxy)-3-isopropylaminobutan-2-ol or an acid-addition salt thereof.

7. The compound erythro-1 -(7-methyl-1 -oxoindan-4-yloxy)-3-isopropylaminobutan-2-ol or an acid-addition salt thereof.

8. A process for the manufacture of an alkanolamine, claimed in any of claims 1 to 7, which comprises the reaction of a compound of the formula:

wherein Rr, R2, R3, R4, R5, R6 and R7 have the meanings stated in claim 1, 2 or 3 and wherein X stands for the group::

or -CHOH-CHR6Z wherein Rs has the meaning stated in claim 1, 2 or 3 and wherein Z stands for a displaceable radical, with isopropylamine; whereafter (a) a compound which has the threo-configuration of the -CHOH- and -CHR8- groups may be converted into the corresponding compound which has the erythro- configuration of said groups by successive protection of the isopropylamino function by acetylation with acetyl chloride, replacement of the hydroxy function by chlorine by reaction with thionyl chloride (this replacement causing no inversion of the stereo-chemistry at the carbon atom of the original -CHOH- group), and then replacement of the chlorine by hydroxy by reaction with an alkali metal hydroxide (this replacement causing inversion of the stereo-chemistry at the said carbon atom), the alkali metal hydroxide simultaneously removing the amino-acetyl protecting group by hydrolysis; or (b) a compound wherein either R1 and R2, or R3 and R4, or R5 and RB form oxo may be reduced by conventional means to the corresponding compound wherein, respectively, R' is hydroxy and R2, R3, R4, R5 and RB are all hydrogen, or R3 is hydroxy and R', R2, R4 R5 and R5 are all hydrogen; or R5 is hydroxy and Ra, R, R3, R4 and R6 are all hydrogen; or (c) a compound wherein either R1, R3 or R5 is hydroxy may be oxidised by conventional means to the corresponding compound wherein, respectively, R' and R2, or R3 and R4, or R5 or R6 form oxo; or (d) optically-active enantiomorphs of the alkanolamine may be obtained by the resolution by conventional means of the corresponding racemic alkanolamine; or (e) an alkanolamine in free base form may be converted into an acid-addition salt thereof by reaction with an acid by conventional means.

9. A pharmaceutical composition comprising as active ingredient at least one alkanolamine or an acid addition salt thereof, claimed in any of claims 1 to 7, in association with a pharmaceutically-acceptable diluent or carrier therefor.

10. A composition as claimed in claim 9 which contains, in addition to the alkanolamine, one or more drugs selected from sedatives, analgesic agents, hypotensive agents, and agents used in the treatment of Parkinson's disease and other tremors.