FI67688B - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA ALANOLAMINDERIVAT - Google Patents

Description

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Patent- OCfl MlJJiatM il / i «Mil AMSktm utbfd odi wtUkrlftwi pubtiearad 31-01.85 (32) (33) (31) Pyydetty icuoikMs —Bsfird prtortut (71) Imperial Chemical Industries Limited, Imperial Chemical House,

Millbank, London SW1P 3JF, Eng 1 anti-Eng 1 and (GB) (72) Howard Tucker, Macclesfield, Cheshire, Engl anti-England (GB) (Jk) Oy Kolster Ab (5A) Method for the preparation of therapeutically useful alkanolamine derivatives - For the preparation of tera-peutiskt användbara alkanolaminderivat

The invention relates to a process for the preparation of therapeutically useful alkanolamine derivatives of the formula: wherein R is an alkyl group having up to 6 carbon atoms on a branched carbon atom, R 2 is an alkyl group having up to 3 carbon atoms, R 3 is a hydrogen or halogen atom or at least 3 alkyl group and n is 1 or 2, and their acid addition salts.

67688

The compounds according to the invention are novel alkanolamine derivatives which selectively act on peripheral, adrenergic (?) Receptors.

It is known that many 1-aryloxy-3-amino-2-propanol derivatives have the properties of adrenergic β-blockers and that the separation of adrenergic receptors from blockade can be achieved in the heart and peripheral vasculature. For certain compounds, a dose can be determined that causes blockade of cardiac (or β1) receptors, but not blockade of peripheral (or β1 receptors) Such compounds, such as practolol and atenolol, are referred to as cardiac selective adrenergic β-blockers. In response to cardiac selective blockers, such compounds are termed vascular-selective adrenergic β-blockers. receptor blocker, however, being so effective that it causes cardinal blockade even in the smallest doses.

It is also known that the addition of a methyl group to the propanol side chain to give 1-aryloxy-3-amino-2-butanol derivatives increases the vascular selectivity of the compounds in some cases, but generally reduces the overall potency of the adrenergic β-blocker. This has been particularly pronounced in the case of N, N-methylpropranolol, where potency is markedly reduced and vascular selectivity is questionable (Todd, Pharmacologist, 1976, 18, 138).

1-Indanyloxy and tetrahydronaphthyloxy-3-amino-2-propanol derivatives are known, for example, from GB Patents 1,023,214 and 1,160,448 and DE-A-2,333,846, which have cardinal beta-adrenergic blocking activity. The present invention relates to the preparation of similar compounds having an alkyl substituent propranolol in the side chain and which are surprisingly peripheral-selective beta-adrenergic blockers. The drug dose can be selected so that the new compound provides beta-adrenergic blockade in peripheral blood vessels without affecting the heart.

ti 3 67688

The alkanolamine derivatives prepared according to the invention have two asymmetric carbons, carbons of the -CHOH and CHR groups, so that they can have two racemic diastereoisomers, the threo and erythro forms, and four optically active forms, each of the (+) and (-) - isomers. The invention comprises any of these isomers having selective peripheral adrenergic β 3 blocking activity; it is well known how a particular isomer can be isolated or how its potential selective peripheral adrenergic β 3 -blocking effect can be measured.

It should be borne in mind that, in general, an optical isomer having the absolute (S) configuration of the -CHOH group is more effective as an adrenergic β-blocker than the corresponding isomer having the absolute (R) configuration of that group. It has also been found that the erythro isomer is generally more selective peripherally than the threo form, although both forms of the novel compounds are sufficiently active for the invention.

Suitable acid addition salts of alkanolamine derivatives include, for example, salts of inorganic acids such as hydrochloride, hydrobromide, phosphate or sulfate, salts of organic acids such as oxalate, lactate, tartrate, acetate, salicylate, citrate, benzoate, β-naphthoate, β-naphthoate. , 1-methylene bis- (2-hydroxy-3-naphthoate) and salts derived from acidic synthetic resins such as sulfonated polystyrene resin.

The novel alkanolamine derivatives are described in more detail below by way of examples. The best of these compounds are erythro-1- (7-methylindan-4-yloxy) -3-isopropylaminobutan-2-ol, threo-1- (7-methylindan-4-yloxy) -3-isopropylaminobutan-2- was, erythro- (indan-4-yloxy) -3-isopropylaminobutan-2-ol and the corresponding acid addition salts.

The new alkanolamine derivatives can be prepared by the same methods as the chemically analogous compounds.

In a preferred process for the preparation of said alkanolamine derivatives, an amine of the formula R 1 N 1 · 2, wherein R 2 is the same as above, is reacted with a compound of the formula _ - ΊΓΖ-- 4 67688

OCH, X

, ch200 3 where R and n are the same as in the above formula and X is xA 2 2

-CH_CHR or -CHOH.CHR Z

2 wherein R is the same as above and Z is a leaving group.

Z may be, for example, a halogen atom such as a chlorine or bromine atom, or it may be a sulfonyloxy radical such as methanesulfonyloxy or p-toluenesulfonyloxy radical. The reaction may take place in a diluent or solvent in e.g. water, alcohol, e.g. methanol or ethanol or in an excess of an amine of formula 1 1 R NH 2 in which R is the same as above, and the reaction may be carried out at a temperature up to the boiling point of the diluent or solvent.

The starting material can be prepared by reacting a compound of formula icvn II, R3 3 wherein R and n are the same as above with an epoxide of formula A 2

CH2-CH-CHR Z

2.

67688 where R and Z are the same as above. Alternatively, it can be prepared by reacting a compound of formula och2.ch = chr2 R3 2 3 wherein R, R and n are the same as above with a peroxide, e.g. hydrogen peroxide.

2

A compound having the -CHOH and -CHR groups in the threo configuration can be converted to the corresponding erythro-configurable compound by protecting the secondary amino group with -NHR -acetyl chloride acetylation, replacing the hydroxy group with chlorine in the reaction with thionyl chloride (which does not cause the initial -CH change of stereochemistry) and finally exchanging chlorine for a hydroxy group in a reaction with an alkali metal hydroxide (the reaction causes inversion of the stereo structure of the above-mentioned carbon atom), whereby the alkali metal hydroxide simultaneously hydrolyzes the protecting aminoacetyl group.

The optically active enantiomers of the new alkanolamine derivatives are separated by conventional methods for partitioning the racemic mixture of the corresponding alkanolamine derivative.

Partitioning is accomplished by reacting a racemic mixture of an alkanolamine derivative with an optically active acid, and partitioning the diastereoisomeric mixture of the resulting salts from a diluent or solvent, e.g., ethanol, followed by alkali treatment of the optically active alkanolamine derivative. 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.

Partitioning can be facilitated by treating the salts of the partially separated alkanolamine derivative obtained after one fractional crystallization of the diastereoisomeric mixture with a solubilizing agent, e.g. a primary amine such as allylamine, in a relatively non-polar solvent, e.g. petroleum ether.

67688

The alkanolamine derivative in base form can be converted into an acid addition salt by a conventional acid reaction.

As mentioned above, the novel alkanolamine derivative is a selective blocker of peripheral adrenergic β receptors. This can be illustrated by its ability to resist the effect of a catecholamine, such as isoprenaline, in lowering the blood pressure of a perfused hind leg of a dog from which the nerve has been removed at a dose that does not resist the effect of the same catecholamine in increasing the dog's heart rate. Due to this selective effect, in a warm-blooded mammalian medicine with such an alkanolamine derivative, a dose can be selected at which adrenergic β-blockade of peripheral blood vessels is achieved without undesired effects on the heart. No toxic effects were observed when the alkanolamine derivative was administered to a dog at a dose that produced effective peripheral adrenergic blockade.

The alkanolamine derivative prepared according to the invention can be administered to warm-blooded animals, including humans, as a pharmaceutical composition in which the active ingredient is at least one novel alkanolamine derivative, or an acid addition salt thereof, in a pharmaceutically acceptable solvent or carrier.

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

The pharmaceutical composition may contain, in addition to the alkanolamine derivative in question, one or more sedatives such as, for example, phenobarbitone, memprobamate, chlorpromazine and benzodiazepine sedatives such as chlorodiazepoxide and diazepam; antihypertensive agents such as reserpine, betanidine and quanetidine; and agents used to treat Parkinson's disease and other tremors, such as benzhexol.

For the treatment of human tremor, migraine, restlessness, schizophrenia, cataracts or hypertension, the daily dose of the alkanolamine derivative should probably be 2-100 mg orally - 6-8 hours apart - and 0.2-5 mg intravenously.

7 67688

The best oral dosage forms are tablets or capsules containing 2-100 mg, preferably 1-10 mg of the active ingredient Akti: vista. The best intravenous dosage form is a sterile aqueous solution of the alkanolamine derivative or a non-toxic haoo addition salt thereof containing 0.05 to 1% w / v, preferably 0.1% w / v, of the active ingredient.

The invention is illustrated by the following examples.

Example 1 A mixture of trans-2,3-epoxy-1- (7-methyl-Idan-4-yloxy) butane (19.9 g), isopropylamine (100 ml) and water (100 ml) was heated at reflux for 16 hours, after which the mixture is evaporated to dryness under reduced pressure. The residue is dissolved in a mixture of concentrated hydrochloric acid (50 ml) and water (50 ml), whereupon the solution is heated. It is cooled and filtered, and the solid product is crystallized from a 4: 1 v / v mixture of ethanol and methanol. There is thus obtained erythro-1- (7-methylindan-4-yloxy) -3-isopropylaminobutan-2-ol hydrochloride, m.p. 222-224 ° C.

The starting trans-2,3-epoxy-1- (7-methylindan-4-yloxy) butane is obtained by one of the following methods: A. 7-methylindan-4-ol (118 g) and dry N, N A solution of -dimethylformamide (296 ml) is added to a stirred suspension of sodium hydride (20.8 g) and N, N-dimethylformamide over 30 ml at such a rate that the temperature of the mixture does not rise above 30 ° C. The mixture is stirred at room temperature for half an hour, after which 106 ml of trans-crotyl chloride are added over 30 minutes. The mixture is stirred for 16 hours at room temperature, after which water (1200 ml) is added at such a rate that the temperature of the mixture does not rise above 30 ° C. The aqueous layer is decanted and the residue is stirred with cyclohexane (340 ml). The mixture is filtered, the filtrate is washed once with 2N sodium hydroxide (240 nlA and six times with saturated sodium hydroxide (120 ml each), dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is crystallized from ethanol (-7 ° C) to give 1- (7-methyl). -indan-4-yloxy) -but-trans-2-ene, mp 29-2 9.5 ° C.

A mixture of the above compound (110 g), acetonitrile (115 ml), hydrogen peroxide (125 ml of a 50% w / w aqueous solution), anhydrous potassium bicarbonate (44 g) and methanol (1300 ml) was stirred at room temperature for 5 days. then it is poured into water (5.3 liters). The mixture is filtered and the solid product is washed with water (700 ml), dried at room temperature and crystallized from petroleum ether, b.p. 60-80 ° C (570 mL). The product obtained is trans-2,3-epoxy-1- (7-methylindan-4-yloxy) butane, m.p.

68-6 9 ° C.

B. methylene chloride (50 mL), and bromine (63.3 a) in between, and added dropwise to a cooled stirred cis-crotyl alcohol (28.5 g) and methylene chloride (50 mL), and the mixture was stirred for half an hour at room temperature, after which it washed successively with dilute sodium thiosulphate solution and water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is vacuum distilled to give threo-2,3-dibromobutan-1-ol, b.p. 108-110 ° C / 14 mmHg.

The solutions between the above compound (140 g) and diethyl ether (700 ml) and potassium hydroxide (45 g) and water (400 ml) are stirred vigorously together for 6 hours, after which the layers are separated. The ether layer is washed repeatedly with saturated sodium chloride solution until the washings are no longer alkaline, after which it is dried over magnesium sulphate and evaporated to dryness. The residue is distilled in vacuo to give erythro-3-bromo-1,2-epoxybutane, b.p. 39-42 ° C / 20 mmHg.

A stirred mixture of the above compound (33 g), 7-methylindan-4-ol (25.2 g), sodium hydroxide (7.5 g), water (250 ml) and 1,2-dimethoxyethane (25 ml) is heated. At 60 ° C for 15 hours, after which it is cooled and extracted 4 times with chloroform (75 ml at a time). The extracts are combined, the mixture is washed with water until the washings are no longer alkaline, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is stirred with petroleum ether (b.p. 40-60 ° C) until it solidifies and the solid is crystallized from a 2: 1 v / v mixture of cyclohexane and petroleum ether (b.p. 60-80 ° C). The compound obtained is trans-2,3-epoxy-1- (7-methylindan-4-yloxy) butane, m.p. 68-69 ° C.

Example 2

The process is otherwise the same, except that the cis isomer is used instead of trans-2,3-epoxy-1- (7-methylindan-4-yloxy) butane (prepared in the same manner as in Example 1, 9 67688). J. Organic Chemistry, 1956, 21, 429-threo-3-bromo-1,2-epoxybutane). The product obtained is threo-1- (7-methylindan-4-yloxy) -3-isopropylaminobutan-2-ol hydrochloride, m.p. 164-166 ° C.

Example 3

The process of Example 1 (first paragraph; starting material is prepared by Method B) or the process of Example 2, except that instead of the appropriate 7-substituted or unsubstituted indan-4-ol, the appropriate 3-bromo-1,2-epoxybutane and the appropriate amine are used as starting material. The products obtained are grouped in the following table: OCH 0.CHOH.CH.NHR1 3! 3 1 3 R RJ isomer m.p. (° C) isopropyl H erytro free base 1Q3-106 isopropyl H threo hydrochloride 179-181 t-butyl H threo hydrogen oxalate 162-163 isopropyl ethyl threo hydrochloride 175-177 isopropyl chloro threo hydrochloride 174.5-175.5 Used 7- ethyl indan-4-ol can be obtained by the following method: 3-Chloropropionyl chloride (133 g) is added in 5-10 ml portions to molten 4-ethylphenol (63.8 g) heated to 95-100 ° C. After the addition is complete, the mixture is heated to 95-100 ° C for 90 minutes, after which it is kept at room temperature for 18 hours. The mixture is shaken with ice water (200 ml) and diethyl ether (100 ml), and the organic layer is separated. The aqueous layer is treated with diethyl ether (50 ml) and the combined organic solutions are washed 12 times with 2N sodium hydroxide solution (50 ml each), then the mixture is dried over magnesium sulphate and evaporated to dryness. The residue is distilled to give 4-ethylphenyl-3-chloropropionate, b.p. 121-122 ° C / 1.5 mmHg.

A mixture of the above compound (87.9 g) and aluminum chloride (110 g) is heated to 165-170 ° C for 5 hours, cooled and carefully treated with ice water (200 ml). The mixture is quenched with water and the distillate is extracted three times with diethyl ether (50 ml at a time). The combined extracts are dried over magnesium sulphate, evaporated to dryness and the residue is crystallized from cyclohexane.

The product obtained is 4-ethyl-7-hydroxyindan-1-one, m.p. 39-94 ° C.

A stirred mixture of the above compound (9.3 g), zinc amalgam (35 g), water (35 ml) and concentrated hydrochloric acid (35 ml) was heated at reflux for 16 hours, after which the liquid layer was decanted from scrap metal and extracted with toluene (25 ml). The toluene is evaporated off, the residue is dissolved in diethyl ether and the solution is dried over magnesium sulphate and evaporated to dryness. The residue is crystallized from petroleum ether (b.p. 60-80 ° C) to give 7-ethylindan-4-ol, m.p. 49-51 ° C.

Example 4

The procedure is otherwise the same as in Example 2, except that threo-2,3-epoxy-1- (1,2,3,4-tetrahydro-naphth-5-yloxy) butane is used as starting material. The product thus obtained is threo-1- (1,2,3,4-tetrahydronaphth-5-yloxy) -3-isopropylaminobutan-2-ol hydrochloride, m.p. 218-224 ° C.

Example 5 A mixture of trans-2,3-epoxy-1- (7-methylindan-4-yloxy) pentane (1.3 g), isopropylamine (10 ml) and water (10 ml) was heated at reflux for 16 hours, after which it is cooled and evaporated to dryness under reduced pressure. The residue is shaken with 2N hydrochloric acid (25 ml) and ethyl acetate (25 ml), and the organic layer is separated, dried over magnesium sulphate and evaporated to dryness. The residue is taken up in ethyl acetate solution on preparative chromatography silica gel plates (20 cm x 20 cm x 2 mm thick, Merck F254® plates are developed with a 100: 20: 3 v / v mixture of ethyl acetate, ethanol and triethylamine. The appropriate band is separated and extracted with methanol, the solution is filtered and filtered. The residue is dissolved in chloroform, the solution is filtered and the filtrate is evaporated to dryness, the residue is crystallized from petroleum ether (b.p. 60-80 ° C) to give erythro-1- (7-methylindan-4-yloxy). ) -3-isopropylaminopentan-2-ol, mp 72-73 ° C.

The starting trans-2,3-epoxy-1- (7-methylindan-4-yloxy) pentane is obtained by the following method: 7-methylindan-4-ol (1.48 g), tetrahydrofuran (25 ml) and a mixture of sodium hydride (0.4 g of a 60% dispersion in mineral oil) is stirred at room temperature for 90 min, and erythro-3-bromo-1,2-epoxypentane (2.2 g; prepared from cis-pent-2-en-1-ol by the same method as in Example 1B) and a solution between tetrahydrofuran (10 ml) is added over 10 minutes.

The mixture is refluxed for 16 hours, N, N-dimethylformamide (10 ml) is added and the mixture is refluxed for a further 84 hours, after which it is poured into an amount of water corresponding to the volume of the mixture. The mixture is extracted twice with diethyl ether (25 ml at a time), the extracts are combined and washed with 2N sodium hydroxide (25 ml) and twice with saturated sodium chloride solution (10 ml at a time), dried over magnesium sulphate and evaporated to dryness. The residue contains the desired trans-2,3-epoxy-1- (7-methylindan-4-yloxy) pentane, which is used without further purification.

Example 6 To a well-stirred mixture of threo-1- (7-methylindan-4-yloxy) -3-isopropylaminobutan-2-ol (4.0 g), methylene chloride (50 ml) and triethylamine (1.5 ml) acetyl chloride (1.03 ml) is added and the mixture is stirred at room temperature for 2 hours, then washed successively with water (25 ml), twice with 2N hydrochloric acid (25 ml at a time) and three times with water (25 ml at a time), dried over magnesium sulphate and evaporated to dryness in vacuo. . Thionyl chloride (6 ml) is added to the residue, and after completion of the exothermic reaction, the mixture is kept at room temperature for 30 min. Excess thionyl chloride is distilled off in vacuo and the residue is stirred for 48 hours with 7N sodium hydroxide, water (15 ml) and Ν, Ν-dimethylformamide (15 ml). 30 ml of water are added to the mixture, which is extracted three times with ethyl acetate (25 ml at a time). The extracts are combined, dried over magnesium sulphate and evaporated to dryness, and the residue is crystallized from isopropanol. The product obtained is erythro-1- (7-methylindan-4-yloxy) -3-isopropylaminobutan-2-ol, m.p. 90.5 to 93.5 ° C.

Example 7 15 ml of ethanol containing 7.13 g of (-) - di-p-toloyl- (L) -tartaric acid are added to (-) - threo-1- (7-methylindan-4-yloxy) -3 -isopropylaminobutan-2-ol (5.12 g) and ethanol (15 ml), which is boiled for 3 min, then allowed to cool. The mixture is filtered and the solid residue is crystallized twice from ethanol. The di-p-toloyl tartrate thus obtained (m.p. 114.5-116 ° C) is shaken with 2N sodium hydroxide (50 ml) and ethyl acetate (50 ml), the organic layer is separated, washed with water, dried over magnesium sulphate and evaporated to dryness. The residue is dissolved in diethyl ether, an excess of saturated ethereal hydrogen chloride is added to the mixture, and the mixture is filtered. The residue is crystallized from isopropanol to give (+) - threo-1- (7-methylindan-4-yloxy) -3-isopropylaminobutan-2-ol hydrochloride, m.p. 173.5 to 175 ° C; Δ = + 41.3 ° (methanol).

the ethanolic filtrates obtained from the separation and crystallization of di-p-tololyl tartrate are combined and evaporated to dryness, and the residue is shaken with 10N sodium hydroxide (25 ml) and ethyl acetate (25 ml). The organic layer is separated, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in ethanol (10 ml), and a solution of (+) - di-p-toloyl- (D) -tartaric acid (2.1 g) and ethanol (10 ml) is added to this mixture. The mixture is boiled for 3 minutes, then allowed to cool. The precipitated salt is crystallized, and the free base is isolated and converted to the hydrochloride by the method described in the previous paragraph. The product obtained is (-) - threo-1- (7-methylindan-4-yloxy) -3-isopropylaminobutan-2-ol hydrochloride, m.p. 173.5 to 175 ° C; 0 ^ 23 = 4141.1 ° (methanol).

li

Claims (2)

13 676 88 1. A process for the preparation of therapeutically useful alkanolamine derivatives of the formula och_chohchr1nhr1 (CH2> n ^ T ^ i2 wherein R is an alkyl group having up to 6 carbon atoms branched at a d-carbon atom, R1 is containing up to 3 carbon atoms. alkyl group, R is a hydrogen or halogen atom or an alkyl group having up to 3 carbon atoms and n is 1 or 2, and for the preparation of their acid addition salts, characterized in that the compound of formula Pch2x, CH2> nT 'and R 2 3 in which R and n are the same as above and X is A 2. -CH-CHR or -CHOHCHR Z in which R is the same as above and Z is a leaving group is reacted with an amine of the formula R NH ", where R is the same as above, after which the compound in which the 2 2 groups -CHOH- and -CHR- have the threo configuration is, if necessary, converted into a compound in which said groups have the erythro configuration, after which the racemic mixture of the alkanolamine derivative divided into optically active enantiomers; and after which the free base obtained is, if necessary, converted into an acid addition salt. ___ - · li .. ___ 1 4 67688 Process according to Claim 1, characterized in that the starting material used is a compound in which R is isopropyl. 2 3 pyl, R is methyl, R is methyl, n is 1 and the final product has an erythro configuration. 15 Patentkrav 67688 1. A compound for the preparation of a therapeutically active alkanolamine derivative having the formula och2chohchr2nhr1 h color R is an optional 6-membered alkyl group, each of which is a mixture of 0 (-cholatorane, R is an alkyl group with 3-membered, or a halogen atom or an alkyl group having 3 carbon atoms and 1 or 2, as the case may be, in the form of a mixture, to give a formulation of och2x R3 3 color 2 -CH-CHR or -CHOHCHR Z 2 i vilka Gruppen R har den ovan angivna betydelsen och S är en avgäende 1 1 grupp, omsätts med en Amin med formuleln R NH2, color R har den ovan engivna betydelsen, varefter en förening, color the group -CHOH- and 2 -CHR - in the form of a group, in which case they are used in the same way, color of this group in the erythro configuration; the racemic bleaching of the alkanolamine derivatives in the form of an optically active enantiomer; och varefter den erhällna fria basen vid behov omvandlas account ett syraadditionssalt.