IL44003A - 1-(p-(alkylthioalkoxy)phenoxy)-3-(substituted amino)-2-propanols their preparation and pharmaceutical compositions containing them - Google Patents

Description

-(-innm i J »ί3κ)-3-/"*ορικ3ί}( on ι c» *:>»n nin - 'T?3ni Dnaan ,o*«nn ο'^ιαπηε·^ New 1-/p-( lky11hioalkox )phenoxy7-3-(substituted amino) 2-propanols, their preparation and pharmaceutical compositions containing them CIBA-GEIGY A.G C: 42159 44 The invention relates to new 1- ip- (alkylthio-alkoxy) phenoxy] -3- (substituted amino) -2-propanols of the formula I OH I Al^ - S - alk2 - 0 - Ph - 0 - CH2 - CH - CH2 - NH - R (I) wherein Alk^ is lower alkyl, alk2 is lower alkylene, Ph is p-phenylene optionally substituted by halogen, lower alkyl, lower alkenyl or lower alkoxy, R is lower alkyl or phenyl- lower alkyl, and to their condensation products with formaldehyde or carbonic acid, as well as to processes for their manufacture ar.d pharmaceutical compositions containing ■ them.

. In the preceding and following text, a lover radical is in particular understood as a radical v/ith up to 7 C atoms, above all v/ith up to 4 C atoms.

.Lover alkyl Alk-^ preferably has up to 7 C atoms, above all up to C atoms, such as iso-propyl or n-propyl, straight or branched butyl, penty } hexyl or heptyl, bonded in any desired position, and especially ethyl and above all methyl.

.Lower alkylene lkg is branched or above all straight-chain lov/er alkylene, preferably vvith at least 2 C atoms in the alkylene chain and v/ith especially 2 or 3 C atoms in the alkylene chain, such as 1, 3-propylene or above all 1 , 2 -ethylene.

Halogen as a substituent of the para-phenylene radic is, for example, fluorine, bromine and especially chlorine, and lower alkyl in particular has the meaning given for Alk^. Lower alkenyl has, for example, 2 to 7 C atoms, above all 2 to 4 C atoms, such as vinyl, methallyl and especially allyl. Lower alkoxy is above all lower alkoxy wherein the lower alkyl part has the meaning given for Alk^, such as ethoxy, iso- or n-propoxy and especially methoxy. The p-phenylene radical Ph is preferably monosubstituted, one substituent above all being in the ortho-position to the 2-hydroxy-propoxy radical.

Above all, however, the p-phenylene radical Ph is ^unsubstituted. ■ .

Lower alkyl R preferably has up to 7 C atoms, above all up to 4 C atoms, and is unbranched or preferably branched, in particular branched at the -C atom, and is, for example, sec.-butyl or especially tert.-butyl or above all isopropyl.

Phenyl-lower alkyl R preferably has up to 12 C atoms, above all up to 10 C atoms, and is unbranched or preferably branched in the lower alkyl part, in particular branched at the a-C atom of the lover alkyl part. Examples of phenyl-lower alkyl R are l-methyl-3-phenyl-propy1 and especially 1-methyl-2-pheny1-ethy1.

Condensation products of compounds of the formula I with form aldehyde are those of the formula II Alkj^ - S - alk2 - 0 - Ph - 0 - CH2 - CH CH2 (II) wherein Alk^, alk2, Ph and R have the above meanings.

Condensation products of compounds of the for I vith carbonic acid are those of the formula Ila wherein Alk^ , alk^, Ph and R have the above meanings.

The new compounds possess valuable pharmacological properties. Thus, they block cardiac p- eceptors, as can be shown on cats or on isolated guinea pig hearts in vitro and block vascular p-receptors, as can be shown on cats.

The new compounds therefore are useful as cardioselec ive antagonistic agents of adrenergic p- receptor stimulants, for example for the treatment of arrhythmias and angina pectoris. However,.' they -can also be used, as- valuabl-e ^intermediate . products for the manufacture of other useful substances, especially of pharmaceutically active compounds. . ..

Compounds of a structure similar to that of the compounds of the present invention are known from U.S. Patent Specifications 3,723,476 and 3,674,840.

Thus in U.S. Patent Specification No. 3,723,476 the compound 1-tert . -butylamino-3- [o- (2-meth lthioethoxy) -phenoxy] -2-propanol-1/2 fumarate is mentioned, this compound possessing strong beta-adrenergic blocking activity. v In U.S. Patent Specification No. 3,674,840 the compound l-isopropylamino-3- [p- ( 2-methoxy-ethoxy) -phenoxyl] -2-propanol-1/2 fumarate representing the ox¾-analogue of. the corresponding thio-compound mentioned above has been described.

Comparative tests with the above two known compounds ί have surprisingly shown that the para-thio-compound of the present invention is superior over a corresponding ortho isomer a as well as the corresponding ox<-analogue .

Compounds' to. be singled out are amines of the . formula III v/herein Alk^, alk2 and R have the above meanings and is hydrogen, lower alkyl, lov.'er alkenyl, lov/er alkoxy, or halogen.

Amongst the compounds of the formula III, those vherein Alk^ has the above meanings, alk2 is 1,2-ethylene or 1,3-propylene', R is c-branched lov:er alkyl or phony1-lo er alkyl with an oc-branched lov/er alkyl part and R-L has the above meanings, should be singled out particularly.

Compounds of the formula III to be singled out very especially are those wherein Alk^ is lower, alkyl with up . to 4 C atoms, especially methyl, alk is 1,3-propylene or especially 1,2-ethylene , R is phenyl-lower alkyl with up \. to 10 C atoms and an a-branched lovrer alkyl part, especially l-methyl-2-phenyl-ethyl, or above all a-branched lower alkyl with up to 4 C atoms, such as tert.-butyl or above all isopropyl, and R-^ is lower alkyl with up to 4 C atoms, especially methyl, lower alkenyl with 2 to 4 C atoms, especially methallyl or above all allyl, lower alkoxy with up to 4.C atoms, especially raethoxy, halogen, especially chlorine, or above all hydrogen.

Preferably, the compounds mentioned are not condensed with formaldehyde or carbonic acid. - l-[4-(2-Methylthio-ethoxy)-phenoxy]-2~hydroxy-3-isopropylamino-propane and the compounds mentioned in the examples should be mentioned particularly.

The new compounds can be obtained according to methods which are in themselves known.

For example, a compound of the formula IV I1 Alk^S-alk^O-Ph-O-CH^-CH-CH^-Z (IV) wherein Alk^,' alk2 and Ph have the above meanings, X-L represents the hydroxyl group and Z represents a reactive esterified hydroxyl group, or χ and Z together form an epoxy group, can be reacted with an amine of the formula NH2-R, wherein R has the above meaning, or a condensation product thereof with form aldehyde or a condensation product thereof with carbonic acid, for example a compound of the formula R-N=C=0, wherein R has the above meanings.

A reactive, esterified hydroxyl group is in ^ particular a hydroxyl group esterifiedby a strong inorganic or organic acid, above all a hydrogen halide acid, such as hydrochloric acid, hydrobromic acid or hydriodic acid, or sulphuric acid or a strong organic sulphonic acid, ' such as a strong aromatic sulphonic acid, for example benzene-sulphonic acid, -bromobenzenesulphonic acid or -toluene-sulphonic acid. Thus Z in particular represents chlorine, bromine or iodine.

This reaction is carried out in the usual manner. If a reactive ester is used as the starting material, the reaction is. preferably carried out in the presence of a basic condensation agent and/or with an excess of amine.

Suitable basic condensation agents are, for example, alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, alkali metal carbonates, such as potassium carbonate, and alkali metal alcoholates, such as sodium methylate, potassium ethylate and potassium tertiary-butylate .

In resulting compounds it is. possible, v/ithin the definition of the end products, to modify, introduce or split off substituents in the usual manner; resulting compounds can also be converted into other end products in the usual manner.

Thus, condensation products of the formula II can be obtained by reacting an amine of the formula I with formaldehyde or with a reactive carbonyl derivative carbony - dcrivativc thereof.

Reactive carbonyl derivatives are above all acetals, ketals, hemithioketals, thioketals, especially dimethyl- or diethyl-acetals, -ketals or -thioketals, or acylals, especially those with acetic acid or with a hydrogen halide acid, f r example compounds of the formula CH2C12 or Cl^Br^ This reaction is carried out i the usual manner, in the presence or absence of a solvent, at room temperature o preferably at elevated temperature, if necessary in the presence of a condensation agent, especially of a acid condensation agent. ' · .

Condensation products of the formula Ila can be obtained by reacting an amine of the formula I with carbonic acid or one of its reactive derivatives.

Reactive carbonic acid derivatives are, for example, carbonyl halides, such as, in particular, phosgene or carbonyl bromide, and also carbonic acid monoesters or diesters, such as lower alkyl esters, for example carbonic acid dimethyl ester and chloroformic acid methyl ester.

This reaction is carried out in the usual manner, preferably in the presence of a solvent and at lowered temperature, room temperature or elevated temperature, if necessary in the presence of a condensation agent, especially of a basic condensation agent.

Analogously, a condensation product of the formula II or Ila can be converted in the usual manner by hydrolysis into a compound of the formula I, for example in a basic medium or preferably in an acid medium.

The reactions mentioned can optionally be carrie¾-out simultaneously or successively and in optional sequence.

The reactions mentioned are carried out in the usual manner, in the- presence or absence of diluents, condensation agents and/or catalytic agents, at lowered, ordinary or elevated temperature and in a closed vessel if appropriate.

Depending on the process conditions and starting materials, the end products are obtained in' the free form or in the form of their acid addition salts which is also encompassed by the invention. Thus, for example, basic, neutral or mixed salts and possibly also hemihydrates, monohydrates , sesquihydrates or polyhydrates thereof, can be obtained. The acid addition salts of the new compounds can be converted into the free compound in a manner which is in itself known, for example with basic agents, such as alkalis or ion exchangers. On the other hand, the resultin free bases can form salts with organic or inorganic acids.

The acids used for the manufacture of acid addition salts are in particular those which are suitable for 'forming therapeutically usable salts. As examples of such acids there may be mentioned: Hydrogen halide acids, sulphuric acids, phosphoric acids, nitric acid and aliphatic, ali-cyclic, aromatic or heterocyclic carboxylic acids or sul-phonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycollic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxy aleic acid or pyruvic acid, benzoic acid, V p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or embonic acid, methanesulphonic acid, ethanesulphonic acid, hydroxye hanesulphonic acid, ethylene-sulphonic acid, halogenobenzenesulphonic acids, toluene-sulphonic acid, naphthalenesulphonic acid or' sulphanilic acid.

These or other salts of the new compounds such as, for example, the picrates, can also be used for the purification of the free bases obtained, by converting the free bases into salts, isolating these and again liberating the bases from the salts. Because of the close relationships between the new compounds in the free form and in the form of their salts, the free compounds, in the preceding and following text, are where, appropriate also to be understood as the corresponding salts, .with regard to general sense and intended use.

The invention also relates to those embodiments of the process in which a reactant is present in the form of its salts .

Depending on the choice of the starting materials and procedures the new compounds can be in the form of optical antipodes or racemates or, if they contain at least two asymmetrical carbon atoms, also in the form of isomer mixtures (racemate mixtures).

Resulting isomer mixtures (racemate mixtures) can be separated into the two stereomeric (diastereomeric) pure racemates in a known manner on the basis of the physico-chemical differences of the constituents, for example by chromatography and/or fractional crystall sation.

Resulting racemates can be resolved into the dia-stereorners according to known methods, for example by recrystallisation from an optically active solvent, with the aid of micro-organisms or by reaction v/ith an optically active acid which forms salts with the racemic compound and separation of the salts obtained in this manner, for example on the basis of their different solubilities, and the antipodes can be liberated from the diastereoraers by treatment v/ith suitable agents. Particularly customary optically active acids are, for example, the D- and L~forras of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid or quinic acid. Advantageously, the more active of the antipodes is isolated.

Preferably, those starting materials are used for carrying out the reaction according to the invention which lead to the initially particularly mentioned groups of end products and especially to the end products which have been particularly described or singled out.

The starting materials are known or can, if they are new, be obtained according to methods .which are in themselves known. · . . .

The new compounds can be used as medicaments, for · example in the form of pharmaceutical preparations, in which they or their salts are present as a mixture with a pharma- ceutical, organic or .inorganic, solid or liquid excipient v/hich is suitable for, for example, enteral or parenteral administration. Suitable substances for forming the - · excipient are those which do not react with the new compounds such as, for example, water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gum, polyalkylene glycols, white petroleum jelly, cholesterol or other known medicinal excipients. The pharmaceutical preparations can be, for example, in the form of tablets, dragees, capsules, suppositories, ointments or creams, or in a liquid form, as solutions (for example as an elixir or syrup), suspensions or emulsions. They are optionally sterilised and/or contain auxiliaries, such as preservatives, stabilising agents, wetting agents or emul- sifiers, salts for regulating the osmotic pressure or buffers They can also contain yet other therapeutically valuable substances. The preparations, which can also be used in veterinary medicine, are formulated according to customary methods. .

The examples v/hich follow explain the invention without, however, limiting it.

Example 1 A solution of 20 g of l-[4-(2-methylthioethoxy)~ . phenoxy]-2-hydroxy-3-chl0ro-propane and 30 g of isopropyl- amine in 50 ml of isopropanol is heated for- 12 to 14 hours under reflux. The volatile constituents are then evaporated •off under reduced pressure and the evaporation residue is dissolved in 300 ml of ethyl acetate and the. solution is extracted with 50 ml portions of 2 hydrochloric acid.

The aqueous phase is separated off and rendered strongly alkaline with concentrated sodium hydroxide solution. The oil which precipitates is extracted with about 200 ml of ethyl acetate and distilled in a bulb tube at 150 to l60°C/0.0 mm Hg. l-[ -(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane is thus obtained as an almost colourless oil v/hich solidifies to crystals. Its hydrochloride melts at 102 to 103°C (recrystallised from butanone) . . ■ · Example 2 · An. analogous method to Example 1, using 35 g of t-butylamine in place of the isopropylamine, gives l-[4-(2-methylthioethoxy) -phenoxy] -2 -hydroxyr3-t-butylamino-propane of melting point '62-63° C (from ether/petroleum ether). Its hydrochloride melts at 131-133° C (from acetone-ether). 1-[4- (2-Kethylthioe hoxy)-phenox ]-2-hydroxy~3-chloropropane , required as the starting material can be obtained as follows: - . 2-(p-Hydroxyphenoxy)-tetrahydropyran is reacted analogously to Example' 4 with 2-methylthioethyl chloride and is hydrolysed for 2 to 3 hours with dilute hydrochloric acid in ethanol. p-(2~Methylthioethoxy)-phenol, thus obtained, is used in the crude form for the next stage, 20 g of crude p-(2-methylthioethoxy)-phenol, 0 ml of epichlorohydrin and 0.2 ml of piperidine are heated for 1 hour under reflux. The excess epichlorohydrin is then distilled off at 100°C bath temperature and 10 mm Hg.

The crude l~[4-(2-methylthioethoxy)~phenoxy]--2-hydroxy-3-chloropropane thus obtained is used direct for the next stage. · ' - Example 3 3- g of 3-isopropyl-5~[4-(2~methylthioethoxy)-phenoxy-inethyl]-oxazolidine are dissolved in 20 ml of 2 N hydrochloric acid and the solution is warmed for 1 hour on a water bath (about 80°C). After cooling, the solution is rendered alkaline with 10 ml of concentrated sodium hydroxide solution and the mixture is extracted with 100 ral of ether. The resulting l-[4-(2~methylthioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane is distilled at 150 - l60°C/0..04 mm Hg in a bulb tube. Its hydrochloride melts at 102 to 103°C (recrystallised from butanone) and is identical with the product described in Example 1.

Example 4 4.7 g of 3-isopropyl-5-(4~hydroxyphenoxy--methyl)-oxazolidine, dissolved in 7 ral of acetone,. g of potassium carbonate and 2.2 g of 2-methylthio-ethyl chloride are heated for 20 hours under reflux whilst stirring. After addition of a further 1.5 g of potassium carbonate and 1.1 g of 2-methylthio-ethyl chloride, the reaction mixture is heated for a further 20 to 24 hours. · It is then filtered and the filtrate is evaporated under reduced pressure.

The resulting oil is taken up in 100 ml of ether and extracts three times with 10 ml of concentrated sodium hydroxide at a time. ' The ether phase is dried, filtered a d evaporated and the evaporation residue is distilled in a bulb tube ^ 140 to 150°C/0.03 mm Hg. 3~Isopropyl~5-[4-(2-methylthio-ethoxy)-phenoxy-n.ethyl]-oxazolidine is thus obtained as a yellowish oil.

Example 5 ■ - 4.5 E of l-(4-hydroxyphenoxy)-2-hydroxy-3-isopropylamino-propane are reacted analogously to Example 4 v/ith a total of .3 & of 2-methylthio-ethyl chloride and the reaction'mixture is worked up. This gives l-[4~(2-methyl~ thioethoxy)-phenoxj']-2-hydroxy~3~isopropylamino-propane of which the hydrochloride melts at 102 to 103°C (from butanone), and is identical with the product described in Example 1. ' · Example 6 3.7 g of 4- (2-methylthioethoxy)-phenol, 3-5 g of l-chloro-2-hydroxy-3-isopropylamino-propane and 5 g of potassium carbonate in 50 ml of acetone are stirred for 5 to 7 hours at 50°C. The undissolved matter is filtered off and the filtrate is evaporated under reduced pressure. The evaporation residue is taken up in 100 ml of ether and extracted 3 times with 10 ml of concentrated sodium hydroxid* solution at a time. The organic phase is separated off, dried, filtered and evaporated and gives, after distillatio at 150 to l60°C/0.04 mm Hg (bulb tube), l-[4-(2-methylthio-ethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane , melting point of the hydrochloride .102 to 103°C (from butanone). The product is identical with the product described in Example 1. jSxajp.ple 7 21 g of crude l~[3-chloro-4-(2-raethylthioetho y¾p phenoxy]~2, 3-epoxy-propane , 21 g of isopropylamine and 100 ml of isopropanol are heated for 3 hours under reflux. The crude l-[3-chloro- -(2-methylthioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane obtained by working up as in Example 1 gives, on reaction v/ith half the equivalent amount of fumaric acid, a crystalline neutral fumarate of melting point 149~150°C (from isopropanol-ether) .

The starting material can be prepared as follows: 43· 3 g of chlorohydroquinonc , 33 g of 2~methylthio-ethyl chloride and 42 g of potassium hydroxide in 400 ml of acetone are heated for 20 hours under reflux v.'hilst stirring. The reaction mixture is cooled and filtered. After evaporating off the solvent in vacuo, the evaporation residue is taken up in 500 ml of ethyl acetate and extracted v/ith a total of 500 ml of 2 N sodium hydroxide solution in portions. The aqueous phase is acidified v/ith 6 N hydrochloric acid v/hilst cooling v/ith ice and the oil /hich separates out is extracted v/ith ethyl acetate. The ethyl acetate is evaporated off in vacuo and the residue is distilled. in a bulb tube. The fraction boiling at 140°C bath temperature and 0.01 mm Hg contains 3-ohloro-4-(2-methylthioethoxy)~ phenol. . 21.5 g of 3-ohloro-4-(2-methylthioethoxy)-phenol, 15 g of epichlorohydrin and 11 g of potassium carbonate in 250 ml of acetone are heated for 16 to 20 hours under reflux. The undissolved salts are then filtered off and the filtrate is evaporated in vacuo. The evaporation residue is up in 300 ml of ethyl acetate and washed with 100 ml of cold 2 N sodium hydroxide solution. After drying and evaporation, crude l-[3-chloro- -(2-methylthioethoxy)~phenoxy]-2,3-epoxy-propane is obtained, which can be used without further purification.

Example 8 - . 18.9 g of l,2~epoxy-3-[2-methyl-4-(2-methylthio-ethoxy)-phenoxy]-propane , 20 ml of isopropylamine and 100 ml of isopropanol are heated for 3 hours under reflux. '. Working up analogously to Example 1 gi\'es l-[2-methyl-4-(2~methyl~ thioethoxy)-phenoxy]-2-hydroxy-3-isopropylamino-propane as an oil which with half the theoretical amount of fumaric acid forms the neutral fumarate of melting point 134-135°C (from methanol-ether) . .. ' • ". The starting material can be prepared as follows: 50 g of toluhydroquinone , 50 g of 2-inethylthio-ethyl chloride and 45 g of potassium carbonate in 600 ml of acetone are heated under reflux. After 18,· 33 and 55 hours, a further 9 g of 2--methylthioethyl chloride and 11 g of potassium carbonate are added in each case. The mixture is then heated for a further 2 hours. The reaction mixture is worked up analogously to Example 7 and gives 2~methyl-4~ (2-methylthioethoxy)~phenol as an oil of boiling point 130°C/0.01 mm Hg". "24 g of 2-methyl-4-(2-methylthioethoxy)~ phenol, 250 ml of diethyl ketone, 18 g of epichlorohydrin and 18 g of potassium carbonate are reacted analogously to Exampl 7 and worked up to give the oily l-[2-methyl-4-(2-mcthylthio- ethoxy)~phenoxy]~2, 3-epoxy-propane . This is used in th crude form for the ne t stage. · ' Examole 9' 12 g of l-[4-(3-raethylthio-propoxy)-phenoxy]-2 , 3-epoxy-propane , 120 ml of isopropanol and 15 ml of isopropyl-amine are heated for 3 to 4 hours under reflux. After evaporating off the volatile constituents in vacuo, crude l-[4-(3--methylthio-propoxy)-phenoxy]-2-hydroxy-3-isopropyl-amino-propane is obtained, which is isolated analogously to Example 1 and then converted into its hydrochloride. After recrystallisation from acetone-ether, the hydrochloride melts at 102~103°C. · The epoxypropane required as the starting material can be obtained as follows: 18 g of potassium carbonate, 26.2 g of 1 , 3-dibromo-propane and 25 g of 2-(p-hydrox3^henoxy)-tetrahydropyran^ in 500 ml of acetone are heated for 20 hours under reflux. The 2-[4- (3-bromopropoxy)-phenoxy]-tetrahydropyran thus obtained, in 100 ml of ethanol, is left to stand with a solution of 42 g of sodiua raethylmercaptide in 400 ml of ethanol for 3 hours at 0-5°C. .

After addition of concentrated hydrochloric acid until pH 1 is reached, the reaction mixture is left to stand for 2 to 3 hours at room temperature and then evaporated in vacuo, and the residue is partitioned" between 100 ml of water and 300 ml of ether. The ether phase is exhaustively extracted with 2 N sodium hydroxide solution, the aqueous phase is again rendered acid and 4-(3-niethylthiopro oxy)- phenol is extracted with ether. It boils at 125-128°C/ ^ C.01 mm Hg. 10 g of ~(3-niethylth o-propoxy)-phenol, 100 ml of acetone, 8 g of epichlorohydrin and 8 g of potassium carbonate are heated for 48 hours under reflux. After cooling, the insoluble constituents are filtered off and the filtrate is evaporated. Crude l-[4-(3~H3ethylthio-propoxy)-phenoxy]~ 2,3-epoxypropane is thus obtained, which is used further vithout additional purification. " • Examole 10 . 22 g of l-(4-hydroxyphenoxy)-2-hydroxy~3-tert,~ butyl-amino-propane , 13 g of potassium carbonate and' 11 of 2-methylthio-ethyl chloride in 350 ml of acetone are heated for 16 hours under reflux whilst stirring. After 2 and 48 hours, a further 13 g of potassium carbonate and 11 g of methy thio-ethyl chloride are added in each case, and heating is continued. After a total of 60 to 70 hours' reaction time the suspension is filtered, the filtrate is evaporated and the residue is dissolved in 300 ml of ether. The ether solution is first -washed 3 times with 10 ml of concentrated sodium hydroxide solution at a time and then extracted twice wit 75 ml of 2, N hydrochloric acid at a time.

The combined hydrochloric acid extracts are rendered alkaline v/ith concentrated sodium hydroxide solution (pH about 10) and extracted twice with 200 ml of ether at a time. After distilling off the ether, crude l-[4-(2-methylthioethoxy)~ phenoxy]-2-hydroxy-3-tert.-butylamino-propane is obtained, which is identical with the product from Example 2.

. Example 11 · · .

; · . A solution of 11.0 g of l~[ -(2-m'ethylthioethoxy)--2~ allylphenoxy]-2 , 3-epoxy-propane and 28 g of isopropylainine in 200 ml of isopropanol is heated for 14 hours under reflux. The volatile constituents are then evaporated off under' reduced pressure and the evaporation residue is dissolved in ethyl acetate and extracted v/ith 25. mi of 2 N hydrochloric acid at a time. The aqueous phase is separated off and rendered strongly alkaline vith concentrated sodium hydroxide solution. The" oil which separates out is extracted with ethyl acetate and the extract is washed vith vater, dried over sodium sulphate, filtered and evaporated. l~[2~Allyl~ . ~(2-methylthioethoxy)-phenoxy]~2-hydroxy~3~isopropy1amino-propane is obtained as an almost colourless oil. Its hydrogen-oxalate melts at 116-117°C (when recrystallised from acetone). · The epoxypropane derivative required as the starting substance can be obtained as follows: 42.0 g (Ο.276 mol) of 2-allylhydroquinone , dissolved in 300 ml of acetone, 39 g of potassium carbonate and 28 ml of 2-raethylthioethyl chloride are heated for 20 hour's under reflux whilst stirring. Filtration and evaporation of the filtrate gives 67 g of evaporation residue as a brown oil. This is dissolved in ether, and the solution is extracted four times vith a total of 300 ml of 2 N sodium hydroxide solution. The alkaline extracts are brought to pH 9 by · passing in carbon dioxide and then extracted three times v/ith ether. The ether extracts are dried with sodium sulphate, filtered and evaporated and the evaporation residue is distilled in a bulb tube.. The fraction of boiling range 110-150°C/0.05 mm Hg gives 4-(2-methylthioethoxy)-2~ allyl-phenol of melting point 117-119°C after recrystal-lisation from carbon tetrachloride. '. 13.0 g of 4-(2-methylthioethoxy)-2-allyl-phenol, dissolved in 100 ml of diethyl ketone, are heated with 8.4 g of potassium carbonate and 6 ml of epichlorohydrin for >6 hours whilst stirring under reflux. The mixture. is then evaporated to dryness in vacuo and the residue is partitioned between water and ethyl acetate. The organic phas is washed with water, dried over sodium sulphate, filtered and evaporated. 1-[ -(2-Methy1thioethoxy)-2-allylphenox ]-2, -epoxy-propane is obtained as a yellowish oil.

Example 12 22.5 g of l-(4-hydroxyphenoxy)-2-hydroxy-3-iso~ propylarnino-propane , 18.7 £ of 2-t-butylthio-ethyl chloride and 17 g of potassium carbonate in 200 ml of acetone are stirred for 18 hours under reflux. The same amounts of potassium carbonate and 2-t-butylthio-ethyl chloride are then added once more and the mixture is heated for a" further 2 hours. Working up as described in Example 10 gives l-[4-(2-t-butylthioethoxy)-phenox ]-2-hydroxy-3-isopropyl-amino-propane as an oil which distils at 150-l60°C/0.01 mm K in a bulb tube and forms a neutral fumarat " of melting point 127-128°C (from acetone). " . . . Example 13 - isopropylaiaino-propane and a total of 40 g of potassium carbonate and 37 g of 2-ethylthio-ethyl chloride give, analogously to Example 12, l~[4~(2-ethylthioethoxy)-pherioxy 2-hydroxy-3-isopropylamino-propane as an oil which distils at 150-155°C/0.02 mm Hg in a bulb tube. Its hydrochloride melts at 86-88°C (from isopropanol-ether) .

Example 14 .

Analogously to Example 12, 22.5 g of l~(4-hydroxy~ phenoxy)-2-hydroxy~3-isopropylamino-propane , 25 g of 2-chloropropyl methyl, sulphide and 28 g of potassium carbonate give l-[ -(l-methyl-2-methylthio-ethoxy)-phenoxy] -2-hydroxy-3-isopropylamino--propane as an oil which distils at 150-155°C/0.02 nun. Hg in a bulb tube. Its neutral fumarate roelts at 113°C (from isopropanol-ether) .

Example 1 Tablets containing 50 mg of active substance are prepared in the usual manner, in the following composition: Composition · l-[4-(2-Methylthioethoxy)~phenoxy]- i 2--hydroxy-3-isopropylamino-propane . 50 mg iheat starch " 59 JQ Lactose ". 70 rag Colloidal silica " · * 10 rag Talc : . « 10 rag Magnesium stearate ·' · 1 rag 200 mg Preparation; The 1-[4-( -methylthioethox )-phenoxy]-2-hyctroxy- 3-isopropylamino-propane is mixed with a part of the wheat starch, with lactose and with colloidal silica. and the ^ mixture is forced through a sieve, giving a powder mixture. A further part of the wheat starch is worked into a paste with a five-fold amount of water on a water bath and the powder mixture is kneaded v/ith this paste until a slightly plastic mass has been produced.

The plastic mass is pressed through a sieve of about 3 mm mesh width and dried and the resulting dry granules are again forced through a sieve. The remaining wheat starch, talc and magnesium stearate are then mixed in and the mixture is pressed to give tablets weighing 200 mg and having a breaking groove . " .

The daily dose is about -- to tablets in the case of a warm-blooded animal of about 75 kg body weight, and the appropriate dose of active substance can also be administered as a single tablet of appropriate composition.

Example 16 22 g of l-(4-hydroxyphenoxy)-2-hydroxy-3-[(l-methyl-3-phenyl-propyl)amino]-propane> 8.5 g of 2-chloro- ethyl methyl sulphide and 11 g of potassium carbonate are heated for 6 hours at the reflux temperature, whilst stirring. After adding the same amounts of 2-chloroethy2 methyl sulphide and potassium carbonate, the reaction mixture" is heated fo a further 18 hours. Filtration, and evaporation of the filtrate in vacuo, gives an oil which is chromatographed on 600 g of silica gel. After elution vith benzene containing % of methanol, and subsequent elution with benzene which contains 20>o of methanol, the latter "fraction gives pure 1~[4- (2-methylthloethoxy)~ phenoxy ]-2-hydroxy-3-[ ( '-phenyl- 11-methylpropyl)-amino]-propane, of which the hydrochloride melts at * 154-156oC (sintering at 1480C ) (from methanol/acetone) .

Example 17 · · 12 g of l-[4- (2-methylthioethoxy)-ph¾oxy]~2,3-epoxy-propane , 7.5 g of l-methyl-3-phenyl-propylamine and 100 ml of isopropanol are heated for 4 hours under reflux. After evaporating the volatile constituents, ultimately in a high vacuum at 130°C/0.01 mm -Hg, the reaction mixture is taken up in a mixture of 50 ml of ethyl acetate and 50 ml of ether, and the solution is clarified "by filtration through Hyflo and shaken with 100 ml of 2 N hydrochloric. acid.

Hereupon 1-[4-( 2-methylthioethoxy)-phenoxy] -2-hydroxy-3-[ (1 l-methyl~3'-phenyl-propyl)-amino]-propane precipitates as the crystalline hydrochloride. ' After recrystallisation from water, with addition of active charcoal, this substance melts at 154-156°C (sintering from 1 8°C onwards).

The epoxide used as the starting substance can "be prepared as follows: 2-(4- enzyloxy-phenoxy)-tetrahydropyran is prepared, from hydroquinone onobenzyl ether and 2 , 3-d.ihydro-pyran in benzene, using p-toluenesulphonic acid as the catalyst (melting point 67-69°C after crystallisation from petroleum ether).

This substance is debenzylated with the addition of a palladium/charcoal catalyst, and thus gives 2-(4-hydroxy- phenox )-tctrahydropyran of melting point 90-93°C after recrystallisation from ether/petroleum ether. " " ^ Reaction of the latter phenol with double the equivalent amount of methylthioethyl chloride and potassium carbonate in acetone for 3 days at the reflux temperature, followed by acid hydrolysis, gives 4-(2~methylthioethoxy)-phenol, an oil which boils at 120-130°C/0.03 ram Hg. Λ mixture of 142 g of 4-(2-methylthio-ethoxy)-phenol, 171 g of potassium carbonate and 115 g of epichloro hydrin is heated for 40 hours under reflux, whilst stirring The dark suspension is cooled and filtered and the filtrate is evaporated in vacuo. The dark brown oil which remains is dissolved in 1,500 ml of "ether and extracted twice with 500 ml of 2 N sodium hydroxide solution at a time. The ether solution is then washed three times with 500 ml of water at a time, dried over magnesium sulphate and evaporat Crude oily l-[4-(2-methylthioethoxy)-phenoxy]~2, 3-epoxy-propane is obtained, which after recrystallisation from ether/petroleum ether melts at 53-58°C.

Example 18 .A solution of 4.2 g of 5- ^[4-(2-methylthioethoxy)-phenoxy]-methyl^ -3-isopropyl~oxazolidin-2~one in 50 ml of n-butanol is boiled with 10 ml of 2 N sodium hydroxide solution for 14 hours under reflux. The solution is evaporated in vacuo, 20 ml of 2 N hydrochloric acid are added and the mixture is thoroughly shaken with 20 ml of ether. The aqueous phase is separated off and evaporated in vacuo. The crystals which precipitate are recrystallis - - from butanone. This gives l~[4-(2-inethylthioethoxv)-phenoxyJ-2-hydroxy~3-isopropylamino-propane as the hydrochloride of melting point 102-103°C.

Example 19 The Schiff's base obtained from l-amino-2-hydroxy-3-[4-(2-methylthioethoxy)-phcnoxy]-propane and benzylacetone is dissolved in 50 ml of isopropanol and stirred with 2 g of sodium borohydride for 16 hours. The reaction mixture is evaporated in vacuo and the residue is extracted with 50 ml of ethyl acetate. The ethyl acetate solution is washed with 20 ml of water and then brought to pH 2 with 2 N hydrochloric acid. The crystals which precipitate are filtered off and recrystallised from water. This gives l-[4- (2- ethylthio~ ethox )-phenoxy]-2-hydroxy-3-[ (1 '-methyl-31 -phenyl-propyl)-amino]~propane as the hydrochloride of melting point l-Amino-2~hydroxy-3-[4-(2-methylthioethoxy)-phenoxy] propane, used as the starting substance is obtained by reaction of l-[4-(2-methylthioethoxy)-phenoxy]-2, -epoxy-propane and ammonia in methanol. It melts at 74-81°C after distillation in a high vacuum at 180°C/0.05 mm Hg. Ν·· Example 20 Analogously to Example 4, 5-[4-hydroxy-phenoxy)-raethyl]-3-isopropyl-oxazolidin-2-one/01-if , which is obtainable by debenzylation of 5-[ (4-benzyloxy-phenoxy)-methyl]~3-iso- with palladium-charcoal/hydrogen, and 2-methylthioethyl -chloride gives 5- ^[4~(2-methylthio-ethoxy)-phenoxy]-methy^ -3-isopropyl-oxazolidin-2-one0/) of melting point 77-78°C (from ethyl-acetate/petroleum ether).

Claims (18)

1. 44003-2 WHAT WE CLAIM IS: 1. New 1- [p- (alkylthioalkoxy) -phenoxyJ -3- (substituted amino) -2-propanols of the formula I OH I Alk^ - S - alk2 - 0 - Ph - 0 - CH2 - CH - CH2 - NH-R (I) wherein lk^ is lower alkyl, alk2 is lower alkylene, Ph is p-phenylene optionally substituted by halogen, lower alkyl, lower alkenyl or lower alkoxy, and R is lower alkyl or phenyl- lower alkyl, and their condensation products ,with formaldehyde or carbonic acid.

2. Compounds of the formula III vherein Alk^, alk2 and R have the above meanings and R-, is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, or halogen.

3. Compounds of the formula III according to Claim 2, wherein Alk^ has the above meanings, alk2 is 1,2 -ethylene or 1, 3-propylene, R is α-branched lower alkyl or phenyl-lower alkyl with an a-branched lower alkyl part, and R^ has the above meanings.

4. Compounds of the formula III according to Claim 2, wherein Alk^ is methyl, alk2 is 1 , 3-propylene or 1, 2 -ethylene, R is l-methyl-2-phenyl-ethyl, tert. -butyl or isopropyl, and 44003/3 · is methyl, methallyl, allyl, methoxy, chlorine or hydrogen.

5. The compounds of the general formula I as mentioned in anyone of the Examples 1-14. *

6. The compounds of the general formula I as mentioned in anyone of the Examples 16-20.

7. 1- [4- (2-Kethylthioethoxy)-phenoxy]-2-hydroxy-3-iso-propylamino-propane .

8. The compounds mentioned in one of Claims 2-5 and 7, in the form of their dextro-rctatory optical antipodes.

9. The compounds mentioned in one of Claims 2-5 and 7, in the form of their laevo-rotatay optical antipodes.

10. One of the compounds mentioned in one of Claims 2-5 and 7-9, in the .free form.

11. One of the compounds mentioned in Claims 2-5 and 7-9, in the form of its salts.

12. One of the compounds mentioned in Claims 2-5 and 7-9, in the forai of its therapeutically usable salts.

13. The compounds mentioned in on of Claims 1 and 6, in the form of their dextro- otatoy optical antipodes.

14. The compounds mentioned in one of Claims 1 and 6, in the form of their laevo-ro atory optical antipodes.

15. One of the compounds mentioned in one of Claims 1, 6, 13 and 14, in the free form.

16. One of the compounds mentioned in Claims 1, 6, 13 and 14, in the form of its salts.

17. One of the compounds mentioned in Claims 1, 6, 13 and 14, in the form of its therapeutically usable salts. 44003-2 17. One of the compounds mentioned in Claims 1, 6, 13 and 14, in the form of its therapeutically usable salts.

18. Process for the preparation of new 1- [p- (alkylthio- alkoxy) -phenoxy ] -3- (substituted amino) -2-propanols of the formula I wherein Alk^ is lower alkyl, alk2 is lower alkylene, Ph is p-phenylene optionally substituted by halogen, lower alkyl, lower alkenyl or lower alkoxy and R is lower alkyl or phenyl lower alkyl, and their condensation products with formaldehyde or carbonic acid, characterised in that a compound of the formula IV Alk ~S-alk2-0-Ph-0-CH2~CH--CH2-Z (IV) ■ vherein Alk^, alk2 331(1 ph ha.v the above meanings, χ represents the hydroxy1 group and Z represents a reactive esterified hydrox 1 group, or X^ and Z together form an epoxy group, is reacted with an amine of the formula N¾-: v/herein R has the above meaning, or a condensation prcduc thereof with form^aldehyde or carbonic acid, resulting isomer mixtures are separated into the pure isomers and/or resulting race ates are resolved, into the optical antipodes and/or resulting free bases are converted into their salts or resulting salts are converted into the free bases. - 28 - 19· Process according to Claim 18, characterised in that -the reactive, esterified hydroxyl group is a hydroxy1 group esterified v/ith a hydrogen halide acid, sulphuric acid or sulphonic acid. 20. Process according to one of Claims 18-19, characterised in that a reactant is employed in the form of one of its salts, if appropriate. 21. Process according to Claim 20, characterised in that an aldehyde of the formula XXI * OH I Alk^S-alkg-O-Ph-O-CKg-CK-CKO (XXI) wherein Alk^, al*^ and Ph have the above meanings, is reacted _3¾≥.ό«β> v.'ith an amine of the formula ^N-R, wherein R has the above meaning, in the presence of a reducing agent, to give compounds of the formula I. *^ 22. Process according to Claim 20, characterised in that an amine of the formula V ■ OH · Alk^S-alk^O-Ph-CHg-CH-CH^-NHg (V) vherein the above meanings, is reacted 3?« wo& v/ith an aldehyde or ketone of the formula -0=R' , v/herein R'H is the same as R, and R has the above meanings, in the presence of a reducing agent, to give compounds of the formula I. 23. Process according to Claim 18-22,characterised in that resulting compounds of the formula I are reacted with formaldehyde or with a reactive carbonyl derivative thereof, to give compounds of the formula II wherein Alk-^, alk2» Ph a"d R have the above meanings. 24. Process according to Claim 23, characterised in "that reactive carbonyl derivatives are acetals, ketals, hemithioketals or thioketals. . . . 25'. Process according to one of Claims 18-22, characterised in that resulting compounds of the formula I are reacted with carbonic acid or with its reactive derivatives to give compounds of the formula Ila Alk, -S-alk -0-Ph-0-CH wherein Alk^, alk2, Ph and R have the meanings indicated in Claim 1. " . . 26. Process according to Claim 25, characterised in that -reactive derivatives of carbonic acid are carbonyl -halides, and carbonic acid monoesters or diesters. 27. Process according to Claim 26, characterised in that carbonyl halide represents phosgene. - 30 - I 28. \ Process according to one of Claims 18-22, character ised in that resulting compounds of the 'formula II are converted into compounds of the formula I by hydrolysis. 29. Process according to one of Claims 18-22, charactci ised in that resulting compounds of the, formula Ila are converted into compounds of the formula I by hydrolysis. 30.,. Process according to one of Claims 28 and 29, characterised in that the hydrolysis is carried out in an acid medium. 31. Process according to one of Claims 18-22, 28, 29, and 30, characterised in that compounds of the formula III vhcrein Alk^, alk^ and R have the above meanings and is hydrogen, lov,*er alkyl, lower alkenyl , - lower alkoxy, or halogen are manufactured. 32. Process according to one of Claims 18-22, 28, 29, and 30, characterised in that compounds of the formula III according to Claim 31 are manufactured, wherein Alk^ has the above meanings, alk2 is 1,2-ethylene or 1, 3-propylene, R is oi-branched lower alkyl or phenyl-lower alkyl with an a-branched lower alkyl part, and has the above meanings. 33. Process according to one of Claims 18-22, 28, 29 and 30, characterised in that compounds of the formula III according to claim 31 are manufactured, wherein Alk^ is 44003-2 ' methyl, alk2 is 1 , 3-propylene or 1,2 -ethylene, R is 1-methyl- 2-phenyl-ethyl, tert. -butyl or isopropyl and is methyl, methallyl, allyl, methoxy, chlorine or hydrogen. 34. Process according to one of Claims 18-24 characterised in that condensation products of the compounds mentioned in one of Claims 31-33 with formaldehyde are manufactured. 35. Process according to one of Claims 18-22, 25, 26 and -27-Ϊ- haracterised in .that condensation products of the compounds mentioned in one of Claims 31-33 with carbonic acid or with their derivatives are manufactured. 36. Process according to one of Claims 23, 24 and 28-34, characterised in that the compounds mentioned,, in Examples 1-14 are manufactured. 37.. Process according to one of Claims 18-22 and 25-27 and 35,. characterised -in that the compounds mentioned in Examples 16-20 are manufactured. 38. Process according to one of Claims 18-22, 28, 29 r and 30,, characterised in that l~[4-(2-methylthicethoxy)~ phenoxy]-2-hydroxy-3-isopropylamino-propane is manu actured . -39. Process according to one of Claims- 23, 24, 28-34, 36 and 38, characterised in that the new compounds are manufactured in their dextro-rotatory form. · · -40. Process according to one of Claims 23, 24, 28-34, 36" and 38', characterised in that the new compounds are manu actured in their laevo-rotatory form. •41. · Process according to one of Claims 23, 24, 28-34, 36 and 38, characterised in that the new compounds are manufactured in the free form. % ·· 9 44003-2 42. Process according to one of Claims 23, 24, 28-34, . 36 and 38,, characterised in that the new' compounds are manufactured in the form of their salts. 43... Process according to one of Claims 23, 24, 28-34, 36 and 38, characterised in that the new compounds are manu actured in the form of their therapeutically usable salts. -.· . · . · 44. Process according to one of Claims- 18-22^ 25-27, 35 and 37,- characterised in that the new compounds are manufactured in their dextro-rotatory form, . 45. Process according to one of Claims 18-22, 25-27, 35 and 37,- characterised in that the new compounds are manufactured in their laevo-ro'tatory form. 46.. Process according to one of Claims 18-22, 25-27, 35" anci 37^ characterised in that the new compounds are manufactured, in the free form. 47. Process according to one of Claims' 18-22, · 25÷27, 35 and.3.7,_ characterised in that the new compounds are-' manufactured in the form of their salts. 48. Process according to o\e of Claims 18-22, 25-27, 35 and 37, characterised in that the new compounds are in the form. of their therapeutically usable salts. 49. Pharmaceutical preparations containing one of the compounds mentioned in one of Claims 1,6, 13-15 and 17, together with a therapeutically usable excipient. 50. Pharmaceutical preparations containing one of the compounds mentioned in one of Claims 2-5, 7-10 and 12, together with a therapeutically usable excipient.