SE443782B - CERTAIN NEW THERAPEUTICALLY ACTIVE ALKYLTIOPHENOXYPROPANOLAMINES - Google Patents

Description

'J7s1o574-9 L. Villa et al .: Il. Farmaco. Sci. gi (1969) 349-357 in particular discloses the following alkylthiophenoxypropanolamines as part of a study on the structure / activity relationship.

OH I C338 - OCHZCHCHZNHCPKCHQZ U.S. Patent 3,542,874 discloses 2- (alkylthio) phenoxypropanolamines of the formula I OH 'AND, CHCH ¿ZNH-az wherein R 1 is a C 1 -C 4 alkyl group and R 2 includes C 1 -C 2 alkyl. alkyl group or a C 3 -C 12 cycloalkyl group. This patent states that compounds of this type have very effective beta-adrenergic blocking properties. Compounds specifically disclosed in said patent are those in which R1 is methyl or ethyl and R2 is isopropyl, R1 is methyl, ethyl or propyl and R2 is tert-butyl, R1 is methyl and R2 is cyclopropyl, cyclopentyl or cyclohexyl and R 1 is tert-butyl and R 2 is cyclopentyl. U.S. Pat. No. 3,501,769 generically discloses compounds of the type I on H and H, cncu-Nu-H2 '~ v Is R åä- R wherein R 1 is alkyl of up to 10 carbon atoms, R 2 is alkyl of up to 20 carbon atoms. carbon atoms, cycloalkyl having up to 10 carbon atoms, etc. and R 3 is hydrogen or alkyl having up to 10 carbon atoms. However, not a single example of a specific "alkylthio" compound is disclosed in said patent. >; -. n --- ~ ~~~ -fl-§ =; f .... 7810574-9 U.S. Patent 3,872,147 generically discloses alkylthiophenoxypropanolamines of the formula ou I 2. ocuzcacnzm-a nl-s wherein R is alkyl of 1-4 carbon atoms, R1 is alkyl of 1-5 carbon atoms and R2 is alkyl with 5-8 carbon atoms, containing at least one quaternary carbon atom, directly bonded to the amino nitrogen atom via an alkylene chain of 1-4 carbon atoms. However, none of the specifically stated compounds in said patent are examples of an "alkylthiophenoxypropanolamine".

Finally, German Offenlegungsschrift 2,551,141 describes the alkylthiophenoxypropanolamine OH as J I 3 OCHZCIICEIZNH I N H3.

As can be seen from the above description of the prior art, numerous alkylthiophenoxypropanolamines have been generically disclosed, but relatively few alkylthiophenoxypropanolamines have been specifically indicated. Compared to the compounds of the prior art, which compounds are stated to be beta-adrenergic blocking agents, the alkylthiophenoxypropanolamines of the present invention are unique in that they reduce vascular resistance with the least possible admixture of beta-adrenergic blocking effects. 7s1os74-9 OH HI | Wherein R is hydrogen or lower alkyl of 1-4 carbon atoms, R 1 is alkyl of 1-8 carbon atoms and R 2 is alkyl of 6-12 carbon atoms or cycloalkylalkyl of 5-8 ring carbon atoms, which are attached to the amine nitrogen atom via an alkyl chain having 2-6 carbon atoms, and pharmaceutically acceptable acid addition salts thereof.

By "lower alkyl" in the present context is meant straight or branched chain carbon chains having 1-4 carbon atoms. Examples of such groups are methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl and tert-butyl.

In the present context, the term "alkyl" refers to straight-chain or branched-chain carbon chains with the specified number of carbon atoms. The term "cWdoaUqdaUqd" as used herein means a cycloalkyl group containing 5-8 carbon atoms (ie cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl) which is attached to the amino nitrogen atom via an alkylene chain of 2-6 It will be appreciated that the alkylene chain linking the cycloalkyl group to the amino nitrogen atom may be straight chain or branched chain.

The term "pharmaceutically acceptable acid addition salts" as used herein means salts of compounds of formula I, which are formed by reaction with organic or inorganic acids, the anions of which are relatively free. Such acid addition salts are considered pharmacologically equivalent to the bases represented by structural formula I. Examples of useful salt-forming acids are acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, cinnamic acid, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrochloric acid, sulfuric acid, sulfuric acid such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid and related acids. The acid addition salts of the present invention are prepared and isolated by conventional methods: an example thereof is to treat a solution or suspension of the free base in a reaction-inert solvent with the desired acid and recover the salts formed by concentration under reduced pressure or by crystallization technique. or any other standard chemical method. Acid addition salts, which are slightly toxic and therefore do not meet the above criteria for pharmaceutical acceptability, are sometimes useful as intermediates for isolating and purifying the bases of formula I or for other chemical purposes, such as cleavage of the optical isomers. Such salts also fall within the scope of the present invention.

As will be appreciated by those skilled in the art, the compounds of general formula I have one or more asymmetric carbon atoms and may thus exist as optically active isomers, racemates and diastereoisomers, all of which fall within the scope of the present invention. The diastereoisomeric mixtures can, depending on the physicochemical differences of the components, be cleaved into pure diastereoisomeric racemates by conventional techniques, such as chromatography and / or fractional crystallization. Cleavage of the racemates of the present invention to obtain optically active isomers of the compounds of formula I is carried out by conventional cleavage methods. For example, by reacting the bases of formula I with optically active acids, salts thereof are obtained, from which the enantiomers can be separated by means of fractional crystallization.

Acids suitable for the cleavage of the compounds of formula I are the optically active forms of tartaric acid, di-o-tolyl tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid and other optically active acids, which are known in the art. Preferably, the more biologically active, optically active stereoisomer is isolated.

The alkylthiophenoxypropanolamines of formula I can be prepared by reacting an alkylthiophenol derivative of the formula OH (II) R 1 -S wherein R and RE have the meanings given above, with an epihalohydrin of the formula ca; ---- ca-: az- x (III) 0 wherein X is halogen, preferably chlorine or bromine, and condenses the epihalohydrin reaction product with an amine of the formula HZN-R 2 (IV) to go -fi wherein R 2 is as defined above. Thereafter, if desired, the product of formula I in the form of the free base is reacted with an acid to produce an acid addition salt thereof.

The required alkylthiophenols of formula II are obtained by coupling a diazotized aminophenol with an alkyl mercaptan to produce a diazosulfide, which is then decomposed to give the corresponding alkylthiophenol. This is a conventional method and applications thereof are described by R.B. Wagner and H.D. Zook in Synthetic Organic Chemistry, p. 789 (1953 Wiley); E. Miller et al in J.Am.Chem.Soc. (1933) 1224 and S. Asaka et al. and Chem. Abrs. Qi l3243a. get? Suitable alkylthiophenol reactants of formula II which may be used in the above process include 4-methylthiophenol, 4-ethylthiophenol, 4-Q-propylthiophenol, 4-Q-butylthiophenol, 4-3-pentylthiophenol, 4- 5-hyxylthiophenol, 4-n-heptylthiophenol, 4-3-octylthiophenol, 4-isopropylthiophenol, 4- (3-methylbutylthio) phenol, 2-Q-butylthiophenol, 3-Q-butylthiophenol, 2-ethylthiophenol; 2-3--propylthiophenol, 2-isopropylthiophenol, 3-ethylthiophenol, 3-n--propylthiophenol, 3-isopropylthiophenol, 2-methyl-4- (methylthio) phenol, 3-methyl-4- (methylthio) phenol, Suitable amines of formula IV, which can be used in the above process, include Q-hexylamine, n-heptylamine, Q-octylamine, 3-nonylamine, Q-decylamine, Q-undecylamine, Q-dodecylamine, Q--isooctylamine, 2, 2-dimethylhexylamine, 1,1-dimethylheptylamine.

Since the epihalohydrin molecule of formula III has two reactive positions, reaction with an alkylthiophenol of formula II can give a mixture of reaction products of formulas V and VI below R ou x I OCHZCHCH2-X OCHZCH-CH \ o / 2 I. I fi- s '' RI-S. 0 v - 1-1 - ~~ _¿ --_ (p ¥) wherein R, RJ and X have the meanings given above.

During the further course of the precession, however, the two possible intermediates of formula V and VI on condensation with an amine of formula IV give the same final alkylthiophenoxypropanolamine product. Accordingly, it is not necessary to separate any mixture of intermediates of formulas V and VI, which mixture may be obtained by reacting a phenol of formula II with an epihalohydrin of formula III. Under the reaction conditions used in the present process, the epoxides of formula VI are mainly formed. If desired, the epihalohydrin reaction product can be taken up in an inert solvent, such as chloroform, and shaken with an excess of concentrated hydrochloric acid to convert the epoxide of formula VI to the corresponding alkylthiophenoxyhalohydrin with Formula V. Conversely, if desired, the halohydrin of formula V may be converted to the corresponding compound of formula VI by conventional techniques, e.g. by treatment with a base according to the procedure set forth by 0. Stephenson in J. Chem. Soc. (1954) 1574.

The reaction of the phenols of formula II with the epihalohydrins of formula III is carried out in the presence of a sufficient amount of a dilute aqueous solution of an alkali metal hydroxide, such as sodium hydroxide, to neutralize the acidic phenol groups at temperatures in the range 0-1000 and preferably at 25 ° C. -350 1 in accordance with the procedure set forth by YM Beasly, et al. and J. Pharm. Pharmacol. lg (1958) 47-59.

Alternatively, the reaction of the phenols of formula II with the epohalohydrins of formula III can also be accomplished with catalysts such as N-benzylisopropylamine hydrochloride, pyrrolidine, pyridine, pyloridine, piperidine acetate, piperidine hydrochloride and the like, with an excess of epihalohydrin.

The condensation of the epohalohydrin reaction product of formula A - Q V or formula VI with an amine of formula IV is preferably carried out in an organic solvent which is inert under the prevailing reaction conditions. Suitable solvents include methanol, ethanol, butanol, hexanol, toluene, dioxane, tetrahydrofuran, dibutyl ether, dimethoxyethane and ethylene glycol. The condensation can also be achieved in the absence of a reaction solvent with equimolar amounts of the reactants.

The compounds of the invention may also be prepared by reacting a phenol of formula II with a precursor. i 'se e. Aff._'. ~ _ = ¿_. ' 7-7 e 7810574-9 compound of formula VII cs --_ ~, v _ _ \ \ ¿í {/ Ph Ch: f 32 VII R 3 in alkaline medium to obtain a compound of formula VIII I OCHZCHCH -NR vixi 2 wherein R 1, R 1 and R 2 have the same meanings as in formula I and R 3 is a hydrogenolysable group, such as benzyl or benzhydryl, and converts the compound of formula VIII to an alkylthiophenoxypropanolamine of formula I. Removal of the hydrogenolysable blocking group can is achieved by catalytic hydrogenation, for example by hydrogenation in the presence of a palladium catalyst on carbon in an inert solvent, for example ethanol or aqueous ethanol.

The compounds of formula VII can be obtained according to known methods. 1 - [(N-benzyl) -n-octylamino] -2,3-epoxypropane is obtained, for example, by reacting N-benzyl-n-octylamine and epi-h1, chlorohydrin in alkaline medium (eg an aqueous solution of potassium hydroxide) according to the method set forth by L. Villa et al in Farmaco., Ed. Sci., 24§3) (1969) 349-357.

A further process for the preparation of compounds of formula I, wherein R is hydrogen or lower C 1 -C 4 alkyl, R 1 is C 1 -C 8 alkyl and R 2 -alkyl is n; the carbon atom attached to the amino nitrogen atom via one is straight chain or branched C 6 -C 12 divalent methylene group (ie via -CH 2 -) or C 5 -C 8 cycloalkyl, which is attached via an alkylene chain having 2 to 6 carbon atoms, the alkylene chain being attached to the amino nitrogen atom via a divalent V: 7810574-9 Q ~ 10 Ä 'F methylene group (ie via -CH 2 -); means ^ that "man. - # 2 .Å li luck and order reduces a compound of formula IX» s \ _> 'IIR OH HII AND CH-C-NO. 2 2 _ _ ._ H:. ^ ~ "' ; _f> ~>.

R 1 S, wherein A, B, R and R 1 have the meanings given above, for obtaining a primary amino compound of formula X OH H g I I _ _ fi; . V. I I. I ny, ri-r v _ V.

U. ~. I V (w.

W j \ / ocuz R -S .i *.-§ ...'-.- “x r; wherein Å, P., R mvh Rl how above cxnfjívnclllacltt services OC C redukiïfl fl vftlï 'H -alkylcrar nn compound of formula X with an aldehyde of formula fXI Ä C.) II. _ r - _ HU-Y .V_ »* XI wherein Y is rakkndïiw or grcnkcdjiq alkylÄmed Sell Kola fi omerßc" or cycloalkylalkyl with 5-8 ring carbon atoms and 1-5 carbon atoms ° 'gift. I. ef; »ïwzï fl v hä; \ I a' I '' f '.' .v 'ø- fl c n ».sl .UI .fi the itroalcohols of formula IX are obtained by the condensation of aldol type of the appropriate nitroalkanes and the aldehyde matter in the presence of a base or by condensation of the salt of the nitroalkane with sodium bisulfite. ~ a _ .. * 2 ~ '.. ¿} _.;: .-.;. «* :. -1 -i-sf' of the aldehyde in the presence of trace amounts of alkali elléräem_flf- acid. The alkylthiophenoxyaldehyde starting material-obtained fl ' Reaction of the appropriate alkylthiophenol in question with the bromoacetaldehyde acetal, followed by acid-catalyzed formation of the acetal groups. .p z 3 _ vi ï ä, L? As stated above, the alkylthiophenoxypropanolamines of the present invention increase peripheral blood flow, relax vascular smooth muscle, and inhibit platelet aggregation.

The compounds are substantially free of beta-adrenergic blocking effects, which inhibit the peripheral vasodilating activity of endogenous beta-adrenergic stimulating amines.

Standard in vivo and in vitro pharmacological test methods can be used to determine the activity of the compounds of formula I. Among such test methods considered useful are the method of preparation of perfused hind leg in dogs (vasodilating effect), spasmogenic preparation of rabbit aortic preparation (antispasmodic activity). and inhibition of adenosine diphosphate and collagen-induced platelet aggregation in platelet-rich human plasma (antithrombogenic action). The test method for isoproterenol-prepared guinea pig trachea, which is a standard method in this technical field, is suitable for measuring the beta-adrenergic blocking effect.

In addition to exhibiting vasodilating and antispasmodic effects and inhibiting platelet aggregation, some of the compounds of formula I have the property of inhibiting lipolysis (which can be demonstrated by the rat epidimalipolysis model) and cholesterol biosynthesis. Compounds of this type are valuable as hypocholesterolemic agents. Another aspect of the present invention relates to a therapeutic method for treating a mammal in need of vasodilation, which method comprises administering to the mammal an effective vasodilating amount of a compound of formula I or a pharmaceutically acceptable, non-toxic acid addition salt thereof.

The term "effective vasodilating amount" in the present context means a dose which exerts a vasodilating effect on the treated animal without undue "toxic side effects". '_ * flf. , §F7s1os74-9 l2 By systemic administration is meant both oral and parenteral administration. Examples of parenteral administration are intramuscular administration. For rectal administration, both ointments and intravenous, intraperitoneal, rectal and subcutaneous adjuvants can be used. Although the dosage varies to some extent depending on the mode of administration and the particular compound in question, the desired vasodilating effect is generally achieved when administering from about 0.5 mg per kg of body weight to 25 ng per kg of body weight of a compound of formula I or a non-toxic pharmaceutically acceptable salt thereof in effective single or multiple dose units.

In carrying out the therapeutic process of the present invention, the compounds of formula I for vasodilating purposes are generally administered in the form of a pharmaceutical composition containing a compound of formula I either in the form of the free base or in the form of a pharmaceutically acceptable, non-toxic acid addition salt thereof as an active ingredient in combination with a pharmaceutically acceptable carrier. The carrier can be solid, semi-solid, a liquid diluent or a capsule. Accordingly, a further feature of the present invention relates to pharmaceutical compositions containing the compounds of formula I or non-toxic, pharmaceutically acceptable acid addition salts thereof in combination with a pharmaceutically acceptable carrier.

For the preparation of pharmaceutical compositions containing the compounds of formula I in the form of dosage units for oral administration, the compound is mixed with a solid, powdered carrier (for example, lactose, sucrose, sorbitol, mannitol, potato starch, maize starch, amylopectin, cellulose derivative or gelatin) as well as with a lubricant (for example magnesium stearate, calcium stearate, polyethylene glycol wax or the like) and compressed into tablets. The tablets can be used without a coating or provided with a coating by means of known technology in order to delay dissolution and absorption in the gastrointestinal tract and thereby give a delayed effect for a longer period of time. If coated tablets are desired, the core prepared in the manner indicated above can be coated with a concentrated sugar solution, such as e.g. may contain gum arabic, gelatin, talc, titanium dioxide or the like. The tablets can further be coated with a lacquer layer, which is dissolved in a volatile organic solvent or a mixture of solvents. If desired, dye can be added to this coating.

In the manufacture of soft gelatin capsules or in the manufacture of similar sealed capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules may contain granules of the active ingredient in combination with a solid powdered carrier, such as lactose, sucrose, sorbitol, starch (for example, potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration may be prepared in the form of suppositories containing the active substance of formula I in admixture with a neutral fat base, or in the form of a gelatin rectal capsule containing the active substance in admixture with a vegetable oil or paraffin oil.

Liquid preparations for oral administration may be in the form of tinctures, mixtures, syrups or suspensions containing from about 0.2% to about 20% by weight of the active ingredient. Such liquid preparations may contain dyes, flavors, solvents and carboxymethylcellulose as thickeners. Suitable solutions for parenteral administration by injection may be prepared as an aqueous solution of a water-soluble pharmaceutically acceptable salt of a compound of formula I to which aqueous solution has been adjusted. a physiologically acceptable pH. These solutions may also contain stabilizers.

Pharmaceutical tablets for oral use are prepared by conventional techniques containing a mixture of the therapeutic compound of formula 1 and the required additives. Specific alkylthiophenoxypropanolamines according to the invention are described in more detail below in the working examples. Of these, the following compounds are preferred due to their vasodilating properties and the absence of significant beta-adrenergic blocking effect: 1- / 4- (methylthio) phenoxy / -3- (octylamino) -2-propanol, 1- / 4- [(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol, 1- [3- [(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol, 1- 4 - [(1-methylethyl) thio] phenoxy] -3- (dodecylamino) -2-propanol, 1- [(2-cyclohexylethyl) amino] -3- [4 - [(1-methylethyl) thio] phenoxy] - -2-propanol, 1- [4-cyclohexylbutyl) amino] -3- [4 - [(1-methylethyl) thio] -phenoxy] -2-propanol, 1- [2-methyl-4- (methylthio) phenoxy / -3- (octylamino) -2-propanol, 1- [2- (methylthio) phenoxy] -3- (octylamino) -2-propanol.

The invention is further illustrated by the following working examples, in which the temperatures refer to degrees Celsius.

Example 1- 1- [4- (methylthio) phenoxy] -3- (octylamino) -2-propanol oa I CH 3 S -Q- ocuzcxynzxa- (C112) 7cH3 A solution of 5.6 g (0.04 mol) of 4- ( methylthio) phenol and 2.4 g (0.06 mol) of sodium hydroxide in 50 ml of water were treated with 7.4 g (0.08 mol) of epichlorohydrin. The resulting mixture was first stirred at 30-350 for 24 hours and then extracted with chloroform. After washing the chloroform extract with water and drying over magnesium sulfate, distilled products were removed under reduced pressure to obtain the epichlorohydrin derivative 1- (4-methylthio) phenoxy-2,3-epoxypropane, which was taken up in 30 ml of ethanol, treated with 7.5 g (0.06 mol) of n-octylamine and refluxed for 4 hours. Concentration of the reaction mixture under reduced pressure to about half volume gave a white solid which was recovered and crystallized from ethanol to give a 21% yield of ox. Analytically pure 1- [4- (methylthio) phenoxy] -3- (octylamino) -2-propanol, m.p. 79.5-80.50 (corr.).

Analysis Ber. for C 18 H 31 NO 2 S: C 66.42 H 9.60 N 4.30 S 9.85% Found: C 66.30 H 9.69 N 4.13 S 9.58% Exemgel 2 l- / 4 - / (1- methylethyl) thyphenoxy [-3- (octylamino) -2-quropanol hydrochloride or I ((m3) Zen-oxo] cyclo [(xx)) 7czea3 (a) 4- (isopropylthio) phenol - A solution of 113.8 g (1.65 mol) of sodium nitrite in 210 ml of water was added to a stirred solution of 163.7 g (1.5 mol) of p-aminophenol in 825 ml of 4 N hydrochloric acid at -50. After stirring for an additional 2 hours at -50, the solution of the diazotized phenol was added over a period of 45 minutes to a pre-prepared cooled (-50) solution of 270.6 g (6.77 mol) of sodium hydroxide and 126.4 g ( 1.66 mol) of 2-propanethiol in 525 ml of water, allowing the reaction to proceed under a nitrogen atmosphere. After complete addition, the mixture was allowed to reach a temperature of 270 and kept at this temperature for 16 hours. The mixture was then cooled to 0 DEG C. and acidified with 570 ml of 12 N hydrochloric acid. The excess 2-propanethiol was removed by bubbling nitrogen through the acidified solution into a permanganate trap for 2 hours. The resulting solution was extracted with several portions of dichloromethane and the combined extracts were washed with water, dried over magnesium sulphate containing charcoal and filtered. Concentration of the filtrate under reduced pressure the yeast oil residue, which was distilled to give 81 g (32% yield) of 4- (isopropylthio) phenol, b.p. 114-1230 (1.2 mm Hg). (b) A solution of 6.6 g (0.04 mol) of 4- (isopropylthio) phenol and 2.6 g (0.065 mol) of sodium hydroxide in 50 ml of water was treated with 7.4 g (0.08 mol) of epichlorohydrin. The resulting mixture was first stirred at 30-350 for 24 hours and then extracted with chloroform. After washing the chloroform extract with water and drying over magnesium sulfate, distillable products were removed under reduced pressure to obtain the epichlorohydrin intermediate 1- (4-isopropylthiophenoxy) -2,3-epoxypropane. The epichlorohydrin intermediate was taken up in 30 ml of ethanol, treated with 7.5 g (0.06 mol) of n-octylamine and refluxed for 4 hours. Concentration of the reaction mixture under reduced pressure gave a residue, which was taken up in ethanol and treated with 6 ml of 12 N hydrochloric acid. Concentration of the acidified solution under reduced pressure and crystallization of the residue from ethanol gave analytically pure (20% yield) 1- [4 - [(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol. -hydrochloride, m.p. 171-173-186.50 (corr.) (double melting point).

Analysis Ber. for C 20 H 35 NO 2 S.HCl: C 61.59 H 9.30 N 3.59 S 8.22 Cl 9.09% CS Found: 61.68 H 9.29 N 3.47 8.15 Cl 9.15% Example 3 1- [3 - [(1-methylethyl) thio] phenoxy-3- (octylamino) -2-propanol hydrochloride OH I ocu _ zc fl cuzxn (ca2) 7cH3 (CH3) 2cx-s Reaction of 4.85 g ( 0.029 mol) of the epichlorohydrin derivative of 3- (isopropylthio) phenol with 4 g (0.03l mol) of n-octylamine according to the procedure of Example 2 (b) and crystallization of the crude product from ethanol-ether gyeett 13% - yield of analytically pure 1- [3 - [(1-methylethyl) thio] phenoxy] -3- (octylamino) -2--propanol hydrochloride, m.p. 125-127 (corr.). ï \ .å 'íïr fl r vr m “*“ 7' r Éäâ 7810574-9 17 Analysis Ber. for C 20 H 35 NO 2 S.HCl: C 61.59 H 9.30 N 3.59% Found: C 61.22 H 9.09 N 3.53% Example gel 4 1- [4 - [(1-methylethyl) thio / phenoxy] -3- (dodecylamino) -2-propanol-hydrochloride OH \\ /, ocxzcxcnzx fl- (ca (CH) ca-s .. ___ 3.2 Y. Z> 11 ° „3 Reaction of 15.7 g (0.07 mol) of the epichlorohydrin derivative of 4- (isopropylthio) phenol with 13.9 g (0.075 mol) of n-dodecylamine according to the procedure of Example 2 (b) and crystallization of the crude product from methanol gave a 13% yield of analytically pure 1- [4- [(1-methylctyl) thio] phenoxy] -3-dodecylamino) -2-propanol nyarochloride, m.p. 153.5-156.6-19o, 5 ° (corr.) (Double melting point).

Analvs _ .. í .._ d__ Ber. for C 24 H 43 NO 2 S.HCl: C 64.61 H 9.94 N 3.14% Found: C 64.38 H 10.07 N 2.97% Example gel 5 l - / (2-cyclohexylethyl) amino / -3- / 4 - [(1-methylethyl) thio] phenoxy] -2-propanol hydrochloride. __ ou (CH) cx-s ~ '»~ _ - 3 2 \ / ocxzcacuzaa (ca2> 2» _ 37810574-9 18 Reaction of 5.0 g (0.022 mol) of the epichlorohydrin derivative of 4- (isopropylthio) phenol with 3.3 g (0.026 mol) of cyclohexylethylamine according to the procedure of Example 2 (b) and crystallization of the crude product from isopropyl alcohol gave an 18% yield of analytically pure 1- [(2-cyclohexylethyl) amino] - 3- [4 - [(1-methylethyl) thio] phenoxy] -2-propanol] hydrochloride, mp 180-150 ° (corr.).

Analysis Ber. for C 2 OH 33 NO 2 S.HCl: C 61.91 Found: C 61.73 H 8.83 H 8.71 N 3.61% N 3.88% Example gel 6 l - / (4-cyclohexylbutyl) amino / -3- / 4 - [(1-methylethyl) thio] phenoxy] -2-propanol hydrochloride OH I ocx cncn. L / 2 t * Reaction of 9.0 g (0.04 mol) of the epichlorohydrin derivative of 4- (isopropylthio) phenol with 6.7 g (0.043 mol) of cyclonexylbutylamine according to the procedure of Example 2 (b ) and crystallization of the crude product from ethanol gave a 11.4% yield of analytically pure 1- [(4-cyclohexylbutyl) amino] -3- / 4 - [(1-methylethyl) thio] phenoxy] -2 -propanol hydrochloride, m.p. 1790, softened already at 11a °. (cu3) 2cx-s_ "Analysis Calculated for C22H37NO2S.HCl: C 63.51 H 9.20 N 3.37% Found: C 63.46 H 9.35 N 3.29% Example gel 7 l- / 2- methyl-4- (methylthio) phenoxy / -3- (octylamino) -2-Qropanol OH CH -s' 3 OCHZCHCHZNH- (C52) 7CH3 7810574-9 19 3.14 g (0,05 mol) of the epichlorohydrin derivative of 2-Methyl-4- - (methylthio) phenol was reacted with 1.93 g (0.015 mol) of n-octylamine according to the procedure of Example 1. Concentration of the reaction mixture and crystallization of the remaining material from ethyl acetate / hexane gave a 19 % yield of analytically pure 1- [2-methyl-4- (methylthio) phenoxy] -3- (octylamino) -2-propanol, mp 59-600 (corr.).

Analysis Ber. for C 19 H 33 NO 2 S: C 67.21 H 9.80 N 4.13% Found: C 66.80 H 9.92 N 3.81% Example gel 8 1- [2- (methylthio) phenoxy] -3- (octylamino) - 2-propanol hydrochloride OH I cu cucn NH- (cu,) 7cH 2 2 3 -Cas Reaction of 14 g (0.07l mol) of the epichlorohydrin derivative of 2- (methylthio) phenol with 9.04 g (0, 07 mol) of n-octylamine according to the procedure of Example 2 (b) and crystallization of the crude product from methanol-ether gave an 18% yield of analytically pure 1- [2- (methylthio) phenoxy] -3 - (octylamino) -2-propanol-hydrochloride, m.p. 105.5-1o7.5 ° Analysis Calc. for C 18 H 31 NO 2 S.HCl: C 59.73 H 8.91 N 3.87% Found: C 59.86 H 9.07 N 3.71% Exemgel 9 1- [4 - [(1-methylethyl) thio / phenoxy] -3 - [(2-methyl-2-octyl) amino] -2--Eroganol OH CHB (CH) CH-S. (A) 2-methyl-2-octanol - A solution of 14.5 g (0.1 mol) of methyl heptanoate in OCHZCHCHZAH-O- (cg2) 5g3 w: 7810574-9 200 ml of ether was added to 200 ml of a 3M solution (0.6 mol) of methylmagnesium bromide in ether at a rate sufficient to maintain reflux. After complete addition, the resulting mixture was refluxed for 1 hour and then stirred at 260 for 16 hours.

The mixture was hydrolyzed by adding a dilute ammonium chloride solution and filtered and the filter cake was dissolved in 2N hydrochloric acid and extracted with ether. The ether extract and filtrate were combined and washed successively with water, dilute sodium bicarbonate solution and brine, and dried over magnesium sulfate. Concentration of the dried solution and distillation of the remaining material under reduced pressure gave 13.1 g (91% yield) of 2-methyl-2-octanol with a boiling point of 130 ° (100 mm Hg). (b) §: (2-methyl-2-octyl) acetamide. A solution of 5.55 g (0.055 mol) of concentrated sulfuric acid in 32 ml of glacial acetic acid was treated with 2.5 g (0.016 mol) of acetonitrile and 8.0 g (0.055 mol) of 2-methyl--2-octanol and the the resulting mixture was stirred at 260 for 17 hours. After dilution with 125 ml of water, the mixture was extracted with ether and the ether extract was washed successively with water, dilute sodium bicarbonate solution and brine and dried over magnesium sulphate. Concentration of the dried solution gave 8.7 g (85% yield) of N- (2-methyl-2-octyl) acetamide, which was used in the subsequent steps without further purification. (c) 2-methyl-2-octylamine. A solution of 10.0 g (0.8 mol) of potassium hydroxide in 100 ml of ethylene glycol was treated with 13.0 g (0.07 mol) of N- (2-methyl-2-octyl) acetamide and the mixture was heated at 100 64 hours. The reaction mixture was diluted with 400 ml of water and extracted with ether. The ether extract was washed with water and brine and then dried over sodium sulfate. Concentration of the dried solution under reduced pressure gave 10.4 g (62% yield) of 2-methyl-2-octylamine, which was used in subsequent steps without further purification. 7810574-9 21 (d) 1- [4 - [(1-methylethyl) thiophenoxy] -3- [(2-methyl-2-octyl) amino) -2-Eroganol. A solution of 7.8 g (0.035 mol) of the epichlorohydrin derivative of 4- (isopropylthio) phenol and 5.0 g (0.035 mol) of 2-methyl-2-octylamine in 100 ml of ethanol was refluxed for 17 hours. The reaction mixture was concentrated under reduced pressure and the remaining material was heated at 800 (0.5 mm Hg) to remove residual excess reagent. The crude product in the form of the free base was treated with 6N hydrochloric acid to give the hydrochloride salt, which on crystallization from ether-hexane gave 3.0 g (21% yield) of 1- [4 - [(1-methyl- ethyl) thio [phenoxy] -3- [(2-methyl-2-octyl) amino] -2-propanol hydromine, m.p. 1650

ExemQgLlQ_ Tablets The ingredients listed below were mixed in the amounts indicated in accordance with conventional pharmaceutical techniques to obtain a tablet base. 7810574-9 22 Ingredient Weight components Lactose 79 Maize starch 10 Talc 6 Dragant gum 4 Magnesium stearate l This tablet base was mixed with a sufficient amount of 1- [4 - [(1-methylethyl) thio] phenoxy / -3- (octylamino) -2-propanol- hydrochloride to obtain tablets containing 10, 20, 40, 80, 160 and 320 mg of active ingredient and compressed into tablets in a conventional tablet press.

Example 11 Dry-filled capsules The ingredients listed below were mixed in the amounts indicated below in a conventional manner.

Ingredient Weight Parts Lactose, U.S.P. Starch Magnesium stearate A sufficient amount of 1- [4 - [(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol hydrochloride was added to the mixture to give capsules containing 10, 20 , 40, 80, 160 and 320 mg of active ingredient, which mixture was filled into hard gelatin capsules of suitable size.

Example 1g Comparison of peripheral vasodilator effect in anesthetized dog Test method. Mixed breed dogs of either sex weighing between 11 and 16 kg each were anesthetized with pentobarbital (30 mg / kg) by intravenous administration. The left brachial vein was cannulated and pentobarbital was infused continuously during the experiment at a rate of 5 mg / kg / hour. A tracheotomy was performed and the dogs were mechanically ventilated with room air at a speed of 18 beats / min. and a volume corresponding to 20 ml / kg. Nervous vagus is cut through on both sides in the middle area of the neck. The right brachial vein and artery were cannulated for injection of test compounds and to control blood pressure via a Statham pressure transducer. All measurements were recorded on a Beckman-Offner dynamograph. The abdominal aorta was exposed through a mid-section and a loose bandage was placed around the aorta at a distance from the left renal artery. The right (donor) and left (recipient) femoral arteries were exposed for cannulation and subsequent hind leg perfusion. Following intravenous administration of heparin (5 mg / kg) and gallamine triiodiodide (2 mg / kg), the superior femoral artery was cannulated and the tip of the catheter was inserted into the abdominal aorta at the level of the renal arteries. The left femoral artery was cannulated and the hind leg was perfused using a Harvard perfusion pump. The dressing that had previously been placed around the aorta was then knotted to minimize secondary circulation. Heparin and gallamine intriodiodide were infused intravenously in amounts of 2.5 and 1 mg / kg / hour, respectively. The perfusion pressure, which was measured in a pump at a distance from the perfusion pump, was set at 150 mm Hg by controlling the pump speed. The blood flow to the bone was determined volumetrically at the end of the experiment. The test compound was administered by infusion in an amount of 0.1-1.0 mg / min. for a period of 6 minutes and the maximum reduction of the pressure was determined. One to three animals were used for each test compound.

Results. Table I below sets forth the results obtained in the above experiments for representative alkylthiophenoxypropanolamines of the present invention. Data are also given for the alkylthiophenoxypropanolamines known in the art according to U.S. Pat. No. 3,542,874 (1- (isopropylamino) -3- / 2- (methylthio) phenoxy / -2-propanol ("tiprenolol") and Villa et al. et al .: Il. Pharmaco. Sci., Ed. gg (1969) 349-357 (1- (isopropylamino) -3- / 4- (methylthio) phenoxy / -2-propanol), hereinafter referred to as "A" and "respectively" B ", and for the standard reference compound papaverine. 7810574-9 24 Regarding the prior art compounds" A "and" B "and the compound of Example 2 (test compound 2), the comparative experiments were repeated in the manner described above with the modification that the three compounds was tested on the same dog (blood pressure was allowed to return to the control value between infusions of the test compounds.) In this way, any effects arising from variations in different animals could be ruled out, thus allowing a direct comparison side by side with the vascular system. The results of this comparison are also presented below in ta bell I.

Table I Vasodilating effect - perfused dog hind leg R ou I o-cuzcuc fl znu-R2 R1-S Test- Pressure reductionb compound Dose (mg / min.) R RI R: 023 1.0 1 x 4-cua E; c8Hl7 -22 -59 2 H 41¿fPr 3fC8Hl7 -44d -99 -63 3 H 3f¿fPr 3fC8Hl7 -20 -87 7 2-cua 4-cn3 ¿¿c8xl7 -se -ao 8 H 2-CH3 3; c8 fl l7 -is -sa A u 2 -cu3 ¿; Pr -zod -zvd BH 4-cua '¿;? r - 3d -29d Papaverin -31 -55 7810574-9 25 a. The test association number corresponds to the number of the working example. b. mm Hg. c. Infusion rate d. Side-by-side comparison in the same animal.

Conclusions. Compared to compounds "A" and "B", all of the alkylthiophenoxypropanolamines tested according to the invention (ie test compounds 1-3 and 5-8) produced significantly greater vasodilating effects in that at an infusion dose of 1.0 mg /my. gave a pressure reduction of 59-99 mm Hg, while the compounds "A" and "B" at an identical dose produced a pressure reduction of about 27-29 mm Hg. In comparison with the prior art compounds "A" and "B", the tested compounds were at a dose of 0.3 mg / min. 0.8-3.2 and 5-21 times more active respectively. All tested compounds are of interest in terms of vasodilating effect in that at an infusion rate of 1.0 mg / min. gave a pressure reduction which was significantly greater than or approximately equal to that of the poppy. According to the comparison side by side of test compound 2 and the alkylthiophenoxypropanolamines "A" and "B" according to the prior art at identical dose levels of 0.3 mg / min. test compound 2 exhibited a vasodilating effect, which was approximately 3.2 and 21 times greater, respectively, than the corresponding effect of test compounds "A" and "B". This shows that the test compound 2 is a substantially superior vasodilator compared to the alkylthiophenoxypropanolamines "A" and "B" of the prior art. ._ Example 13 Inhibition of platelet aggregation (antithrombogenic effect) Test method. A method similar to that described by Born in Nature 194 (1962) 927 and by O'Brien in J. Clinical Pathology lä (1962) 446 was used. This test method is a nephelometric -__. <._->: w- = ~ _. <. ~ »« = 1.- ~ _ 7810574-9 26 method, in which the change in turbidity of a sample of platelet-rich human plasma measured by inducing blood-light aggregation by the addition of adenosine diphosphate (ADP) and collagen as thrombogenic agents. An increase in the transmitted light occurs when the thrombogenic agent is added to the platelet-rich plasma sample due to platelet aggregation. The effectiveness of the test compounds was determined on the basis of their ability to prevent aggregation and thereby increase the transmittance of light.

Different concentrations of the test compounds were used and the concentration causing a 50% reduction in the thrombogenic response was determined from a concentration-response curve.

Results. Table II below shows the results obtained in the above tests for representative compounds of the invention and for the prior art compounds A "and" B "representing the prior art of Example 12. Table II Inhibition of In Vitro Platelet Aggregation ED 50 Ob Test QQE ëoll å l 69 42 ï »2 56 31 3 53 24 5 56 47 6 53 29 7 82 39 8 65 32 AC 137 33 BC 107 28 a. The number of the test compound corresponds to the number of the working example b. Micrograms / 0.5 ml platelet-rich human plasma using 1 micrograms adenosine 5'-diphosphate (ADP) for induction of aggregation or when using the minimum amount of collagen (coll.) that gave the maximum degree of aggregation. c. See Example 12. 7810574-9 27 Conclusions. The above data show that all of the compounds tested are significantly more active in inhibiting ADP-induced platelet aggregation than the prior art alkylthiophenoxypropanolamines "A" and "B".

Example gel 14 Isolated guinea pig trachea (beta-adrenergic blocking effect) Test method. - Tracheae removed from adult guinea pigs (body weight over 400 g) were cut helically and suspended vertically in 20 ml of modified Tyrode's solution, which was kept at 37.50 and continuously aerated with oxygen. The lower end of a tracheal segment was fixed to a stationary glass rod and the upper end was connected via wire to an isometric voltage transducer. The change in the spontaneous tone of the smooth tracheal muscles was transmitted via the transducer and recorded continuously on an electronic printer. The adrenergic beta-receptor blocking effect was determined on the basis of the ability of the test compound to inhibit the response of the isolated tissue to the adrenergic beta-stimulating compound isoproterenol at a concentration of 0.1 micrograms / ml bath liquid. The tissues were exposed to solutions of the test compounds for a period of 15 minutes before the addition of isoproterenol to the bath fluid. The beta-receptor blocking potency of a test compound is determined by the concentration-response ratio, where the response is expressed as percent inhibition of isoproterenol-induced tissue response. The IC50 value, which is the concentration of the test compound that gives a 50% inhibition of the effect of the relaxing dose of isoproterenol, was determined by interpolation. Each test compound solution was added to the tissue bath medium in a constant volume of 0.2 ml / ml. bath fluid and only one concentration of the test compound was used for each tissue segment.

The potency of the test compound relative to the potency of the beta-adrenergic blocking agent propanolol, which was used as the standard reference, was determined by comparing the IC 50 values.

Results. Table III below sets forth the results obtained in the above tests for representative alkylthiophenoxypropanolamines of the present invention, identified by a test number referring to the corresponding working examples, and for the known alkylthiophenoxypropanolamines. " A "and" B ", which are described in more detail in Example 12 above.

Table III Beta-adrenergic blocking effect on isolated guinea pig air- StrUEe oH I o-cazcncuzßrx-Rz Rl-s a Beta-adrenergic test compound blocking effect a RL a: 1 u "'4-c113 g-carïu <0, 001 2 u 4-_1_-Pr _r_1-c axl? <0, 001 3 iu 3-_1_-Pr g-caun <0,00 ~ _ 4 H 4-32: g-clzuzs 5 H 4-_1_-Pr (CHQZ-Q 6 u ß-yPr (C112) aQ <0.002 7 z-c fl s 443113 g-csnn 8 _- _ H ° CHB _13 Carin. 0.004 A ° n 2-cH3 'yr: 1, o B ° a a-cu 1-21.- 0, 2 3 _ .. 7810574-9 29 a. The test compound number corresponds to the number of the working example b. Blocking effect in relation to propanolol (blocking effect = 1) in determining the concentration of the test compound which causes a 50% blocking of the isoproterenoline-induced tissue response (EC50 for propanolol = 0.028 micrograms / ml bath fluid) c. See Example 12.

Conclusions. The data in Table III clearly show that with regard to the beta-adrenergic blocking effect, there is a marked difference between the test compounds 1-8 according to the invention and the alkylthiophenoxypropanolamines according to the prior art. It can be seen that the test compounds 1-8 of the invention are substantially devoid of beta-adrenergic blocking action in contrast to the corresponding alkylthiophenoxypropanolamines "A" and "B" according to the prior art, which have significant activity. Accordingly, the compounds of the present invention, when used for the above purposes, are relatively free from the side effects associated with beta-adrenergic blocking action.

Example Isolated rabbit chest aorta (antispasmodic effect in relation to potassium chloride) Test method. Antispasmodic activity was determined in vitro by determining the effect of the test compounds on induced contraction of arterial smooth muscle as follows. Adult male New Zealand white rabbits (body weight 2.5-4 kg) were used.

Each rabbit was sacrificed by intravenous air injection. The thorax was opened and the descending thoracic aorta was removed and introduced into Krebs bicarbonate solution. Foreign tissue was removed and the aorta was cut helically along its entire length. Four spiral segments, each with an approximate length of 2 cm in the unstretched state, were obtained from each thoracic aorta. A coil segment was inserted into a 10 ml volume chamber had a lower chamber, the lower end of the coil segment was fixed to a glass rod tissue holder and the upper free end was connected via a wire to a voltage transducer which exerted a constant baseline voltage of 7810574-9. 3 g on the tissue. The bath medium surrounding the aortic coil (Krebs bicarbonate solution) was maintained at 37.50 and constantly aerated with a mixture of 95% oxygen and 5% carbon dioxide. The activity of the smooth aortic muscle was recorded on an electronic polygraph via its connection to the voltage transducer. After an equilibrium period of 60 min. a cumulative dose-response curve with respect to an agonist (eg potassium chloride or chlor-epinephrine) was recorded and the tissue was then washed. 75 minutes later, a second cumulative dose-response curve was taken with respect to the agonist and the tissue was washed again. 60 minutes later, a solution of the test compound was added to the tissue bath fluid, and after 15 minutes of drug exposure and without washing, a third and final agonist response curve was recorded. All additives to the bath liquid consisted of 0.1 ml of aqueous solutions.

Results. Table IV below presents the results for a comparison of the potency with respect to papaverine in the above test using potassium chloride as an agonist for the alkylthiophenoxypropanolamines of Example 14 and compounds "A" and "B" of the prior art (see Example 12). . Papavirin is considered a direct-acting antispasmodic and is a standard compound in the art.

TABLE IV Antispasmodic activity (rabbit thoracic aorta) Test compounds Antispasmodic potency b l ._ 2 0.6 3 0.7 4 0.08 5 2.4 6 0.02 7810574-9 31 Table IV (cont.) U. a. . b Test compound Antispasmodic potency 7 0.8 8 2.6 AC 0.04 BC 0.04 a. The test compound number corresponds to the number of the working example. b. Potency in relation to papaverine (potency = 1), calculated on the basis of pA2 values, which have been determined for potassium chloride-induced contractions. The pA2 value represents the negative logarithm of the molar concentration of the antagonist which reduces the effect of a double dose of the agonist to the effect of a single dose of the agonist in the absence of the antagonist. c. See Example 12.

Conclusions. - The antagonist activity against potassium chloride-induced seizures is an indication of non-adrenergic, direct-acting antispasmodic activity. Accordingly, the results in Table IV above show that most of the compounds tested have a substantial antispasmodic action, while the prior art compounds "A" and "B" have relatively low activity.

The data in the table above also show that, in the case of potassium chloride-induced seizures, the test compounds 2, 3, 5, 7 and 8 are about 15-65 times more potent as non-adrenergic, antispasmodic agents than the corresponding alkylthiophenoxypropanolamines "A "and" B "according to the state of the art. The antispasmodic potencies of the test compounds 4 and 6 are approximately the same as those of the prior art compounds "A" and "B", the test compound 4 being twice as potent as the known compounds and the test compound 6 exhibiting half the potency of the known compounds. ß .y-fa: '- 7šÉos74-9 š fi 32 Example 16 Isolated rabbit thoracic aorta (antispasmodic activity in relation to norepinephrine) Test compounds l-8 and compounds "A" and "B" according to the prior art were further tested for on anti-alpha-adrenergic activity according to the method described in Example 15 but using the alpha-adrenergic stimulant norepinephrine as an agonist instead of potassium chloride. A selective activity against norepinephrine-induced seizures is an indication of alpha-adrenergic blocking action (ie antispasmodic action). This modification of the antispasmodic test showed that all alkylthiophenoxypropanolamines of the invention with the exception of test compound 8 were substantially absent from anti-alpha adrenergic activity with an activity of 0.3% or less of that activity. exhibited by phentolamine. Phentolamine is an alpha-adrenergic blocking agent and is a standard reference compound in the art.

While the prior art compound "B" is substantially inactive as an anti-alpha adrenergic agent, the test compound 8 and the prior art compound "A" have slightly higher activity than the compounds 1-8 in that they are 1-2% as potent as phentolamine. This experiment shows that the compounds of the present invention are non-anti-alpha-adrenergic antispasmodic agents in that they have a substantial smooth muscle relaxing direct action (as shown in Example 15), which is complicated to a relatively small extent by any significant selection. active alpha-adrenergic blocking effect.

Example 17 Additional biological tests of 1- [4 - [(1-methylethyl) thio] -phenoxy] -3- (octylamino) -2-propanol The vasodilating effect of the above compound of Example 2 was further evaluated according to various pharmacological test methods used for this purpose. In summary, the following can be said: (a) Rats with intra-arterial catheters show periods of shortened platelet survival time. This shortened survival time is normalized with the compound of Example 2. 2 increases the basalt tone of mesenteric (b) The compound of Example This effect is considered to be the vertebral arteries of dogs and rabbits. defull in the treatment of peripheral and cerebral vascular diseases (c) The compound of Example 2 reduces the stiffness of red blood cells, which can be ascertained by testing using the technique using chromium isotope labeling. Consequently, they have the ability to pass through the sclerosis-suppressing cells that are affected by vascular disease. da capillaries in tissues,

Claims (10)

7810574-9 3% Patent Claim Alkylthiophenoxypropanolamines, characterized in that they have the formula R R 1 is alkyl of 1-8 carbon atoms and R 2 is alkyl of 6-12 carbon atoms or cycloalkylalkyl of 5-8 ring carbon atoms and 2-6 carbon atoms in the alkyl chain. The compound 1- [N- (methylthio) phenoxy] -3- (octylamino) -2-propanol and non-toxic, pharmaceutically acceptable acid addition salts thereof according to claim 1. The compound 1- [4- [n-methylethyl] thiophenoxy] -α- (octylamino) -2-propanol and non-toxic, pharmaceutically acceptable acid addition salts thereof according to claim 1. The compound 1- [N- [11-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol hydrochloride and non-toxic, pharmaceutically acceptable acid addition salts thereof according to claim 1. The compound 1- [3- [Y1-methylethyl] phenoxy] -3- (octylamino) -2-propanol and non-toxic, pharmaceutically acceptable acid addition salts thereof according to claim 1. The compound 1- [N- [11-methylethyl) thio] phenoxy] -3- (dodecylamino) -2-propanol and non-toxic, pharmaceutically acceptable acid addition salts thereof according to claim 1. The compound 1- [12-cyclohexylethyl) amino] -3- [α - [(1-methylethyl) thiophenoxy] -2-propanol and non-toxic, pharmaceutically acceptable acid addition salts thereof according to claim 1. The compound 1- [14-cyclohexylbutyl) amino] -3- [N- [Y1-methylethyl) thi] phenoxy] -2-propanol and non-toxic, pharmaceutically acceptable acid addition salts thereof according to claim 1. The compound 1- [E-methyl-4- (methylthio) phenoxy] -3- (octylamino) -2-propanol and non-toxic, pharmaceutically acceptable acid addition salts thereof according to claim 1. The compound 1- [E- (methylthio) phenoxy] -3- (octylamino) -2-propanol and non-toxic, pharmaceutically acceptable acid addition salts thereof according to claim 1.