FI70883C - REFERENCE FOR THERAPEUTIC USE OF THERAPEUTIC THERAPEUTIC ALYLTIOFENOXIPROPANOLAMINER - Google Patents

Description

ΠΓ ^ Π rBl m ADVERTISEMENT

1S @ 11 UTLAGG NIN GSSKRIFT / Uöö0 C,. ,, PatDi.tti uy anne tty '«ÖÄI' Psi3 :: t;: 7 10 1020 '' (51) Kv.lk.7lnt.ci. 'C 07 C 11 (9/32, 149/1 (2 SUOMI FINLAND (21) Patent application - Patentansökning 783068 (22) Filing date - Ansöknlngsdag 09.1 0. ~ J% (Fl) (23) Starting date - Giltighetsdag 09.10.78 (41) Published public - Blivit offentlig 1 2.0A.79

National Board of Patents and Registration {44) Date of publication of the publication.

Patent- oeh registerstyrelsen 'Ansökan utlagd och utl.skriften publicerad 1 ö. 0 /. öb (86) Kv. application - Int. trap (32) (33) (31) Privilege claimed - Begärd priority 11 .10.77, 1A.09.78 USA (US) 8A1168, 9A2222 (71) Bristol-Myers Company, 3 ^ 5 Park Avenue, New York, New York 10022, USA (US) (72) Duane F. Morrow, Evansville, Indiana, William L. Matier, Evansville,

Indiana, USA (US) (7A) Oy Koister Ab (5A) Process for the preparation of therapeutically useful alkylthiophenoxypropanolamines - For the preparation of therapeutically useful alkylthiophenoxypropanolamines

The invention relates to a process for the preparation of therapeutically useful alkylthiophenoxypropanolamines of the formula I and their acid addition salts, ° H?

\\ OCH2CH-C-NH-R2 I

R. J-S

wherein R is hydrogen and lower alkyl of 1 to 4 carbon atoms; R 1j is alkyl of 1 to 8 carbon atoms; R 2 is alkyl of 6 to 12 carbon atoms, or cycloalkylalkyl of 5 to 8 ring carbon atoms and 2 to 6 carbon atoms in the alkylene chain.

70883

The alkylthiophenoxypropanolamines of the invention increase peripheral blood flow, relax vascular smooth muscle, and prevent platelet aggregation, and are considered particularly useful in the treatment of diseases caused by peripheral vasoconstriction, such as arteriosclerosis, cerebrovascular accident, and cerebrovascular accident.

Various alkylthiophenoxypropanolamine variants have been described and studied in the field of adrenergic agents with the primary aim of finding more potent and selective beta-adrenergic blocking agents that are free of undesirable pharmacological effects. Such compounds are generally considered useful in the treatment of various forms of hypertension, angina pectoris, cardiac arrhythmias, and chromaffin tumors. These studies are described in the following patents and publications: L. Villa, et al., II. Farmaco. Sci., Ed. 24, (1969), p. 349-357, discloses in particular the following alkylthiophenoxypropanolamine compound as part of a structure-activity relationship study.

_ / = \ _? H

CH3S - (v Λ- OCH2CHCH2NHCH (CH3) 2

Keizer et al., U.S. Patent 3,542,874 (November 24, 1970) discloses 2- (alkylthio) phenoxypropanolamines of the formula? -OCH 2 CHCH 2 NH-R 2

R1 -S

3 70883 1 2 wherein R is an alkyl (C 1 -C 4> group and R is, inter alia, an alkyl (C 1 -C 12) or cycloalkyl 2> group. This patent illustrates that compounds of this type have very potent beta-adrenergic Specific compounds disclosed by Keizer et al., are those wherein R is methyl or ethyl and R is isopropyl; R 1 is methyl, ethyl or propyl and R is tert-butyl; R is me - 2 1 style and R is cyclopropyl, cyclopentyl or cyclohexyl, R is 2 tert-butyl and R is cyclopentyl.

Crowther, et al., U.S. Patent 3,501,769 (March 17, 1970), generally discloses compounds of the type / = \? H 2 XJj 2 «3

R1S

1 2 wherein R is alkyl (C atoms up to 10); R is alkyl (up to C and 20), cycloalkyl (up to 10 C), etc .; R 1 is hydrogen or alkyl (C atoms up to 10). Despite the scope of the general presentation, Crowther et al. does not describe any example of a specific "alkylthio" compound.

Koppe et al., U.S. Patent 3,872,147 (March 18, 1975), generally discloses alkylthiophenoxypropanolamines represented by the formula

R

y = \ _? h

U Λ-OCH 2 CHCH 2 NH-R

R 1 -s 12 wherein R is alkyl (1-4C); R is alkyl (C 1 -C 4); R is alkyl (C 1 -C 4) containing at least one quaternary carbon attached directly via an alkylene chain to the (C 1 -C 6) amino type atom. However, none of the compounds specifically disclosed by Koppe et al. Includes an example of "alkylthiophenoxypropanolamine".

4 70883 DE-A-2,551,141 (May 18, 1977) discloses in particular alkylthiophenoxypropanolamine ('(H) CH3S-CH3-CHCH2NH2) -CH3

As can be seen from the prior art disclosed, numerous alkylthiophenoxypropanolamines have been generally described, but relatively few alkylthiophenoxypropanolamines have been specifically described. Compared to prior art compounds reported to be beta-adrenergic blocking agents, the alkylthiophenoxypropanolamines of this invention are unique in that they reduce vascular resistance while minimizing the associated beta-adrenergic blocking effects.

The term "lower alkyl", as used herein, means a carbon chain having both straight and branched carbon chain groups of 1 to 4 carbon atoms. Examples of these carbon chain groups are methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl and tert-butyl.

The term "alkyl", as used herein, refers to straight or branched carbon chain groups in which the number of carbon atoms contained in the alkyl group is denoted by a standard notation such as (C1-C4), (C1-C8) and (C6-C12-8) The term "cycloalkylalkyl", such as as used herein, is intended to refer to a cycloalkyl group having 5 to 8 carbon atoms (e.g., cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl) attached to an amino nitrogen atom by an alkylene chain of 2 to 6 carbons. , which connects a cycloalkyl group to an amino nitrogen atom, may be straight or branched.

The term "non-toxic pharmaceutically acceptable acid addition salts" as used herein means salts of the compounds of formula I formed with various inorganic and organic acids whose anions are relatively non-toxic. Such acid addition salts are considered to be pharmacologically equivalent to the bases characterized by Structural Formula I. Examples of useful salt-forming acids include acetic, lactic, succinic, maleic, tartaric, lemon, gluconic, ascorbic, benzoic, cinnamon, fumaric , sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and related acids. The acid addition salts of this invention are prepared and isolated in a conventional manner; for example, by treating a solution or suspension of the free base in a reaction-inert solvent with the desired acid and recovering the salts formed by evaporation under reduced pressure or by crystallization methods or other standard chemical treatments. Acid addition salts which are somewhat toxic and therefore do not meet the above criteria for pharmaceutical acceptability are sometimes useful as intermediates for the isolation and purification of bases of formula I or for other chemical purposes such as the separation of optical isomers.

As will be appreciated by those skilled in the art, the compounds of formula I have one or more asymmetric carbon atoms and may thus exist as optically active isomers, racemates and diastereoisomers, all of which are considered part of this invention. Diastereoisomeric mixtures, depending on the physicochemical differences of the components, can be separated into diastereoisomers into pure racemates by conventional methods, such as chromatography and / or fractional crystallization. The resolution of the racemates of this invention to give the optically active isomers of formula I is carried out by conventional resolution methods. For example, by reacting bases of formula I with optically active acids, salts thereof are obtained from which the enantiomers can be separated by fractional crystallization. Acids suitable for the resolution of compounds of formula I include optically active acids of tartaric acid, di-o-tolyltartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid and other optically active acids known in the art. Preferably, the more biologically active optically active stereoisomer is isolated.

The compounds of formula I are prepared by reacting an alkylthiophenol derivative of formula 6 70883

TyV- oh

R1 -S

wherein R and R 2 are as defined above, is reacted with an epi-halohydrin of formula ch2-ch-ch2x

\ III

O

wherein X is halogen, preferably chlorine or bromine, and the epihalohydrin reaction product is condensed with an amine of formula

H2N "R2 IV

wherein R 2 is as defined above; after which, if desired, the product of formula I in the form of the free base is reacted with an acid to form its acid addition salt.

If necessary, alkyl thiophenols of formula II are obtained by coupling a diazotized aminophenol with an alkyl mercaptan to form a diazosulfide, which is then decomposed to give the corresponding alkyl thiophenol. This is a conventional method and its applications are described by R. B. Wagner and H. D. Zook in Synthetic Organic Chemistry, Wiley (1953), p. 789; E. Miller et al., J. Am. Chem. Soc. 55 (1933), pp. 1224; and S. Asaka et al., Chem. Abstr. 61, 13243a.

Suitable alkylthiophenol reactants of formula II which can be used in this process include 4-methylthiophenol, 4-ethylthiophenol, 4-n-propylthiophenol, 4-n-butylthiophenol, 4-n-propylthiophenol, 4-n-butyl. itophenol, 4-n-pentylthiophenol, 4-n-hexylthiophenol, 4-n-heptylthiophenol, 4-n-octylthiophenol, 4-isopropylthiophenol, 4- (3-methylbutylthio) phenol, 2 -n-butylthio-7,70883 phenol, 2-ethylthiophenol, 2-n-propylthiophenol, 2-isopropylthiophenol, 3-ethylthiophenol, 3-n-propylthiophenol, 3-isopropylthiophenol, 2- methyl 4- (methylthio) phenol and 3-methyl-4- (methylthio) phenol.

Suitable amines of formula IV that can be used in this process include n-hexylamine, n-heptylamine, n-octylamine, n-nonylamine, n-decylamine, n-undecylamine, n-dodecylamine, n-isooctylamine. i.ini, 2,2-dimethylhexylamine and 1,1-dimethylheptylamine.

To the extent that the epihalohydrin Mole alkyl of formula II has two reactive positions, reaction with an alkylthiophenol of formula II can give a mixture of reaction products of formula V and VI, wherein R and X are as defined above.

^ OH Rx / - ^ r \ (v, OCHoCHCH_-X (OCH_CH-CH_

2 \ γ V

R ^ S R ^ “S

V VI

However, as the process proceeds, the two possible intermediates of formula V and formula VI after condensation with the amine of formula IV give the same final alkylthiophenoxypropanolamine product. Thus, it is not necessary to carry out the separation of mixtures of intermediates of formulas V and VI which can be obtained from the reaction of a phenol of formula II with an epihalohydrin of formula III. Under the reaction conditions used in this process, epoxides of formula VI are preferably formed.

If desired, the epihalohydrin reaction product can be combined in an inert solvent such as chloroform and shaken with excess concentrated hydrochloric acid to convert the epoxides of formula VI to the corresponding alkylthiophenoxy-halo-70703 gene hydride of formula V. Conversely, if desired, the halohydrins of formula V can be converted to formula VI by conventional methods, e.g. by treatment with base 0. According to the method of Stephenson (J. Chem. Soc. (1954), p. 1574).

The reaction of phenols of formula II with epihalohydrins of formula III is carried out in the presence of a sufficient amount of dilute aqueous alkali metal hydroxide, such as sodium hydroxide, to neutralize the acidic phenol group at temperatures of 0 to 100 ° C and preferably between 25 and 35 ° C (YM Beasley a). J. Pharm. Pharmacol., 10 (1958), pp. 47-59).

Alternatively, the reaction of phenols of formula II with epihalohydrins of formula III can also be performed with catalysts such as N-benzyl-isopropylamine hydrochloride, pyrrolidine, pyridine, piperidine, piperidine acetate, epidinium hydrochloride, piperidine hydrochloride, etc.

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

As noted above, the alkylthiophenoxy propanolamines of this invention increase peripheral blood circulation, relax smooth vascular muscles, and prevent platelet aggregation. The compounds are essentially free of beta-adrenergic blocking effects that block the peripheral vasodilatory effect of beta-adrenergic stimulating endogenous amines. Standard in vivo and in vitro pharmacological test methods can be used to determine the activity of compounds of formula I. Such tests are considered useful for the treatment of the hind limb of a perfused dog (vasodilating effect); spasmogenically induced rabbit aortic opening (anticonvulsant effect); inhibition of adenosine diphosphate and collagen-induced platelet aggregation in human platelet-rich plasma (anti-vascular occlusion effect); the isoprotein-derived guinea pig tracheal test, which is standard in the art, is suitable for measuring the beta-adrenergic blocking effect.

In addition to their vasodilatory, antispasmodic, and antiplatelet properties, some of the compounds of formula I inhibit fat degradation (as shown in the rat epidermal fat plug degradation model) as well as cholesterol biosynthesis. Compounds of this type are valuable as blood cholesterol lowering agents.

The compounds of formula I may be administered for therapeutic purposes both orally and parenterally. Examples of the digestive system from an external administration are intramuscular, intravenous, intraperitoneal, rectal and subcutaneous routes. for rectal administration suppositories and creams that can be used. When the dose varies to some extent depending on the route of administration and the compound selected, from about 0.5 mg / kg body weight to 25 mg / kg body weight of the Absorbent Compound of Formula or non-toxic pharmaceutically acceptable salts thereof administered in effective single or multiple dosage units, it usually gives the desired vasodilating effect.

The compounds of formula I are generally administered in the form of a pharmaceutical preparation containing either the free base of formula I or a pharmaceutically acceptable non-toxic acid addition salt thereof as an active ingredient together with a pharmaceutically acceptable carrier. The carrier may be a solid, semi-solid, liquid diluent or capsule.

For the preparation of pharmaceutical compositions containing the compounds of formula I in unit dosage form for oral administration, the compound is mixed with a solid, powdered carrier (e.g. lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, gelatine derivatives or cellulose derivatives) or with a substance (e.g. magnesium stearate, Kals; Lumst arate, polyethylene glycol waxes, etc.) and compressed into tablets. The tablets may be used uncoated or coated by conventional methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. If coated tablets are desired, the core prepared above is coated with a concentrated solution of sugar, which may contain e.g. gum arabic, gelatin, talc, titanium dioxide, etc. In addition, the tablets may be coated with a varnish dissolved in a volatile organic solvent or solvent mixture. If desired, dye can be added to this coating.

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

Dosage units for rectal administration prepared in the form of suppositories which contain the active substance of the formula I mixed with a neutral fat base, or they may be prepared in the form of gelatin-peräsuolikapseleiden containing kasvilöljyn mixed with paraffin oil or active agent.

Liquid preparations for oral administration may be in the form of elixirs, syrups or suspensions containing from about 0.2% to about 20% by weight of active ingredient. Such liquid preparations may contain coloring agents, flavoring agents, sweetening agents, and carboxymethylcellulose as a thickening agent.

Suitable solutions for parenteral injection may be prepared as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the compounds of formula I adjusted to a physiologically acceptable pH. Such solutions may also contain stabilizers.

Oral pharmaceutical tablets are prepared by conventional methods comprising mixing the therapeutic compound of formula I and the required excipient.

11 70883

Of the alkylthiophenoxypropanolamines of the formula I, the following compounds are particularly advantageous due to their vasodilatory properties and the absence of a significant beta-adrenergic blocking effect: 1- / 4- (methylthio) phenoxy-3- (3- (octylamino) -2-propanol, 1-4- [(1-methylethyl) tig] phenoxy] -3- (oxylamino) -2-propanol, 1- [3 - [(1-methylethyl) tig] phenoxy] -3- (octylamino) -2-propanol , 1- [4 - [(1-methylethyl) thio] phenoxy] -3- (dodecylamino) -2-propanol, 1 - ([(2-cyclohexylethyl) amine] -3- { 4 - [(1-methylethyl) -thio] -phenoxy} -2-propanol, 1- [E (4-cyclohexylbutyl) amino] -3- [4 - [(1-methylethyl) -tig] phenoxy] -2-propanol, 1 - [(2-methyl-4- (methylthio) phenoxy] -3- (octylamino) -2-propanol and 1- [2- (methylthio) phenoxy] -3- (octylamino) -2-propanol.

Therapeutic experiments

Test 1

Comparison of peripheral vasodilatory effect in anesthetized dogs

Test Method:

Mixed breed dogs of both sexes weighing 11-16 kg were anesthetized with pentobarb.ital (30 mg / kg) administered intravenously. The left upper arm vein was fitted with a connecting tube and pentobarbital was continuously injected at a rate of 5 mg / kg / h throughout the experiment. the trachea was opened and the dogs were ventilated with room air at a rate of 18 strokes / min, corresponding to a volume of 20 ml / kg. The circulatory nerves were cut on both sides in the middle neck area. The right upper arm vein and artery were equipped with a connecting tube for drug injection and blood pressure monitoring via a Statham pressure sensor, respectively. All measurements were recorded on a Beckman-Offner dynograph. The abdominal artery was exposed by opening the midline, and a loose ligament was placed around the artery separately from the left renal artery. The right (donor) and left (recipient) femoral arteries were exposed for cannulation 12 70883 and subsequent hind limb perfusion. Following administration of heparin (5 mg / kg) and gallamine triiodide (2 mg / kg) intravenously, the right femoral artery was cannulated and the catheter head progressed in the abdominal artery to femoral artery level. The left femoral artery was cannulated and the hind limb was perfused using a Harvard perfusion pump. Previously, a suture placed around the artery was contracted to reduce lateral rotation. Heparin and gallamine triiodide were injected intravenously at rates of 2.5 and 1 mg / kg / h, respectively. The perfusion pressure, measured at a point away from the perfusion pump, was set at 150 mm Hg by adjusting the pump speed. Blood flow to the limb was determined analytically at the end of the experiment. The test substance was injected at a rate of 0.1 to 1.0 mg / min for six minutes and the maximum pressure drop was determined. One to three animals were used per test substance.

Score:

The following Table I gives the results obtained according to the above test for representative alkylthiophenoxypropanolamines of this invention. Data have also been reported for prior alkylthiophenoxypropanolamine compounds in the field of Keizer et al., U.S. 3,542,874: 1- (isopropylamino) -3- [2- (methylthio) phenoxy] -2-propanol ("tiprenolol"), and Villa et al. Oh. II. Farma-co. Sci., Ed. 24 (1969), ss. 349-357: for 1- (isopropylamino) -3- [4- (methylthio) phenoxy] -2-propanol, designated herein as Test Agents A and B, respectively, and for the reference standard papaverine.

For the prior art compounds (A and B) and the compound of Example 2 (Test Substance 2), comparative testing was repeated essentially as described above with the change that the three compounds were tested in the same dog (blood pressure was allowed to return to reference values between test substance injections). This test excludes the effects of animal replacement, thus allowing a direct parallel-to-parallel comparison of the vasodilating effect. The results of this comparison are also shown in Table I.

70883

Table I

Vasodilating effect - perfused dog's hind limb

Ry = \? H

/ -O-CH2CHCH2NH-R2

Rrs

Pressure drop ^ · a o d d Dose (mg / min) c

Test substance3 RR, R2 0.3 1.0 1 H A-CII3 B.'C8H17 -22 -59 2 H 4-i-Pr n-COH1T -44, -99 - 8 17 -63d 3 H 3-i-Pr J1 ~ C8H17 ~ 20 ”87 5 H 4 -i-Pr (CH2) 2-4) -63-876H4-i-Pr (CH2) 4- ^ -47 -74 7 2-CH3 4-CH3 H ~ C8H17 -56 -80 8 H 2-CH3 -_C8H17 _15 ~ 64 AH 2-CH3 _i-Pr -20d -27d BH 4-CH3 i_-Pr - 3d -29d

Papaverine -31 -55 a. Test substance numbers correspond to the numbered in the example b. Mercury millimeters c. Spray rate d. Parallel comparison in the same animals 14 70883

Conclusions:

Compared to prior art compounds (A and B), all of these alkylthiophenoxypropanolamines tested (i.e., Test Materials 1-3 and 5-8) provided substantially greater vasodilatory effects in that at an injection dose of 1.0 mg / min they gave a pressure drop between 59 and 99 mm Hg, while A and B give a pressure drop between 27 and 29 mm Hg at a similar dose. Compared to prior art compounds A and B, the tested compounds were 0.8 to 3.2 and 5 to 21 times more active at 0.3 mg / min, respectively. All the compounds tested are interesting in terms of their vasodilatory effect, in that at an injection rate of 1.0 mg / min they gave a reduction at a pressure substantially greater than or approximately the same as that of papaverine. A parallel comparison of the test substance and prior art alkylphenoxypropanolamines A and B at the same doses of 0.3 mg / min has a vasodilatory effect of test substance 2 of about 3.2 and 2 times greater than that of test substances A and B, respectively. a better vasodilator than alkylthiophenoxypropanolamine A and B known in the art.

Test 2

Prevention of platelet aggregation (effect of blocking blood vessels

Test Method:

A method similar to that described by Born, Nature 194 (1926), p. 927, and O'Brien, J. Clinical Pathology 15 (1926), p. 446. This test comprises a method for measuring turbidity in which the change in human abundance the turbidity of a plasma sample containing platelets is measured after induction of platelet aggregation by the addition of adenosine diphosphate (ADP) or collagen as a vasoconstrictor. An increase in light transmission occurs when the anti-vascular agent is added to a platelet-rich plasma sample due to platelet agglomeration. The potency of a test compound is determined by its ability to inhibit caking and the associated increase in permeability. Different concentrations of test substance are tested and the concentration that causes a 50% reduction in thrombogenic responses is determined from the concentration-response curve.

is 70883

Score:

The following Table II gives the results obtained according to the above tests for the representative compounds of this invention and for the prior art compounds A and B of Experiment 1.

Table II

Inhibition of platelet aggregation in vitro a b

Test substance EDP «

5U

ADP Koli 1 69 42 2 56 31 3 53 24 5 56 47 6 53 29 7 82 39 8 65 32 A c 137 33 B c 107 28 a. The numbers of the test substance correspond to the numbers of the examples b. Micrograms / 0.5 ml platelet-rich human plasma , when 1 microgram of adenosine 5'-diphosphate (ADP) or a minimal amount of collagen (Koli), which produces the maximum degree of xenogenesis, is used to cause aggregation c. refers to experiment 2.

Conclusions:

The above figures indicate that all of the compounds tested are significantly more active in inhibiting ADP-induced platelet aggregation than the alkylthiophenoxypropanolamines A and B known in the art.

16 70883

Test 3

Isolated guinea pig horn (be ta - ad ren erg i nen s alpausv effect)

Test method: Tracheas removed from adult guinea pigs (body weight greater than 400 g) are helically cut and suspended vertically in 20 ml of modified Tyrode's bath solution maintained at 37.5 ° C and continuously aerated with oxygen. The lower end of the tracheal section is attached to a stationary glass rod and the upper end is threaded into an isometric tension transducer. Changes in spontaneous tracheal smooth muscle tension are monitored through a transducer and continuously recorded in an electronic recorder. Adrenergic beta-blocker activity is determined by the ability of a test substance to inhibit the response of isolated tissue to the adenergic beta-stimulant "isoproterenol" at a concentration of 0.1 micrograms / ml bath fluid. Tissues are exposed to the test substance solution for 15 minutes before adding isoprotenol to the bath fluid. The beta-receptor blocking ability of the test compound is confirmed by the concentration-response ratios, the reaction being expressed as the percentage inhibition of the isoproterenol-induced tissue reaction. The IC 50 value, which is the concentration of test drug that provides 50% inhibition of the stress-triggering dose of iso-proterenol, was determined by interpolation. A constant volume of 0.2 ml / ml bath fluid is added to each tissue solution in the tissue bath medium and only one concentration of test substance is used for a single tissue fraction. The potency of the test substance relative to the potency of the beta-adrenergic blocking agent "Propanolol" as a reference standard is determined by comparison with IC, -q values.

Score:

The following Table III gives the results obtained according to the above test for representative alkylthiophenoxypropanolamines of the present invention, denoted by test numbers (exemplary number) compared to Keyl et al., Supra, and Villa et al. Supra, prior art alkylthiophenoxypropanolamine compounds. which are labeled as test substances A and B, respectively (see Experiment 1 for chemical name).

17 70883

Table III

Beta-adrenergic blocking effect in isolated guinea pig horn

° H

Ε-O-CH2CHCH2MH-R2

Rrs and Beta-adrenergic

Test substance R 1 · ^ R? blocking capacity 1 H 4-CH3 n-cgHi7 <0.001 2 H 4-_i-Pr H "C8H17 <0.001 3 H 3-1.-Pr n_ — csHi7 <0.001 4 H 4-i-? r u-ci2H25 <0.001 5 H 4 -i-Pr CCH 2) 2 -O <0.0006 6 H 4-i-Pr (CH 2) -O <0.002 7 2-CH 3 4-C «3 H" C8H17 <0.0006 8 H 2-CH3 -_C8H17 ° ' 04 °

Ac H 2-CH 3 i.-Pr 1.0

Bc H 4-CH 3 i-Pr 0.2 a. The numbers of the test substances correspond to the numbers of the examples b. Ability in relation to propanol (which = 1) as estimated from the determinations of the concentrations of the test drug causing 50% isoproterenol-induced tissue reaction blockade (propanol EC ^ q = 0.028 micrograms / ml bath fluid) c. Refers to experiment 1.

18 70883

Conclusions:

The numerical values in Table III clearly confirm that there is a significant difference in the beta-adrenergic blocking effect between the poor compounds of test substances 1-8 and the alkylthiophenoxypropanolamines of the prior art. It is apparent that test substances 1 to 8 do not substantially have a beta-adrenergic blocking effect in contrast to the corresponding prior art alkylthiophenoxipropanolamines A and B, which have a considerable effect. Thus, these compounds, when used for the purposes described herein, would be relatively free of the side effects associated with the beta-adrenergic blocking effect.

Test 4

Isolated rabbit thoracic aorta (anticonvulsant effect against calcium chloride)

Test Method:

The anticonvulsant effect was determined in vitro by determining the effect of test substances on the induced contraction of arterial smooth muscle as follows. Adult male New Zealand white rabbits (body weight 2.5 to 4 kg) were used. Each rabbit was killed by intravenous air injection. The thorax was opened and the settled thoracic aorta was removed and placed in Kreb's bicarbonate solution. Non-essential tissue was removed and the aorta was helically cut along its entire length. Four helical divisions were obtained from each thoracic aorta, each about n.

2 cm (unstretched). The helical fraction was placed in a 10 ml bath chamber, attached at its lower end to a glass rod tissue holder, and the upper, free end, threaded into a tension transducer, which provided a constant three grams of basic tension in the tissue. The bath medium surrounding the aortic coil (Kreb's bicarbonate solution) was maintained at 37.5 ° C and continuously aerated with a mixture of 95% O 2 and 5% CO 2. · Aortic smooth muscle activity was recorded on an electronic polygraph through its connection to a stress transducer.

After a 60 minute equilibration period, a cumulative dose-response curve for the agonist (e.g., potassium chloride or norepinephrine) was obtained and the tissue was then washed. After 75 minutes, a second cumulative dose-response curve for the agent was obtained and the tissue was washed again. After 16 minutes, a solution of 19,708,83 test compounds was added to the tissue bath, and after 15 minutes, exposed to the drug and without washing, a final agonist-response curve was obtained. All additions to the bath fluid were 0.1 ml of aqueous solutions.

Score:

The following Table IV shows the anticonvulsant ability of papaverine in the above test using potassium chloride as an agonist for the alkyl iophenoxeproprolamines of the invention and the prior art (Keizer et al., Supra) compounds A, and (Villa et al., Supra) for compounds B (see Experiment 1 for chemical name). Papaverine is considered a direct anticonvulsant and is standard in the art.

Table IV

Anticonvulsant effect (rabbit thoracic aorta) to

Test substance Anticonvulsant ability 2 0.6 3 0.7 4 0.08 5 2.4 6 0.02 7 0.8 8 2.6 A c 0.04 B c 0.04 a. The numbers of the test substance correspond to the example numbers b. Ability relative to papaverine (which = 1) as assessed by pA 2 values determined against potassium chloride-induced contractions. The pA2 value represents the negative logarithm of the molar concentration of the antagonist, which concentration reduces the potency of the antagonist to twice the potency of the antagonist in the absence of the antagonist c. Refers to experiment 1.

20 7 0 8 8 3

Conclusions:

The effect of the antagonist against potassium chloride-induced convulsions is an indication of a non-adrenergic direct-acting anticonvulsant effect. Accordingly, the results shown in Table IV show that most of these tested compounds have a fairly low level of anticonvulsant activity, while the prior art compounds A and B have a relatively weak effect. The figures further confirm that, relative to the potassium chlorine-induced seizures, test substances 2, 3, 5, 7 and 8 have about 15-65 times higher potency as non-adrenergic anticonvulsants than the corresponding prior art alkylthiophenoxypropanolamines A and B. The anticonvulsant potencies of test substances 4 and 6 are approximately the same as those of compounds A and B, with test substance 4 being twice as effective and test substance about 1/2 times as effective.

Test 5

Isolated rabbit thoracic aorta (anticonvulsant effect against norepinephrine)

Test substances 1 to 8 and prior art compounds A and B in Experiment 4 were further tested for anti-alpha-adrenergic activity by the method of Experiment 4, but using the alpha-adrenergic stimulant norepinephrine as an agonist instead of potassium chloride. The selective effect against norepinephrine-induced seizures shows an alpha-adrenergic blocking (i.e., anticonvulsant) effect. This variant of the anticonvulsant test confirmed that all these alkylthiophenoxypropanolarines, with the exception of test substance 8, essentially lacked anti-alpha-adrenergic activity and had 0.3% or less of the activity shown by phentolamine. Phentolamine is an alpha-adrenergic blocking agent and is a standard comparison in the art. While prior art compound B is predominantly inactive as an anti-alpha-adrenergic agent, test substance 8 and prior art compound A have somewhat more activity than compounds 1-7, in that they are 1-2% as potent as phentolamine. . This experiment demonstrates that these compounds are non-ant alpha-adrenergic anticonvulsants in that they have a substantial direct smooth muscle relaxant effect (as demonstrated in Experiment 4) substantially without any significant selective alpha-adrenergic blocking effect. complications.

Experiment 6 70883 1- (Z 4 Z71-methylethyl) thio (phenoxy) -3- (octylamino) -2-propanol biological testing

The vascular activity of the compound of Example 2 above was further evaluated according to various pharmacological tests used for this purpose. Thus, a) Rats with intravenous catheters have periods in which platelet survival is shortened.

This survival time is normalized by the compound of Example 2.

b) The compound of Example 2 increased the basal strain of the intestinal arteries of dogs and rabbits. This effect is considered valuable in the treatment of peripheral and cerebrovascular diseases.

c) The compound of Example 2 reduced the stiffness of the red blood cell 51 as determined by the chromium labeling method and thus the cells were better able to pass through the hardened, narrowed tissue capsules caused by vascular diseases.

Example 1 1- / 4- (methylthio) phenoxy-3- (octylamino) -2-propanol

/ = \ ° H

CH3s - / Λ— och2chch2nh- (ch2) 7ch3

A solution of 4- (methylthio) phenol (5.6 g, 0.04 mol) and sodium hydroxide (2.4 g, 0.06 mol) in 50 ml of water is treated with epichlorochlorohydrin (7, 4 g, 0.08 mol). The resulting mixture was first stirred at 30 to 35 ° C for 24 hours and then extracted with chloroform. After washing the chloroform extract with water and drying over magnesium sulfate, the distillates are removed under reduced pressure to give the epichlorohydrin.i derivative 1- (4-methylthio) -phenoxy-2,3-epoxypropane.i, which is taken up in 30 ml of ethanol, 22 70883 treated with n-octylamine (7.5 g, 0.06 mol) and refluxed for four hours. Concentration of the reaction mixture under reduced pressure to about half its volume gives a white solid which is collected and crystallized from ethanol to give 1? in analytical purity in 1% yield of 1-N- (methylthio) phenoxy] -3- (octylamino) -2-propanol, m.p. 79.5-80.5 ° (corrected).

Analysis for C 9 H 31 NO 2 S:

Calculated: 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.

Example 2 1- (4- (1-Methylethyl) thio) phenoxy] -3- (octylamino) -2-propanol hydrochloride

/ = \ OH

(ch3) 2ch-s -? y - och2chcn2nh- (ch2)? ch3 (a) 4- (isopropylthio) phenol - A solution of sodium nitrite (113.8 g, 1.65 mol) in 210 ml of water is added to the stirred p-amine. to a solution of .ophenol (163.7 g, 1.5 mol) in 825 ml of 4 N hydrochloric acid at -5 ° C. After stirring for an additional 2 hours at -5 °, a solution of the diazotized phenol is added over 45 minutes to the previously prepared cold (-5 °) sodium hydroxide (270.6 g, 6.77 moles) and 2-propanethiol (126.4 g, 1.66 moles) in 525 ml of water, keeping the reaction under a nitrogen atmosphere. When the addition is complete, the mixture is allowed to warm to 27 ° and maintained at this temperature for 16 hours. The mixture is then cooled to 0 ° and acidified with 570 ml of 12 N hydrochloric acid. Excess 2-propanethiol is removed by passing nitrogen gas through the acidified solution into the permanganate trap for two hours. The resulting solution is extracted with several portions of dichloromethane and the combined extracts are washed with water, dried over magnesium sulfate and filtered. Evaporation of the filtrate under reduced pressure gives a residual oil which is distilled to give 81 g (32% yield) of 4- (isopropylthio) phenol, bp 114-123 ° (1.2 mm Hg).

23 708 8 3 (b) A solution of 4- (isopropylthio) phenol C6.6 g, 0.04 mol) and sodium hydroxide (2.6 g, 0.065 mol) in 50 ml of water is treated with epichlorohydrin (7.4 g, 0.08 moles). The resulting mixture is first stirred at 30-35 ° for 24 hours and then extracted with chloroform. After washing the chloroform extract with water and drying over magnesium sulfate, the distillates are removed under reduced pressure to give the epichlorohydrin intermediate 1- (4-isopropylthiophenoxy) -2,3-epoxypropane. The epichlorohydrin intermediate is taken up in 30 ml of ethanol, treated with n-octylamine (75 g, 0.06 mol) and heated to reflux for four hours. Evaporation of the reaction mixture under reduced pressure gives a residue which is taken up in ethanol and treated with 6 ml of 12 N hydrochloric acid. Evaporation of the acidified solution under reduced pressure and crystallization of the residue from ethanol gives analytically pure (20% yield) 1- [4 - [(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol hydrochloride, m.p. 171 -173-186.5 ° (corr.) (Double melting point).

Analysis for ^ gHggNC ^ S'HClr:

Calculated: C 61.59 H 9.30 N 3.59 S 8.22 Cl 9.09 Found: C 61.68 H 9.29 N 3.47 S 8.15 Cl 9.15.

Example 3 1 1-Methylethyl) thio] phenoxy} -3- (octylamino) -2-propanol hydrochloride

/ = \? H

d Λ— OCH 2 CHCH 2 NH- (CH 2) 7 CH 3

(CH 3) 2 CH-S

Reaction of the epichlorohydrin derivative of 3- (isopropylthio) phenol (4.85 g, 0.029 mol) with n-octylamine (4 g, 0.031 mol) according to the procedure of Example 2 (b) and crystallization of the crude product from ethanol ether gives 13% yield of analytically pure 1- (3- (Ό-methylethyl) thio] phenoxy} -3- (octylamino) -2-propanol hydrochloride, m.p. 125-127 ° (corr.).

24 70883

Analysis for ^ gH ^ j-NC> 2S * HCl:

Calculated: C 61.59 H 9.30 N 3.59 Found: C 61.22 H 9.09 N 3.53.

Example 4 1 1-Methylethyl) thia-phenoxy-3- (dodecylamino) -2-propanol hydrochloride Reaction of the epichlorohydrin derivative of 4- (isopropylthio) phenol (15.7 g, 0.07 mol) with n-dodecylamine (13.9 g, 0.075 moles) according to the method of Example 2 (b) and crystallization of the crude product from methanol gives analytically pure 1- [4 '- (1-methylethyl) thio] phenoxy} -3- (dodecylamino) -2-propanol in 13% yield. hydrochloride, m.p. 153.5 - 156.6 - 190.5 ° (corr.) (Double melting point).

Analysis for C ^ H ^ NC ^ S · HCl:

Calculated: C 64.61 H 9.94 N 3.14 Found: C 64.38 H 10.07 N 2.97.

Example 5 1 - [(2-Cyclohexylethyl) amino] -3- [4- (1-methylethyl) thio] phenoxy} -2-propanol hydrochloride ) -OCH 2 CHCH 2 NH- (CH 2) 2 - and 4- (isopropylthio) phenol 'epichlorohydrin derivative (5.0 g, 0.022 mol) with cyclohexylethylamine (3.3 g, 0.026 mol) according to Example 2 (b) and crude Crystallization of the product from isopropyl alcohol gives, in 18% yield, analytically pure 1- [2- (2-cyclohexylethyl) amino] -3- [4 - [(1-methoxyethyl) thio] phenoxy] -2-propanol hydrochloride. , mp 180-182 ° (corr.).

Analysis for C? QH33NO2S · HCl:

Calculated: C 61.91 H 8.83 N 3.61 Found: C 61.73 H 8.71 N 3.88.

Example 6 1-Z- (4-Cyclohexylbutyl) amino-3- to C4-Z- (1-methylethyl) -thio] phenoxy-2-propanol hydrochloride _H = (H3) (CH3) 2CH-S- £ A Reaction of the epichlorohydrin derivative (9.0 g, 0.04 mol) of -OCH 2 CHCH 2 NH- (CH 2) 4- (4-) 4- (isopropylthio) phenol with cyclohexylbutylamine (6.7 g, 0.043 mol) according to the procedure of Example 2 (b) and crystallization of the crude product from ethanol gives, in 11.4% yield, analytically pure 1 - ["(4-cyclohexylbutyl) amino] -3- [4-Z" (1-methylethyl) thio] phenoxy} -2-propanol hydrochloride, m.p. 179 °, first softening from 118 °.

Analysis for C22H37NO2S · HCl:

Calculated: C 63.51 H 9.20 N 3.37 Found: C 63.46 H 9.35 N 3.29.

Example 7 1 - Ci. 2-methyl-4- (methylthio) phenoxy-3- (octylamino) -2-propanol

/ = V? H

CH 3 S OCH 2 CHCH 2 NH- (CH 2) 7 CH 3 ch 3 26,708 8 3 The epichlorohydrin derivative of 2-methyl-4- (methylthio) phenol (3.1 * 4 g, 0.015 mol) is reacted with n-octylamine (1.93 g, 0.015 moles) according to the method of Example 1. Evaporation of the reaction mixture and crystallization of the residue from ethyl acetate-hexane gives analytically pure 1-L (2-methyl- * 4- (methylthio) phenoxy) -3- (octylamino) -2-propanol in m.p. 59-60. ° (corrected)

Analysis gH ^ NC ^ S: He

Calculated: C 67.21 H 9.80 N 4.13 Found: C 66.80 H 9.92 N 3.81.

Example 8 1- [2- (Methylthio) phenoxy-7-3- (octylamino) -2-propanol hydrochloride

/ = \ _ OH

Reaction of n-och2chch2nh- (ch2) 7ch3 s-ch3 2- (methylthio) phenol epichlorohydrin derivative (14 g, 0.071 mol) with n-octylamine (9.04 g, 0.07 mol) according to the procedure of Example 2 (b) and crystallization of the crude product from methanol / ether gives analytically pure 1- [2- (methylthio) phenoxy] -3- (octylamino) -2-propanol hydrochloride in 18% yield, m.p. 105.5 - 107.5 ° (corr.)

Analysis for NO 2 S · HCl:

Calculated: C 59.73 H 8.91 N 3.87 Found: C 59.86 H 9.07 N 3.71.

70883

Example 9 1 - [[1- (C 1 -methylethyl) thio] phenoxy] -3 - [(2,2-dimethyl-1-hexyl) amino] -2-propanol] -? - H 2 H 3 (CH 3) 2 CH-S- (v / v) > -OCH2CHCH2NH-CH2C- (CH2) 3CH34-ych3 (a) 2,2-Dimethylhex-1-ylamine - Solution of capronitrile (25 g, 0.26 mol) and methyl iodide (75 g, 0.53 mol) 80 In 80 ml of dry toluene is heated to 80 [deg.] C. and gradually treated with a suspension of sodium amide (25.4 g, 0.65 mol) in 100 ml of toluene at a rate sufficient to maintain general reflux, the mixture is stirred and refluxed. for 2 hours, cooled and treated with 150 ml of water The organic layer is separated, washed with water and dried over magnesium sulphate Evaporation of the dried solution under reduced pressure and distillation of the residue gives 2,2-dimethylcapronitrile in 81% yield.

A solution of 2,2-dimethylcapnitrile (10.0 g, 0.078 mol) in 100 mL of ether is slowly added to a suspension of lithium aluminum hydride (6.0 g, 0.158 mol) in 200 mL of ether keeping the reaction at 0-5 °. After stirring the reaction mixture for a further two hours at 0.5 °, the mixture is hydrolysed by successive addition of 6.0 ml of water, 6.0 ml of 15% sodium hydroxide solution and finally 18 ml of water. The hydrolyzed mixture is stirred for a further hour, filtered and the ether phase is concentrated under reduced pressure. Distillation of the residue gives 2,2-dimethylhex-1-ylamine.

(b) Reaction of the epichlorohydrin derivative of 4- (isopropylthio) phenol with 2,2-dimethylhex-1-ylamine according to the method of Example 2 (b) and conversion of the free base to the hydrochloride gives 1- [4 - [(1-methylethyl) thia] phenoxy] } -3- [f (2,2-dimethyl-1-hexylamino] -propanol hydrochloride.

70883 28

Example 10 1- {4- [1- (1-Methylethyl) thio] phenoxy] -3-C (2-methyl-2-octyl) amino] -2-propanol] = = CH2 (CH3) 2CH-S- [ A solution of V-OCH 2 CHCH 2 NH-C- (CH 2) 5 CH 3 - / CH 3 (a) 2-methyl-2-octanol-methylheptanoate (14.5 g, 0.1 mol) in 200 ml of ether is added to 200 ml of methyl a 3M solution of magnesium bromide in ether at a rate sufficient to maintain recovery. When the addition is complete, the resulting mixture is heated to reflux for one hour and then stirred at 26 ° for 16 hours. The mixture is hydrolyzed by adding dilute ammonium chloride solution, filtered and the filter cake is dissolved in 2N hydrochloric acid and extracted with ether. The ether extract and filtrate are combined, washed successively with water, dilute sodium bicarbonate solution and brine, and dried over magnesium sulfate. Evaporation of the dried solution and distillation of the residue under reduced pressure gives 13.1 g (91% yield) of 2-methyl-2-octanol, b.p. 130 ° (100 mm Hg).

(b) N- (2-Methyl-2-octyl) acetamide - A solution of concentrated sulfuric acid (5.55 g, 0.055 mol) in 32 mL of glacial acetic acid is treated with acetonitrile (2.5 g, 0.016 mol) and 2-methyl-2 -octanol-1a (8.0 g, 0.055 mol) and the resulting mixture is stirred at 26 ° for 17 hours. After dilution with 125 ml of water, the mixture is extracted with ether and the ether extract is washed successively with water, dilute sodium bicarbonate solution and brine and dried over magnesium sulfate. Evaporation of the dried solution gives 8.7 g (85% yield) of N- (2-methyl-2-octyl) acetamide, which is used in the next step without purification.

(c) 2-Methyl-2-octylamine - A solution of potassium hydroxide (10.0 g, 0.18 mol) in 100 mL of ethylene glycol is treated with N- (2-methyl-2-octyl) acetamide (13.0 g, 0, 07 moles) and the mixture is heated at 200 ° C for 64 hours. The reaction mixture is diluted with 400 29 70883 ml of water and extracted with ether. The ether extract is washed with water and brine and then dried over sodium sulfate. Evaporation of the dried solution under reduced pressure gives 10.4 g (62% yield) of 2-methyl-2-octylamine, which is used in the next step without further purification.

(d) Preparation of 1- {4 - [(1-methylethyl) thio] phenoxy] -3 - [(2-methyl-2-octyl) amino] -2-propanol - Solution of 4- (iso-propylthio) phenol epichlorohydrin derivative (7.8 g, 0.035 mol) and 2-methyl-2-octylamine (5.0 g, 0.035 mol) in 100 ml of ethanol are heated at reflux for 17 hours. The reaction mixture is evaporated under reduced pressure and the residue is heated at 80 ° (0.5 mm Hg) to remove any remaining reagents. The crude free base is treated with 6 N hydrochloric acid to give the hydrochloride salt which is crystallized from ether / hexane to give 3.0 g (21% yield} 1- {4- [f (1-methylethyl) thiophenoxy} -3-f (2-methyl-2-octyl) amino] -2-propanol hydrochloride, mp 165 °.

Examples 11-26

The compounds of the following Table A are prepared according to the method of Example 1 by reacting the epichlorohydrin derivative of the starting phenol with n-octylamine.

30

Table A 70883

/ = X OH

OCH2CHCH2NH- (CH2) 7CH3

R-j -S

Example Starting thiophenol Product

R-, S

11 4-Ethylthiophenol U-CH 2 Cl 2

12 4-n-propylthiophenol ^ -n-C ^ H ^ S

13 4-n-butylthiophenol 4-n-CH 2 HgS

14 4-n-Pentylthiophenol 4-n-CgH2S

15 4-n-Hexylthiophenol 4-n-C_H..O5S

16 4-n-Heptylthiophenol 4-n-CnH.cS

- - / 15

17 4-n-Octylthiophenol 4-n-CgH2S

18 4- (3-methylbutylthio) phenol 4- (CH3 ^ CHCH2CH2S

19 2-n-butylthiophenol 2-n-CH 2 HgS

3-n-butylthiophenol 3-n-CH 2 HgS

21 2-ethylthiophenol 2-CgHgS

22 2-n-propylthiophenol 2-n-CgH7S

23 2-Isopropylthiophenol 2-1-C3H7S

24 3-ethylthiophenol S-C 2 H 2 S

3 3-n-propylthiophenol 3-n-C3H7S

26 3-Isopropylthiophenol 3-1-C3H7S

Example 27 Tablets

The following ingredients are mixed in the given weight ratios according to conventional pharmaceutical methods to give the tablet base.

Ingredient Amount lactose 79 corn starch 10 talc 6 gum tragacanth 4 magnesium stearate 1 3i 70883 This tablet base is mixed with a sufficient amount of 1- [4- [7- (1-methylethyl) thio] phenoxy} -3- (octylamino) -2-propano-1-hydrochloride to give tablets containing 10, 20, 40 ,. 80, 160 and 320 mg of active ingredient and compressed in a conventional tablet press.

Example 28

Dry filled capsules

The following ingredients are mixed in the usual manner in the given weight ratio.

Ingredient Amount of lactose, U.S.P. 50 starch 5 magnesium stearate 2

Sufficient 1- {4- [* (1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol hydrochloride is added to the mixture to make capsules containing 10, 20, 40, 80, 160 and 320 mg of active ingredient. to fill hard gelatine capsules of suitable size.

Claims (12)

32 70883 A process for the preparation of therapeutically useful alkylthiophenoxypropanolamines of the formula I and their acid addition salts, ° H? Λ X — OCHOCH-C-NH-R0 (I) V / 1 t 2 X__f H R1-S wherein R is hydrogen and lower alkyl of 1 to 4 carbon atoms; is alkyl of 1 to 8 carbon atoms; R 1 is alkyl of 6 to 12 carbon atoms or cycloalkylalkyl of 5 to 8 ring carbon atoms and 2 to 6 carbon atoms in the alkylene chain, characterized in that an alkylthiophenol derivative of formula II is obtained. (II) R 1 -S wherein R and R 1 are as defined above, to react with an epihalohydrin of formula III CH 2 - - - t-CH-CH 2 X (III) wherein X is halogen, preferably chlorine or bromine, and condensing the epihalohydrin reaction product with an amine of formula IV h2n-r2 (IV) wherein R2 is as defined above; after which, if desired, the product of formula I in the form of the free base is reacted with an acid to form its acid addition salt. Process according to Claim 1, characterized in that 1- [E- (methylthio) phenoxy] -3- (octylamino) -2-propanol or a non-toxic, pharmaceutically acceptable acid addition salt thereof is prepared. 33 7 0 8 8 3 Process according to Claim 1, characterized in that 1- [N-methylethyl] phenoxy] -3- (octylamino) -2-propanol or a non-toxic pharmaceutically acceptable acid addition salt thereof is prepared. Process according to Claim 3, characterized in that 1- [4- [4- (1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol hydrochloride is prepared. Process according to Claim 1, characterized in that 1- [3- (1- (methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol or a non-toxic, pharmaceutically acceptable acid addition salt thereof is prepared. Process according to Claim 1, characterized in that 1 - E - 4- (1-methylethyl) thiophenoxy] -3- (dodecylamino) -2-propanol or a non-toxic pharmaceutically acceptable acid addition salt thereof is prepared. Process according to Claim 1, characterized in that 1-L (2-cyclohexylethyl) amino] -3- [4- (1-methylethyl) thiophenoxy] -2-propanol or a non-toxic, pharmaceutically acceptable the acid addition salt. Process according to Claim 1, characterized in that 1- (4- (4-cyclohexylbutyl) amino) -3- [4-Z '(1-methylethyl) thiophenoxy] -2-propanol or a non-toxic pharmaceutically acceptable acid addition salt thereof is prepared . Process according to Claim 1, characterized in that 1-7-methyl-4- (methylthio) phenoxy-3- (Coctylamino) -2-propanol or a non-toxic, pharmaceutically acceptable acid addition salt thereof is prepared. Process according to Claim 1, characterized in that 1-7 * 2- (methylthio) phenoxy-3- (octylamino) -2-propanol or a non-toxic, pharmaceutically acceptable acid addition salt thereof is prepared. 70883 34 A process for the further preparation of a therapeutically active alkylthiophenoxypropanolamine with a formula I and a cyclic addition salt, OH R 1 is alkyl of 1 to 8 cholatomers; R 2 is alkyl of 6-12 cholaters or cycloalkylalkyl of 5-8 ring cholomers and 2-6 cholatomers of the alkyl chain, which can be converted to alkylthiophenol derivatives by means of formula II OH R ^ -S color R och R ^ har ovan anhydrous betehyde, with an epihalohydrin with formula III CH0 -CH-CH2 X color X is halogen, with chlorine or bromine, and a condenser with epihalohydrin reaction products with an amine with formula IV h2n-r2 iv