NO146161B - ANALOGY PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE ALKYLTIOPHENOXYPROPANOLAMINE - Google Patents

Description

The present invention relates to an analogous method for the production of a therapeutically active alkylthiophenoxypropanolamine with the general formula

and acid addition salts thereof, where

R is hydrogen or alkyl with 1-4 carbon atoms,

R"<1>" is alkyl with 1-8 carbon atoms,

2 R is alkyl with 6-12 carbon atoms or cycloalkylalkyl

with 5-8 ring carbon atoms and 2-6 carbon atoms in the alkylene chain.

The alkylthiophenoxypropanolamines produced according to the invention increase peripheral blood flow, relax vascular smooth muscle and inhibit plaque aggregation, and they are believed to be particularly valuable for the treatment of peripheral vascular diseases such as intermittent claudication as well as cerebrovascular diseases accompanying arteriosclerosis.

Various modifications of alkylthiophenoxypropanolamines have been described and studied among the adrenergic agents, primarily with a view to discovering more potent and selective beta-adrenergic blocking agents without undesirable pharmacological effects. Such compounds are generally considered valuable in the treatment of certain purposes for hypertension, angina pectoris, cardiac arrhythmia and pheochromocytoma. Representative of these efforts are compounds described in the following patents and publications.

L. Villa et al., II. Pharmaco. Sei., Ed. 24, 349-357 (1969) relates specifically to the following alkylthiophenoxypropanolamine compound as part of a structure-activity relationship study:-

From US patent 3,542,874 there are known 2-(alkylthio)-phenoxypropanolamines of the formula 1 2 where R is an alkyl (C^-C^) group and R is, inter alia, an alkyl 'C1~C12'~ e- '--'-is a cycloalkyl (C^-C^^) ~9ruPPe • In this patent it is stated that compounds of this type have very effective beta-adrenergic blocking properties. Specific compounds as described in said patent include those where R 1 is methyl or ethyl and R 2 is methyl, ethyl or 2 12 propyl and R is tert-butyl, R is methyl and R is cyclopropyl, cyclopentyl or cyclohexyl, and R 1 is tert-butyl and R<2>is cyclopenty1. From US patent 3,501,769, generic compounds of the type are known where R<1> is alkyl (up to 10 C), R<2> is alkyl (up to 20 C), cycloalkyl (up to 10 C) etc, and R" ^ is hydrogen or alkyl (up to 10 C). Regardless of the extent of the generic description, the patent document does not indicate a single example of a specific "alkylthio" compound. From US patent document 3,872,147, generic alkylthiophenoxypropanolamines are known with the formula where R is alkyl (1-4 C), R1 is alkyl (C^-C^), R<2> is alkyl (Cj--Cg) containing at least one quaternary carbon bonded directly through a (C^-C^) -alkylene chain to the aminonitrogen atom. However, none of the compounds specifically described in the patent constitute an example of an "alkylthiophenoxypropanolamine". DE-OS 2,551,141 specifically describes the alkylthiophenoxypropanolamine

As can be seen from the prior art discussed above, numerous alkylthiophenoxypropanolamines have been described generically, but relatively few alkylthiophenoxypropanolamines have been specifically described. In relation to the known compounds described as beta-adrenergic blocking agents, the alkylthiophenoxypropanolamines according to the invention are unique in that they reduce vascular resistance with minimal involvement of beta-adrenergic blocking effects.

In the present context, the term "lower alkyl" refers to a carbon chain that includes both unbranched and branched carbon radicals with 1-4 carbon atoms. Examples of such carbon chain radicals are methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl and tert-butyl.

The term "alkyl" refers to unbranched or branched carbon radicals with the number of carbon atoms corresponding to the specifically indicated alkyl group or as indicated by standard notation such as (C1-c4), (C1-Cg) and (Cg-C12).

The term "cycloalkylalkyl" refers to a cycloalkyl group containing 5-8 carbon atoms (ie, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl) which is attached to the amino nitrogen atom by an alkylene chain of 2-6 carbon atoms. It should be understood that the "alkylene chain" which connects the cycloalkyl group with the amino nitrogen atom can be branched or unbranched.

The term "non-toxic pharmaceutically acceptable acid addition salts" refers to salts of compounds of formula I which are formed with a variety of inorganic or organic acids whose anions are relatively non-toxic. Such acid addition salts are believed to be pharmacologically equivalent to the bases of formula I. Examples of valuable salt-forming acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric -, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic acid, sulfonic acids such as methane sulfonic, benzene sulfonic, p-toluenesulfonic acid and related acids. The acid addition salts are prepared and isolated in a conventional manner, e.g. by treating a solution or suspension of the free base in a reaction-inert solvent with the desired acid and extracting the salts that are formed by concentration under reduced pressure or by crystallization techniques or other standard chemical methods. Acid addition salts which are slightly toxic and therefore do not meet the above criteria with regard to pharmaceutical acceptability,

are occasionally valuable as intermediates for the isolation and purification of the bases of formula I or for other chemical purposes, such as the separation of optical isomers. Such salts also fall within the scope of the invention.

As will be clear to those skilled in the art, the compounds of the general formula I have one or more asymmetric carbon atoms, and they can therefore exist as optically active isomers, racemates and diastereoisomers, all of which fall within the scope of the invention. Depending on the physico-chemical differences of the components, the diastereoisomeric mixtures can be separated into diastereomerically pure racemates in a conventional manner, such as chromatography and/or fractional crystallization. Resolution of the racemates to form optically active isomers of the formula I is carried out using conventional resolution methods. E.g. reaction of bases of the formula I with optically active acids gives salts thereof, from which the enantiomers can be separated by fractional crystallization. Acids suitable for cleaving the compounds of formula I are the optically active forms of tartaric acid, di-o-tolyltartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid and other optically active acids known for this purpose. Preferably, the most biologically active optically active stereoisomer is isolated.

The analog method according to the invention is characterized by reacting an alkylthiophenol derivative with the formula II

where R and R 1 have the meanings given above, with an epihalohydrin of the formula III

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

IV

where R 2 has the meaning stated above, for the preparation of a compound of the formula I, after which, if desired, a prepared compound of the formula I is reacted in free base form with an acid to form an acid addition salt thereof.

The required alkylthiophenols of the formula II are obtained

by coupling a diazotized aminophenol with an alkylmercaptan to form a diazosulphide which is then cleaved to form the corresponding alkylthiophenol. This is a conventional method, and adaptations of this are described in R.B. Wagner and H.D. Zook, Synthetic Organic Chemistry, page 789 (1953 Wiley). E. Miller, et al., J. Am. Chem. Soc. , 5_5, 1224 (1933), S. Asaka, et al., Chem. Abstract 61, 13243a.

Suitable alkylthiophenol reactants of the formula II which can be used in the analog method according to the invention include:

4-methylthiophenol,

4-ethylthiophenol,

4-n-propylthiophenol, 4-n-butylthiophenol, 4-n-pentylthiophenol, 4-n-hexylthiophenol, 4-n-heptylthiophenol, 4-n-octylthiophenol, 4-isopropylthiophenol, 4-(3-methylbutylthio)-phenol, 2-n-butylthiophenol, 3-n-butylthiophenol, 2-ethylthiophenol,

2-n-propylthiophenol, 2- isopropylthiophenol, 3- ethylthiophenol,

2- n-propylthiophenol, 3- isopropylthiophenol, 2- met<y>l-4-(methylthio)-phenol, 3- methyl-4-(methylthio)-phenol,

Suitable amines with the formula IV that can be used in the method according to the invention include:

n-hexylamine,

n-heptylamine,

n-octylamine,

n-nonylamine,

n-decylamine,

n-undecylamine,

n-dodecylamine,

n-isoacetylamine, 2,2-dimethylhexylamine, 1,1-dimethylheptylamine.

As an epihalohydrin molecule of the formula III has two reactive positions, reaction with an alkylthiophenol of the formula II can form a mixture of reaction products of the formula V and VI, where R, R"<*>" and X have the meanings indicated above.

During the further course of the reaction, however, the two possible intermediates of the formula V and the formula VI form the same alkylthiophenoxypropanolamine end product by condensation with an amine of the formula IV. Consequently, it is not necessary to separate any mixtures of the intermediate products with the formula V and VI which may result from the reaction between a phenol with the formula II and an epihalohydrin with the formula III. Under the reaction conditions used for the present analogous method, the epoxides of the formula VI are preferably 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 epoxides of the formula VI into the corresponding alkylthiophenoxy halohydrins of the formula V. Conversely, halohydrins of the formula V can, if desired, be converted into the corresponding compounds of the formula VI by conventional methods, e.g. by treatment with base by the method of 0. Stephenson, J. Chem. Soc., 1574 (1954).

The reaction between phenols of formula II and epihalohydrins of formula III is carried out in the presence of a sufficient amount of a dilute aqueous alkali metal hydroxide, such as sodium hydroxide, for neutralization of the acidic phenolic group at temperatures in the range from 0 to 100°C, preferably at 25- 35°C, by the method according to Y.M. Beasley, et al., J. Pharm. Pharmacol., 10, 47-59 (1958).

Alternatively, the reaction between phenols with the formula

II and epihalohydrins of the formula III are also made with catalysts such as N-benzylisopropylamine hydrochloride, pyrrolidine, pyridine, piperidine, piperidine acetate, piperidine hydrochloride and the like with an excess of epihalohydrin.

The condensation of an epihalohydrin reaction product of the formula V or VI with an amine of the 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, ethylene glycol. The condensation can also be carried out without a reaction solvent with equimolar amounts of the reactants.

As stated above, the alkylthiophenoxypropanolamines produced according to the invention increase peripheral blood flow, relax vascular smooth muscle and inhibit plaque aggregation. The compounds are mostly without beta-adrenergic blocking effects that inhibit peripheral vasodilatory activity of beta-adrenergic stimulating endogenous amines. Standard in vivo and in vitro pharmacological test methods can be used for the detection of the activity of the compounds of formula I. Among such tests which are considered applicable are soaked hindpaw preparation on dogs (vasodilator effect), spasmogen-attacked rabbit aortic strip (antispasmodic activity) and inhibition of adenosine diphosphate as well as collagen-induced platelet aggregation in platelet-rich human plasma (antithrombogenic effect). The isoproterenol exposure test on guinea pig trachea, which is a standard test, is suitable for measuring beta-adrenergic blocking action.

In addition to having vasodilatory and antispasmodic properties as well as the ability to inhibit platelet aggregation, some of the compounds of formula I inhibit lipolysis (proven by the epidimal fat pad lipolysis model in the rat) and cholesterol biosynthesis. Compounds of this type are of value as hypocholesterolemic agents.

Mammals, including humans, in need of vasodilatation can be treated by systemically administering an effective vasodilating amount of a compound of formula I or a pharmaceutically acceptable, non-toxic acid addition salt thereof.

By "effective vasodilator amount" is meant a dose that exerts a vasodilator effect in the mammal in question without significant side effects.

By "systemic administration" is meant both oral and parenteral administration. Examples of parenteral administration are intramuscular, intravenous, intraperitoneal, rectal and subcutaneous administration. For rectal administration, both ointment and suppositories can be used. Although the dose will vary to some extent with the method of administration and the chosen compound, gives from approx. 0.5 mg/kg body weight to 25 mg/kg body weight of a compound of formula I or;.non-toxic,..pharmaceutically--...acceptable salts thereof administered in effective unit doses or multiple dose units usually the desired vasodilating effect. ... For vasodilating purposes, the 'compounds' of the formula I are usually administered in the form of a pharmaceutical preparation containing either a free base of the formula I or a pharmaceutically acceptable acid addition salt thereof as the active component in combination with a pharmaceutically acceptable carrier The carrier may be a solid, semi-solid, liquid diluent or a capsule.

For the production of pharmaceutical preparations containing the compounds of the formula I in the form of dosage units for oral administration, the compound is mixed with a solid, powder-shaped carrier (e.g. lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin , cellulose derivatives or gelatin) as well as with an antifriction agent (e.g. magnesium stearate, calcium stearate, polyethylene glycol wax or the like) and pressed into tablets. The tablets can be used uncoated or coated using conventional methods to slow down breakdown and absorption in the gastrointestinal tract and thereby produce a sustained effect over a longer period of time. If coated tablets are desired, the thus produced core can be coated with a concentrated sugar solution

like for example. may contain gum arabic, gelatin, talc, titanium oxide or the like. In addition, tablets can be coated with a varnish dissolved in a volatile organic solvent or a mixture of solvents. If it is desired, a dye can be added to this coating.

For the production of soft gelatin capsules or similar closed 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 (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration can be prepared in the form of suppositories containing the active compound of formula I in admixture with a neutral fatty base, or they can be prepared in the form of rectal gelatin capsules containing the active compound in admixture with a vegetable oil or paraffin oil.

Liquid preparations for oral administration can be in the form of elixirs, syrups or suspensions containing from 0.2 to 20% by weight of the active ingredient. Such liquid preparations may contain colourants, fragrances, sweeteners and carboxymethyl cellulose as a thickener.

Solutions suitable for parenteral administration by injection can 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 value. These solutions may also contain stabilizers. Pharmaceutical tablets for oral use are prepared using conventional methods which include mixing the therapeutic compound with formula I and necessary auxiliaries.

The following examples describe the production of specific alkylthiophenoxypropanolamines. Among these, compounds which are particularly preferred for their vasodilatory properties and lack of significant beta-adrenergic blocking action are the following: 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]-phenoxyJ-3-(dodecylamino)-2-propanol,

1-[(2-cyclohexylethyl)-amino]-3-[4-[(1-methylethyl)-thio]-phenoxy]-2-propanol,

1-[(4-cyclohexylbuty 1)-aminoJ-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.

Example 1

1- [ 4-( methylthio)-phenoxy]- 3-( octylamino)- 2- propanol

A solution of 5.6 g (0.04 mol) 4-(methylthio)-phenol and 2.4 g (0.06 mol) sodium hydroxide in 50 ml water was treated with 7.4 g (0.08 mol) epichlorohydrin . The resulting mixture was first stirred at 30-35°C for 24 hours and then extracted with chloroform. After washing the chloroform extract with water and drying over magnesium sulfate, distillable substances were removed under reduced pressure, whereby the epichlorohydrin derivative 1-(4-methylthio)-phenoxy-2,3-epoxypropane was produced, which was taken up in 30 ml of ethanol, treated with 7 .5.g (0.06 mol) of n-octylamine and boiled with reflux for a period of 4 hours. Concentration of the reaction mixture under reduced pressure to approx. half the volume gave a white solid which was collected and crystallized from ethanol to give a 21% yield of analytically pure 1-[4-(methylthio)-phenoxy]-3-(octylamino)-2-propanol, melting point 79.5-80.5°C (corr.).

Analysis calculated for C, 0H-,, NO^S :

C; 66.42, H: 9.60, W: 4.30, W: 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

(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° C. After stirring for a further period of 2 hours at

-5°C, the solution of the diazotized phenol was added over a period of 45 minutes to a previously prepared, cold (-5°C) solution of 270.6 g (6.77 mol) sodium hydroxide and 126.4 g ( 1.66

mol) of 2-propanethiol in 525 ml of water, whereby the reaction was kept under a nitrogen atmosphere. After the addition was complete, the temperature of the mixture was allowed to rise to 27°C and was held at this temperature for a period of 16 hours. The mixture was then cooled to 0°C and acidified with 570 ml of 12 N hydrochloric acid. Excess 2-propanethiol was removed by bubbling nitrogen gas through the acidified solution in a permanganate trap for a period of 2 hours. The resulting solution was extracted with several portions of dichloromethane, and the combined extracts were washed with water, dried over magnesium sulfate containing charcoal, and filtered. Concentration of the filtrate under reduced pressure afforded a residual oil which was distilled to give 81 g (32% yield) of 4-(isopropylthio)-phenol, bp 114-123°C (1.2 mm Hg). (b) A solution of 6.6 g (0.04 mol) 4-(isopropylthio)-phenol and 2.6 h (0.065 mol) sodium hydroxide in 50 mL water was treated with 7.4 g (0.08 mol) epichlorohydrin. The resulting mixture was first stirred at 30-35°C for 24 hours and then extracted with chloroform. After washing the chloroform extract with water and drying over magnesium sulfate, distillables were removed under reduced pressure, whereby an epichlorohydrin intermediate 1-(4-isopropylthiophenoxy)-2,3-epoxypropane was obtained. 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 a period of 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 an analytically pure (20% yield) 1-T4-[(1-methylethyl)-thio]-phenoxy]-3-(octylamino)-2-propanol. hydrochloride, melting point 171-173-186.5°C (corr.) (double melting point).

Analysis calculated for C^H-^t^S, HC1:

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-[3-N-methylethyl)-thio]-phenoxy]-3-(octylamino)-2-propanol. hydrochloride

Reaction of 4.85 g (0.029 mol) of the epichlorohydrin derivative of 3-(isopropylthio)-phenol with 4 g (0.031 mol) of n-octylamine according to the procedure in example 2(b) and crystallization of the crude product from ethanol-ether gave 13% yield of analytically pure 1-[3-[(1-methylethyl)-thio]-phenoxy]-3-(octylamino)-2-propanol. hydrochloride, melting point 125-127°C (corr.).

Analysis calculated for C2QH35N02S, HC1:

C: 61.59, H: 9.30, N: 3.59.

Found: C: 61.22, H: 9.09, N: 3.53.

Example 4

1-[4-{_(1-methylethyl)-thio]-phenoxy]-3-(dodecylamino)-2-propanol.

hydrochloride

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 in example 2(b) and crystallization of the crude product from methanol gave a 13% yield of analytically pure 1-[4-[(1-methylethyl)-thio]-phenoxy]-3-(dodecylamino)-2-propanol. hydrochloride, melting point 153.5-156.6-190.5°C (corr.) (double melting point).

Analysis calculated for C24H43N02S.HC1:

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

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 in 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, melting point 180-182°C (corr.) .

Analysis calculated for C2QH33N02S.HC1:

C: 61.91, H: 8.83, N: 3.61.

Found: C: 61.73, H: 8.71, N: 3.88.

Example 6

1-[(4-cyclohexylbutyl)-aminoj-3-[4-[(1-methylethyl)-thio]-phenoxy]-2-propanol. hydrochloride

Reaction of 9.0 (0.04 mol) of the epichlorohydrin derivative of 4-(isopropylthio)-phenol with 6.7 g (0.043 mol) of cyclohexyl-butylamine according to the procedure in example 2(b) and crystallization of the crude product from ethanol gave a 11 .4% yield of analytically pure 1-[(4-cyclohexylbutyl 1)-amino]-3-[4-|1-methylethyl )-thio]-phenoxy]-2-propanol.hydrochloride, melting point 179°C with previous softening from 118°C.

Analysis calculated for C22H37N02S.HC1:

C: 63.51, H: 9.20, N: 3.37.

Found: C: 63.46, H: 9.35, N: 3.29.

Example 7

1-[ 2- methyl- 4-( methylthio)- phenoxy]- 3-( octylamino)- 2- propanol

3.14 g (0.015 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 in example 1. Concentration of the reaction mixture and crystallization of the residual material from ethyl acetate hexane gave a 19% yield of analytically pure 1-[2-methyl-4-(methylthio)-phenoxy]-3-(octylamino)-2-propanol, melting point 59-60°C (corr.).

Analysis calculated for Cig<H>33N02S:

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]-3-(octylamino)-2-propanol. hydrochloride

Reaction of 14 g (0.071 mol) of the epichlorohydrin derivative of 2-(methylthio)-phenol with 9.04 g (0.07 mol) of n-octylamine according to the procedure in example 2(b) and crystallization of the crude product from methanol-ether gave a 18% yield of analytically pure 1-[2-(methylthio)-phenoxy]-3-(octylamino)-2-propanol hydrochloride, melting point 105.5-107.5°C (corr.).

Analysis calculated for C18H31N<0>2S.HCl:

C: 59.73, H: 8.91, N: 3.87.

Found: G: 59.86, H: 9.07, N: 3.71.

Example 9

1-[4-[(1-methylethyl)-thio]-phenoxy]-3-[(2-methyl-2-octyl)-amino]-2-propanol

(a) 2- methyl- 2- octanol. A solution of 14.5 g (0.1 mol) of methyl heptanoate in 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 the addition was complete, the resulting mixture was refluxed for 1 hour and then stirred at 26°C for a period of 16 hours. The mixture was hydrolyzed by addition of dilute ammonium chloride solution and filtered, and the filter cake was dissolved in 2N hydrochloric acid and extracted with ether. The ethereal extract and filtrate were combined, washed successively with water, dilute sodium bicarbonate solution and brine and dried over magnesium sulfate. Concentration of the dried solution and distillation of the residue under reduced pressure gave 13.1 g (91% yield) of 2-methyl-2-octanol, boiling point 130°C (100 mm Hg). (b) N-(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 resulting mixture was stirred at 26°C for a period of 17 hours. After dilution with 125 ml of water, the mixture was extracted with ether, and the ethereal extract was washed successively with water, dilute sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. Concentration of the dried solution gave 8.7 g (85% yield) of N-(2-methyl-2-octyl)-acetamide, which was used in the next step without further purification. (c) 2- methyl 1- 2- octylamine. A solution of 10.0 g (0.18 mol) potassium hydroxide in 100 ml ethylene glycol was treated with 13.0 g (0.07 mol) N-(2-methyl-2-octyl)-acetamide, and the mixture was heated at 200°C in a period of 64 hours. reaction mixture

the mixture was diluted with 400 ml of water and extracted with ether. The ethereal 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 the next step without further purification. (d) 1-[4-[(1-methylethyl)-thio]-phenoxy]-3-[(2-methyl-2-octyl)-amino]-2-propanol preparation. 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 a period of 17 hours. The reaction mixture was concentrated under reduced pressure and the residue was heated at 80°C (0.5 mm Hg) to remove residual excess reactants. The crude free base was treated with 6N hydrochloric acid to form the hydrochloride salt which crystallized from etherhexane gave 3.0 g (21% yield) of 1-[4-[(1-methylethyl)-thio]-phenoxy]-3- [ (2-methyl-2-octyl)-amino]-2-propanol.hydrochloride, melting point 165°C.

Example 10

Comparison of peripheral vasodilatory activity in anesthetized dogs.

Test method. Bastard dogs of both sexes, weighing between

11 and 16 kg were anesthetized with pentobarbital (30 mg/kg) which was administered intravenously. A cannula was inserted into the left brachial vein, and pentobarbital was infused continuously during the experiment at a rate of 5 mg/kg/h. A tracheotomy was performed and the dogs were oxygenated mechanically with room air at a rate of 18 strokes/min. and a volume corresponding to 20 ml/kg. The vagi was divided bilaterally in the mid-cervical region of the neck. Cannulas were placed in the right brachial vein and artery for injection of active compounds and measurement of blood pressure via a "Statham" type pressure transducer, respectively. All measurements were recorded on a "Beckman-Offner" dynograph. The abdominal aorta was opened through a midline incision, and a loose ligature was placed around the aorta distal to the left renal artery. The right (donor) and left (recipient) femoral arteries were opened by cannula insertion and subsequent hindpaw perfusion. After intravenous administration of heparin (5 mg/kg) and bile amine triiodide (2 mg/kg), a cannula was inserted into the right femoral artery, and the catheter tip was advanced in the abdominal aorta to the area of the renal arteries. A cannula was inserted into the left femoral artery, and the hind paw. were perfused using a "Harvard" type perfusion pump. The previously placed ligature about the aorta was then tied to reduce collateral circulation as much as possible. Heparin and gallamine triiodide were infused intravenously at rates of 2.5 and 1 mg/kg/h, respectively. The perfusion pressure, measured at a site distal to the perfusion pump, was set at 150 mm Hg by regulating the pump speed. Blood flow to the paw was determined volumetrically at the end of the experiment. The test agent was administered by infusion at a rate of 0.1-1.0 mg/min.

for a period of 6 minutes, and the maximum pressure drop was determined. From one to three animals were used per sample agent.

Results. Table I below shows the results obtained in the test described above for a representative selection of the alkylthiophenoxypropanolamines produced according to the invention. Data are also shown for known alkylthiophenoxypropanolamines according to US Patent 3,542,874 "1-(isopropyl-amino)-3-[ 2-(methylthio)-phenoxy]-2-propanol (tiprenolol)" and Villa, et al., II . Pharmaco. Sei., Ed. 2_4, 349-357 ( 1969 ) "1-(isopropylamino)-3-[4-(methylthio)-phenoxy]-2-propanol", which in the table is identified as test agents "A" and "B" respectively, as well as papaverine as a control connection.

With regard to the known compounds "A" and "B" as well as the compound from example 2 (test agent 2), a comparison test was carried out largely as described above, with the change that the three compounds were tested in the same pre- paired dog (blood pressure was allowed to return to control values between infusions of test agents). This design excludes effects due to variations from animal to animal and thus allows a direct comparison of vasodilatory activity. The results of this comparison are also shown in Table I.

Conclusions. In relation to the known compounds "A" and "B", all the tested alkylthiophenoxypropanolamines produced according to the invention (i.e. test agents 1-3 and 5-8) produced significantly greater vasodilatory effects, since at an infusion dose of 1.0 mg/min produced a pressure reduction of from 59 to 99 mm Hg, while on the other hand "A" and "B" at the same dose produced a pressure reduction of 27-29 mm Hg. Compared to the known compounds "A" and "B" at a dose of 0.3 mg/min, the tested compounds were respectively from 0.8 to 3.2 and from 5 to 21 times more active. All the tested compounds are of interest with regard to vasodilatory activity, since at an infusion rate of 1.0 mg/min they caused a lowering of the pressure which was significantly greater than that of papaverine, or roughly equivalent to this. According to the direct comparison of test means 2

and the known alkylthiophenoxypropanolamines "A" and "B" at exactly the same dosages of 0.3 mg/min. Test agent 2 had a vasodilatory effect which was respectively approx. 3.2' and 21 times greater than for the test means "A" and "B". This shows that sample 2

is a significantly better vasodilator than the known alkylthiophenoxypropanolamines "A" and "B".

Example 11

Inhibition of platelet aggregation (antithrombogenic activity)

Test method. A method corresponding to it was used

which is described by Born in Natur 194, 927 (1962) and O'Brien in J. Clinical Pathology ljj, 446 (1962). This test involves

a nephelometric method, where the change in turbidity in a sample of platelet-rich human plasma is measured, inducing platelet aggregation by the addition of adenosine diphosphate (ADP) or collagen as a thrombogen-inducing agent. There is an increase in light transmission when the thrombogenic agent is added to the sample of platelet-rich plasma due to the clumping of the platelets.

ping. The effectiveness of the test compound is determined by its ability to prevent clumping and the accompanying increase in transmission. Different concentrations of the test agent were investigated, and the concentration which caused a 50 percent reduction in the thrombogenic reaction was determined from a concentration-response curve.

Results. Table II below shows the results obtained

by the sample described above for a representative selection of the compound according to the invention as well as the known compounds "A" and "B" from example 10.

Conclusion. The above results show that all the tested compounds are significantly more active in inhibiting ADP-induced plaque aggregation than the known alkylthiophenoxypropanolamines "A" and "B".

Example 12.

Isolated guinea pig trachea (beta-adrenergic blocking activity)

Test method. Trachea removed from adult guinea pigs (body weight over 400 g), cut spirally and suspended vertically in 20 ml of modified Tyrode's bath solution maintained at 37.5°C,

and continuously supplied oxygen. The lower end of a trachea segment was attached to a stationary glass rod, and the upper end was connected by a wire to an isometric tension transducer. Changes in the spontaneous tone of the tracheal smooth muscle were measured via the transducer and continuously

recorded on an electrical recording device. Adrenergic beta-receptor blocking activity was determined by the ability of a test agent to inhibit the response of the isolated tissue to the adrenergic beta-stimulating agent "isoproterenol" at a concentration of 0.1 µg/ml bath fluid. The tissues were exposed to the test agent solution for an interval of 15 minutes prior to the addition of isoproterenol to the bath fluid. The beta-receptor blocker

potency for a test compound was determined from concentration-response relationships, where the response was expressed as a percentage inhibition of isoproterenol-induced tissue response. The IC,.Q value, which is the concentration of the test compound that causes a 50 percent inhibition of the action of the relaxing dose of isoproterenol, was determined by interpolation. Each solution of test compound is added to the tissue bath medium at a constant volume of 0.2 ml/ml bath volume, and only one test compound concentration was used for an individual tissue segment. The potency of the test compound in relation to the beta-adrenergic blocking agent "propanolol" as a control preparation was determined by comparison of IC₂. The ^ values . Results. Table III below shows the results obtained in the test described above for a representative selection of the alkylthiophenoxypropanolamines produced according to the invention, identified by sample number (example number) compared with the known alkylthiophenoxypropanolamines according to Keizer et al., see above, and Villa et al., see above, which are respectively named test agents "A" and "B" (see example 10 regarding the chemical name).

Conclusion. The results in Table III clearly show that with regard to beta-adrenergic blocking activity there is a distinct difference between the compounds in test agents 1-8 and the known alkylthiophenoxypropanolamines. It is obvious that test agents 1-8 are relatively without beta-adrenergic blocking activity in contrast to the known alkylthiophenoxypropanolamines "A" and "B", which have significant activity. Consequently, the compounds produced according to the invention for the described purpose will be relatively free of the side effects linked to beta-adrenergic blocking activity.

Example 13

Isolated rabbit thoracic aorta (antispasmodic activity in relation to potassium chloride)

Test method. The antispasmodic activity was demonstrated

in vitro by determining the effect of the test compound 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 killed by i.v. air injection. The thorax was opened, and the descending thoracic aorta was removed and placed in Krebs bicarbonate solution. Extraneous tissue was removed, and the aorta was incised

spiral shape along the entire length. Four spiral segments of each approx. 2 cm length (unstretched) was obtained from each thoracic aorta. A spiral segment was placed in a 10ml volume bath, and attached at the lower end to a glass rod tissue container, and the upper, free end was connected by wire to a tension transducer which exerted a constant baseline tension of 3g on the tissue . The bath medium surrounding the aortic coil (Krebs bicarbonate solution) was kept at 37.5°C and constantly aerated with 95% : 5% CC>2. The activity of the aortic smooth muscle was recorded on an electronic polygraph via its connection to the voltage transducer. After an equilibration period of 60 min, a cumulative dose-response curve to an agonist (eg, potassium chloride or norepinephrine) was obtained, after which the tissue was washed. 75 minutes later, another cumulative dose response curve to the agonist was obtained and the tissue was washed again. 60 minutes later, a solution of the test compound was added to the tissue bath, and after 15 minutes of exposure to the test compound and without washout, a third and final agonist response curve was obtained. All additions to the bath medium were 0.1 ml volume of aqueous solutions.

Results. Table IV below shows a comparison of the potencies relative to papaverine of the above-described test using potassium chloride as an agonist for the alkyl-thiophenoxypropanolamines of Example 12 and the known compounds according to Keizer et al., see above ("A") and Villa et al., supra ("B") (see Example 10 for chemical name). Papaverine was considered a direct-acting antispasmodic agent and is a standard reagent.

a) The numbers of the sample means correspond to the sample numbers.

b) Potency relative to papaverine (equal to 1) estimated from pA^ values determined against potassium chloride-induced contraction. The pA^ value represents the negative logarithm of the molar concentration of the antagonist, which lowers the effect of a double dose of the agonist to

the value for a single dose of the agonist without the presence of the antagonist.

c) See example 10.

Conclusion. Antagonist activity against potassium chloride-induced spasms indicates non-adrenergic, direct-acting antispasmodic action. Accordingly, the results in Table IV show that most of the tested compounds produced according to the invention have a significant degree of antispasmodic activity, while the known compounds "A" and "B" have relatively weak activity. The results also show that the samples 2, 3,

5, 7 and 8 in relation to potassium chloride-induced spasms are from approx. 15 to approx. 65 times more powerful as non-adrenergic anti-spasmotic agents than the corresponding known alkylthiophenoxypropanolamines "A" and "B". The antispasmodic powers of test agents 4 and 6 are approximately the same as for the known compounds "A" and "B", where test agent 4 is twice as powerful and test agent 6 half as powerful.

Example 14

Isolated thoracic aorta from rabbit (antispasmodic activity against norepinephrine)

Test agents 1-8 and the known compounds "A" and "B"

from Example 13 was further tested for anti-alpha-adrenergic activity by the method of Example 13, but using the alpha-adrenergic stimulant norepinephrine as agonist instead of potassium chloride. Selective activity toward norepinephrine-induced spasms indicates alpha-adrenergic blocking (ie, antispasmodic) activity. This modification of the antispasmodic test showed that all the tested alkylthiophenoxypropanolamines' produced according to the invention with the exception of test agent 8 were largely without anti-alpha a-adrenergic action, as they had 0.3% or less of phentolamine's activity. Phentolamine is an alpha-adrenergic blocker

curing agent and a standard control preparation. While known compound "B" is largely inactive as an anti-alpha-adrenergic agent, test compound 8 and known compound "A" have somewhat more activity than compounds 1-7, being 1-2% as potent as phentolamine. This experiment shows that the compounds prepared according to the invention are non-anti-alpha-adrenergic antispasmodics, in that they have a substantially direct relaxing effect on smooth muscle (as shown in Example 13), which is relatively unaffected by any significant selective alpha-adrenergic blocking effect.

Example 15

Further biological action of 1-[ 4- Q1- methylethyl)- thio]- phenoxy]- 3-( octylamino)- 2- propanol

The vasoactivity of the above compound from Example 2 was further investigated by means of various pharmacological tests used for this purpose, namely: (a) rats with intra-arterial catheters have periods of shortened plaque survival time. This shortened survival time is normalized with the compound of Example 2. (b) The compound of Example 2 raised the basal tone of mesenteric arteries in dogs and rabbits. This effect is considered valuable in the treatment of peripheral and cerebral-vascular diseases. (c) The compound of Example 2 decreased the stiffness of the red blood cells as determined by a chromium^-labeling technique, and consequently the cells are better able to pass through calcification-narrowed tissue capillaries affected by vascular disease.

Claims (2)

1. Analogous process for the preparation of a therapeutically active alkylthiophenoxypropanolamine of the general formula and acid addition salts thereof, where R is hydrogen or alkyl with 1-4 carbon atoms, R^~ is alkyl with 1-8 carbon atoms, R 2 is alkyl with 6-12 carbon atoms or cycloalkylalkyl1 with 5-8 ring carbon atoms and 2-6 carbon atoms in the alkylene chain, characterized by reacting an alkyl-thiophenol derivative with the formula II where R and R have the meanings given above, with an epihalohydrin of the formula III where X is halogen, preferably chlorine or bromine, and condenses the epihalohydrin reaction product with an amine of formula IV where R 2 has the meaning stated above, for the preparation of a compound of the formula I, after which, if desired, a prepared compound of the formula I is reacted in free base form with an acid to form an acid addition salt thereof. 2. Analogous method in accordance with claim 1, characterized in that 1-\_ A-\_( 1-methylethyl )-thio]-phenoxy]-3-(octylamino)-2-propanol or acid addition salts of this.