DK146005B - METHOD OF ANALOGUE FOR THE PREPARATION OF ALKYLTHIOPHENOXYPROPANOLAMINES OR ACID ADDITION SALTS THEREOF - Google Patents

Description

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The present invention relates to an analogous process for the preparation of novel alkylthiophenoxypropanolamines of the general formula

R ° HH

V-AND CH-C-NH-R2 (I)

We / * rVs 05 or acid addition salts thereof, wherein R represents hydrogen or alkyl of 1 to 4 carbon atoms, alkyl of 9 to 1 to 8 carbon atoms, R represents alkyl of 6 to 12 carbon atoms or cycloalkylalkyl of 5 to 8 ring carbon atoms and of 2 to 6 carbon atoms in the alkylene chain.

The alkylthiophenoxypropanolamines in question increase peripheral blood flow, relax vascular smooth muscle and inhibit plate aggregation, and are believed to be particularly valuable in the treatment of obstructive peripheral vascular diseases such as intermittent claudication and cerebrovascular disease,

Various modifications of alkylthiophenoxypropanolamines have been described and studied among the adrenergic agents, primarily in order to detect more potent and selective beta-adrenergic blocking agents without undesirable pharmacological effects. Such compounds are generally considered valuable for the treatment of certain forms of 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. Farmaco. Sci., Ed. 7Λ, 349-357 (1969) specifically discloses the following alkylthiophenoxypropanol-amine compound in connection with a study of structure-activity relationships: 30 CH₂S _Q₂OCH₂æCH₂BSCH (CH3) 2

Keizer, et al., U.S. Patent No. 3,542,874 of -24. November 1970 describes 2- (alkylthio) phenoxypropanolamines of the formula

/ V- AND CHCH, NH-R

wherein R represents an alkyl (C ^-C ^) group and R represents 05 inter alia an alkyl (Cj-C ^ 2 ^-e e - - is a cycloalkyl (Cg-C ^) group This patent teaches that compounds of this type have very effective beta-adrenergic blocking properties Specific compounds described by Keizer et al include those wherein R 1 is methyl or ethyl and 2 1 2 10 R is isopropyl; R is methyl, ethyl or propyl and R is 1 2 tert.-butyl; R is methyl and R is cyclopropyl, cyclopentyl 1 2 or cyclohexyl; R is tert-butyl and R is cyclopentyl.

Crowther, et al., U.S. Patent No. 3,501,769 of March 17, 1970, discloses generic compounds of the type

Y-OH

OCH2CHCH-NH-R2

R1S ^ X == y R

wherein R 1 is alkyl (up to 10 C); R 2 is alkyl (up to 20 C), 3 cycloalkyl (up to 10 C) etc; R is hydrogen or alkyl (up to 10 C). Regardless of the scope of the generic description, Crowther et al. a single example of a specific "alkylthio" compound.

Koppe, et al., U.S.A. Patent No. 3,872,147 of March 18, 1975 discloses generic alkylthiophenoxypropanolines of formula 3 146005 *) C

() —OCH.CHCH-NH-K

wherein R is alkyl (1-4 C) / R is alkyl (C 1 -C 4) t R is alkyl (C 6 -C 6). containing at least one quaternary carbon bonded directly through a (C1 ~ C4) alkylene chain to the amino-nitrogen-05 atom. None of those by Koppe et al. however, specifically described compounds are an example of an "alkylthiophenoxypropanolamine".

DE-OS No. 2,551, 141 of May 18, 1977 specifically discloses the alkylthiophenoxypropanolamine

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

In the present context, the term "alkyl" refers to straight-chain or branched carbon radicals having the number of carbon atoms corresponding to the specific alkyl group or referred to by standard notation such as (C1-C4), (C (Cg-C12).

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The term "cycloalkylalkyl" refers to a cycloalkyl group containing from 5 to 8 carbon atoms (i.e., cyclopenethyl, cyclohexyl, cycloheptyl, and cyclooctyl) linked to the amino nitrogen atom by an alkylene chain of 2 to 065 carbon atoms. It is to be understood that the "alkylene chain" linking the cycloalkyl group to the amino nitrogen atom may be linear or branched.

The term "non-toxic pharmaceutically acceptable acid addition salts" refers to salts of compounds of Formula 10 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 vinegar, milk, amber, maleic, wine, lemon, glucon, ascorbic, benzoic, cinnamon, fumaric, sulfuric, phosphorus, hydrochloride, hydrobromide, hydroiodide, sulfamic acid, sulfonic acids such as methanesulfonic, benzenesulfonic, p-toluene sulfonic acids and related acids. The acid addition salts of this invention 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 recovering the salts formed by concentration under reduced pressure or by crystallization technique or other standard chemical methods. Acid addition salts which are somewhat toxic and therefore do not meet the foregoing criteria for pharmaceutical acceptance are sometimes valuable as intermediates for isolating and purifying the bases of formula I or for other chemical purposes such as separation of optical isomers.

Such salts also fall within the scope of the invention.

As will be appreciated by those skilled in the art, the compounds of general formula I have one or more asymmetric carbon atoms and can therefore exist as optically active isomers, racemates and diastereoisomers, all of which fall within the scope of the invention. The diastereoisomeric mixtures can be separated into diastereomerically pure racemates by conventional means such as chromatography and / or fractionated crystallization, depending on the physicochemical differences of the components. Cleavage of the subject racemates to form optically active isomers of formula I is carried out by conventional cleavage methods.

For example. affords reaction of gases of formula I with optically active salts thereof, the acid salts thereof, from which they are enantiomers. can be separated by fractional crystallization. Acids suitable for cleavage of 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, camphor sulfonic acid 10 and other optically active acids known for the purpose. Preferably, the most biologically active optically active stereoisomer is isolated.

The analogous process of the invention is characterized by reacting an alkylthiophenol derivative of formula II

15 (Π)

Rice

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

CH-CH-CH 2 -X (III)

wherein X represents halogen, preferably chlorine or bromine, and the epihalohydrin reaction product condenses with an amine of formula IV

h2n-r2 (IV) 2 wherein R is as defined above and then, if desired, reacting the compound of formula I in free base form with an acid to form an acid addition salt thereof.

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The necessary alkylthicphenols of formula II are obtained by coupling a diazotized aminophenol with an alkylmercaptan to form a diazosulfide which is then decomposed to form the corresponding alkylthiophenol. This is a conventional method and adaptations thereof 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., 5j>, 1224 (1933); S. Asaka, et al., Chem. Abstr. 61, 13243a.

Suitable alkylthiophenol reactants of formula II which may be used in the present process 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-methyl-4- (methylthio) phenol, 3-methyl-4- (methylthio) phenol.

Suitable amines of formula IV which can be used in the present process include: n-hexylamine, n-heptylamine, n-octylamine, n-nonylamine, n-decylamine, n-undecylamine, 05 n-dodecylamine, n-iso c lamin, 2,2-dimethylhexylamine, 1,1-dimethylheptylamine.

Since an epihalohydrin molecule of formula III has two reactive positions, reaction with an alkylthiophenol of formula II can form a mixture of reaction products of formulas V and VI, wherein R, R 1 and X have the meanings given above.

? 8 R '> c == \

Vl / 2 2 Vl / ^ * -s ~ r <*

R1-s (V) (VI)

However, during the further course of the reaction, the two possible intermediates of Formula V and Formula VI, by condensation with an amine of Formula IV, form the same alkylthiophenoxypropanolamine final product. Accordingly, it is not necessary to separate any mixtures of the intermediates of Formulas V and VI which may result from a reaction between a phenol of formula II and an epihalohydrin of formula III. Under the reaction conditions used for the present process, the epoxides of 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 excess concentrated hydrochloric acid to convert epoxy compounds of formula VI into the corresponding alkylthiophenoxyhalohydrogen hydrines of formula V. if desired is converted to the corresponding compounds of formula VI by conventional methods, e.g. at 05 base treatment i.h.t. the method of O. Stephenson, J. Chem. Soc., 1574 (1954).

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

Alternatively, the reaction between phenols of formula II and epihalohydrin hydrines of formula III may also be carried out with catalysts such as N-benzylisopropylamine hydrochloride, pyrrolidine, pyridine, piperidine, piperidine acetate, piperidine hydrochloride with an excess of epihalogen hydrine.

The condensation of an 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, ethylene glycol.

The condensation may also be carried out in the absence of a reaction solvent with equimolar amounts of the reactants.

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As noted above, the subject alkylthiophenoxy-propanolamines enhance peripheral blood flow, relax vascular smooth muscle, and inhibit plate aggregation. The compounds are essentially devoid of beta-adrenergic blocking effects that inhibit peripheral vasodilating activity of beta-adrenergically stimulating endogenous amines. Standard in vivo and in vitro pharmacological test methods can be used to detect the activity of the compounds of formula I. Among such tests considered useful are 10 perfused hind paw preparation (vasodilator effect), spasmogen-attacked rabbit aortic strip ( antispasmo disk activity) and inhibition of adenosine diphosphate as well as collagen-induced plate aggregation in human platelet-containing plasma (antithrombogenic effect). The isoproterenol impact test on guinea pig trachea, which is a standard test, is suitable for measuring beta-adrenergic blocking effect.

In addition to possessing vasodilating and antispasmodic properties, as well as the ability to inhibit platelet aggregation, some of the compounds of Formula I inhibit lipolysis (demonstrated by 2o the epidermal fat-pad lipolysis model in the rat) and cholesterol role biosynthesis. Compounds of this type are of value as hypocholesterolemic agents.

Mammals, including humans in need of vasodilation, 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 vasodilating amount" is meant a dose which exerts a vasodilator effect in the mammal in question without significant side effects.

The following examples describe the preparation of specific alkylthiophenoxypropanolamines. Among these, compounds which are particularly preferred for their vasodilating properties and lack of substantial beta-adrenergic blocking activity 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) -2-10 propanol, 1 - [4 - [(1-methylethyl) thio] phenoxy] -3- (dodecylamino) -2-propanol, 1- ((2-cyclohexylethyl) amino] -3- [4 - [(1-methylethyl) thio] - phenoxy] -2-propanol, 1 - [(4-cyclohexylbutyl) amino] -3- [4 - ((1-methylethyl) thio] phenoxy] -2-propanol, 1- [2-methyl-4- ( methylthio) phenoxy] -3- (octylamino) -2-propanol, 1- [2- (methylthio) phenoxy] -3- (octylamino) -2-propanol · 20 In the following examples, all temperatures are in ° C.

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

/ = \? H

CH3S- ^ A-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 epichlorohydrin (7.4 g, 0 , 08 mol). 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, distillable substances are removed under reduced pressure to produce the epichloro-hydrine derivative 1- (4-methylthio) phenoxy-2,3-epoxypropane, which is taken up in 30 ml of ethanol. with n-octylamine (7.5 g, 0.06 mol) and reflux over a period of 4 hours. Concentrating the reaction mixture under reduced pressure to ca. a half volume gives a white solid which is collected and crystallized from ethanol to give a 21% yield of analytically pure 1- [4- (methylthio) phenoxy] -3- (octylamino) -2-propanol, m.p. 80.5 ° (corr.).

Analysis calculated for C C CH3 ^NO₂S: 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

y = 0 ° H

(CH3) 2CH-SA / O - OCH2CHCH2NH- (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 a stirred solution of p-aminophenol (163.7 g, 1.5 mol) in 825 ml of 4N hydrochloric acid at -5 °. After stirring for another 2 hour period at -5 °, the solution of the diazotized phenol over a 45 minute period is added to a pre-prepared cold (-5 °) solution of sodium hydroxide (270.6 g , 6.77 mol) and 2-propanethiol (126.4 g, 1.66 mol) 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 kept at that temperature for a period of 16 hours. Next, the mixture is cooled to 0 ° and acidified with 12 · 146005 with 570 ml of 12 N hydrochloric acid. Excess 2-propanethiol is removed by bubbling nitrogen gas through the acidified solution in a permanganate trap over a period of 2 hours. The resulting solution is extracted with several portions of dichloromethane and the combined extracts are washed with water, dried over magnesium sulfate containing charcoal and filtered. Concentration of the filtrate under reduced pressure produces a residual oil which is distilled to give 81 g (32% yield) of 4- (isopropyl thio) phenol, boiling point 114-123 ° (1.2 mm Hg).

(b) A solution of 4- (isopropylthio) phenol, (6.6 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 mol). 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, distillers are removed under reduced pressure to produce the epichlorohydrin intermediate 1- (4-isopropylthiophenoxy) -2,3-epoxypropane. The epichlorohydrin intermediate is taken up in 30 ml of ethanol, treated with n-octylamine (7.5 g, 0.06 mol) and refluxed for a period of 4 hours. Concentration of the reaction mixture under reduced pressure gives a residue which is taken up in ethanol and treated with 6 ml of 20N hydrochloric acid. Concentration of the acidified solution under reduced pressure and crystallization of residual material from ethanol gives an analytically pure (20% yield) of 1-14 - [(1-methylethyl) thio] phenoxy] -3- (octyl-amino) -2-propanol, hydrochloride, m.p. 171-173-186.5 ° (corr.) (double melting point).

Analysis calculated for ^HH ^ lK ^SfHCl: 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 - [(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol, hydrochloride

OH

ά Voch2chch2nh- (CH2) 7CH3

(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 a 13% yield of analytically pure 1- [3 - [(1-methyl-ethyl) thio] phenoxy] -3- (octylamino) -2-propanol, hydrochloride, m.p. 125-127 ° (corr.) ·

Analysis calculated for C 20 H 35 NO 2 S, HCl: C, 61.59; H, 9.30; N, 3.59.

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

Example 4 1- [4- [(1-methylethyl) thio] phenoxy] -3- (dodecylamino) -2-propanol, hydrochloride

_ / == \? H

(CH3) 2CH-SA /) - OCH2CHCH2NH- (CH2) i; 1CH3 Reaction of the epichlorohydrin derivative of 4- (isopropylthio) phenol (15.7 g, 0.07 mol) with n-dodecylamine (13.9 g, 0.075 mol) according to the procedure of Example 2 (b) and crystallization of the crude product from methanol gives a 13% yield of analytically pure 1- [4 - [(1-methylethyl) -thio] phenoxy] -3-dodecylamino) -2- propanol, hydrochloride, m.p. 153.5-156.6-190.5 ° (corr.) (double melting point).

Analysis calculated for C 24 H 43 NO 2 S, HCl: C, 64.61; H, 9.94; N, 3.14.

Found: C, 64.38; H, 10.07; N, 2.97.

Example 5 1- [(2-Cyclohexylethyl) amino] -3- [4 - [(1-methylethyl) thio] phenoxy] -20 2-propanol, hydrochloride (CH3) 2CH-S- ^ - -OCH2CHCH2NH- (CH2 ) 2 o

Reaction of the epichlorohydrin derivative of 4- (isopropylthio) phenol (5.0 g, 0.022 mol) with cyclohexylethylamine (3.3 g, 0.026 mol) according to the procedure of Example 2 (b) and crystallization of the crude product from isopropyl alcohol gives an 18 % yield of analytically pure 1 - [(2-cyclohexyl-ethyl) amino] -3- [4 - [(1-methylethyl) thio] phenoxy] -2-propanol, hydrochloride, mp 180-182 ° (corr.).

Analysis calculated for C 20 H 33 NO 2 S, HCl: C, 61.91; H, 8.83; N, 3.61.

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

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Example 6 1- [(4-Cyclohexylbutyl) amino] -3- [4 - [(1-methylethyl) thio] phenoxy] -2-propanol, hydrochloride (ch3) 2ch-s - (2) - and 2chch2nh- ( ch2) 4- ^ 05 Reaction of the epichlorohydrin derivative of 4- (isopropylthio) phenol (9.0 g, 0.04 mol) with cyclohexylbutylamine (6.7 g, 0.043 mol) according to the procedure of Example 2 (b) and crystallization of it crude product from ethanol gives an 11.4% yield of analytically pure 1 - [(4-cyclohexylbutyl) amino] -3- [4 - [(1-methylethyl) thio] phenoxy] -2-propanol, hydrochloride, m.p. 179 ° with prior softening from 118 °.

Analysis calculated for C 22 H 3 NO 2 S, HCl: C, 63.51; H, 9.20; N, 3.37.

Pound: C, 63.46; H, 9.35; N, 3.29.

Example 7 1- [2-Methyl-4- (methylthio) phenoxy] -3- (octylamino) -2-propanol

OH

Ch3-s - (2) - and 2chch2nh- (ch2) -ch3 CH3

The epichlorohydrin derivative of 2-methyl-4- (methylthio) phenol (3.14 g, 0.015 mol) is reacted with n-octylamine (1.93 g, 0.015 mol) according to the procedure of Example 1. Concentration of the reaction mixture and crystallization of the residual material from ethyl acetate-hexane gives a 19% yield of analytically pure 1- [2-methyl-4- (methylthio) phenoxy] -3- (octylamino) -2-propanol, mp 59-60 ° (corr.).

Analysis calculated for C C CH33NNO₂S: 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

/ = \? H

/) - OCH2CHCH2NH- (CH2)? CH3 Ή-0Η3 146005

Reaction of the epichlorohydrin derivative of 2- (methylthio) phenol (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 an 18% yield of analytically pure 1- [2- (methylthio) phenoxy] -3- (octylamino) -2-propanol, hydrochloride, mp 105.5-107.5 ° (corr.).

Analysis calculated for C C CH ^EK ^SHHCl: C, 59.73; H, 8.91; N, 3.87.

Found: C, 59.86; H, 9.07; N, 3.71.

Example 9 1- [4 - [(1-methylethyl) thio] phenoxy] -3 - [(2-methyl-2-octyl) amino] -2-10 propanol anol OH CH3 (ch3) 2ch-s- och2chch2nh-c- (ch2) 5ch3 V- / <* 3 (a) 2-methyl-2-octanol - A solution of methyl heptanoate (14.5 g, 0.1 mol) in 200 ml of ether is added to 200 ml of 3M solution (0.6 mole) of methyl magnesium bromide in ether at a rate sufficient to maintain reflux. After the addition is complete, the resulting mixture is refluxed for 1 hour and then stirred at 26 ° for a 16 hour period. 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 ethereal extract and the filtrate are combined, washed successively with water, diluted sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. Concentration of the dried solution and distillation of residual material under reduced pressure gives 13.1 g (91% yield) of 2-methyl-2-octanol, boiling point 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 glacial acetic acid is treated with acetonitrile (2.5 g, 0.016 mol) and 2-methyl-2-octanol (8.0 g, 0.055 mol) and the resulting mixture is stirred at 26 ° for a 17 hour period. After dilution with 125 ml of water, the mixture is extracted with ether and the ethereal extract is washed successively with water, dilute sodium hydrogen carbonate solution and brine and dried over magnesium sulfate. Concentration 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 further 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 mol) and the mixture is heated at 200 ° for a 64 hour period. The reaction mixture is diluted with 400 ml of water and extracted with ether. The ethereal extract is washed with water and brine and then dried over sodium sulfate. Concentration of the dried solution alleviates reduced pressure to give 10.4 g (62% yield). 2-methyl-2-octylamine, which is 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 the epichlorohydrin derivative 4- (isopropylthio) phenol (7.8 g, 0.035 mol) and 2-methyl-2-octylamine (5.0 g, 0.035 mol) in 100 ml of ethanol are refluxed over a 17 hour period. The reaction mixture is concentrated under reduced pressure and residual material is heated at 80 ° (0.5 mm Hg) to remove 15 residual excess reagents. The crude free base is treated with 6N hydrochloric acid to form the hydrochloride salt which crystallizes from ether-hexane to give 3.0 g (21% yield) of 1- [4 - [(1-methylethyl) thio] phenoxy] -3- [(2 -methyl-2-octyl) amino] -2-propanol, hydrochloride, mp 165 °.

The following examples illustrate the biological effect of the compounds of the present process.

17- 1Λ 6 O O 5

Example 10

Comparison of peripheral vasodilatory activity in anesthetized dogs

Test method. - Both sex bastards weighing between 05 11 and 16 kg were anesthetized with pentobarbital (30 mg / kg) 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 mechanically ventilated with 10 room air at a rate of 18 beats / min. and a volume equal to 20 ml / kg. Vagi was divided bilaterally into the mid-cervical region of the neck. Needles were placed in the right brachial vein and artery, respectively, for injection of active compounds and for measuring blood pressure via a "Statham" pressure transducer. 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 for cannula insertion and subsequent hind paw perfusion. Following intravenous administration of heparin (5 mg / kg) and gallamine triethiodide (2 mg / kg), a cannula was inserted into the right femoral artery and the catheter tip was advanced into the abdominal aorta to the renal artery area. A cannula was inserted into the left femoral artery and the hind paw was perfused using a "Harvard" type perfusion pump. The pre-arranged ligature of the aorta was then pooled to reduce collateral circulation as much as possible. Heparin and gallamine triethiodide were infused intravenously at rates of 2.5 and 1 mg / kg / h, respectively. The perfusion pressure, measured at a location distal to the perfusion pump, was adjusted to 150 mm Hg by adjusting the pump speed. The blood flow to the paw was determined volumetrically at the end of the experiment. The test agent is administered by infusion at a rate of 0.1-1.0 mg / min. for a period of 6 minutes and the maximum reduction in pressure was determined. From one to three animals per test agent was used.

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Results. Table I below shows the results obtained in the previous test for a representative selection of the alkylthiophenoxypropanolamines concerned. Data are also shown for known alkylthiophenoxypropanolamines according to 05 Keizer et al., U.S.A. U.S. Patent No. 3,542,874 "1- (Isopropylamino) -3- [2- (methylthio) phenoxy] -2-propanol (tipranolol)" and Villa, et al., II. Farmaco. Sci., Ed. 24, 349-357 (1969) "1- (isopropylamino) -3- [4- (methylthio) phenoxy] -2-propanol" identified herein as test agents "A" and "B", respectively papaverine as a control compound.

For the known compounds "A" and "B" as well as the compound of Example 2 (test agent 2), repeated comparative tests as described above were performed with the change that the three compounds were tested in the same prepared dog (blood pressure allowed returning to control values between test drug infusion) .This design excludes effects due to animal-to-animal variations and thus allows a direct comparison of vasodilatory activity. The results of this comparison 20 are also listed in Table I.

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Table I

Vasodilatory activity - Perfused hind paw in dogs

Row == \? H 2

/ \ -0-CH2CHCH2NK-R

R -S

12 w

Test R R R Pressure Reduction ..

Dose (mg / min) c: _0_ ^ 3_1.0 05 1 H 4 “CH3 n-cgHi7 -22 -59 -44 -99 2 H 4-i-Pr n-CgH ^ _ ^ d 3 H 3 -i-Pr n-CgH17 -20 -87 5 H 4-i-Pr (CH 2) 2- ^ ~~ ^ -63 -87 6 H 4-i-Pr (CH 2) 4 -47 “74 10 7 2- CHg 4-CHg n-CgH17 -56 -80 8 H 2-CH3 n-CgHi7 -15 -64 AH 2-CH3 i-Pr "20d -27d BH 4-CH3 i-Pr - 3d -29d

Papaverin -31 -55 1 a. The numbers of the test substances correspond to the sample numbers.

b. Millimeters of mercury.

c. Infusion rate, d. Direct comparison in the same animal.

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Conclusions. Compared to the known compounds "A" and "B", all of the alkylthiophenoxy-propanolamines tested (i.e. test substances 1-3 and 5-8) tested here gave significantly greater vasodilatory effects, having an infusion-05 dose of 1, 0 mg / min. produced a pressure reduction of from 59 to 99 mm Hg, whereas "A" and "B" at the same dose produced a pressure reduction of about 27 to 29 mm Hg. Compared to the known compounds "A" and "B" at a dose of 0.3 mg / min. the compounds tested were from 0.8 to 3.2 and 10 from 5 to 21 times more active, respectively. All of the compounds tested have an interest in vasodilatory activity, at an infusion rate of 1.0 mg / min. caused a decrease in pressure that was substantially greater than that of poppies in or roughly equivalent thereto. According to the direct comparison of test agent 2 and the known alkylthiophenoxypropanolamines "A" and "B" at identical doses of 0.3 mg / min. test agent 2 has a vasodilatory effect which is approx. 3.2 and 21 times greater than for test means "A" and "B". This shows that test agent 2 is a substantially better vasodilator than the known alkylthiophenoxy-propanolamines "A" and "B".

Example 11

Inhibition of plate aggregation (antithrombogenic activity) Test method. A method similar to that described in Born in Nature 194, 927 (1962) and O'Brien in J. Clinical Pathology 15, 446 (1962) was used. This test involves a nephelometric method in which the change in turbidity of a sample of human plate-rich plasma is measured, causing plate aggregation by the addition of adenosine diphosphate (ADP) 30 or collagen as thrombogenic inducing agent. There is an increase in light transmission when the thrombogenic agent is added to the plate of plate-rich plasma due to the clotting of the platelets. The effectiveness of the test compound is determined by its ability to prevent clumping and accompanying increase in transmission. Different concentrations of the test agent are tested and the concentration which causes a 50% decrease in thrombogenic reaction is determined from a concentration-reaction curve.

Results. Table II below shows results obtained at 05 the previous test for a representative selection of the subject compounds as well as the known compounds "A" and "B" from Example 10.

Table II

In vitro plate aggregation inhibition ED50b

Testing agent and ADP Koll 1 69 42 2 56 31 3 53 24 15 5 56 47 6 53 29 7 82 39 8 65 32

Ac 137 33 20 BC 107 28 a. The test substance numbers correspond to the sample numbers.

b. Microgram / 0.5 ml plate-rich human plasma when used for aggregation 1μ grams of adenosine-5'-diphosphate (ADP) or the minimum amount of collagen (collagen) which causes the maximum degree of aggregation.

c. See Example 10.

Conclusion. The foregoing results show that all the compounds tested are substantially more active in inhibiting ADP-induced plate aggregation than the known alkyl-thiophenoxypropanolamines "A" and "B".

22 146005

Example H

Isolated guinea pig trachea (beta-adrenergic blocking activity)

Test method. - Trachea removed from adult guinea pigs (body-05 weight greater than 400 g) is cut in spiral form and suspended vertically in 20 ml of modified Tyrode bath solution maintained at 37.5 ° C and vented continuously with oxygen. The lower end of a tracheal segment is fixed to a stationary glass rod and the upper end is connected by a wire to an isometric 10 voltage transducer. Changes in the spontaneous tone of the smooth tracheal muscle are measured via the transducer and recorded continuously on an electronic recording device. Adrenergic beta-receptor blocking activity is determined by the ability of a test agent to inhibit the response of the isolated tissue to the adrenergic beta-stimulant "isoproterenol" at a concentration of 0.1 µg / ml bath liquid. The tissues are exposed to the test agent solution for an interval of 15 minutes before the addition of isoproterenol to the bath liquid. The beta-receptor blocking potency of a test compound is determined from concentration-reaction relationships where the reaction is expressed as a percentage inhibition of isoproterenol-induced tissue reaction. The EC ^ value, which is the concentration of the test compound which causes a 50% inhibition of the effect of the relaxant dose of isoproterenol 25 is determined by interpolation. Each test compound solution is added to the tissue bath medium at a constant volume of 0.2 ml / ml bath volume and only one test compound concentration is used for an individual tissue segment. The potency of the test compound relative to the beta-adrenergic blocking agent "propanolol" as a control preparation is determined by comparing the EC ^ values.

Results. - Table III below shows the results obtained in the previous test for a representative selection of the alkylthiophenoxypropanolamines concerned identified by test number (example number) compared to the known alkylthiophenoxypropanolamines according to the present invention. Keizer et al. supra.

23, 146005 and Villa, et al. supra, which are called test agents "A" and "B" respectively (cf. Example 10 for the chemical name).

Table III

Beta-adrenergic blocking activity in isolated guinea pig-05 trachea f 2

/ \ - 0-CH2CHCH2NH-R2 R ^ S

Testing "i" Beta-adrenergic, agent R R1 Rz blocking strength0 1 H 4-CH3 n-CgH17 0.001 2 H 4-i-Pr n-CgH17 0.001 10 3 H 3-i-Pr n-CgH ^ 7 0.001 4 H 4-i-Pr n-C 12 H 25 0.001 5 H 4-i-Pr (CH 2) 2. -o 0.0006 6 H 4-i-Pr (CH2) 4-0.002 7 2-CHg 4-CH3 n-CgH17 0.0006 15 8 H 2-CHg n-CgH17 0.004 AC H 2-CHg i-Pr 1 0 BC H 4-CHg i-Pr 0.2 a. The numbers of the test agents correspond to the sample numbers.

b. Strength relative to propanolol (equ. 1) estimated from 20 test compound concentration determinations causing 50% blockade of isoproterenol-induced tissue reaction (prqpanolol EC5Q = 0/028 µg / ml bath liquid).

c. See Example 10.

146005 24

Conclusion. - The results in Table III clearly show that with respect to beta-adrenergic blocking activity there is a pronounced difference between the compounds of test agents 1 to 8 and the known alkylthiophenoxypropanolamines. It is obvious that the test agents 1 to 8 are relatively free of beta-adrenergic blocking activity in contrast to the known alkylthiophenoxypropanolamines "A" and "B" having significant activity. be relatively free of the side effects associated with beta-10 adrenergic blocking activity.

Example 13

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

Test method. The antispasmotic 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. Thorax was opened and the descending thoracic aorta 20 was removed and placed in Krebs bicarbonate solution. Unexpected tissues were removed and the aorta was cut in spiral about the entire length. Four spiral segments each approx. 2 cm length (unstretched) was obtained from each thoracic aorta. A spiral segment was placed in a 10 ml volume bath chamber, fixed at the lower end to a glass rod tissue holder, and the upper free end connected by wire to a voltage transducer which exerted a constant baseline. tension of 3 g on the tissue. The bath medium surrounding the aortic helix (Krebs bicarbonate solution) was maintained at 37.5 ° C and was continuously vented at 95% 0: 5% CC The activity of the smooth aortic muscle was recorded on an electronic polygraph via its connection to the voltage transducer. After an equilibration period of 60 minutes, a cumulative dose-response curve was obtained against an agonist (e.g., potassium chloride or norepinephrine) after which the tissue was washed. 75 minutes later, another cumulative dose-response curve was obtained against the agonist 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 leaching, a third and final agonist reaction-05 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 papaverine strengths in the previous test using potassium chloride as the agonist of the subject alkylthiophenoxypropanolamines of Example 33, and the known compounds of Keizer et al. supra. ("A") and Villa et al., Supra. ("B") (see Example 10 for chemical name). Papaverine is considered a direct-acting antispasmodic agent and is a standard reagent.

Table IV

Antispasmotic activity (rabbit thoracic aorta)

Test Agent _ Antispasmodic Strength ”2 0.6 20 3 0.7 4 0.08 5 2.4 6 0.02 7 0.8 25 8 2.6 AC 0.04 BC 0.04 a. The test drug numbers correspond to the sample numbers.

b. Strength relative to papaverine (equation 1) estimated from 30 pA2 values determined for potassium chloride-induced contractions. The pA2 value represents the negative logarithm of the molar concentration of the antagonist which reduces the effect of a double dose of the agonist to the value of a single dose of the agonist without the presence of the antagonist, c. See Example 10.

05 Conclusion. Antagonist activity against potassium chloride-induced spasms indicates non-adrenergic direct-acting antispasmotic action. Accordingly, the results in Table IV show that most of the subject compounds tested have a substantial degree of antispasmotic activity, while the 10 known compounds "A" and UB "have relatively weak activity. The results further show that the test agents 2, 3, 5 , 7 and 8 relative to potassium chloride-induced spasms are from ca.

15 to approx. 65 times more potent as non-adrenergic anti-spasmotic agents than the corresponding known alkylthiophenoxy-propanolamines "A" and "B". The antispasmic strengths of the test agents 4 and 6 are twice and half as great as the known compounds "A" and "B", respectively.

Example 14 20 Isolated rabbit thoracic aorta (antispasmotic activity against norepinephrine)

The test agents 1-8 and the known compounds "A" and "B" of Example 13 were further tested for anti-alpha-adrenergic activity by the method of Example 13, but using the alpha-adrenergic stimulant norepinephrine as agonist in instead of potassium chloride. Selective activity against norepinephrine-induced spasms indicates alpha-adrenergic blocking (i.e., antispasmotic) activity. This modification of the antispasmotic test showed that all of the alkylthiophenoxypropanolamines in question except Test Agent 8 were substantially free of anti-alpha-adrenergic activity, having 0.3% or less of the activity exhibited by phentolamine. Phentolamine is an alpha-adrenergic blocking agent and a standard control preparation.

While the known compound "B" is substantially inactive as anti-alpha-adrenergic agent, test agent 8 and the known compound "A" have somewhat more activity than compounds 1-7, being 1-2% so powerful as phentolamine. This experiment demonstrates that the compounds of the present invention are non-anti-05 alpha-adrenergic antispasmotic agents, having a substantial direct relaxant 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 testing of 1- [4 - [(1-methylethyl) thio] phenoxy] -3- (octylamino) -2-propanol

The vasoactivity of the above compound of Example 2 was further investigated by various pharmacological tests used for this purpose. Namely, (a) rats with intra-arterial catheters have periods of shortened plate 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 reduced the stiffness of the red blood cells determined by a chromium labeling technique and consequently the cells are better able to pass through calcification-constricted tissue capillaries affected by vascular disease.

Claims (2)

28 146005 1, Analogous process for the preparation of alkylthiophenoxypropanolamines of the general formula K OHH 4 ^ OCH2CH-C-NH-R2 (I) \ I // HR ^ S or acid addition salts thereof, 05 wherein R represents hydrogen or alkyl of 1 to 4 carbon - atoms, R 1 represents alkyl of 1 to 8 carbon atoms, 2 R represents alkyl of 6 to 12 carbon atoms or 10 cycloalkylalkyl of 5 to 8 ring carbon atoms and from 2 to 6 carbon atoms in the alkylene chain, characterized by reacting an alkylthiophenol derivative of formula (II) · wherein R and R "*" have the meanings set forth above with an epi-halohydrin of formula (III) + </ CH-CH 2 "X (III)