IE47449B1 - Alkylthiophenoxypropanolamines - Google Patents

Abstract

Alkylthiophenoxypropanolamines of the general formula:- (A,B,R = H,C1-4 alkyl; R1=C1-8 alkyl R2 = C6-12 alkyl, (C5-8 cycloalkyl) - (C2-6 alkyl) ) and the pharmaceutically acceptable acid addition salts thereof increase peripheral blood flow, relax vascular smooth muscle, and inhibit platelet aggregation. They may be administered in the form of pharmaceutical preparations for the treatment of obstructive cerebrovascular deficiencies.

Description

This invention relates fco new and useful alkylthiophenoxypropanolamines, pharmaceutical compositions containing them and processes for their production.

The alkylthiophenoxypropanolamines of this invention increase peripheral blood flow, relax vascular smooth muscle, and inhibit platelet aggregation and are considered to be particularly useful in the treatment of obstructive peripheral vascular diseases such as intermittent claudication and cerebrovascular deficiencies associated with arteriosclerosis.

-Various alkylthiophenoxypropanolanine modifications have been described and studied in the field of adrenergic agents primarily for the purpose of uncovering more potent and selective betaadrenergic blocking agents free of unwanted pharmacologic effects.

Such compounds are generally considered useful in treating certain forms of hypertension, angina pectoris, heart arrhythmia and pheochromocytoma. Representative of these efforts are compounds described in the following patents and publications.

L. Villa, et al., II. Farmaco. Sci., Ed. 24, 349-357 (1969) specifically discloses the following alkylthiophenoxypropanol20 amine compound as part of a structure-activity-relationship study.

/==, OH CHgS —< \— OCH2CHCH2HHCH(CH3)2 7 4 4 9 Keizer, et 1., U.S. 3,542,874 patented November 24, 1970, discloses 2-(alkylth jjphenoxypropanolamines of the formula ’ wherein R is an alky1 (C^-cp radical and R is inter alia an alkyl (Cj-C12) or a c /cloalkyl radical. This patent teaches that compounds of this type have very effective betaadrenergic blocking properties. Specific compounds disclosed by 1 2 Keizer, et al. include those wherein R is methyl or ethyl and R is 2 1 isopropyl; R is methyl, ethyl, or propyl and R is tert.-butyl; R 1 10 is methyl and R is cyclopropyl, cyclopentyl, or cyclohexyl; R is tert.-butyl and R is cyclopentyl.

Crowther, et al., U.S. 3,501,7(9 patented March 17, 1970 generically discloses compounds of the type 2 wherein R is alkyl (up to 10 C); R is alkyl (up to 20 C), cyclo3 alkyl (up to 10 C), etc..; R is hydrogen or alkyl (up to 10 C). Notwithstanding the scope of the generic disclosure, Crowther, et al. does not describe a single example of a specific alkylthio'1 compound.

Koppe, et al., U.S. 3,872,147 patented March 18, 1975 20 generically discloses alkylthiophenoxypropanolamines illustrated by the formula OH • 7 0CH2CHCH2NH-R r3-s wherein R is alkyl (1-4 C); R^ is alky 1^(C£-C£); R7 is alkyl (C£Cg) containing 'at least one quaternary carbon attached directly through an alkylene chain (C£-C^) to the amino nitrogen atom. None of the specifically disclosed Koppe, et al. compounds, however, constitute an example of an alkylthiophenoxpropanolamine.

Offenlegungsschrift 2,551,141 published May IS, 1977, specifically describes the alkylthiophenoxypropanolaaine As can be seen from the above prior art, numerous alkylthiophenoxypropanolamines have been generically disclosed but relatively few alkylthiophenoxypropanolamines are specifically described. Compared to the prior art compounds which are reportedly beta-adrenergic blocking agents, the alkylthiophenoxypropanolamines of the present invention are unique in that they reduce vascular resistance with minimal involvement of beta-adrenergic blocking effects.

Broadly described, the present invention is directed to novel alkylthiophenoxypropanolamines of the formula wherein A, B, and R are independently hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive; R£ is alkyl of 1 to 8 carbon atoms inclusive; R2 is alkyl of 6 to 12 carbon atoms inclusive or cycloalkylalkyl having 7 4 4 9 co 5 ring carbon atoms inclusive attached through an alkylene chain ot 2 to carbon atoms inclusive to the amino nitrogen atom; and che pharmaceutically acceptable acid addition*salts thereof. This invention is also concerned with pharmaceutical compositions containing che alkylthiophenoxypropanclauines, and further contemplates methods for producing the compounds.

More specifically, the alkylthiophenoxypropanolamines provided by this invention are represented by formula I OH A s ....... Λ* \—OCH.CH-C-NH-R, Vl/ i 2 (I) Ri-S wherein A, B and R are independently selected fcom the group consisting of hydrogen and 'lower alkyl of 1 to 4 carbon atoms inclusive; R^ is alkyl oi 1 to 8 carbon atoms inclusive; Rj is alkyl oi 6 to 12 carbon,atoms inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms inclusive and from 2 to 6 carbon atoms in the alkylene chain, and pharmaceutically acceptable acid addition salts thereof.

As used herein, the term lower alkyl refers to a carbon chain comprised of both straight and branched chain carbon radicals of 1 to 4 carbon atoms inclusive. Exemplary of these carbon chain 7 4 4 9 radicals are methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl, and tert.-butyl.

As used herein, the term alkyl refers to straight or branched chain carbon radicals with the number of carbon atoms comprising the particular alkyl radical specifically designated or referred to by standard notations such as (C^-C^), (C^-Cg) and (C6-Ci2).

As used herein, the term cycloalky lalkyl is intended to refer to a cycloalkyl radical containing from 5 to 8 carbon atoms inclusive (i.e., cyclopentyl, eyclohexyl, cycloheptyl and cyclooctyl) connected to the amino nitrogen atom by an alkylene chain of 2 to 6 carbons.

It is to be understood that the alkylene chain connecting the cycloalkyl radical to the amino nitrogen atom may he linear or branched.

As used herein, the term non-toxic pharmaceutically acceptable acid addition salts refers to salts of compounds of formula I formed with a variety of inorganic and organic acids, the anions of which are relatively non-toxic. Such acid addition salts are considered pharmacologically equivalent to the bases characterized by structural formula I. Examples of useful salt forming acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumarie, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic, £-toluenesulfonic, and related acids. Acid addition salts of this invention are prepared and isolated by conventional means; for instance, by treating a solution or suspension of the free base in a reaction inert solvent with the - 6 47449 desired acid ana recovering the salts which fora by concentration under reduced pressure or by crystallization techniques or other standard chemical manipulations. Acid addition salt3 which are somewhat toxic and therefore do not meet the foregoing criteria for pharmaceutical acceptability are sometimes useful as intermediates for isolation and purification of the bases of formula I for other chemical purposes such as separation of optical isomers. Such salts are also considered part of the invention.

As will be apparent to those skilled in the art, the compounds characterized by general formula I have one or more assymmetric carbon atoms and can thus exist as optically active isomers, racemates and diastereoisomers all of which are considered as part of the present invention. The diastereoisomeric mixtures may, depending on physical-chemical differences of the components, he separated into diastereomeric pure racemates by conventional means such as chromatography and/or fractional crystallization.

Resolution of racemates of the instant invention to provide optically active isomers of formula X compounds is carried out by conventional resolution methods. For instance, reacting the bases of formula I with optically active acids provides salts thereof from which the enantiomers may be separated by fractional crystallization. Acids suitable fcr resolving the compounds of formula I are the optically active form3 of tartaric acid, di-£-tolyltartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, and other optically active acids known to the art. Preferably, the more biologically active optically active stereoisomer is isolated. 7 4 4 9 According co a feature of tha present invention, there is provided a process for preparing those alkylthiophenoxypropanolamines of formula I wherein A and B are limited to hydrogen which comprises reacting an alkylthiophenol derivative of formula II wherein R and R^ have meanings hereinabove described with an epihalohydrin of formula III CH,-CH-CH,-X (III) V wherein X signifies halogen, preferably chlorine or bromine, and condensing the epihalohydrin reaction product with an amine of formula IV HjN-Rj (IV) wherein R^ has the meaning hereinabove described; whereafter, if desired the formula I product in free base form is reacted with an acid to form an acid addition salt thereof. - 8 The required formula II alkylchiophenols are obtained by coupling a diazotized aminophenol with an alkyl mercaptan to form a diazosulfide which is then decomposed providing 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., 55, 1224 (1933); S. Asaka, et al,, Chem. Abrs. 61, 13243a.

Suitable Alkylthiophenol reactants of formula II which may be employed in the present process include: 4-methyIthiopheno1, 4-ethylthiophenol, 4-n-propylthiophenol, 4-n-butylthiopl· enol, 4-n-pentylthio shenol, 4-n-hexylthiophenol, 4-n-heptylthiophenol, 4-n-octylthiophenol, 4-isopropylthiophenol, 4-(3-methylbutylthio)phenol, 2- n-butyIthiopheno1, 3- n-butylthiophenol, 2-ethylthiopheno1, 2-n-propylthiophenol, 2- isopropylthiophenol, 3- ethylthiophenol, 3-n-propylthi ophanol, - 9 4 74 4 9 3-isopropylthiophenol, 2- methy1-4-(methylthio)phenol, 3- methyl-4-(methylthio)phenol.

Suitable amines of formula IV which may be employed in 5 the present process include: n-hexylamine, n-hep tylamine, n-octylamine, n-nony lamine, n-decylamine, n-undecylamine, n-dodecylamine, n-isoacmylamine, 2,2-dimethylhexylamine, 1,1-dimethyl heptylamine.

Inasmuch as an epihalohydrin molecule of formula III has two reactive positions, reaction with an alkylthiophenol of formuia II may yield a mixture of formulas V and VI reaction products wherein 8., and X are as defined above.

(V) (VI) During the further course of the prociss, however, the two possible intermediates of formula λ and formula VI on condensation - 10 with a formula IV amine yield the same final alkylthiophenoxypropanolamine product. Consequently, it ls not necessary to effect a separation of any mixtures of formulas V and VI which may result from interaction of a formula IX phenol with a formula III epihalohydrin. Under the reaction conditions employed in the instant process, the epoxides of formula VI are preferentially formed.

If desired, the epihalohydrin reaction product ma;· be taken up in an inert solvent such as chloroform and shaken with excess concentrated hydrochloric acid to convert epoxides of formula VI into the corresponding formula V alkylthiophenoxy-halohydrin. Conversely, if desired, the halohydrins of formula V may be converted to the corresponding formula VI by conventional methods, e.g., by treatment with base according to the procedure of 0. Stephenson, J. Chem. Soc., 1574 (1954).

Ihe interaction of formula II phenols with formula III epihalohydrins is carried out in the presence of a sufficient amount of a dilute aqueous alkaline metal hydroxide such as sodium hydroxide to neutralize the acidic phenolic group at temperatures in the range of 0-100° and preferably at 25-35° according to the procedure of ϊ. M. Beasley, et al., J. Pharm. Pharmacol., 10, 47-59 (1958).

Alternatively, the interaction of formula II phenols with formula III epihalohydrins can also be effected 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 the epihalohydrin reaction produce of formula V or VI with a formula IV amine is carried out preferably in organic solvent inert under the reaction conditions. Suitable solvents include methanol, ethanol, butanol, hexanol, toluene, dioxane, tetrahydrofuran, dibutylether, dimethoxyethane, ethylene glycol. The cordensation can also be effected ia the absence of a reaction solvent with equimolar amounts of the reactants.

Another feature of the present invention involves an alternate method for producing ccmpanaits of formula I wherein A and B are limited to hydrogen which comprises reacting a formula II phenol with a conpound of formula VII in alkaline medium H.-CH.-N-R, z . 2 (VII) j to provide a compound of formula VI tl (VIII) /herein R, R^ and R^ have the same meaning as in formula I and R^ stands for hydrogenolysable radical such as benzyl or benzhydryl; and converting said compound of formula VII to an alkylthiophenoxypropanolamine of formula I. Removal of the hydrogenolysable blocking group may be effected by catalytic hydrogenation, for example by 47 449 hydrogenation in the presence of palladium-on-charcoal catalyst, in an inert solvent, e.g., ethanol or aqueous ethanol.

The compounds of formula VII may be obtained according to known methods. For example, 1-[(N-beuzyl)-n-octylamino]-2,3-epoxypropane is obtained hy reaction of N-benzyl-n-octylamine and epichloro5 hydrin in alkaline medium (e.g., aqueous potassium hydroxide) according to the method described by L. Villa, et al., Farmaco., Ed. Sci., 24(3), 349-357 (1969).

A further feature of the invention is directed to a method for producing compounds of formula I wherein A, B, and R are 10 independently selected from ehe group consisting of hydrogen and lower (C^-C^) alkyl, R^ is (C^-Cg) alkyl, and is (Cg-C^,) straight or branched chain alkyl with the carbon atom thereof attached through a divalent methylene (i.e. radical to the amino nitrogen atom or (C.-Co) cycloalkyl attached through an alkylene □ o chain of 2 to 6 carbon atoms inclusive wherein said alkylene chain i3 attached through a divalent methylene (i.e. -CH^-) radical to the amino nitrogen atom which comprises sequential steps of reducing a compound of formula IX Vs OH A ι ι 0CH2CH-C-N0, B (IX) wherein A, B, R and R^ are as defined to provide the primary amino 20 compound X OH A och2ch-c-nh2 B (X) «herein A, B, R md R^ are as defined, and reductively alk;· lacing a compound of formula X with an aldehyde of formula XI hL > wherein Y is straight or branched chain alkyl of 5 to 11 carbon atoms inclusive ir cycloalkylalkyl having 5 to 8 ring carbon atoms and 1 to 5 carbon atoms in the alkylene chain.

The nitro alcohols of formula IX are obtained by an aldoltype condensation of appropriate nitroalkanes and aldehydes In the presence of base or by condensation of the sodium salt of the nitro alkane with sodium bisulfite addition products of tha aldehyde in the presence of a trace of alkali or weak acid. Alkylthiophenoxy aldehyde starting materials are obtained by reacting the appropriate alkylthiophenol with the diethylacetal of bromoacetaldehyde followed by acid catalyzed hydrolysis of the acetal groups.

As stat id hereinabove, the alkylthiophenoxypropanolamines of the present invention increase peripheral blood flow, relax vascular smooth muscle, and inhibit platelet aggregation. The compounds are substantially free of beta-adrenergic blocking effects which inhibit peripheral vasodilating activity of beta-adrenergic stimulatory endogenous amines. Standard in vivo and in vitro pharmacological test methods can be employed in assessing the activity of compounds characterized by formula I. Among such tests considered useful are the perfused dog hind limb preparation (vasodilator action), the spasmogen-challanged rabbit aortic strip (antispasmodic activity) and inhibition of adenosine diphosphate and collagen-induced plate Let aggregation in human plateletrich plasma (antithrombogenic action). The isoproterenol challenged guinea pig -rachea test, which is standard in the art, is suitable for measuring beta-adrenergic blocking action.

In addition to having vasodilating, antispasmodic inhibition of blood platelet aggregation properties, some of the compounds of Formula I inhibit lipolysis (as shown in the rat epidimal fat lipolysis model) and cholesterol biosynthesis. Compounds of this type are of value as hypocholesterolemic agents.

As used herein, the term effective vasodilating amount is construed to mean a dose which exerts a vasodilator effect in the effected mammal without untoward side effects.

By systemic administration, it is intended to include both oral and parenteral routes. Examples of parenteral administration are intramuscular, intravenous, intraperitoneal, rectal, and subcutaneous administration.

In rectal administration, both ointments and suppositories may be employed. While the dosage will vary to some extent with the mode of administration and the particular compound chosen, from about 0.5 mg. per kg, body weight to 25 mg. per kg. body weight of a compound characterized by formula I or non-toxic pharmaceutically acceptable salts thereof administered in effective single or multiple dosage units generally provides the desired vasodilating effect.

The formula I compounds are generally administered for vasodilating purposes in the form of a pharmaceutical preparation containing either a formula I free base or a pharmaceutically acceptable non-toxic acid addition salt thereof as the active component in combination with a ph rmaceutically acceptable carrier. The carrier may be solid, semi-sol;d, liquid diluent or a capsule. Accordingly, a further feature of the instant invention is directed to pharmaceutical compositions containing the compounds of formula I or non-toxic pharmaceutically acceptable acid aidition salts thereof in combination with a pharmaceutically acceptable carrier.

For the preparation of pharmaceutical compositions containing the compounds of formula I in the form of dosage units for oral administration, the compound is mixed with a solid, pulverulent carrier, (e.g. lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin) as well as with an anti-friction agent (e.g. magnesium stearate, calcium stearate, polyethylene glycol waxes or the like) and pressed into tablets. The tablets may be used uncoated or coated by conventional techniques to delay disintegration and absorption in the gastro20 intestinal tract thereby providing a sustained action over a longer time period. If coated tablets are wanted, the above prepared core may be coated with concentrated solution of sugar, which solution may contain e.g. gum, arabic, gelatin, talc, titanium dioxide, or the like. Furthermore, tablets may be coated with a lacquer dissolved IS 7 4 4 9 in an easily volatile organic solvent or mixture of solvents. If desired, dye may be added to this coating.

In the preparation of soft gelatin capsules or in the preparation of 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, pulverulent carrier such as lactose, saccharose, sorbitol, starch, (e.g., potato starch, corn starch, or amylopectin), cellulose derivatives or gelatin.

Dose units for rectal administration may be prepared in the form of suppositories containing the active substance of formula I in mixture with a neutral fat base, or they may be prepared in form of gelatin-rectal capsules containing the active substance in a mixture with a vegetable oil or paraffin oil.

Liquid preparations for oral administration may be present in the form of elixirs, syrups or suspensions containing from about 0.2% hy weight tc about 20% by weight of the active ingredient.

Such liquid preparations may contain coloring agents, flavoring agents, sweetening agents, and carboxymethylcellulose as a thickening agent.

Suitable solutions for parenteral administration by injection may be prepared as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the conpounds of formula I adjusted to a physiologically acceptable pH. These solutions may also contain stabilizing agents.

Phannaceutical tablets for oral use are prepared by conventional methods involving nixing the therapeutic compound of formula I and necessary axillary agents.

Specific alkylthiophenoxyprcpanolamines of the invention are those hereinafter described in the examples. Of these, compounds particularly preferred for their vasodilating properties and absence of significant beta-adrenergic blocking activity are: 1-[4-(methylthio)phenoxy]-3-(octylamino)-2-propanol, 1-[4-[(1-methyIethyl)thio]phenoxy]-3-(oc tylamino)-2propanol, 1-[3-[(1-methyIethyl)thio]phenoxy]-3-(octylamino)-2propanol, 1-[4-[(1-methylethy1)thio]phenoxy]-3-(dodecylamino)-2propanol, 1-[(2-cyclohexylethyl) amino]-3-[4-[(1-aethyIethyl)thio]phenoxy]-2-propanol, l-[(4-cyclohexylbutyl)amino]-3-[4-[(l-aethylethyl)thio]phenoxy]-2-propanol, 1-[2-methy1-4-(methylthio)phenoxy]-3-(octylamino)-2propanol, 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol.

The following examples illustrate but dc not limit the scope of the invention. All temperatures expressed herein are in degrees centigrade.

EXAMPLE 1 1-[4-(Methylthio)phenoxy]-3-(octylamino)-2-propanol A solution of 4-(methylthio)phenol (5,6 g., 0.C4 moles) and sodium hydroxide (2.4 g., 0.06 moles) in 50 ml. of water is 47 4 49 treated with epichlorohydrin (7.4 g., O.OS moles). The resulting mixture is first stirred at 30-35° for 24 hr. and Chen extracted with chloroform. After washing the chloroform extract with water and drying over magnesium sulfate, distillables are removed under reduced pressure to provide the epichlorohydrin derivative 1-(4methylthio)phenoxy-2,3-epoxypropane which is taken up in 30 ml. of ethanol, treated with n-octylamine (7.5 g., 0.06 mole) and refluxed for a period of 4 hr. Concentration of the reaction mixture under reduced pressure to about one-half volume provides a white solid which is collected and crystallized from ethanol to afford a 21 yield of analytically pure l-[4-(methylthio)phenoxy]-3-(octylamino)2-propanol, m.p. 79.5-80.5° (corr.).

Anal. Calcd. for : 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-oropanol Hydrochloride (CH3)2CH-S OH ι OCH2CHCH2NH-(CH2)?CH3 (a) 4-(Isopropylthio)phenol·.- A solution of sodium nitrite (113.8 g., 1.65 mole) in 210 ml. of water is added to a stirred solution of £-aainophenol (163.7 g., 1.5 mole) in 825 ml. of 4 N hydrochloric acid at -5°. After stirring for an additional 2 hr. period at -5°, the solution of the diazotized phenol is added over a 45 min. period to a previously prepared cold (-5°) solution of sodium hydroxide (270.6 g., 6.77 moles) and 2-propanethiol (126.4 g., 1.66 moles) in 525 ml. of water with the reaction maintained under a nitrogen atmosphere. When addition is complete, the mixture is permitted to warm to 27° and is kept at that temperature for a period of 16 hr. Then, the mixture is cooled to 0° and acidified with 570 ml. of 12 JT hydrochloric acid. Excess 2-propanethiol is removed by bubbling nitrogen gas through the acidified solution into a permanganate trap for a 2 hr. period. The resulting solution is extracted with several portions of diehloromethane and the combined extracts washed with water, dried over magnesium sulfate containing charcoal and filtered. Concentration of the filtrate under reduced pressure provides a residual oil which is distilled affording 81 g. (32% yield) of 4-(isopropylthio)phenol, b.p. 114-123° (1.2 mmHg). (b) A solution of 4-(isopropylthio)phenol, (6.6 g., 0.04 mole) and sodium hydroxide (2.6 g., 0.065 mole) 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 hr. and then extracted with chloroform. After washing the chloroform extract wich water and drying over magnesium sulfate, distillables are removed under reduced pressure to provide the epichlorohydrin intermediate 1-(420 isopropylthiophenoxy)-2,3-epoxypropane. The epichlorohydrin intermediate is taken up in 30 ml. of ethanol, treated with n-octylamine (7.5 g., 0.06 mole) and refluxed for a period of 4 hr. Concentration of the reaction mixture under reduced pressure affords a residue which is taken up in ethanol and treated with 6 ml. of 12 JJ hydrochloric acid. Concentration of the acidified solucion under reduced pressure and crystallization of residual material from ethanol provides an analytically pure (20% yield) 1-[4-[(1-methy120 4 7 4 4 9 ethyl)thio]phenoxy]-3-(octylamino)-2-propanol hydrochloride, m.p. 171173-186.5° (corr.) (double melting point).

Anal. Calcd. for Ο^Η^ΝΟ^.ΗΟΙ: 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 (CH3)2CH-S OH .0CH2CHCH2NH-(CH2)7CH3 Reaction of the epichlorohydrin derivative of 3-(isopropyl10 thio)phenol (4.85 g., 0.029 mole) with n-octylamine (4 g., 0.031 mole) according to the procedure cf Example 2(h) and crystallization of the crude product from ethanol-ether affords a 13% yield of analytically pure 1—[3—[(1-methylethyl)thio]phenoxy J-3-(cctylamino)2-propanol hydrochloride, m.p. 125-127° (corr.).

Anal. Calcd. for C20H35N02S.HC1: C, 61.59; H, 9.30; H, 3.59. Found: C, 61.22; H, 9.09; N, 3.53.

EXAMPLE 4 1- [4- [(1-Methylethyl)thio]phenoxy,-3(dodecylamlno)-2-Propanol Hydrochloride (ch3)2ch-s- OH ι och2chch2nh- (ck2)uch3 Reaction of the epichlorohydrin derivative of 4-(isopropvlthio)phenol (15.7 g., 0.07 mole) with π,-dodecylamir.e (13.9 g., 0.075 mole) according co Che procedure of Example 2(b) and crysCalli2aCion of Che crude produce from mechanol affords a 13* yield of analytically pure l-[4-[(l-methylethyl)thio]phenoxy]-3-dodecylamino)-2-propanol hydrochloride, m.p. 153.5-156.6-190.5° (corr.) (double melting point).

Anal. Calcd. for C^H^NO^.HCl: C, 64.61; H, 9.94, N, 3.14. Found: C, 64.38; H, 10.07; M, 2.97.

EXAMPLE 5 1-[(2-Cyclohexylethyl)amino]-3-[4-[(1methylethyl)thio]phenoxy]-2-pro?anol Hydrochloride (CH3)2CH-S 0CH2CHCH2NH- (CH2) 2 _/ \ Reaction of the epichlorohydrin derivative of 4-(isopropylthio)pheflol (5.0 g., 0.022 mole) with cyclohexylethylamine (3.3 g., 0.026 mole) according to the procedure of Example 2(b) and crystallization of the crude product from isopropyl alcohol affords an 13% yield of analytically pure l-[(2-cyciohexylethyl)amino]-3-[4[(1-methylethyl)thio]phenoxy]-2-propanol hydrochloride, m.p. 180182° (corr.).

Anal. Calcd. for C2OH33NO2S.HC1: C, 61.91; H, 8.83; N, 3.61. Found: C, 61.73; H, 8.71; H, 3.88.

EXAMPLE 6 1-[(4-Cyclohexylbutyl)amino]-3-[4-[(1methylethyl)thio]phenoxy]-2-propanol Hydrochloride 3)2CH-S OH OCH2CHCH2HH-(CH2)Z 7449 Reaction of the epichlorohydrin derivative of 4-(isopropyl thio)phenol (9.0 g., 0.04 mole) with cyclohexyIbutylamine (6.7 g., 0.043 mole) according to procedure of Example 2(b) and crystallization of the crude product from ethanol affords an 11.4% yield of analytically pure l-[(4-cyclohexylbutyl)amino]-3-[4[(l-methylethyl)thio]phenoxy]-2-propanol hydrochloride, m.p. 179° with prior softening from 118°.

Anal. Calcd. for C^H^NOjS.HCl: C, 63.51; H, 9.20; N, 3.37. Founds C, 63.46; H, 9.35; N, 3.29.

EXAMPLE 7 1-[2-Methyl-4-(methylthio)phenoxy]I _3- (octy lamino) -2-propanol CHj-S The epichlorohydrin derivative of 2-methy1-4-(methylthio)phenol (3.14 g., 0.015 mole) is reacted with n-octylamina (1.93 g. 0.015 mole) according to the procedure of Example 1. Concentrating the reaction mixture and crystallization of residual material from ethylacetate-hexane affords a 19% yield of analytically pure l-[2methyl-4-(methylthio)phenoxy]-3-(octylamino)-2-propanol, m.p. 5960° (corr.).

Anal. Calcd. for CigH33N02S: C, 67.21; H, 9.30; N, 4.13.

Found: C, 66.80; H, 9.92; N, 3.31.

EXAMPLE 8 1-[2-(Methylthio)phenoxy]-3(octylamino)-2-propanol Hydrochloride OH I —OCH2CHCH2NH-(CH2)?ch3 S-CH3 Reaction of the epichlorhydrin derivative of 2-(methy15 thio)phenol (14 g., 0.071 mole) with n-octylamine (9.04 g., 0.07 mole) according to the procedure of Example 2(h) and crystallization of the crude product from methanol-ether affords an 18Z yield of analytically puce 1-[2-(methylthio)phenoxy]-3-(oc tylamino)-2-propanol hydrochloride, m.p. 105.5-107.5° (corr.).

Anal. Calcd. for Ο^Η^ΝΟ^.ΗΟΙ: C, 59.73; H, 8.91; N, 3.87. Found; C, 59.86; H, 9.07; Ν, 3.7Ϊ.

EXAMPLE 9 1"[4-[(1-Methylethyl)thio]phenoxy]-3[(2,2-dimethy1-1-hexyl) amino I-2-pronanol OH CH3 och2chch2nh-ch2c-(ch2)3ch3 (CH3)2CH-S (a) 2,2-Dimethylhex-l-ylamine.- A solution of capronitrile (25 g., 0.26 mole) and methyl iodide (75 g., 0.53 mole) in 80 ml. of dry toluene is warmed to 80° and treated gradually with a suspension of sodium amide (25.4 g., 0.65 mole) in 100 ml. of toluene at a rate sufficient to maintain general reflux. After addition is complete, the mixture is stirred and refluxed for an - 24 47449 additional 2 hr. period, cooled and treated wich 150 ml. of water.

The organic layer is separated, washed with water and dried over magnesium sulfate. Concentration of the dried solution under reduced pressure and distillation of residual material affords an 81% yield of 2,2-dimethylcapronitrile.

A solution of 2,2-dimechylcapronitrils (10.0 g., 0.078 aola) in 100 al. of ether is added slowly to a suspension of lithium aluminum hydride (6.0 g., 0.158 mole) in 200 ml. of ether while maintaining the reaction at 0-5°. After stirring the reaction mixture for an additional 2 hr. at 0.5°, the mixture is hydrolyzed by sequentially adding 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. an additional hour, filtered and the ether phase concentrated under reduced pressure. Distillation of residual material provides 2,2-dimethylhex-l-ylamine. (b) Reaction of the epichlorhydrin derivative of 4(isopropylthio)phenol with 2,2-dimethylhex-l-ylamine according to the procedure of Example 2(b) and conversion of che free base co the hydrochloride provides l-t4-[(l-methylechyl)thio]phenoxyj-j[(2,2dimathyl-l-hexylamino]-2-propanol hydrochloride.

EXAMPLE 10 i-[4-[(1-Methylethyl)thiolphenoxyJ-3[(2-methyi-2-octyi)amino]-2-propanol y—, OH CHg (CHg) 2CH-S—(ζ β— OCHjCHCHjHH-C- (CH/ gCHg (a) 2-Methyl-2-octanol.- A solution of methy1heptanoate (14.5 g., 0.1 mole) 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 refluxing. After addition is complete, the resulting mixture is refluxed for 1 hr. and then stirred at 26° for a 16 hour period. The mixture is hydrolyzed by the addition of dilute ammonium chloride solution, filtered and the filter cake dissolved in 2N hydrochloric acid and extracted with ether. The ethereal extract and filtrate are combined, sequentially washed with water, dilute sodium bicarbonate solution and brine and dried over magnesium sulfate. Concentration of the dried solution and distillation of residual material under reduced pressure provides 13.1 g. (91% yield) of 2-methyI-2-octanol, b.p. 130° (100 mm Hg). (b) H-(2-Methyl-2-octyi)acetamide.- A solution of concentrated sulfuric acid (5.55 g., 0.055 mole) in 32 ml. of glacial acetic acid is treated with acetonitrile (2.5 g., 0.016 mole) and 2methyl-2-octanol (8.0 g., 0.055 mole) and the resulting mixture stirred at 26° for a 17 hr. period. After diluting with 125 ml. of water, the mixture is extracted with ether and the ethereal extract sequentially washed with water, dilute sodium bicarbonate solution and brine and dried over magnesium sulfate. Concentration of the dried solution provides 8.7 g. (85% yield) of fi-(2-me thy 1-2-octy 1)acetamide which is used in the next step without further purification. (c) 2-Methy1-2-octylamine.- A solution of potassium hydroxide (10.0 g., 0.18 mole) in 100 ml. of ethylene glycol is treated with H-(2-methv1-2-octyl)acetamide (13.0 g., 0.07 mole) and the mixture heated at 200° for a 64 hr. 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 4 19 over sodium sulfate. Concentration of the dried solution under reduced pressure affords 10.4 g. (622 yield) of 2-methy1-2-octylamine which is used in the next step without further purification. (d) 1-(4-[(1-Methylethyl)thio]phenoxy]-3-[(2-methy1-25 octyl)amino]-2-propanol Preparation.- A solution of the epichlohydrin derivative of 4-(isopropylthio)phenol (7.8 g., 0.035 mole) and 2-methy1-2-octylamine (5.0 g., 0.035 mole) in 100 ml. of ethanol is refluxed for a 17 hr. period. The reaction mixture is concentrated under reduced pressure and residual material heated at 80° (0.5 mm Hg) to remove resitual excess reagents. The crude free base is treated with 6N hydroch oric acid to provide the hydrochloride salt which crystallized from ether-hexane affords 3.0 g. (21% yield) of 1-[4-[(1-methylethyl)thio]phenoxy1-3-[(2-methy1-2-octyl)amino] -2propanol hydrochloride, m.p. 165°.

EXAMPLE 11 3-Methy1-1-[4-[(1-methylethyl)thio]ohenoxy1-3-(octylamino)-2-bu tano1 OH CHj och2ch-c-nh-(ch2)7ch3 ch3 (a) Diethylacetyl of 4-[(l-methylethyl)thlolphenoxyacetaldehyda.- A solution of 4-[(1-methylethyl)thio]phenol (24.2 g., 0.144 mole) in 180 ml. of 2-ethoxyethanol is treated with 7.2 g. of a 50% dispersion of sodium hydride in mineral oil and the mixture stirred until hydrogen evolution ceases. The diethylacetal of bromoacetaldehyde (30.0 g., 0.152 mole) is added to the reaction mixture which is then stirred and refluxed for a 19 hr. period, cooled, diluted with water and extracted with ether. Ether extracts are combined, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to an oil. Distillation of residual oil under reduced pressure provides 28.1 g., (69% yield) of the diethylacetal of 4-[(l-methylethyl)thio]phenoxyacetaldehyde, b.p. 142-146° (0.07 am Hg). (b) 4-[(1-MethyIethyl)thio Iphenoxyacetaldehyde- A solution of the diethylacetal of 4-[(1-methylethy1)thio[phenoxyacetaldehyde (10 g., 0.035 mole) in 100 ml. of aqueous ethanol (60:40) is treated with 5 ml. of 6N hydrochloric acid and t'ne resulting mixture refluxed for a period of 2 hr. Tha cooled mixture is partitioned between ether and water and the ethereal phase washed with water and brine and then dried over magnesium sulfate. Concentration of the dried ethereal solution under reduced pressure and distillation of residual material affords 4-[(1-methyIethyl)thio[phenoxyacetaldehyde. (c) 3-Methyl-l-[4-[(1-methylethy1)thio]phenoxy[-3nitro-2-butanol.- A solution of 2-nitropropane (1.8 g., 0.02 mole) and 1.0 g. of sodium hydroxide in 10 ml. of water is added to a stirred suspension of 4-[(1-methyIethyl)thio[phenoxyacetaldehyde (4.2 g., 0.02 mole) in a solution of sodium bisulfate (2.1 g., 0.02 mole) in 10 ml. of water. The mixture is warmed on a steam bath for 8 hr., cooled and acidified with glacial acetic acid.

The acidified mixture is extracted with ether, and the combined ether extracts sequentially washed with water, dilute sodium bicarbonate solution and brine and dried over magnesium sulfate. Concentration of the dried ethereal solution under reduced pressure - 28 provides 3-methy1-1-[4-[(1-methylethyl)thio]phenoxy]-3-nitro-2butanol. (d) 3-Amino-3-methyl-1-[4-[(1-methylethyl·)thio]phenoxy]2-butanol.- A solution of 3-methyl-l-[4-[(l-methylethyl)thio]phenoxy]5 3-nitro-2-butanol (2.5 g., 0.008 mole) in 100 ml. of ether is treated with lithium aluminum hydride (0.5 g., 0.013 mole). The mixture is stirred at 25° for a 4 hr. period, cooled and then hydrolyzed by the sequential addition of 0.5 ml. of water, 0.5 ml, of 15% sodium hydroxide solution, and 1.5 ml. of water. After stirring at room temperature for 1 hr., the solution is filtered and concentrated under reduced pressure to provide 3-amino-3-methyl-l-[4-[(1-methy 1ethyl)thio]phenoxy]-2-butanol. (e) 3-Meth T-l-[4-[(l-methylethyl) thio 1phenoxy]-3(octylamino)-2-butanol Prepare cion.- A solution of 3-amino-315 methyl-l-[4-r(l-methylathyl)t\io]phenoxy]-2-butanol (2.0 g., 0.007 mole) .n 60 ml. of isopropyl alcohol is treated with n-octanal (1 0 g., 0.008 mole)· and sodium cyanoborohydride (1.0 g., 0.017 mole). After stirring at room temperature for a period of 16 hr., it is poured into water and the product extracted with ether. The ethereal extract is washed with water and brine and dried over magnesium sulfate. Concentration of the dried ethereal solution and conversion of the residual free base to the hydrochloride salt provides 3-methy1-1-[4-[(1-methylethyl)thio]phenoxy]-3-(octy1araino)-2-butanol hydrochloride.

EXAMPLE 12 1- [4-[(1-Methylethyl)thio]phenoxyl-3-(octylamino)-2-butanol· OH OCH,CHCH-NH-(CH2)?CH3 ch3 (a) 3-Amino-l-[4-((1-methylethyl)thio]phenoxy]-2-butanol. 5 This amine precursor is obtained by reducing 1-[4-[(1-methylethyl)thio]phenoxy]-3-nitro-2-butanol with lithium aluminum hydride according to the procedure of Example 11(d). The nitro starting material (1-[4-[(1-methylethyl)thio]phenoxy]-3-nitro-2-butanoI) is obtained by using an equivalent quantity of nitroethane in place of the 2-nitropropane in the procedure of Example 11(c). (b) l-[4-[(1-Methylethyl)thio]phenoxy]-3-octylamino-2butanol Preparation.- Treatment of 3-amino-l-[4-[(1-methylethyl)thio]phenoxy]-2-butanol with n-octanal and sodium cyanoborohydride according to the procedure of Example 11(e) affords the product 1-[4—£(1-methylethyl)thio]phenoxy]-3-octylamino-2-butanol.

EXAMPLES 13-28 The following compounds of Table A are prepared according to the procedure of Example 1 by reacting the epichlorohydrin derivative of the starting phenol with n-octylamine. 4 7 4 4 9 TABLE A Vs OH OCH2CHCH2NH-(CH2)?CH3 Product Example Starting Thlophenol RjS 13 4-ethylthiophenol 4-C2H5S 5 14 4-n-propylthiophenol 4-n-C3H7S 15 4-n-butylthiophenol 4-n-C4H9S 16 4-n-pentylthiophenol 4-n-C5HllS 17 4-n-hexylthiophenol4_-'C6H13S 18 4-n-hep tylthiophenol 4-n-C7H15S 10 19 4-n-octylthiophenol 4-n-C8H17S 20 4-(3-aethylbutylthio)phenol 4-(CH3)2CKCH2CH2S 21 2-n-butylthiophenol 2-n-C^S 22 . 3-n-butylthiophenol 23 2-ethylthiophenol 2-C2H5S 15 24 2-n-propylthiophanol 2-n-C3H73 25 2-isopropylthiophenol 2-i-C3H7S 26 3-ethylthiophenol 3-C2H5S 27 3-n-propylthiophenol 3-n-C3H-,S 20 28 3-isopropylthiophenol EXAMPLE 29 Tablets 3-i-C3H7S The following ingredients are blended into proportion by weight indicated according to conventional pharmaceutical techniques to provide a tablet base. 47 4 49 Ingredient Amount Lactose 79 Corn starch 10 Talcum 6 Tragancanth 4 Magnesium stearate 1 This tablet base is blended with sufficient 1-[4-[(1-methy 1ethyl)thio]phenoxy]-3-(octylamino)-2-propanol hydrochloride to provide cablets containing 10, 20, 40, 80, 160 and 320 mg. of active ingredient and compressed into conventional tablet press.

EXAMPLE 30 Dry-Filled Capsules The following ingredients are blended in a conventional manner in the proportion hy weight indicated.

Ingredient Amount Lactose, U.S.P. 50 Starch 5 Magnesium stearate 2 Sufficient l-[4-[(l-met hylethyI)thiOjphenoxy]-3-(octylamino) 20 2-propanol hydrochloride is addec to the blend to provide capsules containing 10, 20, 40, 80, 160 and 320 mg. of active ingredient which is filled into hard gelatin capsules of a suitable size.

EXAMPLE 31 Comparison of Peripheral Vasodilator Activity In The Anesthetized Dog Test Method.- Mongrel dogs of either sex weighing between 11 and 16 kg., each, were anesthetized with pentobarbital (30 mg./kg.) administered intravenously. The left brachial vein was cannulated and pentobarbital infused continuously throughout the experiment at a rate of 5 m;./kg./hr. A tracheotomy was performed and dogs ventilated mechanically with room air at a rate of 18 strokes/min. and a volume equi/alent to 20 ml./kg. The vagi were sectioned bilaterally in che mid-cervical region of the neck. The right brachial vein and artery were cannulated to inject drugs and to monitor blood pressure via a Statham ( Trade Mark) pressure transducer, respectively.

All measurements were recorded on a Bedonan-Offher ciynograph (Beckman is a Trade ttirk). The abdominal aorta was exposed through midline incision and a loose ligature placed around the aorta distal to the left renal artery. The right (donor) and left (recipient) femoral arteries were exposed for cannulation and subsequent hind-linb perfursicn. Following intravenous administration of heparin (5 mg./kg·) and gallamine triethiodide (2 mg./kg.)» the right femoral artery was cannulated and the tip of the catheter advanced into the abdominal aorta to the level of the renal arteries.

The left femoral artery was cannulated and the hind-limb perfused using a Harvard Perfusion pump. The ligature previously placed around the aorta was subsequently tied to minimize collateral circulation. Heparin and gallamine triethiodide were infused intravenously at rates of 2.5 and 1 mg./kg./hr., respectively. Perfusion pressure, measured at a point distal to the perfusion pump was set equal to 150 mm Hg. by adjusting pump speed. Slood flow to che limb was determined volumetrically at the conclusion of the experiment. The test agent was administered by infusion at a rate of from 0.1-1.0 mg./min. for a six-minute period and maximum reduction in pressure determined. One to three animals were employed per test agent.

Results.- Table 1 below gives results obtained according to Che above test for representative alkylthiophenoxypropanolamines of the instant invention. Data is also shown for the alkylthiophenoxypropanolamine prior art compounds of Keizer, et al., U.S. 3,542,874 l-(isopropylamino-)-3-[2-(methylthio)phenoxy]-2-propanol (tiprenolol) 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, and the reference standard papaverine.

With respect to prior art compounds A and B and the compound of Example 2 (test agent 2), comparative testing was repeated essentially as described above with the modification that the three compounds were tested in the same dog preparation (blood pressure was allowed to return to control values between infusion of test agents). This protocol precludes effects resulting from animal variation thus permitting i direct side-by-side comparison of vasodilating activity. The results of this comparison are also set forth in Table I. 74 4 9 TABLE I Vasodilator Activity - Perfused Dog Hind Xlmb Test Agent R ....... Ry. R, Dose (mg./min.)’ 0.3 1.0 1 H 4-CH3 —"C8H17 -22 -59 2 H 4-i-Pr —"C8H17 -44 -63d -99 3 H 3-i-Pr -_C8H17 -20 -87 5 H 4-i-Pr(CH2>2-O -63 -87 6 H 4-i-Pr (ch2)4^Q -47 -74 7 2-CH3 4-CH3 —_C8H17 -5ό -80 8 H 2-CH3 n-C8K17 -15 -64 A H 2-CHj i-Pr -20d -27d B H 4~CH3 _i-Pr - 3d -29d Papaverine -31 -55 a. Test agent numbers correspond to example numbers. b. Millimeters of mercury. c. Infusion rata. d. Side-by-side comparison in same animals.

Findings.- Compared to prior art compounds A and B, all of the instant alkylthiophenoxypropanolamines tested (i.e. test agents 1-3 and 5-8) provided substantially greater vasodilating effects in that at an infusion dose of 1.0 mg./min. they produced a pressure reduction of from 59-99 mm Hg. whereas A and B at an identical dose provide a reduction in pressure of some 27-29 mm Hg.

In comparison to prior art compounds A and B at a dose of 0.3 mg./min. the compounds tested were, respectively, from 0.8 to 3.2 and 5 to 21 times more active. All of the compounds tested are of interest with respect to vasodilator activity in that at an infusion rate of 1.0 mg./min. they produce a decrease in pressure substantially greater than or approximately equivalent to papaverine.

According to che side-by-side comparison of test agent 2 and prior art alkylthiophenoxypropanolamines A and B at identical 0.3 mg./min. dose levels, test agent 2 has a vasodilator effect approximately 3.2 and 21 times greater than that of test agents A and 3, respectively. This illustrates that test agent 2 is a substantially superior vasodilator compared to the prior art alkylthiophenoxypropanoiamine A. and B.

EXAMPLE 32 Inhibition of Platelet Aggregation (Antithrombogenic Activity) Test Method.- A method similar to that described in 3orn, Mature 194, 927 (1962) and O'Brien, J. Clinical Pathology 15, 446 (1962). This test comprises a nephelometric method in which the change in turbidity of a specimen of human platelet-rich plasma is measured on causation of platelet aggregation hy addition of adenosine diphosphate (ADP) or collagen as the thrombogenic inducing agent. An 7449 Increase In transmittance light occurs when the thrombogenic agent is added to the specimen of platelet-rich plasma due to clumping of platelets. Efficacy of the test compound is determined by ability to prevent the clumping and concommitant Increase in transmittance. Various concentrations of the test agent are tested and that concentration causing a 50% reduction in the thrombogenic response is determined from a concentration-response curve.

Results.- Table II below provides results obtained according to the above test for representative compounds of the instant invention and.prior art compounds A and 3 of Example 31.

TABLE II Inhibition of Platelet Aggregation In Vitro Test Agent3 ADP Coll 1 69 42 2 56 31 3 53 24 5 56 47 6 53 29 7 82 39 8 65 32 AC 137 33 Bc 107 28 a. Test agent numbers correspond to example numbers b. Microgram/0.5 ml. platelet-rich human plasma when 1 meg. of adenosine-5'-diphosfhate (ADP) or the minimal amount of collagen (coll) producing maximal degree of aggregation are used to induce aggregation. c. Refer to Example 3.1.

Findings.- The above data demonstrates that all of the compounds tested are significantly more active in inhibiting ADPinduced platelet aggregation Chan che prior art alkylthiophenoxypropanolamines A and B.

EXAMPLE 33 Isolated Guinea Pig Trachea (heta-Adrenergic Blocking Activity) Test Method.- Tracheas excised from adult guinea pigs (body weight greater than 400 g.) are cut spirally and suspended vertically in 20 ml. of modified Tyrode's bath solution maintained at 37.5°C. and aerated continuously with oxygen. The lower end of a tracheal segment is fixed to a stationary glass rod and the upper end is threaded to an isometric tension transducer. Changes in the spontaneous tonus of the tracheal smooth muscle are monitored via the transducer and recorded continuously on an electronic recorder.

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 meg./ml. bath fluid. The tissues are exposed to the test agent solution for a 15-rain. interval prior to the addition of Isoproterenol to the bath fluid. Beta-receptor blocking potency of a test drug is ascertained from concentration-response relationships wherein the response is expressed as a percent inhibition of isoproterenol induced tissue response. The ΙΟ^θ value, which is the concentration of the test drug providing a 50% inhibition of the effect of the relaxant dose of isoproterenol, is determined by interpolation. Each drug solution is added to the tissue bathing medium at a constant volume of 0.2 ml./ml. of bath fluid and only one test drug concentration is employed for an individual tissue segment. Potency of the test agent relative to that of Che beta-adrenergic blocking agent propanolol as a reference standard is assessed by comparing the ΙΟ^θ values.

Results.- Table III below provides results obtained 5 according to Che above test for representative alkylchiophenoxypropanolamines of the instant invention identified by test number (example No.) compared to the alkylthiophenoxyprooanolamine prior art compounds of Keizer, et al. supra, and Villa, et al. supra, referred to as test agents A." and B, respectively (consult Example 31 for chemical name).

TABLE III Beta-Adrenergic Blocking Activity in the Isolated Guinea Pig Trachea Test Beta-Adrenergic Agent3 R R Blocking Potency 1 H 4-CH3 --C8H17 <0.001 2 H 4-i-Pr -_C8H17 <0.001 3 H 3-i-Pr π-08Η17 <0.001 4 H 4-_i-?r —-C12H25 <0.001 5 H 4-i-Pr 2)2-Q <0.0006 6 H 4-i-Pr2>4-0 <0.002 7 2-CH3 4-CH3 -_C8H17 <0.0006 8 H 2-CH3 --C8H17 0.004 Ac H 2-CH, i-Pr 1.0 3 BC H 4-CH3 i_-Pr 0.2 a. Test agent numbers correspond to example aumhers. b. Potency relative to propanol (equals one) estimated from determinations of test drug concentrations causing 50% blockade of isoproterenol-induced tissue response (propanol EC,, = 0.023 meg./ml. bath fluid). c. Refer to Example 31. 4 7 449 Findings.- The date of Tahle XXI clearlv establishes that, with respect tc beta-adrelerglc blocking activity, a marked distinction exists between the compounds of test agents 1 through 3 and the prior art alkylthiophenox;T)ropanolamines. It is apparent that test agents 1 through 8 are comparatively devoid of beta-adrenergic blocking activity in contrast to the coresponding prior art alkylthiophenoxypropanolamines A" and "B which have substantial activity. Consequently, the instant compounds when used for purposes described herein, would be relatively free of side effects associated with beta-adrenergic blocking activity.

EXAMPLE 34 Isolated Rabbit Thoracic Aorta (Antispasmotic Activity vs. Potassium Chloride) Test Method.- Antispasmodic activity was assessed in vitro by determining the effect of the test substance 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 hy i.v. air injection. The thorax was opened and the descending thoracic aorta removed and placed in Kreb's-bicarbonate solution. Extraneous tissue was removed and the aorta was cut spirally along its entire length. Four spiral segments, each approximately 2 cm. in length (unstretched), were 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 threaded to a tension transducer which exerted a constant baseline tension of 3 gm on the tissue. The bath medium surrounding the aortic spiral (Kret's-hicarbonate ;olution) was maintained at 37.5°C. and constartly aerated witi 95% 0ji5% CO^. Activity of the aortic smooth muscle was recorded on an electronic polygraph via its connection to the tension transducer. After an equilibration period of 60 min., a cumulative dose-response curve was obtained to an agonist (e.g. potassium chloride or norepinephrine) and the tissue then washed. Seventy-five min. later, a second cumulative doseresponse curve to the agonist was obtained and the tissue washed again. Sixty min. later, a test drug solution was added to the tissue bath fluid and, after 15 min., drug exposure and, without washing, a third and final agonist-response curve was obtained. All additions to the bath fluid were 0.1 ml. volumes of aqueous solutions.

Results.- Table TV below provides a comparison of potencies relative to papaverine in the above test employing potassium chloride as agonist for the instant alkylthiophenoxypropanolamines of Example 33 and prior art compounds of Keizer, et al., supra. (A) and Villa, et al., supra. (3) (consult Example 31 for chemical name). Papaverine is considered a direct-acting antispasmodic agent and is a standard in the art.

TABLE IV Antispasmodic Activity (Rabbit Thoracic Aorta) Test Agent Antispasmodic Potency 0.6 0.7 0.08 2.4 0.02 0.8 2.6 0.04 0.04 a. Test agent numbers correspond to example numbers. b. Potency relative to papaverine (equals one) estimated from pAj values determined versus potassium chloride-induced contractions. The pA, value represents the negative log cf the molar concentration of the antagonist which reduces the effect of a double dose of the agonist to that of a single dose of the agonist without the antagonist present. c. Refer to Example 31.

Findings.- Antagonist activity against potassium chlorideinduced spasms is indicative of uon-adrenergic direct-acting antispasmodic action. Accordingly, the results set forth in Table IV illustrate that most of the instant compounds tested have a substantial level of antispasmodic activity whereas the prior art compounds A and B have relatively weak activity. The data further establishes that relative to potassium chloride-induced spasms, test agents 2, 3, 5, 7, and S are frcm about 15 to 65 times more potent as non-adrenergic antispasmodic agents than the corres5 ponding prior art alkylthiophenoxypropanolamines A and B. The antispasmodic potencies of test agents 4 and 6 are approximately the same as prior art compounds A and B with test agent 4 being twice as potent and test agent 6 being about 1/2 as potent.

EXAMPLE 35 Isolated Rabbit Thoracic Aorta (Antispasmodic Activity vs. Norepinephrine) Test agents 1-S and prior art compounds A and B of Example 34 were further tested for anti-alpha-adranargic activity according to the method of Example 34 but employing the aloha15 adrenergic stimulant agent norepinephrine as the agonist rather than potassium chloride. Selective activity against norepinephrineinduced spasms is indicative of alpha-adrenergic blocking (i.e. antispasmodic) activity. The modification of the antispasmodic test established that all of the instant alkylthiophenoxypropanolamines with exception of test agent 8, were essentially devoid of antialpha-adrenergic action having 0.3% or less of the activity exhibited by phentolamine. Phentolamine is an alpha-adrenergic blocking agent and a standard reference in the art. While prior art compound B is essentially inactive as an anti-alpha-adranergic agent, test agent 8 and prior art compound A have somewhat more activity than compounds 1 7 in that they are 1-2% as potent as phentola ine. This experiment illustrates that the instant compounds are nor-anti-alpha-adrenergic antispasmodic agents in Chat they have a substantial direct smooth muscle relaxant effect (as shown in Example 34) relatively uncomplicated by any significant selective alpha-adrenergic blocking effect.

EXAMPLE 36 Additional Biological Testing of l-[4-[(l-Methylethyl)thiolphenoxy]-3-(octylamino)-2-propancl The vasoactivity of the above compound of Example 2 was further evaluated according to various pharmacological tests employed for that purpose. Thus: (a) Rats with Intra-arter:.al catheters have periods of shortened platelet survival time. This shortened survival time is normalized with the compound of Exam; le 2. (b) The compound of Example 2 elevated basal tone of mesenteric arteries of dogs and rabbits. This effect is considered valuable in the treatment of peripheral and cerebral vascular diseases. (c) The compound of Example 2 decreased red blood call rigidity determined via a chromium3''' labeling technique and accordingly the cells are better able to pass through sclerosed narrowed capillaries of tissues affected by vascular disease.

Claims (22)

1. CLAIMS :1An alkylthiophenoxypropanolamine of the general formulaχR ΟΗ A och 2 ch-c-nh-r 2 (I) 5 or an acid addition salt thereofwherein A, B and R are each independently a hydrogen atom or a lower alkyl group containing from 1 to 4 carbon atoms inclusive; 10 R^ is an alkyl group containing from 1 to 8 carbon atoms inclusive; R 2 is an alkyl group contai ling from 6 to 12 carbon atoms inclusive or a cycloalkylal 15 chain.

2. 1-/3-(Methylthio)phenoxy/ - 3 - (octylamino)-2-propanol.

3. 1-/4-/71-Methyleuhyl) thio7phenoxy7 - 3- (octylamino) -2propanol.

4. 1-/3-// 1-Methylet lyl)thiq7phenoxy/-3-(octylamino)-220 propanol.

5. 1-/4-/71-Methylethyl)thiq7phenoxy/-3-(dodecylamino) -2-propanol.

6. . 1-/7 2-Cyclohexy lethyl) aminq7~ 3-/4-/71-methy lethyl) thio7phenoxy7 - 2~propano . 46 47449

7. 1-/74-Cyclohexylbutyl)amino7-3-/4-/71-methylethyl) thiq7phenoxy7“ 2 “Propanol·

8. l-/2-Methyl-4-(methylthio)phenoxy/-3-(octylamino)-2propanol. 5

9. l-/5-(Methylthio)phenoxy/-3-(octylamino)-2-propanol.

10. A pharmaceutically acceptable acid addition salt of a compound as clained in any one of claims 2 to 9.

11. l-/4-/*(Methyleth> 1) thiq7phenoxy7~3- (octylamino) -2propanol hydrochloride. 10

12. A process for preparing an alkylthiophenoxypropanoiamine of the general formula:- ICH 2 CH“C-NH-R 2 OH A (I) or an acid addition salt thereof, wherein 15 A and B are hydrogen R is a hydrogen atom or a lower alkyl group containing from 1 to 4 carbon atoms inclusive; R £ is an alkyl group containing from 1 to 8 carbon atoms inclusive; 20 R 2 is an alkyl group containing from 6 to 12 carbon atoms inclusive or a cycloalkylalkyl group containing from 5 to 8 ring carbon atoms and from 2 to 6 carbon atoms in the alkylene chain, which process comprises reacting an alkylthiophenol derivative of formula II (II) wherein R and R £ are as above defined with an epihalohydrin of formula III CH; —CH-CH_-X / 2 (III) wherein X is a halogen atcn, hydrin reaction product wi th and condensing t le epihaloan amine of formula IV: h 2 n-r 2 (IV) wherein R 2 is as above defined; and thereafter, if desired, reacting the formula I product in free base form with an 10 acid to form an acid addition salt thereof.

13. A process as claimed in claim 12 wherein the reaction of the compound of Formula II with the epihalohydrin of formula III is carried out in the presence of a sufficient amount of a dilute aqueous alkaline metal hydroxide to neutralize the acidic phenolic group at a temperature in the rarge of 0 to 100°C.

14. A process as claimed in claim 13 wherein the reaction is carried out at a ti mperature in the range of 20 from 25 to 35°C.

15. A process as claimed in claim 13 or claim 11 wherein the alkaline metal hydroxide is sodium hydroxide.

16. A process for preparing an alkylthiophenoxypropanolamine of the general formula: or an acid addition salt thereof wherein A and B are hydrogen; R is a hydrogen atom or a lower alkyl group containing from 1 to 4 carbon atoms inclusive; 10 is an alkyl group containing from 1 to 8 carbon atoms inclusive; R 2 is >an alkyl group containing from 6 to 12 carbon atoms inclusive or a cycloalkylalkyl group containing from 5 to 8 carbon atoms ar d from 2 to 6 carbon atoms in the alkylene chain which process comprises reacting a derivative of formula II ?· OH (ii) wherein R and R £ are as above defined with a compound of formula VII 49 47449 in alkaline medium to provide a compound ol: formula VIII wherein R, R^ and R 2 are as defined above and R^ is a hydrogenolysable group, and converting the compound of formula VIII to an alkylthiophenoxypropanolamine of formula I

17. A process as claimed in claim 16 wherein removal of the hydrogenolysable group is effected by catalytic hydrogenation.

18. A process for preparing an alkylthiopher oxypropanol10 amine of the general formula: R^ ,-< OH A I I OCH 2 CH-C-NH-R 2 B wherein A, B, R, R^ and R 2 are as defined in Claim 1, which process comprises reducing a compound of formula IX OH A £· }—och 2 ch-c-no 2 (IX) Rj-S 15 wherein A, B, R and R^ are as defined above to produce the compound of formula X (X) 474 49 and thereafter reductively alkylating a compound <>f formula X with an aldehyde of formula Xl II HC-Y Xl wherein Y is a straight or branched chain alkyl group 5 containing from 5 to Ll carbon atoms or a cycloaikyl group having 5 to 8 iIng carbon atoms and from 1 to 5 carbon atoms in the alkylene chain.

19. A process as claimed in claim 12 substantially as hereinbefore described with reference to any one of 10 Examples 1 to 10, or 13 to 28.

20. A compound of Formula I as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 12 to 19.

21. A pharmaceutical composition which comprises a com15 pound as claimed in any one of claims 1 to 9, or claim 20, or a pharmaceutically acceptable acid addition salt as claimed in claim 10 or claim 11, together with a pharmaceutically acceptable diluent or carrier.

22. A pharmaceutical composition as claimed in claim 21 20 substantially as hereinbe ore described. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.