IE45631B1 - 4-hydroxyphenylalkanolamine derivatives and preparation thereof - Google Patents

Abstract

The compounds of formula in which the substituents have the meaning as defined in Claim 1, are prepared by reducing a corresponding compound having a keto group. The compounds thus produced are particularly useful as antihypertensive agent.

Description

The present invention relates to 4-hydroxyphenylalkanolamine derivatives and specifically derivatives of a-(aminoaikyl) 4-hydroxy-3-(alkylthio, alkylsulfinyl or alkylsulfonyl)-benzenemethanols and 2-[4-hydroxy-3-(alkylthio, alkylsulfinyl or alkyl5 sulfonyl)phenyl]ethylatnines, to processes and intermediates for the preparation thereof.

Patent Wo. 34545 discloses a group of compounds embraced by the generic formula: wherein, inter alia; Rx is SS, RSO or SSO2 (R=H, or C1-C10 alkyl); R2 and S3 are hydrogen, CL-C4 alkoxy or Cj_-C4 alkylthio; r4 is hydrogen or C^-C,} alkyl; and Rg and Rg are independently hydrogen or C-^-C^g alkyl optionally substituted by a phenyl or substituted phenyl group.

The compounds are stated to exhibit β-adrenergic blocking, peripheral vasodilator, anti-arrhythmic and hypotensive activities -245631 U.S. Patent 3,917,704 discloses a group of a-aminoalkyl-4~hydroxy-3-alkylsulfonylmethylbenzyl alcohols having the formula: RS0oCHo2 2'>—, 0HR.3 HO -—<7 CH-CH-NHR, wherein, inter alia; R represents lower alkyl of from 1 to 5 oarbon atoms, straight or branched chain; Rj represents Rg represents hydrogen, methyl or ethyl; Rj and R^ represent hydrogen, hydroxy or methoxy; and Rg represents hydrogen or methyl. The compounds are stated to have utility as β-adrenergic stimulants with relatively greater activity on respiratory smooth muscle than on cardiac muscle, Kaiser, et al. J. Med..Chem. 18, 674-682 (1975) report essentially the work described in aboveidentified U.S. Patent 5,917,704 and in addition disclose the compound having the formula -345631 CH^SOg ch2-nh-c(ch3)3 which is stated to be weakly active as a β-adrenergic agonist and which exhibits β-adrenergic antagonistic activity. The work described in the Kaiser publication was reported orally April 10, 1975 st the 169th national meeting of the American Chemical Society. An abstract of the oral presentation appeared at Abstracts of Papers, ACS Meeting 169: Medi 54 (April 1975).

Lutz, et al., J. Med. Chem. lg, 795-802 (1972), disclose the attempted preparation of 4-hydroxy-3-mercaptophenylethanolamine, i.e.: HS HO CH-CHg-NHg The compound however was neither isolated as a single entity nor characterized.

United Kingdom Patent 1,154,193 discloses as a g-adrenergic agent a- [ (isopropylamino)methyl]-3-(methylthio)benzenemethanol, i.e.s OH' ch-oh2-nh-ch(ch3)2 -443631 In the field of antihypertensive therapy the use of peripheral vasodilator agents to lower blood pressure has often suffered a serious disadvantage, namely the reflex tachycardia elicited by the hypotension induced by systemic vasodilation. Recently efforts have been made to overcome this problem by employing hypotensive vasodilators in combination with β-adrenergic blocking agents, the function of the latter being tc reduce the reflex tachycardia caused by the vasodilator-induced hypotension. This mode of therapy of course suffers the inconvenience of requiring two separate drugs and the attendant need for separate dosage regulation as well as the increased potential for patient error in failing to administer either one or the other of the drugs.

The present Invention provides novel, therapeutically useful compounds which have both hypotensive vasodilator and β-adrenergic blocking activity and which are therefore indicated for use θβ antihypertensive agents free of the undesirable tachycardic side effects associated with currently used vasodilator agents.

The invention relates to a-{[(arylalkyl)amino]alkyl}4-YO-3-(lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl benzenemethanols which are useful as antihypertensive agents having Formula I hereinbelow: -543631 YO I whereins Rlr i?2 and R3 are independently hydrogen or lower alkyl; n is all integer from 1 to 3; Ar is phenyl· or phenyl having from one to three halo, lower alkyl, hydroxy or lower alkoxy substituents; Q is lower alkylthio, lower alkylsulfinyl or lower alkylsuifonyl; Y is hydrogen, lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl; and acid-addition salts thereof. As described more fully hereinbelow certain of these compounds are also useful as antiarrhythmic agents.

A further aspect of the invention resides in [(arylalkyl) amino]alkyl 4-YO-3-(lower alkylthio, lower alkylsulfinyl or lower alkylsuifonyl)phenyl ketones having Formula II hereinbelow; Q.

-CH-NH-C-(CH2)n-Ar ' r3 II wherein Rp R2, R3, n, Ar, Q and Y have the above-given meanings; and acid addition salts thereof.

These compounds are useful as intermediates in the preparation of the corresponding benSenemsthanols of Formula I hereinabove. As described more fully hereinbelow, certain of the ketones are also useful as antihypertensive or antiarrhythmic agents. 'ί ύ ti 3 £ Particular embodiments reside in the compounds of v- - Formulae I and II hereinabove wherein R^, R3, n, Q and Y have the previously indicated meanings and Ar is phenyl or phenyl having one or two lower alkyl, hydroxy or lower alkoxy.

The invention also deals with N-(arylalkyl)-2-[4-YO-3(lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl)phenyl]ethylamines having Formula III hereinbelow wherein Rj, Rj, R3, n, Ar, Q and Y have the previously indicated meanings; and acid-addition salts thereof.

These compounds are useful as antihypertensive agents and as more fully described hereinbelow, certain of them are also useful as antiarrhythmic agents.

The invention also deals with N-(arylalkyl)-2-chloro, bromo or iodo-2-[4-YO-3-(lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl)phenyl]ethylamines having Formula IV herein- wherein R^/ R2, £3» n, Ar, Q and Y have the previously indicated meanings; X is chloro, bromo or iodo; and acid-addition salts thereof.

These compounds are useful as intermediates in the preparation of the compounds of Formula III hereinabove. -7The benzenemethanols of formula I hereinabove can be prepared by reducing the aminoalkyl phenyl ketones having Formula II hereinabove. The aminoalkyl phenyl ketones of formula II can be prepared by reacting a haloketone having Formula V hereinbelow: wherein Q and Y have the previously given meanings and X is chloro, bromo or iodo, with an (arylalkyl)amlne having Formula VI hereinbelow: - Λ VI· wherein Rg, Rj, n and Ar have the previously given meanings.

The 3-(lower alkylsulfinyl)benzenemethanols of Formula I hereinabove, wherein Rj_, R2, ®3' n' and Y have the above given meanings and Q is lower alkylsulfinyl can be prepared by oxidizing the 3-(lower alkylthio)benzenemethanols of Formula I wherein Rj., R2, R3, n, Ar and Y have the above-given meanings and Q is lower alkylthio.

The 2-phanylethylamines of Formula III hereinabove can be prepared by reducing the 2-ohloro, bromo or iodo-2-phenylethylamines of Formula IV hereinabove.

The 2-[3-(lower alkylsulfinyl)phenyl]ethylamines of Formula IXI hereinabove, wherein Rj, R2, R3, n, Ar and Y have the. -8» 43631 previously indicated meanings and Q is lower alkylsulfinyl, can be prepared by oxidizing the 2-[3-(lower alkylthio)phenyl]ethylamines of Formula III wherein Rj_, R2, R3' n» Ar and Y have the previously indicated meanings and Q is lower alkylthio.

The 2-chloro, bromo or iodo-2-phenylethylamines of Formula IV can be prepared by reacting a benzenemethanol of Formula I hereinabove with a halogen acid KX or an inorganic acid chloride or bromide.

One can reduce blood pressure in mammals by administer10 ing to said mammals a blood pressure lowering effective amount of a benzenemethanol of Formula I hereinabove. One can produce vasodilation in mammals by administering to said mammals, in an amount effective to produce vasodilation, a benzenemethanol of Formula I hereinabove. One can reduce blood pressure in mammals by administering to said mammals a blood pressure lowering effective amount of a compound of Formula HI hereinabove.

In the terms lower alkyl, lower alkoxy, lower alkylth lower alkylsulfinyl and lower alkylsulfonylLlower denotes an alkyl moiety having from 1 to 4 carbon atoms which can he arranged as straight or branched chains. There are included methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl, methyl and ethyl being preferred.

By lower alkanoyl is meant straight or branchedchain alkanoyl radicals containing from 1 to 6 carbon atoms as illustrated by formyl, acetyl, propionyl, butyryl, isobutyryl, pivalyl, caproyl -94 3 6 31 The. term halo as used herein denotes fluoro, chloro', bromo or iodo.

The term aroyl as used herein is intended to include benzoyl and benzoyl substituted by from one to two lower alkyl groups, for example: o-toluyl, m-toluyl, ptoluyl, 3,4-dimethylbenzoyl, 3,5~dimethylbenzoyl 2,5and dlmethylbenzoyl, m-lsopropylbenzoyl,/p-tert-butylbenzoyl It will be appreciated that Y in Formula I and II can represent acyl residues other than the above since it is well known that such esters undergo hydrolytic cleavage under physiological conditions to produce in situ the parent phenols which, of course, have the previously indicated biological activity.

As used herein toluenesulfonyl is intended to include ortho, meta and para-toluenesulfonyl.

The benzenemethanols represented by Formula I hereinabove are obtained by reducing the aminoaikyl phenyl ketones of Formula II with an appropriate reducing agent in a suitable solvent as for example sodium borohydride or lithium borohydride in water or a lower alkahol; lithium aluminum hydride in ether, tetrahydrofuran or dioxane; diborane in tetrahydrofuran or diglyme; aluminum isopropoxide in 2-propanol; or by hydrogenation ih the presence of a noble metal catalyst such as palladium or platinum. .

When the aminoaikyl phenyl ketone contains a carboxylic ester group (Formula II wherein Y is lower alkanoyl -104 3 6 31 or aroyl), and it is desired to retain the ester group in the reduction product (Formula I wherein Y is lower alkanoyl or aroyl), the use of reducing means resulting in reduction of carboxylic ester groups should of course be avoided. Accordingly in such instances reduction is preferably effected with an alkali metal borohydride or by catalytic hydrogenation which reducing means result in selective reduction of the ketone function. When the ultimately desired product is the free phenol (Formula I wherein Y is hydrogen) the above reduction reaction can be followed by hydrolysis of the ester group, or alternatively, the esterified aminoalkyl phenyl ketone (Formula II wherein Y is lower alkanoyl or aroyl) can be reduced with a reagent capable of reducing both ketone and carboxylic ester functions e.g. lithium aluminum hydride.

The borohydride reduction method is conveniently carried out by treating the aminoalkyl phenyl ketone withsodium borohydride in methanol at about -10"C. to 650 c. for approximately 15 minutes to 2.5 hours or until reduction is substantially complete as indicated by thin layer chromatography. If the starting material contains an ester group (Formula II wherein Y is lower alkanoyl or aroyl) and it is desired to retain the latter in the final product, the reaction mixture is quenched with acid and the esterified benzenemethanol (Formula I wherein Y is lower alkanoyl or aroyl)is isolated in conventional fashion. If on the other hand the free phenol (Formula I wherein Y is hydrogen) is desired the reaction mixture is treated with an equivalent of sodium or potassium hydroxide in water and stirred at -1145631 about 20°C. to 65°C. for approximately 50 minutes to 15 . hours. The resulting phenol is isolated in a conventional manner.

The catalytic hydrogenation process is conveniently carried out in a suitable solvent, for example Ν,Ν-dimethylformamide, at 20oC.-50°C. under a hydrogen pressure of from 20-50 p.s.i. in the presence of a noble metal catalyst such as palladium. The hydrogenation.is continued until the theoretical amount of hydrogen is absorbed. After removal of the catalyst, the reduction product is isolated In conventional fashion.

Although the 5-(lower alkylsulfinyl)benzenemethanols (Formula I wherein Q is lower alkylsulfinyl)' can be obtained by reducing the corresponding ketones (Formula II wherein Q is lower alkylsulfinyl) according to the foregoing procedures, it is ordinarily preferred to prepare the sulfinyl compounds by oxidizing the corresponding 3-(lower alkylthio)benzenemethanols (Formula I wherein Q is lower alkylthio) with an appropriate oxidizing agent such as a peraeid, hydrogen peroxide or sodium metaperiodate.

The oxidation is preferably carried out by treating the 5-(lower alkylthio)benzenemethanol with commercial 50# peracetic acid in methanol at about -I0°C. to 10°C. for approximately 15 minutes to 1.5 hours or until oxidation is substantially complete as Indicated by thin layer chromatography.

Alternatively, oxidation is effected with 50# hydrogen peroxide in methanol at about 20eC. to 65°c. for from 24 to 72 hours or until oxidation is substantially 1 complete as indicated by thin layer chromatography. The oxidation product is isolated according to conventional methods. >12· The aminoalkyl phenyl ketones of Formula II herein above can be obtained by reacting a haloketone of Formula V with an excess of an ferylalkyl)amine of Formula VI in a suitable solvent such as acetonitrile, dimethylsulfoxide, or N,N-dimethy15 formamide at about -65°C. to 25eC. for from 1 to 4 hours or until the reaction is substantially complete as indicated by thin layer chromatography.

In those instances wherein Y in Formula V is lower alkanoyl or aroyl, reaction with an (arylalkyl)amine may result in partial cleavage of. the ester function, or the ester of Formula II (i.e., when Y is as defined above) can be hydrolysed to the free phenol in a separate step. When desired the partially deacylated or hydrolyzed product, can be re-esterified according to known procedures for example with an acyl halide in the presence of a strong acid such as trifluoroacetic aeid.

Similarly one can convert a free phenol of Formula I or III to the corresponding ester by such esterification.

Although the 3-(lower alkylsulfinylJphenyl ketones (Formula II wherein Q is lower alkylsulfinyl) can be obtained 20 by reacting a haloketone of Formula V wherein Q is lower alkylsulfinyl.· with an appropriate (arylalkyl)amine of Formula VJ it ls generally preferred to prepare the 3-( lower alkylsulfinyl Jphenyl ketones of Formula ll by oxidation of ths -1343631 corresponding sulfides (Formula II, Q is lower alkylthio) as described hereinabove for the preparation of the 3-(lower alkylsulfinyl)benzenemethanols (Formula I wherein Q is lower alkylsulfinyl).' The (arylalkyl)amines of Formula vi are generally known, or if specifically new are obtained according to the procedures described for the preparation of the known compounds Thus for example tertiary carbinamines, i.e. , (arylalkyl)amines of Formula VI wherein both Rg and Rj are ' lower alkyl can be obtained from the corresponding generally known tertiary carbinols via the well known Ritter reaction [Organic Reactions‘17, 213 (1969)1 followed by hydrolysis of the resulting tertiary carbinamides.

(Arylalkyl)amlnea of FormulaVI wherein one of or both Rg and R^ are hydrogen can be obtained by reaction of an aldehyde or ketone of appropriate carbon content with ammonia or an ammonia derivative in accordance with the procedures described in Organic Reactions 4, 174 (1948) and Organic Reactions Jj, 301 (1949).

The haloketohes of Formula V are obtained by halogenating with chlorine or bromine the appropriate phenyl ketone having the Formula VII hereinbelow! wherein Rx and Q have the previously given meanings and Y is 25 methyl, lower alkanoyl or aroyl. The reaction is conveniently "1443631 carried out by treating the ketone of Formula VII in an inert solvent such as chloroform with bromine at approximately 25°C. optionally in the presence of an inorganic base, e.g. calcium carbonate. The reaction generally has an Induction period and in certain instances it may be advantageous to initiate the reaction by exposing the mixture to ultraviolet radiation until bromination has commenced as evidenced by decolori2ation and concomitant evolution of hydrogen bromide. If desired the Y substituent of the resulting haloketone can be removed according to well known procedures, for example by ester hydrolysis when Y is lower alkanoyl or aroyl and by O-demethylatlon with a Lewis acid such as aluminum chloride, hydrogen bromide or boron trlbromlde when Y is methyl.

The corresponding iodoketones (Formula V wherein X is iodo) can be obtained by reacting the chloro or bromoketones with sodium or potassium iodide in acetone under the conditions of the well known Finkelstein reaction.

The phenyl ketones of Formula VII hereinabove can be obtained by a variety of procedures which are generally known in the art.

Thus for example the 2-(lower alkylthio)phenyl ketones of Formula VII wherein Q Is lower alkylthio and Y is lower alkanoyl or aroyl are obtained by alkylation of the parent 2-mercapto-4-hydroxyphenyl ketones (Formula VII wherein Q is mercapto and Y is hydrogen) with an appropriate lower alkyl halide in a suitable solvent such as a lower alkanone in the presence of an acid acceptor, e.g. an alkali metal carbonate, followed by esterification of the resulting 5-154 5 6 31 (lower alkylthio)-4-hydroxyphenyl ketones (Formula vii wherein Q is lower alkylthio and Y is hydrogen) with an appropriate acylating agent such as a lower alkanoyl or aroyl halide or anhydride in an inert solvent such as methylene chloride, chloroform, benzene or toluene in the presence of an acid acceptor such as triethylamine or pyridine. The 3-mebcapto4-hydroxyphenyl ketones are in turn obtained by chlorosulfonation of the generally known 4-hydroxyjhhenyl ketones of Formula VII wherein Q and Y are hydrogen with excess chlorosulfonic acid at about 0°C. to 25°C. preferably in the absence of a solvent followed by reduction of the resulting 3chlorosulfonyl-4-hydroxyphenyl ketones with a suitable reducing agent such as stannous chloride and hydrochloric acid or zinc and sulfuric acid.

Alternatively the 3-(lower alkylthio)phenyl ketones of Formula VII wherein Q is lower alkylthio and Y is lower alkanoyl can be obtained by acylating the generally known o(lower alkylthlo)phenols with an appropriate acyl halide (e»g.. RjCHgCOClj) under Friedel-Crafts conditions followed by esterification of the resulting 3-(lower alkylthio)-4hydroxyphenyl ketones as described above.

It will be appreciated that although the 3-(lower alkylsulfinyl)phenyl ketones of Formula VII can be obtained by oxidizing the corresponding sulfides (Formula V wherein Q is low&r alkylthio) it is generally preferred to employ the latter as a starting material and to carry out any desired oxidation of sulfide to sulfoxide at a later stage in the synthesis as previously described. -1648631 The 3-(lower alkylsulfonyljphenyl ketones of Formula VII wherein Q is lower alkylsulfonyl and Y is methyl are obtained by oxidizing the 3-(lower alkylsulfonyl)*anisoles of Formula VIII hereinhelow: wherein R^ has the previously given meaning and Q is lower alkylsulfonyl with an appropriate oxidizing reagent suoh as ammonium persulfate in the presence of silver nitrate in aqueous medium in the approximate temperature range 20’C. to 70°C. for about 2 to 3 hours. In turn the 3-(lower alkylsulfonyl)anisoles are obtained by sulfonating the generally known anisoles of Formula VIII wherein Q Is hydrogen with an appropriate lower alkylsulfonlc anhydride in an inert solvent, e.g. sym-tetrachloroethane at about 130°C. to l8o°C.

The 2-phenylethylamines of Formula III hereinabove -17.V 43631 be obtained by reducing a 2-halo-2~phenylethylamine of Formula jV with a suitable reducing agent such as lithium aluminum Λ hydride in ether, tetrahydrofuran or dj'oxane, sodium borohydride in a lower alkanol or Ν,Ν-dimethylformamide; or by catalytic hydrogenation.

Reduction is conveniently achieved employing sodium borohydride in Ν,Ν-dimethylformamide at -10°C. to 25°C. for about 0.25 to.2 hours or until.the reaction is substantially complete as indicated by thin layer chromatography.

Of course, when the 2-halo-2-phenylethylamine contains another reducible function such as an ester group (e.g., Formula IV wherein Y is lower alkanoyl or aroyl) and it is desired to retain such function in the reduction product, the precautions described hereinabove for reducing the aminoaikyl phenyl ketone (Formula II) should be taken. Similarly, if the free phenol (Formula III where Y is hydrogen) is desired, an esterified product obtained (Formula III where Y is lower alkanoyl or aroyl) is hydrolyzed with a base.

The 2-halo-2-phenylethylamines of Formula IV herein20 above are obtained by reaction of an appropriate benzenemethanol of Formula I with a halogen aoid Or an inorganic acid halide in a suitable solvent, e.g., hydrogen chloride in tetrahydrofuren or dioxane, hydrogen bromide in acetic acid, sodium or potassium iodide in phosphoric acid, thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride or phosphorus tribromide in benzene, toluene, chloroform or pyridine.

Although the 2-phenylethylamines of Formula III Wherein Q is lower alkylsulfinyl can be obtained by the above-described sequence of halogenation of the appropriate benzenemethanol (Formula I wherein Q is lower alkylsulfinyl) followed by reduction of the -184 3 6 31 resulting halo compound (Formula XV wherein Q is lower alkylsulfinyl) , it is ordinarily preferred to carry out the successive halogenation and reduction starting with the corresponding lower alkylthio benzenemethanol (Formula I wherein Q is lower alkyl5 thio) and then oxidizing in the last step to the desired lower alkylsulfinyl compound. The oxidation is carried out in accordance with the methods earlier described for the preparation of the benzenemethanols of Formula I wherein Q is lower alkylsulfinyl.

Due to the- presence of the basic amino grouping, the free base forms of the final products represented by Formulae I and III and also of the intermediates represented hy Formulae II and IV react with organic and inorganic acids to form acid-addition salts. The compounds of the invention are useful both in the free base form and in the form of acidaddition salts, and both forms are within the purview of the invention. The acid-addition salts are simply a more convenient form for use, and in practice, use of the salt form inherently amounts to use of the base form. -1943631 The acid-addition salte are prepared from any organic or inorganic acid. They are obtained in conventional fashion, for instance either by direct mixing of the base with the acid, or, when this 1b not appropriate, by dissolving either or both the base and the acid separately in water or an organic solvent and mixing the two solutions, or by dissolving both the base and the acid together in a solvent. The resulting acid-addition salt is isolated by filtration, if it is insoluble in the reaction medium, or by evaporation of the reaction medium to leave the acidaddition salt as- a residue. The acid moieties or anions in these salt forms are in themselves neither novel nor critical and therefore can be any acid anion.or acid-like substance capable of salt formation with the base.

Representative acids for the formation of the acid-addition salts Include formic acid, acetic acid, ieobutyrlc acid, alpha-mercaptopr'&pionle acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succlnamic acid, tannic acid, glutamic acid, tartaric acid, dibenzoyltartaric acid, oxalic acid, pyromueic acid, citric acid, lactic aeid, mandelic acid, glycolic acid, gluconic acid, saccharic acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid, anthranilic acid, cholic acid, 2-pyridinecarboxyllc acid, pamoic acid, 3-hydroxy-g-naphthoic acid, picric acid, quinic acid, tropic acid, 3-indoleacetic acid, barbituric acid, cyclohexyl8Ulfamlc acid, isethionic acid, methane-204S631 sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1,4-naphthalenedisulfonic acid, butylarsonic acid, methanephosphonic acid, acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, sulfamic acid, glutaric acid, phosphoric acid, arsenic acid.

All the acid-addition salts are useful as sources of the free base form, by reaction with an inorganic base.

It will thus be appreciated that lf one or more of the characteristics such as solubility, crystallinity molecular weight, physical appearance, toxicity, or the like of a given base or acid-addition salt thereof render that form unsuitable for the purpose at hand it can be readily converted, in accordance with procedures well known in the art, to another more suitable form.

When the compounds of the invention are to be utilised for pharmaceutical purposes, the acids used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, medicinally acceptable salte, that is, salts whose anions are relatively Innocuous to the animal organism in medicinal doBes of the salts so that the beneficial properties inherent in the free base are not vitiated by side effects ascribable te the anions. Appropriate medicinally acceptable salts within the scope of the invention are those derived from acids such as hydrochloric acid, acetic acid, lactic acid, tartaric acid, cyclohexylsulfamic acid, methanesulfonic acid, phosphoric acid and the like.

The compounds of the invention respresented by Formulas 1-JV wherein Y is hydrogen are of course 2l· amphoteric, having both acidic phenol and baBlc amino groups, and thus form salts with both acids and bases.

Due to the presence of at least one and as many as four asymmetric centers in the compounds of the invention represented by Formula I (i.e. the carbinol carbon atom,· the carbon -atom to-which R^’when lower-alkyl-is attached, the carbon atom to whieh Rg and R-j when dissimilar are attached, and the sulfur atom when Q is lower alkylsulfinyl), said compounds can. exist in as many as 16 stereochemically isomeric forms, all of which either individually or as mixtures of any two or more are considered within the purview of this invention. If desired, the isolation or the production of a particular stereochemical form or of a mixture of two or more Stereochemical forms can be accomplished by application of general principles known in the art.

YJhen preparing either a particular stereoisomer or a specific mixture of any two or more stereoisomers it is advantageous to employ intermediates of fixed stereo20 chemical configuration thereby limiting the number of stereoisomeric forms present in the final product and thus simplifying isolation of the desired components. Accordingly prior to reaction with a haloketone of Formula V an (arylalkyl)amine of Formula VI containing an asymmetric center (i.e. the carbon bearing non-identical substituents Rg and R^) is resolved into its (+) and (-) optical antipodes according to conventional techniques and employing conventional resolving agents such as optically active tartaric acid, 0,0dibenzoyl tartaric acid, mandelie acid, malic acid, and -2243631 the like. As desired, either the (+) or the. (-)-(arylalkyl)amlne can then be reacted with a haloketone according to the previously described procedure to produce an amlnoalkyl phenyl ketone of Formula II having a fixed stereochemical configuration at the carbon bearing substituents Rg and R^. .

When the haloketone also contains an asymmetric center (Formula V · wherein R, is lower alkyl and Q is lower alkylthio or lower alkylsulfonyl) reaction with either the (+) or (~)-(arylalkyl)amine produces a pair of diastereomeric aminoalkyl phenyl ketones of Formula II (?U is lower alkyl, Q is lower alkylthio or lower alkylsulfonyl) which can be separated according to conventional methods, e.g. fractional crystallization of a suitable acid addition salt.

Of course when the haloketone contains no asymmetric center (Formula V wherein R^ is hydrogen and Q ia lower alkylthio or lower alkylsulfonyl) reaction with either the (+) or (-)-(arylalkyl)amine produces directly a single (+) or (-) stereoisomer of the aminoalkyl phenyl ketone of Formula II (R^ is hydrogen and Q is lower alkylthio or lower alkylsulfonyl).

Reduction of the ctereochemi cally fixed aminq,alkyl phenyl ketone as described hereinabove creates a new asymmetric center (i.e. the carbinol carbon atom) and therefore produces a pair of diastereomeric 5-(lower alkylthio or lower alkylsulfonyl)benzenemethanols of Formula I. if desired the diastereomers can be separated according to known methods, for example, by fractional crystallization -235· 3 6 31 of the acid-addition salt of an optically active acid such as ( + ) or .(-) mandelic acid, tartaric acid, 0,0-dibenzoyltartaric acid, malic acid and the like, or by converting the diastereomeric mixture’to a suitable ester derivative (i.e. Y in Formula I is lower alkanoyl, aroyl, benzenesulfonyl or £-toluenesulfonyl) e.g. the acetate, benzoate, or £-toluenesulfonate and separating the esters by chromatography or by fractional crystallization of a suitable acid-addition salt thereof.

Each of the individual diastereomers of the J(lower alkylthio)benzenemethanol (Formula I, wherein Q is lower alkylthio) as febove-produced can be oxidized as described hereinabove again giving rise to a new center of asymmetry (i.e. the sulfur atom) and producing thereby a pair of diastereomeric sulfoxides (Formula I, Q is lower alkylsulfinyl) which also can be separated in accordance with the conventional procedures described above.

Alternatively the pair of diastereomeric 3(lower alkylthio)benzenemethanols can be oxidized directly to give a mixture of four diastereomeric sulfoxides which if desired can also be separated according to the abovedescribed procedures, for example by fractional crystallization of a suitable acid-addition salt such as the hydrochloride or cyclohexylsulfamate.

The 2-phenylethylamine of Fornula III, having three potential centers of asymmetry, can thus exist in as many as 8 stereochemically isomeric forms. All such forms either individually or as mixtures of any two or more are, of course, considered within the ambit of the present invention. The production of a particular isomer or mixture of isomers is most -2443631 conveniently achieved by starting with a benzenemethanol of Formula I having the desired stereochemistry as obtained in accordance with the above-described procedures.

The compounds of fche present invention having Formula I hereinabove' exhibit useful antihypertensive, vasodilator and β-adrenergic blocking activity. Of particular advantage is the combination in a single.compound of vasodilator and β-adrenergic blocking activity whereby 2545631 the reflex tachycardia associated with the reduction in blood pressure through vasodilation is effectively reduced or eliminated by β-adrenergic blockade. The compounds are therefore effective in lowering blood pressure without causing undesirable tachycardic effects.

It should be noted, however,, that although both vasodilator and β-adrenergic blocking activity reside in the same compound, the time of onset of each of these actions appears to be somewhat different, vasodilation usually preceding β-adrenergic blockade. This can of course give rise- to a moderate transient increase in heart rate observable on the first day or too of repeated medication. Thereafter, however, β-adrenergic blockade takes full effect and subsequent continuous medication effects sustained blood pressure lowering with no appreciable elevation of heart rate. Moreover as opposed to the antihypertensive response which Ib directly dose-related, the heart rate elevation observed at the lower doses tested is not appreciably Increased either in magnitude or in duration at higher doses. It is therefore possible to raise the dosage level in order to achieve a further reduction in blood pressure without causing a corresponding Increase in heart rate.

A preferred embodiment of this invention is 4hydroxy-a-^3-(4-methoxyphenyl)-l-methylpropyl]aminoj~ methyl>-3-(methylsulfinyl)benzsnemethanol (Formula I wherein Rj, Rg and Y are hydrogen; Rj is methyl; n is 2, Ar lq 4-aethoxyphenyl; and Q is methylsulfinyl) which has high antihypertensive activity and a particularly effective -263 6 3 ί distribution of vasodilator and β-adrenergic blocking activity and is accordingly especially efficacious as an antihypertensive agent with no undesirable tachycardic side effects.

The above-described compound contains three centers of asymmetry (i.e. the carbon atom bearing the methyl group, the carbinol carbon atom, and the sulfur atom) and can therefore exist as a mixture of up to eight stereoisomers. Particularly preferred among these are the four diastereomers derived from (+)-41-hydroxy-2- {[3-(4methoxyphenyl)-1-methylpropyljamino}-?'-(methylthio)acetophenone (Formula II wherein R^, Rg and Y are hydrogen; Rj is methyl; n is 2; Ar is 4-methoxyphenyl,· and Q is methylthio) by reduction of the carbonyl group followed by oxidation of the methylthio group. These isomers either individually or as mixtures of any two or more exhibit potent antihypertensive activity with no undesirable tachycardic side effects. Although each of the four diastereomers can be separated from the mixture as described hereinabove this is generally unnecessary and it is therefore economically advantageous to use the mixture as produced, In carrying out the method aspect of this invention, i.e. the method of reducing hypertension in mammals which comprises administering to said mammals an antihypertensive ly - effective amount of a compound having Formula , in a suitable pharmaceutical composition, e.g., I, said compounds can be administerecT7orally in the form of pills, tablets, capsules, e.g. in admixture with talc, starch, milk sugar or other inert, i.e. non-toxic or pharmacologically acceptable pharmaceutical carrier, or in the -274 3 6 31 form of aqueous solutions, suspensions, encapsulated suspensions, gels, elixirs, aqueous alcoholic solutions, e.g. in admixture with sugar or other sweetening agents, flavorings, colorants, thickeners and other conventional pharmaceutical excipients..

When Injected subcutaneously, intramuscularly, or intravenously, they can be administered, e.g., as an aqueous or peanut oil solution or suspension using excipients and carriers- conventional for this mode of administration. The best route of administration and the best dosage will be apparent from the laboratory,, tests for activity and toxicity of the selected compound -conventionally undertaken as part of the development phase of a pharmaceutical.

The molecular structures of the compounds of the invention were assigned on the basis of the method of their preparation and study of their IR and NMR spectra, and confirmed by the correspondence between calculated and found values for the elemental analyses of representative examples.

The identity and purity of individual stereoisomers as well as the composition of stereoisomeric mixtures were determined on the basis of optical rotation and high pressure liquid chromatography.

The invention is illustrated by the following examples without, however, being limited thereto. Unless otherwise specified optical rotations were determined on a 2% solution of the compound in methanol.

Example 1 A. To 100 g. (Ο.Ο85 mole) of chlorosulfonic acid at °C. was added over a period of 25 minutes 20 g. (0.15 mole) of jo-hydroxyacetophenone. The temperature was allowed -2843 832 to gradually rise to 22eC. as the reaction was stirred overnight. The temperature was then raised to 55-6o°C. and stirring was continued an additional hour. The reaction mixture was quenched in ice-water and the precipitated solid was collected and washed with water. The product was dissolved in ethyl acetate and the resulting solution was dried and evaporated to dryness. The residue was recrystallized from benzene to give 12.5 g. of 4'-hydroxy-3'"(chlorosulfonyl)acetophenone, m.p. 138-l42°C. The filtrate afforded a second crop of 5-0 g., m.p. 124-136*0.

B. Hydrogen chloride was bubbled into a stirred mixture containing 105 g. (0.46 mole) of stannous chloride dihydrate and 400 ml. of glacial acetic acid until a nearly clear solution was obtained. To the latter solution was added portionwise over 20 minutes 18 g. (0.077 mole) of crude 4'-hydroxy-2'-(chlorosulfonyl)acetophenone while the temperature was maintained at 25-30"C. After the addition was complete sitrring was continued an additional 0.5 hours.

The reaction mixture was then poured into 400 »1. of 12N hydrochloric acid, diluted with 800 ml. of water and extracted with chloroform. The extracts were washed with saturated aqueous sodium chloride and evaporated to dryness. The residue was recrystallized from benzene to give 4 g. of 4-hydroxy-3i-mercaptcaeetophenone, m.p. 117-120eC. 0. A mixture containing 1.0 g, (0.006 mole) of 4'hydroxy-2,-mercaptoacetophenone, 0.9 g. (0.0063 mole) of methyl iodide, 0.83 g. (0.006 mole) of potassium carbonate and 12 ml. of acetone was stirred 2.5 hours at room temperature. The reaction mixture was filtered and the filtrate 29S631 evaporated to dryness. The residue was dissolved in chloroform and the resulting solution was washed with IN hydrochloric acid, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in hot benzene and the solution was filtered through a 1/4 pad of silica gel in order to remove a colored impurity. Evaporation of the filtrate afforded 0.9 g. of 4'-hydroxy3'-(methylthio)acetophenone, m.p. 117-120°C.

D. Alternatively, to a stirred solution containing 61.4 g. (0.435 mole) of o-(methylthio)phenol and 35 g. (0.45 mole) of acetyl chloride in 170 ml. of nitrobenzene was added portionwise over a period of 20 minutes 80 g. (0.60 mole) of aluminum chloride. The reaction mixture was stirred overnight at room temperature and then one hr. at 65°C. The reaction mixture was cooled, diluted with Ice and water and extracted with methylene chloride. The organic extracts were evaporated in vacuo, the residue diluted with ether and allowed to stand two days in the refrigerator. The precipitated product was collected and dried to give 27 g. of 4'-hydroxy-3’-(methylthio)acetophenone.

E. To a cooled, stirred solution containing 24.5 g· (0.134 mole) of 4'-hydroxy-3u;(methylthlo)aGetophenone and 21 g. (0.21 mole) of triethylamine in 400 ml, of methylene chloride was added dropwise over a period of 30 minutes 16.4 g. (0.21 mole) of acetyl chloride. After stirring overnight at room temperature the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated to a small volume. The concentrate was -3045631 diluted with ether and cooled in an ice bath. The resulting precipitate was collected to give 23.5 S· of 4'-hydroxy3'-(methylthio)acetophenone 4'-acetate.

F. To a stirred mixture containing 23.2 g„ (0.108 mole) of 4'-hydPoxy-3'-(methylthio)acetophenone 4'acetate and 9 g. of calcium carbonate in 300 ml. of chloroform was added dropwise over a pex’iod of two hours a solution containing 6 ml. (0.108 mole) of bromine in 30 ml. of chloroform. The reaction mixture was filtered, and the filtrate washed with saturated aqueous sodium bicarbonate, and evaporated to dryness. The residue was dissolved in ether and the ethereal solution diluted with cyclohexane and cooled in ice. The resulting precipitate was collected and dried to give 2β·5 g. of 2-bromo-4'-hydroxy-31(methylthio)aeetophenone 4'-acetate.

G. To a stirred solution containing 16.5 g. (o.lo mole) of 2-(4-methoxyphenyl)-l-methylethylamine and 5 g. (0.051 mole) of triethylamine in 40 ml. of N,N-dimethylforraamide at -65°C. was added dropwise over a period of 2 hours 15,5 g. (0.051 mole) of 2-bromo-4'-hydroxy-3 (methylthio)acetophenone 4'-aoetate in 40 ml. of N,Ndimethylformamlde. After the addition was complete stirring at -65°0. was continued an additional hour. The reaction mixture was then acidified with 10 ml. of 12N hydrochloric acid and diluted with 100 ml. of water.· Upon shaking the aqueous solution with 200 ml. of a 2si mixture of ether-methylene chloride the product began to precipitate from the aqueous phase. The layers were separated and the aqueous portion was cooled in ice. The resulting precipitate -3143631 was collected and dried 3 hours over phosphorous pentoxide in a 650 vacuum oven to give 12.1 g. of 4'-hydroxy-2-£[2(4-methoxyphenyl)-l-methylethyl]amino} -3'-(methylthio)acetophenone 4'-acetate hydrochloride.

Example 2 A stirred solution containing 12.5 g. (0.029 mole) of 4'-hydroxy-2-{[2-(4-methoxyphenyl)-l-methylethyl]- amino}-3'-(methylthio)acetophenone 4’-acetate hydrochloride in 200 ml. of methanol was cooled in an ice-acetone bat;h and treated portionwise over 15 minutes with 0.9 g. of sodium horohydride. After the addition was complete stirring wae continued an additional 20 minutes. The reaction mixture was then brought to pH 7 with glacial acetic acid and evaporated to dryness. The residue was diluted with ether and washed thoroughly with saturated aqueous sodium bicarbonate. The ethereal solution was dried over anhydrous sodium sulfate and concentrated to a small volume. The concentrate wae acidified with ethereal hydrogen chloride andt esoled overnight in a refrigerator. The precipitated product was collected and recrystallized from methanolisopropyl alcohol to give 2.1 g. of 4-hydroxy-e-<^f[2"(4methoxyphenyl-l-methylethyl]amino|methyl>-3-(methylthio)benzenemethanol 4-acetate hydrochloride, m.p. l43-l45°C.

In addition to its antihypertensive activity this compound was also found to possess β-adrenergic stimulant activity as evidenced by its ability to block histamineinduced bronchoconstriction in the dog. -3245631 Example 3 To a stirred suspension of 6.9 g. (0,016 mole) of 4'-hydroxy-2"{[2-(4-methoxyphenyl)-l-methylethyl3aminoJ2'-(methylthlo)acetophenone 4'-acetate hydrochloride In 120 ml. of methanol was added 400 mg. of sodium borohydride.. After 25 minutes all the starting material had gone into solution. The reaction mixture was treated with 10 ml. of water snd stirred overnight at room temperature. A solution containing 900 mg. of potassium hydroxide in 10 ml. of water was then added and the mixture heated under reflux 0.5 hour. The resulting solution was concentrated to one half volume, the concentrate made slightly acidic with 12N hydrochloric acid and evaporated nearly to dryness. The residue was dilutddvwith saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate, acidified with glacial acetic acid, and concentrated until crystallization began. The product was collected, triturated with chloroform and finally recrystallized from chloroformmethanol to give 5.9 g. of 4-hydroxy-a- <^[2 -(4-methoxyphenyl)-l-methylethyljamlno|methy l>-5"(methylthio)benzenemethanol acetate salt, m.p. 165-165°C.

Example 4 A solution containing 1.5 ml. of 30# hydrogen peroxide and the free base liberated' from 9 g of 4hydroxy-a-<£[2-(4-methoxyphenyl)-l-methylethyl]aminojmethy 3>5-(methylthio)benzenemethanol 4-acefcste hydrochloride in 150 ml. of methanol wee stirred 2 days at room temperature -33- 42631 and then 1.5 hours at reflux. The reaction mixture was then evaporated to dryness. The residue was dissolved in water, and the solution filtered to remove insoluble impurities.

The filtrate was acidified with 12N hydrochloric acid and evaporated to dryness. The residue was triturated with ether-isopropyl acetate at -65°C. The resulting amorphous solid was dissolved in hot Water, filtered to remove Ineoluble impurities, and the filtrate evaporated to dryness. The residue was triturated with ether and cyclohexane and the resulting solid was collected and dried over phosphorus pentoxide. 6 hours at 85°C. affording 4.6 g. of 4-hydroxy-a<{[2-(4-methoxyphenyl)-1-methylethyl]amlno}methy3>-3~(methylsulfinyl) benzenemethanol hydrochloride as an amorphous tan solid, m.p. 115eC.

In addition to its antihypertensive activity this compound was also found to possess β-adrenergic stimulant activity as evidenced by its ability to block histamineinduced bronchoconstriction in the dog.

Example 5 A. A solution containing 65 g. of £-ethylanisole and g. of methanesulfonic anhydride in 300 ml. of symtetrachloroethaiie was heated under reflux 17.5 hours. After washing with hot water the reaction mixture was evaporated to drynees in vacuo leaving 20 g. of dark oil which was combined with the.product of two previous runs and distilled under reduced pressure. The fraction boiling at 90-120°C./0,5 mm. was collected and redistilled through a short Vigreux column. The im^rities boiling at 45-65*0,/0,5 mm. were discarded and the pot residue waa redistilled. The impurities boiling at 175-187°C./10 mm. were discarded leaving 30 g. of nearly pure 4-ethyl-2-(methylBulfonyl)anIsole. -344 ci ό 3 i B. A solution containing 55 g. (0.242 mole) of ammonium persulfate, 520 mg. of silver nitrate and 26 g. (0.121 mole) of 4-ethyl-2-(methylsulfonyl)anisole in 300 ml. of water was stirred at 20°C. After one hour the temperature had risen to 48°C. and after 2.5 hours had dropped to 30°C.

The product was extracted with chloroform and after drying over anhydrous sodium sulfate the chloroform extracts were evaporated to dryness. The residue was adsorbed on a column of silica gel deactivated with 20% by weight of water. Impurities were washed from the column with ether and the product was eluted with hot methylene chloride to give 18 g. of 4,-methoxy-3l-(methylsulfonyl)acetophenone, m.p. 146-148°C.

C. To a solution containing 14.5 g. (0.063 mole) of 4'-.iietnoxy-3'-(methylsulfonyl)acetophenone in 200 ml. of chloroform was added dropwise a solution containing 10.2 g. of bromine in 40 ml. of chloroform. After a 0.5-hr. induction period the bromine began to be consumed. When the addition was nearly complete the product began to precipitate. The reaction mixture was diluted with methylene chloride and the resulting solution washed successively with saturated aqueous sodium bicarbonate and water and evaporated to dryness.. Recrystallization of the residue from methylene chloridecarbon tetrachloride afforded 17.9 g. of 2-bromo-4'-methoxy3'-(mathylsulfonyl)aoetophenone, m.p. 168-17O°C.

D. A vigorously stirred mixture containing 4.5 g. of 2-bromo-4J—methoxy-3'-(methylBulfony'l)acetophenone, 4.5 g. of aluminum chloride and 100 ml. of chlorobenzene wa3 heated under reflux 2 hours. The reaction mixture was poured into ice-water and extracted with ether-ethyl acetate. The -3Ξ 631 organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residue was triturated with ether and the resulting tan crystalline solid was collected to give 3.0 g. of 2-bromoj-41-hydroxy-3'-(methylsulf onyl )acetophenone.

E. To a stirred solution containing 10 g. (0.06 mole) of 2-(4-methoxyphenyl)-l-methylethylamlne in 50 »1. of Ν,Ν-dimethylformamide at -30°C. (dry ice-carbon tetrachloride) was added dropwise a solution containing 7-g. (0.024 mole) of. 2-bromo-4'-hydroxy-3'-(methylsulfonyl)acetophenone in 20 ml. of Ν,Ν-dimethylformamide. After the addition was complete the.reaction mixture was stirred 2.75 houre at 0eC. and then diluted with water and extracted, with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, acidified with ethanolic hydrogen chloride and stored in a refrigerator overnight. The product which crystallized was colleoted and recrystallized from chloroform affording 3.7 g. of 4'-hydroxy-2-{[2-(4methoxypheny1)-l-methylethyl]aminoj-31-(methylaUlfonyl)acetophenone hydrochloride.

Example 6 A solution containing 3.7 g. of 4'-hydroxy-2-{[2(4-methoxyphenyl)-1-methylethyl]amlno}-5'-(methylsulfonyl)acetophenone hydrochloride in 100 ml. of Ν,Ν-dimethylformamide was hydrogenated under an initial hydrogen pressure of 50 p.s.i. in the presence of 1 g. of 10% palladium-onchsrcoal hydrogenation catalyst. After 15 minutes one molar equivalent of hydrogen had been absorbed. The catalyst was then removed by filtration and the filtrate evaporated to 3643631 dpyness. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to 100 ml. The concentrate was acidified with glacial acetic acid, concentrated to approximately 70 ml. and cooled. The resulting crystalline precipitate was collected to afford 2.9 g. of 4-hydroxy-a<{[2-(4-methoxyphenyl)-l-methylethylJsminoJ methy l>-3-(methylsulfonyl )benzenemethsnol acetate salt, m.p. 130-131°C.

Example 7 To a stirred solution containing 24 g. (0.135 mole) of 3-(4-raefchoxyphenyl)-l-methylpropylamine in 4o ml. of Ν,Ν-dimethylformamide at -50°0. was added dropwise over 15 minutes a solution containing 15 g. (0.05 mole) of 2-37' 43631 bromo-41-hydroxy-3'-(methylthio)acetophenone 4'-acetate In 35 ml. of Ν,Ν-dimethylformamide. After the addition was complete stirring was continued an'additional 1.25 hours. The reaction mixture was then treated with 4 ml. of 12N hydrochloric acid, diluted with 100 ml. of water and extracted with ether-ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate, acidified with ethanolic hydrogen chloride and evaporated to drynesB.

The crude product containing both the 4*-acetate and 4'10 hydroxy compounds was dissolved in a solution containing 10 ml. of acetyl chloride in 120 ml. of trifluoroacetic acid and stirred 2 hours at room temperature. The solution wae then evaporated to dryness and the residue partitioned between ether and water. The ether layer was dri15 anhydrous eodium sulfate and acidified with ethanolic hydrogen 38chloride. The resulting precipitate was collected and triturated with acetone-ether to give 6.0 g. of 4'-hydroxy-2{[?-(4-methoxyphenyl)-l-methylpropyl]amlnoJ-31-(methylthio) acetophenone 4'-acetate hydrochloride, m.p. l6o-l65°C.

Example 8 To a stirred'mixture of 9.0 g. (0.021 mole) of 41-hydroxy-2 £[3-(4-rasthoxyphenyl)-l-inethylpropyl]aminoj-3'(methylthio)acetophenone 4'-acetate hydrochloride and 100 ml. of methanol at -5 to 0°C. there was added portlon10 wise 0.5 g. (0.015 mole) of sodium borohydride. After stirring an additional 0.5 hour, a solution containing 1.0 g. of potassium hydroxide in 10 ml. of water was added and the resulting mixture was stirred at room temperature under nitrogen overnight, and then at reflux 0,5 hour. The pH was adjusted to 7 with glacial acetic acid and the resulting solution was concentrated to a small volume, diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, acidified with glacial acetic acid, concentrated to a small volume and cooled. The product which separated was collected and recrystallized' from ethyl aeetataeethandl affording 7.2 g. of 4-hydroxy-K<{[3-(4-methoxyphenyl)-l-methylpropyl)amino}methyl>-3(methylthlo)benzenemethanQl acetate salt, m.p. 132-134°C.

Example 9 A. To a stirred solution containing 100 g. (0.55 mole) of 4'-hydroxy-3'-(methylthio)acetophenone in 600 ml. of -3945631 pyridine at 15-l8eC. there was added dropwise over one hour 68 ml. (0.58 mole) of benzoyl chloride. After addition was complete stirring was continued at room temperature for 1.5 hours. The reaction mixture was then quenched in l. 5 liters of ice-cold water. The solid which precipitated was collected by filtration, washed successively with water, cold 2-propanol, and n-hexane and dried to give 146 g. of 4'-hydroxy-3'-(methylthio)acetophenone 4'-benzoate, m.p. 126-131e0.

B. To a stirred suspension containing 145 g. (0.51 mole) of 4'-hydroxy-3’-(methyIthio)acetophenone 4'-benzoate in 1200 ml. of benzene at 20°C. was added 15 .ml. of a solution containing 85 g. (0.53 mole) of bromine in 100 ml. of benzene. .The .mixture was irradiated with uv light for about 1 hour in order to initiate the reaction. When the reaction commenced (as Indicated by decolorlzatlon) a slow stream of nitrogen was bubbled through the reaction mixture and the remainder of the bromine solution was added over a period of 2 hours while the temperature was maintained at 20-24’c. The. reaction mixture was stirred, an additional 0.5 hour and then oooled to 16®C. The solid which precipitated was collected by filtration, washed with water and n-hexane, and dried to give .90 g. of .2-bromo-4'-hydroxy-3 (methylthio)acetophenone. 4'-benzoate, m.p. 127-129’C. The benzene solution afforded an additional 21 g. of product m. p, 126-129’C. ’ 0. To a stirred eolution containing 36 g. (0.2 mole) of 3-(4-methoxyphenyl)-l-methylpropylamine in 175 «1· of Ν,Ν-dimethylformamide at-60°C. was added over one hour a -40.4 43631 solution containing 25 g, (0.068 mole) of 2-bromc-4'-hydroxy3'-(methylthio)acetophenone 4'-benzoate in 120 ml, of Ν,Νdimethylformamide. After the addition was complete stirring at -6o°C. was continued an additional 20 minutes. The reaction mixture was then diluted with 200 ml. of chloroform, treated with 20 ml. of 45% hydrogen oromioe and farther diluted with 200 ml. of cols water. The layers were separated and the aqueous layer was re-extracted with chloroform.

The organic layers were combined, washed with water, dried over anhydrous magnesium 3ulfate and concentrated to about 100 ml. The concentrate was diluted with 400 ml. of ether and cooled. The resulting precipitate wascollected by filtration, washed successively with cold 2-propanol and ether and dried to give 26 g. of 4'-hydroxy-2-£[3-(4methoxyphenyl)-1-methylpropyl]amlno}-3' - (methylthio)acetophenone 4'-benzoate hydrobromide.

Example 10 To a stirred mixture of 25 g. (0.046 mole) of 41-hydroxy-2-£(3-(4-me thoxyphenyl)-1-methylpropyl]aminoj-3'(methylthio)acetophenone 4'-benzoate hydrobromide and 160 ml. of methanol at 0°C. was added portionwise over 0.5 hour 1.4 g. (0.037 mole) of sodium borohydride. After stirring an additional 20 minutes the reaction mixture was treated with a solution containing 2.5 g. of potassium hydroxide in 30 ml. of water and heated under reflux·40 minutes. The reaction mixture was concentrated in vacuo until a cloudy suspension formed. The suspension was brought to pH 3 with 6n hydrochloric acid and then made basic with saturated aqueous sodium bicarbonate. The remaining methanol was removed by -4143631 evaporation In vacuo. The resulting suspension was diluted with 200 ml. of ethyl acetate and the resulting biphasic mixture was allowed to stand overnight. The solid which precipitated was collected, washed with water followed by n-pentane and recrystallized from 2-propanol to give 6 g. of 4-hydroxy-a-<£jf[3- (4-methoxyphenyl) - 1-methylpropylJamino} methy3>-3-(methylthio)benzenemethanol, m.p. 126-129°C.

The ethyl acetate layer in the filtrate was separated, washed successively with dilute aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The resulting solution was diluted with 120 ml. . of isopropyl acetate, treated with 3 ml. of glacial acetic acid, seeded and cooled. The resulting precipitate was collected, washed' with Isopropyl acetate and dried at 65*0. in vacuo affording 7 g. of product as the acetate Balt, m.p. 132-134°C.

Example 11 A. To a stirred solution containing 3.5 g. (0.0083 mole) of 4-hydroxy--3-(methylthio)benzenemethanol acetate salt in 100 ml. of methanol at -5°C. was-added dropwise over 0.5 hour a solution containing 630 mg. (0.0083 mole) of commercial 40% peracetic acid in 10 ml. of methanol.

When the addition was complete the reaction mixture was evaporated to dryness. The resulting oil was diluted with ethyl acetate and the gum which separated was allowed to stand 2 days in a refrigerator under a mixture of ethyl acetate and ethanol. The resulting off-white amorphous solid was collected affording 3.2 g. of 4-hydroxy-a-<(£[3-4243621 (4-methoxyphenyl)-1-methylpropyl]amlno}methyI>-3-(methylsulfinyl )benzenemethanol acetate salt, which softened at 95°C. and metled at 1OO-1O5°C.

B. To a stirred solution containing 50 g. (0.119 mole) of 4-hydroxy-a-<{[3-(4-methoxyphenyl)-l-methylpropyl]amino}methy£>-3-(methylthio)benzenemethanol acetate salt in 500 ml. of methanol at 0°C. there was added dropwise over 70 minutes 20.2 ml. (0.119 mole) of commercial 4-0% peracetic acid. When'the addition was complete the reaction mixture was evaporated to dryness in vacuo. The residual oil was taken up in 50 ml. of ethyl acetate and again evaporated tc dryness in vacuo. The remaining oil was dissolved in 350 ml» of tetrahydrofuran and the resulting clear solution was stirred and made slightly cloudy by the gradual addition of ether. After seeding, the mixture was stirred 2 days at room temperature at which point a fine, white solid had begun to precipitate. The mixture was treated dropwise with 50 ml. of ether and stirred 5 hours followed by the dropwise addition of another 50 ml. of ether and stirring an additional 4 hours. After stirring overnight in a refrigerator the mixture waB cooled to 0°C. while 200 ml. of ether was added dropwise over 3 hours. Stirring at 0°0. was continued an additional 3 hours. The precipitated produot was then collected and redissolved in 1250 ml. of tetrahydrofuran. The resulting solution was filtered to remove a small amount of'insoluble material, and concentrated to a volume of 250 ml. The concentrate was cooled in a refrigerator overnight. The resulting white crystalline precipitate was colleofeed, washed with tetra-4345631 hydrofuran and ether and dried affording 14.5 g. of 4hydroxy- 3-(methylsulfinyl)benzenemethanol acetate salt, m.p. 131133°C.

Example 12 To a stirred solution containing 19 g. (0.123 mole) of 3-(4-methoxyphenyl)-l-methylpropylamine in approximately 50 nil. of Ν,Ν-dimethylformamide at -65°C· was added dropwise a solution containing 12 g. (0.042 mole) of 2-brom.o-4'-hydroxy-3'-(methylsulfonyl)acetophenone 4'acetate in approximately 70 ml. of Ν,Ν-dimethylformamide. After the addition was complete, stirring was continued an additional 1.5 hours. The reaotion mixture was then acidified with 8 ml. of 48# hydrobromic acid and extracted with chloroform. The chloroform extracts were cooled to -65°C. and diluted with ether. The supernatant was decanted from the precipitated gum which wsb subsequently dissolved in a minimum volume of chloroform and allowed to stand 2 days in the refrigerator. The resulting 3 g. of hydrobromide salt was dissolved in saturated aqueous sodium bicarbonate and the solution thus-obtained extracted with n-butanolethyl acetate. The organic extracts were acidified with glacial acetic acid and evaporated to dryness to give 2.2 g. of 4'-hydroxy-2-£[3-(4-methoxyphenyl)-l-methylpropyl3aminoJ-3'-(methylsulfonyl)aeetophenotne acetate salt as a yellow oil. -44' 3 6 31 Example 13 A solution containing 2.2 g. of 41-hydroxy-2- <[> (4-methoxyphenyl)-1-methylpropyl]aminoj-3'-(methylsulfonyl)acetophenone acetate salt in 100 ml. of N,N-dimethylformamide was hydrogenated under an initial hydrogen pressure of · approximately 50 p.s.i. in the presence of 0.5 g. of 10% palladium-on-carbon hydrogenation catalyst, After 2. hours one molecular equivalent of hydrogen had been absorbed. The catalyst was removed by filtration and the filtrate evaporat10 ed to dryness. The residue was adsorbed on a column of silica gel which was eluted first with a 95:5 mixture of ethyl acetate-methanol and finally with a 90:10 mixture of ethyl acetate-methanol to give 1.4 g. of crystalline product. Following trituration with acetone and filtration thera was obtained 1.25 g. of 4-hydroxy-a-<£[3-(4-methoxyphenyl)-lmethylpropyl]amino| methy £>-3-(methylsulfonyl)benzeneme.thanol acetate salt, m.p. 151-153’C.

Example 14 A. To a stirred solution containing 376 g, (1.0 mole) of (-)-dlbenzoyltartaric acid in a mixture of 5 1· oi* methanol and 550 ml. of water at 42eC. there was added 179 g. (1.0 mole) of (-)-3-(4-niethoxyphenyl)-l-methylpropylamine. The mixture was stirred 26 hours at 40°C. and then 20 hours at room temperature. The resulting precipitate was collected and dried affording a first crop of 176.5 g. of (-)-3-(4methoxyphenyl)-l-methylpropylamine (-)-dibenzoyltartrafce salt, m.p. 175-17β°0. (dec.), [a]^ „ -88.0°. By cooling the filtrate at 0°C. for 7 hours a second crop of 53-5 g. was obtained, m.p. l67-171°C. (dec.), [a]^ = -86.3®. The final mother liquors were set aside for use in part’B below. The first crop was recrystallized from 90% methanol to give 145.5 g., m.p. 179-l8O.5°C. [a]*5 = -87-5°. This salt wes treated with aqueous sodium hydroxide and the liberated amine extracted into chloroform. The chloroform extracts were dried over anhydrous potassium carbonate and evaporated to dryness. The residual oil was dissolved in 2-propanol, the resulting solution acidified with 25 ml. of 12N hydrochloric acid, and evaporated to dryness. The solid residue was dried, recrystallized from 2-propanol and dried again to give 52.0 g, of (-)-3-(4-methoxyphenyl)-l-methylpropylamine hydrochloride, m.p. 126-129’C., to]p » -6.0’ (2% in water).

B. The mother liquors remaining after isolation of (-)-3-(4-methoxyphenyl)-l-methyipropylamine (-)-dibenzoyltartrate salt were concentrated to a volume of 500 ml. and cooled at O’C. for 2 hours. The resulting precipitate was collected and dried to give 283 g.-of (+)-5-(4-methoxy20 phenyl)methylpropylamine (-)-dibenzoyltartrate salt, m.p. 159-162’C. (dec.). This salt was treated with aqueous sodium hydroxide and the liberted amine extracted into chloroform. Evaporation of the chloroform left 80 g. of oil which was then added to a solution containing 168 g. of (+)-dibenzoyl25 tartaric acid in i860 ml. of 90% methanol. After stirring 20 hours at room temperature the precipitated salt was collected and dried affording 173.5 g· of (+)-3-(4-methoxyphenyl)-l-methylpropylamine (+)-dibenzoyltartrate, m.p. 179-l8o"C. (dec.), (a—-t87.1e. Reorystallization from -46· 36 31 90% methanol afforded l4g g., m.p. l8l°C. (dec.), [a]"^ = +90.3*. Following the procedure described in part A the amine was liberated from the (+()-dibenzoyltartrate salt and converted to the hydrochloride to give 55.0 g. of (+)-3-(4-methoxy5 phenyl)-l-methylpropylamine hydrochloride, m.p. 127-130°C., ία]®5 = +5.6° (2% in water). The nmr spectrum of this product in the presence of the shift reagent tris[(trifluoromethyl )hydroxymethylene-a-caniphorato]europium III, Bu(TPC)^ indicated contamination by approximately 10-15% of the levo isomer.

C. (+)-3-(4-Methoxyphenyi)-l-methylpropylamlne (-)dibenzoyltartrate salt (8781 g.) prepared according to part B above was recrystallized from aqueous methanol to give 7690 g„, m.p. l63-l65eC° A 700-gram sample was recry3tallized twice from aqueous methanol affording 558 g. of the Salt which was then converted to the free amine and distilled under reduced pressure to give 180.5 g. of (+)-3-(4-methoxyphenyl)-l-methylpropylamine, b.p. 88-100eC./0.1 mm. The nmr spectrum of this product in the presence of the shift repgent Bu(TFC)j indicated an optical purity >97%. .47" D. Alternatively (+)-3-(4-methoxyphenyl)-l-methylpropylamine was obtained as follows: A solution of 300 g. (1.67 moles) of dl-3-(4-methoxyphenyl) -1-me thylpropylamine in 2 1. of 95% ethanol was added in one portion to a stirred warm solution (40-45°C.) of 250 g. (1.67 moles) of d-tartaric acid in 2.6 1 of water and 4.2 1 of 95% ethanol. The clear solution was seeded at about 38°C. and was then allowed to come to room temperature overnight with stirring. The crystallized solid was filtered and pressed thoroughly with a rubber dam;. it was washed twice with enough ice-cold 8% aqueous ethanol to cover the cake and was thoroughly pressed dry. The product was dried at 60° in vacuo for., five hours to afford 276 g. of crude d-amine bitartrate, m.p. 181-182°C. Five reerystallizations from aqueous ethanol afforded 125 g. of the bitartrite, m.p. 188-190°C. The optical purity of the liberated (+)-3-(4-methoxyphenyl)-1-methylpropylamine was shown to be £97%, Example 15 To a stirred solution containing 35-7 g. (0.172 mole) of. incompletely resolved (-)-3-(4-methoxyphenyl)-1methylpropylamine hydrochloride, [alp·’ ·« -6.0* (2% in water) in 125 ml. of Ν,Ν-dimethylformamide was added 25 ml. of . triethylamine causing immediate precipitation of triethylamine hydrochloride. The mixture was stirred 20 minutes and then cooled to -50®C. The remainder of the preparation was carried out following a procedure similar to that in 4843631 Example 7 but using 20 g. (0.66 mole) of 2-bromo-4'~ hydroxy-2'-(methylthio)acetophenone 4'-acetate and 8 ml. of acetyl chloride to give 15 g. of Incompletely resolved (-)-41-hydroxy-2-£[3-(4-methoxyphenyl)-1-raethylpropyljaminoJ?'-(methylthio)acetophenone 4'-acetate hydrochloride, m.p. 179-l8l°C., [a]p5 = -10.5°.

Example 16 To a stirred solution containing 12 g. (0.027 mole) of incompletely resolved (-)-4'-hydroxy-2-£[3-(4methoxyphenyl)-1-methylpropyl]aminoj’-3'-(methylthio)aeetophenone 4’-acetate hydrochloride (m.p. 179-l8l°C., ["J? = -10.3°) in 150 ml. of methanol at 0°C. was added portionwise 0.8 g. (0.020 mole) of sodium borohydride.

After stirring an additional 15 minutes, a solution containing 1.6 g. of potassium hydroxide in 25 ml. of water was added and the resulting mixture was heated at reflux under nitrogen 0.5 hours. The reaction mixture was concentrated to a small volume,, acidified with 3N hydrochloric acid, then made basic with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. After drying over anhydrous sodium sulfate the ethyl acetate solution was evaporated to dryness leaving 11 g. of pale yellow oil. This oil was dissolved in 200 ml. of ethyl acetate and a h0 ml. aliquot was adsorbed on a column of silica gel and the product .eluted with 92:8 ethyl acetate-metha'nol to give 1.7 g. of oil which was converted to the acetate salt affording 1.22 g. of levorotstory 4-hydro?cy-a-^/i3-(4-methoxyphenyl)-l-methylpropyljamino.JmethyT>-3-(methylthIo)benzenemethanol acetate salt, m.p. 124-125°C., [aj^5 » -6.4°. 4943631 Example 17 Following a procedure similar to that described in Example 11 but using 1.2 g. (0.0028 mole) of levorotatory 4-hyd roxy-a-<<£[3- (4-me thoxjr pheny 1) -1 -me thyl pro pyljamlno^· methyϊ>-3-(methylthio)benzenemethanol acetate salt (m.p. 124-125°C.> [α]ρ5 = -6.4°) and 216 mg. of commercial 40% peracetic acid there was obtained 0.9 g. of levorotatory 4-hydroxy-o-^£[3-(4-methoxyphenyl)-l-methylpropyl]aminoJmethyl>-3-(methylsulfinyl)benzenemethanol acetate salt, m.p. 103-106®C., [a]^5 = -3.0°.

Example 18 A. Following a procedure similar to that described in Example 15 but using 43 g. (0.20 mole) of incompletely resolved (+)-3-(4-methoxyphenyl)-l-methylpropylamine hydrochloride, £a]p5 +5.6® (2% in water) and 23 g. (0.077 mole) of 2-bromo-4,-hydroxy-3,-(methylthio)acetophenone 4'acetate there waa obtained 17.1 g. of incompletely resolved (+)-4'-hydroxy-2-^[39(4-methoxyphenyl)-1-methylpropyl]aminoJ-3'-(methylthio)acetophenone 4'-acetate hydrochloride, m.p. 178-18o’C.j [a]®5 - +10.2*.

B. Following a procedure similar to the above but acidifying the reaction mixture with 48% hydrogen bromide in place of 12N hydrochloric aoid and omitting the reactylation step afforded, after recrystallization twice from chloroform-isopropyl acetate and once from chloroform-acetone, incompletely resolved (i)-4'-hydroxy-2-{[3-(4-methoxyphenyl)l-methylpropyl]aminoJ-3'-(methylthio)aeetophenone 4'acetat.e hydrobromide, m.p. l82-l83°C., + 9.0®. -504 3 6 3 2 Example 19 A. Following a procedure similar to that described in Example 16 but using 17.1 g. (0.039 mole) of (+)-4'~ hydroxy-2-£[3-(4-methoxyphenyl)-1-methylpropylJamino}-3’(methylthio)acetophenone 4'-acetate hydrochloride (m.p. 178-l80°C., [cdp5 = +10.2°), 1.0 g. (0.025 mole) of sodium borohydride and 2.0 g, of potassium hydroxide there was obtained 15 g. of 4-hydroxy-a-<^£i3-(4-methoxyphenyl)-lmethylpropyl]aminoJmethyI>-3-(methylthio)benzenemethanol as a dextrorotatory pair of diastereomeric benzenemethanols.

A 3.0 -gram sample was dissolved in isopropyl acetate and the resulting solution acidified with glacial acetic acid.

The product was allowed to crystallize slowly over 2 days to give 2.75 Ε» of crystalline acetate salt, m.p. 124-126*0., [a]p5 - +7.7°.

B. When a procedure similar to the above was carried out using (+)-41"hydroxy-2-£i3-(4-methoxyphenyl)-l-methylpropyljaminoJ-3'-(methylthio)-acetophenone 4'-acetate hydrobromide m.p. l82-l83°C., +9.0® there was obtained dextrorotatory 4-hydroxy-o-^£(3-(4-methoxyphenyl)-l-methylpropyl]amlno^methyl>-3-(methylthio)benzenemethanol acetate salt, m.p. 128-129.5°C., [a]^5 = +5.6°.

C. Following a procedure similar to that described in Example 10 but employing 4o g. (O.O75S mole) of optically pure (+)-4'-hydroxy-2-£[3-(4-methoxyphenyl)-l-methylpropy1]amino|-3'-(methylthio)acetophenone 4'-benzoate hydrobromide (m.p. 171-175°C., [a]^ " +11.8°) prepared according to Example 23B hereinbelow, 1.5 g. of sodium borohydride and 4.5 g, of potassium hydroxide there was obtained 25.1 g. of 4-hydroxy-α-^((3-(4-methoxyphenyl)-1-methylpropyllaminoj-5I4 5 6 31 methy^-3-(methylthio)benzenemethanol acetate salt, m.p. 125-127°C., ta]p5 = +7.3°, as a dextrorotatory pair of diastereomerlc benzenemethanols. Another similar run afforded a product with m.p. 129-130°C., [a]p5 = +7.1°. The hydro5 chloride had m.p. 153-155eC· The pair of diastereomeric benzenemethanols of this Example correspond to the products of Examples 21C and 28..

Example 20 A. Following a procedure Similar to that described in Example 11 but using 2.5 g. (0.0049 mole) of dextrorotatory 4-hydroxy-a-<£[3-(4-methoxyphenyl)-l-methylpropyl]aminiJmethy3>-3-(methylthio)benzenemethanol acetate salt (m.p. 124-126’C., [o]p5 » +7.7°) and 375 mg. of commercial 40% peracetic acid there was obtained 2.0 g, of 4-hydroxy—a-<£[3-(4-methoxyphenyl)-1-methylpropyl]amlno}methy]>-3(methylsulfinyljbenzenemethanol acetate salt as an amorphous yellow powder [a]^ = +4.2° containing a mixture of 4 diastereomeric sulfoxides, in addition to its anti20 hypertensive activity this product was found equiactive with procaine as a local ahesthetlc when tested according to the method of Bulbring and Wadja, J. Pharm. Exp. Therap. 8^,78(1945).

B. When the above oxidation was carried out on dex25 trorotatory 4-hydroxy-a-^[3-(4-methbxyphenyl)-l-methylpropyl]aminq|methy£>-3-(methylthio)benzenemethanol acetate salt prepared according to the method of Example 19c the product had m.p. 103-110° and [a »-l.le and consisted of a mixture of 4 diastereomeric sulfoxides. -52· C. A sample oS 4-hydro3^-a-4?i5-i4-:iiethoxypheByl)1-methylpropylJaminojmethy I>-3~(methylsulfinyl)benzenemethanol acetate salt prepared by a procedure similar to that described in part B above was converted by a conventional 5 procedure to the corresponding phosphate, m.p. 136-153°G., [cd25 = 0.0°C, D. A sample of 4-hydroxy-a-,methy&-3·· (methylsulfinyl) benzenemethanol acetate salt prepared by a procedure similar to that des10 cribed in part B- above was converted by a conventional procedure to· the corresponding methanesulfonate, m.p. 142-1«8°C., [a]^5 = +5.0°.

E. A sample of 4-hydroxy-a-<£i3-(4-methoxyphenyl)-lmethylpropylJamlaoj methy 2>-3-(methylsulfinyl)benzenemethanol acetate salt prepared by a procedure similar to that described in part B above was converted by a conventional procedure to the cori’esponding hydrochloride, m.p, 172-175°0., [ajj.-' " -8.1°.

F. Alternatively the hydrochloride salt was prepared directly as follows; To 3 stirred solution containing 844 g. (2 moles) of 4-hydroxy-ci<^£i3"(4-methoxyphenyl)-1-methylpropyl]amino}methyI>-3-(methylthio)benzeneBie-Ehsnol acetate salt in 7 liters of methanol ar 0°C. was added in 25-ml, portions £5 over a period of about 40 minutes 308 ml. of 4C# commercial peracetic acid. Stirring was continued at Q-3°C, an additional 45 minutes. The reaction aixturs was then evaporated under reduced pressure while maintaining the temperature below 35°C. The residue was diluted with 1 liter of 2-5345631 propanol and the solution evaporated to dryness in vacuo.

This was repeated once more and then the residue was dissolved in 6 liters of 2-propanol, and the resulting solution treated with a solution containing 2.14 moles of hydrogen chloride in 2-propanol. The resulting pale yellow solution was cooled in ice. The precipitated product was collected, washed with 2-propanol-ether and dried to give 705 g. of 4hydroxy-a-<^{(3-(4-methoxyphenyl)-1-methylpropyllaminojmethy 3-(methylBUlfinyl)benzenemethanol hydrochloride, (alp'' = -1.6°.

The four dlastereomeric sulfoxides produced4in accordance with the foregoing exanples correspond to the sulfoxides of Examples 50, 31, 32 and 33.

The products of several preparations carried out 15 as described above in Example 20P were converted to the phenol £-toluenesulfonates with £-toluenesulfonyl chloride in excess sodium hydroxide and. analyzed by high pressure liquid chromatography on microparticulate silica gel using n-hexane-2-propanol-2-propylamine (85:15:0.4) as eluent at a flow rate of 0.54 ml./min. and a pressure of about 1200 p.s.i. and were found to have the following composition Sulfoxide of Ex. No. Concentration 30 19-23% 31 23-25.5% 25 32 25.5-28% 33 28-30% -544 3 6 31 The product obtained according to part E or F above, when tested in one or more of the standard biological test procedures described hereinhelow, was found to possess useful cardiotonic activity. The efficacy of this compound was judged, 5 in vitro, on the basis of percent increase in contractile force in isolated cat atria and papillary muscle and, in vitro on the basis of percent increase in cardiac contractile force in the intact anesthetized dog.

The in vitro test procedures used are described as follows: Cardiotonic Test Procedure I - Male cats weighing from 0.8 to 1.5 kg. ware anesthetized with ct-chloralose (80 mg./kg. i.p.). The chest was opened, the heart excised and the two atria dissected. A silk suture was tied to each of two opposite sides of the right atrium. One side of the atrium was tied to a glass rod and then mounted in a 50 ml. organ bath filled with Tyrode's solution. The second suture was attached to a force displacement transducer and the tension on the atrium was adjusted to 1.5 ± 0.5 grams. The transducer was then connected to a Grass -5543631 polygraph and the force and rate of.atrial contraction was recorded continuously. The left atrium was treated similarly using silver wire instead of silk sutures. The silver wire also served as a stimulating electrode. Both atria were mounted in the same bath. The right atrium was beating spontaneously due to the presence of the sinoatrial node, while the left atrium wa3 stimulated electrically at· a rate of 3 beats/sec. by suprathreshold rectangular pulses of 5 millisecond duration. The Tyrode's solution bathing the '10 atria was of the following composition (in mM): NaCl 136.87, KCl 5.36, NaHgPO^ 0.4l, CaClgl.eO, MgClg6H 0 1.05, KaHCO^ H. 90, glucose 5.55'end EDTA 0.04. The solution was equilibrated with a gas mixture consisting of 95% 0% end 5% COg.

The preparation was left to equilibrate for one hour before' 1θ· any drug was added. The bathing fluid was changed 3 to 4 times during the equilibration time. At the end of equilibration period, the drug dissolved in a vehicle or the vehicle alone was added to the tissue bath and the full response recorded. The vehicle used was Tyrode's solution to which, >20 if required, sufficient acid was added to cause solution of the drug. When the response reached a maximum it was abolished by 3 washes at 10 min. Intervals or until pre-drug values of force of contraction were reached. Generally, a dose response study of at least 3 ‘doses was done in the same • 25 preparation.

Cardiotonic Te3t Procedure IB - Male cats 0.8 to I. 5 kg. were anesthetized with α-chloralose (80 mg./kg. i.p.). The chest was Opened and the heart excised,'' The heart was dipped and shaken in Tyrode's solution for the removal of -564563 blood from the cavities. The right ventricle was then slit open and the small and thin (about 1 mm. in diameter and 4 to 7 mm. in length) papillary muscles were dissected out.

A silver wire waa attached to each of the two ends of the papillary muscle. The ventricular end was attached to a platinum electrode and mounted in a tissue bath containing Tyrode's solution described above. The silver wire on tho valvular end of the wue'cle was attached to a force displacement transducer for the measurement of the force and rate of muscle contraction. The muscle was stimulated at a rate of 3 beats/sec. by suprathreshold rectangular pulses of 5 millisecond duration. The rest of the procedure was continued as described above.

Cardiotonic Test Procedure II - The in vivo test procedure used is described as follows: Mongrel dogs of both sexes and varying in weight from 9 to 15 kg. were anesthetized with 30 mg./kg. pentobarbital sodium administered intravenously, ,'fhe trachea was exposed and cannulated. The tracheal cannula was then attached to a Harvard respira'20 tory pump using room air. The right femoral artery and vein were cannulated. The arterial cannula was attached to a Statham P23A .pressure transducer connected to a Grass polygraph for the continuous recording of arterial blood pressure. The venous cannula'was used for'the intravenous administration ’ of drugs. Pin electrodes were attached to the right forelimb and left hindlimb,. The electrodes were then connected to a Grass polygraph for the continuous recording of the' standard limb lead II electrocardiogram. A ventre-dorsal Incision at the third inter-costal space was made, the ribs . laterally retracted and the pericardium slit open to expose •574 5 6 31 the myocardium. The base of the aorta was dissected and a flow probe was fitted around it. The flow probe was.attached to a square wave electromagnetic flowmeter (Carolina Medical Electronics). The flowmeter was then connected to· a Grass 5 polygraph for the continuous recording of aortic blood flow. This flow was used as an index of cardiac output (actual cardiac output is aortic blood flow + coronary blood flow). Cardiac contractile force was measured by suturing a WaltonBrodie strain gauge to the wall of the right ventricle.

At the end of the surgical procedure, the animal was left . to rest and equilibrate for one hour with continuous recording of blood pressure, EKG, cardiac contractile force and aortic blood flow. . After the equilibration period, the vehicle or the drug dissolved in the vehicle was administered by intravenous infusion (i.v. inf.j, intravenous bolus (i.v. bol.) or intraduodenally (i.d.) and the response of all the parameters measured to drug administration was recorded continuously for different periods of times depending on .the t route of drug administration. When the route of administration was i.v. inf., the drug was administered until a peak effect was reached and infusion was then maintained for ten minutes. The above-described test.systems were standardized using dopamine. -584 3 6 31 The·product obtained according to part E and F above, when tested In vitro as above-described at a dose of 1 mg./ml caused Increases of 62 and 52 percent in right atrial rate and right atrial force respectively and a decrease of 14 percent in · papillary muscle force. At a dose of 10 mcg/ml. increases of and 46 percent in right atrial rate and right atrial force respectively and a decrease of 12 percent in papillary muscle force were observed.

When infused Intravenously at a dose of 10 mcg/kg/min. over 3 hrs. in 3 intact anesthetized dogs the product of this example caused a maximum increase in cardiac contractile force of and 42 percent in 2 of 3 dogs with no significant change in heart 'the rate. In/remaining dog decreases in contractile force and heart rate of 30 and 33 percent respectively were observed.

Example 21 A. A solution containing 10.5 g. of dextrorotatory 4~hydroxy-a-<^{[3-(4-methoxyphenyl)-l-methylpropyl]aminojmethyl>-3-(raethylthio)benzenemethanol prepared as described -5945631 in Example 19A and 2.25 g. of (-)-mandelic acid in 60 ml. of isopropyl acetate was stirred 4.5 hours. The precipitated solid was collected to give 3.7 g. of white crystalline solid, m.p. 991OO°C., -20.9° which was labeled solid A and set aside. The filtrate was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness. The residual 6 g. of gum was dissolved in 4o ml. of isopropyl acetate and treated with a solution of 2.0 g. of (+)-mandelic acid in 20 ml. of isopropyl acetate and the resulting solution stirred overnight. The precipitated product was collected giving 4,1 g. of tan crystalline solid m.p. 89-93°, [«Jp'’ +35-4°.

The filtrate was labeled filtrate A and set aside. The solid was recrystallized by dissolving in 55 ml. of 10:1 isopropyl acetate-isopropyl alcohol and stirring overnight. After removing a small amount of solid impurity the clear solution was concentrated to a volume of 30 ml. whereupon the product crystallized to give 1.6 g. of tan crystals m.p. 89-106°, [ajp5 =? +48.7° which was labeled solid B and set aside. The filtrate was labeled filtrate B.

Filtrate A was washed with saturated aqueous sodium bicarbonate, dried over anhydrous.sodium sulfate and evaporated to dryness. The resulting 4„o g. of yellow gum was dissolved in 40 ml. of ethyl acetate and treated with 1.0 g. of (-)-mandelic acid. After standing overnight the precipitated product was collected to give 2.5 g. of crystalline solid m.p. 108-110.5°C., = -33’ which was labeled solid C and set aside. The filtrate was combined with filtrate B above and evaporated to dryness, and the 6043631 residue combined with solid A. The combined materials were dissolved in ethyl acetate, the resulting solution washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness.

The residual 6.4 g. of yellow syrup was dissolved in 4o ml. of ethyl acetate and treated with 1.5 g. of (i-)-mandelie acid. After stirring overnight the precipitated solid was collected to give a first crop of 1,0 g. of tan solid m.p. 105-110’C. Cooling the filtrate in ice afforded a second Crop of 1.3 g. m.p. 86-89° 1^]^ " +48°. The filtrate was labeled filtrate C and set aside. The first crop was combined with solid B above and recrystallized from ethyl 25 acetate to give 1.65 g. of tan solid m.p. 90.5-92° i«]p = +52.2°. This material was combined with the second crop and the whole recrystallized from isopropyl acetate affording 2.7 g. of tan crystalline solid m.p. 89-92.5°C. ® +51.8°. The latter was dissolved in 50 ml. of ethyl acetate and ths resulting solution washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness- leaving 1.7 g. of product which corresponds to the dextrorotatory member of the pair of diastereomeric benzenemethanols present in the product of Example 19A. A 650 -mg. sample was dissolved in isopropyl acetate and the resulting solution acidified with glacial acetic acid and evaporated to dryness. The residue was crystallized from a small volume of isopropyl acetate to OK give 700 mg. of the acetate salt, m.p. 70-72°C. [a]p = +31.3°.

B. Filtrate C was evaporated to dryness. The residue was dissolved in ether-ethyl acetate and the -gl40631 X»resulting solution washed with saturated aqueous sodium bicarbonate, treated with 2 g. of decolorizing carbon, filtered and the filtrate evaporated to dryness leaving 3.8 g. of residue. This material was dissolved in 25 ml. of isopropyl acetate and the resulting solution treated with a solution containing 1.3 g. of (-)-mandelic acid in 10 ml. of isopropyl acetate, After stirring 2 days the precipitated product was collected to give 3.25 g. of white crystalline solid, m.p. 104-106°C., ta]^ = -30.4’, This material was combined with solid C above and the whole recrystallized successively from 25 ml. of ethyl acetate, 40 ml. of ethyl acetate and finally from isopropyl alcohol-ethyl acetate in each instance allowing the product to crystallize slowly at room temperature. There was thus obtained 3-5 g· of white needles m.p. 110-111’C., [a]p5 = -33.4°·. The latter was dissolved in 50 ml. of ethyl acetate, and the resulting solution washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness to give 2.4 g. of product β -5.1’) which corresponds to the levorotatory member of the pair of diastereomeric benzenemethanolB present in the product of Example 19A. A 1.1 -gram sample was converted to the acetate salt as described above for the dextrorotatory diastereomer affording the crystalline acetate salt as white platelets m.p. 124-124.5’C. » -5.4°. - C. A 99-gram sample of dexrorotatory 4-hydroxy-a<({[3-(4-methoxyphenyl)-l-methylpropyl]aminojmethyi>-3(methylthio)benzenemethanol acetate Balt (m.p, 129-130’C., -624SS31 [a= +7.1°) prepared as described in Example 190 was treated with aqueous sodium carbonate and the free base was extracted into 1 liter of ethyl acetate. The ethyl acetate solution was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was dissolved in hot ether and the solution was filtered through a 1-inch pad of silica gel in order to remove a colored impurity. Evaporation of the ether left 85 g. of a pale yellow gum which was dissolved in 200 ml. of ethyl acetate and treated with a solution containing 22 g. of (+)-mandelic acid in 200 ml. of ethyl acetate. The mixture was stirred overnight at room temperature and then overnight at 5°C. The precipitated product was collected by filtration and washed with isopropyl acetate and ether, The mother liquors were set aside. The collected solid was recrystallized from isopropyl acetate containing a small amount of 2-propanol to give 27 g. of product m.p. 89-910C., [a]^ = +49.4". The mother liquors which had been set aside were reconverted to the free base and again ti«ated with 20 g. of (+)-mandellc acid to give after two reerystallizations from isopropyl acetate and one from ethyl acetate an additional 6.0 g. of product = +47.6°. The mother liquors from this second treatment with (+)-mandelic acid were enriched in the levorotatory diastereomei·· and were set aside for use in part D, The solids were combined and recrystallized twice from ethyl acetate to give 22 g. of the (+)-mandelate salt, m.p. 94-95.5°C. [a]^5 = +54.0°. This salt was treated with 80 ml. of 10% aqueous sodium carbonate and the free base extracted into 300 ml. of ethyl acetate. -63· 43631 The ethyl acetate solution was washed with saturated aqueous sodium chloride, dried over, anhydrous sodium sulfate and acidified with 2 ml. of acetic acid. The solution was concentrated and the resulting precipitate was collected and recrystallized from ethyl acetate containing a few drops of acetic acid to give 4.3 g. of 4-hydroxy-o methoxyphenyl)-1-methylpropyl]aminojmethyI>-3-(methylthio)benzenemethanol acetate salt, m.p. 133-134*0., [o]^ = +33·3°, corresponding to the dextrorotatory member of the pair of diastereomeric benzenemethanols present in the product of Example 190, A sample of thie material was reacted With ptoluenesulfoayl chloride in the presence of sodium hydroxide to afford the corresponding 4-p-t0luenesulfonate acetate salt m.p. 90-92° +23.0° which was shown by high pressure liquid chromatography to have an isomeric purity >99%.

D. The mother liquors from part C which were enriched in the levoratatory diastereomer were combined and evaporated to dryness. The residue was treated with aqueous sodium carbonate and the free base extracted into ethyl acetate. Evaporation of the· ethyl acetate left 58 g. of oil. This material was dissolved in 200 ml. of ethyl acetate, treated with a solution containing 20 g. of (-)-raandelic acid in 200 ml. of ethyl acetate and the resulting mixture stirred overnight. The precipitated salt was collected and recrystallized successively from acetone-ether, ethyl acetate, and eight times from methylene chloride-ethyl acetate to give 23 g. of incompletely resolved (as determined by thin layer -6443631 chromatography) (-)-mandelate salt, m.p. 116-117°C., [αΐ^ = -37.1° which was converted by a conventional procedure to the acetate salt (aj^ « -10.6®. Chromatography of a 5.5-gram sample of the latter on a column of silica gel and elution with 7% methanol in ethyl acetate failed to substantially further purify the acetate salt. A 2.6-gram fraction of material which had been eluted from the column was etirred with 25 ml. of 35% aqueous sodium hydroxide and the mixture treated dropwise over 15 minutes with a solution containing 1.33 g. of p-toluenesulfonyl chloride in 30 ml. of acetone.

Over the next 5 minutes the reaction mixture was treated with two additional 150-mg. portions of p-toluenesulfonyl chloride. The acetone layer was separated, diluted with an equal volume of Isopropyl acetate, washed with water followed by saturated aqueous sodium chloride, and evaporated to dryness. The residue was dissolved in ethyl acetate end the solution acidified with acetic acid. The acetate salt which precipitated was recrystallized from ethyl acetate to give 1.0 g. m.p. 115-117°C., £«3§5 * -7.9’. The filtrate afforded an additional 0.5 g.# m.p. ll5-117eC. The crops wei'e combined and converted to 1.2 g. of the (+)-mandelate Of? salt, m.p. 154-156® [alDJ +14.9° according to the procedure described above in part 0. This material was combined with another 250 mg.· m.p. 157-158°C. [cd^5 » +14.3° obtained in £5 a similar run, recrystallized from ethyl acetate, and. then converted by a conventional procedure to the corresponding acetate salt to give 700 ml. of isomerically pure levorotatory 4-hydroxy-a--3"(methylthio)benzenemethsnol"4-g-toluene-6543631 sulfonate acetate salt, m.p. 117-119°C. [a]p^ = -9.60 corresponding to the 4-g-toluenesulfonate ester of the levoratatory member of the pair of diastereomeric bensenemethanols present in the product of Example 19c. This pro5 duct was shown by high pressure liquid chromatography to have an isomeric purity>98%.

Attempts to cleave the ^-toluenesulfonate ester in order to obtain the isomerically pure levoratatory phenol were unsuccessful, however the latter compound was obtained from the corresponding benzoate ae described in Example 28 hereinbelow.

Example 22 Ab To a stirred solution containing 1.05 g. (0.003 mole) of dextrorotatory 4-hydroxy-a-<£[3-(4-methoxyphenyl)1-methylpropyl]amiriqJmethyl>-3-(methylthio)benzenemethanol prepared according to the method of Example 21A in 15 ml. of methanol at 0eC. there was added dropwise over 0.5 hour a solution of 0.45 ml. (0.003 mole) of commercial 4o% peracetic acid in 5 ml. of methanol. When the addition was complete the reaction mixture was evaporated to dryness in vacuo. The residue wae dissolved in 45:5 ethyl acetatemethanol and adsorbed on a column of silica gel. Following elution with ethyl acetate the product was eluted with 90:10 ethyl acetate-methanol. The material so-obtained.was dissolved in ethyl acetate-methanol, · the resulting solution acidified with glacial acetic acid and evaporated to dryness. The residue was taken up in 5 ml. of chloroform, the resulting solution cooled to -65°C. and diluted with ether. The resulting solid was dissolved in tetrahydrofuran, the solution: acidified with glacial acetic acid and evaporated to dryness. -66436 31 The residue was dissolved in chloroform, the solution cooled to -65°c. and diluted with ether. The resulting solid was collected and dried affording 550 mg. of 4-hydroxy-a4£[3-(4-methoxyphenyl)-1-methylpropylJaminojmethy £>-35 (methylsulfinyl)benzenemethanol acetate salt as a dextrorotatory pair of diastereomeric sulfoxides, Lo,]2·3 - +23.5°B. A 5.0-gram sample of isomerlcally pure dexurorotatory 4-hydroxy-a-4^(3-(4-methoxyphenyl)-1-methylpropyl3aminojmethy^-3"(flieihylthio)benzenemethanol acetate salt pc ([a]p - +31.5°) prepared according to the method of Example 21C was oxidized as described in part A above.

When oxidation was complete the reaction mixture was evaporated to dryness and the residue crystallized from ethyl acetate to give 4.2 g. of crystalline product, m.p. 107-115°, [a]^ = +28.2°. A small sample was dissolved in acetone-methanol and the solution treated with oyclohexylsulfamic acid. The precipitated salt was collected to give after drying 4-hydroxy-a~<^f[3-(4-methoxyphenyl)-lmethylpropyljaminoJmethyX>-3-(methylsulfinyl)benzenemethanol cyclohexylsuli'amate salt as a dextrorotatory pair of diastereomeric sulfoxides, m.p. 152-154°C., La)25 = +35.9°.

The pair of diastereomeric sulfoxides of this example correspond to the products of Examples 30 and 32, Example 23 4. Following a procedure simi-lar to that described in Example 9C but employing 128 g. (0.72 mole) of incompletely resolved ( + )-3-(4-methoxypheny1)-1-methylpropylami ne, [a]^ « +4.4° (2# in water), and 120 g. (0.33 mole) of 2bromo-41-hydroxy-31-(methylthio)acetophenone 41-benzoate -67486 31 there was obtained a first crop of 82 g„, m.p. 172-174°C. and a second crop of 43 g., m.p. 171-174°C. The crops were combined and a 16-gram sample was recrystallized from 95% ethanol to give 10 g. of incompletely resolved (+)-4'- . hydroxy-2- £(3-(4-methoxyphenyl)-1-methylpropyl]aminoJ-3'(methylthio)acetophenone 4'-benzoate hydrobrOmides m.p. 174-175°C., [a]p5 = +8.4°.

B. To a vigorously stirred solution containing l80 g. (1.0 mole) of (+)-5-(4-methoxyphenyl)-l-aethylpropylamine [optical purity^97% as indicated by nmr spectroscopy in the presence of Eu(TFC)^] and 55 ml. of triethylamine in 300 ml. of Ν,Ν-dimethylformamide at -6oeC. there was added over 1.5 hours a solution containing 160 g. (0.384 mole) of 2bromo-4'-hydroxy-31-(methylthio)acetophenone 4'-benzoate in 500 ml. of N,N-dimethyIformamide. Stirring was continued an additional 0.5 hour. The reaction mixture was acidified with 48% hydrogen bromide and extracted with methylene dichloride. The organic extracts were washed with water and concentrated to about 320 ml. The concentrate was diluted with 400 ml. of isopropyl acetate and cooled. The solid trtiich precipitated was collected and dried to give 16? g. of optically pure (+)-4'-hydroxy-2£[3-(4-methoxyphenyl)-l-methylpropyl]aminoJ-3'-(methylthio)acetophenone 4'-benzoate hydrobromide, m.p. 171-l73°C., [a]»^ = +11.8°. A 7.0-gram sample was recrystallized from aqueous methanol containing a small amount of HBr to give, after drying, 5.9 g., m.p. 175-177°C. μ25=+ιι„6° Example 24 A. TO a solution containing 106 g. (0.195 mole) of incompletely resolved (+)-4 *-hydroxy-2-£[3-(4-methoxyphenyl)1-methylpropyllaming-31 -(methylthio)a cetophehone 4'-benzoate 68— 4o63i hydrobromide prepared according fco the procedure of Example 23A in 700 ml. of methanol at 0*0. was added over 0.5 hour 6 g. (0.16 mole) of sodium borohydride. Stirring at 0°C. was continued an additional 0.5 hour. A 150-ml. aliquot of the reaction mixture was concentrated under reduced pressure below 50°C. The concentrate was dissolved in ether and the ethereal solution was washed thoroughly with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was dissolved in 75 ml. of isopropyl acetate arid the resulting solution was acidified with acetic aoid then diluted with ether until cloudy and stirred for 3 hours. The solid which precipitated was collected by filtration, washed with isopropyl acetate and ether and dried to give 6.4 g. of 4-hydroxy-a4^(3-(4-mefchoxyphenyl)-1-methylpropylJsminoJmethy£>-3(methylthio)benzenemethanol 4-benzoate acetate salt, m.p. 107-110eC.

B. The remainder of the original reaction mixture was hydrolyzed with a solution containing 9 g. of potassium hydroxide in 100 ml. of water according to the procedure of Example 10 fco give 46 g. of 4-hydroxy~a-^£[3-(4-methoxyphenyl)1-methylpropyljaraino^methy £>-3-(methylthio)benzenemethanol acetate salt, m.p. 130-152°C., [cx]^ = +4.8°.

C. To a solution containing 10.0 g. (0.0188 mole) of optically pure (+)-4'-hydroxy-B*{[3-(4-methoxyphenyl)-lmethylpropyl]amlnoJ-3'-(methylthio)acefcophenone 41-benzoate hydrobromide (m.p. 171-173°C., [a3^ e +11.80) in 100 ml. of methanol at 0°C. was added portionwise 380'mg. of sodium borohydride. Following fche addition of several ml. of -6945631 noetic acid, the mixture was evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and ether and the resulting solution was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, acidified with 2.5 ml. of acetic acid and evaporated to dryness. Recrystallization of the residue from isopropyl acetate-ether afforded 6 g. of 4-hydroxy-a-^f[3-(4-methoxyphenyl )-1-methylpropyljaminojmethy!>-3-(methylthio)benzenemethanol 4-benzoate acetate salt = +^-4° as a dextroj rotatory pair of diastereomeric benzenemethanols corresponding to the products of Example 27A and B.

Example 25 To a stirred solution containing 8.0 g. (0.0147 mole) (+)-41-hydroxy-2-{[3-(4-methoxyphenyl)-l-methylpropyl]5 aminojj-3'-(methylthio)acetophenone 4'-benzoate hydrobromide, = +11.1° in 60 ml. of trifluoroacetic acid at 0°C. was added dropwise 3 ml. of commercial 40% peracetic acid. When the addition was complete the reaction mixture was evaporated to dryness. The residue was dissolved in benzene Ό and the resulting solution was evaporated to dryness. The residual gum was dissolved in Isopropyl acetate and acidified with ethanolic hydrogen chloride. The precipitated solid was collected and recrystallized from methano i-isopropyl acetate , 3-broraoto give 6.0 g. of 4'-hydroxy-2-i[3-/'4-methoxyphenyl)-l- -3'-(methylsulflnyl)acetophenone 4'benzoate hydrochloride, m.p. l65-l67°C.

The product obtained in this example was erroneously Originally identified as being 4'-hydroxy-2-{[3-(4-methoxyphenyl)-1-methylpropyl]amino}-3(methylsulfinyl)acetophenone 4'-benzoate hydrochloride. -704 3 6 31 Example 26 4-Hydrcxy-cx- - (4-methoxyphenyl)-l-methylpropyl]aminojmethyl>benzenemethanol 4-benzoate acetate salt (5.0 g., 0.0095 mole) prepared according to a procedure similar to that of Example 24b was oxidized with 1.5 ml. of commercial 4o% peracetic acid following a procedure similar to that of Example 22. When the oxidation was complete the reaction mixture was treated with 0.9 g. of sulfuric acid and cooled. The solid which precipitated was collected and dried to give 2.8 g. of 4-hydroxy-a-^£[3-(4~methoxyphenyl)1-methylpropyljaminojmethy (methylsulflnyl)benzenemethanol 4-benzoate heml-sulfate, m.p. 193-195°C.

Example 27 A. To a solution containing 7-4 g. of the free base derived from dextrorotatory 4-hydroxy-a-^£[3-(4-methoxyphenyl)-l-methylpropyl]amlnojmethyi>-3-(methylthio)benzenemethanol 4-benzoate acetate salt, [alp· = +6.4° in 60 ml. of isopropyl acetate was added a solution containing 1.8 g. of (+)-mandelic acid in 20 ml. of isopropyl acetate. The resulting solution was diluted with ether until slightly turbid and stirred two days at room temperature. The precipitate was collected and the mother liquors which were enriched in the levorotatory diastereomer were set aside for use in part B below. The collected solid was recrystallized eight times from methylene chloride-ether to give 3.3 g. of the (+)-mandelate salt,m.p. 126-127’C., « +49.1* which was subsequently converted to the acetate salt to give 2.1 g, of 4-hydroxy-a-^£[3-(4-methoxyphenyl)-l-methylpropyllaminoj methy l>-3-(methylthio)benzene-714B63J methanol 4-benzoatq acetate salt, m.p. 88.5-90°C,, [a]^ ' +26.7°, corresponding to the dextrorotatory member of the pair of diastereomeric benzenemethanols present in the product of Example 24b.

B. The mother liquors from part A above were converted to the free base, dissolved ih isopropyl acetate, treated with 1.5 g. of (-)-mandelic acid, and the solution diluted with ether. The precipitate was collected, recrystallized once from isopropyl acetate-ether to give 2.7 g. of the (-)10 mandelate salt, m.p. 120-120.5°C., [σ]^ = -35·0°; Which wae subsequently converted to 4-hydroxy- 1-methylpropylJaminojmethyΐ>-3-(methylthio)benzenemethanol 4-benzoate acetate salt, m.p. 82-83’G., = -10.0°, corresponding to the levorotstory member of the pair of diaBtereomarie benzenemethanols present in the product of Example 24b.

Example 28 A mixture containing 600 mg. of 4-hydroxy-a^£[3"(4-mefchoxyphenyl)-l~methylpropyl38minoJmethyl>-320 (methylthio^benzenemethanol 4-benzoate acetate salt (m.p. 82-836C., ® -10.0®, 5 ml. of 35% aqueous sodium hydroxide and several ml. of methanol was stirred 10 minutes, at room temperature, then diluted with 20 ml. of water and stirred an additional 10 minutes in a warm-water bath. The pH was adjusted to 9 with acetic acid and the methanol was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and after drying over anhydrous sodium sulfate the extracts were evaporated to dryness.

The residue was dissolved in isopropyl acetate, the resulting -7243631 solution acidified with acetic acid and cooled. The precipitated solid was collected by filtration and dried under vacuum to give 500 mg. of 4-hydroxy-a-^£[3-(4methoxyphenyl)-l-methylpropyl]amlnoJmethyi>-3-(methylthio)5 benzenemethanol acetate salt, m.p. 117-120°C., = -17.0° (average of two determinations) corresponding to the levorotatory member of the pair of diastereomeric benzenemethanol3 present in the product of Example 19C.

Example 29 A, To a stirred solution containing 1.0 g. (0.003 mole) of 4-hydroxy-a-4£(3-(4-methoxyphenyl)-1-methylpropylj51 oc aminojmethy]>"3-(methylthio)benzenemethsnol [g3q ·» -5-1°) prepared according to the method of Example 21B, in 15 ml. of methanol at 0°C. there was added dropwise over 0.5 hour a solution of 0.45 ml. of commercial 4o% peracetic aeid in 5 ml. of methanol. When the addition was complete the reaction mixture was evaporated to dryness in vacuo. The residue was diluted with 10 ml. of benzene, the resulting solution acidified with glacial acetic acid and evaporated to dryness. The residual gum was crystallized from tetrahydrofuran-ether and then recrystallized from ethyl acetate2-propanol to give 1.05 g. of 4-hydroxy-a-^(3-(4-methoxyphenyl)-1-me thylpro py1]aminojmethy £>-3-(me thylsulflny1)benzenemethanol acetate salt aa a levorotatory pair of diastereomeric sulfoxides, m.p. 9O95°U·* la]? - -9.V. Β» When the above oxidation was carried out starting with isomerically pure levorotatory 4-hydroxy-α-^(3-(4methoxyphenyl) - 1-raethylpropyl]ami noj me thy l>-3-(methylthio)bensenemethanol acetate salt (m.p. 117-120°C., -73-17.0°) prepared according to the methanol of Example 28 the resulting pair of diastereomeric sulfoxides had ω? -18.8° (determined on the reaction mixture).

The pair of diastereomeric sulfoxides of this example correspond to the products of Examples 31 and 33.

Example 30 Mother liquors obtained in the preparation of several batches of 4-hydroxy-a-^[3-(4-methoxyphenyl)-lmethylpropyl]aminoJmethyl>-3-(methylsulfinyl)bensenemethanol acetate salt according to a procedure similar to that described in Example SOB were combined and evaporated to dryness. The residual oil was triturated successively with ether and isopropyl acetate. The residue (90 g.) was dissolved in 300 ml. acetone and the resulting solution treated with 33 g. of cyclohexylsulfamic acid in 200 ml. of acetone. The precipitated cyclohexylsulfamate was collected and recrystallized five times from aqueous methanol to give 7.3 g. of product which was combined with 7.4 g. of material obtained in previous runs and converted to the hydrochloride. Seerystallization of the latter from methanol-isopropyl alcohol afforded 6,3 g. of 4-hydroxy-os<{£3-(4-methoxyphenyl)-l-methylpropyl]aminojmethy l>-3(methylsulfinyl)benzenemethanol hydrochloride, m,p, 206207°C., +126.6°, corresponding to the dextrorotatory member of the pair of diastereomeric· sulfoxides present in the product of Example 22B. -7.4Example 31 The mother liquors resulting from the fractional crystallization of the product of Example 30 were evaporated and the residue crystallized from acetone. The resulting 12.4 g. of solid was recrystallized twice from methanol- latter material was combined with 3.5 g. obtained in a previous run and converted to the hydrochloride which was sulfinyi)benzenemethanol hydrochloride, m.p. 204-205°C., £cs3~5 *= +70.5°, corresponding to the dextrorotatory member is of the diastereomeric pair of sulfoxides present in the product of Example 29Ξ.

Example 32 The reaction mixture resulting from the oxidation methanol (+)-mandelate salt according to the procedure of Example 22B was evaporated to dryness, the residue dissolved in a mixture of 70 ml. of methanol and 15 ml. of wster, treated with a molar equivalent of cyelohexylBulfamic acid and seeded with the cyclohexylsulfamate salt of the product of Example 30. The 7.9 g· of product which crystallized was collected and set aside. The mother liquors were evaporated to dryness and the residue crystallized from acetone-methanol. The product was converted to 1.1 g. of the hydrochloride and combined with an additional 850 mg. obtained from the mother liquors resulting from the -75. 45631 fractional crystallization of the diastereomer of Example 31. The combined solids were recrystallized from 2-propanol to give 1.4 g. of 4-hydroxy-a-^[3-(4-methOXyphenyl)-lme thylpropyllamino^ me thyI>-3-(methylsulfinyl)benzenemethanol hydrochloride, m.p. 138-l4o’C., [a]^ = -48.2°, corresponding to the levorotatory member of the pair of diastereomeric sulfoxides present in the product of Example 22B.

Example 33 A. The reaction mixture resulting from the oxidation of 3 g. of levorotatory 4-hydroxy-a-<£[3-(4-methoxyphenyl)l-methylpropyljamlnojmethyl>-3-(methylthio)benzenemethanol acetate salt according to the procedure of Example 29B was evaporated to dryness, the residue dissolved in a 90sl0 mixture of acetone-methanol, treated v/ith a molar equivalent of cyclohexylsulfamic acid, and seeded with the Cyclohexylr sulfamate salt of the product of Example 31. The 1.6 g. of product which crystallized was collected and set aside. The mother liquors were evaporated to dryness and the residue crystallized twice from aqueous methanol to give 1.85 g. of crystalline solid, [a]^ = -67,5°.

B. Alternatively, 10.0 g. Of 4-hydroxy-a -φ-(4methoxypheny1)-l-methylpropy1Jaminojmethyl>-3-(methylthio)benzenemethanol 4-£-toluenesulfonate (+)=mandelate salt prepared according to the procedure of Example 21D was oxidized following a procedure similar to that of Example 29A and the product was'isolated as the free base to give 10 g. of crude 4-hydroxy-a-<^£[3-(4-methoxyphenyl)-l-niethylpropyljaminojmethy 1^-3-(methylsulfinyl)benzenemethanol 4£-toluenesulfonate as a pair of diastereomeric sulfoxides. -7643631 A solution containing the latter product and 15 ml. of 10% aqueous potassium hydroxide in 100 ml. of ethanol was stirred 1.5 hours at 45°c. The reaction mixture was then concentrated, diluted with saturated aqueous sodium bicar5 bonate and extracted with chloroform. The organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in acetone and treated with a molar equivalent of cyclohexylsulfamic acid. The product which precipitated was collected, and recrystallised from acetone-methanol to give 1.15 g. of salt corresponding to the cyclohexyleulfamate salt of the product of Example 31. The mother liquors were evaporated to dryness and the residue crystallized from acetone. Pour recrystalllzationa from aqueous methanol afforded 450 mg. of crystalline solid [a]^5 « -66.2°.

C. The levorotstory products of parts A and B were combined, recrystallized once from aqueous methanol snd then converted to the hydrochloride to give 1.1 g. of 4-hydroxy-a4$3-(4-methoxyphenyl)-1-me thylpropyl ]aminoJmethyI>-320 (methylBulfinyl)bensenemethanol hydrochloride, m.p. 178l8o°C., " -102.5°, corresponding to the levorotstory member of the pair of diastereomeric sulfoxides present in the product of Example 293.

Example 54 To a stirred solution containing 20 g. {0.134 mole) of 1,1-dimethyl-2-phenylethylamine in 40 ml. of N,Ndlmethylformamide at -50°C. was added dropwise over 15 minutes a solution containing 14.5 g. (0.048 mole) of 2bromo-4'-hydroxy-31-(methylthio)ccetophenond 4’-acetate in -77i ml. of Ν,Ν-dlmethylformaraide. After the addition was complete stirring was continued an additional 1.25 hours. The reaction mixture was then treated with 3.5 ml, of 12N hydrochloric acid, diluted with 100 ml. of water· and extracted thoroughly with ether. The ethereal extracts were dried over anhydrous sodium sulfate, acidified' with ethanolic hydrogen chloride and cooled in a refrigerator overnight. The 12.5 g. of precipitated product was collected and combined with 6.0'g, of product obtained from a previous run and recrystallized twice from chloroform-methanol affording 15 g. of S—[(1,1-dimethy1-2-phenylethyl)amino]4,-hydroxy-3'-,(methylthlo)acetophenone 4'-aeetate hydrochloride, m.p. 205°C. (dec.).

Example 35 To a stirred suspension of 15 g, (0.037 mole) of 2-[(1, l-dimethyl-2-phenylethyl)amino]-4'-hydroxy-31 (methylthio)acetophenone 4‘-acetate hydrochloride in 200 ml. of methanol at -5°C. was added portionwise over 10 minutes 750 mg. (0.020 mole) of sodium borohydride. After stirring an additional 10 minutes the reaction mixture was brought to pH 7 with glacial acetic acid and evaporated to dryness.

The residue was dissolved in ether-ethyl acetate and the resulting solution washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, acidified with methanesulfonic acid and concentrated to a small volume. The concentrate was diluted with benzene and evaporated to dryness. The proeess was then repeated employing toluene. The resulting solid residue was recrystallized from ethanol-ether to give 12 g. of g-/[(1, l-dimethyl-2---5. -7843631 phenylethyl)amino JmethylJ -4-hydroxy-3-(methylthio)benzenemethanol 4-acetate methanesulfonate, m.p. 112-115°C.

Example 36 A solution containing 9.5 g. (0.020 mole) of 5 a-£[(l,l-dimethyl-2-phenylethyl)amino3raethylj-4-hydroxy-3(methylthio)benzenemethanol 4-acetate methanesulfonate, 3 g. (0.045 mole) of potassium hydroxide and 20 ml. of water in 200 ml. of 95% ethanol was stirred overnight under nitrogen. The reaction mixture was neutralized with glacial acetic ecid and concentrated to a small volume. The concentrate was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated to a volume of 100 ml. The concentrated solution was brought to a pale yellow color by dropwise addition of glacial acetic aeid whereupon crystallization began. The product was collected by filtration and recrystallized from chloroform-methanol to give 5.1 & of a-{[(l,l-diraethyl-2-phenylethyl)amino 3 me thylj· -4-hydroxy-3-(methylthlo)ben zeneme thanol acetate salt, m.p. 165-167°C.

Example 37 Following a procedure similar to that described in Example 34 but using 18.3 g, (0.135 mole) of 1-methyl2-phenylethylamine and 15 g. (0.050 mole) of 2-brorao-4'25 hydroxy-3'-(msthylthlo)aeetophenone 4'-acetate there was obtained 7.1 g. of 4'-hydroxy-2-[(l-methyl-2-phenylethyl)amino3-3'-(methylthio)acetophenone 4'-acetate hydrochloride. 79" 43631 Example 38 Following a procedure similar to that described in Example 8 but using 7.4 g. (0.019 mole) of 4’-hydroxy2-[(l-methy1-3-phenylethyl)amino]-3'-(methylthio)aceto5 phenone 4'-acetate hydrochloride, 600 mg. 0.015 mole) of. sodium borohydride and 1.1 g. of potassium hydroxide there was obtained 6.3 g. of 4-hydroxy-a-£[(l-methyl-3-phenylethyl)amino]methylJ-3-(methylthio)benzenemethanOl acetate salt, m.p. 131-132°C.

Example 39 To a stirred solution containing 4.7 g. (0.012 mole) of cs-£[(l,l-dimethyl-2-phenylethyl)amino]methylJ-4hydroxy-3-(methylthio)benzenemethanol acetate salt in 100 ml. of methanol at 0°C. was added dropwise over 0.5 hours a solution containing 2 ml. (0.012 mole) of commercial 40% peracetic acid in 10 ml, of methanol. After the addition was complete the reaction mixture was evaporated to dryness and the residue was crystallized from ethanol-ether to give 4.3 g. of a-£[(l,l-dimethyl-2-phenylethyl)amino]" methyl)-4-hydroxy-3-(methylsulfinyl)benzenemethanol acetate salt which softened at 100°C. and melted at 138-l4o°C.

Example 40 A. To a stirred solution containing 35 g. (0.25 mole) of o-(methylthlo)phenol and 27.6 g„ (0.30 mole) of propionyl chloride in 100 ml. of nitrobenzene there was added portionwise over 25 minutes 46.5 g. (0.3' mole) of aluminum chloride. The reaction was exothermic and the temperature rose to 45-50’C. When the addition was complete the reaction -8043631 Mixture was stirred 2 hours at 60°C. and 1 hour at 70°C.

The reaction mixture was cooled, diluted with water and extracted with ether. The ethereal extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo.

The residual oil was adsorbed on a column of silica gel and continuously eluted with boiling methylene chloride. The eluate uas evaporated to dryness and the residue recrystallized from ether giving 25 g. of crystalline product which was then triturated with ether'at -65°C. to give 17 g. of pure 4’10 hyaroxy-3’-(methylthio)propiOphenone.

B, To s stirred solution containing 17.4 g. (0.089 mole; of 4'-hydroxy-3'-(methylthio)propiophenone, and 13 ml. (0.090 mole) of triethylamine In 200 ml. of methylene chloride there was added dropwise over 0.5 hour 7.65 g. (0,038 mole) of acetyl chloride. After the addition was complete stirring was continued an additional 2 hours. The reaction mixture was then washed successively with 3N hydrochloric acid and water and evaporated to dryness. The residual cil was dissolved in ether, treated with decoloriz20 ing carbon and filtered through a bed of silica gel. The filtrate was evaporated to dryness affording 21.4 g. 0f4'hydwxy-3'- (methylthio )propiophenone 4'-acetafce as a pale yellow oil.

C. To a stirred solution containing 21.4 g. (0.088 mole) of 4'-hydroxy-3'-{methylthioJproplophenone 4'-acetate in 250 ml. of chloroform was added a'solution containing 14,4 g. (0.090 mole) of bromine in 40 ml. of chloroform.

After a 15-mihhte induction period the bromine began to be consumed. After 1 hour the reaction mixture was washed with 5% aqueous sodium bicarbonate and then water. The -314 S 6 31 chloroform solution was dried over anhydrous sodium sulfate and evaporated to dryness to give 19 g. of 2-bromo-4'hydroxy-31-(methylthio)propiophenone 4'-acetate.

D. To a stirred solution contalnihg 30 g. (0.185 mole) of 2-(4-methoxyphenyl)-l-methylethylamine in 150 ml. of Ν,Ν-dimethylformamide there was added dropwise 19.6 g. (0.062 mole) of 2-bromo-4'-hydroxy-3'-(methylthio)propiophenone 4'-acetate. After the addition was complete stirring was continued an additional 2 hours. The reaction mixture was then diluted with chloroform and washed successively with water, dilute hydrochloric acid and saturated aqueous sodium bicarbonate. The chloroform solution was dried over anhydrous sodium sulfate and evaporated to diyness.

The residue was dissolved in ether,- acidified with glacial acetic acid and cooled. The precipitated product was collected and triturated with chloroform to give 6.35 g. of 4'-hydroxy-2-^[2-(4-methoxyphenyl)-l-methylethyl]amino^3'-(methylthio)prop!ophenone acetate salt, m.p. 110-112°C.

Example 41 To a stirred solution containing 6.2 g. (0.0148 mole) of 4'-hydroxy-2-^t2-(4-methoxyphenyl)-l-methylethyl]aminoJ-3'-(methylthioJpropiophenone acetate salt in 100 ml. of methanol at 0°C. there was added portionwise 0.5 g. of sodium borohydride. After the addition was complete stirring was continued an additional 0.5 hour. The reaction mixture was then acidified with glacial acetic acid and evaporated to dryness. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic extracts were evaporated to dryness and the residue -824 3 0 31 dissolved In ether, Tne ethereal solution was acidified with glacial acetic add and cooled. The precipitated product was collected and dried to give 5.0 g. of 4-hydroxy®"<£[2-(4-methoxyphenyl)-1-msthylethyl]aminoJethy3>-3(methylthio)benzenemethanol acetate salt, m.p. l6o-l62°C.

Example 4S To a stirred mixture of 2.35 g. (Ο.ΟΟ56 mole) of 4-hydiOxy-e-^£i 2-(4-methoxyphenyl)-l-methylethyl3amino/ethyl^3-(m£thylthic)benzenemethanol acetate salt and 4o ml. of mithtnol. at -10*0. there was added dropwise a solution containing 1 al, (0.0055 mole) of commercial 4o% peracetic acid la 5 ml. of methanol. After the addition was complete stirring -«as continued sn additional 0.5 hour. The reaction mixture was then evaporated to dryness and the residual oil suspended in cbloreform and diluted with ether producing a granular solid which was collected and dried to give 2.2 g. of 4~hylxioxy~G«^fl- [2- (4-methoxyphenyl) - 1-methy lethyl ] aminoJethyl>-3-(methylaulfinyl)benzenemethanol acetate salt, m.p. 110‘C, Bxsiaigle 43 To a stiTred solution containing 16 g. (0.082 sole) of 2-(3,4»dimethoxyphenyl)-l-methyl3thylamine and 6 ml. (0.041 sole) of triethylamine in 60 ml, of N,N-dlmethylformamido at -65*0. there was added dropwise over 0.75 hour ε solution containing 12,5 g. (0.041 mole) of 2-bromo-4'hydroxy-3*-(methylthio)acetophenone 4'-acetate in 40 ml. of iLN-diaethylformiJaide. After the addition was complete stirring was eonti?iued an additional hour. The reaction -83' 6 31 mixture was then made slightly acidic with 5 ml. of 12N hydrochloric acid and extracted with chloroform. The organic extracts were evaporated to dryness and the residue was dissolved in trifluoroacetic acid and treated with excess acetyl chloride. After stirring 1 hour the mixture was diluted with water and evaporated to dryness. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give 12 g, of crude 2-£[2-(3,4-dimethoxyphenyl)-l-methylethyl]aminoJ-4lhydroxy-31-(methylthio)acetophenone 4'-acetate.

Example 44 Following a procedure similar to that described in Example 38 but using 12 g. of 2-^[2-(3,4-dlmethoxy15 phenyl)-l-methylethyl]aminoj-4'-hydroxy-31 -(methylthio)acetophenone 4’-acetate, 870 mg. of sodium borohydride and 1.4 g. of potassium hydroxide there was obtained 2.2 g. of a-,/£[2~(3,4-dimethoxyphenyl)-l-methylethyl]aminoJmethyI>4-hydroxy-3-(methylthio)benzenemethanol acetate salt, m.p. 141-144°C.

Example 45 Following a procedure similar to that described in Example 42 but using 2.30 g. (0,0052 mole) of -425 hydroxy-3-(methylthio)benzenemethanol acetate salt and 0.95 ml. (Ο.ΟΟ52 mole) of commercial 40% peracetic acid there was obtained 1.9 g. of o>^[2-(3,4-dimethoxyphenyl)-lmethylethylJaminojmethy 5>4-hydroxy-3-(methylsulfinyl)-844 3 6 31 benzenemethanol acetate salt as a light-yellow amorphous solid.

Example 46 To a stirred solution containing 19.5 S· (0.12 5 mole) of 1,l-dimstkyl-J-phenylpropylamine in 100 ml. of NiN-dimsthylfox^amiCe under nitrogen at -00°C. there was added dropwise over 0,5 hour a solution containing 12 g. (0.04 mole) of 2-fcroao-4'-hydroxy-3'-(methylthio)scetcphenane 4’-acetate in 40 ml. of ibiJ-dimethylformamide.

After the addition was complete stirring was continued 1 hr. at -35°υ.· The reaction mixture was then acidified with 10 ml. of 1251 hydrochloric aeid, diluted with 150 ml, of chloroform und the resulting solution washed with water. The chloroform solution was cooled to -65’C. and diluted with ether. The resulting precipitate was collected and recrystallized from ethanol to give 12 g. of 2-((1,l-diaethyl3-pnenyIpropyl)aminoj-41-hydroxy-3'-(methylthio)acetophenone 4'-acetate hydrochloride, m.p. 188-193°C.

Example 4? SO Following a procedure similar to that described in Exaia&Ie 3 but using 11,0 g. (0.026 mole) of 2-((1,1dimethyl-3-phenylpropyl)aminoj-4'-hydroxy-3'-(methylthio)acetophenone 4'-acetate hydrochloride, 750 mg, (0.02 mole) of sodium borohydride and 1,4 g. (0,026 mole) of potassium hydroxide ther® was obtained 9.2 g. of o-£[(l,i-diraethyl-3phenyipropyl)aainojmethy l| -4-hydroxy-3-(methylthio) benzenemethanol acetate salt, m.p. 171-172OC. '5 6 3 1 Example 48 Following a procedure similar to that described in Example 11 but using 6.2 g. (0.015 mole) of a-^f[(l,ldimethyl-3-phenylpropyl)amlnoJmethyl^-4-hydroxy-3-(methylthio) benzenemethanol acetate salt and 1.17 g. (0.015 mole) of commercial 40# peracetic acid there was obtained 5.5 g. of crude ct-^( 1, l-dlmethyl-3-phenylpropyl)aminoJmethylJ-4hydroxy-3-(methylsulfinyl)benzenemethanol acetate salt. Following rscrystallization twice from chloroform-methanol and once from ethyl acetate-acetone-ethanol the product was dissolved in ethyl acetate-methanol and the resulting solution acidified with glacial acetic acid and evaporated to dryness. Recrystallization of the residue from ethanol-ethyl acetate afforded 1.4 g. of analytically pure material, m.p. 155-157°C.

Example 49 A. To a stirred solution containing 65 g. (1.0 mole) of potassium cyanide and 73.7 g. (0.38 mole) of 4-(j>methoxyphenyl)-2-methyl-2-butanol in 300 ml. of n-butyl ether at 60°C. there was added dropwise over 1 hour 120 ml. of concentrated sulfuric acid. When the. addition was com20 plete stirring was continued an additional hour at 5O-55°C.

The reaction mixture was then poured over 1200 g, of ice, made basic with sodium carbonate and extracted with ether.

The ethereal extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The 76.5 g. of residual oil was heated under reflux 3 hours in 175 ml. of 12N hydrochloric acid. The mixture was cooled, washed with ether, made basic with 35# aqueous sodium hydroxide and extracted with ether. The ethereal extracts were dried over anhydrous -864 ύ 6 31 sodium sulfate and evaporated to dryness. The residual oil was distilled under reduced pressure and the fraction boiling at l6l-l62°C./82 sa. wae collected affording 35 g· of 1,l-dimethyl-3- (4~®sthoxyphenyl)propylamine.

B. Following a procedure similar to that described in Example 7 but using 29 g, (0.15 mole) of 1,l-dimethyl-3(4-ESthoxypiien;?I)propylaiaine, 15 g. (0.05 mole) of 2-brcao^'-hydroxy-y'-fssthylthiojaeetophenone 4’-acetate and 10 ml. of acetyl chloride there was obtained 9»5 g. of 2-^(1,110 dinetiiyl-3-(4-methoxyphenyl)propyl]amino^-41-hydroxy-3'(raethylfchio)scotophenone 4'-acetate hydrochloride, m.p. 1?·β·«150' C.

Examnle^gO Foilowing a procedure similar to that described 15 in Example 8 but using 9.5 g. (0.021 mole) of 2-£(1,1dimethyl-3-(4-mer.fcuxyphenyl)propyl3affiino| -4' -hydroxy-3' (methylthioJcCetophenone 4'-acetate hydrochloride, 600 mg. (0.015 mole) of sodium borohydride and 1.2 g, of potassium hyeroxide tnere was ootained 2.3 g. of α-4βΐ,l-dimethyl-320 (4-raetho:;yphenyl)propyl3aminoJmethyl>-4-hydr&xy-3(aethylthio)benzenemethanol acetate salt, m.p. 173-174*0.

S-tsmple 51 Following, a procedure similar to that described in Example 11 but using 3.9 g. (0.009 mole) of a-<{(l,l£5 dimethyl-3-(4-methoxyphenyl) propyljarainojmethy3>-4-hydroxy3-(methylthio)benzenemethanol acetate salt and 680 mg. of coinaarcial 4o% peracetic acid there was obtained 3.0 g. of l-diffiethyl"3-(4~racthoxyphenyl ji3ropyl3aminoymethy2>-’ -87· „ 43631 4-hydroxy-3-(methylsulfinyl)benzenemethanol acetate salt, m.p. 115°C.

Example 52 Following a procedure similar to that described 5 in Example 7 but using 18 g. (0.12 mole) of l-methyl-3phenylpropylamine, 12 g. (0.04 mole) of 2-bromo-4'hydroxy-3'-(methylthio)acetophenone 4'-acetate and 8 ml. of acetyl chloride there wae obtained 8.3 g. of 4'-hydroxy2-((l-methyl-3-phenylpropyl)aminoJ-3'-(methylthio)aceto10 phenone 4'-acetate hydrochloride.

Example 53 Following a procedure similar to that described in Example 8 but using 8.1 g. (0.02 mole) of 4'-hydroxy2-((l-methyl-3-phenylpropyl)aminoJ-31 -(methylthio)a ceto15 phenone 4'-ecetate hydrochloride, 500 mg, of sodium boro- . hydride and 1.2 g. of potassium hydroxide there was obtained 6.2 g. of 4-hydroxy-K-jf[(l-methyl-3-phenylpropyl)amino]methylJ-3-methylthlo)benzenemethanol acetate salt, m.p. l4o-l42°C.

Example 54 Following a procedure similar to that described in Example 11 but using 4.2 g. (0.011 mole) of 4-hydroxy-a£[(1-methy1-3-phenylpropyl)amino Jmethyl J-3-(methylthio)benzenemethanol acetate salt and 815' mg. (0.011 mole) of commercial 40% peracetic acid there was obtained 4.0 g. of 4-hydroxy-a-£((1-methy1-3-phenylpropyl)amino Jmethy^-3(methylsulfinyl)benzenemethanol acetate salt as a pale yellow amorphous solid. -884 b b S jL Example 55 Following a procedure similar to that described in Example 34 but using 18.2 g. (0.11 mole) of 3-(4methoxyphenyl)propylamine and 11,2 g. (0.037 mole) of 25 bromo-4'-hydroxy-3’-{methyIthio)acetophenone 41-acetate there was obtained 9 g. of crude 4-hydroxy-2-^[3-(4-methoxyphenyl)propyl Jaaino ξ-3' -(methylthio)acetophenone 41 acetate hydrochloride which was suitable for use in the next step.

Example 56 Following a procedure similar to that described in 'teem^le 8 but using 9 g. of crude 4'-hydroxy-2-^[3(A-iaethoxyphenyl)propylJaminol-31-(methylthio)acetophenon@ 4'-aceti. te hydrochloride, 600 mg. of sodium borohydride and S.O 3. of potassium hydroxide there was obtained 1.2 g. of 4-hyd2?33y-is~<<' [3- (4-methoxyphenyl)propyl]aminojmethyi>»3(methylthio)benzenemethanol acetate salt, m.p. 123~125°C.

Example 57 Following a procedure similar to that described 20 in Example 11 but using 1.2 g. (0.003 mole) of 4-hydroxyα<£ί>( 4-methoxyphenyl)propyljaminojmethy j>-3-(methylthicJbensiiJSGEethanoX acetate salt and 0.44 ml. (0.003 mole) of cofc’.isrcial 40% peracetic acid there was obtained 1.1 g. of 4-hydrosy-o«^£i3-(4-methoxyphenyl)propyl3amino^aethy^»35 3«(mcthylBulfinyl)benzenemethanol acetate salt as an amorphous tan solid. -394 5 6 31 Example 58 A. A stirred mixture containing 64 g. (0.334 mole) of 5-(4-methoxyphenyl)~2-pentanone, 80 g. (1.77 moles) of formamide and 6 ml. of formic acid was slowly heated to l65°C. and, treated dropwise over 3.5 hours with 50 ml. of formic acid while the water formed during the reaction was allowed to distill slowly. Stirring at 165°C· was continued an additional 3 hours. The reaction mixture was then cooled, diluted with 1 liter of ice and water and extracted with a mixture of ether and benzene. The organic extracts were evaporated and the residual oil was heated under reflux 1.5 hours in 130 ml. of 12N hydrochloric acid. The mixture was cooled, diluted with 300 ml. of water and washed with a mixture of ether and benzene. The aqueous layer was made basic with 35% aqueous sodium hydroxide and extracted with a mixture of ether and benzene. The organic layer was extracted with IN hydrochloric acid, and the acidic aqueous layer made basic with 35% aqueous sodium hydroxide and extracted with an ether-benzene mixture. The extracts were dried over anhydrous sodium sulfate and the solvent evaporated in vacuo. The residual oil was distilled under reduced pressure to give 37 g. of 4-(4-methoxyphenyl)-l-methylbutylamlne, b.p. 163-166.5°C./ mm.

B. To a stirred solution containing 15·5 g· (0.08 mole) of 4"(4-methoxyphenyl)-l-methylbutylamlne in 80 ml. of N,N-dimethylformamide at -60eC, there was added dropwise over 0.75 hour a solution containing 8.0 g. (0.027 mole) of 2-bromo-4'-hydroxy-3'-(methylthio)acetophenone 4'-9043631 acetate in 28 al, of NjiJ-dimethylforaiaraide. After the addition was complete stirring at -6o° to -45°C. was continued an additional hour. The reaction mixture was then acidified with 48# hydrobromic acid and extracted with chloroform. The chloroform solution was diluted with 2.5 volumes of ether and cooled to -65°C. The resulting precipitate was collected, redlssolved in chloroform and the resulting solution washed thoroughly with water. The chloroform solution was then dried over anhydrous sodium u-f-fate and evaporated to dryness to give 9 g. of crude 4 ‘ -•?iydio;:y-2-£(4-(4-methoxyphenyl)-l-methylbutyl3emisv-f-J -(-iievhylthio)acetophenone 4*-acetate hydrobromide.

Sxaaala „ga Following a procedure similar to that described in lixcrmic δ using 9 g. of crude 4'-hydroxy-2-^[4(4-methoxyphany-, i-aethylbuty 1 .lamino! -3' - (methylthio )ccetcphshone 4*-acetate hydrobromide, 500 mg. of sodium borohydride ί-nd 1 g. of potassium hydroxide there was obti3ir.su 5.5 g. of 4-hydroxy-a-^l4-(4-methoxyphenyl)1-methylbatyl famine <· me thyTr-5- (me thylthio) benzenemetha nol aeetsto Ails, k.s. 15g-127°C.

Example 60 Poliowirg a procedure similar to that described in Ssaunlc 11 cut using 3.0 g. (0,007 mole) of 4-hydroxy·* jiit- thoxy phenyl) - 1-ae thyl hatyl Jaminojme thyl)>3(ffi9thylthio)b3nsjneaethanol acetate salt and i.o4 ral. (0,007 mole) of commercial 40# psrscetlc acid there was obtained 2.6 g. h.-gydvoxy-e-^yt4--(4-methc'iyphenyl)-14 a 6 3 methylbutyl)aminoJmethy]>-3-(methylsulfinyl)benzenemethanol acetate salt as an amorphous yellow solid.

Example 6l A. To a stirred mixture of 52.5 g. (0.253 mole) of 5 4-(4-meth B. Following a procedure similar to that described in Example 58B but using 19 g. (0.09 mole) of 4-(4-methoxyphenyl)-1,1-dimethylbutylamine and 10.0 g. (0.033 mole) of -92&b> 3 2"broK;o~i. ι -hydroxy-3! - (me thyl thio )acetophenone 41 -acetate anti allowing the final product to crystallize from acetone in a refrigerator overnight, there was obtained 10.5 g. of crystalline 4'-hydroxy-2-|[4-(4-ffiethoxyphenyl)-l, 15 dimethylcutyljnsiinoJ-S'-(methylthio)acetophenone 4'acetate hylrcSromide, m.p. IdC-lol0:;, Sidindia 5a Following a procedure similar to that described in Etum of 303+,,.¾. bcithydnae and 1 g. of potassium hydroxide, and recryrSallising the product from methsnol-ether there was obtained 3- of 4-hydroxy-e-«CJ(4-(4"jBethoxyphenyl)-l, 115 dumethylbutyllamino3 «.methy 2>-3-(methylthio)benzenemethanol as the f~_e oas-t 179-I8oec.

SamoleJ? .folltj-.’ing ,3 procedure similar to that described in Sxsm;'-C J but employing 2.7 g. (0,007 mole) of 420 hydrozy-a-<^ [4-{h«riethoxypnenyl)-l, l-diaethylbutyl]amino^methyl>-5-’(muthylth+o)benzenemethanol there was obtained 1.3 g„ of i-hj'drojiy-ci-y, (a-ί 4-methoxyphenyl)-1,1-dimethylbutyllaue.hoj’mothyli-^p- (adthylsulfi nyl) benzenemethanol ae en amorphous white powdsi’, Example 64 ,¾ stii’red mixture containing 7.4 g. (0.015 mole) 3* of optics i.ly pure /+)-4i-.nydi,oxy-2-^[3"(4-aethoxyphenyl)-lmethylpropyl]ai3inc>->'-(methylthioJscetophenone 4’-benzoate . 48631 hydrobromide and 100 ml. of 48% hydrobromic acid was heated under reflux 1.5 hours. The reaction mixture was then evaporated to dryness and the residue triturated with ethanol and isopropyl acetate to give 5.3 g. of (+)-4'~ hydroxy-2-£[3-(4-hydroxyphenyl)-l-methylpropyl]aminoJ-3'(methylthio)acetophenone hydrobromide» Example 65 Following a procedure similar to that described in Example 4l but employing 5.0 g. (0.012 mole) of (+)10 41-hydroxy-2-£[3-(4-hydroxyphenyl)-l-methylpropyl3aminoJ3'(methylthio)acetophenone hydrobromide and 0.455 g. of sodium borohydride, there was obtained 4.2 g. of 4hyd roxy-a-^£[3-(4-hydroxyphenyl)-1-methylpropylJaminoJmethyl>-3-(methylthio)benzenemethanol acetate salt, +5°.

Example 66 Following a procedure similar to that described in Example 22 but employing 4.2 g. (0.01 mole) of crude 4-hydroxy-cs-Z£[3-(4-hydroxyphenyl)-l-raethylpropyl]amino|20 methyi>-3-(methylthio)benzenemethanol acetate salt and eluting the oxidation product from a short (1.5 m.) column of silica gel followed by conversion to the cyclohexylsulfamate salt afforded 2.3 g. of dextrorotatory 4hyd roxy-ra-^£[4-(hyd roxyphenyl)-1-methylpropylJaminojmethyI>25 3-(methylsulfinyl)benzenemethanol cyclohexylsulfamate salt, m.p. 149-151°C., [e]q5 =+2.1°. -9443631 Example 67 A. To a'stirred solution containing 100 g. (0.55 mole) of 4’-hydroxy-3f-(methylthio)acetophenone in 650 ml. of dioxane and 300 ml. of ether was added dropwise over 4 hours a solution containing l4y g. of dioxane dibromide in 1050 ml. of 1:1 dioxane-ether^__When the additionj/as complete the reaction mixture was diluted with 500 ml. of ether and washed with water. The organic layer was separated} washed with saturated aqueous sodium chloride, filtered through cotton and the solvents evaporated under vacuum. The residue was twice slurried in benzene and the benzene evaporated. The final residue was crystallized from benzene-ether to give after drying,.107*5 g. of 2-bromo-4,-hydroxy-3'-(methylthio)acetophenone.

B. To a stirred solution containing 50 g.' (0.28 mole) of (-)3-(4-methoxyphenyl)-l-methylpropylamine(optical purity 3 94% in 150 ml. of Ν,Ν-dimethylformamide at -60’C. was added dropwise over 0.5 hr. a solution containing 3° 8· (0·12 mole) of 2-bromo4'-hydroxy-3'-(methylthio)acet6phenone in 80 ml. of Ν,Ν-dimethylformamide. After addition was complete, stirring at -6O’C. to -40’C, was continued an additional 5.5 hours. The reaction mixture was then acidified with 60 ml. of 48% hydrobromic acid, diluted with 150 ml. of water and washed with ether. The aqueous solution was evaporated to dryness under vacuum. The residue was dissolved in diehloromethane and the resulting solution was washed with water and saturated aqueous sodium chloride. The diehloromethane was evaporated and the residue was diluted with 2-propanol and cooled to O’C. The solid which precipitated was collected to give 9.5 g. of white crystalline hydrobromide salt. Concentration of the filtrate provided an additional 2.9 g. which was converted to the hydrochloride salt in conventional fashion affording 2.5 g. of (-)-4'-hydroxy-2- [3-(4-methoxyphpnyl)-l-methylpropyljaminoj -3·-(methylthio)aeetophenone hydrochloride, m.p. 195-197’C.,i*)|5= -11.4’. -95' Example 68 Following a procedure similar to that described in Example 23 B but employing 25 g. of 2-bromo-4’-hydroxy-3'(methylthiojacetophenone 4'-benzoate and 32 g. of .(-)-3(4-methoxypheny!)-l-methyIpropylamine (optical purity > 94%), there was obtained 29.6 g. of (-)-4'-hydroxy-2-f[3-(4-methoxyphenyl )- 1-methylpropyl lamino.} -3'-(methylthio)acetophenone 4'-benzoate hydrobromide.

Example 69 Following a procedure similar to that described in Example 4l but employing.9.3 g. of (-)-4'-hydroxy-2-[3-(4methoxyphenyl)-1-methylpropyllamino } -3’-(methylthio)acetophenone hydrobromide and 1 g. of sodium borohydride; and precipitating the hydrochloride salt directly from the ethyl acetate extracts, there was obtained 8.4 g. of 4-hydroxy-Q!-<£ [3- (4-methoxyphenyl)1- methylpropyllaminoj- -methyl> -3-(methylthio)benzenemethanol hydrochloride, m.p. 156-157^), ί®!^ = 9·3° as a mixture of two diastereomers.

Example 70 Following a procedure similar to that described in Example 10 but employing 29.6 g. (0.055 mole) of (-)-4'-hydroxy2- £ [3-(4-methoxyphenyl)-l-methylpropyiJamino^-3(methylthio) acetophenone 4’-benzoate hydrobromide, 1.55 ,g. (o.O4l mole) of sodium borohydride and 30 ml. of 35 percent aqueous sodium hydroxide: and isolating the product ae the hydrochloride salt there was obtained l8.6,g. of 4-hydroxy-a-<£ [3-(4-methoxyphenyl)-lmethylpropyllaminojk methyl >-3-( methylthio)benzenemethanol hydrochloride. -96406S1 Example 71 Following a procedure similar to that described in Example 11 but employing 17.6 g. (0.044 mole) of k-hydroxy-2-/ £ (3- (4-methoxyphenyl)-1-methylpropyl jamino methyl> -3" (methylthio)benzenemethanol hydrochloride prepared' according to the method of Example 70 and 3-36 g· (0.044 mole) of commercial 50% peracetic acid, there was obtained 12.5 g. of 4-hydroxy-2- <-£ [3-(4-methoxyphenyl)-1-methylpropylJamino2 methyl/· -3-(methylsulfinyl)benzenemethanol hydrochloride, m.p. ΙΟ7-ΙΙ7Ό., (a]p5 = +7.60, as a mixture of four diastereomers.

Example 72 A chloroform solution containing 10 g. (O.OI85 mole) of (+)-4'-hydroxy-2- £ [3- (4-methoxyphenyl)-l-methylpropyl]amino^3’-(methylthio) acetophenone 4'-benzoate hydrobromide was washed thoroughly with saturated aqueous sodium bicarbonate. The chloroform solution was then acidified with acetic acid and evaporated to dryness. The residue was oxidized with 2.2 ml. of commercial 50% peracetic acid in trifluoroacetic acid according to the method described in Example 25 to give 6.4 g. of 4'-hydroxy-2-·£ [3- (4-methoxyphenyl)-l-methylpropyl jamino^· -3·1(methylsulfinyl)acetophenone 4<-benzoate hydrochloride as a mixture of diastereomeric sulfoxides,m.p. 158-159°C.

Example 73 A mixture containing 15 g. of (+)-4'-hydroxy-2- £ [3(4-methoxyphenyl)-1-methylpropyl jami-no^ -5(methylthio) acetophenone 4'~benzoate hydrobromide, 140 ml. of acetonitrile and 40 ml. of concentrated aqueous ammonia was stirred 5 minutes . whereupon a solid began to precipitate. The mixture was cooled to O’C. and.the precipitated product was collected and washed with ether. Drying at 60*0*. caused the product to turn to a black gum. The latter was dissolved in methanol-ethyl acetate and filtered through silica gel. The filtrate was evaporated -974 3 6 31 to dryness and the residue was dissolved In ethyl acetate. Acidification of the resulting solution with ethanolic hydrogen chloride afforded 2.5 g. of pale yellow crystalline (+)-4’hydroxy-2- [3-(4-methoxyphenyl)-l-methylpropylj-aminoJ -315 (methylthio)acetophenone hydrochloride.

Example 74 Following a procedure similar to that described in Example 25 but employing 2.46 ml. (0.016 mole) of commercial 50% peracetic acid and 5.7 g. (0.016 mole) of (+)-4'-hydroxy10 2- £ [3-(4-methoxyphenyl)-l-methylpropyl]aminOJ -3(methylthio) acetophenone which was prepared as the free base according to the method of Example 73 and used immediately after drying 4 hrs. under vacuum at 45°C., there was obtained after precipitation with ethanolic hydrogen chloride from acetone/2-propanol, 2.5 g. of 4'-hydroxy-2- £(3-(4-methoxyphenyl)-l-methylpropyljaminoj -31(methylsulfinyl)-acebophenone hydrochloride as a mixture of diastereomeric sulfoxides, m.p. 192-194°C. (dec.), [a+19.2®.

In addition ¢0 antihypertensive and antiarrhythmic activity this compound has also been found to possess cardiotonic activity when tested according to the procedures described In Example 20 hereinabove. In the 1n vitro test this compound at doses of 10, 30 and 10C^/ml. caused increases in right atrial rate of 0,3 and 8 percent respectively; in right atrial force of ‘ 1,5 and 6 percent respectively; and in papillary muscle force of 7,23 and 38 percent respectively. In the in vitro test, at doses of 1.0, 3.0 and 10.0 mg/kg., the compound caused increases · in cardiac contractile force of 22,' 25 and 59 percent respectively. In a second, similar series of in vitro tests, increases in cardiac contractile force of 4, 12 'and 50 percent were observed. -984S631 Example 75 2-BrQmo-4*-hydroxy-3(methylthio)acetophenone (26.1 g., 0.1 mole) was reacted with 3,4-dimethoxyphenethylamine (45 g., 0.25 mole) essentially according to the method described in Fxample 67B. The product initially obtained upon evaporation of the aqueous solution was treated with hot methanol and the insoluble Ν,Ν-bis-[4-hydroxy-3-(methylthio/phenacyl )-3,410 dimethoxyphenethylamine was filtered off. The filtrate was concentrated, diluted.with 2-propanol and cooled. The resulting solid was recrystallized' from water, again filtering off insoluble by-product. The product thus obtained was recrystallized from aqueous'ethanol, and a 5.5 gram sample was converted to the hydrochloride salt in conventional fashion affording 4.6 g. of 2-jf [2-(3,4-dimethoxyphenyl)ethyl]amino^ -4'-hydroxy-3'(methylthio)acetophenone hydrochloride, m.p. 208-212*0» Example 76 Following a procedure similar to that described in Example 41 but employing 13.1 g. (0.033 mole) of 2-£ [2-(3,4dimethoxyphenyl) ethylJamino -4'-hydroxy-3>- (methylthio) acetophenone hydrochloride and 2.0 g. (0.053 mole) of sodium borohydride; acidifying the reaction mixture with 6N hydrochloric aeid and isolating the hydrochloride salt afforded IT.5 Z· of a-<£ [2-(3,4-dimethoxyphenyl)ethyllamino^methyl> -4-hydroxy3-(methylthio)benzenemethanol hydrochloride, m.p. 124-126’C.

Example 77 Following a procedure similar to that described in Example 11 but employing 5·6 g. (0.014 mole) of a-<£[2-(3,4- . dimethoxyphenyl)ethyl]amlno^ methyl > -4-hydroxy-3-(methylthio) benzenemethanol hydrochloride and 2.13 ml. of commercial 50% peracetic acid there wae obtained upon crystallization from 2-propanol, 4.9 g. of a-(£ 42-(3,4-dimethoxyphenyl)ethyl]amlno^ methyl>-4-hydroxy-3-(methylsulfinyl)benzenemethanol hydrochloride m.p. 173-175-0. -99. 40631 Example 78 To a stirred solution containing 72.3 g. (0.4 mole) of 3,4-dim'ethoxyphenethyl amine in 275 ml. of Ν,Ν-dimethylformamide at -50°C. vzas added over 2.25 hrs. a solution containing 39·3 g· (Ο.133 mole) of 2-bromo-4’-hydroxy-3(methylsulfonyl)acetophenone in 275 ml. of Ν,Ν-dimethylformamide. After the addition was complete, stirring was continued 1 hr. at -4o°C. to -45°C., then 1.5 hrs. at -3O°C to -40°C., and finally 0.5 hr. at -30°C to -5°C. The reaction mixture was cooled to -20°C. and acidified with 45 ml. of 48% hydrobromic acid. The solvents were evaporated under vacuum and the residual syrup was washed with ether. The syrup was dissolved in 200 ml. of water and allowed to crystallize over a weekend. The precipitated solid was collected, washed with water and ether and recrystallized from 95^ ethanol affording 32.31 g. of 2- £[2-(3,4-dimethoxyphenyl) ethylJaminoJ -4'-hydroxy-3'-(methylsulfonyl)acetophenone hydrobromide, m.p. 220°-227°C. A 10 gram sample was converted to the free base which was crystallized from aqueous methanol and then converted to the hydrochloride; m.p. 227-233’C. (dec.) Example 79 A mixture containing 14.3 g. (0.03 mole) of 2-£[2-(3,4-dimethoxyphenyl)ethylJamino^· -4’-hydroxy-3'-(methylsulfonyl) acetophenone hydrobromide and 1 g. of 10% palladium-on-earbon hydrogenation catalyst in 200 ml. of Ν,Ν-dimethylformamide was shaken under an initial hydrogen pressure of 50 psi until the absorption of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated under vacuum. The residual oil was treated with 100 ml. of 5 percent aqueous potassium bicarbonate, 20 ml. of 10% aqueous sodium carbonate and 40. ml. of ether. The solid which precipitated was collect ahd dissolved in 100 ml. of methanol containing 10 ml. of ethanolie -1004 3 6 31 hydrogen chloride. The solution was treated with decolorizing carbon and evaporated to dryness. The residue was dissolved in 225 ml. of hot methanol and the resulting solution was diluted with 125 ml. of acetonitrile and concentrated to a volume of 125 ml· °n standing a first crop of product crystallised and was collected by filtration. Further concentration of the filtrate afforded a second and third crop of product. The crops were combined to give 11.2 g. of «-<-^[2-(3,4-dimethoxyphenyl) ethylJaminoJ methyl/ -4-hydroxy~3-(methylsulfonyl)benzenemethanol hydrochloride, m.p. 209-210’C, Example 30 Following a procedure similar to that described in Example 6γΒ, 13.5 g. (0.05 mole) of 2-bromo-4'-hydroxy3*-(methylthio)aeetophenone was reacted with 22 g. (0.134 mole) of l-methyl-3-phenylpropylamine. The product initially obtained upon evaporation of the aqueous solution was converted to the hydrochloride salt in conventional fashion. Recrystallisation of the latter from aqueous methanol afforded 7.1 g. of 4'-hydroxy-2- [(l-methyl-3-phenylpropyl)amino]-3'(methylthio)acetophenone hydrochloride, m.p. 205-208’C. -10143631 Example 31 To a solution containing Ϊ4.6 g. (0.05 mole) of 2-bromo-4,-hydroxy-3'-(methylsulfonyl)acetophenone in 100 ml. of Ν,Ν-dimethylformamide at -40° to -50°C. was added a solution containing 22,6 g. (0.15 mole) of 1-methy1-3-phenylpropylamIhe in 100 ml. of Ν,Ν-dimethylformamide. After approximately 30 percent of the solution had been added over 1 hr. the remaining solution was added’rapidly over 10 minutes. Stirring was continued 1.25 hr. at -4o°C. and then 1 hr. at -lO’C. The reaction mixture was acidified with 21 ml. of concentrated hydrochloric acid and diluted with.25 ml» of water and 175 ml. of saturated aqueous sodium chloride. After stirring 0.5 hr. in the. cold the precipitated solid was collected, washed with saturated aqueous sodium chloride and ether and recrystallized from 350 ml. of water containing 20 ml. of 6N hydrochloric acid. The product was collected by filtration and washed with water and acetone. On standing 2 days the filtrate afforded a second crop of product and after standing one month a third crop was obtained. The final filtrate was evaporated to dryness ahd the residue recrystallized ‘ from water to give a fourth crop of product. -1024363 Each of the four crops was recrystallized from methanol-ethanol and the resulting products combined to yield 10.0 g. of 4'-hydroxy-2-[(l-methyl-3-pbenylpropyl)amino]-3 (methylsulfonyl’)acetophenone hydrochloride, m.p. 210‘,-215‘>C.

Example 8g A mixture containing 13 g. (0.032? mole) of 4'-hydroxy2-[(1-methyl-3-phenylpropyl)amino]-3(methylsulfonyl)acetophenone hydrochloride and 0.9 S· of 10 percent palladium-on~carbon hydrogenation catalyst in ISO ml. of Ν,Ν-dimethylformamide and 20 ml. of water was shaken under an initial hydrogen pressure of 38 psi until the absorption of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated under vacuum. The residue was partitioned between ethyl acetate and 5 percent aqueous potassium bicarbonate. The aqueous phase was saturated with sodium chloride and re-extracted with ethyl acetate The organic extracts were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under vacuum. The residual oil was dissolved in 50 ml. of warm ethanol and the resulting solution was acidified with ethanolic hydrogen chloride. The solvent was evaporated and the residue was crystallized from acetonitrile. The product was converted to the free base which crystallized from aqueous methanol. Reconversion to the hydrochloride and crystallization of the latter from acetonitrile afforded 8.95 g. of 4-hydroxyo- £t(l-methyl-3-pbenylpropyl)aminoJmethylJ -3-(methylsulfonyl) benzenemethanol hydrochloride, m.p. 178e-l3o*C.

Example 83 Following a procedure similar to that described in Example 80 but employing 13 g. (0.05 mole) of 2-broroo-4*-hydroxy-103631 3(methylthio)acetophenone and 22 g. (0.135 mole) of 1,1dimefchyl-3-phenylpropylamine, and stirring the reaction mixture 1.5 hrs. at -10°C„ there was obtained 7·θ Ε· of 2-[(1,1-dimethyl3-phenylpropyl)aminoJ-4'-hydroxy-3(methylthio)acetophenone hydrochloride, m.p. 215-220°C.

Example 84 To a stirred solution containing 44.5 g. (0.23 mole) of 3-(4-methoxyphenyl)-l,l-dimethylpropylamine in 185 ml. of Ν,Ν-dimethylformamide afc-50°0. was added over 2.25 hrs. a solution containing 27 g. (0.092 mole) of 2-bromo-4'-hydroxy-3'(methylsulfonyl)acetophenone in 185 ml. of N,Ν-dlmethylformamide. After the addition was complete, stirring was continued an additional 3 hrs. as the reaction mixture was allowed to warm to room temperature. The mixture was then acidified with 23 ml. of 48 percent hydrobromic acid-and evaporated under vacuum. The residual oil was washed with ether and then slurried in 200 ml. of acetone whereupon 3-(4-methoxyphenyl)-1,1-dimethylpropylamlne hydrobromide precipitated. The solid was separated by filtration and the filtrate was diluted with ether to precipitate the desired product. The solid so-obtained was slurried in 500 ml. of-hot acetonitrile, cooled and collected by filtration. This material was slurried In 200 ml. of hot chloroform, cooled ahd filtered to'give 21.9 g. of 4'-hydroxy-2-£[3-(4-methoxyphenyl)1,1-dimethylpropylJaminoj -3(methylsulfonyl)acetophenone hydrobromide, m.p. 220°-224eC (dec.), A 10 gram sample was converted to the free base by dissolving in methanol; basifying with 10 percent aqueous sodium carbonate; evaporating the methanol; diluting with water; and allowing the base to crystallize giving .4 g., m.p. 159°-165°c»j which was then converted to 2.93 g. of the hydrochloride, m.p. 222-232°C. (dec.) -1044S631 Example 85 Following a procedure similar to that described in Example 79 but employing 11.3 g· (0.023 mole) of 4'-hydroxy-2-£ [3-(4-methoxyphenyl )-1,l-dimethylpropyl]amino J· -3(mefchylsulfonyl)ac.etophenone hydrobromide there was obtained 9.66 g. of 4-hydroxy-a f3-(4-methoxyphenyl)-1,1-dimethylpropyljamino^. methyl}·-3-(methylsulfonyl)benzenemethanol hydroehloride, m.p. 202°-204°C.

Example 86 2-Bromo-4'-hydroxy-3’-(methylthio)acetophenone (25.4 g., 0.097 mole) was reacted with 3"(4-methoxyphenyl)propylamine (40 g., 0.242 mole) essentially according to the method described in Example 67B. The product initially obtained upon evaporation of the aqueous solution was treated with aqueous ethanol. The Ν,Ν-bls-(4-hydroxy-3-(methylthio)phenacyl]-3"(4-methoxyphenyl) propylamine which precipitated was filtered off. The filtrate was evaporated to dryness and the residue was crystallized from 2-propanol/ethyl acetate. The product so-obtained was triturated with hot water and the residue was crystallized from ethanol-ethyl acetate to give 6.5 g. of 4'-hydroxy-2- (4-methoxyphenyl) propylJaminoj-3(methylthioJacetophenone hydrobromide.

Example 87 Following a procedure similar to that described in Example 76 but employing 6.5 g. (0.0153 mole) of 4’-hydroxy-2[3-(4-methoxyphenylJpropylJamino^"3(methylthio)acetophenone hydrobromide and 1.2 g. of sodium borohydride, there was obtained 5.1 g. of 4-hydroxy-a- <(£[3-(4-methoxyphenyl)propyl] aminoj methyl>-3-(methylthio)benzenemethanol hydrochloride, m.p. 151e-152’C. -10548631 Example 88 To stirred suspension of 31.6 g, (o,l4 mole) of N-benzyl-3-phertylpropylamine in 280 ml. of methanol at -40’ to -45’( was added in one portion 20.5 g· (0.07 mole) of 2-bromo-4'-hydroxy5 3'-(methylsulfonyl)acetophenone. After stirring 2.5 hrs. the reaction mixture was allowed to warm to room temperature over 1.5 hi Evaporation under vacuum afforded a gummy residue which was slurried in 400 ml. of boiling ethyl acetate to give a solid precipitate of N-benzyl.-3-phenylpropyl amine hydrobromide. The solid was separated by filtration and the filtrate was evaporated to dryness under vacuum. The residue was dissolved in absolute ethanol and the resulting solution acidified with 35 ml. of 6.8 N ethanolic hydr< gen chloride. Evaporation of the acidic solution and crystallizatioi of the residue. from ethanol afforded 18.3 g. of 2-[N-benzyl-315 (phenylpropylJaminoJ-4'-hydroxy-31(methylsulfonyl)aeetophenone hydrochloridej m.p. 190 - 19l°C, The latter was combined with the products of several other runs and’ recrystallized from absolute ethanol to give material with m.p. 193.5-195’C. -106<35631 Example 89 A mixture containing 4.74 g. (0.01 mole) of 2-[N-benzyl-3-(phenylpropyl)amino)-4'-hydroxy-3(methylsulfonyl) acetophenone hydrochloride and 250 mg. of 10 percent palladium5 on-carbon hydrogenation catalyst in 100 ml. of 95 percent ethanol was shaken under an initial hydrogen pressure of 51.5 psi until the theoretical quantity of hydrogen had been absorbed.

It was necessary to dilute the reaction mixture with 200 ml. of percent ethanol and 50 ml. of Ν,Ν-dimethylformamide in order to dissolve the solid which had precipitated. The catalyst was then removed by filtration and the filtrate was evaporated to dryness under vacuum. The residue was triturated with 25 ml. of hot ethanol, cooled and the solid collected by filtration. This material was combined with the products of other runs and re15 crystallized from aqueous methanol to give'12.0 g. of 4'-hydroxy-3'(methylsulfonyl)-2-[(3-phenylpropyl)amlno jacetophenone hydrochloride m.p. 24l-'242°C. (dec.) 107' 43631 Example 90 Following a procedure similar to that described in Example 67B but employing 61 g. (o.29 mole) of mescaline and 28 g. (0.IO7 mole) of 2-bromo-4'-hydroxy-3'-(methylthio) acetophenone there was obtained 33 g. of crystalline product contaminated with a small amount of N,N-bis-[4-hydroxy-3(methylthio)phenacyl)-3,4,5-trimethOxyphenethylamine. The product was taken up in boiling water and the Insoluble by-product was filtered off. Concentration of the filtrate to a small volume produced 18.2 g. of 4'·?hydroxy-3'-(methylthio) -2-£ f2-(3,4,5-trimethoxyphenyl)ethyl)amlno^ acetophenone hydrobromide. The hydrochloride Isolated as the monohydate had m.p.193 195’C. Example 91 .

Following a procedure similar to that described in Example 4l but employing 16 g. of 4'-hydroxy-3'-(methylthio)-2£[2-(3,4,5-trimethoxyphenyl)ethylJamino acetophenone hydrobromide and 2.5 g. of sodium borohydride; and Isolating the product as the hydrochloride there was obtained 14.6 g. of 4-hydroxy-3- (methylthio)-a-<£ (2-. (3,4,5- trimethoxyphenyl) ethylamino^ methyl)>benzenemethanol hydrochloride, m.p. 168O-169.5*C.

Example 92 .

Following a procedure similar to that described in Example 11 but employing 7-7 g. (0.0175 mole) of 4-hydroxy-3-. (methylthio)-a-{£ [2-(3,4,5-trimethoxyphenyl)efchylJaminoJ methyl>hpnzenemethanol hydrochloride and 2.66 ml. (0.0175 mole) of commercial 50 percent peracetic acid; and crystallizing the . product from methanol-ether there was obtained 6.8 g. of 4hydroxy-3- (methylsulfinyl)+o!-/£[2- (3,4,5-trimethoxyphenyl) ethylJamino^ methyl> benzenemethanol hydrochloride, m.p. l64°-l66eC. -108436 31 Example 93 To a stirred solution containing 76.0 g. (0.36 mole) of mescaline in 250 ml. of N,N-dimethylformamide at -65eC. was added over 5.5 hrs. a solution containing 55-2 g. (0.12 mole) of 2-bromo-4’-hydroxy-3’-(methylsulfonylJacetophenone in 250 ml. of N,N-dimethylformamide. After the addition was complete^ stirring was continued at -40 to ~30°C. for Ihr. and then at -JO to -5°C. for 0.75 hr. The mixture was cooled to -20°C., acidified with 32 ml. of 48 percent hydrobromic acid and· evaporated under vacuum. The residual syrup was washed thoroughly with ether and crystallized from 2-propanol. The solid product was collected in several fractions the first few of which contained significant amount; of mescaline hydrobromide. The later fractions contained the desired product essentially free of mescaline hydrobromide. A 15-gram sample of the later fractions was converted to the free base and then to the hydrochloride to give 5.52 g. of 4'-hydroxy-2-£(2-(3,4,5-trimethoxyphenyl)ethyl]aminaj£ 3·"(methylsulfonyl)acetophenone hydrochloride, m.p. 230-234DC. (dec.) -10931 Example 94 Λ mixture of 16.47 g. (0.0357 mole) of 4'-hydroxy-3>(m$thylsulfonyl-2- £ [2-(3,4,5-trimethoxyphenyl)ethyl]amino acetophenone hydrochloride and 1.2 g. of 10 percent palladiumon-carhon hydrogenation catalyst in l8o ml. of Ν,Ν-dimethylformami and 20 ml. of water was shaken under an initial hydrogen pressure· of 48 psi until the absorption of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated under vacuum. The residual oil was crystallized from methanol-ether and recrystallized from methanol. The resulting product was converted with aqueous ammonia to the free base which crystallized from water. Conversion to the hydrochloride afforded 12.56 g. of 4-hydroxy-3-(methylsulfonyl)-a-<(£[2-(3,4,5-trimethoxyphenyl)ethyl aminof methyl>benzenemethanol hydrochloride, m.p. 192-194eC.

Example n5 To a stirred solution containing 12 g. of 4-hydroxyct-<£[3- (4-methoxyphenyl)-l-metliylpropyl]amino^ methyl> -3(iaethylthio)benzenemethanol prepared according to Example 19C in ml. of chloroform at 50°C. was added 29 ml, of thionyl chloride The temperature was maintained at 50β0.' and after stirring a short time the product began to crystallize. After stirring hrs. the mixture was cooled and the precipitated product was collected and washed with benzene to- give after drying, ll g, of 4-hydroxy-a-<)(3-(4-methoxyphenyl )-l-methylpropylJamino £ -3-(methyi thio) · J methyl>/benzyl chloride hydrochloride. -11043631 Example 96 To a stirred solution containing 9.6 g. (0.0226 mole) ,, of 4-hydroxy-a l.o g. (0.05 mole) of sodium horohydride. After stirring an additional hour the reaction mixture was neutralized with glacial acetic acid,· diluted with chloroform and washed with saturated aqueous sodium bicarbonate. The chloroform solution was dried over anhydrous sodium sulfate and evaporated to dryness.

The residue was dissolved in 9:1 2-propanol-m6thanol and the resulting solution was acidified with ethereal hydrogen chloride.

On concentration and cooling there was obtained 5.5 g. of (+)-4-<2- £[3-(4-mefchoxyphenyl)-l-methylpropyl]amino Jeefchyl/ -2' 7 (methylthio)phenol hydrochloride, m.p. 184-185’C.

Example Q7 To a stirred solution containing 5·0 g. (0.0135 mole) of (+)-4-< 2-£ [3-(4-methoxyphenyl)-l-methylpropylJamino^ cthyl>2-(methylthioJphenol hydrochloride in 50 ml. of methanol was added 10 ml, of commercial 50% peracetic acid. The reaction mixture was then cooled to 0-5°C. and treated with an additional 10 ml. of peracetic acid. After the addition was complete the reaction mixture was concentrated to 20 ml. and diluted with 50 ml. of 2-propanol. On standing at 5°C. overnight fche product crystallized. It was collected and dried fco give 4.5 g. of 4-<^ 2- ·£* (3-(4-mefchoxyphenyl)-l-methylpropylJamino^· ethyl/·-2-(methylsulfinyl )phenol hydrochloride, m.p. 205-208’C.

-IllExample 98 A mixture of 50 g· (0,925 mole) of (+)-4'-hydroxy-2£[3-(4-methoxyphenylj-l-methylpropyl]amino^ -3·'-(methylthio)acetophenone 4'-benzoate hydrobromide and 500 ml. of 48 percent hydrobromic acid was stirred and heated under reflux 1 hr. On cooling the product crystallized. It was collected and recrystallized from ethanol-Isopropyl acetate to give 26.7 g. of (+)-4'-hydroxy-2-£[3-(4-hydroxyphenyl)-1-methylpropylJamino^ -3'-(methylthio)acetophenone hydrobromide.

Example 99 Following a procedure similar to that described in Example 76 but employing 33 g. (0.0765 mole) of (+)-4'-hydroxy-2<£ [3*(4-hydroxyphenylj-l-methylpropylJaminoj -3(methylthio) acetophenone hydrobromide and 3.3 g. of sodium borohydride there was obtained 4-hydroxy-a-4^£[3-(4-hydroxyphenyl)-1-methylpropyl] amino 3 -methylz’· -3- (methylthio)benzenemethanol which was used directly in a further reaction.

Example 100 A stirred solution confining 0.075 mole of crude 4-hydroxy-a--3"(methylthio)benzeneme ;hanol In 50 ml. of dry dioxane was saturated with hydroge.n chlo *ide oVer 1.5 hrs. After stirring overnight the reaction mixture was diluted with ether, filtered through cotton and then concentrated to a volume of 150 ml. The concentrate was cooled and the precipitated product was colleoted and dried to give 27.8 g. of 4-hydroxy-a-(£[3 (4-tiydroxyphenyl)-l-methylpropyl]amino3methyl> -3-(methylthio) benzyl chloride hydrochloride. -11243631 Example 101 To a stirred solution containing 27.8 g. (9.0685 mole) of 4-hydroxy-α-(3- (4-hydroxyphenyl )-l-methylpropyl]aminoJ methyl^ · 3-(methylthio)benzyl chloride hydrochloride In 150 ml. of Ν,Ν-dimethylformamide at 0°C,was added portionwise over 0.25 hr. g. of sodium borohydride. After stirring an additional 0.5 hr. the reaction mixture was acidified with 6N hydrochloric acid, concentrated to near dryness, diluted with saturated aqueous sodium bicarbonate and extracted thoroughly with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was dissolved in a mixture of .ether and ethyl acetate and the resulting solution was acidified with ethanolic hydrogen chloride and cooled. The solid which crystallized was collected and recrystallized from acetone-methanol-ether to give 15.Ο g. of (+)-4-<( 2- £ [3-(4-hydroxyphenyl)-1-methylpropyl] aminojj ethyl> -2-(methylthio)phenol hydrochloride. Recrystallization of a sample from methanol-acet,one-ether and then from 2propanol-ether followed by drying 4 hrs. under vacuum at 100-115’C. afforded a material having m.p. 150-151’C. -1134 3 6 31 Example 102 To a stirred solution containing 4.2 g. (0.0114 mole) of (+)-4-< 2- £j3-(4-hydroxyphenyl)-l-methylpropyl]amino^ ethyl)> 2-(methylthio)phenol hydrochloride in 75 ml. of methanol at 0°C. was added over 20 min. I.73 ml. of commercial 50% peracetic acid in 5 ml. of methanol. When the addition was complete the reaction mixture was evaporated to dryness and the residue was crystallized from acetonitrile/2-propanol to give after drying 3 hrs. under vacuum at 100°C.} 5.7 g. of 4-<( 2-£ [3-(hydroxyphenyl)-l-methylpropyl]aminoJ ethyl^-2-(methylsulfinyl)phenol hydrochloride, m.p. 2O'I-2G5°C.

Additional examples of benzenemethanols and amino ketones having respectively Formulas I and II hereinabove and which, it is contemplated, can be obtained in accordance with the above-described procedures are presented in Table A hereinbelow.

Additional examples of haloketones and the corresponding parent phenyl ketones having respectively Formulas V and VII hereinabove which are useful intermediates in the preparation of the amino ketones of Formula II (Table A) and which, it is contemplated, can be prepared in accordance with the above-described procedures are presented hereinbelow in Tables B and C. The phenyl ketones of Table C can in turn be obtained in accordance with the above-described procedures by acylating the generally known 0-(lower alkylthio)phenols with an appropriate acyl halide under Friedel-Crafts conditions followed by esterification of the resulting 3-(lower alkylthio)- l-hydroxyphenyl ketones with an appropriate lower alkanoyl or a-oyl halide according to conventional esterification·procedures.

Additional examples of 2-phenylethylamines and 2-halo-2phenylethylamines having respectively Formulas III and IV hereinabove and which,it is contemplated, can be obtained in accordance with the above-described procedures are presented in Table D herein below. -11443631 benzenemethanols of Formula I: Z is CHOH amino ketones of Formula II:. Z is C=0 Q YR1 v R-, 3 n Ar CH-SO H c2h5 H ch3 2 fc-C^OCgHj, CHjS ι HC2H5 H ch3 2 £-ΟΗ3ΟΟδΗ4 CH-jS HGH3C6H4GO H H ch5 2 £-CH5OCgH4 CH-jS (f5K5)5CCO H H ch5 2 £-ch3oc6h4 CH-jSO (CK-jJjCCOH H CH? 2 £-CH3OCgH4 CgHpSOg KCO H H CpHj. 1c6H5 CH-S C5HnCO H H H 1C6H5 CgH5S . H H H CH-j 2 £CH3C6h4 CgH^SO H H H CHj 2 . fi-CHjCgH^ £-c4H9S H H H ch5 1 m-CH3OCgH4 CH-jS H H H CH(CH3)2 1 c6h5 CHjS H n-C4H9 H H £-(0¾)^¾ CHjS H H CH3 CHj 1 2,5-(0Η3)2-σ6Η3 CH^SOg H H H H 1 ^-(CH^gCHCHgOCgHj, CHjS H -c3h7 Hc4H9 1 °6H5 CK^S H H Ii CH, 1 3,4-(H0)2-CgH3 CH^SOg H H H H 1 3,4,5-(HOj^-CgH CH-.SO 2 H H H ch5 2 3-Br-4-H0-CgH3 CH?S H H H H 1 3-E-CgH, CH-S H H CH, 3 CH- 5 1 4-Br-CgH4 CH,SO H H H CH, 3 1 2,5-(Cl)a~CgH5 CH„S 2 H H H H 1 . 3,4,5-(Cl)jCgHg ch3so2 H . H H H 1 2,4,6-(CH3)3-Cgi CHjS H H H CH, 5 1 2-(C4H90)-3-CH3C 115 3 6 31 TABLE Β ί1 ro—<' ')—c-cH-} Q YR1 X CHjS HC2H5 Br CH-S £-CHjCgH4C0 H Br CHjS (CHj)jC CO H Br c2h5so2 HCO H Cl CHjS C^H^CO H Br c2h5s H H Br n-CjjHgS CHjCO H Cl CHjS H £-¾ Br CHjS H. n-CjRf iir -116TABLE C 631 Q Y Rl CK3S CH-jCO CHjS £-ch2csh4co H CH-S (ch5)5cco H OgKj-SOrj HCO H CH-zS CcH..C0 5 11 H c2h5s CH^CO H n-C^HgS CH-jCO H CH-jS CH-jCO S."c4H9 CH^S CHjCO -11740631 TABLE D a-phenylethylamlnfes of Formula III: B 13 hydrogen 2-Halo-2-phenylefchylamines of Formula IV: B is chloro, bromo or iodo. .

Q YR1R2R3 n Ar ch3so2 H H It CH., 2 ]3-CHjOGgH^ CH^S CHCO 3 HCH3CH3 1 °6H5 CH^SO HCH3 HCH3 1 £-CH3°C6H4 10 CH,S H H H H 2C6H5 CHjSO H H HCR3 1 3,4-(0^0)3-0^ CHjS H H HCH3 3 £-ch5oc6h4 CHjSO ο6κ5οο H H CHj : 2 3-Br-4-CH30-CgHj CH?SO? H HCH3CH3 2 £-CH3OCgH4 15 CH^S ' H It H H 1 3,4,5-(CH3O)3-CgH2 CHjSO H . °2H5 H ch3 2 £-CH3OCgH4 CH^S Hc2«5 H CH^ 2 £-CH3OCgH4 CH-jS jc-CH^CgHijCO H H CH? 2 2-CH-jOCgHj, CH-jS (ch3)5cco H H ch3 2 £-CH3OCgH4 20 CH^SO (ch3)3cco H H CH-j 2 £-CH3OCgH4 c2h5so2 HCO H HC2H5 1c6h5 ch3s c5hi:lco H H H 1 °6h5 c2h5s H H H CH-j 2 £-CH3CgH4 C2HcSO H H H CH-j 2 £-CH3CgH4 25 n~c4H9S H H H ch3 1 m-CH3OCgH4 CH-jS H H H ch(ch3)2 1C6H5 CHjS H £-σ4Η9 H · H 1 £-(CH3)3CCgH4 · CH-jS H H ch3 CH-j 1 2,5-(0Η3)2"06Η3 CHjSOg H H H H 1 £-(CH3)2CHCH20CgH4 30 CHjS H n-C,H - 3 7 HC4H9 1C6H'5 CHjS H H H ch3 1 3,4-(H0)2-CgH3 -118" TABLE D Q YR1 *2R3 n Ar CH^SOg H H H H 1 3,4,5-(HO)5-CgH CHjSO H H HCH3 2 3-Br-4-H0-CgH3 CH,S 3 H H H H 1 3-F"C6H4. . ' CH/ H H 2H-. ch5 1 4«Br-C6H4 CH-.SO 3 H - H HCH3 1 2,5-(Cl)2-CgH5 CH^S H H H H 1 3,4,5- (Cl)rC6H, CH-.SO. 3 2 H H H H 1 2,4,6-(CK3)3-Cgi CH,S 2 H H H CH^ 1 2-(C//)-3-CH/ 11943631 The compounds of this invention having Formula I have been shown to have useful antihypertensive, vasodilator and β-adrenergic blocking activity as can be seen from the results of standard pharmacological tests carried out on representative examples as described below.

Antihypertensive activity was determined on the basis of the observed reduction in systolic blood pressure measured according to the method of H. Kersten et al., J. Lab, and Clin. Med. 32, 1090 (1947) following a single oral medication in the unanesthetized spontaneous hypertensive rat described by Okamato et al», Japan Circulation J. 27, 282 (1963).

Antihypertensive activity was also Judged on the basis of sustained reduction of blood pressure observed in the unanesthetized trained renal hypertensive dog following repeated oral medication according to the procedure described by Lape et al,, Arch. int. Pharmacodyn. 160, 342 (1966).

Vasodilator activity was Judged on the basis of observed reduction in perfusion pressure in the hind limb vasculature' of the anesthetized dog determined according to the procedure described by Jandhyala et al., European J.

Pharm. 17, 357 (1972), and also on the basis of percent reduction in perfusion pressure as measured In the isolated rabbit ear artery according to the method described by De La Lande et al„ Aust. J. Exp. Bio). Med. Sci, 43, 639 (1965).

The β-adrenergic blocking activity was determined In the pentobarbitalized dog as judged by the ability of the test compound to inhibit the elevation in heart rate elicited by a 0.5 mg./kg. i.v. injection of isoproterenol. -1204 3 b 3 1 Acute intravenous and oral toxicity in mice was determined for the compound of Example 11A as follows: The compound was dissolved in distilled water and administered as the base at a volume of 10 ml./kg. for the i.v. ΑΙΒ^θ or 10-40 ml.Ag· for the p.o. ALD^q. The compound was administered in graded doses to groups of three mice each (Swiss-Webster strain males weighing 20 ; 2 g.). Mortality occurred within 1 minute after i.v. administration and within 10 minutes after oral administration. Symptoms of acute Intoxication for the fatalities included atoxia, loss of righting reflux, clonic convulsions and dyspnea followed by respiratory arrest. There were no untoward symptoms observed for up to 7 days for the survivors. The i.v.

ALDj0 was 75 mg./kg. and the p.o. ΑΙΒ^θ was 1500 mg./kg.

The 7-day oral LDjQ in rats was determined for two separate batches of the compound of Example 20B and was found to be 1850 and 1940 mg./kg. respectively. No changes in body weight and no gross tissue changes were observed in animals sacrificed 7 days post-medication.

The results of the above-described phramscologieal tests are presented in Table E hereinbelow.

As noted hereinabove certain of the compounds of this invention also have antiarrhythmic activity. The latter was determined in vivo and efficacy was judged on the ability of the test compound to convert to normal rhythm the arrhythmia induced by barium ion or ouabain intoxication. The test procedures were carried out as follows: -12143631 ψ-fBa -Induced arrhythmia Adult rabbits or either sex, weighing between 1.7-and 2.3 kg, were anesthetized with'3θ to 35 mg/kg Na-pentobarbital l.v. via a marginal ear vein. Monopolar ECG pin electrodes were inserted for a lead II display on a Model 5 Grass Polygraph using standard electrocardiographic procedures. A 23 ga. hypodermic needle, attached via a polyethylene catheter to a 10 cc syringe, was Inserted into the same vein as was used for anesthesia. A BaClg.2HgO solution In saline was then Infused at a constant volume of 0.2 cc/min from a Harvard Apparatus Model 600 infusion pump. This infusion was not stopped until termination of the experiment. In some studies barium chloride in distilled water was used without detectable differences. The standard rate of BaClg.BHgO infusion was established at 0.3 mg/kg/ min (l.2X10_DM/kg/min), and the concentration was adjusted appropriately in each case to accomodate the weight of the rabbit.

When the desired arrhythmia was established, the test compound was Introduced as a water or saline solution into the marginal ear vein of the unused ear. The volume used was between 0.5 and 2.0 cc/kg and was injected as a bolus over approximately 30 seconds. Deviations from standard vehicle, rate of Injection, and total volume administered were at the discretion of the operator. The standard initial does of an unknown compound on the first rabbit was SXlO’^M/kg. In general two to 25 three rabbits were used to determine anti-arrhythmic activity and the dose range of activity; multiple doses were administeredOnce activity and dose was indicated, two additional rabbits were employed to confirm anti-arrhythmic activity against a multifocal tachycardia. -122· 3 6 31 Ouabain-Induced arrhythmia Adult mongrel dogs of either sex, after fasting for to 29 hours, were anesthetized with 35 mg/kg Na-pentobarbital i.v. and tied supine on an· operating table. A patent airway was provided by inserting an endotracheal cannula, and fche animal respired spontaneously. A femoral vein was double cannulated with one cannula for injection and the other as a site for ouabain infusion. The ipsilateral femoral artery vzas cannulated for blood pressure measurement. Na-pentobarbital supplements were given i.v. as needed.

Statham P23A blood pressure transducers were used to measure blood pressure, and electrocardiograms (lead II or Vy) were taken with monopolar pin electrodes. Both parameters were printed out on a Crass polygraph. Each dog was given 36 meg/kg ouabain i.v. over 1 minute (the solution contained 50 mcg/ml ouabain in Isotonic saline) followed by a constant ouabain infusion (0.6meg/kg/min) starting 5 minutes later. The infusion solution was prepared so that the appropriate dose per minute was delivered in 0.5 ml.

When the predominant rhythm of the ensuing arrhythmia was a ventricular tachycardia (or sometimes nodal) an attempt was made to convert this arrhythmia with the test compound. Up to 104 M/kg of test drug was delivered in a volume of 1 ml/kg over a 5 min. Infusion period. If a conversion or cardiotoxic effect was seen before 10-/* M/kg was delivered, the dose was noted and repeated on a second dog. -1234 0 6 31 The te3t was routinely conducted using pairs of dogs with a 15 minute difference in starting time. All ECG interval and duration measurements were made on lead II with a chart speed of 100 mm/sec. Heart rates were made on lead II with a chart speed of 100 mm/sec. Heart rates were taken from lead II QRS eomplexps at 25 mm/sec. Blood pressure was measured using a sensitivity of 10 mm Hg/iran pen · deflection.

The results of the above-described tests are 10 presented in Table F hereinbelow. The test compounds are indicated to be active (A) pr inactive (I) at the dose tested expressed in M/kg. Γ. *12443631 TABLE Ε Pharmacological Properties Cpd, of Ex. No. | Antihypertensive Activity Vasodilator Activity Adrenergic Activity SK Rat mg./kg. P.O. ί i Renal [Hypertensive Dog | HSDiob mg,/kg. 1 tld Dog-Ls-g Perfusion AED5Qe mg. Ag. Rabbit Ear Artery d vasodilation0 (molar cone.) Dog B-blockade AED.oe mg./kg. 2 10,0 0.5 50% ¢¢1.0(60%)1 3 20.0 0.5 (1x10_5M) 56% 0.1 4 β 2.0 1.25 0.25 (2xlO-5M) 53% 0.04 6 «pi >50.0(-26)1 0.5 (6.25xl0~5M) 90% <1.0(70%) 8 15.0 >2.5(0)g 0.5 (1x10 M) 55% 0.1 11A 2.0 0.0316 0.5 (lxl0-Sl) 50% 0.025 11B 9.0 0.5 (5x10"5m) 20% 0.025 13 >50,0(-20) >0.5(0) 0.5 (5xl0"5M) 50% 0.1 17 >20,0(-33) 0.5 (3.5xlO"5M) 10% (lxl0Sl) 49% CaO.5 193 20A 3.0 0.0316 0.5 >0.1(45%) 0.125 200 4.0 ί (5xlO5M) 50% (5x10_5M) <0.25(70%) -1251 TABLE Ε Pharmacological Properties Cpd. of Ex. No. Antihypertensive Activity Vasodilator Activity Adrenergic Activity SH Rat AHD40 mg./kg. P.O. Renal Hypertensive Dog MEDi0b mg./kg. tid Dog-Leg Perfusion aed50 mg./kg. Rabbit Ear Artery d vasodilation0 (molar eonc.) Dog β-blockade AED50 mg.Ag. 20D 4.0 71% (1x10-4M) 20E 64% (1x10_4M) 21A 0.5 >0.1(14%) 21B 0.5-. 0.1 22A 15.0 >0.025(25%)h 58% (5x1O_5M) 0.25 23A >50.0(-22) 24a >50.0(-10) 25 50 26 9 29A 20.0 >0.025(25%) 6l% (5xlO5M) 0.0125 30 >16.0(-17) t >0.5(8%) 5°% (2xl0"4M) >0.10(23%) 51 >16.0(-14) <0.5(14%) 38% (lxl0_4M) 0.25 52 5 <0.5(14%) 50% (2x104M) 0.05 55 5 ' <0.5(17%) 50% (1x104M) 0.0125 -126' S 6 3 fW β Phsrffiacologidsl Properties Antihypertensive I Adrenergic Activity J Vasodilator Activity j Activity ______: j — ~' . j_ _____ ϊ » ί n Cpd. of Ex. No. SH Hat ahd40 mg./kg. P.O. Hyperten- !sive Dog ®Diob mg./kg. tid u ..... .... tt [ Dog Leg f Perfusion AEa50 1 mg./kg. s Rabbit Ear Artery , vasodilation0 !(molar cone.) J ΐϊ ί Dog 1β-blockade abd50 i mg./kg. 36 Sa50.0 ! 0.5 71% ,(1x10_5m) .<1.0(56%) 38 35.0 0.5 I 33% i(2x105M) <1.0(60%) · 39 20.0 0.5 29% (1x10-5M) <1.0(87%) 41 5.20.0(-23) 42 5^20.0(-25) 45 . 15-0 0,5. .... 75% (5x1O-5m) >0.1(38%) 47 . i ty? (5x1O_5M) <1,0(100%). 48 >20.0(-37) 0.5 50% (5x10 5m) 0.05 50 20.0 0.5 0.5 50% (9x1O5M) <1.0(72%)51 >20.0(-26) >0.125(0) 0.5 42% (1χ10"4Μ) <1.0(100%) 53 5-0 0.5 δ i/D 1 (5xlO~5M) 0.1 54 I 20.0 >0.125(0) 0.5 50% (5^10-¾) 1 <0,025(67%) -127TABLE E Pharmacological Properties Antihypertensive Activity SH Rag AHD mg./kg. P.0. 7.0 >50.0(-17) 40.0 >50.0(-12) 40.0 >50(-17) > 50(-31) . > 50(-14) Ca.10 >50(-12) >50(-12) ca.4o.o >50(-22) >50(-13) >50(-26) >50(-20) >50(-22) >50(-22) >50(-31) >50(-12) Vasodilator Activity Adrenergic Activity Renal Hypertensive Dog b '10 mg./kg. tid MED. >0.125(0) >20(0)J Dog-Leg Perfusion aed50 mg./kg.

Rabbit Ear Artery . vasodilation0 (molar cone.) Dog β-blockade ΛΕ050θ •mg./kg. 0.5 (constrictor' <0.1(67%) 50% (lxlO5M) < 0.025(80%) ca.0.10 y 1.0(0%) ca.0.50 > 1.0(10%) > 1.0(33%) ca.0.50 > 1.0(18%) > 1.0(0%) ca.1.0 ca.0.10 z* 1.0(0%) ca.0.10 > 1.0(17%) 1.0(0%) ca,0.05 -128TABLE E Pharmacological Properties Antihypertensive Activity | Vasodilator Activity } Adrenergic Activity Gpd. of Ex. Ho. Sfl Rat AHD4cd mg./kg. P.0. Renal Hypertensive Dog MEDwb mg./kg. tid Dog-Leg Perfusion aed50c mg./kg. Rabbit Ear Artery , vasodilation0 (molar cone.) Dog S-blockade AED~oe mg./kg. 83 > 50(-29) >1.0(11%) 84 ' > 50(-18) >1.0(0%) 85 > 50(-18) ca.0.50 θ7. > 50(-13) < 1.0(67%) 89 > 50(-11) 91 < 50(-51) 92 > 50(-15) 93 ca. 50.0 96 ca.50.0 > 1.0(14%) 97 <20(-54) > 40J >1.0(43%) 101 > 50(-8) 102 >5O(-3) ca.0.50 -12943631 (a) AHDhq = single oral dose required to induce a 40 mm average reduction in systolic blood pressure in the unanesthetized spontaneous hypertensive rat.' (b) MED-iq - minimum repeated oral daily dose required to effect a sustained lowering of blood pressure of 10% or greater in the unanesthetized trained renal hypertensive dog. (c) AEDj-q 04 approximate intraarterial dose required to cause a 50% reduction in perfusion pressure in the hind limb of the anesthetized dog. (d) Vasodilation ls expressed as the percentage reduction in perfusion pressure from the cohtrol level at the Indicated molar dose. (e) AEDj-x = approximate intravenous dose required to cause 50% -3 inhibition- of the heart rate increase elicited by isoproterenol in the pentobarbitalized dog. (f) Actual reduction in blood pressure (in mm Hg) observed at the Indicated dose. (g) Actual percentage reduction in blood pressure observed at the indicated dose. (h) Actual percentage reduction in perfusion pressure observed at the indicated 'dose. (i) Actual percentage inhibition of heart rate increase above control level observed at the indicated dose. (j) AdmlnlafcSFSd'Onee per day. -130TABLE F Antiarrhythmic Activity Cpd. of Ex. No. Conversion of Ouabain-induced arrhythmia Conversion of Ba++induced arrhythmia 6 » .. - ά} 3AlO A, 5X1O5 19D A, 2.5X1O5 A, .5X1O*6 20E,F A, 5X10"6 A, 1X105 23B A, 1X105 43 A, 5X1O6 A, 2.5X106 51 A, 5XIO6 54. A, 5XI05 Α, 2.5Χ1Ο*δ 67B A, 2.5X1O5 68 -5b x 2.5x10 5 A, 5XIO5 87 -5b X 2.5x10 5 A, 1X105 101 A, 5X10δ 102 A, 1X105 A, 2X105 (a) M/kg. (b) Toxic at 2.5X10"inactive below 2.5X10 δ

Claims (14)

1. A compound having in the free base form the Formula I (herein) wherein R]_, R 2 and Rj are independently hydrogen or lower alkyl; ® n is an integer from 1 to 3; Ar is phenyl or phenyl having from one to three halo, lower alkyl, hydroxy or lower alkoxy substituents; Q is lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; and 10 Y is hydrogen, lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl; or an acid-addition salt thereof»

2. A compound according to Claim 1, wherein Ar is phenyl or phenyl having one or two lower alkyl, hydroxy or lower alkoxy substituents,

3. A compound according to claim 2, wherein Rj is hydrogen and Q is methylthio, methylsulfinyl or methylsulfonyl.

4. A compound according to claim 3, wherein Y is hydrogen, lower alkanoyl or aroyl,

5. Alpha-ί[Cl,1-dimethyl-3-phenylpropyl)amino]methyl}-4hydroxy-3-(methylthio)benzenemethanol or an acid addition salt thereof»

6. » 4-Hydroxy-a-{[Cl-methyl-3-phenylpropyl)amino]-methyl}3-(methylthio)benzenemethanol or an acid addition salt thereof. 25 7. 4~Hydroxy-a~{[Cl-methyl-3-phenylpropyl)amino]-methyl}3-(methylsulfinyl)benzenemethanol or an acid addition salt thereof. 8. A compound according to claim 3 or 4, wherein Ar is 4methoxypheny1» -1329. Alpha-<{ [l,l-dimethyl-3-t4-methoxyphenyl)propyl]-amino}methyl>-4-hydroxy-3-(methylthioibenzenemethanol or an acid-addition salt thereof,

7. 10. 4-Hydroxy-a-< {[3- (.4-methoxyphenyl) -1-methyl-propyl] amino} 5 methyl>-3-(methylthio)bensenemethanol or an aoid addition salt thereof.

8. 11. 4-Hydroxy-a-<({3- (4-methoxyphenyl)propyl]amino}-methyl>3-(mathylsulfinyl)benzenemethanol or an acid-addition salt thereof.

9. 12. 4-Hydroxy-a-<{[3-(4-methoxyphenyl)-l-msthyl-pzopyi]amino}· 10 methyl>-3-(methylsulfinyl)benzenemethanol or an acid addition salt thereof.

10. 13. The hydrochloride salt according to claim 12, as a n stereoisomer identifiable by an («Jp “ +126.5® (2% in msthanol).

11. 14. The hydrochloride salt according to claim 12, as a )5 . stereoisomer identifiable by an [aj^ = -48.2° (2% in methanol). 2,5. The hydrochloride salt according to claim 12, as a stereoisomer identifiable by an [a]^ = +70.5° (2% in methanol). 16, The hydrochloride salt according to claim 12, as a stereoisomer identifiable by an Ea]^ = -102.3° (2% in msthanol). 20 17, A compound according to claim 2, wherein is methyl, Q is methylthio, methylsulfinyl or methylsulfonyl, Ar is lower alkoxyphenyl and Y is hydrogen. 18, A compound having in the free base form the Formula 111 (herein), wherein 25 Rp R 2 and R 3 are independently hydrogen or lower alkylj n is an integer from 1 to 3? Ar is phenyl or phenyl having from one t© three halo, lower alkyl, hydroxy or lower alkoxy substituents? Q is lower alkylthio, lower alkylsulfinyl or lower 30 alkylsulfonyl? and 13331 Y is hydrogen, lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl; or an acid addition salt thereof. 19, A compound according to claim 18, wherein R-j_ is hydrogen and Q is methylthio, methylsulfinyl or methylsulfonyl. 20. A compound according to claim 19, wherein Ar is 4-methoxyphenyl and Y is hydrogen. 21. A process for producing a compound according to claim 1, which comprises reducing a compound having in the free base form the Formula II (herein), or an acid addition salt thereof, wherein in the event that Y in the starting compound is lower alkanoyl or aroyl and the reduction is carried out with a reducing agent capable of reducing both ketone and carboxylic ester functions, Y in the resulting compound is hydrogen, if.desired, hydrolyzing a compound obtained wherein Y is lower-alkanoyl or aroyl to obtain the corresponding compound wherein Y is H or esterifying a compound obtained where Y is hydrogen to obtain the corresponding compound where Y is lower alkanoyl or aroyl, if desired, oxidizing a compound obtained wherein Q is lower alkylthio to obtain the corresponding compound wherein Q is lower alkylsulfinyl, and, if desired, converting a free base compound obtained to an acid addition salt thereof or forming a basic salt of a compound obtained wherein Y is hydrogen. 22, A process for producing a compound·according to claim 18, which comprises reducing a compound of the Formula IV (herein) or an acid addition salt thereof, wherein in the event that Y in the starting compound is lower alkanoyl or aroyl and the reduction is carried out with a reducing agent capable of reducing both ketone and carboxylic ester functions,V in the resulting compound is hydrogen, if desired, hydrolyzing a compound obtained -134' wherein Y is lower alkanoyl or aroyl to obtain the corresponding compound wherein y is H or esterifying a compound obtained where Y is hydrogen to obtain the corresponding compound where Y is lower alkanoyl or aroyl, if desired, oxidising a compound obtained wherein Q is lower alkylthio to obtain the corresponding compound wherein Q is lower alkylsulfinyl, and, if desired, converting a free base compound obtained to an acid addition salt thereof or forming a· basic salt of a oompound obtained wherein Y is · · · hydrogen 23. A process according to claim 21 or 22, which does not include esterifying a compound obtained according to any one of claims 1, 2 and 18, or hydrolyzing a compound obtained according to claim 18. 24» k process for preparing a compound according to Glaim 1 or 18, substantially as herein described with reference to the Examples '! to 13 and 15 to 102. 25» A process for preparing a compound according to claim 2, substantially as herein described with reference to Examples 1 to 13 and 15 to 66. 25, A compound when prepared by the process according to any one of claims 21 to 25» 27» A compound according to claim 1 or 18, substantially as herein described with reference to the Examples 1 to 13 and 15 to 302 28» A compound according to claim 2, substantially as herein described with reference to Examples 1 to 13 and 15 to 66 29» A compound having in the free base form the Formula II (herein) wherein R^o Rg an< ^ r 3 are independently hydrogen or lower alkyl; n is an integer from 1 to 3; Ar is phenyl or phenyl having from one to three halo, lower alkyl, hydroxy or lower alkoxy substituents; -135 / v . Q is lower alkylthio, lower alkylsulfinyl or lower alkylsulfonylj Y ie hydrogen, lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl? 5 or an acid addition salt thereof. 30. A compound according to claim 29, wherein Ar is phenyl or phenyl having one or two lower alkyl, hydroxy or lower alkoxy substituents, 31. A compound according to claim 30, wherein Rj_ is hydro10 gen and Q is methylthio, methylsulfinyl or methylsulfonyl. 32. A compound according to claim 31, wherein Q is methylthio and Y is hydrogen, lower alkanoyl or aroyl. 33. A compound according to claim 31 or 32, wherein Ar is 4-methoxyphenyl.

12. 15 34. 4'-Hydroxy-2-{[3- C4-methoxyphenyl)-1-methylpropyl]amino)-3 1 -(methylsulfinyl)acetophenone 4'-benzoate or an acid addition salt thereof. 35. 4 ’-Hydroxy-2-ί [3- (.4-methoxyphenyl) -1-methylpropyl]amino}-3*-(methylthio)acetophenone 4‘acetate or an acid addition 20 salt. 36. t+)-4'-Hydroxy-2-{[3-(4-methoxyphenyl)-1-methyl-propyl] amino}-3'-(methylthio)acetophenone 4'benzoate or an acid addition salt. 37. A compound according to claim 30, wherein R 1 is methyl, 25 Q is methylthio, methylsulfinyl or methylsulfonyl and Ar is lower alkoxyphehyl. 38. A compound according to claim 37, wherein Q is methylthio and Y is hydrogen. 39. A compound having in the free base form the Formula IV 30 (herein) wherein -136- 43631 χ X is chloro, bromo or iodo? &2 a ^d r 3 are independently hydrogen or lower alkyl; n is an integer from 1 to 3; Ar is phenyl or phenyl having from one to three halo, 5 lower alkyl, hydroxy or lower alkoxy substituents; Q is lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; Y is hydrogen, lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl; or an acid addition salt thereof, 40, A compound according to claim 39,, wherein is hydrogen and Q is methylthio, methylsulfinyl or methylsulfonyl, 41, A compound according to claim 40, wherein X is chloro and Y is hydrogen, 15 42, A process for producing a compound according to claim 29, which comprises reacting a haloketone having the Formula V (herein) with an amine having the Formula VI (herein), and, if desired, esterifying a compound obtained wherein Y is hydrogen to obtain the corresponding compound wherein Y is lower alkanoyl or

13. 20 aroyl or hydrolyzing a compound obtained where Y is lower alkanoyl or aroyl to obtain the corresponding compound where Y is hydrogen, if desired, oxidizing a compound obtained where Q is lower alkylthio to obtain th® corresponding compound where Q is lower alkylsulfinyl and if desired, converting a free base compound obtained to an

14. 25 acid addition salt thereof or forming a basic salt of a compound obtained wherein Y is hydrogen, 43, A process according to claim 42, wherein X is bromine, 44, A process for producing a compound according to claim 39, which comprises reacting a compound of the Formula I (herein) 3° with HX or an inorganic acid chloride or bromide, and, if desired. -1375 4aS3i converting a free base compound obtained to an acid addition salt thereof or forming a basic salt of a compound obtained wherein Y is hydrogen» 45, A process according to claim 42 for producing a compound according to claim 29 or 30, which does not include hydrolyzing a compound obtained· 46, A process for producing a compound according to claim 29 or 39, substantially as herein described with reference to the Examples 1 to 13 and 15 to 102. 47, A process for producing a compound according to claim 30, substantially as herein described with reference to Examples 1 ω 13 ahd 15 to 56. according to claim 29 or 39 . 48, A compound/when prepared by the process according to any one of claims 42 to 47. 49, A compound according to claim 29 or 39, substantially as herein described with reference to the Examples,! to 13 and 15 to 102; 50- A compound according to claim 30, substantially as herein described with reference to Examples 1 to 13 and 15 to 66. 51» A method of lowering blood pressure in a mammal, excluding a human, which comprises administering to said mammal a blood pressure lowering effective amount of a compound according to any one of claims 1 to 20, 27 and 28» 52, A method of producing vasodilation in a mammal, excluding a human which comprises administering to said mammal in an amount effective to cause vasodilation, a ccnpound of Formula I according to any one of claims 1 to 17, 27 and 28,,