CH627447A5 - Process for the preparation of 4-(hydroxyphenyl)alkanolamine derivatives - Google Patents

Description

The present invention relates to the preparation derivatives of a- (aminoalkyl) -4-hydroxy-3- (alkylthio, alkylsulfinyl or alkylsul-fonyl) -benzene.

50 British Patent No. 1,321,701 describes a group of compounds represented by the general formula:

55

60

OH R4

I I

CH-CH-NR5R5

in which, among others:

R! is RS, RSO or RS02 (R = H or a Q-Cio alkyl group);

65 R2 and R3 are hydrogen atoms or Q-C4 alkoxy or Q-C4 alkylthio groups;

R4 is a hydrogen atom or a Cj-Q alkyl group; and

3

627,447

Rj and R5 are independently a hydrogen atom or a Cp-C16 alkyl group optionally substituted by a phenyl or substituted phenyl group. The compounds are said to exhibit ß-adrenergic blocking activity, peripheral vasodilator activity, antiarrhythmic activity and hypotensive activity.

The U.S. Patent No. 3,917,704 describes a group of a-aminoalkyl-4-hydroxy-3-aIkylsulfonyIméthylbenzyIi-alcohols of formula

The compound, however, was neither isolated as a single entity nor characterized.

British Patent No. 1,154,193 describes as a beta-adrenergic agent α - [(isopropylamino) methyl] -3- (methylthio) -5 benzenemethanol, that is to say:

CH

rso2ch;

HO

OH

C H-CH2-NH-CH (CH3) 2

OH R,

CH-CH-NHR,

in which, among others:

R represents a lower alkyl group of 1 to 5 carbon atoms, with straight or branched chain; R1 represents

R,

-C-CH, I

CH,

R2 represents a hydrogen atom or a methyl or ethyl group;

R3 and R4 represent a hydrogen atom or a hydroxy or methoxy group; and

R5 represents a hydrogen atom or a methyl group. The compounds are said to be useful as β-adrenergic stimulants with relatively greater activity on the respiratory smooth muscle than on the heart muscle.

Kaiser, et al. J. Med. Chem. lj $, 674-683 (1975) essentially describes the work done in the U.S. patent. No. 3,917,704 mentioned above and further describe the compound of formula

In the field of anti-hypertension therapy, the use of peripheral vasodilators to lower blood pressure has often presented a serious drawback, namely reflex tachycardia due to hypotension induced by systemic vasodilation. Recent efforts have been made to overcome this problem by using hypotensive vasodilators in combination with beta-adrenergic blocking agents, the role of the latter being to reduce reflex tachycardia due to hypotension induced by vasodilator. This mode of treatment obviously has the disadvantage of requiring two separate drugs and in addition requiring different dose regulation as well as increased risks of patient error in not taking one or the other of the drugs. .

The present invention provides novel therapeutically usable compounds which have both a hypotensive vasodilator activity and a beta-adrenergic blocking activity and which, therefore, should be used as antihypertensive agents having no not the undesirable side effects of tachycardia associated with commonly used vasodilators.

The invention relates to the preparation of a - {[(arylalkyl) amino] alkyl} -4-YO-3- (lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl) benzenemethanols which can be used as anti-hypertension agents, of formula I below:

40

YO

OH R! R2 I I

CH-CH — NH-C - (CH2) n-Ar I

R,

CH, SO,

HO

OH

ch-ch2-nh-c (ch3) 3

which is indicated to be weakly active as a ß-adrenergic agonist and which exhibits ß-adrenergic antagonist activity. The work described in Kaiser's publication was described in a conference on April 10, 1975 at the 169th national meeting of the American Chemical Society. A summary of the oral presentation appeared in Abstracts of Papers, ACS Meeting 169; Medi 54 (April 1975).

Lutz et al., J. Med. Chem. 15,795-802 (1972) describe the test for the preparation of 4-hydroxy-3-mercaptophenyletha-nolamine, that is to say:

OH

CH-CH2-NH2

45 in which:

R1, R2 and R3 are independently hydrogen atoms or lower alkyl groups;

n is an integer from 1 to 3;

Ar is a phenyl or phenyl group having one to three halogen, lower alkyl, hydroxy or lower alkoxy substituents;

Q is a lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group;

Y is a hydrogen atom or a lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl group;

and their acid addition salts. As described more fully below, some of these compounds are also usable as antiarrhythmic agents.

Another aspect of the invention relates to the preparation of the 60 [(arylalkyl) -amino] alkyl-4-YO-3- (lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl) phenyl ketones of formula II below:

HO

YO

GOLD,

R?

C-CH-NH-C - (CH2) n-Ar II

R3

627,447

4

in which R ,, R2, R3, n, Ar, Q and Y have the meanings given above; and their acid addition salts, and their transformation into compounds of formula I

The particular embodiments reside in the compounds of formulas I and II above in which Rj, R2, R3, n, Q and Y have the meanings indicated above and Ar is a phenyl or phenyl group bearing one or two lower alkyl substituents, hydroxy or lower alkoxy.

The benzenemethanols of formula I above are prepared by reducing the aminoalkyl phenyl ketones of formula II above. The aminoalkyl phenyl ketones of formula II can be prepared by reacting a haloketone of formula V below:

O Rt

C-CH-X

V

in which R ,, Q and Y have the meanings given above and X is a chlorine, bromine or iodine atom, with an (arylalkyl) amine of formula VI below:

R2

I

Ar- (CH2) n-C-NH2 I

r3

VI

in which R2, R3, n and Ar have the meanings indicated above.

The 3- (lower alkylsulfinyl) benzene-me-thanols of formula I above can be prepared in which Rt, R2, R3, n, Ar and Y have the meanings indicated above and Q is a lower alkylsulfinyl group, by oxidizing the 3- (lower alkyl) benzene methanols of formula I in which R ,, R2, R3, n, Ar and Y have the meanings given above and Q and a lower alkylthio group.

Blood pressure can be reduced in mammals by administering to these mammals an effective blood pressure lowering amount of a benzenemethanol of formula I above. Vasodilation can be produced in mammals by administering to them, in an amount effective to produce vasodilation, a benzenemethanol of formula I above.

In the terms lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl, "lower" means an alkyl part having from 1 to 4 carbon atoms which may be in a straight or branched chain. They include methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, etc. groups, methyl and ethyl groups being preferred.

By “lower alkanoyl”, is meant straight or branched chain alkanoyl radicals having from 1 to 6 carbon atoms, as illustrated by the formyl, acetyl, propionyl, butyryl, isobutyryl, pivalyl, capropyl, etc. groups.

The term "halo" as used herein means fluorine, chlorine, bromine or iodine.

The term “aroyl” as used herein includes the benzoyl groups and benzoyl substituted by one or two lower alkyl groups, for example: o-toluyle, m-toluyle, £ -to-luyle, 3,4-dimethylbenzoyl, 3, 5-dimethylbenzoyl, 2,5-dimé-thylbenzoyle, m-isopropylbenzoyle, pt-butylbenzoyle, etc ...

We will see that Y in formulas I and II can represent acyl residues other than the preceding groups because it is known that such esters undergo a hydrolytic cleavage under physiological conditions by giving in situ the parent phenols which obviously have the biological activity previously indicated.

When used here, the term "toluenesulfonyl" includes ortho, meta and para-toluenesulfonyl groups. s The benzenemethanols represented by formula I above are obtained by reducing the aminoalkyl phenyl ketones of formula II with an appropriate reducing agent in an appropriate solvent, for example sodium borohydride or lithium borohydrid in water or a lower alkanol; lithium aluminum hydride in ether, tetrahydrofuran or dioxane; diborane in tetrahydrofuran or diethylene glycol dimethyl ether; aluminum isopropylate in 2-propanol; or by hydrogenation in the presence of a noble metal as catalyst, for example palladium 15 or platinum.

When the aminoalkyl phenyl ketone contains a carboxylic ester group (formula II in which Y is a lower alkanoyl or aroyl group), and it is desired to keep the ester group in the reduction product (formula I in which Y is a lower alkanoyl or aroyl group), the use of reducing means bringing about the reduction of the carboxylic ester groups must obviously be avoided. Consequently in this case the reduction is preferably carried out with an alkali metal borohydride or by catalytic hydrogenation, which gives a selective reduction in the ketone function. When the product finally desired is free phenol (formula I where Y is a hydrogen atom), the preceding reduction reaction can be followed by the hydrolysis of the ester group, or else the esterified aminoylkyl phenyl ketone can be reduced. (formula II where Y is a lower alkanoyl or aroyl group) with a reagent which can reduce both the ketone and carboxylic ester functions, for example the double hydride of lithium and aluminum.

The borohydride reduction process is conveniently carried out aminoalkyl phenyl ketone by sodium borohydride in methanol at a temperature of about - 10 ° C to +65 ° C, for about 15 minutes to 2 ½ hours or until reduction is essentially complete as indicated by thin layer chromatography. If the starting substance contains an ester group (formula II in which Y is a lower alkanoyl or aroyl group) and it is desired to keep the latter in the final product, the reaction of the mixture with acid is stopped. the esterified benzene methanol (formula I in which Y is a lower alkanoyl or aroyl group) is isolated in a conventional manner. If, on the other hand, the free phenol is desired (formula I in which Y is a hydrogen atom), the reaction mixture is treated with an equivalent of sodium hydroxide or potassium-50 sium in water and stirred at about 20 ° C-65 ° C for about 30 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 N, N-dimé-55 thyl-formamide, at 20 ° C-50 ° C under a hydrogen pressure of 1.4 to 3.5 kg / cm2 in the presence of a noble metal as catalyst, for example palladium. The hydrogenation is continued until the theoretical amount of hydrogen has been absorbed. After removal of the catalyst, the reduction product is isolated in a conventional manner.

Although the 3- (lower alkylsuIfinyl) -benzenemethanols of formula I in which Q is a lower alkylsulfinyl group can be obtained by reducing the corresponding ketones of formula II in which Q is a lower alkyl-65 sulfinyl group according to the above procedures, it is usually preferred to prepare the sulfinyl derivatives by oxidizing the corresponding 3- (lower alkylthio) benzenemethanols of formula I in which Q is an alkylthio group

5

627,447

lower, using an appropriate oxidizing agent such as a peracid, hydrogen peroxide or sodium metaperiodate.

The oxidation is preferably carried out by treating 3- (lower al-kylthio) benzenemethanol with 50% peracetic acid in methanol, which is commercially available, at a temperature of approximately - 10 °. C at + 10 ° C for about 15 minutes to an hour and a half or until the oxidation is essentially complete as indicated by thin layer chromatography.

Or, the oxidation is carried out with 30% hydrogen peroxide in methanol at about 20 ° C-65 ° C for 24 to 72 hours or until the oxidation is essentially complete like the indicates thin layer chromatography. The oxidation product is isolated according to conventional methods.

The aminoalkyl phenyl ketones of formula II above can be obtained by reacting a haloketone of formula V with an axcess of an (arylalkyl) amine of formula VI in a suitable solvent such as acetonitrile, dimethyl sulfoxide or N, N -dimethylformamide, at a temperature of about - 65 ° C to +25 ° C for 1 to 4 hours or until the reaction is essentially complete as indicated by thin layer chromatography.

In the event that Y in formula V is a lower alkanoyl or aroyl group, the reaction with an (arylalkyl) amine may result in a partial cleavage of the ester function, or else the ester of formula II (that is to say when Y is as defined above) can be hydrolyzed to free phenol in a separate step. When desired, the partially de-acylated 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 acid. Likewise, a free phenol of formula I can be transformed into a corresponding ester by such an esterification.

Although 3- (lower alkylsulfinyl) phenyl ketones of formula II in which Q is a lower alkylsulfinyl group can be obtained by reacting a haloketone of formula V in which Q is a lower alkylsulfinyl group with an appropriate (arylalkyl) amine of formula VI, it is generally preferred to prepare the 3- (lower alkylsulfinyl) -phenyl ketones of formula II by oxidation of the corresponding sulfides (formula II, Q is a lower alkylthio group) as described above for the preparation of the 3- (lower alkylsulfinyl) -benzenemethanols of formula I in which Q is a lower alkylsulfinyl group.

The (arylalkyl) amines of formula VI are generally known or, if they are new, they are obtained according to the procedures described for the preparation of the known compounds.

Thus, tertiary carbinamines, that is to say the (arylalkyl) amines of formula VI in which R2 and R3 are both a lower alkyl group, can be obtained from the corresponding tertiary alcohols generally known, by the reaction well known from Ritter [Organic Reactions 17,213 (1969)] followed by hydrolysis of the resulting tertiary carbinamides.

The (arylalkyl) amines of formula VI in which one or both of R2 and R3 are hydrogen atoms can be obtained by reaction of an aldehyde or a ketone having the appropriate number of carbons, with l ammonia or an ammonia derivative according to the procedures described in Organic Reactions 4,174 (1948) and Organic Reactions 5, 301 (1949).

The haloketones of formula V are obtained by halogenating with chlorine or bromine the appropriate phenyl ketone of formula VII below:

10

VII

in which R! and Q have the meanings given above and Y is a methyl, lower alkanoyl or aroyl group. The reaction is conveniently carried out by treating with bromine the ketone of formula VII in an inert solvent such as chloroform, at approximately 25 ° C., and optionally in the presence of a mineral base, for example calcium carbonate. The reaction usually has an induction period and in some cases it may be advantageous to initiate the reaction by exposing the mixture to ultraviolet radiation until bromination has started, as shown by discoloration and the simultaneous release of hydrobromic gas. If desired, the substituent Y can be removed from the resulting haloketone according to well known procedures, for example hydrolysis of the ester when Y is a lower alkanoyl or aroyl group and by O-demethylation with Lewis acid such as aluminum chloride, hydrobromic gas or boron tribromide when Y is a methyl group.

The corresponding iodoketones can be obtained (formula 25 V in which X is iodine), by reacting the chloro- or bromo-ketones with sodium or potassium iodide in acetone, under the reaction conditions well known to Finkelstein.

The phenyl ketones of formula VII above can be obtained by various procedures which are generally known in the art.

Thus, for example, the 3- (lower alkylthio) -phenyl ketones of formula VII are obtained where Q is a lower alkylthio group and Y is a lower alkanoyl or aroyl group, by alkylation of the 3-mercapto-4-hydroxyphenyl ketones formula VII in which Q is a mercapto group and Y is a hydrogen atom, with a suitable lower alkyl halide in a suitable solvent such as a lower alkanone in the presence of an acid acceptor, for example a carbonate of alkali metal, followed by an esterification of the resulting 3- (al-kylthio) -4-hydroxyphenyl ketones (formula VII in which Q is a lower alkylthio group and Y is a hydrogen atom) with an appropriate acylating agent such as a halide or a lower alkanoyl or aroyl 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-mercapto-4-hydroxyphenyl ketones are in turn obtained by chlorosulfonation of the generally known 4-hydroxyphenyl ketones of formula VII in which Q and Y are hydrogen atoms, with an excess of chlorosulfonic acid at approximately 0 ° C-25 ° C, preferably in the absence of solvent, followed by reduction of the resulting 3-chlorosulfonyl-4-hydroxyphenyl ketones with an appropriate reducing agent such as stannous chloride and hydrochloric acid, or zinc and sulfuric acid.

Alternatively, the 3- (lower alkylthio) -phenyl ketones of formula VII where Q is a lower alkylthio group and Y is a lower alkanoyl group can be obtained by acylating the generally known 60 o- (lower alkylthio) phenols with a halide. of appropriate acyl (for example R1CH2COCl) under the Friedel-Crafts conditions, then esterifying the 3- (alkyI-thio) -4-hydroxyphenyl ketones, as described above.

65 The 3- (lower alkylsulfonyl) phenyl ketones of formula VII are obtained in which Q is a lower alkylsulfonyl group and Y is a methyl group, by oxidizing the 3- (lower al-kylsulfonyl) anisoles of formula VIII below:

627,447

6

ch3o

CH2CH2R!

Vili in which R! has the meaning indicated above and Q is a lower alkylsulfonyl group, with an appropriate oxidizing reagent, such as ammonium persulfate, in the presence of silver nitrate in an aqueous medium, at an approximate temperature range of 20 ° C. to 70 ° C. , for about 2 to 3 hours. The 3- (lower alkylsulfonyl) anisoles are obtained by sulphonating the generally known anisoles of formula 8 in which Q is a hydrogen atom, using a suitable lower alkylsulfonic anhydride in an inert solvent, for example the sym-tetrachloroethane at around 130 ° C-180 ° C.

Due to the presence of the basic amino group, the free bases of the final products represented by formulas I and II, and also the intermediates represented by formula II, react with organic and mineral acids to form addition salts. acid. The compounds of the invention can be used both in the form of a free base and in the form of acid addition salts, and both forms fall within the scope of the invention. Acid addition salts are simply a more convenient form of use, and in practice the use of the salt form corresponds to the use of the base form.

The acid addition salts are prepared from any organic or mineral acid. They are obtained in a conventional manner, for example by directly mixing the base with the acid, or when this is not appropriate by dissolving one or the other of the base or the acid or both, separately in water or in an organic solvent, and mixing the two solutions, or dissolving 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 acid addition salt in the form of a residue. The acid parts or anions of these salt forms are not in themselves new or determinative and can therefore be any acid anion or acid-like substance which can form salts with a base.

Typical acids for the formation of acid addition salts include formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, l fumaric acid, succinic acid, succinamic acid, tannic acid, glutamic acid, tartaric acid, dibenzoyltartric acid, oxalic acid, pyromucic acid, citric acid, l lactic acid, mandelic acid, glycolic acid, gluconic acid, sac-charic aciee, ascorbic acid, penicillin, benzoic acid, phthalic acid, slicylic acid, l 3,5-dinitrobenzoic acid, anthranilic acid, cholic acid, 2-pyridine-carboxylic acid, pamoic acid, 3-hydroxy-2-naphthoic acid, acid picric, quinic acid, tropic acid, 3-indole-acetic acid, barbituric acid, cyclohexylsulfamic acid, isethionic acid, methanesulfonic acid, benzenesulfonic acid, 2-toluenesulfoni acid that, 1,4-naphthalene-disulfonic acid, butylarsonic acid, metha-nephosphonic acid, acid resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, l perchloric acid, nitric acid, sulfuric acid, sulfamic acid, glutaric acid, phosphoric acid, arsenic acid, etc ...

All the acid addition salts can be used as sources of the free base form, by reaction with an inorganic base. It will therefore be seen that if one or more of the characteristics of a given base or of an acid addition salt, such as solubility, crystallinity, molecular weight, physical appearance, toxicity, etc. ., make this form unsuitable for final needs, they can easily be made into a more suitable form according to procedures well known in the art.

When the compounds prepared according to the invention are to be used for a pharmaceutical purpose, the acids used to prepare the acid addition salts preferably include those which, when combined with the free base, acceptable salts on medically, that is to say salts whose anions are relatively harmless vis-à-vis the animal body at medical doses of the salts, so that the beneficial properties inherent in the free base are not vitiated by side effects attributable to anions. Appropriate medically acceptable salts within the scope of the invention are those from acids such as hydrochloric acid, acetic acid, lactic acid, tartaric acid, cyclohexylsulfamic acid, methanesulfonic acid, phosphoric acid, etc ...

The compounds represented by formulas I and II in which Y is a hydrogen atom are obviously ampho-teres, since they have both an acid phenol group and a basic amino group, and they therefore form salts with the bases and with acids.

Due to the presence of at least one asymmetric center of up to four, in the compounds of the invention represented by the formula I (i.e. the carbon atom of the alcohol, the carbon atom to which R 1 is attached when it is a lower alkyl group, the carbon atom to which R 2 and R 3 are attached when they are different and the sulfur atom when Q is a lower alkylsulfinyl group), these compounds can exist in as many as sixteen stereoisomeric forms, all of which are individually or as a mixture of two or more compounds considered to be within the scope of this invention. If desired, the separation or production of a particular stereochemical form or a mixture of two or more stereochemical forms can be carried out by applying the general principles known in the art. 40 When preparing a particular stereoisomer or a particular mixture of two or more stereoisomers, it is advantageous to use intermediates of fixed stereochemical configuration, which limits the number of stereoisomeric forms present in the final product and which simplifies isolation of the desired components. Consequently, before the reaction with a haloketone of formula V, an (arylalkyl) amine of formula VI containing an asymmetric center (that is to say the carbon carrying non-identical substituents R2 and R3) is split into its optical antipodes (+) and (-) 50 according to conventional techniques and using conventional resolving agents such as optically active tartaric acid, 0.0-dibenzoyl tartaric acid, mandelic acid, malic acid, etc. . If desired, the (+) or (-) - (arylalkyl) amine can be reacted with a haloketone according to the operating mode described above to obtain an aminoalkyl phenyl ketone of formula II having a stereochemical configuration fixed on the carbon carrying the substituents R2 and R3.

When the haloketone also contains an asymmetric center (formula V where R! Is a lower alkyl group and Q 60 is a lower alkylthio or lower alkylsulfonyl group), the reaction with the (+) or the (-) - (arylalkyl) amine produces two diastereoisomeric aminoalkyl phenyl ketones of formula II (Rj is a lower alkyl group, Q is a lower alkylthio or lower alkylsulfonyl group) which can be separated by conventional methods, for example by fractional crystallization of a salt of appropriate addition.

Obviously, when the haloketone does not contain an asymmetric center (formula V where Ri is a hydrogen atom and Q

is a lower alkylthio or lower alkylsulfonyl group), the reaction with the (+) or the (-) - (arylalkyl) amine directly produces a single (+) or (-) stereoisomer of the aminoalkyl phenyl ketone of formula II (R ! is a hydrogen atom and Q is a lower alkylthio or lower alkylsulfonyl group).

The reduction of the aminoalkyl phenyl ketone with fixed stereochemistry as described above, creates a new asymmetric center (that is to say the carbon atom of the alcohol) and therefore produces two 3- (lower alkylthio or lower alkylsulfonyl ) ben-zenemethanols diastereoisomers of formula I. If desired, the diastereoisomers can be separated according to known methods, for example by fractional crystallization of the addition salt of an optically active acid such as (+) or (- ) -mandelic, tartaric acid, 0,0-dibenzoyl-tartaric acid, malic acid, etc., or by transforming the diastere-reoid isomer mixture into a suitable ester derivative (i.e. saying Y in formula I is a lower alkanoyl, aroyl, benzenesulfonyl or g-toluenesulfonate group, and separating the esters by chromatography or by fractional crystallization of one of their appropriate acid addition salts.

Each of the diastereoisomers of 3- (lower alkylthio) -benzenemethanol (formula I where Q is a lower alkylthio group) obtained previously can be oxidized as described above, which again gives rise to a new center of asymmetry (c ' that is to say the sulfur atom), thereby producing two diastereoisomeric sulfoxides (formula I, Q is a lower alkylsulfinyl group) which can also be separated according to the conventional procedures described above.

Alternatively, the two diastereoisomeric 3- (lower alkylthio) -benzenemethanols can be oxidized directly to obtain a mixture of the four diastereoisomeric sulfoxides which, if desired, can also be separated according to the procedures described above, for example by fractional crystallization of 'an appropriate acid addition salt such as the hydrochloride or cyclohexylsulfamate.

All these forms, either separately or in the form of two or more, are obviously considered to be part of the field of the present invention. The production of a particular isomer or of a particular mixture of isomers is more conveniently obtained starting from a benzenemethanol of formula I having the desired stereochemistry, obtained according to the procedures described above.

The compounds of formula I above exhibit anti-hypertension activity, vasodilator activity and P-adrenergic blocking activity. The combination in a single compound of a vasodilator activity and an adrenergic blocking activity is particularly advantageous since the reflex tachycardia associated with the reduction of the blood pressure by vasodilation is effectively reduced or eliminated by the p-adrenergic blocking . The compounds are therefore effective in lowering blood pressure without causing undesirable effects of tachycardia.

Note, however, that although the vasodilator activity and the P-adrenergic blocking activity both exist in the same compound, the time of onset of each of these actions appears to be different, the vasodilation usually preceding the p- blocking. adrenergic. This can obviously lead to a temporary moderate increase in heart rate that can be seen on the first day or the first two days of repeat medication. However, the P-adrenergic blockage then takes full effect and one can continue a continuous medication with a prolonged lowering of the blood pressure without any appreciable elevation of the cardiac rhythm. In addition, unlike the antihypertension reaction which is directly related to the dose, the increase in heart rate observed at the lower doses tested is not

7,627,447

not appreciably increased either in amplitude or in duration, at higher doses. It is therefore possible to increase the dose to achieve a further reduction in blood pressure without causing a corresponding increase in heart rate.

A preferred embodiment of this invention is 4-hydroxy-a- ({[3- (4-methoxyphenyl) -1 -methylpropyl] ami-no} -methyl) -3- (methylsulfinyl) benzenemethanol (formula I where Ri , R2 and Y are hydrogen atoms; R3 is a methyl group; n is 2; Ar is a 4-methoxyphé-nyle group; and Q is a methylsulfinyl group) which has high anti-hypertension activity and a particularly effective distribution of the vasodilation and p-adrenergic blocking activity and which is therefore particularly effective as an anti-hypertension agent without any undesirable side effects of tachycardia.

The compound described above contains three centers of asymmetry (i.e. the carbon atom carrying the methyl group, the carbon atom carrying the alcohol group and the sulfur atom) and can therefore exist as a mixture of up to eight stereoisomers. Particularly preferred among these are the four diastereoisomers derived from (+) - 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -l-methylpropyl] a-25 mino} -3 '- (methylthio ) acetophenone (formula II where R15 R2 and Y are hydrogen atoms; R3 is a methyl group; n is 2; Ar is a 4-methoxyphenyl group; and Q is a methylthio group) by reduction of the carbo-nyl group followed oxidation of the methylthio group. These iso-30 mothers, either individually or as a mixture of any two or more than two compounds, exhibit potent anti-hypertension activity with no unwanted side effects of tachycardia. Although each of the four diastereoisomers can be separated from the mixture as described above, this is generally not necessary and it is therefore economically advantageous to use the mixture as obtained.

When mammals are administered an effective amount of a compound of formula I to reduce hypertension in these mammals, the compounds may be administered in a suitable pharmaceutical composition, for example orally in the form of pills, tablets, capsules, for example a mixture with talc, starch, lactose or another inert pharmaceutical carrier, that is to say non-toxic or pharmacologically acceptable, or in the form of aqueous solutions, suspensions, suspensions in capsules, gels,

elixirs, aqueous-alcoholic solutions, for example in admixture with sugar or other sweetening agents, flavorings, colorants, thickeners and other conventional pharmaceutical pharmaceutical excipients. When injected subcutaneously, intramuscularly or intravenously, they can be administered as a solution or suspension in water or in peanut oil, using excipients and conventional supports for this mode of administration. The best route for administration and the best dose will be evident from laboratory tests to determine the activity and toxicity of the selected compound, which are typically done in the development phase of a drug. pharmaceutical product.

60 The molecular structures of the above compounds were assigned based on their preparation methods and the study of their IR and NMR spectra, and were confirmed by the correspondence between the values calculated and found for the elemental analysis of representative compounds.

The identity and purity of the individual stereoisomers as well as the composition of the stereoisomeric mixtures were determined based on rotational power and high pressure liquid chromatography.

627,447

8

The invention is illustrated by the following examples without however being limited thereto. Unless otherwise indicated, the rotary powers are determined on a 2% solution of the compound in methanol.

Example 1

A. To 100 g (0.085 mole) of chlorosulfonic acid at 5 ° C., 20 g (0.15 mole) of g-hydroxyacetophene-none are added over 25 minutes. The temperature is allowed to gradually rise to 22 ° C while the reaction mixture is stirred overnight. Then the temperature is raised to 55-60 ° C and the stirring is continued for an additional hour. The reaction mixture is poured into ice water and the precipitated solid is collected which is washed with water. The product is dissolved in ethyl acetate and the resulting solution is dried and evaporated to dryness. The residues are recrystallized from benzene, which gives 12.5 g of 4'-hydroxy-3 '(chlorosulfonyl) acetophenone, m.p. 138-142 ° C. The filtrate provides a second crop of 5.0 g, m.p. 124-136 ° C.

B. Hydrogen chloride gas is bubbled through a stirred mixture containing 105 g (0.46 mole) of stannous dihy-drated chloride and 400 ml of glacial acetic acid until an almost clear solution is obtained. To this latter solution, 18 g (0.077 mole) of crude 4'-hydroxy-3 '- (chlorosulfonyl) -acetophenone are added in portions over 20 minutes, maintaining the temperature at 25-30 ° C. Once the addition is complete, the stirring is continued for an additional half hour. Then the reaction mixture is poured into 400 ml of 12N hydrochloric acid, diluted with 800 ml of water and extracted with chloroform. The extracts are washed with a saturated aqueous solution of sodium chloride and evaporated to dryness. The residue is recrystallized from benzene, which gives 4 g of 4-hydroxy-3'-mercapto-acetophenone, m.p. 117-120 ° C.

C. A mixture containing 1.0 g (0.006 mole) of 4'-hydroxy-3'-mercaptoacetophenone, 0.9 g (0.0063 mole) of methyl iodide is stirred for two and a half hours at room temperature. 0.83 g (0.006 mole) of potassium carbonate and 12 ml of acetone. The reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in chloroform and the resulting solution is washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is dissolved in hot benzene and the solution is filtered through a 6.3 mm pad of silica gel to remove a colored impurity. Evaporation of the filtrate provides 0.9 g of 4'-hydroxy-3 '- (methylthio) acetophenone, m.p. 117-120 ° C.

D. Or, 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, the following are added in portions. 20 minutes 80 g (0.60 mole) of aluminum chloride. The reaction mixture is stirred overnight at room temperature and then for one hour at 65 ° C. The reaction mixture is cooled, diluted with water and ice and extracted with methylene chloride. The organic extracts are evaporated in vacuo, the residue is diluted with ether and left to stand for two days in the refrigerator. The precipitated product is collected and dried, and 27 g of 4'-hydroxy-3 '- (methylthio) -acetophenone are obtained.

E. To a cooled and stirred solution containing 24.5 g (0.134 mole) of 4'-hydroxy-3 '- (methylthio) acetophenone and 21 g (0.21 mole) of triethylamine in 400 ml of methylene chloride, 16.4 g (0.21 mole) of acetyl chloride are added dropwise over 30 minutes. After stirring overnight at room temperature, the reaction mixture is washed with water, dried over anhydrous sodium sulfate and concentrated to a small volume. The concentrate is diluted with ether and cooled in an ice bath. The resulting precipitate is collected, 23.5 g of 4'-acetate of 4'-hydroxy-3 '- (methylthio) acetophen-none.

F. To a stirred solution containing 23.2 g (0.108 mole) of 4'-acetate of 4'-hydroxy-3 '- (methylthio) acetophenone and 9 g of calcium carbonate in 300 ml of chloroform, dropwise added drop in two hours a solution containing 6 ml

5 (0.108 mole) of bromine in 30 ml of chloroform. The reaction mixture is filtered, the filtrate is washed with a saturated aqueous solution of sodium bicarbonate and evaporated to dryness. The residue is dissolved in ether and the ethereal solution is diluted with cyclohexane and cooled in ice. The resulting precipitate is collected and dried, giving 26.5 g of 2'-bromo-4'-hydroxy-3 '4'-acetate - acetophen-none (methylthio).

G. To a stirred solution containing 16.5 g (0.10 mole) of 2- (4-methoxyphenyl) -1-methylethylamine and 5 g (0.051 mole)

15 of triethylamine in 40 ml of N, N-dimethylformamide at -65 ° C, 15.5 g (0.051 mol) of 2'-bromo-4'-hydroxy-3'-acetate are added dropwise over two hours '- (methylthio) -acetophenone in 40 ml of N, N-dimethylformamide. After the addition is complete, stirring is continued at -65 ° C for an additional hour. Then the reaction mixture is acidified with 10 ml of 12N hydrochloric acid and diluted with 100 ml of water. By stirring the aqueous solution with 200 ml of a 2: 1 mixture of ether and methylene chloride, the product begins to precipitate in the aqueous phase. The layers are separated and the aqueous part is cooled in ice. The resulting precipitate is collected and dried for 3 hours on phosphoric anhydride in a vacuum oven at 65 ° C., which gives 12.1 g of 4'-acetate 4'-hydroxy-2 - {[2- (4-methoxyphenyl) -1-methylethyl] amino} -3 '- (methyl-30 thio) acetophenone.

Example 2

An agitated solution containing 12.5 g (0.029 mole) of 4'-35-acetate of 4'-hydroxy-2 - {- {[2- (4-methoxyphenyl) -1) is cooled in an ice-acetone bath. -methyl-ethyl] -amino} -3 '- (methylthio) acetophenone in 200 ml of methanol, and treated in portions over 15 minutes with 0.9 g of sodium borohydride. Once the addition is complete, stirring is continued for an additional 20 minutes. The reaction mixture is then brought to pH 7 with glacial acetic acid and evaporated to dryness. The residue is diluted with ether and washed thoroughly with a saturated aqueous solution of sodium bicarbonate. The ethereal solution is dried over anhydrous sodium sulfate and concentrated to a small volume. The concentrate is acidified with an ethereal hydrochloric gas solution and cooled overnight in a refrigerator. The product which precipitated is collected and recrystallized from a mixture of methanol and isopropyl alcohol, which gives 2.1 g of 4-hydroxy-4-acetate hydrochloride a - <{[2- (4- 50methoxyphenyl-1-methylethyl] -amino} methyl> -3- (methyl-thio) -benzenemethane, mp 143-145 ° C.

In addition to its anti-hypertension activity, it has been found that the compound also has a P-adrenergic stimulating activity as shown by its ability to block broncho-cons-55 friction induced by histamine in dogs.

Example 3

To a stirred suspension of 6.9 g (0.016 mole) of 4'-acetate 4'-hydroxy-2 - {- [[2- (4-methoxyphenyl) -60 l-methyl-ethyl] amino} -3 '- ( methylthio) acetophenone in 120 ml of methanol, 400 mg of sodium borohydride are added. After 5 minutes, all of the starting material has dissolved. The reaction mixture is treated with 10 ml of water and stirred overnight at room temperature. Then a solution containing 900 mg of potassium hydroxide in 10 ml of water is added and the mixture is heated at reflux for half an hour. The resulting solution is concentrated to half volume, the concentrate is slightly acidified with chlorine acid.

9

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12N water and evaporated to practically dryness. The residue is diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic extracts are dried over anhydrous sodium sulfate, acidified with glacial acetic acid and concentrated until crystallization begins. The product is collected, triturated with chloroform and finally recrystallized from a mixture of methanol and chloroform, which gives 3.9 g of 4-hydroxy-a <{[2- (4- methoxyphenyl) -1-methylethyl] amino} methyl> -3- (methyIthio) benzenemethanol, mp 163-165 ° C.

Example 4

Stirred for two days at room temperature and then an hour and a half at reflux a solution containing 1.5 ml of 30% hydrogen peroxide and the free base obtained from 9 g of 4-acetate hydrochloride 4- hydroxy-a - <{[2- (4-methoxyphenyI) -1-methylethyl] amino} methyl> -3- (methyl-thio) benzenemethanol, in 150 ml of methanol. Then the reaction mixture is evaporated to dryness. The residue is dissolved in water and the solution is filtered to remove insoluble impurities. The filtrate is acidified with 12N hydrochloric acid and evaporated to dryness. The residue is triturated with a mixture of ether and isopropyl acetate at -65 ° C. The resulting amorphous solid is dissolved in hot water, filtered to remove insoluble impurities and the filtrate is evaporated to dryness. The residue is triturated with ether and cyclohexane, and the resulting solid is collected and dried over phosphoric anhydride for 6 hours at 85 ° C., which gives 4.6 g of 4-hydroxy-cc hydrochloride - <{[2- (4-methoxyphenyI) -l-methylethyl] ami-no}) methyl> -3- (methylsulfinyl) benzenemethanol in the form of an amorphous yellow brown solid, mp 115 ° C.

In addition to its anti-hypertension activity, it has also been found that this compound has a stimulating activity (3-adrenergic as shown by its ability to block the broncho-constriction induced by histamine in dogs.

Example 5

A. A solution containing 65 g of p-ethylanisole and 92 g of methanesulfonic anhydride in 300 ml of sym-tetrachloroethane is heated at reflux for 17.5 hours. After washing with hot water, the reaction mixture is evaporated to dryness under vacuum, which leaves 20 g of a dark oil which is combined with the product of two previous tests and which is distilled under reduced pressure. The fraction boiling at 90-120 ° C / 0.5 mm is collected, and redistilled on a short column of Vigreux. Impurities boiling at 45-65 ° C / 0.5 mm are rejected and the residue remaining in the flask is again distilled. The boiling impurities are discarded at 175-187 ° C / 10 minutes, leaving 30 g of almost pure 4-ethyl-2- (methylsulfonyl) anisole.

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- (methyl sulfonyl) anisole in 300 is stirred at 20 ° C. ml of water. After one hour the temperature has risen to 48 ° C and after 2.5 hours it has dropped to 30 ° C. The product is extracted with chloroform and, after drying over anhydrous sodium sulfate, the chloroform extracts are evaporated to dryness. The residue is adsorbed on a column of deactivated silica gel with 20% water by weight. The impurities in the column are washed with ether and the product is eluted with hot methylene chloride, which gives 18 g of 4'-methoxy-3 '- (methylsulfonyl) acetophenone, m.p. 146-148 ° C.

C. To a solution containing 14.5 g (0.063 mole) of 4'-methoxy-3 '- (methylsulfonyl) acetophenone in 200 ml of chloroform, a solution containing 10.2 g of bromine in 40 ml is added dropwise chloroform. After a half hour induction period, bromine begins to be consumed. When the addition is almost complete, the product begins to precipitate. The reaction mixture is diluted with methylene chloride and the resulting solution is washed successively with a saturated aqueous solution of sodium bicarbonate and water and evaporated to dryness. Recrystallization of the residue from a mixture of methylene chloride and carbon tetrachloride provides 17.9 g of 2-bromo-4'-methoxy-3 '- (methylsulfonyl) acetophenone, m.p. 168-170 ° C.

D. A vigorously stirred mixture containing 4.5 g of 2-bromo-4'-methoxy- is heated under reflux for two hours.

xo 3 '- (methylsulfonyl) acetophenone, 4.5 g of aluminum chloride and 100 ml of chlorobenzene. The reaction mixture is poured into ice water and extracted with a mixture of ether and ethyl acetate. The organic extracts are dried over anhydrous sodium sulfate and evaporated to dryness. The residue is triturated with ether and the resulting yellow brown crystalline solid, 3.0 g of 2-bromo-4'-hydroxy-3 '- (mes-thylsulfonyl) -acetophenone, is collected.

E. To a stirred solution containing 10 g (0.06 mole) of 2- (4-methoxyphenyl) -1-methylethylamine in 50 ml of N, N-

2odimethylformamide at - 30 ° C (dry ice-carbon tetrachloride), a solution containing 7 g (0.024 mole) of 2-bromo-4'-hydroxy-3 '- (methylsulfonyl) ace-tophenone is added dropwise to 20 ml of N, N-dimethylformamide. After the addition is complete, the reaction mixture is stirred 2.75 hours at 0 ° C and diluted with water and extracted with chloroform. The chloroform extracts are dried over anhydrous sodium sulfate, acidified with ethanolic hydrochloric acid and stored overnight in the refrigerator. The product which crystallizes out is collected and recrystallized from chloroform to give 3.7 g of 4'-hydroxy-2 - {[2- (4-methoxyphenyl) -1-methylethyl] amino} -3 hydrochloride '- (methyl-sulfonyl) aeetophenone.

Example 6

35 A solution containing 3.7 g of 4'-hydroxy-2 - {[2- (4-methoxyphenyl) -l-methylethyl] ami-no} -3 '- (methylsulfonyl) acetophenone hydrochloride is hydrogenated in 100 ml of N , N-di-methylformamide, under an initial hydrogen pressure of 3.5 kg / cm2 in the presence of 1 g of a hydrogenation catalyst which is 40% palladium on carbon. After 15 minutes, a molar equivalent of hydrogen was absorbed. The catalyst is then removed by filtration and the filtrate is evaporated to dryness. The residue is diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated to 100 ml. The concentrate is acidified with glacial acetic acid, concentrated to about 70 ml and cooled. The resulting crystalline precipitate is collected, which gives 2.9 g of 4-hydroxy-a - <{[2- (4-methoxyphenyl) -150 methylethyl] amino} methyl> -3- (methylsulfonyl) acetate. ) benzènemé-thanol, pf 130-131 ° C.

Example 7

To a stirred solution containing 24 g (0.135 mole) of 3- (4-55 methoxyphenyl) -l-methylpropylamine in 40 ml of N, N-di-methylformamide at - 50 ° C, a dropwise addition is made over 15 minutes. solution containing 15 g (0.05 mole) of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone 4'-acetate in 35 ml of N, N-dimethylformamide. Once the addition is complete, the stirring is continued for an additional quarter hour. The reaction mixture is then treated with 4 ml of 12N hydrochloric acid, diluted with 100 ml of water and extracted with a mixture of ether and ethyl acetate. The organic extracts are dried over anhydrous sodium sulfate, acidified with ethanolic hydrochloric acid and evaporated to dryness. The crude product containing the 4'-acetate and 4'-hydroxy derivatives is dissolved in a solution containing 10 ml of acetyl chloride in 120 ml of trifluoroacetic acid and two stirring is carried out.

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hours at room temperature. Then the solution is evaporated to dryness and the residue is divided between ether and water. The ethereal layer is dried over anhydrous sodium sulfate and acidified with ethanolic hydrochloric acid. The resulting precipitate is collected and triturated with a mixture of acetone and ether to give 6.0 g of 4'-hydroxy-2 - {- 3- [4 (methoxyphenyl) 4'-acetate hydrochloride ) -l-methylpropyl] ami-no} -3 '- (methylthio) acetophenone, mp 160-165 ° C.

Example 8

To a stirred mixture of 9.0 g (0.021 mole) of 4'-acetate hydrochloride, 4'-hydroxy-2 {[3- (4-methoxyphenyl) -l-me-thyIpropyl] -amino} -3'- (methylthio) acetophenone and 100 ml of methanol, at a temperature of -5 to 0 ° C., 0.5 g (0.015 mol) of sodium borohydride is added in portions. After a further half hour of stirring, a solution containing 1.0 g of potassium hydroxide in 10 ml of water is added and the resulting mixture is sharpened at room temperature under nitrogen overnight and then at reflux for 1 hour. half hour. The pH is adjusted to 7 with glacial acetic acid and the resulting solution is concentrated to a small volume, diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate, acidified with glacial acetic acid, concentrated to a small volume and cooled. The product which separates is collected and recrystallized from a mixture of ethyl acetate and ethanol, to give 7.2 g of 4-hydroxy-a - <{[3- (4 -methoxy-phenyl) -1-methylpropyl] amino} methyl> -3- (methylthio) ben-zenemethanol, pf 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 pyridine at 15-18 ° C., 68 ml are added dropwise over one hour (0.58 mole) of benzoyl chloride. Once the addition is complete, stirring is continued at room temperature for an hour and a half. Then the reaction mixture is poured into 1.51 of water at ice temperature. The precipitating solid is collected by filtration, washed successively with water, cold 2-propanol and n-hexane and dried, giving 146 g of 4'-4'-hydroxy benzoate. 3 '- (methylthio) acetophenone, mp 126-131 ° C.

B. To a stirred solution containing 145 g (0.51 mole) of 4'-hydroxy-3 '4'-benzoate - (methylthio) acetophenone in 1200 ml of benzene at 20 ° C., 15 ml of a solution containing 85 g (0.53 mole) of bromine in 100 ml of benzene. The mixture is irradiated with ultraviolet light for about one hour to initiate the reaction. When the reaction begins (as indicated by the discoloration), a slow stream of nitrogen is bubbled through the reaction mixture and the remainder of the bromine solution is added over 2 hours while maintaining the temperature at 20-24 ° C. The reaction mixture is stirred for an additional half hour and then cooled to 16 ° C. The precipitating solid is collected by filtration, washed with water and with n-hexane and dried, which gives 90 g of 4-benzoate of 2-bromo-4 '-hydroxy-3' - (methylthio) acetophenone, mp 127-129 ° C. The benzene solution provides an additional 21 g of product, m.p. 126-129 ° C.

C. To a stirred solution containing 36 g (0.2 mole) of 3- (4-methoxyphenyl) -l-methylpropylamine in 175 ml of N, N-di-methylformamide at - 60 ° C, a solution is added in one hour containing 25 g (0.068 mole) of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone 4'-benzoate in 120 ml of N, N-dimethylformamide. Once the addition is complete, stirring is continued at -60 ° C for an additional 20 minutes. The reaction mixture is then diluted with 200 ml of chloroform, treated with 20 ml of 45% hydrobromic acid and then diluted with 200 ml of cold water. The layers are separated and the aqueous layer is again extracted with chloroform. The organic layers are combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to about 100 ml. The concentrate is diluted with 400 ml of ether and cooled. The resulting precipitate is collected by filtration, washed successively with cold 2-propanol and ether and dried, giving 26 g of 4'-benzoate of 4'-hydroxy-2 - {[ 3- (4-methoxyphenyl) -1-methylpropyl] amino} -îo 3 '- (methylthio) acetophenone.

Example 10

To a stirred solution of 25 g (0.046 mol) of 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -1-15 methylpropyl] amino} -3 'hydrobromide 4'-benzoate-3' - (methylthio) acetophenone and 160 ml of methanol at 0 ° C., 1.4 g (0.037 mol) of sodium borohydride are added in portions over half an hour. After 20 minutes of additional stirring, the reaction mixture is treated with a solution containing 2.5 g of potassium hydroxide-20 sium in 30 ml of water and the mixture is heated at reflux for 40 minutes. The reaction mixture is concentrated in vacuo until a cloudy suspension is formed. The suspension is brought to pH 3 with 6N hydrochloric acid and then made alkaline with a saturated aqueous solution of sodium bicarbonate. The remaining methanol is removed by evaporation in vacuo. The resulting suspension is diluted with 200 ml of ethyl acetate and the resulting two-phase mixture is allowed to stand overnight. The solid which precipitated is collected, washed with water then with n-pentane and recrystallized from 2-pro-30 panol, which gives 6 g of 4-hydroxy-a - <{[ 3- (methoxyphé-nyl) -l-methylpropyl] amino} -methyl> -3- (methylthio) benzè-néméthanol, pf 126-129 ° C.

The ethyl acetate layer is separated from the filtrate, washed successively with a dilute aqueous solution of sodium bicarbonate and with water and dried over anhydrous magnesium sulfate. The resulting solution is diluted with 120 ml of isopropyl acetate, treated with 3 ml of glacial acetic acid, inoculated and cooled. The resulting precipitate is collected, washed with isopropyl acetate and dried at 40 65 ° C. under vacuum, which gives 7 g of product in acetate form, m.p. 132-134 ° C.

Example 11

A. To a stirred solution containing 3.5 g (0.0083 mole) 45 of 4-hydroxy-a - <<[[3- (4-methoxyphenyl) -1-me- acetate)

thylpropyl] -amino} methyl> -3- (methylthio) benzenemethanol in 100 ml of methanol at - 5 ° C, a solution containing 630 mg (0.0083 mole) of peracetic acid is added dropwise in half an hour at 40% of the trade in 10 ml of metha-50 noi. When the addition is complete, the reaction mixture is evaporated to dryness. The resulting oil is diluted with ethyl acetate and the gum which separates is left to stand for two days in a refrigerator under a mixture of ethyl acetate and ethanol. The resulting dirty white amorphous solid 55 is collected, which gives 3.2 g of 4-hydroxy-ot acetate - <{[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylsulfinyl) benzenemethanol, which softens at 95 ° C and melts at 100-105 ° C.

B. To a stirred solution containing 50 g (0.119 mole) of 4-hydroxy-α - <{[3- (4-methoxyphenyl) -1-methyl-acetate)

pyl] amino} -methyl> -3- (methyIthio) benzenemethanol in 500 ml of methanol at 0 ° C., 20.2 ml (0.119 mole) of peracetic acid at 40% of commerce are added dropwise over 70 minutes. When the addition is complete, the reaction mixture is evaporated to dryness in vacuo. The residual oil is taken up in 50 ml of ethyl acetate and evaporated again to dryness under vacuum. The remaining oil is dissolved in 350 ml of tetrahydrofuran and the resulting clear solution is stirred and

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it is made slightly cloudy by progressive addition of ether. After seeding, the mixture is stirred for two days at room temperature, after which a fine white solid has started to precipitate. The mixture is treated dropwise with 50 ml of ether and stirred for 5 hours, then an additional 50 ml of ether is added dropwise and the mixture is sharpened for an additional 4 hours. After stirring overnight in a refrigerator, the mixture is cooled to 0 ° C while adding drop by drop over three hours 300 ml of ether. Stirring is continued at 0 ° C for an additional 3 hours. The product which has precipitated is then collected and dissolved in 1250 ml of tetrahydrofuran. The resulting solution is filtered to remove a small amount of insoluble matter and concentrated to a volume of 250 ml. The concentrate is cooled in a refrigerator overnight. The resulting white crystalline precipitate is collected, washed with tetrahydrofuran and ether and dried, giving 14.5 g of 4-hydroxy-a - <{[3- (4-methoxyphenyl) acetate ) -l-methylpropyl] ami-no} methyl> -3- (methylsulfinyl) benzenemethanol, mp 131-133 ° C.

Example 12

To a stirred solution containing 19 g (0.123 mol) of 3- (4-methoxyphenyl) -l-methylpropylamine in approximately 50 ml of N, N-dimethylformamide at - 65 ° C., a solution containing 12 g ( 0.042 mole) of 2-bromo-4'-hydroxy-3 '- (methylsulfonyl) acetophenone 4'-acetate in approximately 70 ml of N, N-dimethylformamide. Once the addition is complete, the stirring is continued for an additional hour and a half. Then the reaction mixture is acidified with 8 ml of 48% hydrobromic acid and extracted with chloroform. The chloroform extracts are cooled to -65 ° C. and diluted with ether. The supernatant liquor is decanted from the gum which has precipitated, and this gum is then dissolved in a minimum volume of chloroform and allowed to stand for two days in the refrigerator. The resulting 3 g of hydrobromide are dissolved in a saturated aqueous solution of sodium bicarbonate and the solution thus obtained is extracted with a mixture of n-butanol and ethyl acetate. The organic extracts are acidified with glacial acetic acid and evaporated to dryness, which gives 2.2 g of 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -l- acetate. methylpropyl] amino} -3 '- (methylsulfonyl) -acetophenone in the form of a yellow oil.

Example 13

A solution containing 2.2 g of 4'-hydroxy-2- {[3 - (4-methoxyphenyl) -1-methylpropyljami-no} -3 '- (methylsulfonyl) acetophenone in 100 ml of N is hydrogenated. , N-di-methylformamide, under an initial hydrogen pressure of approximately 3.5 kg / cm 2 in the presence of 0.5 g of a hydrogenation catalyst which is 10% palladium on carbon. After 2 hours, a molar equivalent of hydrogen was absorbed. The catalyst is removed by filtration and the filtrate is evaporated to dryness. The residue is adsorbed on a column of silica gel which is eluted first with a 95: 5 mixture of ethyl acetate and methanol then with a 90:10 mixture of ethyl acetate and methanol , which gives 1.4 g of crystalline product. After trituration with acetone and filtration, 1.25 g of 4-hydr-oxy-a - <{[3- (4-methoxyphenyl) -1-methylpropyl] amino} -methyl> -3 acetate are obtained. - (methylsulfonyl) benzenemethanol, mp 151—153 ° C.

Example 14

A. To a stirred solution containing 376 g (1.0 mole) of (-) -dibenzoyltartaric acid in a mixture of 51 methanol and 550 ml of water at 42 ° C., 179 g (1.0 m) are added. mole) of (±) -3- (4-methoxyphenyl) -1-methylpropylamine. The mixture is stirred 26 hours at 40 ° C and then 20 hours at room temperature. The resulting precipitate is collected and dried, giving a first harvest of 176.5 g of (-) -dibenzoyltartrate from (-) -3- (4-methoxyphenyl) -l-methylpropylamine, m.p. 175-176 ° C (decomposition), [a] ^ 5 = - 88.0 °. By cooling the filtrate to 0 ° C for 7 hours, a second harvest of 58.5 g, 5 m.p. 167-171 ° C (decomposition), [a] ^ 5 = - 86.3 °. The final mother liquors are set aside for use in part B below. The first harvest is recrystallized from 90% methanol, which gives 145.3 g of product, m.p. 179-180.5 ° C, [a] p = - 87.5 °. This salt is treated with aqueous sodium hydroxide and extracted in chloroform the liberated amine. The chloroform extracts are dried over anhydrous potassium carbonate and evaporated to dryness. The residual oil is dissolved in 2-propanol, the resulting solution is acidified with 25 ml of 12N hydrochloric acid and evaporated to dryness. The solid residue is dried, recrystallized from 2-propanol and dried again, to give 52.0 g of (-) -3- (4-methoxyphenyl) -1-methylpropylamine hydrochloride, m.p. 126-129 ° C, [a] 2D5 = - 6.0 ° (2% in water).

B. The remaining mother liquors are concentrated to a volume of 500 ml after isolation of the (-) -dibenzoyltartrate from (-) -3-

(4-methoxyphenyl) -1-methylpropylamine and cooled to 0 ° C for 2 hours. The resulting precipitate is collected and dried, giving 283 g of (-) -dibenzoyltartrate from (+) - 3- (4-methoxyphenyl) -methylpropylamine, m.p. 159-162 ° C (de-25 composition). This salt is treated with aqueous sodium hydroxide and the liberated amine is extracted into chloroform. The evaporation of chloroform leaves 80 g of an oil which is then added to a solution containing 168 g of (-f) -dibenzoyl-tartaric acid in 1860 ml of 90% methanol. After 20 hours 30 minutes of stirring at room temperature, the precipitated salt is collected and dried, which gives 173.5 g of (+) - diben-zoyltartrate from (+) - 3- (4-methoxyphenyl). ) -l-methylpropylami-ne, pf 179-180 ° C (decomposition), [a] o = +87.1 °. Recrystallization from 90% methanol provides 149 g, m.p. 181 ° C 35 (decomposition), [oi] q = +90.3 °. Following the procedure described in part A, the amine is released from the (+) - dibenzoyl-tartrate and it is transformed into the hydrochloride, and 55.0 g of the hydrochloride of (+) - 3- ( 4-methoxyphenyl) -1-methylpro-pylamine, pf 127-130 ° C, [aß5 = +5.6 ° (2% in water). The NMR spectrum of this product in the presence of a displacement reagent, the tris [6trifluoromethyl) hydroxymethylene-a-camphorator] europium III, Eu (TFC) 3, indicates contamination by approximately 10 to 15% of the Iévogyre isomer.

C. Recrystallized from aqueous methanol 8781 g of (-) -45 dibenzoyltartrate from (+) - 3- (4-methoxyphenyI) -l-methyIpro-

pylamine, prepared according to part B above, and 7690 g of product are obtained, m.p. 163-165 ° C. A 700 g sample is recrystallized twice from aqueous methanol, which gives 558 g of the salt which is then transformed into free amine and which is distilled under reduced pressure, to obtain 180.5 g of (+ ) -3- (4-methoxyphenyl) -1-methylpropylamine, mp 88-100 ° C / 0.1 mm. The NMR spectrum of this product in the presence of the displacement reagent Eu (TFC) 3 indicates an optical purity 5 = 97%.

D. The (+) - 3- (4-methoxy-55 phenyl) -1-methylpropylamine is also obtained as follows:

A solution of 300 g (1.67 mole) of dl-3- (4-methoxyphenyl) -l-methylpropylamine in 21% 95% ethanol is added at once to a hot stirred solution (40-45 ° C ) 250 g (1.67 mole) of d-tartaric acid in 2.61 of water and 4.21 of etha-60 noi at 95%. The clear solution is seeded at about 38 ° C and then allowed to come to room temperature overnight with stirring. The crystallized solid is filtered and pressed carefully with a rubber pad; it is washed twice with sufficient 8% aqueous ethanol at ice temperature 65 to cover the cake and is pressed carefully until it is dry. The product is dried at 60 ° C. under vacuum for 5 hours, which gives 276 g of crude d-amine bitartrate, m.p. 181-182 ° C. Five recrystallizations in

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aqueous ethanol provides 125 g of bitartrate, m.p. 188-190 ° C. The optical purity of the (+) - 3- (4-methoxyphenyl) -1-methylpropylamine released is greater than or equal to 97%.

Example 15

To a stirred solution containing 35.7 g (0.172 mole) of (-) -3- (4-methoxyphenyl) -1-methylpropyl-amine hydrochloride, partially split, [aß5 = -6.0 ° (2% in the water), in 125 ml of N, N-dimethylformamide, 25 ml of triethylamine are added, which causes immediate precipitation of the triethylamine hydrochloride. The mixture is stirred for 20 minutes and then cooled to -50 ° C. The remainder of the preparation is carried out by following a procedure similar to that of Example 7, but using 20 g (0.66 mole) of 2-bromo-4'-hydroxy-3'- 4'-acetate. (methylthio) acetophenone and 8 ml of acetyl chloride, to obtain 15 g of 4'-acetate hydrochloride of (-) 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -l-me- thylpropyl] amino} -3 '- (methylthio) acetophenone incompletely split, mp 179-181 ° C, [aß5 = - 10.3 °.

Example 16

To a stirred solution containing 12 g (0.027 g) of 4'-acetate hydrochloride of (-) -4'-hydroxy-2 - {[3- (4-methoxyphé-nyl) -l-methylpropyl] amino} -3 '- (methylthio) acetophenone incompletely split (mp 179-181 ° C, [aß3 = - 10.3 °)

in 150 ml of methanol at 0 ° C., 0.8 g (0.020 mole) of sodium borohydride is added in portions. After a further 15 minutes of stirring, a solution containing 1.6 g of potassium hydroxide in 25 ml of water is added and the resulting mixture is heated at reflux under nitrogen for half an hour. The reaction mixture is concentrated to a small volume, it is acidified with 3N hydrochloric acid and then it is made alkaline with a saturated aqueous solution of sodium bicarbonate and it is extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the ethyl acetate solution is evaporated to dryness, which leaves 11 g of a pale yellow oil. This oil is dissolved in 200 ml of ethyl acetate and an aliquot of 40 ml is adsorbed on a column of silica gel and the product is eluted with a 92: 8 mixture of ethyl acetate and methanol. , which gives 1.7 g of an oil which is converted into acetate, which gives 1.22 g of 4-hydroxy-a - <{[3- (4-metho-xyphenyI) acetate -l-methylpropyl] amino} methyl> -3 (methylthio) -benzenemethanol levorotatory, mp 124-125 ° C, [aß5 = - 6.4 °.

Example 17

Following a procedure similar to that described in Example 11 but using 1.2 g (0.0028 mole) of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -1-methylpropyl] acetate] -amino} -methyl> -3- (methylthio) benzenemethanol levorotatory (mp 124-125 ° C, faß5 = - 6.4 °) and 216 mg of 40% commercial peracetic acid, 0.9 g of 4-hydroxy-a- <{[3- (4-methoxyphenyI) -1 -methylpropyl] ami-no} -methyI> -3- (methyIsuIfinyl) benzenemethanol levorotatory acetate, pf 103-106 ° C, [aß5 = - 3.0 °.

Example 18

A. By following a procedure similar to that described in Example 15 but using 43 g (0.20 mole) of (+) - 3- (4-methoxyphenyl) -1-methylpropylamine hydrochloride, partially split, [aß5 = + 5.6 ° (2% in water), and 23 g (0.077 mole) of 2'-bromo-4'-hydroxy-3 '4'-acetate - (methylthio) acetophenone, we obtain 17 , 1 g of 4'-acetate hydrochloride of (+) - 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -l-me-thvlpropyl] amino} -3 '- (methylthio) -acetophenone split, pf 178-180 ° C, [aß5 = + 10.2 °.

B. By following a procedure similar to the previous one but by acidifying the reaction mixture with 48% hydrochloric acid instead of 12N hydrochloric acid and omitting the reacylation step, then after two recrystallizations from a mixture of chloroform and isopropyl acetate and recrystallization from a mixture of chloroform and acetone, 4'-acetate hydrobromide of (+) - 4'-5-hydroxy-2 - {[3- (4-methoxyphenyl) is obtained ) -l-methylpropyl] amino} -3 '- (methylthio) acetophenone incompletely split, mp 182-183 ° C, [aß5 = +9.0 °.

Example 19

io A. Following a procedure similar to that described in Example 16 but using 17.1 g (0.039 mol) of 4'-acetate hydrochloride of (+) - 4'-hydroxy-2 - {[3 - (4-me-thoxyphenyl) -1-methylpropyl] amino} -3 '- (methylthio) aceto-phenone (mp 178-180 ° C, [aß5 = + 10.2 °), 1.0 g (0.025 mole ) 15 of sodium borohydride and 2.0 g of potassium hydroxide, 15 g of 4-hydroxy-a - <{f3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- are obtained ( methylthio) benzene metha-nol, in the form of a dextrorotatory pair of diastereoisomeric benzenemethanols. A 3.0 g sample is dissolved in isopropyl acetate and the resulting solution is acidified with glacial acetic acid. The mixture is allowed to crystallize slowly over two days to give 2.75 g of crystalline acetate, m.p. 124-126 ° C, [aß5 = +7.7 °.

B. When using a procedure similar to the previous one using 4'-acetate hydrobromide of (+) - 4'-hydr-

oxy-2 - {[3- (4-methoxyphenyl) -1-methylpropyl] -amino} -3 '- (methylthio) -acetophenone, m.p. 182-183 ° C, [aß5 = +9.0 °, 4-hydroxy-a acetate is obtained - <{[3- (4-methoxyphé-nyl) -l-methylpropyI] amino} -methyI> - 3- (methylthio) benzè-30 nemethanol dextrorotatory, mp 128-129.5 ° C, [aß5 = +5.6 °.

C. By following a procedure similar to that described in Example 10 but using 40 g (0.0758 mole) of 4'-benzoate from (+) - 4'-hydroxy-2 - {[3- (4-me-thoxyphenyl) -1-methylpropyl] amino} -3 '- (methylthio) aceto-

35 optically pure phenone (mp 171-175 ° C, [aß5 = + 11.8 °) prepared according to Example 23B below, 1.5 g of sodium borohydride and 4.5 g of potassium hydroxide, 25.1 g of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylthio) benzenethanol, 40 pf, are obtained. 125-127 ° C., [Aß5 = +7.3 °, in the form of a dextrorotatory pair of diastereoisomeric benzenemethanols. Another similar test provides a product with a m.p. from 129-130 ° C, [aß5 = - + 7.1 °. The hydrochloride has a melting point of 153-155 ° C.

The pair of diastereoisomeric benzenemethanols of this example corresponds to the products of Examples 21C and 28.

Example 20

A. By following a procedure similar to that described

50 in Example 11 but using 2.5 g (0.0049 mole) of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -1-methylpropyl] -amino} methyl-3- (methylthio acetate) ) benzenemethanol dextrorotatory (mp 124—126 ° C, [aß5 = + 7.7 °) and 375 mg of 40% commercial peracetic acid, 2.0 g of 4-hydroxy-55a acetate are obtained - <{[3- (4-methoxyphenyl) -l- methylpropyl] amino} methyl> -3- (methylsulfinyl) benzenemethanol in the form of an amorphous yellow powder, [aß5 = +4.2 °, containing a mixture of 4 diastereoisomeric sulfoxides. In addition to its anti-hypertension activity, it has been found that this product is as active as procaine 60 as a local anesthetic agent when tested according to the method of Bulbring and Wadja, J. Pharm. Exp. Therap. 85.78 (1945).

B. When the preceding oxidation is carried out on 4-hydroxy-a acetate - <{[3- (4-methoxyphenyl) -l-methylpropyl] -

65 amino} methyl-3- (methylthio) benzenemethanol dextrorotatory prepared according to the method of Example 19C, the product has a melting point of 103-110 ° C and a [aß5 = —1.1 ° and is formed from a mixture of 4 diastereoisomeric sulfoxides.

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C. A sample of 4-hydroxy-ct acetate - <{[3- (methoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylsulfinyl) benzenemethanol, prepared by a procedure similar to that described in part B above, is transformed by a conventional procedure into a corresponding phosphate, pf 136-153 ° C, ["] d5 = 0.0 ° C.

D. A sample of 4-hydroxy-a - <{[3- (4-me-thoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylsuIfi-nyl) benzenethanol acetate prepared by a similar procedure to that described in part B above, is transformed by a conventional procedure into the corresponding methanesulfonate, pf 142-148 ° C, [a] n = +5.0 °.

E. A sample of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl acetate> -3- (methylsulfi-nyl) benzenethanol, prepared by procedure similar to that described in part B above, is transformed by a conventional procedure into the corresponding hydrochloride, mp 172-175 ° c, [a] ß = - 8.1 °.

F. The hydrochloride can also be prepared directly as follows:

To a stirred solution containing 844 g (2 moles) of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -l-methylpropyl] -amino} methyl acetate> -3- (methylethyl) benzene methane of methanol at 0 ° C., 308 ml of commercial 40% peracetic acid are added in portions of 25 ml in about 40 minutes. Stirring is continued at 0-3 ° C for an additional 45 minutes. Then the reaction mixture is evaporated under reduced pressure while maintaining the temperature below 35 ° C. The residue is diluted with one liter of 2-propanol and the solution is evaporated to dryness under vacuum. This is repeated once more and then the residue is dissolved in 61 of 2-propanol, and the resulting solution is treated with a solution containing 2.14 moles of hydrogen chloride in 2-propanol. The resulting pale yellow solution is cooled in ice. The precipitated product is collected, washed with a mixture of 2-propanol and ether and dried, which gives 705 g of 4-hydroxy-u hydrochloride - <{[3- (4-methoxyphenyl) - 1 -methylpropyljamino} methyl> -3- (methylsuIfinyl) benzenemethanol [a] n = - 1.6 °.

The four diastereoisomeric sulfoxides obtained according to the preceding examples correspond to the sulfoxides of Examples 30, 31, 32 and 33.

The products of several preparations carried out according to Example 20 F are converted into phenol p-toluenesulfonates using--toluenesulfonyl chloride in an excess of sodium hydroxide, and they are analyzed by liquid chromatography under high pressure on silica gel in microparticles using an 85: 15: 0.4 mixture of n-hexane, 2-propanol and 2-propylamine as eluent at a flow rate of 0.54 ml / minute and a pressure of approximately 84 kg / cm2 and we find that they have the following composition:

Sulfoxide of Example No.

30

31

32

33

Concentration

19-23% 23-25.5% 25.5-28% 28-30%

When tested in one or more of the conventional biological tests described below, it is found that the product obtained according to part E or F above has a usable cardiotonic activity. The efficacy of this compound is judged, in vitro, on the basis of the percentage of increase in contractile force of the atrium and papillary muscle isolated from cats and, in vitro, on the basis of the percentage of increase in cardiac contractile force in an intact anesthetized dog.

The in vivo test procedures used are described below:

Cardiotonic test procedure I - Male cats weighing 0.8 to 1.5 kg are anesthetized with a-ehloralose (80 mg / kg intraperitoneally i.p.). We open the chest, excise the heart and cut the two atria. We make a 5 silk suture on each of the two opposite sides of the right atrium. One side of the headset is attached to a glass rod and then mounted in a 50 ml organ bath filled with Tyrode solution. The second suture is fixed to a displacement transducer and the tension on the atrium is fixed at 1.5 ± 0.5 g. io The transducer is then connected to a Grass polygraph and the force and speed of the contraction of the atrium are continuously recorded. The left atrium is treated in the same way using a silver thread instead of a silk thread. The silver wire also serves as a stimulating electrode. The two ear-15 lettes are mounted in the same bath. The right atrium beats spontaneously due to the presence of the sinoatrial node, while the left atrium is electrically stimulated at a speed of three beats per second, by rectangular pulses above the threshold of a duration from 5 millise-20 condes. The Tyrode solution bathing the atria has the following composition (in mmoles): NaCl 136.87, KCl 5.36, NaH2-P04 0.41, CaCl2 1.80, MgCl26H20 1.05, NaHCOj 11.90, glucose 5 , 55 and EDTA 0.04. The solution is balanced with a gas mixture comprising 95% oxygen and 5% carbonic gas. The preparation is allowed to equilibrate for one hour before adding any medication. The bath fluid is changed 3 or 4 times during the balancing period. At the end of the equilibration period, the drug dissolved in a vehicle or the vehicle alone is added to the tissue bath and the total reaction is noted. The vehicle used is the Tyrode solution to which, if necessary, enough acid is added to cause the drug to dissolve. When the reaction reaches a maximum, it is stopped by three washes at 10 minute intervals or until pre-medication contraction force values are reached. In general, a reaction study is carried out on at least three doses in the same preparation.

Cardiotonic test procedure IB- Male cats weighing 0.8 to 40 1.5 kg are anesthetized with α-chloralose (80 mg / kg i.p.). We open the chest and remove the heart. The heart is immersed and stirred in Tyrode's solution to remove blood from the chambers. Then we split the right ventricle and dissect the small and thin papillary muscles (about 1 mm in diameter and 4 to 7 mm in length). A silver wire is attached to each of the two ends of the papillary muscle. The ventricular end is attached to a platinum electrode and mounted in a tissue bath containing the Tyrode solution described above. The silver wire at the valve end of the muscle is attached to a displacement transducer to measure the force and speed of the muscle's contraction. The muscle is stimulated at a rate of three beats per second by rectangular pulses above the threshold lasting 5 milliseconds. The rest of the procedure is carried out as described above.

55 Cardiotonic test procedure II - The in vivo test procedure described below is used: mongrel dogs of both sexes weighing 9 to 15 kg are anesthetized with 30 mg / kg of sodium pentobarbital administered by the intravenous.

60 The trachea is exposed and a cannula is attached to it. Then attach the trachea cannula to a Harvard breathing pump using the area of the room. We put a cannula in the right femoral artery and vein. The artery cannula is attached to a Statham P23A pressure transducer connected to a Grass 65 polygraph for continuous recording of arterial blood pressure. The vein cannula is used for the intravenous administration of drugs. Pin electrodes are attached to the right front leg and the left rear leg. Then the electrodes

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are connected to a Grass polygraph for the continuous recording of the electrocardiogram of the classic lead II. A ventro-dorsal incision is made in the third intercostal space, the edges of the incision are laterally retracted and the pericardium is split open to open so as to expose the myocardium. The base of the aorta is cut and a flow probe fixed around it. The flow sensor is attached to a square wave electromagnetic flow meter (Carolina Medicai Electronics). Then connect the flow meter to a Grass polygraph to continuously record the aortic blood flow. This flow is used as an index of cardiac output (the actual cardiac output is the aortic blood flow + the coronary blood flow). The force of contraction of the heart is measured by suturing a Walton-Brodie strain gauge on the wall of the right ventricle. At the end of the surgical operation, the animal is left to rest and balance for one hour by continuously recording the blood pressure, the electrocardiogram, the force of the cardiac contraction and the aortic blood flow. After the balancing period, the vehicle or the drug dissolved in the vehicle is administered by intravenous infusion (inf. Iv), intravenous bowl (iv bowl) or intraduodenally (id) and the reaction of all is recorded. the parameters measured with the administration of the drug continuously for several periods of time depending on the route of administration of the drug. When the route of administration is inf. i.v., the drug is administered until maximum effect is achieved and the infusion is continued for ten minutes. The systems described above are standardized using dopamine.

The product obtained according to parts E and F above, when an in vitro test as described above at a dose of 1 mg / ml, causes increases of 62 and 52% respectively in the speed of the right atrium and of the strength of the right atrium and a 14% decrease in the strength of the papillary muscle. At a dose of 10 jxg / ml, there are increases of 53 and 46% respectively in the speed of the right atrium and the strength of the right atrium and a decrease of 12% in the strength of the papillary muscle.

When used intravenously at a dose of 10 Hg / kg / min for 3 hours, in three intact anesthetized dogs, the product of this example causes a maximum increase in the force of cardiac contraction of 25 and 42% in two of the three dogs, with no significant change in heart speed. In the remaining dog, decreases in contraction force and heart speed were observed of 30 and 33% respectively.

Example 21

A. A solution containing 10.5 g of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -l-me-thylpropyl] amino} methyl> -3- (methylthio) is sharpened for 4.5 hours. dextrorotatory benzene methanol prepared as described in Example 19A and 2.25 g of (-) -mandelic acid in 60 ml of isopropyl acetate. The precipitated solid is collected, which gives 3.7 g of white crystalline solid, m.p. 99-100 ° C, [a] o = - 20.9 ° which is called "solid A" and which is set aside. The filtrate is washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness. The remaining 6 g of gum are dissolved in 40 ml of isopropyl acetate and treated with a solution of 2.0 g of (+) - mandelic acid in 20 ml of isopropyl acetate and the the resulting solution is stirred overnight. The precipitate is collected, which gives 4.1 g of yellow-brown crystalline solid, m.p. 89-93 ° C, [a] p = + 35.4 °. The filtrate is called "filtrate A" and set aside. The solid is recrystallized by dissolving it in 55 ml of a 10: 1 mixture of isopropyl acetate and isopropyl alcohol and stirring overnight. After removing a small amount of a solid impurity, the clear solution is concentrated to a volume of 30 ml, and the product then crystallizes, giving 1.6 g of yellow-brown crystals, m.p. 89-106 °, [ci] q = +48.7 °, which we call “solid B” and which we put aside. The filtrate is called "filtrate B".

The filtrate A is washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness. The resulting 4.0 g of yellow gum is dissolved in 40 ml of ethyl acetate and treated with 1.0 g of (-) -mandelic acid. After standing overnight, the precipitated product is collected, which gives 2.5 g of crystalline linen solid, m.p. 108-110.5 ° C, [a] ß = - 33 °, which we call "solid C" and which we set aside. The filtrate is combined with the filtrate B above and evaporated to dryness, and the residue is combined with solid A. The combined materials are dissolved in ethyl acetate, the resulting solution is washed with an aqueous solution. saturated with sodium bicarbonate, it is dried over anhydrous sodium sulphate and evaporated to dryness. The remaining 6.4 g of yellow syrup is dissolved in 40 ml of ethyl acetate and treated with 1.5 g of (+) - mandelic acid. After stirring overnight, the precipitated solid is collected, which gives a first harvest of 1.0 g of yellow-brown solid, m.p. 105—110 ° C. Cooling the filtrate in ice provides a second crop of 1.3 g, m.p. 86-89 °, [a] ^ 5 = +48 °. The filtrate is called "filtrate C" and is set aside. The first crop is combined with solid B above and recrystallized from ethyl acetate to give 1.65 g of a yellow-brown solid, m.p. 90.5-92 °, Md = +52.2 °. This substance is combined with the second harvest and recrystallized from isopropyl acetate, which gives 2.7 g of a yellow brown crystalline solid, m.p. 89—92.5 ° C, [oc] d = +51.8 °. The latter solid was dissolved in 50 ml of ethyl acetate and the resulting solution was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness, leaving 1.7 g of product which corresponds to the dextrorotatory element of the pair of diastereoisomeric benzenemethanols present in the product of Example 19A. A 650 mg sample is dissolved in isopropyl acetate and the resulting solution is acidified with glacial acetic acid and evaporated to dryness. The residue is crystallized from a small volume of isopropyl acetate, which gives 700 mg of the acetate, m.p. 70-72 ° C, 40 ["F = + 31.3

B. The filtrate is evaporated to dryness C. The residue is dissolved in a mixture of ether and ethyl acetate and the resulting solution is washed with a saturated aqueous solution of sodium bicarbonate, treated with 2 g of bleaching charcoal, it is filtered and the filtrate is evaporated to dryness, which leaves 3.8 g of residue. This residue is dissolved in 25 ml of isopropyl acetate and the resulting solution is treated with a solution containing 1.3 g of so (-) -mandelic acid in 10 ml of isopropyl acetate. After two days of stirring, the precipitated product is collected and 3.25 g of white crystalline solid, m.p. 104-106 °, [<*] □ = - 30.4 This material is combined with solid C above and the whole is recrystallized successively from 25 ml of ethyl acetate, 40 ml of acé-55 ethyl tate and finally in a mixture of isopropyl alcohol and ethyl acetate, in each case allowing the product to crystallize slowly at room temperature. 3.5 g of white needles are thus obtained, m.p. 110-111 ° C, [aß5 = - 33.4 °. The latter solid was dissolved in 50 ml of ethyl acetate, and the resulting solution was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness, which gives 2.4 g of product (Md = - 5.1 °) which corresponds to the levorotatory element of a couple of diastereoisomeric benzenemethanols present in the product of Example 19A. A 1.1 g sample is transformed into acetate, as described above for the dextrorotatory diastereoisomer, by obtaining crystalline acetate in the form of white flakes, m.p. 124-124.5 ° C, [a] ^ 5 = - 5.4 °.

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C. 99 g of 4-hydroxy-ct acetate - <{[3- (4-methoxyphenyl) -l-methylpropyl] amino} methyl> -3- (methyl-thio) benzenetemethanol dextrorotatory (mp 129-) 130 ° C, [aß5 = + 7.1 °) prepared as described in Example 19C, with aqueous sodium carbonate and the free base is extracted into 11 of ethyl acetate. The ethyl acetate solution is washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil is dissolved in hot ether and the solution is filtered through a 2.5 cm pad of silica gel to remove a colored impurity. Evaporation of the ether leaves 83 g of a pale yellow gum which is dissolved in 200 ml of ethyl acetate and which is treated with a solution containing 22 g of (+) - mandolic acid. in 200 ml of ethyl acetate. The mixture is stirred overnight at room temperature and then overnight at 5 ° C. The precipitated product is collected by filtration and washed with isopropyl acetate and ether. We put aside the mother liquors. The solid collected is recrystallized from isopropyl acetate containing a small amount of 2-propanol to obtain 27 g of product, m.p. 89-91 ° C [a] 55 = +49.4 °. The mother liquors which had been set aside are converted back to the free base and treated again with 20 g of (+) - mandolic acid, to obtain after two recrystallizations from isopropyl acetate and one from l ethyl acetate additional 6.0 g of product, [aß5 = +47.6 °. The mother liquors of this second treatment with (+) - mandelic acid are enriched in levorotatory diastereoisomer and are set aside for use in part D. The solids are combined and recrystallized twice from acetate of 'ethyl, which gives 22 g of (+) - mandelate, mp 94-95.5 ° C, Md = +54.0 °. This salt is treated with 80 ml of a 10% aqueous solution of sodium carbonate and the free base is extracted with 300 ml of ethyl acetate. The ethyl acetate solution is washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and acidified with 2 ml of acetic acid. The solution is concentrated and the resulting precipitate is collected, which is recrystallized from ethyl acetate containing a few drops of acetic acid, to obtain 4.3 g of 4-hydroxy-a acetate - <{ [3- (4-meth-oxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylthio) benzenemethanol, pf 133-134 ° C, [aß3 = +33.3 °, corresponding to the dextrorotatory element of the pair of diastereoisomeric benzenemethanols present in the product of Example 19C.

A sample of this substance is reacted with p-toluenesulfonyl chloride in the presence of sodium hydroxide to form the corresponding 4-j> -toluenesulfonate acetate, m.p. 90-92 [aß5 = +23.0 °, which high pressure liquid chromatography shows that it has an isomeric purity greater than or equal to 99%.

D. The mother liquors of part C which have been enriched in levorotatory diastereoisomer are combined and evaporated to dryness. The residue is treated with aqueous sodium carbonate and the free base is extracted with ethyl acetate. Evaporation of the ethyl acetate leaves 58 g of oil. This substance is dissolved in 200 ml of ethyl acetate, treated with a solution containing 20 g of (-) -mandelic acid in 200 ml of ethyl acetate and the resulting mixture is stirred for one night. The precipitated salt is collected and recrystallized successively from a mixture of acetone and ether, from ethyl acetate and eight times from a mixture of methylene chloride and ethyl acetate, which gives 23 g of (-) -mandelate incompletely split (as determined by thin layer chromatography), mp 116-117 ° C, [aß5 = - 37.1 °, which is transformed by a standard procedure into acetate, [aß5 = - 10.6 °. Chromatography of a 5.5 g sample of the latter on a silica gel column with elution with 7% methanol in ethyl acetate does not allow the acetate to be purified much more. A 2.6 g fraction of the material which has been eluted from the column is stirred with 25 ml of aqueous sodium hydroxide at 35%, and the mixture is treated dropwise in 15 minutes with a solution containing 1, 3 g of £ -toluè-nesulfonyl chloride in 30 ml of acetone. During the next 5 minutes, the reaction mixture is treated with two additional portions of 150 mg of g-toluenesulfonyl chloride. The acetone layer is separated, diluted with an equal volume of isopropyl acetate, washed with water and then with a saturated aqueous solution of sodium chloride and evaporated to dryness. The residue is dissolved in ethyl acetate and the solution is acidified with acetic acid. The acetate which precipitates is recrystallized from ethyl acetate, and 1.0 g, m.p. 115-117 ° C, [alo = - 7.9 °. The filtrate provides an additional 0.5 g, m.p. 115-117 °. The harvests are combined and transformed into 1.2 g of (+) - mandelate, m.p. 154-156 °, [aß5 = +14.9 °, according to the procedure described above in part C. This material is combined with an additional 250 mg, m.p. 157-158 ° C, [aß5 = +14.3 °, obtained in a similar test, recrystallized from ethyl acetate and then converted by a standard procedure to the corresponding acetate, which gives 700 ml of l 4-p-toluenesulfonate acetate of 4-hydr-oxy-a - <{[3- (4-methoxyphenyl) -l-methylpropyl] amino} -methyl> -3- (methylthio) benzenethanol levogyre in pure point of view isomer, pf 117-119 ° C, [aß5 = - 9.6 °, corresponding to 4-2-toluenesulfonate (ester) of the levorotatory element of the pair of diastereoisomeric benzenemethanols present in the product of Example 19C. High pressure liquid chromatography of the product shows that it has an isomeric purity greater than or equal to 98%.

Attempts to cut the j> -toluenesulfonate (ester) to obtain the levorotatory phenol isomerically pure were not successful, however the latter compound was obtained from the corresponding benzoate as described in Example 28 below.

35

Example 22

A. To a stirred solution containing 1.05 g (0.003 mole) of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -l-methylpropyl] ami-no} methyl> -3- (methylthio) benzenemethanol dextorgyre pre-

40 adorned according to the method of Example 21A in 15 ml of methanol at 0 ° C., a solution of 0.45 ml (0.003 mol) of 40% commercial peracetic acid is added dropwise over a half hour in 5 ml of methanol. When the addition is complete, the reaction mixture is evaporated to dryness under vacuum. The residue is dissolved in a 45: 5 mixture of ethyl acetate and methanol and adsorbed on a column of silica gel. After elution with ethyl acetate, the product is eluted with a 90:10 mixture of ethyl acetate and methanol. The material thus obtained is dissolved in a mixture of ethyl acetate and 50 methanol, the resulting solution is acidified with glacial acetic acid and evaporated to dryness. The residue is taken up in 5 ml of chloroform, the resulting solution is cooled to -65 ° C and diluted with ether. The resulting solid is dissolved in tetrahydrofuran, the solution is acidified with glacial acetic acid and evaporated to dryness. The residue is dissolved in chloroform, the solution is cooled to -65 ° C and diluted with ether. The resulting solid is collected and dried, giving 550 mg of 4-hydroxy-a- <{[3 - (methoxyphenyl) -1-methylpropyl] amino} methyl> -3 -60 (methylsulfinyl) acetate benzene methanol in the form of a dextrorotatory pair of diastereoisomeric sulfoxides, [aß5 = +28.5 °.

B. A 5.0 g sample of 4-hydroxy-a - <^ [3- (4-me-thoxyphenyl) -1-methylpropyl] amino} acetate is oxidized as described in part A above. methyl> -3- (methylthio)

65 dextrorotatory and isomer pure benzene-methanol ([a] gs = + 31.5 °) prepared according to the method of Example 21C. When the oxidation is complete, the reaction mixture is evaporated to dryness and the residue is crystallized from ethyl acetate.

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which gives 4.2 g of a crystalline product, m.p. 107-115 °, [a] p = +28.2 °. A small sample is dissolved in a mixture of acetone and methanol and the solution is treated with cyclohexylsulfamic acid. The precipitating salt is collected and, after drying, 4-hydroxy-a-<- {{3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylsulfinyl) benzene methanol cyclohexylsulfamate is obtained. in the form of a dextro-gyres pair of diastereoisomeric sulfoxides, pf 152-154 ° C, [a] ~ D3 = + 35.9 °.

The pair of diastereoisomeric sulfoxides of this example corresponds to the products of Examples 30 and 32.

Example 23

A. By following a procedure similar to that described in Example 9C but using 128 g (0.72 mole) of (+) - 3- (4-methoxyphenyI) -1-methylpropylamine partially split, [a] ßs = + 4.4 ° (2% in water), and 120 g (0.33 mole) of 2'-bromo-4'-hydroxy-3 '4'-benzoate - (methylthio) aceto-phenone, we obtains a first harvest of 82 g, pf 172-174 ° C, and a second harvest of 43 g, m.p. 171—174 ° C. The harvests are combined and a 16 g sample is recrystallized from 95% ethanol, which gives 10 g of (+) - 4'-hydroxy-2 - {- 3 - 4'-benzoate hydrobromide. - (4-methoxyphenyl) -1-me-thylpropyl] amino} -3 '- (methylthio) acetophenone incompletely split, mp 174-175 ° C, [a] f5s = +8.4 °.

B. To a vigorously stirred solution containing 180 g (1.0 mole) of (+) - 3- (4-methoxyphenyl) -1-methylpropylamine [optical purity 5 = 97%, as indicated by NMR spectroscopy in the presence of Eu ( TFC) 3] and 55 ml of triethylamine in 300 ml of N, N-dimethylformamide at - 60 ° C, a solution containing 160 g (0.384 mol) of 2'-bromo-4'-benzoate is added over an hour and a half. 4'-hydroxy-3 '- (méthyIthio) acetophé-none in 500 ml of N, N-dimethylformamide. Agitation is continued for an additional half hour. The reaction mixture is acidified with 48% hydrobromic acid and extracted with methylene dichloride. The organic extracts are washed with water and concentrated to about 320 ml. The concentrate is diluted with 400 ml of isopropyl acetate and cooled. The solid which precipitates is collected and dried, which gives 167 g of 4'-benzoate (+) - 4'-hydr-oxy-2 - {[3- (4-methoxyphenyl) -l-methylpropyl] hydrobromide. amino} -3 '- (methyithio) optically pure acetophenone, mp 171-173 ° C, Md = +11.8 °. A 7.0 g sample is recrystallized from aqueous methanol containing a small amount of HBr to obtain, after drying, 5.9 g, m.p. 175-177 "C, [a] p = +11.6 °.

Example 24

A. To a solution containing 106 g (0.195 mole) of (+) - 4'-hydroxy-2 - {[3- (4-methoxy-phenyl) -1-methylpropyl] amino} 4'-benzoate hydrobromide - 3 ′ - (methylthio) acetophene-none incompletely split, prepared according to the procedure of Example 23 A, in 700 ml of methanol at 0 ° C., 6 g (0.16 mol) of sodium borohydride. Stirring is continued at 0 ° C for an additional half hour. A 150 ml aliquot part of the reaction mixture is concentrated under reduced pressure below 50 ° C. The concentrate is dissolved in ether and the ethereal solution is washed thoroughly with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is dissolved in 75 ml of isopropyl acetate and the resulting solution is acidified with acetic acid, then it is diluted with ether until it is cloudy and is dissolved. shakes for 3 hours. The solid which precipitated was collected by filtration, washed with isopropyl acetate and ether and dried, giving 6.4 g of 4-hydroxy 4-benzoate acetate. -a - <{[3- (4-methoxyphenyI) -l-methylpropyl] -amino} methyl> -3- (methylthio) benzenemethanol, pf 107-110 ° C.

B. The remainder of the initial reaction mixture is hydrolyzed with a solution containing 9 g of potassium hydroxide in 100 ml of water, according to the procedure of Example 10, which gives 46 g of the acetate (salt) 4-hydroxy-a - <{[3- (4-meth-oxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylthio) 5benzenemethanol, pf 130-132 ° C, [a] "= +4.8 °.

C. To a solution containing 10.0 g (0.0188 mol) of (+) - 4'-hydroxy-2 - {[3- (4-methoxy-phenyl) -1-methylpropyl 4'-benzoate hydrobromide ] amino} -3 '- (methylthio) acetophene-none optically pure (mp 171-173 ° C, [a] f5 = + 11.8 °) in io 100 mol of methanol at 0 ° C, 380 portions are added mg of sodium borohydride. After the addition of several ml of acetic acid, the mixture is evaporated to dryness. The residue is dissolved in a mixture of ethyl acetate and ether and the resulting solution is washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, acidified with 2.5 ml of acetic acid and evaporated to dryness Recrystallization of the residue from a mixture of isopropyl acetate and ether provides 6 g of the acetate (salt) of 4-hydroxy 4-benzoate -a- <{[3 - (4-mejthoxyphenyl) -1 -methylpropyl] ami-2ono} methyl> -3- (methylthio) benzenemethanol, [a] ^ 5 = +6.4 in the form of a dextrorotatory couple diastereoisomeric benzenemethanols corresponding to the products of Examples 27A and B. A similar test gives a product, pf 101-102.5 ° C and [a] = + 7.6 °

25

Example 25

To a stirred solution containing 8.0 g (0.0147 mole) of 4'-benzoate (+) - 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -1-methylpropyl] amino} hydrobromide -3 '-30 (methylthio) acetophenone, [a] g "= + 11.1 °, in 60 ml of trifluoroacetic acid at 0 ° C, 3 ml of 40% commercial peracetic acid is added dropwise When the addition is complete, the reaction mixture is evaporated to dryness, the residue is dissolved in benzene and the resulting solution is evaporated to dryness. The residual gum is dissolved in isopropyl acetate and acidifies it with ethanolic hydrochloric acid. The precipitating solid is collected and recrystallized from a mixture of methanol and isopropyl acetate, which gives 6.0 g of 4'-benzoate hydrochloride. of 4'-hydroxy-2-40 {[3-bromo- (4-methoxyphenyl) -1-methylpropyl] amino} -3 '- (methylsulfinyl) acetophenone, mp 165-167 ° C. (See Notes on page 83).

Example 26

45 One oxidizes with 1.5 ml of 40% commercial peracetic acid, following a procedure similar to that of Example 22, the acetate of 4-hydroxy-4-benzoate a - <{[3 - (4-methoxyphenyl) -1-methylpropyl] amino} methlyl> benzene-methanol (5.0 g, 0.0095 mole) prepared according to an operating mode similar to that of Example 24B. When the oxidation is complete, the reaction mixture is treated with 0.9 g of sulfuric acid and cooled. The precipitating solid is collected and dried, giving 2.8 g of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -1-methylpropyl] 55 amino} 4-benzoate hemisulfate methyl> -3- (methylsulfinyl) -benzenemethanol, mp 193-195 ° C.

Example 27

A. To a solution containing 7.4 g of the free base originating from the acetate of 4-hydroxy-a <{[3- (4-methoxy-phenyl) -1-methylpropyl] amino} methyl 4-benzoate > -3- (methylthio) ben-zenemethanol dextrorotatory, [a] g3 = +6.4 ° C, in 60 ml of isopropyl acetate, a solution containing 1.8 g of (+) acid is added - mandelic in 20 ml of isopropyl acetate. The resulting solution is diluted with ether until slightly cloudy and stirred for two days at room temperature. The precipitate is collected and the mother liquors which are enriched in levorotatory diastereomer are put aside for use

in Part B below. The solid collected is recrystallized eight times from a mixture of methylene chloride and ether, which gives 3.3 g of the (+) - mandelate, m.p. 126-127 ° C, [a] g5 = +49.1 °, which is then transformed into acetate, which gives 2.1 g of the acetate of 4-hydroxy-4-benzoate a - <{ [3- (4-methoxyphenyl) -1-methylpropyl] -amino} methyl> -3- (methyl-thio) benzenemethanol, mp 88.5-90 ° C, [o] q5 = +26.7 °, corresponding to the dextrorotatory element of a pair of diastereoisomeric benzenemethanols present in the product of Example 4B.

B. The mother liquors of part A above are transformed into the free base, they are dissolved in isopropyl acetate, treated with 1.5 g of (-) -mandelic acid and the solution is dissolved with ether. The precipitate is collected and recrystallized once from a mixture of isopropyl acetate and ether, which gives 2.7 g of (-) -mandelate, m.p. 120-120.5 ° C, [aji5 =

- 35.0 °, which is then transformed into 4-hydroxy-cc 4-benzoate acetate - <{[3- (4-methoxyphenyl) -1-methylpropyl] amino {methyl> -3- (methylthio) benzene methanol, pf 82—

83 ° C, [a] f) = - 10.0 °, corresponding to the levorotatory element of the pair of diastereoisomeric benzenemethanols present in the product of Example 24B.

Example 28

A mixture containing 600 mg of 4-hydroxy-4-hydroxy-a - <{[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> - acetate is stirred for 10 minutes at room temperature.

3- (methylthio) -benzenemethanol (mp 82-83 ° C, [a] p =

-10.0 °), 5 ml of 35% aqueous sodium hydroxide and several ml of methanol, then diluted with 20 ml of water and stirred for a further 10 minutes in a warm water bath. The pH is adjusted to 9 with acetic acid and the methanol is evaporated under reduced pressure. The residue is extracted with ethyl acetate and, after drying over anhydrous sodium sulfate, the extracts are evaporated to dryness. The residue is dissolved in isopropyl acetate, the resulting solution is acidified with acetic acid and cooled. The precipitating solid is collected by filtration and dried under vacuum, which gives 500 mg of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> acetate> -3- (methylthio) -benzenemetha-nol, mp 117-120 ° C, [a] gs = - 17.0 ° (average of two determinations), corresponding to the levorotatory element of the pair of diastereoisomeric benzenemethanols 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 - <{[3- (4-methoxyphenyI) -1-methylpropyl] ami-no} methyl> -3- (methylthio) benzenemethanol ([a] g5 =

- 5.1 °) prepared according to the method of Example 21B, in 15 ml of methanol at 0 ° C, a solution of 0.45 ml of 40% peracetic acid is added dropwise in half an hour commercially available in 5 ml of methanol. When the addition is complete, the reaction mixture is evaporated to dryness under vacuum. The residue is diluted with 10 ml of benzene, the resulting solution is acidified with glacial acetic acid and evaporated to dryness. The residual gum is crystallized from a mixture of tetrahydrofuran and ether and then recrystallized from a mixture of ethyl acetate and 2-propanol, which gives 1.05 g of 4-hydroxy-a acetate. - <{[3- (4-methoxyphenyl) -l-me-thylpropyl] amino} methyl> -3- (methylsulfinyl) benzenemetha-nol, in the form of a levorotatory pair of diastereoisomeric sulfoxides, pf 90-95 ° C, [a] p = - 9.4 °.

B. When the preceding oxidation is carried out starting from the acetate of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -l-methyl-propyl] -amino} methyl> -3- (methylthio) isomerically pure levorotatory benzenemethanoI, (mp 117-120 ° C, [a] f5 =

- 17.0 °) prepared according to the procedure of Example 28, the

17,627,447

torque resulting from diastereoisomeric sulfoxides has a rotary power [aß5 = —18.8 ° (determined on the reaction mixture).

The pair of diastereoisomeric sulfoxides of this example corresponds to the products of Examples 31 and 33.

Example 30

The mother liquors obtained in the preparation of several batches of 4-hydroxy-α-<<{[3- (4-methoxyphenyl) -l-methylpropyl] amino} -methyl> -3 are combined and evaporated to dryness. - (methylsulfinyl) benzenemethanol, according to a procedure similar to that described in Example 20B. The residual oil is triturated successively with ether and isopropyl acetate. The residue (90 g) is dissolved in 300 ml of acetone and the resulting solution is treated with 33 g of cyclohexylsulfamic acid in 200 ml of acetone. The precipitated cyclohexylsulfa-mate is collected and recrystallized five times from aqueous methanol, which gives 7.3 g of product which is combined with 7.4 g of product obtained in previous tests and which is 20 transforms into hydrochloride. Recrystallization of the latter from a mixture of methanol and isopropyl alcohol provides 6.3 g of 4-hydroxy-a - <{[3- (4-methoxyphé-nyl) -l-methylpropyl] amino} -methyl hydrochloride -> - 3- (methylsulfinyl). benzene methanol, m.p. 206-207 ° C, [aß5 = +126.6 °, corresponding to the dextrorotatory element of the pair of diastereoisomeric sulfoxides present in the product of Example 22B.

Example 31

The mother liquors resulting from the fractional crystallization of the product of Example 30 are evaporated and the residue is crystallized from acetone. The resulting 12.4 g of solid are recrystallized twice from a mixture of methanol and acetone, which gives 5.1 g of product, [a] ^ 5 = +49.3 °. The latter material is combined with 3.5 g obtained in a previous test and is transformed into the hydrochloride which is crystallized from 2-propanol, which gives the hydrochloride of 4-hydroxy--a - <{ - (4-me-thoxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylsulfinyl) benzenemethanol, mp 204-205 ° C, [a] ^ 5 = +70.5 °, corresponding to the dextrorotatory element of the diastereoisomeric couple 40 of sulfoxides present in the product of Example 29B.

Example 32

The reaction mixture resulting from the oxidation of 12.1 g of (+) - 4-hydroxy-a-mandelate <{[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> is evaporated to dryness. -3- (methylthio) benzene methanol dextrorotatory, according to the procedure of Example 22B, the residue is dissolved in a mixture of 70 ml of methanol and 15 ml of water, it is treated with 50 molar equivalent of acid cyclohexylsulfamic acid and inoculated with the cyclohexylsulfamate of the product of Example 30. The 7.9 g of product which is crystallized are collected and put aside. The mother liquors are evaporated to dryness and the residue is crystallized from a mixture of acetone and methanol. The product is converted to 1.1 g of hydrochloride and combined with the additional 850 mg obtained from the mother liquors resulting from the fractional crystallization of the diastereoisomer of Example 31. The solids combined in 2 are recrystallized -propanol, which gives 1.4 g of 4-hydroxy-a hydrochloride - <{[3-60 (4-methoxyphenyl) -l-methylpropyl] -amino} methyl> -3- (mes-thylsulfinyl) benzenemethanol, pf 138-140 ° C, [a] f5 = - 48.2 °, corresponding to the levorotatory element of the pair of diastereoisomeric sulfoxides present in the product of Example 22B.

65

Example 33

A. The reaction mixture resulting from the oxidation of 3 g of 4-hydroxy-a - <} [3- (4-meth-

627,447

18

oxyphenyl) -1-methylpropyl] amino {methyl> -3- (methylthio) benzenemethanol levorotatory according to the procedure of Example 29B, the residue is dissolved in a 90:10 mixture of acetone and methanol, treated with a molar equivalent of cy-clohexylsulfamic acid and the product of Example 31 is seeded with the cyclohexylsulfamate. 1.6 g of product are collected which crystallizes and is set aside. The mother liquors are evaporated to dryness and the residue is crystallized twice from aqueous methanol, which gives 1.85 g of crystalline solid,

["] £? = —67.5 ° -

B. Or, 10.0 g of 4-p-toluenesulfonate (-t -) - mandelate of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -l-methylpropyl] -amino} are oxidized methyl> -3- (methylthio) benzene-thanol prepared according to the procedure of Example 21D, following a procedure similar to that of Example 29A and the product is isolated in the form of the free base, which gives 10 g of 4-hydroxy-a-4-2-toluenesulfonate - <{[3- (4-methoxy-phenyl) -l-methylpropyl] amino} methyl> -3- (methylsulfinyl) benzenethanol as couple of diastereoisomeric sulfoxides.

A solution containing the last product and 15 ml of 10% aqueous potassium hydroxide in 100 ml of ethanol is stirred for one and a half hours at 45 ° C. The reaction mixture is then concentrated, diluted with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic extracts are dried over anhydrous sodium sulfate and evaporated to dryness. The residue is dissolved in acetone and treated with one molar equivalent of cyclohexylsulfamic acid. The product which precipitates is collected and recrystallized from a mixture of acetone and methanol, which gives 1.15 g of salt corresponding to the cyclohexylsulf amate of the product of Example 31. The mother liquors are evaporated to dryness and l 'The residue is crystallized from acetone. Four recrystallizations from aqueous methanol provide 450 mg of crystalline solid, [a] f35 = - 66.2 °.

C. The levorotatory products of parts A and B are combined, they are recrystallized once from aqueous methanol and then they are converted into the hydrochloride, which gives 1.1 g of 4-hydroxy-a- <{[3- (4-methoxyphenyl) - 1-methylpropyl] ami-no} methyl> -3- (methylsulfinyl) benzenemethanol, mp 178-180 ° C, [a] p = - 102.3 °, corresponding to the levorotatory element of the couple of diastereoisomeric sulfoxides present in the product of Example 29B.

Example 34

To a stirred solution containing 20 g (0.134 mol) of 1,1-dimethyl-2-phenylethylamine in 40 ml of N, N-dimethylfor-mamide at -50 ° C., a solution containing 14 is added dropwise over 15 minutes. , 5 g (0.048 mole) of 2-bro-mo-4'-hydroxy-3 '4'-acetate - (methylthio) acetophenone in 35 ml of N, N-dimethylformamide. Once the addition is complete, stirring is continued for an additional 1.25 hours. The reaction mixture is then treated with 3.5 ml of 12N hydrochloric acid, diluted with 100 ml of water and carefully extracted with ether. The ethereal extracts are dried over anhydrous sodium sulfate, acidified with ethanolic hydrochloric acid and cooled in a refrigerator overnight. The 12.5 g of product which has precipitated are collected and combined with 6.0 g of product obtained in a previous test and the whole is recrystallized twice from a mixture of chloroform and methanol, which gives 15 g of the product. 2'- [(1,1-dimethyl-2-phenylethyl) amino] -4'-hydroxy-3 'hydrochloride 2'-acetate-3'-(methylthio) acetophenone, pf 205 ° C with decomposition.

Example 35

To a stirred suspension of 15 g (0.037 mole) of 2 - [(1,1-dimethyl-2-phenylethyl) amino] -4'-hydroxy-3 '- 4'-acetate hydrochloride in 200 ml of methanol at -5 ° C., 750 mg (0.020 mole of sodium borohydride) are added in portions over 10 minutes. After another 10 minutes of stirring, the reaction mixture is brought to pH 7 with glacial acetic acid and evaporated to dryness. The residue was dissolved in a mixture of ether and ethyl acetate and the resulting solution was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate, acidified with methanesulfonic acid and concentrated to a small volume. The concentrated solution is diluted with benzene and evaporated to dryness. Then the process is repeated using toluene. The resulting solid residue is recrystallized from a mixture of ethanol and ether, which gives 12 g of α - {[(1,1-dimethyl-2-phenylethyl) amino] -methyl} 4-acetate methanesulfonate. -4-hydroxy-3- (me-15 thylthio) benzenemethanol, mp 112—115 ° C.

Example 36

A solution containing 9.5 g (0.020 mole) of α-2o {4-acetate methanesulfonate {[(1,1-dimethyl-2-phenylethyl) amino] methyl} -4-hydroxy is stirred overnight under nitrogen. -3- (methylthio) -benzenemethanol, 3 g (0.045 mole) of potassium hydroxide and 20 ml of water in 200 ml of 95% ethanol. The reaction mixture is neutralized with glacial acetic acid and concentrated to a small volume. The concentrate is diluted with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts are dried over anhydrous sodium sulfate and concentrated to a volume of 100 ml. The concentrated solution is brought to a pale yellow color by dropwise addition of glacial acetic acid and crystallization then begins. The product is collected by filtration and recrystallized from a mixture of chloroform and methanol, which gives 5.1 g of a - {[(1,1-dimethyl-2-phenylethyl) amino] methyl} acetate} -4-hydroxy-3- (methylthio) benzenemethanol, mp 165-167 ° C.

35

Example 37

Following a procedure similar to that described in Example 34, but using 18.3 g (0.135 mole) of 1-me-4o thyl-2-phenylethylamine and 15 g (0.050 mole) of 4'-acetate 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone, 7.1 g of 4'-acetate 4'-hydroxy-2 - hydrochloride are obtained - [(1-methyl-2-phenylethyl) amino] -3 '- (methylthio) acetophenone.

Example 38

Following a procedure similar to that described in Example 8 but using 7.4 g (0.019 mole) of 4'-acetate hydrochloride 4'-hydroxy-2 - [(1-methyl-3-phenylethyl) -ami-50 no] -3 '- (methylthio) acetophenone, 600 mg (0.015 mol) of sodium borohydride and 1.1 g of potassium hydroxide, 6.3 g of 4-hydroxy acetate are obtained a - {[(1-methyl-3-phenyl-ethyl) amino] -methyl} -3- (methylthio) benzenemethanol, mp 131-132 ° C.

Example 39

To a stirred solution containing 4.7 g (0.012 mole) of α - {[(1,1-dimethyl-2-phenylethyl) amino] methyl] -4-60 hydroxy-3- (methylthio) benzenemethanol acetate in 100 ml of methanol at 0 ° C., a solution containing 2 ml (0.012 mole) of 40% commercial peracetic acid in 10 ml of methanol is added dropwise over half an hour. Once the addition is complete, the reaction mixture is evaporated to dryness and the residue is crystallized in a mixture of ethanol and ether, which gives 4.3 g of α - {[( 1,1-dimethyl-2-phenylethyl) amino] methyl-4-hydroxy-3- (methylsulfinyl) benzenemethanol which softens at 100 ° C and melts at 138-140 ° C.

19

627,447

Example 40

A. To a stirred solution containing 35 g (0.25 mole) of o- (methylthio) phenol and 27.6 g (0.30 mole) of propionion chloride in 100 ml of nitrobenzene, the following are added in portions. 25 minutes 46.5 g (0.35 mole) of aluminum chloride. The reaction is exothermic and the temperature rises to 45-50 ° C. When the addition is complete, the reaction mixture is stirred for two hours at 60 ° C and one hour at 70 ° C. The reaction mixture is cooled, diluted with water and extracted with ether. The ethereal extracts are dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residual oil is adsorbed on a column of silica gel and eluted continuously with methylene chloride at the boil. The eluate is evaporated to dryness and the residue is recrystallized from ether, which gives 25 g of crystalline product which is then triturated with ether at 65 ° C, which gives 17 g of 4'- hydroxy-3 '- (methyl-thio) pure propiophenone.

B. To a 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 is added dropwise in half an hour 7.65 g (0.098 mole) of acetyl chloride. Once the addition is complete, the stirring is continued for two additional hours. Then the reaction mixture is washed successively with 3N hydrochloric acid and water and evaporated to dryness. The residual oil is dissolved in ether, treated with bleaching charcoal and filtered through a bed of silica gel. The filtrate is evaporated to dryness, which provides 21.4 g of 4'-acetate of 4'-hydroxy-3 '- (methylthio) propiophenone in the form of a pale yellow oil.

C. To a stirred solution containing 21.4 g (0.088 mole) of 4'-acetate of 4'-hydroxy-3 '- (methylthio) propiophenone in 250 ml of chloroform, a solution containing 14.4 g (0.090) is added mole) of bromine in 40 ml of chloroform. After a 15 minute induction period, bromine begins to be consumed. After one hour, the reaction mixture is washed with a 5% aqueous solution of sodium bicarbonate and then with water. The chloroform solution is dried over anhydrous sodium sulphate and evaporated to dryness, which gives 19 g of 2-bromo-4'-hydroxy-3 '- (methylthio) propiophene-none 4'-acetate.

D. To a stirred solution containing 30 g (0.185 mole) of 2- (4-methoxyphenyl) -l-methylethylamine in 150 ml of N, N-dimethylformamide, 19.6 g (0.062 mole) of 4 are added dropwise 2-bromo-4'-hydroxy-3 '- (methylthio) propiophenone' -acetate. Once the addition is complete, the stirring is continued for two additional hours. Then the reaction mixture is diluted with chloroform and washed successively with water, dilute hydrochloric acid and a saturated aqueous solution of sodium bicarbonate. The chloroform solution is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is dissolved in ether, acidified with glacial acetic acid and cooled. The precipitated product is collected and triturated with chloroform to give 6.35 g of 4'-hydroxy-2 - {[2- (4-meth-oxyphenyl) -1-methylethyl] amino acetate } -3 '- (methylthio) propio-phenone, mp 110-112 ° C.

Example 41

To a stirred solution containing 6.2 g (0.0148 mole) of 4'-hydroxy-2 - {[2- (4-methoxyphenyl) -1-methyl-ethyl] -amino} -3 'acetate - (methylthio) propiophenone in 100 ml of methanol at 0 ° C, 0.5 g of sodium borohydride is added in portions. Once the addition is complete, the stirring is continued for an additional half hour. Then the reaction mixture is acidified with glacial acetic acid and evaporated to dryness. The residue is diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic extracts are evaporated to dryness and the residue is dissolved in ether. The ethereal solution is acidified with glacial acetic acid and cooled. The precipitated product is collected and dried, to give 5.0 g of 4-hydroxy-a- <{[2- (4-methoxyphenyl) -1-methylethyl] ami-5no} ethyl acetate > -3- (methylthio) benzenemethanol, mp 160-162 ° C.

Example 42

To a stirred mixture of 2.35 g (0.0056 mole) of 4-hydroxy-a - <{[2- (4-methoxyphenyl) -1-methylethyl] ami-io no} ethyl acetate> -3 - (methylthio) benzenemethanol and 40 ml of methanol at -10 ° C., a solution containing 1 ml (0.0056 mol) of 40% commercial peracetic acid in 5 ml of methanol is added dropwise. Once the addition is complete, the stirring is continued for an additional half hour. Then the reaction mixture is evaporated to dryness and the residual oil is suspended in chloroform and diluted with ether, which gives a granular solid which is collected and dried, and 2.2 g of acetate of 4-hydroxy-a- <{1 - [2- (4-methoxyphenyl) -1 -methylethyljami-20 no} ethyl> -3- (methylsulfinyl) benzenethanol are obtained, pf 110 ° C.

Example 43

To a stirred solution containing 16 g (0.082 mole) of 2- (3,4-dimethoxyphenyl) -l-methylethylamine and 6 ml (0.041 25 mole) of triethylamine in 60 ml of N, N-dimethylformamide at -65 ° C, a solution containing 12.5 g (0.041 mole) of 4 '~ 2-bro-mo-4'-hydroxy-3' acetate - (methyithio) acetophenone in 40 ml is added dropwise over three-quarters of an hour of N, N-dimethylformamide. Once the addition is complete, the shaking is continued for an additional hour. Then the reaction mixture is slightly acidified with 5 ml of 12N hydrochloric acid and extracted with chloroform. The organic extracts are evaporated to dryness and the residue is dissolved in trifluoroacetic acid and then treated with an excess of acetyl chloride. After one hour of stirring, the mixture is diluted with water and evaporated to dryness. The residue is partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer is dried over anhydrous sodium sulphate and evaporated to dryness, which gives 12 g of 40 4'-acetate of 2 - {[2- (3,4-dimethoxyphenyl) -l-methylethyl] amino} -4 '-hydroxy-3' - (methylthio) acetophenone crude.

Example 44

Following a procedure similar to that described in Example 38 but using 12 g of 2 - {[2- (3,4-dimethoxyphenyl) -1-methylethyl] amino} -4'- 4'-acetate hydroxy-3 '- (methylthio) acetophenone, 870 mg of sodium borohydride and 1.4 g of potassium hydroxide, 2.2 g of acetate (salt) of a - <{[2- (3 , 4-dimethoxyphenyl) -1-methylethyl] ami-50 no} methyl> -4-hydroxy-3- (methylthio) benzenemethanol, mp 141-144 ° C.

Example 45

Following a procedure similar to that described in Example 42, but using 2.30 g (0.0052 mole) of acetate (salt) of a - <{[2- (3,4-dimethoxyphenyl ) -l-methylethyl] ami-no} methyl> -4-hydroxy-3- (methylthio) benzenemethanol and 0.95 ml (0.0052 mol) of 40% commercial peracetic acid, 1.9 g are obtained of acetate (salt) of a - <{[2- (3,4-dimethoxyphé-60 nyl) -l-methylethyl] amino} methyl> -4-hydroxy-3- (methyl-isul-finyl) benzenemethanol in the form of 'a light yellow amorphous solid.

Example 46

65 To a stirred solution containing 19.5 g (0.12 mole) of 1,1-dimethyl-3-phenylpropylamine in 100 ml of N, N-dimethyl-formamide, under nitrogen at - 60 ° C, is added dropwise drop in half an hour a solution containing 12 g (0.04 mole) of 4'-

627,447

20

2-bromo-4'-hydroxy-3 'acetate (methylthio) acetophenone in 40 ml of N, N-dimethylformamide. Once the addition is complete, stirring is continued for one hour at -35 ° C.

The reaction mixture is then acidified with 10 ml of 12N hydrochloric acid, diluted with 150 ml of chloroform and the resulting solution is washed with water. The chloroform solution is cooled to - 65 ° C. and diluted with 1 ml. 'ether. The resulting precipitate is collected and recrystallized from ethanol to give 12 g of 2 - [(1,1-dimethyl-3-phenylpropyl) amino] -4'-hydroxy-3 hydrochloride. '- (methylthio) acetophen-none, pf 188-193 ° C.

Example 47

Following a procedure similar to that described in Example 8, but using 11.0 g (0.026 mole) of 2- [1,1-dimethyl-3-phenylpropyl) -ami- 4'-acetate hydrochloride no] -4'-hydroxy-3 '- (methylthio) acetophenone, 750 mg (0.02 mole) sodium borohydride and 1.4 g (0.026 mole) potassium hydroxide, 9.2 g d acetate (salt) of a - {[(1,1-dimethyl-3-phenylpropyl) amino] methyl} -4-hydroxy-3- (methylthio) benzenemethanol, mp 171-172 ° C.

Example 48

Following a procedure similar to that described in Example 11 but using 6.2 g (0.015 mole) of acetate (salt) of α- {[(1,1-dimethyl-3-phenylpropyl) amino ] methyl} -4-hydroxy-3- (methylthio) benzenemethanol and 1.17 g (0.015 mol) of 40% commercial peracetic acid, 5.5 g of acetate (salt) of a- { [(1,1-dimethyl-3-phenylpropyl) amino] -methyl} -4-hydroxy-3- (methylsulfinyl) benzenemethanolbrut. After a double recrystallization from a mixture of chloroform and methanol and a single recrystallization from a mixture of ethyl acetate, acetone and ethanol, the product is dissolved in a mixture of ethyl acetate and methanol and the resulting solution is acidified with glacial acetic acid and then evaporated to dryness. Recrystallization of the residue from a mixture of ethanol and ethyl acetate provides 1.4 g of the 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- (2 ~ methoxyphé-nyl) -2-methyl-2-butanol in 300 ml of n-butyl ether at 60 ° C., 120 ml of concentrated sulfuric acid are added dropwise over one hour. When the addition is complete, stirring is continued for an additional hour at 50-55 ° C. Then the reaction mixture is poured onto 1200 g of ice, it is made alkaline with sodium carbonate and it is extracted with ether. The ethereal extracts are dried over anhydrous sodium sulfate and evaporated to dryness. The 76.5 g of residual oil is heated under reflux for 3 hours in 175 ml of 12N hydrochloric acid. The mixture is cooled, washed with ether, made alkaline with 35% aqueous sodium hydroxide and extracted with ether. The ethereal extracts are dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil is distilled under reduced pressure and the boiling fraction is collected at 161-162 ° C! 22 mm, which gives 35 g of 1,1-dimethyl-3- (4-methoxyphenyl) propylamine.

B. Following a procedure similar to that described in Example 7 but using 29 g (0.15 mole) of 1,1-dimethyl-3- (4-methoxyphenyl) propylamine, 15 g (0.05 mole ) of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophen-none and 10 ml of acetyl chloride 4'-acetate, 9.5 g of 2-' 4'-acetate hydrochloride are obtained {[1,1-dimethyl-3- (4-methoxyphenyI) propyl] amino} -4'-hydroxy-3 '- (methylthio) acetophenone, pf 186-190 ° C.

Example 50

Following a procedure similar to that described in Example 8 but using 9.5 g (0.021 mole) of 2 - {- [[1,1-dimethyl-3- (4-methoxyphenyl) 4'-acetate hydrochloride pro-spyl] amino} -4'-hydroxy-3 '- (methylthio) acetophenone, 600 mg (0.015 mol) of sodium borohydride and 1.2 g of potassium hydroxide, 2.3 g of the acetate (salt) of a - <{[1,1-dimethyl-3- (4-methoxyphenyl) propyl] amino} methyl> -4-hydroxy-3- (methylthio) -benzenethanol, mp 173-104 ° C.

Example 51

Following a procedure similar to that described in Example 11 but using 3.9 g (0.009 mole) of acetate (salt) of a - <{[1,1-dimethyl-3- (4 -methoxyphenyl) propyl] ami-no} -methyl> -4-hydroxy-3- (methylthio) benzenemethane 680 mg of 40% commercial peracetic acid, 3.0 g of acetate (salt) of a - <{[1,1-dimethyl-3- (4-methoxyphenyl) propyl] amino} méthyI> -4-hydroxy-3- (méthyIsulfinyl) benzè-2onéméthanol, pf 115 ° C.

Example 52

Following a procedure similar to that described in Example 7 but using 18 g (0.12 mole) of 1-methyl-3-25 phenylpropylamine, 12 g (0.04 mole) of 4'-acetate of 2 -bromo-4'-hydroxy-3 '- (methylthio) acetophenone and 8 ml of acetyl chloride, we obtain 8.3 g of 4'-acetate hydrochloride of 4'-hydroxy-2 - [(l-methyl -3-phenylpropyl) amino] -3 '- (methyl-thio) acetophenone.

30

Example 53

Following a procedure similar to that described in Example 8 but using 8.1 g (0.02 mole) of 4'-acetate hydrochloride 4'-hydroxy-2 - [(1-methyl-3- phenylpropyl) -35 amino] -3 '- (methylthio) acetophenone, 500 mg of sodium borohydride and 1.2 g of potassium hydroxide, 6.2 g of 4-hydroxy acetate (salt) are obtained a - {[(1-methyl-3-phenylpro-pyl) amino] methyl} -3-methylthio) benzènmethanol, pf 140-142 ° C.

40

Example 54

Following a procedure similar to that described in Example 11 but using 4.2 g (0.011 mol) of acetate (salt) 45 of 4-hydroxy-a - {[(1-methyl-3-phenylpropyl) amino] mesethyl} -3- (methylthio) benzenemethanol and 815 mg (0.011 mol) of 40% commercial peracetic acid, 4.0 g of 4-hydroxy-a- {acetate (salt) are obtained [(1-methyl-3-phenyIpropyl) ami-no] methyl} -3- (methyIsulfinyl) benzenemethanol in the form of a pale yellow amorphous solid.

Example 55

Following a procedure similar to that described in Example 34 but using 18.2 g (0.11 mole) of 3- (4-me-55 thoxyphenyl) propylamine and 11.2 g (0.037 mole) of 4 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone, 9 g of 4'-acetate 4'-hydroxy-2 - {[3- (4-methoxyphenyl) - - hydrochloride are obtained propyl] amino} -3 '- (methylthio) acetophenone which can be used in the next step.

60

Example 56

Following a procedure similar to that described in Example 8 but using 9 g of 4'-acetate 4'-hydroxy-2 - {[3- (4-methoxyphenyI) propyI] amino} -3'- hydrochloride 65 (methylthio) acetophenone, 600 mg of sodium borohydride and 2.0 g of potassium hydroxide, 1.2 g of 4-hydroxy-a acetate are obtained - <[3- (4-methoxyphenyl) propyl] amino} mé-thyI> -3- (methylthio) benzenemethanol, pf 123-125 ° C.

21

627,447

Example 57

Following a procedure similar to that described in Example 11 but using 1.2 g 0.003 mole) of 4-hydroxy-a - <{[3- (4-methoxyphenyl) propyl] amino} acetate (salt) methyl> -3- (methylthio) benzenemethanol and 0.44 ml (0.003 mole) of 40% commercial peracetic acid, 1.1 g of 4-hydroxy-a acetate (salt) are obtained <<[ 3- (4-methoxyphenyl) pro-pyl] amino} methyl> -3- (methylsulfinyl) benzenemethanols in the form of an amorphous brown yellow solid.

Example 58

A. A stirred mixture containing 64 g (0.334 mole) of 5- (4-methoxyphenyl) -2-penta-none, 80 g (1.77 mole) of formamide and 6 ml of is slowly heated to 165 ° C. formic acid, then treated dropwise over 3.5 hours with 50 ml of formic acid while allowing the water formed to slowly distil during the reaction. Stirring is continued at 165 ° C for an additional 3 hours. The reaction mixture is then cooled, diluted with one liter of ice and water and extracted with a mixture of ether and benzene. The organic extracts are evaporated and the residual oil is heated under reflux for one and a half hours in 130 ml of 12N hydrochloric acid. The mixture is cooled, diluted with 300 ml of water and washed with a mixture of ether and benzene. The aqueous layer is made alkaline with 35% aqueous sodium hydroxide and extracted with a mixture of ether and benzene. The organic layer is extracted with IN hydrochloric acid and the acidic aqueous layer is made alkaline with 35% aqueous sodium hydroxide and extracted with a mixture of ether and benzene. The extracts are dried over anhydrous sodium sulfate and the solvent is evaporated in vacuo. The residual oil is distilled under reduced pressure, which gives 37 g of 4- (4-methoxyphé-nyl) -l-methylbutylamine, mp 163—166.5 ° C / 18 mm.

B. To a stirred solution containing 15.5 g (0.08 mole) of 4- (4-methoxyphenyl) -l-methylbutylamine in 80 ml of N, N-dimethylformamide at - 60 ° C, is added dropwise 0.75 hour a solution containing 8.0 g (0.027 mole) of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone 4'-acetate in 25 ml of N, N-dimethylformamide. Once the addition is complete, stirring is continued for an additional hour at a temperature of -60 ° to -45 ° C. The reaction mixture is then acidified with 48% hydrobromic acid and extracted with chloroform. The chloroform solution is diluted with two and a half volumes of ether and cooled to

- 65 ° C. The resulting precipitate is collected, redissolved in chloroform and the resulting solution is washed thoroughly with water. Then the chloroform solution is dried over anhydrous sodium sulphate and evaporated to dryness, which gives 9 g of 4'-acetate 4'-hydroxy-2 - {[4- (4-methoxy-phenyl) hydrobromide -1 -methyIbutyI] amino} -3 '-methyIthio) crude acetophenone.

Example 59

Following a procedure similar to that described in Example 8 but using 9 g of 4'-acetate 4'-hydroxy-2 - {[4- (4-methoxyphenyl) -l-methylbutyl] ami-no hydrobromide } -3 '- (methyIthio) raw acetophenone, 500 mg of sodium borohydride and 1 g of potassium hydroxide, 5.5 g of the acetate (salt) of 4-hydroxy-a - <{[4 - (4-methoxyphenyI) -1-methylbutyI] amino} methyl> -3- (methylthio) benzenemetha-nol, pf 155-157 "C.

Example 60

Following a procedure similar to that described in Example 11 but using 3.0 g (0.007 mol) of the acetate (salt) of 4-hydroxy-a - <{[4- (4-methoxyphenyl) - l-methylbu-tyl] amino} -methyl> -3- (methylthio) benzenemethanol and 1.04 ml (0.007 mol) of 40% commercial peracetic acid, 2.6 g of acetate (salt) are obtained of 4-hydroxy-a - <{[4- (4-me-thoxyphenyl) -1-methyl-butyl] amino} methyl> -3- (methylsulfinyl) benzenemethanol in the form of an amorphous yellow solid.

5 Example 61

A. To a stirred mixture of 52.5 g (0.253 mole) of 4- (4-methoxyphenyl) -1,1-dimethylbutyl alcohol and 44.5 g (0.685 mole) of potassium cyanide powder in 200 ml of n-butyl ether at 60 ° C., is added dropwise over one hour 80

io ml of concentrated sulfuric acid. The temperature is maintained at 60-65 ° C during the addition and stirring is continued at 50-55 ° C for an additional hour after the addition is complete. Then the reaction mixture was poured into 850 ml of ice, made alkaline with 35% aqueous sodium hydroxide and extracted with ether. The ethereal extracts are evaporated to dryness and the residual oil is heated to reflux for 3 hours in 125 ml of 12N hydrochloric acid. The resulting mixture is diluted with 300 ml of water and washed with a mixture of ether and benzene. The aqueous layer was basified with 35% aqueous sodium hydroxide and extracted with a mixture of ether and benzene. Then the organic layer is extracted with IN hydrochloric acid, the acidic aqueous layer is made alkaline with 35% aqueous sodium hydroxide and extracted with a mixture of ether and benzene. The extracts are dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 12.2 g of 4- (4-methoxy-phenyl) -1,1-dimethyl-butylamine as an oil straw-colored.

B. By following a procedure similar to that described

In Example 58B but using 19 g (0.09 mole) of 4- (4-methoxyphenyl) -1, l-dimethylbutylamine and 10.0 g (0.033 mole) of 2-bromo- 4'-acetate 4'-hydroxy-3 '- (methylthio) acetophenone and by leaving the final product to crystallize from acetone in a refrigerator overnight, 10.5 g of 4'-hydroxy-4'-acetate hydrobromide are obtained 2 - {[4- (4-methoxyphenyI) -1, l-dimethyl-butyI] amino} -3 '- (methyI-thio) crystalline acetophenone, pf 180-181 ° C.

Example 62

40 Following a procedure similar to that described in Example 8 but using 10.5 g (0.021 mole) of 4'-hydroxy-2 - {- 4- [4 (methoxyphenyl) 4'-acetate hydrobromide -1,1-dimethylbutyl] amino} -3 '- (methylthio) acetophenone, 250 mg of sodium borohydride and 1 g of potassium hydroxide 45 and by recrystallizing the product from a mixture of methanol and ether, we obtain 4 g of 4-hydroxy-a - <{[4- (4-methoxyphé-nyl) 1,1 -dimethylbutyl] amino} -methyl> -3- (methylthio) benzene-methanol in the form of the free base, pf 179—180 ° C.

50 Example 63

Following a procedure similar to that described in Example 42 but using 2.7 g (0.007 mole) of 4-hydroxy-a- <{[4- (4-methoxyphenyl) -1, 1 -dimethylbutyl] amino } methyl-> -3- (methylthio) benzenemethanol, 1.8 g of 55 4-hydroxy-a - <{[4- (4-methoxyphenyl) -1, 1-dimethylbutyl] amino} methyl> -3 are obtained - (methylsulfinyl) benzenemethanol in the form of an amorphous white powder.

Example 64

60 A stirred mixture containing 7.4 g (0.015 mole) of 4'-ben-zoate hydrobromide from (+) - 4'-hydroxy-2 - {[3- (4- optically pure methoxyphenyl) -1-methyl-propyl] amino} -3 '- (methylthio) acetophenone and 100 ml of 48% hydrobromic acid. The reaction mixture is then evaporated to dryness and the residue is triturated with ethanol and isopropyl acetate, which gives 5.3 g of (+) - 4'-hydroxy- hydrobromide. 2 - {[3- (4-hydroxyphenyl) -1 -methylpropyl] amino} -3 '- (methylthio) acetophenone.

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22

Example 65

Following a procedure similar to that described in Example 41 but using 5.0 g (0.012 mole) of (+) - 4'-hydroxy-2 - {[3- (4-hydroxyphenyl) -1-hydrobromide -methyl-propyl] amino} -3 '- (methylthio) acetophenone and 0.455 g of sodium borohydride, 4.2 g of the acetate (salt) of 4-hydroxy-a- <{[3- (4 -hydroxyphenyl) -1-methylpropyl] ami-no} methyl> -3- (methylthio) -benzenemethanol, [a] o = +5 °.

Example 66

Following a procedure similar to that described in Example 22 but using 4.2 g (0.01 mole) of 4-hydroxy-a- <{[3- (4-hydroxyphenyl) acetate (salt) -1 -methylpropyl] amino} -methyl> -3- (methylthio) benzenemethanol, and eluting the oxidation product in a short column (1.5 m) of silica gel then transforming into cyclohexylsulfamate (salt), 2.3 g of 4-hydr-oxy-a - <[4- (hydroxyphenyl) -1-methylpropyl] amino} methyl> -3- (methyl sulfinyl) benzenemethanol dextrorotatory cyclohexylsulfamate (salt) are obtained 149-151 ° C, [<x] d = + 2.1 °.

Example 67

A. To a stirred solution containing 100 g (0.55 mole) of 4'-hydroxy-3 '- (methylthio) acetophenone in 650 ml of dioxane and 300 ml of ether, a solution is added dropwise over 4 hours containing 147 g of dioxane dibromide in 1050 ml of a 1: 1 mixture of dioxane and ether. When the addition is complete, the reaction mixture is diluted with 500 ml of ether and washed with water. The organic layer is separated, washed with a saturated aqueous sodium chloride solution, filtered through cotton and the solvents are evaporated in vacuo. The residue is diluted twice with benzene and the benzene is evaporated. The final residue is crystallized from a mixture of benzene and ether, which gives after drying 107.5 g of 2-bromo-4'-hydroxy-3 '- (methylthio) -acetophenone.

B. To a stirred solution containing 50 g (0.28 mol) of (-) 3- (4-methoxyphenyl) -l-methylpropylamine (optical purity & 94%) in 150 ml of N, N-dimethylformamide at

- 60 ° C, a solution containing 30 g (0.12 mole) of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone in 80 ml of N, N is added dropwise in half an hour -dimethylform-amide. Once the addition is complete, stirring is continued at a temperature of -60 ° C to 40 ° C for an additional half hour. The reaction mixture is then acidified with 60 ml of 48% hydrobromic acid, diluted with 150 ml of water and washed with ether. The aqueous solution is evaporated to dryness under vacuum. The residue is dissolved in dichloromethane and the resulting solution is washed with water and with a saturated aqueous solution of sodium chloride. The dichloromethane is evaporated and the residue is diluted with 2-propanol and cooled to 0 ° C. The solid which precipitates is collected and 9.5 g of the white crystalline hydrobromide are obtained. The concentration of the filtrate provides an additional 2.9 g which is converted into the hydrochloride in a conventional manner, which provides 2.5 g of the hydrochloride of (-) -4'-hydroxy-2 - {[3- (4 -methoxyphenyl) -1-methyl-propyl] amino} -3 '- (methylthio) acetophenone, pf 195-197 ° C, [ct] o = - 11.4 °.

Example 68

Following a procedure similar to that described in Example 23 B but using 25 g of 2'-bro-mo-4'-hydroxy-3 '4'-benzoate - (methylthio) acetophenone and 32 g of (- ) -3- (4-methoxyphenyl) -l-methylpropylamine (optical purity & 94%), 29.6 g of 4'-benzoate hydrobromide of (-) - 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -1-methylpropyl] amino} -3 '- (methylthio) acetophenone.

Example 69

Following a procedure similar to that described in Example 41 but using 9.3 g of (-) -4'-hydroxy-2 - {[3- (4-methoxyphenyl) -l-methylpropyl] amino hydrobromide } -5 3 '- (methylthio) acetophenone and 1 g of sodium borohydride, and by precipitating the hydrochloride directly from the ethyl acetate extracts, 8.4 g of 4-hydr-oxy hydrochloride are obtained -a - <{[3- (4-methoxyphenyl) -l-methylpropyl] amino} -methyl> -3- (methylthio) benzenemethanol, pf 156-157 ° C, io Md = - 9.3 ° in the form of a mixture of two diastereoisomers.

Example 70

Following a procedure similar to that described in Example 10 but using 29.6 g (0.055 mole) of 4'-benzoate hydrate from (-) -4'-hydroxy-2 - {[3- (4 -methoxy-phenyl) -1-methylpropyl] amino} -3 '- (methylthio) acetophen-none, 1.55 g (0.041 mole) sodium borohydride and 30 ml of a 35% aqueous solution of sodium hydroxide sodium, and by isolating the product in the hydrochloride form, 18.6 g of 4-hydroxy-a - <{[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl}> -3- are obtained. (methylthio) benzenemetha-nol.

25 Example 71

Following a procedure similar to that described in Example 11 but using 17.6 g (0.044 mole) of 4-hydroxy-2 - <{[3- (4-methoxyphenyl) -1-methylpro-pyl hydrochloride ] amino} methyl> -3- (methylthio) benzenemethanol prepared according to the method of Example 70 and 3.36 g (0.044 mole) of 50% commercial peracetic acid, 12.5 g of hydrochloride are obtained. 4-hydroxy-2 - <{[3- (4-methoxyphenyl) -1-methylpro-pyl] amino) methyl> -3- (methylsulfinyl) benzenemethanol, pf 107—117 ° C, [a] o = + 7.6 °, as a mixture of four diastereoisomers.

Example 72

A chloroform solution containing 10 g (0.0185 mole) of 4'-benzoate hydrobromide of (+) - 4'-hydroxy-2 - {[3- is washed carefully with a saturated aqueous sodium bicarbonate solution. (4-methoxyphenyl) -1-methylpropyl] amino} -3 '- (methylthio) acetophenone. Then the chloroform solution is acidified with acetic acid and evaporated to dryness. The residue is oxidized with 2.2 ml of 50% commercial 50% peracetic acid in trifluoroacetic acid, according to the method described in Example 25, and 6.4 g of 4 'hydrochloride are obtained. 4'-hydroxy-2 benzoate - {[3- (4-methoxyphé-nyl) -l-methylpropyl] amino} -3 '- (methylsulfinyl) -acétophé-none, in the form of a mixture of diastereoisulfoxides- 50 mothers, pf 158-159 ° C.

Example 73

A mixture containing 15 g of 55 4'-benzoate of (+) - 4'-hydroxy-2 - {[3- (4-methoxy-phenyl) -1-methylpropyl] amino} is stirred for 5 minutes. -3 '- (methylthio) aceto-phenone, 140 ml of acetonitrile and 40 ml of concentrated ammonia and after 5 minutes a solid begins to precipitate. The mixture is cooled to 0 ° C and the precipitated product is collected 60 which is washed with ether. Drying at 60 ° C causes the product to become a black gum. The latter is dissolved in a mixture of methanol and ethyl acetate and filtered through silica gel. The filtrate is evaporated to dryness and the residue is dissolved in ethyl acetate. Acidification of the resulting solution 65 with ethanolic hydrochloric acid provides 2.5 g of (+) - 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -l-methylpropyl] hydrochloride amino} -3 '- (methylthio) acetophenone pale yellow crystalline.

23

627,447

Example 74

Following a procedure similar to that described in Example 25 but using 2.46 ml (0.016 mole) of (+) - 4'-hydroxy-2- {[3- (4-methoxyphenyl) -1-methylpropyl ] amino} -3 '- (methylthio) acetophenone which was prepared in the form of the free base according to the procedure of Example 73 and which is used immediately after drying for 4 hours under vacuum at 45 ° C, 2.5 g of 4'-hydroxy-2 - {[3- (4-methoxy-) hydrochloride are obtained after precipitation with ethanolic hydrochloric acid from a mixture of acetone and 2-propanol phenyl) -1-methyIpropyl] -amino} -3 '- (methyIsulfinyI) aceto-phenone in the form of a mixture of diastereoisomeric sulfoxides, 192-194 ° C with decomposition, [a] g5 = +19.2 °.

In addition to anti-hypertension and antiarrhythmic activity, this compound was also found to have cardiotonic activity when tested according to the methods described in Example 20 above. In the in vitro test, this compound at doses of 10.30 and 100 (xg / ml causes increases in the speed of the right atrium of 0.3 and 8% respectively; in the strength of the right atrium 1, 5 and 6% respectively and papillary muscle strength of 7.23 and 38% respectively. In the in vitro test, at doses of 1.0, 3.0 and 10.0 mg / kg, the compound causes increases in cardiac contraction force of 22.25 and 59% respectively In a similar series of in vitro tests, increases in cardiac contraction force of 4.12 and 50% are observed.

Example 75

26.1 g (0.1 mole) of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone are reacted with 45 g (0.25 mole) of 3,4-dime-thoxyphenethylamine, essentially according to the process described in Example 67B. The product initially obtained by evaporation of the aqueous solution is treated with hot methanol and the insoluble N, N-bis- [4-hydroxy-3- (methylthio) phenacyl] -3,4-dimethoxy-phenethylamine is filtered. The filtrate is concentrated, diluted with 2-propanol and cooled. The resulting solid is recrystallized from water and then the insoluble by-product is again filtered. The product thus obtained is recrystallized from aqueous ethanol and a 5.5 g sample is transformed into the hydrochloride in a conventional manner, which gives 4.6 g of the hydrochloride of 2 - {[2- (3, 4-dimethoxyphenyl) ethyl] amino} -4'-hydroxy-3 '- (methylthio) -acetophenone, pf 208-212 ° C.

Example 76

Following a procedure similar to that described in Example 41 but using 13.1 g (0.033 mole) of 2 - {[2- (3,4-dimethoxyphenyl) ethyl] amino} -4'-hydr- hydrochloride oxy-3 '- (methylthio) acetophenone and 2.0 g (0.053 mol) of sodium borohydride, by acidifying the reaction mixture with 6N hydrochloric acid and isolating the hydrochloride, 11.5 g of hydrochloride are obtained. 'a - <{[2- (3,4-dimethoxyphé-nyI) éthyI] amino} -méthyl> -4-hydroxy-3- (méthyIthio) benzè-methanol, pf 124-126 ° C.

Example 77

Following a procedure similar to that described in Example 11 but using 5.6 g (0.014 mole) of α- {{2- (3,4-dimethoxyphenyl) ethyl} amino] -me- hydrochloride thyl> -4-hydroxy-3- (methylthio) benzenemethanol and 2.13 ml of 50% commercial peracetic acid, 4.9 g of a - <{hydrochloride are obtained by crystallization from 2-propanol [2- (3,4-dimethoxyphenyl) -ethyl] amino} methyl>> -4-hydroxy-3- (methylsulfinyl) benzenemethanol, mp 173-175 ° C.

Example 78

To a stirred solution containing 72.3 g (0.4 mole) of 3,4-dimethoxyphenethylamine in 275 ml of N, N-dimethylform-amide at -50 ° C., a solution containing 39 is added over two hours. 3 g (0.133 mol) of 2-bromo-4'-hydroxy-3 '- (methylsulfonyl) -acetophenone in 275 ml of N, N-dimethyl-formamide. Once the addition is complete, stirring is continued for one hour at a temperature of - 40 ° C to - 45 ° C, then one and a half hours at a temperature of - 30 ° C to - 40 ° C, and finally half an hour at a temperature of - 30 ° C to - 5 ° C. The reaction mixture is cooled to -20 ° C. and acidified with 45 ml of 48% hydrobromic acid. The solvents are evaporated in vacuo and the residual syrup is washed with ether. The syrup is dissolved in 200 ml of water and allowed to crystallize for a Saturday and a Sunday. The precipitated solid is collected, washed with water and ether and recrystallized from 95% ethanol, which gives 32.31 g of 2- {[2- (hydrobromide 3,4-dimethoxyphenyl) ethyl] amino} -4 '-hydroxy-3' -15 (methylsulfonyl) acetophenone, pf 220-227 ° C. A 10 g sample is transformed into a free base which is recrystallized from aqueous methanol and then converted to the hydrochloride; m.p. 227—233 ° C with decomposition.

20 Example 79

The mixture is stirred under an initial hydrogen pressure of 3.5 kg / cm 2 until the absorption of hydrogen stops, a mixture containing 14.3 g (0.03 mole) of 2- {hydrobromide [2- (3,4-dimethoxyphenyl) ethyl] amino} -4'-hydroxy-3 '- (methyl-25 sulfonyl) -acetophenone and 1 g of a hydrogenation catalyst which is 10% palladium on carbon in 200 ml of N, N-dimethylformamide. The catalyst is removed by filtration and the filtrate is evaporated in vacuo. The residual oil is treated with 100 ml of a 5% aqueous solution of sodium bicarbonate, 20 ml of a 10% aqueous solution of sodium carbonate and 40 ml of ether. The solid which precipitates is collected and dissolved in 100 ml of methanol containing 10 ml of ethanolic hydrochloric acid. The solution is treated with bleaching charcoal and evaporated to dryness. The residue is dissolved in 225 ml of hot methanol and the resulting solution is diluted with 125 ml of acetonitrile and concentrated to a volume of 125 ml. By standing, a first crop of product crystallizes and is collected by filtration. Further concentration of the filtrate provides a second and third crop of product. The crops are combined and 11.2 g of a - <{[2- (3,4-dimethoxyphenyl) ethyl] amino} methyl> -4-hydr-oxy-3- (methylsulfonyl) hydrochloride are obtained. benzene methanol, pf 209-210 ° C.

Example 80

45 Following a procedure similar to that described in Example 67B, 13.5 g (0.05 mole) of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone are reacted with 22 g ( 0.134 mol) of 1-methyl-3-phenylpropylamine. The product initially obtained is transformed into the hydrochloride in the conventional manner by evaporation of the aqueous solution. Recrystallization of the hydrochloride from aqueous methanol provides 7.1 g of 4'-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] -3 'hydrochloride, m-thylthio) acetophenone, m.p. 205-208 ° C.

55 Example 81

To a solution containing 14.6 g (0.05 mole) of 2-bromo-4'-hydroxy-3 '- (methylsulfonyl) acetophenone in 100 ml of N, N-dimethylformamide at a temperature of - 40 to - 50 ° C, a solution containing 22.6 g (0.15 mole) of 1-me-6o thyl-3-phenylpropylamine in 100 ml of N, N-dimethylformamide is added. After adding approximately 30% of the solution in one hour, the rest of the solution is quickly added in 10 minutes. Agitation is continued for a quarter of an hour at -40 ° C. and then for one hour at -10 ° C. The reaction mixture is acidified with 21 ml of concentrated hydrochloric acid and diluted with 25 ml of water and 175 ml of a saturated aqueous solution of sodium chloride. After half an hour of stirring in the cold, the solid which precipitates is collected and washed with a saturated aqueous solution of

627,447

24

sodium chloride and ether and recrystallized from 350 ml of water containing 20 ml of 6N hydrochloric acid. The product is collected by filtration and washed with water and acetone. A two-day rest of the filtrate provides a second crop of product and a one-month rest provides a third crop. The final filtrate is evaporated to dryness and the residue is recrystallized from water, which gives a fourth crop of product. Each of the four crops is recrystallized from a mixture of methanol and ethanol and the resulting products are combined to obtain 10.0 g of 4'-hydroxy-2- [(1-methyl-3-phenylpropyl hydrochloride ) amino] -3 '- (methylsulfonyl) -acétophé-none, pf 210 ° -215 ° C.

Example 82

The mixture is stirred under an initial hydrogen pressure of 2.25 kg / cm 2, until the absorption of hydrogen stops, a mixture containing 13 g (0.0327 mole) of 4'-hydrochloride -oxy-2 - [(1-methyl-3-phenylpropyl) amino] -3 '- (methylsulfonyl) -acetophenone and 0.9 g of a hydrogenation catalyst which is 10% palladium on carbon in 180 ml of N, N-dimethyl-formamide and 20 ml of water. The catalyst is removed by filtration and the filtrate is evaporated in vacuo. The residue is partitioned between ethyl acetate and 5% aqueous potassium bicarbonate. The aqueous phase is saturated with sodium chloride and extracted again with ethyl acetate. The organic extracts are combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The residual oil is dissolved in 50 ml of hot ethanol and the resulting solution is acidified with ethanolic hydrochloric acid. The solvent is evaporated and the residue is crystallized from acetonitrile. The product is transformed into a free base which is crystallized from aqueous methanol. The conversion to the hydrochloride and the crystallization of the latter in acetonitrile provides 8.95 g of 4-hydroxy-a - {[((1-methyl-3-phenylpropyl) amino] -methyl} -3- (methylsulfonyl) hydrochloride) benzene methanol, pf 178-180 ° C.

Example 83

Following a procedure similar to that described in Example 80 but using 13 g (0.05 mole) of 2-bromo-4'-hydroxy-3 '- (methylthio) acetophenone and 22 g (0.135 mole) of 1,1-dimethyl-3-phenylpropylamine, and by stirring the reaction mixture for one and a half hours at -10 ° C., 7.8 g of 2 - [(1,1-dimethyl-3-phenylpropyl) amino hydrochloride are obtained ] -4'-hydroxy-3 '- (methylthio) -acetophenone, pf 215-220 ° C.

Example 84

To a stirred solution containing 44.5 g (0.23 mole) of 3- (4-methoxyphenyl) -1,1-dimethylpropylamine in 185 ml of N, N-dimethylformamide at - 50 ° C, added in 2.25 hours a solution containing 27 g (0.092 mole) of 2-bromo-4'-hydroxy-3 '- (methylsuIfonyl) acetophenone in 185 ml of N, N-dime-thylformamide. Once the addition is complete, stirring is continued for an additional three hours, allowing the reaction mixture to warm up to room temperature. Then the mixture is acidified with 23 ml of 48% hydrobromic acid and evaporated in vacuo. The residual oil is washed with ether and then diluted with 200 ml of acetone, which allows the precipitation of 3- (4-methoxyphé-nyI) -l, l-dimethylpropylamine hydrobromide. The solid is filtered off and the filtrate is diluted with ether to precipitate the desired product. The solid thus obtained is suspended in 500 ml of hot acetonitrile, cooled and collected by filtration. The latter substance is suspended in 200 ml of hot chloroform, cooled and filtered, which gives 21.9 g of 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -l, l hydrochloride -dimethylpropyl] amino} -3 '- (methylsulfonyl) acetophenone, mp

220-224 ° C with decomposition. A 10 g sample is transformed into the free base by dissolving it in methanol; by basifying with a 10% aqueous solution of sodium carbonate; evaporating the methanol; diluting with water; and 5, leaving the base to crystallize, which gives 5.4 g, m.p. 159-165 ° C, which is then transformed into 2.93 g of hydrochloride, m.p. 222-232 ° C with decomposition.

Example 85

Following a procedure similar to that described in Example 79, but using 11.3 g (0.023 mole) of 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -1, l- hydrobromide dimethyl-propyI] amino} -3 '- (methyIsuIfonyl) acetophenone, 9.66 g of 4-hydroxy-a hydrochloride are obtained - <[3- (4-methoxyphé-15nyl) -1, l-dimethylpropyl] amino} methyl> -3- (methylsulfonyl) benzenemethanol, mp 202-204 ° C.

Example 86

25.4 g (0.097 mole) of 2-bromo-4'-hydroxy-20 3 '- (methylthio) acetophenone is reacted with 40 g (0.242 mole) of 3- (4-methoxyphenyl) propylamine, essentially according to the method described in Example 67B. The product initially obtained by evaporation of the aqueous solution is treated with aqueous ethanol. The precipitated N, N-bis- [4-hydroxy-3- (methylthio) phena-cyl] 3- (4-methoxyphenyl) propylamine is filtered. The filtrate is evaporated to dryness and the residue is crystallized from a mixture of

2-propanol and ethyl acetate. The product thus obtained is triturated with hot water and the residue is crystallized from a mixture of ethanol and ethyl acetate, which gives 6.5 g of the

4'-hydroxy-2 - {[3- (4-methoxyphenyl) propy-1] amino} -3 '- (methylthio) -acetophenone hydrobromide.

Example 87

Following a procedure similar to that described in Example 76 but using 6.5 g (0.0153 mole) 4'-hydroxy-2 - {[3- (4-methoxyphenyl) propyl] ami hydrobromide -no} -3 '- (methylthio) acetophenone and 1.2 g of sodium borohydride, 5.1 g of 4-hydroxy-a hydrochloride are obtained - <{[3- (4-methoxyphenyl) propyl] amino} methyl>> 3 (methyl-40 thio) benzenemethanol, mp 151-152 ° C.

Example 88

To a stirred suspension of 31.6 g (0.14 mole) of N-benzyl-

3-phenylpropylamine in 280 ml of methanol at a temperature of -40 ° to -45 ° C, 20.5 g (0.07

mole) of 2-bromo-4'-hydroxy-3 '- (methylsulfonyl) acetophen-none. After 2.5 hours of stirring, the reaction mixture is allowed to warm to room temperature in one and a half hours. Evaporation in vacuo provides a soft gom-50 residue which is suspended in 400 ml of ethyl acetate at the boiling point, which gives a solid precipitate of N-benzyl-3-phenylpropylamine hydrobromide. The solid is separated by filtration and the filtrate is evaporated to dryness under vacuum. The residue is dissolved in absolute ethanol and the resulting solution is acidified with 35 ml of 6.8N ethanolic hydrochloric acid. Evaporation of the acid solution and crystallization of the residue in ethanol supply 18.3 g of 2- [N-ben-zyl-3- (phenylpropyl) amino] -4 '-hydroxy-3' - (methylsulfonyl) acetophenone hydrochloride, pf 190-191 ° C. This product is combined with the 60 products of several other tests and recrystallized from absolute ethanol which gives a substance having a melting point of 193.5-195 ° C.

65

Example 89

The mixture is stirred under an initial hydrogen pressure of 3.6 kg / cm 2 until the theoretical quantity of hydrogen has been absorbed, a mixture containing 4.74 g (0.01 mole) of chlorhy-

25

627,447

2- [N-Benzyl-3- (phenylpropyl) amino] -4'-hydroxy-3'- nyl) ethyl] amino} -3 '- (methylsulfonyl) acetophenone drate, m.p.

(methylsulfonyl) acetophenone and 250 mg of a catalyst at 230-234 ° C with decomposition.

drogenation which is 10% palladium on carbon in 100 ml of 95% ethanol. It is necessary to dilute the reaction mixture - Example 94

with 200 ml of 95% ethanol and 50 ml of N, N-dimethylform. The mixture is stirred under an initial hydrogen pressure of 3.36 kg /

mamide to dissolve the solid which precipitated. Remove in cm2 until the absorption of hydrogen stops, a met

the catalyst is then filtered and the filtrate is evaporated to dryness of 16.47 g (0.0357 mol) of 4'-hydroxy hydrochloride

under vacuum. The residue is triturated with 25 ml of hot ethanol, it is 3 '- (methylsuFonyl-2 - {[2- (3,4,5-trimethoxyphenyl) ethyl] ami-

cools and the solid is collected by filtration. This no} acetophenone and 1.2 g of a hydrogenation catalyst which produced with the products of other tests are combined and recrystallized from 10 and 10% palladium on carbon, in 180 ml of N, N- dime-

aqueous methanol, which gives 12.0 g of 4'-thylformamide hydrochloride and 20 ml of water. The catalyst is removed by filtration

hydroxy-3 '- (methylsulfonyl) -2 - [(3-phenylpropyl) amino] acetation and the filtrate is evaporated in vacuo. The phenone oil is crystallized, m.p. 241-242 ° C with decomposition. residual in a mixture of methanol and ether and recrystallized from methanol. We transform the resulting product with

Example 90 15 free base ammonia which crystallizes in water. The

Following a procedure similar to that described in transformation into hydrochloride provides 12.56 g of the hydrochloride Example 67B but using 61 g (0.29 mole) of 4-hydroxy-3- (methylsulfonyl) -a- mescaline <{[2- (3,4,5-trimethoxy-

and 28 g (0.107 mole) of 2-bromo-4'-hydroxy-3 '- (methylthio) - phenyl) ethyl] amino} methyl> benzenemethanol, m.p. 192-

acetophenone, 33 g of 194 ° C. contaminated crystalline product are obtained.

with a small amount of N, N-bis- [4-hydroxy-3- (methylthio- 20

) phenacyl] -3,4,5 -trimethoxyphenetylamine. We resume the pro Example 95

added to boiling water and the insoluble byproduct is filtered to a stirred solution containing 12 g of 4-hydroxy-a-

corn. Concentrating the filtrate to a small volume produces 18.2 g <{[3- (4-methoxyphenyl) -1-methylpropyl] amino} methyl> -

4'-hydroxy-3 'hydrobromide - (methylthio) -2 - {[2- (3,4,5- 3- (methylthio) -benzenemethanol, prepared according to Example 19,

trimethoxyphenyl) ethyl] amino} -acetophenone. Chlorhy- in 50 ml of chloroform at 50 ° C, 20 ml of drate chloride isolated in monohydrate form is added to a melting point of thionyl. The temperature is maintained at 50 ° C. and after a

193-195 ° C. short stirring period the product begins to crystallize.

After 2 hours of stirring, the mixture is cooled and

EXAMPLE 91 Picking up the precipitated product which is washed with benzene

Following a procedure similar to that described in obtaining, after drying, 11 g of the hydrochloride chloride of Example 41 but using 16 g of 4'-hydr-4-hydroxy-a - <{[3- ( 4-methoxyphenyl) -1-methylpropyl]

oxy-3 '(methylthio) -2 - {[2- (3,4,5-trimethoxyphenyl) ethyl] - amino} methyl-3- (methylthio)> benzyl.

amino} -acetophenone and 2.5 g of sodium borohydride and by isolating the product in the form of the hydrochloride, 14.6 g are obtained Example 96

4-hydroxy-3- (methylthio) -cc - <{[2- (3,4,5- 35 A hydrochloride solution containing 9.6 g (0.0226 mole) of trimethoxyphenyl) ethyl] -amino } methyl> benzenemethanol, 4-hydroxy-a chloride hydrochloride - <{[3- (4-methoxy-

m.p. 168-169.5 ° C. phenyl) -1-methylpropyl] amino} methyl-3- (methylthio)> ben-

zyle in 80 ml of N, N-dimethylformamide at 0-10 ° C under

Example 92 nitrogen, 1.9 g (0.05) are added in portions over a quarter of an hour.

By following a procedure similar to that described in 40 mol) of sodium borohydride. After an additional hour

in Example 11, but using 7.7 g (0.0175 mole) of stirring chlorhytary, the reaction mixture is neutralized with 4-hydroxy-3- (methylthio) -a - <{[2 - (3,4,5-trimet glacial acetic acid, diluted with chloroform and thoxyphenyl) -ethyl] amino} methyl> benzenemethanol and 2.66 washed with a saturated aqueous solution of sodium bicarbonate ml (0.0175 mole) of 50% commercial peracetic acid and dium. The chloroform solution is dried over sodium sulphate crystallizing the product in a mixture of methanol and ether, "anhydrous and evaporated to dryness. The residue is dissolved in a 6.8 g of 4-hydroxy-3- hydrochloride (methylsuIfi- 9: 1 mixture of 2-propanol and methanol are obtained and the nyl is acidified) -a - <{[2 - (3,4,5-trimethoxyphenyl) -ethyl] amino} me- resulting solution with ethereal hydrochloric acid. By thyl> benzenemethanol, m.p. 164—166 ° C. concentration and cooling, 5.5 g of (+) - 4- <2 - {[3- (4-methoxyphenyl) -1-methylpropyl] hydrochloride are obtained -

Example 93 50 amino} ethyl> -2- (methylthio) phenol, m.p. 184—185 ° C.

To an agitated solution containing 76.0 g (0.36 mol) of mescaline in 250 ml of N, N-dimethylformamide at -65 ° C., Example 97 is added over three and a half hours to a solution containing 35.2 g. stirred solution containing 5.0 g (0.0135 mole) of (0.12 mole) of 2-bromo-4'-hydroxy-3 '- (methylsulfonyl) aceto hydrochloride of (+) -4- <2- { [3- (4-methoxyphenyl) -1-methyl-phenone in 250 ml of N, N-dimethylformamide. Once 55 propyl] amino} ethyl> -2- (methylthio) phenol in 50 ml of the addition is completed, stirring is continued at a methanol temperature, 10 ml of peracetic acid at 50% of the corneo are added. - 30 ° C for one hour then at sea temperature. Then the reaction mixture is cooled to 0-5 ° C and it is - 30 to - 5 ° C for three quarters of an hour. The process is cooled with an additional 10 ml of peracetic acid. Once mixed at -20 ° C., it is acidified with 32 ml of hydrobromide; the addition completed, the reaction mixture is concentrated to 20 ml only to 48% and evaporated in vacuo. The 60 is washed thoroughly and diluted with 50 ml of 2-propanol. By standing at 50 ° C. residual syrup with ether and it is crystallized from 2-propa overnight, the product crystallizes. We collect it and we drown it. The solid product is collected in several fractions, the dries of which give 4.5 g of hydrochloride of 4- <2 - {[3- (4-some first contain significant amounts of methoxyphenyl) -l-methylpropyl] amino} ethyl> -2- (methylsul-mescaline hydrobromide. The last fractions contain finyl) phenol, pf 205-208 ° C.

the desired product essentially free of 65 hydrobromide

mescaline. We transform a 15 g sample of the last Example 98

fractions in free base then in hydrochloride, which gives 5.52 g. Stirred and heated at reflux for one hour.

4'-hydroxy-2 - {[2- (3,4,5-trimethoxyphéange) hydrochloride of 50 g (0.925 mole) of 4'-benzoate hydrobromide

627,447

26

(+) - 4'-hydroxy-2 - {[3- (4-methoxyphenyI) -l-methylpropyI] - ethyl tate and the resulting solution is acidified with amino acid} -3 '- (methylthio) acetophenone and 500 ml of ethanolic hydrochloric acid and cooled. We collect the so-

hydrobromic at 48%. By cooling the product crystallizes. liquid which crystallizes and it is recrystallized in a mixture of acé. It is collected and it is recrystallized in a mixture of ethanol and tone, methanol and ether, which gives 15.0 g of chlorhy-acetate. of isopropyl, which gives 26.7 g of 5 drate hydrobromide of (+) - 4- <2 - {[3- (4-hydroxyphenyl) -1-methylpropyl] - (+) - 4'-hydroxy- 2 - {[3- (4-hydroxyphenyl) -1-methylpropyl] - amino} ethyl> -2- (methylthio) phenol. Recrystallization of an amino} -3 '- (methylthio) acetophenone. sample in a mixture of methanol, acetone and ether then in a mixture of ether and 2-propanol, and drying of Example 99 4 hours under vacuum at 100-115 ° C, provide a product having

By following a procedure similar to that described in io a melting point of 150-151 ° C.

Example 76 but using 33 g (0.0765 mole) of (+) - 4'-hydroxy-2 - {[3- (4-hydroxyphenyl) -l-methyl- Example 102 propyl] amino} hydrobromide - 3 '- (methylthio) acetophenone and 3.3 g of boro. A stirred solution containing 4.2 g (0.0114 mole) of sodium hydride gives 4-hydroxy-a - <{[3- ( (+) - 4- <2 - 4-hydrochloride {{3- (4-hydroxyphenyl) -1-methyl-oxyphenyl) -1-methylpropyl] amino} methyl> -3- (methylthio) -propyl] -amino} ethyl> -2- (methylthio) phenol in 75 ml of benzenemethanol which is used directly in a methanol reaction at 0 ° C, 1.73 ml of per-subsequent acid are added in 20 minutes. 50% commercial acetic acid in 5 ml of methanol. Once the addition is complete, the reaction mixture is evaporated to dryness and Example 100 the residue is crystallized from a mixture of acetonitrile and

Saturated with hydrochloric acid in one hour and 2-propanol, which gives after 3 hours of drying under vacuum at half a stirred solution containing 0.075 mole of 4-hydroxy- 100 ° C 5.7 g of hydrochloride 4- <2 - {[3- (hydroxyphenyl) -1 - "- <{[3- (4-hydroxyphenyl) -1-methylpropyl] amino} methylpropyl] amino} ethyl> -2- (methylsulfinyl) phenol, pf

thyl> -3- (methylthio) -benzenemethanol crude in 50 ml of dio- 204-205 ° C.

xanne sec. After stirring overnight, the reaction mixture is diluted. Additional examples of benzene methanols and tional with ether, filtered through cotton and then concentrated with aminoketones having the formulas I and II respectively. at a volume of 150 ml. The concentrate is cooled and on top of it and which can be obtained according to the procedures, collects the product which precipitates and is dried, which gives previously described, are given in Table A below. 27.8 g of 4-hydroxy-a chloride chloride - <{[3- (4- Additional examples of haloketones and phe-

hydroxyphenyl) -1-methylpropyl] -amino} methyl> -3- (corresponding parent methylnyl ketones having thio) benzyl respectively. 30 formulas V and VII above, which are useful intermediates in the preparation of the amino ketones of formula II (Table Example 101 A) and which can be prepared according to the procedures described

To a stirred solution containing 27.8 g (0.0685 mole) of the above are given below in Tables B and C. 4-hydroxy-a- <{[3- (4-hydroxy- Les chloride chloride) hydrochloride phenylketones in Table C are obtained according to the phenyl) -1-methylpropyl] amino} methyl> -3- (methylthio) modes described above by acylating the o- (alkylthio zyls in 150 ml of N, N-dimethylformamide to 0 ° C, lower is added) -phenols generally known using a halogen-in portions in a quarter of an hour 4 g of sodium borohydride. acyl nure suitable under Friedel-Crafts conditions, After an additional half hour of stirring, the acidified and then esterified the 3- (lower alkylthio) -4-hydroxyphenyl-reaction mixture with 6N hydrochloric acid , the resulting ketones with a lower alkanoyl halide or concentrated to almost dryness, diluted with an appropriate aroyl solution according to conventional test procedures.

saturated aqueous sodium bicarbonate and extract it is terification.

generously with ethyl acetate. The extracts are washed with other examples of 2-phenylethylamines and 2-halo-2-

a saturated aqueous solution of sodium chloride, the phenylethylamines of formulas III and IV respectively below are

dried over anhydrous sodium sulfate and evaporated to dryness and can be obtained according to the procedures described under vacuum. The residue is dissolved in a mixture of ether and ace- 45 previously given in Table D below.

Table A

Z-CH-NH-C - (CH2) n — Ar benzenemethanols of formula I: Z is CHOH aminoketones of formula II: Z is C = 0

Q

y

R.

r2

R3

not

Ar

CH3SO

h c2h5

h ch3

2

£ -ch3oc6h4

ch3s h

C2H5

h ch3

2

2-ch3oc6h4

CH-jS

£ -ch3c6h4co h

h ch3

2

£ -ch3oc6h4

ch, s

(ch3) 3cco h

h ch3

2

2-ch3oc6h4

ch3so

(ch3) 3cco h

h ch3

2

£ -ch3oc6h4

c, h5so2

hco h

h c2h5

1

c6h5

ch3s c5hnco h

h h

1

c6hs c, h, s h

h h

ch3

2

e-ch3c6h4

27

627,447

q y

Ri

R2

r3 n

Ar

C2H5SO

h h

H

CH3 2

2 "CH3C6H4

n-C4Hi, S

h

H

h

CH3 1

m-CH, OC „H4

CH, S

h h

H

CH (CH3) 2 1

c6h5

CH, S

h n-C4H,)

H

H 1

E- (CH3) 3CC6H4

CH, S

H

H

CH3

CH3 1

2.5- (CH3) 2-C6H3

CH, SO;

H

H

H

H 1

e- (CH3) 2CHCH, OQ, H4

CH, S

H

n-C \ H7

h

C4H9 1

c6h3

ch3s

H

H

h ch3 1

3,4- (HO) 2-C6H3

CH3SO,

H

h

H

H 1

3,4,5- (HO) 3-C6H2

CH, SO

H

H

H

CH3 2

3-Br-4-HO-C6H3

CH, S

H

H

H

H 1

3-F-C6H4

CH, S

H

H

ch3

ch3 1

4-Br-C6H4

CHÎSO

H

H

h

CH3 1

2.5- (Cl) 2-C6H3

CH3S

H

H

H

H 1

3,4,5- (Cl) 3-C6H2

CH, SO,

H

H

h

H 1

2,4,6- (CH3) 3-Q, H2

CH, S

h

H

H

CH3 1

2- (C4H90) -3-CH30-C6H

q y

r.

x

O

o y

r.

ch, s h

c2hs

Br ch3s ch3co qhs ch, s

£ -ch, c „h4co h

Br ch3s

2-ch3c6h4co h

ch, s

(ch3) 3cco h

Br ch3s

(ch3) 3cco h

c2h5so,

hcó

h ci c2h5so2

hco h

ch3s c5HuCO

h

Br ch3s cjhuco h

c; h5s h

h

Br c2h5s ch3co h

n-c4H9s ch, co h

Cl n-C4H9S

ch3co h

ch, s h

n-C4H9

Br ch3s ch3co n-C4Hg ch, s

H

n-C3H7

Br

„Ch3s

40 ■>

ch3co n-C3H7

Table D

YO

Qv

_ / W

B Rt R2 I • I 1 • CH-CH-NH-C - (CH2) n-Ar i r3

2-phenylethylamines of formula III: B is hydrogen 2-halo-2-phenylethylamines of formula IV: B is chlorine, bromine or iodine.

Q

y r.

r2

r3

not

Ar ch3so2

h h

h ch3

2

2-ch3oc6h4

ch3s ch3co h

ch3

ch3

1

C6hs ch3so h

chj h

ch3

1

e-ch3oc6h4

ch3s h

h h

h

2

c6h5

ch3so h

h h

ch3

1

3,4- (ch30) 2-c6h3

ch3s h

h h

ch3

3

e-ch3oc6h4

ch3so qhsco h

h ch3

2

3-Br-4-CH30-C6H3

ch3so2

h h

ch3

ch3

2

e-ch3oc6h4

ch3s h

h h

h

1

3,4,5- (ch30) 3-c6h2

ch3so h

c2h5

h ch3

2

e-ch3oc6h4

ch3s h

c2h5

h ch3

2

e-ch3oc6h4

627,447

28

q y

Ri r2

r3

not

Ar ch3s

2-ch3c6h4co h

h ch3

2

£ -ch3oc6h4

ch, s

(ch3j3cco h

h ch3

2

2-ch3oc6h4

ch, so

(ch3) 3cco h

h ch3

2

2-ch3oc6h4

c, h5so2

hco h

h c2h5

1

c6h5

ch., s c5h „co h

h h

1

c6h5

c2h5s h

h h

ch3

2

2-ch3c6h4

c2h5so h

h h

ch3

2

2-ch3c6h4

n-C4H9S

h h

h ch3

1

m-CH3OC6H4

ch3s h

h h

ch (ch3) 2

1

c6h5

ch3s h

n-C4H9

h h

1

£ - (ch3) 3cc6h4

ch3s h

h ch3

ch3

1

2.5- (ch3) 2-c6h3

ch3so2

h h

h h

1

2- (ch3) 2chch2oc6h4

ch3s h

n-C3H7

h

C4Hy

1

c6h5

ch3s

H

h

H

ch3

1

3,4- (ho) 2-C6h3

ch3so2

H

H

H

h

1

3,4,5- (ho) 3-C6h2

ch3so

H

H

H

CH3

2

3-Br-4-HO-C6H3

ch, s

H

H

h

H

1

3-F-C6H4

ch3s

H

H

CH3

CH3

1

4-Br-C6H4

CH3SO

H

h

H

CH3

1

2.5- (Cl) 2-C6H3

ch3s

H

H

h

H

1

3,4,5- (Cl3-C6H2

ch3so2

h

H

H

h

1

2,4,6- (ch3) 3-c6h2

ch3s

H

h

H

CH3

1

2- (c4h90) -3-ch30-c6h

Notes Example 25

The product obtained in this example had originally been identified as 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -1-methylpropyl] amino} - 3- (methylsulfinyl) 4'-benzoate hydrochloride acetophenone.

In the examples, when the name of the acid derivative bears a position indication (4 or 4 ′), it is the ester derivative formed on the hydroxy group in the 4 or 4 ′ position. Otherwise it is the acid addition salt. 35

The compounds of this invention of formula I have been shown to have anti-hypertension activity, vasodilation activity and p-adrenergic blocking activity, as can be seen from the results of standardized pharmacological tests. performed on representative examples as described below.

Anti-hypertension activity was determined based on the observed reduction in systolic blood pressure as measured by the method of H. Kersten et al., J. Lab. and Clin. Me. 32, 1090 (1947), after a single oral administration in the normally hypertensive and non-anesthetized rat, described by Okamato et al., Japan Circulation J. 27,282 (1963).

Anti-hypertension activity has also been judged on the basis of the prolonged reduction in blood pressure observed in trained hypertensive renal dogs, not anesthetized, after repeated oral administration, according to the procedure described by Lape et al. Arch. int. Pharmacodyn. 160.342 (1966).

The vasodilation activity is judged on the basis of the reduction observed in the perfusion pressure in the vascular system of the hind paw of an anesthetized dog, determined according to the procedure described by Jandhyala et al., European J. Pharm. 17,357 (1972), and also on the basis of the percentage reduction in the perfusion pressure measured in the artery of the isolated rabbit ear, according to the method described by De La Lande et al., Aust. J. Exp. Biol. Med. Sci. 43.639 (1965).

Ss-adrenergic blocking activity is determined in pentobarbital anesthetized dogs based on the ability of the test compound to inhibit the increase in heart rate due to an intravenous injection of 0.5 mg / kg isoproterenol .

The acute toxicity is determined intravenously and orally in mice for the compound of Example IIA as follows: the compound is dissolved in distilled water and

45

50

55

60

65

administered as the base, at a volume of 10 mg / kg for DLASU iv or 10-40 ml / kg for DLA50 in. The compound is administered in graduated doses to groups of three mice each (male mice of the Swiss-Webster strain weighing 20 ± 2 g). Mortality occurs within 1 minute after IV administration and within 10 minutes after oral administration. Symptoms of acute poisoning in fatal cases include atoxia, loss of righting reflex, clonic convulsions and dyspnea, followed by respiratory arrest. No untoward symptoms are observed for up to seven days for survivors. The DLA50 i.v. is 75 mg / kg and the DLA5 () p.o. is 1500 mg / kg.

The seven-day oral LD50 in rats was determined for two separate lots of the compound of Example 20B and was found to be 1850 and 1940 mg / kg, respectively. No change in body weight or marcroscopic change in tissue was observed in animals sacrificed seven days after the medication.

The results of the pharmacological tests described above are given in Table E below.

As indicated above, some of the compounds of this invention also exhibit antiarrhythmic activity. The latter is determined in vivo and the efficacy is judged on the ability of the test compound to transform the arrhythmia induced by barium ion or oua-baine into normal rhythm. The test procedures are carried out as follows:

Ba ++ induced arrhythmia

Adult rabbits of either sex, weighing between 1.7 and 2.3 kg, are anesthetized with 30 to 35 mg / kg of sodium pentobarbital intravenously through a marginal ear vein. Monopolar electrocardiogram electrodes for lead II are inserted on a Grass Model No. 5 polygraph using standard procedures for electrocardiography. A hypodermic needle, attached by a polyethylene catheter to a 10 cm3 syringe, is inserted into the same vein as that used for anesthesia. Then a solution of BaCl2.2H20 in saline is infused at a constant volume of 0.2 ml / minute using a Harvard Apparatus Model 600 infusion pump. This infusion is not stopped before the termination of the experiment. In some studies, barium chloride has been used in distilled water without detecting differences. The normal infusion rate of BaCl2.2H20 has

29

627,447

was set at 0.3 mg / kg / minute (1.2 X10 "6 M / kg / minute) and the electrocardiograms (leads II or VI) with electrodes adjust the concentration appropriately in each monopolar case. Both parameters are recorded on a po-to take into account the weight of the rabbit Grass lygraph We administer to each dog 36 jxg / kg of oua-

When the desired arrhythmia has been established, the combination is introduced intravenously in one minute (the solution contains posed as a solution in water or saline, 5 50 [xg / ml of ouabain in isotonic saline) then one in the vein of the marginal ear of the unused ear. The constant infusion of ouabain (0.6 [ig / kg / minute) at the start-volume used is between 0.5 and 2.0 ml / kg and is injected 5 minutes later. The infusion solution is prepared in the form of a bowl in approximately 30 seconds. Changes that the appropriate dose per minute is provided in 0.5 ml. of the conventional vehicle, the injection speed and the total volume When the predominant rhythm of the consequent arrhythmia administered are left to the discretion of the operator. Dose 10 is a ventricular (or sometimes nodal) tachycardia, a normal initial of an unknown compound is made on the first rabbit is tried to transform this arrhythmia with the test compound. 5 X 10 "5 M / kg. Typically two or three rabbits are used to administer up to 10" 4 M / kg of test compound in determining the antiarrhythmic activity and the dose interval pro - volume of 1 ml / kg in an infusion period of 5 minutes. If combining this activity; several doses are administered. Once a transformation or a cardiotoxic effect is seen before the activity and the dose have been found, two rabbits are used, the administration of 10 "4 M / kg, the dose is noted and repeated on additional to confirm antiarrhythmic activity against a second dog.

vis a multifocal tachycardia.

The test is carried out in a conventional manner using neck-Ouabain-induced arrhythmias from dogs with a difference of 15 minutes from the time of

Adult mongrel dogs from either departure are anesthetized. All the electrosex duration and interval measurements, after having made them fast for 16 to 20 hours, with 35 cardiograms are made on lead II with a mg / kg speed of sodium pentobarbital iv and they are fixed on the back on the 100 mm / second paper. Heart rates are in operation. An air passage is foreseen by inserting a recorded on lead II with a paper speed of 100 cannula in the trachea, and the animal breathes spontaneously. On mm / second. The cardiac speeds are made from introduces two cannulas into a femoral vein, one cannula for 25 QRS complexes of lead II at 25 mm / second. They inject me and one as an ouabain infusion site. The blood pressure is introduced using a displacement sensitivity of a cannula in the femoral artery on the same side for measuring the pencil of 10 mm of mercury / mm.

rer blood pressure. Administered intravenously The results of the tests described above are given as necessary sodium pentobarbital supplements. in Table F below. The compounds are indicated

Statham 30 blood pressure transducers are used as active (A) or inactive (I) at the dose tested, expri-P23 A to measure blood pressure, and measurements are made in M / kg.

Table E

Pharmacological properties

Anti-hypertension activity

Vasodilation activity

Activity

adrenergic

Composed of

DAH4Ua,

DEM10b, dog

DEAC, per

Vasodilatation,

DEA 50th,

the SH rat example,

hypertensive fusion in ß blocking artery

mg / kg renal, mg / kg ear paw in dogs,

p.o.

three times dog lapind mg / kg

daily mg / kg

(molar conc.)

2

10.0

0.5

50%

<1.0 (60%) '

(1X 10 ~ 5M)

3

20.0

0.5

56%

0.1

(2X 10 ~ 5M)

4

2.0

1.25

0.25

53%

0.04

(6.25X10-5M)

6

> 50.0 (- 26) f

0.5

90%

<1.0 (70%)

(1X10 ~ 4M)

8

15.0

2.5 (0) 6

0.5

55%

0.1

(1X 10_4M)

IIA

2.0

0.0316

0.5

50%

0.025

(5 X 10_5M)

IIB

9.0

0.5

20%

0.025

(5 X10 "5M)

13

> 50.0 (- 20)

> 0.5 (0)

0.5

50%

0.1

(3,5X10_5M)

17

> 20.0 (—33)

0.5

10%

0.5

(1X10 ~ 4M)

19B

> 0.1 (45%)

20A

3.0

0.0316

0.5

49%

0.125

(5 X10 "5M)

20C

4.0

50%

<0.25 (70%)

(5 X10 "5M)

627,447

30

Table E

Pharmacological properties

Anti-hypertension activity

Composed of the Example

DAH4Ua rat SH, mg / kg p.o.

DEM10b, renal hypertensive dog, mg / kg three times daily

Vasodilation activity

DEAC, infusion in dog's paw mg / kg

Vasodilation, artery of the lapind ear

(molar conc.)

DEA 50e adrenergic activity, ß blocking in dogs, mg / kg

20D

4.0

20E

21A

21B

22A

15.0

23A

> 50.0 (-

24A

> 50.0 (-

25

30

26

9

29A

20.0

30

> 16.0 (-

31

> 16.0 (-

32

5

33

3

36

-50.0

38

35.0

39

20.0

41

> 20.0 (-

42

> 20.0 (-

45

15.0

47

-10.0

48

> 20.0 (-

50

20.0

51

> 20.0 (-

53

5.0

54

20.0

57

7.0

59

<50.0 (-

60

40.0

63

66

19D

23B

24B

67B

68

> 50.0 (- 12) 40.0

> 50 (- 17)> 50 (- 31)> 50 (- 14) -10

> 0.5 (8%) <0.5 (14%) 0.5 (14%) 0.5 (17%)

0.5

0.125 (0)

> 0.125 (0)> 0.125 (0)

0.5 0.5

> 0.025 (25%) h

> 0.025 (25%)

0.5 0.5 0.5

0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

71%

(1X10-4M) 64%

(1 X10 ~ 4M)

58%

(5 X10 "5M)

0.1 0.25

> 0.1 (14%)

61%

0.0125

(5X10-5M)

50%

> 0.10 (23%)

(2XlO_4M)

38%

0.25

(1X10 "4M)

50%

0.05

(2 X 10 ~ 4M)

50%

0.0125

(1X 10 "4M)

71%

<1.0 (56%)

(1X10 "5M)

33%

<1.0 (60%)

(2X10 ~ 5M)

29%

<1.0 (87%)

(1X 10 ~ 6M)

75%

> 0.1 (38%)

(5 X 10 "5M)

70%

<1.0 (100%)

(5XlO_5M)

50%

0.05

(5 X10 "5M)

50%

<1.0 (72%)

(9 X10 "5M)

42%

<1.0 (100%)

(1X10 ~ 4M)

81%

0.1

(5X10-5M)

50%

<0.025 (67%)

(5X 10 ~ 5M)

(constriction)

<0.1 (67%)

50%

(1X10 "3M)

<0.025 (80%)

-0.10

> 1.0 (0%)

-0.50

> 1.0 (10%)

> 1.0 (33%)

31

627,447

Table E

Pharmacological properties

Anti-hypertension activity

Composed of the Example

DAH4ua, rat SH, mg / kg p.o.

DEMltlb, renal hypertensive dog, mg / kg three times daily

Vasodilation activity

DEAC, infusion in dog's paw mg / kg

Vasodilation, artery of the lapind ear

(molar conc.)

DEA 5ue adrenergic activity, ß blocking in dogs, mg / kg

71

> 50 (- 12)

-0.50

72

> 50 (- 12)

74

-40.0> 20 (0) '

> 1.0 (18%)

75

> 50 (- 22)

> 1.0 (0%)

76

> 50 (- 13)

-1.0

77

> 50 (—26)

-0.10

78

> 50 (- 20)

-1.0 (0%)

79

> 50 (- 22)

-0.10

80

> 50 (- 22)

> 1.0 (17%)

81

> 50 (—31)

> 1.0 (0%)

82

> 50 (- 12)

-0.05

83

> 50 (- 29)

> 1.0 (11%)

84.

> 50 (- 18)

> 1.0 (0%)

85

> 50 (- 18)

-0.50

87

> 50 (- 13)

<1.0 (67%)

89

> 50 (- 11)

91

> 50 (- 51)

92

> 50 (- 15)

93

-50.0

96

-50.0

> 1.0 (14%)

97

<20 (- 54)> 40 '

> 1.0 (43%)

101

> 50 (- 8)

102

> 50 (- 3)

-0.50

(a) DHA40 = Single oral dose necessary to induce an average reduction of 40 mm in systolic blood pressure in the normally hypertensive and non-anesthetized rat.

(b) DEM10 = Daily oral dose repeated and minimum necessary to effect a lowering followed by blood pressure of 10% or more in the hypertensive renal dog trained and not anesthetized.

(c) DEA5o = Approximate intra-arterial dose necessary to cause a 50% reduction in the perfusion pressure in the hind paw of the anesthetized dog.

(d) Vasodilation is expressed as the percentage reduction in the infusion pressure from the control level at the indicated molar dose.

(e) DEA50 = Approximate intravenous dose necessary to cause 50% inhibition of the increase in heart rate due to isoproterenol in dogs anesthetized with pentobarbital.

(f) Actual reduction in blood pressure (in mm of mercury) observed at the indicated dose.

(g) Actual percentage reduction in blood pressure observed at the indicated dose.

35 (h)

(i)

40

(j)

Actual percentage reduction in infusion pressure observed at the indicated dose. Actual percentage inhibition of the increase in heart speed compared to the control value, observed at the indicated dose. Administered once a day.

Table F

Anti-arrhythmic activity

50

55

Composed of

Transformation

Transformation Example No.

induced arrhythmia induced arrhythmia

by ouabain by Ba ++

6

A, 5X 10 ~ 5a

A, 5X10-5

19D

A, 2.5X10-5

A, 5 X10-6

20E, F

A, 5X10-6

A, IXIO-5

23B

A, A X10 "5

A, 1 X10-5

48

A, 5X10r6

A, 2.5X10-6

51

A, 5 X10 ~ 6

54

A, 5X10-5

A, 2.5X10-6

67B

A, 2.5X10-5

68

I2,5X10_sb

87

12.5 X10 "5b

A, IX10-5

101

A, 5X10 "6

102

A, IX IO "5

A, 2X10-5

60

(a) M / kg

(b) Toxic at 2.5 X 10 "

5; inactive below 2.5 X10

VS

Claims (14)

627,447 2 CLAIMS no} -3 '- (methylthio) acetophenone and the compound re-oxidized 1. Process for the production of a compound having the form of sultani. base, formula 11. Process for preparing a compound of formula I according to claim 1, characterized in that a halo-reacted OH R, R2 YO CH-CH-NH-C - (CH2) n — Ar I r3 YO GOLD, R2 C-CH-NH-C - (CH2) „- Ar I r3 II 5 tone of formula Q 10 in which: R1, R2 and R3 are independently hydrogen atoms or lower alkyl groups; n is an integer from 1 to 3; Ar is a phenyl or phenyl group having one to three substituents halogen, lower alkyl, hydroxy or lower alkoxy; Q is a lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group; Y is a hydrogen atom or a lower alkanoyl, aroyl, benzenesulfonyl or toluenesulfonyl group; or one of its acid addition salts, characterized in that a compound having the form of base in which X is a chlorine, bromine or iodine atom is reduced with an amine of formula 15 20 r2 I Ar- (CH2) n-C —NH2 I Ri VI 25 30 or one of its acid addition salts, and if desired, the compound obtained in the form of the free base is converted into one of its acid addition salts or a salt is formed with a base of a compound obtained when Y is a hydrogen atom. 2. Method according to claim 1, characterized in that the compound obtained is hydrolyzed where Y is a lower alkanoyl or aroyl group to obtain the corresponding compound in which Y is a hydrogen atom. 3. Method according to claim 1, characterized in that an esterified compound obtained in which Y is a hydrogen atom to obtain the corresponding compound in which Y is a lower alkanoyl or aroyl group. 4. Method according to claim 1, characterized in that one oxidizes a compound obtained in which Q is an alkylthio group to obtain the corresponding compound in which Q is an alkylsulfinyl group. 5. The method of claim 1, wherein Ar is a phenyl or phenyl group having one or two substituents lower alkyl, hydroxy or lower alkoxy. 6. Method according to claim 5, where R! is a hydrogen atom and Q is a methylthio, methylsulfinyl or methylsulfonyl group. 7. The method of claim 6, wherein Y is a hydrogen atom or a lower alkanoyl or aroyl group. 8. The method of claim 6, wherein Ar is a 4-methoxyphenyl group. 9. The method of claim 5, wherein Rt is a methyl group, Q is a methylthio, methylsulfinyl or methylsulfonyl group, Ar is a lower alkoxyphenyl group and Y is a hydrogen atom. 10. The method of claim 4 for preparing 4-hydroxy-a - <{[3- (4-methoxyphenyl) -l-methylpropyl] -ami-no} 3-methyl> -3- (methylsulfinyl) -benzenethanol or a of its acid addition salts, characterized in that the (+) - 4'-hydroxy-2 - {[3- (4-methoxyphenyl) -1-methyl-propyl] amino- is reduced 35 if desired, the compound obtained of formula II is converted in the form of the free base into one of its acid addition salts or a basic salt of a compound obtained in which Y is a hydrogen atom is formed, and this compound of formula II is transformed into a compound of formula I by the process according to claim 1. 12. The method of claim 11, characterized in that the compound of formula II is esterified in which Y is a hydrogen atom, to obtain the corresponding compound in which Y is a lower alkanoyl or aroyl group. 13. Method according to claim 11, characterized in that a compound of formula II is hydrolyzed in which Y is a lower alkanoyl or aroyl group to obtain the corresponding compound in which Y is a hydrogen atom. 14. Method according to claim 11, characterized in that one oxidizes a compound of formula II in which Q is a lower alkylthio group to obtain the corresponding compound in which Q is a lower alkylsulfinyl group. 15. The method of claim 11, characterized in that X is bromine. 45