NO132865B - - Google Patents

Description

This invention relates to an analogous process for the production of new, therapeutically active amino alcohols and salts thereof.

The new amino alcohols produced according to the invention are represented by the formula

where means RS or RS02, where

R is a straight or branched C 1 -C 4 alkyl group, and

where R2 and R^ are different and mean hydrogen, halogen, a C^-C^ alkyl-, C^-C^ carbolic- or C^-C^ alkoxy group,

R^ means hydrogen or a straight or branched C^-

C 4 alkyl group,

R^ and R^, which may be the same or different, mean hydrogen, a straight or branched C-^-Cj^q alkyl-, a C5-C6 cycloalkyl-, a C-j-C4 alkenyl-, or an optionally with one or several chlorine atoms or hydroxyl groups substituted with a C^-C5 alkylphenyl group, or R^ and Rg can together with the adjacent nitrogen atom form a piperidine ring optionally substituted with a C^-C^ alkyl, benzyl, or hydroxyl group, a morpholine ring, an optionally with a C^-C^ alkylphenyl group substituted piperazine ring or a 3-azabicyclo [3.2.1.]-octyl ring, and when R^ denotes hydrogen and R& a C4-C10 alkyl group, R2 and R3 can both be hydrogen or methyl groups,

as well as salts of these compounds.

Amino-alcohols covered by the aforementioned formula I are discussed later in the examples and fSaid "amino-alcohols are of particular interest because of their beneficial effect.

1-(2-chloro-4-methylthiophenyl)-2-N-piperidinoethanol hydrochloride, 1-(3-chloro-4-methylthiophenyl)-2-sec.butylaminopentanol hydrochloride, 1-(3-methyl-4-isopropylthiophenyl )-2-n-octylaminopropanol hydrochloride, 1-(4-isopropylthiophenyl)-2-n-octylaminopropanol,

1-(3-methyl-4-nethylthiophenyl)-2-n-octylaminoethanol hydrochloride, 1-(4-ethylthiophenyl)-2-n-octylaminopropanol hydrochloride,

1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol hydrochloride.

Some amino alcohols are already previously known and are described in the following publications: 1. Dutch patent application no. 67/0984, corresponding to French patent no. 1,573,832 (Pratesi, Villa, Grana) 2. Farmaco Edizione Scientifica, vol.24 (3), pages 329-340 (1969) 3. Farmaco Edizione Scientifica, vol.22(8), pages 573-581 (1967) (Chemical Abstracts, vol. 67, 80849 - 1967) 4. French Patent No. 1,503 .517 (Bayer), equivalent to the U.S. Patent No. 3,334,188 (Wollweber) 5. Austrian Patent No. 252,215 (P.Somani, J. Med. Chem. 9, 823 - 1966)

As particular previously known compounds, according to the above-mentioned publications, the following can be mentioned:

1-(4-methylthiophenyl)-2-isopropylaminoethanol hydrochloride,

(called compound "A" hereinafter and known from all the above publications),

1-(4-methylsulfonylphenyl)-2-isopropylaminoethanol hydrochloride,

(called compound "B" hereafter and known from publication no. 5) , 1-(3,4-dimethylthiophenyl)-2-isopropylaminoethanol hydrochloride (called compound "C" hereafter and known indirectly from publication no. 5)

Said known compounds have less interesting properties

in relation to the above-mentioned especially mentioned compounds according to the invention, which will be shown in the following.

The invention also encompasses the production of non-toxic salts of amino alcohols with formula 1, such as hydrochlorides, hydrobromides, phosphates, sulphates, oxalates, lactates, tartrates, acetates, citrates and maleates.

It is known that the 1-aryl-2-aminoethanol derivatives have the property of blocking the (3-adrenergic receptors.

It has been found that although the compounds of the general formula I always have the aforementioned properties, they will, even if they are free from sympathomimetic effects, also exhibit other pharmacological activities which distinguish them from known products.

Thus, the products produced according to the present invention have a marked peripheral vasodilatory effect, which is evident at very small doses.

It has also been noted that said products can lead to an oxygen saving in height with the myocardium.

Due to the fact that the "blocking substances" for the adrenergic receptors are often administered when there is a lack of cardiac oxygen (angina pectoris), the accompanying increase in the heart's effective performance with the aforementioned β-lytic action is of obvious therapeutic interest.

The products produced according to the invention also show an anti-arrhythmic and hypotensive effect. The pharmacological properties of the mentioned products therefore make them useful in the treatment and prevention of coronary vessel disorders, and in the treatment of heart disorders, as a peripheral vasodilator and as an anti-hypertensive.

Their blocking effect of the (3-adrenergic receptors) compared to known nearby compounds gives a metabolic effect of adrenergic amines and glucose and free fatty acids in particular are mobilized. Moreover, the mentioned compounds show low toxicity, which allows a long-term and sound therapy .

Said compounds are prepared so that they can be administered orally, rectally or parenterally.

Thus, e.g. the compounds for oral administration be liquid or solid. They can be prepared as tablets, capsules, granules, powders, syrups or suspensions. Such compounds contain additives and excipients, which are usually used in galenic pharmacy, inert additives, disintegrants, binders and plasticizers, such as e.g. lactose, starch, talc, gelatin, stearic acid, silicic acid, magnesium stearate, polyvinylpyrrolidone, calcium phosphate and calcium carbonate.

The new amino alcohols and their salts are produced by

a) a compound of formula II

is reduced, or

b) a compound of formula II, wherein Q is

where X means a halogen atom,

is reacted with an amine of formula NHR^Rg,

and for the preparation of compounds of the general formula I, where R 1 means hydrogen

c) a compound of formula II, where Q is CO-CO-R^ is reacted simultaneously with an amine of formula NH2R5 or

a hydroxylamine of formula MH(OH)R5 and et. reducing agent, or

d) a compound of formula II, where Q is <:> is reacted under reducing conditions with a compound of formula where R» and Rg have meanings such that the group R^-CH-Rg has the meanings given for R^ above with the exception of hydrogen. e) reducing a compound of formula II, wherein Q is

where Rg is a group cleavable by reduction.

Some of the alternative methods mentioned in claim 1 are described in the following, and for the sake of simplicity they are defined as methods A to E.

Procedure.. A

According to this method, an α-amino ketone of formula (II), where Q denotes the group, is reduced

where R, to Rg have the aforementioned meaning.

This reduction can be carried out in the usual way, e.g. by .

hydration in the presence of a catalyst, such as palladium on carbon, Raney nickel or platinum, in the presence of a solvent such as methanol or ethanol at normal or octane pressure. The reduction can also be carried out with alkali metal hydrides,

as sodium borohydride, and in a solution such as methanol or ethanol, preferably at a lower temperature, or by the action of aluminum and lithium hydride in ether or tetrahydrofuran, preferably at a low temperature, or further under the action of aluminum alkoxide, as aluminum isopropoxide in a solution such as isopropanol, and then preferably in the case of a relapse of the latter. It should be noted that the reduction can possibly be carried out

with a salt of compound II (hydrochloride or

oxalate) in the case of a preparation of an amino-alcohol-

salt.

Starting compounds of the general formula II, where Q has

the above meaning, can be easily obtained by e.g. in-

action of an amine R^R^NH or an α-halo ketone in inert solvents, such as ether, benzene, chloroform, dioxane, a lower alcohol such as methanol, ethanol or isopropanol, or also acetonitrile. Hereby, normal room temperature or a lower temperature is used. Said output connections can also

is obtained by the Houben-Hoesch reaction of an aminoalkylnitrile

of the type CN-CH(R4)

and of suitably substituted benzene-

connections. H. D. Courage Ree. Trot. Chim. 71,933 (1952).

Procedure B

According to this modified method, a compound of formula (II) reacts, where Q denotes one of the groups

I with an amine of the type Rj-RgNH. In these formulas, to Rg ! and X deh the same meaning as previously mentioned.

1

i This particular modified procedure can be better shown ! using the following reaction core:

The reduction of the compounds of formula III can be carried out according to conventional methods described previously.

It is known from the literature that either compound IV or a mixture of compounds IV and V can be obtained when the reductions are carried out using metal hydrides. One of the aforementioned compounds or both can directly react with an amine derivative R^R^NH. It is likewise well known from the literature that by allowing an amine to act on a compound of type IV to obtain compound I, the reaction will proceed

via an intermediate epoxide of type V. For practical reasons, however, it is sometimes easier to form epoxide V quantitatively by treating the product IV with a basic agent, such as sodium hydroxide, potassium hydroxide or a sodium alkoxide.

In the production of the first epoxide, a solvent was used, e.g. methanol, ethanol, isopropanol, dioxane, benzene, dimethylformamide. During production, instead of solvents, an excess of amine derivatives can be used. The reaction is carried out at a temperature between room temperature and the reflux temperature for the chosen solvent. The reaction can also advantageously be carried out under pressure in an autoclave and a condensing agent, such as sodium hydroxide or acetate, can be used.

Compounds of formula I can also be obtained by starting from compound IV, and allowing this to react with an amine R^RgNH in a solvent, such as dioxane, chloroform, ethanol, isopropanol or diglyme. It is easiest to carry out the reaction at the reflux temperature of the chosen solvent. This reaction can be carried out in the presence of a product which binds the liberated hydrogen halide, e.g. a mineral base or an excess of the amine used.

The starting products with formula III are easiest to obtain by halogenation of the corresponding ketones, or also by the Friedel-Crafts reaction starting from a suitably substituted benzene compound and from acid halides of the type X-CH(R^)-COX

(X halogen).

An epoxide of type V can be obtained by reacting an appropriately substituted benzaldehyde with a dimethylsulfoxonium or dimethylsulfonium methylide.

In E.J. Corey J. Am. Chem. Soc. 87, 1353 (1965)

! A.Z. Britten Chem. & Ind. 771 41968).

in

Method C: According to this method, the new amino alcohols j are prepared by converting one dicarbonyl compound with formula II, where Q I denotes the group

in

I and R have the previously mentioned meaning,

: by simultaneous action of an amine R^RgNH or of a hydroxylamine RgR^NOH, where R^ to Rj. has the previously mentioned meaning while R 1 denotes hydrogen and a reducing agent.

I The reduction is carried out by catalytic hydrogenation in the presence of platinum or Raney nickel in e.g. a "solution, as methanol precipitates ethanol, at either atmospheric pressure or at elevated pressure. The reduction can also be carried out with the aid of alkali metal hydrides, e.g. sodium borohydride, and in a solution of !methanol and preferably at a lower temperature.

: It should be noted that the reduction can be carried out with the help of bisulphite derivatives, hydrates or acetal derivatives of the previously mentioned dicarbonyl compound. The mentioned compound is most easily represented by the corresponding acetophenone, when R^ = H,

under the influence of an oxidizing agent, such as selenium dioxide

in a solution of dioxane or water, or by the action of dimethylsulfoxide on an oc-haloacetof enone of the type according to formula III [N. Kornblum J. Am. Chem. Soc. Jl 6562 (1957)], ;or also of oc-dihaloacetophenones [F. Venien CR. Acad. Pollock. 266 1950 (1968)] or by means of other conventional methods well known in the literature [Org. Synth.

II 511 et 48 109] .

in

Method D According to another modification of the method, they are obtained

the new amino alcohols according to the invention by reacting a starting compound of formula II, where Q denotes the group

Y denotes either a radical - CO - or

the radical - CHOH- and R . has the previously mentioned meaning, under reducing conditions with a carbonyl compound of the type R"7RgC = 0, where R^ and Rg have such meanings that the group R7 - CH - Rg takes on the meanings given for R^ with the exception of hydrogen.

The reductive alkylation of a starting compound of the aforementioned type is carried out in the presence of hydrogen and a hydrogenation catalyst, such as platinum, platinum oxide or palladium on

charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid. The alkylation takes place at normal pressure or advantageously at higher pressure, and further with an alkali metal hydride such as sodium borohydride in a solvent such as methanol, or with aluminum and lithium hydride in a solvent such as ether or tetrahydrofuran. One can also work without a solvent in the presence of an excess of the ketone compound ice.

Said starting compound can be formed in situ from compounds according to formulas VI and VII:

! Y = CO A = CN, -N3, = N2, = NOH

!y = CHOH A = .NO 2 , -CN, - N^

Ia-cyanophenyl ketones (VI: Y = CO, A = CN) are obtained, e.g. by 'reaction of a suitable substituted benzyl chloride with a cupro-: cyanide [G. Zols Sei. Pharm. 32 76 (1964)]; The a-azido- and o-diazo-!alkyl ketones (VI: Y .= CO, A = N^ and = N2) are prepared according to methods well known in the literature (Houben-Weyl; Methoden der 'Organischen Chemie "Stickstoff Verbindingen I Vol 10 /3); the isonitroketones (VI: Y = CO, A = NOH) are obtained, for example, from suitably substituted acetophenones (R4 = H), propiophenones (R^ = CH^) and the like by allowing these to react with an alkyl nitrite , such as methyl, butyl or amyl nitrite in acidic or basic environments;

|l-phenyl-2-nitroalkanols (VK: Y = CHOH, A = - NO 2 ) are obtained E.g. by reacting a suitable substituted benzaldehyde with a nitroalkane (nitromethane, nitroethane); cyanohydrins (VI; Y = CHOH; A = CN) are obtained from a suitable substituted benzaldehyde

and a cyanohydrogen acid or a salt thereof with an alkali metal; 1-phenyl-2-azidoalkanols (VI: Y = CHOH, A = N3) are obtained, e.g. by reacting a type V epoxide with sodium azide [CA. Vanderwerf. J. Am. Chem. Soc 76 1231 (1954)];

an oxazolidone of type VII is obtained, e.g. of a connection

of type Ar -

of Curtius rearrangement.

The above-mentioned starting compound can also be obtained from a halogen ketone of type III under the influence of phthalimide, hexamethylenetetramine or ammonia, or also from an epoxide of type V under the influence of ammonia.

A halide of the type R'X can also be used, where X denotes a halogen and R' an alkyl, substituted alkyl, cycloalkyl, alkenyl or alkynyl radical.

Procedure E

According to this method, amino alcohols are obtained as follows

the invention by reducing a starting compound of formula

(II) where Q denotes - CHOH - CO -

the group, and R^

and Rg has the previously mentioned meaning.

The reduction of such an output connection is done most simply

by means of an alkali metal hydride, such as lithium aluminum hydride in a solution of diethyl ether or tetrahydrofuran, at lower temperatures or preferably at the reflux temperature of the solvent used.

Salts of amino alcohols can be prepared according to the invention, and as previously mentioned by means of the previously described general method.

Said process includes several variants. In general, the aforementioned salts can be prepared using well-known methods according to the aforementioned general method, such as e.g.

by reaction of equimolar amounts of the amino alcohol with an acid in a suitable solvent such as e.g. an alcohol. The salt is precipitated by adding another solvent,

which is miscible with the former and in which the salt is insoluble. Such a solvent is e.g. ether. The precipitation can also be carried out by neutralization with a

base or acid of an ether solution of the acid or base. Acids used are either inorganic acids or organic acids. As inorganic acids, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and perchloric acid are preferably used. Of the organic acids used are carboxylic acids, or sulphonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid,

lactic acid, citric acid, ascorbic acid, fumaric acid, maleic acid, pamoic acid, succinic acid, tartaric acid, phenylacetic acid, benzoic acid:, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzosy^e.^: salicylic acid, metransulfonic acid and. ethanedisulfonic acid rev

Another variant of the general: method" for: preparation of salts, where Q- i. formula II denotes one: of the groups

groups, Y and R4 to

Rg has the previously indicated meaning, consists in a direct reduction to a salt of the starting compound. Thus a salt corresponding to an amino alcohol of formula (I) is obtained.

Each of the aforementioned variants of the method according to the invention is illustrated in the following by means of relatively detailed production examples of a series of compounds. The mentioned examples are accompanied by a table showing the properties of an important group of compounds, which were prepared according to the mentioned modifications of the method of preparation.

Example 1

1-(3-methyl-4-methylthiophenyl)-2-t-butylaminobutanol

a) 160 g aluminum chloride in 650 ml chloroform is added at a temperature of 0 - 5°C 125 g butyryl chloride and then

slowly 138 g of 1-methyl-2-methylthiobenzene. The mixture is stirred for 2 hours at room temperature, and then the mixture is poured into ice and hydrochloric acid. The mixture is extracted with ether and dried over magnesium sulfate. After evaporating the solvent

the evaporation residue is distilled in vacuum. 166 g of 3-methyl-4-methyltidebutyrophenone are obtained. Boiling point (b.p.) =132 137°C

(0.1mm); melting point (m.p.: 45 - 46°C; yield 80%

b) 165 g of 3-methyl-4-methylthiobutyrophenone in 500 ml of ethereal anhydride is slowly added while stirring with 128 g of bromine. The temperature

kept at 10°C. After the addition, the mixture is allowed to reach room temperature, and it is treated with a 10% aqueous NaHCO 3 solution until a discoloration of the organic phase appears. The organic phase is dried over magnesium sulphate and the solvent is evaporated in vacuo. 160 g of 3-methyl-4-methylthio-a-bromobutyrophenone is obtained. S. p. (°C): 86.5 - 88.5; yield: 71%.

c) 8.64 g of 3-methyl-4-methylthio-a-bromobutyrophenone in 100 ml of acetonitrile anhydride is added to 8.76 g of t-butylamine, and the mixture

stirred for 24 hours at room temperature. Then add 200

ml of ether and the t-butylamine hydrobromide is filtered off and washed with ether.

The organic phase is washed with water, dried over magnesium

sulfate and evaporated in vacuo. The remaining red oil,

whose homogeneity is proven by thin-film chromatography, is used as such in the subsequent work operations.

d) To the product obtained from the previous work

operation and 100 ml of methanol, slowly add 2.3 g of sodium borohydride while stirring. The temperature is kept at 10°C.

Stirring continues for a further 2 hours at room temperature, and then the solvent is evaporated in vacuo. The residue is taken up with water and extracted with ether. The organic phase is solidified over magnesium sulfate, and the hydrochloride is obtained by passing through dry HCl gas. 4.9 g of the product is obtained. Total yield for work operations c and d: 51%.

An analytical sample is recrystallized several times in a methanol-ether mixture. S. p. (°C): 235 - 237°.

I Analyzes ' Calculated (%): C: 66.45 H: 8.88 N: 4.41

Found (%): C: 60.25 H-s": 8.80 N:.4.21

in

j Example 2

j 1-( 3- methyl- 4- methylthiopheni)- 2^ N-( 4- benzylpiperidino) ephanol

In a) 116 g of aluminum chloride in 600 ml of chloroform are added - 65 g of acetyl chloride. Then add;; slowly at a temperature of

jo - 5°c, 105 g of 1-methyl-2-methylthiobenzene. The mixture is stirred for 2.5 hours at room temperature, then poured into ice. and hydrochloric acid. It is extracted with ether and dried over magnesium-i , ■ -

j sulfate. After evaporation of the solvent, distill ! the evaporation residue in vacuum. 109 g of 3-methyl-4-methylthioacetophenone are obtained. Kp.: 125° (1 mm)5 n^ (refractive index) 1.61205 yield: 80%.

ib) 600 g 3-methyl-4-methyltibacetophenone (3.3 M) in 2000 ml ! 169 ml of bromine (3.3 M) are added dropwise to anhydrous ether. After the addition, stirring is continued for 1.5 hours at room temperature. The mixture is then treated with 500 ml of 10% bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated until 1/3 of the original volume remains. 300 ml of petroleum ether are added and the precipitate obtained is filtered. 790 g of 3-methyl-4-[methylthio-oc-bromoacetof enone are obtained. S. p. (°C) : 66 - 68°; yield: 92%.

jc). 13.5 g of 3-methyl-4-methylthio-α-bromoacetophenone (0.05 M) in

100 ml of anhydrous ether is added to 17.5 g of 4-benzylpiperidine (0.1 M). • This is stirred overnight at room temperature. The hydrobromide is filtered from the starting amine and the solvent is evaporated in vacuo. The product obtained is used directly in the subsequent work operation.

d) 16 g of 3-methyl-4-methylthio-a-N-(4-benzylpiperidino)acetophenone in 75 ml of methanol and 6 ml of 0.02 N sodium hydroxide are added slowly while stirring using an ice bath 1.5 g of sodium borohydride. The mixture is stirred for 90 minutes at room temperature, then acidified with 2-N HCl and diluted with the same volume of water. The aqueous phase is then washed with ether. - Make alkaline with 20% NaOH and extract with ether. The organic phase is dried over magnesium sulfate and hydrogen chloride, which is obtained by flowing through dry HCl gas. 14 g of the product is obtained (yield: 87%). A sample is recrystallized for analysis in a methanol-ether mixture. S. p. (°C): 234 - 235.

Analyze

% calculated: C: 67.40 H: 7.71 N: 3.57

% found: C: 67.47 H: 7.55 N: 3.55

Example 3

1- ( 3- carbomethoxy- 4- methylthiophenyl)- 2- N- piperidinoethanol

a) 3- carbomethoxy- 4- methylthioacetophenone

The product is obtained by the Friedel-Crafts reaction of 1-carbomethoxy-2-methylthiobenzene (CH^COCl, CS, AlCl^; under reflux for 4 hours on a water bath).

Yield: 43%; s.p. (°C): 99 - 102 (isopropanol).

b) 3- carbomethoxy- 4- methylthio- a- bromoacetophenone Obtained by bromination of the preceding product with bromine

(solvent: ether-dioxane 2/1, room temperature).

Yield: 73%, s.p. (°C): 145 - 146 (benzene-ethyl acetate).

Analyze

% calculated: C: 43.58 H: 3.66

% found: C: 43.71 H: 3.85

c) 3-carbomethoxy-4-methylthio-oc-N-piperidino-acetofenone Obtained by reacting piperidine with the above-mentioned product

(solvent: acetonitrile, 24 hours at room temperature). The product is not cleaned; its homogeneity is proven by thin-layer chromatography i. d) 1-(3-carbomethoxy-4-methylthiophenyl)-2-N- piperidinoethanol Obtained by reduction of the above-mentioned product with sodium borohydride (solvent: methanol, temperature: 10°C. Yield: 63%, mp (°C): 199.5 - 201.5 (methanol-ether).

I Preparation of the corresponding hydrochloride according to previous examples.

! Analyze

calcd: C: 55.56 H: 6.99 N: 4.05

J % found: C: 55.40 H: 6.90 N: 3.90'

in

, Example 4

1-(4-n-butylthio-3-methylphenyl)-2-piperidinoethanol in a) To a well-stirred mixture of 283 aluminum chloride in 1150 ml of anhydrous chloroform, add slowly at a temperature of 0 - 10°C 180 g of acetyl chloride and then 520 g of 4-n-butylthio-3-methylbenzene. The mixture is allowed to reach room temperature and is then hydrolysed by adding ice and hydrochloric acid. After the usual treatment, 324 g of 4-n-butylthio-3-methylaceto- are obtained. in phenone. iK.p.: 164 - 166° (2 mm)5 n£<5> = 1.5763; yield: 82%..

1b) By bromination of the preceding product with bromine in anhydrous ether, 4-n-butylthio-3-methyl-a-bromoacetophenone is obtained.

S. p. (°C): 59.5 - 60.5 (isopropanol).

c) The product obtained from the preceding work operation is treated with two equivalent amounts of piperidine (solvent: anhydrous ether; 18 hours at room temperature). Piperidine hydrobromide is filtered off and washed with ether. After evaporation of the solvent, the homogeneity of the obtained oc-piperidino-4-n-butylthio-3-methylacetophenone is tested by means of thin-layer chromatography, and the aforementioned product is used as such in the subsequent work operation. d) The reduction of the preceding product with sodium borohydride 1 methanol at 0°C gives 1-(4-n-butylthio-3-methylphenyl)-2-piperidinoethanol.

S. p. (°C): 157 - 159 (MeOH-ether).

Analyze

% calcd: C: 62.86 H: 8.79 N: 4.07

% found: C: 62.98 H: 8.77 N: 3.90

Example 5

1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol 11.8 g α-isopropylamino-3-methyl-4-methylthioacetophenone (0.05 mol)

in 100 ml of methanol, 3.8 g of NaBH^ (0.2 mol) are added by keeping the temperature at 0 - 10°. Stirring continues for one hour at this temperature, and then the solvent is evaporated in vacuo. The mixture is treated with water, and then ex-

it is extracted with ether. The organic phase is dried over magnesium sulfate and evaporated. 9.6 g (yield of 81.3%) of the free base is obtained, and this can be recrystallized in a mixture of ether-petroleum ether. M.p.: 89.5 - 90.5°. 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol hydrochloride is obtained by flowing through dry HCl gas in an ethereal solution of the free base and by recrystallization in a methanol-ether mixture. M.p.: 154.5 - 155.5°C.

Analyze

% calcd: C: 56.58 H: 8.04 N: 5.08

% found: C: 56.52 H: 8.04 N: 5.28

Example 6

1-(4-n-butylthio-3-methylphenyl)-2-cyclohexylaminoethanol 5.7 g (0.0158 mol) α-cyclohexylamino-4-n-butylthio-3-methyl-acetophenone hydrochloride in 50 cc of methanol are added slowly at a temperature of 0 - 10° 1.2 g NaBH^. Stirring is continued for two hours at room temperature, and then the solvent is evaporated in vacuo. Water is added and additional

here with ether. The ether phase is dried over magnesium sulphate and after filtration and a flow of dry HCl gas. 4.2 g of 1-(4-n-butylthio-3-methylphenyl)-2-cyclohexylaminoethanol HC1 are obtained. This is recrystallized in ethyl acetate. M.p.: 135.5 - 136.5°C.

Analyze

% calcd: C: 63.75 H: 9.01 N: 3.91

% found: C: 63.78 H: 8.90 N: 8.83

Example 7

I 1-(3-methyl-4-methylthiophenyl)-2-N.N-dipropylaminoethanol

j a) 55 g 3-methyl-4-methylthio-a-bromoacetophenone in 200 ml iso-j propanol and 125 g aluminum isopropoxide in 300 ml isopropanol

.-j are boiled under a gentle heat "each separately.

in

in

Both mixtures are mixed and boiled for 15 minutes. Then cool down and acidify with 50% hydrochloric acid in the presence of ice. The precipitate obtained is filtered and washed with water. After distillation, 50.8 g of 1-(3-methyl-4-methylthiophenyl)-2-ibromethanol are obtained. S. p. (°C): 74 - 76; yield 92%. The product <!> can be recrystallized in cyclohexane. S. p. (C): 78-79.

1 Analyze

1% calculated: C: 45.99 H: 5.02

\% found: C: 45.95 H: 5.05

in

b) 13 g of 1-(3-methyl-4-methylthiophenyl)-2-bromoethanol in 50 ml of ethanol is added to a solution of 4.2 g of KOH in 25 ml of ethanol. The mixture is stirred for 30 minutes at room temperature, and then the formed salt is filtered off.

jDilution is carried out with the same volume of water, and extraction I is carried out with ether. The organic phase is dried over magnesium sulfate and evaporated. The oil-like evaporation residue

in

..is used as such in the following work operation.

:c) 6.5 g of 3-methyl-4-methylthiophenylethylene oxide in 50 ml of ethanol is added to 15 g of di-n-propylamine, and this is boiled overnight. The solvent and excess amine are evaporated in vacuo. The oil-like evaporation residue is taken up with ether and treated with dry HCl gas. • The oil obtained is treated with acetone, then with ethyl acetate. The product obtained is recrystallized in isopropanol.

S.p.' (°C) : 161 - 162.

Analyze

% calcd: C: 60.44 H: 8.88 N: 4.41

% found: C: 60.30 H: 8.85 N: 4.28

Example 8

1-( 3- methyl- 4- methylthiophenyl)- 2-( ococ- dimethylphenvletylamino) ethanol

a) 20 g of 1-(3-methyl-4-methylthiophenyl)-2-bromoethanol in 100 ml methanol is treated with 1.5 equivalent parts of NaOH in 30 ml

methanol. The mixture is stirred for 30 minutes at room temperature and then diluted with water. The product is extracted with ether, dried over magnesium sulfate and the solvent is evaporated in vacuo. The epoxide obtained, whose homogeneity is proven by means of thin-layer chromatography, is used as such in the subsequent work operation.

b) The oil obtained from the preceding work operation, 50 ml of methanol and 20 g of a,oc-dimethylphenylethylamine are boiled for 48 hours

during return run. The solvent and excess amine are evaporated in vacuo. The oil-like evaporation residue is taken up with ether and extracted with 20% HCl. The aqueous phase is made basic with 50% NaOH and extracted with ether. The ether phase is dried over magnesium sulfate and evaporated. The oil-like evaporation residue crystallizes in a refrigerator. This is treated with diisopropyl ether and 5 g of product is isolated. S. p. (°C): 99 - 100; hydrochloride: m.p. (°C): 144 - 145.5.

Analyze (free base)

% calculated: C: 72.90 H: 8.26 N: 4.25

% found: C: 72.70 H: 8.30 N: 4.05

Example 9

1-(4-ethylthio-3-methylphenyl)-2-cyclopentylaminoethanol hydrochloride a) 4-ethylthio-3-methylacetophenone is prepared by reacting acetyl chloride and aluminum chloride in chloroform with l-ethylthio-2-methylbenzene according to methods already described.

B.p.: 117 - 119°C (0.25 mm). b) 4-ethylthio-3-methyl-a-bromoacetophenone is obtained by bromination of the preceding product with bromine in anhydrous ether.

In S. p. (°C): 72 - 73°.

] c) 1-(4-ethylthio-3-methylphenyl)-2-bromoethanol is obtained by reduction of the preceding product with aluminum isopropoxide

' ', in isopropanol. S. p. (oC) : 74 - 75.

in

! d) 5.5 g (0.02 M) 1-(4-ethylthio-3-methylphenyl)-2-bromoethanol and ! 13.2 g (0.12 M) cyclopentylamine is dissolved in 100 ml absolute ! ethanol. The solution is boiled for 24 hours under reflux. I The solution is evaporated to 1/4 of its original volume

\ and then poured into 1-N hydrochloric acid solution. The aqueous phase is extracted with ether (3 x 15 ml) and made alkaline; with a saturated solution of sodium carbonate, and re-extracted with ether (3 x 30 ml).

in

;i The ether phase is dried over magnesium sulfate and evaporated. Excess I of cyclopentylamine evaporates under reduced pressure, and the residue is taken up in anhydrous ether. 4.5 g of 1-(4-ethyltib-3-methylphenyl)-2-•cyclopentylamineethanol hydrochloride is obtained by flowing through anhydrous hydrogen chloride.

;Yield: 75%; s.p. (°C): 123 - 124.

!This derivative crystallizes in methanol-ether.

■ Analyze

calculated: :C: 60.80 H: 8.30 N: 4.40

found: C: 60.60 H: 8.15 N: 4.30

t Example 10

1-(3-chloro-4-methylthiophenyl)-2-isopropylaminoethanol 1. 13.9 g (0.05 mol) a-bromo-3-chloro-4-methylthioacetophenone; in 150 cc of isopropanol and 30.6 g of aluminum isopropoxide ( 0.15 mol) in 200 cc of isopropanol are boiled separately under reflux.

The two solutions are mixed and simmered for 30 minutes. After cooling, the product is poured into a mixture of water and ice and acidified with 20% HC1. The precipitate is filtered off and dried. 10 g of 1-(3-chloro-4-methylthiophenyl)-2-bromoethanol are obtained. Yield: 71.4%; m.p.: 86 - 87°C.

2. 7 g of 1-(3-chloro-4-methylthiophenyl)-2-bromoethanol (0.025 mol)

in 50 cc of ethanol is treated with 1.4 g of sodium hydroxide (0.035

moles). The product is stirred for 10 minutes and then diluted with water. It is extracted with ether and dried over magnesium sulfate. The solvent is evaporated in vacuo and the oil-like residue is treated with 100 cc of EtOH and 5.9 g of isopropylamine (0.1 mol). The product is stirred at 50° overnight. The solvent and excess isopropylamine are evaporated in vacuo. The oil-like residue crystallizes after some time (m.p. 111 - 112°C

after recrystallization in cyclohexane). The free base dissolves in ether. By flowing through dry HCl gas, 4.88 g of 1-(3-chloro-4-methylthiophenyl)-2-isopropylaminoethanol hydrochloride is obtained, which is recrystallized in a methanol-ether mixture. Melting point: 139 - 141°C.

Analyze

% calcd: C: 55.48 H: 6.98 N: 5.39

% found: C: 55.47 H: 6.91 N-: 5.27

Example 11

1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol 1. 26.1 g (0.1 mol) 1-(3-methyl-4-methylthiophenyl)-2-bromoethanol in 150 cc ethanol, add 7, 8 g (0.15 mol) of potassium hydroxide in 100 cc of ethanol. The mixture is stirred for 15 minutes. by. room temperature and the formed salt is filtered off. The mixture is diluted with water and extracted several times with ether. The organic phase is dried over magnesium sulphate and the solvent is evaporated in vacuo. The yellow oil obtained is used directly in the subsequent work operation. 2. 5.7 g of 3-methyl-4-methylthiophenylethylene oxide in 30 cc of isopropanol is added to 7.6 g of isopropylamine. The solution is boiled under reflux overnight. The solvent and excess of the amine are evaporated in vacuo. The oil obtained crystallizes a little later. 12.1 g of 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol is obtained, which is recrystallized in cyclohexane. M.p.: 89.5 - 90.5°. The hydrochloride is recrystallized in a methanol-ether mixture. M.p.: 154 - 155.5°C.

• Analyze

% calcd: C: 56.58 H: 8.04 N: 5.08

in% found: C: 56.52 H: 8.04 N: 5.28

in

1 Example 12 1-(3-methyl-4-isopropylthiophenyl)-2-n-octylaminoethane61-hydrochloride

a) 3-methyl-4-isopropylthioacetophenone is obtained by reacting acetyl chloride and aluminum chloride in chloroform with 1-methyl-2-

in

; isopropylthiobenzene according to a previously described conventional method. |B.p.: 111 - 114°C (0.5 mm).

jb) 3-methyl-4-isopropylthio-a-bromoacetophenone is obtained by bromination of the preceding product with trimethylanil tribromide in o

ji tetrahydrofuran at 0 C.

S.p. (°C): 40 - 41°.

in

in

; Analyze !% calcd:' C: 50.20 H: 5^25

\% found: C: 50.05 H: 5.15

c) 3-methyl-4-isopropylthiophenylglyoxal is obtained by reacting dimethylsulfoxide with the preceding product (36 hours at

•room temperature). The homogeneity of the compound obtained

;proved by means of thin-layer chromatography before it is used

..jvedden following the work operation.

d) 240 g (1 M) 3-methyl-4-isopropylthiophenyl-glyoxal, 780 g: (6 M) n-octylaithin and 1 liter anhydrous methanol are stirred 1/2

Itime at room temperature. The solution is cooled to 0°c and 114 g (3 M) of sodium borohydride are added over the course of 1/2 hour. The solution is then kept for 3 hours at 20°C.

The solution is evaporated to 1/10 of its original volume and poured into 1 N hydrochloric acid solution. The aqueous phase is extracted with ether (3 x 40 ml), then made alkaline with 1 N sodium hydroxide solution and then extracted again with ether (3 x EO ral).

The ether phase is dried over magnesium sulfate and evaporated to dryness. Excess n-octylamine is evaporated off under reduced pressure. The residue is taken up in anhydrous ether. By passing through dry HCl gas, 153 g of 1-(3-methyl-4-isopropylthio) are obtained -phenyl)-2-n-octylaminoethanol hydrochloride.

Yield: 40%; s.p. (°C): 169.

Analyze

% calculated: C: 64.30 H: 9.70 N: 3.75,

% found: C: 64.20 H: 9.70 N: 3.60 ....

Example 13 r ■ • ■...• _ 1- ( 3- methoxy- 4- methylthiophenyl)- 2- tert. butylaminoethanol hydrochloride a) 3-methoxy-4-methylthioacetophenone is obtained by reacting acetyl chloride and aluminum chloride with :1-mGthoxy.-2-rmethylthio-benzene (solvent CHCl^ - 2 hours at room temperature). K.p.: 160° (2 mm).

Analyze

% calculated: C: 61.20 H: 6.15

% found: C: 60.90 H: 5.95

The site of acetylation is determined using the magnetic

• the atomic resonance spectrum.

b) 3-methoxy-4-methylthio-a-brpmacetophenone is obtained by bromination of the preceding product in ether according to already

described technique. .

S. p. (°C): 67 - 68..

Analyze

% calculated: C: 43.65 H: 4.05 ■ • • % found: C: 43.35 H: 3.95.

c) 3-methoxy-4-methylthiophenylglypxar is obtained by reacting dimethylsulfoxide with the preceding product (48 hours at

room temperature). The product's purity is tested using thin-layer chromatography1, and the product is used as such

at the following work operation.

d) 13.2 g (0.06 M) 3-methoxy-4-methylthiophenyl-glyoxal, 27 g (0.36 M) tert-butylamine and 50 ml anhydrous . methanol is stirred for 30 minutes at room temperature. The solution is cooled to 0°C and a small portion of 6.8 g (0.18 M) of sodium borohydride is added. The solution is allowed to reach room temperature and kept at this temperature for 2 hours. It is then evaporated to 1/10 of its original volume and poured into 1 N hydrochloric acid solution.

i The aqueous phase is extracted with ether (3x 15 ml). After that; it is made alkaline with a 1 N sodium hydroxide solution and re-extracted with ether (3 x 35 ml). The ether phase; dried over magnesium sulfate and evaporated to dryness. I The residue is dissolved in anhydrous ether and by flowing through I anhydrous HCl, 12.3 g of 1-(3-methoxy-4-methylthiophenyl)-2-j tert-butylaminoethanol hydrochloride is obtained. This becomes recrystallized

' lysed in methanol-ether mixture.

Yield: 60%; s.p. (°C): 192 - 193.

1 Analyze

!% calculated: C: 54.95 H: 7.90 N: 4.55

% found: C: 54.90 H: 7.85 N: 4.45

in

in

Example 14

1 1- ( 3- methyl- 4- methylsulfonylphenyl)- 2- isopropylaminoethanol

<:> a) 3- methyl- 4- methylsulfonylacetophenone

This product is obtained by oxidation of 3-methyl-4-methylthioacetophenone with hydrogen peroxide in acetic acid.

Yield: 90%; s.p. (°C): 67 - 68 (cyclohexane).

;b) 3-methyl-4-methylsulfonyl-a-bromoacetophenone

■ Obtained by bromination of the preceding product with bromine in acetic acid.

Yield: 88%; s.p. (°C): 102 - 104 (benzene),

c) 3- methyl- 4- methylsulfonylphenylglyoxal

Obtained by reacting dimethylsulfoxide with the preceding product. (48 hours at room temperature) . The homogeneity of the product is tested using thin-layer chromatography.

d) 1-(3-methyl-4-methylsulfonylphenyl)-2-isopropylaminoethanol 7 g of the previous product (0.03 M) and 10.8 g of isopropylamine

(0.18 M) in 100 ml of methanol is added, slowly with stirring at a temperature of 0 - 10°C. .3 g... of sodium borohydride. Stirring is continued for a further 3 hours at this temperature. The solvent and excess amine are then evaporated in vacuo. The residue is treated with water and extracted with ether. The organic phase is dried over magnesium sulphate, and by flowing through dry HCl gas, 3.2 g of the product is obtained, which is purified by recrystallization in isopropanol. S. p. (°C): 182 - 183.

Analyze

% calculated: C: 50.72 H: 7.20 N: 4.55

% found: C: 50.55 H: 7.30 N: 4.35

Example 15 1-(3-chloro-4-methylthiophenyl)-2-N-(1-phenyl-2-aminopropanol)ethanol a) 93 g aluminum chloride in 380 ml anhydrous chloroform is added to 60 g acetyl chloride, and then 92 g o -chlorothioanisole at a temperature maintained at 10°. The product is stirred for a further 2 hours at room temperature. Then, after the usual treatment, 97.2 g of 3-chloro-4-methylthioacetophenone is obtained. K.p. = 142 - 146 (0.7 mm). S. p. (°C): 49.5 - 50.5; yield: 83.6%. b) 52 g of 3-chloro-4-methylthioacetophenone in 250 ml of anhydrous ether is added to 41.6 g of bromine. The addition takes place at 20°C and at

a slow stream of nitrogen through the solution. 200 ml of petroleum ether are then added, and the precipitate obtained is filtered off and washed with a 10% aqueous bicarbonate solution. After drying, 60.4 g of 3-chloro-4-methylthio-α-bromoacetophenone are obtained. S. p. (°C): 84-86; yield: 83.5%.

c) 28 g of 3-chloro-4-methylthio-a-bromoacetophenone and 215 ml of dimethyl sulfoxide are stirred for 36 hours at room temperature. The dissolved solution is poured into ice and extracted with ether. The organic

the phase is dried over magnesium sulfate, and then evaporated ! the solvent in vacuo. 22.1 g of yellow oil is obtained and this crystallizes quickly.

, in ...

i • i 3-chloro-4-methylthiophenylglyoxal, whose homogeneity is proven by ! using thin-layer chromatography, is used as such

j in the subsequent work operation.

; d) 7 g of 3-chloro-4-methylthiophenylglyoxal (0.033 M) in 50 ml of ethanol Add 37.4 g of 1-phenyl-2-aminopropanol hydrochloride (0.2 M). Then slowly add 4.4 g of sodium borohydride while stirring; ing and cooling down in a water bath. The product is stirred further overnight at room temperature. Alcohol and excess amine are then evaporated in a vacuum. The residue is taken up in water and

■extracted with ether. The organic phase is washed with water and dried over magnesium sulfate. When dry iHCl gas is passed through, 2.7 g of hydrochloride is obtained.

Yield: 33%. An analytical sample is recrystallized in a methanol-ether mixture.

; (°C): 212.5 - 213.5.

' Analyze

,% calculated: C: 55.67 H: 5.97 N: 3.61

<!>% found: C: 55.85 H: 5.75 N: 3.45

t

■ Example 16

^ 1-( 3- methyl- 4- methylthiophenyl)- 2- sec. butylaminoethanol

12.7 g (0.06 M) of 3-methyl-4-methylthiophenylglyoxal and 21.9 g of sec.-butylamine in 100 ml of methanol are cooled to 10° C. and 6.8 g of sodium borohydride are slowly added. The solution is then brought to room temperature and held for 2 hours at said temperature. The solution is evaporated to 1/4 of its original volume

and surgjbres with IN HC1. The aqueous phase is washed with ether and rendered alkaline with 20% NajSO 4 -. The product is extracted with ether, dried over magnesium sulphate and evaporated. The oil-like residue is taken up with anhydrous ether and 1-(3-methyl-4-methylthiophenyl)-2-sec.butylaminoethanol hydrochloride is obtained by flowing through dry HCl gas.

S. p. (°C): 123 124 (MeOH ether)

Analyze

% calculated:. C: 58.00 H: 8.20 N: 4.65

% found: C: 57.90 H: 8.20 N: 4.55

Example 17

1-(3-ethyl-4-methylthiophenyl)-2-isopropylaminoethanol 20.6 g of 3-ethyl-4-methylthiophenylglyoxal (0.1 M) and 17.7 g of isopropylamine in 100 ml of methanol are hydrated in the presence of 0.1 g platinum oxide (normal pressure and temperature). The solvent and excess amine are evaporated in vacuo. The residue is taken up

in anhydrous ether and the hydrochloride is obtained by passing through dry HCl gas.

S. p. (°C).: 109 - 110 (MeOH-ether).

Analyze

% calculated: C: 58.05 H: 8.35 N: 4.80

% found: C: 58.05 H: 8.40 N: 4.75

Example 18

1-(3-ethyl-4-methylthiofenyl)-2- s eq. butylaminoethanol 10.3 g 3-ethyl 4-methylthiophenylglyoxal (0.05.M)

and 10.95 g of sec-butylamine in 100 ml of absolute ethanol are hydrated at normal pressure and temperature in the presence of 0.1 g of platinum oxide. The solvent and excess amine are evaporated in vacuo. The residue is taken up in anhydrous ether and 10.6 g of hydrochloride is obtained by passing through HCl gas (yield: 71%). S. p. (°C): 108 - 109 (MeOH-ether).

Analyze...

% calculated:: C: 59.30. H: 8.60 N: 4.60

% found: C: 59.15 H: 8.65 N: 4.50

Example 19 1-(4-n-butylthio-3-methylphenyl)-2-(3-methoxypropylamino)ethanol 11.8 g 4-n-butylthio-3-methylphenylglyoxal (0.05 M) and. 26.5 g of 3-methoxypropylamine in 80 ml of methanol are added slowly at a temperature of 0 - 5°C. 4.8 g of sodium borohydride. After tilsethin-! The product is then allowed to reach room temperature, and it is stirred for a further 2 hours. Separation of the product is done according to the method previously described. 10.4 g of hydrochloride are obtained (yield: 62%). S. p. (°C): 109 -110 (benzene-petroleum ether).

! Analyze

|% calcd: C: 58.87 H: 8.69 N: 4.02

in !% found: C: 58.59 H: 8.55 N: 3.95

- Example 20

j 1-(3-methyl-4-methylthiophenyl)-2-(1,2-dimethylpropylamino)ethanol-I hydrochloride ..... a) 259 g (1 M) α-bromo-3-methyl-4-methylthio -acetophenone is dissolved in 1500 ml of chloroform. 140 g (1 M) of hexamethylene tetramine are added and the solution is stirred for 2 hours at ordinary temperature, the precipitate is filtered and washed with water and then with ; acetone. 248 g are obtained. Yield: 60%.

; b) 411 g (1 M) of the previous precipitate is dissolved in 900 ml of ethanol containing 450 ml of concentrated hydrochloric acid. ■ The solution is stirred overnight at normal temperature. I The ammonium chloride is filtered off and washed with ethyl alcohol. The filtrate is evaporated to dryness. 186 g of α-amino-3-methyl-4-I methylthioacetophenone hydrochloride (yield: 80%) are isolated,

.which is recrystallized in a methanol-ether mixture.

c) 116 g (0.5 M) of α-amino-3-methyl-4-methylthio-acetophenone hydrochloride are dissolved in 1 liter of methanol. The solution is cooled to 0°C and 39 g (1 M) sodium borohydride is added in the course of

15 minutes. The solution is stirred for two hours at normal temperature. The solution is evaporated to one-tenth of its original volume and poured into water, then the solution is made alkaline with 1 N sodium hydroxide solution and extracted with ether. • The ether phase is dried over magnesium sulphate and evaporated to dryness. 54 g of 1-(3-methyl-4-methylthiophenyl)-2-amichoethanol are isolated.

The hydrochloride is obtained by passing through dry HCl gas

in an ether solution of the base. The hydrochloride is recrystallized 1 -methanol-ether mixture.

S. p. (°C) 187 - 188°.

Analyze

% calculated: C: 51.40 H: 6.90 N: 6.00

found: C: 51.30 H: 6.85 N: 5.80

d) 19.7 g of 1-(3-methyl-4-methylthiophenyl)-2-aminoethanol (0.1 M) are dissolved in 50 ml of methyl isopropyl ketone. The solution is heated

during return run 5 hours. Excess ketone is distilled and the residue is dissolved in 30 ml of methanol. This solution is cooled to 0°C and 0.8 g (0.2 M) sodium borohydride is added over 15 minutes. The solution is brought to normal temperature, and after 2 hours it is evaporated to a quarter of its original volume and the rest is poured into water. It is made alkaline with a 20% lg NaOH solution and extracted with ether. The ether phase is dried over magnesium sulfate. By passing through dry HCl gas, 15 g of 1-(3-methyl-4-methylthiophenyl)-2-(1,2-dimethylpropylamino) ethanol hydrochloride are obtained.

S. p. (°C): 177 - 178 (methanol-ether).

Analyze

% calculated: C: 59.30 H: 8.60 N: 4.60

% found: C: 59.00 H: 8.45 N: 4.45

Example 21

1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol hydrochloride 19.7 g (0.1 M) 1-(3-methyl-4-methylthiophenyl)-2-aminoethanol is dissolved in 50 ml of acetone. The solution is heated under reflux for 5 hours. The acetone is distilled off because the residue is dissolved in 30 ml of methanol. This solution is cooled to 0°C and 0.8 g (0.2 M) sodium borohydride is added over 15 minutes. The solution is brought to room temperature and kept at this temperature for 2 hours. The solution is evaporated to 1/4 of its original volume and poured into water. The aqueous phase is made alkaline with sodium hydroxide solution and extracted

with ether. The ether phase is dried over magnesium sulfate. By passing dry HCl gas through, 11 g of 1-(3-methyl-4-

methylthiophenyl)-2-isopropylaminoethanol hydrochloride.

Yield: 40%; s.p. (°C) : 154.5 - 155.5.

in

In Analyses

In % calculated: C: 56.58 H: 8.04 N: 5.08

“! % found: C: 56.60 H: 8.10 N: 5.10

in ........

j

In Example 22

1-(4-n-butylthio-3-methylphenyl)-2-N,N-dipropylamihoethanol in 3.8 g of lithium aluminum hydride (0.1 M) in 50 ml of anhydrous ether, add slowly while stirring 3.37 g of N, N-dipropyl-4-n-

IN

in butylthio-3-methylmandelamide (0.1 M) in 50 ml of anhydrous ether. ,| After the addition, the product is stirred for a further 30 minutes at room temperature. 3.3 ml of water and 3.3 ml of an aqueous solution of sodium hydroxide are then slowly added and then a further 10 ml of water. After filtration, the organic phase is dried over I magnesium sulphate. By passing through dry HCl gas, 2.44 g of 1-(4-n-butylthio-3-methylphenyl)-2-N,N-dipropylaminoethanol hydrochloride are retained. Yield: 72%. S. p. (°C): 144 - 145 (acetone-petroleum ether).

IN

in Analyzes

,% calculated: C: 63.39 H: 9.52 N: 3.89

!% found: C: 63.21 H: 9.62 N: 3.67

in

Example 23 ] 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol oxalate 1.20 g 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol in 40 ml of ether is added dropwise while stirring 0.45 g oxalic acid in 50 ml of ether. The precipitate is filtered off and washed with ether,

■ then crystallized in a methanol-ether mixture.

is.p. (°C): 165.5 - 167.5.

1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol gluconate 1.20 g of 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol in 40 ml of water is added to 1.96 ml of a 50% gluconic acid -lbsning. The mixture is heated in a water bath for 1 hour at 70°. Then done

the solution is lyophilic (2.18 <j of the salt obtained is soluble in 5 ml of water and gives a -pH of 4.6).

Example 24

1-(3-methyl-" 4-methylethyl of enyl)-2- isopropylaminoethanol lactate 1.2 g of 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol in 32 inl of water is added to 0.53 g of a 85% aqueous lactic acid solution. The product is heated in a water bath for 2 hours at 50°. The solution is then lyophilized. (1.55 g of the obtained salt is soluble in 5 ml of water).

0

Example 25

1-(4-isopropylthiophenyl-2-n-octylaminopropanol) 57 g of α-bromo-4-isopropylthiopropiophenone (0.2 M), 26 g n-octylamine (0.2 M) and 300 ml of methanol are refluxed in

3 hours. The solution is stirred until approx. 0°C and under stirring

a solution of 8 g of NaBH^ in 100 ml of water is added. The stirring is continued overnight at room temperature and the methanol is evaporated. The residue is diluted with 200 ml of water and extracted with methylene chloride. The oxalic phase is dried over MgSO 4 , the residue is recrystallized in n-pentane or in a methanol-water mixture..40.2 g is obtained. Yield: 60%. Melting point (°C):

62-63 and 232-234 for the hydrochloride.

Percentage Analysis:

Calculated % -C 71.46, H 10.45, N 4.15 Found % C 71.40, H 10.30, "N 4.20.

The erythro configuration of the product is shown by examination of the nuclear magnetic resonance spectrum.

Example 26

1-(4-isopropylthiophenyl)-2-n-octylaminopropanol

a) . To 28.7 g of cc-bromo-4-isopropylthiopropiophenone (0.1 M) in 100 ml of isopropanol, quickly add 14.2 g of n-octylamine under

stirring, and the mixture is kept at 80°C for 1 hour. The solvent is evaporated under vacuum, the residue is diluted with 1 liter

ether and leave overnight in a refrigerator. Wrong-^

the solution obtained is filtered and dried. 25 g of a-n-octylamino-4-isopropylthiopridepiophenone hydrobromide are thus obtained. Dividend:

60%-Melting point (°C) : 162-164.

Percentage Analysis:

% calculated: C 57.70, H 8.25, N 3.35

% found: C 57.85 H 8.05 N 3.10

The reaction can also be carried out in acetonitrile and methanol. b) 41.6 g of the above-mentioned product (0.1 M) in 200 ml of methanol are cooled in an ice bath to 0°C. A solution of 4.1 g of NaBH^ in 50 ml of water is added dropwise while stirring at 2 ml 5% NaOH, and then it is stirred for 2 hours at room temperature. The methanol is evaporated under vacuum, it is diluted with 200 ml of water, it is extracted with methylene chloride or ether, the organic phase is dried over MgSO^ and the solvent is evaporated under vacuum. oily residue which is obtained very quickly and recrystallized in pentane 33.2 g is obtained in this way Yield: 90% - Melting point (°C): 62-63.

Example 27 1-(4-methylthiophenyl)-2-n-octylaminopropanol To 52 g of ct-bromo-4-methylthiopropiophenone (0.2 M) in 200 ml of ethanol, 26 g of n-octylamine (0.2 M) are quickly added while stirring. and it is refluxed for 4 hours. The mixture is cooled to 0°C and 8 g of NaBH^ is added gradually, keeping the temperature between 0 and 5°C. Stirring is carried out overnight at room temperature and the solvent is evaporated under vacuum. The residue is diluted with 200 ml of water, acidified with 20% HCl, washed twice with 100 ml of ether, alkalized with 20% NaOH and extracted with ether. The organic phase is dried over MgSO 4 and filtered. A stream of dry gaseous hydrochloric acid is passed through the ethereal solution and the precipitate obtained is filtered. This latter is recrystallized in a mixture of acetone and methanol. 43 g of 1-(4-methylthiophenol)-2-n-octylaminopropanol hydrochloride are obtained.

Yield: 62% - Melting point (°C): 231-232.

Elemental analysis:

%~calculated: C 62.49, H 9.32, N 4.05

% found: C 62.70, H 9.40, N 3.95.

Example 28

1-(4-isopropylthiophenyl)-2-n-octylaminopropanol

..29 g of a-bromo-4-isopropylthiopropiof enone (10.1 M), 43.8 g of benzyl-octylamiri (0-.2 M) and 300 ml of anhydrous acetonitrile are stirred for 20 hours at room temperature. The precipitate is filtered and the organic phase is evaporated. The obtained oily residue is taken up in 200 ml of anhydrous ether and a solution of 4 g of H^LiAl in 150 ml of anhydrous ether is added dropwise. The mixture is refluxed for 2 hours and the excess hydride is removed by the addition of 4 ml of water. The organic phase is filtered by passing through a dry gaseous stream of hydrochloric acid and 38 g of 1-(4-isopropylthiophenyl)-2-benzyloctyl-aminopropanol are obtained. Melting point (0°C)^ 104-105.

Percentage analysis

% calculated: C 69.86., H 9.12, N 3.02 56<T>found: -C 69.64, H 8.92., N 2.8-7 10 g of the aforementioned product, 100 ml ethanol, 1 g of palladium on 10% carbon and ml of concentrated HC1 are hydrogenated at room temperature and normal pressure..

The solution is filtered and evaporated under vacuum. After recrystallization in methanol ether, the following is obtained: 7.8 g of 4-(isopropylthiophenyl)-2-n-octylaminopropanol hydrochloride. Melting point (0°<C>) :

222-224 (under cleavage}.

Percentage analysis:

% calculated: C 64-, 22, H 5.70, N 3.74

% found: X: 64.20, H 9.50, N 3.60.

The product's triple configuration is shown by examinations of the nuclear magnetic resonance spectrum.

Example 29

1-(4-isopropylthiophenyl)-2-n-octylaminopropano1

a) To 15 g of a-bromo-4-isopropylthiopropiophenone in 200 ml of methanol cooled to 0°C, gradually add 4.5 g of NaBH^ while stirring.

Stirring is carried out for 30 minutes at room temperature and then it is diluted with 200 ml of water and acidified with 45% HBr. Extraction with ether is carried out and the organic phase is dried over MgSO 4 and evaporated. 15.6 g of an oil is obtained, the homogeneity of which is confirmed by CCM and which oil is used in the following procedure. b) 15 g of the aforementioned product, 75 ml of n-octylamine and 100 ml of absolute ether are refluxed for 20 hours. The solvent and excess amine are evaporated under vacuum. The residue is treated with 200 ml of 5% HCl, the precipitate is filtered and washed with water bg with diisopropyl ether. Recrystallization is carried out in acetone and 10 g of 1-(4-isopropylthiophenyl)-2-n-octylaminopropanol hydrochloride is thus obtained. Yield: 51% (steps a and b). Melting point: 222-224°C (under decomposition). The free base is recrystallized in pentane. Melting point (°C): 51-52.

Percentage Analysis:

% calculated C 71.46, H 10.45, N 4.15

% found C 71.50, H 10.45, N 4.30.

The triplet configuration of the product is shown by examination of the nuclear magnetic resonance spectrum.

Example 30

8.4 g (0.03 M) I, 5.1 g (0.06 M) piperidine and 100 ml anhydrous ether were stirred overnight at room temperature. The filtrate is filtered and evaporated. The oil obtained is dissolved in 100 ml of methanol and 2.3 g of NaBH4 is gradually added at a temperature of

10°C. After addition, the mixture is stirred for 2 to 3 hours at ambient temperature and then the solvent is evaporated. The residue is diluted with water (100 ml) and extracted with ether. The organic phase is dried over MgSO4 and filtered. Gaseous dry HCl is passed through and 8.3 g of III is obtained, which is recrystallized from methanol-ether and then from acetone. Melting point: 218 - 219°C.

Analysis;

% Calculated: C 52.17; H 6.57; N 4.35

% Found: C 52.30;. H 6.70; -N 4.15.

Example 31

34 g (Q., 11 M) I, 32 g sec-butylamine 44 M) and 250 ml -acetonitrile are stirred for 24 hours at ambient temperature. 250 ml of ether are then added and filtered. The filtrate is evaporated. The oil obtained is dissolved in 100 ml of methanol and added eventually 8.3 g (0.22 M) NaBH4 at a temperature of 0-5°C, and then stir for 2 hours at room temperature. The solvent is evaporated, the residue is diluted with 200 ml of water and extracted with ether. The organic phase is dried over MgSO4 and filtered. Dry gaseous HCl is passed through and 14.4 g of III is obtained, which is recrystallized from methanol-ether and then from isopropanol. Melting point: .193-194., 5°C .

- Analysis:

% Calculated: C 54.54? H 7.7 2; N 3.98.; % Found: C 5 4.51; H 7.76; N 3,-73. Example 32 8 g of I (0.025 M), 4.1 g of n-octylamine (0.025 M) and 25 ml of acetonitrile are refluxed for 3 hours. The solvent is then evaporated and the residue diluted with 25 ml of methanol. 1.9 g of NaBH^ are gradually added at a temperature of - 5°C, after which the mixture is stirred overnight at room temperature. The solvent is evaporated and the residue is diluted with 100 ml of anhydrous ether.

Acidify with an ethereal hydrochloric acid solution and filter the precipitate which is recrystallized from methanol-ether. 3 g of III is thus obtained. Melting point: 2lO-212°C.

Analysis:

% Calculated: C 64.99; H 9.87; N 3.61;

% Found: C 65.10; H 9.95; N 3.45.

Example 33

55 g I (0.2-M), 26 g n-octylamine \Q_, 2 M) and 200 ml ethanol are refluxed for 4 hours.: The solution is cooled to +5°C and gradually added 8 g of NaBH^ and then stir for 12 hours at room temperature. The solvent is evaporated and the residue is diluted with 200 ml of water and extracted with ether. An ethereal phase is dried over MgSQ^, filtered and, after passing through dry gaseous HCl, 35 g of III is obtained which is recrystallized from methanol-acetone. • -Melting point: 230-232 oC. Analysis: % Calculated: C 63.39; :H 9.52; N 3.89;

% Found: -C 63.70; H 9.75; ■ N 3.85.

Example 34

1-( 3- methyl-4- methylthiophenyl)- 2- n- octylaminoethano1 (CP 365 S)

260 g - 3-meth<y>1-4-jnet<y>ltio-a-brQmacetof enone., 150 ml of n-octylamine and 500 ml of methanol are refluxed with stirring for 1 hour. The mixture is dressed for other purposes. 5°C and gradually adds a solution of 37 g of NaBH^ in 120 ml of water and 3 ml of 8N NaOH. After addition, one stirs overnight at ordinary temperature and evaporates the solvent.

Add 50 ml of 8N NaOH to the residue and extract 3 times with 200 ml of ether. The organic phase is washed successively with an aqueous solution of sodium-potassium tar t-rat., an aqueous solution of -NaCl and then with water. It is dried over MgSO^ and filtered. 130 ml of a solution of HCl -2.5 M in ether is added to the -obtained ethereal solution.

The precipitate is filtered, washed with acetone and recrystallized from a mixture of isopropanol and methyl ethyl ketone

In this way, _205 g of the hydrochloride of .1-(3-methyl-4-methylthiophenyl)-2-n-octylaminoethanol is obtained. Melting point: 198-200°C. Analysis:

% Calculated: C 62.50; H 9.30; H 4.05

% Found: C 62.42; H 9.40; H 4,10 1 The previously mentioned tables, which relate to compounds prepared in the same way as the compounds treated in detail in the forthcoming examples, are shown below as tables I and II.

Table I shows compounds of the general formula I, where R 3 and R 1 denote a hydrogen atom, while Table II shows compounds where R 1 and/or R 1 do not denote hydrogen. Table VI shows compounds, where R 2 = R 2 = H and table VII shows pharmacological results for the compounds according to table VI.

A number of pharmacological results for products according to the invention, compared with known products, are given below. The LD 0 value was obtained according to the technique of Campbell and Richter (Acta pharmacol. et toxicol. 1967, 25, 345).

It has unexpectedly been established that 1-(4-isopropylthiophenyl)-2-n-octylaminopropanol (CP 556S) has a greater degree of activity than 1-(4-isopropylthio-3-methyl}phenyl-2-n-octylaminopropanol (b ) and than 1-(4-isopropylthiophenyl)-2-n-octylaminoethanol (c) in terms of peripheral vasodilatory activity..

These findings are based on Table VIII which follows below:

In the following tables IX and X, further comparisons of six examples are shown between the therapeutic activity of compounds according to the invention and known compounds, and in table IX a comparison between the following compounds is reproduced:

CP 236 S = 1-(4-methylthiophenyl)-2-isopropylaminoethanol

CP 237 S = Hydrochloride of CP 236 S

CP 240 S = 1(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol CP 366 S = 1-(3-methyl-4-isopropylthiophenyl)-2-n.octylaminoethanol

CP 365 S = 1-(3-methyl-4-methylthiophenyl)rr2-n.octylaminoethanol.

of which the two former are known compounds.

In the following table XI, comparative activity is shown for two known compounds, namely CP 527 S and CP 237 S, and a particularly preferred compound which is produced according to the present invention, namely CP 556 S [vi-(4-isopropylthiophenyl) -2-n-octylaminopropanol] j Peripheral-~ vasodllatori sk. activity in.-

Designations, O = not active

+ - low activity " "-

++ = medium activity

+++ = effect is similar to the effect of papaverine

(30 mcg/kg intra-arterial) r-++++ = effect superior to the effect for ~

papaverine.

B- lvtic activity.

Activity for 1 dose of 1.10-6 g/ml product.

Designation: O = inhibition of the chronotropic effect of 1.10 — 8g/ml norepinephrine < 50%

+ - inhibition of the chronotropic effect of 1.10 _7g/-

ml norepinephrine < 50%

++ - inhibition of the chronotropic effect of l.10~<6>g/-

ml norepinephrine <. 75%

Antispasmodic activity;

low inhibition (+)

partial inhibition (+)

complete inhibition (++)

at a specific dose of antagonist, contractions by histamine, acetylcholine and BaCl2 or at lower doses by a multiple of three (+++).

In the following, additional therapeutic data are shown for some of the particularly preferred compounds produced according to the present invention, namely: CP 422 S; 1-(2-Chloro-4-methyltibphenyl)-2-N-piperidinoethanol hydrochloride

CP 545 S: 1-(3-Chloro-4-methylthiophenyl)-2-sec-butylaminopentanol-hydroxy ori d

CP 453 S; 1-(3-methyl-4-isopropyltibphenyl)-2-n-octylaminopropanol hydrochloride

CP 556 S; 1-(4-isopropylthiophenyl)-2-n-octylaminopropanol

CP 365 S; 1-(3-methyl-4-methylthiophenyl)-2-n.octylaminoethanol hydrochloride

CP 579 S; 1-(4-Ethylthiophenyl)-2-r.tylarinopropanol hydrochloride

CP 240 S; 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol hydrochloride.

which is compared with the known compounds "A", "B" and "C", discussed on page 3 of the present description.

Symbols used in tables XII - XIV

Vasodilation:

O: no activity

+: very low activity

++: approx. half the activity of papaverine +++: activity equal to papaverine

++++: -activity surpassing that of papaverine.

Antispasmodic activity:

0: no activity at 15 µg/ml concentration +_:_: , weak inhibition of the spasmogen response at 15 µg/ml

concentration

+: partial inhibition of the spasmogenic response at 15 p<g>/ml

concentration on

++: total inhibition of the spasmogenic response at 15 ug/ml concentration; this level of antispasmodic activity corresponds to that of papaverine

+++: total inhibition of the spasmogen response at 5 ug/ml concentration

I ++++: total inhibition of the spasmogen's response with. 1.5 ug/ml ■

concentration. v

t

[ 3- blocking activity

O: inhibition of the chronotropic effect of 1.10~ —8g/ml of

norepinephrine less than 50%_7

+: inhibition of the chronotropic effect of 1.10 g/ml of

norepinephrine less than 50%.

++: inhibition of the chronotropic effect of 1.10<->^ g/ml of norepinephrine less than 75% -5

+++: inhibition of the chronotropic effect of 1.10 g/ml of

norephrine more or to 60

++++: total inhibition of the effects of these concentrations of norepinephrine. This is the activity level of propranolol, a standard [3-blocker.

The following table XV shows vasodilatory action in perfused dog paw for the particularly preferred compound CP 556 S and several known peripherally vasodilator active compounds, administered i.a. at a dose of 30 ug/kg.

Comments on Tables XII XV

From tableXII it can be seen that the compounds CP 453 S and CP

556 S exhibits significantly better properties than compounds "A", "B" and "C" with respect to their vasodilatory and antispasmodic properties. With regard to their vasodilator properties, CP 453 S and CP 556 S are much more active than papaverine, a very well-known reference compound, while "A", "B" and "C" are inactive or much less active than papaverine, and therefore cannot expected to have some clinical interest. These compounds "A", "B" and "C" cannot normally be considered as potential compounds. On the other hand, the valuable properties of CP 556 S have been further substantiated by comparing this compound with other well-known compounds. compounds and in this respect CP 556 S is found to be superior to all the other reference compounds, as shown in Table XV.

With regard to antispasmodic activity, again CP 453 S and CP 556 S exhibit superior properties than compounds "A",

"B" and "C", as the activity level for "A", "B" and "C" is too low for their activity ratio to be calculated. The combination of the very important activities for CP 453 S and CP

556 S, namely vasodilatation and antispasmodic effect, are of the greatest importance for their therapeutic use in obstructive vascular diseases. It can also be noted with regard to CP 556 S that these conclusions have already been substantiated by various controlled clinical trials in claudication

intermittent and in case of cerebrovascular insufficiency. E.g. is CP in 556 S found to be superior to placebo, cinnerazine and "Hyde* rgin R!.'. on the other hand, the adrenergic (3-blocking effect for compounds "A", "B" and "C" , which is absent for CP 453 S and CP 556 S, to be considered an undesirable side effect for such medical use.Furthermore, the toxicity of CP 453 S and CP 556 S appears to be very weak.

o

From Table XIII, it can be concluded that compounds CP 365 S and CP 579 S are significantly better than compounds "A", "B" and "C" with respect to their antihypertensive activity, compounds "B" and "C" being completely without activity, while compound "A" is somewhat active, but also exhibits an adrenergic β-blocking effect, which is undesirable. CP 365 S and CP 579 S are on a mg/kg dose basis approx. 13 times more effective than methyldopa. The two compounds also show important vasodilatory and antispasmodic properties which are only very little for the compounds "A", "B" and "C" as indicated above, properties which are however useful in the treatment of hypertension. It should also be noted that the first controlled clinical trials with CP 365 S support its importance in the control of hypertensive diseases in humans.

From Table XIV it can be concluded that the compounds CP 422 S,

CP 454 S and CP 240 S are significantly better than compounds "A", "B" and "C" with respect to their protective action against anoxia in the heart muscle, compounds "B" and "C" showing no activity in respect, while the conjunction: "A" was somewhat active. It is also of interest to note that for CP 240 S the protective effect is associated with an adrenergic (3-blocking effect, in the same way as for compound "A", however, in this respect CP 240 S is more than 5 times as active as compound "A". The combination of these two properties is of theoretical interest in the treatment of cardiac disorders such as angina pectoris. However, for cases with an associated heart failure, the adrenergic P-bl-occlusive activity is contraindicated, and this explains the interest for in CP 422 S and 454 S which exhibit a protective effect against anoxia without an Ø-blocking effect.

Claims (11)

1. Analogous process for the production of amino- alcohols with pharmaceutical properties and with it general formula where R means RS or RSO 2 , where R is a straight or branched C 1 -C 0 alkyl group, and where R 2 and R 2 are different and mean hydrogen, halogen, a C 2 -C 3 alkyl, C 3 -C 3 carbaicoxy or C^-C-j alkoxy group, R^ means hydrogen or a straight or branched C^-C^ alkyl group, Rg and R^, which may be the same or different, means hydrogen, a straight or branched C^-C^q alkyl-, a Cg-C^ cycloalkyl-, a C3~C4 alkenyl-, or a C-^-Cg alkylphenyl group optionally substituted with one or more chlorine atoms or hydroxyl groups, or Rg and Rg can together with the adjacent nitrogen atom form an optionally with a C^ ~ C^ alkyl, benzyl or hydroxyl group substituted piperidine ring, a morpholine ring, a piperazine ring optionally substituted with a C^-C^ alkylphenyl group or a 3-azabicyclo [3.2.1.]-octyl ring, and when Rg denotes hydrogen and R^ a C4-c10 alkyl group, R2 and R^ can both be hydrogen or methyl groups, as well as salts of these compounds, characterized in that a) a compound of formula II where Q is reduced, or b) a compound of formula II, where Q is and where X means a halogen atom, is reacted with an amine of formula NHRgR^, and for the preparation of compounds of the general formula I, where R 1 means hydrogen. c) a compound of formula II, where Q is CO-CO-R4 is reacted simultaneously with an amine of formula N^Rg, or a hydroxylamine of formula NH (OH)Rg and a reducing agent, or d) a compound of formula II, where Q is is reacted under reducing conditions with a compound of formula where R7 and Rg have meanings such that the group Rj - CH - Rg gets the meanings given for Rg above with the exception of hydrogen, or e) reduce a compound of formula II in which Q is where Rg is a group that can be removed by reduction, after which the product is optionally reacted with an acid to form a salt. 2. Process according to claim 1 for the production of 1-(2-chloro-4-methylthiophenyl)-2-N-piperidinoethane, characterized in that cc-N-piperidino-2-chloro-4-methylthioacetophenone is reduced. 3. Method according to claim 1 for the production of 1-(3-chloro-4-methylthiophenyl)-2-sec0-butylaminopentanol, characterized in that oc-sec„ -butylarnino-(3-chloro-4-methylthiophenyl)-n-butylketone is reduced, 4. Method according to claim in the production of 1-(3-methyl-4-isopropylthiophenyl)-2-n-octylaminopropanol, characterized in that a-n-octylamino-3-methyl-4-isopropylthio-propiophenone is reduced. 5. Process according to claim 1 for the production of 1-(4-ethylthiophenyl)-2-n-octylaminopropanol, characterized in that α-n-octylamino-4-ethylthiopropiophenone is reduced. 6. Process according to claim 1 for the production of 1-(3-methyl-4-methylthiophenyl)-2-n-octylaminoethanol, characterized in that <x-n-octylamino-3-methyl-4-methylthioacetophenone is reduced. 7. Process according to claim 1 for the production of 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol, characterized in that oc-isopropylamino-3-methyl-4-methylthioacetophenone is reduced. 8; ± Process according to claim 1 for the production of 1-S(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol, characterized in that 3-methyl-4-methylthiophenylethylene oxide is reacted with isopropylamine. 9. Process according to claim 1 for the production of 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol, characterized in that 1-(3-methyl-4-methylthiophenyl)-2-aminoethanol is reacted under reducing conditions with acetone. 10. Method according to claim 1 for the production of 1-(4-isopropylthiophenyl)-2-n-octylaminopropanol, characterized in that α-n-octylamino-4-isopropylthiopropiophenone is reduced. 11. Method according to claim 1 for the production of 1_ (4-isopropylthiophenyl)-2-n-octylaminopropanol, characterized in that α-N-benzyl-N-octylamino-4-iso-propylthiopropiophenone is reduced.