DE2927789A1 - 1-PHENYL-1-PROPANOL DERIVATIVES - Google Patents

Description

Applicant: Stuttgart, July 5, 1979

Continental Hiarma P- 5741 S-ef

135 Avenue Louise Brussels, Belgium

Representative:

Kohler - Schwindling - Späth Patent Attorneys Hohentwielstraße 41 " 7000 Stuttgart 1

1-phenyl-i-propanol-J derivatives

The invention relates to derivatives of 1-phenyl-1-ppopanol the general formula

in the

E ^ Ilassstoff, a linear or branched one

909884/0818

Alkylthio radical with 1 to 3 G, a linear or branched one Alkylsulfinyl radical with 1 to 3 C, a linear or branched alkylsulfonyl radical with 1 to 3 C or a Mercaptorest and

R ~ denotes the hydroxyl group, an oxo-2-pyrrolidinyl-i radical optionally substituted by a hydroxyl group, or an NHR ^ group, in which R ^ in turn is either hydrogen or if R _x . is not an alkylthio radical, a linear or branched alkyl radical with 6 to 16 G or a linear alkyl radical with 2 to 4 C substituted by a phenyl or Ehenoxy radical, or also a in the CO position by a carboxyl or carbalkoxy radical with 1 up to 3 C substituted, linear or branched alkyl radical with 1 to 7 C, as well as the nontoxic and pharmaceutically usable salts and esters of these derivatives.

A preferred class of the compounds of the invention includes the derivatives of the general formula (I) in which

R _{1 is} a linear or branched alkylthio radical with 1 to 3 C and

Rp is an NHR, residue in which R, is linear or branched Is an alkyl radical with 1 to 3 C, which is in the CO position by a carboxyl or carbomethoxy radical is substituted.

Another preferred class of compounds according to the invention is that in which

H ,, a linear or branched alkylsulfinyl radical with 1 to 3 C and

Rp is an NHR ^ group in which R, a linear or branched alkyl radical with 6 to 14 C, or a linear one

$ 909884/081

Λ 3 -

Alkyl radical with Ibis 3 G means that in the 6J position substituted by a carboxyl or carbomethoxy radical is.

Examples of derivatives according to the invention are 1- (4-Isopropylsulfynylphenyl) -2-n-octylamino-1-propanol 1- (4-Isopropylthiophenyl) -2- ^ 3- (methoxycarbdnyl) propylaminoj

-1-propanol 1- (4-isopropylthiophenyl) -2- [3- (carboxy) propylainino3 -1-

propanol

1- (4-methylthiophenyl) -2- (j5- (methoxycarbonyl) propylaminoj

-1-propanol

1- (4-methylthiophenyl) -2- ^ 3- (carboxy) propylamino] -1-

propanol ΐ- (4-isopropylsulfinylphenyl) -2- [3- (methoxycarbonyl)

propylamino I-1-propanol 1 - (4-Isopropylsulfynylphenyl) ^ - 2- [3- (carboxy) propylamineq |

-1-propanol 1- (4-isopropylsulfinylphenyl) -2- [1 - (2-oxopyrrolidinyl) J

-1-propanol 1- (4-mercaptophenyl) -2-n-octylamino-1-propanol

The derivatives of the formula (I) can be in the form of their Salts, especially in the form of the chlorohydrates and sulfates, are isolated. These derivatives can also be used by means of common method using acids in salts implemented. If, on the other hand, the derivatives are obtained directly in the form of salts, they can also be converted into theirs convert free bases or into the salts of other acids.

According to the invention, it is in particular light toxic, pharmaceutically acceptable acid addition salts formed with suitable inorganic acids,

909884/0818

such as hydrochloric acid, sulfuric acid or phosphoric acid, and with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, Malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, Aspartic acid, glutamic acid, benzene acid, aminobenzoic acid, hydroxybenzenic acid, salicylic acid, phenylacetic acid, Mandelic acid, emboxylic acid, methanesulfonic acid, ethanesulfonic acid, Pantothenic acid, toluenesulfonic acid, sulfanilic acid, Cyclohexylaminosulfonic acid, stearic acid, alginic acid, ft-hydroxypropionic acid, ft-hydroxybutyric acid, oxalic acid, Malonic acid, galactaric acid and galacturonic acid. Such salts can also be derived from natural or artificial Derive amino acids, for example from lysine, glycine, arginine, ornithine, asparagine, glutamine, alanine, Valine, Threonine, Serine, Leucine, Cysteine, etc.

Most of the derivatives according to the invention have two centers of asymmetry. The derivatives where R _x . is an alkylsulfinyl radical, even have three centers of asymmetry.

Two racemates can be obtained from the products according to the invention, which have two centers of asymmetry correspond to the configurations erythro and threo. These two racers can be separated using classical methods are, for example, by the formation of diastereoisomeric salts by means of optically active acids, such as for example tartaric acid, biacetyltartaric acid, the Tartranilic acid, dibenzoyltartaric acid or ditoluene tartaric acid and separating the mixture of diastereoisomers

909884/08 1 β

by crystallization, distillation or chromatography and subsequent release of the optically active bases from the salts.

Eight optical isomers can be obtained from the products according to the invention which have three centers of asymmetry will. The same procedures can be used to separate the ingredients of these mixtures from one another separate.

The most active derivatives according to the invention can therefore either be used in the form of mixtures containing several diastereoisomers in any ratio, such as in the form of antipodes in the same ratio (racemic mixture), as well as in the form of optically pure compounds. A certain preference is given to the derivatives with respect to the two asymmetric carbon atoms of the propanol chain Have an erythro configuration.

The invention also has a method of making the named derivatives of 1-phenyl-i-propanol and their Salts and esters are the subject.

The method is characterized in that a connection the general formula

(II)

in which Z is either one of the above-defined substituents E _-1 or a group YS in which Y is a protective group which can be replaced by hydrogen, while Q is one of the following groups

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Vf ₆ -

-CO-CO-CH ₃ ; -CO-CHOH-CH ₃ ; -CO-CH-X;

CH,

-CH-CH-CH,; -CO-CH-NHR,: -CHOH-CH-X;

3 ι 3 'ι' CH, CH,

-CHOH-CH-E ₂

in which Rp and R _{3 have} the meanings given above and X represents a halogen atom, such as, for example, Cl, Br, F, is converted into a compound of the general formula (I). For the preparation of derivatives according to the general formula (I), in which Rp is the hydroxyl group, it is advantageous to use ketones according to the general formulas

δ -w

(IH)

and. -Kyi "ν f * \ jKj— LftiUn. — On, V ₁ IvJ ₅ in which R _{1 has} the meaning given above, reduced.

This reduction can be carried out in the usual way, for example by reacting the ketones with hydrides such as NaBH ₄ , LiAlH, LiAl (OAlkyl) ₃ H, AlH ,, (alkyl) ₂ AlH, NaB (OCH,), H ₁ \ iBH _per ON, B _o H _r , (alkyl), SnH, (alkyl), SiH or

0 0 ρ cO 0 O

NaH, in solvents such as ether, tetrahydrofuran, ethanol, methanol, diglyme, toluene or xylene.

903884/0813

by reacting with alkali metals such as sodium or
Lithium, in solvents such as ammonia or ethanol,
by reacting with hydrogen in the presence of hydrogenation catalysts such as platinum or palladium, in solvents such as ethanol, or by reacting with an aluminum alcoholate such as aluminum isopropoxide in a solvent
like isopropanol.

When the process of reducing ketones according to the general Formulas (III) and (IV) is not stereoselective, the erythro-threo mixtures can be made according to classical methods be separated, for example by distillation or thin layer or column chromatography.

The compounds according to the general formula (I) in which R- is an oxo-2-pyrrolidinyl-i-ring optionally substituted by a hydroxyl group are advantageous
obtained according to the general relationships given below:

CHO HCH-N. \

F. - 2. S. ((\ CHOHCB- ! tr > .CO-CH-Br Λ CH ₅ reduction -K

3 base (cyclization)

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In these relationships, R ,. the meaning given above.

In reaction (a), the condensation of the epoxide with 2-pyrrolidinone takes place very easily either without a solvent, in which, if appropriate, an excess of 2-pyrrolidinone is used, or in the presence of solvents, such as methanol or ethanol.

This process enables alcohols with a threo configuration to be obtained.

In reaction (b), the (ÖC-promo-ketone) condenses with an ester of 6J-aminobutyric acid in a solvent such as methanol, ethanol, chloroform, acetonitrile, Benzene or a mixture of such solvents, preferably at ambient temperature.

The reduction can be effected through the use of alkali metal hydrides and in particular NaBIL ·, and in a solvent such as methanol or ethanol at ambient temperature. The cyclization to pyrrolidinone can take place through the action of an organic or inorganic base, for example through an alcoholate or by sodium or potassium hydroxide, in an alcoholic, optionally water-containing solvent, such as methanol, ethanol or isopropanol, at a temperature which is between ambient temperature and the reflux temperature of the selected solvent. It is best to work at ambient temperature.

This process allows the production of alcohols with an erythro configuration.

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Those compounds of the general formula (I) in which Rp is an NHR, group can start from a compound according to the general formula

or, depending on the meaning of Q, optionally also starting from a salt of a compound according to the general formula (V) in which R ^ the above has given meaning and Q has one of the groups

-CH-GH-CH ₂ -COCH-NHR, -CHOHCH-X -GOCH-X

GH, CH, CH ₃ ,

represents, in which R * has the meaning given above

and X represents a halogen atom.

The above method can be twofold To be carried out in a manner »The procedure to be followed is essentially determined by the starting product, i.e. by the meaning of Q in general Formula (V).

Procedure A

In the first way -a -cCr-amino-ketone after the _ Formula (V) in which Q is the group

-GO-GH-NHR,

i 2 »■ ~

isind R ₅ , which has the meaning given above, reduced. The reduction can be carried out in a customary manner, particularly simply, for example, by the action _; from

309S34 / ^: 0818

-fto -

Alkali metal hydrides such as sodium borohydride in a solvent such as methanol or ethanol, preferably at low temperatures. The reduction can also take place under the Exposure to aluminum or lithium hydride in a solvent such as diethyl ether or tetrahydrofuran, as well as by the action of an aluminum alcoholate, such as aluminum isopropylate, all in one Solvent such as isopropanol, preferably under reflux of the solvent. Furthermore, the reduction can through a hydrogenation take place in the presence of a catalyst, such as palladium on carbon, Raney nickel or platinum oxide in a solvent such as methanol, ethanol or dioxane.

As indicated above, the most interesting of the products according to the invention can have two configurations, namely the erythro and the threo configuration. The choice of the amino ketone used as the starting material and the reduction conditions enable a stereoselective production of one or the other of the two forms. Thus, the reduction of an aminoketone χ _η the Q leads the group

-CO-CH-NHR ₂ Ί 3

CH,
0

means, under the general conditions described above, to an amino alcohol with an erythro configuration.

To obtain a compound with a threo configuration, an aminoketone is reduced in which Q is the group

-CO-CH-NBLE ,. I 3 4 CH,

9 0 ') ¹ C U / 0 l · 1 B

means in which R ^ has the meaning given above has and R ^, represents a protecting group following the reduction can be eliminated by hydrolysis or hydrogenolysis. Such a protecting group can, for example, be a Benzyl, trityl, acetyl, formyl or benzhydryl radical be. In this case, the reduction is preferably below Use of alkali metal hydrides carried out, such as sodium borohydride or lithium aluminum hydride.

The aminoketones used as starting materials are easy to prepare, for example by the action of an amine R-, NHp or R., R ₂ , NH on an e> (r-halogenoketoh in a solvent such as ether, benzene, chloroform, dioxane, methanol, isopropanol or acetonitrile.

Procedure B

After this manufacturing process a connection wixd according to the general formula (V), in which Q is a group

-CHOH-GH-X

means reacted with an amine R ^ NH «. In the formulas given above, R ₃ and X have the meanings given above. This reaction is carried out in a solvent such as an alcohol, chloroform, dioxane, carbon tetrachloride, and preferably in the presence of a product which fixes the hydrazine halide formed. This can be an inorganic or organic base or an excess of amine. It is well known that in this case the group

-GHOH-GH-X

V - :; ■■

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first an oxirane of the type

O -CH-GH-CH ₃

forms which reacts with the amine compound. This process therefore also includes the production of amino alcohols from oxiranes.

The compounds of the general formula (I) in which iL is the mercapto group, starting from a compound according to the general formula

YS- ^ Λ-CHOHCH-R ₂ (VI) ^ ⁸⁸ 'CH ₃

getting produced,

in which R _{2 has} the meaning given above and Y is a protective group which can be replaced by hydrogen according to processes known from the literature. The protective group can be formed, for example, by an alkyl radical such as an isopropyl or an optionally substituted benzyl radical, which is formed by the action of an alkali metal, such as sodium or lithium, in a solvent such as ammonia, or by the action of hydrogen in the presence of a hydrogenation catalyst or by the effect of lead diacetate or hydrofluoric acid can be eliminated. It can also be an optionally substituted diphenylmethyl radical, which can be eliminated by the action of acids, such as trifluoroacetic acid or hydrobromic acid, to an optionally substituted triphenylraethyl radical, which can be eliminated by the action of acids such as hydrochloric acid or hydrobromic acid or compounds such as HgCl ₂ , AgNO, or Hg (OAc) ₂ can be eliminated by a benzylthiomethyl residue, which can be eliminated by oxidizing agents such as HgCl ₂ or Hg (OAc) ₂

909884/0816

is an acetamidomethyl radical, which can be eliminated, for example, by mercury salts, a carboxymethyl radical which can be eliminated in an acidic medium by oxidizing agents, or a tetrahydropyranil or tetrahydrofuranyl radical which can be reacted by oxidizing agents such as AgNO ,, I ₂ , SO ₂ Cl ₂ or ( SCN) ₂ -Zn and can be eliminated by acids.

The compounds of the general formula (I) in which R _{2 is} an alkylsulphinyl or alkylsulphonyl radical can be prepared starting from compounds of the general formula (II) in which Z is an alkylthio radical, by oxidation according to processes described in the literature . This oxidation can be carried out at any stage of the synthesis of the products according to the invention.

Oxidizing agents can therefore be used to produce the sulfoxides use, such as iodine, bromine in water or in the presence of acetate ions as well as in complex with pyridine, peracids such as peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid, N-halosuccinimides such as the n-bromosuccinimide, hypochlorites such as sodium hypochlorite, t-butyl hypochlorite or i-propyl hypochlorite, periodates such as sodium periodate, hydrogen peroxide in the presence of acetic anhydride or vanadium pentoxide in t-butanol, nitrates such as acetyl, ammonium or cerium nitrate, Oxides such as chromium VI oxide in pyridines or vanadium pentoxide in the presence of oxygen or nitrogen pentoxide, Peroxides, ozone, oxygen in the singlet or triplet state, acids such as nitric acid, chromic acid or Caro's acid, as well as other agents such as thionyl chloride, 1-chlorobenzotriazole, chloramine, n-chloronylon 66, iodobenzene dichloride, ipdosobenzene, iodobenzene

909 884/0816 · / ■

diacetate, n-chlorotriazoles, 2,4-, 4,6-tetrabromocyclohexadienone and chloroauric acid (HAuCl ^). The oxidation takes place in solvents such as water, Acetic acid, chloroform, dichloromethane, carbon tetrachloride, methanol, t-butanol or acetone.

Oxidizing agents such as hydrogen peroxide, preferably in, are preferably used to prepare the sulfones Presence of zirconium salts, peracids such as peracetic acid, Monoperphthalic acid and m-chloroperbenzenic acid, potassium permanganate in an acidic or basic medium, sodium or potassium dichromate, osmium tet.t.aoxide, selenium oxide, t-butyl hypochlorite, Nitric acid, ozone, oxygen, preferably in the presence of iridium or rhodium salts, iodobenzene dichloride and periodic acid. When using peracids for the oxidation, a catalyst is preferred used on the basis of transition metals. Electrochemical oxidation is also possible. The reactions found in solvents such as water, acetic acid, chloroform, dichloromethane, methanol, ethanol, isopropanol, t-butanol, Dioxane or acetone instead.

In some cases it can be advantageous to apply the above-mentioned oxidation reactions to compounds of the general formula (I) in which R ^ is an alkylthio radical is, and with ^ en the functions sensitive to the oxidizing agent used have been protected beforehand are, for example, by the formation of esters in the case of hydroxyl groups or of ketals in the case of ketone groups.

This is followed by detailed examples for the preparation of some derivatives of 1-bienyl-i-propanol the invention. The main purpose of these examples is

909884/0818

specific details of the method according to the invention to explain further.

example 1

1- (4-Isopropylsulfinylphenyl) -2-n-octylaminopropanol (Table I, No. 6):

To 14 g of 1- (4-Iaopropylthiophenyl) -2-n-octylaminopropanol, dissolved in 25Ο ml of chloroform, 6.4 g are gradually added m-chloroperbenzenic acid added. The mix will stirred overnight "at ambient temperature, then with a saturated aqueous solution of NaHGO, washed and evaporated in vacuo.

The residue obtained is treated with 50 ml of ether and filtered.

The organic base is dried over MgSO ^, filtered and evaporated. The oily residue is dried in vacuo overnight and then redissolved in anhydrous ether. The hydrochloride is obtained by passing gaseous dry hydrochloric acid through it. After recrystallization in a mixture of methanol and ether, 8.4 g of the product are obtained. The yield is 60%, the melting point 16? up to 169 ⁰ C.

Elemental analysis

C. , 59 H 30th N , 59 calculated 61 , 28 9, 05 3 , 4-5 found 61 9, 3

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-You -

Example 2

1- (4-Isopropylthiophenyl) -2- [_1- (2-oxopyrrolidinyl) j -1-

propanol (Table I, No. 7)

a) 2-methyl-3- (4-isopropylthiophenyl) oxirane

To a solution consisting of 28.5 g of 2-bromo-1- (4-isopropylthiophenyl) -1-propanone, 350 ml of ethanol and 125 ml of ethoxyethanol, 3.83 g of NaBH ^ in are gradually added at -25 ° G with stirring 25 ml of water added. After the addition, the temperature of the mixture is allowed to slowly rise to ambient temperature and stirring is continued for a further 1:30 h. A solution of 3.8 g of KOH in 4-0 ml of water is then added dropwise and the mixture is stirred for a further 30 minutes. The reaction medium is diluted with water and extracted with chloroform. The chloroform phase is separated off, dried and filtered. The solvent is then removed by distillation in vacuo. This gives 23.6 g of an oil which is rectified under vacuum. 19.2 g of the product are obtained, which corresponds to a yield of 65 % . The boiling point is 81 to 84 ⁰ C (0.7 mm). The MNR spectrum is consistent with the structure of 2-methyl-3- (4-isopropylthiophenyl) oxirane.

b) 1- (4-Isopropylthiophenyl) -2- / _1- (2-Ojcopyrrolidinyl) J -1-

propanol

10.4 g of the product obtained previously, 4.25 g of 2-pyrrolidinone and 0.5 g of NaOH are ^{heated to 120 °} C. for 17 hours under nitrogen. After cooling, the oil obtained is

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- 37 -

solidified by the addition of petroleum ether. The solid is filtered, washed with a minimum of petroleum ether, dried and recrystallized from diethyl ether. In this way, 4.68 g of the product (yield 45%) with a melting point of 115 to 116 ^° C. are obtained. The structural correspondence is checked by mass spectrometry and MNR spectrometry (threo configuration).

Elemental analysis Example 3 calculated G , 49 H 90 N 77 % found 65 A3 7, 80 4, 70 % 65 7, 4,

1- (4-Isopropylsulfonylphenyl) -2- £ i - (2-oxopyrrolidinyl)] - 1-

propanol (Table I, No. 9)

A solution comprising 2.93 S 1- (4-isopropylthiophenyl) -2- £ i- (2-oxopyrrolidinyl) J-1-propanol, 6.5 ml acetic acid and 6.5 ml 30% HgOg is slowly increased to 85 to 90 ⁰ C heated and held at this temperature for two hours. After cooling, a solution of 6 g Na ₂ SoO, - in 15 ml water is gradually added. It is then diluted with 50 ml of water. The residue is extracted with chloroform, the organic phase over MgSQ. dried, filtered and evaporated. The oily Büekstand obtained is solidified by adding petroleum ether and recrystallized from a mixture of ether and methanol. 1.95 S cLes of product with a melting point of 170.5 ° 0 are obtained in this way. The MNR spectrum confirms the Threo configuration.

909884/0818

-as -

C. , 05 H 12th N 30th 59 , 95 7, 15th 4, 10 58 7, 4-,

Element ar analysis

% calculated% found

Example 4

1- (4-Isopropylthiophenyl) ~ 2- £ 3- (carbomethoxy) propylaminoJ

-1-propanol (Table I, No. 13)

17 g of 2-bromo-1- (4-isopropylthiophenyl) -1-propanone, 200 ml of methanol, 17.3 ml of triethylamine and 10 g of the hydrochloride of W-methylaminobutyrate are refluxed for 17 hours. The solution is then cooled to a temperature of 5 ⁰ C and treated gradually with 4.5 g NaBH ^ _7. The reaction medium is then touched overnight at ambient temperature. After evaporation of the solvent in vacuo and dilution of the residue with water, extraction is carried out with chloroform. The chloroform solution is separated off, dried and filtered. The solvent is then removed by distillation in vacuo. Obtained in this manner 13.4 g of crude product which g after the preparation of the hydrochloride in a mixture of equal parts of diethyl ether and methanol 12.4 of product (yield 58%, mp 175.6 ⁰ C). The agreement with the structure was determined by mass spectrometry. The MNR spectrum confirms the erythro configuration.

Elemental analysis CHN

% calculated 56.41 7.79 3.87% found 56.10 7.65 3.75

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example 5

1- (4-isopropylthiophenyl) -2- [3- (carboxy) propylamino} -1- :. - propanol

(Table I, No. 23). .-. : ^

7 g of 1- (4-isopropylthiophenyl) -2- £ 3 ~ (methoxycarbonyl) propylaminoJ-1-propanol are dissolved in 70 ml of water, and 7 ml of concentrated hydrochloric acid are added to the solution. The mixture is heated for 1 hour at 80 ⁰ G. After cooling, the solvent is in vacuo; removed. The residue is crystallized from a mixture of methanol and ether. There, 4.5 g of the product (yield 68%) having a melting point of 197.5 ⁰ G.

Elemental analysis Example 6 calculated C. , 24 H , 53 ": N 03 '% found 55 , 35 7th , 50 4-, 80 % 55 7th 3,

1- (4-isopropylthiophenyl) -2- [i- (2-oxopyrrolidiryl) J-1-

propanol (Erythrö) (Table I, No. 24) -

There are 6 g / l-C4-Isopropylthiophenyl-2- £ 3- (carboxy) propylaminoJ-1-propanol in a mixture of 100 ml Dissolved methanol and 50 ml of water. The pH of this Mixture is brought to 13 by adding a 1On solution of NaOH. This is followed by 1 hour at ambient temperature stirred, the methanol evaporated, the solution with chloroform

■■ - "- ■ ./. 90988470816

-3ο -

extracted, the organic phase dried over MgSCk and the solvent evaporated. The product solidified in petroleum ether is recrystallized with ether. Is recovered 1.3 g of product (27% yield) having a melting point of 80 ⁰ C. The structure and the erythro configuration was determined by MNE- and mass spectrometry.

Elemental analysis CHN

% calculated 65.49 7.90 4.77 % found 65.15 7.70 4.75

Example 7

1- (4-isopropylthiophenyl) -1,2-propanediol (Table I, No. 18)

170 g of 1- (4-isopropylthiophenyl) -2-hydroxy-1-propanone are dissolved in 15ΟΟ ml of methanol. After cooling to 0 ^° C., 57.4 g of sodium borohydride are gradually added. The mixture is stirred at ambient temperature overnight. The solvent is then evaporated, diluted with water, extracted with chloroform and dried over MgSO ^. After the solvent has evaporated, it is recrystallized in a benzene-hexane mixture. 66.8 g (yield 39 %) of a product with a melting point of 83 to 85 ^° C. are obtained. The MNR spectrum confirms the erythro configuration of the product obtained.

Element aranalyse

C. , 68 H 01 calculated 63 , 50 8th, 05 found 63 8th,

909884 / 081S

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Example 8

1 - (4-Mercaptophenyl) -2-n-octylamino-1-propanol (Table I, No. 40)

A solution containing 16 g of 1- (4-isopropylthiophenyl) -2-n-octylamino-1-propanol in 500 ml of tetrahydrofuran is added successively to a solution containing 5-25 g of lithium in 1000 ml of liquid ammonia and 500 ml of tetrahydrofuran. After the addition, stirring is continued for about 15 minutes. Then 16 g of "NILCl" are added in small amounts. The ammonia is then slowly evaporated in a water bath. The residue is diluted with water. The solid obtained is filtered off and recrystallized in methanol. In this way 12 g of 1- (4-mercaptophenyl ) -2-n-octylamino-1-propanol (yield 82.1%, melting point 110 to 112 ⁰ O.

Elemental analysis G HN

% calculated 69.10 9.90 4.74% found 69.40 10.10 4.60

As already indicated above, the invention Derivatives are in the form of their salts or esters. Specific esters satisfy the following formulas;

CH ₃ .__ CH ₃

^ CH-SO - # VcH-CH-NHnC ₈ H _n . HCI

"I.

OC-CH ₂ -C (CH ₃ ) ₃

Melting point:. 112-114 ⁰ C

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Λ ^ ³

CHSO ^ \ CH-CH-NIInC ₈ II ₁₇ .HCl

^J 0-C-CH

i: Ü

Melting point: MU, 5 - IbO ⁰ G

The melting points of the derivatives dealt with in the examples are, as well as other derivatives made according to the invention, are in the following table specified.

Behind the melting points is the recrystallization solvent given in brackets. For the compounds listed in the table, the elemental analysis for the elements G-H and N performed. It always showed agreement with the theoretical values.

909684/0816

Table I.

CH

OO

Melting point C ⁰ CJ

1 2 3 4th to O 5 to co co 6th O OO

10

iso C ₃ H ₇ SO ₂

HS

IsOC ₃ H ₇ SO ₂

HS '.

iso C ₃ H ₇ SO ₂ iso C ₃ H ₇ SO ISoC ₃ H ₇ S

ISoCH ₇ SO ■ 0 7

ISoC ₃ H ₇ SO ₂ ,

OH
OH

NHnC ₈ H ₁₇ NHnC ₈ H ₁₇

25, 1-252! (MeOH-acetone) 75-78 (C ₆ H ₆ J ⁽²⁾ ■■■.

209-211 (MeOH ether)

68-69 petrolether), 167-169 (MeOH-lther 115-116 ,, (ether)

(5)

146-148 (acetone),.

■ j. ■■ 170.5 (MeOH ether)

(5)

107.2 (C ₆ H ₆ - petroleum ether)

Table I (continued)

No. CH R ₁ R ₉ O 11 3 ^pp 0 CH 12th ₃ S0 ₂

co
CD 13th TSoC ₃ H ₇ S CO
co 14th CH, S co 15th IsOC ₃ H ₇ SO 2 ' O
OO 16 ISoC ₃ H ₇ p D.
ω —Λ
o> 17th Is ₀ C ₃ H ₇ S 13th ISoC ₃ H ₇ p co 19th TSoC ₃ H ₇ SO %
m
σ 20th
21 TScC ₃ H ₇ SU ₂
ISoC ₃ H ₇ SO ₂ 22nd CH ₃ S 23 ISoC ₃ H ₇ p 24 ISoC ₃ H ₇ p

NH (CH _? ) .COOCH ₃ NH (CH ₀ ) COOCH ₀

NHj,

NHCH ₉ COOH

OH

OH

NHiCH ₉ ) ^ CUOCH,

NH (CH ₂ J ₂ COOH

NH (CH _{2) 3} C00h

NH (CHp) ₃ COOH

Melting point E ⁰ C J

121.2 (CHC1 ₃ petroleum ether)

158-159 (MeOH ether)

! 75.6 (HeOH) '" ^{0 (2)} 168-169 (MeOH) 390-191 (MeOH-acetone) 161-16 3 (MeOH-ether) 171 (MeOH-ether) ^ ¹ '

83-85
Oil ⁽²⁾

18 2.8 (MeUH ether) 190-192 (MeOH ether) 190.5-191 (MeOH)

19 7.5 (MeOH ether)

(3)

⁽²⁾

80 (ether)

(2)

CO IS *

-33 -

r-1 OJ ο > - • O (Ο -P X ■ a QJ
rc a ft CM H CM Φ Ö ι
- I O CM CQ

CM

CC

-P U O

(D it ι-Γ

OJ

OJ

OJ

OJ

• Ρ

ο ω ζ:

OJ

VD

r— {

CTl

LT)

U φ

CM cn

O CTi

Φ OJ

rc -

cd rc

ξ: ο

^ _- CU

(4 φ

CJ

in

«- <VO cr>

ι co

CM I 5 "

Ln Ln ο

t-f CO t- <

ο O 4-5 CU iCU *? * U -> CO crt CM τ — Ι 1 CM CTl

Γ rc rc ο σ ο ο σ CJ ο -. - CM

O = ο O

O O O CO

CM O LO

rc

οο ο ο

O CM co O rc CO ro ro CJ rc O CJ IA • r—

co ro

rc CJ

O, O co CO co Ln rc rc rc ro ro CM O CJ CJ O O (Λ to • r— "I.

O OO

rc

CM CJ

in

CM

co

CM

CTl CM

O I CM

co ro co

co ro

909884/0816

ORIGINAL INSPECTED

iDable I (continued)

No.

co

35 36

37

• 3 O j '

O co 4 0 2 OO 41 Q OO Z r- O 4 2 Z OO co TI «■ * 43 ΓΠ OO O 44 4 5 O 4 6 47

ISoC ₃ H ₇ SO

ISoC ₃ H ₇ SO

ISoC ₃ H ₇ SO

CH ₃ SO isoC, H-, SO

HS

ISoC ₃ H ₇ S ISoC ^ H ₇ SQ isoc 3H ₇ S ISoC ₃ H ₇ SO isoC., H ₇ SO ₀

is 0 C ο H., p. 1 /

NHnC ₁₄ H ₂₉

NH (CH

NH (CH _? ) ₃ C00CH ₃

CH-CH.

NHCH-nC _f H ₁₀ ! 6 13

NH (CH ₂ ) J-

NH (CH ₂ ) ₅ COOH

NH (CHo) ₅ COOH

NH (CH.

NH.

Melting point

143-146
167-168

143-144

(1) (2) (1) (2)

(1) (2)

169-170 (acetone). 139-141 (acetone). ^^

110-112 (MeOH)
199-? 01 (MeOH-ether) 160 (MeOH-ether) 175-177 (MpOH)
175 (MeOH-acetone O

16 Γ> -16 7 itOH ether) ^ 9 7-98 (Ither petroleum ether)

The compounds of the present invention, though low in toxicity, generally have an effect on the cardiovascular system, especially an antispasmodic, antihypertensive, peripheral vasodilatorxsche, Protects the heart muscles from a lack of oxygen, lowers blood lipids, normalizes lipids and lipoproteins and platelet agglination inhibitory effect. They can therefore be used in particular for the treatment of diseases of the cardiovascular system, regardless of whether these diseases are associated with arteriosclerosis related or not. They can also be used as a means of stimulating the cerebral metabolism or with a tranquilizing effect.

The effect on behavior was examined using a method different from the method of S-. Irwin (Gordon Res. Gonf. On Medicinal Chem., 133, "; ■ 1959). The substances in a 1% Mucilagium suspended by gum tragacanth were made administered by means of a gastric tube consisting of groups of five male mice each (strain CD1, Charles River, 18 hours sober). When the available amount of the substances allows, the doses were 3000, 1000 and 300 mg / kg. In the pail that the latter dose is active is, the effect of the drug with doses of 100, 30, 10 and possibly 3 mg / kg examined. The behavior is each Examined 2, 4, 6 and 24 hours after the administration. Observation continues when symptoms occur persisted. The mortality was recorded during 14 days after treatment see the lethal dose DL 50 would be based on the method of Litchfield and Wilcoxon (J. Hiarmacol. Exp. Ther., 96, 99, 1949) and in mg / kg expressed.

903334/0818

-B ^Q -

The results obtained with regard to the effect on behavior give the minimum effective dose (dose minimale active DMA) and the symptoms observed. The DL 50 is specified with its safety limits (limites de confiance ρ = 0.95). Considerable activity was observed under these conditions, particularly for compounds 6, 13 and 20 observed.

The antihypertensive effect was measured with oral administration in rats spontaneously placed under high pressure, not anesthetized, whose systolic arterial pressure at the level of the median coccygic artery was measured by means of a plethysmographic method (J. Roba, G. Lambelin, AF De Schaepdryver, Arch. Int Pharmacodyn, 200, 182, 1972). The arterial pressure was measured every 30 minutes for 2 hours before and 3 hours after the administration of 60 mg / kg of the tested product or a placebo (mucilagium with 1 % tragacanth gum). Only rats with a systolic pressure between 180 and 220 mm Hg were used. Two rats were used per product. The products were administered without the knowledge of the person performing the measurement. The antihypertensive effect is assessed using a point system, followed by an index. The point system is as follows.

0: reduction of less than 10 mm Hg

+: Reduction of 10 to 20 mm Hg

++: reduction of 20 to 30 mm Hg

+++: reduction of 30 to 50 mm Hg

++++: Reduction of more than 50 mm Hg

909884/0816

The index is calculated by taking the difference in systolic Pressure, which occurs in the measurements at an interval of 30 minutes after the treatment, with a coefficient is multiplied by 1 to 6, which corresponds to the times of 30 assigned to 180 minutes.

Under the test conditions, alpha-methyldopa is used in a Dose of 100 mg / kg with +++ (47), reserpine at one dose of 3 mg / kg with +++ (53) and guanethidine at a dose of 60 mg / kg with +++ (62). In the trials A significant antihypertensive effect was found especially for products 6 and 7.

The peripheral vasodilator effect of the invention Products was made at the level of the femoral artery anesthetized dog. For this purpose, the femoral artery is used to tie off its parallel arteries blood withdrawn from the aorta had been passed through at a constant front volume. The one in the amount of The perfusion pressure measured by the fermoral artery varies accordingly as a function of the area flowed through. The tested products and the corresponding solvents were at a dose of 30 / mg / kg directly into the circulation injected. If the flow of blood is kept constant, vasodilation manifests itself in a decrease of the perfusion pressure. This is with the effect of Papaverine, which is used as a reference product and injected once for a group of four products will. In cases of interest, the products were tested in other dosages under the same conditions. The vasadilatory effect was rated as follows:

909884/0816

O: no effect (reduction of less

than 10 mm Hg)

+ J 1/3 the effect of papaverine

++: 2/3 the effect of papaverine

+++: same effect as papaverine

++++: stronger effect than papaverine

Of the products according to the invention, in particular compounds 5, 6 and 20 have a peripheral vasodilator Effect shown which is as great as or even greater than that of papaverine.

The antispasmodic effect of the products according to the invention was tested on the basis of the contractions of the hay of the guinea pig caused by histamine and acetylcholine. These experiments make it possible to demonstrate the effect of the products as antihistamine, anticholinergic or musculotropic antispasmodic. The reaction to the contraction agent, which was used in an amount below the maximum dose, is repeated 5 minutes before and after the injection of increasing doses of the tested products (10 -4 M to 10 ^-4 M). The percentage of the prevention under the influence of the tested products and is determined graphically for each experiment, the theoretical concentration giving a 50% prevention These values are as -. log CIC ₀ (μ) ückt ^from S ^EDLL in this experiment, in particular the compounds have. 5 and 6 proven effective.

The anti-platelet agglination effect was investigated according to the method described by G. V. R. Born and M. J. Gross (J. Physiol, 168, 178-195, 1973).

908834/0816

A platelet-rich plasma is administered before the agglination-inducing agent (thrombofax) is introduced. pretreated for 4 minutes. The light ones Variations are recorded over a period of 10 minutes using an "Upchurch" agglination meter. It becomes the inhibition of the amplitudes of the maximal agglination measured. The tests have shown that compounds 5-6, 13 and 14 in particular have such an effect.

To investigate an effect that prevents lipolysis: epididymal fat is taken from empty hats. Fractions of the adipose tissue (+ - 150 mg) are placed in a Krebs-Ringer tampon, which contains 3 % albumins from bovine serum and the substance to be examined. After an incubation period of 30 minutes bsi 37 ⁰ C, an initial sample is taken. Norepinephrine is used to initiate lipolysis. The content of free amino acids is measured 20 minutes after the incubation (W. G * Duncombe, Clin. Chim. Acta, 8, 122, 1964 ·). In this test, the connections 5 »- 6» and 13 in particular have proven to be effective.

To study the inhibition of the biosynthesis of cholesterol a homogenized, unbuffered product from rat liver was enriched with suitable cofactors.

Equal proportions of this product are made 60 minutes ago

14th

the further processing with 1- C-acetate and the to be examined Connection. After the preparation has been saponified, the sterols are extracted with petroleum ether and the dry residue is precipitated in an alcohol-acetone solution using digitonin. The content of

C in the precipitate dissolved in pyridine is through

a scintillation count based on that of N. Bucher

909834/0816

method described (J. Biol. Chem. 222, 1-15, 1956). Under these conditions, compounds 1, 13 and 15 in particular have shown considerable activity.

It was investigated to what extent the derivatives according to the invention the capture of bioamines by synaptosomes inhibit. For this purpose, the synaptosomes of rat brains were subjected to partial cell disruption in a sucrose gradient isolated (E. G. Gray and V. P. Whittaker, J. Anat., 92, 79, 1962). Capturing 5-HT (Serotonin) takes place in the following way:

Synaptosomes are left on the compound to be tested

Leave on for 5 minutes. The preparation is then 5 minutes

ο 14

incubated at 37 C in the presence of C-5HT and then filtered using a "Millipore" filter. The filters are washed with iced buffer solution. The radioactivity of the filters is determined by means of a scintillation count. The success depends on the difference between the measured at 37 ° C and at 0 ⁰ C radioactivity. In this test, compounds 5, 6, 13 and 14- have proven to be particularly effective.

The active substances of the invention can be administered in conjunction with various pharmaceutical carriers oral, parenteral or rectal routes. For oral administration, coated tablets, Granules, tablets, capsules, compacts and capsules with controlled release of the active ingredients, sublingual tablets, Solutions, syrups and emulsions can be used which are those known in galenic pharmacy Contain additives and carriers. For the

903834/0816

2827789

parenteral administration is sterile water or an oil used, such as peanut oil or ethyl oleate. For rectal administration, suppositories or Rectal capsules used.

The active compounds can be used alone or in combination used with other active products that have the same or different effects.

The products according to the invention can be in different Shapes are used. The following examples do not represent any restriction and relate to pharmaceutical formulations, as the active ingredient, hereinafter referred to by the The letter A denotes contain any of the following substances:

1- (4-Isopropylsulfinylphenyl) -2 £ i- (2-oxopyrrolidinyl) J-1-

propanol 1- (4-isopropylsulfinylphenyl) -2-n-octylamino-i-propanol

Intramuscular injection

Isopropyl myristate Peanut oil qs. ad.

Intravenous injection

L-aspartic acid benzyl alcohol aqua dest. qs. ad.

10 , 75 mg 0 ml 3 ml

10 mg 6th mg 50 .mg 5 ml

909884 / 08Ί6

Oral solution

Ethyl alcohol propylene glycol acetic acid 10 %

Simple syrup (sucrose 65%) qs. ad.

Ethyl alcohol acetic acid 10% simple syrup qs. ad.

Tablets

Lactose

Aerosil

Starch STA-RX 15OO Calcium Phosphate (CaHPO ₄ ) Microcrystalline Cellulose Sodium Acetate

Corn starch sodium acetate magnesium stearate Aerosil

Strength STA-RX 15OO

5 mg 0.1 ml 0.05 ml 0.05 ml 1 ml 5 mg 0.2 ml 0.04 ml 1 ml

50 mg 20th mg 2 mg 18th mg 25th mg 100 mg 15th mg 50 mg 50 mg 15th mg 2 mg 3 mg 80 mg

909884/0816

Sublinffualtabletten

A ■. . ■ Lactose Soluble Starch Saccharin gelatin

Lactose sucrose glycine stearic acid

Capsules

Strong STA-SX 1500 magnesium stearate Sodium Lauryl Sulphate Microcrystalline Cellulose Aerosil

Soft capsules

Liquid paraffin soy lecithin

25th mg 117.75 mg 10 mg 0.25 mg 3 mg 25th mg 150 mg 25th mg 2.5 mg 0.5. mg

50 mg 100 mg 1 mg 10 "- - mg 30th mg 1 mg

200 _: mg 222 mg 8th mg

909884/0818

50 mg 45 mg 15th mg 5 mg 1 mg

Capsules with a depot effect

Lactose Polyvinylpyrrolidone Mannitol Eudragit E

Suppositories

Lidocaine Novata 299 degrees.

Witepsol S 58 degrees.

The meanings of certain terms that have been used in the above pharmaceutical formulations are given below explained:

- Aerosil (TM): Commercial name for silicon

high fineness dyoxid

- Starch STA-RX 15OO (Vz): corn starch

- Lidocaine: Commercial name for lignocaine

100 mg 20th mg 2000 mg 100 mg 2000 mg

809884/0816

- Novata 299 degrees (watermark):

Mixture of the triglycerides of saturated fatty acids with 11 to 1? "G and partial glycerides of acetylated fatty acids

- Novata B grad. (Watermark):

Mixture of tri-, di- and monoglycerides of saturated fatty acids from 11 to 17 C.

Witepsol S 58 grad. (WM): Mixture of natural tri

glyceride with 12 to 18 G

Eudragit E (TM) Röhm: polymer of acrylic acid

Dimethylaminoethyl ester

Depending on the "particular case, the type of administration, the type of effect desired and the particular compound used are those according to the invention 1-phenyl-1-propanol derivatives in daily doses of 50 to 300 mg administered. If injected intravenously, these Derivatives given in daily doses of 1 to 20 mg.

909884/0816

ORIGINAL INSPECTED

Claims (30)

Patent entitlements S ^. Hydrogen, a linear or branched alkylthio radical with 1 to 3 G »a linear or branched one Alkylsulfinyl radical with 1 to 3 G, a linear or branched one Alkylsulfonyl radical with T up to 3 G or a mercapto radical and Rp denotes the hydroxyl group, an oxo-2-iyrrolidinyl-i-group optionally substituted by a hydroxyl group, or an NHB ~ group, in which R, in turn, is either hydrogen or, if E ^ is not an alkylthio radical, a linear one or branched alkyl radical with 6 to 16 G or a linear alkyl radical with 2 to 4 G substituted by a phenyl or phenoxy radical, or a linear alkyl radical with Λ to 3 G substituted in the CP position by a carboxyl · ^ or carbalkoxyl radical or branched alkyl radical with 1 to 7 C, as well as its non-toxic and pharmaceutically acceptable salts and esters. 2. derivative according to claim 1, characterized in that E, a linear or branched alkyl radical with 10 to 12 G is. 3 · derivative according to claim 1, characterized in that R ₇ T is a linear or branched alkyl radical with 6 to 10 C. 909884/0816 _ O 4. A derivative according to claim 3, characterized in that R ₇ T is a linear or branched octyl radical. 5- derivative according to claim 1, characterized in that R ₇ . is a linear or branched alkyl radical having 1 to 3 C which is substituted in the ^ -position by a carboxyl or carbomethoxy radical. 6. derivative according to one of claims 1 to 5, characterized in that that fi, a linear or branched alkylthio radical with 1 to 3 C is. 7 · Derivative according to one of Claims 1 to 5 _5, characterized in that R. is a linear or branched alkylsulfinyl radical with 1 to 3 G. 8. derivative according to any one of the preceding claims, characterized indicated that it is one of the following compounds: 1- (4-Isopropylsulfinylphenyl) -2-n-octylamino-1-propanol 1- (4-isopropylthiophenyl) -2- ^ 3- (methoxycarbonyl) propylamino} -1-propanol
1- (4-Isopropylthiophenyl) -2-i3- (carboxy) propylamineql -1- propanol
1- (4-methylthiophenyl) -2- [3- (methoxycarbonyl) propylaminol -1-propanol 1-C4-methylthiophenyl) -2- (3- (carboxy) propylaminoj -1-propanol 1- (A-isopropylsulfinylphenyl) -2- (3- (methoxycarbonylpropyl- amino J -1-propanol
1 - (4-Isopropylsulfynylphenyl) -2- JJ? - C carboxy) propylamine -1 - propane oil 1- (4-Isopropylsulfinylph-eiiyl) -2H- (2-oxopyrrolidinylI-1-propanol i-C ^ -Mercaptophenyl ^ -n-octylamino-i-propane oil 909884/0816 Λ Λ S ⁰ Ti ^ l FJ 9 · derivative according to one of the preceding claims, characterized marked that it is in relation to the "two < asymmetric carbon atoms of the propano! chain Has erythro configuration. 10. Process for the preparation of 1-phenyl-propano! Derivatives, according to one of the preceding claims, characterized in that a compound of the general formula (II), in the Z either one of the above-defined substitutes R- or a group YS in which X is one through hydrogen replaceable protecting group, while Q is a of the following groups -CG-GO-CH,; -CO-CHOH-CH ₅ ξ -CO-CH-X;
'4η,
2 -CH-CH-CH ₅ ; -CO-CH-NHR ₅ j
CH ₅ -GHOH-CH-X
ί -CHOH-CH-R ₅
1 ■ 2. - is, in which Rp and R, the meanings given above and X represents a halogen atom into a compound the general form (I) is implemented. OS884 / 0816 11. The method according to claim 10, characterized in that that for the preparation of derivatives according to the general formula (I) »in which ß £ is the hydroxyl group, Ketones according to the general formulas R. - ν / -CO-CO-CH, (III) and -CO-CHOH-CH _x (IV) 2 in which R. has the meaning given above, reduced will. 12. The method according to claim 11, characterized in that the ketones are used to reduce the action of metal hydrides or complex hydrides in an aromatic solvent, an ether or alcohol, the action of alkali metals such as sodium or lithium in a solvent such as ammonia or ethanol, the action of hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium in a solvent such as Ethanol or the action of an aluminum alcoholate such as aluminum isopropylate in a solvent such as Exposing to isopropanol. 13. The method according to any one of claims 10 to 12, characterized in that one has the erythro or threo configuration owning proportions of the derivatives obtained, in particular by distillation or thin-layer or Column chromatography separates from one another. $ 909884/081 14. The method according to claim 11, characterized in that for the preparation of derivatives according to the general Forii ^ l (I), in which R ^ an optionally replaced by a Oxo-2-p5rrolidinyl-1 radical substituted by hydroxyl group is, a compound according to the general formula (II), in which Q denotes the radical -CH-CH-CH *, with 2-PjIToIidinon condensed, either without a solvent, optionally using an excess of 2-fyrrolidinone, or in the presence of a solvent like methanol or ethanol. 15. The method according to claim 11, characterized in that to prepare derivatives of the general formula (I) in which Rp is optionally replaced by a Oxo-2-pyrrolidinyl-i radical substituted by hydroxide group is a compound of the general formula -CHOH-CH-NH (CHo) ^ COOR ₁ - CH, * ^{? p} ' in the R ,. has the meaning given above and R ₁ - represents an alkyl radical, in particular a lower alkyl radical having 1 to 3C, hydrolyzed in a basic medium. 16. The method according to claim 15? characterized in that one the compound to hydrolyze the action of an organic or inorganic base, for example a Alcoholate or sodium or potassium hydroxide, in an alcoholic, optionally water-containing solvent such as methanol, ethanol or isopropanol at a temperature between the ambient temperature and the reflux temperature of the selected Solvent is, preferably at ambient temperature, 9 098 84/0 81 β 17 · The method according to claim 10, characterized in that one for the preparation of derivatives according to the general formula fr), in which R2 is an NHR, group, in the IU means an alkyl radical in the <£> Position is substituted by the carboxyl or carbomethoxy group, a compound according to the general formula (II) in which Q denotes the best -GO-CH-X with a OJ -aminoalkanoic acid or the ester of such an acid is condensed and then the reaction product is reduced. 18. The method according to claim 171, characterized in that the condensation in a solvent such as methanol, ethanol, chloroform, acetonitrile, benzene or a Mixing of these solvents and preferably carried out at ambient temperature. 19 · The method according to claim 17 »characterized in that the reduction by means of alkali metal hydrides, in particular by means of NaKL ,, in a solvent such as methanol or ethanol at ambient temperature. 20. The method according to claim 10, characterized in that for the preparation of derivatives according to the general FornßLÜ), ia which Ro is an HHR, group, from one Compound according to the general formula R ₁ ■ / _}) or, depending on the meaning of Q, possibly also starting from a salt of a compound according to the general formula (V), in which R ^ the above 909884/0818 interpretation has "and Q is one of the Eeste ₅ -COCH-NHR ₅ -CHOHCH-X -COCH-X CHt; CH _x CH-2 represents, in which Ε »has the meaning given above and X represents a halogen atom. 21. The method according to claim 20, characterized in that for the preparation of compounds according to the general formula (I) with erythro configuration, an eC-aminoketone according to the general formula (V), in which Q is the radical -CO-CH- NHR ₅ means and R ^ the above has given meaning. 22. The method according to claim 21, characterized in that the reduction by the action of iron alkali metal hydrides such as sodium borohydride in a solvent such as methanol or ethanol, preferably at low temperatures, or from lithium aluminum hydride in a solvent such as diethyl ether or hydrofuran, or by the action of an aluminum alcoholate, such as aluminum isopropylate, in a solvent such as isopropanol, preferential prices under reflux of the solvent, or by hydrogenation in the presence of a catalyst such as palladium on charcoal, Raney nickel or platinum oxide in a solvent such as methanol, ethanol or dioxane. 909884/0816 23 · Method according to claim 20, characterized in that an aminoketone is used to prepare compounds of the general formula (I) with a threo configuration of the general formula (V), in which Q -CO-CH-NR ^ E means, preferably by the action of Alkali metal hydrides such as sodium borohydride or lithium aluminum hydride. 24-. Method according to claim 20, characterized in that a compound according to the general formula (V), in which Q is the radical CHOH-CH-X, with an amine I. reacts, preferably in a solvent such as an alcohol, chloroform, dioxane, carbon tetrachloride, and particularly easily in the presence of a hydrazinium halide-fixing product such as one inorganic; or organic base and an excess of amine. 25. The method according to claim 20, characterized in that an oxirane according to the general formula (V), in which Q is the radical -CH-CH-CH *, is reacted with an amine r, NH ₂ , preferably in one Solvents such as an alcohol, chloroform, dioxane, carbon tetrachloride, and particularly easily in the presence of a product which fixes the hydrazinium halide formed, such as an inorganic or organic base and an excess of amine. 909884 / 081S 26. The method according to claim. 10, characterized in that for the preparation of compounds of the general formula (I) in which R _{x is} the mercapto group, in a compound of the general formula (II) in which Z is the group YS, in particular Protective group Y formed by an alkyl group such as a linear or branched lower alkyl group is replaced by hydrogen by the action of alkali metals. "_; -. 27 · The method according to claim 10, characterized in that to prepare compounds of the general formula (I) in which R ,, is an alkylsulfinil or alkylsulfinol radical is, a compound according to the general formula (II) in which Z is an alkylthio radical, a Exposing the oxidizing agent after groups that may be sensitive to the oxidizing agent used the compound have been protected, for example by the formation of esters in the case of hydroxyl groups or of ketals in the case of ketone groups. 28. Pharmaceutical preparation, characterized in that it is a 1-phenyl-i-propanol derivative as the active ingredient according to one of claims 1 to 9 in connection with a carrier substance and / or optionally in connection with Contains at least one further therapeutic agent. 29.A pharmaceutical preparation containing an antihypertensive, peripheral vasodilator, fight reliever, the cardiac muscle protective against oxygen deficiency. Normalizing lipids and lipoproteins, counteracting thrombosis, platelet agglomeration inhibitory effect has, characterized in that it is an active component 909 834/08 1 6 partly a 1-phenyl-i-propanol derivative according to one of the claims 1 to 9 in connection with a carrier substance and / or optionally in conjunction with at least one further therapeutic active ingredient. 30. Use of a derivative according to one of claims 1 to 10 or a pharmaceutical preparation according to claim 28 or 29, characterized by administration of the 1-pheny 1-1-propane-1 derivatives with a daily dose of 5 to 300 mg as well, in the case of an intravenous injection or infusion, with daily doses of 1 to 20 mg. 909884/0818