NO157895B - ANALOGUE PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE BENZOCSAZOL DERIVATIVES. - Google Patents

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL Benzoxazoles of general formula see diagramm : EP0034743,P9,F2 in which R1 represents a hydrogen atom ; a straight or branched alkyl group with 1 to 7 carbon atoms which can be substituted by an alkoxy group with 1 to 3 carbon atoms ; a cycloalkyl group with 3 to 7 carbon atoms ; an alkyl group with 1 to 3 carbon atoms substituted by a phenyl group which can be substituted by one or two alkoxy groups with 1 to 3 carbon atoms ; or a phenyl group which can be substituted by an alkyl or alkoxy group each with 1 to 3 carbon atoms, by a trifluormethyl, nitro or cyano group or by a fluorine, chlorine or bromine atom ; and in addition one of the mono-substituted phenyl groups mentioned above can be substituted by one or two alkyl groups with 1 to 3 carbon atoms or by an alkoxy group with 1 to 3 carbon atoms or by a fluorine, chlorine or bromine atom ; and R2 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms ; and their optically active antipodes as well as their physiologically compatible acid addition salts with inorganic or organic acids. 1. Claims for the Contracting State : AT Process for producing benzoxazoles of general formula see diagramm : EP0034743,P10,F4 in which R1 represents a hydrogen atom ; a straight or branched alkyl group with 1 to 7 carbon atoms which can be substituted by an alkoxy group with 1 to 3 carbon atoms ; a cycloalkyl group with 3 to 7 carbon atoms ; an alkyl group with 1 to 3 carbon atoms substituted by a phenyl group which can be substituted by one or two alkoxy groups with 1 to 3 carbon atoms ; or a phenyl group which can be substituted by an alkyl or alkoxy group each with 1 to 3 carbon atoms, by a trifluormethyl, nitro or cyano group or by a fluorine, chlorine or bromine atom ; and additionally one of the mono-substituted phenyl groups mentioned above can be substituted by one or two alkyl groups with 1 to 3 carbon atoms or by an alkoxy group with 1 to 3 carbon atoms or by a fluorine, chlorine or bromine atom ; and R2 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms ; and their optically active antipodes as well as their physiologically compatible acid addition salts with inorganic or organic acids characterised in that see diagramm : EP0034743,P11,F1 in which R1 and R2 are as defined in the introduction, X represents a mercapto, alkylmercapto, arylmercapto or aralkylmercapto group, and Y represents a hydrogen atom or an acyl radical, is cyclised ; or b) a carboxylic acid of general formula see diagramm : EP0034743,P11,F3 in which R1 and R2 are as defined in the introduction, or its amides, esters, thioester or halides, is reacted with hydrazine ; and if desired a compound of general formula I, in which R1 represents a hydrogen atom, obtained according to processes a) or b) is subsequently converted by means of alkylation into a corresponding compound of general formula I, in which R1 is defined as in the introduction with the exception of the hydrogen atom and the phenyl radicals mentioned in the introduction, and/or a racemate obtained, of general formula I, is separated by means of racemate separation into its optically active antipodes, and/or a compound obtained, of general formula I, is converted into its physiologically compatible acid addition salts with inorganic or organic acids.

Description

This invention relates to the preparation of new benzoxazole derivatives with the general formula

where

Ri means a hydrogen atom; a linear or branched alkyl group

with 1-7 carbon atoms which may be substituted with an alkoxy

group with 1-3 carbon atoms; a cycloalkyl group with 3-7

carbon atoms; an alkyl group of 1-3 carbon atoms substituted by a phenyl group which may be substituted with one or two alkoxy groups of 1-3 carbon atoms; or a phenyl group which may be substituted with an alkyl or alkoxy group each having 1-3 carbon atoms, with a trifluoromethyl, nitro or cyano group or with a fluorine, chlorine or bromine atom and furthermore one of the above mono-substituted phenyl groups may be substituted with one or two alkyl groups with 1-3 carbon atoms or with an alkoxy group with 1-3 carbon atoms or with a fluorine-, chlorine-

or bromine atom;

and their optically active antipodes as well as their physiologically acceptable acid addition salts with inorganic or organic acids.

The new compounds exhibit valuable pharmacological properties

properties, particularly cardiovascular effects, namely cardio-

tonic, blood pressure lowering and/or antithrombotic.

Particularly preferred compounds of the general formula

I are those where Ri means a hydrogen atom or a cyclohexyl group,

an alkyl group with 1 to 5 carbon atoms or a phenyl group optionally substituted with 1 or 2 methoxy groups, especially 4-methoxyphenyl, and their physiologically compatible acid addition

salts.

According to the invention, the new compounds are produced

with the general formula I by the following methods:

a) Ring closure of a possibly in the reaction mixture prepared compound with the general formula

where

Ri is, as indicated at the outset,

X means a mercapto, alkyl mercapto, aryl mercapto or aralkyl mercapto group, and

Y is a hydrogen atom or an acyl group.

For Y as an acyl group, e.g. in consideration of an acetyl, propionyl, benzoyl or p-toluenesulfonyl group, and for X e.g. in consideration a mercapto, methyl mercapto, ethyl mercapto, propyl mercapto, benzyl mercapto or phenyl mercapto group.

The reaction is conveniently carried out in a solvent such as tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide, dimethylethylene glycol or sulfolane, optionally in the presence of a condensation agent such as N,N'-dicyclohexylcarbodiimide, carbonyldiimidazole, p-toluenesulfonic acid, phosphorus oxychloride, thionyl chloride, hydrochloric acid, sulfuric acid , phosphoric acid or polyphosphoric acid at temperatures between 25 and 300°C, preferably at the boiling temperature of the reaction mixture, e.g. at temperatures between 50 and 285°C. However, the turnover can also be carried out in melt.

b) Reaction of a carboxylic acid with the general formula

where

Ri is, as indicated at the outset,

or its esters, thioesters, amides or halides, with hydrazine.

The reaction is conveniently carried out in a solvent

such as methanol, ethanol, isopropanol, glacial acetic acid, propionic acid and/or in an excess of hydrazine or hydrazine hydrate at temperatures between 0 and 200°C, e.g. at temperatures between 20 and 150°C, preferably at the boiling temperature of the reaction mixture, and optionally in the presence of an acid as condensing agent, such as sulfuric acid or p-toluenesulfonic acid. The reaction can also be carried out without a solvent.

A compound of the general formula I where Ri is hydrogen can optionally be subjected to alkylation so that a compound of formula I is formed where Ri has the meanings given at the outset with the exception of hydrogen and the aforementioned phenyl residues.

The alkylation is carried out with a suitable alkylating agent such as a phenylalkyl halide, alkyl halide, dialkyl sulfate or trialkyloxonium tetrafluoroborate, e.g. with benzyl chloride, phenylethyl bromide, methyl iodide, dimethyl sulfate, diethyl sulfate or ethyl bromide, suitably in a solvent such as methanol, ethanol, methanol/water, dimethylformamide or dioxane, optionally in the presence of a base such as sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methylate or potassium carbonate at temperatures up to the boiling temperature of the solvent used.

They thus obtained compounds of the general formula

Due to its optically active carbon atom in the 5-position of the pyridazinone ring, I can be separated into its optically active antipodes by racemate resolution. The racemate separation is conveniently carried out by fractional crystallization of the appropriate salts with optically active acids such as tartaric acid, dibenzoyltartaric acid, malic acid, camphoric acid or camphorsulfonic acid, or by chromatography on optically active adsorbents.

Furthermore, the obtained compounds of the general formula I can be transferred to their physiologically compatible salts with inorganic or organic acids. As acids, e.g.

hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid are used.

The compounds with the general formulas II and III used as starting materials are obtained by methods known from the literature. Thus, you get e.g. a compound of the general formula II by reaction of a suitable 3-(nitro-hydroxybenzoyl)-butyric acid ester with hydrazine, subsequent reduction of the nitro group and subsequent reaction of the compound thus obtained with a suitable carboxylic acid derivative.

A compound with the general formula III is obtained by reacting a compound with the general formula

with malonic acid ester. The compound thus obtained is then saponified, decarboxylated, nitrated, the chlorine atom is replaced by a hydroxy or mercapto group, the nitro group is reduced, and the compound thus obtained, after reaction with a suitable carboxylic acid derivative, is ring-closed to the desired benzoxazole.

The new compounds of general formula I and their optically active antipodes and their physiologically compatible acid addition salts with inorganic or organic acids exhibit, as mentioned at the outset, valuable pharmacological properties, in particular cardiovascular properties, namely a cardiotonic, blood pressure-lowering and/or antithrombotic effect.

As examples were the compounds

A = 5-methyl-6-[2'-ethylamino-benzoxazol-5'-yl]-4,5-dihydro-3(2H)pyridazinone,

B = 5-methyl-6-[2'-cyclohexylamino-benzoxazol-5'-yl]-4,5-dihydro-3(2H)pyridazinone,

C = 5-methyl-6-[2'-n-butylamino-benzoxazol-5'-yl]-4,5-dihydro-3(2H)pyridazinone,

D = 5-methyl-6-[2'-(4-methoxyphenylamino)-benzoxazol-5'-yl]-4,5-dihydro-3(2H)pyridazinone,

examined for its biological properties as follows:

1• Determination of platelet aggregation according to Born and Cross (J. Physiol. 170, 397 (1964)): Platelet aggregation was examined in platelet-rich plasma from healthy subjects. Below was the course of the reduction of the optical density after the addition of commercially available collagen from the company Sigma, St. Louis, USA, which contained 1 ing of collagen fibrils per ml, measured photometrically and recorded. On the basis of the bending angle of the density curve, the agglomeration velocity (Vmax) was calculated. The point on the curve where the greatest light transmission occurred was used to calculate the optical density (O.D.). For maximum clumping release, set approx. 0.01 ml of the collagen solution to 1 ml of platelet-rich plasma. The following table contains the values found: 2. Determination of blood pressure-lowering and positive inotropic effect on anesthetized cats: The investigations were carried out on cats that were anesthetized with pentobarbital sodium (40 mg/kg i.p.). The animals breathed spontaneously. The arterial blood pressure was measured in the abdominal aorta with a Statham pressure transducer (P 23 Dc). To find the positive inotropic effect, the pressure in the left ventricle was measured with a catheter tip manometer (Milliar PC-350-A). On this

basis, the contractility parameter dp/dtmax was determined using an analogue differentiator.

The test compounds were injected into a femoral vein. A physiological saline solution or polydiol 200 served as a solvent. Each compound was examined in at least 3

cats, dose 0.1 or 2.0 mg/kg i.v. The duration of action of the test compounds is in each case at least 45 minutes.

In this determination, the following compounds A', B", C and D' were used as comparison compounds, which are described in Norwegian explanatory document 142.402 (see page 5, compounds A-D): A' = 2-methyl-5(6)-(3 -oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole hydrochloride,

B' = 2-methyl-5(6)-(3-oxo-2H-6-pyridazinyl)-benzimidazole hydrochloride,

C = 2-(2,4-dimethoxy-phenyl)-5(6)-(3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole and

D' = 2-(2-fluorophenyl)-5(6)-(3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole hydrochloride.

The following table contains the mean values:

When comparing these data for the new compounds and the known comparison compounds respectively, it appears that the hitherto unknown compounds are superior to the known compounds with regard to blood pressure-lowering properties and, in the case of most compounds, also with regard to the cardiotonic properties.

Acute toxicity

The acute toxicity of the test compounds was determined for reference on white mice after oral administration of a single dose (observation time: 14 days):

Due to their pharmacological properties, the new compounds of the general formula I and their optically active antipodes and their physiologically compatible acid addition salts with inorganic or organic acids are suitable for the treatment of chronic heart failure or angina pectoris and/or for the prevention of arterial thromboembolism and arterial ti1occlusion diseases.

For these purposes, the new compounds, possibly in combination with other active substances, can be incorporated into the usual pharmaceutical application forms such as tablets, dragées, powders, suspensions, suppositories or ampoules. The single dose is here for adults 1-4 times a day for intravenous administration 10-50 mg, preferably 20-40 mg, and for oral administration 50-150 mg, preferably 75-100 mg.

The following examples shall further illustrate the invention.

A. Preparation of starting materials

Example I

N- ethyl- N'-[ 2- hydroxy- 5-( 5- methyl- 4, 5- dihydro- 3( 2H) pyridazinon-6- yl) phenyl] thiourea

10.8 g (50 mmol) of 2-amino-4-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)phenol are suspended in 250 ml of tetrahydrofuran, 25 ml (0.29 mol) ethyl isothiocyanate, and the mixture is heated for 3.5 hours with stirring to reflux temperature• A clear solution is thereby formed after a short time. After the end of the reaction time, the solvent is evaporated, and the yellow, oily residue crystallizes when ether is added. •The precipitated product is filtered off, washed with ether and dried at room temperature.

Yield: 13.0 g (91.5% of the theoretical)

Melting point: 137-139°C

C .H „N O-S (306.4)

Example II

2- ethylamino- 5-( 3- me, tyl- 4- oxo- butyric acid- 4- yl) benzoxazole

Dissolve 3.24 g (10.0 mmol) of N-ethyl-N'-[2-hydroxy-5-(3-methyl-4-oxo-butyric acid-4-yl)phenyl]thiourea in 150 ml of tetrahydrofuran, add 4 .17 g (20.0 mmol) of N,N'-dicyclohexylcarbodiimide and heated under reflux for 5 hours. After the reaction time has ended, the mixture is evaporated to half the volume, the mixture is briefly boiled again and cooled to crystallization. The product formed is filtered off, recrystallized from tetrahydrofuran and dried at room temperature.

Yield: 0.71 g (24.3% of the theoretical)

Melting point: 160-162°C.

B. Preparation of compounds of formula I

Example 1

5- methyl- 6-[ 2'- methylamino- benzoxazol- 5'- yl]- 4, 5- dihydro- 3( 2H)-pyridazinone

Dissolve 3.36 g (11.5 mmol) of N-methyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)phenyl]thiourea in 150 ml tetrahydrofuran, 3.13 g (15 mmol) of N,N'-dicyclohexylcarbodiimide are added and heated for 5 hours under reflux. After the reaction time has ended, the mixture is evaporated to half the volume, the mixture is boiled briefly again and cooled until crystallization. The product formed is filtered off with suction, recrystallized from methanol and dried at room temperature.

Yield: 0.84 g (28.3% of the theoretical),

Melting point: 241-242°C.

<C>13H14N4°2 (258'3)

Example 2

5- methyl- 6-[ 2'- n- butylamino- benzoxazol- 5'- yl]- 4, 5- dihydro-3( 2H)- pyridazinone

Prepared analogously to example 1 from N-n-butyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)phenyl]-thiourea.

Yield: 39.7% of the theoretical,

Melting point: 186-188°C

<C>16<H>20<N>4°2 (<3>0°'4)

Example 3

5- methyl- 6-[ 2'- isopropylamino- benzoxazol- 5'- yl]- 4, 5- dihydro-3( 2H) pyridazinone

Prepared analogously to example 1 from N-isopropyl-N'-.

[2-Hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)phenyl]-thiourea.

Yield: 52% of the theoretical,

Melting point: 239-241°C.

ci*HiRN4°9 (286.34)

Example 4

5- methyl- 6-[ 2'- cyclohexylamino- benzoxazol- 5'- yl]- 4, 5- dihydro-3 ( 2H) pyridazinone

Prepared analogously to example 1 from N-cyclohexyl-N<1->

[2-Hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)-phenyl]thiourea.

Yield: 59.1% of the theoretical,

Melting point: 235-237°C

<C>18H22N4°2 (326'4)

■ Example 5

5- methyl- 6-[ 2'-( 3, 4- dimethoxyphenethylamino) benzoxazol- 5'- yl]-4, 5- dihydro- 3( 2H) pyridazinone

Prepared analogously to example 1 from N-3,4-dimethoxy-phenethyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)phenyl]thiourea .

Yield: 48.2% of the theoretical,

Melting point: 70-72°C.

<C>22<H>24<N>4°4 x HC1 (444'93>

Example 6

5- methyl- 6-[ 2'- phenylamino- benzoxazol- 5'- yl]- 4, 5- dihydro- 3( 2H)-pyridazinone

Add 5 ml of hydrazine hydrate (99% strength) in portions

20 ml glacial acetic acid at approx. 20°C with stirring and ice cooling. 6.5 g (20.0 mmol) of 2-phenylamino-5-(3-methyl-4-oxo-butyric acid-4-yl)benzoxazole are then added, and the suspension thus obtained is heated at reflux temperature. After a reaction time of 1 hour, the reaction mixture is cooled to room temperature, diluted with water, the precipitated product is filtered off with suction, washed with water and dried at 80°C.

Yield: 2.80 g (43.7% of the theoretical),

Melting point: 214-217°C

<C>18<H>16<N>4°2 <<3>20'34>

Example 7

5- methyl- 6-[ 2'-( 2- chloranilino)- benzoxazol- 5'- yl]- 4, 5- dihydro-3( 2h) pyridazinone

Prepared analogously to example 1 from N-2-chlorophenyl-N<1->

[2-Hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)-phenyl]thiourea.

Yield: 33.9% of the theoretical,

Melting point: 193-195°C

•<C>18<H>15N4°2C1 (354'8>

Example 8

5- methyl- 6-[ 2'-( 4- trifluoromethylphenylamino) benzoxazol- 5'- yl]-4, 5- dihydro- 3( 2H) pyridazinone

Prepared analogously to example 1 from N-4-trifluoromethyl-phenyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)-phenyl]thiourea.

Yield: 57.3% of the theoretical,

Melting point: 249-251°C,

<C>19<H>15<N>4°2F3 (388'36)

Example 9

5- methyl- 6-[ 2'-( 3, 4- dichlorophenylamino) benzoxazol- 5'- yl]- 4, 5-dihydro- 3( 2H) pyridazinone

Prepared analogously to example 1 from N-3,4-dichlorophenyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)-phenyl]-thiourea .

Yield: 73.5% of the theoretical,

Melting point: 253-256°C

<C>18H14N4°2C12 (389'3>

Example 10

5- methyl- 6-[ 2'-( 4- bromophenylamino)- benzoxazol- 5'- yl]- 4, 5-dihydro- 3( 2H) pyridazinone

Prepared analogously to example 1 from N-4-bromophenyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)-phenyl]thiourea.

Yield: 65.4% of the theoretical,

Melting point: 243-245°C.

'<C>18<H>15<N>4°2<Br> <390'27)

Example 11

5- methyl- 6-[ 2'-( 4- methoxyphenylamino) benzoxazol- 5'- yl)- 4, 5-dihydro- 3( 2H) pyridazinone

Prepared analogously to example 1 from N-4-methoxyphenyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)-phenyl]-thiourea.

Yield: 40.3% of the theoretical,

Melting point: 220-222°C.

<C>19<H>18<N>4°3 (<3>50'4)

Example 12

5- methyl- 6-[ 2'-( 2- methoxy- 4- nitrophenylamino) benzoxazol- 5'- yl]-4, 5- dihydro- 3( 2H)- pyridazinone

Prepared analogously to example 1 from N-2-methoxy-4-nitro-phenyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)- phenyl]thiourea.

Yield: 65.6% of the theoretical,

Melting point: 223-225°C.

<C>19<H>17<N>5°5 (<3>95'4)

Example 13

5- methyl- 6-[ 2'-( 4- methylphenylamino)- benzoxazol- 5'- yl]- 4, 5-dihydro- 3( 2H) pyridazinone

Prepared analogously to example 1 from N-4-methylphenyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)-phenyl]thiourea.

Yield: 52.1% of the theoretical,

Melting point: 273-275°C

<C>19H18N4°2 (334.39)

" Example 14

5- methyl-6-[2'-(2,4,6-trimethylphenylamino)benzoxazol-5'-yl]-4,5-dihydro-3(2H)pyridazinone

Prepared analogously to example 1 from N-2,4,6-trimethyl-phenyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)- phenyl]thiourea.

Yield: 76.4% of the theoretical,

Melting point: 225-228°C

C .H 2 2 N 0 (362.4)

Example 15

5- methyl- 6-[ 2'-( 4- cyanophenylamino) benzoxazol- 5'- yl]- 4, 5- dihydro- 3( 2H) pyridazinone

Prepared analogously to example 1 from N-4-cyanophenyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)-phenyl]thiourea.

Yield: 59.7% of the theoretical,

Melting point: 318-320°C

C1QH1C.N 0, (345.37)

• Example 16

5-methyl-6-[2'-n-pentylamino-benzoxazol-51-yl]-4,5-dihydro-3(2H)pyridazinone

Prepared analogously to example 1 from N-n-pentyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]thiourea.

Yield: 52.3% of the theoretical,

Melting point: 154-155°C.

<C>17<H>22<N>4°2 (<3>14'4)

Example 17

5- methyl- 6-[ 2'- ethylamino- benzoxazol-5'— yl1— 4, 5- dihydro- 3( 2H)-pyridazinone

Prepared analogously to example 1 from N-ethyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)phenyl]thiourea. Yield: 71.9% of the theoretical,

Melting point: 244-246°C.

<C>14<H>16<N>4°2 <<2>72'3>

Example 18

5- methyl- 6-[ 2'-( 3- methoxypropylamino) benzoxazol- 5'- yl]- 4, 5-dihydro- 3( 2H) pyridazinone

Prepared analogously to example 1 from N-3-methoxypropyl-N'-[2-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinon-6-yl)-phenyl]-thiourea .

Yield: 55.5% of the theoretical,

Melting point: 153 - 154°C

• Example 19

pyridazinone 5-methyl-6-f2'-amino-benzoxazol-5'-ylI- 4. 5- dihvdrn-^ 9Hi-

Prepared analogously to example 1 from N-[2-hydroxy-5-(S-methyl-4,5-dihydro-3(2H)pyridazinon-6-yl)phenyl,thiourea Yield: 42.1% of the theoretical, Melting point : 285-287°C.

Claims (1)

Analogous process for the preparation of therapeutically active benzoxazoles of the general formula wherein R 1 means a hydrogen atom; a linear or branched alkyl group of 1-7 carbon atoms which may be substituted with an alkoxy group of 1-3 carbon atoms; a cycloalkyl group of 3-7 carbon atoms; an alkyl group of 1-3 carbon atoms substituted by a phenyl group which may be substituted with one or two alkoxy groups of 1-3 carbon atoms; or a phenyl group which may be substituted with an alkyl or alkoxy group each having 1-3 carbon atoms, with a trifluoromethyl, nitro or cyano group or with a fluorine, chlorine or bromine atom and furthermore one of the above mono-substituted phenyl groups may be substituted with one or two alkyl groups of 1-3 carbon atoms or with an alkoxy group of 1-3 carbon atoms or with a fluorine, chlorine or bromine atom; and their optically active antipodes as well as their physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that a) a thiourea with the general formula where Ri is, as stated above, X means a mercapto, alkyl mercapto, aryl mercapto or aralkyl mercapto group, and Y means a hydrogen atom or an acyl radical, ring is closed; or b) a carboxylic acid of the general formula where Ri is as indicated above, or amides, esters, thioesters or halides thereof, are reacted with hydrazine; and optionally a compound of the general formula I prepared according to methods a) or b) is then transferred by alkylation to a corresponding compound of the general formula I where Ri is as indicated above with the exception of a hydrogen atom and the initially said phenyl residues, and/or an obtained racemate of the general formula I is split into its optically active antipodes by racemate resolution, and/or an obtained compound of the general formula I is transferred to its physiologically reliable acid addition salts with inorganic or organic acids.