CS241496B2 - Method of pyrimidine new fussed derivatives - Google Patents

Description

Depending on the substituents present, one of the tautomeric forms predominates, or alternatively, the two tautomeric forms form an equilibrium mixture in an amount detectable by spectroscopic methods. Geometric Z — E isomerism is possible between the individual tautomeric forms. The invention also encompasses the preparation of possible geometric isomers of the racemic or optically active forms of the compounds of formula I.

It is already known that 2-methyl-4-oxo-6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-9-carboxylic acid derivatives can be prepared by catalytic hydrogenation of the corresponding unsaturated compounds [J. Het. Chem. 13, (1976)].

The process according to the invention is characterized in that the compound of the formula II is used

where

R, R ^1, R ^Z, R ⁵ n are defined as above, is reacted with a compound of formula III

R 4_N = C = Y (III) where

R ⁴ and Y are as defined above and optionally the compound of formula I obtained is converted into another compound of formula I and / or is converted into a pharmaceutically acceptable salt or released from its salt and / or the optionally obtained racemate of formula I is separated into their optically active antipodes.

Surprisingly, it has been found that the methylene group of the compound of formula II which occupies the β position with respect to nitrogen atoms has active hydrogen atoms involved in electrophilic substitution reactions.

In the reaction according to the invention, the compound of the formula II is reacted without solvent or in the presence of an inert solvent with an isocyanate or isothiocyanate of the formula III. When working in the presence of a solvent, the primarily formed compound of formula (Ia) is formed

wherein R, R ¹ , R ² , R ³ , R ⁴ , Y and ⁿ are defined as above, from the reaction mixture and can be separated by filtration. If the compound of formula (Ia) is not formed from the mixture, it is concentrated under reduced pressure and the residue is recrystallized from a suitable solvent.

When working without a solvent, the reaction mixture can be recrystallized from a suitable solvent after the reaction is complete. The reaction is preferably carried out in the presence of a Lewis base at a temperature of 0 to 250 ° C. The reaction temperature depends on the starting materials.

1 to 3 moles of compound (III) is used per mole of compound (II).

In this specification, the term C _r to C ₄ alkyl means an alkyl group with straight or branched chain. The term substituted phenyl means that this group is substituted one or more times with a halogen atom, a C ₁ -C ₄ -alkyl or a C 1 -C ₄ -alkoxy group, which substituents may be the same or different. C 1 -C 4 alkoxy includes linear and branched alkoxy groups.

Heterocyclic compounds of formula (II) used as starting materials can be prepared by the methods described in Hungarian patents 156,119, 158,089, 162,384, 162,373, 166,577 and in Dutch patent application No. 7,212,286, while compounds of the general formula and the reagents used to make them are commercial products.

The compounds of formula (I) may, when the carboxyl group is to form alkali metal salts such as sodium or potassium salts, alkali metal salts such as calcium and magnesium salts, or organic amines (e.g. triethylamine).

In particular, the compounds of the formula I can be used as pharmaceutical intermediates. The compounds can be reacted with the aryldisonium salts and converted to the 9-position of the pyridoyl 1,2-apyrimidine substituted with a hydrazone group, which derivatives are the final products having a number of pharmaceutical effects, for example an antiallergic effect.

Several representatives of the compounds of formula (I) are PG-antagonists per se, additionally having an analgesic, antiarteriosclerotic, transquilizing or other effect.

When the compounds of formula (I) are used as pharmaceutical active substances, depending on the field of application, patients may be administered a dose of 1 to 1500 mg per die once daily or in divided doses.

The compounds of formula I may be formulated in dragees, tablets, suspensions, injections, capsules, powders, suppositories, or other forms, and disintegrants and carriers may be added.

The invention will be explained in more detail by the following examples, without being limited thereto.

Examples 1 to 4

To a solution of 0.05 mol of pyridoy 1,2-a] pyrimidine II in dichloromethane is added dropwise 0.055 mol of isocyanate at room temperature. The reaction mixture was heated at reflux for 10 hours and allowed to stand at room temperature for 2 days, after which time the solvent was distilled off. The residue was recrystallized from ethanol. The produced compounds, their physicochemical data and the corresponding starting products are listed in Table 1.

Examples 5 to 9

A mixture of 23.6 g of 3-ethoxycarbonyl-6-methyl-4-oxo-4-H-pyrido [1,2-a] pyrimidine and 0.1 mole of isocyanate was stirred at 40-50 degrees Celsius for 72 hours. The thick, viscous reaction mixture formed is suspended in 200 ml of ethanol, filtered and the residue is washed with ethanol. When the reaction is carried out using n-butyl isocyanate, the reaction is carried out at 80 to 100 degrees Celsius. The produced compounds of the formula I, their physicochemical data and the compounds of the formula III used are shown in Table 2.

Table 1

example C. starting material of formula II isocyanate product yield % melting point ° C 1 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine phenyliso- 3-ethoxycarbonyl-6-methylcyanate -9- (N-phenylaminocarbonyl) - -4-oxo-1,6,7,8-tetrahydro-4H-pyrido) 1,2-apyrimidine 46 200-: 201 2 3-Ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine chloro-3-ethoxycarbonyl-6-methyltyliso- -6-methyl 1-9- (chloroacetylaminocyanate nocarbonyl) -4-oxo-1,6,7,8- -tetrahydr o-4H-pyrido [1,2-a] pyrimidine 74 158—160 3 3-Ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine tosyliso- 3-ethoxycarbonyl-6-methylcyanate -9- (tosylaminocarbonyl) -4- -oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine 80 182—183 4 3-Aminocarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidine 6-methyl-9- (tosylaminocarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido-6-methyl-9- (tosylaminocarbonyl) cyanate 49 164

[1,2-a] pyrimidine continued Table 1 Elemental analysis calculated

example no. empirical formula c% H% N% 1 C ₁₉ H ₂₁ N ₃ O ₄ 64.21 5.95 11.83 63.95 5.81 11.65 2 C ₁₅ H ₁₈ N ₃ O _with C1 50.63 5.06 11.80 51.02 5.02 11.63 3 C20H23N3O6S 55.42 5.35 9.69 55.92 5.30 9.72 4 C26H27N5O8S2 51.90 4.52 11.64 52.28 4.48 11.51

2.1 mol of isocyanate is used per mole of starting material

Table 2

an example of an isocyanate product yield temperature empirical C. i% ^! mp ° C formula

5 n-butyl- isocyanate 3-ethoxycarbonyl-6-methyl-9 - [(n-butylamino) carbonyl] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine 35 152—155 C ^ HHq iNsO /, 6 phenyliso- cyanate 3-ethoxycarbonyl-6-methyl-9 - [(phenylamino) carbonyl] -4-ox 0-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine 74 198—200 CigHatNaU.j 7 4-chloro- phenyliso- cyanate 3-ethoxycarbonyl-6-methyl-9- - [(4-chlorophenylamino} carbonyl] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine 82 206—210 ^ 19 ^ 20 ^ 3 (44111 8 3-chloro- phenyliso- cyanate 3-ethoxycarbonyl-6-methyl-9 - [(3-chlorophenylamino) carbonyl] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine 78 194—198 D19H20N3U4Cl 9 ( 3,4-di- chlorine- phenyliso- cyanate 3-ethoxycarbonyl-6-methyl-9 - [(3,4-dichlorophenylamino) carbonyl] -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine 79 208—212 C ₁₉ H ₁₉ N ₃ O ₄ C1 ₂

continuation of Table 2

example no. C% elemental analysis calculated H% N% 5 60.90 7.47 12.52 60.25 7.41 12.40 6 no reduction melting point with the product of Example 20 7 58.50 5.13 10.78 58.10 5,07 10.59 8 58.50 5.13 10.78 58.21 5,05 10.61 9 53.80 4.48 9.90 53.28 4.40 9.78

Example 10

A mixture of 2.0 g of 3-aminocarbonyl-2,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine and 2.2 g of phenyl isocyanate is heated to 80 ° C. ° C and the resulting solution is stirred at 50-60 ° C. After cooling, the reaction mixture is treated with 30 ml of ether, the precipitated crystals are dissolved in ethanol and the solution is filtered, then the filtrate is placed in a refrigerator for crystallization, the precipitated crystals are filtered off and washed with ethanol. 1.4 g of 3-aminocarbonyl-9- (phenylaminocarbonyl) -2,6-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine are obtained. Mp 187-188 ° C.

Analysis for 0 ₁₈ Η ₂ οΝζ, 0 ₃ :

calculated:

% C, 63.51;% H, 5.92;% N, 16.46.

S, 63.49; H, 6.00; N, 16.26. Example 11

Dissolve 1.6 g of potassium hydroxide in 20 ml of ethanol. To the ethanolic potassium hydroxide solution is added an ethanolic solution of 3.6 g of 3-ethoxycarbonyl-9- (phenylaminocarbonyl) -6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] The reaction mixture was heated to boiling for 30 hours and after cooling the precipitated crystals were filtered off, washed with chloroform and dried to give 3.1 g of potassium-9- (phenylaminocarbonyl) -6-methyl-4-oxo-1,6, m.p. 7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylate, melting at 276-280 ° C with decomposition.

Analysis for C ₁₇ H ₁₆ N ₃ O ₄ K:

calculated:

% C, 55.88;% H, 4.41;% N, 11.50.

H, 4.50; N, 11.42. Example 12

3.1 g of potassium 9- (phenylaminocarbonyl) -6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylate was dissolved with heating in 250 ml of water. The pH of the solution is adjusted to 1 at 38-50 ° C (w / v% hydrochloric acid).

The crystals precipitated from the cooled mixture are filtered, washed with water and dried. It is obtained

2.2 g of crystals which are recrystallized from acetonitrile. 9- (Phenylaminocarbonyl) -3-carboxy-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine is obtained in a yield of 25%.

Analysis for C _{17 H! 7} N ₃ O _4:

calculated:

% C, 62.37;% H, 5.24;% N, 12.84.

H, 5.18; N, 12.45. Example 13

0.416 g of 3-ethoxycarbonyl-4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrimidine is dissolved in 4 ml of benzene and 0.24 g of phenyl isocyanate is added to this solution. The reaction mixture was allowed to stand for 5 days at room temperature, the precipitated crystals were filtered off and washed with benzene. 0.50 g (76.5%) of 3-ethoxycarbonyl-8- (N-phenylaminocarbonyl) -4-oxo-1,4,6,7-tetrathydropyrrolo [1,2-a] pyrimidine is obtained, which melts. at 240-241 ° C.

Analysis for C H _{L7) 7} N ₃ O _4:

calculated:

% H, 5.23%, 12.84% N, found:

% C, 62.51;% H, 5.15;% N, 12.90.

Example 14

0.66 g of an 80% oily suspension of sodium hydride is added to 50 ml of benzene, then a solution of 4.72 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro- 4H-pyrido [1,2-a] pyrimidine in 15 mL of benzene. After stirring for 30 minutes, a solution of 2.96 g of methyl isocyanate in 10 ml of benzene was added over 10 minutes at 25-35 ° C.

The reaction mixture was stirred for 2 hours. After addition of 80 ml of ether, the sodium salt of 3-ethoxycarbonyl-6-methyl-9- (methylaminothiocarbonyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine precipitates. in oily form. The solvent was decanted, the residue was triturated with ether and dried in a vacuum mixer. There was thus obtained 3-ethoxycarbonyl-6-methyl-9- (methylaminothiocarbonyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine as the sodium salt.

Example 15

To the sodium salt of 3-ethoxycarbonyl-6-methyl-9- (methylaminothiocarbonyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine, prepared according to Example 14, was added 15 ml of acetone, then 130 ml of water, and the pH of the solution obtained is adjusted to 3-4 with acetic acid. The precipitated crystals are filtered, washed with water, dried and recrystallized from ethanol to obtain 3.2 g (52%) of 3-ethO. 1-Carbonyl-6-methyl-9- (methylaminothiocarbonyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine, mp 199-200 ° C.

Analysis for C H _{J4 JG} N3O ₃ S:

calculated:

% C, 54.35;% H, 6.19;% N, 13.58.

H, 6.18; N, 13.72. Example 16

0.66 g of an 80% oily suspension of sodium hydride is added to 50 ml of benzene, then a solution of 4.72 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- is added dropwise. pyrido [1,2-a] pyrimidine in 15 ml benzene. After stirring for 30 minutes, a solution of 5.4 g of phenyl isothiocyanate in 10 ml of benzene is added over 10 minutes at 25 to 35 ° C. The reaction mixture was stirred for 2 hours. After addition of 80 ml of ether, 3-ethoxycarbonyl-6-methyl-9- (phenylaminothiocarbonyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyridoph 1,2-a] pyrimidine sodium formed. in oily form. The solvent is decanted, the residue is triturated with ether and dried in a vacuum desiccator. There was thus obtained 3-ethoxycarbonyl-6-methyl-9- (phenylaminothiocarbonyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine sodium salt.

Yield 6.1 g (76%).

Example 17

To the sodium salt of 3-ethoxycarbonyl-6-methyl-9- (phenylamino) thiocarbonyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine, prepared according to Example 16, 15 ml of acetone and 130 ml of water are added and the pH of the solution obtained is adjusted to 3-4 with acetic acid. The precipitated crystals are filtered, washed with water, dried and recrystallized from acetonitrile to give 3.2 g (52%) of 3-ethoxycarbonyl. 6-methyl-9- (phenylaminothiocarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine, m.p. 173 DEG-175 DEG C .;

Analysis for C ₁₉ H ₂ IN3: O ₃ S:

calculated:

% C, 61.44;% H, 5.70;% N, 11.31.

C, 61.75; H, 5.57; N, 11.40

The procedure is as in Examples 5 to 9, but the isocyanate used is 4-methoxyphenyl isocyanate. 3-Ethoxycarbonyl-9 - [(N-4-methoxyphenyl) aminocarbonyl] -6-methyl-4-OXG-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] was obtained. 183%, m.p. 183-184 ° C.

Analysis for C ₂₀ H ₂₃ N ₃ O ₅ :

calculated:

% C, 62.33;% H, 6.02;% N, 10.90.

% C, 62.45;% H, 6.00;% N, 10.85

The procedure is as in Examples 5-9, but starting from 3-methoxycarbonyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidine and phenyl isocyanate. 3-Methoxycarbonyl-9- (phenylaminocarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine is obtained, yield: 71%, m.p. 173-175 ° C.

Analysis for C ₁₇ Hi7N ₃ O ₄ :

calculated:

% C, 62.38;% H, 5.24;% N, 12.84.

% C, 62.47;% H, 5.21;% 12.79

However, the starting materials used were 3-methoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidine and phenylisocyanate. 3-Methoxycarbonyl-9- (phenylaminocarbonyl) -6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidine is obtained, yield: 74%, m.p. 200 ° C. Analysis for C ₁₈ H ₁₉ N ₃ O ₄ :

calculated:

% C, 63.33;% H, 5.61;% N, 12.31;

ΤΊ A1Ρ7ΡΤΊ Π *

% C, 63.21;% H, 5.70;% N, 12.32.

Example 21

The procedure was as in Examples 5-9, except that 3-ethoxycarbonyl-7-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidine and phenyl isocyanate were used as starting materials. to give 3-ethoxycarbonyl-9- (phenylaminocarbonyl) -7-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidine.

Yield 55 mp 216-217 ° C. Analysis for C 19 H 21 N 3 O 3: calculated:

% C, 64.21;% H, 5.95;% N, 11.83.

Found: C, 64.34; H, 5.88; N, 11.90

The procedure is analogous to Examples 11 and 12 except that 3-ethoxycarbonyl-9 - [(4-methoxyphenyl) aminocarbonyl] -6-methyl-4-oxo-1,6,7,8-tetrahydro- 4H-pyrido [1,2-a] pyrimidine, 44% yield.

Mp 201-202 ° C.

Analysis for C ₁₈ H ₁₉ N ₃ O ₅ : calculated:

% H, 5.36;% N, 11.67.

60.38% C, 5.19% H, 11.85% N. Example 23 mmol of 3-ethoxycarbonyl-6-methyl-9- (methylaminothiocarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H -pyrido [1,2- a] pyrimidine, 10 mmol of sodium acetate and 3 ml of methyl iodide are heated to boiling in ethanol for 30 minutes and the mixture is concentrated under reduced pressure. To the residue was added 10 mL of water and 60 mL of diethyl ether. After stirring for 20 minutes, the ether phase was separated and after drying and filtering over anhydrous sodium sulfate, the mixture was concentrated to opalescence and allowed to crystallize at -20 ° C.

The filtered crystals were recrystallized from ether. 3-Ethoxycarbonyl-6-methyl-9 - [(methylthiomethylamino) methylene] -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine is obtained in a yield of 65%, m.p. Mp 168-170 ° C.

Analysis for C ₁₅ H ₂₀ N ₃ O ₃ S:

calculated:

H, 6.21; N, 12.95. Found:

% H, 6.06;% N, 12.78.

Example 24 of Example 23, but starting from 3-ethoxycarbonyl-6-methyl-9- (ethylaminothiocarboinyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine to give 3-ethoxycarbonyl-6-methyl-9 - [(methylthioethylamino) methylene] -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidine in 53% yield. mp 119-121 ° C.

Analysis for C ₁ H ₂₂ N ₃ O ₃ S:

calculated:

% C, 57.12;% H, 6.89;% N, 12.49.

H, 7.01; N, 12.42. Example 25

The procedure is as described in Example 23, but starting from 3-ethoxycarbonyl-6-methyl-9- (phenylaminothiocarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] -a] pyrimidine to give 3-ethoxycarbonyl-6-methyl-9 - [(methylthiophenylamino) methylene] -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidine in a yield of 56 why mp 110-112 ° C.

Analysis for C ₂ oH ₂₂ N ₃ 0 ₃ S:

calculated:

% C, 62.46;% H, 5.77;% N, 10.93.

H, 5.81; N, 11.01. Example 26

3.2 g of 3-ethoxycarbonyl-6-methyl-9 - [(methylthiomethylamino) methylene] -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine is heated in 150 ml. The precipitated crystals are filtered off and dried in a vacuum drying gun over phosphorus pentoxide at the boiling point of toluene.

2.3 g (73%) of 3-ethoxycarbonyl-9- (methylthiocarbonyl) -6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine.

Melting point 170-172 ° C.

Analysis for C ₁₄ H ₁₆ N ₂ O ₄ S: calculated::

% C, 54.17;% H, 5.84;% N, 9.01.

H, 5.90; N, 8.94. Example 27

The procedure is as described in Examples 11 and 12, but starting from 3-ethoxycarbonyl-6-methyl-9- (phenylaminothiocarbonyl) -4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2] and α-pyrimidine to give 9- (phenylaminothiocarbonyl) -3-carboxy-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido. Proceed as described in Example 241 [1,2-a] pyrimidine in 58% yield, mp 119-121 ° C (dec.).

Analysis for C ₁₇ H ₁₇ N ₃ O ₃ S: calculated ·:

% C, 59.45;% H, 4.99;% N, 12.23.

H, 5.03; N, 12.31. Example 28

The procedure is analogous to Examples 14 and 15, but isocyanate is

Claims (2)

SUBJECT A process for the preparation of novel fused pyrimidine derivatives of the general formula I wherein R, R ¹ and R ^{2 are each} independently hydrogen or C 1 -C 4 -alkyl, R ³ is hydrogen, C ₁ -C ₄ -alkyl, alkali metal carboxy or carboxylate, C 2 -C 5 alkoxycarbonyl, carbamoyl, cyano or —CO — NH — CO — NH — SO _and —C ₆ H ₄ —CH ₃ , Y represents oxygen or sulfur and X represents nitrogen and n represents 0 or 1 and (a) in the case where R ¹⁰ represents hydrogen and R ⁹ and R ⁸ as well as R ⁶ and R ⁷ together represent another bond, R ⁴ represents chloroacetyl, C 1 -C 4 -alkyl or, optionally, halogen, C 1-4 - C ₄ -C ₄ -alkyl or C ₄ -C ₄ -alkoxy-substituted phenyl and R ^{5 is} hydrogen or C ₁ -C ₄ -alkyl, or b) in case R ⁶ and R ⁷ as well as R ⁹ and R ¹⁰ together represent another bond and use ethyl isocyanate. 3-Ethoxycarbonyl-6-methyl-9- (ethylaminophthiocarbonyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine is obtained in a yield of 32% which is recrystallized from ethyl acetate and melts at 179-181 ° C. Analysis for C C ^^ iNNS: calculated: % C, 55.71;% H, 6.54;% N, 12.99%. H, 6.42; N, 13.07; S. 9.95. YNÁLEZU R ⁸ is hydrogen, R ⁴ and R ⁵ have the same meaning as in (a), or c) when R ⁷ and R ⁸ as well as R ⁹ and R ¹⁰ together represent another bond, R ⁴ and R ⁵ are as defined in (a) and R ⁶ is hydrogen or C 1 -C ₄ -alkyl as well as their optically active antipodes and their salts, characterized in that the compound of formula II wherein R, R ^1, R ^2, R ^{3 and} n have the above meanings, is reacted with a compound of formula III R ⁴ —N = C — Y (III) wherein R ⁴ and Y are as defined above and, if desired, the compound of formula I obtained is converted into another compound of formula I and / or converted into a pharmaceutically acceptable salt or released from its salt and / or the racemate of formula I optionally obtained in its optically active antipodes. 2. A process according to claim 1, wherein the reaction is carried out in the presence of a Lewis acid or base at a temperature of 0 to 250 ° C.