NO814458L - PROCEDURE FOR THE PREPARATION OF TETRAHYDRO-1,2,4-OXADIAZIN-5-ON DERIVATIVES WITH ANTICONVULSIVE ACTIVITY - Google Patents

Description

The present invention relates to a method for the production of new tetrahydro-1,2,4-oxadiazin-5-one derivatives with anticonvulsant activity. More specifically, the invention relates to a process for the production of new tetrahydro-1,2,4-oxadiazin-5-one derivatives of general formula (I)

in which

R 2 is hydrogen, an acyl radical of an aliphatic carboxylic acid

with T to 12 carbon atoms, optionally substituted with halogen, benzoyl, optionally substituted with methoxy, halogen or trifluoromethyl, ethoxycarbonyl, phenoxycarbonyl, optionally N-substituted carbamoyl or N-benzyloxycarbonylglycyl;

R 3 is alkyl with 1 to 5 carbon atoms or optionally

31 3 3' substituted phenyl and R is hydrogen, or R and R together form a pentamethylene group;

R 4 is hydrogen or acetyl,

R is hydrogen, alkyl of 1 to 4 carbon atoms, benzyl or phenyl and R 1 is hydrogen or

6 61

R and R each denote a phenyl group.

The new compounds exhibit valuable central nerve-stimulating activity, in particular anticonvulsant activity. Another aspect of the invention is therefore a method for the production of pharmaceutical preparations comprising an active ingredient of a pharmaceutically effective amount of a compound of formula (I) with at least one pharmaceutically inert carrier or diluent.

Substituted derivatives of tetrahydro-1,2,4-oxadiazine have recently become known in the art. The synthesis of such compounds was first described by Calcagno et al. fj.Org. Chem. 39, 162 (1974)^] . The authors prepared 4-aroyl-tetrahydro-1,2,4-oxadiazines by cycloaddition of a nitrine and a corresponding 1-aroyl-aziridine. Recently, F. G. Riddel et al. Tetracycles 9, 267 (1978); Tetrahedron 35, 1391 (1979 f] prepared a tetrahydro-1,2,4-oxadiazine skeleton by condensation of an N-alkyl-O-(methylamino)-ethyl-hydroxyl-amine with formaldehyde. The biological activity of these compounds was not reported nor were tetrahydro-1,2,4-oxadiazine derivatives containing an oxo group in the 5-position described.

It has now been found that the new compounds of general formula (I) in which R 2 R<3>, R<31>, R<4>, R<6> and R 6 as defined above can be prepared by

a) that a tetrahydro-1,2,4-oxadiazin-5-one of general formula (II)

wherein R 2 ' is benzyloxycarbonyl and

3 31 6 61

R , R , R and R have the meanings given above, are subjected to catalytic hydrogenation, whereupon the obtained tetra-hydro-1,2,4-oxadiazin-5-one derivative of general formula (II) in which R 21 is hydrogen and R 3 , R 3' , R 6 and R 61 are as defined above, reacted with an acid derivative of general formula (III)

in which

X is halogen or an acyloxy group of formula

R -CO-0-, wherein

R 2 " -CO- is an acyl group as defined by the definition

2

by R ,

or with an isocyanate of general formula (IV),

wherein R 2 "'is an alkyl group of 1 to 6 carbon atoms, or with formic acid, in the presence of a condensing agent; or b) for the preparation of compounds of general formula (I) wherein R 2 is carbamoyl or N-substituted carbamoyl,

3 3' 4 6 6'

R , R , R , R and R are as defined above, that a compound-. deis of general formula (II), wherein R is phenoxycarbonyl,

3 3' 6 61

R , R , R and R are, as defined above, reacted with ammonia or a primary or secondary amine.

The hydrogenation of the compound of formula (II) according to method alternative a) is carried out in a suitable organic solvent or solvent mixture, preferably using a palladium-on-carbon catalyst under atmospheric pressure. To avoid the formation of unwanted by-products, the course of the reaction is monitored by thin-layer chromatography. The reaction ends when no unreacted starting material can be detected in the reaction mixture and at the same time no significant amount of the by-product is present. The catalyst is then filtered from the reaction mixture, the solvent is evaporated and the residue is triturated with an inert solvent and/or crystallized.

N 2 -acylation of 2-unsubstituted tetrahydro-1,2,4-oxadiazin-5-one derivatives of general formula (II) with acid halides or acid anhydrides of general formula (III) is carried out according to generally known methods within the organic chemistry, under suitable reaction conditions. In a solution of the starting compound in an anhydrous organic solvent, preferably a cooled solution of a corresponding acid halide, preferably acid chloride of general formula (III) in an organic solvent, is added at a temperature of around 0°C in the presence of an acid binding agent. If an acid anhydride in which X accounts for an R group is used as an acid derivative of general formula (III), this acid anhydride can also serve as a reaction medium.

In the starting compound of general formula (II), in addition to the R 2 1 group bound to the nitrogen atom in the 2-position, the hydrogen bound to the 4-nitrogen is also prone to undergo acylation. If the acylation is carried out under the reaction conditions described above, it will always take place in the 2-position selectively, but under more drastic conditions (with an excess of acylating agent and under boiling) the corresponding 2,4-diacyl compounds are obtained.

According to a particularly preferred embodiment of this method, the catalytic hydrogenation is carried out in an acid anhydride, corresponding to the acyl group to be attached to the 2-position. In this case, parallel to the cleavage of the 2-benzyloxycarbonyl group, acylation will also take place.

The progress of the acylation can be monitored by thin-layer chromatography. As soon as the reaction is finished, the reaction mixture is filtered, the solvent is removed and the desired product is isolated from the residue by trituration with an inert solvent and/or crystallization.

In the preparation of compounds of general formula (I), in which R 2 denotes a carbamoyl or N-substituted carbamoyl group according to process alternative b), a starting compound of general formula (II) in which R 2 is phenoxycarbonyl is reacted with the corresponding organic amine or - if N-unsubstituted carbamoyl derivatives must be prepared - aqueous ammonium hydroxide solution in a reaction-inert organic solvent, preferably chloroform or tetrahydrofuran. If organic amines are used, the reaction proceeds in a homogeneous medium, while when using an aqueous ammonium hydroxide solution it proceeds in a heterogeneous phase. The phenol formed during the reaction can be bound by the excess of the amine reactant or an organic tertiary amine, preferably triethylamine. At room temperature, the reaction is completed within several hours to several days, while at reaction

the boiling temperature of the mixture is., the reaction time several days.

The product obtained is isolated in the same way as in method alternative a).

In the compound of general formula (I) in which R is different from hydrogen and R 6 * is hydrogen, the carbon atom in the 6-position has an asymmetric configuration and consequently these compounds are either in racemic or optically active form. The invention includes preparation of both the racemic and optically active compounds of general formula (I).

According to the invention, the optically active compounds of general formula (I) are prepared by starting from optically active compounds of general formula (II). In this way, the optically active compounds of general formula (I) are obtained.

The pharmaceutical activity of the new compounds according to the invention was tested by conventional animal tests. The tests were performed on CFLP (LATI) mice of both sexes, both weighing 18 to 22 g each, in groups of 10 animals. The test compounds were suspended in a 5% aqueous Tween® 80 solution and the suspension was administered orally. through a' probe. When testing anticonvulsant activity, doses of 20 mg/kg were used, while doses of 80 mg/kg were used for the tests regarding neurotoxic activity. The induced effect was measured one hour after administration by the following methods:

1. Test of anticonvulsant activity

a) Maximum electric shock (MES):

According to the method described by E.A. Swinyard et al. J.

Pharmacol. 106, 319 (1952)_ the test animals were subjected to shock with a corneal electrode (20 mA, 0.2 sec.). Upon stimulation, 100% of the control animals responded with a tonic extensor spasm of the lower limbs. Absence of this phenomenon was considered a protection against the treatment. b) Inhibition of spasms induced by pentetrazole (PTT).

According to the method described by Cr.N. Everett and R.K.

Richards J. Pharmacol. Exp. Therap. 81_, 4 02 (1944) became

125 mg/kg pentetrazole (pentamethylene tetrazole) administered to the animals subcutaneously. One hour after administration, the animals were observed. Absence of clonic spasm (Kl) and a tonic,

lower limb extensor spasm (TE) was considered a protection due to the administration of the test compounds.

2. ' Test of neurotoxic activity

Muscle coordination. (RR) in mice

Change in coordinated muscular movement was tested according to the method of W.J. Kinnard and CF. Carr jBrit. J. Pharmacol. 121, 354 (1957) Cf on a rotating rod (diameter: 20 mm, frequency: 12/min.). Normally trained animals were able to remain on the rotating rod for approx. 120 seconds* One hour after administration, it was investigated how many percent of the test animals showed muscle incoordination, i.e. the number of animals that fell from the rotating rod within 120 seconds was determined and expressed as a percentage of the control animals.

3. Acute toxicity

Toxicity to the animals was investigated by administration of different single doses. The assessment was carried out 14 days after administration. The LD^Q values were calculated on the basis of the number of animals that died within 14 days by probit analysis, using a TPA/101 calculator.

As a reference substance in the tests indicated above

diphenylhydantoin and 3-methyl-5-ethyl-5-phenyl-hydantoin were used. The results obtained are. shown in the following table.

MES: maximum electric shock

PTT: pentetrazole spasm inhibitory activity

TE: tonic extensor spasm

Cl: clonic spasm

From the data in the above table it can be concluded that most of the compounds of general formula (I) exhibit an excellent anticonvulsant activity while their neurotoxic activity can be almost neglected.

The tested compounds are lethal only in very high doses

and their therapeutic breadth is consequently higher than that of known compounds with similar activity. The new compounds of general formula (I) can thus, due to their excellent pharmaceutical properties, be advantageously used for the treatment of epileptic diseases and in this area give better results than the hydantoin derivatives used for comparison.

The compounds of general formula (I) can be used in therapy in the form of pharmaceutical preparations containing an effective amount of these active ingredients in admixture with organic or inorganic carriers or diluents suitable for enteral or parenteral administration. The preparations can be prepared as tablets, injections, dilute or concentrated suspensions or emulsions or other suitable formulations. These formulations are produced according to conventional techniques within the pharmaceutical industry.

The pharmaceutical preparations generally contain from

30 to 100 active ingredient per unit dose. Administration in human therapy includes oral or parenteral administration, preferably in the form of intravenous injections. The relevant doses depend on the disease to be treated,

on the patient's condition, method of administration and the desired effect. In general, daily doses of between 200 and 600 mg are used.

Further details of the invention are illustrated in

the following examples. The abbreviations used in the examples are entirely in line with the IUPAC rules.

The melting points for the described compounds in the examples were determined in the apparatus according to Dr. Tottoli. The thin-layer chromatograms were prepared on "Kiselgel G" silica gel plates according to Stahl, which were sensitized to ultraviolet radiation. The following solvent mixtures were used to prepare the chromatograms:

(A) : 1:1 mixture of benzene and acetone

(B) : 3:1 mixture of chloroform and methanol

(C) : 30:4:2:1 mixture of ethyl acetate, acetic acid, water and

pyridine

(D) : 1:4:8 mixture of n-hexane, acetic acid and chloroform

(E) : 63:4:2:1 mixture of ethyl acetate, acetic acid, water and

pyridine

(F) : 1:1 mixture of chloroform and methanol

The thin-layer chromatograms were developed, by a or

several of the following methods:

1. UV irradiation at 254 nm..

2. treatment with iodine vapor

3. tolidine/potassium iodide spray after chlorination.

The structure of the compounds produced was analyzed by elemental analysis, and on the basis of IR and NMR spectra. The IR spectra were determined on a "Perkin-Elmer 257" system and the NMR spectra were recorded on a "Varian EM-60" apparatus.

The evaporation of the reaction mixture was carried out on a "Rotavapor R" vacuum evaporator at a temperature not exceeding 50°C.

If the NMR spectra were recorded in a water-immiscible solvent, e.g. deuterochloroform, the spectra were also recorded after shaking with heavy water, when the signal of the protons that were easily replaceable by deuterium disappeared from the spectrum (these deuteriums are marked with an asterisk) and the multiplicity of the protons bound to them was simplified (e.g. .“d—*s” shows that a doublet was converted to a singlet.

The following examples illustrate the invention.

Example 1

3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one (method a).

To a solution of 6.8 g (21.8 millimoles) of 2-benzyloxycarbonyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one in a mixture of 100 ml of methanol and 125 ml of ethyl acetate, 1.0 g of one 5% palladium on activated carbon catalyst added and hydrogen gas was bubbled through the solution. The progress of the reaction was monitored by thin-layer chromatography. When the reaction was complete, i.e. when no further starting compound was present, the catalyst was filtered off and the filtrate evaporated to dryness. The residue was recrystallized from a mixture of 10 ml of ethyl acetate and 30 ml of n-hexane. 3.0 g. (77%) of 3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one was obtained, mp 118 to 119°C. R^ = 0.35.

Analysis for C9<H>1QN2O2 (molecular weight: 178.19): calculated: C 60.66%, H 5.66%, N 15.72%;

found: C 60.33%, H 5.57%, N 15.94%.

IR spectrum (KBr): 3160 (-NH-), 1670 ()c=0),

1420, 806 (ring), 700 (aromatic).

NMR spectrum (DMSO- dg + CDCl 3 , TMS) ppm: 4.22

singlet (CH2~), 5.53 d—>S, J = 6.5 Hz ()CH-) , 7.02 d<*>,

I = 6.5 Hz (-NH-), 7.47 singlet (5H, aromatic), 8.80 broad<*>)-NH-) .

Example 2

2-acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one

(method b)

38.5 g (216 millimoles) of 3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one in 190 ml of acetic anhydride was stirred for one hour. The initial suspension was quickly transferred into a solution followed by precipitation of the product. When the reaction was complete, the solvent was evaporated under reduced pressure and the residue recrystallized from 150 ml of ethanol. 36.3 g (81%) of 2-acetyl-3-phenyl-tetrahydrb-1,2,4-oxadiazin-5-one was obtained, mp ~167 to 168°C. R f = 0.7

Analysis for c-\-\ H-\ 2U2°3 (molecular weight: 220.23): calculated: C 59.99%, H 5.49%, N 12.72%; found: C 60.12%, H 5.92% . N 12.73%. IR spectrum (KBr) cm"1: 3180 (-NH-), 1690, 1668 ()c=0, amide), 1412, 790 (ring), 740, 700 (aromatic). NMR spectrum (DMSO-dg + CDC13, TMS) ppm: 2.13 s 4-CH3), 4.56 AB quadruple (-CH2~). 6.70 (broad singlet ^ CE- ■., 7.45 singlet (5H, aromatic), 9, 2 broad<*>(-NH-).

Example 3

2-acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one

(method c)

6.28 g (20 millimoles) of 2-benzyloxycarbonyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one was dissolved in 50 ml of acetic anhydride. 0.5 g of a 5% palladium on activated carbon catalyst was added and hydrogen was bubbled through the solution. The progress of the reaction was monitored by thin-layer chromatography. When the reaction was complete, the catalyst was filtered off, the filtrate was evaporated to dryness and the residue recrystallized from 15 ml of ethanol. 3.55 g (80%) of 2-acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one was obtained. The physical constants for the compound obtained are identical to those for the product according to 2.

Example 4

2,4-diacetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one

1.1 g (5 millimoles) of 2-acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one was dissolved in 10 ml of dry tetrahydrofuran. To the solution was added 1.5 ml of triethylamine, the solution was cooled to 0°C and 0.8 ml (11 millimoles) of acetyl chloride was added. The reaction mixture was then refluxed for 20 hours. After cooling, the precipitated triethylamine salt was filtered off and the filtrate was evaporated to dryness. The residue was passed through a silica gel column using a 1:1 mixture of benzene and acetone as eluent. Fractions containing the desired product were evaporated and then recrystallized from a mixture of 2 ml of ethyl acetate and 6 ml of n-hexane. 0.3 g (23%) of 2,4-diacetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one was obtained, mp 104 to 106°C. R^ = 0.8.

Analysis for C13H14<N>2°4 (molecular weight: 262.27): calculated: C 59.54%, H 5.38%, N 10.68%, found: C 59.30%, H 5.12% ,. N 10.84

IR spectrum (KBr) cm"<1>: 1710, 1680, 1648 ()c=0), 1585, 755,

700 (aromatic).

NMR spectrum (DMSO-dg. +CDC13+TMS) ppm: 2.13 singlet (-CH3),

2.56 singlet (-CHg), 4.8 AB quadruple(-CH,,-),

7.36 singlet (5H, aromatic), 7.5 singlet (^CH-).

Example 5

2-phenoxycarbonyl-3-n-propyl-tetrahydro-1,2,4-oxa-diazin-5-one (method d)

11.25 ml (13.9 g, 89 millimoles) of phenoxycarbonyl chloride was dissolved in 75 ml of dry tetrahydrofuran, the solution was cooled to a temperature below 0°C and at this temperature a solution of 10.8 g (75 millimoles) 3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one in a mixture of 150 ml dry tetrahydrofuran and 11.4 ml dry triethylamine added dropwise. After addition, the mixture was warmed to room temperature and stirred for 3 hours. The triethylamine hydrochloride precipitate was filtered off, the filtrate was evaporated under reduced pressure, the residue triturated with a mixture of water and ether and filtered. 14.7 g

(80%) 2-phenoxycarbonyl-3-n-propyl-tetrahydro-1,1,4-oxadiazin-5-one was obtained, mp 106 to 107°C.

Analyzes for c-|3<H>i6<N>2^4 (molecular weight: 264.28): Calculated: C 59.08%, H 6.10%, N 10.60%;

Found: C 59.31%, H 5.70%, N 10.70%.

IR spectrum (KBr) cm"<1>: 3180 (-NH-), 1735 ()c=0,Z), 1680

(>C=0, amide), 1210 (^C-O-cf),

1592, 690, 742 (aromatic).

NMR spectrum (DMSO-dg+CDC13,TMS) ppm: 0.95 (-CHg), 1.44

multiplet (-CH2-CH3), 2.10 multiplet (^CH-CH2~), 4.5 AB quadruple (^CH_2-C0-), 5.3 multiplet -

—>triplet OCH-) , 7.5 multiplet (5H,

aromatic), 9.0 doublet (-NH-).

Example 6

2-carbamoyl-3-n-propyl-tetrahydro-1, 2,4-oxadiazin-5-one (method e)

7/94 g (30 millimoles) of 2-phenoxycarbonyl-3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one in a mixture of 75 ml of chloroform and 75 ml of concentrated ammonium hydroxide solution was vigorously stirred at room temperature until in a sample taken from the organic phase could not detect traces of the starting material by thin-layer chromatography (1 to 2 days). When. the reaction was complete, the precipitated product was separated by filtration, washed with water and then with ether and dried. The organic phase was separated from the filtrate, dried with anhydrous sodium sulfate and evaporated. The evaporation residue was triturated with ether and filtered. The second mass obtained was combined with the product from the previous step. Thus, 4.6 g of 2-carbamoyl-3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one (82%) with melting point 189°C were obtained.

Example 7

2-(n-butylcarbamoyl)-3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one

3.0 g (20.8 mmol) of 3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one was dissolved in 40 ml of dry tetrahydrofuran. The solution was cooled to a temperature below 5°C, and at that temperature a solution of 2.5 ml (2.2 g, 22.5 millimoles) of n-butyl isocyanate in 20 ml of dry tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 4 days.

When the spot corresponding to the starting compound was no longer present on the thin-layer chromatogram, the reaction mixt. evaporated to dryness in vacuo, the residue triturated with n-hexane, filtered and recrystallized from a mixture of ethyl acetate and n-hexane. 4.23 g (87%) of 2-(n-butylcarbamoyl)-3-n-propyl-tetrahydro-1,2,4-oxadiazin-5-one was obtained with melting point 105 to 106°C.

Analyzes for C11H21N3O3 (molecular weight: 243.31'%): calculated: C 54.30%, H 8.70%, N 17.27%;

found: C 54.68%, H 8.77%, N 17.54%.

IR spectrum (KBr) cm"1: 3320, 3180 (-NH-), 1690 ()c=0,

carbamoyl-), 1660 (^C=0, amide),

1421 , 820 (call).

<1>H-NMR spectrum (DMSO-dg+CDC13, TMS) ppm: 0.7-1.9 multiplet (14H, aliphatic) 3.15 quadruple—>triplet (-NH-CH2-) , 4.21 quadruple (-Q-CH,,-) , 5.30 multiplet—>triplet (CH-) 7.13 doublet<*>,

J = 6 Hz (-NH-), 8.70 doubled J = 3 Hz (-NH-).

Example 8

2-formyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one

5.4 g (30 millimoles) of 3-phenyl-tetrahydro-1,2,4-oxa-diazin-5-one (prepared according to Example 1) and 10.5 g (51 millimoles) of dicyclohexylcarbodiimide were dissolved in 50 ml of absolute tetra -hydrophuranium. The solution was cooled to a temperature below

-5°C, and at this temperature 2.3 ml (2.35 g, 51 millimoles) of formic acid was added dropwise. The mixture was stirred for 30 minutes at -5°C, after which the dicyclohexylcarbamide precipitate was filtered off. The filtrate was evaporated to dryness in vacuo, the oily residue was dissolved in hot water, the insolubles were filtered off and the filtrate was evaporated to dryness in vacuo. Recrystallization of the residue from ethyl acetate gave 1.52 g (24%) of 2-formyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one, mp 115 to 116°C. R^= 0.4.'

Analyzes for Ci0H10N2°3 (molecular weight: 206.20): calculated: C 58.25%, H 4.89%, N 13.59%;

found: C 58.30%, H 4.69%, N 13.59%.

IR spectrum (KBr) cm"<1>: 3180 (-NH-), 3050, 1700 (-CHO), 1670

(C=O, amide), 1585, 755, 702

(aromatic).

<1>H-NMR spectrum (DMSO-dg + CDC13 TMS) ppm: 4.5 AB quadruple (-CH2-C-0), 6.5.broad, singlet ( CH-); 7.3 broad (5H, aromatic), 8.5 (singlet, -CHO), 9.2 broad<*>

(NH-).

The compounds of general formula (I) indicated in the following table can be prepared in an analogous manner. The table indicates the method used for the preparation of these compounds, their physical constants, the yields and solvents used for recrystallization etc. Different reaction media or other differences compared to the detailed examples are given in the last column as "Remarks" .

Claims (3)

1. Process for the preparation of tetrahydro-1,2,4-oxadiazin-5-one derivatives of general formula (I) in which R 2 is hydrogen, an acyl radical of an aliphatic carboxylic acid with 1 to 12 carbon atoms, optionally substituted with halogen, benzoyl, optionally substituted with halogen, methoxy or trifluoromethyl, ethoxycarbonyl, phenoxycarbonyl, optionally N-substituted carbamoyl or N-benzyloxycarbonylglycyl; R 3 is alkyl with 1 to 5 carbon atoms or optionally substituted 3 1 tuated phenyl and R is hydrogen, or 3 3' R and R together form a pentamethylene group; R 4 is hydrogen or acetyl, R^ is hydrogen, alkyl of 1 to 4 carbon atoms, benzyl or phenyl and R is hydrogen, or 6 6 <1> R and R each denote a phenyl group, characterized by ata) a tetrahydro-1,2,4-oxadiazin-5-one derivative of general formula (II) wherein R is ben.zyloxycarbonyl and 3 31 6 61 R , R / R and R are as indicated above, subjected to catalytic hydrogenation, whereupon the obtained tetrahydro-1,2,4-2' oxadiazin-5-one derivative of general formula (II) in which R is 3 21 6 6' hydrogen R , R , R and R are as indicated above, reacted with an acid derivative of general formula (III) in which X is halogen or an acyloxy group of formula R -CO-0- in which 2 ii 2 R -CO- is an acyl group as defined for R, or with an isocyanate of general formula (IV) 2 "1 wherein R is alkyl of 1 to 6 carbon atoms, or with formic acid, in the presence of a condensing agent, or b) for the preparation of compounds of general formula (I) wherein R 2 is carbamoyl or N-substituted carbamoyl, or R , R"^ , R^ and R^ are, as indicated above, that a compound . 2' 3 31 of general formula (II) in which R is phenoxycarbonyl, R , R , R 6 and R 6' are as indicated above, is reacted with ammonia or with a primary or secondary amine. 2. Method according to claim 1, characterized in that in method alternative a) an acid anhydride containing an acyl group which is to be bound to the nitrogen in the 2-position is used as reaction medium for the catalytic hydrogenation. 3. Method according to claim 1 or 2 for the preparation of optically active compounds of general formula (I), in which 6 2 3 3' 4 61 R is different from hydrogen, R , R , R , R and R are as defined in claim 1 , characterized in that optically active compounds of general formula (II) are used as starting compounds •