FI67079C - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC ANALYZED 4-UBSTITUERADE 1,3,4,5-TETRAHYDRO-2H-1,4-BENZODIAZEPIN-2-ON DEIVAT - Google Patents

Description

67079

Process for the preparation of therapeutically useful 4-substituted 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives 5 Separated from Patent Application No. 751898.

The invention relates to a process for the preparation of therapeutically useful racemic or optically active 4-substituted 1,3,4,5-tetrahydro-2H- (1,4) -benzodiazepin-10 2-one derivatives of general formula I

R2 15 '

C/O

| CH 2 (I) 1 k R o 20 wherein R 1 is hydrogen, halogen, trifluoromethyl, amino or nitro, R 2 is hydrogen or C 1-4 alkyl, R 3 is carbamoyl optionally substituted by C 1-4 alkyl, phenyl, naphthyl or phenyl-C 1-4 alkyl and R 9 is phenyl or halophenyl.

All of the above compounds are novel.

The compounds of the invention have a sedative and sedative-relieving effect.

Numerous 1,4-benzodiazepine derivatives are already known, many of which are widely used sedatives and hypnotics.

By studying known compounds, some conclusions have been drawn about the relationship between chemical structure and pharmaceutical effects. Studies have shown that a double bond between positions 4 and 5 was necessary for the high activity of the compound, as tetrahydro-67079 derivatives in which this double bond was saturated showed significantly lower activity in all pharmacological tests than the corresponding unsaturated 4 compounds. The activity was further reduced by the substituent /L.H attached to the N-position. Sternbach et al .: Drugs Affecting the Central Nervous System (A. Berger ed.), 1968, vol. 2, page 2377. These facts explain why the number of tetrahydrodiazepine derivatives prepared so far is much smaller than the number of dihydro compounds.

The following methods have been used to prepare 4-substituted tetrahydro-1,4-benzodiazepine derivatives: 1-Monosubstituted and 1,4-disubstituted tetrahydrobenzodiazepine derivatives have been prepared by direct alkylation of 1,4-tetrahydrobenzodiazepine.

Med. Chem. 7, 386 (1964), FR Patent Publication No. 1,339,762 /.

According to U.S. Patent No. 3,501,474 and NL Application Publication No. 69,173,320, N-substituted tetra-20 hydro-1,4-benzodiazepin-2-one derivatives have been prepared by ring extension of suitable isoquinolin compounds. JP Patent Publication No. 48-25,199 describes the preparation of tetrahydro-1,4-benzodiazepin-2-one derivatives having a substituted carbamoyl group at position 4.

The method according to the invention is characterized in that

that a racemic or optically active 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivative of general formula II

30 * 2

Ä— CO

r ^ V x || £ H2 (II)

35 P -NH

R1 R6 3 67079

wherein R 1 # R 2 and R 8 are as defined above, or a salt thereof, is reacted with a compound of general formula IV

With a compound of formula R 5 to Y (IV) 5 wherein R 1 is hydrogen, an alkali metal, C 1-4 alkyl, phenyl, naphthyl or phenyl-C 1-4 alkyl, and Y is of the formula NCO or OCH- group and, if desired, a racemic or optically active compound in which R 1 and R 8 are as defined above and R 2 is hydrogen are alkylated in a manner known per se.

The starting materials of general formula (II) can be prepared according to HU patent publication 155 251.

In the starting materials of general formula (IV), when R 1 - denotes an alkali metal, it is preferably potassium. When R 1 represents C 1-4 alkyl, it may be branched or unbranched. When R 1 in the compound of formula (IV) is an alkali metal, the compound of formula (II) is preferably in the form of an acid addition salt. Suitable acid addition salts are hydrohalides, especially the hydrochloride.

However, other salts of mineral acids or organic acids can also be used. In a preferred embodiment, the compound of general formula (II) is dissolved in a suitable organic solvent inert to the reactants and the reaction product, and hydrogen chloride is introduced into the solution, the separated hydrochloride is filtered and suspended in a suitable solvent for use in the next reaction step. To the suspension is added a compound of formula (IV) wherein R 1 is an alkali metal and Y is an NCO- group. A particularly suitable solvent for use in this reaction is acetic acid. The reaction temperature can vary within wide limits, however, the reaction is preferably carried out at room temperature. The reaction time depends on the starting materials, the solvent and the reaction temperature and can range from about 20 minutes to about 10 hours.

4 67079

When the compound of formula (IV) is C 1-4 alkyl, phenyl, naphthyl or phenyl-C 1-4 alkyl, the reaction with the compound of formula (II) is preferably carried out in an organic solvent inert to the reactants and the final product. Suitable organic solvents are, for example, halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane and other aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether, dioxane and tetrahydrofuran, and dimethylformamide, dimethyl sulfoxide and the like are preferably used. The reaction temperature can vary within wide limits, preferably the reaction is carried out at room temperature. In a preferred process embodiment, the compound of general formula (II) is suspended in an organic solvent, for example diethyl ether, and the resulting suspension is treated at room temperature with an alkyl isocyanate.

A compound of general formula (I) in which R 1, R 2 and R 8 are as defined above and R 10 is hydrogen may, if desired, be alkylated to a compound in which R 6 is alkyl. Conventional alkylating agents such as alkyl halides (preferably alkyl iodide) or dialkyl sulfate can be used in this reaction.

For example, a compound of general formula (I) is first converted into an alkali metal derivative and the alkali metal compound thus obtained is reacted with a suitable alkylating agent. The alkali metal compound can be prepared, for example, by reacting a suitable compound of general formula (I) wherein R 2 is hydrogen and R 1, R 2 and R 8 each have the same meaning as above, with an alkali metal, alkali hydride or alkali metal, especially sodium or sodium with the compound at 0-150 ° C in an inert solvent such as dioxane, dimethylformamide, benzene or toluene.

The reaction product is usually obtained in crystalline form.

However, if an oily substance is obtained, this can generally be easily crystallized using conventional solvents, e.g. aliphatic or cyclic ethers such as diethyl ether, dioxane, tetrahydrofuran, etc.

If necessary, the compounds of general formula (I) in which R 1, R 2, R 3 and R 8 each have the same meaning as above can be recrystallized. As the recrystallization solvent, for example, an aliphatic alcohol such as methanol or ethanol, an aromatic hydrocarbon such as benzene, a ketone such as acetone, an aliphatic ester, especially an alkane carboxylate such as ethyl acetate, an aliphatic hydrocarbon such as C -hexane, an ether, especially a dialkyl ether such as diethyl ether, a saturated cyclic ether such as tetrahydrofuran, in addition to acetonitrile and also mixtures thereof (e.g. a mixture of tetrahydrofuran and hexane or a mixture of ethyl acetate and ether).

By the process of the invention, the compounds of formula (I) are obtained in high yields and are easily identifiable. The values of the elemental analysis are in good agreement with the values calculated.

Depending on whether a racemic or optically active starting material of general formula (II) is used, the final products of general formula (I) are obtained in racemic or optically active forms.

The 4-substituted-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives according to the invention have an excellent analgesic and analgesic effect. The most preferred compound of formula (I) is 1-methyl-4-carbamoyl-5-phenyl-7'-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one.

Pharmacological experiments were performed on CFLP mice of both sexes weighing 18-22 g. In the screening experiments, the compounds were administered intraperitoneally one hour before the start of the study, 1-methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2 -one, the most potent of the compounds of the invention, as well as the reference substances, were administered orally 67079 hours before the start of the studies. The following test methods were used, the results of which are summarized in Table I:

Investigation of the anticonvulsant effect 1) The first series of studies was performed according to the method of Everett 5 and Richards / feverett G.M., Richards R.K .: J. Pharm. Exp. Ther. 81, 402 (1944) ./. 125 mg / kg metrazole was administered subcutaneously to experimental animals. One hour after administration, animals with no extensor spasm and 10 surviving animals were counted. ED 2 values were determined from these values by probit analysis.

2) The maximum electric shock test (100 Hz, 30 V, 0.2 s) was performed according to Swinyard et al. according to the method / Swinyard E.A., Brown W.C., Goodman, L.S .: J. Pharmacol.

15 106, 319 (1952), /. The drug was considered to be effective when the test animal did not show continuous extension of the hind limb after irritation.

Strychnine-kouristuskoe

Persistent spasm of the extensor muscle was induced by administering to the animals intraperitoneally a dose of 2 mg / kg strychnine / Kerley T.L., Richards A.G., Begley, Aberen B.E. and Weaver, L.C .: J. Pharmacol. Exp. Ther. 132, 360 (1961), /. The drug was considered effective when the test animal did not have seizures.

25 Investigation of muscle dysfunction and ataxia (acidification) a) The rotating rod test was performed according to the method of Kinnard and Carr / Brit. J. Pharmacol. Exp. Ther. 121, 354 (1957) _ /. The control animals were able to stay for 30 120 s with a rod rotated at 12 rpm. ED 2 q values were calculated from the percentage of animals that fell within 120 seconds.

b) The tensile test was performed according to Theobald et al. according to the method. Inst. Pharmacodyn 148, 560 (1964) _7.

35 Both forelegs of the test animal were placed on a horizontal rod so that the animals could adhere to the rod. Control animals pulled their hind limbs onto the rod in five 7,67079 seconds. ED 2 values were calculated from the percentage of animals that showed a negative reaction.

Sleep and sleep enhancing effect

As is known, the liver does not metabolize sodium barbiturate 5 / E Bert A.G., Yin G.K.W., Miya T.S .: Biochem.

Pharmacol 13, 2161 (1964) ./. One hour after administration of the test compound at various doses, the animals were administered 100 mg / kg of sodium barbiturate intraperitoneally and the ED 1 values of the test compounds were calculated from the percentage of 10 sleeping animals (control animals receiving sodium barbiturate alone at the above dose did not fall asleep).

The potentiating effect of hexobarbital was determined by the method of Riimke et al. according to the method / Ärch. Int.

15 Pharmacodyn 146, 10 (1963) _7 by administering hexobarbital at a dose of 60 mg / kg to the tail vein of mice one hour after administration of the test compound. The change in sleep period was expressed as a percentage of the comparisons.

Acute toxicity The experiments were performed at room temperature (24 ° C) and the death of the animals was monitored for one week.

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The anxiolytic (anxiolytic) activity of the compound can be measured, in particular by the antimetrazole test. The results in Table I show that the anxiolytic effect of CBM is essentially the same as that of diazepam.

5 However, CBM has the advantage that its sedative effect, which consists of a combination of three modes of action, namely a combination of anxiolytic, muscle relaxant and sedative effects, is negligible. CBM is clearly more advantageous in this respect than the reference compounds. Added 10 CMB has its low ethanol-enhancing effect.

Table I compared the properties of the preferred compound prepared according to the invention with the properties of known drugs.

Table II summarizes the experimental results obtained with the compounds of formula (I) and the reference compounds in the experiments described above.

Table II

Compound Antimeters- Electric- Rotating Hexobar- LD ^ i * P · 2Q example- Razole Irritation Rod for Bitual Cry EDcrt EDcri i.p. EDca enhancement 50 50 c 50 „no% 4 4.9 14.0 13.5 89 366.6 5 19.5 20 20 75 936 7 14.0 20 20 77 320 25 9 13.5 20 20 96 271.1 CDX 0.92 15.7 7.2 205 225.1 D 0.36 4.5 1.2 489 517.7

Notes: All doses are expressed in mg / kg at 30 i.p. = intraperitoneally CDX = chlorodiazepoxide D = diazepam

The invention is illustrated in detail by the following examples.

The purity of the substances prepared was determined using thin layer chromatography. R 1 values were determined on a Stahl "C" silica gel plate (Merck) using one of the following systems as eluent: (1) 1: 4: 8 mixture of n-hexane, ethyl acetate and chloroform: (2) 1: 1 : A mixture of 8 n-hexane, acetic acid and chloroform; (3) 9: 1 mixture of chloroform and methanol. Spots were developed by the chloro-tolidine-5 method. Melting points were determined by dr. In a Tottoli type device (the melting points given in the examples are uncorrected values). In some cases, the structures of the products were identified using infrared (IR) or nuclear magnetic resonance (NMR) or mass spectra.

Example 1 1-Methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one

Dry gaseous hydrochloric acid is introduced for a few minutes into a solution of 5.72 g (0.02 mol) of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4 -benzodiazepin-2-one in 20 ml of chloroform. The separated hydrochloride is filtered off and suspended in 200 ml of acetic acid. 4.5 g of solid potassium cyanate are added to the suspension and the mixture is stirred for two hours at room temperature. During this time a clear solution is formed. The solution is cooled, neutralized with concentrated ammonia, the separated product is filtered off and washed with water. 6.0 g (94.9%) of 1-methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one are obtained. The product melts at 217-25 219 ° C after recrystallization from ethanol.

R f = 0.28.

Analysis for C 18 H 19 N 2 O 2 Cl 2 N 2 Cl (M = 329.76) Calculated: C 61.95 H 4.9 N 12.7%

Found: C 61.90 H 4.9 N 13.0%.

30 In this way, the following compounds are prepared from suitable starting materials:

Example 2 4-Carbamoyl-5-phenyl-7-nitro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one Starting material: 7-nitro-5-phenyl-1,3, 4,5-Tetrahydro-2H-1,4-benzodiazepin-2-one.

Yield: 73.5%. Melting point 239-241 ° C (after recrystallization from ethanol). R f = 0.22.

11 67079

Analysis for C 18 H 28 N 2 O 2 (M = 326.32) Calculated: C 58.85 H 4.3 N 17.2%

Found: C 59.1 H4.5 N 16.8%.

Example 3 4-Carbamoyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one Starting material: 5-phenyl-1,3,4,5-tetrahydro-2H- l, 4-benzodiazepin-2-one.

Yield: 74.2%. Melting point: 227-228 ° C (after recrystallization from ethanol). R f = 0.45.

Analysis for C 18 H 18 O 2 N 2 (M = 281.30) Calculated: C 68.3 H 5.4 N 15.0%

Found: C 68.0 H 5.2 N 15.0%.

Example 4 4-Carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one Starting material: 7-chloro-5-phenyl-1,3, 4,5-Tetrahydro-2H-1,4-benzodiazepin-2-one.

Yield: 88.5%. Melting point 241-245 ° C (after recrystallization from ethanol). R f = 0.35.

Analysis for C 19 H 19 N 2 O 2 Cl (M = 315.75) Calculated: C 60.75 H 4.5 N 15.3%

Found: C 60.4 H 4.2 N 15.0%.

Example 5 4-Methylcarbamoyl-5-phenyl-7-nitro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one 5.6 g (0.02 mol) of 7- nitro-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one is suspended in 25 ml of dry ether and 4.8 ml (0.08 mol) of 30 ml are added. methyl isocyanate. The reaction mixture is stirred at room temperature for 16 hours, then the solid crystalline solid is filtered off and washed with ether. 6.03 g (96.7%) of 4-methylcarbamoyl-5-phenyl-7-nitro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one are obtained, m.p. 176-180 ° C.

After recrystallization from ethanol, the product melts at 179-180 ° C. R f = 0.4.

12 67079

Analysis for c 17 H 16 O 4 N 4: 113 (M = 312.31) Calculated: C 60.0 H 4.7 N 16.45%

Found: C 60.3 H 4.6 N 16.2%.

In a similar manner, the following compounds are prepared from the starting materials.

Example 6 4-Ethylcarbamoyl-5-phenyl-7-nitro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one Starting material: 7-nitro-5-phenyl-1,3 , 4,5-tetrahydro-2H-1,4-benzodiazepin-2-one.

Yield: 72.5%. Melting point 185-189 ° C (after recrystallization from ethanol). = 0.2.

Analysis for C 18 H 19 N 2 O 4 N 4 (M = 354.36) Calculated: C 61.0 H 5.1 N 15.8% Found: C 61.3 H 4.3 N 16.0%.

Example 7 4-n-Butylcarbamoyl-5-phenyl-7-nitro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one Starting material: 7-nitro-5-phenyl-1,3 , 4,5-tetrahydro-2H-1,4-benzodiazepin-2-one.

Yield: 82.3%. Melting point: 204-208 ° C (after recrystallization from acetonitrile). = 0.3.

Analysis for C 22 H 22 N 2 O 2 (M = 382.4) Calculated: C 62.75 H 5.8 N 14.7% Found: C 62.95 H 6.2 N 14.8%.

Example 8 4-Phenylcarbamoyl-5-phenyl-7-nitro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one Starting material: 7-nitro-5-phenyl-1,3,4 , 5-tetrahydro-2H-1,4-benzodiazepin-2-one.

Yield: 63.3%. Melting point 222-224 ° C (after recrystallization from a mixture of tetrahydrofuran and hexane-2). R f = 0.6.

Analysis for C 22 H 19 gO 4 N 4 (M = 402.41) 35 Calculated: C 65.8 H 4.5 N 14.0%

Found: C 65.8 H 4.7 N 13.7%.

67079 13

Example 9 1-Methyl-4- (1-methyl-benzylcarbamoyl) -5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one Starting material: 1 -methyl-7-chloro-5-phenyl-1,3,4,5-5 tetrahydro-2H-1,4-benzodiazepin-2-one.

Yield: 75.7%. Melting point: 163-165 ° C (after recrystallization from ethyl acetate). = 0.6.

Analysis for C 25 H 24 O 2 N 3 Cl 2 (M = 433.92) Calculated: C 69.15 H 5.6 N 9.7% Found: C 68.9 H 5.6 N 9.7%.

Example 10 4- (1-Methylbenzylcarbamoyl) -5-phenyl-7-chloro-1,3,4,5-tetrahydro-1,4-benzodiazepin-2-one Starting material: 7-chloro-5-phenyl-1 , 3,4,5-tetrahydro-15H-1,4-benzodiazepin-2-one.

Yield: 78%. Melting point: 170.172 ° C (after recrystallization from a mixture of ethyl acetate and ether). R f = 0.55.

Analysis for C 24 H 22 O 2 N 3 Cl 2: = 419.90) Calculated: C 68.6 H 5.25 N 10.0%

Found: C 68.2 H 5.9 N 10.4%.

Example 11 1-Methyl-4- (1-naphthylcarbamoyl) -5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one Starting material: 1-methyl- 7-chloro-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one.

Yield: 72%. Melting point 271-273 ° C (after recrystallization from dimethylformamide). R f = 0.80.

Analysis for C 27 H 22 O 2 N 3: = 455.95) Calculated: C 71.13 H 4.96 N 9.22%

Found: C 71.52 H 4.52 N 9.18%.

Example 12 4- (1-Naphthylcarbamoyl) -5-phenyl-7-nitro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one Starting material: 7-nitro-5-phenyl- 1,3,4,5-Tetrahydro-2H-1,4-benzodiazepin-2-one.

67079 14

Yield: 95%. Melting point 194-196 ° C (after recrystallization from ethyl acetate). Rf = 0.70.

Analysis for C 26 H 20 O 4 N 4: H0 = 452.47) Calculated: C 69.02 H 4.56 N 12.38% Found: C 69.36 H 4.38 N 12.22%.

Example 13 1-Methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one 0.16 g (6.85 mmol) of metal sodium is dissolved in 2 ml of absolute methanol and a suspension of 0.9 g (2.86 mmol) of 4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro is added at room temperature. -2H-1,4-benzodiazepin-2-one in 50 ml of absolute methanol, with stirring. The suspension is stirred at room temperature for 30 minutes and then evaporated under reduced pressure. the oily residue is dissolved in 9 ml of dimethylformamide and 0.48 ml of methyl iodide is added to the stirred solution at room temperature. The mixture is stirred for a further two hours, then diluted with 50 ml of hydrogen and extracted with 3 x 10 ml of chloroform. The chloroform extracts are combined, dried over sodium sulfate, filtered and evaporated under reduced pressure to give 0.85 g of a residue which is recrystallized from ethanol. 0.75 g (79.5%) of 1-methyl-4-carbamoyl-5-phenyl-25-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one are obtained; mp. 217-220 ° C.

The following compounds are prepared from the appropriate starting materials by the method described in Example 5:

Example 14 (+) - 1-Methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one Starting material: (-) - 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one (prepared as described in Hungarian Patent No. 160,769). Saan-35 to: 77.4%. Melting point: 215-217 ° C (after recrystallization from ethanol), = + 613.9 ° ± 2 ° (c = 1, in chloroform).

15 67079

Example 15 (-) - 1-Methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one Starting material: (+) - 1 -methyl-5-phenyl-7-chloro-1,3,4,5-5-tetrahydro-2H-1,4-benzodiazepin-2-one (prepared as described in Hungarian Patent No. 160,769. Yield: 89.2%. Melting point 215-217 DEG C. m.p. = -612.8 ± 2 DEG (c = 1, in chloroform).

Claims (4)

67079 Claim: A process for the preparation of therapeutically useful racemic or optically active 4-substituted 1,3,4,5-5 tetrahydro-2H-1,4-benzodiazepin-2-one derivatives of the general formula I 10 r 2 .N-CO R 1 wherein R 1 is hydrogen, halogen, trifluoromethyl, amino or nitro, 1 * 2 is hydrogen or C 1-6 alkyl, is carbamoyl which is optionally substituted with C 1-4 alkyl, phenyl, naphthyl or phenyl-C 1-4 alkyl and R 9 is phenyl or halophenyl, characterized in that the racemic or optically active 1,3,4,5-tetrahydro-2H- A 1,4-benzodiazepin-2-one derivative represented by the general formula II wherein R 1, R 0 and R 2 are as defined above, or a salt thereof, is reacted according to the general formula IV with a compound of R 5 to Y (IV) 5 wherein R 1 is hydrogen, an alkali metal, C 1-4 alkyl, phenyl, naphthyl or phenyl-C 1-4 alkyl, and Y is van NCO or OCN, and, if desired, a racemic or optically active compound in which R1, R4 and R8 are as defined above and R2 is hydrogen, are alkylated in a manner known per se. 18 67079 For the preparation of therapeutically active racemic or optically active H-substituents 1,3 *, 5 4,5-tetrahydro-2H-benzodiazepine-2-one derivatives with the form of I-2 [ch2 (i) R 2 is CH 2 V-R 6 is a color R 1, halogen, trifluoromethyl, amino or nitro, R 2 is a C 1-6 alkyl, R 8 is carbamoyl, optionally substituted with C 1-4 alkyl, phenyl, naphthyl or phenyl-C 1-4 alkyl, and Rg is phenyl or halophenyl, converted to racemic or optically active 1,3,4,5-tetrahydra-2H-1,4-benzodiazepin-2-one -derivat med den allmänna formeIn II 20. JAp f f \ (II) Il ch2 Λα / * 1 ^ CH — w 25 R6 color R · ^, R2 ooh Rg har ovan angivna betydelse, ellet ett sait därav, omsätts med en förening med den allmänna for-Meln IV R5 - γ (IV) color R8 is an alkali metal, C1-4 alkyl, phenyl, naphthyl or phenyl C1-4 alkyl, and a group of NCO or OCN,