DE2216837C3 - 1,4,5-Benzotrlazocine derivatives, their salts, processes for their preparation and medicinal preparations containing these compounds - Google Patents

Description

The invention further relates to a process for the preparation of the 1,4,5-benzotriazocine derivatives of the general Formula I, which is characterized in that a benzophenone hydrazone is used in a manner known per se of the general formula II

R '

CH,

NO"

'5

(D

C = N

in which X is a hydrogen or halogen atom or an alkyl radical, R 'is a hydrogen atom or a Alkyl radical and R ″ a hydrogen atom or the groupings

NH

C = N-NH ₁

(II)

with at least 2 moles of a haloacetyl halide of the general formula III

Y - CO

(IH)

CH ₂ - Y

converts and the reaction product of the general formula IV

-CO-CH ₂ -Y -CO-CH ₁ -N

I.
N-COCH ₂ Y

K ₂

-CO-CH ₂ -N

40

means where Y is a halogen atom, R _{1 is} a hydrogen atom, an alkyl or an allyl group and R _{2 is} a hydrogen atom, an alkyl, allyl, anilino, benzyl, phenylethyl or phenyl group, the latter being replaced by one or two methyls - or ethyl groups or can be substituted by a chlorine atom or a methoxy group, or R ₁ and R ₂ together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or piperazino group, and R ₃ denotes an alkyl group or R ₁ , F. ₂ and R ₃ together with the nitrogen atom to which they are bonded form a hexamethylenetetramine group, the alkyl radicals being understood to be those having 1 to 4 carbon atoms.

If in the general formula IX and Y denote a halogen atom, this halogen atom can be a chlorine, bromine, fluorine or iodine atom. When X, R ', R ₁ . R ₂ or R ₃ denote an alkyl radical, this alkyl radical can be straight-chain or branched. Special alkyl radicals are the methyl, ethyl, propyl, isopropyl, butyl or isobutyl groups. Specific examples of R "are the aminoacetyl. Methylaminoacetyl, Dimethylaminoaeetyl-, Trimethylam-

(IV)

C = N-NHCOCH ₂ Y

cyclized without prior isolation and optionally the reaction product of the general formula V

N-COCH ₂ Y

(V)

a) for the preparation of compounds in which R "is a hydrogen atom, with a base enlacylated or

b) for the preparation of compounds in which R 'denotes the groupings

-CO-CH ₇ -N

or

-CO-CH ₂

l \
R ₃ R ₂

means with an amine of the general formula VI or VII

HNR ₁

R ₃ -N- R ₁

(VI)

(VIII

implements.

Preferred deacylating agents in process variant a) are amines, alcoholates and inorganic ones Hydroxides and their basic salts because of their good solubility in various solvents in particular amines and alcoholates, such as aminopyridines, thioureas and sodium alcoholates, used as a deacylating agent.

The reaction is preferably carried out in a solder such as chloroform, or methylene chloride Benzene. The reaction already takes place at room temperature, but can be achieved by heating be accelerated. The reaction product can be obtained from the reaction mixture according to known methods Methods are separated. If z. B. the reaction mixture contains the deacylating agent, is this is first removed and the residue is concentrated. The concentrate is then cooled © who treated with ether. The concentrate can also be subjected to column chromatography.

The reaction in process variant b) is preferably carried out in a solvent, to control the course of the reaction and to ensure a smooth reaction. Special examples Solvents that can be used according to the invention • in chloroform, carbon tetrachloride, methylene chloride, Benzene and alcohols. The implementation runs »both at room temperature and at lower temperatures or higher temperatures. In many cases it is advisable to carry out the reaction at room temperature or with heating. The reactants can be used in equimolar amounts will. In some cases, however, higher bulges are obtained when one of the reactants, z. B. the amine of the general formula VI, is used in excess.

The reaction product can be separated off from the reaction mixture by methods known per se. If the reaction mixture contains unreacted amine, it is treated with water or an acid, hydrochloric acid, to remove the amine, and then extracted with an organic solvent. The extract can be purified by chromatography on silica gel, as required.
The implementation of a benzophenone hydrazone

ίο general formula II with a haloacetyl ha'ogenid of general formula III is preferably used in an organic solvent such as chloroform. Methylene chloride, carbon tetrachloride or benzene, carried out. The reaction temperature is preferred

wisely kept as low as possible.

To ensure a smooth reaction process and a condensation agent can be added to the reaction mixture to increase the yield. how a small amount of sodium hydroxide, sodium hy-

add drug carbonate or sodium carbonate. The benzophenone derivative of the general form) JV can optionally be separated from the reaction mixture by methods known per se can e.g. B. neutralize the reaction mixture, then concentrate the organic phase and press / B Ether.

The cyclization of the benzophenone derivative of the general formula IV is already occurring. if the Compound is allowed to stand at room temperature or at lower or higher temperatures. the However, cyclization is accelerated by heating and in the presence of an alkali such as sodium hydroxide. The cyclization is preferably carried out in a solvent such as benzene, chloroform or methylene chloride and carbon tetrachloride. The cyclization product of the general formula V can be separated from the reaction mixture by methods known per se. So z. B. the reaction mixture concentrated under reduced pressure and the concentrate with benzene or Ether are added to the compound of general formula V to crystallize.

The 1,4,5-benzotriazocine derivatives of the general formula I according to the invention have an advantageous effect on the central nervous system and are therefore valuable medicines. They can be known in and of themselves Way to be processed into medicinal products.

Test report

a) Analgesic effect

To study the analgesic effects of the compounds of the invention, mice become electrical irritated. The mice are divided into 6 groups of 5 animals each. The individual groups the compounds of the invention listed in Table I or amidopyrine are used as comparison compounds administered at doses of 100 mg / kg by the oral route. 45 and 90 minutes after administration, respectively the animals are electrically stimulated by the tail (50 V, 10 m sec, I Hz square wave). Included the number of stimuli necessary for the mice to start screaming is determined. The results are in Table I as the ratio of the number of stimuli required before administration to the number of Stimuli listed after administration.

Test connection

Number of stimuli in front of the

Administration. Number of stimuli

after the administration

No.
1

4th
5

12th

CH,

CHj

CH ₃
H

CH ₃

R "

CO - CH, - Br

CO - CH ₂ - NH

C ₂ H ₅

CO-CH ₂ -NH-CH,

egg egg

Cl

Amidopyrine (comparison) ...

a ei

45 minutes ⁰ O minutes 2.0 2.5 1.8 2.9 2.0 2.5 1.9 2.3 1.5 2.3 2.0 2.3 2 "* 2.1

b) Extension of the hexobarbital sleep time Mice are divided into groups of 5 animals each assigned. The compounds according to the invention are given to the animals of the individual groups in doses of 100 mg / kg or Dia; repam in a dose of 10 mg / kg administered by the oral route. Thirty minutes after the dosing, the mice are given hexobarbital sodium injected intraperetoneally at a dose of 100 mg / kg. Then the sleep time is determined. In Table II is the ratio of the sleep time of mice to which the compounds to be examined administered at the sleep time of no compound administered control mice, specified.

Table H.

60

(general formula as in table 1)

f> CH,

Test connection
R.
H

Cl

factor of

renewal

> 3.6

No. R. 7th CH ₃ 8th CH, 9 H 10 CH ₃ 11th CH, 12th CH ₃

Test connection

CO-CH ₂ -NH

CO-CH ₁ N

H
H
H

CO-CH ₂
Bir

Cl

CH;

Br

Cl

—N

Factor the

Bedroom

vcrlän-

cerung

Diazepam (comparison) ... 3.0

509 631,175

c) Suppression of the coordination reflex

The torsion bar method according to N. W. D u η h a in et al., J. Amer. Pharmac. Ass. Sei .. Vol. 46 (1957), p. 208, applied. Male mice of the ddy strain (5 weeks old, 24 to 28 g body weight) are divided into groups of 10 animals each. The test compounds, Diazepam and chlorpromazine administered by the oral route. 1 hour or 3 hours after the The mice are administered on a stick rotating around a horizontal axis (wooden stick with a diameter of 25 mm, 10 rpm). The number of mice that died within 2 minutes fall down is determined. The results are shown in Table III.

Table III dose
(mg kg) I hour 3 SId Tesi connection 0 0 0 control 0
120
240 0
1
0 0
0
1 (No administration)
Number 1*) 120
240 0
1 0
0 No. 2 120
240 0
0 0
0 No. 3 120
240 0
0 0
0 No. 4 120
240 0
0 1
0 No. 5 120
240 1
0 0
1 No. 6 120
240 0
0 1
0 No. 7 120
240 ι,
0 0
0 No. 8 120
240 0
0 0
0 No. 9 120
240 0
0 0
0 No. K) 120
240 0
2 0
2 No. 11 120
240 1
0 0
1 No. 12 15th
30th 4th
10 (P Diazepam 5
in 0
} 0
] Chlorpromazine 20th 7th 6th

ίο fertilize are administered, not down from the rotating rod.

d) Influence on spontaneous motility

Male mice from the ddy strain (5 weeks old, weight 24 to 28 g) are divided into groups of 7 animals divided. The compounds to be investigated are given to the individual groups in doses of 50 mg / kg and diazepam as a comparison compound administered at a dose of 5 mg / kg. The animals no test compound is administered to the control group. 60 minutes after administration put the mice in the middle of an open-topped wooden box. The wooden box has the dimensions 75 χ

75 χ 30 cm and is divided on the floor into grid squares with a side length of 15 cm. During the investigation the walking and straightening of the animals is observed. To determine walking around the number of grid squares is recorded

that a mouse passes through in 1 minute. The results are shown in Table IV.

Test connection Table IV

Number of tarpaulin passed through) uadrale

1.4 ± 1.3 ± 2.2 ±

0.5 1.0 1.0

1.4 ± 0.5

• | See Tables I and II

From these results it can be seen that mice not administered test compound! will ensure that they do not fall off the torsion bar by moving their legs. In contrast, mice fall. who are administered diazepam or chlorpromazine in low doses. These results / own that Dia / epam and Chlorproma / in have a muscle-relaxing effect. On the other hand, mice which were given the compounds of the t-findune in about 1 (! Times the amount of the comparison compound control (no
Administration) 19 t 5.0

No. 1 *) 19 t 5.0

No. 2 18 ± 4.0

No. 3 19 ± 5.0

No. 4 19 ± 5.0

No. 5 18 ± 5.0

No. 6 19 ± 4.0

No. 7 19 ί 4.0

No. 8 20 ± 4.0

No. 9 19 ± 5.0

No. 10 20 ± 5.0

No. 11 17 ± 4.0

No. 12 18 ± 4.0

Diazepam 25 ± 4.0

• I See Tables I and II.

From these results, it can be seen that the administration increased from diazepam in mice

Walking around causing an increased number of righting movements. This shows that diazepam stimulates spontaneous movement and thus has an undesirable side effect for sedatives. in the In contrast, stimulate the invention

Compounds do not involve spontaneous movement and are therefore suitable as sedatives.

e) Acute toxicity

The LD ₅₀ (mg / kg) is determined on mice. The results are shown in Table V.

Number of movements

1.5 ± 1.4 ±

1.0 ±

1.2 -i

1.3 ±

1.4 ±

1.6 ±

2.5 ± 1.4 ±

4.1 r

0.5 0.5 1.0 1.0 0.7 0.5 0.5 1.4 0.5 1.0

Table V TcMicrhmduiig

No l * |

No. 2 .

LH «, line kt'i

1,000 1,500

continuation fixed connection 1_I) _M , Imi! ki; 500
300 No. 3 1,300 500 No. 4 200
800 No. 5 5,000 No. 6 500
000 No. 7 T 000 No. 8 9 (X) No. 9 No. 10 No. 11 No. 12 Diazepam * l See Tables I and II.

summary

The above pharmacological studies show that the compounds of the invention have a greater analgesic effect than amidopyrine after 90 minutes. Your sleep-prolonging Effect is much less than that of diazepam. In addition, the administration causes of the compounds of the invention at effective doses do not interfere with coordinated movements and no undesirable influence on spontaneous mobility. For this reason the compounds of the invention can be used as sedatives. Also show the connections of the invention has lower acute toxicity than diazepam.

The examples illustrate the invention.

Example I.

4 g (0.009523 mol) of 4-bromoacetyl-8-chloro-3,4-dihydro-1-methyl-6-phenyl-1.4.5-benzotriazocin-2 (l H) -one dissolved. This solution is mixed with a solution of 9.5 g (0.1 mol) 2-aminopyridine was added in 20 ml of chloroform. The mixture is stirred for 30 to 40 minutes 60 C implemented. The solvent is then distilled off under reduced pressure. Of the 1 η hydrochloric acid is added to the residue until the pH is 4. The mixture is then with Chloroform extracted. The extract is washed three times with water and dried over sodium sulfate and evaporated under reduced pressure. The concentrate is acid chromatographed (silica gel : Eluent: benzene chloroform ether in a ratio of 1: 1: 1). The F.lual is under diminished Evaporated pressure, and the oily concentrate is mixed with ether. Here is 8-chloro-3.4 - dihydro -1 - methyl - 6 - phenyl - 1.4.5 - benzotriazocin-2 (l H) -one obtained in the form of white crystals with a temperature of 145 ° C.

are reacted according to Example 1 with 13 g (0.138 mol) of 2-aminopyridine, with 3,4-dihydro-1 -methyl -6-phenyl-1,4,5-benzotriazocin-2 (1 H) -Or is obtained in the form of white crystals Recrystallization from chloroform-n-hexane gives crystals with a melting point of 110 ° C.

Q ₆ H ₁₅ N ₃ O:

Calculated ... C 72.43, H 5.70, N 15.84%;
.ο Found .... C 72.20, H 5.85, N 15.55%.

Example 3

5g (0.0123 mol) 4 - bromoacetyl - 8 - chloro - 3,4 - dihydro - 6 - phenyl - 1,4.5 - benzotriazocin - 2 (1H) - one are mixed with 20 ml of chloroform and then with a solution of 15 g (0.16 mol) of 2-aminopyridine in 30 ml of chloroform are added. The mixture is reacted with stirring for 30 minutes at 6O ⁰ C. The solvent is then distilled off under reduced pressure. 1η hydrochloric acid is added to the residue until the pH is 4. The mixture is then extracted with chloroform. The extract is washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is column chromatographed (eluent: benzene-chloroform-ether in a ratio of 1: 1: 1). The eluate is evaporated under reduced pressure, and the oily residue is treated with ether, S-chloro ^^ - dihydro-ö-phenyl-IAS-benzotriazocin-2 (1 H) -one is obtained in the form of white crystals. After recrystallization Crystals with a melting point of 192 to 194 ° C. are obtained from chloroform-ether-η-hexane.

C ₁₅ H ₁₂ ClN ₃ O:

Calculated ..
«Found ...

C 63.05. H 4.23, N 14.71%;
C 63.17. H 4.07, N 14.74%

Example 4

5 g (0.0134MoI) of 4-bromoacetyl-3,4-dihydro-6-phe nyl-1.4.5-benzotriazocin-2 (1 H) -one are according to. Example 3 reacted with 15 g (0.16 mol) of 2-aminopyridine, 3,4-dihydro-6-phenyl-1,4,5-benzotria / ocin-2 (l H) -one is obtained. The compound is recrystallized from chloroform-ether-n-hexane white crystals with a melting point of 159 to 160 ° C are obtained.

C ₁₅ H ₁₃ N ₃ O:

Calculated
found .

C 71.70. H 5.21. N 16.72%:
C 71.43. H 5.11, N 16.65%.

C ₁₁₁ H ₁₄ ClN ₃ O:

Calculated ..
found ...

C 64.11. H 4.71. N 14.02%:
C 63.86. H 4.46. N 13.80%

Example 2

1.5 f. (0.01294 mol) 4 - bromoacetyl - 3.4 - dih \ dro-1 - methν I - 6-phenyl -1.4.5 - ben / otriazocin -2 (1Hl- on) of 2-ammo pyridine and of ethanol can be made in place of chloroform by the method described above.

Example 5

In 20 ml of chloroform Ig (0.00238 mol 4-Bromoacetyl-8-chloro-3.4-dihydro-1-methyl-6-phenyl-1.4.5-benzotriazocin-2 (1 H) -one dissolved this The solution is poured into a solution of 1 {{0.0147 Mo!) Sodium ethylate in 500 ml of ethanol while stirring carried. The mixture is 40 minutes at room

stirred temperature and then mixed with a small amount of chloroform. The mixture is washed with water, dried over sodium sulfate and evaporated under reduced pressure at low temperature. The residue is column chromatographed (elution medium: benzene-ether-chloroform in a ratio of 1: 1: 1). The eluate is combined and evaporated under reduced pressure. Ether is added to the concentrate, with 8-chloro-3,4-dihydro-1-methyl-6-phenyl-1,4,5-benzo | ₀ triazocin-2 (l H) -one is obtained in the form of white crystals with a temperature of 145 ° C.

Example 6

5 g (0.0108 mol) of 4-bromoacetyl-8-bromo-3.4-dihydro-1-methyl-6-phenyl-1,4,5-benzotriazocir-2 (1 HI-one) are dissolved in 50 ml of chloroform solution is treated with a solution of 20 g (0.212 mol) of 2-aminopyridine in 200 ml of chloroform. the mixture is reacted Unler stirring for 30 minutes at 30 to 40 ⁰ C. the solvent is then distilled off under reduced pressure. the residue is washed with 1 n-hydrochloric acid is added until the pH is 4. The mixture is then extracted with chloroform. The extract is washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. The concentrate is treated with ether, whereby 8 - bromine - 3,4-dihydro-i-methyl-6-phenyll, 4,5-benzotriazocin-2 (l H) -one is obtained in the form of white crystals, after recrystallization from ethanol, crystals with a melting point of 143 to 145 ° C. are obtained.

C ₁₆ H ₁₄ BrN ₃ O:

Calculated ... C 55.83, H 4.10. N 12.21%:
found .... C 55.64, H 4.00, N 11.89%.

Example 7

A mixture of 20 g (0.0443 mol) of 4-bromoeetyl-8-bromo -3,4-dihydro-6-phenyl -1,4,5-benzo triazoci n-2 (1H) -one and 100 ml of chloroform is with a Solution of 94.1 g (1.0 mol) of 2-aminopyridine in 950 ml of chloroform. The mixture is reacted at 60 ° C. for 30 to 40 minutes with stirring. The reaction mixture is treated as in Example 6, 8-bromo-3,4-dihydro-6-phenyl-1,4,5-benzotriazocin-2 (1 H) -one being obtained in the form of white crystals. After recrystallization from chloroform-ether-n-hexane, crystals are obtained which decompose at 208 to 209 ° C.

40

C ₁₅ H ₁₂ BrN ₁ O:

Calculated ..
found ...

C 54.56. H 3.66. N 12.73%:
C 54.63. H 3.60. N 12.66%.

55

60

Example 8

10 ml of chloroform are mixed with 1 g (0.00256 mol) of 4-bromoacetyl-8-fluoro-3.4-dihydro-6-phenyll.4.5-benzotriazocin-2 | l H (-one. The resulting solution is dissolved in a solution of 2.4 g (0.0256 mol) of 2-aminopyridine is added to 15 ml of chloroform. The mixture is reacted with stirring for 5 minutes at 50 ° C. The reaction mixture is then evaporated under reduced pressure. The concentrate is treated with 1N hydrochloric acid, while cooling with ice, until the pH is 4. The Gemiscl is then extracted with chloroform. The Extrak is washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue is treated with .n-Hexai, whereby 8 - fluorine - 3,4 - dihydro - 6 - phenyl-1,4,5 beiizotriazocin-2 (1 H) -one as white stalle Kri, mp 145 to 150 ⁰ C is obtained.

The IR absorption spectrum of the aforementioned compound in a KBr compact shows characteristic bands at 1670, 3040, 3180 and 3400 cm 'The nuclear magnetic resonance spectrum (solvent: CDCl ₃ standard: TMS) shows characteristic signals at 3.5 and 4.1 ppm ( 2H) and 8.8 ppm (1H).

Example 9

A mixture of 1 g (0.00247 mol) of 4-bromoacelyl 8-l3uor-3.4-dihydro-1-methyl-6-phenyl-1.4.5-benzotriazocin-2 (1 H) -one and 20 ml of chloroform is ir a mixture of 5 g (0.053 mol) of 2-aminopyridine and 50 ml of chloroform was added. The mixture obtained in this way is reacted for 10 minutes at 30 to 40 ° C. with stirring. The reaction mixture is then evaporated under reduced pressure. There; Concentrate is used with 1N hydrochloric acid while cooling with ice until the pH is 4. There; The mixture is extracted with chloroform. The extract is washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue obtained is column chromatographed (eluent: benzene-chlorine-ether in a ratio of 1: 1: 1). The eluate was evaporated under reduced pressure. The oily concentrate is treated with a mixture of n-hexai and ether, with 8-fluoro-3,4-dihydro 1 -methyl-6-phenyl-1,4,5-benzotriazocin-2 (1 H) -Ot in as white crystals, mp 80-81 C ^c is erhaltei.

C ₁₁₁ H ₁₄ FN ₃ O:

Calculated ... C 67.83. H 4.98, N 10.96%;
found .... C 67.68, H 5.18. N 10.71%.

Example 10

In 20 ml of chloroform, 1 g (0.0021 mol) of 4-bromoacetyl-8-bromo-3,4-dihydro-1-methyl-6-phenyl is added 1.4.5-benzotriazocin-2 (l H) -one dissolved. The receive « The solution is poured into a solution of 0.9 pounds (0.0132 mol) of sodium ethylate in 500 ml of ethanol, while stirring ' carried. The mixture is stirred for 40 minutes at room temperature and then with a gerin added amount of chloroform. The mixture thus obtained is washed three times with water, over Sodium sulfate dried and evaporated under reduced pressure at low temperature. Of the The residue is subjected to column chromatography (elution medium: benzene ether chloroform in the ratio 1: 1: 1). The eluate is combined and mined evaporated under the current pressure. The residue is mixed with ether, with 8-bromo-3,4-dihydro-1-methyl 6-pheml-1.4.5 - benzotriazocin - 2 (1 H) -one in form After recrystallizing from ethanol, crystals of F 14 are obtained: up to 145 C.

Example 11

A suspension of 2.5 g (0.00647 moles) of 4-bromoacetyl 1 - 3,4 - dihydro - 8 - methyl - 6 - phenyl -1,4,5 - benzotriazocin-2 ( 1H) -one in 60 ml of chloroform is treated with a solution of 10 g (Q'06 mol) of 2-aminopyridine added in 50 ml of chloroform. The mixture is reacted at 60 ° C. for 30 to 40 minutes with stirring. The reaction mixture is then evaporated under reduced pressure. The residue will 1 η hydrochloric acid is added until the pH is 4. The mixture is extracted with chloroform. Of the The extract is washed three times with water, dried over sodium sulfate and reduced under reduced pressure Pressure evaporated. The concentrate is mixed with ether, whereby 3,4 - dihydro - 8 - methyl - 6 - phenyl, 4,5-benzotriazocin-2 (l H) -one is kept in the form of white crystals. After recrystallizing from Chloroform-ether-n-hexane crystals with a melting point of 212 to 213 ° C. are obtained.

C ₁₆ H ₁₅ N ₃ O:

Calculated ... C 72.43, H 5.70, N 15.84%;
found .... C 72.23, H 5.41, N 15.56%.

Example 12

1 g (0.0025 mol) of 4-bromoacetyl-3,4-dihydro-1,8-dimethyl - 6 - phenyl -1,4,5 - benzotriazocin - 2 (1 H) - one and 4 g (0.0425 mol) of 2-aminopyridine are prepared according to Example 11 implemented, with 3,4-dihydro-1,8-dimethyl - 6 - phenyl -1,4,5 - benzotriazocin - 2 (1 H) - one is obtained. After recrystallizing from In chloroform-ether-n-hexane, white crystals with a melting point of 191 ° to 192 ° C. are obtained.

C ₁₇ H ₁₇ N ₃ O:

Calculated ... C 73.09, H 6.13, N 15.04%;
found .... C 72.96, H 6.11, N 14.88%.

35

40

Example 13

In 50 ml of ethanol 1 g (0.0026 mol) of 4-bromoacetyl - 3,4 - dihydro - 8 - methyl - 6 phenyl -1,4,5 - benzolriazocin-2 (1 H) -one and then 0, 2 g (0.0026 mol) thiourea entered. The mixture is reacted with stirring at 60 ° C. for 1 hour and then refluxed for 45 minutes. The solvent is distilled off under reduced pressure and 14 ml of water are added to the residue. The mixture is refluxed for a few minutes and then allowed to cool. The solution is then extracted with chloroform. The extract is washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is column chromatographed (silica gel; eluent: benzene-chloroform
Ether in a ratio of 1: 1: 1). The eluate is evaporated under reduced pressure and ether is added to the residue to give white crystals. After recrystallization from chloroform-ether-η-hexane, 3,4-dihydro-8-methyl-6-phenyl-1,4,5-benzotriazocin-2 (1 H) -one is obtained in the form of crystals from F. 212 to 213 "C hall.

Example 14

1 g (0.00238 mol) 4-bromoacetyl-8-chloro-3,4-dihydro -! - methyl - 6 - phenyl - 1,4,5 - benzotriazocin-2 <1 H) -one is replaced with 30mJ chloroform /. Tue-s obtained mixture is cooled with ice in 10 ml of an aqueous 40% solution of methylamine registered. The mixture is stirred at room temperature for 30 minutes. Then the Solvent is distilled off under reduced pressure, and the residue is mixed with water. The resulting solution is extracted with chloroform. The extract is washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue will ether is added and the mixture is left to stand in the cold, with 8-chloro-3,4-dihydro-4-methylaminoacetyl-1 -methyl-6-phenyl-1,4,5-benzotriazocin-2 (1 H) -one obtained in the form of white crystals will. After recrystallization from chloroform-ether-n-hexane, crystals with a melting point of 160 "C obtain.

C ₁₉ H ₁₉ ClN ₄ O ₂ :

Calculated ... C 61.54, H 5.16. N 15.11%;
found .... C, 61.29. H 5.09. N 15.40%.

Following the procedure described in Example 14, the following compounds are prepared:

1. 3,4-Dihydro-4-methylaminoacetyl-1-methyl-

6-phenyl-1,4,5-benzotriazocin-2 (l H) -one

The compound is obtained in the form of white crystals with a melting point of 146 to 148 ° C. After recrystallization the following analytical data are obtained from chloroform-ether-n-hexane.

C ₁₉ H ₂₀ N ₄ O ₂ :

Calculated ... C 67.84, H 5.99, N 16.66%;
found .... C 67.55, H 5.83, N 16.40%.

2. S-chloro-S ^ -dihydro ^ -methylaminoacet yl-6-pheny 1-1,4,5-benzotriazocin-2 (IH) -Oi,

The compound is obtained in the form of white crystals with a melting point of 191 to 192 ° C. After recrystallization the following analytical data are obtained from chloroform-ether-n-hexane.

C ₁₈ H ₁₇ ClN ₄ O ₂ :

Calculated ... C 60.59, H 4.80, N 15.70%:
found .... C, 60.17. H 4.61, N 15.40%.

3. 3,4-Dihydro-4-methylaminoacetyl-6-phenyl-

1,4,5-benzotriazocin-2 (1 H) -one

The compound is obtained in the form of white crystals with a melting point of 164 to 166 ° C. After recrystallization the following analytical data are obtained from chloroform-ether-n-hexane.

C ₁₈ H ₁₈ N ₄ O ₂ :

Calculated . .. C 67.10. H 5.63, N 17.38%;
found .... C 66.87, H 5.51, N 17.00%.

4. 8-chloro-3,4-dihydro-4-dimethylaminoacetyl-

I-methyl-6-phenyl-1,4.5-benzotriazocin-2 (1 H) -one: white crystals, F. I26C

C _2n H ₂₁ ClN ₄ O ₂ :

Calculated ... C 62.41. H 5.50. N 14.56%;
found .... C 62.23, H 5.45. N 14.79%.

5. S-chloro ^ -dihydro ^ -dimelhylaminoacetyl-

509 631/175

■ o

6-phenyl-1,4,5-benzotriazocin-2 (1 H) -one: white crystals, m.p. 178'C

C ₁₉ H ₁₉ ClN ₄ O ₂ :

Calculated ... C 61.54, H 5.16, N 15.11%; found .... C 61.35, H 5.08, N 14.90%.

6. 3,4-Dihydro-4-meth'-aminoacetyl-8-methyl-6-phenyl-1,4,5-benzotriazocin-2 ( 1 H) -on:

white crystals, m.p. 198 to 199 C after

Recrystallize from chloroform-ether-n-hexane

C ₁₉ H ₂₀ N ₄ O ₂ :

Calculated ... C 67.84, H 5.99, N 16.66%; found .... C 67.64, H 5.90, N 16.44%.

7. 8-Bromo-3,4-dihydro-4-methyl aminoacetyl-6-phenyl-l, 4,5-benzotriazocin-2 (l H) -one, mp 196 ^C C

C ₁₈ H ₁₇ BrN ₄ O ₂ :

Calculated ... C 53.88, H 4.27, N 13.96%; found .... C 53.69, H 4.15, N 13.60%.

8. S-bromine ^^ - dihydro ^ -methylaminoacetyll-methyl-6-phen \ l-l, 4.5-benzotria / ocin-2 ( 1 H) -one,

F. 167 C

C ₁₉ H ₁₉ BrN ₄ O ₂ :

Calculated ... C 54.95. H 4.61, N 13.49%; found.. . C 54.88, H 4.75, N 13.55%.

9. S-bromo-S ^ -dihydro ^ -dimethylaminoacetyl-1-methyl-6-phenyl-1,4,5-benzotria;? Ocin-2 ( 1 H) -one, F. 143 C

C ₂₀ H ₂₁ BrN ₄ O ₂ :

Calculated . . C 55.95, H 4.93. N 13.05%; found .... C, 55.70. H 4.52. N 12.80%.

Example 15

Ig (0.00238MoI) 4 - bromoacety) - 8 - chloro - 3.4 - dihydro - 1 - methyl - 6 - phenyl - 1,4,5 - benzctriazocin-2 (1 H) -one is added to 30 ml of chloroform. That The resulting mixture is introduced into 10 ml of diethylamine solution while cooling with ice. The received Mixture is stirred for 30 to 40 minutes at room temperature and then the solvent is added peeled off under reduced pressure. The residue is mixed with water and then with chloroform extracted. The extract is washed three times with water, dried over sodium sulfate and taken under evaporated under reduced pressure. The oily residue is with a mixture of 6 ml of acetone and 0.5 ml of water and then 1 g of tartaric acid. After the tartaric acid has dissolved, the mixture is filtered through a glass filter. The acetone solution is reduced to half of the original Reduced in volume and then left to stand in the cold. Here, 8-chloro-3,4-dihydro-4-diethylaminoacetyl-1-methyl-6-phenyl-1,4,5-benzotriazocin-2 (l H) -on-tartrate in the form of white needles. After recrystallization from acetone - water (5: 1) white crystals with a melting point of 113 to H5 ° C are obtained. Similarly, the corresponding Picrat obtained with a mp of 175 ° C.

η _m Aefi the procedural ^ ^ nwtrdendi described in Example below sclerotherapy prepared:

r-S ^ dihydro- ^ äthylaminoacetyl-

Maats is, 99 C C ₀ H ₂₁ ClN ₄ O ₂ C ₆ H ₃ N ₃ O ₇ (picrates ,:

6 H 3.94, N 15.97%;

: kNi634%

11. ^ DiethylaminoacetyW ^ -düiydro-o-phenyl-

4 5-benzotriazocin-2 (1 H) -one, m.p. 174-176 ° C

after recrystallization from acetone-hexane

C ₂₁ H ₇₄ N ₄ O ₂ :
Calculated

C 69.21. H 6.64, N 15.37%; C 69.07. H 6.62, N 15.01%.

Example 16

1 ο (000247 mol) 4 - bromacety! - 3.4 - dihydro-8 - fluo -Ί - methyl - 6 - phenyl -1,4 5 - benzotriazoan- ^ (1 H) -one is dissolved in 50 ml of benzene. This solution is added dropwise, with stirring, to 0 g of a 70% strength aqueous solution of monoethylamine. The mixture is stirred for 30 minutes at room temperature and then evaporated under reduced pressure. The residue is mixed with water and benzene. The benzene phase is separated off, washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. The residue wira * fJ ^ f "": "^ ³ ! ¹ left to crystallize. ^^ Dihydro ^ -athyl. After recrystallization from ethanol, crystals with a melting point of 135 to 136 ° C are obtained.

C ₂₀ H ₂₁ N ₄ FO ₂ :

Calculated . .
found ...

C 65.20. H 5.75, N 15.21%. C 65.33. H 5.83. N 15.13%.

C ₂₂ H ₂₅ ClN ₄ O ₂

Calculated ..
found ...

C ₆ H ₃ N ₃ O ₇ (picrate):

C 52.38, H 4.40, N 15.27%:

C 52.23, H 4.36, N 14.98%.

Example 17

In 30 ml of chloroform 1 g (0.00238 mol) of 4 - bromoacetyl - 8 - chloro - 3.4 - dihydro - 1 - methyl-6-phenyl- 1,4,5-benzotriazocin-2 (1 H) -one entered. The mixture thus obtained is poured under ice-cooling mixed with 10 ml of diallylamine. The mixture is stirred for 30 to 40 minutes at room temperature, and the solvent is then distilled off under reduced pressure. The residue is washed with water added and the mixture is extracted with chloroform. The extract is washed three times with water washed, dried over sodium sulfate and evaporated under reduced pressure. The Concentral a mixture of 6 ml of acetone and 0.5 ml of water and then 1 g of tartaric acid are added After the tartaric acid has dissolved, the mixture is filtered through a glass filter. The acetone-containing Solution is concentrated to half of the original volume and then in the KälU ditched. Here, 8-chloro-3,4-dihydro falls 4-diallylaminoacety! -L-methyl-6-phenyl-l, 4,5-benzo triazocine 1 H) -on-tartrate in the form of a white needle the end. After recrystallization from acetone-water

(5: 1) white crystals with a melting point of 86 "C are obtained. C ₂₄ H ₂₅ ClN ₄ O ₂ · C ₄ H ₆ O ₆ · 2H ₂ O: Calculated ... C 53.98, H 5.66, N 8.99%; found ... C 54.06, H 5.34, N 8.91%.

Example 18

5 g (0.01188 moles) of 4-bromoacety 1-8-chloro-3,4-dihydro - 1 - methyl - 6 - phenyl -1,4,5 - benzotriazocin-2 (1 H) -one are mixed with 50 ml of chloroform. the The solution obtained is introduced into 25 g (0.268 mol) of aniline. The mixture is stirred for ί 2 hours reacted at room temperature. Then the solvent is under reduced pressure distilled off. The residue is treated with 0.5N hydrochloric acid added until the pH is about 3. The mixture is extracted with chloroform. The extract will be washed three times with Wasocr, dried over sodium sulfate and evaporated under reduced pressure. Ether is added to the concentrate, with 8-chloro-3,4-dihydro-1-methyl-4-phenylaminoacetyl-6-phenyl-1 A5-benzotriazocin-2 (l H) -one is obtained in the form of white crystals. After recrystallization from chloroform-n-hexane Crystals of F. 182 "C obtained.

C ₂₄ H ₂₁ ClN ₄ O ₂ :

Calculated . .
found ....

C 66.58, H 4.89, N 12.94%; C 66.42. H 4.86, N 12.66%.

Following the procedure described in Example 58 the following connections are made:

12. S-chloro-SA-dihydro ^ -phenylaminoacetyl-6-phenyl-1,4,5-benzotriazocin-2 (l H) -on,

white crystals, m.p. 13O ¹ C

C ₂₃ H ₁₉ ClN ₄ O ₂ :

Calculated ... C 65.95, H 4.57, N 13.38%; found .... C 66.02, H 4.39, N 13.13%.

13. 8-Chloro-3,4-dihydro-4- (p-methoxyphenyl) aminoacetyl-1 -methyl-6-phenyl-1,4,5-benzo-

triazocin-2 (1H) -one, m.p. 191 ° C

C ₂₅ H ₂₃ ClN ₄ O ₃ :

Calculated ... C 64.86, H 5.01, N 12.10%; found .... C 64.57, H 4.90, N 12.08%.

14. 8-chloro-3,4-dihydro-4- (p-methoxyphenyljaminoacetyl-6-phenyl-1,4,5-benzotriazocin-

2 (1H) -one, m.p. 197 ° C

C ₂₄ H ₂₁ ClN ₄ O ₃ :

Calculated ... C 64.21, H 4.72, N 12.48%; found .... C 63.92, H 4.76, N 12.53%.

15. 8-Chloro-3,4-dihydro-4- (p-methylphenyl) -aminoacetyl-1 -methyl-6-phenyl-1,4,5-benzo-

triazocin-2 (1 H) -one, m.p. 188 ° C

C ₂₅ H ₂₃ ClN ₄ O ₂ :

Calculated ...
found

C 67.18, H 5.19, N 12.54%; C 66.86, H 5.06, N 12.12%.

16. 8-chloro-3,4-dihydro-4- (p-methylphenyl) -aminoacetyl-ö-phenyl-lAS-benzotriazocin-

2f lH) -on. F. 226 ⁰ CC ₂₄ H ₂₁ ClN ₄ O ₂ :

Calculated ...
found ....

C 66.58, H 4.89, N 12.94%; C 66.50, H 5.10, N 12.70%.

Example 19

5 g (0.0134MoI) 4-bromoacetyl-3,4-dihydro-6-phe- * iyl-l, 4,5-benzotriazocin-2 (lH) -one with 50 ml

ίο added chloroform. The mixture is introduced into 25 g (0.206 mol) of 2,6-xylidine with stirring. The mixture obtained is ^{reacted at 60 °} C. for 2 hours. The solvent is then distilled off under reduced pressure. 0.5N hydrochloric acid is added to the residue until the pH is about 3. The mixture is extracted with chloroform. The extract is washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. The concentrate is column chromatographed (eluent: benzene-ether-chloroform in a ratio of 1: 1: 1). The eluate is combined and evaporated. The residue is mixed with ether, with 4- (2 ', 6'-dimethylphenylamino) acetyl-3,4-dihydro-6-phenyl-1,4,5-benzotriazocin-2 (l H) -one in Form of white crystals is obtained. After recrystallization from chloroform-ether-n-hexane, crystals with a melting point of 225 to 226 ° C. are obtained.

C ₂₅ H ₂₄ N ₄ O ₂ :

Calculated .
found ..

C 72.79. H 5.86, N 13.58%: C 72.50. H 5.75, N 13.34%.

Following the procedure described in Example 19, the compounds shown are prepared.

17. 4- (2 ', 6'-Dimethylphenylamino) -acetyi-

3,4-dihydro-1-methyl-6-phenyl-1,4,5-benzotriazocin-2 (l H) -one, white crystals, m.p. 161 to 162C after recrystallization

Chloroform-ether-n-hexane

C ₂₆ H ₂₆ N ₄ O ₂ :

Calculated ... C 73.22, H 6.14, N 13.14%: found .... C 73.00, H 6.09, N 12.96%.

18 8-chloro-4- (2 ', 6'-dimelhylphenylamino) -

acetyl-3,4-dihydro-1 -methyl-6-phenyl-

1.4.5-benzotnazocin-2 (1 H) -one, m.p. 170 C

C ₂₆ H ₂₅ ClN ₄ O ,:
Calculated . ..

found

C 67.74, H 5.47, N 12.16%; C 67.58, H 5.50, N 12.00%.

19. 8-chloro-4- (2 ', 5'-dimethylphenylamino) -

acetyl-3,4-dihydro-1 -methyl-6-phenyl-

l, 4,5-benzotriazocin-2 (l H) -one, m.p. 210X

C ₂₆ H ₂₅ ClN ₄ O ₂ :

Calculated ...
found ....

C 67.74. H 5.47, N 12.16%: C 68.03, H 5.42, N 12.12%.

20. 8-chloro-4- (2'.6'-diethylphenylamino) -

acetyl-3,4-dihydro-1-methyl-6-phenyl-

1,4,5-benzotriazocin-2 (l H) -one, m.p. 125 ° C

C ₂₈ H ₂₉ ClN ₄ O ₂ :

Calculated ...
deeply ....

C 68.77. H 5.98, N 11.46%; C 68.99. H 6.02, N 11.00%.

21. 8-chloro-3,4-dihydro-4- (2 \ 5'-dimethylphenylamino) acetyl-6-phenyl-1,4,5-benzo-

triazocin-2 (1 H) -one, m.p. 23PC

C ₂₅ H ₂₃ ClN ₄ O ₂ :

Calculated ...
found ....

C 67.18, H 5.19, N 12.54%; C 66.83, H 5.25, N 12.59%.

22. 8-chloro-3,4-dihydro-4- (2 ', 6'-dimethylphenylaraino) -acetyl-6-phenyl-1,4.5-benzo-

triazocin-2 (1 H) -one, m.p. 138 ^C C

C ₂₅ II ₂₃ ClN ₄ O ₂ :

Calculated ... C 67.18, H 5.19, N 12.54%; Found ... C 67.23, H 5.12, N 12.49%.

23. 8-chloro-3,4-dihydro-4- (2 ', 6'-diethylphenylamino) acetyl-6-phenyl-1,45-benzo-

triazocin-2 (1 H) -one, m.p. 186 C

C ₂₇ H ₂₇ ClN ₄ O ₂ :

Calculated ... C 68.27, H 5.73, N 11.80%; found .... C 68.36, H 5.71, N 11.61%.

24. 3,4-Dihydro-4- (2 ', 5'-dimethylphenylamino) -acetyl-6-phenyl-1,4,5-benzotriazocin-2 ( 1 H) -one,

F.253C

C ₂₅ H ₂₄ N ₄ O ₂ :

Calculated ... C 72.79, H 5.86, N 13.58%; found .... C 73.00, H 5.86, N 13.63%.

25. 3,4-Dihydro-4- (2 ', 6'-diethylpheEylamino) -acetyl-6-phenyl-1 , 4,5-benzotriazocin-2 (1 H) -one,

F. 20FC

C ₂₇ H ₂₀ N ₄ O ₂ :

Calculated ... C 73.61, H 6.41, N 12.72%; found .... C 73.31, H 6.34, N 12.49%.

26. 8-3rom-3,4-dihydro-4- (2 ', 6'-dimethylphenylamino) acetyl-6-phenyl-1,4,5-benzo-

triazocin-2 (1 H) -one, m.p. 144 C

C ₂₅ H ₂₃ BrN ₄ O ₂ :

Calculated
found .

C 61.11, H 4.72, N 11.40%; C 61.05, H 4.69. N 11.48%.

27. 8-Bromo-3,4-dihydro-4 ι2 ', 6'-dimethylphenylamino) acetyl-1 -methyl-6-phenyl, 4,5-benzotriazocin-2 (1H) -one, m.p. 162C

C ₂₆ H ₂₅ BrN ₄ O ₂ : C. 61.79, H 4.99, N 11.09%; Calculated C. 62.02. H 4.94. N 10.91%. found . • ·

28. 3,4-Dihydro-4- (2 ', 6'-dimethylphenylamino) acetyl-1,8-dimethyl-6-phenyl-1,4,5-benzotriazocin-2 (t H) -one, white crystals, mp 170.5 to 171.5 ° C after recrystallization

Chloroform-ether-n-hexane

28 N ₄ O ₂ :

Calculated ... C 73.61, H 6.41, N 12.72%; found .... C 73.34, H 6.35, N 12.57%.

The mixture is introduced into 25 g (0.196 mol) of o-chloranilm. The mixture thus obtained is reacted with stirring at room temperature for 12 hours. The solvent is then distilled off under reduced pressure. 0.5 N acid is added to the residue until the pH is about 3. The mixture is treated with chloroform and then washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. The concentrate is column chromatographed (eluent 1: benzene-ether chloroform in a ratio of 1: 1: 1. The eluate is combined and evaporated. Ether is added to the residue, whereby 4- (2'-chlorophenylammo) -ac _e t _> 1- R-chloro ^ -dihydro-l-methyl-o-phenyl-lAS-benzotriazocin-2 (l H) -one is obtained in the form of white crystals. After recrystallization from chloroform-ether-n-hexane, crystals from F. 174 to 175 C.

C ₂₄ H ₂₀ ClN ₄ O ₂ :

Calculated ... C 61.68, H 4.31, N 11.99%: found .... C 61.42, H 4.22, N 11.87%.

Following the procedure described in Example 20, the following compounds are prepared:

29 8-chloro-3,4-dihydro-4- (2'-chlorophenylamino) -

acetyI-6-phenyl-l, 4,5-benzotriazocin-2 (IH) -On,

M.p. 215 to 216 ° C

C ₂₃ H ₁₈ Cl ₂ N ₄ O ₂ :

Calculated ... C 60.94, H 4.00, N 12.36%: found .... C 61.17, H 4.04, N 12.53%.

30. 8-chloro-3,4-dihydro-4- (3'-chlorophenylarhino) -acetvl-l-methyl-o-phenyl-lAS-benzotriazocin-

2 (1 H) -one, mp 113 ° C

C ₂₄ H ₂₀ ClN ₄ O ₂ :

Calculated ... C 61.68, H 4.31, N 11.99%; found .... C 61.99, H 4.53, N 11.67%.

31. 8-Chloro-3,4-dihydro-4- (3'-chlorophenylamino) -acet yl-6-phenyl-1 A5-benzotriazocin-2 (1 H) -oii,

Mp 193 ° C

C ₂₃ H ₁₈ Cl ₂ N ₄ O ₂ :

Calculated ... C 60.94, H 4.00, N 12.36%; found .... C 61.02, H 4.25, N 12.49%.

32. SA-Dihydro ^ -P'-chlorophenylaminohacetyl-methyl-6-phenyl-1,4,5-benzotriazocin-2 (l H) -on.

152 ° C

C ₂₄ H ₂₁ ClN ₄ O ₂ :

Calculated ... C 66.58. H 4.89, N 12.94%; found .... C, 66.43. H 4.82, N 12.94%.

33. 3,4-Dihydro-4- (2'-chlorophenylamino) -acetyl e-methyl-o-phenyl-1,4,5-benzolriazocin-2 (1 H) -one.

F. 202 C

Example 20

5 g (0.01188 moles) of 4-bromoacetyl-8-chloro-3,4-dihydro - 1 - methyl - 6 - phenyl - 1,4,5 - benzotriazocin-2 (1H) -OIi are mixed with 50 ml of chloroform.

C ₂₄ H ₂₁ ClN ₄ O ₂ : C. 66.58, H 4.89, N 12.94 %; Calculated ... C. 66.78, H 4.81, N 12.83 %. found ....

34.3,4-Dihydro-4- (2'-chlorophenylamino) -acetyl.S-dimethyl-o-phenyl-IAS-benzotriazocin-

2 (1H) -on. F. 18TC

2 \ 6 837 / f3

C ₂₅ H ₂₃ ClN ₄ O ₂ :

Calculated
found ·...·.

C 67.18, H 5; 19, N 12.54%;
C 67.01, H 5.09, N 12.11%. C ₂₅ H ₂₃ ClN ₄ O ₂ :

Calculated ...
found ....

C 67.18, H 5.19, N 12.54%; C 66.97, H 5.37, N 12.14%.

35. 8-Bromo-3,4-dihydro-4- (3'-chlorophenylamino) -aetyl-6-phenyl-1 , 4,5-benzotriazocin-2 (l H) -Oh,

white crystals, m.p. 192 to 193 ⁹ C after
Recrystallize from chloroform-ether-hexane

40.3,4-Dihydro-4- (benzylamine-p) acetyl-6-phenyl-

l, 4,5-benzotriazocin-2 (l H) -one, white crystals,

F. 198 to 205 ⁰ C after recrystallization

Chloroform-n-hexane

C ₂₃ H ₁₈ BrClN ₄ O ₂ C. 55.49, H 3.64, N 11.26%: _{| o} C ₂₄ H ₂₂ N ₄ O ₂ H ₂ O 69.22, H 5.81, N 13.45% Calculated ... C. 55.29. H 3.52, N 11.03%. Calculated ... C 69.67, H 5.25, N 13.32% found .... found . ... C

36. 8-Bromo-3,4-dihydro-4- (3'-chlorophenylamino) -acetyl-1-methyl-o-phenyl-IAS-benzotriazocin-

2 (1 H) -one, m.p. 127 C

C ₂₄ H ₂₀ BrClN ₄ O ₂ :

Calculated ... C 56.32. H 3.94. N 10.95%;
found .... C 56.00, H 3.92. N 10.51%.

37. 3,4-Dihydro-4- (3'-chlorophenylamino) acetyl-1,8-dimethyl-6-phenyl-1 , 4,5-benzotriazocin-

2 (1H) -on. M.p. 145 to 146 ° C

C ₂₅ H ₂₃ ClN ₄ O ₂ :

Calculated
found .

C 67.18. H 5.19, N 12.54%:
C 66.88, H 5.12, N 12.14%.

Example 21

20th

25th

5 g (0.01188MoI) of 4-bromoacetyl-8-chloro-3,4-dihydro - 1 - methyl - 6 - phenyl -1,4,5 - benzotriazocin-2 (1 H) -one are mixed with 50 ml of chloroform and then mixed with 25 g (0.233 mol) of benzylamine. The resulting mixture is stirred for 12 hours reacted at room temperature. Then the solvent is under reduced pressure distilled off. The residue will be mi! O.5N hydrochloric acid added until the pH is about 3. Chloroform is added to the mixture and then three times washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is column chromatographed (solvent: benzene-ether-chloroform in the ratio 1: 1: 1). The eluate is combined and evaporated. Ether is added to the residue, 4 - (benzylamino) - acetyl - 8 - chloro - 3.4 - dihydro-1 - methyl - 6- phenyl -1.4.5 - benzotriazocin - 2 (1 H) - one in the form of white crystals with a melting point of 137 to 138 ° C is obtained.

C ₂₅ H ₂₃ ON ₄ O ₂ :

Calculated ... C 67.18, H 5.19, N 12.54%;
found .... C, 67.12. H 5.12, N 12.16%.

Following the procedure described in Example 21, the following compounds are prepared:

38. 8-chloro-3,4-dihydro-4- {1-phenylethylamino) -acetyl-l-methyi-o-phenyl-IAS-benzotriazocm-

2 (1 H) -one, m.p. 160 ° C

C _2n H ₂₅ ON ₄ O ₂ :

Calculated ... C 67.74. H 5.67. N 12.16 ^O <>:
found .... C 67.45. H 5.40. N 12.42%.

39. 8-Oi! Or-3.4-dihydro-4- (1-phenylethylamino) -acetyJ-6-phenyte-1,4,5-benzotriazocin-2 (! H) -on.

F.146 C

41.S-bromo-S ^ -dihydro ^ -fbenzylaminoi-acetyl-

1 -methyl-6-phenyl-1,4,5-benzotriazocin-2 (1 H) -one,

M. 147 ⁰ C

C ₂₆ H ₂₃ BrN ₄ O ₂ :

Calculated ... C 61.11, H 4.72, N 11.40%; found .... C 60.82. H 4.69, N 11.00%.

42.3,4-Dihydro-4- (benzylamino) -acetyl-

1,8-dimethyl-6-phenyl-1,4,5-benzotriazocin-

2 (1H) -one, F. 142 "C

C ₂₆ H ₂₆ N ₄ O ₂ :

Calculated ... C 73.22, H 6.14, N 13.14%; found .... C 73.00. H 6.17. N 12.89%.

B e i s ρ i e 1 22

In 30 ml of chloroform, 1 g (0.00238 mol) 4 - bromoacetyl - 8 - chloro - 3,4 - dihydro - 1 - methyl-6-phenyl-1,4,5-benzotriazocin-2 (l H) -on entered. This mixture is poured into 10 ml of aqueous while cooling with ice. 40% solution of piperidine entered. The mixture thus obtained is stirred at room temperature for 30 minutes. Then the Solvent distilled off under reduced pressure. The residue is mixed with water. That The mixture is extracted with chloroform. The extract is washed three times with water over sodium sulfate dried and evaporated under reduced pressure. The oily residue is with Äthei added, and the mixture is left to stand in the cold, where e-chloro-S ^ -dihydro ^ -piperidinoacetyl-1-methyl-6-phenyl-1,4,5-benzotriazocin-2 (1 H) -or is obtained in the form of white crystals. After recrystallization from chloroform-ether-n-hexar Crystals with a temperature of 171 ° C. are obtained

C ₂₃ H ₂₅ ON ₄ O ₂ :

Calculated
found ....

C 65.00, H 5.93, N 13.19%; C 64.73, H 5.84, N 12.93%.

Following the process described in Example 22, the following compounds are established posed:

43. 8-chloro-3,4-dihydro-4-pyiTolidJnoacety1-1 -methyl-6-phenyl-1.4.5-benzotriazocin-2 (1H con. F. 154 C

C ₂₂ H ₂₃ ClN ₄ O ₂ : C. 64.30, H 5.64. N 13.64%; Calculated C. 64.53. H 5.59. N 13.56%. found

44 8-chloro-3,4-dihydro-4-morpholinoacetyl-

I-methyl-6-phenyl-1.4.5-ben7otria7ocin-2 (1H J-one,

F.142 C

509631/17

221a837

C ₂₂ H ₂₃ ClN ₄ O ₃ :

Calculated ... C 61.8.9, H 5.43, N 13.12%: found .... C 61.59, H 5.34, N 12.92%.

45, S-chloro ^ A-dihydro ^ -morphiolinoacetyl-6-phenyl-1,4,5-benzotfiazocin-2 (l H) -one, m.p. 117 ^C C

C ₂₁ H ₂₁ ClN ₄ O ^_3:

Calculated ... C 61.09, H 5.13, N 13.57%; found .... C 80.80, H 4.97, N 13.22%.

46.S-chloro-S ^ -dihydro ^ -piperidinoacetyl-6-phenyl-1,4,5-benzotriazocin-2 (1H) -one, 129 ° C

C ₂₂ H ₂₃ ClN ₄ O ₂ :

Calculated ... C 64.30, H 5.64, K 13.64%; found .... C 64.40. H 5.67, N 13.48%.

47.S-chloro-SA-dihydro ^ -pyrrolidinoacetyl-6-phenyl-1,4,5-benzotriazocin-2 (l H) -one, F. 168'C

C ₂₁ H ₂₁ ClN ₄ O ₂ :

Calculated ... C 63.55, H 5.33, N 14.12%; found .... C 63.24, H 5.19, N 13.77%.

48. 3,4-Dihydro-4-pyrrolidinoacetyl-6-phenyl, 4,5-benzotriazocin-2 (1 H) -one, T \ 103 ⁰ C

C ₂₁ H ₂₂ N ₄ O ₂ :

Calculated ... C 69.59. H 6.12. M 15.46%; found .... C 69.98, H 6.43, N 15.10%.

49.S-bromo - ^ - dihydro ^ -piperidinoacetyl-6-phenyl-1,4,5-benzotriazocin-2 (1H) -one, 130 ° C

C ₂₂ H ₂₃ BrN ₄ O ₂ :

Calculated ... C 58.03, H 5.09, N 12.30%; found .... C 58.15. H 5.01, N 12.25%.

50.S-bromo ^ -dihydro- ^ - piperidinoacetyl-

1 -methyl-6-phenyl-1,4,5-benzotriazocin-2 (1 H) -one F. 133 ^f C

C ₂₃ H ₂₅ BrN ₄ O ₂ :

Calculated ... C 58.85, H 5.37. N 11.94%; found .... C 58.50. H 5.24. N 11.50%.

Example 23

In 30 ml of chloroform 1 g (0.00238 mol) of 4-bromoacetyl-8-chloro-3,4-dihydro-1-methyl-6-phenyl-1,4,5-benzotria7ocine-2 (I. H ^ -on solved. The obtained solution is poured into a solution dropwise of 5 g (0.058 mol) of piperazine in 60 ml of chloroform. When the addition is complete, the Mixture stirred for 30 minutes at room temperature. After adding water, the reaction mixture is 5ma! washed with water. The chloroform phase is separated off, dried over sodium sulfate and evaporated under reduced pressure. Ether-n-hexane is added to the residue, with 8 - chloro - 3.4 - dihydro - 1 - methyl - 4 - piperazinoacetyl - 6- phenyl -1.4.5- benzotriazocin - 2 (1 H) -one is obtained as a white powder.

The IR absorption spectrum of this compound in a KBr compact shows characteristic bands at 1675 cm "'and 3400 cm". The nuclear magnetic resonance spectrum (solvent: CDCl _3. Standard: TMS) shows characteristic signals at 1.9 ppm (IH), 2.68 ppm (4H 2.87 ppm (4H). 3.3 ppm (3Hi. 3.8 ppm (2H), 4.06 ppm (1 H), 5.23 ppm (1 H) and 7.1 to 7.6 ppm (8H) .

Following the procedure described in Example 23, the following compounds are prepared:

51. S-bromo-S 1-4 -dihydro-1-methyM -piperazinoacetyl-6-phenyl-1,4,5-benzot riazocin-2 (1 H) -one,

F. 143 to: 145 ° C

ίο C ₂₂ H ₂₄ BrN ₅ O ₂ :

Calculated ... C 56.18, H 5.14, N 14.89%; found .... C, 56.23. H 5.22, N 14.75%.

52. S-fluoro-SA-dihydro-l-methyM-piperazinoacetyl-6-phenyl-1,4,5-benzotriazocin-2 (l H) -on,

M.p. 64 to 66 ° C

The IR absorption spectrum of this compound in a KBr compact shows characteristic bands at 1670, 1700 and 3300 cm " ^1. The nuclear magnetic resonance spectrum (solvent: CDCl ₃ , standard: TMS) shows characteristic signals at 2.23 ppm (1 H), 2 , 71ppm (4H), 2.90ppm (4H), 3.33ppm (3H), 3.82ppm (2H), 4.08ppm (1H), 5.24ppm (1H) and 6.7 up to 7.8 ppm (8H).

Example 24

5 g (0.01188MoI) of 4-bromoacetyl-8-chloro-3,4-dihydro-1-methyl-6-phenyl-1,4,5-benzotriazocin-2 (IH) -On are dissolved in 200 ml of chloroform. The solution obtained is introduced into a solution of 1.67 g (0.0119 mol) of hexamethylenetetramine in chloroform. The mixture is stirred for 20 to 30 minutes at room temperature, and then ⁴ / s of the original volume of solvent is distilled off under reduced pressure. Ether is added to the residue, with (8-chloro-3,4-dihydro -1-methyl-2-oxo-6-phenyl-1,4,5-benzotriazocin-4-yl) -carbonylmethylhexamethylenetetraminium monobromide in the form of white Crystals are obtained which decompose at 180 to 185 "C.

C ₂₄ H ₂ -BrCIN- ^ ₂ :

Calculated ... C 51.39, H 4.85. N 17.48%: found .... C 51.05. H 4.99, N 17.18%.

Example 25

Fine solution of 1 g (0.00238 MoU 4-bromoacet \ l-8-chloro-3.4-dihydro-1 -methyl-6-phenyl-1.4.5-benzotriazocin-2 <l H) -one in 15 ml of chloroform is added to 5 g (0.0462 mol) of phenylhydrazine. The mixture is reacted with stirring for 15 hours at room temperature. The reaction mixture is then evaporated under reduced pressure 1 η hydrochloric acid is added to the concentrate until the pH is around 3. The mixture is then mixed with 50 to 100 ml of chloroform.

öo form phase is washed 3 to 5 times with water, dried over sodium sulfate and evaporated under reduced pressure. The syrup obtained is column chromatographed (eluent: benzene chloroform ether in a ratio of 1: 1: 1). The eluate

* 5 is evaporated under reduced pressure Ether-n-hexane is added to the residue, whereby 8-chloro-3,4-dihydro-1-methyl -4-phenylhydrazinoaceti \ l-6-phen \ l-1.4.5-benzotriazocin-2 (1 H) -on in

■ r t.

Form pale yellowish crystals is obtained, which decompose at 100 ° C.
C ₂₄ H ₂₂ N ₅ CiO ₂ : '.V ..: -.

Calculated ^! ; :. C 64.35, H 4.95, N 15.64%;
• Found.: .. ^: C 64.43, H 5.16, N 15.34%.

'■■ ^: Example 26

'.. \. 10 g (0.04070 mol) of 2-amirio-5-chlorobenzophenone hydrazone are dissolved in 100 ml of chloroform. This solution is mixed with 30 ml of 0.5N sodium hydroxide solution while cooling with ice and while stirring. 30 g (0.1486 mol) of bromoacetyl bromide are added dropwise to this mixture at 0 to 5 ° C. When the addition is complete, the mixture is stirred for 30 minutes. The acidic solution obtained is neutralized with 0.5N sodium hydroxide solution. The chloroform phase is then separated off, washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. Ether is added to the obtained concentrate, whereby 18.8 g of 2-bromoacetamido-5-chlorobenzophenone bromoacetylhydrazone are obtained in the form of white crystals. The yield is 94.8%. After recrystallization from chloroform-ether-hexane, crystals with a melting point of 161 ° C. are obtained.

₁₄ ClBr ₂ N ₃ O ₂ :

Calculated ... C41.88, H 2.89, N 8.62%:
found .... C 42.03. H 2.80, N 8.44%.

2. 10 g (0.02051 mol) of the 2-bromoacetamido-5-chlorobenzophenone bromoacet \ lhydrazone prepared above are dissolved in 1 l of chloroform. The solution is cooled to 10 to 15 C and then while stirring with a solution of 1.5 g (0.0375 mol) sodium hydroxide in 200 ml of water The mixture is kept at 10 to 15 ° C. for 1 to 1.5 hours. The temperature is then increased to 25 to 33 C, and the mixture is held at this temperature for 5 to 6 hours. After full Reaction, the chloroform phase is separated off. Washed 3 times with water over sodium sulfate dried and evaporated under reduced pressure. The concentrate is mixed with ether, whereby 4-bromoacetyI-8-chloro-3,4-dihydro-6-phenyl-1.4.5-benzotriazocin-2 (I H) -one in the form of white crystals is obtained. After recrystallization from chloroform-n-hexane, crystals of F. 211 to 212 C.

C ₁₇ H ₁₃ ClBrN ₃ O ₂ :

Calculated ... C 50.21, H 3.22, N 10.33%;
found .... C 50.49, H 3.30, N 10.03%.

Example 27

1. 20 g (0.09466 moles) of 2-aminobenzophenone hydrazone and 100 g (0.4953 moles) of bromoacetyl bromide are used implemented according to Example 26, wherein 30 g (0.662 mol) of 2-bromoacetamidobenzophenone bromoacetylhydrazone can be obtained in 70% bulge. After recrystallization from chloroform-ether-hexane white crystals of F 151'C obtain.

Calculated ... C 45.06. H 3.34. N 9.27%:
found .... C 44.79. H 3.10. N 8.94%.

2. 10 g (0.0221 mol) of the 2-bromoacetamidobenzophenone bromoacetylhydrazone prepared above! are reacted with a solution of 1.5 g (0.0375 mol of sodium hydroxide in 200 ml of water according to Example 26, with 4-bromoacetyl-3,4-dihydro 6 - phenyl -1,4,5 - benzotriazocin - 2 (1 After recrystallization from chloroform · ether-n-hexane, white crystals with a melting point of 190 ^° C. are obtained.

C _n H ₁₄ BrN ₃ O ₂ :

Calculated ... C 54.8 "\ H 3.79, N 11.29%;
found .... C 54.55, H 3.58, N 10.94%. ·

Example 28

4 g (0.0163 mol) of 2-methylamino - 5 - chlorobenzophenone hydrazine are dissolved in 100 ml of benzene. This solution is mixed with 75 ml of 1 η sodium hydroxide solution while stirring and cooling with ice. The resulting mixture is added dropwise at 0 to 5 ^C C with 10 g (0.0495 mol) of bromoacetyl bromide. When the addition is complete, the mixture is stirred for 30 minutes. The acidic reaction mixture obtained is adjusted to a pH of about 8 with 1 η sodium hydroxide solution. The temperature of the mixture is increased to 10 to 15 ° C. without prior separation of the reaction product, and the mixture is then stirred for 30 minutes. The benzene phase is then separated off in a separating funnel, washed 3 times with water, dried over sodium sulfate and evaporated under reduced pressure. Ether is added to the oily residue, 4 - bromoacetyl - 8 - chloro - 3.4 - dihydro - 1 - methyl- 6 - phenyl -1,4,5 - benzotriazocin - 2 (i H) - one, after recrystallization from chloroformn-hexane, white crystals with a melting point of 200 ° C. are obtained.

Q ₆ H ₁₅ ClBrN ₃ O ₂ :

Ber ^ rhnet ... C 51.39, H 3.59, N 9.99%:
found .... C 51.24, H 3.66. N 9.99%.

Example 29

36g2-methylaminobenzophenone hydrazone in the form of an oil obtained by reacting 37 g (0.175 mol) of 2-methylaminobenzophenone with 100% hydrazine hydrate is not crystallized, but dissolved in 500 ml of benzene. The solution will be cooled with stirring and then with a solution of 25 g (0.625 mol) of sodium hydroxide in 750 ml of water are added. The mixture is then stirred while cooling with ice and then at 5 100 g (0.495 mol) of bromoacetyl bromide are added dropwise up to 10 C. The conversion product will flour isolated. When the addition is complete, the The mixture was stirred at 10 to 15 ° C. for 1 hour. The acidic reaction mixture obtained in this way is diluted with sodium hydroxide solution adjusted to a pH of about 8. The benzene layer is separated. 3 times with water washed, dried over sodium sulfate and evaporated under reduced pressure. The concentrate ether is added, with 4 ~ bromoacetyl-3,4-dihydro - 1 - methyl - 6 - phenyl - 1.4.5 - benzotria / orin-2 (1Ηκ> η is obtained in the form of white crystals. After recrystallization from chloroform-n-hexane white crystals with a melting point of 160 ° C. are obtained.

tr.

216

The separation and purification of the reaction product can also be carried out in a simple manner by column chromatography the concentrate on silica gel (eluent: benzene-ether-chloroform in a ratio of 1: 1: 1).

C ₁₈ H ₁₆ BrN ₃ O ₂ :

Calculated ... C 55.97, H 4.18, N 10.88%;
found .... C 56.09, H 4.00, N 10.59%.

Example 30

1. 10 g (0.0345 mol) of 2-amino-5-bromobenzophenone hydrazone are dissolved in 500 ml of chloroform. the Solution is stirred while cooling with ice. The solution is then mixed with a solution of 8 g (0.2 mol) Sodium hydroxide in 350 ml of water is added, and the mixture is further stirred while cooling with ice. 75 g (0.37 mol) of bromoacetyl bromide are then added dropwise at 5 to 10 ° C. to the mixture When the addition is complete, the mixture is stirred for a further 1 hour at 10 to 15 ° C. Then the The reaction mixture is adjusted to a pH of about 8 with 0.5N sodium hydroxide solution. The chloroform phase is separated off, washed with water, dried and evaporated under reduced pressure. The concentrate is mixed with ether, whereby 2-bromoacetamido - 5 - bromobenzophenone bromoacetylhydrazone is obtained in the form of white crystals. After recrystallization from chloroform-ether-hexane Crystals with a melting point of 148 to 149 ° C are obtained.

C ₁₇ H ₁₄ Br ₃ N ₃ O ₂ :

Calculated ... C 38.38. H 2.65, N 7.90%:
found .... C 38.34, H 2.42, N 7.82%.

(0.4953 mol) of bromoacetyl bromide were added. After full The mixture is stirred for 30 minutes and then neutralized with 1 η sodium hydroxide solution. The chloroform phase is separated off, washed with water, dried over sodium sulfate and under evaporated under reduced pressure. Ether is then added to the residue, with 2-bromoacetamido - 5 - fluorobenzophenone bromoacetylhydrazone is obtained in the form of white crystals. After the

ίο crystallize from chloroform — hexane will become crystals which decompose at 154-156 ° C.

C ₁₇ H

2. 10 g (0.018 mol) of the above prepared 2 - bromoacetamido - 5 - bromobenzophenone bromoacetylhydrazone; dissolved in 300 ml of chloroform. the 240 ml of acetone are added to the solution. The mixture is then stirred at room temperature A solution of 0.7 g (0.019 mol) of sodium hydroxide in 38 ml of water is added dropwise. The mixture is stirred for 2 hours at 30 C and then mixed with water. The chloroform phase is separated off, washed with water, dried over sodium sulfate and evaporated under reduced pressure. A small amount of benzene is added to the concentrate, and the mixture is ready Let stand room temperature, whereby 4-bromoacetyl-B ^ -dihydro-S-bromo-o-phenyl-IAS-benzotriazocin-2 (1 H) -one is obtained in the form of white crystals. After recrystallization from chloroform-ether-hexane Crystals with a melting point of 204 to 206 ° C are obtained.

C ₁₇ H ₁₃ Br ₂ N ₃ O ₂ :

Calculated ... C 45.26, H 190. N 9.31%:

found C 45.00. H 2.73. N 9.00%

₁₄ Br ₂ FN ₃ O ₂ :

Calculated ... C 43.34, H 3.00, N 8.92%;
found .... C 43.06, H 2.88, N 8.78%.

2. 10 g (0.0256MoI) 2 - bromoacetamido - 5 - fluorobenzophenone bromoacetylhydrazone are dissolved in a mixture of 200 ml of chloroform and 200 ml of acetone. This solution is then mixed with a mixture 50 ml of 0.5N sodium hydroxide solution and 50 ml of acetone are added. The resulting mixture is stirred. The organic phase is separated off, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The concentrate comes with Ether added, whereby 4-bromoacetyl-6-phenyl-8-fluoro-3,4-dihydro-1,4,5-benzotriazocin-2 (l H) -one is obtained in the form of white crystals. After recrystallization from chloroform hexane crystals are obtained which decompose at 198 ° C.

C ₁₇ H ₁₃ BrFN ₃ O ₂ :

Calculated ... C 52.32. H 3.36, N 10.77%:
found .... C, 52.25. H 3.23, N 10.81%.

35

Example 32

1. In 11 chloroform, 25 g (0.111MoI) 2-Amino-5-methylbenzophenone hydrazine is dissolved, and the solution is cooled with stirring. The solution a solution of 10 g (0.25 mol) of sodium hydroxide in 250 ml of water is then added, and that The mixture is stirred further while cooling with ice. The mixture is then added dropwise at 5 to 10 ° C 75 g (0.37 mol) of bromoacetyl bromide were added. After the addition is complete, the mixture is 1 hour at Stirred at 10 to 15 C. The reaction mixture is brought to a pH of about 8 with 0.5N sodium hydroxide solution set. The chloroform phase is separated off, washed with water and dried over sodium sulfate and evaporated under reduced pressure. The concentrate is mixed with ether, whereby 2-bromoacetamido - 5 - methylbenzophenone bromoacetylhydrazone is obtained in the form of white crystals. To recrystallization from chloroform-ether · η-hexane gives crystals with a melting point of 142 to 143 ° C obtain. c

C ₁₈ H ₁₇ Br ₂ N ₃ O ₂ :

Calculated
found .

C 46.28, H 3.67, N 8.99%:
C 46.00. H 3.48, N 8.79%.

Example 31 2. In 60 ml of chloroform, 4.67 g of the before

1. 1 g (0.0785 mol) of standing 2 - bromoacetamido - 5 - methyl are prepared in 800 ml of chloroform

2-Amino-5-fluorobenzophenone hydrazone dissolved. This 65 benzophenonbromoacetylhydrazone dissolved, and di

The solution is stirred and cooled with ice. 100 ml of acetone are added to the solution

300 ml of 1 η sodium hydroxide solution are added. The mixture is then bend at room temperature

the mixture at 5 C dropwise with 100 g stirring dropwise with a mixture of 100 π

t.

Acetone and an aqueous solution containing 0.4 g (0.01 mol) of sodium hydroxide in 20 ml of water are added. The resulting mixture is stirred at room temperature for 30 minutes. The reaction mixture is then extracted with chloroform. The extract is washed 3 times with water, dried over sodium sulfate and evaporated under reduced pressure. A small amount of benzene is added to the concentrate and the mixture is then allowed to stand at room temperature, giving 4 - bromoacetyl - 3,4 - dihydro - 8 - methyl-6 - phenyl -1,4,5 - benzotriazocin - 2 (1 H) - one is obtained in the form of white crystals. After recrystallization from chloroform-ether-n-hexane, crystals with a melting point of 211 to 212 ^° C. are obtained.

C ₁₈ H ₁₆ BrN ₃ O ₂ :

Calculated ... C 55.97, H 4.18, N 10.88%;
found .... C 55.72, H 3.92. N 10.66%

20th

Example 33

A mixture of 50g (0.1723 Mo!) 2-methylamino-5-bromobenzophenone and 200 ml of ethanol are mixed with 200 ml of ethanol saturated with hydrogen chloride. 500 g of 100% hydrazine hydrate are then added to the mixture. After adding 800 ml Ethanol, the mixture is refluxed for 7 to 8 hours while stirring. After cooling down the solution is extracted to room temperature with chloroform. The extract is made with water washed, dried over sodium sulfate and evaporated under reduced pressure. Here is 2 - methylamino - 5 - bromobenzophenone hydrazone obtained in the form of an oil. This oil is in 1 liter of benzene dissolved, and the solution is cooled with stirring. The solution is then mixed with a solution of 50 g (0.472 mol) of sodium carbonate in 1 1 of water are added, and the mixture obtained is with cooling with Keep stirring the ice. The mixture is then added dropwise at 5 to 10 ° C. with 150 g of bromoacetyl bromide offset. When the addition is complete, the mixture is stirred at 10 to 15 ° C. for 1 hour. Afterward the pH of the mixture with 0.5N sodium hydroxide solution set to about 8. The benzene phase is separated off, washed with water, over sodium sulfate dried and evaporated under reduced pressure. The concentrate is then made with ether and a little benzene added, with 4-bromoacetyl-8-bromo-3,4-dihydro-1-methyl-6-phenyl-1,4,5-benzo- triazocin-2 (l H) -one is obtained in the form of white crystals. After recrystallization from chloroform-ether-n-hexane Crystals with a melting point of 195 to 197 ° C are obtained

C ₁₈ H ₁₅ Br ₂ N ₃ O ₂ :

Calculated ... C 46.48, H 3.25, N 9.03%;
found .... C 46.33. H 3.03, N 8.71%.

55

60

Example 34

15 g (0.0654MoI) of 2-methylamino-5-fluorobenzophenone are mixed with 100 ml of ethanol. 60 ml of ethanol saturated with hydrogen chloride are added to this mixture while stirring. The mixture obtained is admixed with 150 g of 100% hydrazine hydrate and then with 200 ml of ethanol while cooling. The mixture is refluxed for 7 hours with stirring. The reaction mixture is cooled to room temperature and extracted with chloroform. The extract is washed 3 times with water, dried over sodium sulfate and evaporated under reduced pressure. This gives 35 g of 2-methylamino-5-fluorobenzopbenone hydrazone in the form of an oil. This oil is dissolved in 300 ml of benzene, and a solution of 15 g (0.1415 mol) of sodium carbonate in 250 ml of water is added. The mixture is stirred with cooling. Then, while maintaining the temperature of the resulting solution at 5 to 10 C, this solution is added dropwise with 60 g (0.297 mol) of bromaceityl bromide. After the addition is complete, the mixture is stirred for 30 minutes at 10 to 15 ° C. and then adjusted to a pH of about 10 with 0.5 η sodium hydroxide solution. The benzene phase is separated off, washed 3 to 5 times with water and dried over sodium sulfate evaporated and unier reduced pressure. The concentrate is added with a small amount of benzene, and ether to give ^4-t Bromace y! -8-fluoro-3,4-dihydro-1-methyl-6-phenyl-1,4 ,. -benzotriazocin-2 (1H) -one is obtained in the form of white crystals After recrystallization from benzo / ether, crystals with a melting point of 143 to 144X are obtained.

C ₁₁₁ H ₁₅ BrFW ₃ O ₂ :

Calculated ... C 53.48, H 3.74, N 10.40%;
found .... C 53.55, H 3.55. N 10.29%.

Example 35

A mixture of 50 g (0.222 mol) of 2-methylamino-5-methylbenzophenone and 200 ml of ethanol is mixed with 20 (3 ml of ethanol saturated with hydrogen chloride and then with 500 g of 100% hydrazine hydrate. The resulting mixture is then mixed with 900 ml of ethanol added and un 7 to 8 hours · refluxed After complete reaction άά · ^ reaction mixture is cooled to room temperature and treated with chloroform This mixture is washed 3 times with water, and the chloroform layer is separated, dried over sodium sulfate and concentrated under reduced pressure... evaporated. This gives Z-methylamino-S-methylbenzophenonhydrazone in the form of an oil. This oil is dissolved in 5 (X) ml of benzene, and the solution is cooled with stirring. The solution is then mixed with a solution of 25 g (0.625 mol) of sodium hydroxide in IOOO ml of water, and the resulting mixture is stirred under cooling with ice. then, the mixture is at 5 to 10 ⁰ C was added dropwise 150 g (0.743 mol) of Bro macetyl bromide added. After the addition is complete, the mixture is 1 hour at 10 to. Stirred at 15 ° C. and then adjusted to a pH of about 8.5 with sodium hydroxide solution. The benzene phase is separated off, washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. Ether is added to the concentrate, 4-bromoacetyl-3,4-dihydro-1,8-dimethyl-6-phenyl-1,4,5-benzotriazocin-2 (l H) -one being obtained in the form of white crystals. After recrystallization from chloroform-n-hexane, crystals with a melting point of 189 ° to 191 ° C. are obtained.

C ₁₉ H ₁₈ BrN ₃ O ₂ :

Calculated ... C 57.01, H 4.53, N 10.50%;
found .... C 56.80, H 4.40, N 10.11%.

Claims (3)

Claims: A / genids of the general formula III Y-CO-CH2 - Y 1. lAS-benzotriazocine derivatives and their salts of the general formula I 5 converts and the reaction product of the general R 'O ^F0melIV I Il R ' N-C (D -CO-CH ₂ -Y -CO-CH ₇ -N R, -CO-CH ₇ -N R ' NH C = N-NH ₁ (III IO in which X is a hydrogen or halogen atom or an alkyl radical, R 'is a hydrogen atom or a Alkyl radical and R ″ a hydrogen atom or the groupings means in which Y is a halogen atom, R _{1 is} a hydrogen atom, an alkyl or an allyl group and R _{2 is} a hydrogen atom, an alkyl, allyl, anilino, benzyl, phenylethyl or phenyl group, the latter being replaced by one or two methyls - or ethyl groups or can be substituted by a chlorine atom or a methoxy group, or R ₁ and R ₂ together with the nitrogen atom to which they are bonded form a pyrrolidino, piperidino, morpholino or piperazino group, and R ₃ an alkyl group or R ₁ , R ₂ and R ₃ together with the nitrogen atom to which they are bonded form a hexamethylenetetramine group, the alkyl radicals being understood to be those having 1 to 4 carbon atoms. 2. Process for the preparation of the Benzotriazoeins according to claim 1, characterized in that a benzophenone hydrazone is used in a manner known per se of the general formula II 55 60 Χ- ' with at least 2 moles of a Haloiienacetylhalo-N-COCH ₂ Y (IV) C = N-NHCOCH ₂ Y cyclized without prior isolation and optionally the reaction product of the general formula V R 'O N-C N-COCH ₇ Y (V) a) for the preparation of compounds in which R "denotes a hydrogen atom, with a base deacylated or b) for the preparation of compounds in which R ″ denotes the groupings CO-CH ₇ -N R ₇ R. -CO-CH ₂ -N means with an amine of the general formula VI or VII H - N - Ri R ₂ R ₃ -NR ₁ (VI) (Viii implements. 3. Medicinal preparations consisting of a Benzotria2Qcin according to claim 1 and customary auxiliaries. The invention relates to IAS benzotriazorine derivatives and their salts of the general formula I. R 'O I Il N-C monium acetyl and N-methylpiperidinium acetyl groups.