DE1670593C3 - Molecular compound of the empirical formula C deep 18 H deep 16 Cl deep 4 N deep 2 O deep 3 from 7-chloro-1-methyl-5-phenyl-1,2-dlhydro-3H-1,4-benzodiazepin-2-one and chloral hydrate - Google Patents

Description

OH

IO

.. Cl ₃ C - HC

OH

C ₆ H ₅

Sg solvent with each other

^ Method according to claim 2, characterized in that that the reaction is carried out in benzene, Κ xylene or η-hexane

4 The method according to claim 2 or 3, characterized characterized in that the implementation above At room temperature.

5 Pharmaceutical preparation, consisting of a compound according to claim 1 and a conventional pharmaceutical carrier.

The invention relates to a novel molecular compound with pharmaceutical activity, which is formed from chloral hydrate and 7-chloro-1-methyl-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one. This compound has a melting point of approximately 110 to 118 ° C, _{a molecular formula of C 18} H ₁₆ Cl ₄ N ₂ O ₃ and a molecular weight of 450.16. It can be represented by the following structural formula:

OH Dharma-logical properties. In particular shows Soothing, anticonvulsant and muscle relaxing

Eie SS therefore also refers to a "Medicines which from the inventive vStaS and a usual pharmaceutical

C ₆ H ₅

In particular, the product according to the invention shows characteristic infrared bands at approximately 1670 cm " ¹ and at approximately 3430 cm" ¹ . The entire infrared spectrum recorded in potassium bromide is shown in the drawing.

The process according to the invention for the preparation of this compound is characterized in that one 7-chloro-1 -methyl-5-phenyl-1,2-dihydro-3H-1,4 - benzodiazepin - 2 - one and chlorohydrate without solvent at a temperature above room temperature or reacted with one another in an essentially non-polar organic solvent.

The compound according to the invention shows valuable When tested on mice, the effect was compound according to the invention on the central nerve

system both qualitatively and quantitatively

scheden of that of ^ chloro-l-methyl-S-phenyl- * 2 dihydro-3H-1,4-benzodiazepin-2one and of the physical mixture of the latter with chloral hydrate in a proportion of 1: 1 and 1: 1

"The connection according to the invention is a muscle relaxant, as shown in Table 1, and an andconsulsive agent (against strychnine-induced Convulsion) as shown in Table 2. In the following comparative experiments, the inventive method is

dukf is designated with A, while BT-chloro-1-methyl-5 phenyl l, 2-dihydro-3H-l, 4-benzodia _Z ep.n-2on and C chloral hydrate, D is an equimolar mechanical mixture of B and C and E is a mechanical mixture of B and C in a molar ratio of 1: 2

^ Those given in the tables below Muscle relaxation data were obtained using mice as test animals of the standard lattice test with inclined lattice and

with the help of a set up at an angle of 45 Glass surface obtained, the preliminary tests showing that the movement of untreated Mice was not changed.

Table 1
determination muscle relaxation (ED ₅₀ ) ED ₅₀ mg / kg
(per os) Area*) P value
against A ReI. Wirksanikeil from A
against B, C, D and E Connect
fertilize number of
Mouse 5.4
14.0
270.0
11.5
24.0 3.27 to 8.91
10.77 to 18.20
142.1 to 513
6.4 to 20.7
15.0 to 38.4 <0.05
<0.05
RS.
<0.05 2.6 (1.5 to 4.55)
50.0 (22.5 to 112.5)
2.13 (0.99 to 4.5)
4.44 (2.24 to 8.79) A.
B.
C.
D.
F. 50
40
74
40
40

·) Range for 19/20 average experience value.

NS. = insignificant with average experience value of 19/20.

Table 2

Protective dose (PD ₅₀ ) against 0.58 mg / kg strychnine hydrochloride (iv.)

Connect number of fertilize Mice A. 50 B. 40 C. 24 D. 40 E. 40

PD ₅₀ ma ■!
(per os)

Area*)

P-Wcrt
against A

ReI. Effectiveness A
against B, C, D and E

5.5 3.24 to 9.35 -

13.0 9.0 to 18.9 <0.05

even at 500 mg / kg - no effect (100% mortality) 14.5 9.4 to 22.48 <0.05

10.5 6.77 to 16.28 N. S.

1.63 (1.24 to 4.48)

2.64 (1.3 to 5.23)
1.9 (0.96 to 3.76)

*) Area for 19/20 average experiences.

N. S. = insignificant at 19/20 average experience value.

Acute toxicity study

With the compound according to the invention, fourteen-day standard examinations of the acute Toxicity performed by oral administration in rats. The acute toxicity was used for comparison the compounds or mixtures designated on page 2 as B, C and D and that of a mixture from 37% chloral hydrate and 63% 7-chloro-1-methyl-5 - phenyl -1,2 - dihydro - 3 H -1,4 - benzodiazepin - 2 one (Product F) tested. All the results obtained in these experiments have been recognized with the help of Standard methods are statistically evaluated and can be seen from Table 3.

Table 3

Connection or LD ₅₀ product (mg / kg) A. 1499.0 B. 926.0 C. 1015.0 D. 1260.0 F. 1345.0

From the data given above it can be seen that when administered orally in this animal species, Compound A has a significantly lower toxicity, as indicated by the LD ₅₀ value, than any of the other products tested.

Effect of compound A according to the invention
on the behavior in the test
on "fighting mice"

The experimental procedure used in these tests was essentially the same as that originally used by Tedeschi et al (cf. Pharm. Exptl. Therap., 125 [1959], p. 28). Male albino mice weighing 18 to 20 g were placed in small single animal cages for 4 to 6 weeks isolated. At the end of the isolation period, all mice were tested for their propensity to argue, when they were brought together. Only mice that were proven to show belligerent used to test the effects of different dose levels of compound A, from diazepam, 7-chloro-imethyl-5-phenyll, 2-dihydro-3H-1,4-benzodiazepin-2-one (Compound B) on its own and in physical mixtures in a ratio of 1: 1 with chloral hydrate (Product D) and with chloral hydrate in a ratio of 1: 2 (Product E). All connections or products were given by oral administration on a mg / kg body weight basis. The tendency to argue of a pair of the treated animals was given 30 minutes after the treatment as an alternative result, i.e. H.

Arguing or not, recorded. The results collected were based on the Litchfield method and W i 1 c ο χ ο η statistically evaluated.

The results are shown in Table 4 below.

Table 4

Evaluation of the data for the effect of various orally administered products on the behavior of fighting mice

Connection or
product number of
Couples ED ₅₀
ED ₅₀ *) Data evaluation in
± SEM mg kg
EDso area **) Effectiveness ratio
and area opposite
Connection A Connection A
Connection B 33
32 2.6
(2.0
7.4 0.65
0.59)
2.41 (1.53 to 4.42)
(4.23 to 12.95) . 2.8 (2.33 to 3.36)
[3.7 (3.08 to 4.44)]

* i Dnsis. which prevents fighting or arguing for 50% of the duration of the experiment. · *) For a confidence limit of 95%.

continuation Λη /. Number of
Couples ι ·: η, ₍ , *) Dat.
i-.d ,,, ι s. I-: • Evaluation in mg
. M. kg
1-.D ₅₀ -BeIC I*·) Effective principle
and area opposite
Connection Λ Connection or
product 32 9.1
10.5 4.31
5.X4 4.6 to
4.77 to 18.2
23.1 3.5 (1.45 to 8.4)
[4.6 (1.90 to 10.90)]
4.0 (2.79 to 7.25)
[5.3 (2.92 to 9.45)] Product D
Product I.

* 1 dose that prevents fighting or quarreling for 50 "of the duration of the experiment

*) I ur a limit of 95%

The results show that the dose level for Compound A which required tin inhibition of the dispute propensity in 50% of the animals was 2.6 mg / kg, while the ED ₅₀ value for diazepam was 7.4 mg / kg.

Physical combinations of diazepam and chloral hydrate in the ratio of 1: 1 and 1: 2 showed ED ₅₀ values of 9.1 and 10.5 mg / kg, respectively. Expressed as activity ratios, based on the entire molecule, it was found that compound A was 2.8 times more active than diazepam and 3.5 and 4.0 times more active than physical combinations of diazepam and chloral hydrate in the ratios 1: 1 or . 1: 2. Based on the diazepam content (ED ₅₀ value in brackets), compound A was found to be 3.7 times more active than physical combinations of diazepam and chloral hydrate in the ratios 1: 1 and 1: 2, respectively.

As can be seen from the above description, the product according to the invention, with lower toxicity, is more effective than the starting materials and also than their mechanical mixtures even in lower doses. These high efficiencies could not have been foreseen from the efficacies of the ingredients and the results of their tests and are unexpected and surprising.
The compound according to the invention can be processed for administration as a medicament with the usual pharmaceutical carriers for oral administration, for example lactose, starch or gelatin.

In preparing the product according to the invention, the best results are obtained when the reactants are brought together in approximately equimolar amounts. It is preferred to heat the reaction mixture , but when a solvent is used, the reaction takes place even at room temperature. Mere mechanical mixing of the two reactants in the absence of a solvent does not give the desired product at room temperature. The reaction is preferably carried out in a medium of an essentially non-polar organic solvent, for example benzene. Toluene, xylene or hexane. However, the product of the invention can also be obtained when the two reactants are fused together in the absence of a solvent.

The nature of the bond obtained in the reaction is not clear. Possibly the high partial positive charge <lcs with 3 chlorine atoms substituted carbon atoms in the chloral hydrate is partially compensated by the partial negative charge of the imino nitrogen of the other reactant. Another hypothesis is that the iminodipole is discharged from the chloral hydrate by addition of a hydroxyl group.

For a better understanding of the invention the following examples are presented.

example 1

To a stirred solution of 6.8 g of chloral hydrate in 12 ml of benzene at a temperature of approximately 4 ° C. 10 g of 7-chloro-1-methyl-5-phenyl-1,2-dihydro-3H-1,4-benzodiazipin-2-one become admitted. This latter compound immediately goes into solution and the reaction product falls in a short time from the reaction mixture. It is collected by filtration, washed with benzene and treated Room temperature dried. The yield is approximately 15 g.

An analysis sample is prepared by recrystallization from benzene and has a melting point from about 110 'C.

Analysis for C ₁₈ H ₁₆ Cl ₄ N ₂ O ₃ :

Calculated ... C48.02, H 3.58, Cl 31.51. N 6.22%; found .... C 48.01, H 3.77, Cl 31.52, N 6.10%.

Example 2

The procedure is as described in Example I.

carried out, with the difference that toluene on

Instead of benzene being used as a solvent

It is the same product as in Example 1 in one

Received amount of 13.2 g.

Example 3

When xylene is used instead of benzo as the reaction medium, the same procedure as described in Example 1 is otherwise carried out. The same product as in Example 1 is obtained in a yield of 13 g.

Example 4

10 g of 7-chloro-1-methyl-5 are added to a boiling solution of 6.8 g of chloralhydra in 100 ml of hexane phenyl -1,2 - dihydro - 3H -1,4 - benzodiazepin - 2 one given. This latter starting material dissolves immediately and the reaction product slurps Cooling off. The yield is 14.1 g, and the product is identical to that in Example 1 be wrote.

Example 5

An intimate mixture of 1.4 g of chloralhydra and 2 g of 7-CMOT-l-methyl-5-phenyl-l, 2- <imydro-3H

1,4-benzodiazepin-2-one is heated to 100 ° C. and kept at this temperature for 10 minutes. To after cooling, the product is triturated in benzene and collected by filtration. The bulge is 2.25 g; the product is identical to that described in example 1.

Example 6

10 g of 7-chloro-1-methyl-5 are added to a stirred solution of 6.8 g of chloral hydrate in 15 ml of benzene - phenyl -1,2 - dihydro - 3H -1,4 - benzodiazepin - 2 - one added at room temperature. This latter compound immediately goes into solution, and so does the reaction product precipitates out of the reaction mixture in a short time. It is collected by filtration, washed with benzene and dried at room temperature. The yield is 14.3 g, and that The product is identical to that described in Example 1.

Example 7

0.024 moles of chloral hydrate and 0.01 moles of 7-chloro-I - methyl - 5 - phenyl -1,2 - dihydro - 3H -1,4 - benzodiazepin-2-one are dissolved in 6 ml of benzene. The resulting solution is stirred at room temperature for 48 hours and then with an ether-hexane mixture diluted. The product is collected by filtration, washed with benzene and treated with Dried room temperature to give an off-white crystalline product which is essentially has the same properties as the product according to example 1. One by recrystallization Analytical sample obtained from benzene shows the following physical properties:

Melting point 113 to 118 ° C;
Molecular weight 450.16.

X-ray diffraction diagram

The X-ray diffraction pattern is determined as follows: 200 mg of the sample are placed in a polyethylene bottle, a plastic ball is inserted and the contents are vibrated for 10 seconds. Then the sample is placed in the cavity of a glass slide with a micro-well and irradiated with a bundle of X-rays. The device used is a Philips X-ray generator and diffractometer equipped with a scintillation detector. The radiation used is the K _a line of copper of 1.54 Angstrom units (voltage = 13 Amp.). The diagrams are recorded automatically. The diffraction diagram obtained in this way shows the following peaks with characteristic intensity.

there) Relative intensity 7.19 ± 0.05 0.26 5.70 ± 0.05 0.53 5.27 ± 0.05 0.47 5.15 ± 0.05 1.00 4.34 ± 0.02 0.30 4.26 ± 0.02 0.46 3.47 ± 0.02 0.30

A comparison of these X-ray diffraction data with

the door 7-ChloΓ-l-methyl-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one and chloral hydrate confirmed that the molecular compound contains the two substances in a ratio of 1: 1.

Solubility: Split up solvents solvent 1 part of the solute 200 Methanol 60 acetone 150 chloroform 150 ether 1200 benzene insoluble water Example 8

0.175 mol of 7-chloro-l-methyl-5-phenyl-l, 2-dihydro-3H-l, 4-benzodiazepin-2-one are added with stirring to a solution of 0.424 mol of chloral hydrate in 125 ml of benzene, which has a temperature of 45 ° C. The mixture is filtered while warm and the clear filtrate is stirred for about 10 minutes. The precipitated white crystalline product is collected by filtration, washed with ether and dried, 26.5 g of a product having a melting point of 113 to 116 ^° C. being obtained. The mother liquors are further diluted with hexane, whereby a second portion in an amount of 28.5 g and with a melting point of 112 to 115 ° C. is obtained.

1 sheet of drawings

609628/56

Claims (1)

Patent claims: 1. Molecular compound with the empirical formula C ₁₈ H ₁₆ Cl ₄ N ₂ O ₃ from 7 - chloro -1 - methyl - 5 - phenyl -1,2 - dihydro-3H-1,4-benzodiazepin-2-one and chloral hydrate: ι Process for the preparation of the compound Ih 1, characterized in that _l 5 phenyl - 1,2-dihydro- and chloral hydrate