DE1745668C2 - Process for the preparation of an imfnodibenzyl derivative - Google Patents

Description

The effects of the two test compounds on weight gain were determined during seven consecutive periods Days observed. It was shown that thioproperazine when it is in a dose of 200mg / kg / day is administered as a sign of it Toxicity an abruptly reduced feed consumption on the 2nd day combined with a sharp decrease of body weight and, as a result, a noticeable growth disorder. Agreement of the growth curves for doses of 50 mg / kg thioproperazine and 200 mg / kg Defekton show that the latter affects weight only about ½ as much as thioproperazine. About that J.D e 1 a y and colleagues in La Presse Medicate 67 (4), 123 to 126 (1959), found that half of the test rats one month after continuous oral administration of thioproperazine in at a dose of 25 mg / kg / day.

3. Cataleptogenic effect

This experiment was carried out after that of W. W i r th and coworkers in »Archives Internationales de Pharmacodynamie et de therapy «115, if. (1958) Way done.

The test compounds were injected into male Wistar King rats weighing 200 to 250 g. A group of 8 animals was used for each dose. The stages of catatonia induced by the test compounds were determined as described in the above reference. _{step 1}

The animal has no tendency to make any movement; it stays quietly where it is has been seated. A slight push against the animal, however, causes short movements.

Level 2

The animal behaves as in level 1, but no movement is caused by a push.

level 3

The animal maintains positions, e.g. when its front paw is placed on a 3 cm high cork.

Level 4

The animal maintains its given position if, while sitting on its hind paws, it has one front paw is placed on a 9 cm high cork and the other front paw hangs freely.

After observing the grades in which the test animals were classified, the rats became from level 3 placed on a table with one front paw on a 3 cm high cork for 10 seconds was set. In level 4 rats, a front paw was placed on a 9 cm high cork, the other left hanging freely. At both stages, both the right and the toad became paws tested. Each paw from level 3 was awarded a V2 point, each from level 4 is rated with 1 point. Rats in a state of complete catatonia were therefore given 3 points. The cataleptogenic effect was calculated using the following equation:

Cataleptogenic Activity (%) = ^ L

where A denotes the total number of all points of 8 test animals which were observed every hour for 6 hours after the input of the 'solder connections and showed maximum catatonia. When determining the dose which corresponds to a 50% cataleptogenic activity (ED ₅₀ ), the following results were obtained:

Subcutaneous ¹ )
Oral ² )

ED ₅₀ (mg / kg)! Defective thioproperazine

> 80 ³ )
> 32O *)

0.96 4.6

') 0.9% saline solution (0.1 ml / 100 g of body weight).

² ) 0.5% methyl cellulose suspension (0.1 ml / 100 g of body weight).

³ ) Activity was 16.7% at a dose of 8OnIgAg. *) Activity was 12.5% at a dose of 320 mg / kg.

The ED ₅₀ value of thioproperazine is less than V _{70 of} the value of Defekton, ie thioproperazine

ίο is 70 times stronger in the intensity of the side effects. While thioproperazine results in severe and undesirable side effects, such as extrapyramidal Syndromes including tremor, muscle rigidity, salivation, tasikinesia, etc., shows the Iminodibenzyl compound obtained according to the method hardly any extrapyramidal syndromes. The side effects are comparatively mild (insomnia) and of low frequency. In the following two clinical trials were obtained at the same clinic thioproperazine and the procedure Iminobenzyl compound tested.

Clinical trials in which Thioproperazin and Defekton in the same clinic at the same or similar j, stored cases of schizophrenia were tested sequentially

! Professor N. Suwa, Department of Neuropsychiatry, School of Medicine, Hokkaido University

In the report "Clinical Trial of Thioproperazine in Schizophrenia" by N. Suwa et al in "Saishin Igaku" I Modern Medicine) 16 (10), 2766 bis 2772 (1961), it is reported that five cases of acute schizophrenia treated with thioproperazine were, no noticeable effect was observed, but that in two cases out of 14 cases chronic Schizophrenia the effect was excellent and good in 6 cases. However, the degree and frequency of occurrence was of side effects, such as from the following

so table emerges (table 1), very high, and even inability to walk and inability to eat has been observed. It will be

., that led to the side effects of thioproperazine

Ί are unexpectedly difficult.

SS table 1

Daily dose: 10 to 60mg (or 10mg solid!

Dose)
Total number of cases: 19

Fog effects

Torticollis (spastic

torticollis)

Trism

input

in the cfa increasing Tuesday

10 fab 6B mg

fixed dose.

509611

1 745 6158

continuation

Side effects

Tongue protrusion

Opisthotonus (tonic
Spasm of the back muscles

Parkinsonism

tremor

Walking disorders ...

Dysphagia

Salivation

Sweating,

input

gradually
increasing

Dose,
10 to 60 mg

9 (47.3%)
6 (31.5%)

3
6 (31.5%)

fixed dose,
10 mg

4th
2

In contrast, the same author reports in “Clinical Experience with PZ-1511 (Defekton) in Chronic Schizophrenia ”by N. S and co-workers in“ Shinyaku to Rinsho ”(Journal of New Remedies & Clinics), 17 (3), 298 to 302 (1968) that of 31 cases of chronic schizophrenia, the usual Therapies resisted, in the treatment with Defekton in 2 cases an excellent healing effect and In 9 cases a noticeable improvement effect was observed, the side effects only being minor were and focused on trembling fingers in 6, insomnia in 5 and mild anxiety and Limited irritation in 2 cases (see Table 2).

Table 2

Daily dose 75 to 300 mg

Total number of cases 31

Side effects [number of cases

Trembling of fingers and

Eyelids 6 (19.3%)

Sleep disorders 5 (16.1%)

Anxiety and irritation

2. Department of Neuropsychiatry, Faculty of Medicine, Juntendo University

In "Clinical Application of Thioproperazine" by Dr. S. Yamaguchi and coworkers in “Seishin Igaku «(Clinical Psychiatry) 3 (7), 629 to 639 (1961), it is reported that the effectiveness of thioproperazine in 2 of 31 cases of acute and chronic schizophrenia excellent, in 20 cases good and in 2 cases was negative, but that the occurrence of side effects, especially extrapyramidal Symptoms such as muscle spasms and tasikinesia was very high (see table below).

Daily dose 5 to 90 mg

Total number of cases 3i

Symptoms

Tasikinesia

Anxiety excitement
Muscle rigidity

number of the falls

22nd
18th
15th

Appear of side effects

71.0%
58.1%
48.4%

Symptoms

Finger tremor

Salivation

headache

insomnia

Sensation of pressure in the chest
(Anxiety).

General tiredness ...

Tremor of the mouth.

fever

Twisting the tongue.

Vomit

depression

Disinhibition

Convulsion of the lower
extremities

Spastic torsion

Other

..Ul Appear «ΙΠΙ
L- "ti, of addition Γ ill IC effects ίο 32.3% 5 16.1% 5 16.1% 4th 12.9% 4th 12.9% 4th 12.9% 2 6.5% 2 6.5% 2 6.5% 2 6.5% 2 6.5% 2 6.5% 1 3.3% I. 3.3% 13th 41.9%

₃ . ₅ On the other hand, the same author reported in "Clinical Experience of PZ-1511 (Defekton) on Schizophrenia" in "Seishin Igaku" (Clinical Psychiatry) 7 (10), 919 to 927 (1965) that in the treatment of 20 'cases of chronic Schizophrenia with defect in

Excellent efficacy in 2 cases and good efficacy in 7 cases, none of which notable side effect apart from mild insomnia in 8 cases and anxiety irritation in 4 cases was observed. In none of the cases was the occurrence of extrapyramidal symptoms, Thirstiness or dizziness due to orthostatic hypotension has been observed, which is common in the Administration of neuroleptics or thymoleplics occurs. There were no abnormalities in the laboratory test either Values found.

The following example explains the method according to the invention:

To a mixture of 40 ml of water and 30 ml of ethanol, first 3.3 g of potassium cyanide and other

then 16.7 g of N- [3- (4-ketopiperidino) propyl] iminodibenzyl and 61 g of piperidine hydrochloride were added The mixture is refluxed for 4 hours. After cooling, the precipitate becomes collected by filtration and poured into 100 ml

so dissolved 90% sulfuric acid. Then the mixture heated on a water bath for 1 hour. The reaction mixture is placed in ice water, Made alkaline with sodium hydroxide and extracted with benzene. The benzene extract is made with water washed and dried and the benzene was distilled off therefrom. An oily residue remains, which is in dry ether is dissolved. Dry gaseous hydrogen chloride is converted into this dry solution initiated; white crystals precipitate. Recrystalline

Co-sieving the product from a mixture of methanol and ether (1:10) gives 15 g of N- [3- (4-carbamoyl-4 - piperidino - piperidino) - propyl] - iminodibenzyl dihydrochloride, which contains crystal methanol and that at 279 "C. (uncorrected) melts with decomposition.

⁽ * Analysis for C ₂₈ H ₃₈ N ₄ O 2 HQ CH ₃ OH:

Calculated ... C63.13, H 8.04, N 10.19%;
found .... C 62.98, H 8.Π. Ν 10.25%.

Claims (1)

Claim: Process for the preparation of an iminodibenzyl derivative of the formula CONH ₂ CH ₂ - CH ₂ - CH, - CH ₂ -CH _2, characterized in that a compound of the formula CH ₂ -CH ₂ - _CH;: -NC = O