DE2241566C3 - 1-curly bracket on 1-square bracket on 3- (p-fluorophenylthio) -1-propenyl, square bracket on-4-piperidyl-curly bracket on-2-oxo-benzimidazoline - Google Patents

Description

ill

and its pharmaceutically acceptable salts.

2. A process for the preparation of the compounds according to claim 1. cij.murch characterized in that one in itself bekja, inter way a 3-p-fluoro

\ ■

(IU)

ην-;

reacted and optionally converted the reaction product into an acid addition salt.

The invention concerns! I -; 1- | 3- (p-F! uorpheny! thio) -l-propenyl] -4-piperidyli -: - oxo-benzimidazoline of the formula 1

VS CH ₂ CH = CH-H

NH

its pharmaceutically acceptable salts and a process for the preparation of these compounds.

2-oxo-benzimidazuline of the formula IH

The inventive! Manufacturing process is thereby «marked. 1: let one be known in itself

These compounds are thought to be antipsychotic, calming, analgesic anticonvulsant, antihypcrlensive and anti-inflammatory agents valuable.

Way is a 3-p-Fluoroplaeiiiylthio-1-propenyl halide the general form? 11th

H-N

> —SK ¹ H ₂ CH = CH-Z

(II)

in which Z is a halogen atom, with 1 - (4-piperidyl) - (111)

converts and, if necessary, the reaction product obtained into a pharmaceutically acceptable one Acid addition salt converted therefrom.

The propenyl halides of the general formula used as starting materials according to the invention U can pond; Prepare according to the usual method according to the following reaction equation:

SH f Z - CH ₁ CH == CH - Z

Dell cleaning agents

CH ₂ CH = CH-Z

The radical Z here has the meaning given above. \

The implementation is according to the invention in a Temperature between I) i 'and the boiling point of the in the presence or absence of a suitable Dehydrohalogenation ice cubes using the solvent used in an inert organic solvent such as benzene, toluene, xfrlul. Dimethylformamide, pyridine. Methanol, etharfol, n-propanol, isopropanol, n-Butanol or Gemisfcren carried out thereof.

Examples of usable dehydrohulogenating agents are for example alkali carbonals such as sodium carbonate and potassium carbonate, alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali bicarbonals such as sodium bicarbonate and potassium bicarbonate, Alkali hydrides such as sodium hydride and potassium hydride, alkyl amines such as trimethylamine, and the like Materials.

The compound of the formula I according to the invention forms acid addition salts with a large number of other

organic or organic acids, such as sai / acid. hydrochloric acid, sulfuric acid, phosphoric acid, Nitric acid, tartaric acid, salicylic acid, p-toluenesulfonic acid. Oxalic acid. Maleic acid, fumaric acid, succinic acid. Malic acid. Formic acid or acetic acid.

The compounds according to the invention are compared to the compounds of the Swiss patent 4 88 708 clearly superior, as can be seen from the following comparison tests.

The following test procedures were used:

Apomorphine antagonism

The test compounds were administered subcutaneously to groups of three male Wistar dogs weighing between 190 and 240 g. One hour after the administration of the compound, each rat received an intravenous injection of 1.25 mg kg body weight of apomorphine hydrochloride. After 5, 10 and 20 minutes, the animals were observed for one minute by an observer who was unaware of the treatment given. The absence of the typical gnawing movements immediately after the injection of the apomorphine was assessed as a connection effect (positive effect). _{The ED 50} value determined by a probit analysis is the dose in mg / kg body weight which, when administered subcutaneously, resulted in positive effects in 50% of the animals examined.

Acute toxicity (LD ₅₀ )

The acute toxicity (LD ₅₀ ) was determined by oral administration. Each group consisted of three mice. The LD ₅₀ value was calculated by probit analysis after 10 days of observation. The values are summarized in Table I below.

Table I.

Apo- LD ₅₀ LD ₅₀ morphine Ip.o.) —__ Anta- ED ₅₀ gonism ED _5n (subcutaneous) According to the invention c connection l- {l- [3- (p-F1uor- 0.85 200 245 phcnylthio) -l-pro- (mg / kg) (mg / kg) penyl] -4-pipcridyl} - 2-oxo-benzimide azoline oxalate Table Il

50 apo-

morphine

Anta-

"iinism

ED ₅₁ ,

!subcutaneous)

(p. O. I

LD ₅₁ , ED ₅ ,,

i0

600

60

Connection according to
the Swiss
U.S. Patent 4,88,708

l- [3- (p-fluorobenzene-

zoyl) propyl] -

4- (1-hydroxyethyl) -

piperazine

It can be seen from the table above that the compound of the present invention is extremely strong Anti-apomorphine effect shows that this compound is extremely valuable as an antipsychotic agent. she is in this respect the compounds of the Swiss patent 4 88 708 by more than tenfold think.

To demonstrate the technical superiority of the compounds according to the invention over the "Benperidol" known from BE-PS 6 26 307 was carried out as follows.

Female Wistar rats weighing 250 g were placed in separate metal cages and subjected to food deprivation set at 22 hours, taking them standard pellets in indefinite Extent between 10 a.m. and 12 p.m. and 2 a.m. to 4 p.m. Water was always freely available to the animals. Each rat was before and after the feeding time weighed to determine weight gain. Food consumption in grams per 2 hours and fecal excretion (number of pellets every 22 hours after each feeding period) were also determined definitely. After several weeks of implementing this food deprivation plan, the daily reached Values of the following 3 parameters surprisingly constant maximum values, while body weight determined before food began to increase gradually and slowly. At this time, groups of 3 rats were formed to examine the effect of the drug. After 2 days of control, the drug is given to a group of appropriately pretreated rats '2StUiIdC before the usual feeding period of Administered subcutaneously for 2 hours. The results obtained are shown in Table II below.

Apomorpliin-Antnuon snius I '' test * I
(SC)

I PO)

Compound according to the invention

-S-CH ₂ CH = CH-N> -N UH 0.85 mg / kg 0.85 mg / kg

4.25 mg / kg -

200 mg / kg

continuation

Apniorphin III-I csl '] LIX, Anonymism ISC) (Pole HLX ₁ JSCl

Benperidol

> - CO-CH, CH, CH, -N

*) Anorexia activity I lit test l.
= Strong anorexia activity.
= No anorcxic acliviiäl.

N NH 0.03ms; kg 0.03 mil kg ir 200 mg kg

The test for apomorphine antagonism and LD _{50 was} carried out as indicated above.

These test results show that the compound according to the invention in contrast to the known Means benperidol does not show any undesirable anorexic activity. Although the connection according to the invention, compared to benperidol, has a poorer apomorphine antagonism, it is thus the well-known benperidol, which when administered in effective amounts the undesirable Shows side effect of anorexic activity and is therefore certain when used as a medicinal product Subject to restrictions, consider.

The compounds according to the invention can thus be used orally as antipsychotic, calming, analgesic, anti-convulsive, antihypertensive or anti-inflammatory Agents in the usual dosage form, such as tablets, capsules, solutions, suspensions, Elixirs or the like are administered.

A typical tablet contains, for example, 1 to 20% binder, for example tragacanth, 5 to 20% lubricant, e.g., talc, magnesium stearate and the like, an average dose of the active ingredient and optionally up to 10% filler, for example lactose. The usual oral dosage is 1 to 100 mg daily.

The following example serves to further illustrate the preparation of the compounds according to the invention.

example

A mixture of 2.23 g of l- (p-fluorophenylthio) -3-chloro-2-propene, 2.17 g of l- (4-piperidyl) -2-oxobenzimidazoline, 0.52 g of sodium carbonate and 30 ml of dimethylformamide was added a temperature of 80 to 90 ⁰ C heated for 12 hours. After cooling, the reaction mixture was poured into 100 ml of water and extracted with benzene. The extract was then evaporated under reduced pressure. The oily residue was dissolved in isopropyl alcohol, and to this solution was added a warm solution of oxalic acid in an amount equimolar to the reaction material in isopropyl alcohol. After cooling, the precipitated oxalate was filtered off and dried, and the l- {l- [3- (p-fluorophenyithio) - 2 - propenyl] - 4 - piperidyl} - 2 - oxobenzimidazoline oxalate with a melting point of 130 to 170 ° C (decomposition ) receive. Recrystallization from ethanol gave a purified product with a melting point of 196 to 198 ° C (decomposition).

Claims (1)

I. 1-! 1- [3- (P-F "•" alcntanspriich * ;: !,. rphetnlthiol-1-propcny!] - phenylthio-1-propenyl halide of the general 4-piperidvl! -2-oxobe | zmidazoline of formula 5 formula 11 F - ( VS-CH ₂ CII-CH-Z (11) S-CHXtH = CH-N / -N in which Z denotes a halogen atom, with 1- (4-pipendyl) -2-oxobenzimidazoline the formula i!