DE2145683C3 - Piperazine propanols and their acid addition compounds - Google Patents

Description

in which A is a hydrogen atom, B is a hydrogen, Fluorine or chlorine atom, a methyl, methoxy, nitro or trifluoromethyl group or A a chlorine atom in the 2-position and B a methyl group in the 5-position, as well as their acid addition compounds.

The compounds according to the invention are prepared by processes known per se by that one fiperazine propanols of the general form! II

HN

OH

N-CH ₂ -CH-CH ₂ -O

Ax

in which A and B have the meaning given above, with a j'-halobutyrophenone in common Formula III

V-

CO- _(CH2), - Y

where Y is a halogen atom, preferably a chlorine atom, at an elevated temperature in the presence of one acid-binding agent, for example a tertiary amine, such as triethylamine, sodium carbonate, sodium bicarbonate, preferably potassium carbonate. Ali's acid binding agent can also be in excess of the amine used. The reaction can also be carried out in an inert solvent Boiling temperature of the same can be made. Examples of suitable solvents are XyIn !. Toluene, n-butanol or methyl isobutyl kelon. The compound obtained in the reaction is used to obtain the compound Raw base is converted into an acid addition compound, for example the dihydrochloride, about.

This reaction of the piperazine propanols of the general formula II with the y-halobutyrophenones of the general formula III in an inert solvent in the presence of an acid-binding agent can in some cases under gentler conditions and carry out with better yields if you use the y-Halogcnbulyrophenon before the implementation to protect the keto group with ethyl glycol under acidic conditions in the corresponding - Halogenbutyrokelal of the general formula IV

-C- (CH ₂ )., - Y
OO

convicted. The desired compound of the general formula I is then obtained by after the reaction has ended, the Kelal group is split off with dilute hydrochloric acid. The connection can then be isolated in the form of the dihydrochloride. For the production of non-toxic acid addition salts acetic acid are suitable, for example. Propionic acid. Diethyl acetic acid. Malonic acid. Succinic acid. Fumaric acid, maleic acid. Lactic acid. Tartaric acid, malic acid, citric acid. Sulfuric acid. Hydrobromic acid or orthophosphoric acid These acid caddilionic compounds are as well as to use the free base pharmaceutically and have the particular advantage that they are soluble in water are.

The substances according to the invention surprisingly represent Sedatives with analgesic effects and antihistamine effects are and have a low toxicity.

In terms of their mode of action, the following substances according to the invention were compared with that in the British Patent specification 12 41 263 used for the same purpose compound 1-p-I luophenyl-4- (3-nico tinamidobutyl) - piperazine - trihydrochloride - hemihydnit (Substance II) compared:

1. Ni [3- (4'-lluorobenzoyl) propyl] -N, - (3-phenoxy-2-hydroxypropyl) piperazine dihydrochloride.
2. N, - | 3- (4'-Fluorobenzoyl-propylJ-N, - [3- (3'-trifluoromethylphenoxy) -2-hydroxypropyl] -pipcrazine dihydrochloride hydrate.

3. N, - | 3- (4'-Fluorobenzoyl) -propyM-N _r [3- (2'-chlorophenoxy) -2-hydroxypropyl] -piperazine dihydrochloride.

4. N, - [3- (4'-fluorobenzoyl) propyl ·] -

piperazine dihydrochloride.

5. Ni [3- (4'-fluorobenzene / oyl) prop \ l] -

N; - [3- (2'-methoxyphynoxy) -2-hydro. \ YpropylJ-pipcrazine dihydrochloride.

6. N _! - [3- (4'-Fluorbcnzoyl) -prop \ Tj-N, - [3- (4'-nitrophenoxy) -2-hydroxypropyl J-

7. N, - [3- {4'-Fluorbcn / oyl) -piopyl] -N ₂ - [3- (4'-ynethoxyphenoxy) -2-hydrox \ propvl] -pipcrazine dihydrochloride.

8. N [- [3- (4'-Fluorobenzoyl) -prop \ lJ-N -, - [3- (4'-chloro- \ o phenoxy) -2-hydroxypropylj-piperazine dihydrochloride.

9. N, - [3- (4'-Fluorobin / oyl) -propyl] -N ₂ - [3- (2'-chloro-5'-methylphenoxy) -2-hydropropyl] -piperazine dihydrochloride.

10. N, - [3- (4'-Fluorobenzoyl | -propyl] -N _; - [3'-nitrophenoxy ^ -hydroxypropj.lj-pipcra / in-cii hydrochloride.

The following data were determined:

1. The mean lethal doses (LD ₅₁₁ ) were determined by administering the substances orally to male albino mice (strain NMRI1. The results are shown in Table 1/11.

2. The hexobarbital visual lengthening

To determine the Hexobarbital Sehlafzeii prolonging effect, the mice were given the substances per os 30 minutes before the i. v. Hexobarhiial

Table 1

would be appli / .iert. The required was determined Amount of the one substance in milligrams per kilogram of body weight, which increases sleep time of the hexobarbitals from 6 to 30 minutes.

3. The analgesic effect was determined with the Writhing-Tcst using the reference substance Aminophenazon 100 mg kg determined.

4. The anlihisiamin effect was determined according to Magnus on the 2 cm long ileum piece of Pirbright guinea pigs (Pharmacological methods. Leopold Ther. Wissenschaftliche Verlagsanstalt Stur.gari. 1 ^L J4y).

The tests carried out thus provide an overview of the sedative and analgesic effects as well as the antihistamine effects of the substances. In addition, the mean lethal doses LD ₅ ,, were determined. The therapeutic range of the substances can therefore be seen from the last 3 columns of Table 1.

The values in the table show. that the according to the invention Substances of comparison substance / 1 I superior to i> ind. All substances show a better anaigetic Effect as the comparative subsidiary. The sedative The effect of most substances is quite comparable to that of the comparative substance. as well the an'ihistamine effect. The substances should therefore for treating the mentally ill! People marriages be suitable.

Sub »ian /

LD ₁₀ ρ. ο

390
248
365
390
464
147
215
250
390
282
485

1
I lc \ i'harbii.il-
Sleep
Verlanueruni! π
Wrilhn
I CM (mg kill In the;.! ku 32 6.S n. b. 32 25th 31.6 50 21.5 21.5 7th 4.6 K) 20th 14th 10 46.4 46.4 25.0 n. b. 31.6 75

Anlihisl.imm-Wirkuni:

mil

1.1.) ,,. i

Hc \ olxiibil.il-SchlaOeit-Yerlaniicniiii:

12th

IX
P.5
11.5
15th

LI) ,,, Il

Wrilhini;

test

1 2

IS

-11

32
Il
25th

P.5
6.5

in ,,, 111

AnlihiMamm-W irkuni

2,000
6 200

6 100

7 100

4 650

5 9 (K)

3 100
830

7 S (K)
14 6 (X)

6 9 (X)

The examples listed below illustrate the subject matter of the invention.

example 1

N, - [3- (4'-fluorobenzoyl) propyl] -

N ₂ - [3- (4'-chlorophenoxy) -2-hydroxyprop \ l] -

piperazine dihydrochloride

CO- (CH ₂ ), NN _Ί

OH
-CH ₂ -CH-CH ₂ -O

[• in (iiiiisch from 13.5 g of N- [3- | 4'-chlorophenox> ) -2-hydrox; .propylj-piperazine. 12.2 g - chlorine-p-fluorobutyrophenone-ethylene glycol ketal and 10 g of potassium carbonate in 200 ml of xylene were heated to 130 ° C. for 20 hours heated. After filtering and evaporation, the crude base was dissolved in benzene and the solution over Aluminum oxide 11 filtered according to B rock m a η η, were collected and mixed with 25 ml of 150 ml of isopropanol for 1 hour The precipitated in the cold and filtered off from isopropanol. The yield was 6.2 g. Connection was 209 bis

The benzene eluates
10 iger HCl and
Heated to reflux.
Crystals were
Recrystallized water.
[5 melting point of

--Cl- 2HCl 216 C.

Example 2

N, - [3- (4'-fluorobenzoyl) propyl] -

N, - (3-phenoxy-2-hydroxypropyl) -piperazine-

dihydrochloride

CO - (CH ₂ )., - N "Ν-ι

In accordance with the procedures listed in the examples below, those listed in Table 2 were followed Connections 3 to 10 made.

• —CO (Ci Κ)., Ν N-

- CH ₂ -CH-CH ₂ -O- <f / -2HC1 OH

A mixture of 23.7 g of y-chloro-p-fluorobutyrophenone and 28 g of N- (2-hydroxy-3-phenoxypropyl) -pipcrazine were heated to 130 ° C. for 12 hours. After that the reaction product was treated with chloroform and dilute sodium hydroxide solution. The received organic phase was evaporated, the crude base was dissolved in benzene and the solution over aluminum oxide Il filtered. The eluate containing the product were evaporated, dissolved in isopropanol and washed with HCl in isopropanol is added. The precipitating dihydrochloride was filtered off and extracted from isopropanol Recrystallized water. The yield was 12 g. The compound had a melting point of 192 to 197 "C.

table

OH

> —CH ₂ —CH —CH ₂ —O — R,

1-p,

3 2-Cl-Q ₁ H ₄ 2 HCl 197 200 4th 2-CH ₄ -CJ-I ₄ 2 HCl 199 -204 5 2-H ₁ CO-Q ₁ H ₄ 2 HCl 183 -1X7 6th 4-O ₂ N - QH ₄ 2 HCl IW 195 7th 2-Cl 5-CH, -CJl, 2 HCl 200 215 8th 3-CF, -C ₁₁ H ₄ 2 HCl 232 235 9 4-H ₃ CO-Q ₁ H ₄ 2 HCI 185 1X9 IO 3-0, N -CJI ₄ 2 HCl 219 223

Claims (1)

Palent claim: Piperazine propanols of the general formula I F-yV-CO- (CH ₂ )., - N _- 'N-CH ₂ -CH-CH ₂ -O- in which A denotes a hydrogen atom, B denotes a hydrogen, fluorine or chlorine atom, a methyl, methoxy atom. Nitro or trifluoromethyl group or A is a chlorine atom in the 2-position and B is a methyl group in 5-position means, as well as their acid addition compounds. The invention relates to new piperazine propanols of the general formula I OH Λ F- / '^ -CO - (CH ₂ ) ₃ - N N-CH ₂ -CH-CH ₂ - O f'