FR2496661A1 - 1,4-SUBSTITUTE DERIVATIVES OF PIPERAZINE, THEIR PREPARATION AND DRUG CONTAINING THESE SUBSTANCES - Google Patents

Abstract

PIPERAZINE DERIVATIVES AND THEIR ACID ADDITIONAL SALTS. THESE DERIVATIVES HAVE THE GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH R REPRESENTS A 1-METHYL-BENZIMIDAZOLYL, 1-BENZYL-BENZIMIDAZOLYL OR BENZOXAZOLYL GROUP AND R A METHYL. THEY MAY BE USED AS ANALGESIC AGENTS IN MEDICINAL PRODUCTS.

Description

The present invention relates to 1,4-substitution derivatives of the

  piperazine and their preparation, derivatives which may be of interest in human medicine by

  following their excellent analgesic action.

  The derivatives according to this invention have the general formula: R 1 - (CH 2) 4 -N NC O-R 2 [I] wherein R 1 is 1-methylbenzimidazolyl, 1-benzylbenzimidazolyl or benzoxazolyl, and R 2 is methyl, and the invention also includes the addition salts

  of these compounds, acceptable from the pharmacological point of view

  ceutical. The present compounds can be prepared in various ways: 1) The piperazines of the formula (II) are first prepared by reacting piperazines of the formula II with o-phenylenediamine (III), and then reacting the

  piperazines of formuletiv with form alkylating agents

general mule [vl:

C2H500OC (CH2) 4-N3 -CO_ + -, NH2

  e s t / (CH2) 4-30 a

* C I IV]

- (CH 2) 4-N N-CO-

  R X n N [1a] R2 having the above meaning, R3 being a group

  methyl or benzyl and X a halogen atom.

  2) Piperazines of the general formula are reacted

  [VI] with phosphorus pentoxide: [vi] N 8 (CH 2) -N N [co C [Ib] 3) with piperazines of formula VIII acid halides of formula VIII /

R (CH2) NH + XCO-

[viI] [VIII]

X being a halogen atom.

  The 1,4-disubstituted piperazines according to this invention can be used in the form of free bases or their pharmaceutically acceptable acid addition salts, such as hydrochlorides, maleates, fumarates and tartrates, for

medical applications.

  The analgesic action and acute toxicity of

  The present compounds are indicated in the table below.

  (see table on next page) Brady Assay Test - Toxicity 3) Kinin Cleavage Compound2) LD50 (ng / kg) pain; in the mouse rabbit

LD50 (mg / kg) IV mice inhibited

  sc Po (mg / kg) tion (%) Example 2 7.7 63.6 10 100 1039 Example 4 6.4 42.0 10 100 404 Example 8 2.7 17.3 20 100 270 Amidopyrin 21.2 68, 0 60 50 920

  1) Test according to R. Koster and Ai., Fed. Proc., 18, 412 (1959).

  2) Test according to H. Takagi et al., Japan J. Pharmacol., 26, 634

(1976).

  3) Calculations by the method "up and down" (maintenance and reversal) Thus, the compounds according to this invention are considered as interesting in human medicine, having a

  excellent analgesic activity. -

  The examples which follow illustrate the present products and their methods of preparation, without in any way

limit the scope of the invention.

EXAMPLE 1

  1- [4- (2-Benzimidazolyl) butyl] -4-p-toluyl

piperazine, 2 maleate.

  9.7 g of o-phenylenediamine and 33 g of 1- (4-ethoxycarbonylbutyl) -4-p-tolylpiperazine (as hydrochloride, mp 181 ° C.) are added to 2.3 g of sodium in 150 g. ml of ethanol, then the solvent is removed in vacuo, the mixture is heated for 4 hours at 140-160 ° C, and after cooling is poured into water and extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate and evaporated to dryness in vacuo and the remaining material is dissolved.

  in ethyl acetate and the solution is added to a solution

  20 g of maleic acid in 200 ml of ethyl acetate.

  The precipitate formed is filtered off, dried and recrystallized from isopropanol to give 20.8 g of

  colorless crystals melting at 144 and 145 C.

  Analysis. Calculated for C 31 H 36 N 4 O 9: C 61.17 H 5.96 N 9.21

Found: 61.17, 6.01, 9.28.

EXAMPLE 2

  1- [4- 4- (1-Benzyl-2-benzimidazolyl) butyl] -7-

toluyl-piperazine, 2 maleate.

  Water (17 g) is dissolved in 150 ml of water.

  benzimidazolyl) butyl7-4-p-toluylpiperazine, 2 maleate of example 1, the solution is neutralized with sodium carbonate.

  sodium and extracted with chloroform, the chloro

  formic anhydrous sodium sulfate and evaporated in vacuo. To a mixture of the remaining material and 100 ml of acetone is added 5 g of potassium hydroxide powder and dropwise 5.3 g of benzyl bromide, while stirring,

  then stirring is continued for 1 hour at room temperature.

  it is then poured into water and extracted with chloroform. The chloroform layer is well washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo, and the remaining material is dissolved in ethyl acetate and the solution is added to a solution. of 6.5 g of maleic acid in 100 ml of ethyl acetate. The precipitate formed is filtered off, dried and recrystallized from isopropanol to give 15 g of

  colorless crystals melting at 145-146 C.

  Analysis. Calculated for C38H32N4O9: C 65.32 H 6.06 N 8.02

Found: 65.30 6.09 7.97.

EXAMPLE 3

  1- (4-Benzyl-2-benzimidazolyl) butyl-4-p-

  tolyl-piperazine. In 50 ml of water, 7 g of 1-ethyl-4- (1-benzyl-2-benzimidazolyl) butyl) -P-tolyl-piperazine are suspended.

  2 maleate of Example 2, it is neutralized with carbonate of

  sodium and extracted with chloroform and the chloroform layer is dried over anhydrous sodium sulfate and evaporated in vacuo. Recrystallizing the remaining solid material in ethyl acetate gives 4 g of colorless crystals.

melting at 94-95 C.

  Analysis. Calc'd for C 30 H 34 N 4 O: C 77.22 H 7.35 N 12.01

Found: 77.01 7.46 11.88.

EXAMPLE 4

  1-! 4- (1-Methyl-2-benzimidazolyl) butyl -4-p-

toluyl-piperazine, 2 maleate.

  This compound is obtained by the same method as in Example 2, from a mixture of 1 - [4- (2-benzimidazolyl) butyl] -4-p-tolylpiperazine, methyl iodide. and potassium hydroxide powder, in acetone. Point

from fusiont140-141 C.

  Analysis. Calcd for C32H38N4O9: C 61.74 H 6.15 N 9.00

Found: 61.62 6.23 8.99.

EXAMPLE 5

  1- [4- (1-Methyl-2-benzimidazolyl) butyl] -4-p-

tolyl-piperazine.

  6.2 g of 1-L4- (1-) was dissolved in 100 ml of water.

  methyl-2-benzimidazolyl) butyl7-4-p-toluylpiperazine, 2 maleate

  (prepared by the method of Example 4), the solution is neutralized

  with sodium carbonate and extracted with chloroform, the chloroform layer is dried over anhydrous sodium sulfate and evaporated in vacuo, and then the remaining solid is recrystallized from ethyl acetate to give

  3.3 g of colorless crystals melting at 84-85 C.

  Analysis. Calc'd for C24H30N4O: C 73.81 H 7.74 N 7.73

Found: 73.65 7.82 7.51.

EXAMPLE 6

  1- [1- (1-Methyl-2-benzimidazolyl) butyl] -4-p-

toluyl-piperazine, 3/2 fumarate.

  A solution of 3.9 g of 1 - / * - (1-

  methyl-2-benzimidazolyl) butyl-4-p-tolyl-piperazine of the example in 50 ml of ethyl acetate to a solution of 2.5 g

  of fumaric acid in 50 ml of acetone is separated by filtration.

  The resulting precipitate is dried and recrystallized from isopropanol to give 5 g of colorless crystals.

melting at 191.5-192.5 C.

  Analysis. Calcd for C30H36N4O7: C 63.81 H 6.43 N 9.92

Found: 63.64 6.66 9.68.

EXAMPLE 7

  1- / 4Z- (l-methyl-2-benzimidazolyi) butyii7-4-p

toluyl-piperazine, 3/2 succinate.

  This compound is obtained by the same method as in Example 6 from a mixture of 1 - / - 4- (1-methyl-2-

  benzimidazolyl) butyl7-4-p-toluyl-piperazine and succinic acid

Picnic. Melting point 130-131.

  Analysis. Calc'd for C30H39N4O7: C 63.38 H 6.92 N 9.87

: 63.51 6.71 9.58.

EXAMPLE 8

  1 - / - 4- (2-benzoxazolyl) butyl7-4-p-toluyl-PIPE

razine, maleate.

  It is heated between 150 and 170 ° C. for 4 hours

  a mixture of 40 g of 1 - / - 4-o-hydroxyphenylcarbamoyl) butyl 7

  4-p-toluyl-piperazine (in the hydrochloride state: mp 250 ° C.) and 6 g of phosphorus pentoxide, after cooling, the remaining material is poured into an aqueous solution of sodium carbonate.

  sodium and extracted with chloroform. The chloro

  formique with water, it is dried over anhydrous sodium sulphate then evaporated under vacuum, the remaining material is dissolved

  in ethyl acetate and the solution is added to a solution

  717 g of maleic acid in 150 ml of ethyl acetate.

  The precipitate formed is filtered off, dried and recrystallized from a mixture of methanol and isopropanol.

  35 g of colorless crystals melting at 150-151 ° C. are obtained.

  Analysis. Calcd for C27H31N3O6: C 65.70 H 6.33 N 8.51

Found: 65.52 6.36 8.49.

Claims (8)

  1. 1,4-Dibustituted piperazines of the general formula: R1- (CH) N N-CO   Wherein R 1 is 1-methylbenzimidazolyl, 1-benzylbenzimidazolyl or benzoxazolyl, and R 2 is methyl, and their pharmaceutically acid addition salts thereof acceptable.   2.- 1 - / - 4- (1-Benzyl-2-benzimidazolyl) butyl 17-4-   p-toluyl-piperazine according to claim 1, of the formula: ## STR2 ## CH C 6H5 and its 2 maleate.   3.- 1- / F4- (1-Methyl-2-benzimidazolyl) butyl7-4-   p-toluyl-piperazine according to claim 1, of the formula: ## STR1 ## as well as the 2 maleate, the 3/2 fumarate and the 3/2 succinate of this piperazine.   4.- 1- [4- (2-Benzoxazolyl) butyl] -4-p-toluyl-   Piperazine, maleate, according to Claim 1, of formula: ## STR2 ## 2) 4-N - CH3 CHCOOH   5. A process for the preparation of the compounds of formula Ia below, according to which one starts by preparing a   1 - / - 4- (2-benzimidazolyl) butyl-7-piperazine substituted for   4 of formula IV] by reaction of 1- (4-ethoxycarbonyl)   butyl) -piperazine corresponding substituted at the 4-position, of formula [II], with the o-phenylenediamine of formula III, then piperazine [IV] is reacted with an alkylating agent [V] in the presence of potassium: C2H500C (CH2) 4 / e-o-C0-2t-NH> [II] [III] Nv-NH CH2) -N N-C-R 3 (CH2) 4-N N.2c Re (CH2.) -N _..- C O- 2   R3 [lxa] R2 representing methyl, R3 methyl or benzyl and X a halogen.   6. A process for preparing the compounds of   formula Ib below, according to which the 1 - / - 4- (o-   hydroxyphenylcarbamoyl) butyl7-piperazine corresponding substitute   killed at position 4, of formula [Vi, with phosphorus pentoxide: 0 -NHC0- (CH2) 4 3 - C- O -OHv- [vI] 9 2496661   i) <(CH) O o O [Ib]. 7. A process for the preparation of compounds of the formula according to claim 1, wherein the corresponding substituted piperazine of the formula [VI] is reacted with a substituted benzoyl halide of the formula [VIII] R (CH2) o- 21C) 4-N NH + [vil] [VIII] R (CH2) -O   4-CO [I] X representing a halogen atom, as well as their salts   addition of pharmaceutically acceptable acids.   8.- Medication with particular analgesia-   which contains as active ingredient a compound according to one of the   any of claims 1 to 4.