Title: Medicine comprising the benzilic ester of (dimethyl-2',5' pyrrolidino)-2-ethanol

Description: The present invention relates to the introduction in human and veterinary therapeutics of a benzilic ester of the (dimethyl-2', 5'-pyrrolidino)-2-ethanol having a very noticeable anti-ulcerous effect and a very important spasmolytic activity.

The present invention particularly uses the N-methyl bromide of the benzilic ester of (dimethyl-2', 5'-pyrrolidino)-2-ethanol.

The benzilic ester of (dimethyl-2', 5'-pyrrolidono)-2-ethanol is a new compound and is prepared by condensing the chloro-amine obtained from the preceding amino-alcohol on the benzilic acid in isopropanol, according to the usual method of HORENSTEIN and PAHLICKE (Ber-1938, 71 B, 1654).

According to the invention, the anti-ulcerous and spasmolytic medicine comprises the benzilic ester of (dimethyl-2',5'-pyrrolidino)-2-ethanol, prepared by condensation of chloroamine obtained from the preceding amino-alcohol on benzilic acid in isopropanol.

Benzilic ester of (dimethyl-2',5' pyrrolidino)-2-ethanol

Preparation

The compound is prepared by: introducing in a flask, having a capacity of 250 ml provided with a mechanical stirrer and a cooling device, 22.8 g (0.10 mole) of benzilic acid, 16.2 g (0.10 mole) of (dimethyl-2', 5' pyrrolidino)-2 chloro-1 ethane and 60 ml of isopropanol; heating at reflux during 12 hours; dry-evaporating in a water-bath under vacuum; stirring; the obtained residue with 250 ml of water; alkalinizing with soda carbonate(aqueous solution at 10 %); extracting with ether, then washing the ethereal solution with water; drying on anhydrous soda sulfate and lastly evaporating the solvent and then distilling.

Obtained amount: 22.6 g

Yield: 64 %

Properties:

Light yellow sticky oil, BP.sub.0.1 = 185.degree. - 187.degree.C.

Ir spectrum

2.84 (OH), 3.25 ##SPC1##

3.37 (ch.sub.2, ch.sub.3) 5.80 (c=0) 8.10 .mu. (c -- o -- c).

n-methyl bromide of the benzilic ester of (dimethyl-2', 5' pyrrolidino)-2-ethanol ##SPC2##

Preparation

The compound is prepared by: letting in contact at room temperature during one night 3.53 g (0.01 mole) of benzilic ester dissolved in 25 ml of acetone with 5 ml of methyl bromide; drying the crystals so formed; washing them with acetone and then drying at 55.degree.C under reduced pressure.

Obtained amount: 4.2 g

Yield: 95 %

Properties

Colorless crystals, MP = 183.degree. - 184.degree.C (after recrystallization in ethanol at 95% - ethyl acetate, the product melts at 186.degree.C - 187.degree.C); soluble in water and in alcohol, little solubility in acetone, ether, ethyl acetate.

Analysis: C.sub.23 H.sub.30 Br N O.sub.3 = 448

             C         H          N
    ______________________________________
    Calculated %
               61.65       6.69       3.12
    Found      61.40       6.69       3.24
    ______________________________________

Pharmacology elements for the N-methyl bromide of the benzilic ester of (dimethyl-2', 5' -pyrrolidino)-2-ethanol

Acute toxicity

The LD.sub.50 has been determined for the mouse SWISS by two methods of administration: intra-peritoneal method and oral method.

Results:

I.p. method LD.sub.50 = 125 mg/Kg

Oral method LD.sub.50 = 1120 mg/Kg

Spasmolytic activity

Tested on the isolated duodenum of rat.

Neurotrope field: the contraction caused by 0.4 .mu.g of acetylcholine is inhibited by 50% through addition of:

0.4 .mu.g of N-methyl bromide of the benzilic ester of (dimethyl-2', 5' pyrrolidino)- 2-ethanol,

or through 2 .mu.g of N-butyl-hyoscine bromide (Buscopan),

or through 2 .mu.g of thiemonium (Visceralgine).

Muscolotrope field: the contraction caused by 2 mg of barium chloride is inhibited by 50 % through addition of:

2 to 2.5 .mu.g of N-methyl bromide of the benzilic ester of (diemethyl-2',5' pyrrolidino)-2-ethanol,

or 20 to 25 mg of N-butyl-hyoscine bromide,

or 150 .mu.g of papaverine chlorhydrate.

Besides the cholinolytic activity of the N-methyl bromide of the benzilic ester of (dimethyl-2',5' pyrrolidino)-2-ethanol has been compared to the activity of atropine in rats. The effect has been measured in vivo on the carotid pressure and on the intestinal motivity.

The average results (obtained each time on lots of five rats) are as follows:

    ATROPIN     Time after Tensional  Intestinal
    (sulphate)  injection  effect     motivity
    ______________________________________
    1 mg/kg
    I.V. method
    Cholinolytic
                 5 min     43 %       47 %
    effect after
                10 min     42 %       42 %
    injection   20 min     41 %       38 %
                30 min     39 %       28 %
    ______________________________________

N-methyl bromide of the benzilic ester of (dimethyl-2', 5'pyrrolidino)-2-ethanol

              Time after
                       Tensional  Intestinal
              injection
                       effect     motivity
    ______________________________________
    1 mg/kg
    I.V. method
    Cholinolytic
                 5 min     45 %       36 %
    effect after
                10 min     45 %       36 %
    injection   20 min     45 %       36 %
                30 min     45 %       36 %
    ______________________________________

In such conditions the lowered blood pressure is of:

37 % with atropine

25 % with the N-methyl bromide of the benzilic ester of the (dimethyl-2', 5'-pyrrolidino)-2-ethanol.

In both cases, said low blood pressure remains no more than 2 or 3 minutes.

Anti-ulcerous activity

This study has been made on rats having reserpinic ulcers according to the following test.

Female rats of WISTAR stock, are placed in separate metallic cages, without any food and drink for 72 hours.

At times 24 h and 48 h, the rats are given by introperitoneal method, 0.5 mg/rat of reserpine (Serpasil injectable). At times 0, 24 and 48 h, the rats are given by oral method the N-methyl bromide of the benzilic ester of (dimethyl-2', 5' pyrrolidino) 2-ethanol in suspension in sticky water at 2 %, the grade of the different suspensions is calculated in such a way that the animals are given 0.5 ml/100 g.

After 72 hours, the animals are killed, the stomachs taken out and it is noticed the eventual presence of ulcers, the seriousness of the same and their number by rat. All these readings are made blindly.

The animals which were used are:

Batch 1 - Standards (reserpine only)

Batch 2 - N-methyl bromide of the benzilic ester of (dimethyl-2',5'-pyrrolidino)-2-ethanol: 12.5 mg/kg;

Batch 3 - N-methyl bromide of the benzilic ester of (dimethyl-2,5'-pyrrolidino)-2-ethanol: 37.5 mg/kg.

Batch 4 - N-methyl bromide of the benzilic ester of the (dimethyl-2',5'-pyrrolidino)-2-ethanol: 50 mg/kg.

    Results:
                                Index of
                                average
            ULCERATIONS         ulcer
            Incidence
                    Seriousness
                               Number
            %                  per rat
    ______________________________________
    STANDARDS 100 %     1.22       2.88   14.1
    N-methyl
    bromide
    of the
    benzilic
    ester of
    (dimethyl-
    2',5'-pyrro-
    lidino)-2-
    ethanol
    12.5 mg/kg
               86 %     1.14       3.14   12.9
    37.5 mg/kg
               71 %     0.71       0.86   8.7
    50 mg/kg  43        0.43       1.28   6.0
    ______________________________________

Other info:


Inventors: Sarbach, Raymond Francois (Chatillon-sur-Chalaronne, FR)

Application Number: 345480
Filing Date: 1973-03-27
Publication_date: 1976-04-13
Assignee: Institut de Recherche Scientifique I.R.S. (Chatillon-sur-Charlaronne, FR)
Primary Class(es): 514/408 514/925
Other Classes:
US Patent Ref:
Other Refs: Other References: chemical Abstracts 57:16544e- 16545f (1962).