FR2482965A1 - 1- (4-CHLOROBENZHYDRYL) -4- (2,3-DIHYDROXYPROPYL) -PIPERAZINE, ITS PREPARATION METHOD AND ITS THERAPEUTIC APPLICATION - Google Patents

Abstract

1- (4-CHLOROBENZHYDRYL) -4- (2,3-DIHYDROXYPROPYL) -PIPERAZINE OF FORMULA (CF DRAWING IN BOPI) AS WELL AS ACID ADDITIONAL SALTS. MEDICINAL PRODUCT WITH ANTI-TUSSIVE, ANTI-HISTAMINIC, SEDATIVE, ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY.

Description

The present invention relates to a piperazine derivative, and more

  specifically 1 - (4-chlorobenzhydryl) -4- (2,3-dihydroxypropyl) piperazine of formula (I)

CH-NI-CH-CH-CH OH

> -H21 2

I OH

(I)

  and its addition salts with organic and inorganic acids

  pharmaceutically acceptable.

  The invention further relates to a process for obtaining the compound (I) and its salts, and the application of said compound (or its salts) as an active ingredient

  for anti-tussive pharmaceutical compositions, anti-

  histamine, sedative, analgesic and anti-inflammatory

  res. Piperazine derivatives had already formed

  the subject of research by the plaintiff, these searches

  inter alia led to the patent application

  Italian patent No 20915 A / 79, and to the corresponding patent applications

  weights, French (79.17906), German (2950378.4), bri--

  tannic (7929842), Japanese (88017/79) and South African (79/6355). The compounds which are the subject of the said applications

  patents, however, did not exhibit the anti-

  tussive which is particularly pronounced for the compound (I). As a result of its basic double function, the compound of formula (I) can be salified by both organic and inorganic acids, giving with each acid, mono-salts or di-salts. If an organic or inorganic acid with a double acid function is used, acid salts or neutral salts can be obtained. Among the synthetic methods according to the invention for obtaining the compound of formula (I), mention will be made of the following: a) treatment of 1- (p-chlorobenzhydryl) piperazine with 2,3-epoxy-1 propanol, according to the scheme: b) treatment of 1- (p-chlorobenzhydryl) -piperazine with a 3-halogeno-1,2-propanediol, according to scheme: CH-M NE + Cl - CHu - Cc-CH2-o x (I)

X OH

in which X = halogen.

  1- (p-Chlorobenzhydryl) -piperazine, starting material for the preparation of the compound of formula (I), is mentioned in some patents (French Patent No. 73,03599, British Patent No. 817,231, United States Patent No. 2,899,436) without

  specify its characteristics and its method of preparation

  ration. The intermediate was here obtained by reacting a p-chlorobenzhydryl-halide with piperazine, or more preferably with a piprrazine derivative having a single N-blocking position by a group easily.

  eliminable, such as, for example, 1-ethoxycarbonyl-

  piperazine or 1-benzylpiperazine.

  In experimental tests in animals, the compound (I), which will now be briefly called S1498 for the sake of brevity, has been found to possess relatively low toxicity and activity.

248L290O3

  pronounced anti-tussive, accompanied by anti-histal activity

  the mineral, sedative, analgesic and anti-inflammatory of a certain importance. (Unless otherwise specified, doses of S-1498 should be understood as free base quantities). The toxicity (LD50) is equal to 750 mg / kg orally in mice, and 690 mg / kg orally

in the rat.

  The anti-tussive effect has been studied by experi-

  these multiples in guinea pigs, rats and cats.

  In unanesthetized guinea pigs subjected to an aerosol effect

  of 36% citric acid in water, the administration

  preventive treatment of S-1498, either orally or intraperitoneally, has been shown to significantly inhibit the number of coughing episodes per unit of time, as can be seen from the reported experience.

  for example in Table I, which also contains

  comparison with the anti-tussive activity of the

  codeine. Both pharmaceuticals were administered

  50 mg / kg, orally, one half

  hour before subjecting the animals to the aerosol effect.

Table I:

  Activity of S-1498 and codeine (50 mg / kg orally) on citric acid cough in guinea pigs Physiological Solution S-1498 Codeine (Controls) (+) No. of No. of No. of Number Number of the animal's number five times the animal the fifth programmed programmed coughing animal programmed cough cough - in 10O 'in 10O' in 10 '1 36 -l] 0 1 7

2 24 2 8 2 16

3 26 3 7 3.12

4 32 -10 4 q5

31 5.1 5 9

6 35 6 9 6 24

7 27 7 17 7 22

8 34 8 13 8 12

9 36 9 10 9 25

30 10 9 10 20

  11 28 he 1. 1il 16 12 34 1 2 10] 12 he M + * e s. 31.08 1.0.42 15.75

+ 1> 18 +0.74 +], 71

Var. % compared - 66.48 - -4932

to witnesses -

P - <0 001 <0, 001

  (+) 5 ml / kg orally The ED50 (effective dose for the 50% reduction in the number of coughing fits) is 42 mg / kg, both orally and endoperitoneally. Under the same experimental conditions, the ED50 of codeine (also expressed as free baseline) is found to be 55 mg / kg orally. The toxicity of codeine, however, is higher, as can be seen in

comparison reported below.

  Table I: Acute oral toxicity: LD50 mg / kg: Animal species S-1498 Codeine - Mouse 750 405 Rat 690 515

  In rats, preventive administration (one half

  hour before) oral S-1498 at a dose of 40 mg / kg

  resulted in a 55.7% inhibition, statistically

  fictitious, in the trials comparing the provoked cough with

  10% acetic acid solution in water, as can be seen from the experiment reported in Table II Table III: Activity of S-1498 (40 mg / kg orally) on cough with acetic acid in the rat Physiological solution (+) (controls) S-1498 Nuytro Number of Nmiéro Number of the animal's fifths of the animal program's fifths cough in 101 programmed cough in 10 '

1 20 1 4

2 16 2 6

3 13 3 7

4 17 4 11il

19 5 10

6 15 6 5

7 21 7 6

8 23 8 3

9 14 9 11

17 10 he Il 17 11 6

12 16 12 13

  M eoS. 17.33 0.85 7.67 + 0.96 Variation from controls - 55.74

P - <0.001

  l (+) 5 mg / kg orally, half an hour before treatment] In the cat anesthetized with intravenous cloralosis (75 mg / kg), the dose of 45 mg / kg of S-1498 administered intraduodenally, proves to be able to significantly inhibit (by 62% on average) the stimulation of the superior aryed nerve according to Domenjoz (Arch Exp Path Pharmacol., 1952, 215, 19). The same

  dose of S-1498, still administered intraduodenally.

  the, in the anesthetized cat, decreased significantly

  (50-60%) the tussogenic response to the

  mechanical stimulation of the trachea.

  In vitro, on the guinea pig trachea rings, according to Castillo and De Beer (J. Pharmacol., 1947, 90, 104), S-1498 showed obvious antagonistic activity in histamine spasm tests (DE50 = 4 y / ml) and acetylcholine (ED50 = 16 μg / ml); the compound exerted antagonistic activity in the vicinity of the same order of

  magnitude, also in the tests of spasms in history.

  tamin and acetylcholine isolated guinea pig intestine.

  In vivo, in guinea pigs, S-1498 has been shown to be capable of

  terestotally bronchospasm caused by a histamine aerosol from the dose of 60 mg / kg, both orally and intraperitoneally, as can be seen from the experiment reported by way of example

in Table IV.

Table IV:

  Activity of S-1498 (60 mg / kg orally, half an hour before aerosol) on the resistance time of guinea pigs to a histamine aerosol Physiological solution (+) (controls) (controls) Treated animals

  Resistance Time Number Resistance Time Number

  the animal in minutes the animal tances in programmed minutes programmed

1 220 1> 600

2 130 2> 600

3,165 3> 600

4,170 4> 00

180 5> 600

6,160 6> 600

7 130 7> 600

8 190 8--600

9 185 9> 600

210 10> 600

11,155 11> 600

12,200 12> 600

  M + e.s. 174.58 + 8.26> 600 Protection% 0 100 (+) 5 ml / kg orally At slightly higher doses of administration (100 mg / kg orally and more), S-1498 shown to exert obvious sedative activity in spontaneous motility tests in mice (Table V), anti-inflammatory activity in carrageenan edema of the rat's paw (Table VI), and a analgesic activity in intraperitoneal acetic acid contraction tests in mice. (Twist test, Table VII) Table V: Activity of S-1498 (110 mg / kg orally, half an hour before observation) on spontaneous motility in mice Physiological solution (+) Animals treated ( witnesses) Animals treated (witnesses) Number Number Number Number of the animal passages the animal passages programmed in 5 'programmed in 5'

M + e.s.

  % Change from controls - 49

, 31 + 1.74

-1. ] 6

2S, 911 + 2.39

- 48 44

  0 () 01 P (+) 25 ml / kg orally Table VI: Antiinflatmatory activity of S-1498 on the evolution of carrageenin edema of the paw in the rat Phosphological solution (+) S-1498, 130 mg / kg per route (controls) oral half an hour before edema volume number volume number of the animal (ml x 100) after hours the animal (ml x 100) programmed programmed after hours

1 2 3 1 2 3

1 35 115] 65 1 20 45 85

2 25 70 130 2 10 60 110

3 30 60 145 3 10 75 90

4 35 80 110 4 10 55 140

25 i45 160 5 15 60 85

6 40 65 155 6 25 45 160

7 30 40 130 7 15 60 95

8 50 135 125 8 10 55 65

9 30 120 120 9 10 45 105

35 85 170 10 10 40 135

11 25 70 145 11 -15 45 90

12 30 95 130 12 20 60 120

13 35- 90 165 1.3.S 40 95

14 40 85 140 14 '10 45 105

25 70 155 15 10 55 125

  M + e.s. 32.67 81.67 143 13.67 52.33 107.0

  + 1.82 + 6.88 + 4.75 + 1.24 + 2.53 + 6.17

  Var. % vs - - - 58.16 - 35.93 - 25.17 at tenoins P - - - <0.01 001 <0.01l (+) 5i ml / kg orally

f, .. ,, ..

  The substance was administered simultaneously with the injection of carrageenin into the paw. The measurements of

  edema were made 1, 2 and 3 hours later.

  TABLE 7: S-1498 Antagonist Activity in Acetic Acid Contraction Tests, 0.8%

  intraperitoneally in mice.

  Physiological solution (+) S-1498, 50 mg / kg / S-1498, 100 mg / kg Au (tiins) orally (++) orally 'Animal No. No. Animal Control No. . Number of Contests Number of Programs in 15 'Programmed in 15' Animal Contored Programs in 15 '

1 52 1 4 1 6

2 48 2 11 2 6

3 40 3 29 3 10

4 34 4 32 4 he

28 5 17 S 9

6 29 6 9 6 10

7 30 7 O10 7 8

8 33 8 18 8 10

9 28 9 11 9 9

10 31 10 17 10 O10

11 30 11 21 11 1]

12 35 12 12 12 10

13 29 13 20 13 6

M + e.s. 34.38 16.23 8.92

+ 2.15 + 2.22 + 0.51

  Var.% Versus - 52.79 - 74.05 at p <0.001 <0.001 (+) 25 ml / kg oral (++) half an hour prior to administration of acetic acid. of these particular pharmacodynamic activities and its relatively low toxicity, compound S-1498 was subjected to a toxicity test

  long-term in rats and dogs.

  Administration to these two animal species of 25 and 50 mg / kg per day of oral substance, during

  the duration of 180 days, was toleratedoptimally.

  Preliminary human research was then conducted by administering the substance at 25 mg doses three times a day for 1-3 days to 12 male and female patients 20 to 55 years irritative cough resulting from laryngotracheitis or

acute or chronic bronchitis.

  In all cases, the disappearance or

  significant decrease in coughing

  In four patients with cutaneous allergic manifestations, S-1498

  indicated above, resulted in a quick cure.

  According to the invention, S-1498 can be used therapeutically.

  both in free base form and in the form of salts with pharmaceutically acceptable organic or inorganic acids. The pharmaceutical compositions containing S-1498 and / or at least one of its salts can be produced as pure product as well as in the presence of

diluent or coating.

  Said pharmaceutical compositions can be

  used orally, rectally, parenterally.

  According to the invention, it is possible to use as compositions

  solid pharmaceuticals, tablets, powders or granules.

  In said pharmaceutical compositions, the active product is mixed with inert diluents, such as sucrose, lactose, starch. It is also possible to envisage the presence of substances which are different from the diluents, for example

  lubricants, such as magnesium stearate.

  As liquid pharmaceutical compositions for oral administration, it is possible to use emulsions, solutions, suspensions, syrups and elixirs containing inert diluents, such as water or paraffin oil; said pharmaceutical forms may contain other substances, in addition to diluents, for example emulsifiers, dyes, flavoring agents. In addition, the pharmaceutical compositions for parenteral administration may be aqueous or nonaqueous sterile solutions, suspensions or emulsions. As solvents or carriers, there may be used, for example, propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and / or injectable organic esters, such as ethyl oleate. The sterilization can be carried out in various ways: for example, by means of a bacteriological filter or by incorporating into the composition, a sterilizing agent,

  or by irradiation or heating.

  Injectable dosage forms can also be prepared in the form of sterile solid compositions, intended to be solubilized at the time of use.

  in sterile injectable liquids.

  The pharmaceutical compositions for rectal administration are in the form of suppositories containing, apart from the active product, excipients such as

  cocoa butter or waxes appropriate for suppositories.

  The following examples are intended to illustrate the preparation of the compound of the invention and are indicative without in any way limiting said invention to

his frame and his spirit.

Example 1

  a) 1- (4-Chlorobenzhydryl) -4-ethoxycarbonylpiperazine A anhydrous xylene (50 ml) is added 4-chlorobenzhydryl bromide (boiling point 136-392 at 0.25 mm) (22, 3 g, 0.079 moles); N-ethoxycarbonylpiperazine (12.51 g, 0.079 mol) and anhydrous sodium carbonate (8.4 g, 0.079 mol). While stirring, the mixture is boiled

  for 10 hours. After allowing to cool to

  At room temperature, the inorganic salts present are filtered off, washed on the filter with anhydrous benzene, and finally, combined filtrate and washing liquor, made anhydrous (Na 2 SO 4), filtered and evaporated under reduced pressure, leave as an oil residue ( 28.2 g, 100%), which exhibits, in thin layer chromatography, a main spot of Rf 0.78 (Merck F 254 silica gel plate, solvent: anhydrous ethyl acetate, visualization:

  UV light), and which is hydrolyzed without further purification.

  b) 1- (4-Chlorobenzhydryl) -piperazine To a solution of potassium hydroxide (120 g) in ethanol,

  95% (535 ml) is added 1- (4-chlorobenzhydryl) -4-

  prepared crude ethoxycarbonylpiperazine (28.1 g, 0.079 mol) and refluxed for about 20 hours. The solution was filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue is taken up with water and the aqueous solution is extracted with diethyl ether (350 ml x 4). The combined ether extracts, washed with water, dried (K 2 CO 3) and evaporated, leave as an oil residue (17.5 g, 0.061 mol, 77.2% relative to

4-chlorobenzhydryl bromide).

  Crude 1- (4-chlorobenzhydryl) -piperazine obtained

  has a purity of 90-93% (titration with HC104).

  c) 1- (4-Chlorobenzhydryl) -4- (2,3-dihydroxypropyl) -piperazine An aliquot of the above-mentioned organic base (5.0 g, 0.017 mol) dissolved in ethanol (7 , 6 ml) to a solution of 2,3-epoxypropan-1-ol (1.29 g, 1.2 ml, 0.017 mol) in water (3.6 ml). The addition is done slowly, with stirring, so as not to exceed 50 ° C. The mixture is stirred for a further 7 hours at room temperature, and the solvent is then distilled off under reduced pressure, the residue being taken up twice with hexane. anhydrous benzene and evaporating each time so

to bring the residue to dryness. -

  The crude product obtained is taken up in free base form with a little absolute ethanol and is treated dropwise with stirring, with an anhydrous ethanolic solution of hydrochloric acid, thereby causing the precipitation of the product.

  (4-chlorobenzhydryl) -4- (2,3-dihydroxy) hydrochloride

  propyl) -piperazine, which is recrystallized from absolute ethanol (4.2 g, 57%) and having a melting point of 215-217 ° C (uncorrected). Chromatography on a layer

  thin (as above) shows a unit spot of Rf 0.67.

  Analysis for C20H27Cl3N2O2 (433.82) Found%: C, 55.32; H, 6.15; N, 6.32 calculated% C, 55.37; H, 6.27; N, 6.46 Argentimetric title of the chlorine ion: 100%

EXCEPTION 2

  a) 1- (4-Chlorobenzhydryl) -4-benz-1-erazine A mixture of 4chlorobenzhydryl bromide (44.6 g, 0.158 mole) of 1-benzylpiperazine (MeOH) was boiled under reflux in dry xylene (100 ml) ( 27.85 g; 0, 158 moles) and anhydrous potassium carbonate (21.85 g, 0.158 moles) for about 12 hours. Allowed to cool to room temperature, filtered, the filtrate dried, and evaporated under reduced pressure, obtaining as residue

  an oil consisting of 1- (4-chlorobenzhydryl) -4-benzyl-

  crude piperazine (58.9 g, 99%), which is used for the subsequent hydrogenolysis (purity: about 92%;

titration with HC104).

  b) 1- (4-Chlorobenzhydryl) -piperazine An aliquot of the above compound (6.0 g, 0.016 mol), dissolved in ethanol (40 ml) is hydrogenated at 50 ° C and in three atmospheres in the presence of 10% palladium carbon (1.0 g). After having removed the catalyst, by filtration, it is evaporated under

  reduced pressure the solvent, obtaining 1- (4-chloro

  crude benzhydryl) -piperazine (3.03 g, 66%) having a purity of about 94% (HC104 titration) and with the same chromatographic characteristics as those obtained

in example 1 b).

  c) 1- (4-Chlorobenzhydryl) -4- (2,3-dihydroxypropyl) -piperazine The above-mentioned crude organic base (2.8 g, 0.01 mole) treated with 2,3-epoxypropan-1-ol (0, 76 g, 0.01 mole)

  as in the previous example, provided 1- (4-chloro)

  crude benzhydryl) -4- (2,3-dihydroxypropyl) -piperazine, free base (2.0 g, 55%) which is solubilized with the minimum amount of absolute ethanol. To the heated solution at 50 ° -60 ° C., an alcoholic solution of maleic acid, which is also preheated to 50.degree.-60.degree. C., is added dropwise with stirring. The salt forming is allowed to cool. it is recrystallized from absolute ethanol.

  1- (4-Chlorobenzhydryl) -4- (2,3-difluoric acid dimaleate)

  dihydroxypropyl) -piperazine has a melting point of 124-126 ° C

(uncorrected)

  Analysis for C28H33Cl N2O10 (593.04) Found%: C, 56.69; H, 5.41; N, 4.78 calculated%: C, 56.71; H, 5.61; N 4.72

EXAMPLE 3

  a) 1- (4-Chlorobenzhydryl) piperazine To a solution of anhydrous piperazine (3.5 g, 0.04 mol) in toluene (20 ml) was added 4-chlorobenzhydryl bromide (2.8 g; 0; 01 mole) drip,

shaking.

  The mixture is then boiled for 12 hours, allowed to cool to room temperature, the piperazine hydrobromide which has formed is filtered, the solvent is removed under reduced pressure and the residue is distilled off.

  under vacuum, collecting the distilled fraction at 231-

234 C (10 mm Hg) (1.35 g, 48%).

  The product can be further purified on a column of silica gel and eluting with diethyl ether: petroleum ether (1: 1) to obtain a yield of

slightly better reaction.

  b) 1- (4-Chlorobenzhydryl) -4- (2,3-dihydroxypropyl) -piperazine By treating the 1- (4-chlorobenzhydryl) -piperazine thus obtained, as in Examples 1 and 2,

  1- (4-chlorobenzhydryl) -4- (2,3-dihydroxypropyl) -

  piperazine base, which, added with a saturated alcoholic solution of picric acid, provides the corresponding dipicrate which is recrystallized from absolute ethanol, point

Melting point 203-205 ° C.

  Analysis for C32H31ClN8016 (819; 11) Found%: C, 46.77; H, 3.73; N, 13.51 calculated%: C, 46.92; H, 3.81; N, 13.68

EXAMPLE 4

  1- (4-Chlorobenzhydryl) -4- (2,3-dihydroxypropyl) -piperazine A mixture of 1- (4-chlorobenzhydryl) -piperazine base (28.6 g, 0.1 mole), obtained according to US Pat. one of the methods

  described in the previous examples, 3-chloro-1,2-

  propanediol (22.1 g, 0.02 mol) and triethylamine (10.1 g, 0.1 mol) in dry xylene (50 ml) were heated for 8 hours at 130 ° C. After cooling to room temperature The reaction liquid is diluted with anhydrous benzene (200 ml), filtered and washed.

  filtrate with water and an aqueous solution of hydro-

  10% sodium hydroxide. After drying out the phase

-2482965

  organic (K 2 CO 3) is evaporated under reduced pressure.

  The residue is heated under vacuum at 50-60 ° C (0.1 nmmHg), the residual triethylamine is removed,

  and 1- (4-chlorobenzhydryl) -4- (1-propan-2,3-

  diol) -piperazine base, sufficiently pure to be

  salified, as indicated in one of the above examples.

Claims (7)

  1. 1- (4-Chlorobenzhydryl) -4- (2,3-dihydroxypropyl) - piperazine of formula (I) CH-N -CU CHHOH   OH x (1) and its addition salts with pharmaceutically acceptable organic and inorganic acids, both mono and   di-salts, neutral, basic or acidic.   2. Pharmaceutical composition, especially with anti-activity   tussive, antihistamine, sedative, analgesic and anti-   inflammatory, characterized in that it comprises at least   a compound according to claim 1.   3. Pharmaceutical compositions which can be administered orally, in particular with regard to their anti-tussive, anti-histaminic, sedative, analgesic and anti-inflammatory activity, characterized by the fact that as active ingredients   they contain 1- (4-chlorobenzhydryl) -4- (2,3-   dihydroxypropyl) piperazine and / or at least one of its acceptable.   4. Injectable pharmaceutical compositions with activity   anti-tussive, anti-histamine, sedative, analgesic   anti-inflammatory, characterized by the fact that as active ingredient> they contain 1- (4-chlorobenzhydryl) -4- (2,3dihydroxypropyl) piperazine   and / or at least one of its pharmaceutically acceptable salts.   5. Pharmaceutical compositions with anti-tussive, antihistaminic, sedative, analgesic and anti-inflammatory activity, for rectal administration, characterized by the fact that as principles   actir, they contain 1- (4-chlorobenzhydryl) -4- (2,3-   dihydroxypropyl) -piperazine and / or at least one of its pharmaceutic salts acceptable.   6. Process for the preparation of 1- (4-chlorobenzyl)   dryl) -4- (2,3-dihydroxypropyl) piperazine and / or its salts,   characterized by the fact that the 1- (4-   chlorobenzhydryl) -piperazine with 2,3-epoxy-1-propanol,   and that eventually the product obtained is salified.   7. Process for the preparation of the product according to claim 1, characterized by the fact that   react 1- (4-chlorobenzhydryl) -piperazine with a 3-   halogeno-1,2-propanol-diol and that eventually we salify the product obtained.