LU81562A1 - PHENYL-1 PIPERAZINE DERIVATIVES - Google Patents

Description

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The present invention relates to 1-phenyl piperazine derivatives, their addition salts with pharmaceutically acceptable acids / their preparation and their use in therapy.

5 The compounds correspond to the formula (I) \ y —-r2 (i> 10 <in which R4 R. represents a radical S (O) R,, S (0) CF_ or S0o — N "'X mjnjz v_ 15 in which m is 0, 1 or 2, n is 1 or 2, Rgest an alkyl radical of 1 to 10 carbon atoms and and Rg represent H or an alkyl radical of 1 to 4 carbon atoms or NR ^ Rg together form a heterocycle which itself may contain another hetero-atom, and represents a hydrogen atom, the radical CHj-C ^ -OH or a radical CH2 “CE2 ~ 0-CORg, CI ^ -C ^ -O-CONHRg or CI ^ -C ^ -O-Rg in which Rg is an alkyl of 1 to 6 carbon atoms, with the exception of the compound for which R2 is K when R ^ is the radical S (0) m Rg in which m = 0 and Rg = CEg.

The addition salts of the compounds (I) with pharmaceutically acceptable acids form part of the invention.

The compounds of the invention can be prepared according to the following reaction scheme: ry ™ 2 + W / 2 X-CH, -CE, ^ \ _ / 2 V R1 X = halogen or OH or alkyl * SOg or aryl-SOg or the 2 x = 0 U '1 · -2-

The cyclization is carried out in the presence of a solvent such as an alcohol or in the absence of solvent.

Compounds (ï) in which R2 is other than H can be obtained from the corresponding compound (I) in which R2 5 is H, by reaction with a compound R2Y (Y = halogen or alkyl-SO ^ or aryl-SO ^).

One can also prepare the compounds for which R2 = CH2-CH2 * -OR £ CK2_CH2 ”OCORç or CE2“ CH2-OCONHRg from compound (I) in which R2 = CH2-CH2-OK by reaction with an acid or a functional acid derivative (halide, anhydride) or with a halide Rg Hal or with an isocyanate.

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It is also possible to prepare the compounds (I) in which R- ^ SÎOJ ^ R ^

or S (0) CF-, by oxidation of the corresponding compounds (I) in n O

which R ^ SR ^ or SCF ^ *

Finally, the compounds (I) in which R2 is 20 CH'2CH2OH can be obtained from the corresponding phenylpiperazine J ~ \

\ / -N NH by reaction with a compound XCH9CH90H

(X = Hal, mesyle or tosyle).

The nonlimiting examples below illustrate the invention.

The analyzes and the IR and NMR spectra confirm the structure of the compounds.

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Example 1 (Trifluoromethyl-3-sulfonylphenyl) -1 piperasinc? and its monohydrochloride.

[Ri = S02CP3. R2 = Hj

In a 100 ml Erlenmeyer flask / equipped with a reflux condenser and a magnetic stirrer, 13.5 g of 3-trifluoromë-5 thylsulfonyl-aniline and 10.7 g of di- (2-chloroethyl) hydrochloride are put )-amine. This mixture is heated for 32 hours at 150 °. During the reaction, a 3% excess of the hydrochloride of the halogenated amine is added.

When all the starting aniline has reacted, the reaction mass is taken up in methylene chloride, it is made alkaline with sodium hydroxide N, it is decanted, washed with water, the solution is dried organic on sodium sulfate and evaporated to dryness. The desired oily base is thus isolated. It is taken up in toluene, discolored with animal black at the reflux temperature. After hot filtration, the solvent is evaporated off and the base is distilled off. The hydrochloride is prepared by reaction of the liquid base with hydrochloric acid in ether. The precipitated salt is recreated in a mixture of acetone and absolute ethanol. (3-Trifluoromethylsulfonylphenyl) -1 piperazine hydrochloride melts at 176 ° C.

Example 2 [(3-Octylsulfonylphenyl) -4 piperazinyl-1j -2 ethanol and its acid fumarate.

^ = so2-ch2- (ch2) 6-ch3, r2 = ch2-ch2-oh | 25 6.4 g (0.018 mole) of fc> 3-ctylsulfonylphenyl) -1 piperazine, 2.3 g of a 250 ml Erlenmeyer flask, equipped with a reflux refrigerator and a magnetic stirrer sodium carbonate, 2.8 g (1.6 ml = 0.022 mole) of glycol hydrobromine, a few crystals of sodium iodide and 150 ml of ethanol. (The starting piperazine 30 is prepared in the same way as in Example 1, the cyclization being carried out in butanol).

The reflux of ethanol is brought to the temperature and maintained for 8 hours. After this period, an 80% excess of glycol hydrobromine and sodium carbonate is added.

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When all of the piperazine has reacted, the ethanol is evaporated and the residual oil is taken up again, with a mixture of water and ether, it is decanted, the ethereal phase is washed with water, it is known over soda sulfate {and concentrates it at. siccitë.

The oily piperazino ethanol derivative is thus isolated.

Its acid fumarate is prepared by the action of the acid on the base. acetone breast. The salt crystallizes slowly by adding a pe of ether. It is isolated by filtration, dried and recrystallized from acetone. It melts at 113.6 ° C, *! 0 ‘

Example 3 (Trifluoromethyl-suifinvl-3 phenyl) -1 piperazine and its acid fumarate SOCF3? R2 = h] 15 Cn introduces 6.27g (0/03 mole) of trifluoromethyl-3-sulfinyl anili: and 5.34g (0.03 mole) of di- (2-chloroethyl) hydrochloride in a vial d '' 50ml Erlenmeyer flask. This mixture is brought to 170 ° and maintained for 8 hours at this temperature. When all the starting aniline has reacted, the reaction mass is taken up with methylene chloride, it is made alkaline with sodium hydroxide, the organic layer is decanted and washed with water. this organic phase is dried over sodium sulfate and evaporated to dryness. The desired base is thus obtained in the form of an oil which is taken up in toluene and discolored with animal black at reflux temperature. After filtration, 1 solvent is evaporated and the base is distilled.

Its acid fumarate is prepared by reaction of the base and fumaric acid within ethanol. The salt is filtered and recrystallized from ethanol.

The acid fumarate of (trifluoromethyl-3-sulfinylphenyl) -1 piperazine melts at 176.2 ° C.

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Example 4 | (Trifluoromethyl-3-sulfinyl phenyl) -4 piperazinol -2 1 1 1 1 · * · t ethanol and its acid oxalate.

SOCF3; R2 = -CH2-CH20h] v

Into a 250 ml Erlenneyer flask, I0''ç (0.0359 mol 5 of (trifluoromethylsulfinyl-3 phenyl) -l piperazine, 4 / 99g (2.83ml or 0.039 mole) of glycol bromihydrin is introduced. , 24g of sodium carbonate, a few crystals of sodium iodide and 100ml of ethanol.

The temperature is brought to reflux and the boiling is maintained for 6 hours. After evaporation to dryness, the oily residue is taken up with water and ether. The organic phase is decanted, washed with water and dried over sodium sulfate and evaporated to dryness. ·.

The crude oily base is thus obtained. Its oxalate is prepared by dissolving the base in the minimum quantity of absolute ethanol, and adding oxalic acid. The precipitated salt is filtered, dried and recrystallized from ethanol.

The acid oxalate of T (trifluoromethy] sulfinyl-3 phenyl) -4 to 20 piperazino ^ -2 ethanol melts at 119th c.

Example 5 forifluoromëthvl-sulfinvl-3 Phënvl) -4 piperazinol -2 ’acetoxy-l ethane and. its acid oxalate Tr; l = SOCF3? R2 = CK2 CR2OCOCH31 25

2g (0.062 mole of | (trifluoromethylsulfinyl-3 phenyl) -4 piperazinoJ-2 ethanol 11.42 ml of anhydride are placed in a 100 ml Erlenmeyer flask equipped with a reflux condenser and a magnetic stirrer acetic acid and 1 or 2 drops of acetyl chloride, dissolved in 50 ml of anhydrous toluene. It is maintained for 30 i hour at a temperature of 60 °, then evaporated to dryness, the residue is taken up in ether and the organic phase is washed with a sodium hydroxide solution N. After decantation, it is dried over magnesium sulfate and evaporated again.

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! ! -6- j The ester obtained is an oil which is transformed · into an acid oxalate in absolute ethanol. By crystallization from a mixture of ethanol * and methanol (80/20), the acid oxalate of [(trifluoromethyl sulfinyl-3 phenyl) -4 pipérazinoj -2 acétoxy-l'éthane pure which melts at 190 ° C is obtained .

5 Example 6 [(3-methÿlthio-phenyl) -4 piperazinyl-1]) - 2 ethanol and its hydrochloride.

[R1 = CH3S R2 = CH2CH20HJ

100 ml of ethanol, 10 g 10 (0.048 mol) of (3-methylthio-phenyl) -1 piperazine (prepared according to the patent) are introduced into a 250 ml erlenmeyer flask fitted with a magnetic stirrer and a reflux condenser. USA 2,976,290), 5.5g of sodium carbonate, a few crystals of sodium iodide, 3.7ml of glyco hydrobromine! It is brought to reflux temperature for 6 hours, then 3.7 ml of glycol hydrobromine and 5.5 g of sodium carbonate are added. The insoluble material is filtered after 4 hours of reflux; the ethanol is evaporated to dryness, the evaporation residue is taken up in water and it is made alkaline with sodium hydroxide; extracted with chloroform; washed with water, dried over sodium sulfate and evaporated to dryness. An oil is obtained which is directly transformed into hydrochloride. Preparation of the salt. The base is solubilized in a minimum of absolute alcohol, hydrochloric ether 4.6Ν, 3θ1 · ί 9.3ml is added dropwise. The hydrochloride precipitates; it is filtered, wrung and dried before recrystallizing from ethanol. The product melting at 147 ° C. is obtained.

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In the following table (I) are shown the compounds prepared by way of examples.

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TABLE I

Compounds R2 F ° C

1 SC ^ H ^ n CI ^ -C ^ -OH Monohydrochloride 114/3 2 SC ^ -CF ^ CH2-CE2-OH Monohydrochloride 193.4 3 (ex.l) S02 ~ CF3 H Monohydrochloride 176, 4 SO2-CK2 “ (0Η2) g-CH ^ H Acid fumarate - 161.5 5 (ex.2) S02-CH2 "(CH2) g-CH ^ C ^ -CKj-OH Acid fumarate 113.6 * 6 S02“ CH3 CH2-CH2 “OH Monohydrochloride 247.2 7 (ex. 3) SGCF3 H Acid fumarate 176.2 8 (ex. 4) SOCF3 CH2CH2OH Acid oxalate 119 9 (ex. 5) SOCF3 CK2CH2OCOCH3 Acid oxalate 190 10 (ex. 6) SCH3 CK2CH2OH Hydrochloride 147

The compounds of the invention have been subjected to pharmacological tests in various fields, in particular in the field of the central nervous system and in the analgesic field.

The acute toxicity of the compounds was determined orally in mice. The LD5Q varies from 150 to 700 mg / kg

The compounds of the invention are psychotropic agents. Their activity was measured using the 4-plate test (ARON C. Thèse de Médecine, Paris 1970; BOISSIER J.R., SIMON P. and ARON C. European Jour.Pharmacol. 1968,4,145-151).

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The compounds of the invention are administered in several doses orally.

The inhibition percentages are measured in mice. For the compounds of the invention these percentages vary from 40 to 100% at the dose of 1 mg / kg, from 120 to 200% at the dose of 3 mg / kg and from 140 to 270% at the dose of 10 mg / kg .

The compounds of the invention have psychotropic properties which allow them to be used for the treatment of anxiety and depression.

10 They can be administered orally, endorectally or parenterally with any suitable excipient and in all forms * * of administration corresponding to these routes: capsules, capsules, cachets, tablets, dragees, oral solutions or suspensions, suppositories, injectable solutions.

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The daily dosage can range from 5 to 200 mg.

Furthermore, the compounds of the invention have also been subjected to pharmacological tests in the analgesic field; in particular to the test of the intraperitoneal injection of acé-2q tick in the mouse of Koster et al. (Fed.proc.1959,18,42) modified by Peterfàlvi, Branceni et al. (Med.Pharmacol.Exp. 1966,15,254) in which for one of the compounds the active dose 5. is 7 mg / kg orally; and the hot plate test (Eddy and Leimbach) (J. Pharmac. Exp. Therap. 1953,107,386) in which the active doses 50 are 50 mg / kg at 30 min and 100 mg / kg at 60 min for one compounds chosen by way of example.

These results show that the compounds of the invention have an essentially peripheral analgesic activity. Indeed the DAC Λ in the Koster test is low while the DAcr ”in 30 50 50 the test of the hot plate is higher.

They can be used for the treatment of various painful conditions such as headache, neuralgia, dental pain, rheumatic and traumatic pain, visceral pain.

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The compounds of the invention can for this purpose be presented in any form of administration suitable for the oral, parenteral or endorectal route, for example in the form of tablets, capsules, injectable solutions or suppositories .... with an appropriate excipient .

The daily dosage can range from 50mg to 1000mg.

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Claims (8)

1- Derivatives of 1-phenyl piperazine corresponding to the general formula (] / T \ / '\ (I> \ / ~ \ / - * 2 E1 in which R represents a radical ® (0) mR3 · S ^ nCF3 or S02 ~ N- ^ ^ "" R5 in which m is 0/1 or 2, n is 1 or 2, R ^ is an alkyl radical of 1 to 10 carbon atoms and and represent H or an alkyl radical of 1 to 4 atoms of carbon or NR ^ R ^ together form a heterocycle which may itself contain another heteroatom, and R2 represents a hydrogen atom, the radical CH2-CH2-OE- or a radical CH2-CH2 ~ 0-C0Rg, CE2- CH2-0-C0NHRg or CH2-CH2 ~ 0-Rg, in which Rg is an alkyl of 1 to 6 carbon atoms, with the exception of the compound for which R2 is H when R ^ is the radical S (0) m R ^ in which m = O and R ^ = CH ^; as well as their addition salts with pharmaceutically acceptable acids. * 2. Compounds according to claim 1, in which m or n is 1 or 2 3. Compounds according to claim 1, in which R2 is H, CH2 ~ CH2-OH or ch ^ ci ^ -o-coch ^. 4. Compounds according to claim 1, in which R2 is H or CH2 CH2 OR and Rx is S02 CF3-1 5. Compounds according to claim 1, in which R ^ is SO CF ^ j and R2 is H, CH2 CH2 OE or CH2 CH2 OCOCH3. -11- 6. J (3-methylthio-phenyl) -4 piperazinyl-1] -2 ethanol and its pharmaceutically acceptable addition salts with acids. 7. Process for preparing the compounds (I), process characterized in that an aniline derivative ^ is reacted with x-CH2-CH2 R1 a compound - NR ", R. and R ~ having the significant X -CK2-CH2 ^^ 'tions given above and X = halogen, OH, alkyl-SO3, aryl-S03 or 2X = 0. - r 8. A medicament containing as active ingredient one of the compounds specified in any one of claims 1 to 6.