NO792502L - PROCEDURE FOR THE PREPARATION OF PHENYL PIPERAZINE DERIVATIVES - Google Patents

Description

The present invention relates to a method for the production of therapeutically active 1-phenylpiperazine derivatives with the general formula I

in which

4

R., stands for a radical S(0) R_, S(0) CF- or SO-N „

± m j n o z where m is 0, 1 or 2, n is 1 or 2, R^ is an alkyl radical with 1-10 carbon atoms and and R^ and R,, stand for H or alkyl with 1-4 carbon atoms or NR4 .R5r forms together a hetero-

cyclic ring which may optionally contain an additional hetero-

atom, and

R„ stands for a hydrogen atom, the radical GH„CH„0H or CH„CHo0-G0R,._

zz. z z . z b CH-CH-O-CONHR, or CH.C1L0-R,,

z 2 6 2 z o

wherein Rg is alkyl of 1-6 carbon atoms,

with the exception of the compound in which R 2 is H when R 1 is

the radical S(0) R-, in which m is 0 and R-, is CH-,,

m 3 J 3 i

and the peculiarity of the method according to the invention

is that an aniline deriv

in which R^ has the above-mentioned meaning, is reacted with an amine

in which x is halogen, OH, alkyl-SO^ or 2x stands for 0, and 1*2 has the above meaning, and if desired, a) for the preparation of a compound I in which R 2 has the above meaning except for H, an obtained compound I, in which R has the above-mentioned meaning and R2 is H, with a compound R2Y in which R2 has the above-mentioned meaning except for H and Y is halogen or alkyl-SO₂ or aryl-SO₂, or b) for the preparation of a compound In which R2 means CH2~CH„-0Rc, CH„-CHo-0C0Rr or CH„-CH»-0C0NHR,, in which Rchar 26 22 6 22 6 6 the above-mentioned meaning, an obtained compound is reacted In in which R2 is CH2-CH2- OH with an acid or a functional acid derivative (hagenide, anhydride) or with a halide R^-Hal or isocyanate Rg-N=C=0 in which Rg has the above meaning, or c) for the preparation of a compound I in which R1 is S (0)mR3 or S(0)nCF3 in which m and n are 1 or 2 and R^ has the above meaning, a compound obtained is oxidized I in which R^ is SR^ or SCF^ and R^ has the above meaning, or d) for the manufacture of compounds. In which R2 is CH2-CH2~OH, an obtained phenylpiperazine I is reacted

with a compound XCH2~CH2-OH where X is Hal, mesyl or tosyl,

an obtained free base is optionally transferred in its acid addition salts.

In what follows, the invention will be illustrated with the help of

of examples of preferred embodiments.

Example 1

1-trifluoromethyl-3-sulfonyl-phenyl-piperazine and its mono-hydrochloride (1^ = SO 2 CF 3 , R 2 = H).

In a loo ml Erlenmeyer flask, fitted with a reflux condenser

and magnetic stirrer, 13.5 g of 3-trifluoromethyl-sulfonyl-aniline and 10.7 g of the hydrochloride of di-2-chloro-ethyl-amine are introduced. This mixture is heated for 32 hours at 150°C. During the course of the reaction, an excess of 30% of the halogenated amine hydrochloride is added.

After the starting aniline has reacted, the reaction mixture is taken up in methylene chloride, made alkaline with sodium hydroxide IN, washed with water, the organic solution is dried over sodium sulfate and evaporated to dryness. The desired oily base is isolated and taken up in toluene, decolorized with animal charcoal at the reflux temperature, and after filtration in a hot state, the solvent is evaporated and the base is distilled. The hydrochloride is produced by reaction between the liquid base and ethereal hydrochloric acid solution. The precipitated salt is recrystallized from a mixture of acetone and absolute ethanol. The hydrochloride of 1-3-trifluoromethyl-sulfonyl-phenyl-piperazine melts at 176°C.

Example 2

2- 4-3-toctylsulfonyl-phenyl-l-piperazinyl-ethanol and its acid fumarate (Rx = SO2-CH2~(CH2)6~CH3, R2= CH2-CH2"OH).

In a 250 ml Erlenmeyer flask, fitted with a reflux condenser

and magnetic stirrer, introduce 6.4 g (0.018 mol) 1-3-octylsulfonyl-phenyl-piperazine, 2.3 g sodium carbonate, 2.8 g (1.6 ml = 0.022 mol) glycol-bromohydrin, some crystals of sodium hyodide and

150 ml of ethanol (the starting piperazine is prepared in the same way as in example 1, with the ring closure being carried out in butanol).

The mixture is brought to the ethanol reflux temperature

and kept boiling for 8 hours. After this period, an excess of 80% glycol-bromohydrin and sodium carbonate is added.

After all the piperazine has reacted, the ethanol is evaporated and the remaining oil is taken up in a mixture of water and ether, decanted, the ether phase is washed with water, dried over sodium sulphate and evaporated to dryness.

The oily derivative of piperazine-ethanol is thereby isolated. Its acid fumarate is prepared by the action of the acid on the base in acetone. The salt crystallizes slowly by adding a little ether. It is isolated by filtration, dried and recrystallized from acetone. It melts at 113.6°C.

Example 3

1-trifluoromethyl-3-sulfinyl-phenyl-piperazine and its acid fumarate (R1= SOCF3; R2= H).

6.27 g (0.03 mol) of trifluoromethyl-3-sulfinyl-aniline and 5.34 g (0.03 mol) of the hydrochloride of di-2-chloro-ethylamine in a 50 ml Erlenmeyer flask. The mixture is brought to 170°C and kept at this temperature for 8 hours. When all the starting aniline has reacted, the reaction mixture is taken up in methylene chloride, made alkaline with sodium hydroxide, the organic layer is decanted and washed with water, the organic phase is dried over sodium sulphate and evaporated to dryness. The desired base is then obtained in the form of an oil which is taken up in toluene and decolorized with animal charcoal at the reflux temperature. After filtration, the solvent is evaporated and the base is distilled.

Its acid fumarate is produced by reaction between the base and fumaric acid in ethanol. The salt is filtered and recrystallized from ethanol.

The acid fumarate of 1-trifluoromethyl-3-sulfinyl-phenyl-piperazine melts at 176.2°C.

Example 4

2- 4-trifluoromethyl-3-sulfinyl-phenyl-piperazino-ethanalo and its acid oxalate.

(Rx = SOCF3; R2 = CH2-CH2OH)

Into a 250 ml Erlenmeyer flask, introduce 10 g (0.0359 mol) 1~_ 3- trifluoromethyl-sulfinyl-phenyl-piperazine, 4.99 g (2.83 ml or 0.039 mol) glycol-bromohydrin, 4.24 g sodium carbonate, some crystals of sodium iodide and 100 ml of ethanol.

The mixture is brought to the reflux temperature and kept boiling for 6 hours. After evaporation to dryness, the yellowish residue is taken up in water and ether. The organic phase is decanted and washed with water, dried over sodium sulphate and evaporated to dryness.

In this way, an impure oily base is obtained.

The oxalate of the base is prepared by dissolving the base in the smallest possible amount of absolute ethanol and adding oxalic acid. The precipitated salt is filtered off, dried and recrystallized from ethanol.

The acid oxalate of 2-4-trifluoromethyl-3-sulfinyl-phenyl-piper-azino-ethanol melts at 119°C.

Example 5

2-4-trifluoromethyl-3-sulfinyl-phenyl-piperazino-1-acetoxy-

ethane and its acid oxalate.

(R1= SOCF3; R2= CH2CH2OCOCH3)

2 g (0.062 mol) 2-4-trifluoromethyl-3-sulfinyl-phenyl-piperazino-ethanol, 11.42 ml acetic anhydride and 1 or 2 drops of ethyl chloride in solution in 50 ml of anhydrous toluene. The temperature is maintained for 1 hour at 60°C, after which it is evaporated to dryness, the residue is taken up in ether and the organic phase is washed with a solution of 1N sodium hydroxide. After decantation, it is dried over magnesium sulphate and evaporated again to dryness.

The ester obtained is an oil which is converted to the acidic oxalate in absolute ethanol. By crystallization in a mixture of ethanol and methanol (80/20), the acid oxalate of 2-4-trifluoromethyl-3-sulfinyl-phenyl-piperazino-acetoxy-1-ethane is obtained which melts at 190°C.

Example 6

2-4-3-methylthio-phenyl-1-piperazinyl-ethanol and its hydrochloride { R± = CH3S; R 2 = CH 2 CH 2 OH).

In an Erlenmeyer flask of approximately 250 ml, equipped with a magnetic stirrer and a reflux condenser, 100 ml of ethanol, 10 g (0.048 mol) of 1-3-methylthio-phenyl-piperazine (prepared according to US Patent 2,976,290), 5 .5 g of sodium carbonate, some crystals of sodium iodide, 3.7 ml of glycol-bromohydrin. The mixture is kept at the reflux temperature for 6 hours, then 3.7 ml of glycol-bromohydrin and 5.5 g of sodium carbonate are added. Insoluble substance is filtered off after refluxing for 4 hours, the ethanolic mixture is evaporated to dryness, the evaporation residue is taken up in water and made alkaline with NaOH, after which it is extracted with chloroform, washed with water, dried over sodium sulfate and evaporated to dryness. An oil is obtained which is converted directly to the hydrochloride.

Preparation of the salt.

The base is dissolved in the smallest possible amount of absolute alcohol, and hydrochloric acid ether 4.6 N is added dropwise, in a quantity of 9.3 ml. The hydrochloride is precipitated and sucked off on a filter and dried before recrystallization from ethanol. A product is obtained which melts at 147°C.

In the following Table I, exemplary prepared compounds are listed.

The new compounds were subjected to pharmacological testing in various areas, particularly with regard to effects on the central nervous system and as analgesically active agents.

Acute toxicity of the compounds was determined by oral administration in mice and the LD 50 varies from 150 to 700 mg/kg.

The new compounds are psychotropic agents and their activity

was measured using the so-called 4-plate test (ARON C.

Theses de Médecine, Paris 1970; BOISSIER J.R., SIMON P. and

ARON C. European Jour.Pharmacol. 1968, 4, 145-151).

The new compounds were administered orally in several doses.

Percent disinhibition is measured in mice. For the new compounds, percentage disinhibition varies from 40 to 100% at a dose of 1 mg/kg, from 120 to 200% at a dose of 3 mg/kg and 140 to 270% at a dose of 10 mg/kg.

The new compounds have psychotropic properties that allow their use in conditions of anxiety and depression.

They can be administered orally, endorectally or parenterally together

with all usual additives and in all usual delivery forms for these purposes, namely gels, capsules, tablets, dragees, solutions or suspensions that can be ingested,

further suppositories and injectable solutions.

Total dose can be from 5 to 200 mg.

The new compounds were also subjected to pharmacological trials in the analgesic area, especially in the test

by intraperitoneal injection of acetic acid in mice according

to Cost a coil. (Fed. proe . 1959 ,_18 , 42) modified by Peter-falvi, Branceni et coil. (Med. Farmacol. Exp. 1966, JL5, 254) where the active dose 50 for one of these compounds is 7 mg/kg by oral administration. Furthermore, the so-called heated plate test (Eddy et Leimbach) was carried out (J.Pharm.Exp.Therap.1953,107,386) where the active doses 50 are 50 mg/kg at 30 min. and 100 mg/kg at 60 min. for one of the compounds chosen as an example.

The results show that the new compounds have an analgesic activity which is mainly peripheral. In fact, AD is 50

in the Koster test somewhat worse, while AD 50 in the heated plate test is higher.

The new compounds can be used for various disorders, such as headaches, neuralgias, toothaches, rheumatic and traumatic pains and abdominal pains.

The new compounds can be administered in a suitable manner either orally, parenterally or endorectally, e.g. in the form of

tablets, gels, injectable solutions or suppositories, possibly in conjunction with suitable additives.

The total dose can range from 50 mg to 1000 mg.

Claims (1)

Process for the preparation of therapeutically active 1-phenyl-piperazine derivatives of the general formula I 1-10 carbon atoms and and R,, stands for H or alkyl with 1-4 carbon atoms or NR^R,. form together a heterocyclic ring which may optionally contain a further heteroatom, and R2 stands for a hydrogen atom, radical CH2 CH2 OH or CH2CH20-CORg CH2 CH2 0-CONHRg or CH2CH20-R6 in which Rg is alkyl with 1-6 carbon atoms, with the exception of the compound in which R 2 is H when R, is the radical S (0) R-, where m is 0 and R-, is CH-,, 1 m 3 ^3 3 characterized in that an aniline derivative in which R^ has the above meaning is reacted with an amine in which x is halogen, OH, alkyl-SO^ or 2x stands for 0, and <*> 1*2 has the above meaning, and if desired, a) for the preparation of a compound I in which R2 has the above meaning except H, an obtained compound I, in which it has the above meaning and R2 is H, but a compound R2 Y in which R2 has the above meaning except H and Y is reacted means halogen or alkyl-SC>3 or aryl-SO3, or b) for the preparation of a compound I in which R2 means CH2~ CH„0R^ , CH^ CH^ OCOR, or CH<_> CH ~0C0NHR ,, in which R, has the above-26 22 6 22 6 6 meaning, an obtained compound is reacted in which R2 is CH2 CH2 OH with a acid or a functional acid derivative (halide, anhydride) or with a halide R^ -Hal or isocyanate RgN=C=0 in which R^ has the above meaning, .or c) for the preparation of a compound I in which R1 is S(0)m R3 or S(0) CF-, in which m and n are 1 or 2 and R-, the above- n 3 J 3 mentioned meaning, an obtained compound I is oxidized in which R 3 is SR 3 or SCF 3 and R 3 has the above meaning, or d) for the preparation of compounds I in which R2 is CI^ Ct^ OH, an obtained phenyl-piperazine I is reacted with a compound XCI^CI^OH in which X is Hal, mesyl or tosyl, and a free base obtained is optionally transferred into its acid addition salts.