NOVEL PHENYLPIPERAZINE DERIVATIVES, PROCESS FOR PREPARING THEM AND THERAPEUTIC COMPOSITIONS CONTAINING THEM

Abstract: Novel phenylpiperazine derivatives of phenylpropionic acid, of general formula: wherein R¹ is a hydrogen or chlorine atom or a trifluoromethyl group and pharmaceutically acceptable salts thereof, a pro­ cess for their production, and pharmaceutical compositions containing the same are disclosed. The compounds have anal­ gesic properties.

Description: NOVEL PHENYLPIPERAZINE DERIVATIVES, PROCESS FOR PREPARING THEM AND THERAPEUTIC COMPOSITIONS CONTAINING THEM This invention relates to meta-substituted phenylpiperazine derivatives that have valuable therapeutic properties as non-narcotic analgesics, and to a process for preparing them. It also relates to therapeutic compositions comprising as active ingredient one of these derivatives, for oral, rectal or parenteral administration. According to Manoury et al., J. Med. Chem. 22, 5, 554 (1979), the esterification of certain quinoline anthranilic acids (used as antiinflammatory and analgesic agents in clinical practice) with phenylpiperazinyl alkanols gives rise to compounds with increased analgesic activity and reduced anti inflammatory activity, so that they are less ulcerogenic. The compounds are better absorbed by virtue of their increased liposolubility. The compound 2-(4-isobutylphenyl) propionic acid is well known and widely employed in general clinical practice as an antiinflammatory analgesic. In the hope of obtaining compounds with higher analgesic activity and lesser degree of toxicity, we have prepared several derivatives of the 2-(4-isobutylphenyl) butyric acid of the formula EMI2.1 wherein R1, is an ethyl group and R2 is a hydrogen or chlorine atom or a trifluoromethyl group (see Spanish Patent No. 515,541). The compounds were found to have interesting analgesic properties and low toxicity. We have now found that the compounds of general formula: EMI2.2 wherein R1 (equivalent to R2 in Formula I) represents a hydrogen or chlorine atom or a trifluoromethyl group have a therapeutic index (ratio of LD50/ED50) higher than those of their individual components and that they have more reduced antiinflammatory properties and better absorption and bioavailability due to their increased liposolubility. The compounds of Formula Ia have been found to have very surprising analgesic properties and pharmacological studies have shown that they do not exhibit the harmful side effects of narcotic type analgesics probably because (so it is believed) their mechanism of action does not involve the same type of receptors. The compounds of general formula Ia may be also used as medicaments in the form of the free bases as well as under the form of the physiological acceptable salts obtained from the addition of organic or inorganic acids (hydrochloric acid, sulphuric acid, malic acid, succinic acid, citric acid, maleic acid) to the piperazinyl nitrogens. The invention also provides processes for preparing the general formula Ia. One such process involves esterifying a phenylpiperazinyl ethanol of general formula: EMI3.1 wherein R2 represents a hydrogen or chlorine atom or trifluoromethyl group with 2-(4-isobutylphenyl)-propionyl chloride: EMI3.2 The reaction can be carried out at low temperatures ( < 5 C) and in the presence of a base such as sodium carbonate or pyridine. Compounds of formula II may readily be obtained by reaction of the corresponding phenylpiperazine: EMI3.3 wherein R2 repesents a hydrogen or chlorine atom or trifluoromethyl group with 2-chloroethanol. An alternative process for preparing a compound according to the invention involves esterifying 2-chloroethanol with the acid chloride III to give the compound: EMI4.1 which upon subsequent reaction with a phenylpiperazine of formula IV in a basic medium yields a compound of formula Ia. The compounds of the invention can be presented for administration to human beings by the oral, rectal or parenteral routes in the form of the free bases as well as in the form of their physiologically acceptable salts. For oral administration they may be presented in the form of tablets, capsules, granules, sugar coated tablets, suspensions or solutions. These preparations may incorporate acceptable auxiliary agents as talc, magnesium stearate, vegetable gums, sucrose, mannitol, lactose, starch, polyvinylpyrrolidone, a tween surfactant and flavouring and colouring agents. For rectal administration they may be presented as suppositories containing a compound of the invention together with neutral fats such as mono-, di- and triglycerides of fatty acids or polyethyleneglycols. The compounds of the invention may be presented for parenteral use in association with an appropriate hydroalcoholic vehicle and with an antioxidant and heavy metal chelating agents. The unit dosage presentations may contain 100 to 700 mg of a compound according to the invention as active ingredient. Unit dosage forms for oral administration preferably contain 200 to 500 mg of the compound, those for parenteral administration preferably contain 100 to 200 mg, and suppositories preferably contain 500-700 mg thereof. Such preparations may be made by methods well known in the art, and the active ingredients of the present invention may also be incorporated into the novel composition with other known therapeutically active compounds. The studies of analgesic activity for these compounds have been carried out over 2,178 mice by using the "writhing test" method. 2-Phenylbenzoquinone was used as nociceptive agent and the material under test was administered by the oral route. In all the cases the ED50, ED16 and ED84 (minimum dose for each product which reduces the writhes by 50, 16 and 848 respectively) were calculated, as well as the 95% confidence limits for the ED50. The oral acute toxicity study (LD50 determination) has been performed using 770 Swiss mice (half males and half females) weighing 18-22 g. A. Analgesic activity (ED5n): A slight modification of the method described by Hendershot and Forshait J. Pharmacol. Exp. Ther. 125, 237 (1959) which employs as nociceptive agent a 0.02% hydroalcoholic solution of 2-phenyl 1-4 benzoquinone, was used. 0.2 ml Of this solution was administered by the i.p. route at a constant temperature of 370 C. The administration of this substance produced in the animals abdominal writhes which were easy to count. The animals used were female Swiss mice of weight 20 + 2 g. The products to be studied, i.e. the compounds of the invention, phenylpiperazinoethanols of formula II and 2 (4-isobutylphenyl) propionic acid, were administered to the animals by the oral route one hour before the administration of the nociceptive agent. The value of ED50 was calculated according to the method of Litchfield and Wilcoxon J. Pharmacol. Exp. Ther. 99, 96 (1949). B. Acute toxicity (LDEn): This test was carried out by administering the compounds of general formula I, the reference compounds phenylpiperazinoethanols of formula II and 2-(4isobutylphenyl) propionic acid suspended in Tween 80 by gastric sondage at different dose levels. The doses administered were within those that do not produce any death in the animals LDo, and those killing all the animals LD100 during a 7-day observation period. The calculation of LD50 was made according to Litchfield and Wilcoxon, and when this method could not be used, the method described by Reed and Muench Am. J. Hyg. 27, 493 (1938) was employed. The results of these studies together with the ratio between LD50 and ED50, which gives an idea of the therapeutic margin of each product are shown in tables 1 and 2. The invention is further described in the following examples. Example 1 2-(4-isobutylphenyl)-propionic acid chloride To a 250 ml flask provided with a magnetic stirrer containing 20.6 g (0.1 mol) of 2-(4-isobutylphenyl) propionic acid was added 11 ml (0.15 mol) of thionyl chloride and 1 ml of pyridine. The mixture was left at room temperature for a period of 3 hours, after which it was evaporated under vacuum. 100 ml Of toluene were then added and the mixture evaporated again. The residue obtained was used without further purification. In this manner 19.9 g (858) of 2-(4-isobutylphenyl) propionic acid chloride were obtained. Example 2 2-[4-( 3-chlorophenyl)-l-piperazinyl] ethanol 24.2 ml Of 2-chloroethanol were added slowly from a dropping funnel to a mixture of 46.8 g of l-(3- chlorophenyl) piperazine and 38.2 g of sodium carbonate in 300 ml of ethanol in a flask provided with mechanical stirrer and reflux condenser. The mixture was heated at reflux for 30 hours and then was filtered and washed with 100 ml of chloroform. The solvent was distilled off to dryness and the residue recrystallized from ethyl acetate to yield 52.3 g (91%) of a solid with a melting point of 98-100 C. IR (nujol) 3 cm-l, 1590, 1550, 1460, 1050, 780. TABLE 1 EMI7.1 <tb> <SEP> Compounds <SEP> of <SEP> LD50 <SEP> ED50 <SEP> LD50 <tb> <SEP> general <SEP> formula <SEP> I <SEP> mg/kg <SEP> p.o. <SEP> mg/kg <SEP> p.o. <SEP> ED50 <tb> <SEP> R2 <SEP> = <SEP> H <SEP> 2,060 <SEP> 10.9 <SEP> 190 <tb> <SEP> R2 <SEP> = <SEP> Cl <SEP> 1,930 <SEP> 6.75 <SEP> 286 <tb> <SEP> R2 <SEP> = <SEP> CF3 <SEP> 2,180 <SEP> 7.08 <SEP> 310 <tb> 2(4-isobutylphenyl) <tb> propionic <SEP> acid <SEP> 1,050 <SEP> 4.21 <SEP> 240 <tb> TABLE 2 EMI7.2 <tb> <SEP> Compounds <SEP> of <SEP> LD50 <SEP> ED50 <SEP> LD50 <tb> <SEP> II <tb> general <SEP> formula <SEP> III <SEP> mg/kg <SEP> p.o. <SEP> mg/kg <SEP> p.o. <SEP> ED50 <tb> <SEP> R2 <SEP> = <SEP> II <SEP> <SEP> 388 <SEP> 8.8 <SEP> 44 <tb> <SEP> R2 <SEP> = <SEP> Cl <SEP> 408 <SEP> 4.11 <SEP> 100 <tb> <SEP> R2 <SEP> = <SEP> CF3 <SEP> 384 <SEP> 3.13 <SEP> 122 <tb> Example 3 2-[4-E 3 (trifluoromethyl )phenyl]-l-piperazinyl] ethanol This compound was obtained in a similar manner to compound of example 2 by reacting 46 g of 1 [3(trifluoromethyl)phenyl]-piperazine with 32.1 g of sodium carbonate and 20 ml of 2-chloroethanol. 43.3 g (80%) of an oil were obtained. IR (pure oil) cm-l: 3400, 1590, 1570, 1460, 1050 and 750 Example 4 2- (4-phenyl-l-piperazinyl) ethanol This compound was also obtained in a similar manner to compound of example 2 by treating 48.6 g of 1phenylpiperazine with 47 g of sodium carbonate and 30 ml of 2-chloroethanol. There was obtained 47.7 g (72%) of a solid melting at 84-850C. IR (nujol)9 cm¯l: 1600, 1580, 1460, 1380, 1050, 760. Example 5 2-[4-[3(trifluoromethyl)phenyl)]-1-piperazinyl] ethyl 2 (4-isobutylphenyl) propionate, Hydrochloride In 1 1. flask 27 g (0.12 mol) of 2 (4isobutylphenyl) propionic acid chloride dissolved in 100 ml of toluene was added dropwise to a mixture of 27.4 g (0.1 mol) of 2-[4-[3(trifluoromethyl) phenyl]-1- piperazinyl] ethanol in 400 ml of toluene and 12.7 g of sodium carbonate. The temperature was maintained below 50C. Once the addition had been completed, the mixture was stirred overnight. Then it was filtered and the filtrate was washed with water. The organic layer was dried over MgSO4, filtered again and the filtrate was evaporated to dryness. The residue obtained was dissolved in isopropanol, and 50% HC1 was added to the precipitate the hydrochloride. In this manner were obtained 35 g (72%) of a white solid melting 174-176 C with a single spot in TLC (Rf = 0.67, n-butanol 9/acetic acid 1/water 3). Its elemental analysis gave: z C % H % N % C1 Calculated for C26H34C1F3N202 62.59 6.82 5.62 7.12 Found " 1 62.93 7.16 6.02 7.00 IR (nujol)#cm-1: 1725 and 1175 (ester). Example 6 2-[4-(3-chlorophenyl)-l-piperazinyl] ethyl 2(4isobutylphenyl) proprionate, Hydrochloride This compound was obtained in a similar manner to the compound of example 5 by reacting at low temperatures 24.05 g (0.1 mol) of 2-[4-(3 chlorophenyl) -1-piperazinyl] ethanol in toluene with 27.00 g (0.12 mol) of the acid chloride. The hydrochloride was isolated by bubbling hydrogen chloride into a solution of the base in isopropanol. 30 g (658) Of colorless crystals melting 165-1670C, were obtained. % C % H % N % C1 Calculated for C25H34C12N2 2 64.51 7.31 6.02 15.25 Found " " 64.41 7.43 6.20 15.59 IR (nujol)#cm-1: 1730 and 1190 (ester) Example 7 2-(4-phenyl 1-piperazinyl) ethyl 2-(4-isobutylphenyl) propionate, Hydrochloride The above compound was obtained as in example 5 by reacting 20.6 g (0.1 ml) of 2-(4-phenyl l-piperazynyl) ethanol dissolved in toluene with 27 g (0.1 mol) of 2 (4isobutylphenyl) propionyl chloride, and obtaining the hydrochloride as described above. The hydrochloride obtained, 33 g (75%), melted at 153-1550C and its elemental analysis and IR spectrum were as follows: % C % H % N % C1 Calculated for C25H35ClN2O2 69.69 8.13 6.50 8.24 Found " " 69.61 8.40 6.78 8.28 IR (nujol)9 cm -1: 1725 and 1180 (ester). Example 8 The compounds of the invention may be provided in unit dosage forms as follows: (a) HARD GELATIN CAPSULES Compound of the invention 300 mg Mannitol 200 mg Talc 10.5 mg Magnesium stearate 3.5 mg (b) TABLETS Compound of the invention 500 mg Microcrystalline cellulose 115 mg Monocalcium phosphate. 2H20 200 mg Magnesium stearate 2.5 mg (c) SUPPOSITORIES Compound of the invention 700 mg Microcrystalline cellulose 800 mg Triglycerides of fatty acids 2,500 mg (d) INJECTABLE SOLUTION Compound of general formula I 100 mg EDTA Na2Ca 0.025 mg Butyl hdroxyanisole 0.1 mg Monosodium phosphate 1.5 mg Hydroalcoholic vehicle s.q. 10 ml

Claims: CLAIMS: 1. Compounds of the general formula: EMI11.1 wherein R1 represents a hydrogen or chlorine atom or a trifluoromethyl group; and the non-toxic physiologically acceptable salts thereof with organic or inorganic acids. 2. 2-(4-Phenyl 1-piperazinyl) ethyl 2-(4-isobutylphenyl) propionate and its non-toxic physiologically acceptable salts. 3. 2- [4- ( 3-Chlorophenyl)-l-piperazinyl] ethyl 2-(4isobutylphenyl) propionate and its non-toxic physiologically acceptable salts. 4. 2-[4-[3(trifluoromethyl) phenyl] l-piperazinyl] ethyl 2-(4-isobutylphenyl) propionate and its non-toxic physiologically acceptable salts. 5. A process for preparing a compound of the general formula Ia which comprises esterifying a phenyl piperazine ethanol derivative of general formula: EMI11.2 wherein R2 is as defined in claim 1, with acid chloride of general formula: EMI11.3 at low temperatures and in presence of a base, and isolating the ester in the form of an organic or inorganic salt. 6. A process for preparing a compound of the general formula Ia which comprises esterifying 2-chloroethanol with 2-(4-isobutylphenyl)-propionyl chloride to give a compound of formula: EMI12.1 and substituting the chlorine atom thereof with a phenylpiperazine of formula: EMI12.2 (wherein R2 is as previously defined) by reaction in a basic medium. 7. Solid or liquid therapeutic compositions for oral, rectal or parenteral administration comprising a compound of general formula Ia or a non-toxic organic or inorganic salt thereof in association with a pharmaceutically acceptable diluent or carrier.

Inventors: ALAMO GONZALEZ, CECILIO, CARRETERO COLON, JOSE MA., MARTIN JIMENEZ, JOSE LUIS
Applicants: JUSTE, S.A. QUIMICO-FARMACEUTICA
Application year: 1983
Main classification: C07D295
IPC codes: C07D295