PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES

Abstract: Pharmacologically active compound of formula (III), and pharmaceutically acceptable acid addition salts thereof. The process for preparing the compound (III) involves the use as a new intermediate of 2-(N-3-trifluoromethylphenylaminomethyl)-piperidine (II). Pharmaceutical formulations containing the compound of formula (III) or an acid addition salt thereof.

Description: PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES This invention relates to a new pharmacologically active compound and to the pharmaceutically acceptable acid addition salts thereof, the pharmaceutical compositions containing same, the process for preparation thereof and a new intermediate useful in said process. More particularly, this invention relates to a compound having -1 an IR spectrum (CC 14) showing a band near 1675 cm , which is obtained reacting a compound of formula CH3-CHX-COOR ' (I) wherein X is a leaving group selected from halogen and O-S02-R where R is methyl, phenyl, e-methylphenyl or triphenylmethyl; and R' is 1-6 C alkyl; with a mpound of the formula EMI1.1 The compound of formula (II) is also new and therefore is a further object of this invention together with its preparation method which comprises reacting a 2-halomethyl-piperidine or an acid addition salt thereof with m-trifluoromethyl-aniline. The product obtained reacting compound (I) with compound (II) consists mainly of a compound the physico-chemical and spectrophotometric characteristics of which are in favour of the following formula EMI2.1 Although formula (III) above is not representative of the arrangement of the molecule in space as far as geometric isomerism, stereoisomerism and configuration are concerned, this invention relates to all the compounds of formula (III) whether pure or in admixture one another. 3-oxo-octahydro-pyrido(l,2-a)pyrazines are not very known. Concerning numbering of substituents, reference is made to "The Ring Index", Am. Chem. Soc., page 208, No. 1612). The only precedent is an article of 1972 (J. Chem. Soc. Perkin, 2, 1972, 1374) which relates to their stereochemistry. None of the three 3-oxo-octahydro-pyrido(1,2-a)pyrazines described by said article anticipate the compound of formula (III). It does not appear that the preparation of other 3-oxo-octa hydro-pyrido(l,2-a)pyrazines or the pharmacological properties of the known ones have been described subsequently. The compounds obtained reacting (II) with (I) may be divided in two groups: the compounds which have an IR spectrum in CCl4 -1 showing a broad band near 1655 cm and the compounds showing in -1 the same solvent a band near 1675 cm . The second group exhibits the most interesting pharmacological properties. The physicochemical and spectrophotometric properties taken together lead to impute formula (III) to the compounds of the second group. Among them, the product which exhibits the most interesting pharmacological properties is the one the NMR (CC 14) of which shows a centered quartet at 2.81 + 0.05 p.p.m. ( ). For the sake of brevity it will be referred to hereinafter as "Compound C". For correct interpretation of the pharmacological properties of "Compound C" express reference is made to the entire literature originated by the Applicant regarding another compound: trazodone. This drug exhibits three basic properties. They are a well proved antidepressive and anxiolytic-antidepressive effect in man, adrenolytic activity either in the experimental animal or in man, and the ability to inhibit response to unpleasant stimuli in the experimental animal (Physiisn:s Desk Reference, 38th Ed., 1202, 1984). This profile agrees well with the assumption that depression is related to a painful mental condition (Silvestrini, B. Activ. Nerv. Super. 21, 301-303, 1979). In contrast, the adrenolytic activity of trazodone is not related to antidepressive effects but to secondary effects such as orthostatic hypotension and priapism. This is why a compound which inhibits the response to unpleasant stimuli in the experimental animal without possessing adrenolytic effects and which therefore maintains the antidepressive activity of trazadone without exhibiting its peculiar side effects would be useful. The preparation of the compounds of this invention may be carried out reacting a compound of formula (I) with a compound of formula (it), discharging the compounds extractable by means of solvents from the acid solutions which have an IR spectrum (CC 14) -1 showing a broad band near 1655 cm, collecting the compounds -1 which have an IR spectrum (CCl4) showing a band near 1675 cm and, when desired, preparing a pharmaceutically acceptable acid addition salt thereof. Preferred meanings of X in formula (I) are chlorine and bromine; preferred meanings of R' are methyl, ethyl and propyl. The reaction of compound (I) with compound (II) is preferably carried out at at least 1500C, still more preferably at 1700-1800C and in the absence of diluents. The preferred ratio of compound (I) to compound (II) is of one mole to from 1 to 3 moles. The reaction of compound (I) with compound (II) may last from 1-2 hrs to 3-4 days; preferably the reaction time is of about 24 hrs. The thus obtained reaction mixture contains also some 4-oxo (position) isomer of the compounds of this invention; they have -1 an IR spectrum (CC 14) showing a broad band near 1655 cm and are insoluble in acids. After separation of the 4-oxo, (position)isomers, it is obtained a mixture of compounds of this invention; i.e. each component of the mixture has an IR spectrum (CC 14) showing a band -1 near 1675 cm Further separation by column chromatography, affords two fractions. One of the fractions has an NMR spectrum (CCl4) showing a centered quartet at 2.81 + 0.05 p.p.m. (6) (Compound C). Also the reaction of a 2-halomethyl piperidine or an acid addition salt thereof with m-trifluoromethyl-aniline to afford the compound of formula (II) is preferably carried out at at least 1500C and without adding diluents. Preferred piperidine derivative is 2-bromomethyl piperidine hydrobromide. Preferably the reaction time is of from 1 to 12 hours. "Compound C", shows a pharmacological profile very close to the profile of trazodone as regards sedative and miorelaxing effects when assayed according to the Irwin test (Animal and Clinical Pharmacological Techniques in Drug Evaluation, Eds: J.H. Nodine and P.E. Siegler, Chicago, 237-240, 1959) and as regards analgesic activity when assayed according to the phenylquinone test (Hendershot L.C. and Forsaith J.J. Pharmacol. Exp. Ther. 125, 237-240, 1959). In contrast, this compound is devoid of adrenolytic effects both in vitro, when assayed according to the isolated deferent test (Patil P.N., Lapidus J.B., Tye A.J. Pharmacol. Exp. Ther. 155, 1-12, 1967 Metodiche sperimentali di Fisiologia e Farmacologia in vivo Tamburini Ed. Milano 1974, pag. 71-74), and in vivo when assayed according to the pressure response to noradrenaline in the rat and clonidine adrenergic tremor in the mouse (Silvestrini B. e Lisciani R. Curr. Ther. Res. 20, 716, 1976) up to doses substantially higher than those which are active in case of trazodone, as summarized in Table 1. TABLE 1 Test Species Dose Compound Trazodone (mg/kg) "C" Irwin Mouse 2-20 i.p. Sedation Sedation Tranquility Tranquility Phenylquinone Mouse 6 os Analgesia Analgesia Deferent Rat 0.2-2.10 No effect Inhibition Adrenergic Rat 1 i.v. No effect Hypotension Hypertension Tremor Mouse 25-50 os No effect Inhibition The results shown in the Table prove that "Compound C" exhibits sedative, tranquillizing and analgesic action while it is free of adrenolytic effects both centrally and peripherally. "Compound C" is thus endowed with pharmaceutical and therapeutical properties similar to those of trazodone and has the advantage of being free of the adrenolytic action which is responsible for some side effects of trazodone. Preliminary tests in man have confirmed the favourable properties of "Compound C". It is another object of this invention to provide the acid addition salts of the compound of formula (III) with pharmaceutically acceptable organic and inorganic acids such as hydrochloric, sulfuric, succinic, malic, pyruvic, tartaric, mandelic acid and the like. For pharmaceutical use the compound according to this invention and the pharmaceutically acceptable acid addition salts thereof will be preferably administered in pharmaceutical formulations. Therefore, further objects of this invention are the pharmaceutical formulations containing a compound of formula (III) or a pharmaceutically acceptable acid addition salt thereof together with one or more suitable pharmaceutical excipients as well as a method for treating depression by administering said pharmaceutical forms. Said pharmaceutical forms will be preferably administered by oral or injectable route. Therefore, they will be preferably solid such as tablets, sugar coated pills, powders and capsules, or liquid such as solutions or suspensions. They may also be slow release preparations. The compound of formula (III) or a pharmaceutically acceptable acid addition salt thereof will be dosed in the formulation as such or microincapsulated. Examples of suitable solid excipients are lactose, saccarose, talc, gelatin, agar, terra alba, pectin, acacia, magnesium stearate, stearic acid, potato starch and the like. The amount of the excipients will change substantially but each tablet or capsule will not preferably exceed 1 gram. Examples of suitable liquid excipient are water, olive oil, syrups and the like. In addition, said pharmaceutical forms may contain other active ingredients, preserving agents, stabilizers, dyes, sweetening agents, emulsifiers, surfactants or flavouring agents, and will be prepared by ordinary operations such as granulation, compression, dissolution and sterilization. The active ingredient will be dosed in each dosage unit in such an amount as to exert the desired therapeutic action. The posology of the compound of formula (III) and of the pharmaceutically acceptable acid addition salts thereof will change in accordance with the formulation, the chosen administration route, the kind and severity of the illness to be treated and the general conditions of the patient, according to parameters which are well known to prescribers. In view of the analogy with trazodone, the skilled man will not have any difficulty in determining the posology of the compound of formula (III) and of the pharmaceutically acceptable acid addition salts thereof. Preferably, each dosage unit will contain an amount of from 25 to 250 mg, as base, of a compound of formula (III) or of a pharmaceutically acceptable acid addition salt thereof, and each dosage unit will be administered from one to six times a day. The following examples are intended to illustrate this invention without limiting it. EXAMPLE 1 a) A mixture of 2-bromomethylpiperidine hydrobromide (80 g; 0.309 mol) and m-trifluoromethylaniline (149.4 g; 0.927 mol) is heated at 160-1700C for four hrs. The hot reaction mixture is poured into water (1 1), 160 ml of 2N sodium hydroxide (0.32 mol) are added, the organic layer is extracted with ethyl ether, the solvent is removed and the oily residue is distilled, collecting the fraction which boils at 138-142oC at 1 mmHg. 53 g of 2-(N-3-trifluoromethylphenylaminomethyl)-piperi dine, viscous and colourless oil are thus obtained. Analysis Found % C:60.10 H:6.77 N:10.98 for C13H17F3N2 Calcd % C:60.45 H:6.63 N:10.85 b) A mixture of the above product (45.5 g; 0.176 mol) and of ethyl 2-chloropropionate (41 g; 0.3 mol) is heated at 170-1800C for 24- hrs. The hot mixture is poured into a 10% sodium carbonate solution (600 ml). After cooling, the organic layer is extracted with chloroform. The volatile portion is removed at 20 mmHg and 1500C, and the residue thus obtained (59 g) is dissolved in ethyl ether (300 ml). The solution thus obtained is extracted 4 times with 100 ml of 1N hydrochloric acid. The organic phase which contains two (4-oxo) position isomers (A and B) of the compounds of formula (III) is separated and discharged. The aqueous layer is made alkaline with 2N sodium hydroxide (120 ml) and the separated oil is extracted with ethyl acetate. The solvent is removed, the residue thus obtained (30 g) is chromatographed on a silica column (900 g), eluting with: hexane/ethyl acetate 1:4. 13.5 g of the product which has been named "Compound C" are thus obtained while, eluting again with ethyl acetate/methyl alcohol 4:1 (800 ml) there are eluted 4.5 g of another crude compound (D) which is embraced by formula (III). "Compound C" solidifies spontaneously. After ricrystalliz ation from hexane, it melts at 75-770C. Analysis Found % C: 61.45 H: 6.16 N: 8.86 for C16H19F3N20 Calcd Z 61.53 6.13 8.97 -1 IR (CCl4) vC=O 1674 cm NMR (CCl4) 1.35 (d,J=6cps),3H 1.10-2.60 (non resolved multiplets), 8H 2.81 + 0.05 p.p.m. (6) (q,J=6cps), 1H 3.00-3.80 (multiplet), 3H 7.47 (s), 3H 7.61 (m), 1H Hydrochloride, m.p. 231-3 C(from ethyl alcohol/ethylacetate) Analysis Found % C:55.00 H:5.82 N:7.91 Cl:10.05 for C16H19F3N20.HCl Calcd % 55.10 5.78 8.03 10.16 -1 -1 IR (KBr) 9C=0 1680 cm ; vN-H 2310 cm (broad). The characteristics of the fractions prepared and separated according to the process described in Example 1 b) are shown in Table 2. TABLE 2 m.p. IR (C=O),CCl4 NMR(CCl4) (significant peaks) ( 0C) (cm-1) 4 -5(#) (7-8) 2,6-3(#) 4-5C) C 75-7 1674 - 7.47 2.81+0.05 p.p.m. (q,J=6cps) D oil 1673 - 7.47 A 110-13 1654-8 4.2-4.8(m,2H) 7.2 B 100-03 1654-7 4.2-4.8(m,2H) 7.2 EXAMPLE 2 a) 25 mg vials "Compound C" 25 mg Sorbitol 115 mg Water for- injection q.s. to 2.5 ml b) 50 mg Capsules "Compound C" 50 mg Starch 33.5 mg Lactose 35 mg Magnesium Stearate 1 mg Precipitated Sylica 0.5 mg c) Tablets "Compound C" 100 mg 250 mg Microgranulated Cellulose 59 mg 147.5 mg Starch 20 mg 50 mg Polyvinylpyrrolidone 9 mg 22.5 mg Sodium Methyl Starch 0.75 mg 1.875 mg Magnesium Stearate 1.25 mg 3.125 mg d) 2.5% D±Qs 100 ml contain 2.5 g "Compound C" 0.1 g Sodium Saccharinate 4 g 95% Alcohol 4 g Glycerol 60 ml Purified water q.s. to 100 ml

Claims: CLAIMS 1. A compound of formula EMI11.1 and pharmaceutically acceptable acid addition salts thereof. 2. A compound according to claim 1 above which has an NMR spectrum (CCl4) showing a centered quartet at 2.81 + 0.05 p.p.m. ( a). 3. A compound according to anyone of claims 1 and 2 above which exhibits inhibition to an animal including humans, in response to unpleasant stimuli without possessing adrenolytic effects. 4. A pharmaceutical compositions containing an effective amount of a compound according to anyone of claim from 1 to 3 above and a pharmaceutical excipient. 5. A pharmaceutical composition according to claim 4 above, wherein each dosage unit contains from 25 to 250 mg of a compound according to anyone of claim from 1 to 3, calculated as base. 6. A compound of formula EMI11.2 7. A process for preparing a compound of formula EMI12.1 and pharmaceutically acceptable acid addition salts thereof, which comprises reacting a compound of formula CH3-CHX-COOR' (I) where X is a leaving group selected from halogen and 0-SO 2-R where R is methyl, phenyl, p-methylphenyl and triphenylmethyl; and R' is 1-6 C alkyl, with a compound of formula EMI12.2 discharging the compounds insoluble in acids which have an IR -1 spectrum (CCl4) showing a broad band near 1655 cm, collecting the compounds which have an IR spectrum (cm 14) showing a band -1 near 1675 cm and, when desired, preparing a pharmaceutically acceptable acid addition salt thereof. 8. A process according to claim 7 above, wherein a compound of formula (I) is used where X is chlorine or bromine, and R' is methyl, ethyl or propyl. 9. A process according to anyone of claims 7 and 8 above, wherein the reaction of compound (I) with compound (II) is carried out at at least 1500C. 10. A process according to anyone of claims from 7 to 9 above, wherein the reaction of compound (I) with compound (II) is carried out in the absence of diluents. 11. A process according to anyone of claims from 7 to 10 above, wherein the reaction of compound (I) with compound (II) is carried out for a time ranging from 1 to 4 days. 12. A process according to claim 11, wherein the reaction lasts 24 hours. 13. A process according to anyone of claims from 7 to 12 above, wherein the compounds which have an IR spectrum (CCl4) -1 showing a band near 1675 cm are separated to afford a compound which has an NMR spectrum (CCl4) showing a centered quartet at 2.81+0.05 p.p.m. (6). 14. A process according to claim 13 above, wherein the separation is carried out via chromatography. 15. A process according to anyone of claims from 7 to 12 above, wherein compound (II) is prepared reacting a 2-halomethyl piperidine or an acid addition salt thereof with m-trifluoromethylaniline. 16. A process according to cLaim 15 above, wherein 2-bromo methyl piperidine hydrobromide is used. 17. A process according to anyone of claims 15 and 16 above, wherein the reaction is carried out at at least 1500C. 18. A process according to anyone of claims from 15 to 17 above, wherein the reaction is carried out in the absence of diluents. 19. A process according to anyone of claims from 15 to 18 above, wherein the reaction time ranges from 1 to 12 hours. 20. A process for preparing a pharmaceutical composition which comprises mixing an effective amount of a compound prepared according to anyone of claims from 7 to 19 with a pharmaceutical excipient.

Inventors: BAIOCCHI LEANDRO, SILVESTRINI BRUNO, BAIOCCHI, LEANDRO, SILVESTRINI, BRUNO
Applicants: ACRAF, AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO A.C.R.
Application year: 1987
Main classification: C07D471
IPC codes: C07D211, C07D471