WO1987005022A2 - PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES - Google Patents

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

Info

Publication number
WO1987005022A2
WO1987005022A2 PCT/EP1987/000070 EP8700070W WO8705022A2 WO 1987005022 A2 WO1987005022 A2 WO 1987005022A2 EP 8700070 W EP8700070 W EP 8700070W WO 8705022 A2 WO8705022 A2 WO 8705022A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
anyone
process according
formula
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1987/000070
Other languages
French (fr)
Other versions
WO1987005022A3 (en
Inventor
Leandro Baiocchi
Bruno Silvestrini
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Angelini Acraf SpA
Original Assignee
Aziende Chimiche Riunite Angelini Francesco ACRAF SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aziende Chimiche Riunite Angelini Francesco ACRAF SpA filed Critical Aziende Chimiche Riunite Angelini Francesco ACRAF SpA
Publication of WO1987005022A2 publication Critical patent/WO1987005022A2/en
Publication of WO1987005022A3 publication Critical patent/WO1987005022A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms

Definitions

  • 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.
  • this invention relates to a compound having an IR spectrum (CCl 4 ) showing a band near 1675 cm -1 , which is obtained reacting a compound of formula
  • 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
  • formula (III) above is not representative of the arrangement of the molecule in space as far as geometric isomerism, stereoi someri sm and configuration are concerned, this invention relates to all the compounds of formula (III) whether pure or in admixture one another.
  • the compounds obtained reacting (II) with (I) may be divided in two groups: the compounds which have an IR spectrum in CCl 4 showing a broad band near 1655 cm -1 and the compounds showing in the same solvent a band near 1675 cm -1 .
  • the second group exhibits the most interesting pharmacological properties.
  • the physico-chemical and spectrophotometric properties taken together lead to impute formula (III) to the compounds of the second group.
  • the preparation of the compounds of this invention may be carried out reacting a compound of formula (I) with a compound of formula (II), discharging the compounds extractable by means of solvents from the acid solutions which have an IR spectrum (CCl 4 ) showing a broad band near 1655 cm -1 , collecting the compounds which have an IR spectrum (CCl 4 ) showing a band near 1675 cm -1 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 150°C, still more preferably at
  • the preferred ratio of compound (I) to compound (II) is of one mole to from 1 to 3 moles.
  • reaction of compound (I) with compound (II) may last from
  • reaction mixture contains also some 4-oxo
  • composition i somer of the compounds of this invention; they have an IR spectrum (CCl 4 ) showing a broad band near 1655 cm -1 and are insoluble in acids.
  • each component of the mixture has an IR spectrum (CCl 4 ) showing a band near 1675 cm -1 .
  • 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 150°C and without adding diluents.
  • Preferred piperidine derivative is 2-bromomethyl piperidine hydrobromide.
  • 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 mi ore laxi ng 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).
  • this compound is devoid of adreno lyt i c 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 8. 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.
  • 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”.
  • the compound according to this invention and the pharmaceutically acceptable acid addition salts thereof will be preferably administered in pharmaceutical formulations.
  • 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.
  • 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.
  • suitable liquid excipient are water, olive oil, syrups and the like.
  • 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 desi red 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.
  • 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 hot reaction mixture is poured into water (1 I), 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 138-142°C at 1 mmHg.
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

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 an IR spectrum (CCl4) showing a band near 1675 cm-1, which is obtained reacting a compound of formula
CH3-CHX-COOR' (I) wherein X is a leaving group selected from halogen and O-SO2-R where R is methyl, phenyl, p-methylphenyl or triphenylmethyl; and R' is 1-6 C alkyl; with a compound of the formula
Figure imgf000003_0001
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
Figure imgf000004_0001
Although formula (III) above is not representative of the arrangement of the molecule in space as far as geometric isomerism, stereoi someri sm 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(1,2-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-octahydro-pyrido(1,2-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 showing a broad band near 1655 cm-1 and the compounds showing in the same solvent a band near 1675 cm-1. The second group exhibits the most interesting pharmacological properties. The physico-chemical 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 (CCl4) 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 anxio lyti c-anti depressive 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 (Physician s Desk Reference, 38th Ed., 1202, 1984).
This profile agrees well with the assumption that depression is related to a painful mental condition (SiIvestrini, B. Activ. Nerv. Super. 21, 301-303, 1979). In contrast, the adreno lyti c 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 (II), discharging the compounds extractable by means of solvents from the acid solutions which have an IR spectrum (CCl4) showing a broad band near 1655 cm-1, collecting the compounds which have an IR spectrum (CCl4) showing a band near 1675 cm-1 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 150°C, still more preferably at
170°-180°C 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) i somer of the compounds of this invention; they have an IR spectrum (CCl4) showing a broad band near 1655 cm-1 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 (CCl4) showing a band near 1675 cm-1.
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. (δ) (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 150°C 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 mi ore laxi ng 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 adreno lyt i c 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 8. 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.
Figure imgf000007_0001
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 desi red 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-trifluoromethylani line (149.4 g; 0.927 mol) is heated at 160-170°C for four hrs.
The hot reaction mixture is poured into water (1 I), 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 138-142°C at 1 mmHg.
53 g of 2-(N-3-trif luoromethylphenylaminomethyl)-piperidine, viscous and colourless oil are thus obtained.
Analysis Found % C:60.10 H:6.77 N:10.98 for C13H17F N2 Calcd % C:60.45 H:6.63 N:10.85 3 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 170-180°C 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 150°C, 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 ricrystallization from hexane, it melts at 75-77°C.
Analysis Found % C: 61.45 H: 6.16 N: 8.86 for C16H19F3N2O Calcd % 61.53 6.13 8.97
IR (CCl4) vC=0 1674 cm- 1
NMR (CCl4) 1.35 (d,J=6cps),3H 1.10-2.60 (non resolved multiplets), 8H
2.81 ± 0.05 p. p.m. (δ) (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 C16H19F3N2O.HCI Calcd % 55.10 5.78 8.03 10.16
IR (KBr) vC=0 1680 cm-1; vN-H 2310 cm-1 (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=0),CCI4 NMRCCCl4) (significant peaks) (ºC) (cm-1) 4-5 (δ) 7-8(δ) 2,6-3(δ)
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% Drops 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
Figure imgf000017_0001
Figure imgf000018_0001

Claims

1. A compound of formula
Figure imgf000013_0001
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.
(δ).
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
Figure imgf000013_0002
7. A process for preparing a compound of formula
Figure imgf000014_0001
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 O-SO2-R where R is methyl, phenyl, p-methylphenyl and triphenylmethyl; and
R' is 1-6 C alkyl, with a compound of formula
Figure imgf000014_0002
discharging the compounds insoluble in acids which have an IR spectrum (CCl4) showing a broad band near 1655 cm-1, collecting the compounds which have an IR spectrum (CCl4) showing a band near 1675 cm-1 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 150°C.
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) showing a band near 1675 cm-1 are separated to afford a compound which has an NMR spectrum (CCl4) showing a centered quartet at
2.81+0.05 p.p.m. (δ).
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-bromomethyl 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 150°C.
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 whi c h comprises mixing an effective amount of a compound prepared according to anyone of claims from 7 to 19 with a pharmaceutical excipient.
PCT/EP1987/000070 1986-02-17 1987-02-09 PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES Ceased WO1987005022A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT19431A/86 1986-02-17
IT19431/86A IT1204803B (en) 1986-02-17 1986-02-17 PHARMACOLOGICALLY ACTIVE COMPOUND AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT, PROCEDURE TO PREPARE IT AND INTERMEDIATE USEFUL IN THAT PROCEDURE

Publications (2)

Publication Number Publication Date
WO1987005022A2 true WO1987005022A2 (en) 1987-08-27
WO1987005022A3 WO1987005022A3 (en) 1987-10-22

Family

ID=11157870

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1987/000070 Ceased WO1987005022A2 (en) 1986-02-17 1987-02-09 PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES

Country Status (6)

Country Link
EP (1) EP0257072A1 (en)
AU (1) AU7122387A (en)
ES (1) ES2004255A6 (en)
IT (1) IT1204803B (en)
PT (1) PT84299A (en)
WO (1) WO1987005022A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0380217A1 (en) * 1989-01-23 1990-08-01 Pfizer Inc. Bis-aza-bicyclic anxiolytic agents and antidepressants
US5852031A (en) * 1994-09-30 1998-12-22 Pfizer Inc. 2,7-substituted octahydro-1H-pyrido 1,2-a!pyrazine derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3503980A (en) * 1965-10-04 1970-03-31 Ciba Geigy Corp Tetrahydroazacycloalkano(1,2-a) pyridazines
GB1125112A (en) * 1966-01-07 1968-08-28 Science Union & Cie New derivatives of diazabicyclo-decane and process for preparing them

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0380217A1 (en) * 1989-01-23 1990-08-01 Pfizer Inc. Bis-aza-bicyclic anxiolytic agents and antidepressants
AP128A (en) * 1989-01-23 1991-03-20 Pfizer Bis-aza-bicyclic anxiolytic agents.
US5852031A (en) * 1994-09-30 1998-12-22 Pfizer Inc. 2,7-substituted octahydro-1H-pyrido 1,2-a!pyrazine derivatives

Also Published As

Publication number Publication date
AU7122387A (en) 1987-09-09
WO1987005022A3 (en) 1987-10-22
ES2004255A6 (en) 1988-12-16
IT1204803B (en) 1989-03-10
EP0257072A1 (en) 1988-03-02
IT8619431A0 (en) 1986-02-17
PT84299A (en) 1987-03-01

Similar Documents

Publication Publication Date Title
JPS6049192B2 (en) New substituted benzamides, their production methods, and psychotropic drugs containing them as active ingredients
JPH0224821B2 (en)
JPS6253504B2 (en)
KR20170061615A (en) New salt of fimasartan
JPS6230780A (en) Naphthyridine derivative and pharmaceutical containing said derivative
KR850000216B1 (en) Method for preparing piperazine derivatives
JPS636058B2 (en)
KR20170061616A (en) New salt of fimasartan
EP0338746B1 (en) 2-Alkyl-3-benzoylbenzofurans and pharmaceutical compositions containing them
US3483221A (en) 1 - (isopropylamino)-2-hydroxy-3-(alkenyloxyphenoxy) - propanes and the salts thereof
HU193523B (en) Process for preparing 2-/2'-hydroxy-3'-/1,1-dimethyl-propyl-amino /-propoxy/-beta-phenyl-propiophenone
HU198454B (en) Process for production of new derivatives of tetrahydrospiridin and medical compositions containing these compounds
EP0085870B1 (en) Dibenz(b,e)oxepin derivatives and pharmaceutical compositions containing them
WO1987005022A2 (en) PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES
US3337539A (en) Tetraethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivatives and salts thereof
KR900003301B1 (en) Method for preparing 2-piperazinyl-4-phenyl quinazoline derivatives and their salts
JPS60158190A (en) Hydantoin derivative, its preparation, and drug containing it
AU568704B2 (en) Ether of n-propanolamine derivative
US3275654A (en) 1-isopropylamino-2-hydroxy-3-phenoxy-propanes and salts thereof
US3485873A (en) N-benzyl-n-methyl-omega-phenyl-omega-cycloalkyl-lower-alkylamines
JPS5935387B2 (en) Di-substituted phenol ethers of 3-amino-2-hydroxypropane, their preparation and pharmaceutical uses
US3549656A (en) Antidepressant 1 - aminoalkyl - thiophthalanes and acid addition salts thereof
US3502724A (en) P-chloro-n-(chloropropyl)-alpha-methyl-phenethylamines and the salts thereof
KR900006856B1 (en) Oxime ether of 2, 6-dioxabicyclo [3.3.0] octanone
KR100226328B1 (en) 4- (4-or6- (trifluoromethyl-2-pyridinyl))-1-piperazinylalkylsubstituted lactam

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AU FI HU JP KR SU US

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH DE FR GB IT LU NL SE

AK Designated states

Kind code of ref document: A3

Designated state(s): AU FI HU JP KR SU US

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AT BE CH DE FR GB IT LU NL SE