EP0257072A1 - PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES - Google Patents

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

Info

Publication number
EP0257072A1
EP0257072A1 EP87901432A EP87901432A EP0257072A1 EP 0257072 A1 EP0257072 A1 EP 0257072A1 EP 87901432 A EP87901432 A EP 87901432A EP 87901432 A EP87901432 A EP 87901432A EP 0257072 A1 EP0257072 A1 EP 0257072A1
Authority
EP
European Patent Office
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.)
Withdrawn
Application number
EP87901432A
Other languages
German (de)
English (en)
French (fr)
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 EP0257072A1 publication Critical patent/EP0257072A1/en
Withdrawn legal-status Critical Current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)
EP87901432A 1986-02-17 1987-02-09 PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES Withdrawn EP0257072A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT19431/86A IT1204803B (it) 1986-02-17 1986-02-17 Composto farmacologicamente attivo e composizioni farmaceutiche che lo contengono,procedimento per prepararlo e intermedio utile in detto procedimento
IT1943186 1986-02-17

Publications (1)

Publication Number Publication Date
EP0257072A1 true EP0257072A1 (en) 1988-03-02

Family

ID=11157870

Family Applications (1)

Application Number Title Priority Date Filing Date
EP87901432A Withdrawn EP0257072A1 (en) 1986-02-17 1987-02-09 PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES

Country Status (6)

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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX19222A (es) * 1989-01-23 1993-12-01 Pfizer Agentes ansioliticos bis-aza-biciclicos
JP3287574B2 (ja) * 1994-09-30 2002-06-04 ファイザー・インク ２，７−置換オクタヒドロ−１ｈ−ピリド［１，２−ａ］ピラジン誘導体

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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8705022A2 *

Also Published As

Publication number Publication date
IT1204803B (it) 1989-03-10
PT84299A (en) 1987-03-01
ES2004255A6 (es) 1988-12-16
WO1987005022A2 (en) 1987-08-27
WO1987005022A3 (en) 1987-10-22
IT8619431A0 (it) 1986-02-17
AU7122387A (en) 1987-09-09

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Inventor name: BAIOCCHI, LEANDRO

Inventor name: SILVESTRINI, BRUNO