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
Application number
PCT/EP1987/000070
Other languages
English (en)
French (fr)
Other versions
WO1987005022A3 (en
Inventor
Leandro Baiocchi
Bruno Silvestrini
Original Assignee
Aziende Chimiche Riunite Angelini Francesco A.C.R.
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 A.C.R. filed Critical Aziende Chimiche Riunite Angelini Francesco A.C.R.
Publication of WO1987005022A2 publication Critical patent/WO1987005022A2/en
Publication of WO1987005022A3 publication Critical patent/WO1987005022A3/en

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)
PCT/EP1987/000070 1986-02-17 1987-02-09 PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES WO1987005022A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT19431A/86 1986-02-17
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

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 WO1987005022A2 (en) 1986-02-17 1987-02-09 PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES

Country Status (6)

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

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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR6363M (es) * 1966-01-07 1968-10-07
GB1137410A (en) * 1965-10-04 1968-12-18 Ciba Ltd Novel aza-cycloalkano-[1,2-a]-pyrazines and process for preparing same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1137410A (en) * 1965-10-04 1968-12-18 Ciba Ltd Novel aza-cycloalkano-[1,2-a]-pyrazines and process for preparing same
FR6363M (es) * 1966-01-07 1968-10-07

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

Similar Documents

Publication Publication Date Title
JPS6049192B2 (ja) 新規置換ベンズアミド、その製造方法及びこれを有効成分とする向精神薬
JPH0224821B2 (es)
JPS6253504B2 (es)
KR20170061615A (ko) 피마살탄의 신규 염
KR850000216B1 (ko) 피페라진 유도체의 제조방법
JPS6230780A (ja) １，７−ナフチリジン誘導体及びこれを含有する薬剤
KR20170061616A (ko) 피마살탄의 신규 염
JPS636058B2 (es)
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
KR900003301B1 (ko) 2-피페라지닐-4-페닐 퀴나졸린 유도체 및 그의 산염의 제조 방법
JPS6344749B2 (es)
AU568704B2 (en) Ether of n-propanolamine derivative
JPS60158190A (ja) ヒダントイン誘導体およびその製法ならびにそれを含有する医薬
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 (ja) ３−アミノ−２−ヒドロキシプロパンのジ−置換フエノ−ルエ−テル類、その製法ならびに医薬用途
US3502724A (en) P-chloro-n-(chloropropyl)-alpha-methyl-phenethylamines and the salts thereof
KR900006856B1 (ko) 2, 6-디옥사비시클로[3.3.0]옥타논의 옥심 에테르
DK164867B (da) Pyrimidooe4,5-gaaquinolin-derivater eller salte deraf og farmaceutiske formuleringer indeholdende disse
US3303095A (en) Compositions and methods for producing tranquilizing activity

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