EP0108780A1 - Nouvelles phenyloxoalcoyle piperidines, leurs procedes d'obtention et les compositions pharmaceutiques en renfermant - Google Patents

Nouvelles phenyloxoalcoyle piperidines, leurs procedes d'obtention et les compositions pharmaceutiques en renfermant

Info

Publication number
EP0108780A1
EP0108780A1 EP83901601A EP83901601A EP0108780A1 EP 0108780 A1 EP0108780 A1 EP 0108780A1 EP 83901601 A EP83901601 A EP 83901601A EP 83901601 A EP83901601 A EP 83901601A EP 0108780 A1 EP0108780 A1 EP 0108780A1
Authority
EP
European Patent Office
Prior art keywords
general formula
radical
cyano
lower alkyl
piperidine
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Withdrawn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
EP83901601A
Other languages
German (de)
English (en)
French (fr)
Inventor
Pierre-Jean Cornu
Claude Perrin
Bernard Dumaitre
Gilles Streichenberger
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.)
BOUCHARA, EMILE DR.
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP0108780A1 publication Critical patent/EP0108780A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

Definitions

  • the present invention relates to new piperidines substituted for nitrogen by a phenyloxoalkyl group and the methods for obtaining them.
  • a more particular subject of the invention is new phenyloxoalkyl piperidines, the piperidine ring of which is also substituted by an alkylguanidine or alkylisourea group.
  • X 1 and X 2 identical or different, represent hydrogen, a lower alkyl radical, a lower alkoxy radical, a halogen or a trifluoromethyl radical or together form an alkylene dioxy residue.
  • K represents the oxygen of a cstone function or the group in which R 1 and R 2 are lower alkyl radicals or together form a lower alkylene chain.
  • Y is chosen from the group consisting of a radical ZR 5 (in which Z is oxygen or sulfur and R 5 is a lower alkyl radical) and by a radical in which R 3 represents a lower alkyl radical, a lower alkenyl radical, a lower cycloalkyl radical or a heterocyclanyl radical having 5, 6 or 7 members.
  • R 4 represents hydrogen, a lower alkyl radical or the acyl residue of an organic carboxylic acid or R 3 and R 4 together form the alkylene residue of a nitrogenous heterocycle which may include another heteroatom.
  • n is equal to 1, 2 or 3 and n 'is equal to O or 1
  • the general formula I represents one of the possible structures of cycnogu ⁇ nidines.
  • any of the nitrogen atoms of the guanidine function can be protonated.
  • the compounds according to the invention can exist in the two tautomeric forms imino-cyanoamine and (amino-cyano) imine.
  • the invention also relates to the addition salts with a mineral or organic acid, preferably a therapeutically compatible acid, of a compound of general formula I.
  • the invention also relates to the optically active forms of the compounds of general formula I as well as to the diastereoisomers of the compounds of general formula I.
  • hydrochlorides hydrobromides, sulphates, nitrates, phosphates, thiosulphates, formates, acetates, maledtes, fumarates, benzoates, dichloro 2,6-benzoates, citrates, tartrates, (methoxy salicylates), 3, 4, 5 - trimethoxy benzoates, vanill ⁇ tes, O-carbethoxy syringoates, n ⁇ phtoates, benzene sulfonates, methane sulfonates, isethionates, nicotinates, isonicotinates, embonates and glucose phosphates.
  • R 3 and R 4 together form the olene alkylene residue of a nitrogen heterocycle, they can form, with the nitrogen atom to which they are linked, a pyrolidinyl, piperidinyl, hexamethylene imino, heptamethylene imino residue or when they include in in addition to another heteroatom, a residue, morpholinyl, tetrahydrothiazinyl, hexohydropyrimidinyl, hexdhydropyrazinyl, pyrazolidinyl or imidazolidinyl.
  • An acyl radical is derived from an organic carboxylic acid having 1 to 12 carbon atoms, for example an alkyl carboxylic acid, an arylcarboxylic acid, an arylalkyl carboxylic acid, a cycloalkyl carboxylic acid or a heteroaryl carboxylic acid. Mention may be made in this regard of an acetyl, a butyryl, a benzoyl, a 3, 4, 5 - trimetho ⁇ y benzoyl, a cyclopropylcarbonyl or a nicotinoyl.
  • n and n ' are important and plays a significant role in the pharmacological properties of the compounds of general formula I.
  • the intensity or the duration of action of the compounds, according to the invention, can be modulated by modifying the length of the carbon chain of either part of the molecule.
  • a lower alkyl radical is a hydrocarbon-based chain having from 1 to 6 carbon atoms, in straight or branched chain, such as for example methyl, ethyl, isopropyl, secbutyl , terbutyl, pentyl, neopentyl and n-hexyl.
  • a lower alkoxy radical has from 1 to 6 carbon atoms in the alkyl chain which may be straight or branched such as methoxy, ethoxy, isopropoxy, terbutoxy or pentyloxy.
  • R 1 and R 2 are lower alkyl radicals or together form a lower alkylene chain and the substituents X 1 , X 2 , Z, R 5 , n and n have the same meanings as above
  • the compounds according to the invention are distinguished by their advantageous pharmacological properties and in particular by their anti-hypertensive and vasodilatory properties associated with a sedative action on the CNS. Due to their high level of activity, the compounds of general formula I or their addition salts find use in human or animal therapy as active principles of medicaments intended to combat or reduce the effects of hypertensive disease, or to treat peripheral or brain vascular conditions.
  • compositions intended for administration by the line, buccal, rectal or sublingual route.
  • compositions contain, as active principle, at least one compound of general formula I or one of its addition salts with a mineral or organic acid, in combination or in mixture with an excipient or an inert pharmaceutically acceptable carrier.
  • compositions according to the invention can be used. in addition to contain one or more active principles of similar, complementary or synergistic action. It will thus be possible to add a diuretic of the thiazide type or of the triaminopterididine type; or a beta blocker such as propranolol, pindolol or atenolol.
  • the daily dosage can vary between wide limits depending on the therapeutic indication, the route of administration, the patient and the duration of the hypertensive disease. As a rule, in adults the dosage ranges between 0.1 and 50 mg per dose and between 0.1 and 150 mg per day.
  • the pharmaceutical compositions according to the invention contain between 0.1 and 20 mg per unit dose.
  • the invention also includes a process for preparing the compounds of general formula I characterized in that a 4-amino-piperidine of general formula II is reacted
  • R 1 and R 2 are lower alkyl radicals or together form a lower alkylene chain with a cyanoimination reagent chosen from the group consisting of cyanoimino isodithiocarbonates of alkyl of general formula III in which R 5 and R 6 are lower alkyl radicals and the mixed alkyl cyanoimino isothiocarbonates of general formula IV in which R 5 and R 6 are defined as above to form the isothiourea or the isourea of general formula (Ic).
  • a cyanoimination reagent chosen from the group consisting of cyanoimino isodithiocarbonates of alkyl of general formula III in which R 5 and R 6 are lower alkyl radicals and the mixed alkyl cyanoimino isothiocarbonates of general formula IV in which R 5 and R 6 are defined as above to form the isothiourea or the isourea of general formula (Ic).
  • R 3 and R 4 together form the alkylene residue of a nitrogen heterocycle which can be hydrolyzed in an acid medium to form the carbonyl derivative of general formula IA
  • X 1 , X 2 , R 3 , R 4 , n and n have the internal meanings which can, if desired, when R 4 is hydrogen, be acylated by the action of a functional derivative of carboxylic acid to form an N '- acyl N-cyano-guanidine of general formula IA
  • R 3 , n and n have the previous definitions and R 4 the acyl residue of a carboxylic acid having from 1 to 12 carbon atoms or else split by the action of an optically active organic acid in its optical somers or still salt well by adding a mineral or organic acid
  • the compounds of formula Ia can easily be hydrolyzed to ketone derivatives Ib with a mineral or organic acid, preferably in the presence of a carbonyl derivative.
  • the 4-umino piperidines of general formula II can be obtained - when n 'is equal to zero - by a process which consists in condensing a reactive phenyl (oxoalkyl) ester of general formula V
  • R 6 and R 7 are identical or different lower alkyl radicals, or else together form an alkylene chain having 2 to 4 carbon atoms to form a blocked phenyl (oxoalkyl) piperidone from which the ketone function is selectively released from the piperidone by functional exchange with an ⁇ -ketonic acid to form a piperidone of formula VII
  • the 4-amino piperidines of general formula II can be obtained - when not equal to 1 - by a process which consists in condensing a reactive ester of phenyloxoalkyl V with 4-carboxamido piperidine, then in reducing by the action of a hydride mixed alkali metal phenyloxoalkyl - piperidino-carboxamide to (alkyl) piperidinyl methylamine of general formula III
  • the reactive phenyloxoalkyl ester is preferably a chloride, a bromide, an iodide, a methane sulfonate or a p. toluene sulfonate.
  • the condensation reaction with piperidone or carboxamidopiperidine is carried out in a polar medium, preferably in the presence of an alkali metal iodide.
  • the polar solvent is generally pyridine, dimethyl form ⁇ mide, methyl ethyl ketone or hexamethyl phosphoro triamide.
  • the mixed alkali metal hydride is a sodium or lithium alumino hydride, sodium or potassium borohydride, lithium trimethoxy borohydride or lithium cyano-borohydride.
  • the hydrolysis of the blocked piperidone is carried out by exchange of function with an ⁇ -ketonic acid such as pyruvic acid, tartronic acid, mesoxalic acid or the acid
  • an ⁇ -ketonic acid such as pyruvic acid, tartronic acid, mesoxalic acid or the acid
  • the mixture is then brought to the boiling point of the solvent for one hour. After cooling, the excess reagent is hydrolyzed by careful addition of water and the alumina precipitate is filtered through Celite. The clear solution is concentrated to dryness; the residue is taken up in ether, dried over sodium sulfate and evaporated to dryness.
  • reaction mixture is then concentrated to dryness and the oily product obtained is treated with isopropyl ether to make it crystallize.
  • reaction mixture After absorption of 25 g of methylamine, the reaction mixture is stirred at room temperature. It is possible to follow the reaction by thin layer chromatography, eluting in the chloroform-isopropylamine mixture: 1-1.
  • the crystals are separated by filtration, washed with the minimum of water and then with cyclohexane.
  • the crystals are quickly heated to boiling for 1 minute with 50 ml of normal Hcl and 50 ml of ethanol and the mixture rapidly cooled.
  • the editorial solution is then treated with sodium hydroxide until basic reaction and the aqueous solution is exhausted with chloroform.
  • Stage B The selective hydrolysis of the ketal is carried out by (dissolving this product in 150 ml of a normal hydrochloric acid solution and 50 ml of water. The mixture is left to stand for 17 hours at room temperature.
  • Example VII 1 - [(4-p.fluorophenyl 4-oxo butyl -1] 4 - [(N-cyano N'-morpholyl guanidinyl) methyl] piperidine.
  • N 'morpholyl guanidinyl) methyl] piperidine precipitates. It is collected by filtration, washed with cold water and dried under vacuum. It melts around 225-227 °.
  • the oxalate is converted to the base by redissolution in dio ⁇ ane, alkalization by addition of sodium carbonate and exhaustion with methylene chloride.
  • the methylene chloride solution is separated, washed with water, dried over sodium sulfate and evaporated to dryness.
  • the oily residue is taken up in hot ethanol. It crystallizes on cooling.
  • LD 50 lethal dose
  • mice At high doses (60 mg / kg) there is significant hypothermia in mice, ptosis of the eyelids, reduced motor skills and arousal reactions.
  • the test was carried out on batches of alert male rats rendered hypertensive by ligation of the abdominal aorta.
  • the products according to the invention were administered orally at doses of 2.5 or 10 mg / kg. They cause a clear and prolonged pressure drop.
  • these same compounds also cause very marked hypotension for doses of 100 and 500 ⁇ g / kg when they are administered intravenously to normotensive rats or to anesthetized normoteridus dogs.
  • the compounds according to the invention cause a peripheral vasodilator effect which is observed in the rat, particularly in the hind legs, for which an increase in the skin temperature is observed from 3 to 4 ° C. This effect is manifested , depending on the product, for doses varying from 10 to 20 mg / kg.
  • This vasodilator effect is accompanied by a very marked inhibitory effect on diuresis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Earth Drilling (AREA)
EP83901601A 1982-05-18 1983-05-18 Nouvelles phenyloxoalcoyle piperidines, leurs procedes d'obtention et les compositions pharmaceutiques en renfermant Withdrawn EP0108780A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8208648 1982-05-18
FR8208648A FR2527205A1 (fr) 1982-05-18 1982-05-18 Nouvelles phenyloxoalcoyl piperidines, leurs procedes d'obtention et les compositions pharmaceutiques en renfermant

Publications (1)

Publication Number Publication Date
EP0108780A1 true EP0108780A1 (fr) 1984-05-23

Family

ID=9274143

Family Applications (1)

Application Number Title Priority Date Filing Date
EP83901601A Withdrawn EP0108780A1 (fr) 1982-05-18 1983-05-18 Nouvelles phenyloxoalcoyle piperidines, leurs procedes d'obtention et les compositions pharmaceutiques en renfermant

Country Status (9)

Country Link
EP (1) EP0108780A1 (OSRAM)
JP (1) JPS59501324A (OSRAM)
CA (1) CA1253149A (OSRAM)
ES (1) ES522531A0 (OSRAM)
FR (1) FR2527205A1 (OSRAM)
HU (1) HUT35644A (OSRAM)
IT (1) IT1197654B (OSRAM)
OA (1) OA07636A (OSRAM)
WO (1) WO1983004022A1 (OSRAM)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2641278B1 (fr) * 1989-01-05 1991-03-22 Lipha Piperidines, procedes de preparation et medicaments les contenant

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2034305B (en) * 1978-10-24 1982-12-22 Wyeth John & Brother Ltd Preparation of piperidine derivatives
GR73576B (OSRAM) * 1980-03-01 1984-03-20 Wyeth John & Brother Ltd

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8304022A1 *

Also Published As

Publication number Publication date
IT8348301A0 (it) 1983-05-16
CA1253149A (fr) 1989-04-25
JPS59501324A (ja) 1984-07-26
OA07636A (fr) 1985-05-23
IT1197654B (it) 1988-12-06
HUT35644A (en) 1985-07-29
FR2527205A1 (fr) 1983-11-25
ES8402821A1 (es) 1984-03-01
ES522531A0 (es) 1984-03-01
WO1983004022A1 (fr) 1983-11-24
FR2527205B3 (OSRAM) 1985-01-18

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PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

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Inventor name: CORNU, PIERRE-JEAN

Inventor name: PERRIN, CLAUDE

Inventor name: DUMAITRE, BERNARD

Inventor name: STREICHENBERGER, GILLES