EP0000869A1 - Nouvaux dérivés de la pipéridine, procédé pour leur préparation et compositions pharmaceutiques les contenant - Google Patents

Nouvaux dérivés de la pipéridine, procédé pour leur préparation et compositions pharmaceutiques les contenant Download PDF

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Publication number
EP0000869A1
EP0000869A1 EP78100431A EP78100431A EP0000869A1 EP 0000869 A1 EP0000869 A1 EP 0000869A1 EP 78100431 A EP78100431 A EP 78100431A EP 78100431 A EP78100431 A EP 78100431A EP 0000869 A1 EP0000869 A1 EP 0000869A1
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Prior art keywords
hydrogen atom
radical
formula
group
lower alkyl
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German (de)
English (en)
Inventor
Herbert Dr. Schröter
Kurt Dr. Eichenberger
Hans Dr. Kühnis
Christian Dr. Egli
Oswald Dr. Schier
Franz Dr. Ostermayer
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Novartis AG
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Ciba Geigy AG
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • lower radicals are those radicals which contain no more than 7 carbon atoms and preferably up to 4 carbon atoms.
  • a heteroaryl radical R 1 is an optionally substituted one heterocyclic, preferably monocyclic and bicyclic heteroaryl, primarily an optionally, for example mono-, disubstituted or polysubstituted, preferably monocyclic azaaryl radical having 5 to 6 ring members and 1 to 2 ring nitrogen atoms, such as optionally substituted pyridyl, for example 2-, 3- or 4-pyridyl, imidazolyl, for example 2-imidazolyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, pyridazinyl, for example 2-pyridazinyl, or pyrazinyl, for example 2-pyrazinyl, furthermore an optionally substituted bicyclic azaaryl radical, in particular benzoazaaryl radical, with 5 to 6 Ring members and 1 to 2 ring nitrogen atoms in the azaaryl radical, such as optionally substituted indolyl, for example 4-indolyl, quinoliny
  • Lower alkylene residues alk 1 or alk 2 are, for example, 2,3-butylene residues, 1,2-butylene residues, 1,1-dimethyl-1,2-ethylene residues, or preferably 1,2-propylene residues or in particular 1,2-ethylene residues.
  • the o-phenylene radical Ph can carry one, two or more substituents; however, it preferably contains no more than two substituents.
  • Possible substituents of the o-phenylene radical are in particular: lower alkyl radicals, lower alkoxy groups, halogen atoms, trifluoromethyl groups, hydroxyl groups and secondly also acylamino groups, nitro groups and amino groups.
  • An optionally acylated hydroxyl group R 2 is, for example, a lower alkanoyloxy group, such as, for example, an acetoxy, propionyloxy or butyryloxy group or preferably the pivaloyloxy group, or above all a free one Hydroxy group.
  • Optionally substituted aliphatic hydrocarbon radicals as substituents of a heteroaryl radical R 1 are corresponding lower alkyl, as well as lower alkenyl or lower alkynyl, where substituents of lower alkyl are primarily optionally etherified or esterified hydroxy or mercapto, acyl or optionally substituted amino.
  • Lower alkyl radicals are, for example, methyl, ethyl, n-propyl or isopropyl radicals, or straight-chain or branched butyl, pentyl or hexyl radicals, which can be bound in any position.
  • Lower alkenyl radicals are in particular allyl or methallyl radicals, and the propargyl radical is particularly suitable as the lower alkynyl radical.
  • Etherified hydroxy is, in particular, lower alkoxy or phenyl-lower alkoxy, furthermore lower alkenyloxy or lower alkynyloxy, and also hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, lower alkylthione-lower alkoxy or lower alkanoyl-lower alkoxy, while esterified hydroxy is especially halogen, furthermore lower alkanoyloxy.
  • Etherified mercapto is primarily lower alkylthio, while esterified mercapto is e.g. Niederalkanoylthio is.
  • Acyl is preferably the corresponding radical of an organic carboxylic acid and is, for example, aroyl or lower alkanoyl.
  • Acyl also represents the corresponding residue of a carbonic acid derivative, such as lower alkoxycarbonyl or optionally substituted carbamoyl.
  • An acyl radical in the broadest sense of the definition is also cyan.
  • Preferred acyl radicals are in particular benzoyl or acetyl.
  • Optionally substituted amino is acylamino, in particular lower alkanoylamino or lower alkoxycarbonylamino, furthermore optionally substituted ureido.
  • Substituted amino is also lower alkylamino the lower alkylamino, and lower alkylene amino, lower oxaalkylene amino the lower azaalkylene amino, the latter being preferably substituted for the aza nitrogen, for example by lower alkyl.
  • Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy.
  • Phenyl-lower alkoxy is e.g. benzyloxy or 1- or 2-phenyl-ethoxy.
  • Hydroxy lower alkoxy is e.g. 2-hydroxyethoxy, also 2- or 3-hydroxypropyloxy.
  • Lower alkoxy lower alkoxy includes Lower alkoxymethoxy or 1- and especially 2-lower alkoxy-ethoxy, e.g. Methoxymethoxy, 2-methoxy-ethoxy or 2-ethoxy-ethoxy.
  • Lower alkylthione lower alkoxy is especially lower alkylthiomethoxy or 1- and primarily 2-lower alkylthioethoxy, e.g. 2-methylthio-ethoxy or 2-ethylthio-ethoxy.
  • Lower alkanoyl lower alkoxy is especially acetonyloxy.
  • Lower alkenyloxy is e.g. Allyloxy, 2- or 3-methallyloxy or 3,3-dimethylallyloxy.
  • Lower alkynyloxy is especially propargyloxy.
  • Halogen is preferably halogen with an atomic number up to 35, i.e. Fluorine, chlorine or bromine.
  • Lower alkanoyloxy is e.g. for acetyloxy, propionyloxy or pivaloyloxy.
  • Lower alkylthio is e.g. Methylthio, ethylthio, n-propylthio or isopropylthio.
  • Niederalkanoylthio is i.a. Acetylthio or propionylthio.
  • Lower alkanoyl is e.g. Acetyl, propionyl or butyryl.
  • Lower alkoxycarbonyl is e.g. Methoxycarbonyl or ethoxycarbonyl.
  • Optionally substituted carbamoyl is e.g. Carbamoyl, or N-lower alkyl or N, N-di-lower alkylcarbamoyl, such as N-methyl-carbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl or N, N-diethylcarbamoyl.
  • Lower alkanoylamino is, for example acetylamino or P ropionylamino.
  • Lower alkoxycarbonylamino is e.g. Methoxycarbonylamino or ethoxycarbonylamino.
  • Optionally substituted ureido is e.g. Ureido or 3-lower alkyl or 3-cycloalkyl-ureido, in which cycloalkyl e.g. Has 5-7 ring links, e.g. 3-methylureido, 3-ethylureido or 3-cyclohexylureido.
  • N-lower alkylamino and N, N-di-lower alkylamino are e.g. Methylamino, ethylamino, dimethylamino or diethylamino.
  • Lower alkylene amino preferably contains 5-7 ring carbon atoms and is e.g. Pyrrolidino or Piperidino.
  • Niederoxaalkylenamino is primarily morpholino, while Niederazaalkylenamino in particular corresponding N-Niederalkyl-Niederazaalkylenamino, e.g. 4-methyl-l-piperazino.
  • the substituted lower alkyl groups include, for example, hydroxy lower alkyl, lower alkoxy lower alkyl, halogen lower alkyl, lower alkanoylamino lower alkyl or lower alkoxycarbonyl to call amino lower alkyl.
  • Hydroxy-lower alkyl is preferably hydroxymethyl or 1- and primarily 2-hydroxyethyl.
  • Lower alkoxy lower alkyl is preferably lower alkoxymethyl or 1- and primarily 2-lower alkoxyethyl, e.g. Methoxymethyl, ethoxymethyl, 2-methoxy-ethyl or 2-ethoxy-ethyl.
  • Suitable halogen lower alkyl radicals are in particular those which are derived from the alkyl radicals mentioned and in which the halogen atom is a bromine atom or in particular a chlorine or fluorine atom, such as, for example, Chloromethyl, 2-chloroethyl, dichloromethyl and especially trifluoromethyl.
  • Lower alkoxycarbonylamino lower alkyl groups e.g. understood those radicals whose lower alkyl parts are derived from the lower alkyl groups mentioned. Such groups are e.g. Methoxycarbonylaminomethyl, Aethoxycarbonylaminomethyl, 4-Methoxycarbonylamino-n-butyl, 2-Aethoxycarbonylaminoäthyl, 3-Aethoxycarbonylamino-n-propyl and especially 2-Methoxycarbonylamino-ethyl and 3-Methoxycarbonylamino ⁇ n-propyl, carbamethylamethyl or 2-carbamethylmethyl.
  • Lower alkanoylamino lower alkyl is especially lower alkanoylaminomethyl or 1- and primarily 2-lower alkanoyiamino-ethyl, e.g. Acetylaminomethyl, 2-acetylamino-ethyl or 2-propionylamino-ethyl.
  • the new compounds have valuable pharmacological properties. They show a long-lasting hypotensive effect, as shown in animal experiments, e.g. at i.v. Administration in doses of approximately 0.01-3.0 mg / kg to the anesthetized cat shows.
  • the new compounds have a noradrenolytic effect, which can be demonstrated in vitro, for example in experiments on isolated vas deferens of rats in concentrations of 0.001-0.1 ⁇ M.
  • the new compounds also have an inhibitory effect on tachycardia, as can also be shown in animal experiments, for example in vitro experiments at concentrations of 1-2.7 pg / ml on the isolated guinea pig heart according to Langendorff (inhibition of tachycardia by isoproterenol [5 x 10 -9 ⁇ g / ml ] or histamine [3 x 10-7 ⁇ g / m1]).
  • these compounds lower the spontaneous frequency and increase the contraction force, thus acting negatively chromotropically and simultaneously positively inotropically in concentrations of 0.1-10 ⁇ g / ml. Furthermore, the new compounds extend the functional refractory period in the isolated guinea pig atrium.
  • the new compounds can accordingly be used as antihypertensive agents or as agents for the treatment of heart failure or coronary heart disease. They can also serve as starting or intermediate products for the production of other, in particular therapeutically active compounds.
  • R 1 represents optionally substituted, monocyclic heteroaryl or benzoheteroaryl having 5 to 6 ring members and 1 or 2 ring nitrogen atoms
  • substituents of the heterocyclic aryl radical optionally substituted lower alkyl, for example lower alkyl, lower alkoxy lower alkyl, lower alkanoylamino lower alkyl or lower alkoxycarbonylamino lower alkyl, or, if appropriate, etherified, or esterified, for example, or esterified, Lower alkoxy, lower alkoxy lower alkoxy, lower alkylthione lower alkoxy, lower alkylthio or halogen
  • R 2 can be a lower alkanoyl radical, such as in particular the acetyl, propionyl or pivaloyl radical, or especially a hydrogen atom
  • R 3 represents a hydrogen atom or the hydroxyl group
  • R 5 represents a hydrogen atom or R 3 and R 5 together represent a
  • the invention relates in particular to compounds of the formula Ia in which R 1 is monocyclic monoazaaryl or diazaaryl optionally substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, lower alkylthio, for example methylthio or ethylthio, and / or having an atom number of up to 35, for example chlorine or bromine with six ring members, such as pyridyl, for example 2-, 3- or 4-pyridyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, or pyrazinyl, for example 2-pyrazinyl, R 2 is lower alkanoyl, for example acetyl, propionyl or in particular Pivaloylrest or above all a water
  • Substance atom means R 3 represents a hydrogen atom or the hydroxyl group and R 5 represents a hydrogen atom or R 3 and R 5 together represent a second bond and R 4 and R 6 each represent a hydrogen atom,
  • the invention relates in particular to compounds of the formula Ia in which R 1 is optionally substituted by lower alkyl, for example by methyl, lower alkoxy, for example methoxy, lower alkylthio, for example methylthio or ethylthio, and / or halogen with an atom number of up to 35, for example chlorine or bromine -Pyrazinyl, and also optionally appropriately substituted pyridyl, for example 2- or 3-pyridyl, where substituents can have any position, but at least one, but preferably the ortho position, to the linking ring carbon atom of the heteroaryl radical, and R 2 , R 3 , R 4 , R5 , R 6 and R have the meanings given in the previous section or their non-toxic acid addition salts.
  • R 1 is optionally substituted by lower alkyl, for example by methyl, lower alkoxy, for example methoxy, lower alkylthio, for example methylthio or ethylthio,
  • the invention relates primarily to compounds of the formula Ia, in which R 1 is 2-pyrazinyl, furthermore pyridyl, for example 2- or 3-pyridyl, which are in the ortho-position to the linking carbon atom, preferably by lower alkyl, for example methyl, lower alkoxy, for example Methoxy, lower alkylthio, for example methylthio or ethylthio, or halogen with atomic numbers up to 35, for example chlorine or bromine, are substituted, and optionally further substituents of this type are ent can hold, and R 2 , R 3 , R 4 , R 5 , R 6 and R are hydrogen, and salts, especially acid addition salts, primarily pharmaceutically acceptable, non-toxic acid addition salts thereof.
  • R 1 is 2-pyrazinyl, furthermore pyridyl, for example 2- or 3-pyridyl, which are in the ortho-position to the linking carbon atom, preferably by lower alkyl, for example methyl, lower
  • R 1 represents optionally substituted, monocyclic heteroaryl or benzoheteroaryl having 5 to 6 ring members and 1 or 2 ring nitrogen atoms
  • substituents of the heterocyclic aryl radical optionally substituted lower alkyl, for example lower alkyl, lower alkoxy lower alkyl, lower alkanoylamino lower alkyl or lower alkoxycarbonylamino lower alkyl, or, if appropriate, etherified, or esterified, for example, or esterified, Niederalkoxy, Niederalkoxyniederalkoxy, Niederalkylthioniederalkoxy, Niederalkylthio or halogen
  • R can each be a hydrogen atom, a lower alkyl radical, a hydroxy group, a lower alkoxy radical, a halogen atom, a trifluoromethyl group, the nitro group, an amino group, a lower alkanoylamino group
  • R 2 is
  • the invention particularly relates to compounds of the formula Ib in which R 1 is optionally substituted by lower alkyl, for example by methyl, lower alkoxy, for example methoxy, lower alkylthio, for example methylthio or ethylthio, and / or halogen with an atomic number of up to 35, for example chlorine or bromine -Pyrazinyl, as well as optionally appropriately substituted pyridyl, for example 2- or 3-pyridyl, where substituents can have any position, but at least one, but preferably the ortho position to the linking ring carbon atom of the heteroaryl radical, R is a hydrogen atom, the methyl, methoxy or Acetylamino group, R 2 is a hydrogen atom, or a lower alkanoyl, for example the acetyl, propionyl or pivaloyl group, R 5 and R 6 each represent a hydrogen atom, and their salts.
  • R 1 is optionally substituted by lower alky
  • the invention relates primarily to compounds of the formula Ib, in which R 1 is 2-pyrazinyl, furthermore pyridyl, for example 2- or 3-pyridyl, which is ortho to the linking carbon atom, preferably by lower alkyl, for example methyl, lower alkoxy, for example Methoxy, lower alkylthio, for example methylthio or ethylthio, or halogen with atom numbers up to 35, for example chlorine or bromine, is substituted, and may optionally contain further substituents of this type, and R 2 is a hydrogen atom, the acetyl, propionyl or the pivaloyl group and R, R 5 and R 6 represent a hydrogen atom, and their non-toxic acid addition salts.
  • R 1 is 2-pyrazinyl, furthermore pyridyl, for example 2- or 3-pyridyl, which is ortho to the linking carbon atom, preferably by lower alkyl, for example methyl, lower alkoxy, for example
  • R 1 is optionally lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, lower alkylthio, e.g. methylthio or ethylthio, and / or halogen with atomic numbers up to 35, e.g. chlorine or bromine, substituted monocyclic monoazaaryl or diazaaryl with six ring members, such as pyridyl, e.g.
  • the new compounds of formula I are obtained by methods known per se.
  • the compound of the formula IIa can preferably be used in the form of its metal phenolate, such as alkali phenolate, for example sodium phenolate, or one works in the presence of an acid-binding agent, in particular a condensing agent, which co-operates with the compound of formula IIa can form a salt, such as an alkali alcoholate.
  • metal phenolate such as alkali phenolate, for example sodium phenolate
  • an acid-binding agent in particular a condensing agent, which co-operates with the compound of formula IIa can form a salt, such as an alkali alcoholate.
  • the new compounds in which R 3 is hydroxy can be prepared by reacting in a compound of the formula in which R 1 , alk 1 , alk 2 , Ph, n, R 3 , R 4 , R 5 and R 6 have the above meanings, the oxo group of the propyl chain is reduced to a hydroxyl group.
  • This reduction is carried out in a customary manner, in particular using a light metal hydride such as sodium borohydride.
  • the reduction can also be carried out with nascent hydrogen.
  • Nascent hydrogen can be obtained by the action of metal or metal alloys on hydrogen-supplying agents, such as carboxylic acid, alcohols or water, zinc or zinc alloys in particular together with acetic acid or alkali metal and alcohol, such as sodium and ethanol, being suitable.
  • the reduction can be carried out by catalytic hydrogenation, such as with hydrogen in the presence of a hydrogenation catalyst, for example heavy metals such as palladium, platinum or Raney nickel.
  • a hydrogenation catalyst for example heavy metals such as palladium, platinum or Raney nickel.
  • the new compounds can be obtained if one in a compound of the formula wherein R 1 , R 2 , R 3 , R 4 ' R 5 , R 6 , Ph and n have the above meanings, R x and R independently of one another are lower alkyl radicals or hydrogen atoms and r and s are 1 or 2, and A ⁇ an anion means the pyridinium ring is reduced to the piperidine ring.
  • the reduction can be carried out in a conventional manner, preferably by catalytic hydrogenation, such as with hydrogen in the presence of a hydrogenation catalyst, for example heavy metals, such as palladium, platinum or Raney nickel, or with nascent hydrogen, such as sodium and alcohol, such as lower alkanol, e.g. Ethanol.
  • a hydrogenation catalyst for example heavy metals, such as palladium, platinum or Raney nickel, or with nascent hydrogen, such as sodium and alcohol, such as lower alkanol, e.g. Ethanol.
  • the new compounds can be obtained by using a compound of the formula wherein R 1 , R 2 , alk 1, alk 2 , Ph, n, R 3 , R 4 ' R 5 and R 6 have the meanings given and X' represents a reactive esterified hydroxyl group, condensed intramolecularly.
  • a reactive esterified hydroxyl group is especially one of the above.
  • the cyclization can be carried out in a conventional manner, preferably in the presence of a solvent, such as an inert, polar solvent such as an alcohol, for example ethanol or isopropanol, or of dimethylformamide and advantageously in the presence of a condensing agent, especially a basic condensing agent.
  • a solvent such as an inert, polar solvent such as an alcohol, for example ethanol or isopropanol, or of dimethylformamide
  • a condensing agent especially a basic condensing agent.
  • an alkali or alkaline earth metal hydroxide, carbonate or bicar bonates for example sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate or potassium bicarbonate, or an alkali acetate, such as sodium acetate, or an alkali alcoholate, such as sodium methylate, or organic tertiary nitrogen bases, such as trialkylamines, for example trimethylamine or
  • the reaction can be carried out in a manner known per se. It is advantageous to work in the presence of an organic base, such as a tertiary amine, especially pyridine, which base can also serve as a solvent at the same time. But you can also in the presence of other solutions work medium.
  • an organic base such as a tertiary amine, especially pyridine, which base can also serve as a solvent at the same time. But you can also in the presence of other solutions work medium.
  • the new compounds can be obtained by using a compound of the formula wherein R 1 , R 2 , alk 1 , alk 2, R 3 , R 4 ' R 5 , R 6 , n and Ph have the meanings given and Y 2 is a free or preferably a functionally modified carboxyl group containing an oxo group, intramolecularly condensed.
  • a functionally modified carboxyl group containing an oxo group is, for example, an esterified carboxyl group such as, in particular, a carboxyl group esterified with a lower alkanol or aralkanol, such as methanol, phenol, p-nitrophenol, or benzyl alcohol, or an activated esterified carboxyl group, such as a carboxyl group esterified with cyanomethanol, or an acid halide -, In particular acid chloride grouping or an acid azide, acid amide or acid anhydride grouping.
  • Suitable acid anhydride groups are, in particular, those of mixed anhydrides, in particular of mixed anhydrides with carbonic acid monoalkyl esters, such as carbonic acid monoethyl or isobutyl ester.
  • the implementation can be carried out in the usual way. It is preferable to work at an elevated temperature.
  • the reaction is advantageously carried out in a solvent such as an inert solvent, e.g. a hydrocarbon such as benzene or toluene or in a high boiling inert solvent such as e.g. Diphenyl ether performed.
  • a solvent such as an inert solvent, e.g. a hydrocarbon such as benzene or toluene or in a high boiling inert solvent such as e.g. Diphenyl ether performed.
  • R 2 is hydrogen
  • R 1 , alk 1 , alk 2 , Ph, n, R 3 , R 4 , R 5 and R 6 have the meanings given and R 2 'is a radical which can be split off by hydrogenolysis, R' 2 is split off by hydrogenolysis.
  • a radical which can be split off by hydrogenolysis is above all an ⁇ -aralkyl radical, such as the benzyl radical, or an ⁇ -aralkoxycarbonyl radical, such as the carbobenzoxy radical.
  • the hydrogenolysis can be carried out in a conventional manner, preferably by means of hydrogen in the presence of a hydrogenation catalyst, such as a nickel, palladium, platinum or ruthenium catalyst.
  • the new compounds of the formula I in which R 6 together with R 5 forms an oxo group can be obtained if a compound of the formula wherein R 1 , R 2 alk 1 and alk 2 have the above meanings, with a compound of the formula wherein R 3 , R 4 , n and Ph have the above meanings and the substituents Y 3 independently of one another for a free, or preferably a functionally modified carboxyl group containing an oxo group or together for the grouping stand, implements.
  • a functionally modified carboxyl group containing an oxo group is, for example, an esterified carboxyl group such as, in particular, a carboxyl group esterified with a lower alkanol or aralkanol, such as methanol, phenol, p-nitrophenol, or benzyl alcohol, or an activated esterified carboxyl group, such as a carboxyl group esterified with cyanomethanol, or an acid halide -, In particular acid chloride grouping or an acid azide, acid amide or acid anhydride grouping.
  • Suitable acid anhydride groups are in particular those of mixed anhydrides, in particular of mixed anhydrides with carbonic acid monoalkyl esters, such as carbonic acid monoethyl or isobutyl ester.
  • the implementation can be carried out in the usual way. It is preferable to work at an elevated temperature.
  • the reaction is advantageously carried out in a solvent such as an inert Solvents, for example a hydrocarbon, such as benzene or toluene, or in a high-boiling inert solvent, such as, for example, diphenyl ether.
  • a solvent such as an inert Solvents, for example a hydrocarbon, such as benzene or toluene, or in a high-boiling inert solvent, such as, for example, diphenyl ether.
  • reducing agent used is preferably catalytically activated hydrogen, in the case of a triple bond also a chemical reducing agent, such as sodium in the presence of liquid ammonia.
  • a compound of the formula I which contains hydroxy or mercapto in the form of a primary carbinol or a phenolic hydroxyl group as a substituent
  • this if appropriate in salt, for example alkali metal salt form, by treatment with a reactive ester of an alcohol, such as an optionally substituted lower alkyl halide, in etherified hydroxy or mercapto, for example lower alkoxy or lower alkylthio.
  • hydroxy in a hydroxy-lower alkyl or hydroxy-lower alkoxy substituent usually in the form of a reactive esterified hydroxy group, such as halogen, for example chlorine, with an alcohol, for example lower alkanol, or a mercaptan, for example lower alkyl mercaptan, preferably in the presence of a basic agent, for example can convert an alcohol or a mercaptan into a metal compound, react and thus arrive at compounds of the formula I which have correspondingly etherified hydroxy or mercapto lower alkyl or lower alkoxy.
  • a reactive esterified hydroxy group such as halogen, for example chlorine
  • a reactive esterified hydroxyl group such as halogen, for example chlorine
  • halogen for example chlorine
  • an alcoholate or thio-alcoholate compound such as an alkali metal
  • a propargyloxy group e.g. by hydration in an acidic medium and in the presence of a mercury II salt, e.g. by treatment with an aqueous mineral acid, e.g. Convert dilute hydrochloric or sulfuric acid into the acetonyloxy group in the presence of mercury-II chloride.
  • amino can be treated, for example, by treating the amino compound with a suitable acid derivative, such as an optionally mixed anhydride, for example a appropriate chloride, if necessary in the presence of a basic agent, acylate.
  • a suitable acid derivative such as an optionally mixed anhydride, for example a appropriate chloride, if necessary in the presence of a basic agent, acylate.
  • the said amino group can be acylated, e.g. by reaction with an acylating agent.
  • Suitable acylating agents are carboxylic acids, for example aliphatic, araliphatic or cycloaliphatic carboxylic acids, preferably in the form of their functional derivatives, such as halides, in particular chlorides, or anhydrides, e.g. pure or mixed anhydrides, or internal anhydrides such as ketenes.
  • compounds of the formula I which contain hydroxyl groups can be acylated (esterified).
  • the acylation is carried out in the usual way, e.g. by reaction with carboxylic acids, advantageously in the form of their reactive functional derivatives, such as acid halides, e.g. Chlorides, esters, especially esters with lower alkanols, such as methanol and ethanol, or activated esters, such as cyanomethyl esters, or pure or mixed anhydrides, e.g. mixed anhydrides with carbonic acid monoalkyl esters such as carbonic acid monoethyl and isobutyl esters.
  • carboxylic acids advantageously in the form of their reactive functional derivatives, such as acid halides, e.g. Chlorides, esters, especially esters with lower alkanols, such as methanol and ethanol, or activated esters, such as cyanomethyl esters, or pure or mixed anhydrides, e.g. mixed anhydrides with carbonic acid
  • the CC double or triple bond by catalytic hydrogenation such as by hydrogen in the presence of a hydrogenation catalyst, for example nickel, platinum or Palladium, such as Raney-Nicket platinum black or palladium on activated carbon, can be converted into a CC single bond. Care must be taken to ensure that other reducible groups are not attacked.
  • a hydrogenation catalyst for example nickel, platinum or Palladium, such as Raney-Nicket platinum black or palladium on activated carbon
  • a C-C triple bond can be reduced to a C-C double bond, for example, by hydrogenation with 1 mol of hydrogen in the presence of a less active hydrogenation catalyst, such as iron or palladium, for example Raney iron or palladium on barium sulfate, in particular at elevated temperature.
  • a less active hydrogenation catalyst such as iron or palladium, for example Raney iron or palladium on barium sulfate, in particular at elevated temperature.
  • the reduction to a C-C-cis double bond can take place, for example, using 1 mol of hydrogen in the presence of a deactivated catalyst, such as palladium on animal charcoal in the presence of quinoline, palladium on calcium carbonate in the presence of lead salts, or Raney nickel.
  • a deactivated catalyst such as palladium on animal charcoal in the presence of quinoline, palladium on calcium carbonate in the presence of lead salts, or Raney nickel.
  • the reduction to a C-C-trans double bond can take place, for example, by means of sodium in liquid ammonia, with short reaction times and no excess of reducing agent being used, in particular with regard to a urea group, and where appropriate an ammonium halide, such as ammonium chloride, is added as a catalyst.
  • the reduction can be carried out in the usual way, e.g. by nascent hydrogen (e.g. with iron and hydrochloric acid or with aluminum amalgam) or with catalytically excited hydrogen, such as hydrogen in the presence of platinum, nickel or palladium catalysts.
  • nascent hydrogen e.g. with iron and hydrochloric acid or with aluminum amalgam
  • catalytically excited hydrogen such as hydrogen in the presence of platinum, nickel or palladium catalysts.
  • the oxo group is reduced in a conventional manner, e.g. by metallic reduction, such as by treatment with sodium in alcohol, or with complex metal hydrides, such as sodium borohydride, or by catalytically excited hydrogen, e.g. Hydrogen in the presence of a platinum, palladium, nickel or copper catalyst, such as platinum oxide, palladium-carbon, Raney nickel or copper chromite.
  • the reaction is preferably carried out in the presence of diluents and / or solvents, at low, normal or elevated temperature, in an open or in a closed vessel under pressure.
  • the oxo group can also be reduced by the Meerwein-Ponndorf-Verley method.
  • the oxo compound can be treated in the usual way with a lower alkanol such as isopropanol in the presence of a corresponding alkanolate such as aluminum isopropylate.
  • the cleavage can take place in the usual way, e.g. by treatment with strong acids, such as sulfuric acid, p-toluenesulfonic acid, concentrated hydrochloric acid, oxalic acid or other water-releasing agents, such as phosphorus pentoxide, zinc chloride or boron trioxide.
  • strong acids such as sulfuric acid, p-toluenesulfonic acid, concentrated hydrochloric acid, oxalic acid or other water-releasing agents, such as phosphorus pentoxide, zinc chloride or boron trioxide.
  • water is removed using a water separator.
  • the reaction can be carried out in a boiling hydrocarbon, such as benzene or toluene.
  • the catalytic hydrogenation can be carried out in a customary manner, in particular using hydrogen in the presence of a hydrogenation catalyst, such as a palladium, platinum or nickel catalyst.
  • a hydrogenation catalyst such as a palladium, platinum or nickel catalyst.
  • the reactions mentioned can be carried out in the customary manner in the presence or absence of solvents or diluents, acidic or basic condensing agents and / or catalysts at reduced, customary or elevated temperature, if appropriate in a gel-closed vessel under elevated pressure and / or under an inert gas atmosphere.
  • the end products are obtained in free form or in the form of their acid addition salts which are also included in the invention.
  • basic, neutral or mixed salts optionally also hemi-, mono-, sesqui or polyhydrates thereof, can be obtained.
  • the acid addition salts of the new compounds can be converted into the free compound in a manner known per se, e.g. with basic agents such as alkalis or ion exchangers.
  • the free bases obtained can form salts with organic or inorganic acids.
  • acids are used which are suitable for the formation of therapeutically usable salts. Examples of such acids are: hydrohalic acids, e.g.
  • Hydrochloric acid sulfuric acids, e.g. Sulfuric acid, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, vinegar, propionic, amber, glycolic, lactic, apple, wine, lemon, ascorbic , Maleic, hydroxymaleic or benz grape, fumaric, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acid; Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acid or sulfanilic acid; Methionine, tryptophan, lysine or arginine.
  • salts of the new compounds can also be used to purify the free bases obtained by converting the free bases into salts, separating them and again making the bases free from the salts.
  • the new compounds in free form and in the form of their salts the previous and the following are among the to understand free compounds appropriately and appropriately, if appropriate, the corresponding salts.
  • the invention also relates to those embodiments of the process according to which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing process steps, or terminates the process at any stage, or in which a starting material is formed under the reaction conditions, or in which a reaction component is optionally in the form of an optical antipode and / or a salt.
  • the new piperidines can be obtained by using a compound of the formula wherein R 1 , R 2 , alk 1 and alk 2 have the meanings given, with a compound of the formula implements in which n, R 3 , R 4 ' R 5 and R 6 have the meanings given and X' and Y 3 have the meanings given in the formulas VI and IX.
  • the order Settlement can be carried out in the usual way, for example as described above for the intramolecular condensations.
  • the new compounds can be present as optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, also as racemate mixtures and / or as pure geometric isomers or as mixtures thereof (isomer mixtures).
  • Obtained isomer mixtures can be separated into the two pure geometric isomers in a known manner due to the physico-chemical differences in the constituents, for example by chromatography in a suitable stationary phase, such as with a complex-forming heavy metal compound, e.g. with a silver compound, pretreated silica gel or alumina, or by forming a heavy metal addition compound, e.g. of the silver nitrate complex, separation of them into the addition compounds of the pure isomers, e.g. by fractional crystallization and subsequent release of the pure isomers.
  • a complex-forming heavy metal compound e.g. with a silver compound, pretreated silica gel or alumina
  • a heavy metal addition compound e.g. of the silver nitrate complex
  • Pure isomers obtained, e.g. trans isomers can be used in a conventional manner, e.g. photochemically, for example by irradiation with light of suitable wavelength, advantageously in a suitable solvent, such as an aliphatic hydrocarbon, or in the presence of a suitable catalyst, into the isomers of the opposite configuration, e.g. be converted into the cis isomers.
  • a suitable solvent such as an aliphatic hydrocarbon
  • Racemate mixtures can be separated in a known manner into the two stereoisomeric (diastereomeric) pure racemates due to the physico-chemical differences in the constituents, for example by chromatography and / or fractional crystallization.
  • Racemates obtained can be obtained by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by reaction with an optically active acid which forms salts with the racemic compound and separation of the salts obtained in this way, e.g. due to their different solubilities, break down into the diastereomers from which the antipodes can be released by the action of suitable agents.
  • optically active acids are e.g. the D and L forms of tartaric acid, di-o-toluene tartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. The more effective L-antipode is advantageously isolated.
  • the starting materials are known or, if they are new, can be obtained by methods known per se.
  • the compounds of the formula used as preferred starting materials can be obtained, for example, by using a compound of the formula wherein alk 1 and alk 2 have the meanings given and R 7 is an a-aralkyl radical, such as a benzyl radical, with a compound of the formula is implemented in which n, R 3 , R 4 , R 5 and R 6 have the meanings indicated and X 'and Y 2 have the meanings indicated in the formulas VI and IX, and in the compound of the formula obtained the a-aralkyl radical R 7 replaced by hydrogen, for example by catalytic hydrogenation as described above.
  • the new compounds can be used as medicaments, for example in the form of pharmaceutical preparations, which they or their salts are mixed with, for example for enteral, for example oral, or parenteral administration contain suitable pharmaceutical, organic or inorganic, solid or liquid carrier material.
  • suitable pharmaceutical, organic or inorganic, solid or liquid carrier material such as water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, rubber, polyalkylene glycols, petroleum jelly, cholesterol or other known pharmaceutical carriers, are suitable for the formation of the same.
  • the pharmaceutical preparations can be present, for example, as tablets, dragées, capsules, suppositories, ointments, creams or in liquid form as solutions (for example as an elixir or syrup), suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary substances, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.
  • the preparations that can also be used in veterinary medicine are obtained using conventional methods.
  • the dosage of the new compounds depends on the type of conditions to be treated and on individual needs.
  • the new compounds can be administered to a warm-blooded animal of approximately 75 kg body weight in a daily dose of approximately 5-100 mg, in particular approximately 5 to 60 mg.
  • the new compounds can also advantageously be used in combination with other antihypertensives and / or diuretics in pharmaceutical preparations.
  • Compounds which are active as antihypertensive are in particular those of the type of ⁇ -amino- ⁇ -hydroxyphenylpropionic acid, ⁇ -amino- ⁇ -alkoxyphenylpropionic acid, and in particular hydrazinopyridazines and sympathicolytics.
  • Suitable diuretics are substances that increase diuresis through both renal and extrarenal effects on the tissues. Thereby come substances with an inhibitory effect on the reabsorption in the tubule, e.g. especially saluretics and aethacrylic acid and their analogues.
  • Benzothiadiazine derivatives such as thiazides and hydrothiazides, benzenesulfonamides, phenoxyacetic acids, benzofuran-2-carboxylic acids and benzofuran-2,3-dihydro-2-carboxylic acids are particularly suitable.
  • the hydrochloride produced with methanolic hydrochloric acid crystallizes from water / acetone, mp. 167-169 ° / 190-193 °.
  • the combined hydrochloric acid extracts are concentrated with.
  • Sodium hydroxide solution made alkaline and extracted with methylene chloride.
  • the combined methylene chloride extracts are washed with water, dried with sodium sulfate and evaporated in a water jet vacuum, the residue crystallizing.
  • the hydrochloride produced with methanolic hydrochloric acid crystallizes from methanol / ether, mp. 200-202 °.
  • the 2- ⁇ 1- [3- (3-Methoxy-2-pyrazinyloxy) -2-hydroxy-1-propyl] -4-piperidylf -3,4-dihydro-l (2H) -isoquinolone has an mp of 122-124 ° .
  • the quaternary starting material is in by heating 3- (3-methoxy-2-pyrazinyloxy) -2-hydroxy-l-bromopropane with 2- (4-piperidinyl) -3,4-dihydro-l (2H) -isoquinone Dimethylformamide produced at 100 °.
  • the starting material is obtained by acylation of 1- [3- (3-methoxy-2-pyrazinyloxy) -2-hydroxy-l-propyl] -4-amino-piperidine with 2- (2-chloroethyl) benzoyl chloride in acetone with the addition of Get triethylamine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP78100431A 1977-07-27 1978-07-19 Nouvaux dérivés de la pipéridine, procédé pour leur préparation et compositions pharmaceutiques les contenant Withdrawn EP0000869A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
LU77856 1977-07-27
LU77856A LU77856A1 (de) 1977-07-27 1977-07-27 Verfahren zur herstellung von neuen piperidin-derivaten

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EP0000869A1 true EP0000869A1 (fr) 1979-03-07

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EP (1) EP0000869A1 (fr)
JP (1) JPS5424880A (fr)
AU (1) AU3836078A (fr)
CA (1) CA1103250A (fr)
DK (1) DK334078A (fr)
IT (1) IT7850455A0 (fr)
LU (1) LU77856A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2533567A1 (de) * 1974-07-31 1976-02-19 Ciba Geigy Ag Piperidin-derivate und verfahren zu ihrer herstellung
BE850556A (fr) * 1976-01-21 1977-07-20 Ciba Geigy Nouveaux n-aryl-diazacycles oxygenes utiles comme medicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2533567A1 (de) * 1974-07-31 1976-02-19 Ciba Geigy Ag Piperidin-derivate und verfahren zu ihrer herstellung
BE850556A (fr) * 1976-01-21 1977-07-20 Ciba Geigy Nouveaux n-aryl-diazacycles oxygenes utiles comme medicaments

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IT7850455A0 (it) 1978-07-25
JPS5424880A (en) 1979-02-24
DK334078A (da) 1979-01-28
AU3836078A (en) 1980-01-31
LU77856A1 (de) 1979-03-26
CA1103250A (fr) 1981-06-16

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