EP0000869A1 - New piperidine derivatives, process for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Piperidine derivatives of the formula I <IMAGE> in which R1 is an optionally substituted heteroaryl radical, alk1 and alk2 are, independently of one another, lower alkylene radicals which each separate the nitrogen atom bonded to them and the methine group bonded to them by 2 carbon atoms, R2 is an optionally acylated hydroxyl group, Ph is an optionally substituted o-phenylene radical, n = 0 or 1, R3 is a hydrogen atom, a lower alkyl radical or the hydroxyl group and R5 is a lower alkyl radical or a hydrogen atom or R3 and R5 together are a second bond and R4 and R6 are each a hydrogen atom, or R4 together with R3 is an oxo group, R5 is a lower alkyl radical or a hydrogen atom and R6 is a hydrogen atom, or R6 together with R5 is an oxo group, R3 is a hydrogen atom, a lower alkyl radical or the hydroxyl group, and R4 is a hydrogen atom, and the salts thereof, and processes for preparing these compounds and pharmaceutical products containing these compounds are described.

Description

worin R₁ einen gegebenenfalls substituierten Heteroarylrest bedeutet, alk₁ und alk₂ unabhängig voneinander niedere Alkylenreste sind, die jeweils das mit ihnen verbundene Stickstoffatom und die mit ihnen verbundene Methingruppe durch 2 Kohlenstoffatome trennen, R₂ eine gegebenenfalls acylierte Hydroxylgruppe bedeutet, Ph einen gegebenenfalls substituierten o-Phenylenrest bedeutet, n = O oder 1 bedeutet, R₃ ein Wasserstoffatom, einen niederen Alkylrest oder die Hydroxylgruppe und R₅ einen niederen Alkylrest oder ein Wasserstoffatom bedeutet oder R₃ und R₅ zusammen für eine zweite Bindung stehen und R₄ und R₆ je ein Wasserstoffatom bedeuten, oder R₄ zusammen mit R₃ für eine Oxogruppe steht, R₅ einen niederen Alkylrest oder ein Wasserstoffatom und R₆ ein Wasserstoffatom bedeutet, oder R₆ zusammen mit R₅ für eine Oxogruppe steht, R₃ ein Wasserstoffatom, einen niederen Alkylrest oder die Hydroxylgruppe bedeutet und R₄ für ein Wasserstoffatom steht, und deren Salze, sowie Verfahren zur Herstellung dieser Verbindungen und pharmazeutische Präparate enthaltend diese Verbindungen.The invention relates to new piperidine derivatives of the formula I

wherein R _{1 represents} an optionally substituted heteroaryl radical, alk ₁ and alk _{2 are} independently lower alkylene radicals, each of which separates the nitrogen atom and the methine group connected to them by 2 carbon atoms, R _{2 represents} an optionally acylated hydroxyl group, Ph an optionally substituted one means o-phenylene radical, n = O or 1, R _{3 represents} a hydrogen atom, a lower alkyl radical or the hydroxyl group and R _{5 represents} a lower alkyl radical or a hydrogen atom or R ₃ and R ₅ together represent a second bond and R ₄ and R ₆ one hydrogen each represent atom, or R ₄ together with R _{3 represents} an oxo group, R _{5 represents} a lower alkyl radical or a hydrogen atom and R _{6 represents} a hydrogen atom, or R ₆ together with R _{5 represents} an oxo group, R _{3 represents} a hydrogen atom, a lower alkyl radical or the hydroxyl group and R _{4 represents} a hydrogen atom, and their salts, and processes for the preparation of these compounds and pharmaceutical preparations containing these compounds.

und, wenn n = 0 ist, betrifft die Erfindung Verbindungen der Formel

worin in den oberen Formeln R₁, R₂, R₃, R_4' ^R ₅, ^R _6' ^{Ph, alk}1 und alk₂ die vorher angegebenen Bedeutungen haben.If n = 1, the invention relates to compounds of the formula

and, when n = 0, the invention relates to compounds of the formula

wherein in the above formulas R ₁ , R ₂ , R ₃ , R _{4 '} ^R ₅ , ^R _6' ^{Ph, alk} 1 and alk _{2 have} the meanings given above.

Unless otherwise stated, 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, quinolinyl, for example 4-quinolinyl, or isoquinolinyl, for example 1-isoquinolinyl. Substituents of a heteroaryl radical include optionally substituted aliphatic hydrocarbon radicals, optionally etherified or esterified hydroxy or mercapto, acyl, nitro or optionally substituted amino.

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.

Furthermore, 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 µM. 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 µg / ml ] or histamine [3 x 10-7 µg / m1]). In the isolated guinea pig atrium, 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 µg / 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.

worin R₁ gegebenenfalls substituiertes, monocyclisches Heteroaryl oder Benzoheteroaryl mit 5 bis 6 Ringgliedern und 1 oder 2 Ringstickstoffatomen bedeutet, wobei Substituenten des heterocyclischen Arylrestes gegebenenfalls substituiertes Niederalkyl, z.B. Niederalkyl, Niederalkoxyniederalkyl, Niederalkanoylaminoniederalkyl oder Niederalkoxycarbonylaminoniederalkyl, oder gegebenenfalls veräthertes oder verestertes Hydroxy oder Mercapto, z.B. Niederalkoxy, Niederalkoxyniederalkoxy, Niederalkylthioniederalkoxy, Niederalkylthio oder Halogen, sein können R₂ einen niederen Alkanoylrest, wie insbesonders den Acetyl-, Propionyl- oder Pivaloylrest, oder vor allem ein Wasserstoffatom bedeutet, R₃ ein Wasserstoffatom oder die Hydroxylgruppe und R₅ ein Wasserstoffatom bedeutet oder R₃ und R₅ zusammen für eine zweite Bindung stehen und R₄ und R₆ je ein Wasserstoffatom bedeuten, oder R₄ zusammen mit R₃ für eine Oxogruppe steht und R₅ und R₆ je ein Wasserstoffatom bedeuten, oder R₆ zusammen mit R₅ für eine Oxogruppe steht und R₃ und R₄ je ein Wasserstoffatom bedeuten, und R einen Niederalkanoylaminorest, die Aminogruppe, die Nitrogruppe oder vor allem einen niederen Alkylrest, eine niedere Alkoxygruppe, ein Halogenatom, den Trifluormethylrest, die Hydroxylgruppe oder insbesondere ein Wasserstoffatom bedeutet, und ihren Salzen.The compounds of the formula Ia should be mentioned in particular

wherein 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 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, or R ₄ together with R _{3 represents} an oxo group and R ₅ and R ₆ each represent a hydrogen atom, or R ₆ together with R _{5 represents} an oxo group and R ₃ and R ₄ each represent a hydrogen atom, and R represents a lower alkanoylamino radical, the amino group, the nitro group or especially a lower alkyl radical, a lower alkoxy group, a halogen atom, the trifluoromethyl radical, the hydroxyl group or in particular a Means hydrogen atom and its salts.

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, or R ₄ together with R _{3 represents} an oxo group and R ₅ and R ₆ each represent hydrogen, or R ₆ together with R _{5 represents} an oxo group and R3 and R ₄ each represent a hydrogen atom, R ₄ and R ₆ each representing hydrogen and R ₃ and R ₅ either represent a second bond or each represent a hydrogen atom, and R represents a lower alkyl radical, for example methyl, a lower alkoxy radical, for example methoxy, a halogen atom, for example chlorine, the trifluoromethyl radical or in particular a hydrogen atom, and their salts.

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.

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. Particular mention should be made of the compounds described in the examples, in particular those of the formula I which have a preferably substituted 2-pyrazinyl radical as R ₁ and R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R are hydrogen, and their non-toxic acid addition salts.

worin R₁ gegebenenfalls substituiertes, monocyclisches Heteroaryl oder Benzoheteroaryl mit 5 bis 6 Ringgliedern und 1 oder 2 Ringstickstoffatomen bedeutet, wobei Substituenten des heterocyclischen Arylrestes gegebenenfalls substituiertes Niederalkyl, z.B. Niederalkyl, Niederalkoxyniederalkyl, Niederalkanoylaminoniederalkyl oder Niederalkoxycarbonylaminoniederalkyl, oder gegebenenfalls veräthertes oder verestertes Hydroxy oder Mercapto, z.B. Niederalkoxy, Niederalkoxyniederalkoxy, Niederalkylthioniederalkoxy, Niederalkylthio oder Halogen sein können, und R je ein Wasserstoffatom, einen niederen Alkylrest, eine Hydroxygruppe, einen niederen Alkoxyrest, ein Halogenatom, eine Trifluormethylgruppe, die Nitrogruppe, eine Aminogruppe, eine Niederalkanoylaminogruppe, R₂ ein Wasserstoffatom oder eine niedere Alkanoylgruppe, insbesondere den Acetyl-, Propionyl- oder Pivaloylrest, R₅ und R₆ je ein Wasserstoffatom, oder R₅ und R₆ zusammengenommen eine Oxogruppe bedeuten und ihre Salze. In den genannten Verbindungen befindet sich der Substituent R bevorzugt in meta-Stellung zur Carbonylgruppe und in paraStellung zur Methylengruppe.Compounds of the formula Ib should also be emphasized

wherein 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, and 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} a hydrogen atom or a lower alkanoyl group, especially the acetyl, propionyl or pivaloyl group, R ₅ and R ₆ each represent a hydrogen atom, or R ₅ and R _{6 taken} together represent an oxo group and their salts. In the compounds mentioned, the substituent R is preferably in the meta position to the carbonyl group and in the para position to the methylene group.

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.

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.

The invention relates in particular to compounds of the formula Ib in which 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. 2-, 3- or 4 -Pyridyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, or pyrazinyl, for example 2-pyrazinyl, and R, R ₂ , R ₅ and R ₆ each represent a hydrogen atom, and their non-toxic acid addition salts.

The new compounds of formula I are obtained by methods known per se.

mit einer Verbindung der Formel

umsetzen, wobei R₁, alk_l, alk₂, Ph, n, R₃, R₄, ^R ₅ und ^R ₆ die angegebenen Bedeutungen haben, Y₁ für einen Rest der Formel

steht, und X für die Gruppe R₂ steht, wobei R₂ die angegebene Bedeutung hat, und Z eine reaktionsfähige veresterte Hydroxylgruppe bedeutet, oder X und Z zusammen eine Epoxygruppe bilden.For example, you can use a compound of the formula

with a compound of the formula

implement, wherein R ₁ , alk ₁ , alk ₂ , Ph, n, R ₃ , R ₄ , ^R ₅ and ^R _{6 have} the meanings given, Y ₁ for a radical of the formula

represents, and X represents the group R ₂ , where R _{2 has} the meaning given, and Z represents a reactive esterified hydroxyl group, or X and Z together form an epoxy group.

worin R₁ obige Bedeutungen hat, mit einer Verbindung der Formel

worin X, Z, alk₁, alk₂, Ph, n, R₃, R₄, R₅ und R₆ obige Bedeutungen haben, umsetzen.You can also use a compound of formula

wherein R _{1 has the} above meanings, with a compound of the formula

wherein X, Z, alk ₁ , alk ₂ , Ph, n, R ₃ , R ₄ , R ₅ and R _{6 have the} above meanings.

This implementation is carried out in the usual way. If reactive esters are used as the starting material, 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.

worin R₁, alk_l, alk₂, Ph, n, R₃,R₄,R₅ und R₆ obige Bedeutungen haben, die Oxogruppe der Propylkette zu einer Hydroxylgruppe reduziert.Furthermore, 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.

In addition, 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. During the reduction, care must be taken that other reducible groups are not attacked.

worin ^R ₁, ^R ₂, ^R ₃, ^R _4' ^R ₅, R₆, Ph und n obige Bedeutungen haben, R_x und R unabhängig voneinander niedere Alkylreste oder Wasserstoffatome bedeuten und r und s für 1 oder 2 stehen, und A^Θ ein Anion bedeutet, den Pyridiniumring zum Piperidinring reduziert.Furthermore, 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 ^Θ 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. During the reduction, care must be taken that other reducible groups are not attacked.

worin ^R1_, ^R2_, ^alk _l, ^alk ₂, ^{Ph, n, R} ₃, ^R _4' ^R ₅ und R₆ die angegebenen Bedeutungen haben und X' eine reaktionsfähige veresterte Hydroxylgruppe bedeutet, intramolekular kondensiert.Furthermore, 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 (intramolecular condensation) 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. Is preferably carried out in the presence of 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 triethylamine, or pyridine.

mit einer Verbindung der Formel

worin ^R ₁, ^R ₂₁ R₄, R₆, alk_l, alk₂ und Ph die angegebenen Bedeutungen haben, umsetzt.The new compounds in which R ₃ and R ₅ together represent a second bond when n = 1 can also be obtained by using a compound of the formula

with a compound of the formula

wherein ^R ₁ , ^R ₂₁ R ₄ , R ₆ , alk ₁ , alk ₂ and Ph have the meanings given.

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.

worin ^R1_, ^R2_, ^alkl_, ^alk _2, ^R ₃, ^R _4' ^R ₅, R₆, n und Ph die angegebenen Bedeutungen haben und Y₂ eine freie oder vorzugsweise eine Oxogruppe enthaltende funktionell abgewandelte Carboxylgruppe bedeutet, intramolekular kondensiert.Furthermore, 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.

worin R₁, alk_l, alk₂, Ph, n, R₃, R₄, R₅ und R₆ die angegebenen Bedeutungen haben und R₂' einen durch Hydrogenolyse abspaltbaren Rest bedeutet, R'₂ durch Hydrogenolyse abspaltet.Furthermore, the new compounds in which R _{2 is} hydrogen can be obtained by using a compound of the formula

wherein 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 α-aralkyl radical, such as the benzyl radical, or an α-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.

worin R₁, R₂ alk₁ und alk₂ obige Bedeutungen haben, mit einer Verbindung der Formel

worin R₃, R₄, n und Ph obige Bedeutungen haben und die Substituenten Y₃ unabhänig voneinander für eine freie, oder vorzugsweise eine eine Oxogruppe enthaltende funktionell abgewandelte Carboxylgruppe oder zusammen für die Gruppierung

stehen, umsetzt.Furthermore, 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.

In the compounds obtained, substituents can be split off, introduced or converted within the scope of the end products.

Thus, in compounds of the formula I with unsaturated substituents, for example _{lower alkenyl, lower alkenyloxy} or _{lower alkynyloxy} , these can be reduced by suitable reduction _methods to corresponding saturated compounds or, in the case of _VOJ substituents with a triple bond, to compounds with a double bond. The 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.

In a compound of formula I obtained which contains halogen, such as bromine or iodine, as a substituent of an aromatic radical, this can e.g. by treating with trifluoromethyl iodide in the presence of copper powder and a suitable aprotic solvent such as pyridine, dimethylformamide or acetonitrile, replace with trifluoromethyl.

In a compound of formula I obtained, an a-phenyl-lower alkyl group, e.g. in benzyloxy, by treating the corresponding compound with catalytically activated hydrogen and by hydrogen, e.g. replace a benzyloxy group with hydroxy.

Furthermore, in 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. In addition, 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. Furthermore, in a compound obtained, a reactive esterified hydroxyl group, such as halogen, for example chlorine, in particular in the a-position to a ring nitrogen atom in a radical R ₁ , for example by treatment with an alcoholate or thio-alcoholate compound, such as an alkali metal, for example Convert sodium or potassium lower alkanolate or thione lower alkanolate into an etherified or esterified hydroxy or mercapto group, for example into lower alkoxy or lower alkylthio.

In a compound of formula I, 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.

It can also be substituted in a compound of the formula I which contains primary amino as a substituent; for example, 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.

Furthermore, in compounds of the formula I in which Ph is an o-phenylene radical containing an amino group, 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.

Furthermore, 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.

In compounds of the formula I which contain an acylated hydroxyl or amino group, these can be cleaved in a conventional manner to give the free hydroxyl or amino group, in particular hydrolytically, depending on the suitability, acid or base catalyzed, e.g. with inorganic acids or alkali bases (bases), e.g. with hydrochloric acid or with sodium hydroxide solution. If such cleavage already occurs in the course of one of the above production methods, a free hydroxyl or amino group obtained can optionally be acylated as described above.

Furthermore, in compounds of the formula I which contain substituents with a CC double or triple bond, 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.

In compounds of the formula I which contain substituents with a C-C triple bond, this can furthermore only be reduced to a C-C double bond and, if desired, stereospecifically to a C-C-cis or C-C - trans double bond. 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. 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. 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.

In compounds of the formula I obtained which have nitro groups on an aromatic nucleus, these can be reduced to amino groups.

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.

Furthermore, compounds of the formula I in which R ₃ and R ₄ together represent an oxo group can be reduced to compounds in which R _{3 represents} hydroxyl and R _{4 represents} hydrogen.

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. For example, 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.

In compounds of the formula I in which R _{3 is} hydroxyl, the hydroxyl group can also be split off. This gives compounds in which R ₃ and R _{5 represent} a second bond.

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. If necessary, the water is removed using a water separator. For example, the reaction can be carried out in a boiling hydrocarbon, such as benzene or toluene.

Compounds of the formula I in which R ₃ is hydroxyl can also be replaced by hydrogen. This can be done, for example, by catalytic hydrogenation.

Furthermore, in compounds of the formula I in which R ₃ and R _{5 represent} a second bond, hydrogenation is possible to give compounds in which R ₃ and R _{5 represent} hydrogen atoms. This can be done in particular by catalytic hydrogenation.

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.

The reactions mentioned can optionally be carried out simultaneously or in succession and in any order.

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.

Depending on the process conditions and starting materials, the end products are obtained in free form or in the form of their acid addition salts which are also included in the invention. For example, 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. On the other hand, the free bases obtained can form salts with organic or inorganic acids. For the production of acid addition salts, in particular those 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.

These or other salts of the new compounds, such as, for example, the picrates, 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. As a result of the close relationships between 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.

worin R_l, R₂, alk₁ und alk₂ die angegebenen Bedeutungen haben, mit-einer Verbindung der Formel

umsetzt, worin ^{n, R} ₃, ^R _4' R₅ und R₆ die angegebenen Bedeutungen haben und X' und Y₃ die bei den Formeln VI bzw. IX angegebenen Bedeutungen haben. Dabei entsteht intermediär eine Verbindung der Formel VI, die dann erfindungsgemäss zur Verbindung der Formel I weiterreagiert. Die Umsetzung kann in üblicher Weise durchgeführt werden, z.B. wie oben für die intramolekularen Kondensationen beschrieben.For example, 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. This creates an intermediate compound of formula VI, which then reacts according to the invention to the compound of formula I. The order Settlement can be carried out in the usual way, for example as described above for the intramolecular condensations.

Depending on the choice of the starting materials and procedures, 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.

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.

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. Particularly common 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.

For the implementation of the reactions according to the invention, those starting materials are expediently used which lead to the groups of end products which were particularly mentioned at the outset and in particular to the end products which have been specifically described or highlighted.

The starting materials are known or, if they are new, can be obtained by methods known per se.

kann man beispielsweise erhalten, wenn man eine Verbindung der Formel

worin alk₁ und alk₂ die angegebenen Bedeutungen haben und R₇ einen a-Aralkylrest, wie einen Benzylrest, bedeutet, mit einer Verbindung der Formel

umsetzt, worin n, R₃, R₄, R₅ und R₆ die angegebenen Bedeutungen haben und X' und Y₂ die bei den Formeln VI bzw. IX angegebenen Bedeutungen haben, und in der erhaltenen Verbindung der Formel

den a-Aralkylrest R₇ durch Wasserstoff ersetzt, z.B. durch katalytische Hydrierung wie oben beschrieben.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. Substances that do not react with the new compounds, 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. For example, 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 α-amino-β-hydroxyphenylpropionic acid, β-amino-β-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 following examples illustrate the invention without restricting it. The temperatures are given in degrees Celsius.

example 1

24.2 g (0.13 mol) of 2-chloro-3- (2,3-epoxypropoxy) pyrazine and 23 g (0.1 mol) of 1- (4-piperidinyl) -3,4-dihydro-l (2H) -isoquinolone in 250 ml of isopropanol are stirred at about 20 ° C. for 24 hours. The precipitated crystals are filtered off with suction, washed with ether and 36.6 g of 2- {1- [3- (3-chloro-2-pyrazinyloxy) -2-hydroxy-1-propyl] -4-piperidyl} -3 are obtained. 4-dihydro-1 (2H) -isoquinolone, m.p. 115-116 °.

The hydrochloride produced with alcoholic hydrochloric acid crystallizes from alcohol, mp. 215 ° (decomposition)

Example 2

13.5 g (0.032 mol) of 2- {1- [3- (3-chloro-2-pyrazinyloxy) -2-hydroxy-1-propyl] -4-piperidyl -3,4-dihydro-1 (2H) -isochino- Ion and 1.95 g (0.036 mol) of sodium methylate in 150 ml of methanol are refluxed for 10 hours with stirring. The reaction mixture is evaporated in a water jet vacuum. The residue is dissolved in ethyl acetate and extracted with 2N hydrochloric acid. 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 over sodium sulfate and evaporated in a water jet vacuum. The residue crystallizes from methanol / ether.

8.2 g of 2- {1- [3- (3-methoxy-2-pyrazinyloxy) -2-hydroxy-1-propyl] -4-piperidyl} -3, 4-dihydro-1 (2H) -isochifiolone, mp . 122-124 °.

The hydrochloride produced with methanolic hydrochloric acid crystallizes from water / acetone, mp. 167-169 ° / 190-193 °.

Example 3

12.5 g (0.03 mol) of 2- {1- [3- (3-chloro-2-pyrazinyloxy) -2-hydroxy-1-propyl] -4-piperidyl} -3,4-dihydro-1 (2H) -iso - Quinolone, 2.78 g (0.045 mol) of ethyl mercaptan and 2.43 g (0.045 mol) of sodium methylate in 200 ml of methanol are refluxed for 10 hours with stirring. The reaction mixture is totally evaporated in a water jet vacuum. The residue is dissolved in methylene chloride and washed with water. The methylene chloride solution is extracted with 2N hydrochloric acid. 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.

13 g of 2- {1- [3- (2-ethylthio-3-pyrazinyloxy) -2-hydroxy-1-propyl] -4-piperidyl} -3.4-dihydro-1 (2H) -isoquinolone, mp . 136-138 °.

The hydrochloride produced with methanolic hydrochloric acid crystallizes from methanol / ether, mp. 200-202 °.

Example 4

5.0 g of 1- [3- (3-methoxy-2-pyrazinyloxy) -2-hydroxy-l-propyll-4- (3,4-dihydro-1 (2H) -2-isoquinolonyl) piperidinium bromide hydrogenated in a mixture of 30 ml of water and 30 ml of ethanol with 2.0 g of platinum oxide at 40 °. The catalyst is then filtered off, the filtrate is evaporated in vacuo, 2N sodium hydroxide solution is added to the residue, and the alkaline phase is extracted with ethyl acetate, dried, evaporated and recrystallized from methanol / ether. 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 °.

Example 5

44.9 g of 1- [3- (3-methoxy-2-pyrazinyloxy) -2-hydroxy-l-propyl] -4- [2- (2-chloroethyl) benzoylamino] piperidine are dissolved in 200 ml of dimethylformamide and 90 ml of 30% sodium methylate solution are slowly added dropwise. The mixture is then heated to 50 ° for 3 hours. After evaporating the dimethylformamide in vacuo, the residue is dissolved in ethyl acetate and the organic phase is extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are concentrated with. Sodium hydroxide solution made alkaline and extracted with methylene chloride. The combined methylene extracts are washed with water, dried with sodium sulfate and evaporated in vacuo. The residue is recrystallized from methanol / ether. The 2- {1- [3- (3-methoxy-2-pyrazinyloxy) -2-hydroxy-1-propyl] -4-piperidyl} -3,4-di-hydro-l (2H) -isoquinolone obtained has one Mp 122-124 °. 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.

Claims (15)

1. Piperidines of the formula

wherein R _{1 represents} an optionally substituted heteroaryl radical, alk ₁ and alk _{2 are} independently lower alkylene radicals, each of which separates the nitrogen atom and the methine group connected to them by 2 carbon atoms, R ₂ denotes an optionally acylated hydroxyl group, Ph an optionally substituted one means o-phenylene radical, n = 0 or 1, R _{3 represents} a hydrogen atom, a lower alkyl radical or the hydroxyl group and R _{5 represents} a lower alkyl radical or 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, or R ₄ together with R _{3 represents} an oxo group, R _{5 represents} a lower alkyl radical or a hydrogen atom and R _{6 represents} a hydrogen atom, or R ₆ together with R _{5 represents} an oxo group, R _{3 represents} a hydrogen atom, represents a lower alkyl radical or the hydroxyl group and R _{4 represents} a hydrogen atom and its salts. 2. Compounds of formula Ia

wherein 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 _{2 is} a lower alkanoyl radical, such as in particular the acetyl, propionyl or pivaloyl radical, or especially a hydrogen atom, R _{3 is} a hydrogen atom or the hydroxyl group and R _{5 is} 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 or R ₄ together with R _{3 represents} an oxo group and R ₅ and R ₆ each represent a hydrogen atom or R ₆ together mi t R _{5 represents} an oxo group and R ₃ and R ₄ each represent a hydrogen, and R represents a lower alkanoylamino radical, the amino group, the nitro group or especially a lower alkyl radical, a lower alkoxy group, a halogen atom, the trifluoromethyl radical, the hydroxyl group or in particular Means hydrogen atom and its salts. 3. Compounds of the formula Ia, in which R _{1 is} optionally lower alkyl, for example 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, substituted monocyclic monoazaaryl or diazaaryl 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 represents} the acetyl, propionyl or in particular pivaloyl radical or especially a hydrogen atom, 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 or R ₄ together with R _{3 represents} an oxo group and R ₅ and R ₆ each represent a hydrogen or R ₆ together with R _{5 represents} an oxo group and R ₃ and R ₄ each represent a hydrogen atom, where especially R ₄ and R ₆ each represent hydrogen and R and R ₅ either represent a second bond or each represent a hydrogen atom, and R represents a lower alkyl radical, for example methyl, one never whose alkoxy radical, for example methoxy, is a halogen atom, for example chlorine, the trifluoromethyl radical or in particular a hydrogen atom, and their salts. 4. Compounds of formula Ia, wherein R _{1 is} 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 Aethylthio, or halogen with atomic numbers up to 35, for example chlorine or bromine, is substituted, and may optionally contain further substituents of this type, and R ₂ , R ₃ , R ₄₁ R ₅ , ^R ₆ and ^{R are} hydrogen, and salts, in particular Acid addition salts, primarily pharmaceutically acceptable, non-toxic acid addition salts thereof. 5. Compounds of the formula Ia which have a preferably substituted 2-pyrazinyl radical as R ₁ , and R ₂ , R3, ^R ₄ , ^R ₅ , R ₆ and R represent hydrogen, and their non-toxic acid addition salts. 6. 2- [1 _{- [} 3- (3-methoxy-2-pyrazinyloxy) -2-hydroxy-l-propyl] -4-piperidyl] -3,4-dihydro-l (2H) -isoquinolone and its therapeutically useful Salts. 7. Compounds of formula Ib

wherein R _{1 is} optionally substituted, monocyclic heteroaryl or benzoheteroaryl having 5 to 6 ring members and 1 or 2 ring nitrogen atoms in the radical R ₁ , where substituents of the heterocyclic aryl radical are optionally substituted lower alkyl, for example lower alkyl, lower alkoxy lower alkyl, lower alkanoylaminone lower alkyl or lower alkoxycarbonyl ester ether lower alkyl, or optionally veroxy, or optionally or mercapto, for example lower alkoxy, lower alkoxy lower alkoxy, lower alkylthione lower alkoxy, lower alkylthio or halogen, R each represents a hydrogen atom, a lower alkyl radical, a hydroxyl group, a lower alkoxy radical, a halogen atom, a trifluoromethyl group, the nitro group, an amino group, an alkanoylamino group, R _{2 is} a hydrogen atom or R ₂ a lower alkanoyl group, in particular the acetyl, propionyl or pivaloyl radical, R ₅ and R ₆ each represent a hydrogen atom, or R ₅ and R _{6 taken} together represent an oxo group, and their salts. 8. Compounds of the formula Ib, in which R _{1 is} 2-pyrazinyl which 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 , 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 each represents a hydrogen atom, the methyl, methoxy or acetylamino group , R _{2 is} a hydrogen atom, the acetyl, propionyl or the pivaloyl group, R ₅ and R ₆ each represent a hydrogen atom, and their salts. 9. Compounds of the formula Ib, 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 halogen with an atom number of up to 35, for example chlorine or bromine 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, and R _{2 is} a hydrogen atom, the acetyl, propionyl or the Pivaloyl group and R, R ₅ and R ₆ each represent a hydrogen atom, and their non-toxic acid addition salts. 10. Compounds of formula Ib, wherein R _{l is} 2-pyrazinyl, furthermore pyridyl, for example 2- or 3-pyridyl, which is 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 an atom number of up to 35, for example chlorine or bromine, is substituted, and may optionally contain further substituents of this type, and R, R ₂ , R ₅ and R ₆ each represent a hydrogen atom, and their non-toxic acid addition salts. 11. Pharmaceutical preparations containing one of the compounds of claims 1 to 10. 12. The compounds of claims 1 to 10 for use as pharmaceuticals. 13. The compounds of claims 1 to 10 for use as antihypertensives. 14. Process for the preparation of new piperidines of the formula I.

wherein R _{1 represents} an optionally substituted heteroaryl radical, alk ₁ and alk _{2 are} independently lower alkylene radicals, each of which separates the nitrogen atom and the methine group connected to them by 2 carbon atoms, R _{2 represents} an optionally acylated hydroxyl group, Ph an optionally substituted one means o-phenylene radical, n = O or 1, R _{3 represents} a hydrogen atom, a lower alkyl radical or the hydroxyl group and R _{5 represents} a lower alkyl radical or e which 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, or R ₄ together with R _{3 represents} an oxo group, R _{5 represents} a lower alkyl radical or a hydrogen atom and R _{6 represents} a hydrogen atom, or R ₆ together with R _{S represents} an oxo group, R _{3 is} a Hydrogen atom, a lower alkyl radical or the hydroxyl means group and R _{4 represents} a hydrogen atom, and their salts, characterized in that a) a compound of the formula

with a compound of the formula

converts, wherein R ₁ , alk ₁ , alk ₂ , Ph, n, R ₃ , ^R ₄ , R ₅ and ^R _{6 have} the meanings given, Y ₁ for a radical of the formula

and X represents the group R ₂ , where R _{2 has} the meaning given, and Z represents a reactive esterified hydroxyl group, or X and Z together form an epoxy group, or b) a compound of the formula

wherein R _{1 has the} above meaning, with a compound of the formula

wherein X, Z, alk ₁ , alk ₂ , Ph, n, R ₃ , R ₄ , R ₅ and R _{6 have the} above meanings, or c) 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 _y independently of one another are lower alkyl radicals or hydrogen atoms and r us s are 1 or 2, and A ^Θ an anion means the pyridinium ring to

wherein R _1, R 2, alk _l, alk ₂ Ph, n, R _3, R _4, R ₅ and R ₆ have the given ^e-g at meanings and X 'is a reactive ver esterified hydroxyl group means intramolecularly condensed, or e) for compounds of the formula I in which R ₃ and R together represent a second bond if n = 1 is a compound of the formula

with a compound of the formula

wherein ^R ₁ , R ₂ , R ₄ , R ₆ , alk ₁ , alk ₂ and Ph have the meanings given, or f) 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 denotes a free or preferably a functionally modified carboxyl group containing an oxo group, intramolecularly condensed , or g) for compounds of the formula I in which R _{2 is} hydrogen, in a compound of the formula

wherein R ₁ , alk ₁ , alk ₂ , Ph, n, R ₃ , R ₄ , R ₅ and R _{6 have} the meanings given for ^g and R2 means a radical which can be split off by hydrogenolysis, R2 splits off by hydrogenolysis, or h) for compounds of the formula I in which R ₆ together with R5 forms an oxo group, 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 ₂ independently of one another for a free, or preferably a functionally modified carboxyl group containing an oxo group or together for the grouping

stand, converts, and, if desired, introduces, modifies or cleaves and / or separates an isomer mixture obtained into the pure isomers and / or an obtained racemate into the optical ones in the compounds of formula I within the scope of the definition of the end products Antipodes are split and / or a salt obtained is converted into the free compound in one of its salts. 15. The procedure described in Examples 1-5.