Basic carbonyl derivatives.

0001The invention relates to new basic carbonyl compounds and their salts, processes for their preparation, pharmaceutical preparations containing them and their use.

0002The compounds according to the invention corresponding to the formula<chemistry id="chem0001" num="0001"><img file="EP0222702A2_D0001.tif" /></chemistry>wherein R represents a carbocyclic or heterocyclic aryl radical, R_i Lower alkyl represents one of the groups R₂ and R₃ represents lower alkyl and the other represents lower alkyl, cyano or amino, X represents oxygen or the group -NH-, and alk means alkylene substituted by a carbocyclic aryl which separates the group X from the ring nitrogen atom by at least two carbon atoms, Y represents alkylene or the Groups -CH (OH) - or -C (= 0) - stands for a simple bond, and Ar₁ represents a monocyclic aryl or heteroaryl radical, and include salts of compounds of formula I.

0003A carbocyclic or heterocyclic aryl radical R is primarily a corresponding monocyclic radical, but can also be a bi- or polycyclic, carbocyclic or heterocyclic radical with aromatic properties.

0004Carbocyclic radicals R of this type and the carbocyclic radical contained as a substituent in an alkylene group Alk are in particular optionally substituted phenyl, furthermore naphthyl.

0005Heterocyclic aryl radicals R are preferably corresponding monocyclic radicals, but can also be corresponding bicyclic or polycyclic radicals, the latter being able to consist of several heterocyclic rings, or of one or more rings with one or more fused-on carbocyclic rings, in particular one or more fused-on benzo rings. The usually present heterocyclic radicals R, which preferably consist of five or six ring members, can contain up to four, identical or different hetero, in particular nitrogen, oxygen and / or sulfur atoms, preferably one, two, three or four nitrogen atoms, one oxygen - Or contain sulfur atom, or one or two nitrogen atoms together with an oxygen or sulfur atom as ring members. They are usually bonded to the 4-position carbon atom of the 1,4-dihydropyridine ring via a ring carbon atom.

0006Monocyclic five-membered heteroaryl radicals R are, for example, corresponding monoaza, diaza, triaza, tetraza, monooxa, monothia, oxaza, oxadiaza, thiaza or thiadiazacyclic radicals, such as pyrryl, pyrazolyl, imidazolyl, triazolyl Tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl or thiadiazolyl radicals, while monocyclic, six-membered heteroaryl radicals R, for example corresponding monoaza, diaza or triazacyclic radicals, such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl radicals. Bicyclic heteroaryl radicals are, in particular, monocyclic heteroaryl radicals with fused-on benzo ring; the hetero ring can be five- or six-membered, a five-membered heteroaryl group, for example a monoaza, diaza, monooxa, monothia, oxaza or thiazacyclic group, and a six-membered heteroaryl group, for example represents a monoaza or a diazacyclic heteroaryl radical. Such bicyclic radicals which can be bonded via a ring carbon atom of the heterocyclic or carbocyclic radical are, for example Indolyl, isoindolyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzthiadiazolyl, quinolinyl or isoquinolinyl residues, nitrogen-containing mono- or bicyclic heteroaryl residues of the type mentioned, in particular unsubstituted, especially unsubstituted, also unsubstituted N, Oxides can be present, for example pyridyl-N-oxide.

0007A monocyclic, carbocyclic aryl radical Ari primarily represents an unsubstituted or mono- or polysubstituted, for example bi- or trisubstituted, phenyl radical, while a monocyclic heteroaryl radical

0008Ar_i for example a monocyclic monooxa, monoaza or monothiaaryl radical, for example those as defined for R, are primarily unsubstituted or mono- or polysubstituted, for example twice or three times, identical or differently substituted furyl, pyridyl or thienyl.

0009The carbocyclic and heterocyclic aryl radicals R and Ar_i and the carbocyclic radical contained as a substituent in an alkylene group Alk may be unsubstituted or mono- or polysubstituted, for example twice or three times, with primarily ring carbon atoms, but also ring nitrogen atoms being substituted, mono- to triple-present and identical or different, preferably but can simply be present. Substituents of ring carbon atoms include optionally substituted hydrocarbon radicals, such as corresponding aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, for example lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, cycloalkyl, cycloalkyl-lower alkyl, phenyl or phenyl-lower alkyl. Substituents of such hydrocarbon radicals, in particular lower alkyl, phenyl or phenyl lower alkyl, are, for example optionally etherified or esterified hydroxy groups, such as hydroxy, optionally substituted, for example, by optionally etherified or esterified hydroxy, lower alkoxy, eg lower alkoxy, lower alkoxy-lower alkoxy or halogenated lower alkoxy, optionally, eg substituted by etherified or esterified hydroxy, lower alkenyloxy, for example Lower alkenyloxy or halogenated lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy or halogen, and / or optionally functionally modified carboxy, such as carboxy, esterified carboxy, for example lower alkoxycarbonyl, amidated carboxy such as carbamoyl, N-lower alkylcarbamoyl or N, N-dinierderalkyl or carbam Cyan. Cyclic substituents, especially phenyl, can also lower alkyl, which, if necessary, for example as indicated, may be substituted as a substituent. Further substituents of aryl radicals R and Ari and also the carbocyclic aryl radical contained in an alkylene group Alk are, for example, optionally etherified or esterified hydroxyl groups, such as hydroxyl, optionally, for example substituted or unsubstituted or etherified hydroxyl, substituted lower alkoxy, for example lower alkoxy, lower alkoxy lower alkoxy or halogenated lower alkoxy, for example by optionally etherified or esterified hydroxy, substituted lower alkenyloxy, for example lower alkenyloxy or halogenated lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy or halogen, nitro, optionally substituted amino, such as amino, N-lower alkylamino, N, N-di-lower alkylamino, N-lower alkyl-N-phenyl Niederalkylenamino, Oxaniederalkylenamino, Thianiederalkylenamino or Azaniederalkylenamino, wherein the aza-nitrogen is unsubstituted or, for can be substituted by optionally substituted, for example as described above, lower alkyl, phenyl or phenyl-lower alkyl, or acylamino, for example lower alkylanoylamino, azido, acyl, such as lower alkanoyl or optionally functionally modified carboxy, such as carboxy, esterified carboxy, for example Niederalkoxycarbonyl, or amidated carboxy, such as carbamoyl, N-Niederalkyl-carbamoyl or N, N-Diniederalkyl-carbamoyl, furthermore cyan, optionally functionally modified sulfo, such as sulfo, aminosulfonyl, N-Niederalkylaminosulfonyl or N, N-Diniederalkylaminosulfonyl and / or etherified mercapto , which can optionally be oxidized, such as lower alkylthio, halogen-lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl. Substituents of ring nitrogen atoms are primarily the above-mentioned, optionally substituted hydrocarbon radicals, such as lower alkyl, furthermore hydroxy or oxido.

0010Heterocyclic aryl radicals R or Ar_i can, for example, depending on the type of substitution, exist in various tautomeric forms.

0011The alkylene radical alk substituted by carbocyclic aryl separates the group X from the ring nitrogen atom by 2 to 8 carbon atoms and is, for example, appropriately substituted ethylene, 1,2- or 1,3-propylene, 1,4-butylene or 1,6-hexylene, where the carbocyclic aryl can be attached to any carbon atom in the unbranched chain, but in particular to the carbon atom bonded to the group X. Accordingly, the alkylene radical Alk is, for example, 1- or 2- (carbocyclic aryl) ethylene, or 1- or 2- or 3- (carbocyclic aryl) propylene.

0012Alkylene as group Y has 1 to 6 carbon atoms and is, for example, methylene, ethylene, 1,2- or 1,3-propylene, 1,4-butylene, 1, S-pentylene or 1,6-hexylene.

0013Unless specifically defined, the definitions used above and below have the following meanings:<ul id="ul0001" list-style="none"><li>The term "lower" means that correspondingly defined groups or compounds, unless otherwise defined, contain up to and with 7, preferably up to and with 4, carbon atoms.</li></ul>

0014Substituted radicals can contain one or more, for example two, furthermore three, identical or different substituents; these can take any suitable position.

0015Naphthyl can be 1- or 2-naphthyl.

0016Pyrryl is, for example, 2- or 3-pyrryl, pyrazolyl, for example 3- or 4-pyrazolyl, imidazolyl, for example 2- or 4-imidazolyl, triazolyl, for example 1,3,5-1H-triazol-2-yl or 1,34-triazole 2-yl and tetrazolyl, for example 1,2,3,4-1H-tetrazolyl-5-yl, while furyl is 2-or 3-furyl and thienyl is 2- or 3-thienyl. Isoxazolyl is, for example, 3-isoxazolyl, oxazolyl, for example 2- or 4-oxazolyl, oxadiazolyl, for example 1,3,4-oxadiazol-2-yl, isothiazolyl, for example 3-isothiazolyl, thiazolyl, 2- or 4-thiazolyl, and thiadiazolyl, for example 1,3,4-thiadiazolyl-2-yl.

0017Pyridyl is 2-, 3- or 4-pyridyl, pyridazinyl, for example 3-pyridazinyl, pyrimidinyl 2-, 4- or 5-pyrimidinyl, pyrazinyl, 2-pyrazinyl and triazinyl, for example 1,3,5-triazin-2-yl.

0018Indolyl is, for example, 2-, 3- or 5-indolyl, isoindolyl, for example 1-isoindolyl, benzimidazolyl, for example 2- or 5-benzimidazolyl, benzofuranyl, for example 2- or 3-benzofuranyl, benzofuranyl (also 2,1,3-benzoxadiazolyl), for example 4 -Benzofurazanyl, benzothienyl e.g. 3-benzothienyl, benzthiazolyl e.g. 2-benzthiazolyl, 2,1,3-benzthiadiazolyl e.g. 2,1,3-benzthiadiazol-4-yl, quinolinyl e.g. 2- or 4-quinolinyl, and isoquinolinyl e.g. 1-isoquinolinyl .

00191-oxido-pyridyl is, for example, 1-oxido-2-, 1-oxido-3- or 1-oxido-4-pyridyl.

0020Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, furthermore n-pentyl, n-hexyl or n-heptyl, while lower alkenyl is, for example, allyl or methallyl, and lower alkynyl is, for example, propargyl, wherein the multiple bond is preferably located in a higher position than the a position.

0021Cycloalkyl preferably has 5 to 7 ring carbon atoms and is, for example, cyclopentyl or cyclohexyl, while cycloalkyl-lower alkyl can be, for example, cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl.

0022Phenyl-lower alkyl is, for example, benzyl or 1- or 2-phenylethyl.

0023Lower alkoxy is primarily methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy.

0024In a lower alkoxy lower alkoxy group, the terminal lower alkoxy group is preferably separated from the linking oxygen atom by more than one carbon atom; such residues are, for example, 2-methoxyethoxy or 2-ethoxyethoxy.

0025One or more halogen atoms, which preferably have an atom number of up to 35 and in particular are fluorine and / or chlorine, can be present in a halogen-lower alkoxy radical; such residues are, for example, difluoromethoxy, 1,1,2,2-tetrafluoroethoxy or 1,1,2-trifluoro-2-chloroethoxy.

0026Lower alkenyloxy is, for example, allyloxy or methallyloxy, and halogen-lower alkenyloxy, which can contain one or more halogen atoms, the latter preferably having an atomic number up to 35 and particularly representing fluorine and / or chlorine. is, for example, 1,2-dichlorovinyloxy, but the double bond is preferably located higher than the a position.

0027Lower alkynyloxy is, for example, propargyloxy, the triple bond preferably being located in a higher position than the a position.

0028Lower alkylene is, for example, 1,2-ethylene or 1,3-propylene, while lower alkylene is, for example, methylenedioxy or 1,2-ethylenedioxy.

0029Lower alkanoyloxy is, for example, acetyloxy, propionyloxy or pivaloyloxy.

0030Halogen preferably has an atomic number up to and with 35 and is in particular fluorine or chlorine, furthermore bromine, but can also be iodine.

0031Halogen-substituted lower alkyl is, for example, trifluoromethyl, 1,1,2-trifluoro-2-chloroethyl, 1,1,2,2-tetrafluoroethyl or chloromethyl.

0032Lower alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl or tert-butyloxycarbonyl.

0033N-Lower alkyl carbamoyl is, for example, N-methyl-carbamoyl or N-ethylcarbamoyl, while N, N-di-lower-alkyl carbamoyl is, for example, N, N-dimethyl-carbamoyl or N, N-diethyl-carbamoyl.

0034N-Lower alkylamino is, for example, N-methylamino, N-ethylamino, Nn-propylamino or N-isopropylamino.

0035N, N-di-lower alkylamino is, for example, N, N-dimethylamino, N-ethyl-N-methylamino or N, N-diethylamino, while N-lower alkyl-N-phenyl-lower alkylamino is, for example, N-benzyl-N-methylamino or N-methyl-N- Represents (2-phenylethyl) amino.

0036Lower alkylene amino preferably contains 4 to 6 ring carbon atoms and is, for example, pyrrolidino or piperidino, while oxane-lower alkylene amino, for example 4-morpholino, thiane lower alkylene amino, for example 4-thiomorpholino, and optionally aza-substituted azane-lower alkylene amino, for example piperazino, 4-methylpiperazino or 4-phenyl-piperazino 4- (2-phenylethyl) piperazino can represent. Lower alkylanoylamino is, for example, acetylamino or propionylamino.

0037Lower alkanoyl is, for example, formyl, acetyl, propionyl or pivaloyl.

0038Lower alkylthio is, for example, methylthio, ethylthio, n-propylthio or isopropylthio, while halogen-lower alkylthio is, in particular, fluoro-lower alkylthio, for example mono- or difluoromethylthio. Lower alkylsulfinyl is, for example, methylsulfinyl, while lower alkylsulfonyl is, for example, methylsulfonyl or ethylsulfonyl. N-Lower alkylaminosulfonyl is, for example, N-methylaminosulfonyl, while N, N-di-lower alkylaminosulfonyl is, for example, N, N-dimethylaminosulfonyl.

0039In a substituted lower alkoxycarbonyl, the substituent is usually separated from the oxygen by at least 2, preferably by 2 or 3, carbon atoms. Such residues are, for example, hydroxy-lower alkoxycarbonyl, such as 2-hydroxyethoxycarbonyl or 2,3-dihydroxypropylcarbonyl, lower alkoxy-lower alkoxycarbonyl, for example 2-methoxyethoxycarbonyl, di-lower alkylamio-lower alkoxycarbonyl, for example 2-dimethylaminoethoxycarbonyl, 2-diethylaminoethoxycarbonyl or 3-dimethylaminopropyloxycarbonyl, lower alkyleneamino lower alkoxycarbonyl, for example 2-pyrrolidinoethoxycarbonyl or 2-piperidinoethoxycarbonyl, morpholino-lower alkoxycarbonyl, for example 2- (4-morpholalkyl) -poxyoxycarbonyl , for example 2- (4-methylpiperazino) ethoxycarbonyl.

0040Phenyl-lower alkoxycarbonyl is, for example, benzyloxycarbonyl or 2-phenylethoxycarbonyl.

0041N, N-lower alkylene carbamoyl is, for example, pyrrolidinocarbonyl or piperidinocarbonyl, corresponding radicals in which the lower alkyl part is interrupted by oxygen, sulfur or unsubstituted or substituted nitrogen, for example 4-morpholinocarbonyl, 4-thiomorpholinocarbonyl, 1-piperazinocarbonyl or 4-methyl- 1-piperazinocarbonyl means.

0042Compounds of formula 1 can be in the form of salts, especially acid addition salts, primarily corresponding pharmaceutically usable, non-toxic acid addition salts. Such salts are, for example, those with hydrohalic acids, for example hydrochloric acid or hydrobromic acid, furthermore nitric acid, sulfuric acid or phosphoric acid, or organic acids, such as carboxylic acids, for example Acetic acid, propionic acid, glycolic acid, oxalic acid, succinic acid, maleic acid, hydroxymaleic acid, methyl maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxybenzoic acid, 2-phenoxybenzoic acid, 2-aconic acid, 2-acetic acid, 2-acetic acid, 2-acetic acid, 2-acetic acid, 2-acetic acid, 2-phenoxybenzoic acid, 2-acetic acid, 2-acetic acid, 2-acetic acid, 2-acetic acid, Isonicotinic acid, furthermore amino acids, or organic sulfonic acids, such as hydroxy-containing lower alkanesulfonic acids, for example Methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid or ethane-1,2-disulfonic acid, or arylsulfonic acid, for example benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid, or with other acidic organic substances, such as ascorbic acid.

0043Salts which are unsuitable for pharmaceutical use are also included, since these can be used, for example, for the isolation or purification of free salts according to the invention or their pharmaceutically usable salts.

0044The compounds of formula 1 and their salts have valuable pharmacological properties, especially in the cardiovascular field. They act as calcium antagonists and have α-receptor blocking and serotonin-antagonistic properties, as can be seen, for example, in in-vitro experiments on isolated perfused mesenteric vessels in the rat [McGregor, D .: J.Physiol. 177, 21-30, (1965)] as inhibition of potassium, noradrenaline and serotonin-induced vasoconstriction, for example using 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3- carboxylic acid methyl ester-5-carboxylic acid [2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1-phenyl] ethyl ester (mixture of diastereomers) at a concentration of approx. 5 nmol / liter (IC₅₀) for the inhibition of potassium-induced vasoconstriction, of approximately 4 nMol / liter (ICso) for the inhibition of noradrenaline-induced vasoconstriction and of approximately 80 nMol / liter for the inhibition of serotonin-induced vasoconstriction.

0045Furthermore, the binding of the new compounds or their salts to dihydropyridine receptors can be suppressed by displacing the binding of ³H-Nitrendipine on membranes of sea gooseberries in in-vitro experiments [Erne, P. et al ,: Biochem. Biophys. Res. Commm., 118, 842-847 (1984)] e.g. using 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [2- [ 4- (p-fluorobenzoyl) piperidin-1-yl] -1-phenyl] ethyl ester (mixture of diastereomers) at a concentration (IC₅₀) of about 0.2 nmol / liter. Likewise, the binding of the compounds according to the invention to ai receptors can be suppressed by³H-prazosin from its binding sites on the rat cerebral cortex membrane according to the methodology of P. Greenengass et al., Eur. J. Pharmacol. 55, 323, (1979), can be detected significantly at approximately 300 nmol / liter in vitro. In addition, the binding of the new compounds or their salts to serotonin (5HT₂) Receptors by displacing the binding of ³H-ketanserin on membranes of the rat brain [Leysen, JE et al .: Molecul. Pharmacol. 21, 301-304, (1982)] e.g. using 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [2- [4- (p -fluorobenzoyl) -piperidin-1-yl] -1-phenyl] ethyl ester (mixture of diastereomers) at a concentration (IC_so) of about 6.0 nmol / liter.

0046The new compounds or their salts furthermore inhibit the pressor effects induced by angiotensin 11, by electrical stimulation or by phenylephrine or norepinephrine on the "pithed rat" [JS Gillespie: Br.J.Pharmacoi. 30, 78 (1967)] at a dose of about 2 mg / kg, and an inhibition of the serotonin-induced press effects at a dose of about 6 mg / kg. The new compounds or their salts also have an antihypertensive effect, for example by lowering blood pressure in the renal hypertensive rat [Goldblatt et al .: J.exp.med. 59, 347 (1934)]. For example, 2 hours after po application of approximately 2.0 mg / kg of 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid [2- [ 4- (p-fluorobenzoyl) -piperidin-1-yl] -1-phenyl] ethyl ester (mixture of diastereomers) in the renal hypertensive rat a drop in blood pressure of approx. -70 mm Hg was observed.

0047The new compounds and their salts also have a special feature of affinity for binding sites of the calcium channel and for αi and 5HT₂Receptors and differ from other calcium antagonists.

0048The compounds of the formula I and salts of such compounds can therefore be used, for example, as coronary dilators and antihypertensives for the treatment of cardiovascular disease states such as angina pectoris and its consequences, central and peripheral circulatory disorders, high blood pressure, arrhythmias and heart failure. The new compounds are also valuable intermediates for the production of other, in particular pharmaceutically active compounds. Another object of the invention is the use of the compounds according to the invention for the production of medicaments, for example for the treatment of cardiovascular disease states and high blood pressure, for therapeutic and prophylactic treatment. The commercial preparation of the active substances can also be included.

0049The invention particularly relates to new compounds of formula I in which R represents a mono- or bicyclic, carbocyclic aryl radical or for a five- or six-membered, one to four ring nitrogen atoms, a ring oxygen or ring sulfur atom, or one or two ring nitrogen atoms together with one Ring oxygen or a ring sulfur atom as ring members containing monocyclic heteroaryl radical, which is connected via a ring carbon atom to the carbon atom of the 4-position of the 1,4-dihydropyridine ring and which optionally contains a fused-on benzo ring, and in particular phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, Oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothienyl, Benzthiazolyl, 2,1,3-benzthiadiazolyl, quinolinyl or isoquinolinyl means, in these radicals ring carbon atoms optionally by lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, cycloalkyl, phenyl and / or phenyl-lower alkyl, lower alkyl, phenyl or phenyl-lower alkyl optionally hydroxyl, lower alkoxy, lower alkoxynyl , Halogenated lower alkoxy, lower alkenyloxy, halogenated lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, carboxy, Niederalkoxycarbonyl, carbamoyl, N-Niederalkyl-carbamoyl, N, N-Diniederalkylcarbamoyl and / or cyano, and cyclic radicals also Niederalkyl, which in turn can be substituted as indicated, can contain as substituents, and / or by hydroxy, Niederalkoxy, Niederalkoxyniederalkoxy, halogen-lower alkoxy , Lower alkenyloxy, halogenated lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, nitro, amino, N-lower alkylamino, N, N, -di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, lower alkyleneamino, Oxaniederalkylenamino, Thianiederalkylenamino and / or Azaniederalkylenamino wherein the Azastickstoffatom by lower alkyl, phenyl or phenyl which may be substituted, these radicals being hydroxy, lower alkoxy, Niederalkoxyniederalkoxy, haloloweralkoxy, lower alkenyloxy, Halogenniederalkenyloxy, lower alkynyloxy, Lower alkylenedioxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl carbamoyl, N, N-di-lower alkyl carbamoyl and / or cyano, the cyclic radicals may also contain lower alkyl as substituents and / or by lower alkanoylamino, azido, lower alkanoyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl carbamoyl, N. , N-Diniederalkyl-carbamoyl, cyan, sulfo, aminosulfonyl, N-Niederalkylaminosulfonyl. N, N-diniederalkylaminosulfonyl, lower alkylthio, halogen-lower alkylthio, lower alkylsulfinyl and / or lower alkylsulfonyl, and / or ring nitrogen atoms, optionally by lower alkyl, which may optionally be hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, halogen-lower alkoxy, lower alkenyloxy, halo-lower alkenyloxy, halogenoalkylenoxy, lower alkenyloxy, Lower alkoxycarbonyl, carbamoyl, N-lower alkyl carbamoyl, N, N-di-lower alkyl-carbamoyl or cyano, or may be substituted by hydroxy or oxido, R 1 is lower alkyl, one of the radicals R₂ and R₃ represents lower alkyl and the other represents lower alkyl, cyano or amino, X represents oxygen or the group -NH-, and Alk by a carbocyclic aryl, for example by optionally, for example as follows below for carbocyclic aryl Ar_i indicated, substituted phenyl or naphthyl, substituted alkylene which separates the group X from the ring nitrogen atom by 2 to 8 carbon atoms, Y for alkylene with 1 to 6 carbon atoms or for the groups -CH (OH) - or -C (= 0) - stands or represents a simple bond, and Ari represents a monocyclic carbocyclic aryl or heteroaryl radical, and in particular represents phenyl, naphthyl, pyrryl, furyl, thienyl or pyridyl, wherein in these radicals ring carbon atoms are optionally substituted by lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, cycloalkyl, phenyl and / or phenyl-lower alkyl, with lower alkyl, phenyl or phenyl-lower alkyl being substituents hydroxy. Lower alkoxy, lower alkoxy-lower alkoxy, halogen-lower alkoxy, lower alkenyloxy, halogen-lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N, N-di-lower alkyl-carbamoyl and / or cyanide, and the, and also, cyan, and its, and cyano, and the, and also, C, and its, and Cyan, and its, and cyclo, and also, and lower, and its, and cyano, and its, and cyclo, and also, and lower, and also cyano, and its, and cyano, lower, and its, and cyano, and its, and also cyano, and its cyan, and lower, and also cyano, and its cyan, and lower, and cyano, and its, and also, and lower, and cyano, and its, and Cyan, and lower, and lower, and also, Cyan, may be substituted as indicated, and / or by hydroxy, lower alkoxy, lower alkoxy lower alkoxy, halogen lower alkoxy, lower alkenyloxy, Halogeno lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, nitro, amino, N-lower alkylamino, N, N-di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkylamino, lower alkyleneamino, oxo-lower alkyleneamino, thianiederalkyleneamino and / or wherein azaniederalkylenam Lower alkyl, phenyl or phenyl-lower alkyl can be substituted, these radicals being hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, halogen-lower alkoxy, lower alkenyloxy, Halogen lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N, N-din-lower alkyl-carbamoyl and / or cyano, which cyclic radicals can also contain lower alkyl as a substituent, and / or by lower alkyl anoylamino, Azido, lower alkanoyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl carbamoyl, N, N-di lower alkyl carbamoyl, cyan, sulfo, aminosulfonyl, N-lower alkylaminosulfonyl, N, N-di-lower alkylaminosulfonyl, lower alkylthio, lower alkylsulfinyl and / or lower alkylsulfonyl, and / or ring nitrogen atoms, optionally by lower alkyl, which may optionally be hydroxyl, lower alkoxy, lower alkoxy lower alkoxy, halogen lower alkoxy, lower alkenyloxy, halogen lower alkenyloxy, lower alkynyloxy, lower carboxyloxy, lower carboxyloxy, lower carboxy Carbamoyl, N-lower alkylcarbamoyl, N, N-di-lower alkyl-carbamoyl or cyano may be present as a substituent, or may be substituted by hydroxy or oxido, and salts, in particular pharmaceutically usable, non-toxic acid addition salts of such compounds.

0050The invention relates primarily to new compounds of formula 1, in which R and Ari each represent phenyl or naphthyl, optionally by lower alkyl, phenyl and / or phenyl-lower alkyl, such radicals in turn being hydroxyl, lower alkoxy, halogen-lower alkoxy, lower alkylenedioxy, halogen, carboxy, Lower alkoxycarbonyl and / or cyano, the cyclic radicals may also contain lower alkyl as substituents, and / or by hydroxy, lower alkoxy, halogen-lower alkoxy, lower alkenyloxy, Halogen-lower alkenyloxy, lower alkylenedioxy, halogen, nitro, amino, N-lower alkylamino, N, N-di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, cyano, sulfo, aminosulfonyl, N-lower alkylaminosulfonyl, N, N-diniederalkylaminosulfonyl or lower alkylsulfonyl or lower Lower alkylsulfonyl, or R and Ari each represent pyrryl, furyl, thienyl, pyridyl, 1-oxidopyridyl or imidazolyl bonded via a ring carbon atom, R also stands for benzofurazanyl, such radicals optionally being as for a phenyl or naphthyl radical R or Ar_i indicated, are substituted, and in particular may contain lower alkyl, lower alkoxy, halogen and / or phenyl optionally substituted by lower alkyl, lower alkoxy, halogen and / or nitro, R is lower alkyl, one of the groups R₂ and R₃ Is lower alkyl and the other is lower alkyl or cyano, X is oxygen or the group -NH-, and alk is substituted by a phenyl or naphthyl optionally substituted by lower alkyl, lower alkoxy, hydroxy, halogen-lower alkyl, halogen, cyano and / or nitro with 2 to 6 carbon atoms, which separates the group X from the ring nitrogen atom by 2 to 6 carbon atoms and Y means alkylene with 1 to 4 carbon atoms or the groups -CH (OH) - or -C (= 0). and salts, in particular pharmaceutically usable. non-toxic acid addition salts of such compounds.

0051The invention particularly relates to new compounds of the formula wherein R and Ar_i each represent phenyl which is optionally substituted by lower alkyl, hydroxy, lower alkoxy, halogen-lower alkoxy, halogen-lower alkenyloxy, lower alkylenedioxy, halogen, trifluoromethyl, nitro, lower alkanoylamino, optionally substituted by optionally esterified or etherified hydroxy or phenyl or phenyl-lower alkyl, and / or cyano, where a phenyl radical R or Ari can have one or more, identical or different substituents, or R and Ar₁ each pyridyl, furyl, 1-oxidopyridyl, or thienyl, R also means benzofuranyl, for example 4-benzofurazanyl, which can be substituted by lower alkyl or halogen, R₁, R₂ and R₃ each represent lower alkyl, X for the group -NH-. in particular, however, stands for oxygen, Alk denotes substituted alkylene having 2 to 4 carbon atoms, optionally containing lower alkyl, lower alkoxy, hydroxy, halogen-lower alkyl, halogen, cyano and / or nitro, the optionally substituted phenyl radical preferably being attached to the carbon atom adjacent to group X. and Alk separates the group X from the ring nitrogen atom by 2 to 4 carbon atoms, Y stands for alkylene with 1 to 3 carbon atoms or the groups -CH (OH) - or in particular -C (= 0) -, and salts, in particular pharmaceutically usable non-toxic acid addition salts of such compounds.

0052The invention relates in particular to new compounds of the formula I in which R is unsubstituted or preferably by lower alkyl, for example methyl, lower alkoxy, for example methoxy, halogeno lower alkoxy, for example difluoromethoxy or halogeno lower alkenyloxy, in which halogen has an atomic number up to and including 35 and is in particular fluorine or chlorine , e.g. 1,1-difluorovinyloxy, halogen with an atomic number up to and including 35, in particular chlorine and fluorine, trifluoromethyl, nitro and / or cyano mono- or di-substituted phenyl, where substituents are in the 2- and / or 3-position, R_i Lower alkyl, for example methyl or ethyl, and R₂ and R₃ Lower alkyl, in particular methyl, mean, X represents the group -NH-, but especially oxygen, alk by an alkylene substituted by lower alkyl, lower alkoxy, hydroxy, halogen-lower alkyl, halogen, cyano and / or nitro, but especially by an unsubstituted phenyl with 1 to 3 carbon atoms, the optionally substituted phenyl radical being bonded to the carbon atoms adjacent to group X, and Alk separates the group X from the ring nitrogen atom by 2 to 3 carbon atoms, Y represents alkylene with 1 to 3 carbon atoms or in particular the group -C (= O) -, and Ar₁ phenyl or pyridyl optionally substituted by halogen with an atom number up to and including 35, for example fluorine or chlorine, and salts, in particular pharmaceutically usable, non-toxic acid addition salts of such compounds.

0053The invention relates in particular to new compounds of the formula I in which R is halogeno lower alkoxy, in particular with an atom number of up to and with 35 and with up to 4 carbon atoms, such as difluoromethoxy, lower alkylenedioxy, in particular with up to and with 3 carbon atoms, such as methylenedioxy, halogen , in particular with an atom number up to and including 35, such as chlorine, trifluomethyl or nitro mono- or disubstituted phenyl, where substituents are in the 2- and / or 3-position, benzofurazanyl, in particular 4-benzofurazanyl, or 1-oxido-pyridyl, such as 1-oxido-3-pyridyl, means R_i, R₂ and R₃ independently of one another lower alkyl, in particular with up to and with 4 carbon atoms, such as methyl, X is oxygen, alk by optionally lower alkyl, lower alkoxy, in each case in particular with up to and with 4 carbon atoms, such as methyl or methoxy, halogeno lower alkyl, in particular with an atom number up to and with 35 and with up to and with 4 carbon atoms, such as trifluoromethyl, halogen, in particular with an atom number up to and with 35, such as chlorine, or Cyan-substituted phenyl-containing alkylene with 2 to 4 C atoms, where Alk separates the group X from the ring nitrogen atom by 2 to 4 C atoms, Y for alkylene with 1 to 3 C atoms, the groups -CH (OH) - or in particular -C (= 0) - or a bond, and Ari is optionally halogen, in particular with an atom number up to and including 35, such as chlorine, substituted phenyl or thienyl, such as 2-thienyl, and salts, in particular pharmaceutically usable , non-toxic acid addition salts of such compounds.

0054The invention relates in particular to new compounds of the formula I in which R is mono- or disubstituted phenyl by halogen with an atomic number up to and including 35, such as chlorine, trifluoromethyl or nitro, substituents preferably occupying the 2- or 3-position, R 1, R 3₂ and R₃ independently of one another lower alkyl with up to and with 4 carbon atoms, such as methyl or ethyl, X stands for oxygen, alk through a through lower alkyl, lower alkoxy each with up to and with 4 carbon atoms, such as methyl or methoxy, halogen lower alkyl with an atom number up to and with 35 and with up to and with 4 C atoms, such as trifluoromethyl, halogen with an atom number up to and with 35, such as chlorine or cyano substituted or unsubstituted phenyl substituted alkylene with 2 to and with 6 C atoms, means, where the optionally substituted phenyl radical is preferably bonded to the C atom adjacent to the group X and the group X is separated from the ring nitrogen atom by at least two C atoms, Y for alkylene with 1 to 3 C atoms, the groups -CH (OH) - or -C (= O), furthermore there is a bond, and Ari is unsubstituted or substituted by halogen with an atom number up to and including 35, such as fluorine, substituted phenyl or thienyl, such as 2-thienyl, and salts, in particular pharmaceutically usable, non-toxic acid addition salts of such compounds.

0055The invention particularly relates to new compounds of the formula I. in which R represents 2-, 3-nitrophenyl, 2-, 3-trifluoromethylphenyl or 2,3-dichlorophenyl, R_i, R₂ and R₃ independently of one another in each case lower alkyl having up to and with 4 C atoms, in particular methyl, X is oxygen, alk is a through lower alkyl having up to and with 4 C atoms, such as methyl, lower alkoxy having up to and with 4 C atoms, such as methoxy, halo-lower alkyl with an atom number up to and with 35 and with up to and with 4 C atoms, such as trifluoromethyl, halogen with an atom number up to and with 35, such as chlorine, or cyano means monosubstituted or unsubstituted phenyl substituted alkylene with 2 to and with 6 C atoms and where the group X is separated from the ring nitrogen atom by at least two C atoms, Y for methylene, hydroxymethylene, the group -C (= O) - or there is a bond. and Ari is unsubstituted or halogenated with an atomic number up to and including 35, such as fluorine, monosubstituted phenyl or thienyl, such as 2-thienyl, and salts, in particular pharmaceutically acceptable, non-toxic acid addition salts of such compounds.

0056The invention relates in particular to new compounds of the formula I in which R represents phenyl which is mono- or disubstituted by halogen with an atom number of up to 35, especially fluorine or chlorine, or monosubstituted by trifluoromethyl, nitro or cyano, where or take the 3-position, R 1 lower alkyl, for example methyl or ethyl, and R₂ and R₃ each lower alkyl, primarily methyl, mean X is oxygen. Alk by one by lower alkyl, eg methyl, lower alkoxy, eg Methoxy, trifluoromethyl, cyano and / or nitro is substituted, but in particular by an unsubstituted, phenyl substituted alkylene having 2 to 3 carbon atoms, the optionally substituted phenyl radical being bonded to the carbon atom adjacent to group X, and alk by X from the ring nitrogen atom Separates 2 to 3 carbon atoms, Y represents alkylene with 1 to 2 carbon atoms or in particular the group -C (= O) -, and Ar_i optionally, in particular in the 4-position, means phenyl substituted by halogen with an atom number up to and including 35, for example fluorine, and salts, in particular pharmaceutically usable, non-toxic acid addition salts of such compounds.

0057The invention relates primarily to new compounds of the formula I in which R is 3-nitrophenyl or 2-trifluoromethylphenyl, R i is methyl or ethyl, R₂ and R₃ M is methyl, X is oxygen, Alk is 1-phenylethyl, Y is the group -C (= O) - and Ari is optionally substituted in the 4-position by fluorine-substituted phenyl, and salts, in particular pharmaceutically usable, non-toxic acid addition salts of such connections.

0058The invention relates in particular to the specific new compounds and processes for their preparation described in the examples.

0059The compounds of formula I and salts of such compounds with salt-forming properties can be prepared in a manner known per se, for example by<ul id="ul0002" list-style="none"><li>a) a compound of the formula<chemistry id="chem0002" num="0002"><img file="EP0222702A2_D0002.tif" /></chemistry>wherein one of the radicals X 'and Y' for the group of the formula -NH₂ stands and the other hydroxy or the group of formula -NH₂ means, or a tautomer thereof or a corresponding tautomer mixture closes, or</li><li>b) a compound of the formula R-CHO (III) or a reactive functional derivative thereof with a compound of the formula<chemistry id="chem0003" num="0003"><img file="EP0222702A2_D0003.tif" /></chemistry>or a tautomer thereof or a corresponding tautomer mixture, or</li><li>c) in a compound of the formula<chemistry id="chem0004" num="0004"><img file="EP0222702A2_D0004.tif" /></chemistry>in which one of the residues Aco and AcJ belongs to the group -COOR₁ or in the rest of the formula<chemistry id="chem0005" num="0005"><img file="EP0222702A2_D0005.tif" /></chemistry>convertible group means and the other group -COOR₁ or the group of the formula Va or a radical which can be converted into the group -COORi or the group of the formula Va, the radical Ac o into the group -COOR₁ and / or the rest <maths id="math0001" num=""><img file="EP0222702A2_D0006.tif" /></maths>converted into a remainder of the formula Va, or</li><li>d) a compound of the formula<chemistry id="chem0006" num="0006"><img file="EP0222702A2_D0007.tif" /></chemistry>or a reactive ester thereof, with a compound of the formula<chemistry id="chem0007" num="0007"><img file="EP0222702A2_D0008.tif" /></chemistry>implements, or</li><li>e) a compound of the formula<chemistry id="chem0008" num="0008"><img file="EP0222702A2_D0009.tif" /></chemistry>in which Z has the meaning of Alk or represents a group which can be converted into the group Alk by reduction, <maths id="math0002" num=""><img file="EP0222702A2_D0010.tif" /></maths>has the meaning of Y, or represents a group which can be converted into the alkylene group corresponding to Y by reduction, at least one of the groups Z and <maths id="math0003" num=""><img file="EP0222702A2_D0011.tif" /></maths> represents a group which can be converted into the group Alk or into the alkylene group corresponding to the group Y, and which means alk or the group Y, reduced, the starting materials of the formulas II to VII, provided they have salt-forming properties, also in the form their salts can be used, and the groups R, R₁, R2, R₃, X, Y, Ar_i and Alk have the meanings given under the formula and, if desired, converts a compound of the formula obtained into another compound of the formula I and / or, if desired, converts a salt obtained into the free compound or into another salt, and / or, if desired, converting a free compound of the formula I obtained into a salt, and / or, if desired, converting a racemate mixture into the pure racemates or Separates diastereomers and / or a racemate obtained into the optical antipodes.</li></ul>

0060The starting materials of the formula II used in process variant a) are usually formed in situ and the ring closure according to the process can take place under the reaction conditions for the preparation of the starting material. For example, the starting materials of the formula II and, under the reaction conditions, the corresponding end products of the formula I can usually be obtained by aa) a compound of the formula III, or a reactive functional derivative thereof, with a compound of the formula<chemistry id="chem0009" num="0009"><img file="EP0222702A2_D0012.tif" /></chemistry> and a compound of the formula<chemistry id="chem0010" num="0010"><img file="EP0222702A2_D0013.tif" /></chemistry>and ammonia or with a compound of formula XIII<chemistry id="chem0011" num="0011"><img file="EP0222702A2_D0014.tif" /></chemistry>reacts, or ab) a compound of formula III or a reactive functional derivative thereof with a compound of formula<chemistry id="chem0012" num="0012"><img file="EP0222702A2_D0015.tif" /></chemistry>and a compound of formula XI or a compound of formula XII with a compound of formula XV<chemistry id="chem0013" num="0013"><img file="EP0222702A2_D0016.tif" /></chemistry>reacts, or ac) a compound of formula III or a reactive functional derivative thereof with a compound of formula<chemistry id="chem0014" num="0014"><img file="EP0222702A2_D0017.tif" /></chemistry>and a compound of formula X or XII or a compound of formula XIII with a compound of formula XIV<chemistry id="chem0015" num="0015"><img file="EP0222702A2_D0018.tif" /></chemistry>converts, or ad) ammonia with a compound of the formula<chemistry id="chem0016" num="0016"><img file="EP0222702A2_D0019.tif" /></chemistry>and a compound of the formula XI, or ae) ammonia with a compound of the formula<chemistry id="chem0017" num="0017"><img file="EP0222702A2_D0020.tif" /></chemistry>and a compound of the formula X or XII, or af) ammonia with a compound of the formula<chemistry id="chem0018" num="0018"><img file="EP0222702A2_D0021.tif" /></chemistry>reacts, or ag) a compound of formula XII with a compound of formula XV or the formula<chemistry id="chem0019" num="0019"><img file="EP0222702A2_D0022.tif" /></chemistry>reacts, or ah) a compound of formula XIII with a compound of formula XIV or with a compound of formula<chemistry id="chem0020" num="0020"><img file="EP0222702A2_D0023.tif" /></chemistry>implements. With the exception of the compound of the formula 111, the compounds of the formulas X to XVIII can be used in the form of tautomers thereof or in the form of tautomer mixtures; Starting materials of the above formulas with salt-forming properties can also be used in the form of salts. Furthermore, in the abovementioned compounds, the groups R, Ri, R₂, R₃, X, Y, Ari and Alk have the meanings given in connection with the formula I.

0061Reactive functional derivatives of the aldehyde of the formula III include the corresponding acetals, ie the di- (etherified hydroxy) methyl compounds corresponding to group R, such as di-lower alkyl, eg dimethyl or diethyl acetals, acylals, eg the corresponding di-acyloxymethyl or di-halomethyl compounds, such as diniederalkanoylacylals, for example diacetylacylals, or the corresponding dihalo, for example Dichloro or dibromo compounds, also addition compounds, such as those with an alkali metal, for example potassium hydrogen sulfite.

0062The ammonia used for the ring closure reactions described above can also be used in the form of an agent which releases this compound in situ, for example in the form of an ammonium salt, such as ammonium acetate or ammonium hydrogen carbonate.

0063The ring closure reaction a) and the condensation reactions aa) to ah) for the preparation of the starting material for the ring closure reaction, which is usually formed in situ, are variants of the Hantzsch dihyropyridine synthesis. In variant aa) a total of three molecules of water are split off; in other variants, an addition reaction sometimes takes the place of water elimination, ie the elimination of water takes place during the production of one or two starting materials. When reacting compounds of the formula III with compounds of the formulas XIII and XII according to step ac), of compounds of the formula XII with compounds of the formula XVII according to step ag), or of compounds of the formula XIII with compounds of formula XVII according to step ah), ammonia is split off in addition to or instead of water. If, according to variant aa), compounds of the formula I are to be prepared in which R₂ and R₃ differ from one another, by-products can arise which contain the same substituents in the 2- and 6-positions. By not simultaneously combining the reaction participants, the formation of such by-products can be reduced by promoting a certain course of the reaction, which in a different version takes place, since, for example, according to the staggered addition of the reaction components initially a compound of the general formula XII or the formula XIII can be formed.

0064The ring closure or condensation reactions according to the process, for example variants a) and b), are carried out in a manner known per se, if necessary in the presence of a condensing agent, in particular a basic condensing agent, such as an excess of a basic reaction component or an additional, for example organic base, such as piperidine or ethyldiisopropylamine, or a metal alcoholate, such as alkali metal lower alkanolate, and / or a suitable dehydrating or water-absorbing agent, furthermore usually in the presence of an inert organic solvent and at reaction temperatures in the range from about room temperature to about 150 ° C, especially at the boiling point of the solvent. If appropriate, the reaction is carried out in an inert gas, for example Nitrogen atmosphere, and / or, for example when using a low-boiling solvent and / or ammonia, in a closed vessel under increased pressure.

0065The starting materials used in the process variants are known or can be prepared by processes known per se.

0066For example, starting materials of the formula XI can be obtained by reacting compounds of the formula<chemistry id="chem0021" num="0021"><img file="EP0222702A2_D0024.tif" /></chemistry>with compounds of the formula<chemistry id="chem0022" num="0022"><img file="EP0222702A2_D0025.tif" /></chemistry>make in the usual way. Instead of carboxylic acids of the formula Xla, it is also possible to use functional derivatives thereof, such as corresponding carboxylic anhydrides, in particular mixed anhydrides, such as those with lower alkanecarboxylic acids, for example formic acid, furthermore acid halides, for example corresponding chlorides, bromides, furthermore acid azides, further activated esters, for example cyanomethyl ester. These, optionally in the presence of condensing agents, can be converted into compounds of the formula XI by reaction with a compound of the formula Xlb, free carboxylic acids of the formula Xla by reaction with compounds of the formula Xlb, in which the azido group is instead of the HX group. Carboxylic acids of the formula Xla can also be used as salts, in particular as alkali metal or alkaline earth metal salts with reactive esters of alcohols of the formula Xlb, in which X is oxygen, such as corresponding halides, for example chlorides, bromides or iodides, or organic sulfonic acid esters, for example lower alkanesulfonic acid or arenesulfonic acid esters , such as methanesulfonic acid or p-toluenesulfonic acid esters are converted into corresponding carboxylic acid esters, or corresponding hydrolyzable imino esters, such as corresponding imino lower alkyl esters, are hydrolyzed to give the esters. Iminoesters of this type are, for example, corresponding nitriles of the formula from the compounds of the formula Xla<chemistry id="chem0023" num="0023"><img file="EP0222702A2_D0026.tif" /></chemistry>by reaction with compounds of the formula Xlb, in which X represents oxygen, in the presence of an acidic condensing agent, for example hydrogen chloride, in a suitable solvent, for example such an inert character, such as an aromatic, for example benzene, in a customary manner.

0067Compounds of the formula Xlb are in turn known in a manner known per se by reacting compounds of the formula HX-Alk-A (Xld), wherein A represents a suitable leaving group, for example a reactive esterified hydroxy group, such as halogen, for example chlorine, bromine or iodine, or a sulfonyl group, for example an arylsulfonyloxy such as p-toluenesulfonyloxy group, with compounds of the formula<chemistry id="chem0024" num="0024"><img file="EP0222702A2_D0027.tif" /></chemistry>expediently in the presence of a basic condensing agent such as an oxide, hydroxide or carbonate of an alkali metal or alkaline earth metal. such as sodium hydroxide or calcium carbonate, and usually in the presence of a solvent, such as a lower alkanol such as ethanol, accessible at elevated or reduced temperature. Compounds of the formula Xle can also be used in the form of their metal derivatives, in which the hydrogen atom on the nitrogen is replaced by a suitable metal, for example lithium or potassium. In such cases, the reaction described with compounds of the formula Xld takes place in an inert anhydrous solvent, such as an ether-like character, such as tetrahydrofuran, or an aromatic solvent, such as toluene.

0068Metal compounds corresponding to formula Xle are expediently accessible in a customary manner, for example by reaction with a suitable organic alkali metal compound, for example butyllithium in an anhydrous solvent, such as tetrahydrofuran, under a protective gas, for example argon, the metal compound present in the reaction mixture being isolated without isolating it , can be used for the implementation described above.

0069Compounds of the formula Xle in turn can be prepared in a manner known per se, for example from those starting materials which, instead of the piperidine ring, contain a suitable group which can be converted into a piperidine ring. Such groups are, for example, those that form the piperidine ring by means of reduction or by means of ring-closing condensation, for example a corresponding 2-piperidone, which can be converted into a starting material of the formula Xle by means of a suitable reducing agent, such as lithium aluminum hydride. Or you go, for example from a corresponding 1,5-di-halopentane, for example a corresponding 1,5-dibromopentane, which, using ammonia, optionally in a closed vessel and under pressure, gives a starting material of the formula Xle.

0070The reaction of free carboxylic acids of the formula Xla with compounds of the formula Xlb is advantageously carried out in the presence of an acidic catalyst which promotes the elimination of water, such as a protonic acid, for example hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid or boric acid, benzenesulfonic acid or toluenesulfonic acid, or a Lewis acid, e.g. boron trifluoride etherate, in an excess of the alcohol used and / or in an inert solvent, if necessary with distillation, for example azeotropic, removal of the water liberated in the reaction. The reactions can also be carried out in the presence of water-binding condensing agents, such as suitably substituted carbodiimides, for example Perform N, N'-diethyl, N, N'-dicyclohexyl or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide in inert organic solvents. Mixed anhydrides, in particular acid halides, are, for example, in the presence of acid-binding agents, for example organic, in particular tertiary, nitrogen bases, such as triethylamine, ethyldiisopropylamine or pyridine, or else inorganic bases, for example Alkali metal or alkaline earth metal hydroxides or carbonates, such as sodium potassium or calcium hydroxide or carbonate, are reacted with alcohols or with alcoholates, for example alkali metal lower alkanolates.

0071The reactions of reactive esters, for example cyanomethyl or pentachlorophenyl esters, with compounds of the formula Xlb are carried out, for example, in a solvent which is inert to the reactants in the temperature range from about 0 ° C. to about 120 ° C., preferably at room temperature to about 60 ° C.

0072The hydrolysis of imino ester starting materials is carried out, for example, by means of water-containing mineral acids, such as hydrochloric acid or sulfuric acid, where, for example, the imino ester salts, for example unsubstituted or substituted lower alkanols, obtained after the addition of hydrogen chloride to nitriles and reaction with anhydrous alcohols, in particular unsubstituted or substituted lower alkanols can hydrolyze from water directly to the corresponding esters. You can, for example also contain the desired ester compound of the formula XI from a mixture of nitrile, alcohol and sulfuric acid with a suitable water content without isolating the iminoester formed in situ.

0073Starting materials of the formulas XIII, XV, XVI and XVII can be prepared in an analogous and customary manner starting from corresponding starting materials.

0074Starting materials of the formula IV are formed in situ in a manner analogous to that described for the production of starting materials of the formula II, and the ring closure according to the process to give the end products of the formula 1 can take place in the same reaction mixture under the conditions given for the production of the starting material. Accordingly, starting materials of the formula IV are accessible by reacting compounds of the formula XI with those of the formula X and ammonia, or of compounds of the formula XI with those of the formula XII, or of compounds of the formula XIII with those of the formula X or XII, where such Reaction usually in a suitable solvent, for example a lower alkanol, such as ethanol, if appropriate at elevated or reduced temperature, advantageously under a protective gas, such as nitrogen.

0075Starting materials of the formula V can be Aco and / or corresponding to the radical (s) contained in them <maths id="math0004" num=""><img file="EP0222702A2_D0028.tif" /></maths>, for example carboxylic acids (Aco and / or Ac? is carboxyl), carboxylic anhydrides, in particular mixed anhydrides, such as acid halides, for example chlorides or bromides or azides (Acound / or Ac is halocarbonyl, for example chloro- or bromocarbonyl or azidocarbonyl) Esters, e.g. Cyanomethyl ester (Aco and / or Acoi is cyanomethoxycarbonyl); these can, if appropriate in the presence of condensing agents, be converted into the corresponding esters by treatment with an appropriate alcohol, for example to convert the group Aco into a carboxy ester group corresponding to the group -COORi by reaction with an unsubstituted or substituted lower alkanol corresponding to the meaning of Ri , or a reactive derivative thereof, e.g. a corresponding alcoholate, free carboxylic acids also by reaction with suitable diazo compounds, such as unsubstituted or substituted diazo lower alkanes, compounds of the formula I which contain the group -COORi being formed.

0076To convert the group Ac? In the group of formula Va defined above, a starting material of formula V is reacted with a compound of formula Xlb in the usual way. Carboxylic acid esters of the specified type, in which X represents oxygen. can also be obtained if salts, in particular alkali metal or alkaline earth metal salts of the free carboxylic acids are used as starting materials and these with reactive esters of alcohols corresponding to the compounds of the formula Xlb, in which X is oxygen, such as corresponding halides, for example chlorides, bromides or iodides, or organic sulfonic acid esters, for example lower alkanesulfonic acid or arenesulfonic acid esters, such as methanesulfonic acid or p-toluenesulfonic acid esters. are treated, or if corresponding hydrolysable imino esters, such as corresponding imino lower alkyl esters, are hydrolyzed to the esters.

0077Imino esters of this type are, for example, from starting materials of the formula V, in which Aco and / or <maths id="math0005" num=""><img file="EP0222702A2_D0029.tif" /></maths>represents the cyano group by reaction with one of the meanings of R_i corresponding lower alkanol and / or an alcohol of the formula Xlb, wherein X is oxygen, in the presence of an acidic condensation agent, such as hydrogen chloride or conc. Sulfuric acid accessible.

0078The reaction of free carboxylic acids with alcohols, such as unsubstituted or substituted lower alkanols or with compounds of the formula Xlb, is advantageously carried out in the presence of an acidic catalyst which promotes the elimination of water, such as a protonic acid, for example hydrochloric, hydrogen bromide, sulfuric, phosphoric or boric acid , Benzenesulfonic or toluenesulfonic acid, or a Lewis acid, for example boron trifluoride etherate, in an excess of the alcohol used or the compound of formula Xlb and / or in an inert solvent, if necessary with distillative, for example azeotropic, removal of the water released in the reaction. The reactions can also be inert in the presence of water-binding condensing agents, such as suitably substituted carbodiimides, for example N, N'-diethyl, N, N'-dicyclohexyl or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide organic solvents. Mixed anhydrides, in particular acid halides, are, for example, in the presence of acid-binding agents, for example organic, in particular tertiary nitrogen bases, such as triethylamine, ethyldiisopropylamine or pyridine, or else inorganic bases, for example alkali metal or alkaline earth metal hydroxides or carbonates, such as sodium, potassium or calcium hydroxide or the like carbonate, with alcohols or with alcoholates, for example alkali metal lower alkanolates.

0079The reactions of reactive esters corresponding to formula V, for example cyanomethyl, benzotriazol-1-yl or pentachlorophenyl esters, with the meaning of Ri corresponding lower alkanols or with compounds of formula Xlb, are carried out, for example, in a solvent which is inert to the reactants in the temperature range from about 0 ° C to about 120 ° C, preferably at room temperature to about 60 ° C, performed.

0080The hydrolysis of amino ester starting materials. takes place, for example, by means of water-containing mineral acids, such as hydrochloric acid or sulfuric acid, for example the imino ester salts, for example hydrochloride, obtained when hydrogen chloride is added to nitriles and reacted with anhydrous alcohols, in particular unsubstituted or substituted lower alkanols, after addition of water directly to the corresponding esters can hydrolyze. You can, for example also obtain the desired ester compound of the formula I from a mixture of nitrile, alcohol and sulfuric acid with a suitable water content without isolating the imidoester formed in situ.

0081Starting materials of formula V with free carboxyl group Aco and / or <maths id="math0006" num=""><img file="EP0222702A2_D0030.tif" /></maths>can be obtained, for example, by preparing the corresponding 2-cyanoethyl ester, using, for example in one of the processes described above) or ag), a compound of the formula XII in which, instead of the group, -COOR_i represents a 2-cyanoethoxycarbonyl group; for example, one can group R₂ reacting 3-aminocrotonic acid-2-cyanoethyl ester with the other reaction components, and then the 2-cyanoethyl ester compound thus obtained under mild conditions, for example by means of aqueous or aqueous-lower alkanolic 1-n. Split sodium hydroxide at room temperature to free carboxylic acid. If necessary, the latter can be converted into the desired reactive functional derivatives in a manner known per se.

0082The nitrile compounds of the formula V which are also suitable as starting materials for process variant c) can be prepared, for example, analogously to one of the process variants aa) to ah) by using starting materials which, instead of the radical -COOR or the group of the formula Xlb contain a cyano group, such as, for example, the group R instead of a compound of the formula XII₂ containing 3-aminocrotonitrile.

0083The starting materials of the formula VI required for process variant d) can be prepared in a manner known per se, for example analogously to the reactions described in process steps aa) to ah), such starting materials being used instead of the compounds XI, XIII, XV, XVI or XVII be that instead of the group of formula<chemistry id="chem0025" num="0025"><img file="EP0222702A2_D0031.tif" /></chemistry>the group of the formula -COX-Alk-OH (Vlb) or a reactive ester. of them. Reactive esters are, for example, those formed with a hydrohalic acid, for example hydrochloric acid, or an organic sulfonic acid, such as an arylsulfonic acid, for example p-toluenesulfonic acid, in which the hydroxyl group, for example by halogen, such as chlorine or bromine, or, for example, by arylsulfonyloxy, such as p- Toluenesulfonyloxy is replaced. For example, a starting material of the formula<chemistry id="chem0026" num="0026"><img file="EP0222702A2_D0032.tif" /></chemistry>analogous to the methods described for the preparation of starting materials of the formula XI, for example by reacting compounds of the formula Xla with compounds of the formula HX-Alk-OH (Vld) or a reactive ester, for example a halide, such as bromide or iodide, as described, be preserved. Or a nitrile of the formula Xlc is reacted with a compound of the formula Vld, in which X is oxygen, in the presence of an acidic condensing agent, for example hydrogen chloride, to give the corresponding iminoester salt, which is then dissolved in water in an acidic medium, for example as described above corresponding carboxylic acid ester is hydrolyzed.

0084The above reactions and also process variant d) can be carried out under reaction conditions known per se, in the absence or usually in the presence of solvents or diluents, depending on the type of reaction and / or reactants at reduced or elevated temperature, for example in the temperature range from about -10 ° C to about 150 ° C, under atmospheric pressure or in a closed vessel, optionally under pressure, and / or in an inert atmosphere, for example under a nitrogen atmosphere. If necessary, the reaction can be carried out in the presence of a base.

0085The groups Z which can be converted into the alk group by reduction or the alkylene group corresponding to the group Y by means of reduction contain double and / or triple bonds and / or carbonyl or thiocarbonyl groups in the corresponding alkylene radical. The reduction of unsaturated groups to the carbon-carbon single bond takes place, for example, by means of activated hydrogen, such as hydrogen in the presence of a hydrogenation catalyst, for example a nickel, platinum or palladium catalyst, while the reduction of carbonyl groups to methylene group by means of hydrogen in the presence of, for example, a copper chromite catalyst or by the Clemmensen method, e.g. by means of optionally analgamated zinc in a mineral acid, such as hydrochloric acid. The reduction of thiocarbonyl groups can be carried out in a similar manner, for example using a sulfur-resistant catalyst. The above-mentioned groups can also be reduced by means of a hydride reducing agent, for example sodium borohydride or diborane. When reducing it, care must be taken, if desired, to ensure that other groups sensitive to reduction, e.g. Unsaturated groups or nitro groups are not attacked, for example by selecting the suitable reducing agent, the dosage required for the reduction to be carried out and / or suitable process conditions, for example elevated or reduced temperature and / or by using a suitable solvent. These reactions are carried out in a manner known per se, usually in the presence of solvents and diluents, depending on the type of reaction and / or reactants at reduced or elevated temperature, for example in the temperature range from about -15 ° C. to about 120 ° C. under normal Pressure or in a closed vessel, possibly under pressure and / or under a protective gas, such as nitrogen.

0086If they are new, starting materials of the formula VII can be prepared by methods known per se, for example analogously to the processes described under a) to d). For example, one can proceed analogously to the reaction steps described in steps aa) to ah) if, instead of the compounds XI, XIII, XV, XVI or XVII, those compounds are used which instead of the group Va defined above are the group of the formula<chemistry id="chem0027" num="0027"><img file="EP0222702A2_D0033.tif" /></chemistry>contains.

0087For example, a starting material of the formula<chemistry id="chem0028" num="0028"><img file="EP0222702A2_D0034.tif" /></chemistry>analogous to the methods described for the preparation of compounds of the formula XI, for example by reacting compounds of the formula Xla or reactive derivatives thereof, for example anhydrides. Acid halides, such as chlorides. Azides. mixed esters such as cyanomethyl esters or pentachlorophenol esters. getting produced. Carboxylic acids of the formula Xla can also be used as salts. in particular as alkali metal or alkaline earth metal salts with reactive esters of the formula<chemistry id="chem0029" num="0029"><img file="EP0222702A2_D0035.tif" /></chemistry>such as corresponding halides, for example chlorides, bromides or iodides, or organic sulfonic acid esters, for example those which are reacted with lower alkanesulfonic acids, such as methanesulfonic acid, or arylsulfonic acids, such as benzenesulfonic acid, to give corresponding carboxylic acid esters. On the other hand, alcohols of the formula VIIIc can be reacted with nitriles of the formula Xlc in the customary manner in the presence of acidic condensing agents, such as a mineral acid, for example hydrochloric or sulfuric acid, to give the salts of corresponding imino esters, which are then hydrolyzed to the carboxylic acid esters by means of water, as described. These reactions are carried out under customary and known reaction conditions. Starting materials of the formula Vllc are in turn. insofar as they are new, in a conventional manner, for example by reacting compounds of the formula HO-ZA (VIII), in which A is a suitable leaving group, for example halogen, such as chlorine, bromine or iodine or a sulfonyloxy such as p-toluenesulfonyloxy group, with compounds of the formula Xle accessible in the usual way.

0088The above reactions can be carried out under known reaction conditions, in the absence or usually in the presence of solvents or diluents, depending on the type of reaction and / or reactants at reduced or elevated temperature, for example in the temperature range from about -10 ° C. to about 150 ° C, under atmospheric pressure or in a closed vessel, optionally under pressure, and / or in an inert atmosphere, for example under a nitrogen atmosphere. Compounds of the formula I obtainable by the process can be converted into other compounds of the formula in a manner known per se. for example by converting substituents contained in compounds of the formula into other substituents encompassed by formula 1.

0089For example, an esterified carboxy group -COOR can be converted into another ester group by transesterification. Appropriate alcohol compounds which have a boiling point which is significantly higher than that of the alcohol of the esterified group in the compound of formula 1 to be converted are preferably used, and the reaction is carried out, for example in an excess of the hydroxy compound and / or an inert organic solvent, preferably also boiling well above the alcohol of the esterified group, preferably in the presence of a catalyst, for example an alkali metal lower alkanolate. such as sodium or potassium methanolate or ethanolate, in the heat and usually by distilling off the alcohol released

0090Compounds of the formula I. in which Y represents the group - (C = 0) - can be converted in a conventional manner by reduction into compounds of the formula I in which Y, optionally via the group -CHOH- as an intermediate stage, the group - CH₂- represents, where any unsaturated groups present are converted into the saturated or triple bonds group into those with double bonds.

0091For the reduction, one can use, for example, catalytically activated hydrogen, for example hydrogen in the presence of a hydrogenation catalyst, such as a noble metal catalyst, for example platinum or palladium, and also Raney nickel. A suitable hydride reducing agent, such as diborane, can also be used. or sodium borohydride, also lithium aluminum hydride in a suitable solvent. about such an ethereal character, such as tetrahydrofuran, can be used.

0092Furthermore, compounds of formula I. in which R and / or Ar₁ represent suitable azaheterocyclic groups. whose ring nitrogen atoms can be N-oxidized, convert them into corresponding N-oxides. The oxidation can be carried out in a manner known per se. eg by treatment with organic peracids. such as lower alkanoic acids or arenic acids, such as optionally suitably substituted perbenzoic acids. eg peracetic or 3-chloroperbenzoic acid. preferably at room temperature or slightly above the reaction temperature. or with aqueous hydrogen peroxide, for example at temperatures of up to 100 C. in the presence or absence of lower alkanoic acids, for example acetic acid. When using peracids in particular, care must be taken to ensure that overoxidation cannot occur due to an excessively long reaction time.

0093Depending on the reaction conditions, compounds of the formula I can be obtained in free form or in the form of salts.

0094Acid addition salts obtained in this way can be obtained in a manner known per se. eg by treating with a base. such as an alkali metal hydroxide, into which free compounds or converted into other salts, for example by treatment with suitable acids or derivatives thereof. Free compounds of the formula I obtained can be converted into their salts, for example by treatment with acids or corresponding anion exchangers.

0095As a result of the close relationship between the compounds of formula 1 in free form and in the form of salts, the preceding and following, the free compounds or their salts are also to be understood as meaningful and expedient, if appropriate, also the corresponding salts or free compounds.

0096The compounds of formula I, including their salts, can also be obtained in the form of their hydrates, or their crystals can include, for example, the solvent used for the crystallization. Depending on the process reaction and / or the nature of the starting materials, the compounds of the formula 1 can be obtained in the form of racemate mixtures, racemates or optical antipodes.

0097Racemic mixtures obtained can be separated into the pure racemates or diastereomers in a known manner on the basis of the physico-chemical differences between the racemates, for example by chromatography and / or fractional crystallization.

0098Racemates can be broken down into the optical antipodes by methods known per se, for example by recrystallization from an optically active solvent, with the aid of suitable microorganisms or by reacting a compound of the formula I with salt-forming, for example basic, properties with an optically active, salt-forming agents, such as an optically active acid, and separating the mixtures of salts thus obtained, e.g. due to their different solubilities, into the diastereomeric salts from which the antipodes can be released, for example by treatment with a base.

0099Optical antipodes of neutral compounds of the formula I can also be used, for example, in accordance with process c) using an optically active acid of the formula V (Aco means carboxy, Ac₁° is esterified or amidated carboxy) obtained, for example from the corresponding racemic acid in a conventional manner, for example by salt formation with an optically active base. Separation of the diastereomeric salts and release of the optically active acid and their conversion into a corresponding to formula 1, the group -COOR₁- contains containing connection.

0100It is also possible, for example, to transesterify compounds of the formula I with the group -COORi- using an optically active alcohol using the process described above and to separate the diastereomer mixture thus obtained, for example by means of fractional crystallization, into the antipodes.

0101The pharmacologically more active diastereomer or the more active antipodes is advantageously isolated from a mixture of diastereomers or racemate.

0102The 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 steps or uses a starting material in the form of a derivative, for example salt, and / or its racemates or antipodes, or forms under the reaction conditions.

0103Salts of starting materials with salt-forming basic properties are, for example, those with mineral acids, such as hydrochloric acid, sulfuric acid or phosphoric acid. or with organic acids, eg acetic acid.

0104In the processes of the present invention, those starting materials are preferably used which lead to the compounds described at the outset as being particularly valuable. New starting materials and intermediates as well as processes for their production also form a subject of the present invention.

0105The invention also relates to the use of the compounds of the formula I or of pharmaceutically acceptable salts of such compounds with salt-forming properties, in particular as pharmacological, primarily as coronary dilators and antihypertensives for the treatment of cardiovascular disease states such as angina pectoris and their consequences. central and peripheral circulatory disorders, high blood pressure, arrhythmias and heart failure effective connections. They can be, preferably in the form of pharmaceutical preparations, in a process for the prophylactic and / or therapeutic treatment of the animal and human body, in particular for the treatment of cardiovascular disease states such as angina pectoris and its consequences, vascular spasms. use high blood pressure and heart failure.

0106The dosage of the active ingredient, which is administered alone or together with the usual carrier and auxiliary material, depends on the species to be treated, its age and individual condition. and the mode of administration. The daily doses are, for example, for mammals with a body weight of approximately 70 kg, depending on the type of disease, individual condition and age, preferably between approximately 10 and 100 mg, in particular between approximately 20 mg and approximately 80 mg. and especially from about 25 mg to about 75 mg when administered orally.

0107The invention further relates to pharmaceutical preparations which contain compounds of the formula I or pharmaceutically usable salts of such compounds having salt-forming properties as active ingredients, and to processes for their preparation.

0108The pharmaceutical preparations according to the invention are those for enteral, such as peroral or rectal, further for sublingual. as well as for parenteral administration to warm-blooded animals. Corresponding dosage unit forms. in particular for oral and / or sublingual administration, for example coated tablets. Tablets or capsules preferably contain from about 10 mg to about 100 mg, in particular from about 20 mg to about 80 mg of a compound of the formula or a pharmaceutically acceptable salt of a corresponding compound capable of salt formation together with pharmaceutically usable excipients.

0109Suitable carriers are in particular fillers, such as sugar. e.g. lactose. Sucrose, mannitol or sorbitol. Cellulose preparations and / or calcium phosphates. eg tricalcium phosphate or calcium hydrogen phosphate. also binders, such as starch paste using, for example, maize. Wheat, rice or potato starch. Gelatin, tragacanth. Methyl cellulose and / or. if wanted. Disintegrants, such as the above-mentioned starches, also carboxymethyl starch. cross-linked polyvinyl pyrrolidone, agar. Alginic acid or a salt thereof, such as sodium alginate. Aids are primarily flow regulators and lubricants, such as silica. Talk. Stearic acid or salts thereof, with magnesium or calcium stearate. and / or polyethylene glycol. Dragee kernels can be provided with suitable, optionally gastric juice-resistant coatings, including concentrated sugar solutions, which may contain arabic gum, talc. Contain polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings. Solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate, are used. The tablets or dragee coatings can contain dyes or pigments, for example for identification or for labeling different doses of active ingredient. Other pharmaceutical preparations that can be used orally are plug-in capsules made of gelatin, and soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can contain the active ingredient in the form of granules. e.g. in a mixture with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols. dissolved or suspended, stabilizers may also be added. Preferred are, inter alia Capsules that can be easily chewed in order to achieve the quickest possible effect through sublingual absorption of the active ingredient, and can also be swallowed whole.

0110Suitable rectally applicable pharmaceutical preparations are, for example, suppositories which consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Gelatin rectal capsules can also be used, which contain a combination of the active ingredient with a base material; come as basic materials, for example liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

0111Aqueous solutions of an active ingredient in water-soluble form are primarily suitable for parenteral administration. For example, a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions. whereby suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters. eg ethyl oleate, or trigylceride used, or aqueous injection suspensions containing viscosity-increasing substances, eg Contain sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally stabilizers.

0112The pharmaceutical preparations of the present invention can be produced in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes. So you can get pharmaceutical preparations for oral use. by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and the mixture or granules, if desired or necessary. after the addition of suitable additives, processed into tablets or coated tablets.

0113The following examples illustrate the invention described above; however, they are not intended to limit the scope in any way. Temperatures are given in degrees Celsius.

0114Example 1: A mixture of 1.8 g of oxalyl chloride in 4.5 ml of acetonitrile is added dropwise to a mixture of 12 ml of dimethylformamide and 7 ml of acetonitrile at -25 ° over the course of 15 minutes, the mixture is subsequently stirred at the same temperature for 15 minutes and then 3.15 g 1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid monomethyl ester was added and the suspension was stirred at -15 "for 20 minutes, a red solution is formed. A mixture of 3.1 g of 2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1-phenylethanol is then added. 9.5 ml of pyridine and 2 ml of dimethylformamide were added dropwise at -25 'and stirring was continued for 15 hours at room temperature. The reaction solution is poured onto a mixture of 2N aqueous sodium carbonate solution and ice and extracted exhaustively with ethyl acetate. The organic phase is with 2N sodium hydroxide solution. Water. 2N hydrochloric acid. Washed water and IN aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. The remaining oil is chromatographed on a medium pressure column with a mixture of methylene chloride / methanol 9: 1. after working up the 2,6-dimethyl-4- (3-nitrophenyte) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- (2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1 -phenyl] ethyl ester as a mixture of diastereomers in amorphous form. The connection is characterized by the following physical characteristics: 250 mHz FT-¹H-NMR (CDCI₃): 1.7 (m, 4H, 3,5-piperidyl-CH₂): 2.5 (m.2H; N-CH₂): 2.4 (d, 6H. DHP-CH₃); 2.6 (m.2H) and 2.9 (m.1H) and 3.05 (m.2H) 2.6-piperidyl-CH₂ and 4H-piperidyl): 3.7 (d.3H, COOCH₃); 5.2 (d, 1H, 4-dihydropyridyl-H); 5.8 (s, 1H-NH-); 5.9 (m, 1H, phenyl-CH-O-CO-); 6.9-8.2 (several m, 14H, phenyl-H).<chemistry id="chem0030" num="0030"><img file="EP0222702A2_D0036.tif" /></chemistry>

0115The 2- [4- (4-fluorobenzoyl) piperidin-1-yl] -1-phenylethanol used as the starting material is prepared as follows:<ul id="ul0003" list-style="none"><li>A mixture of 4- (4-fluorobenzoyl) piperidine, 2.9 g of styrene oxide and 80 ml of tetrahydrofuran is heated under reflux for 15 hours, the reaction solution is then evaporated and the residue is chromatographed on a flash column in a mixture of methylene chloride and methanol 98: 2 . The compound obtained after working up is further processed as such.</li></ul>

0116Example 2: According to the procedure described in Example 1, by reacting 3.37 g of 1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethyl-phenyl) pyridine-3,5-dicarboxylic acid monomethyl ester with 3, 1 g of 2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1-phenylethanol and, after working up there, the 2,6-dimethyl-4- (2-trifluoromethylphenyl) -1, Methyl 4-dihydropyridine-3-carboxylate-5-carboxylic acid - [2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1-phenyl] ethyl ester as a mixture of diastereomers in amorphous form. This connection is characterized by the following physical characteristics:<ul id="ul0004" list-style="none"><li>100 mHz 1H NMR (CDCI₃): 2.35 (d, 6H); 3.75 (d. 3H); 5.2 (d. 1H); 5.85 (s, 1H): 5.9 (m, 1H): 6.8-8.2 (m, 13H).</li></ul>

0117Example 3: According to the procedure in Example 1, the 5.0 g of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid monoethyl ester becomes 4.2 g of 2- (4-phenylpiperidine -1-yl) -1-phenylethanol, 1.96 ml oxal chloride, 20 ml DMF, 28 ml acetonitrile and 10 ml pyridine or 1.4 dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3 -carboxylic acid methyl ester-5- [2- (4-phenlypiperidin-1-yl) -1-phenyl] ethyl ester, which is purified by flash chromatography in a mixture of methylene chloride / methanol 95: 5 and is obtained in an amorphous form.

0118250 mHz FT-¹H-NMR (CDCI₃), TMS: 2.4 (d, 6H, DHP-CH₃): 3.7 (d, 3H, COOCH₃; 5.22 (s, 1H, 4-DHP-H; 5.7 (s, 1H, NH): 5.9 + 6.0 (2m, 1H, phenyl-CH-O-CO); 6.95-8.15 (several m, 14H, phenyl-H ).<chemistry id="chem0031" num="0031"><img file="EP0222702A2_D0037.tif" /></chemistry>

0119Example 4: Analogously to the process described in the description and illustrated in Examples 1 to 13, the following compounds of the formula I or their salts, in particular their pharmaceutically usable, non-toxic acid addition salts, can also be prepared starting from corresponding starting materials or their salts:<ul id="ul0005" list-style="none"><li>a) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [6- [4- (p-fluorobenzoyl) piperidin-1-yl] -1 -phenyl] -n-hexyl ester; NMR data 100 mHz,¹H NMR CDCI₃: 2.4 (d, 6H); 3.7 (d. 3H); 5.2 (d. 1H); 5.8 (s, 1H); 5.9 (m. 1H); 6.8-8.2 (m, 13H).</li><li>b) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester- [2-4- (p-chlorobenzoyl) piperidin-1-yl] -1-phenyl] ethyl ester ; NMR data 100 mHz,¹H-NMR (CDCl₃: 2.3 (d, 6H); 3.75 (d. 3H); 5.2 (d, 1H); 5.8 (s, 1H); 5.9 (m. 1H); 6.8-8.2 (m, 13H).</li><li>c) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid - [2- [4- (2-thenoyl) piperidin-1-yl] - 1-phenyl] ethyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.25 (d, 6H); 3.8 (d. 3H); 5.1 (d. 1H); 5.7 (s, 1H); 5.8 (m, 1H); 7.1-8.2 (m, 12H).</li><li>d) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid - [2- [4- (p-fluorophenyl) piperidin-1-yl] - 1-phenyl] ethyl ester: NMR data, 100 mHz. ¹H-NMR (CDCl₃): 2.35 (d, 6H); 3.7 (d. 3H); 5.1 (d. 1H); 5.6 (s, 1H); 5.9 (m. 1H); 6.8-8.2 (m.14H).</li><li>e) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [2- [4- (p-fluorophenyl) hydroxymethylene-piperidin-1-yl] -1-phenyl] ethyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.4 (d, 6H); 3.65 (d. 3H); 5.15 (d. 1H); 5.65 (s, 1H); 5.85 (m, 1H); 6.8-8.2 (m, 14H).</li><li>f) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [2- [4- (p-fluorobenzyl) piperidin-1-yl] -1 -phenyl] ethyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.45 (d, 6H); 3.7 (d. 3H); 5.1 (d. 1H); 5.7 (s, 1H); 5.9 (m. 1H); 6.8-8.2 (m, 14H).</li><li>g) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1 - (p-methoxyphenyl)] - ethyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.35 (d, 6H); 3.75 (d, 3H): 5.15 (d, 1H); 5.6 (s, 1H); 5.75 (m, 1H); 6.8-8.2 (m, 12H).</li><li>h) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid - [2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1- (p-cyanophenyl)] - ethyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.3 (d, 6H); 3.8 (d. 3H); 5.2 (d. 1H); 5.75 (s, 1H); 5.9 (m. 1H); 6.8-8.2 (m, 12H).</li><li>i) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1- ( p-methylphenyl] ethyl ester; NMR data, 100 mHz, ¹H-NMR (CDCl₃): 2.35 (d, 6H); 3.7 (d. 3H); 5.1 (d. 1H); 5.65 (s, 1H); 5.85 (m, 1H); 6.8-8.2 (m, 12H).</li><li>j) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1 - (p-chlorophenyl)] - ethyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.45 (d, 6H); 3.85 (d. 3H); 5.05 (d. 1H); 5.8 (s, 1H); 5.85 (m, 1H); 6.8-8.2 (m, 12H).</li><li>k) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1 - (p-trifluoromethylphenyl)] - ethyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃: 2.45 (d, 6H); 3.7 (d. 3H); 5.15 (d. 1H); 5.6 (s, 1H); 5.75 (m, 1H); 6.8-8.2 (m, 12H).</li><li>I) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [2- [4- (p-fluorobenzoyl) piperidine - 1-yl] - 1-phenyl] propyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.4 (d, 6H); 3.65 (d. 3H); 5.2 (d. 1H); 5.75 (s, 1H); 5.8 (m, 1H); 6.8-8.2 (m, 13H).</li><li>m) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid - [4- [4- (p-fluorobenzoyl) piperidin-1-yl] - 1-phenyl] butyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.35 (d, 6H); 3.8 (d. 3H); 5.1 (d. 1H); 5.6 (s, 1H); 5.9 (m. 1H); 6.8-8.2 (m, 13H).</li><li>n) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid - [2- [4- (p-fluorobenzoyl) piperidin-1-yl] - 2-phenyl] ethyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.3 (d, 6H); 3.65 (d. 3H); 5.15 (s, 1H); 5.7 (m, 1H); 6.8-8.2 (m, 13H).</li><li>o) 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid - [3- [4- (p-fluorobenzoyl) piperidin-1-yl] - 3-phenyl] propyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.45 (d, 6H); 3.7 (d. 3H); 5.2 (d. 1H); 5.7 (s, 1H); 5.85 (m, 1H); 6.8-8.2 (m, 13H).</li><li>p) 2,6-Dimethyl-4- (3-trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1 -phenyl] ethyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.4 (d, 6H); 3.8 (d. 3H); 5.3 (d. 1H); 5.8 (s, 1H): 5.95 (m, 1H); 6.8-8.2 (m, 1H).</li><li>q) 2,6-Dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid - [2- [4- (p-fluorobenzoyl) piperidin-1-yl] - 1-phenyl] ethyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.45 (d, 6H); 3.7 (d. 3H); 5.25 (d. 1H); 5.8 (s, 1H); 5.85 (m, 1H); 6.8-8.2 (m, 12H).</li><li>r) 2,6-Dimethyl-4- (2-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid- [2- [4- (p-fluorobenzoyl) piperidin-1-yl] -1 -phenyl] ethyl ester; NMR data, 100 mHz,¹H-NMR (CDCl₃): 2.35 (d, 6H); 3.75 (d. 3H); 5.2 (d. 1H); 5.8 (s, 1H); 5.9 (m, 1H); 6.8-8.2 (m, 13H).</li></ul>

0120Example 5: Tablets containing 20 mg of active substance are manufactured in the following composition in the usual way:

Composition:

0121<tables id="tabl0001" num="0001"><img file="EP0222702A2_D0038.tif" /></tables> Manufacturing:<ul id="ul0006" list-style="none"><li>The active ingredient is mixed with a portion of the wheat starch, milk sugar and colloidal silica and the mixture is passed through a sieve. Another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath and the powder mixture is kneaded with this paste until a weak plastic mass has formed.</li></ul>

0122The plastic mass is pressed through a sieve with a mesh size of approx. 3 mm, dried and the dry granules obtained are again passed through a sieve. Then the remaining wheat starch, talc and magnesium stearate are mixed in and the mixture is compressed into tablets of 145 mg weight with a notch.

0123Example 6: Tablets containing 1 mg of active substance are produced in the following composition in the usual way:

Composition:

0124<tables id="tabl0002" num="0002"><img file="EP0222702A2_D0039.tif" /></tables>

0125Manufacturing:<ul id="ul0007" list-style="none"><li>The active ingredient is mixed with part of the wheat starch, milk sugar and colloidal silica, and the mixture is passed through a sieve. Another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath and the powder mixture is kneaded with this paste until a weak plastic mass has formed.</li></ul>

0126The plastic mass is pressed through a sieve with a mesh size of approx. 3 mm, dried and the dry granules obtained are again passed through a sieve. Then the remaining wheat starch, talc and magnesium stearate are mixed in and the mixture is compressed into tablets weighing 126 g with a notch.

0127Example 7: Capsules containing 10 mg of active substance are produced in the usual way as follows:

Composition:

0128<tables id="tabl0003" num="0003"><img file="EP0222702A2_D0040.tif" /></tables>

0129Manufacturing:<ul id="ul0008" list-style="none"><li>The active substance is intimately mixed with talc and colloidal silica, the mixture is passed through a sieve with a mesh size of 0.5 mm and this is filled into portions of 11 mg each in hard gelatin capsules of a suitable size.</li></ul>

0130Example 8: Instead of the compounds used as active substance in Examples 4 to 6, the compounds of the formula mentioned in Examples 2 to 4 or their pharmaceutically acceptable, non-toxic acid addition salts can also be used as active ingredients in tablets, tablet, capsules etc. .