DD228547A5 - PROCESS FOR PREPARING NEW AMID COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of new amide compounds for use as medicaments. The aim of the invention is the provision of novel compounds with valuable pharmacological properties, in particular with antihypertensive and hypotensive action for the treatment of, for example, angina pectoris, hypertension, arrhythmias, circulatory disorders and other diseases. According to the invention, compounds of the formula I are prepared in which, for example: n is 1, 2 or 3, Ar is a carbocyclic or heterocyclic aryl test, Ac is the acyl radical of an acid, Z is a radical -OR 7 or -NR 8 R 9, R 1 is hydrogen, unsubstituted or substituted lower alkyl and the like. a, R2 and R3 independently of one another hydrogen, unsubstituted or substituted lower alkyl u. a, R4 is hydrogen or lower alkyl, R5 and R6 independently of one another are hydrogen, unsubstituted or substituted lower alkyl and the like. a, R7, R8 and R9 independently of one another are hydrogen, unsubstituted or substituted alkyl or a carbocyclic or heterocyclic aryl radical.

Description

Berlin, March 11, 1985 AP C 07 D / 269 486/4 64 569/12

Process for the preparation of new amide compounds

Field of application of the invention

The invention relates to novel amide compounds and their salts, to processes for their preparation, to pharmaceutical preparations containing such compounds, and to their use for the preparation of pharmaceutical preparations or as pharmacologically active compounds. The compounds according to the invention are used as medicaments, for example for the treatment of angina pectoris, hypertension and other cardiovascular diseases.

Characteristic of the known technical solutions

There is no information available on which compounds have been used to treat angina pectoris, hypertension and other cardiovascular diseases. There is also no information available about processes for the preparation of compounds of the formula I.

Object of the invention

The aim of the invention is the provision of novel compounds with valuable pharmacological properties, in particular with antihypertensive and hypotensive action,

- la -

which are suitable for the treatment of angina pectoris, hypertension, arrhythmias, cerebral and peripheral circulatory disorders, migraine, vascular spasms or heart failure and other indications.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

Erfindungsgeraäß be substituted 3-Carbamoy1-1,4-dihydropyridine compounds of the formula I.

Ar

ΐ ή '

O ^R 4 ^R 5 -C Il. ! I l! c- -N - - C - O I R-

R.

wherein η is 1, 2 or 3, Ar is a carbocyclic or heterocyclic aryl radical, Ac is the acyl radical of an acid, Z is a radical -OR ₇ or

-NR ₀ R-, R "is hydrogen, unsubstituted or substioy χ

tuiertes lower alkyl, a carbocyclic or heterocyclic aryl radical or free, etherified or esterified hydroxy, R ₂ and R _{3 are} independently hydrogen, unsubstituted or substituted lower alkyl, formyl or functionally modified formyl, carboxy

-Ib-

or functionally modified carboxy, a carbocyclic or heterocyclic aryl radical or unsubstituted, mono- or disubstituted amino, R. hydrogen or lower alkyl, R ₅ and R _g

independently of one another represent hydrogen, unsubstituted or substituted lower alkyl or a carbocyclic or heterocyclic aryl radical, R, R and R independently of one another represent hydrogen, unsubstituted or substituted alkyl or a carbocyclic or heterocyclic aryl radical, in which R ₁ and R "together or R and R together unsubstituted or substituted lower alkylene in which a carbon atom is optionally replaced by a heteroatom, wherein

R, and R _r together, as well as R. and R, together and / or R ₀ and R_ 4 5 5 6 8 9

together, independently of one another, may denote unsubstituted or substituted lower alkylene in which a carbon atom may be replaced by a heteroatom, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds having a salt-forming group, processes for the preparation thereof Compounds containing such compounds pharmaceutical agents and their use for the preparation of pharmaceutical preparations or as pharmacologically effective Verb indungen.

Unless otherwise defined, the definitions used hereinbefore and hereinafter have the following meanings:

The term "lower" means that correspondingly defined groups or compounds contain up to and including 7, preferably up to and including 4 carbon atoms.

Substituted radicals may contain one or more, identical or different substituents; these may substitute any suitable position.

In the above formula I, η is primarily 1, but may also be 2 or 3. If η is 2 or 3, then they are multiply occurring

Radicals R ,, R _r and R _{r are} each independently. 4 j o

A carbocyclic or heterocyclic aryl radical is primarily a corresponding monocyclic radical, but may also be a bi- or polycyclic, carbocyclic or heterocyclic radical having aromatic properties.

Carbocyclic radicals of this type are in particular phenyl, furthermore naphthyl, e.g. 1- or 2-naphthyl.

Heterocyclic aryl radicals are preferably corresponding monocyclic radicals, but may also be corresponding bi- or polycyclic radicals, the latter being able to consist of a plurality of heterocyclic rings, or of one or more heterocyclic rings having one or more fused carbocyclic rings, in particular one or more fused benzo rings. The usually present heterocyclic radicals, 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, an oxygen atom. or 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-ring carbon atom of the 1,4-dihydro-pyridine ring via a ring carbon atom.

Monocyclic five-membered heteroaryl radicals are e.g. corresponding monoaza-, diaza-, triaza-, tetraza-, monooxa-, tnonothia-, oxaza-, oxadiazd-, 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, for example corresponding monoaza-, diaza- or triazacyclic radicals, such as

Pyridyl, 'pyridazinyl, pyrimidinyl, pyrazinyl or Triazinylreste and. Bicyclic heteroaryl radicals are especially monocyclic ^ Heteroarylreste with fused benzo ring; the hetero ring may be five- or six-membered, the five-membered heteroaryl group e.g. a monoaza-, diaza-, monooxa-, monothia-, oxaza-, thiaza-, oxadiaza- or thiadiazacyclic residue, and the six-membered heteroaryl residue e.g. a monoaza- or a diazacyclic heteroaryl radical. Such bicyclic groups are e.g. Indolyl, isoindolyl, benzimidazolyl, benzofurany1, benzothienyl, benzthiazolyl, benzoxadiazolyl, benzthiadiazolyl, quinolinyl or isoquinolinyl radicals.

The carbocyclic and heterocyclic aryl radicals Ar may be unsubstituted or substituted, it being possible for ring carbon atoms in the first place and ring nitrogen atoms to be substituted in the first place. Substituents of ring carbon atoms include i.a. optionally substituted hydrocarbon radicals, such as corresponding aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, cycloalkyl, cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, phenyl-lower alkylthio and / or phenyl-lower alkyloxy, where substituents of such hydrocarbon radicals, in particular lower alkyl, phenyl, Phenylniederalkyl, Phenylniederalkylthio and / or Phenylniederalkoxy, eg optionally etherified or esterified hydroxy groups, such as hydroxy, lower alkoxy,

Lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy or halogen, and / or optionally functionally modified carboxy such as carboxy, esterified carboxy, e.g. Lower alkoxycarbonyl, amidated carboxy such as carbamoyl, N-lower alkylcarbamoyl or N, N-di-lower alkylcarbamoyl, or cyano. In addition, cyclic substituents, in particular phenyl, may also be lower alkyl, optionally substituted, e.g. as indicated, may be substituted as substituents. Further substituents of aryl radicals Ar are, for example,

if etherified or esterified hydroxy groups, such as hydroxy, lower alkoxy, haloalkoxy, lower alkenyloxy, halo-lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy or halo nitro, optionally substituted amino, such as amino, lower alkylamino, di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkylamino, lower alkyleneamino, oxanoweralkyleneamino, thia-lower alkylamino or Azaniederalkylenamino, wherein the aza nitrogen is unsubstituted or, for example by optionally, e.g. As described above, substituted lower alkyl, phenyl or Pheiiylniederalkyl may be substituted, or acylamino, e.g. Lower alkanoylamino, azido, acyl, such as lower alkanoyl, or optionally, functionally modified carboxy, such as carboxy, esterified carboxy, e.g. Lower-caseoxycarbonyl or amidated carboxy, such as carbamoyl, N-lower-alkylcarbamoyl or Ν, Ν-di-lower alkylcarbamoyl, or cyano, optionally functionally modified radical, such as sulfo or aminosulfonyl, and / or etherified mercapto, which may optionally be oxidized, such as 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 or lower alkoxycarbonyl, furthermore hydroxy or oxido.

Heterocyclic aryl radicals Ar can be e.g. depending on the nature of the substituents in various tautomeric forms.

Partially saturated five- or six-membered monoazo, diaza or triaza heteroaryl radicals are e.g. Dihydropyrrolyl, dihydroimidazolyl, dihydropyridinyl, dihydropyrimidinyl or tetrahydrotriazinyl. Examples of such radicals with oxo substituents are 2-0xo-l, 2-dihydro-lpyrrolinyl, 2-oxo-l, 2-dihydro-4-pyrimidinyl or 5,6-dioxo-l, 4,5,6-tetrahydro -l, 2,4-triazine-3-yl. A very saturated heteroaryl radical corresponds to heterocyclyl. Five- or six-membered monoaza- or diaza-heterocyclyl is e.g. Pyrrolidinyl, piperidinyl, imidazolidinyl or piperazinyl. Examples of such radicals having oxo substituents are 2-pyrrolidinon-1-yl, 2-piperidinon-1-yl and especially 2-imidazolidinon-1-yl.

An acyl radical Ac may be the corresponding radical of a carboxylic acid, especially lower alkanoyl, furthermore unsubstituted or substituted, e.g. Lower alkyl, lower alkoxy ,. Nitro and / or halogen containing benzoyl, or an organic sulfonic acid, especially lower alkyl sulfonyl or unsubstituted or substituted, e.g. Lower alkyl, lower alkoxy, nitro and / or halogen-containing phenylsulfonyl represent. Acyl radicals Ac are, however, primarily acyl radicals of monoesters, and also monoamides of carbonic acid, such as especially unsubstituted or substituted, e.g. free or etherified hydroxy, such as lower alkoxy, or unsubstituted or substituted amino, e.g. amino as described above, and primarily disubstituted amino such as di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, or optionally substituted by oxygen, sulfur or unsubstituted or, e.g. lower alkylene amino interrupted by lower alkyl, substituted nitrogen, or an unsubstituted or e.g. phenyl, thienyl, furyl, pyrryl or pyridyl radical-containing lower alkoxycarbonyl, lower alkenyloxy or lower alkynyloxycarbonyl, but also N-unsubstituted or N-mono- or N, N-disubstituted carbamoyl, which are substituted by lower alkyl, lower alkoxy, nitro and / or halogen such as N-lower alkylcarbamoyl, Ν, Ν-di-lower alkylcarbamoyl, N-hydroxcarbamoyl, or optionally in the lower alkyl part by oxygen, sulfur or unsubstituted or, for example lower alkyl, substituted nitrogen interrupted Ν, Ν-lower alkylene-carbamoyl. Furthermore, acyl radicals Ac also include acyl radicals of cyclic carbonic acid derivatives, such as. 5-tetrazolyl or unsubstituted or substituted by lower alkyl or phenyl 4,5-dihydro-2'-oxazolyl or 5,6-dihydro-4H-l, 3-oxazin-2-yl.

Alkyl preferably contains 1 to 12 carbon atoms, e.g. n-decyl, and is primarily lower alkyl. Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl or tert-butyl, furthermore n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl or n-heptyl.

A substituted lower alkyl radical R contains as substituents e.g. unsubstituted or in particular mono- or disubstituted amino,

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lower alkylamino, di-lower alkylamino, N-lower-alkyl-N-phenyl-lower alkyl-amino or optionally substituted by oxygen, sulfur or unsubstituted or, e.g. lower alkylene amino interrupted by lower alkyl or lower alkanoyl, substituted nitrogen, such substituent being preferably separated from the ring nitrogen atom by at least 2 carbon atoms. It may also be e.g. by carboxy or functionally modified carboxy, e.g. Carboxymethyl, or by lower alkoxy, with such lower alkoxy being preferred, which in turn is substituted by lower alkoxy, e.g. 2-methoxyethoxymethyl, or by phenyl, which in turn optionally contains lower alkyl, lower alkoxy, halogen and / or nitro as substituents, e.g. Benzyl, or by N-pyrrolyl, N-imidazolyl, N-pyrazolyl, N-indolyl or N-isoindolyl, e.g. N-imidazolylmethyl be substituted.

Functionally modified carboxy is e.g. esterified carboxy, e.g. Lower alkoxycarbonyl, or amidated carboxy, e.g. Carbamoyl, N-lower-alkyl-carbamoyl or Ν, Ν-di-lower alkyl-carbamoyl, or cyano. Functionally modified carboxy as meaning of R and R is preferably cyano.

In the case of an amino-lower-alkyl radical Rc which is substituted by functionally modified carboxy, the latter is preferably carbamoyl or C-amidino [-C (NHNH) -NH].

Phenyl-lower alkyl is e.g. Benzyl or 1- or 2-phenylethyl. It may be present in the phenyl ring e.g. be substituted by free or etherified hydroxy, lower alkyl, nitro, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino and / or halogen.

Lower alkylene contains, for example, two to seven, in particular three to five chain carbon atoms and is, inter alia, 1,3-propylene or 1,4-butylene. Lower alkylene in which one carbon atom is replaced by a heteroatom is, for example, oxa, thia or azido lower alkyl, lower alkylene, aza, oxa or thiene lower alkylene, formed from the radicals R "and R together, is preferably C" -C lower alkylene ₅ C ^ -C, -Aza-, C -C, -Oxa- or

C 1 -C 3 -thio lower alkylene, in particular C 1 -C 3-lower alkylene, C 1 -C 8 -oxa or C 2 -A 3 -alkylene, in particular 1,5-pentylene, 3α-oxa or 3 -zaza-1, 5-pentylene and above all 3-aza-1, 5-pentylene.

Lower alkylene, aza-, oxa or Thianiederalkylen, formed from the radicals R and R together, is preferably lower alkylene with

J O

2 to 5 chain carbon atoms, aza, oxa or thia-lower alkylene having in each case 3 or 4 chain carbon atoms, in particular C -C-lower alkylene or C, -Azaniederalkylen and primarily 1,5-pentylene.

Lower alkylene, aza, oxa or thia-lower alkylene, formed from the radicals R and R together, is preferably C 1 -C 4 -loweralcylene, C 2 -C 4 -oxa or C 3 -C 3 -thio lower alkyl, in particular 1,3-propylene, Oxa- or 2-thia-l, 3-propylene and primarily 1,3-propylene.

Lower alkylene, in which a carbon atom is optionally replaced by a heteroatom, formed from the radicals R ₁ and R together or R ₁ and R taken together, is preferably C -C-lower alkylene, wherein the with the C2 or C6 carbon atom of the 1, Optionally substituted by an oxygen, sulfur or a nitrogen atom which is substituted by hydrogen or lower alkyl, in particular C 1 -C 4 -alkoxyalkylene or 3-oxa, 3-thia or 3-aza-4-dihydropyridine ring. l, 3-propylene - the numbering of the C atoms starts here on the nitrogen atom -, and especially 1,2-ethylene, 1,3-propylene or 1,4-butylene.

Lower alkylene, oxa, thia and azane-lower alkylene radicals can be e.g. by hydroxy, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, halogen, carboxy and / or functionally modified carboxy, on the aza nitrogen also be substituted by lower alkanoyl, phenyl or phenyl-lower alkyl or in particular by lower alkyl. leftovers

such as C _n -C -A za-, C -Oxa or C ₀ -C thia-lower alkylene contain 3 4 4 3 4

the indicated number of carbon atoms and additionally the cited heteroatom.

Naphthyl may e.g. Be 1- or 2-naphthyl.

Pyrryl is e.g. 2- or 3-pyrryl, pyrazolyl e.g. 3- or 4-pyrazolyl, imidazolyl e.g. 2- or 4-imidazolyl, triazolyl e.g. 1,3,5-1H-triazol-2-yl or 1, 3,4-triazol-2-yl, and tetrazolyl, e.g. 1,2,3,4-1H-tetrazol-5-yl, while furyl is 2- or 3-furyl and thienyl is 2- or 3-thienyl. Isoxazolyl is e.g. 3-isoxazolyl, oxazolyl e.g. 2- or 4-oxazolyl, oxadiazolyl e.g. 1, 3,4-oxadiazol-2-yl, isothiazolyl e.g. 3-isothiazolyl, thiazolyl, 2- or 4-thiazolyl, and thiadiazolyl e.g. 1,3,4-thiadiazol-2-yl. Benzoxadiazolyl and benzthiadiazolyl are preferably 2, i, 3-benzoxadiazol-4-yl and 2, l, 3-benzthiadiazol-4-yl.

Pyridyl is 2-, 3- or 4-pyridyl, pyridazinyl e.g. 3-pyridazinyl, pyrimidinyl is 2-, 4- or 5-pyrimidinyl, pyrazinyl is 2-pyrazinyl, and triazinyl is e.g. l, 3,5-triazin-2-yl.

Indolyl is e.g. 2-, 3- or 5-indolyl, isoindolyl e.g. 1-isoindolyl, benzimidazolyl e.g. 2- or 5-benzimidazolyl, benzofuranyl e.g. 2- or 3-benzofuranyl, benzothienyl e.g. 3-benzothienyl, benzothiazolyl, e.g. 2-benzthiazolyl, quinolinyl e.g. 2- or 4-quinolinyl, and isoquinolinyl e.g. 1-isoquinolinyl.

Lower alkenyl is e.g. Allyl or methallyl, and lower alkynyl e.g. Propargyl.

Cycloalkyl preferably has 5 to 7 ring carbon atoms and is e.g. Cyclopentyl or cyclohexyl, while cycloalkyl-lower alkyl e.g. Cyclopropylmethyl, cyclcpentylmethyl or cyclohexylmethyl.

Etherified hydroxy is primarily lower alkoxy, further e.g. Phenyl, lower alkoxy, aryloxy or heteroaryloxy.

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Acyloxy is e.g. hydroxy substituted by one of the above-defined acyl radicals Ac, preferably benzoyloxy, which is optionally substituted by hydroxy, lower alkoxy, halogen, lower alkyl and / or nitro, and in particular lower alkanoyloxy.

Lower alkoxy is 2.3. for methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy.

In a lower alkoxy-lower alkoxy group, the terminal lower alkoxy group is preferably separated from the linking carbon atom by more than one carbon atom; such radicals are e.g. 2-methoxy-ethoxy or 2-ethoxy-ethoxy.

Lower alkenyloxy is, for example, allyloxy or methallyloxy, and Halogenniederalkenyloxy _s may include one or more halogen atoms, the latter preferably having an atomic number of up to and including 35, and are in particular fluorine and chlorine, is for example 1,2-dichloro-vinyloxy.

In a halo-lower alkoxy group, one or more halogen atoms, preferably having an atomic number up to and including 35 and especially representing fluorine or chlorine, may be present; such radicals are e.g. 1,1,2-trifluoro-2-chloroethoxy, or preferably difluoromethoxy.

Lower alkynyloxy is e.g. Propargyloxy, while lower alkylenedioxy e.g. Methylenedioxy or ethylenedioxy means.

Lower alkanoyloxy is e.g. Acetyloxy, propionyloxy or pivaloyloxy.

Halo-substituted lower alkyl is e.g. Trifluoromethyl, 1,1,2-trifluoro-2-chloro-ethyl or chloromethyl.

Halogen preferably has an atomic number up to and including 35 and is especially fluorine or chlorine, but also bromine, but may also be iodine.

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Lower alkoxycarbonyl is e.g. Methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl or tert-butyloxycarbonyl.

N-lower alkylcarbamoyl is e.g. N-methyl-carbamoyl or N-ethyl-carbamoyl, while Ν, Ν-di-lower alkyl-carbamoyl e.g. Ν, Ν-dimethylcarbamoyl or Ν, Ν-diethyl-carbamoyl.

Lower alkylamino is e.g. N-methylamino, N-ethylamino, N-n-propylamino or N-isopropylamino.

Diniederalkylamino is e.g. N, N-dimethylamino, N -ethyl-N-methylamino or Ν, Ν-diethylamino, while N-lower alkyl-N-phenyl-lower alkylamino e.g. N-benzyl-N-methylamino or N-methyl-N- (2-phenylethyl) -amino.

Lower alkylene amino contains e.g. 2 to 7, preferably 4 or 5 ring carbon atoms and is e.g. Pyrrolidino or piperidino, while oxan-lower alkylene-amino e.g. Morpholino such as 4-morpholino (3-oxa-1, 5-pentyleneamino), thian-lower alkylene-amino, e.g. Thiomorpholines, such as 4-thiomorpholino, and optionally azasubstituted azanoweralkyleneamino, e.g. Piperazino, such as 1-piperazino (3-aza-l, 5-pentyleneamino), 4-methylpiperazino, 4-phenyl-piperazino, 4-benzyl-piperazino or 4- (2-phenylethyl) piperazino.

Acylamino is e.g. by one of the acyl radicals Ac as defined above substituted amino, preferably benzoylamino, which is optionally substituted by hydroxy, lower alkoxy, halogen, lower alkyl and / or nitro, and especially lower alkanoylamino.

Lower alkanoylamino is e.g. Acetylamino or propionylamino.

Acyl as such is e.g. one of the above-defined acyl radicals Ac, preferably benzoyl, which is optionally substituted as indicated for benzoylamino, and in particular lower alkanoyl, e.g. Formyl, acetyl, propionyl or pivaloyl. Further preferred acyl radicals are

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Furanylcarbonyl, thienylcarbonyl, pyrrylcarbonyl or pyridinylcarbonyl, and especially furan-2-ylcarbonyl.

Etherified mercapto is primarily lower alkylthio but also e.g. Phenylthio. Oxidized etherified mercapto is preferably lower alkylsulfinyl or lower alkylsulfonyl. Lower alkylthio is e.g. Methylthio, ethylthio, n -propylthio or isopropylthio, while lower alkylsulfine inyl e.g. Methylsulfinyl, and lower alkylsulfonyl e.g. Methylsulfonyl or ethylsulfonyl mean.

In an amino-lower alkyl group R., amino is preferably separated from the linking carbon atom by at least 2 carbon atoms; such radicals are primarily 2-disubstituted amino-lower alkyl such as 2-di-lower alkylaminoethyl, e.g. 2-dimethylaminoethyl or 2-diethylaminoethyl, 2-loweralkyleneaminoethyl, e.g. 2-pyrrolidino-ethyl or 2-piperidino-ethyl, 2- (4-morpholino) -ethyl, or 2- (4-lower alkylpiperazino) ethyl, ZoB. 2- (4-methylpiperazino) ethyl "

In 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 e.g. Hydroxy-lower alkoxycarbonyl, such as 2-hydroxyethoxycarbonyl or 2,3-dihydroxypropyloxycarbonyl, lower alkoxy-lower alkoxycarbonyl, e.g. 2-methoxyethoxycarbonyl, di-lower alkylamino-lower alkoxycarbonyl, e.g. 2-dimethyl-aminoethoxycarbonyl, 2-diethylaminoethoxycarbonyl or 3-dimethylaminopropyloxycarbonyl, lower alkyleneamino-lower alkoxycarbonyl, e.g. 2-pyrrolidinoethoxycarbonyl or 2-piperidinoethoxycarbonyl, morpholino-lower alkoxycarbonyl, e.g. 2- (4-morpholino) -ethoxycarbonyl, or 4-lower-alkyl-piperazino-lower alkoxycarbonyl, e.g. 2- (4-methylpiperazino) ethoxycarbonyl.

Phenyl-lower alkoxycarbonyl is e.g. Benzyloxycarbonyl or 2-phenylethoxy-carbonyl.

Ν, Ν-lower alkylene carbamoyl is e.g. Pyrrolidinocarbonyl or piperidinocarbonyl, where corresponding radicals in which the lower alkyl

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is interrupted by oxygen, sulfur or unsubstituted or substituted nitrogen, e.g. 4-morpholinocarbonyl, 4-thiomorpholino-carbonyl, 1-piperazinocarbonyl or 4-methyl-1-piperazino-carbonyl.

Salts of compounds of the invention are primarily pharmaceutically acceptable non-toxic salts, such as those of compounds of formula I having acidic groups, e.g. with a free carboxy or sulfo group. Such salts are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. Sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, wherein primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for the formation of salts come into question, such as lower alkylamines, eg Triethylamine, hydroxy = lower alkylamines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. A-aminobenzoic acid Z-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethyl-piperidine, cycloalkylamines, e.g. Dicyclohexylamine, or benzylamines, e.g. N, N'-dibenzyl-ethylenediamine, also pyridine-type bases, e.g. Pyridine, collidine or quinoline. Compounds of formula I with basic groups can be acid adiponite salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. Trifluoroacetic acid, as well as with amino acids such as arginine and lysine. In the presence of several acidic or basic groups, mono- or polysalts can be formed. Compounds of formula I with an acidic, e.g. free carboxy group, and a free basic, e.g. an amino group, may also be in the form of internal salts, i. in zwitterionic form, or it may be a part of the molecule as an inner salt, and another part as a normal salt.

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For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For therapeutic use, only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred.

The compounds of the formula I and salts of such compounds having salt-forming properties have valuable pharmacological properties. Above all, they show strong antihypertensive and hypotensive effects, which are found, for example, in the awake, renal-hypertensive rat on the basis of those of Byrom and Wilson * J. Physiol. (London), Vol. 93, p. 301 (1938), Gerold et al., HeIV, Physiol. Pharmacol. Acta, Vol. 24, p. 58 (1966), and Goldblatt et al., J. Exp. Med., Vol. 59, p. 347 (1934), can be detected in doses from about 0.3.mg / kg po. The antihypertensive effect can also be demonstrated, for example, in the anesthetized cat with intravenous administration of doses from about 0.001 mg / kg. Furthermore, the compounds have long-lasting pharmacological effects, such as a long-lasting hypotensive or vasodilating effect, which can be detected, for example on waking dog and the anaesthetized dog bei.intravenöser administration of doses from about 0.01 mg / kg. The compounds of formula I are also distinguished by the fact that they have negative inotropic and negative chronotropic effects; the former can be vitro demonstrated by an inhibition of the contraction force of the isolated, left, at a constant frequency stimulated ¹ guinea pig atrium at a concentration of about 10 nmol / 1 and the latter on the right, spontaneously beating guinea pig atrium at a concentration of about 1 nmol / 1, for example in. The compounds of the formula I are distinguished by the fact that they have only weak negative inotropic effects relative to the negative chronotropic effect. Furthermore, the compounds of the formula I, as is common with calcium antagonists, cause, for example, an anesthetized dog due to the reflex cardio stimulation an increase in the heart rate, which occurs, however, delayed and is limited. In the anesthetized rat heart rate is reduced by the administration of compounds of the formula I, despite an increase in the activity of the sympathetic nervous system.

- 15 -

The compounds of formula I continue to act coronary-dehydrating, as shown e.g. can be detected in isolated, perfused guinea pig hearts according to Langendorff in concentrations of about 0.1 nmol / 1. It should be emphasized that the compounds of formula I have only weak negative inotropic effects relative to the coronary dehydrating effect. The affinity of the compounds for calcium channels can be demonstrated in the nitrendipine receptor binding assay in vitro.

H-nitrendipine is specifically bound by guinea pig heart membrane preparations. The IC values, which indicate the concentration of test compound needed to control the specific binding of

H-nitrendipine to reduce by 50%, are in the inventive

Compounds at about 0.1 nmol / 1 or above. Further, electrophysiological studies indicate: compounds of formula I, e.g. the registration of the intercellular derivative of the action potential at the isolated papillary muscle of guinea pig heart, on a strong

2+

Inhibition of Ca-ion influx out. For example, the papillary muscle preparation partially depolarized by K ions in concentrations of 10 nmol / l or less inhibits the slow potential by 50%. Remarkably, in studies on the non-depolarized preparation, compounds of the formula I prolong the duration of the action potential in concentrations of 10 nmol / l, possibly as a result of an additional effect on the potassium outflow. Furthermore, preference is given in vitro to the rat's perfused mesenteric vascular bed. or calcium ions (from about 0.1 nmol / 1) induced by norepinephrine (from about 10 nmol / 1) induced vasoconstriction by compounds of formula I inhibited. The compounds of formula I are further characterized by relatively rapid onset of pharmacological effects, chemical resistance and, compared to cardiovascular effects, relatively low toxicity.

The compounds of formula I and salts of such compounds having salt-forming properties can therefore be used e.g. as antihypertensives and coronary dilators for the treatment of cardiovascular disease

- 16 -

conditions, especially angina pectoris and hypertension, also e.g. Arrhythmias, cerebral and peripheral circulatory disorders, pulmonary hypertension, migraine, vascular spasms or heart failure and other indications such. Arteriosclerosis, spasms of smooth muscle, such as bronchi, uterus, intestine, etc., or general brain dysfunction are used. But the new compounds are also valuable intermediates for the preparation of other, especially pharmaceutically active compounds.

The invention relates in particular to compounds of the formula I in which η is 1, 2 or 3, Ar is a mono- or bicyclic, carbocyclic aryl radical or a five- or six-membered, one to and four ring nitrogen atoms, a ring oxygen or ring sulfur atom , or one or two ring nitrogen atoms together with a ring oxygen or a ring sulfur atom containing as ring members, monocyclic heteroaryl radical optionally containing a fused 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, benzoxadiazolyl, benzthiadiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolinyl or isoquinolinyl, in which radicals ring carbon atoms optionally substituted by lower alkyl, lower alkenyl , Niederalk inyl, lower alkylene, cycloalkyl, phenyl, phenyl-lower alkyl, phenyl-lower-alkoxy and / or phenyl-lower alkylthio, where lower alkyl, phenyl, phenyl-lower alkyl, phenyl-lower-alkoxy and / or phenyl-lower alkylthio optionally hydroxy, lower-alkoxy, halo-lower-alkoxy,

Lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, Ν, Ν-di-lower alkylcarbamoyl and / or cyano, which may also contain cyclic radicals as lower alkyl, which in turn may be substituted as indicated and / or by hydroxy, lower alkoxy, halo-lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen,

- 17 -

Nitro, amino, lower alkylamino, di-lower alkylamino, N-lower-alkyl-N-phenyl-lower alkylamino, lower alkyleneamino, oxanoweralkylenatnino, thia-lower alkylene-amino and / or azanoweralkyleneamino-amino, in which the azido-nitrogen atom may be substituted by lower alkyl, phenyl or phenyl-lower alkyl, these substituents hydroxy, lower alkoxy, halo-lower alkoxy, lower alkenyloxy, Lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower-alkyl-carbamoyl, N, N-di-lower alkylcarbanioyl and / or cyano may contain as substituents, and / or by lower alkanoylamino, azido, carboxy, lower alkoxycarbonyl, carbamoyl, N- Lower alkylcarbamoyl, Ν, Ν-di-lower alkyl-carbamoyl, cyano, sulfo, aminosulfonyl, lower alkylthio, lower alkylsulfinyl and / or lower alkylsulfonyl, and / or ring nitrogens optionally substituted by lower alkoxycarbonyl or lower alkyl optionally substituted by hydroxy, lower alkoxy, halo-lower alcohol as substituents xy, lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, Ν, Ν-di-lower alkyl-carbamoyl or cyano, or may be substituted by hydroxy or oxido, the radical Ac for lower alkanoyl, unsubstituted or lower alkyl, lower alkoxy, nitro and / or halo substituted benzoyl, lower alkylsulfonyl, unsubstituted or lower alkyl, lower alkoxy, nitro and / or halo substituted phenylsulfonyl, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkylamino lower alkoxycarbonyl, di-, lower alkylamino, lower alkoxycarbonyl, lower N-lower alkyl -N-phenyl-lower alkyl-alinone-lower alkoxycarbonyl, N, N-lower alkylene-amino-lower alkoxycarbonyl, morpholinone-lower alkoxycarbonyl, thiomorpholinone-lower alkoxycarbonyl, piperazinone-lower alkoxycarbonyl, 4-lower-alkyl-piperazino-lower alkoxycarbonyl, unsubstituted o the phenyl, thienyl, furyl, pyrryl or pyridyl lower alkoxycarbonyl, lower alkoxy or lower alkynyloxycarbonyl which is substituted by lower alkyl, lower alkoxy, nitro and / or halogen,

Carbamoyl, N-lower-alkyl-carbamoyl, Ν, Ν-di-lower alkylcarbamoyl, N-hydroxycarbamoyl, Ν, Ν-lower alkylenecarbamoyl, morpholinocarbonyl,

18 is thiomorpholinocarbonyl, piperazinocarbonyl, 4-lower alkylpiperazinocarbonyl, 5-tetrazolyl, unsubstituted or lower alkyl or phenyl substituted 4,5-dihydro-2-oxazolyl or 5,6-dihydro-4H-1,3-oxazin-2-yl, Z is a radical -OR or -NR R, R is hydrogen; Lower alkyl optionally substituted by lower alkylamino, di-lower alkylamino, lower alkyleneamino, morpholino, thiomorpholino, piperazino which optionally carries lower alkyl or lower alkanoyl as a substituent on a nitrogen atom, carboxy, functionally modified carboxy, lower alkoxy, lower alkoxy-lower alkoxy or phenyl, which in turn optionally represents lower alkyl, lower alkoxy, Halogen and / or nitro as substituent, or N-pyrrolyl, N-imidazolyl, N-pyrazolyl, N-indolyl or N-isoindolyl substituted; Phenyl which is optionally substituted as a phenyl-Niederaikyl radical R ₁ ; Hydroxy, lower alkoxy or phenyl-lower alkoxy,

R "and R are independently hydrogen, lower alkyl optionally substituted by hydroxy, lower alkoxy optionally containing amino, lower alkylamino, di-lower alkylamino or acylamino as substituents, acyloxy or phenyl, formyl, di-lower alkyl acetal or dithioacetal, lower alkylene acetal or dithioacetal, functionally modified carboxy; Phenyl which optionally contains lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, halogen, nitro, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, functionally modified carboxy and / or lower alkylthio as substituents; Pyrryl, furyl, thienyl or pyridyl, where these radicals are optionally substituted as a phenyl radical R- or R_; R 1 is hydrogen, unsubstituted or by free or etherified hydroxy, free or etherified mercapto, which may optionally be oxidized, by carboxy, functionally modified carboxy, by amino, which may itself in turn lower alkyl, Carboxy, functionally modified carboxy or acyl as substituent, by a mono- or bicyclic carbocyclic aryl radical or a five- or six-membered heteroaryl radical as defined above for Ar substituted lower alkyl, unsubstituted or by free or

- 19 -

etherified hydroxy, lower alkyl, nitro, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino and / or halogen-substituted phenyl or an optionally equally substituted monocyclic five- or six-membered heteroaryl radical as defined above for Ar, R, hydrogen, lower alkyl, unsubstituted or substituted free or etherified hydroxy, lower alkyl, nitro, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino and / or halogen-substituted phenyl-lower alkyl, unsubstituted or as a phenyl-lower alkyl

R is substituted phenyl or an optionally substituted in the same way monocyclic five- or six-membered heteroaryl, and R, R "and R are independently hydrogen; Alkyl, optionally substituted by amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, oxa, thia or Azaniederalkylenamino in which the aza-nitrogen optionally lower alkyl or lower alkanoyl as a substituent ₃ acylamino, free or etherified hydroxy or a carbocyclic aryl radical or heteroaryl radical as above for the Group Ar is substituted; or a carbocyclic aryl radical or heteroaryl radical as defined above for the group Ar, in which R and R together or R ₁ and R together may denote C 2 -C 3 lower alkylene in which the radical having the C 2 or C 6 carbon atom of the 1,4 Optionally substituted by an oxygen, sulfur or a nitrogen atom which is substituted by hydrogen or lower alkyl, wherein R, and R together unsubstituted or by free or etherified hydroxy, amino, lower alkylamino, di-lower alkylamino and / or Halogen, on the aza nitrogen also lower alkyl, substituted lower alkylene, oxa, thia or Azaniederalkylen, wherein R _c and R, together may represent lower alkyl, aza-, oxa- or Thianiederalkylen, wherein these radicals are optionally substituted on carbon atoms by free or etherified hydroxy, amino, lower alkylamino, di-lower alkylamino, halogen, carboxy and / or functionally modified carb optionally substituted by lower alkyl and aza nitrogen, and wherein R ₀ and R together are lower alkylene, aza,

ο y

- 20 -

Oxa or Thianiederalkylen, wherein these radicals are optionally substituted on carbon atoms by free or etherified hydroxy, amino, lower alkylamino, di-lower alkylamino, halogen, carboxy, functionally modified carboxy or a five- or six-membered monoazo, diazo or triaza heteroaryl, optionally wholly or partially saturated and optionally substituted on oxo by oxo and optionally substituted on the azole nitrogen atoms by lower alkyl or phenyl, which in turn may contain lower alkyl, halogen, lower alkoxy and / or nitro as substituents; and at the aza-nitrogen, optionally by lower alkyl, which in turn optionally defines a carbocyclic aryl or heteroaryl radical as defined above for the group Ar and / or contains free or etherified hydroxy, acyloxy, amino, lower alkylamino and / or di-lower alkylamino as substituents; are substituted by acyl or phenyl, which in turn may contain lower alkyl, halogen, lower alkoxy and / or nitro as substituents, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds with salt-forming groups.

The invention relates in the first place to compounds of the formula I in which η is 1, 2 or 3, Ar phenyl is optionally substituted by lower alkyl, phenyl, phenyl-lower alkyl, phenyl-lower-alkoxy and / or phenyl-lower alkylthio, such radicals themselves being hydroxy, lower-alkoxy, lower-alkylenedioxy, halogen, Carboxy, lower alkoxycarbonyl and / or cyano, which cyclic radicals may also contain lower alkyl as substituents, and / or by hydroxy, lower alkoxy, halo-lower alkoxy, lower alkylenedioxy, halogen, nitro, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, Or pyrryl, furyl, thienyl, pyridyl, benzoxadiazolyl or benzothiadiazolyl, these radicals being optionally substituted as a phenyl radical Ar, and in particular lower alkyl, lower alkoxy, halogen and / or optionally by lower alkyl, lower alcohol xy, halogen and / or nitro contain substituted phenyl as substituent, the radical Ac represents lower alkanoyl, lower alkyl

- 21 -

sulfonyl, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, Ν, Ν-di-lower alkylamino-lower alkoxycarbonyl, N-lower alky 1-N-phenyl-lower alkyl-amino-lower alkoxycarbonyl, N, N-lower alkyleneamino-lower alkoxycarbonyl, (4-morpholino) -n-lower alkoxycarbonyl, lower alkenyloxy or Lower alkynyloxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, Ν, Ν-di-lower alkyl-carbamoyl, N, N-lower-alkylcarbamoyl, 4-morpholinocarbonyl or 4-lower-alkyl-1-piperazino-carbonyl, Z represents a radical -OR or -NR R, R ^ is hydrogen, lower alkyl, di-lower alkylamino lower alkyl, lower alkyleneamino-lower alkyl, (4-morpholino) -lower alkyl, carboxy-lower alkyl, lower alkoxycarbony1-lower alkyl

or lower alkoxy-lower alkoxy-lower alkyl wherein di-lower alkylamino, lower-alkylene-amino or 4-morpholino are separated by at least two carbon atoms from the ring nitrogen atom or is phenyl-lower alkyl, phenyl, hydroxy or lower-alkoxy, R "and R 'are independently lower alkyl optionally substituted by hydroxy, lower-alkoxy, optionally substituted amino, lower alkylamino or di-lower alkylamino, lower alkanoyloxy or phenyl substituted, formyl, di-lower alkyl acetal or dithioacetal, lower alkylene acetal or dithioacetal, cyano, phenyl, thienyl or amino, R. hydrogen or lower alkyl, R is hydrogen, unsubstituted or substituted Hydroxy, lower alkoxy, mercapto, lower alkylthio, carboxy, carbamoyl, amino, lower alkanoylamino, carbamoylamino, guanidino, by phenyl, which in turn may be substituted by hydroxy and / or halogen, imidazolinyl or indolyl substituted lower alkyl, unsubstituted or dur ch is hydroxy, lower alkoxy, lower alkyl, nitro, amino, lower alkylamino, di-lower alkylamino and / or halogen-substituted phenyl or pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, unsubstituted or substituted as indicated for a phenyl radical R, Oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, R, hydrogen, lower alkyl, phenyl-lower alkyl, unsubstituted or substituted by hydroxy, lower alkoxy, · lower alkyl, nitro, amino, lower alkylamino, di-lower

- 22 -

alkylamino and / or halogen-substituted phenyl-lower alkyl or an unsubstituted or substituted in the same manner as for a phenyl-lower alkyl radical R from the group phenyl, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl , Thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, and R ₇ , R and R independently represent hydrogen, lower alkyl or amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, oxa, thia or azano-lower alkylamino wherein the aza nitrogen is optionally is substituted by lower alkyl, lower alkanoylamino, hydroxy, lower alkoxy or by phenyl which may be unsubstituted or substituted in turn by amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydroxy, lower alkoxy, halogen and / or nitro, or by pyrryl, furyl, thienyl or pyridyl, these groups being in the same Way, such as phenyl, substituted lower alkyl or phenyl, pyrryl, furyl, thienyl or pyridyl, these groups may be substituted in the same way as a phenyl-lower alkyl radical R, R or R, wherein R ₁ and R together and R ₁ and R together may denote C 2 -C 3 lower alkylene in which the carbon atom directly connected to the C 2 or C 6 carbon atom of the 1,4-dihydropyridine ring is optionally substituted by an oxygen, sulfur or nitrogen atom which is replaced by Is hydrogen or lower alkyl substituted, in which R and R together may denote unsubstituted or hydroxy-substituted C -C ^ lower alkyl, C -C -Oxa or C -C -thio lower alkyl, wherein R and R, together lower alkylene with 2 to 5 chain carbon atoms or Azaniederalkylen with 3 or 4 chain carbon atoms, these radicals being unsubstituted or substituted by hydroxy, lower alkoxy, amino, lower alkylamino or di-lower alkylamino su can be substituted, and

in which R _g and R may together denote C -C-lower alkylene, C -C -azo, C -C -Oxa or C -C -thio-lower alkylene, these radicals being optionally substituted on carbon atoms by hydroxy, lower alkoxy, amino, lower alkylamino, Di-lower alkylamino or five- or six-membered monoaza- or diazo-heterocyclyl which is optionally substituted by oxo on carbon atoms and attached to the

- 23 -

optionally substituted by lower alkyl or phenyl, which may in turn contain lower alkyl, halogen, lower alkoxy and / or nitro as substituents; and at the Aza-nitrogen optionally by lower alkyl, which in turn by phenyl, pyrryl, furyl, thienyl and / or pyridyl, these radicals themselves optionally lower alkyl, hydroxy, lower alkoxy, halogen and / or nitro as substituents, and or by hydroxy, lower alkoxy , Lower alkanoyloxy, amino, lower alkylamino and / or di-lower alkylamino; by benzoyl, lower alkanoyl, furanylcarbonyl, thienylcarbonyl, pyrrylcarbonyl, pyridinylcarbonyl or phenyl, which in turn may contain lower alkyl, halogen, lower alkoxy and / or nitro as substituents, optical isomers of compounds of formula I, mixtures of these optical isomers and salts thereof Compounds with salt-forming groups.

The invention more particularly relates to compounds of the formula I in which η is 1 or 2, Ar is phenyl, thienyl, furyl or benzoxadiazolyl, these groups being optionally substituted by lower alkyl, lower alkoxy, halo-lower alkoxy, phenyl-lower alkoxy, phenyl-lower alkylthio, lower-alkylenedioxy, halogen, trifluoromethyl, Mono-, di- or tri-substituted nitro, lower alkanoylamino and / or cyano, the radical Ac is lower alkanoyl, lower alkylsulfonyl, lower alkoxycarbonyl, 2-lower alkoxy-lower alkoxycarbonyl, Ν, Ν-di-lower alkylaminone-lower alkoxycarbonyl, N-lower-alkyl-N-phenyl-lower alkyl-amino-lower alkoxycarbonyl, carbamoyl, N is lower alkylcarbamoyl, N is ₅ -di-lower alkylcarbamoyl, Ν, Ν-lower-alkylenecarbamoyl or 4-morpholinocarbonyl, Z is a radical -OR or -NRp.R _q , R _{1 is} hydrogen, lower alkyl, 2- ( Di-lower alkylamino) -lower alkyl, 2- (lower alkyleneamino) -lower alkyl, 2- (4-morpholino) -lower alkyl, carboxy-lower alkyl or lower alkoxy-lower alkyl

alkoxy-lower alkyl, R "and R are independently lower alkyl, hydroxy lower alkyl, cyano or amino, R. hydrogen or lower alkyl, R is hydrogen, unsubstituted or by hydroxy, lower alkoxy, mercapto, lower alkylthio, carboxy, carbamoyl, amino, carbamoylamino, guanidino , Phenyl, which in turn may be substituted by hydroxy, or imidazo1-4-yl or

- 24 -

Indol-3-yl substituted lower alkyl or phenyl ,. Thiazolyl, imidazolyl, furyl, thienyl, pyridyl or pyrimidinyl, -said these radicals are optionally substituted by hydroxy, lower alkoxy and / or amino group, _R is hydrogen, lower alkyl, phenyl-lower alkyl which is unsubstituted or substituted by hydroxy, lower alkoxy and / or amino is, or phenyl, thiazolyl, imidazolyl, furyl, thienyl, pyridyl or pyrimidinyl, these radicals being optionally substituted as a phenyl-lower alkyl radical R, and R, R and R are independently hydrogen or unsubstituted or by amino, lower alkylamino, di-lower alkylamino Lower alkyleneamino, oxa or azanoweralkyleneamino, wherein the aza nitrogen is optionally substituted by lower alkyl, hydroxy, lower alkoxy, phenyl, which may be unsubstituted or substituted by amino, hydroxy, lower alkoxy and / or halogen, or by thienyl or pyridyl, wherein these groups may be substituted in the same way as phenyl, sub substituted lower alkyl, wherein R, and R together

C -C, -N-lower alkylene, wherein R_ and R .. together 3 4 j ο

C ₀ -C lower-alkylene or C -Azaniederalkylen and wherein R and R together C -C-lower alkyl, which is optionally substituted by 2-imidazolidinone-1-yl, which may contain 3-position phenyl or lower alkyl as a substituent , C-oxa or C -Azaniederalkylen, wherein the aza-nitrogen by lower alkyl, which in turn unsubstituted or by phenyl, which may contain lower alkyl, lower alkoxy, halogen and / or nitro as substituents, thienyl and / or pyridyl mono- or is substituted by benzoyl, furanylcarbonyl, phenyl or lower alkoxyphenyl, optical isomers of compounds of formula I, mixtures of these optical isomers and pharmaceutically acceptable salts of such compounds with salt-forming groups.

The invention relates mainly to compounds of the formula I in which η is 1 or 2, Ar is unsubstituted or lower alkyl, lower alkoxy, halo-lower alkoxy, benzyloxy, benzylthio, halogen, tri

- 25 -

fluoromethyl, nitro and / or cyano mono- or disubstituted. Phenyl, 2- or 3-thienyl, but also 2, l, 3-benzoxadiazol-4-yl,

the radical Ac is lower alkylsulfonyl or lower alkoxycarbonyl, Z is a radical -OR or -NRgR ₁ , R is hydrogen, furthermore 2- (4-morpholino) -ethyl, R is lower alkyl, hydroxymethyl, cyano or amino, R_ is lower alkyl , R, represents hydrogen or lower alkyl, R_

Is hydrogen, unsubstituted or substituted by phenyl, which in turn may be substituted by hydroxy, substituted lower alkyl, phenyl or unsubstituted or amino-substituted thiazolyl, R, hydrogen, lower alkyl or phenyl, R is hydrogen, lower alkyl or lower alkyl represented by phenyl, amino , Lower alkylamino, di-lower alkylamino, 4-morpholino, 1-piperazino, which in turn may contain 4-nitrogen lower alkyl substituents, or lower alkoxy, Rg and R independently represent hydrogen, unsubstituted or lower alkoxy, phenyl or pyridyl substituted lower alkyl in which R and R together may be 1,3-propylene,

wherein R _r and R, may together represent 1,5-pentylene, and wherein 5 ο

R ₀ and R together are 1,5-pentylene, 3- (3-phenyl-2-imidazolidinon-1-yl) -1,5-pentylene, 3- (2-imidazolidinon-1-yl) -1, 5-pentylene or 3-aza-1 or 3-aza-1, 5-pentylene, where the aza nitrogen is optionally substituted by lower alkyl, benzyl, diphenylmethyl, where the radicals benzyl or diphenylmethyl optionally contain halogen, lower alkyl and / or lower alkoxy as substituents, benzoyl , Furanylcarbonyl, phenyl or lower alkoxyphenyl, optical isomers of compounds of the formula I, mixtures of these optical isomers and pharmaceutically acceptable salts of such compounds with salt-forming groups.

The invention relates in particular to compounds of the formula I in which η is 1, Ar is 2- or 3-nitrophenyl, 2- or 3-difluoromethoxyphenyl, 2- or 3-methylphenyl, 2- or 3-trifluoromethyl -phenyl, 2,3-dimethyl-phenyl,

- 26 -

2,3-dichloro-phenyl, 2- or 3-benzyloxy-phenyl or 2- or 3-benzylthiophenyl, Ac represents lower alkoxycarbonyl, Z represents a radical -OR., Or -NR ₀ R _n , R _{1 is} hydrogen , R ₀ and R are independently lower alkyl, R is hydrogen, R_ is lower alkyl or phenyl, R represents _fi is hydrogen, R ₇ is unsubstituted or substituted by 4-morpholino, 1-piperazino or 4-lower alkyl-l-piperazino lower alkyl, R and R independently

ο y

are hydrogen, unsubstituted or substituted by phenyl or pyridyl lower alkyl, and wherein R _R and R together may be 3-aza-1,5-Pentyleh in which the aza nitrogen is optionally substituted by benzyl or Dipheny! methyl, optical Isomers of compounds of the formula I, mixtures of these optical isomers and pharmaceutically acceptable salts of such compounds with salt-forming groups.

Preference is given to the compounds of the formula I in which Ar is 2- or 3-nitrophenyl, 2- or 3-difluoromethoxyphenyl, 2- or 3-methylphenyl, 2- or 3-trifluoromethylphenyl, 2,3-dimethylphenyl phenyl, 2,3-dichlorophenyl, 2 = or 3-benzyloxy-phenyl or 2- or 3-benzylthio-phenyl, but also also 2, l, 3-benzoxadiazol-4-yl. Of particular importance are the compounds of formula I wherein Ar is 2- or 3-nitrophenyl, and more particularly 3-nitrophenyl. A further preferred embodiment of the invention are the compounds of the formula I in which Ac is lower alkoxycarbonyl, 2-lower alkoxy-lower alkoxycarbonyl, lower alkylsulfonyl, carbamoyl, N-alkyl or Ν, Ν-dialkylcarbamoyl, in particular lower alkoxycarbonyl, 2-lower alkoxy-lower alkoxycarbonyl, carbamoyl, N-alkyl or Ν, Ν-dialkylcarbamoyl, and especially lower alkoxycarbonyl means. Particular mention should be made of the compounds of the formula I in which Z is an -NR R radical. Preference is given to the compounds of the formula I in which Z is a radical -OR. Preference is furthermore given to the compounds of the formula I in which R is hydrogen. Preference is also given to the compounds of the formula I in which R ₀ and / or R are lower alkyl, hydroxy-lower alkyl, in particular hydroxymethyl, cyano or amino. Particular mention should be made of the compounds of the formula I in which one of the radicals R and R is lower alkyl and the other is the radical specified for R and R under formula I, in particular lower alkyl, hydroxy-lower alkyl,

- 27 -

Cyan or amino, means. Of particular interest are the compounds of formula I wherein R is lower alkyl, especially methyl or ethyl, and especially methyl. Also preferred are the compounds of formula I, wherein R is lower alkyl, especially methyl or ethyl, and especially methyl. Of particular importance are the compounds of formula I wherein R. is hydrogen. Preference is given to the compounds of the formula T in which R is lower alkyl or phenyl, in particular C -C lower-alkyl or phenyl, especially isopropyl, sec-butyl ( ^1- methylpropyl) or phenyl, and isopropyl in the first place. Also to be emphasized are the compounds of the formula I in which R-

stands for hydrogen. Furthermore, the compounds of the formula I are preferred in which R is unsubstituted or substituted by 4-morpholino or 4-lower alkyl-1-piperazino lower alkyl, and in particular C _? -C, -lower alkyl. Also to be emphasized are compounds of the formula I in which R _R and R together are 3-aza-1, 5-pentylene, where the aza nitrogen is substituted by benzyl or diphenylmethyl.

The invention more particularly relates to the specific compounds described in the Examples. It also relates to all optical isomers and any mixtures of optical isomers, for example mixtures consisting of all optical isomers, the in the examples be '<. written specific links.

The compounds of formula I and salts of such compounds having salt-forming properties can be prepared in a manner known per se, e.g.

a) a compound of formula II

Ar Il

^A w ^c -

Il N ^R l

RR _r I ⁴ I ⁵

-N C-

(II)

wherein n 'is 0, 1 or 2 and R ^ is an optionally activated carboxy group, with the proviso that ^ of a radical

- 28 -

C (= 0) -z is different when η ^{1 is} 1 or 2, with a compound of formula III

R '0

(III)

wherein n "is 1, 2 or 3, and R 'R' and R 'are those of formula I * 4 5 6

for R ,, R ₁ . and R, have the meaning indicated, but may be different from the radicals R 1, R 3 or R 2 in formula II, with the proviso that the sum of n 'and n "is not greater than 3, or

a ') in a compound of formula Ha

Ar I

I * H

• ·

11 I I "

C N - Ο

R, -

(Ha)

² i ³

^R l

wherein n 'is 1, 2 or 3 and R is one in the radical C (= O) -Z

is convertible group, these converted into the rest C (O) -Z, or

b) reacting a compound of formula IV, or a reactive derivative thereof, with a compound of formula V, or a tautomer thereof, and with a compound of formula VI,

(IV)

Ar I

CH + "+

O Il

CHO CH

/\H

ρ R ₄ R

R, O

(V)

- 29 -

b ') completely analogously to process b), a compound of the formula Va is reacted with a compound of the formula VI,

(VI)

^AC

CH H

O χ II

al

-οι κ

»6 ° ι

(Va)

or

c) a compound of formula VII

Ac

Ar Il

H 8

• ·

-N-

(VII),

wherein one of the radicals X and Y is the group of the formula -NH-R ₁ and the other is hydroxy or both denote the group of the formula -NH-R, or a tautomer thereof or a corresponding Tautomerengemisch ringschliesst, or

d) a compound of the formula Ar-CHO (IV) or a reactive functional derivative thereof with a compound of the formula VIII

Ao

R

R

Il

-S

Il

(VIII)

- 30 -

or a tautomer thereof or a corresponding mixture of tautomers, or

e) in a compound of the formula IX

Λ ^

IJ I,

^R 2

R

(ix),

wherein Ac represents a radical convertible into the group Ac, converts it into the group Ac,

it being possible to II, used to IX, Ha and Va, which if they have salt-forming properties even in the form of their salts in the above starting materials of the formulas, the symbols n, Ar, Ac, R .., R2, R ^ ₉

R., R _c , R ,. and Z have the meanings given under formula I, 4 j ο

and, if desired, converting a compound of formula I obtained into another compound of formula I, and / or, if desired, converting a salt obtained into the free compound or into another salt, and / or, if desired, a product obtained converting free compound of formula I having salt-forming properties into a salt, and / or, if desired, separating a resulting mixture of isomers or racemates into the individual isomers or racemates and / or splitting racemates obtained, if desired, into the optical antipodes,

In a compound of formula II, R, e.g. a free carboxy group or a carboxy group activated for the purpose of forming an amide or peptide bond. '

For carrying out process variant a), the carboxy group can be converted, for example, by conversion into an acid azide, anhydride, imidazolide, isoxazolide or an activated ester, such as one of those mentioned below, or by reaction with a carbodiimide,

- 31 -

such as N, N'-dicyclohexylcarbodiimide, optionally with the addition of N-hydroxysuccinimide, an unsubstituted or e.g. halogen-substituted, methyl or methoxy-substituted 1-hydroxybenzotriazole or 4-hydroxybenzo-l, 2,3-triazine-3-oxide (et al., see DE-OS 1 917 690, DE-OS 1 937 656, DE-OS 2 202 613), or in particular of N-hydroxy-5-norbornene ~ 2,3-dicarboximide, or activated with Ν, Ν'-carbonyldiimidazole. Furthermore, it can also be activated by first applying it, e.g. with trimethylsilyl chloride to the corresponding trimethylsilyl ester and then with a suitable halogenating agent, e.g. Thionyl chloride, converted into the corresponding acid halide, in particular acid chloride.

To form activated esters mentioned above, ZoB are suitable. optionally substituted by electron-withdrawing substituents substituted phenols and thiophenols such as phenol, thiophenol, thiocresol, p-nitrothiophenol, 2,4,5- and 2,4,6-trichlorophenol, pentaCfluor or chloro) phenol, o- and p-nitrophenol, 2,4 -Dinitrophenol, p-cyanophenol, further eg N-hydroxysuccinimide, N-hydroxyphthalimide and N-hydroxypiperidine.

To carry out the process a) are each a compound of formula II and III in a conventional manner a condensation reaction

subjected.

The most commonly used method for the formation of amide or peptide bonds is the carbodiimide method, as well as the azide method, the activated ester method and the anhydride method, as well as the Merrifield method, the method of N-carboxyanhydrides or N-Thiocarboxyanhydride and acid chloride method.

In a particularly preferred preparation of the compounds of the formula I, the carbodiimide method with N, N'-dicyclohexylcarbodiimide in the presence of 1-hydroxybenzotriazole is used as the coupling method. In this case, a compound of formula II, wherein IL is a free carboxy group, is first intermediately converted by 1-hydroxy-benzotriazole in the corresponding benzotriazol-1-yl ester,

- 32 -

which then reacted with the compound of the formula III, preferably one in which Z is OR and R is optionally substituted lower alkyl or in which Z denotes NR R, to give a compound of the formula I under the action of the abovementioned carbodiimide

ο y

The starting materials of the formula II and of the formula III can be used independently of one another as a racemate, racemate mixture, as an optical isomer or as a mixture of a plurality of optical isomers. For example, Chem. Pharm. Bull. 2%, 2809-2812 (1980) discloses the preparation of optical isomers of formula II from a racemic compound of formula II.

Very many starting materials of the formula III-amino acids, di- and tripeptides and their C-terminal optionally substituted lower alkyl esters-are known, both as racemates, racemic mixtures and as optical isomers, and others can be prepared analogously to the known ones.

Starting materials of the formula II in which n 'is 0 are known, for example from European Patent Application 11706, and others can be prepared analogously to the known ones. Starting materials of the formula II in which n ^{T is} 1 or 2 can be prepared, for example, by reacting compounds of the formula II in which n 'is 0 with a compound of the formula IIIa

H-N-C-IL (UIA),

ι Ο

^R 6

or a compound of formula IHb

- 33 -

H-N-C-C-N-C-B, (HIb), I Il I · »

^R 6 ° ^R 6

wherein R, the formula under formula II and R ,, R_ and R, that under formula I D 4 5 6

have the meaning given and R !, R 'and R' are those of formula I

4 _> ö

have the meaning given for R, R and R, but of R ,, R_ or

R _c can be different, in the same way as above for the ο

Preparation of compounds of the formula I from in each case one compound of the formula II and III. Compounds of formula IHa and IHb are known; they are either identical to compounds of the formula III in which Z is OR and R is hydrogen and n is 1 or 2, or can be prepared from precisely these compounds by the same activation methods as described above for compounds of the formula II ,

Process variant a ') comprises inter alia the conversion of compounds of formula Ha, wherein R is e.g. a protected and / or functionally modified carboxy group, in compounds of the formula I. Under a protected carboxy group by a protective group, as is commonly used in peptide chemistry used, protected carboxy group to understand. Such protecting groups are light, that is without unwanted side reactions take place, for example, solvolytic, reductive, photolytic or even under physiological conditions; cleavable, which usually compounds of formula I are obtained in which Z is OR and R is hydrogen.

Protecting groups of this type, as well as their cleavage, are described for example in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, also in "The Peptides", Vol. I, Schröder and Lübke, Academic Press, London, New York, 1965, as well

- 34 -

in "Methods of Organic Chemistry", Houben-Weyl, 4th Edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart, 1974.

For example, carboxy groups are protected by hydrazide formation or by esterification. Suitable for esterification are e.g. lower substituted alkanols such as cyanomethanol, 2,2,2-trichloroethanol or benzoylmethanol. A particularly advantageous category of the substituted alkanols are ethanols which carry a trisubstituted silyl group in the β-position, such as triphenylsilyl, dimethyl-butyl-silyl or, especially, trimethylsilyl. Such as. in Belgian Patent No. 851,576, these alcohols are particularly well-suited for protecting the carboxy groups because the corresponding β-silyl ethyl esters, e.g. Although having the stability of conventional alkyl esters, β- (trimethylsilyl) ethyl esters can be obtained under mild conditions by the action of fluoride ion donating reagents, e.g. Fluorides quaternary organic bases, such as tetraethylammonium fluoride, selectively split off. However, they may also, like the usual substituted alkyl esters, be prepared by alkaline hydrolysis, e.g. be cleaved by means of alkali metal hydroxides, carbonates or bicarbonates.

If in a compound of the formula Ha (or I) R is a functionally modified carboxy group, for example cyano, an imidoester, in particular an imido-lower alkyl ester, an optionally substituted carbamoyl group or an acid halide, this can be carried out in a manner known per se, in particular by hydrolysis in an alkaline or acidic medium, to convert a compound of formula I, wherein Z is OR and R _{7 is} hydrogen, which in the former case can also directly obtain a salt. A compound of the formula Ha, in which R is cyano, can furthermore be prepared in a customary manner, for example by addition of optionally substituted lower alkanols in the presence of a water

- 35 -

free acid, such as hydrogen chloride, and subsequent careful hydrolysis of the resulting imido ester to compounds of formula I, wherein R is optionally substituted lower alkyl, transfer; The same is also possible by the reaction of a compound of formula Ha, wherein R is an acid halide, with optionally substituted lower alkanols.

In this process variant, however, it is also possible to use starting materials of the formula II in which R is, for example, formyl or a reactive derivative thereof, as defined below, hydroxymethyl or methyl, which are prepared by conventional oxidation methods in compounds of the formula I, preferably in those in which Z is OR ₇ and R _{7 is} hydrogen, can be converted.

In particular when carrying out the 'process variant a') care must be taken ₉ that unwanted side reactions, which may have the conversion of additional groupings in the molecule result, do not occur.

Starting materials of the formula Ha, in which n ^{1 is} 1, 2 or 3, can be prepared, for example, in an analogous manner as described above for the compounds of the formula II in which n 'is 1 or 2, namely by reacting a compound of the formula II, where n ^! is 0 or 1, with compounds which differ from those of the formula IHa and IHb by the presence of R instead of R.

Reactive, functional derivatives of the aldehyde of the formula IV used as starting material in process variant b), as well as of formyl groups in general, are i.a. the corresponding acetals, such as dilower alkyl, e.g. Dimethyl or diethyl acetals, acylals such as di-lower alkanoyl-acylals, e.g. Diacetylacylals, or especially the corresponding dihalomethyl, e.g. Dichloromethyl or dibromomethyl compounds, and addition compounds such as those with water or an alkali metal, e.g. Potassium hydrogen sulfite.

- 36 -

A variant of this method consists of first reacting a compound of formula IV with a compound of formula V, e.g. in the presence of an organic or inorganic base, e.g. a catalytic amount of piperidine, or preferably in the presence of an inorganic or organic acid, e.g. Mineral acid such as hydrochloric acid, or e.g. p-toluenesulfonic acid, and the forming intermediate of formula Va

Il

A.

(Va)

U. ti

after its isolation or without isolating it, reacting with a compound of formula VI.

Starting materials of the formula IV and VI are known, and further analogous to the known produced. The starting material of the formula V can be obtained in a manner known per se, for example by reacting a compound of the formula III, for example with diketene according to Pharm. Acta. Helv. _38.> Δ * ⁶ (1963).

Usually, the starting materials of the formula VII used in process variant c) are formed in situ , and the ring closure according to the invention takes place under the reaction conditions for the preparation of the starting material. Thus, it is possible to obtain the starting materials of the formula VII and, under the reaction conditions, also the corresponding end products of the formula I by reacting a compound of the formula IV or a reactive functional derivative thereof defined above with a compound of the formula

^AC \

CH "

(VIb)

co

R

- 37 -

a compound of formula V and a compound of formula R-NH (X), or cb) a compound of formula IV or a reactive functional derivative thereof with a compound of formula

(Vb)

and a compound of formula VIb or VI, or cc) a compound of formula X with a compound of formula

Ac. Jh. (VIa)

R-

or a compound of formula V, or cd) reacting a compound of formula X with a compound of formula Va and a compound of formula VIb or .VI, or ce) a compound of formula X with a compound of formula

4

(XI)

CO OC ^R 2>

or cf) a compound of formula VI with a compound of formula Va or the formula

J η

(Vc)

- 38 -

or, for example) a compound of the formula Vb with a compound of the formula VIa or with a compound of the formula

(VIc)

implements. In this case, with the exception of the compounds of the formulas IV and X, the compounds of the formulas V, Va-c, VI, Vla-c, VII and XI can be used in the form of tautomers 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 symbols n, Ar, Ac, R, R, R_, R, R5, Rg and Z have the meaning given under formula I.

A compound of formula X may also be used in the form of an agent which releases this compound in situ , for example ammonia in the form of an ammonium salt such as ammonium acetate or ammonium bicarbonate, or a light metal eg alkali metal compound such as sodium amide or lithium N-methylamide.

The ring closure reaction c) and the condensation reactions ca) to cg) for the preparation of the usually in situ formed starting material for the ring closure reaction, as well as in process variant b), are variants of the dihydropyridine synthesis of Hantzsch. In variant ca), a total of three molecules of water are split off; in other variants, partial elimination takes place in place of dehydration, i. the elimination of water already takes place during the production of one or two starting materials. In the reaction of compounds of the formula IV with compounds of the formula Vb and VI according to variant cb), of compounds of the formula VI with compounds of the formula Vc according to variant cf), or of compounds' of the formula Vb with compounds of the formula VIc according to variant cg ) a compound of formula X is cleaved in addition to or instead of water.

- 39 -

If, according to variant (c), compounds of the formula I are to be prepared, unwanted by-products, for example of the type of 1,4-dihydro-pyridine-3,5-dicarboxylic acid derivatives, such as corresponding diesters, can be formed. By not simultaneously merging the. Reactants, however, the formation of such by-products can be reduced meanwhile, by promoting a particular course of reaction, which proceeds in situ according to another variant, since according to the staggered addition of the reaction components, for example, first a compound of general formula VI or formula Vb can arise.

The ring closure or condensation reactions according to the invention 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, eg organic, base such as piperidine or ethyldiisopropylamine or a metal alcoholate, such as alkali metal lower alkanolate, or, if a compound of formula X is present as such with a light metal, such as sodium amide, in the presence of acidic agents, such as an organic carboxylic acid, eg acetic acid, and / or a suitable dehydrating agent - or water-absorbing agent, further usually in the presence of an inert organic solvent and at reaction temperatures in the range of about room temperature to about 150 ⁰ C, in particular at the boiling temperature of the solvent. Optionally, the reaction takes place in an inert gas, for example nitrogen atmosphere, and / or, for example when using a low-boiling solvent and / or a starting material of the formula X, in a closed vessel under elevated pressure.

The starting materials used in the process variants are known or can be prepared by processes known per se. Thus, for example, a compound of the formula Va can be prepared from in each case one compound of the formulas V and IV, a compound of the

- 40 -

Formula Via from in each case one of the formulas VIb and IV, a compound of the formula Vb from in each case one of the formulas V and X, a compound of the formula Vc from in each case one of the formulas Vb and IV, a compound 'of the formula VIc from in each case one of the formulas VI and IV and one of the formula XI from each one of the formulas VIb and Va.

Process variant d) is carried out in a manner known per se. Reactive functional derivatives of the aldehyde of the formula IV are described above. The reaction is carried out in Ab-, preferably in the presence of a solvent or diluent or a corresponding mixture and / or a condensing agent, wherein with cooling, at room temperature, or preferably with heating, for example in a temperature range of about ^{0 0} C to about 200 ⁰ C, preferably from about 40 ⁰ C to about 15O ⁰ C, and, if necessary, working in a closed vessel, optionally under pressure, and / or under an inert gas atmosphere.

The starting material of the formula VIII can be prepared in a manner known per se; e.g. can be obtained by reaction of a compound of formula V, preferably one in which Z is different from a hydroxy group, with a compound of formula VI directly to the starting material of the formula VIII.

The starting materials of the formula IX used in process variant e) can be used according to their content

Rest Ac, for example, carboxylic acids (Ac is carboxy), Carbonsäureo ο

anhydrides, especially mixed anhydrides, such as acid halides, eg chlorides or bromides (Ac is halocarbonyl, for example chloro- or bromocarbonyl), further activated esters, for example cyanomethyl or Pentachlorphenylester (Ac _q is Cyanmethoxycarbonyl or Pentachlorpheny loxycarbony1) be. Such starting materials may, optionally in the presence of condensing agents, by treating with an alcohol such as an unsubstituted or substituted lower alkanol, or a reactive derivative thereof, eg, a corresponding alkoxide such as alkali metal alcoholate, also free carboxylic acids by reaction with suitable diazo compounds such unsubsti-

- 41 -

tuierten or substituted Diazoniederalkanen be converted into compounds of formula I, in which Ac represents the acyl radical of a monoester of carbonic acid. Such compounds may also be obtained when using as starting materials of formula IX salts, in particular alkali metal or alkaline earth metal salts, of the free carboxylic acid and reacting them with reactive esters of alcohols, such as unsubstituted or substituted lower alkanols, such as corresponding halides, e.g. Chlorides, bromides or iodides, or organic sulfonic acid esters, e.g. Niederalkansulfonsäure- or Arensulfonsäureestern, such as methanesulfonic or p-toluenesulfonic acid, are treated, or if corresponding hydrolyzable imino esters, such as corresponding imino-lower alkyl esters, hydrolyzed to the esters.

The reaction of free carboxylic acids with alcohols, such as unsubstituted or substituted lower alkanols, is advantageously carried out in the presence of an acid, dehydrating catalyst, such as a protic acid, for example hydrochloric, hydrobromic, 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 and / or in an inert solvent, if necessary, under distillative, eg azeotropic, removal of the water liberated in the reaction. Furthermore, the reactions can also be carried out in the presence of water-binding condensing agents, such as suitably substituted carbodiimides, for example N, N'-diethyl, Ν, Ν'-dicyclohexyl or N-ethyl-N ^f - (3-dimethylaminopropyl) -carbodiimide , optionally in inert organic solvents. Mixed anhydrides, in particular acid halides, are used, 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 of alkali metal or alkaline earth metal hydroxides or carbonates, such as sodium, potassium or calcium hydroxide or carbonate, with alcohols or with alcoholates, ζ.S. Alkali metal lower alkoxides reacted.

- 42 -

The reactions of reactive esters, for example cyanomethyl or Pentachlorphenylestern, with alcohols, for example, in a relation to the reactants inert solvent and in the temperature range of about 0 ° to about 12O ⁰ C, preferably at room temperature to about 60 ⁰ C, performed.

The hydrolysis of Iminoester-, in particular Iminoniederalkylester starting materials, for example, by means of hydrous mineral acids, such as hydrochloric acid or sulfuric acid, wherein, for example, in the addition of hydrogen chloride to nitriles and reaction with anhydrous alcohols, in particular unsubstituted or substituted lower alkanols. obtained Iminoestersalze, eg hydrochlorides, after addition of water can hydrolyze directly to the corresponding esters. It is also possible, for example, to obtain the desired ester compound of the formula 1 from a mixture of the nitrile starting material, an alcohol and sulfuric acid with a suitable water content, without isolation of the imino ester formed in situ .

Compounds of the formula I in which the radical Ac represents the acyl radical of a carbonic acid monoamide can be obtained from compounds of the formula IX in which Ac represents a carboxy group, an acid anhydride group such as halocarbonyl, e.g. Chlorocarbonyl, or an activated ester group, such as Cyanmethoxycarbonyl or Pentachlorpheny loxycarbonyl, by reacting such starting materials, optionally in the presence of a suitable condensing agent, with ammonia or an ammonia donating agent or an N-mono- or N, N-disubstituted amine.

These conversions of carboxy and suitably functionally modified reactive carboxy groups into optionally fö mono- or Ν, Ν-disubstituted carbamoyl groups can be carried out in a manner known per se, e.g. according to the procedures described for the formation of the ester groups. ·.

Compounds of the formula I in which the group Ac is carbamoyl can be obtained starting from compounds of the formula IX in which

- 43 -

the residue Ac represents cyano, also obtained. Such starting materials may be hydrolytically, preferably under acidic or basic conditions, e.g. in the presence of an alkali metal such as sodium hydroxide and, if desired, hydrogen peroxide, in an aqueous-alcoholic solvent such as aqueous ethanol, into the desired compounds of formula I with a carboanyl group Ac.

The above or below given reactions can be carried out under known reaction conditions, in the absence or usually 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 of about -1O ⁰ C to about 150 ⁰ C, under atmospheric pressure or in a closed vessel, optionally under pressure, and / or.in an inert atmosphere, for example under a nitrogen atmosphere.

Starting materials of the formula IX with free carboxy group Ac can e.g.

can be obtained by preparing the corresponding 2-Cyanoäthy! ester and this, under mild conditions, e.g. by means of aqueous or aqueous-lower alkanolic 1-n. Sodium hydroxide at room temperature, splits to the free carboxylic acid. The 2-cyanäthylester itself can be, for example, by reacting a compound of formula IV with a compound of formula VT, wherein Ac represents a 2-cyanoethyloxycarbonyl group, and a compound of formula V. If necessary, the free carboxy group present in the starting material of the formula IX can be converted into the desired reactive, functionally modified form in a manner known per se. °

The nitrile compounds of the formula IX which are likewise suitable as starting materials for the process variant e) may e.g. are prepared analogously to the above-mentioned 2-Cyanäthylester compounds by using intermediates which contain a cyano group in place of the radical Ac.

- 44 -

Compounds of formula I wherein R is functionally modified formyl can be e.g. according to process b) from a compound of formula V wherein R is functionally modified formyl, e.g. a di-lower alkyl acetal, and in each case one compound of the formulas IV and VI are prepared (see also European Patent Application 107 203).

Compounds of the formula I in which R is functionally modified formyl can be converted in a manner known per se into compounds of the formula I in which R is formyl, which in turn is converted in a manner known per se into other compounds of the formula I in which R is, for example, hydroxymethyl Hydroxyimino or cyano can be converted (see Belgian Patent 879,263). Likewise, it is possible, for example, analogously to process b) from a compound of formula V in which η = 0, R is functionally modified formyl and Z is preferably a group -OR ₇ , where R_> for example, an acid protecting group, such as 2-cyanäthyl or carbamoylmethyl, and in each case one compound of the formulas IV and VI first produce a compound of the formula II in which η = 0 and R denotes a functionally modified formyl. In the latter case, the radical R can in turn be converted, as indicated above, for example, into formyl, hydroxymethyl, hydroxyimino or cyano. The compounds of the formula II mentioned can be converted into compounds of the formula I according to process a).

Analogously, compounds of formula I wherein R is functional formyl are also available, e.g. according to process cb) by reacting each compound of formula IV and Vb with a compound of formula VIb, wherein R is functionally modified formyl. Such compounds of the formula I can in turn be converted in a manner known per se into other compounds of the formula I in which R is e.g. Formyl, hydroxymethyl, hydroxyimino or cyano means.

- 45 -

Compounds of the formula II analogously also of the formula I -, in which R represents amino, may be e.g. according to process c), in particular according to variant cb), from a compound of formula Vb ', which is completely analogous to a compound of] amino and η e.g. stands for 0,

is completely analogous to a compound of formula Vb, wherein R

COZ HC II / C _x (Vb ')

NH NH I ^L

and in each case a compound of the formulas IV and VIb are prepared (see Liebigs Ann. Chem. 1977 , 1895-1908). Starting compounds of the formula Vb 'are obtainable according to the customary amidine syntheses, for example by conversion of a compound NC-CH-COZ into the corresponding imino ether, for example by means of methanol and HCl, and treatment of the latter, for example with ammonia.

In the same way, it is also possible to prepare compounds of the formula I in which R is amino, namely according to method b) each of a compound of formula IV and V with a compound of formula VI, wherein R is amino.

Compounds of formula I in which Ac is an acyl radical of cyclic carbonic acid derivatives and / or R "is a carbocyclic or heterocyclic aryl radical may be e.g. according to process b), wherein the starting compounds of formula VI are e.g. analogous to those described in US Pat. No. 4,414,213. * "

Compounds of formula I in which R represents unsubstituted or substituted lower alkyl may be e.g. by N-alkylation

- 46 -

from corresponding compounds of formula I wherein R is hydrogen (see US Patent 4,258,042).

Compounds of the formula I in which R is, for example, hydroxyl can be prepared, for example, according to process c), in particular variant ce), from a compound of the formula XI and hydroxylamine (cf., European Patent Application 93 945). From those compounds of the formula I in which R _{1 is} hydroxy, compounds of the formula I in which R is etherified or esterified hydroxy are obtained by methods known per se for O-alkylation and O-acylation.

Compounds of the formula I in which R ₁ and R "together are unsubstituted or substituted lower alkylene, in which a carbon atom is optionally replaced by a heteroatom, can be prepared, for example, according to process b ¹ ) (cf., Liebigs Ann. Chem. 1977 , 1888- 1894). Compounds of the formula I in which R and R together are unsubstituted or substituted lower alkylene, in which a carbon atom is optionally replaced by a heteroatom, are, for example, in a reaction of a compound of the formula VIa with a compound of the formula Vb according to process cg). available.

Compounds of formula I wherein R is hydrogen are e.g. by reaction of a compound of formula VIa with a compound of formula Vb in which R represents di-lower alkylamino or lower alkylene-amino. There are initially formed 3,4-dihydropyridines, which by hydrogenation, for example in glacial acetic acid over PtO ", in an addition-elimination reaction to give the desired compounds [cp. Angew. Chem. _9_3, 755-763 (1981)]. Compounds of the formula I in which R "is hydrogen are completely analogously obtainable from a compound of Va and a compound of the formula VI in which R is di-lower alkylamino or loweralkyleneamino.

- 47 -

There are numerous references in the literature to the preparation of 4-aryl-l, 4-dihydropyridines, for example in Angew. Chem. 93, 755-763 (1981), Liebigs Ann. Chem. 1977 , 1888-1894 and 1895-_ 1908, BE 879 263, DE-A-3 207 982, European Patent Applications 26 317, 60 897, 93 945 and 107 203 and US Pat. Nos. 4,258,042 and 4,414,213.

Compounds of the formula I which can be obtained according to the invention can be converted into other compounds of the formula I in a manner known per se.

So you can, for example in compounds of the formula I in which R is hydrogen, by treatment with a reactive ester of an alcohol of the formula R -OH (XH) to introduce an organic radical R and thus obtain compounds of the formula I in which R is different from hydrogen.

Reactive esters of compounds of formula XH, 2.B. unsubstituted or substituted lower alkanols are those with strong, inorganic or organic acids; in this case, for example, the corresponding halides, in particular chlorides, bromides or iodides, further sulfates, further Niederalkansulfonsäure- or Arensulfonsäureester, for example Methansulfonsäure-, benzenesulfonic or p-toluenesulfonic, into consideration. The reaction is, if necessary, while cooling or heating, for example in a temperature range from about 0 ⁰ C to about 100 ⁰ C, in the presence of a suitable basic condensation agent, for example an alkali metal, alkali metal amide or hydride, or a Alkalimetallniederalkoxids such as sodium or potassium -methoxide, -äthoxid or tert-butoxide, in the presence or absence of a solvent or diluent, at reduced or elevated temperature, for example in a temperature range of about 0 ⁰ C to about 100 ⁰ C, and / or under atmospheric pressure or carried out in a closed vessel.

- 48 -

In such N-substitution reactions, preference is given to using compounds of the formula I which have no other primary or secondary amino groups as substituents, since these may also react with the reactive ester of an alcohol of the formula XII under certain circumstances.

Compounds of the formula I in which Z is the radical NR ₀ R or 0R_,

ο y /

wherein R 1 is optionally substituted lower alkyl, may be described in the same manner as described above for compounds of formula Ha, wherein R represents a functionally modified carboxy group, e.g. by hydrolysis in alkaline or acid medium, to a compound of formula I wherein Z is hydroxy. Conversely, compounds of the formula I in which Z is hydroxyl can be prepared in a manner known per se by the customary methods of esterification, e.g. with an excess of a lower alkanol in the presence of an acid, e.g. Hydrogen chloride, as a catalyst, in a compound of formula I, wherein Z is 0R_ and R is optionally substituted lower alkyl, transfer. Similarly, compounds of formula I wherein Z is hydroxy may also be prepared by the usual methods of amide formation, e.g. by reaction with ammonia or a primary or secondary amine, optionally with removal of the water formed in the reaction, in compounds of the formula I in which

Z is the group NR R, transferred. 8 9

Compounds of formula I in which η is 1 or 2 and Z is hydroxy are identical to compounds of formula II wherein n 'is 1 or 2 and R is carboxy. They can be converted according to process a) by reaction with a compound of formula III into other compounds of formula I, wherein η is 2 or 3.

Compounds of the formula I in which Z is OR ₇ and R is benzyl can be converted, for example, by hydrogenolysis into other compounds of the formula I in which Z is hydroxyl.

- 49 -

In addition, substituents present in the process according to the invention of compounds of the formula I can be converted into other substituents.

Thus, for example, esterified carboxy groups, such as corresponding groups Ac and / or CC = O) -OR ₇ , can be converted by transesterification into other esters. In this case, it is preferable to use corresponding alcohol compounds which have a boiling point which is significantly above that of the alcohol of the esterified group in the compound of the formula I to be converted, and leads to the reaction, for example, in an excess of the hydroxy compound and / or an inert organic, preferably likewise clearly over the alcohol of the esterified group boiling solvent, preferably in the presence of a catalyst, for example an alkali metal lower alkoxide, such as sodium or Kaliummethoxid or -äthoxid, or Orthotitansäure niederalkylesters, such as isopropyl orthotitanic acid, in the heat and usually with distilling off the released alcohol.

Esterified carboxy groups, for example corresponding radicals Ac or especially a radical Z = CC = O) -OR _79, can also be converted into other esters, for example by first saponifying them, for example acidically or preferably alkaline, and the acid obtained in a manner known per se transferred to another ester.

Compounds of the formula I having esterified carboxy groups, such as lower alkoxycarbonyl groups, in particular corresponding groups Ac or the radical C (O) -OR, can be converted into those with corresponding carbamoyl groups, e.g. by treatment with ammonia, furthermore mono- or di-substituted amines, if necessary under elevated temperature and / or in a closed vessel.

Suitable substituents of an aromatic radical, e.g. Halogen, in particular fluorine, may be substituted with other substituents, e.g. an optionally substituted "amino group (e.g., by treatment with a primary or secondary amine, e.g., a compound of Formula X).

- 50 -

All starting materials which contain one or more optically active carbon atoms and are mentioned in the described processes and after-operations can be employed as racemic mixtures, racemates, optical isomers or mixtures of optical isomers in the corresponding reactions and generally give compounds of the formula I in which the corresponding carbon atoms have the same configuration or configurations as in the starting product.

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

Obtained acid addition salts can be prepared in a manner known per se into the free compounds, e.g. by treatment with a base, such as an alkali metal hydroxide, or in other salts, e.g. by treatment with suitable acids or derivatives thereof. Obtained free compounds with salt-forming properties, e.g. with corresponding basic groups, may e.g. be converted into their salts by treatment with acids or corresponding anion exchangers.

Due to the close relationship between the compounds of the formula I in free form and in the form of salts, in the preceding and following among the free compounds or their salts meaningful and expedient, if appropriate, to understand the corresponding salts or free compounds.

The compounds, including their salts, may also be obtained in the form of their hydrates, or their crystals may be e.g. Include the solvent used for crystallization.

Depending on the process reaction and / or the nature of the starting materials, the compounds of the formula I can be obtained in the form of racemates, racemate mixtures or optical antipodes.

Resulting Racematgemische can due to the physico-chemical differences of the racemates in a known manner in the pure race

- 51 -

mate or diastereomers are separated, for example by chromatography and / or fractional crystallization.

Racemates may be resolved into the optical antipodes by methods known per se, for example by recrystallization from an optically active solvent, by means of suitable microorganisms or by reacting a compound of formula I with salt-forming, e.g. basic properties with an optically active salt-forming agent such as an optically active acid and separation of the mixtures of salts thus obtained, e.g. because of their different solubilities, in the diastereomeric salts from which the antipodes, e.g. by treatment with a base, can be released.

Optical antipodes of neutral compounds of formula I can be obtained e.g. also obtained according to process e) using an optically active acid of the formula IX, these being e.g. from the corresponding racemic acid in the usual manner, e.g. by salification with an optically active base, separation of the diastereomeric salts and liberation of the optically active acid, or by using a reactive functional derivative of an optically active acid. can form.

Furthermore, one can e.g. Compounds of formula I which contain an esterified carboxy group, e.g. a corresponding group Ac, transesterify using an optically active alcohol according to the method described above and the diastereomeric mixture thus obtained, e.g. by fractional crystallization, split into the antipodes.

Advantageously, the pharmacologically active isomer or active antipode is isolated from a diastereomer mixture or racemate. The pharmacological activity is usually particularly high when the following configuration is present at the C4 carbon of the 1,4-dihydropyridine scaffold: 4R, if, according to the rule, of

- 52 -

Cahn, Ingold and Prelog the substituent in the 5-position, i. the amino acid side chain, lower priority than the Ac radical has in the 3-position of Dihydropyridingerüsts and higher priority than the radical Ar. Conversely, 4S if the remainder Ac has a lower priority than the amino acid side chain and a higher priority than the remainder Ar. Thus, the following configuration at the C4 carbon is preferred, wherein the carbon atoms C3, C4 and C5 are in the paper plane, the remainder Ar in front and the hydrogen atom behind the paper plane:

Ar

The invention also relates to those embodiments of the process according to which one proceeds from a compound obtainable as intermediate at any stage of the process and carries out the missing steps or a starting material in the form of a derivative, e.g. Salt, and / or its racemates or antipodes used or forms under the reaction conditions.

In the methods of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable. New starting materials and processes for their preparation also form an object of the present invention. The invention also relates to novel intermediates obtainable by the process, and to processes for their preparation,

The invention also relates to the use of the compounds of the formula I or of pharmaceutically usable salts of such compounds having salt-forming properties, in particular as phanacologically, primarily as coronary dilatory and / or anti-corrosive agents.

Hypertensive compounds. In doing so, they can be used, preferably in the form of pharmaceutical preparations, in a process for

- 53 -

phylactic and / or therapeutic treatment of the animal or human body, in particular for the treatment of angina pectoris, hypertension and other cardiovascular diseases.

The dosage of the active ingredient administered alone or in conjunction with the usual carrier and adjuvant material will depend on the species to be treated, its age and individual condition, as well as the mode of administration. The daily doses are for Maomalien with a body weight of about 70 kg, depending on the nature of the disease, individual condition and age, preferably between 1 and 100 mg and in particular between 2 and 20 mg.

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

The pharmaceutical preparations according to the invention are those for enteral, such as peroral or rectal administration, further for sublingual administration and for parenteral administration to warm-blooded animals. Corresponding dosage unit forms, especially for peroral and / or sublingual administration, e.g. Dragees, tablets or capsules preferably contain from about 0.5 to about 100 mg, more preferably from about 5 to about 50 mg of a compound of formula I or a pharmaceutically acceptable salt of a corresponding salt-competent compound together with pharmaceutically acceptable carriers.

Suitable carriers are, in particular, fillers, such as sugars, e.g. · Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch pastes using e.g. corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrating agents, such as the abovementioned starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone

- 54 -

don, agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow regulators and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores can be provided with suitable, optionally gastric juice-resistant coatings, which u.a. concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate used. The tablets or dragee coatings may contain dyes or pigments, e.g. for the identification or labeling of different doses of active substance.

Other orally applicable pharmaceutical preparations are gelatine capsules, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules may contain the active ingredient in the form of granules, e.g. in admixture 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 dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible for stabilizers to be added. Preferred are u.a. Capsules which can be easily bitten, e.g. in case of signs of seizure of angina by sublingual absorption of the active substance to achieve the fastest possible effect, as well as swallowed can be swallowed.

As rectally applicable pharmaceutical preparations are e.g. Suppositories which consist of a combination of the active ingredient with a suppository base. As suppository base, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Further

- 55 -

it is also possible to use gelatin rectal capsules containing a combination of the active substance with a basic mass; as basic materials there are e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, e.g. 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, e.g. Sesame oil, or synthetic fatty acid esters, e.g. Ethyl oleate, or triglycerides, or aqueous injection suspensions containing viscosity increasing agents, e.g. Sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally stabilizers.

The pharmaceutical preparations of the present invention can be prepared in a manner known per se, e.g. be prepared by conventional mixing, granulation, coating, solution or lyophilization process. Thus, one can obtain 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 addition of suitable excipients, processed into tablets or dragee cores ,

The following examples a) to c) are intended to illustrate the preparation of some typical application forms, but by no means represent the only embodiments of such.

a) Tablets containing 25 mg of active ingredient can be prepared as follows:

Composition: (for 1000 tablets)

Active ingredient 25.Og

Cornstarch 70.0 g

Lactose (fine) 78.5 g

Cellulose 75.0 g

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Magnesium stearate 1.5 g

Water q.s.

The active ingredient is mixed with 60 g of corn starch and lactose and kneaded with a paste made from 10 g of corn starch and water. The wet mass is granulated, dried and mixed with the crystalline cellulose and the magnesium stearate. The homogeneous mixture is compressed into tablets of 250 mg (with scored groove); These have a diameter of 9 mm.

b) Capsules containing 10 mg of active ingredient can be prepared as follows:

Composition:

Active ingredient 2500 mg

Talcum 200 mg

Colloidal silica 50 mg

The active ingredient is intimately mixed with talc and colloidal silica, the mixture is forced through a sieve of 0.5 mm mesh size and this is filled into portions of 11 mg each in hard gelatin capsules of suitable size.

c) a sterile solution of 5.0 g of active ingredient in 5000 ml of distilled water is filled into 5 ml ampoules containing 5 ml of active ingredient in 5 ml of solution.

AusfOhrungsbeispiel

The following examples illustrate the preparation of the novel compounds of the formula I, but are intended to scope

- 55a -

restrict the invention in any way. Temperatures are given in degrees centigrade.

- 57 -

Example 1: A mixture of 9.6 g of gl, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid 3- (1-benzotriazolyl) -star-5-methyl ester, 3.6 g L-valine ethyl ester hydrochloride and 2.5 ml of N-ethylmorpholine in 90 ml of anhydrous dimethylformamide is stirred for 16 hours at 80 ° under nitrogen atmosphere. The yellow reaction mixture is mixed with ice-cold water with 300 ml of ice-water. The mixture is then stirred for 1 hour in an ice bath at 0-5 °, wherein the crude product separates as a highly viscous mass. The solvent is decanted off and the residue is dried under reduced pressure. The resinous crude product obtainable in this way is a 1: 1 diastereomer mixture of (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5 carboxylic acid N ~ t (IS) -l-ethoxycarbonyl-2-methyl-l-propyl] -amide.

To separate the diastereomers, the crude product is mixed with 30 ml of diisopropyl ether and stirred for 1 hour at 0-5 °, whereby (+) - (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -1-ethoxycarbony1-2-methyl-1-propyl] -amide crystallized in the form of pale yellow crystals. This first diastereomer is configurationally uniform; it melts at 198-200 ° and its specific rotation is [α] = + 75 ° (c = 0.6, ethanol),

To isolate dffi second diastereomers, the mother liquor is evaporated under reduced pressure. The residue is purified by chromatography on about 100 times the amount of silica gel (Elutibn with a 7: 3 mixture of hexane and ethyl acetate) and crystallized the crude second diastereomer by stirring in 20 ml of diethyl ether at 0-5 °. The thus obtainable (-) - (4R) -l, 4-dihydro-2,6-dimethyl

- 58 -

3-Methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -I-ethoxycarbonyl-2-methyl-1-propyl] -amide melts at 147-148 °. The crude product is further purified by recrystallization from acetone. The pale yellow thus obtained; fine-leaved needles melt at 156-157 °, at the same time as a new crystal modification deep yellow, rhombic crystals start to grow from the melt; remelting takes place at 171-172 °. This crystalline second diastereomer is configurationally uniform and displays a

20 specific rotation of [α] = -34.9 ° (c = 1.0, ethanol).

The starting material can be prepared as follows: A solution of 6.7 g of glom, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3 _r 5-dicarboxylic acid monomethyl ester [s. European Patent Application 11,706], 3.4 g of 1-hydroxybenzotriazole and 4.6 g of N, N'-dicyclohexylcarbodiimide in 100 ml of anhydrous dimethylformamide are allowed to stand for 16 hours at 0-5 ° under nitrogen atmosphere. The crystallized Ν, Ν'-dicyclohexylurea is filtered off. The yellow filtrate is mixed with 300 ml of water under ice-bath cooling and stirred for 1 hour at 0-5 °, wherein the amorphous crude product is deposited. It is filtered off: riert, washed the filter residue with 400 ml of water and dried in vacuo. For further purification, the crude product is dissolved in 40 ml of ethyl acetate and stirred for 1 hour at 0-5 °. Then the crystallized Ν, Ν'-dicyclohexylurea is removed by filtration and the filtrate is evaporated under reduced pressure,

to give l, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid 3- (1-benzotriazolyl) ester 5-methyl ester as a high-viscosity foam in quantitative yield : FT 250 MHz ¹ H NMR (CDCl ₃₎ 2.46 (2s, 6H, dihydropyridyl-CH); 3.70 (s, 3H, -COOCH ₃ ); 5.44 ( _s , IH, 4-dihydropyridyl-H); 6.78 (s, IH, NH); 6.92, 7.39, 8.04 (3m, AH, BenzotriazoIyI-H); 6.48, 7.79, 8.14, 8.24 (4m, 4H, phenyl-H).

- 59 -

Example 2: A mixture of 12.5 g of (S) -N-acetoacetyl-a-aminoisovaleric acid ethyl ester [prepared analogously to Pharm. Acta HeIv.

38 , 616 (1963) 3, 6.2 g of 3-amino-crotonic acid methyl ester and 8.2 g of 3-nitrobenzaldehyde in 100 ml of ethanol is stirred for 16 hours at 80 ° under a nitrogen atmosphere. The yellow reaction mixture is evaporated under reduced pressure. The oily residue is dissolved in 300 ml of dichloromethane and washed twice with 100 ml of water. The organic phase is dried with sodium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by chromatography on about 100 times the amount of silica gel (elution with a 7: 3 mixture of hexane and ethyl acetate). The resinous crude product thus obtained is a 1: 1 diastereomeric mixture of (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5 carboxylic acid N - [(IS) -l-ethoxycarbonyl-2-methyl ~ l-propyl] -amide. The separation of the diastereomers is carried out as described in Example 1.

Example 3: To a solution of 3.5 g, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid chloride [s. Chem. Pharm. Bull. 28., 2809 (198O)] and 1.3 ml of N-ethylmorpholine in 30 ml of anhydrous tetrahydrofuran is added dropwise at 0-10 °, a solution of 1.8 g of L-valine ethyl ester hydrochloride in 30 ml of anhydrous tetrahydrofuran. After the addition is allowed to warm to room temperature. The reaction mixture is evaporated under reduced pressure. The residue is dissolved in 100 ml of dichloromethane

- 60 -

and washed several times with water. The organic phase is dried with sodium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by chromatography on about 100 times the amount of silica gel (elution with a 3: 7 mixture of ethyl acetate and hexane). The crude product obtainable in this way is a 1: 1 diastereomer mixture of (4R) - and (4S) -I, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(lS) -l-ethoxycarbonyl-2-methyl-l-propyl] -amide. The separation of the diastereomers is carried out as described in Example 1.

EXAMPLE 4 Analogously to the process described in Example 1, a mixture of 42 g of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid is obtained. Methyl 3- (1-benzotriazoyl) ester 5-methyl ester, 16 g D-valine ethyl ester hydrochloride and 11 ml N-ethylmorpholine in 350 ml anhydrous dimethylformamide (-) - (4R) -l, 4-dihydro- 2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(1R) -1-ethoxycarbonyl-2-methyl'-1-propyl] -amide, which, after recrystallization from a mixture of acetone and diisopropyl ether at 199-200 ° melts. This diastereomer is configurationally uniform and exhibits a specific rotation of [η] = -75 ° (c = 0.7, ethanol).

From the mother liquor, analogously to the process described in Example 1, (+) - (4S) -I, 4-dihydro-2,6-dimethyl-3-methoxycarbony1-4- (3-nitrophenyl) -pyridine-5-carboxylic acid -N - [(1R) -1-ethoxycarbonyl-2-methyl-1-propyl] amide. By trituration of the amorphous crude product with diethyl ether crystallizierr. this diastereomer in configurationally uniform form; it melts at 144-145 ° and shows a specific rotation of [α] = + 30 ° (c = 0.4, ethanol).

Example 5 Analogously to the process described in Example 1, from a mixture of 10.2 g, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid-3- (1 benzotriazoIyI) -5-isopropyl ester, 3.5 g of L-valine ethyl ester hydrochloride and 2.5 ml

- 61 -

N-ethylmorpholine in 90 ml of anhydrous dimethylformamide (-) - (4R) -l, 4-dihydro-2,6-dimethyl-S-isopropoxycarbonyl- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -l-ethoxycarbonyl-2-methyl-1-propyl) -amide, which melts after recrystallization from ethyl acetate at 178-179 °. The specific rotation of this configurationally uniform diastereomer is [α] = -28 "(c = 0.9, ethanol).

From the mother liquor, (+) - (AS) -1,4-dihydro-2,6-dimethy1-3-isopropoxycarbonyl-A- (3-nitrophenyl) -pyridine-5-carboxylic acid is prepared analogously to the process described in Example 1 -N - [(IS) -l-ethoxycarbonyl-2-methyl-1-propylT] -amide in amorphous form. The specific rotation of this amorphous diastereomer is [et] = + 46 ° (c = 0.45, ethanol); According to the H-NMR spectrum, it still contains about 20% of (-) - (4R) -1, 4 = Dxhydro-2 ₁ 6-dimethyl-1-3-isopropoxycarbonyl-1-4- (3-nitrophenyl) -pyridine 5-carboxylic acid-N ~ {(IS) -1-äthoxycarbony1-2-methyl-1-propy1] -amide.

The starting material can be obtained as follows. Analogously to the process described in Example 1 is obtained from a mixture of 16.2 g of l, 4-dihydro-2,6-dimethy1-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid monoisopropyl ester [s. European Patent Application 11,706], 7.6 g of 1-hydroxybenzotriazole and 10.2 g of Ν, Ν'-dicyclohexylcarbodiimide in 225 ml of anhydrous dimethylformamide 1, 4-dihydro-2,6-

triazolyl) ester 5-isopropyl ester as an amorphous product. FT- 250 mHz ¹ H-NMR (CDCl _3): 1.13 1.30 (2d, 6H, I sopropyl-C ^); 2.44, 2.46 (2s, 6H, dihydropyridyl CH ₃ ); 5.00 (m, IH, -0-CH-); 5.40 (s, IH, 4-dihydropyridyl-H); 6.28 (s, IH, -NH-); 6.89, 7.40, 8.05 (3m, 4H, benzotriazolyl-H); 7.49, 7.79, 8.15, 8.25 (4m, 4H, phenyl-H)

- 62 -

Example 6 Analogously to the process described in Example 1, a mixture of 30 g, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid-3- (1) BenzotriazoIyI) ester 5-isopropyl ester, 9.8 g of D-valine ethyl ester hydrochloride and 6.8 ml of N-ethylmorpholine in 120 ml of anhydrous dimethylformamide (+) - (4S) -1,4-dihydro-2,6-dimethyl-3 -isopropoxycarbonyl-4- (3-nitropheny1) -pyridine-5-carboxylic acid N - [(IR) -l-ethoxycarbonyl-2-methyl-l-propyl] -amide.

This configurationally uniform diastereomer melts at 176-177 °

20 and shows a specific rotation of [et] = +24 (c = 0.53, ethanol),

From the mother liquor, analogously to the process described in Example 1, (-) - (4R) -I, 4-dihydro-2,6-dimethy1-3-isopropoxycarbony1-4- (3-nitrophenyl) -pyridine-5-carboxylic acid -N - [(1R) -1-ethoxycarbonyl-2-methyl-1-propyl] -amide in amorphous form. The specific rotation of this amorphous diastereomer is [α] = -47 ° (c = 0.65, ethanol); According to the H-NMR spectrum, it still contains about 5% of (+) - (4S) -I, 4-dihydro-2,6-dimethy1-3-isopropoxycarbony1-4- (3-nitrophenyl) -pyridine-5- carboxylic acid N - [(lR) -l-ethoxycarbonyl-2-methyl-lpropyl] -amide.

Example 7 Analogously to the process described in Example 1, a mixture of 42 g, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3, 5-dicarboxylic acid 3- (1 -benzotriazolyl) -ester-5-isopropyl esterj 14 g of L-leucine methyl ester hydrochloride and 9.6 ml of N-ethylmorpholine in 250 ml of anhydrous dimethylformamide (+) - (4S) -l, 4-dihydro-2,6 -dimethyl-3-isopropoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(1S) -1-methoxycarbonyl-3-methyl-1-butyl] -amide, which, after recrystallization from ethyl acetate at 176 -177 ° melts. This crystalline diastereomer is configurationally uniform and shows eii (c = 0.48, ethanol).

uniform and shows a specific rotation of [<*] ^{= +} 106

- 63 -

From the mother liquor, (-) - (4R) -I, 4-dihydro-2, 6-dimethyl-S-isopropoxycarbonyl-A- (3-nitrophenyl) -pyridine-5-carboxylic acid N is prepared analogously to the process described in Example 1 - [(IS) -l-methoxycarbonyl-3-methyl-1-butyl] -amide isolated. Trituration of the amorphous crude product with diethyl ether crystallizes this diastereomer in a configurationally uniform form; it melts at 154-155 ° and shows a specific rotation of [aJ _D = -55 ° (c = 0.78, ethanol).

Example 8: "Analogously to the process described in Example 1, a mixture of 21 g, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid-3- ( 1-benzotriazolyl) -ester-5-isopropyl ester, 6.9 g of D-leucine methyl ester hydrochloride and 4.8 ml of N-ethylmorpholine in 120 ml of anhydrous dimethylformamide (-) - (4R) -l, 4-dihydro-2,6-dimethyl 3-isopropoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(1R) -1-methoxycarbonyl-3-methyl-1-butyl] -amide, which, after recrystallization from ethyl acetate at 175.degree This configurationally uniform diastereomer shows a specific rotation of [ot] = -109 ° (c. = 0.28, ethanol).

From the mother liquor, (+) - (4S) -l, 4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4- (3-ni tropheny1) -pyridine-5, analogously to the method described in Example 1, carboxylic acid N - [(IR) -1-methoxycarbony1-3-methyl-1-butyl] -amide in amorphous but configurationally uniform form. The specific rotation of this diastereomer is [α] = + 48 ° (c = Ο »79, ethanol).

Example 9 Analogously to the process described in Example 1, a mixture of 23 g, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl-pyridine-S, S-dicarboxylic acid, S-benzotriazoly-D-ester-S) is obtained. methyl ester, 9.3 g of D-leucine ethyl ester hydrochloride and 3.5 ml of N-ethylmorpholine in 150 ml of anhydrous dimethylformamide (-) - (4R) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbony1-4- (3 -nitropheny1) -pyridine-5-carboxylic acid N- [(IR) -1-ethoxycarbonyl-S-methyl-1-butyl] -amide,

- 64 -

which melts after recrystallization from a mixture of ethyl acetate and diisopropyl ether at 207-209 °. This diastereomer is configurationally uniform, which is specific rotation

[α] = -116 ° (c = 0.76, ethanol).

From the mother liquor, analogously to the process described in Example 1, (+) - (4S) -I, 4-dihydro-2,6-dimethy1-3-methoxycarbony1-4- (3-nitrophenyl) -pyridine-5-carboxylic acid -N - [(1R) -1-ethoxycarbonyl-3-methyl-1-butyl] -amide. After recrystallization of the crude product; a mixture of diethyl ether and hexane gives a crystalline product which melts at 112-114 ° and whose specific rotation is [α] = + 21 ° (c = 0.5, ethanol). This crystalline form contains 5-10% (-) - (4R) -l, 4-dihydro-2,6-dimethy1-3-methoxycarbony1-4- (3-nitrophenyl) -pyridine based on the H-NMR spectrum. 5-carboxylic acid-N - [(lR) -l-ethoxycarbonyl-3-methyl-l-butyl] -amide.

EXAMPLE 10 Analogously to the process described in Example 1, from a mixture of 19.2 g of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl-pyridine-S, S-dicarboxylic acid, -Cl-benzotriazoly-D, ester S-methyl ester, 7.8 g of L-leucine ethyl ester hydrochloride and 2.9 ml of N-ethylmorpholine in 120 ml of anhydrous dimethylformamide (+) - (4S) -l, 4-dihydro-2,6-dimethy1-3- methoxycarbony1-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(1S) -1-ethoxycarbonyl-3-methyl-1-butyl] -amide, which, after recrystallization from a mixture of ethyl acetate and diisopropyl ether at 206 This crystalline form is configurationally uniform, the specific rotation is [et] = + 105 ° (c = 0.26, ethanol).

From the mother liquor, analogously to the process described in Example 1, (-) - (4R) -I, 4-dihydro-2,6-dimethy1-3-methoxycarbony1-4- (3-nitrophenyl) -pyridine-5-carboxylic acid -N - [(IS) -l-ethoxycarbonyl-3-methyll-butyl] -amide as a crude product isolated. By recrystallization from a mixture of diethyl ether and hexane to obtain a crystalline

-i 65 -

Product which melts at 118-120 ° and whose specific rotation is [α] = -23 ° (c - 0.7, ethanol). This crystalline form contains, due to the H-NMR spectrum for about 20% (+) - (4S) -l, 4-dihydro-2,6-dimethyl-3-Methox> ^r carbonyl-4- (3-nitrophenyl) pyridine-5-carboxylic acid-N - [(IS) -l-ethoxycarbonyl-3-methy1-1-butyl] -amide.

Example 11 Analogously to the process described in Example 1, a mixture of 25 g of di-1-dihydro-C₁-dimethyl-O-nitropheny-pyridine-S-dicarboxylic acid S-Cl-benzotriazoly-D-ester-5-methyl ester is obtained , 8.6 g of L-proline methyl ester hydrochloride and 6.6 ml of N-ethylmorpholine in 120 ml of anhydrous dimethylformamide (+) - (4S) -5 - [(2S) -2-methoxycarbonyl-pyrrolidin-1-ylcarbonyl] -l , 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine, which melts after recrystallization from a mixture of ethyl acetate and hexane at 180-181 °. This crystalline diastereomer is configurable

1 ^{2C J} D

uniform, the specific rotation is [α] = + 104 "

(c = 0.7, ethanol). '

From the mother liquor, analogously to the process described in Example 1, (-) - (4R) -5 - [(2S) -2-methoxycarbonylpyrrolidin-1-ylcarbonyl] -1,4-dihydro-2,6 -dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) pyridine, which melts after recrystallization from a mixture of ethyl acetate and diisopropyl ether at 118-119 °. This configurationally uniform diastereomer shows a specific rotation of [ct] _ = -59 ° (c = 0.5, ethanol).

Example 12 Analogously to the process described in Example 1, a mixture of 23 g, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid-3- (1) benzotriazolyl) ester 5-methyl ester, 7.9 g of D-proline methyl ester hydrochloride and 6 ml of N-ethylmorpholine in 150 ml of anhydrous dimethylformamide (-) - (4R) -5 - [(2R) -2-methoxycarbonyl-pyrrolidine l-yl-carbonyl] -l, 4-dihydro-2,6 ~ dimethyl-3-

- 66 -

methoxycarbonyl-4- (3-nitrophenyl) -pyridine, which melts after recrystallization from a mixture of acetone and diisopropyl ether at 180-181 °. This crystalline diastereoniere is configurationally uniform and Zt ethanol).

lends and shows a specific rotation of [ctL · = -97 ° (c = 0.97,

From the mother liquor, analogously to the process described in Example 1, (+) - (4S) -5 - [(2R) -2-methoxycarbonyl-pyrrolidin-1-ylcarbonyl] -1,4-dihydro-2,6 -dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) pyridine, which melts after recrystallization from a mixture of acetone and diethyl ether at 120-122 °. This configurationally uniform diastereomer zi (c = 0.55, ethanol).

Liechten diastereomers shows a specific rotation of [α] = + 56 °

EXAMPLE 13 Analogously to the process described in Example 1, from a mixture of 18 g of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl-pyridine-S, 5-dicarboxylic acid, S-Cl-benzotriazoly-D-ester- S-methyl ester, 4.7 g of glycine methyl ester hydrochloride and 4.7 ml of N-ethylmorpholine in 150 ml of anhydrous dimethylformamide racemic l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-ni trophenyD-pyridine-5 -carboxylic acid-N- (methoxycarbonyl-methyl) -amide in amorphous form 250 MHz FT ¹ H-NMR _(CDCl3): 2.32 2:35 (2s, 6H, dihydropyridyl-CH ^, 3.67, 3.73 (2s, 6H,. -COOCH _3); 4.00 (d, 2H, _-N-CH2); 4.96 (s, IH, 4-dihydropyridyl-H); 5.75 (s, IH, 1-dihydropyridyl-H); 5.90 (t, IH, -CONH); 7.4-8.18 (m, 4H, phenyl-H).

Example 14 Analogously to the process described in Example 1, a mixture of 15 g, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl-pyridine-SjS-dicarboxylic acid-Sd-benzotriazolyD-ester-S) is obtained. Methyl ester, 5.2 g of ethyl α-aminoisobutyrate hydrochloride and 3.6 ml of N-ethylmorpholine in 100 ml of anhydrous dimethylformamide racemic l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyD-pyridine-S- carboxylic acid N, N-ethoxycarbonyl-1-methyl-1-ethyl) amide which, after recrystallisation, is prepared from a mixture of acetic acid

- 67 -

ethyl ester and diethyl ether at 160-161 ° melts.

Example 15 Analogously to the process described in Example 1, a mixture of 18.5 g, 4-dihydro-2,6-dimethyl-4- (3-nitropheny-D-pyridine-SjS-dicarboxylic acid-Sd-benzotriazolyD-ester-S) is obtained. methyl ester, 6 g of L-alanine ethyl ester hydrochloride and 4.6 ml of N-ethylmorpholine in 100 ml of anhydrous dimethylformamide a 1: 1 diastereomer mixture of (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl-3 -methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -I-ethoxycarbonyl-1-ethyl] -amide, which after recrystallization from a mixture of ethyl acetate and diisopropyl ether at 134 ° -135 ° melts.

, EXAMPLE 16 Analogously to the process described in Example 1, from a mixture of 21.7 g of 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl-pyridine-S, S-dicarboxylic acid, S-benzotriazoly-D-ester-S) are obtained. methyl ester and 8.2 g of L-tyrosine methyl ester in 100 ml of anhydrous dimethylformamide a 1: 1 mixture of diastereomers of (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3- nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -methmethoxycarbony1-2- (4-hydroxyphenyl) -I-ethyl] -amide in amorphous form 250 MHz FT ¹ H-NMR (CDC1_) _: 2.18, 2.21 , 2.30, 2.32 (4s, 6H, dihydropyridyl-CH); 2.80-3.10 (m, 2H, phenyl-CH); 3.65, 3.75 (2ä, 6H, -COOCH ₃ ); 4.74-4.94 (m, IH, -CON 4.83 (s, IH, 4-dihydropyridyl-H), 5.5-5.8 (m, 3H, -NH and -OH), 6.52-6.78 (m, 4H, hydroxyphenyl-H), 7.30-8.06 ( m, 4H, nitrophenyl-H).

Example 17 Analogously to the process described in Example 1, a mixture of 20 g of glglazole, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid-3- benzotriazolyl) ester 5-methyl ester, 11.5 g of D, La-phenylglycine benzyl ester hydrochloride and 5.2 ml of N-ethylmorpholine in 90 ml of anhydrous dimethylformamide a racemic 1: 1 diastereomer mixture of l, 4-dihydro-2,6-dimethyl 3-Methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- (1-benzyloxycarbonyl-1-benzyl) -amide in amorphous form. 250 MHz FT-H NMR

- 68 -

(CDCl _3): 2.23 2.26 2.32 2:33 (4s, 6H, dihydropyridyl-H); 3.63, 2.67 (2s, 3H, COOCH _3); 4.96, 5.09 (2s, 2H, -COOCH ₂ ); 5.15, 5.16 (2s, IH, 4-dihydropyridyl-H); 5.55 (m, IH, -N-CH-); 5.6, 5.65 (2s, IH, 1-dihydropyridyl-H); 6.32, 6.40, (2d, IH, -CONH-); 7.04-8.12 (a, 14H, phenyl-H).

Example 18 Analogously to the process described in Example 1, from a mixture of 20 g of 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (1-benzotriazolyl ) ester 5-methyl ester, 7 g L-valine ethyl ester hydrochloride and 4.9 ml N-ethylmorpholine in 150 ml anhydrous dimethylformamide a 1: 1 diastereomer mixture of (4R) - and (4S) -4- (2-difluoromethoxyphenyl) -1,4-dihydro-2, ö-dimethyl-3-methoxycarbony1-pyridine-in-5-carboxylic acid N - [(IS) -l-ethoxycarbonyl-2-methyl-1-propyl] -amide, which after recrystallization from melts a mixture of diethyl ether and diisopropyl ether at 98-99 °.

The starting material can be obtained as follows: Analogously to the process described in Example 1 is obtained from a mixture of 17 g of 4- (2-difluoromethoxyphenyl) -1, 4-dihydro-2,6-dimethylpyridine-SS-dicarboxylic acid monomethyl ester [preparation analogously to EP 11.706; Mp 150-152 °], 8 g of 1-hydroxybenzotriazole and 11 g of Ν, Ν'-dicyclohexylcarbodiimide in 150 ml of anhydrous dimethylformamide 4- (2-difluoromethoxyphenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3 , 5-dicarboxylic acid 3- (1-benzotriazolyl) -ES.ter-5-methyl ester as a crude product in amorphous form, which is used without further purification in the following reaction.

Example 19 Analogously to the process described in Example 1, a mixture of 20 g of glglazole, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid, 3- (1) benzotriazolyl) ester 5-methyl ester, 8.9 g of La-phenylglycine ethyl ester hydrochloride and 5.2 ml

-69-

N-ethylmorpholine in 150 ml of anhydrous dimethylformamide a 1: 1 diastereomeric mixture of (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5 -carboxylic acid N - [(IS) -1-ethoxycarbonyl-1-benzyl] -amide as a resinous crude product.

To separate the diastereomers, the crude product is mixed with a mixture of ethyl acetate and diisopropyl ether and stirred for 1 hour at 0-5 °, wherein a first diastereomer crystallized. This configurationally uniform diastereomer melts at 193-194 ° and shows ei (c = 0.7, ethanol).

193-194 ° and shows a specific rotation of [α] ..,. = -66

4.3ο

To isolate the second diastereomer, the mother liquor is evaporated under reduced pressure and the residue purified by chromatography on about 100 times the amount of silica gel (elution with a 1: 1 mixture of hexane and ethyl acetate). The eluate is evaporated under reduced pressure and the residue recrystallized from a mixture of ethyl acetate and hexane. The second diastereomer so obtainable melts at 139-140 ° and exhibits a specific rotation of [<*] _. ⁼ + 46 ° (c = 0.8, ethanol); this crystalline form is still contaminated with about 20% of the first diastereomer according to the H-NMR spectrum.

EXAMPLE 20 Analogously to the process described in Example 1, a mixture of 20% of gl, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl-1-pyridine-S, 5-dicarboxylic acid S-Cl-benzotriazoly-D-ester- S-methyl ester, 8.9 g Da-phenylglycine ethyl ester hydrochloride and 5.2 ml of N-ethylmorpholine in 150 ml of anhydrous dimethylformamide a 1: 1 diastereomer mixture of (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl 3-methoxycarbonyl-4- (3-nitriphenyl) -pyridine-5-carboxylic acid N - [(IR) -I-ethoxycarbonyl-benzyl] amide as a highly viscous crude product.

- 70 -

To separate the diastereomers, the crude product is treated with a mixture of ethyl acetate and diisopropyl ether and allowed to stand for 16 hours at 0-5 °, wherein a first diastereomer crystallized. The crystals are filtered off and recrystallized from ethyl alcohol. The first diastereomer so obtainable is configurationally uniform; it melts at 196-197 ° and shows a specific rotation of [a]., _c = + 61 ° (c = 0.34, ethanol).

4Jo

To isolate the second diastereomer, the mother liquor is evaporated under reduced pressure and the residue purified by chromatography on about 100 times the amount of silica gel (elution with a 1: 1 mixture of hexane and ethyl acetate). The eluate is evaporated under reduced pressure and the residue is recrystallized twice from a mixture of ethyl acetate and diethyl ether,

The second diastereomer so obtainable melts at 134-135 ° and shows a specific rotation of [c] = -45 ° (c = 0.7, ethanol); this crystalline form is contaminated with about 15% of the first diastereomer according to H-NMR spectrum.

Example 21: A mixture of 5.9 g of gl, 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid 3- (1-benzotriazolyl) ester 5-isopropyl ester, 5.34 g L-phenylalanyl-L-phenylalanine-O- (2-trimethylsilyl-ethyl-di-ester hydrochloride and 1.5 ml of N-ethylmorpholine in 90 ml of anhydrous dimethylformamide are stirred for 15 hours at 80 ° in a nitrogen atmosphere Cooling with 200 ml of water The crystals are filtered off, washed with water and dried under reduced pressure This crude product is purified by chromatography on about 100 times the amount of silica gel (elution with a 1: 1 mixture of chloroform and methanol) available amorphous product is a 1: 1 diastereomeric mixture of N- [1,4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4- (3-nitrophenyl) -5-pyridoyl] -L-phenylalanyl-

- 71 -

L-phenylalanine-0- (2-trimethylsilyl-ethyl) ester; it shows a thin-layer chromatographic Rf value of 0.65 in the elution system toluene-acetone 1: 1.

For cleavage of the 2-trimethylsilyl ethyl ester, a mixture of 3.6 g of the ester obtained above in 34 ml of a 0.7 M solution of tetraethylammonium fluoride in dimethyl sulfoxide for 20 minutes at 20 °. The clear reaction solution is cooled in an ice bath and 24 ml of 1N hydrochloric acid and 150 ml of water are added. The deposited precipitate is filtered off, the filter residue washed with water and dried over potassium hydroxide under reduced pressure. The crude product is taken up in ethyl acetate, filtered and the filtrate is evaporated under reduced pressure. Trituration of the viscous residue with diisopropyl ether to obtain amorphous N- [l, 4 'dihydro-2 ₉ 6 = dimethyl-3-isopropoxycarbonyl-4- (3-nitrophenyl) -5-pyridoyl] -L-phenylalanyl-L-phenylalanine as It shows a thin-layer chromatographic Rf value of 0.70 in the elution system acetonitrile-water 3: 1.

The starting material can be obtained as follows: A mixture of 8.2 g of N-benzyloxycarbonyl-L-phenylalanine and 8.3 g of L-phenylalanine (2-trimethylsilylethyl) ester hydrochloride in 125 ml of anhydrous dichloromethane at 0 ° with 3.50 ml N-Aethylmorpholin and 6.7 g of NN-dicyclohexylcarbodiimide. It is stirred for 1 hour at 0 ° and then for 15 hours at room temperature. The reaction mixture is filtered and the filtrate is diluted with 80 ml of dichloromethane. Wash the dichloromethane solution with 1N citric acid, 1N sodium bicarbonate and water. The organic phase is dried over sodium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue crystallizes from a mixture of ethyl acetate and petroleum ether. The thus obtainable N-benzyloxycarbonyl-L-phenylalanyl-L-phenylalanine O- (2-trimethylsilyl-ethyl) ester melts at 89-90 °.

- 72 -

1.80 g of this intermediate product are subjected to hydrogenolysis in 20 ml of methanol in the presence of 180 mg of 10% palladium-carbon, the pH of the reaction mixture being kept constant at 4.0 with 1 N hydrochloric acid. After completion of the reaction, the catalyst is filtered off and the filtrate is evaporated under reduced pressure, whereby L-phenylalanyl-L-phenylalanine-O - ^ - trimethylsilyl-ethyl-D-ester hydrochloride is obtained as a white foam. The product shows a thin-layer chromatographic Rf value of 0.75 in the elution system chloroform-methanol 8: 2.

Example 22: 10 g of (-) - (4R) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) - 1-ethoxycarbonyl-2-methyl-1-propyl] -amide are stirred for 15 hours at room temperature in a mixture of 300 ml of methanol and 300 ml of 0.1 N sodium hydroxide solution. The clear, yellow solution is then evaporated to dryness under reduced pressure. The solid, yellowish residue is stirred in 160 ml of 1N sodium hydroxide solution at room temperature, treated with charcoal, filtered and the filtrate is acidified with 200 ml of 1N hydrochloric acid. The precipitated acid is filtered off, washed several times with water and dried for 12 hours at 50 ⁰ C under high vacuum. The (-) - (4R) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -l-carboxy- 2-methyl-1-propyl] -amide melts at 217-219 °; [a] = -8.1 ° (c = 0.87, ethanol).

Example 23: In a manner completely analogous to Example 22, but starting from (+) - (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5 carboxylic acid N - [(1S) -1-ethoxycarbonyl-2-methyl-1-propyl] -amide, (+) - (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl- 4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -l-carboxy-2-methyl-1-propyl] -amide which melts at 198-202 ° with decomposition and whose specific (c = 1.0, ethanol).

melts and its specific rotation [a] = + 84.1

- 73 -

Example 24: 47 g of (-) - (4R) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbony1-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) - 1-carboxy-2-methyl-1-propyl] -amide are mixed with 30.5 g of on-butyl-Ν, Ν'-dicyclohexyl-isourea [preparation according to Chem. Ber. 99, 14 79 (1966)] in 400 ml of ethyl acetate for 15 hours under nitrogen at 80 °. The initial suspension becomes clear and after one hour Ν, Ν'-dicyclohexylurea begins to precipitate. The urea is filtered off, washed with ethyl acetate and the filtrate is evaporated. The residue is chromatographed on a 1050 g flash column in a mixture of ethyl acetate / hexane 3: 7 as the eluent. The product thus purified (51 g) is extracted from 60 ml of abs. A recrystallized ether and washed with a mixture of ether / hexane 95: 5. The thus obtained (-) - (4R) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- [(IS) - I- (n-butoxycarbonyl) -2-methyl-1-propyl] -amide has a mp of 69-70 °; [a] p ° = -22 ° (c = 0.6, ethanol).

Example 25: In a completely analogous manner to Example 24, but starting from (+) - (4S) -1,4-dihydro-2, 6-dimethyl-S-methoxycarbonyl-4- (3-nitrophenyl) pyridine-5- carboxylic acid N - [(IS) -l-carboxy-2-methyl-1-propyl] -amide, (+) - (4S) -l, 4-dihydro-2,6-dimethy1-3-methoxycarbony1- 4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -I- (n-butoxycarbonyl) -2-methyl-1-propyl] -amide of

20 m.p. 144-145 °; [a] = + 66 ° (c = 1.0, ethanol).

Example 26: In a completely analogous manner to Example 24, but starting from the corresponding 0-substituted N, N'-dicyclohexyl-isoureas [prepared according to Chem. Ber. _99_, 1479 (1966) and Liebigs Ann. Chemie 597 , 235 (1956)], the following compounds are obtained in a configurationally uniform form:

- 74 -

a) (-) - (4R) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitro-)

phenyl) -pyridine-5-carboxylic acid-N - [(IS) -1- (n-hexyloxycarbonyl) -2-methyl-l-propyl] -amide; [a] ° = -15.7 + 3.2 ° (c = 0.31, ethanol).

b) (-) - (4R) -1,4-dihydro-2, δ-dimethyl-S-methoxycarbonyl-3- (3-ni-trophenyl) -pyridine-5-carboxylic acid N - [(IS) -I- ( benzyloxycarbonyl) -2-

20

methyl-l-propyl] -amide; [a] _D = -15.5 ° (c = 0.9, ethanol).

c) (-) - (4R) -I, 4-Dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- (1S) -l- [ 3- (4-methyl-l-piperazinyl) -l-propoxy] carbonyl-2

(c = 0.93, ethanol).

1-propoxy] -carbonyl-2-methyl-1-propyl} -amide; [a] _n ⁼ ~ 10.0

d) (-) - (4R) -I, 4-Dihydro-2,6-dimethyl-3-methoxycarbony1-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -1- [ 3- (4-benzyl-l-piperazinyl) -l-propoxy] carbonyl-2-methyl-l-propyl ^ -amide; [a] _n = -12.7 ° ( ^c = 0.6, ethanol).

Example 27: In a completely analogous manner to Example 24, but starting from a 1: 1 diastereomer mixture of (4R) - and (4S) -I, 4-dihydro-2,6-dimethy1-3-methoxycarbony1-4- (3 -nitrophenyl) -pyridine-5-carboxylic acid N- [(IS) -l-carboxy-2-methyl-1-propyl] -amide and the corresponding O-substituted Ν, Ν'-dicyclohexyl-isoureas obtained compounds listed below as amorphous 1: 1 diastereomer mixtures:

a) (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -I- (2-dimethy1-amino-1-ethoxy) carbonyl-2-methyl-l-propyl] -amide. FT- 250 MHz ¹ H-NMR _(CDCl3): 0.75 (m, 6H, -CH _3); 2.1 (m, IH, -CH); 2.3 (m, 12H, dihydropyridyl -CH ₃ -N-CH _3); 2.5 5, 4.20 (2m, 4H, -O-CH ₂ -CH ₂ -N); 3.65 (2s, 3H, COOCH _3); 4.55 (m, IH, -CON-CH); 5.0 (2s, IH, 4-dihydropyridyl-H); 5.65 (2s, IH, 1-dihydropyridyl-H); 5.85 (2d, IH, -CONH); 7.4-8.2 (m, 4H, phenyl-H).

- 75 -

b) (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- [(LS) -1- (3-dimethyl-1-amino-1-propoxy) -carbony1-2-methyl-1-propyl] -amide. FT- 250 MHz ¹ H-NMR _(CDCl3): 0.75 (m, 6H, -CH _3); 1.8 (m, 2H, -CH ₂ "); 2.1 (m, IH, -CH-); '2.2-2.4 (m, 15H, dihydropyridyl-C ^; -CH ₂ -N-CH ₃ ); 3.65 (2s , 6H, COOCH ₃ ), 4.15 (m, 2H ₅ COOCH ₂ ), 4.5 (m, IH, -CON-CH), 5.0 (2s, IH, 4-dihydropyridyl-H), 5.6 (2s, IH, 1- Dihydropyridyl-H); 5.8 (2d, IH, -CONH); 7.4-8.2 (m, 4H, phenyl-H).

c) (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N-E (IS) -I- [2- (4-morpholino) -1-ethoxy] -carbonyl-2-methyl-1-propyl] -amide. FT- 250 MHz ¹ H-NMR _(CDCl3): 0.75 (m, 6H, -CH _3); 2.1 (m, IH, -CH-); 2.3 (m, 6H, dihydropyridyl CH ₃ ); 2.4-2.65 (m, 6H, -N-CH ₂ ); 3.7 (m, 7H, -COOCH; -O-CH ₂ -); 4.05-4.4 (m, 2H _S COOCH ₂ ); 4.55 (m, IH, CON-CH-); 5.0 (2 _{s s} , 4-dihydropyridyl H), 5.62 (2 s, IH, 1-dihydropyridyl H); 5.8 (2d, IH, -CONH); 7.4-8.2 (m, 4H, phenyl-H).

d) (4R) - and (4S) -l, 4-dihydro-2, o-dimethyl-S-methoxycarbonyl ^ - (3-nitrophenyl) -pyridine-5-carboxylic acid N- [(IS) -1- ( 2-meth'oxy-läthoxy) carbonyl-2-methyl-l-propyl] -amide. FT- 250 MHz ¹ H-NMR _(CDCl3): 0.75 (m, 6H, -CH _3); 2.1 (m, IH, -CH-); 2.2-2.36 (4s, 6H, dihydropyridyl CH ₃ ); 3.36 (2s, 3H, - -OCH ₃ ); 3.55 (m, 2H, -OCH ₂ -); 3.62 (2s, 3H, COOCH _3); 4.25 (m, 2H, - ₂ 4.60 (m, IH, -CON-CH-); 4.98 (2s, IH, 4-dihydropyridyl-H); (2s, IH, 1-dihydropyridyl-H); 5.8 (2d, IH, -CONH-); 7.4-8.2 (m, 4H, phenyl-H).

Example 28 Analogously to the process described in Example 1, a mixture of 54.5 g of 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid-3- (1- benzotriazolyl) ester 5-methyl ester, 31 g of DjL-phenylglycine-carbamoylmethyl ester hydrochloride [prepared analogously to Tetrahedron Lett. 2A, 5219 (1983)] and 16.2 ml of N-ethylmorpholine in 300 ml of anhydrous

- 76 -

Dimethylformamide a racemic 1: 1 diastereomeric mixture of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- [1- (carbamoyl-methoxycarbonyl) - 1-phenylmethyl] -amide as a resinous intermediate.

16 g of the above intermediate are stirred in a mixture of 67 ml of 0.5 N sodium hydroxide solution and 50 ml of N, N-dimethylformamide for 2 hours at room temperature. Subsequently, the dark reaction solution is evaporated to dryness under reduced pressure. The dark residue is dissolved in 100 ml of 0.02 N sodium hydroxide solution, washed several times with ethyl acetate, additionally treated with activated charcoal, filtered and the filtrate is acidified with 2 N hydrochloric acid. The precipitated acid is filtered off, the filter residue washed several times with water and dried for 12 hours at 50 ° in a high vacuum. The racemic 1: 1 diastereomeric mixture of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-AO-nitrophenyl-pyridine-S-carboxylic acid Nd-carboxy-1-phenyl-methyl) amide obtainable in this way melts at 126.degree. 128 °.

Example 29:

a) 4-gl, 4-Dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- (1-carboxy-1-phenyl-methyl) -amide (racemic 1: 1 diastereomer mixture) with 2.6 g of 0- (2-dimethylamino-ethyl-N, N'-dicyclohexyl-isourea [preparation analogous Liebigs Ann. Chem. 597 , 235 (1956)] in 60 ml of ethyl acetate for 15 hours under a nitrogen The mixture is heated to 80 ° C. The precipitated urea is filtered off and the filtrate is evaporated under reduced pressure, the residue is purified by chromatography on approximately 100 times the amount of silica gel (elution with a 9: 1 mixture of methylene chloride and methanol) to the crude base thus obtained, 1 equivalent of 1.7 N alcoholic hydrochloric acid and the solution is evaporated under reduced pressure, the resinous residue being taken up in a mixture of

- 77 -

20 ml of ethyl acetate and 50 ml of diethyl ether are stirred in an ice bath, wherein the l ^ -Dihydro ^ jö-dimethyl-S-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- [l- (2-dimethylamino) 1-ethoxy) -carbonyl-1-phenylmethyl] -amide hydrochloride. This 1: 1 mixture of diastereomers melts at 100-112 ° with decomposition.

b) In a completely analogous manner to a), but starting from 0- (2-morpholino-ethyl) -N, N'-dicyclohexyl-isourea [preparation analog Liebigs Ann. Chem. 597 , 235 (1956)], one obtains 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N-E-l- [2- (4-morpholino) -1-ethoxy] -carbonyl-phenyl-methyll-amide hydrochloride as a 1: 1 mixture of diastereomers, melting at 127-129 °.

Example 30:

a) Analogously to the process described in Example 1 is obtained from a mixture of 50 g of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid 3- (l- benzotriazolyl) ester 5-methyl ester, 20.4 g of L-isol eucine ethyl ester hydrochloride and 12.2 ml of N-ethylmorpholine in 300 ml of anhydrous dimethylformamide (+) - (4S) -l, 4-dihydro-2,6-dimethyl 3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS, 2S) -1-ethoxycarbonyl-2-methyl-1-butyl] -amide, which after recrystallization from a Mixture of methyl acetate and diisopropyl ether at 170-171 ° melts. This diastereomer α is configurationally uniform and exhibits a specific rotation of [α] = + 93 ° (c = 0.44, ethanol).

From the mother liquor, analogously to the process described in Example 1, (4R) -l, 4-dihydro-2, 6-dimethyl-S-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- [ (IS, 2S) -l-ethoxycarbonyl-2-methyl-1-butyl] -amide isolated. By trituration of the amorphous crude product with diethyl ether crystallized

- 78 -

this diastereomer β, which after further recrystallization from a mixture of ethyl acetate and η-hexane at

20 117-118 ° melts. The specific rotation is [cc] = +5 '(c = 0.91, ethanol); According to the H-NMR spectrum, this β-diastereomer still contains about 25% of the above α-diastereomer.

b) In a completely analogous manner to a), but starting from L-isoleucine methyl ester hydrochloride, a 1: 1 diastereomer mixture of (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl 3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS, 2S) -l-methoxycarbonyl-2-methyl-1-butyl] -amide of

Mp 139-140 °. '. '

Example 31 Analogously to the process described in Example 2, from a mixture of 9.4 g of ethyl N-acetoacetyl-α-aminocyclohexylcarboxylate [prepared analogously to Pharm. Acta HeIv. 3, 616 (1963)], 4.1 g of methyl 3-aminocrotonate and 5.5 g of 3-nitrobenzaldehyde in 70 ml of ethanol are amorphous 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl ) -pyridine-5-carboxylic acid N- (1-ethoxycarbonyl-1-cyclohexyl) -amide, which crystallizes on stirring with diethyl ether, mp. 166-168 °.

Example 32 Analogously to the "process described in Example 2, from a mixture of 8.1 g of N-acetoacetyl-α, α-diphenylglycine ethyl ester [prepared analogously to Pharm. Acta HeIv. 38 , 616 (1963)], 2.8 g of 3- Aminocrotonic acid methyl ester and 3.6 g of 3-nitrobenzaldehyde in 45 ml of ethanol amorphous 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- (1-ethoxycarbonyl -1,1-dipheny1-methy1) amide.

FT- 250 MHz ¹ H-NMR _(CDCl3): 1.15 (t, 3H, -COO-C-CH); 2.18, '2.3O (2s, 6H, dihydropyridyl-H); 3.61 (s, 3H, -COOCH); 4.19 (q, 2H, -COO-CH-); 5.05 (s, IH, 4-dihydropyridyl-H);

- 79 -

5.72 (s, IH, 1-dihydropyridyl-H); 6.96 (s, lH, -CONH-); 7.1-8.18 (m, 14H, phenyl-H).

EXAMPLE 33 Analogously to the process described in Example 1, 7.9 g of 1,4-dihydro-2,2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid 3- (1-benzotriazolyl ) ester 5-methyl ester and 5 g of D, La [2- (N-tert-butoxycarbonyl-amino) -4-thiazolyl] -glycine ethyl ester in 30 ml of anhydrous dimethylformamide racemic 1,4-dihydro-2, dimethyl-S-methoxycarbonyl ^ - (3-nitrophenyl) -pyridine-5-carboxylic acid-N- (l- [2- (N-tert-butoxycarbonyl-amino) -4-thiazolyl] -l-äthpxycarbonyl-methylj-amide as a resinous intermediate.

This is dissolved in 40 ml of hydrochloric acid, ice-cold glacial acetic acid and stirred for 1 1/2 hours at 0 °. Subsequently, the cold reaction solution is neutralized with 2N sodium hydroxide solution and the crude product extracted several times with ethyl acetate. The combined organic extracts are evaporated under reduced pressure to give 1,4-dihydro-2,6-dimethy1-3-methoxycarbony1-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- [1- (2-amino 4-thiazolyl) -l-ethoxycarbonyl-methyl] -amide remains as an amorphous 1: 1-Diasterome.rengemisch.

250 MHz FT-H-NMR (CDCl3): 1.2 (2t, 3H, -COO-C-CH); 2.32 (2d, 6H, dihydropyridyl CH); 2.65 (2s, 3H, -COOCH); 4.15 (2m, 2H, -COO-CH ₂ -); 5.0 (2s, IH, 4-dihydropyridyl-H); 5.06 (s, IH, -NH ₂ ); 5.40 (2s, IH, -N-CH-); 5.60 (2s, IH, 1-dihydropyridyl-H); 6.42 (2s, IH, thiazolyl-H); 6.50, 6.65 (2d, IH, -CONH); 7.35-8.20 (m, 4H, phenyl-H).

Example 34:

a) A solution of 7 g of 1,4-dihydro-2,6-dimethyl-3-methylsulfonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid [prepared analogously to EP 11.706; Mp 228-229 °], 3.4 g of 1-hydroxybenzotriazole and 4.6 g

- 80 -

N, N'-dicyclohexylcarbodiimide in 100 ml of anhydrous dimethylformamide is allowed to stand for 16 hours at 0-5 ° under a nitrogen atmosphere. The crystallized N, N'-dicyclohexylurea is filtered off. The yellow filtrate is mixed with 4 g of L-valine ethyl ester hydrochloride and 2.8 ml of N-ethylmorpholine and stirred for 16 hours under a nitrogen atmosphere. 250 ml of ice-water are added to the yellow reaction mixture while cooling with ice-ice, and stirring is continued for 1 hour at 0-5 °, the crude product crystallizing. It is filtered off, the filter residue washed with 1 1 of water and dried in vacuo. The 1: 1 diastereomeric mixture of (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl-3-methylsulfonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- [(IS) -l-ethoxycarbonyl-2-methyl-1-propyl] -amide melts after recrystallization from ethyl acetate at 191-192 °.

b) In a completely analogous manner to a), but starting from D-valine ethyl ester hydrochloride, a 1: 1 diastereomer mixture of (4R) - and (4S) -I, 4-dihydro-2,6-dimethyl-3 is obtained -methylsulfonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IR) -l-ethoxycarbonyl-2-methyl-1-propyl] -amide, which melts at 188-191 °.

Example 35: A mixture of 44.6 g of (S) -N- (3-nitrobenzylideneactoacetyl) -α-amino-isovaleric acid ethyl ester and 14.1 g of methyl 3-aminocrotonic acid in 350 ml of ethanol is heated for 16 hours at 80 ° under a nitrogen atmosphere touched. The yellow reaction mixture is evaporated under reduced pressure and the residue purified by chromatography on about 100 times the amount of silica gel (elution with a 7: 3 mixture of n-hexane and ethyl acetate). The resinous crude product obtainable in this way is a 1: 1 diastereomer mixture of (4R) - and (4S) -1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5 carboxylic acid N - [(1S) -1-ethoxycarbonyl-2-methyl-1-propyl] -amide.

- 81 -

The separation of the diastereomers is carried out as described in Example 1.

The starting material can be prepared as follows:

In a solution of 21.6 g of 3-nitrobenzaldehyde and 32.8 g of (S) -N-acetoacetyl-a-amino-isovaleric acid ethyl ester [prepared analogously to Pharm. Acta HeIv. _38_, 616 (1963)] in 140 ml of anhydrous toluene is introduced for 2 hours at 5-15 ° HCl gas. The mixture is then stirred for 2 hours at room temperature and the reaction mixture is evaporated under reduced pressure. The residue is stirred for 4 hours at 80 ° under aspirator vacuum, hydrochloric acid is split off. The thus obtained crude (S) -N- (3-nitrobenzylidene-acetoacetyl) -α-amino-isovaleric acid ethyl ester melts after recrystallization from a mixture of 24 ml of tetrahydrofuran and 180 ml of diethyl ether at 114-116 °.

EXAMPLE 36 In a completely analogous manner to Example 35, but starting from 2-nitrobenzaldehyde, (S) -N- (2-nitrobenzylidene-acetoacetyl) -α-amino-isovaleric acid ethyl ester [mp. 106-107 °] as an intermediate, and from this by condensation with 3-amino-crotonic acid methyl ester, a resinous diastereomer mixture of (4R) - and (4S) -I, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4 - (2-nitrophenyl) -pyridine-5-carboxylic acid N- [(IS) -1-ethoxycarbonyl-1-methyl-1-propyl] -amide.

The separation of the diastereomers is carried out as described in Example 1, whereby, after recrystallization from a mixture of ethyl acetate and hexane, a configurationally uniform diastereomer α is obtained,

• 20 whose specific rotation [α] = -363.5 ± 6.4 ° (c = 0.15, ethanol) and which melts at 179-180 °. From the mother liquor, the amorphous diastereomer β is isolated, which still contains about 15% of the above α-diastereomer according to H-NMR spectrum.

- 82 -

250 MHz FT-H NMR (CDCl) spectrum of diastere oromers β: 0.52, (2d, 6H, -CH ₃ ); 1.3 (t, 3H ₅ -O-CH ₂ -); 1.98 (m, IH, -CH-); 2.28, 2.48 (2s, 6H, dihydropyridyl CH ₃ ); 3:55 (s, 3H, COOCH _3); 4.12 (m, 2H, -COOCH ₂ -); 4.6 (m, IH, -CON-CH-); 5.7, 5.83 (2s, 2H, 1- or 4-dihydropyridyl-H); 7.25-7.8 (m, 4H, phenyl-H).

Example 37 Analogously to the process described in Example 1, 18.7 g of 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylic acid 3- (1-benzotriazolyl) ester are obtained 5-methyl ester and 6.7 g of L-valinamide in 100 ml of anhydrous dimethylformamide a 1: 1 diastereomeric mixture of (4R) - and (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- ( 3-nitrophenyl) -pyridine-5-carboxylic acid N - [(LS) -1-carbamoyl-2-methyll-propyl] -amide, which, after recrystallization, melts from a mixture of acetone and diethyl ether at 190-191 °.

Example 38;

a) To a mixture of 8.6 g of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- (1-carboxy-2-methyl-1 Propyl) -amide (racemic 1: 1 diastereomer mixture) and 2.5 ml of N-ethylmorpholine in 50 ml of anhydrous tetrahydrofuran are added dropwise within 10 minutes 1.9 ml of isobutyl chloroformate under. Cool so that the temperature does not exceed -15 °. Then it is stirred for 10 minutes at -20 ° to -15 ° and then added dropwise with cooling 2.8 ml of 2- (2-aminoethyl) -pyridine so that the temperature does not exceed -10 °. After completion of the addition, the reaction mixture is allowed to warm to room temperature and stirred for 3 hours, after which it is evaporated under reduced pressure. The resinous residue is purified by

- 83 -

Chromatography on about 100 times the amount of silica gel (elution with a 95: 5 mixture of methylene chloride and methanol). The resinous l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- / 1- [2- (2-pyridyl) -l- Ethylamino] carbonyl-2-methyl-l-propylj-amide crystallized from a mixture of methylene chloride and diethyl ether as a 1: 4 diastereomer, mp. 158-160 °.

b) In a completely analogous manner to a), but starting from N-methyl-benzylamine, a 1: 4 diastereomer mixture of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl ) -pyridine-5-carboxylic acid N- [1- (N-benzylmethylamino) carbonyl-2-methyl-1-propyl] -amide, m.p. 94-95 °.

c) In a completely analogous manner to a), but starting from N-benzyl-piperazine, an amorphous 3: 7 diastereomer mixture of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3 nitrophenyl) -pyridine-5-carboxylic acid-N- [l- (4-benzyl-l-piperazinyl) carbonyl-2-methyl-l-propyl] -amide.

250 MHz FT- ¹ H-NMR (CDCl3): 0.6-0.85 (m, 6H, -CH); 1.85 (m, IH, -CH-), 2.2-2.35 (4s, 6H, dihydropyridyl-CH); 2.4 (m, 4H, -N-CH ₂ ); 3.44-3.66 (m, 9H, N-CH _2, -COOCH _3); 4.85 (m, IH, -CON-CH-); 5.0 (2s, IH, 4-dihydropyridyl-H); 5:55 ,. 5.6 (2s, IH, 1-dihydropyridyl-H): 6.15, 6.30 (2d, IH, -CONH); 7.25-8.18 (m, 9H, phenyl-H).

d) In a completely analogous manner to a), but starting from N-diphenylmethyl-piperazine, gives an amorphous 3: 7 diastereomeric mixture of l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl ) -pyridine-5-carboxylic acid-N- [l- (4-diphenylmethyll-piperazinyl) carbonyl-2-methy1-1-propyl] -amide.

- 84 -

250 MHz FT- ¹ H-NMR (CDCl3): 0.55-0.9 (m, 6H, -CH); 1.8 (m, IH, -CH-); 2.15-2.45 (4s, 1 OH, dihydropyridyl-CH, -N-CH-); 3.4-3.6 (m, 4H, 8 _λΤ ""; 3.55, 3.65 (2s, 3H, -COOCH-);

4.2 (2s, IH, -CHPh; 4.8 (m, IH, -CON-CH); 4.98 (2s, IH, 4-dihydropyridyl-H); 5.45, 5.55 (2S, IH, 1-dihydropyridyl-H); 6.1 , 6.28 (2d, IH, -CONH-); 7.15-8.15 (m, 14H, phenyl-H).

e) In a completely analogous manner to a), but starting from n-butylamine, an amorphous 1: 2 diastereomeric mixture of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) is obtained. - pyridine-5-carboxylic acid N- [1- (n-butylaminocarbonyl) -2-methyl-1-propyl] -amide.

250 MHz FT- ¹ H-NMR (CDCl3): 0.65-0.98 (m, 9H, -CH); 1.25-1.55 (m, 4H, -CH ₂ -CH ₂ -); 1.95 (m, IH, -CH-); 2.18-2.38 (4s, 6H, dihydropyridyl CH); 3.22 (m, 2H, -CON-CH ₂ -); 3.65 (2s, 3H, COOCH _3); 4.15 (m, IH, -CON-CH-); 4.98 (2s, IH, 4-dihydropyridyl-H); 5.55, 5-65 (2s, IH, 1-dihydropyridyl-H); 5.8, 6.05 (2m, 2H, -CONH); 7.4-8.15 (m, 4H, phenyl-H).

f) In a completely analogous manner to a), but starting from Nn-heptyl-methylamine, there is obtained an amorphous 1: 1 diastereomeric mixture of 1-dihydro-dimethyl-S-methoxycarbonyl-3- (3-nitrophenyl) -pyridine -5-carboxylic acid-N- [l- (N-methyl-n--heptylaminocarbonyl) -2-methyl-l-propyl] -amide.

250 MHz FT- ¹ H-NMR (CDCl3): 0.63-0.98 (m, 9H, -CH); 1.2-1.6 (m, 1OH, -CH ₂ -); 1.9 (m, IH, -CH-); 2.15, 2.35 (2d, 6H, dihydropyridyl CH ₃ ); 2.89, 3:02 (2d, 3H, _N-CH3); 3.1-3.55 (m, 2H, N -CH ₂ ); 3.6, 3.65 (2s, 3H, COOCH ₃ ); 4.8 (m, IH, -CON-CH-); 5.0 (2s, IH, 4-dihydropyridyl-H); 5.52, 5.62 (2s, IH, 1-dihydropyridyl-H); 6.08-6.30 (m, IH, -CONH); 7.38-8.18 (m, 4H, phenyl-H).

- 85 -

Example 39: In a manner completely analogous to Example 22, but starting from (+) - (4S) -1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5 carboxylic acid N - [(IR) -1-ethoxycarbonyl-2-methyl-1-propyl] -amide, gives (+) - (4S) -1,4-dihydro-2, 6-dimethyl-S-inethoxycarbonyl ^ - (3-nitrophenyl) pyridine-5-carboxylic acid N - [(IR) -l-carboxy-2-methyl-1-propyl] -amide, which melts at 216-218 ° and whose specific

20 rotation [α] = + 8.0 ° (c = 1.0, ethanol).

Example 40: In a completely analogous manner to Example 22, but starting from (-) - (4R) -1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5- carboxylic acid N - [(IR) -1-ethoxycarbonyl-2-methyl-1-propyl] -amide, one obtains (-) - (4R) -l, 4-dihydro-2, o-dimethyl-S-methoxycarbonyl ^ - (3-nitrophenyl) pyridine-5-carboxylic acid N - [(IR) -l-carboxy-2-methyl-1-propyl] - amide, which melts at 121-122 ° with decomposition and whose specific is <

is.

specific rotation [a] _ = -77.0 ° (c = 1.0, ethanol)

Example 41: In a manner completely analogous to Example 24, but starting from (+) - (4S) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-S- carboxylic acid N - [(IR) -I-carboxy-2-methyl-1-propyl] -amide, to give (+) - (4S) -l, 4-dihydro-2,6-dimethyl-3- methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IR) -1- (n-butoxycarbonyl) -2-methyl-1-propyl] -amide, which melts at 67-68 ° and a specific one

20 rotation of [α] = -21 ° (c = 1.0, ethanol).

Example 42: Analogously to Example 24, but starting from (-) - (4R) -1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5 carboxylic acid N - [(IR) -I-carboxy-2-methyl-1-propyl] -amide, one obtains (-) - (4R) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl- 4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(lR) -l- (n-butoxycarbonyl) -2-methyl-

- 86 -

l-propyl] amide, which melts at 143-144 ° and whose spe-

20

zifische rotation [α] = -65 ° (c = 1.0, ethanol) is.

Example 43 ; In a completely analogous manner to Example 35, but starting from 3-aminocrotonic acid ethyl ester, gives an approximately 1: 1 diastereomeric mixture as a resinous crude product. Crystallization from a 2: 1 mixture of ethyl acetate and diisopropyl ether gives crystalline (-) - (4R) -l, 4-dihydro-2,6-dimethyl-3-ethoxycarbonyl-4- (3-nitrophenyl) pyridine. 5-carboxylic acid N - [(1S) -1-ethoxycarbonyl-2-methyl-1-propyl] -amide in configurationally uniform form. It melts at 169-170 °. Its specific rotation is

[a] _D = -46.6 ° (c = 0.476, ethanol). The mother liquor yields crystalline (+) - (4S) -I, 4-dihydro-2,6-dimethyl-3-ethoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) - l-ethoxycarbonyl-2-methyl-l-

20

propyl] amide isolated; Mp 135-136 °; [α] = + 40.6 ° (c = 0.94, ethanol)

Example 44 ; In a completely analogous manner to Example 35, but starting from 3-aminocrotonic acid (n-propyl) ester, an approximately 1: 1 mixture of diastereomers is obtained as a resinous crude product. Crystallization from a 2: 1 mixture of ethyl acetate and diisopropyl ether gives crystalline (-) - (4R) -l, 4-dihydro-2,6-dimethyl-3- (n-propyloxycarbonyl) -4- (3-nitrophenyl ) -pyridine-5-carboxylic acid N - [(IS) -l-ethoxycarbonyl-2-methyl-1-propyl] -amide in configurationally uniform form. It melts at 148-149 °. Its specific rotation is [α] = -19.9 ° (c = 0.55, ethanol). From the mother liquor crystalline (+) - (4S) -l, 4-dihydro-2,6-dimethyl-3- (n-propyloxycarbonyl) -4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- [ (1S) -1-ethoxycarbonyl-2-methyl-1-propyl] -ε 0.67, ethanol). ,

methyl-1-propyl] -amide isolated; Mp 119-121 °; [α] = + 70.9 * (c =

Example 45 : 2.4 g (butyl Si-NO-nitrobenzylidene-acetoacetyl-α-amino-isovalerate and 0.92 g methyl amidinoacetate hydrochloride [see Chem., 1977 , 1895] are dissolved in 6 ml of abs Reflux was added dropwise to a sodium methylate solution prepared from 140 mg sodium and 6 ml abs. Of methanol and refluxed for one more hour, the precipitated sodium chloride was filtered off, the filtrate was evaporated under reduced pressure and the residue was evaporated

- 87 -

a medium-pressure column in a 1: 1 mixture of hexane and ethyl acetate chromatographed. The resulting amorphous 2-amino-1,4-dihydro-6-methyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(1S) -l- (n-butoxycarbonyl ) -2-methyl-l-propyl] -amide is a S, 4 R: S, 4S diastereomer mixture and shows the following NMR data: FT 250 MHz ¹ H-NMR _(CDCl3): 0.80 (2m, 6H, isopropyl -CH ^; 0.95 (2t, 3H, -COO-CCC-CH ₃₎ J 1.34 1.60 (2m, 4H ₅ -COO-C-CH ₂ -CH ₂ -C); 2:06 (m, IH, '"-CHC); 2.10, 2.18 (2s, 6H, dihydropyridyl-CH ^, 2.62 (2s, 6H ₅ -COOCH _3);

4.1 (m, 2H, -COOCH -C-); 4.46 (m, IH, -O-C-CH-N-CO-); 4.80, 4.86

(2s, IH, 4-dihydropyridyl-H); 5.84, 5.98 (2d, IH, -NH-); 6.35 (Is, 2H, -NH ₂ ); 6.76, 6.90 (2d, IH, -CO-NH-); 7.40, 7.64, 8.20, 8.14 (m, t, d, m, 4H, phenyl-H).

The starting material can be prepared as follows:

Analogously to the process described in Example 35 is obtained from a mixture of 14.0 g of (Si-N-acetoacetyl-a-amino-isovaleric acid .. butyl ester, prepared analogously to Pharm. Acta HeIv. ^ 8_, 616 (1963), and

8.2 g of 3-nitrobenzaldehyde in 50 ml of toluene the (S) -N- (3-nitrobenzylidene-acetoacetyl-a-amino-isovaleric acid-butyl ester.

Example 46 : 26.5 g of S-ethoxycarbonyl-diethoxymethyl-1,1-dihydro-omethyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(1S) -1-oxycarbonyl-2-methyl -l-propyl] -amide are dissolved in 160 ml of acetone and 26.5 ml of 6N hydrochloric acid added. The mixture is stirred for one hour at room temperature, the reaction solution is evaporated under reduced pressure and the residue is chromatographed on a flash column in an 8: 2 mixture of hexane and ethyl acetate. The amorphous 3-ethoxycarbonyl-l, 4-dihydro-2-formyl-6-methyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- [O-S] -l-ethoxycarbonyl-2- methyl-l-propyl] -amide is an S, 4R: S, 4S mixture of diastereomers and shows the following NMR data:

250 MHz FT- ¹ H-NMR (CDCl3): 0.80 (2m, 6H, -C (CH)); 1.26 (2m, 6H, _-COO-C-CH3); 2.06 (m, IH, -CHC ₂ ); 2.28, 2.36 (2s, 3H, dihydropyridyl-CH); 4.18 (m, 4H ₅ -COO-CH-C); 4.53 (m, IH ₅ -OOC-CH-N-CO-); 5.00, 5.16 (2s, IH ₅ 4-dihydropyridyl-H); 5.72, 5.88 (2d, IH, -NH-); 6.83, 6.90 (2s, IH, -CO-NH-); 7.47, 7.70, 8.10, 8.18 (t, m, m, m, 4H,

- 88 -

Phenyl-H).

The starting material can be synthesized as follows:

A mixture of 29.0 g of (S) -N- (3-nitrobenzylidene-acetoacetyl) -a-amino-isovaleric acid ethyl ester (see Example 35), 17.4 g of 3-amino-4,4-diethoxy crotonic acid ethyl ester, 50 g of molecular sieve (Union Carbide

3A) and 160 ml abs. Alcohol is refluxed for 40 hours. The molecular sieve is filtered off, the filtrate is evaporated under reduced pressure and the residue is chromatographed on a flash column in a 1: 1 mixture of hexane and ethyl acetate. The thus obtained 3-ethoxycarbonyl-2-diethoxymethyl-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -1-ethoxycarbonyl-2-one methyl-1-propyl] -amide is immediately reacted.

Example 47 : 6.5 g of 3-ethoxycarbonyl-l, 4-dihydro-2-formyl-6-methyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -l-ethoxycarbonyl 2-methyl-1-propyl] -amide are dissolved in 100 ml of alcohol and with stirring at 0 ° within 5 minutes 0.65 g of sodium borohydride are added and stirred for 30 minutes at room temperature. It is then acidified with 2N hydrochloric acid and evaporated to dryness under reduced pressure. The residue is partitioned between water and ethyl acetate, the organic phase is dried, evaporated and the residue is chromatographed on a medium-pressure column in a 1: 1 mixture of hexane and ethyl acetate. The resulting amorphous 3-ethoxycarbonyl-1,4-dihydro-2-hydroxymethyl-6-methyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(1S) -1-ethoxycarbonyl-2-methyl -l-propyl] -amide is a S, 4R: S, 4S mixture of diastereomers and shows the following NMR data:

FT- 250 MHz ¹ H-NMR _(CDCl3): 0.74 (2m, 6H, -C (CH) _2); 1.28 (2m, 6H, _-COO-C-CH3); 2.06 (m, IH, -CHC ₂ ); 2.26, 2.32 (2s, 3H, dihydropyridyl-CH ₃ ); 2.76, 2.96 (2m, IH, -OH); 4.1 (m, 4H, -COO-CH ₂ -C-); 4.50 (m, IH, -OOC-CH-N-CO-); 4.68, 4.84 (2m, 2H, -CH ₂ -O); 4.98, 5.02, (2s, IH, 4-dihydropyridyl-H); 5.72, 5.98 (2d, IH, -NH-); 6.96, 7.12 (2s, IH, -CO-NH-); 7.46, 7.67, 8.05, 8.16 (t, t, m, m, 4H, phenyl-H).

- 89 -

Example 48 : A mixture of 12.0 g of 3-ethoxycarbonyl-l, 4-dihydro-2-formyl-6-methyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -I - ethoxycarbonyl-2-methyl-1-propyl] -amide, 2.0 g of hydroxylamine hydrochloride, 1.6 g of sodium carbonate and 150 ml of abs. Alcohol is stirred for 2 hours at room temperature. Then it is evaporated under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic phase is dried, evaporated and the resulting oxime immediately reacted further.

A mixture of 12.5 g of 3-ethoxycarbonyl-1,4-dihydro-2-hydroxyiminomethyl-6-methyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -I-ethoxycarbonyl 2-methyl-1-propyl] -amide, 12.9 g of Ν, Ν-dicyclohexylcarbodiimide and 50 ml of abs. Pyridine is refluxed for 5 hours. Then the solution is evaporated under reduced pressure, the residue partitioned between 1N hydrochloric acid and .Essigsäureäthylester and filtered from the precipitated urea. The organic phase is washed with water and brine, dried and evaporated. The residue is chromatographed on a medium-pressure column in a mixture of hexane and ethyl acetate. The resulting amorphous 3-ethoxycarbonyl-2-cyano-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(1S) -1-ethoxycarbonyl-2-methyl -l-propyl] -amide is an S, 4R: S, 4S mixture of diastereomers and shows the following NMR data:

250 MHz FT- ¹ H NMR (CDCl3):

- 90 -

0.74 (2m, 6H, -C (CH ₃ ) _£ ); 1.26 (m, 6H, _-COO-C-CH3); 2.05 (m, IH, -CHC ₂ ) J 2.24, 2.32 (2s, 3H, dihydropyridyl-CH ₃ ); 4.2 (m, 4H, -COO-CH ₂ -C-); 4.50 (m, IH, -O-C-CH-N-CO-); 5.06, 5.10 (2s, IH, 4-dihydropyridyl-H); 5.74, 5.86 (2d, IH, -NH-); 6.26, 6.38 (2s, IH, -CO-NH-); 7.50, 7.70, 8.14 (t, m, m, 4H, phenyl-H).

Example 49: In a completely analogous manner to Example 26, the following compounds are also obtained in a configurationally uniform form:

3.) (-) - (4R) -l, 4-Dihydro-2, 6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -I- (2-furylmethoxycarbonyl) -2-

20-methyl-1-propyl] -amide; [α] = -38.4 ° (c = 0.91, ethanol); Mp. 76-78 '

b) (-) - (4R) -I, 4-Dihydro-2,6-dimethy1-3-methoxycarbony1-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(1S) -1-isopropyloxycarbonyl -2-

20

methyl-l-propyl] -amide; Ia] -Q = -18.5 ° (c = 0.56, ethanol); Mp. 166-167 °.

c) (4R) -l, 4-Dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - [(IS) -I- (tert-butyloxycarbonyl) -2-methy1-1-propyl] -amide; Mp 163-164 °.

Claims (16)

Claims: χ, Process for. Preparation of Compounds of the Formula IO Ar 11 Ac \ A / S 5 -υ (D, in which η is 1, 2 or 3, Ar is a carbocyclic or heterocyclic aryl radical, Ac is the acyl radical of an acid, Z is an -OR radical or -NR R, R is hydrogen, unsubstituted / substituted or substituted lower alkyl, a carbocyclic or heterocyclic aryl radical or free, etherified or esterified hydroxy, R and R independently of one another are hydrogen, unsubstituted or substituted lower alkyl, formyl or functionally modified formyl, carboxy or functionally modified carboxy, a carbocyclic or heterocyclic aryl radical or unsubstituted, mono- or disubstituted amino, R, hydrogen or lower alkyl, R. and R are independently hydrogen, unsubstituted or substituted lower alkyl or a 'carbocyclic or heterocyclic Aryl, R, R0 and R independently of one another W represents an unsubstituted or substituted alkyl or a carbocyclic or heterocyclic aryl radical in which R and R "together or R and R together may denote unsubstituted or substituted lower alkylene in which a carbon atom may be replaced by a heteroatom, where R and R together are as well as Rr and R. together and / or R0 and R ,. 4 5 5 ο o 9 together, independently of one another, unsubstituted or substituted lower alkylene, in which a carbon atom may be replaced by a heteroatom, optical isomers of compounds of the formula I, mixtures of these optical isomers, salts of such compounds which have a salt-forming group and of pharmaceutical preparations containing these compounds, characterized by a) a compound of formula II Ac; 2, Il I I ¹ (ν) b ') completely analogously to process b), a compound of formula Va is reacted with a compound of formula VI, CH
Il τ 11 -CI !! R ₆ O _x (Va) c) a compound of formula VII 0
Ar Il -N- -ΟΙ -C-Il ^R 6 ° (VII), - 94 - wherein one of the radicals X and Y is the group of the formula -KH-R and the other is hydroxy or both denote the group of the formula -NH-R, or a tautomer thereof or a corresponding Tautomerengemisch ringschliesst, or d) a compound of the formula Ar-CHO. (IV) or a reactive functional derivative thereof with a compound of formula VIII (VIII) or a tautomer thereof or a corresponding mixture of tautomers, or e) in a compound of the formula IX (IX), wherein Ac represents a group which can be run over into the group Ac, converts it into the group Ac, wherein in the above starting materials of the formulas II to IX, Ha and Va, which, if they have salt-forming properties, can also be used in the form of their salts, the symbols n, Ar, Ac, R.,, R2> Ro> R., R, R and Z have the meanings given under formula I, 4 5 ο - 95 - and, if desired, a compound of the forms! I converts to another compound of formula I, and / or, if desired, converts a salt obtained into the free compound or into another salt, and / or, if desired, a resulting free compound of formula I having salt-forming properties Salt converts, and / or, if
desirably separates a resulting mixture of isomers or racemates into the individual isomers or racemates, and / or resolves racemates obtained, if desired, into the optical antipodes and / or obtains a compound obtainable
processed pharmaceutical preparation. 2. The method according to item 1, characterized by reacting compounds of formula I, wherein η is 1, 2 or 3,
Ar is a mono- or bicyclic, carbocyclic aryl radical or a monocyclic heteroaryl radical containing one to and four ring nitrogen atoms, a ring oxygen or ring sulfur atom, or one or two ring nitrogen atoms together with a ring oxygen or a ring sulfur atom as ring members, which optionally contains a fused benzo ring, and in particular phenyl, naphthyl, pyrryl, pyrazolyl, iridazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
Triazinyl, indolyl, isoindolyl, benzoxadiazolyl, benzthiadiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolinyl or isoquinolinyl, wherein in these radicals
Ring carbon atoms optionally substituted by lower alkyl,
Lower alkenyl, lower alkynyl, lower alkylene, cycloalkyl,
Phenyl, phenyl-lower alkyl, phenyl-lower alkoxy and / or
Phenyl-lower alkylthio, wherein lower alkyl, phenyl, phenyl - 95a - lower alkyl, phenyl and / or phenyl-lower alkylthio optionally hydroxy, loweralkoxy, haloloweralkoxy, Niederaiksnyloxy, lower alkynyloxy, f ^ -liederalkylendioxy, Niaderalkanoyloxy _t halo, carboxy, Nisderalkoxycarbonyl, Carbaraoyl, N-Niedsralkylcarbamoyl, Ν, Ν-Diniedaralkyl-carbamoyl and / or cyano, - 96 - the cyclic radicals are also lower alkyl, which in turn may be substituted as specified, and / or by hydroxy, lower alkoxy, halo-lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, nitro, amino, lower alkylamino, di-lower alkylamino, N-lower alkyl -N-phenyl-lower alkylamino, lower alkylene-amino, oxo-lower alkylene-amino, thio-lower alkylene-amino and / or azino-lower alkylene wherein the azole-nitrogenatoxy may be substituted by lower alkyl, phenyl or phenyl-lower alkyl, said substituents being hydroxy, lower alkoxy, halo lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, Carboxy, lower alkoxycarbonyl, carbamoyl, N-lower-alkyl-carbamoyl, N, N-di-lower alkylcarbamoyl and / or cyano may contain as substituents, and / or by lower alkanoylamino, azido, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, Ν, Din-di-lower alkyl carba moyl, cyano, sulfo, aminosulfonyl, lower alkylthio, lower alkylsulfinyl and / or lower alkylsulfonyl, and / or ring nitrogens optionally substituted by lower alkoxycarbonyl or by lower alkyl optionally substituted with hydroxy, lower alkoxy, halo-lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halo, carboxy, lower alkoxycarbonyl , Carbamoyl, N-loweralkylcarbamoyl, Ν, Ν-di-lower alkylcarbamoyl or cyano, or the group Ac for lower alkanoyl, unsubstituted or lower alkyl, lower alkoxy, nitro and / or halogen substituted benzoyl, lower alkylsulfonyl unsubstituted or lower alkyl, lower alkoxy, nitro and / or halo substituted phenylsulfonyl, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, lower aminoalkoxycarbonyl, lower alkylamino-lower alkoxycarbonyl, N, N-di-lower alkylamino-lower alkoxycarbonyl, N Lower alkyl-N-phenyl-lower alkylamino-lower alkoxycarbonyl, N, N-lower - 97 - Alkylenaminoniederalkoxycarbonyl, Morpholinoniederalkoxycarbonyl, Thiomorpholinoniederalkoxycarbonyl, Piperazinoniederalkoxycarbonyl, 4-lower alkyl-piperazino-lower alkoxycarbonyl, unsubstituted or dur.ch lower alkyl, lower alkoxy, nitro and / or halogen-substituted phenyl, thienyl, furyl, pyrryl or pyridyl-lower alkoxycarbonyl, lower alkenyloxy or Niederalkinyloxycarbonyl, Carbamoyl, N-lower-alkyl-carbamoyl, Ν, Ν-di-lower alkylcarbamoyl, N-hydroxycarbamoyl, Ν, Ν-lower alkylenecarbamoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazinocarbonyl, 4-lower alkylpiperazinocarbonyl, 5-tetrazolyl, unsubstituted or lower alkyl or phenyl substituted 4,5-dihydro 2-oxazolyl or 5,6-dihydro-4H-1,3-oxazin-2-yl, Z is a radical -OR or -NR R, R is water / ay 1 material; Lower alkyl optionally substituted by lower alkylamino, di-lower alkylamino, lower alkylene-diolino, morpholino, thiomorpholine, piperazino which optionally carries lower alkyl or lower alkanoyl as a substituent on a nitrogen atom, carboxy, functionally-modified carboxy, lower alkoxy, lower alkoxy-lower alkoxy or phenyl, which in turn may be substituted. Lower alkyl, lower alkoxy, halogen and / or nitro as substituents, or N-pyrrolyl, N-imidazolyl, N-pyrazolyl, N-indolyl or N-isoindolyl substituted; Phenyl which is optionally substituted as a phenyl-lower alkyl radical R; Hydroxy, lower alkoxy or phenyl-lower alkoxy, R "and R are independently hydrogen, lower alkyl optionally substituted by hydroxy, lower alkoxy optionally substituted with amino, lower alkylamino, di-lower alkylamino or acylamino, acyloxy or phenyl, formyl, di-lower alkyl acetal or dithioacetal; Lower alkylene acetal or dithioacetal, functionally modified carboxy; Phenyl which optionally contains lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, halogen, nitro, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, functionally modified carboxy and / or lower alkylthio as substituents; Pyrryl, furyl, thienyl or pyridyl, these radicals optionally being substituted by a phenyl radical R or R-; - 98 - Amino, Niederalkylami.no or di-lower alkylamino, R is hydrogen or lower alkyl, R is hydrogen, unsubstituted or by free or etherified hydroxy, free or etherified mercapto, which may be optionally oxidized, by carboxy, functionally modified carboxy, by amino, which may itself in turn Lower alkyl, carboxy, functionally modified carboxy or acyl as substituents, by a mono- or bicyclic carbocyclic aryl radical or a five- or six-membered heteroaryl radical as defined above for Ar substituted lower alkyl, unsubstituted or by free or etherified hydroxy, lower alkyl, nitro, amino , Lower alkylamino, di-lower alkylamino, lower alkanoylamino and / or halogen-substituted sulfonyl or an optionally equally monocyclic five- or six-membered heteroaryl radical as defined above for Ar, R. hydrogen, Lower alkyl, unsubstituted or substituted by free or etherified hydroxy, lower alkyl, nitro, amino, .Niederalkylamino, di-lower alkylamino, lower alkanoylamino and / or halogen-substituted phenyl, unsubstituted or as a Phenylniederalkyl- R is R, substituted phenyl or an optionally equally substituted monocyclic five- or six-membered heteroaryl radical, and R, R and R _{n are} independently / ö 9 Hydrogen; Alkyl, optionally substituted by amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, oxa, thia or Azaniederalkylenamino wherein the aza-nitrogen optionally lower alkyl or lower alkanoyl as substituents, acylamino, free or etherified hydroxy or a carbocyclic aryl or heteroaryl as above for the Group Ar is substituted; or a carbocyclic aryl radical or heteroaryl radical as defined above for the group Ar, wherein R ₁ and R together - 99 - or R and R may together be C -C-lower alkylene in which the carbon atom directly connected to the C2 or C6 carbon atom of the 1,4-dihydropyridine ring is optionally substituted by an oxygen, sulfur or nitrogen atom represented by hydrogen or. Is substituted, wherein R, and R together unsubstituted or substituted by free or etherified hydroxy, amino, Niederalkylami no, di-lower alkylamino and / or halogen, at the aza sticks toff also substituted by lower alkyl, lower alkylene,
Oxa, thia or Azaniederalkylen, wherein R ,. and R, together may denote lower alkylene, aza-, oxa- or thian-lower alkylene, these radicals optionally being attached to carbon atoms by free or etherified hydroxy, amino, lower alkylamino, di-lower alkylamino, halogen, carboxy and / or functionally modified
Carboxy and aza-Sti.ckstoff optionally substituted by lower alkyl, and wherein R ₀ and R may together be lower alkylene, aza-, oxa- or Thianiederalkylen, wherein these radicals
optionally carbon atoms by free or etherified
Hydroxy, amino, lower alkylamino, di-lower alkylamino, halogen,
Carboxy, functionally modified carboxy or a five- or six-membered monoazo, diazo or triaza heteroaryl radical which is optionally fully or partially saturated and optionally substituted on oxo by oxo and the Azastickstoffatomen optionally by lower alkyl or phenyl, which in turn
Lower alkyl, halogen, lower alkoxy and / or nitro may be substituted as substituents; and at the aza-nitrogen, optionally by lower alkyl, which in turn optionally defines a carbocyclic aryl or heteroaryl radical as defined above for the group Ar and / or contains free or etherified hydroxy, acyloxy, amino, lower alkylamino and / or di-lower alkylamino as substituents; by acyl
or phenyl, which in turn may contain lower alkyl, halogen, lower alkoxy and / or nitro as substituents, are optical isomers of compounds of the formula I, mixtures of these
optical isomers and salts of such compounds with salt-forming groups. - 100 - Optionally substituted by lower alkyl, benzyl, diphenylmethyl , wherein the radicals benzyl or diphenylmethyl optionally halogen, lower alkyl and / or lower alkoxy as substituents, ßenzoyl, furanylcarbonyl, phenyl or lower alkoxyphenyl , isomers of compounds of formula I, mixtures of these optical isomers and pharmaceutically acceptable salts of such compounds with salt-forming groups, 3. The method according to item 1, characterized in that compounds of formula I, wherein η is 1, 2 or 3, Ar phenyl, optionally substituted by lower alkyl, phenyl, Phsnylniederalkyl, Phenylnisderalkoxy and / or Phsnylniederalkylthio, such radicals in turn Hydroxy, lower alkoxy, lower alkylenedioxy, halogen, carboxy, lower alkoxycarbonyl and / or cyano, which cyclic radicals may also contain lower alkyl as substituents, and / or by hydroxy, lower alkoxy, halo lower alkoxy, lower alkylenedioxy, halogen, nitro, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, Carboxy, lower alkoxycarbonyl, carbamoyl, cyano, sulfo, aminosulfonyl, lower alkylthio, lower alkylsulfinyl and / or lower alkylsulfonyl, or pyrryl, furyl, thienyl, pyridyl, benzoxadiazolyl or benzthiadiazolyl, these radicals optionally being substituted by a phenyl radical Ar, and in particular lower alkyl, Ni.-alkoxy, halogen and / or optionally dur the group Ac represents lower alkanoyl, lower alkylsulfonyl, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, Ν, Ν-D-lower alkylamino-lower alkoxycarbonyl, N-lower-alkyl-N-phenyl-lower alkyl -amino-lower alkoxycarbonyl, N, N-lower alkyleneamino-lower alkoxycarbonyl, (4-morpholino) -lowo-alkoxycarbonyl, lower alkenyloxy or lower alkynyloxycarbonyl, carbamoyl, N-lower-alkyl-carbamoyl, Ν, Ν-di-lower alkyl-carbamoyl, N, N-lower-alkylcarbamoyl, 4- Z is a radical -OR ₇ or -NR ₃ R ₉ , R _{1 is} hydrogen, lower alkyl, di-lower alkylamino lower alkyl, lower alkyleneamino-lower alkyl, (4-morpholino) -lower alkyl, - 100a - Carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or lower alkoxy-lower alkoxy-lower alkyl, where di-lower alkylamino, lower alkyl-alkylamino or 4-morpholino are separated by at least two carbon atoms from the ring nitrogen atom, or phenyl- - 101 - R 1 and R 4 independently of one another are lower alkyl which is optionally substituted by hydroxy, lower alkoxy which optionally contains amino, lower alkylamino or di-lower alkylamino as substituent, lower alkanoyloxy or phenyl, formyl, di-lower alkyl acetal or dithioacetal, lower alkylene acetal or dithioacetal, cyano, phenyl, thienyl or amino, R is hydrogen or lower alkyl, R is hydrogen, unsubstituted or substituted by hydroxy, lower alkoxy, mercapto, lower alkylthio, carboxy, carbamoyl, amino, lower alkanoylamino, carbamoylamino, guanidino, by phenyl, which in turn is represented by hydroxy and / or halogen may be substituted, imidazolyl or indolyl substituted lower alkyl, unsubstituted or substituted by hydroxy, lower alkoxy, lower alkyl, nitro, amino, lower alkylamino, di-lower alkylamino and / or halogen-substituted phenyl or unsubstituted or in the same manner as for a phenyl radical Ra denotes substituted pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, R, hydrogen, lower alkyl, phenylloweralkyl, unsubstituted or by Hydroxy, lower alkoxy, lower alkyl, nitro, amino, lower alkylamino, di-lower alkylamino and / or halogen-substituted phenyl or an unsubstituted or substituted in the same manner as for a phenyl-lower alkyl radical R, from the group phenyl, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, Furyl _; Thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, and R, R "and R are independently hydrogen, lower alkyl or amino, lower alkylamino, di-lower alkylamino, lower alkylene-amino, oxa, Thia- or azan-lower alkylene-amino wherein the aza nitrogen is optionally substituted by lower alkyl, lower alkanoylamino, hydroxy, lower alkoxy or by phenyl which is unsubstituted or in turn substituted by amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydroxy, lower alkoxy, halogen - 102 - and / or nitro, or by pyrryl, furyl, thienyl or pyridyl, where these groups may be substituted in the same way as phenyl, substituted lower alkyl or phenyl, pyrryl, furyl, thienyl or pyridyl, these groups being the same as a phenyl-lower alkyl radical R, R or R may be substituted, in which R and R together or R and R together may denote C -C -L-lower alkylene, in which the with the C2 or C6 carbon atom of the 1, Optionally substituted by an oxygen, sulfur or nitrogen atom which is substituted by hydrogen or lower alkyl, wherein R and R together are unsubstituted or hydroxy-substituted C 1 -C 4 lower alkylene, C 2 -C 8 oxo-4-dihydropyridine ring. or C 1 -C 3 -thio lower alkyl, in which R and R 1 together may denote lower alkylene having 2 to 5 chain carbon atoms or azanyl lower alkylene having 3 'or 4 chain carbon atoms, wherein ei these radicals may be unsubstituted or substituted by hydroxy, lower alkoxy, amino, lower alkylamino or di-lower alkylamino, and in which R_ and R together may denote C -C-lower alkylene, C -C -azo, C -C -Oxa or C -C -thio-lower alkylene, these radicals being optionally substituted on carbon atoms by hydroxy, lower alkoxy, amino, lower alkylamino, di-lower alkylamino or five- or six-membered monoaza- or diaza-heterocyclyl which is optionally substituted on oxo by carbon atoms and substituted on the azole nitrogen atoms optionally by lower alkyl or phenyl, which in turn may contain lower alkyl, halogen, lower alkoxy and / or nitro as substituents; and at the aza-nitrogen optionally by lower alkyl, which in turn contains phenyl, pyrryl, furyl, thienyl and / or pyridyl, these radicals themselves optionally having lower alkyl, hydroxy, lower alkoxy, halogen and / or nitro as substituents, and or by hydroxy, Lower alkoxy, lower alkanoyloxy, amino, lower alkylamino and / or di-lower alkylamino; by benzoyl, lower alkanoyl, furanylcarbonyl, thienylcarbonyl, pyrrylcarbonyl, - 103 - Pyridinylcarbonyl or phenyl, which in turn may contain lower alkyl, halogen, lower alkoxy and / or nitro as substituent, substituted, optical isomers of compounds of formal I, mixtures of these optical isomers and salts of such compounds with salt-forming groups, manufactures * 4. Process according to item 1, characterized in that compounds of the formula I in which η is 1 or 2, Ar is phenyl, thienyl, furyl or benzoxadiazolyl, these groups being optionally substituted by lower alkyl, lower alkoxy, halo-lower alkoxy, phenyl-lower alkoxy, phenyl-lower alkylthio , Lower alkylenedioxy, halogen, trifluoromethyl, nitro, lower alkanoylamino and / or cyano are mono-, di- or trisubstituted, the radical Ac is lower alkanoyl, lower alkylsulfonyl, lower alkoxycarbonyl, 2-lower alkoxy-lower alkoxycarbonyl, Ν, Ν-di-lower alkylamino-lower alkoxycarbonyl, lower N-lower alkyl N-phenyl-lower alkylamino-lower alkoxycarbonyl, carbamoyl, N-lower-alkyl-carbamoyl, N, N-di-lower alkyl-carbamoyl, Ν, Ν-lower-alkylene-carbainoyl or 4-morpholinocarbonyl, Z is a radical -OR-, or -NR ₀ R ₁ - , stands, R "water / ο y ι lower alkyl, 2- (di-lower alkylamino) -lower alkyl, 2- (lower alkylene amino) -lower alkyl, 2- (4-morpholino) -lower alkyl, lower-alkoxy or lower alkoxy-lower alkoxy-lower alkyl, R "and R independently represent lower alkyl, hydroxy lower alkyl, cyano or amino R, is hydrogen or lower alkyl, R _{5 is} hydrogen, unsubstituted or substituted by hydroxy, lower alkoxy, mercapto, lower alkylthio, carboxy, carbamoyl, amino carbamoylamino, guanidino, phenyl, which in turn may be substituted by hydroxy, or imidazol-4-yl or indole -3-yl substituted lower alkyl - 104 - or phenyl, thiazolyl, imidazolyl, furyl, T'nienyl pyridyl or pyrimidinyl, where these radicals are optionally substituted by hydroxy, lower alkoxy and / or amino, R, - hydrogen, lower alkyl, Phenylniedsralkyl which is unsubstituted or by hydroxy, lower alkoxy and or amino, or phenyl, thiazolyl, imidazolyl, furyl, thionyl, pyridyl or pyrimidinyl, these radicals being optionally substituted as a phenyl-lower alkyl radical R, -, and R ₇ , R and Rq are independently hydrogen or unsubstituted or by amino, lower alkylamino. Di-lower alkyl-amino, lower-alkylene-amino, oxa-or -za-lower alkylene-amino, wherein the aza-nitrogen is optionally substituted by nisodaralkyl. Hydroxy, lower alkoxy, phenyl, which may be unsubstituted or substituted in turn by amino, hydroxy, lower alkoxy and / or halogen, or by thienyl or pyridyl, which groups may be substituted in the same white as phenyl, substituted lower alkyl, wherein R. and R together may denote C, -C, lower-alkylene, wherein R, _ and R _{fi may} together be Cp-CU-lower alkylene or C-azanone-alkylene and wherein R ₀ and R- together are C ₁ -C 1 -lowoalkylene, said optionally substituted by 2-imidazolidinone-1-yl, which may contain in the 3-position phenyl or lower alkyl as a substituent, C, -Oxa- or C.-azanone may mean * wherein the aza-nitrogen by lower alkyl, which in turn unsubstituted or by phenyl which may contain lower alkyl, lower alkoxy, halogen and / or nitro as substituents, thienyl and / or pyridyl mono- or disubstituted, or by benzoyl, furanylcarbonyl, phenyl or lower al koxyphenyl may be substituted, optical isomers of compounds of formula I, - 105 - Mixtures of these optical isomers and pharmaceutically acceptable salts of such compounds with salt-forming GruppenQn produces. 5 »method according to item 1, characterized in that compounds of formula I, wherein η is 1 or 2, Ar is unsubstituted or by lower alkyl, lower alkoxy, halo-lower alkoxy, benzyloxy, benzylthio, halogen, trifluoromethyl, nitro and / or cyano mono - or disubstituted phenyl, 2- or 3-thienyl or 2, l, 3-benzoxadiazol-4-yl, the radical Ac is lower alkylsulfonyl or lower alkoxycarbonyl, Z is a radical -OR ₇ or -NR ₃ R ₉ , R. R _{2 is} hydrogen, further R _{2 is} lower alkyl, R _{5 is} hydrogen or lower alkyl, R _{5 is} hydrogen, unsubstituted or substituted by phenyl, which in turn is substituted by hydrogen, furthermore 2- (4-morpholino) ethyl, R _{2 is} lower alkyl, hydroxymethyl, cyano or amino R 1 is hydrogen, lower alkyl or phenyl, R _{7 is} hydrogen, lower alkyl or lower alkyl represented by phenyl, Am ino, lower alkylamino, di-lower alkylaraino. 4-Morpholines 1-piperazino, which may in turn contain 4-nitrogen nisderalkyl as substituents, or lower alkoxy, Rg and Rg independently of one another represent hydrogen, unsubstituted or lower alkoxy, phenyl or pyridyl-substituted lower alkyl, in which R ₄ and R _g together may be 1,3-propylene, wherein R _e and R- together are 1,5- o o Pentylene, and wherein R _g and R _q together are 1,5-pentylene, 3- (3-phenyl-2-imidazolidinon-1-yl) -1, 5-pentylene, 3- (2-imidazolidinon-1-yl ) -l, 5-pentylene or 3-oxa or - 105 - 6. Process according to item 1, characterized in that compounds of the formula I in which η is 1, Ar is 2- or 3-nitrophenyl, 2- or 3-difluoromethoxyphenyl, 2- or 3-methyl- phenyl, 2- or 3-trifluoroethylphenyl, 2,3-dimethyl-phenyl, 2,3-dichloro-phenylj, 2- or 3-benzyloxy-phenyl or 2- or 3-benzenylthiophenyl, Ac represents lower alkoxycarbonyl, Z represents a radical -OR ₇ or -NRgR _n, R ₁ is hydrogen, mean R_ and R _{3 are} independently lower alkyl, is R. is hydrogen, R ₅ is lower alkyl or phenyl, R represents _ß hydrogen, R ₇ is unsubstituted or substituted by 4- Morpholino, i-piperazino or 4-lower alkyl-1-piperazino substituted lower alkyl, R ₈ and Rg independently represent hydrogen, unsubstituted or substituted by phenyl or pyridyl lower alkyl, and wherein R _g and Rg together 3-aza-l, 5 -Pentylen in which the aza-nitrogen is optionally substituted by benzyl or diphenylmethyl, meaning can, optical isomers of compounds of formula I, mixtures of these optical isomers and pharmaceutically acceptable salts of such compounds with salt-forming groups produced. - 107 - 6 - ¹   R η ' (Ha), - 93 - vorin η 'is 1, 2 or 3 and R is one in the radical C (= O) -Z convertible group is, these converted into the rest C (O) -Z, or b) reacting a compound of the formula IV, or a reactive derivative thereof, with a compound of the formula V, or a tautomer thereof, and with a compound of the formula VI, (IV) Ar
I CH + Il + CH
Il O
Il -C t R, 6 -i (II). wherein η 'is 0, 1 or 2 and R represents an optionally activated carboxy group, with the proviso that R is different from a radical C (= O) -Z when n ^{1 is} 1 or 2, with a Compound of formula III R "'O
ο (III) n ¹ wherein η "stands for 1, 2 or 3, and R under formula I for R, and R 'the R_ and R_ have the same meaning, but differ from the radicals R., R_ or R _g in formula II- - 92a - which can be, with the proviso that the sum of n * and n "is not greater than 3, or a ') in a compound of formula Ua Ar Ac, O. R ₄ R ₅ Ii i R ₂ IR ₃ R- 7. Process according to item 1, characterized in that compounds of the formula I in which the C, carbon of the 1,4-dihydropyridine skeleton has the following configuration in which the carbon atoms C3, C4 and C5 in the paper plane, the radical Ar before and the hydrogen atom lies behind the paper plane, produces: 8. The method according to item 1, characterized in that one (-) _ (4R) _1,4-dihydro-2,5-dimethyl-3-methoxycarbonyl-4- (3-nitro-phenyl) -pyridine-5-carboxylic acid -N - ((1S) -1-ethoxycarbonyl-2-methyl-1-propyl) -amide or pharmaceutically acceptable salts thereof. 9. The method according to item I _1, characterized in that (-) - (4R) -lj4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4- (3-nitro-phenyl) -pyridine-5-carboxylic acid N - ((1S) -1-ethoxycarbonyl-2-methyl-1-propyl) amide or pharmaceutically acceptable salts thereof. 10. The method according to item 1, characterized by reacting (-) - (4R) -l, 4-dihydro-2 _J 6-dimethyl-3-methoxycarbonyl-4- (3-nitro-phenyl) -pyridine-5 carboxylic acid N - ((1S) -l- (n-butoxycarbonyl) -2-methyl-1-propyl) -amide or pharmaceutically acceptable salts thereof. - 103 - 11. The method according to item 1, characterized in that (4R, 4S) -I, 4-dihydro-2,5-dimethyl-3-methoxycarbonyl-4- (3-nitro-phenyl) -pyridine-5-carboxylic acid N - ((1S, 2S) -1-methoxycarbonyl-2-methyl-1-butyl) amide, pharmaceutically acceptable salts or the optical isomers thereof. 12. The method according to item 1, characterized in that (4R) -l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3 ~ nitrophenyl) -pyridine-5-carboxylic acid N - (( IS ^ SJ-1-ethoxycarbonyl-2-methyl-1-butyl) -araid or pharmaceutically acceptable salts thereof, 13. The method according to item I _1, characterized in that (4S, 4R) -l, 4-dihydro-2,6-dimethyl-3-raethoxycarbonyl-4- (3-nitro-phenyl) -pyridine ~ 5-carboxylic acid N- (1S) -1- (2- (4-morpholino) -1-ethoxy) -carbonyl-2-methyl-1-propyl3-amide, pharmaceutically acceptable salts or the optical isomers thereof. 14. The method according to item 1, characterized in that l, 4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitro-phenyl) -pyridine-5-carboxylic acid 8-N- (l- ( 4-benzyl-1-piperazinyl) -carbonyi-2-methyl-i-propyl) -araid, pharmaceutically acceptable salts or the optical isomers thereof. 15. The method according to item 1, characterized by reacting (-) - (4R) -l, 4-dihydro-2,6-dimethyl-3-ethoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N - ((IS) -l-ethoxycarbonyl-2-methyl-1-propyl) -amide or pharmaceutically acceptable salts thereof. - lOSa - 16 «method according to item 1, characterized in that (4S, 4R) -1 _# 4-dihydro-2,6-di-ethyl-3-methoxycarbonyl-4- (3-nitrophenyl) -pyridine-5-carboxylic acid N- ((1S) -l- (4-diphenylmethyl-1-piperazinyl) carbonyl-2-methyl-i-propyl) amide, pharmaceutically acceptable salts or the optical isomers thereof.