NO844560L - NEW AMID RELATIONS. - Google Patents

Description

The invention relates to new amide compounds and their salts, methods for their preparation, pharmaceutical preparations containing such compounds and their use for the preparation of pharmaceutical preparations or as pharmacologically active compounds.

The invention relates in particular to substituted 3-carbamoyl-1,4-dihydropyridine compounds of formula I

where n stands for 1, 2 or 3, Ar means a carbocyclic or heterocyclic aryl residue, Ac means the acyl residue of an acid, Z stands for a residue -OR^ or -NRgRg, R^ means hydrogen, unsubstituted or substituted lower alkyl,

a carbocyclic or heterocyclic aryl radical or free, etherified or esterified hydroxy, R2 and R^ stand independently of each other for hydrogen, unsubstituted or substituted lower alkyl, formyl or functionally converted formyl, carboxy or functionally converted carboxy, a carbocyclic or heterocyclic aryl radical or unsubstituted, mono- or disubstituted amino, R^ means hydrogen or lower alkyl, R,, and R^ independently mean hydrogen, unsubstituted or substituted lower alkyl or a carbocyclic or heterocyclic aryl residue, R7, Rg and Rg independently mean hydrogen, unsubstituted or substituted alkyl or a carbocyclic or heterocyclic aryl radical, wherein R^ and R^, or R^ and R^ together may mean unsubstituted or substituted lower alkylene, wherein

a carbon atom is optionally replaced by a heteroatom, in which R. and R<- together, as well as R,- and R^ together and/or Rg and R^ together, can independently mean unsubstituted or substituted lower alkylene, in which a carbon atom can be replaced by a heteroatom, optical isomers of compounds of the formula I, mixtures of these optical isomers and salts of such compounds containing a salt-forming group, methods for the preparation of these compounds, such compounds containing pharmaceutical agents and their use for the preparation of pharmaceuticals preparations or as pharmacologically active compounds.

The definitions used above, as well as subsequently, have, if not specifically defined, the following meanings: The expression "lower" means that correspondingly defined groups or compounds contain up to and including 7, preferably up to and including 4 carbon atoms.

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

In the above-mentioned formula I, n primarily stands for

1, but can also mean 2 or 3. If n is 2 or 3, then the multiple uptrending residues R^, R,, and Rg are each independent of one another.

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

Carbocyclic residues of this kind are especially phenyl,

further naphthyl, e.g. 1- or 2-riaphthyl.

Heterocyclic aryl residues are preferably corresponding monocyclic residues, but can however also be corresponding bi- or polycyclic residues, whereby the latter can consist of several heterocyclic rings, or of one or more heterocyclic rings with one or more fused carbocyclic rings, especially one or more fused benzo rings . The usually present heterocyclic residues, which preferably consist of 5 or 6 ring members, may contain up to 4, the same or different hetero atoms, in particular nitrogen, oxygen and/or sulfur atoms, preferably one, two or three or four nitrogen atoms, an oxygen - or a sulfur atom, or one or two nitrogen atoms together with an oxygen or sulfur atom as a ring member. They are bonded with the 4-ring carbon atom of the 1,4-dihydro-pyridine ring usually over a ring carbon atom.

Monocyclic five-membered heteroaryl residues are e.g. corresponding monoaza-, diaza-, triaza-, tetraza-, monooxa-, monothia-, oxaza-, oxadiaza-, thiaza- or thiadiaza-cyclic residues, such as pyrryl-, pyrazolyl-, imidazolyl-, triazolyl-, tetrazolyl-, furyl -, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl or thiadiazolyl residues, while monocyclic, six-membered heteroaryl residues are e.g. corresponding monoaza-, diaza- or triazacyclic residues such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl residues. Bicyclic heteroaryl radicals are particularly monocyclic heteroaryl-

residues with fused benzoring, the heteroring can be five- or six-membered, whereby the five-membered heteroaryl residues produce e.g. a monoaza-, diaza-, monooxa-, monothia-, oxaza-, thiaza-, oxadiaza- or thiadiazacyclic residue, and the six-membered heteroaryl residues produce e.g. a monoaza or a diazacyclic heteroaryl residue. Such bicyclic residues are e.g. indolyl, isoindolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzthiazolyl, benzoxadiazolyl, benzthiadiazolyl, quinolinyl or isoquinolinyl residues.

The carbocyclic and heterocyclic aryl residues can be unsubstituted or substituted, whereby primarily ring carbon atoms, but also ring nitrogen atoms can be substituted. The substituent of ring carbon atoms is, among other things, possibly substituted hydrocarbon residues, such as corresponding aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon residues, such as lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, cycloalkyl, cycloalkyl lower alkyl, phenyl, phenyl lower alkyl, phenyl lower alkyl thio and/or phenyl lower real oxy, whereby substituents of such hydrocarbon residues, especially of lower alkyl, phenyl, phenyl lower alkyl, phenyl lower alkyl thio and/or phenyl lower alkyl, can be e.g. etherified or esterified hydroxy groups, such as hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy or halogen, and/or optionally functionally converted carboxy, such as carboxy, esterified carboxy, e.g. lower alkoxycarbonyl, amidated carboxy, such as carbamoyl, N-loweralkylcarbamoyl or N,N-diloweralkylcarbamoyl, or cyan. Cyclic substituents, especially phenyl, can also contain as substituents lower alkyl which can optionally be substituted, e.g. as indicated. Further substituents of aryl residues Ar are e.g. optionally etherified or esterified hydroxy group, such as hydroxy, lower alkoxy, halolower alkyloxy, lower alkenyloxy, halogenolower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy or halogen, nitro, optionally substituted amino, such as amino, lower alkylamino, dilower alkylamino, N-lower alkyl-N-phenyl lower alkylamino, lower alkylene amino, oxal lower alkylene amino, thialaverealkyleneamino or azalaverealkyleneamino, whereby the aza nitrogen can be unsubstituted or substituted, e.g. with possibly, e.g. as described above, substituted lower alkyl, phenyl or phenyl lower alkyl, or acylamino, e.g. lower alkanoylamino, azido, acyl, such as lower alkanoyl, or optionally functionally converted carboxy, such as carboxy, esterified carboxy, e.g. lower alkoxycarbonyl or amidated carboxy, such as carbamoyl, N-lower alkyl-carbamoyl or N,N-di-lower alkyl-carbamoyl, or cyan, optionally functionally converted sulfo, such as sulfo or aminosulfonyl and/or etherified mercapto, which may optionally be oxidized, such as lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl. Substituents for ring nitrogen atoms are in the first row

the above-mentioned, optionally substituted hydrocarbon residues, such as lower alkyl or lower alkoxycarbonyl, further hydroxy or oxido.

Heterocyclic aryl residues Ar can be present, e.g. everything

according to the nature of the substituents in various tautomeric forms.

Partially saturated five- or six-membered monoaza-, diaza- or triaza-heteroaryl residues are e.g. dihydropyrrolyl, dihydroimidazolyl, dihydropyridinyl, dihydropyrimidinyl or tetrahydrotriazinyl. Examples of such residues with oxo substituents are 2-oxo-1,2-dihydro-1-pyrrolinyl, 2-oxo-1,2-dihydro-4-pyrimidinyl or 5,6-dioxo-1,4,5,6 -tetrahydro-1,2,4-triazin-3-yl. A fully saturated heteroaryl residue corresponds to heterocyclyl. Five- or six-membered monoaza- or diazaheterocyclyl is e.g. pyrrolidinyl, piperidinyl, imidazolidinyl or piperazinyl. Examples of such residues with oxo substituents are 2-pyrrolidinon-1-yl, 2-piperidinon-1-yl and above all 2-imidazolidinon-1-yl.

An acyl residue Ac can mean the corresponding residues of a carboxylic acid, especially lower alkanoyl, further unsubstituted or substituted, e.g. lower alkyl, lower alkoxy,

nitro and/or halogen containing benzoyl, or an organic sulfonic acid, especially lower alkylsulfonyl or unsubstituted or substituted, e.g. lower alkyl, lower alkoxy, nitro and/or halogen containing phenylsulfonyl. Acyl residues Ac are, however, in the first row

for acyl residues of monoesters, further also of monoamides of the carboxylic acid, which are mainly unsubstituted or substituted, e.g. free or etherified hydroxy, such as lower alkoxy, or unsubstituted or substituted amino, such as e.g. above-described amino, and primarily for disubstituted amino, such as dilower alkylamino, N-lower alkyl-N-phenyl lower alkyl-amino or optionally with oxygen, sulfur or unsubstituted or, e.g. with lower alkyl, substituted nitrogen interrupted lower alkyleneamino, or an unsubstituted or e.g. with lower alkyl, lower alkoxy, nitro and/or halogen substituted phenyl-, thienyl-,

furyl, pyrryl or pyridyl residue containing lower alkoxycarbonyl, further lower alkenyloxy or lower alkynyloxycarbonyl, but also N-unsubstituted or N-mono- or N,N-disubstituted carbamoyl, such as N-lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl, N-hydroxycarbamoyl, or optionally in the lower alkylene part with oxygen, sulfur or unsubstituted or, e.g. with lower alkyl substituted nitrogen interrupted N,N-lower alkylene carbamoyl. In addition, acyl residues Ac also include acyl residues of cyclic carboxylic acid derivatives, such as e.g. 5-tetrazolyl or unsubstituted or with lower alkyl or phenyl substituted 4,5-dihydro-2-oxazolyl or 5,6-dihydro-4H-1,3-oxazin-2-yl.

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

A substituted lower alkyl radical R contains as substituents e.g. unsubstituted or especially mono- or disubstituted amino, such as lower alkylamino, dilower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino or optionally

with oxygen, sulfur or unsubstituted or, e.g. with lower alkyl or lower alkanoyl, substituted nitrogen

interrupted lower alkyleneamino, whereby such a substituent is preferably separated by at least 2 carbon atoms from the ring nitrogen atom. It can further be substituted, e.g. with carboxy or functionally converted carbokay, e.g. carboxymethyl, or with lower alkoxy, whereby such lower alkoxy is preferred, which in turn is substituted with lower alkoxy, e.g. 2-methoxyethoxymethyl, or with phenyl, which in turn optionally contains lower alkyl, lower alkoxy, halogen and/or nitro as substituents, e.g. benzyl, or be substituted with N-pyrrolyl, N-imidazolyl, N-pyrazolyl, N-indolyl or N-isoindolyl, e.g. N-imidazolylmethyl.

Functionally converted carboxy is e.g. esterified

carboxy, e.g. lower alkoxycarbonyl, or amidated carboxy, such as e.g. carbamoyl, N-lower alkyl-carbamoyl or N,N-dilower alkyl-carbamoyl, or cyan. Functionally converted carboxy as meaning of and R_ is preferably cyan.

With an amino-lower alkyl residue R^, which is substituted with functionally converted carboxy, the latter is preferably

show carbamoyl or C-amidino[-C(=NH)~NH2]•

Phenyl lower alkyl is e.g. benzyl or 1- or 2-phenylethyl. It can be substituted in the phenyl ring, e.g. with free or etherified hydroxy, lower alkyl, nitro, amino, lower alkylamino, dilower alkylamino, lower alkanoyl-

amino and/or halogen.

The lower alkyl contains e.g. two to seven, especially three

to five chain carbon atoms and is i.a. 1,3-propylene or 1,4-butylene. The lower alkyl, in which a carbon atom is replaced by a heteroatom, is e.g. oxa-, thia- or aza-lower alkylene. Lower alkylene, aza-, oxa- or thialelower alkylene, formed together by the radicals Rg and Rg,

is preferably C2-C7-lower alkylene, C3-C3-aza-, C3-C3-oxa-

or C₁-C₂-thialaverealkylene, especially C₁-C₄-lower alkylene, C₄-oxa- or C₄-azalaverealkylene, primarily 1,5-pentylene, 3-oxa- or 3-aza-1,5- pentylene and above all 3-aza-1,5-pentylene.

The lower alkylene, aza-, oxa- or thialeweralkylene, formed together by the radicals R,, and R^, preferably means the lower alkylene with 2 to 5 chain carbon atoms, the aza-, oxa- or thialeweralkylene with each 3 or 4 chain carbon atoms, especially C2~C,- -lower alkylene or C 1 -aza lower alkylene and primarily 1,5-pentylene.

The lower alkylene, aza-, oxa- or thialeveralkylene, formed together by the radicals R. and Rc, is preferably C-.-C. 1,3-propylene, 2-oxa- or 2-thia-1,3-propylene and primarily 1,3-propylene.

The lower alkylene, in which a carbon atom is optionally substituted

with a heteroatom, formed together by the radicals R 1 and R 2

or formed together by R^ and R^, preferably means the C^-C^-lower alkylene, in which with C2~resp. The C6 carbon atom of the 1,4-dihydropyridine ring directly bonded carbon atom is optionally replaced by an oxygen, sulfur or nitrogen atom which is substituted by hydrogen or lower alkyl, especially C^-C^-lower alkylene or 3-oxa-, 3-thia - or 3-aza-1,3-propylene - the numbering of the C atoms thereby begins on the nitrogen atom - and means

above all 1,2-ethylene, 1,3-propylene or 1,4-butylene.

Lower alkylene, oxa-, thia- and aza-lower alkylene residues

can be substituted e.g. with hydroxy, lower alkoxy, amino, lower alkylamino, dilower alkylamino, halogen,

carboxy and/or functionally converted carboxy, on the aza nitrogen also with lower alkanoyl, phenyl or phenyl lower alkyl or especially with lower alkyl. Residues such as The C-.-C.-aza-, C.-oxa- or C..-C.-thialavere-3 4 4 3 4 alkylene contains the indicated number of carbon atoms and additionally the indicated heteroatom.

Naphtyl can be e.g. 1- or 2-naphthyl.

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

Pyridyl is 2-, 3- or 4-pyridyl, pyridazinyl is e.g. 3-pyridazinyl, pyrimidinyl is 2-, 4- or 5-pyrimidinyl, pyrazinyl is 2-pyrazinyl and triazinyl is e.g. 1,3,5-triazin-2-yl.

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

Lower range alkenyl is e.g. allyl or methallyl and lower alkynyl are e.g. propargyl.

Cycloalkyl preferably contains 5 to 7 ring carbon atoms and is e.g. cyclopentyl or cyclohexyl, while cycloalkyl lower alkyl can be e.g. cyclopropylmethyl,

cyclopentylmethyl or cyclohexylmethyl.

Etherated hydroxy is primarily lower alkoxy, further e.g. phenyl lower aryloxy, aryloxy or heteroaryloxy.

Acyloxy is e.g. with one of the above defined

acyl residues Ac substituted hydroxy, preferably benzoyloxy, which is optionally substituted with hydroxy, lower alkoxy, halogen, lower alkyl and/or nitro and is primarily lower alkanoyloxy.

Laverealkoksy stands for e.g. for methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy.

In a lower alkoxy lower carboxylic acid residue, the terminal lower alkoxy group is preferably separated by more than one carbon atom from the connecting carbon atom, such residues are e.g. 2-methoxy-ethoxy or 2-ethoxy-ethoxy.

Lower alkenyloxy is e.g. allyloxy or metallyloxy,

and halogen-lower alkenyloxy, which may contain one or more halogen atoms, whereby the latter preferably has an atomic number up to and including 35 and stands for fluorine and chlorine in particular, are e.g. 1,2-dichloro-vinyloxy.

In a halogen-lower carboxylic acid residue, one or more halogen atoms may be present, which preferably have an atomic number up to and including 35 and stand in particular for fluorine or chlorine, such residues are e.g. 1,1,2-trifluoro-2-chloroethoxy or preferably difluoromethoxy.

Lower realkynyloxy is e.g. propargyloxy, while lower alkylenedioxy means e.g. methylenedioxy or ethylenedioxy.

Lower alkanoyloxy is e.g. acetyloxy, propionyloxy

or pivaloyloxy.

Halogen-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, further bromine, but can also be iodine.

Lower oxycarbonyl is e.g. methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl or tert-butyloxycarbonyl.

N-lower alkyl-carbamoyl is e.g. N-methyl-carbamoyl or N-ethyl-carbamoyl, while N,N-dilaverealkyl-carbamoyl is e.g. N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl.

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

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

Lower alkyleneamino contains e.g. 2 to 7, preferably 4 or 5 ring carbon atoms and is e.g. pyrrolidino or piperidino, while oxalaverealkyleneamino can be e.g. morpholino, such as 4-morpholino (3-oxa-1,5-pentyleneamino), thia-lower alkyleneamino, e.g. thiomorpholino, such as 4-thiomorpholino, and optionally aza-substituted azalaverealkyleneamino, e.g. piperazino, as 1-piperazino can mean (3-aza-1,5-pentyleneamino), 4-methylpiperazino, 4-phenyl-piperazino, 4-benzyl-piperazino or 4-(2-phenylethyl)-piperazino.

Acylamino is e.g. with one of the above-defined acyl residues Ac substituted amino, preferably benzoylamino, which is optionally substituted with hydroxy, lower alkoxy, halogen, lower alkyl and/or nitro, and is primarily lower alkanoylamino.

Lower alkanoylamino is e.g. acetylamino or propionylamino.

Acyl as such is e.g. one of the above-defined acyl residues Ac, preferably benzoyl, which is optionally substituted as indicated for benzoylamino and is primarily lower alkanoyl, e.g. formyl, acetyl, propionyl or pivaloyl. Further preferred acyl residues are furanylcarbonyl, thienylcarbonyl, pyrrylcarbonyl or pyridinylcarbonyl and especially furan-2-ylcarbonyl.

Etherated 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 alkylsulfinyl means e.g. methylsulfinyl and lower alkylsulfonyl mean e.g. methylsulfonyl or ethylsulfonyl.

In an amino lower alkyl group, amino is preferably separated by at least 2 carbon atoms from the connecting carbon atom, such residues are primarily 2-disubstituted amino lower alkyl, such as 2-di lower alkyl aminoethyl, e.g. 2-dimethylaminoethyl or 2-diethylaminoethyl, 2-lower alkyleneaminoethyl, e.g. 2-pyrrolidino-ethyl or 2-piperidino-ethyl, 2-(4-mofolino)-ethyl, or 2-(4-lower-alkylpiperazino)-ethyl, e.g. 2-(4-methylpiperazino)-ethyl.

In a substituted lower alkoxycarbonyl, the substituent is usually separated by at least 2, preferably by 2 or 3 carbon atoms from the oxygen. Such residues are e.g. hydroxy lower oxycarbonyl, such as 2-hydroxyethoxycarbonyl or 2,3-dihydroxypropyloxycarbonyl, lower alkoxy-lower alkoxycarbonyl, e.g. 2-methoxyethoxycarbonyl, dilower alkylamino-lower alkyl oxycarbonyl, e.g. 2-dimethylaminoethoxycarbonyl, 2-diethylaminoethoxycarbonyl or 3-dimethylaminopropyloxycarbonyl, lower alkyleneamino-lower oxycarbonyl, e.g. 2-pyrrolidinoethoxycarbonyl or 2-piperidinoethoxycarbonyl, morpholino-lower oxycarbonyl, e.g. 2-(4-morpholino)-ethoxycarbonyl, or 4-lower alkyl-piperazino-lower oxycarbonyl, e.g. 2-(4-methylpiperazino)-ethoxycarbonyl.

Phenylvareal oxycarbonyl is e.g. benzyloxycarbonyl or 2-phenylethoxycarbonyl.

N,N-lower alkylene-carbamoyl is e.g. pyrrolidinocarbonyl or piperidinocarbonyl, whereby corresponding residues in which the lower alkyl part is interrupted by oxygen, sulfur or unsubstituted or substituted nitrogen, means e.g. 4-morpholinocarbonyl, 4-thiomorpholinocarbonyl, 1-piperazinocarbonyl or 4-methyl-1-piperazino'-carbonyl.

Salts of compounds according to the invention are primarily pharmaceutically usable, non-toxic salts, such as those of compounds of formula I with acidic groups, e.g. with a free carboxy or sulfo group. Such salts are primarily metal or ammonium salts, such as alkali metal or alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, whereby primarily aliphatic, cycloaliphatic, cyclo-aliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines are mentioned , as well as heterocyclic bases for salt formation, such as lower alkylamines, e.g. triethylamine, hydroxyl lower alkylamine, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethyl-piperidine, cycloalkylamines, e.g. dicyclohexylamine, or benzyl amines, e.g. N,N'-dibenzyl-ethylenediamine, further bases of the pyridine type, e.g. pyridine, collidine or quinoline. Compounds of formula I with basic groups can form acid addition 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 poly-salts can be formed. Compounds of formula I with an acid, e.g. free carboxy group, and a free basic, e.g. an amino group, can also exist in the form of internal salts, i.e. in zwitterionic form, or part of the molecule can exist as an internal salt and another part as a normal salt.

Pharmaceutically unsuitable salts can also be used for isolation or purification. For therapeutic use, only the pharmaceutically usable, non-toxic salts are used, which are therefore preferred.

The compounds of formula I and salts of such compounds with salt-forming properties have valuable pharmacological properties. They primarily exhibit strong antihypertensive and hypotensive effects which can be demonstrated, for example, in the awake, renally hypertensive rat in analogy to that of Byrom and Wilson, J.Physiol. (London), vol 93, page 301

(1938), Gerold et al, Heiv. Physiol. Pharmacol. Acta, vol. 24, page 58 (1966) and Goldblatt et al., J. Exptl. Med., vol. 59, page 347 (1934) described test device in doses from approx. 0.3 mg/kg p.o.. The blood pressure-lowering effect can be shown e.g. also on the anesthetized cat by intravenous administration from doses of approx. 0.001 mg/kg. Furthermore, the compounds have long-lasting pharmacological effects, e.g. a long-lasting hypotensive resp. vasodilatory effect, which can be demonstrated, e.g. on awake dogs and on anesthetized dogs by intravenous administration of doses from approx. 0.01 mg/kg. The compounds of formula I are further distinguished by the fact that they exhibit negative inotropic and negative chronotropic effects, the former can be demonstrated, for example, in vitro by an inhibition of the contraction force of the isolated, left, with constant frequency stimulated guinea pig heart atrium from a concentration of approx. 10 nmol/1 and the latter on the right, spontaneously beating guinea pig heart atria from a concentration of approx. 1 nmol/l. Hereby, the compounds of formula I are distinguished by the fact that they exhibit only weak negative inotropic effects relative to the negative chronotropic effect. In addition, the compounds of formula I, which are generally common with calcium antagonists, for example in the narcotized dog, according to the reflex cardio-stimulation, cause an increase in the heart rate, which, however, occurs delayed and is limited. In the anesthetized rat, the heart rate is reduced

in the administration of compounds of formula I on

despite an increase in the activity of the sumpatixen.

The compounds of formula I also act as coronary dilators, which can be demonstrated e.g. on the isolated, perfused guinea pig heart according to Langendorff in concentrations of

about. 0.1 nmol/1. Hereby, it must be emphasized that the compounds of formula I exhibit only weak negative inotropic effects relative to the coronary dilating effect. The affinity of the compounds for calcium channels can be demonstrated in vitro in the nitrendipine receptor binding test.<3>H-nitrendipine is specifically bound by membrane preparations of the guinea pig heart. The IC^Q values, which indicate the concentration of the test compound, which is necessary to reduce the specific binding of<3>H-nitrendipine if 50% lies with the compounds according to the invention at approx. 0.1 nmol/1 or above. Furthermore, electrophysiological investigations allude to compounds of formula I, e.g. the recording of the intercellular conduction of the action potential on the isolated papillary

2+

muscle to the guinea pig heart, on a strong inhibition of Ca ion influx. Thus, e.g. on it partly of

K<+->ion depolarized papillary muscle preparation in concentrations of 10 nmol/1 or less an inhibition of "slow potentials" of 50%. When examined in the non-depolarized preparation, compounds of formula I remarkably prolong the duration of the action potential at concentrations from 10 nmol/l, possibly according to an additional effect on potassium efflux. Moreover, also in vitro on the isolated perfused rat mesenteric vessel layer, that of potassium or calcium ions (from about 0.1

nmol/1) induced above that of norepinephrine (from approx.

10 nmol/1) induced vasoconstriction inhibited by for-

compounds of formula I. The compounds of formula I are further distinguished by relatively rapid onset of the pharmacological effects, chemical stability and, in comparison with the cardiovascular effects, a relatively low toxicity.

The compounds of formula I and salts of such compounds

with salt-forming properties can therefore find use e.g. as antihypertensives and coronary dilators for the treatment of cardiovascular diseases, such as mainly angina pectoris and hypertension, further e.g. arrhythmias, cerebral and peripheral blood circulation disorders, pulmonary hypertension, migraine, vasospasm or heart insufficiency and further indications, such as e.g. arteriosclerosis, spasms of smooth muscles, such as bronchi, uterus, intestines, etc., or general functional disorders of the brain.

However, the new compounds are also valuable intermediates for the production of other, especially pharmaceutical active compounds.

The invention relates in particular to compounds of formula I,

where n stands for 1, 2 or 3, Ar stands for a mono- or bicyclic, carbocyclic aryl residue or a 5- or 6-membered one up to and including 4 ring nitrogen atoms, a ring oxygen or

ring sulfur atom or one or two ring nitrogen atoms together with a ring oxygen atom or a ring sulfur atom as a ring member containing, monocyclic heteroaryl residue, which optionally contains a fused benzo ring, and means in particular phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl . lower alkynyl, lower alkylene, cycloalkyl, phenyl, phenyl lower alkyl, phenyl lower alkyl oxy and/or phenyl lower alkyl thio, whereby lower alkyl, phenyl, phenyl lower alkyl, phenyl lower alkyl oxy and/or phenyl lower alkyl thio may optionally contain as substituents hydroxy, lower alkoxy, halogen-lower alkyl oxy, lower alkenyloxy, lower alkyne yloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl and/or cyan, the cyclic residues may also contain lower alkyl as substituents, as on

its side may be substituted as indicated, and/or with hydroxy, lower alkoxy, halogeno-lower oxy, lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, nitro, amino, lower alkyl-amino, di-lower alkylamino, N-lower alkyl-N-phenyl lower alkylamino, lower alkyleneamino, oxalaverealkyleneamino, thia lower alkyleneamino and/or aza lower alkylene amino, in which the aza nitrogen atom may be substituted with lower alkyl, phenyl or phenyl lower alkyl, whereby these substituents may contain hydroxy, lower alkoxy, halogen lower alkyl oxy, lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl -carbamoyl,. N,N-diloweralkylcarbamoyl and/or cyan as substituents and/or may be substituted with loweralkanoylamino, azido, carboxy,

lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl, cyano, sulfo, aminosulfonyl, lower alkylthio, lower alkylsulfinyl and/or lower alkylsulfonyl, and/or ring nitrogen atoms may optionally be substituted with lower alkoxycarbonyl or with lower alkyl, as substituents may optionally contain hydroxy, lower alkoxy, halogeno-lower oxy, lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl or cyan, or may be substituted with hydroxy or oxido, residues Ac stands for lower alkanoyl, unsubstituted or with lower alkyl, lower alkoxy, nitro and/or halogen substituted benzoyl, lower alkylsulfonyl, unsubstituted or with lower alkyl, lower alkoxy, nitro and/or halogen substituted phenylsulfonyl, lower alkoxycarbonyl, hydroxy lower aryl oxycarbonyl, lower alkoxy-lower rel oxy carbonyl, amino lower rel oxy carbonyl nyl, lower alkylamino-lower alkyl, N,N-dilower alkylamino-lower alkyl, N-lower alkyl-N-phenyl lower alkyl-amino lower alkyl, N,N-lower alkyleneamino lower oxycarbonyl, morpholino lower alkyl, thiomorpholino lower oxycarbonyl, piperazinola lower oxycarbonyl, 4-lower alkyl-piperazino-lower alkyl, unsubstituted or with lower alkyl , lower alkoxy, nitro and/or halogen substituted phenyl-, thienyl-, furyl-, pyrryl-•or pyridyl-lower oxycarbonyl, lower alkenyloxy- or lower alkynyloxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-dilower alkylcarbamoyl, N-hydroxy-carbamoyl , N,N-lower alkylenecarbamoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazinocarbonyl, 4-lower alkyl-piperazinocarbonyl, 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 represents a residue -OR 7 or -NR 9 R 9 , R 9 represents hydrogen; lower alkyl which is optionally substituted with lower alkylamino, dilower alkylamino, lower alkyleneamino, morpholino, thiomorpholino, piperazino, which carries a nitrogen atom optionally lower alkyl or lower alkanoyl as substituents, carboxy, functionally converted carboxy, lower alkoxy, lower alkoxy-lower alkyl or phenyl, which in turn optionally contains as substituents lower alkyl, lower alkoxy, halogen and/or nitro, or N-pyrrolyl, N-imidazolyl, N-pyrazolyl, N-indolyl or N-isoindolyl; phenyl which is optionally substituted as a phenyl lower alkyl radical R ; hydroxy, lower methoxy or phenyl lower oxy,

R2 and R^ independently mean hydrogen, lower alkyl, which is optionally substituted with hydroxy, lower alkoxy, which optionally contains amino, lower alkylamino, dilower alkylamino or acylamino as substituents, acyloxy or phenyl, formyl, dilower alkyl acetal or -dithioacetal, lower alkylene acetal or -dithioacetal, functional converted carboxy; phenyl, optionally containing lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, halogen, nitro, amino, lower alkylamino, dilower alkylamino, lower alkanoylamino, carboxy, functionally converted carboxy and/or lower alkylthio as substituents; pyrryl, furyl, thienyl or pyridyl, whereby these residues are optionally substituted as a phenyl residue R 2 or R 1 ; amino, lower alkylamino or dilower alkylamino, R^ means hydrogen or lower alkyl, R,, means hydrogen, unsubstituted or with free or etherified hydroxy, free or etherified mercapto, which may optionally be oxidized, with carboxy, functionally converted carboxy, with amino which optionally on on its side contains lower alkyl, carboxy, functionally converted carboxy or acyl as substituents, with a mono- or bicyclic carbocyclic aryl residue or a five- or six-membered heteroaryl residue according to the definition given above for Ar substituted lower alkyl, unsubstituted or with free or etherified hydroxy, lower alkyl, nitro, amino, lower alkylamino, dilower alkylamino, lower alkanoylamino and/or halogen-substituted phenyl or an optionally similarly substituted, monocyclic five- or six-membered heteroaryl residue according to the above definition of Ar, Rb, means hydrogen, lower alkyl, unsubstituted or with free or etherified hydroxy, lower alkyl,

nitro, amino, lower alkylamino, dilower alkylamino, lower alkanoylamino and/or halogen substituted phenyl-lower alkyl, unsubstituted or as a phenyl lower alkyl residue R^-substituted phenyl or an optionally similarly substituted monocyclic five- or six-membered heteroaryl residue, and R^, Rg and R^ independently hydrogen; alkyl which is optionally substituted with amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, oxa-, thia- or azalower alkyleneamino, in which the aza-nitrogen optionally carries lower alkyl or lower alkanoyl as substituents, acylamino, free or etherified hydroxy or a carbocyclic aryl residue or heteroaryl residue as defined above for the group Ar; or a carbocyclic aryl radical or heteroaryl radical as defined above for the group Ar, in which R 1 and R 2 together or R 2 and R 2 together can mean C 2 -C 3 -lower alkylene, in which with C 2~resp. The Cg carbon atom of the 1,4-dihydropyridine ring directly bonded carbon atom is optionally replaced by an oxygen, sulfur or nitrogen atom,

which is substituted with hydrogen or lower alkyl, in which R^ and R,, together can mean unsubstituted or with free or etherified hydroxy, amino, lower alkylamino, dilower alkylamino and/or halogen, on the azanite nitrogen also with lower alkyl, substituted lower alkylene, oxa-, thia- or the aza-lower alkylene, in which R,- and R^ together can mean lower alkylene, aza-, oxa- or thiale-lower alkylene, whereby these residues are optionally substituted on carbon atoms with free or etherified hydroxy, amino, lower alkylamino, dilower alkylamino, halogen, carboxy and/or functional converted carboxy and optionally substituted on the aza-nitrogen with lower alkyl, and in which Rg and Rg together can mean lower alkylene, aza-, oxa- or thialeweralkylene, whereby these residues are optionally substituted on carbon atoms with free or etherified hydroxy, amino, lower alkylamino, dilower alkylamino, halogen, carboxy, functionally converted carboxy or a five- or six-membered monoaza-, diaza-

or triaza-heteroaryl residue, which is optionally fully or partially saturated and is optionally substituted on carbon atoms with oxo and is optionally substituted on the azanitrogen atoms with lower alkyl or phenyl, which in turn may contain lower alkyl, halogen, lower alkoxy and/or nitro as substituents; and is optionally substituted on the aza nitrogen with lower alkyl, which in turn optionally contains a carbocyclic aryl residue or heteroaryl residue as defined above for group Ar and/or free or etherified hydroxy, acyloxy, amino, lower alkylamino and/or dilower alkylamino as substituents; with 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 primarily relates to compounds with

formula I, where n stands for 1, 2 or 3, Ar means phenyl which is optionally substituted with lower alkyl, phenyl, phenyl lower alkyl, phenyl lower alkyl oxy and/or phenyl lower alkyl thio, whereby such residues can in turn contain hydroxy, lower alkoxy, lower alkylene dioxy, halogen, carboxy , lower alkoxycarbonyl and/or cyan, the cyclic residues also lower alkyl as substituents, and/or are substituted with hydroxy, lower alkoxy, halogen-lower alkoxy, lower alkylenedioxy, halogen, nitro, amino, lower alkylamino, dilower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, cyan . /or optionally with lower alkyl, lower alkoxy, halogen and/or nitro su substituted phenyl as substituents, the residue Ac stands for lower alkanoyl, lower alkylsulfonyl,

lower alkoxycarbonyl, hydroxy-lower alkyl, lower alkyl lower alkyl, N,N-dilower alkylamino-lower oxycarbonyl, N-lower alkyl-N-phenyl lower alkyl-amino-lower oxycarbonyl, N,-N-lower alkyleneamino-lower oxycarbonyl, (4-morpholino)-lower oxycarbonyl, lower alkenyloxy or lower alkynyloxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-diloweralkylcarbamoyl, N,N-loweralkylenecarbamoyl, 4-morpholinocarbonyl or 4-loweralkyl-1-piperazinocarbonyl, Z means a residue -OR., or -NR0Rn, R. stands for hydrogen, lower alkyl, dilower alkylaminolower alkyl, lower alkyleneamino lower alkyl, (4-morpholino)-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or lower alkyl-lower alkyl-lower alkyl, whereby dilower alkylamino, lower alkyleneamino resp. 4-morpholino is separated by at least two carbon atoms from the ring nitrogen atom, or stands for phenyl lower alkyl, phenyl, hydroxy or lower alkoxy,

R 2 and R 3 independently mean lower alkyl, which is optionally substituted with hydroxy, lower alkoxy,

which optionally contain amino, lower alkylamino or dilower alkylamino as substituents, lower alkanoyloxy or phenyl, formyl, dilower alkyl acetal or -dithioacetal, lower alkylene acetal or -dithioacetal, cyan, phenyl, thienyl or amino, R4 means hydrogen or lower alkyl, R5 means hydrogen, unsubstituted or with hydroxy, lower alkoxy, mercapto, lower alkylthio, carboxy, carbamoyl, amino, lower alkanoylamino, carbamoylamino, guanidino, with phenyl, which in turn may be substituted with hydroxy and/or halogen, imidazolyl or indolyl substituted lower alkyl, unsubstituted or with hydroxy, lower alkoxy, lower alkyl, nitro, amino, lower alkylamino, dilower alkylamino and/or halogen substituted phenyl or unsubstituted or in the same manner as indicated for a phenyl residue R^substituted pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl , pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, R^

means hydrogen, lower alkyl, phenyl lower alkyl, unsubstituted or with hydroxy, lower alkoxy, lower alkyl, nitro, amino, lower alkyl amino, di lower alkyl amino and/or halogen substituted phenyl lower alkyl or an unsubstituted or in the same way as indicated for a phenyl lower alkyl residue Rg specified substituted residue 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^, Rg, and Rg are independently hydrogen , lower alkyl or with amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, oxa-, thia- or azalower alkyleneamino, in which the Aza nitrogen atom is optionally substituted with lower alkyl, lower alkanoylamino, hydroxy, lower alkoxy or with phenyl, which may be unsubstituted or in turn substituted with amino , lower alkylamino, dilower alkylamino, lower alkyleneamino, hydroxy, lower alkoxy, halogen and/or nitro, or means with pyrryl, furyl, thienyl or pyridyl, whereby these groups can be substituted in the same way as phenyl, substituted lower alkyl or phenyl, pyrryl, furyl, thienyl or pyridyl, whereby these groups can be substituted in the same way manner as a phenyl-lower alkyl radical R^, Rg or Rg, wherein R^ and R2 together or R^

and R^ together can mean C^-C^-lower alkylene, in which with C2 resp. The C6 carbon atom of the directly bonded carbon atom of the 1,4-dihydropyridine ring is optionally replaced by an oxygen, sulfur or nitrogen atom, which is substituted by hydrogen or lower alkyl, in which R4

and R,- together can mean unsubstituted or hydroxy-substituted C₁-C₂-lower alkylene, C₁-C₂-oxa- or C2-C₄-thial lower alkylene, in which R,, and Rg can together mean the lower alkylene with 2 to 5 chain carbon atoms or the azalower alkylene with 3 or 4 chain carbon atoms whereby these residues may be unsubstituted or substituted with hydroxy, lower alkoxy, amino, lower alkylamino or dilower alkylamino, and wherein Rg and Rg together may mean

C^-C-y-lower alkylene, C^-C^-aza-, C^-C^-oxa- or C^-C^-thialower alkylene, whereby these residues are optionally substituted on carbon atoms with hydroxy, lower alkoxy, amino, lower alkylamino, dilower alkylamino or five- or six-membered monoaza- or diazaheterocyclyl which is optionally substituted on carbon atoms with oxo and on the aza hydrogen atoms optionally with lower alkyl or phenyl, which in turn may contain lower alkyl, halogen, lower alkoxy and/or nitro as substituents; and is substituted on the azanitrogen optionally with lower alkyl, which in turn can be substituted with phenyl, pyrryl, furyl, thienyl and/or pyridyl, whereby these residues themselves optionally contain lower alkyl, hydroxy, lower alkoxy, halogen and/or nitro as substituents and /or may be substituted with hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino and/or dilower alkylamino;

with benzoyl, lower alkanoyl, furanylcarbonyl, thienylcarbonyl, pyrrylcarbonyl, pyridinylcarbonyl or phenyl, which in turn may contain loweralkyl, 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 entirely specifically to compounds of formula I, in which n stands for 1 or 2, Ar stands for phenyl, thienyl,

furyl or benoxadiazolyl, whereby these groups are optionally mono-, di- or tri-substituted with lower alkyl, lower alkoxy, halolower oxy, phenyl lower oxy, phenyl lower alkylthio, lower alkylenedioxy, halogen, trifluoromethyl, nitro, lower alkanoylamino and/or cyan, residues Ac means lower alkanoyl, lower alkylsulfonyl, lower alkoxycarbonyl, 2-Lower-Alkoxy^lcj.VerealCoxycarbonyl, N,N-DiLoweralkylamino-LowerElkoxycarbonyl, N-Loweralkyl-N-Phenylloweralkyl-Amino-LowerElkoxycarbonyl, Carbamoyl, N-Loweralkyl-Carbamoyl, N,N-DiLoweralkyl-Carbamoyl, N,N- lower alkylene-carbamoyl or 4-morpholinocarbonyl, Z stands for

a residue -OR^or -NRgRg, R^ denotes hydrogen, lower alkyl, 2-(dilower alkylamino)-lower alkyl, 2-(lower alkyleneamino)-lower alkyl, 2-(4-morpholino)-lower alkyl, carboxy lower alkyl or lower carboxy lower alkyl oxy-lower alkyl, R 2 and R^ means independently of each other lower alkyl, hydroxylower alkyl, cyan or amino, R^ means hydrogen or lower alkyl, R^ means hydrogen, unsubstituted or with hydroxy, lower alkoxy, mercapto, lower alkylthio, carboxy, carbamoyl, amino, carbamoylamino, guanidino, phenyl, which in turn may be substituted with hydroxy, or imidazol-4-yl or indol-3-yl substituted lower alkyl or phenyl, thiazolyl, imidazolyl, furyl, thienyl, pyridyl or pyrimidinyl, whereby these residues are optionally substituted with hydroxy, lower alkoxy and/ or amino, Ro, means hydrogen, lower alkyl, phenyl lower alkyl, which is unsubstituted or substituted by hydroxy, lower alkoxy and/or amino, or phenyl, thiazolyl, imidazolyl, furyl, thienyl, pyridyl or pyrimidinyl, whereby these residues are optionally substituted as a phenyl lower alkyl residue Rg, and R^, Rg and Rg independently of each other mean hydrogen or unsubstituted or with amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, oxa- or azalower alkyleneamino, in which the aza nitrogen is optionally substituted with lower alkyl, hydroxy, lower alkoxy, phenyl, which may be unsubstituted or in turn substituted with amino, hydroxy, lower alkoxy and/or halogen, or with thienyl or pyridyl, whereby these groups may be substituted in the same way as phenyl-, substituted lower alkyl, in which R4 and R^ together can mean the C^-C^-lower alkylene, in which R,, and Rg can together mean the C^-C^-lower alkylene or the C^-azallower alkylene and in which Rg and Rg can together mean C^-C The ^-lower alkylene, which is optionally substituted with 2-imidazolidinon-1-yl, which in the 3-position may contain phenyl or lower alkyl as a substituent, the C4oxa- or C4~aza lower alkylene, whereby the aza nitrogen is mono- or disubstituted substituted with lower alkyl, which in turn may be unsubstituted or substituted with phenyl, which may contain lower alkyl, lower alkoxy, halogen and/or nitro as a substituent, thienyl and/or pyridyl, or may be substituted with benzoyl, furanylcarbonyl, phenyl or lower alkoxyphenyl, optical isomers of compounds of formula I, mixtures of these optical isomers and pharmaceutically usable salts of such compounds with salt-forming groups.

The invention mainly relates to compounds of formula I, in which n stands for 1 or 2, Ar stands for unsubstituted or with lower alkyl, lower alkoxy, halolower oxy, benzyloxy, benzylthio, halogen, trifluoromethyl, nitro and/or cyan mono- or disubstituted phenyl, 2- or 3-thienyl,

but also stands for 2,1,3-benzoxadiazol-4-yl, the residue Ac means lower alkylsulfonyl or lower alkoxycarbonyl, Z stands for a residue -0R7 or -NRgRg, R2 means hydrogen, further 2-(4-morpholino)-ethyl, R2 means lower alkyl , hydroxymethyl, cyan or amino, R^ stands for lower alkyl, R^ means hydrogen or lower alkyl, R^ means hydrogen, unsubstituted or with phenyl, which in turn may be substituted with hydroxy, substituted lower alkyl, phenyl or unsubstituted or amino-substituted thiazolyl,

R6 means hydrogen, lower alkyl or phenyl, R^ stands for hydrogen, lower alkyl or lower alkyl, which is substituted with phenyl, amino, lower alkylamino, dilower alkylamino, 4-morpholino, 1-piperazino, which in turn can contain lower alkyl as substituents on the 4-nitrogen . 1,5-pentylene, and in which Rg and Rg together can mean 1,5-pentylene, 3-(3-phenyl-2-imidazolidinon-1-yl)-1,5-pentylene, 3-(2-imidazolidinone-1- yl)-1,5-pentylene or 3-oxa- or 3-aza-1,5-pentylene, whereby the aza nitrogen is optionally substituted with lower alkyl, benzyl, diphenylmethyl, whereby the residues contain benzyl or diphenylmethyl optionally halogen, lower alkyl and /or lower alkoxy as substituents, benzoyl, furanylcarbonyl, phenyl or lower alkoxyphenyl, optical isomers of for compounds of formula I, mixtures of these optical isomers and pharmaceutically usable salts of such compounds with salt-forming groups.

The invention primarily relates to compounds of formula I, in which n stands for 1, Ar means 2- or 3-nitro-phenyl,

2- or 3-difluoromethoxy-phenyl, 2- or 3-methyl-phenyl,

2- or 3-trifluoromethyl-phenyl, 2,3-dimethyl-phenyl, 2,3-dichloro-phenyl, 2- or 3-benzyloxy-phenyl or 2- or 3-benzylthiophenyl, Ac means lower alkoxycarbonyl, Z stands for a residue -OR^ or -NRgRg, R^ is hydrogen, R2 and R^ independently mean lower alkyl, R^ is hydrogen,

R,, means lower alkyl or phenyl, R^ means hydrogen, R^ means unsubstituted or with 4-morpholino, 1-piperazino or 4-lower alkyl-1-piperazino substituted lower alkyl,

Rg and Rg stand independently of each other for hydrogen, unsubstituted or lower alkyl substituted with phenyl or pyridyl, and in which Rg and Rg together can mean 3-aza-1,5-pentylene, in which the aza nitrogen is optionally substituted with benzyl or diphenylmethyl, optical isomers of compounds of formula I, mixtures of these optical isomers and pharmaceutically usable salts of such compounds with salt-forming groups.

Preferred are the compounds of formula I, in which Ar represents

2- or 3-nitro-phenyl, 2- or 3-difluoromethoxy-phenyl,

2- or 3-methyl-phenyl, 2- or 3-trifluoromethyl-phenyl, 2,3-dimethyl-phenyl, 2,3-dichlorophenyl, 2- or 3-benzyloxy-phenyl or 2- or 3-benzylthio-phenyl, but also 2,1,3-benzoxadiazol-4-yl. Of particular importance are the compounds of formula I, in which Ar means 2- or 3-nitrophenyl and especially 3-nitrophenyl. A further preferred embodiment of the invention is the compounds of formula I, in which Ac means lower alkoxycarbonyl,2-lower-

Alkoxy-lower-alkyloxycarbonyl, lower-alkylsulfonyl, carbamoyl, N-alkyl- or N,N-dialkylcarbamoyl, especially lower-alkylcarbonyl, 2-lower-alkyl-lower-alkylcarbamoyl, carbamoyl, N-alkyl- or N,N-dialkylcarbamoyl, and especially lower-alkylcarbonyl. To be highlighted are the compounds of formula I, in which Z stands for a residue -NRgRg. Preferred are the compounds of formula I, in which Z represents a residue -OR^. Further preferred are the compounds of formula I, in which R^

is hydrogen. Also preferred are the compounds of formula I in which R^ and/or R^ means lower alkyl, hydroxy lower alkyl, especially hydroxymethyl, cyan or amino. Preferred are the compounds of formula I, in which one of the radicals R 2 and R 1

stands for lower alkyl and the other stands for R^ and R^

residues indicated under formula I, in particular means lower alkyl, hydroxyl lower alkyl, cyan or amino. Of particular interest are the compounds of formula I, in which R 1 means lower alkyl, especially methyl or ethyl, and above all means methyl. Further preferred are the compounds of formula I, in which R 1 means lower alkyl, especially methyl or ethyl, and above all methyl. Of particular importance are the compounds of formula I, in which R^ is hydrogen. Preferred are the compounds of formula I, in which R 1 - means lower alkyl or phenyl, especially C 1 -C 4 lower alkyl or phenyl, preferably isopropyl, sec-butyl (1-methylpropyl) or phenyl, and primarily means isopropyl. Further preferred are the compounds of formula I, in which R^ stands for hydrogen. Furthermore, preference is given to the compounds of formula I, in which R 1 means unsubstituted or with 4-morpholino or 4-lower alkyl-1-piperazino substituted lower alkyl, and in particular means C2~C4-lower alkyl. Further preferred are the compounds of formula I, in which Ro0

and Rg together means 3-aza-1,5-pentylene, whereby the aza nitrogen is substituted with benzyl or diphenylmethyl.

The invention relates in particular to the specific compounds described in the examples. It also relates to all optical isomers as well as any mixtures of optical isomers, e.g. mixtures consisting of all optical isomers, such as the specific compounds described in the examples.

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

a) reacts with a compound of formula II

wherein n' stands for 0, 1 or 2 and R fe means an optionally activated carboxy group, with the proviso that R is different from a residue C(=0)-Z, when n' stands for 1 or 2 with a compound of the formula III

where n" stands for 1, 2 or 3, and R!, R' and R' have it

4 b b

under formula I for R^, R,- and R^ given meaning, may, however, be different from the residues R^, R^ respectively. R^ in formula II, with the proviso that the sum of n<1> and n" is not greater than 3 or a<1>) in a compound of formula IIa

in which n<1> stands for 1, 2 or 3 and Rcer is a transferable group in the residue C(=0)-Z, this transfers in the residue C(=0)-Z, or

b) reacts 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

WE,

or

b<1>) reacts completely analogously to method b) a compound of formula Va with a compound of the formula

WE,

or

c) ring-closes a compound of formula VII

in which one of the residues X and Y stands for the group with the formula

-NH-R^ and the other is hydroxy or both means the group of the formula -NH-R^, or a tautomer thereof or a corresponding tautomer mixture, or

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

compound with the formula VIII

or a tautomer thereof or a corresponding tautomer mixture, or

e) in a connection with formula IX

in which Acq means a in the group Ac transferable residue, transfers

this in the group Ac,

whereby in the above-mentioned starting substances with the formulas II to IX, Ila and Va, which if they exhibit salt-forming properties can also be used in the form of their salts, the symbols n, Ar, Ac, , R2, R^, R^, R^, Rg and Z have the meanings given under formula I, and if desired converts a formed compound of formula I into another compound of formula I, and/or if desired converts a formed salt into the free compound or into another salt, and/ or if desired converts a formed free compound of formula I with salt-forming properties into a salt, and/or if desired splits a formed mixture of isomers or racemates into the individual isomers or racemates, and/or if desired splits formed racemates into the optical antipodes.

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

For implementation of method variant a), the carboxy group can, for example, by transfer in an acid azide, -anhydride,

-imidazolide, -isoxazolide or an activated ester, such as one of

those mentioned below, or by reaction with a carbodiimide,

as N,N<1->dicyclohexylcarbodiimide, optionally with the addition of N-hydroxysuccinimide, an unsubstituted or e.g. with halogen, methyl or methoxy substituted 1-hydroxybenzotriazole or 4-hydroxybenzo-1,2,3.-triazine-3-oxide (cf. e.g. 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 with N,N<1->carbonyldiimidazole is activated. Furthermore, they can also thereby be activated by transferring them first, e.g. with trimethylsilyl chloride to the corresponding trimethylsilyl ester and then transfer with a suitable halogenating agent, e.g. thionyl chloride, in .the corresponding acid halide, especially acid chloride.

For the formation of activated esters, as discussed above,

suitable for e.g. optionally with electron-withdrawing substituents substituted phenols and thiophenols such as phenol, thiophenol, tibcresol, p-nitrothiophenol, 2,4,5- and 2,4,6-trichlorophenol, penta(fluorine or chloro)phenol, o- and p-nitrophenol, 2 ,4-dinitrophenol, p-cyanophenol, further e.g. N-hydroxysuccinimide, N-hydroxyphthalimide and N-hydroxy-piperidine.

To carry out method a), a compound with the formula II and III is always subjected to a condensation reaction in a manner known per se.

As the most used method for attaching amide or peptide bonds must be mentioned the carbodiimide method, also the acid method, the activated ester method and the anhydride method, as well as the Merrifield method, the N-carboxylic anhydride method or the N-thiocarboxylic anhydride and the acid chloride method.

In a particularly preferred preparation of the compounds of formula I, the carbodiimide method with N,N<1->dicyclohexylcarbodiimide in the presence of 1-hydroxybenzotriazole is used as coupling method. Hereby, a compound of the formula II, in which K is a free carboxy group, is first intermediately transferred with 1-hydroxy-benzotriazole into the corresponding benzotriazol-1-yl ester, which is then reacted under the influence of the above-mentioned carbodiimide with a compound of the formula III, preferably one in which Z is OR^ and R^ is optionally substituted lower alkyl or in which Z means NRgRg, to a compound of the formula I.

The starting substances with formula II and formula III can be used independently of each other as a racemate, racemate mixture, as an optical isomer or as a mixture of several optical isomers. For example, Chem. Pharm. Bull. 28, 2809-2812 (1980) the preparation of optical isomers of formula II from a racemic compound of formula II.

A great many starting substances with the formula III - amino acids, di- and tripeptides and their C-terminal optionally substituted lower alkyl esters - are known, as well as racemates, racemate mixtures and also as optical isomers, and can further be prepared in an analogous way to the known starting substances.

Starting substances with the formula II, in which n<1> stands for 0, are known from e.g. European patent application 11,706 and further can be produced in an analogous manner to the known starting materials. Starting substances with formula II, in which n<1> stands for 1 or 2 can be e.g. thereby produced by reacting compounds of formula II, in which n' stands for 0, with a compound of formula Illa

respectively a compound of formula IIIb

wherein R, has the meaning given under formula II and R^, R,- and Rg have the meaning given under formula I and

R 4 , R 1 and R 2 have the meaning given under formula I for R 4 , R 2 and R 2 , but may be different from R 2 , R 2 , respectively. Rg,

in the same way as described above for the preparation of compounds of formula I from each of a compound of formula II and III. Compounds with the formula Illa and the form Illb are known, they are either identical to compounds with the formula III, in which Z means OR^ and R^ stands for hydrogen and n" means 1 or 2, or can be prepared from precisely these compounds according to the same activation methods as those described above for compounds of formula II.

The method variant a') includes, among other things, the transfer of compounds with the formula IIa, in which Rc means e.g.

a protected and/or functionally converted carboxy group,

in compounds of formula I. By a protected carboxy group is meant one of a protecting group, which is usually used in peptide chemistry, protected carboxy group. Such protective groups are easily cleavable, for example solvolytically, reductively, photolytically or also under physiological conditions, i.e. without unwanted side reactions taking place, whereby as a rule compounds of the formula I are obtained, in which Z means OR^ and R^ is hydrogen.

Protective groups of this kind as well as their cleavage are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, further in "The Peptides", Vol. I, Schroder and Llibke, Academic Press, London, New York, 1965, as well as in "Methoden der organischen Chemie", Houben-Weyl, 4th edition vol. 15/1, Georg Thieme

Verlag, Stuttgart, 1974.

Thus, carboxyl groups are protected, for example, by hydrazide formation or by esterification. For esterification, e.g. lower substituted alkanols such as cyanomethanol, 2,2,2-trichloroethanol or benzoylmethanol. A particularly advantageous category of substituted alkanols are ethanols which in the (i) position carry a trisubstituted silyl group, such as triphenylsilyl, dimethyl-butyl-silyl or above all a trimethylsilyl group. As, for example, described in Belgian patent no. 851,576 is particularly suitable well these alcohols for protection of the carboxy groups, as the corresponding silyl ethyl esters, e.g. .eg fluorides of quaternary organic bases, such as tetraethylammonium fluoride. But they can also be cleaved in the same way as the usual substituted alkyl ester, by alkaline hydrolysis, for example by means of alkali metal hydroxides, carbonates or

-bicarbonates.

Is in a compound with the formula Ila (or I) R one

c

functionally converted carboxy group, also e.g. cyan, an imido ester, especially an imido lower alkyl ester, an optionally substituted carbamoyl group or an acid halide, then

allows this in a manner known per se, especially by hydrolysis in an alkaline or acidic medium, to be transferred into a compound of formula I, in which Z means OR^ and R^ stands for hydrogen, whereby in the former case one can also directly obtain a salt. A compound of the formula IIa, in which Rcer is cyan, can also be transferred in the usual way, e.g. by addition of optionally substituted lower alkanols in the presence of an anhydrous acid, such as hydrogen chloride, and subsequent careful hydrolysis of the formed imidoester to compounds of the formula I, in which R7 is optionally substituted lower alkyl, the same also succeeds in the reaction of a compound

with the formula Ia, in which Rcer is an acid halide, with optionally substituted lower alkanols.

In this process variant, however, starting material f is with the formula Ila, in which Rcer e.g. formyl or a reactive derivative thereof - as defined below -, hydroxymethyl or methyl, which can be transferred according to usual oxidation methods in compounds of formula I, preferably in those in which Z means OR^ and R-,

stands for hydrogen.

Especially when carrying out method variant a'

care must be taken that unwanted side reactions, which may result in the transformation of additional groupings in the molecule, do not occur.

Starting substances with the formula IIa, in which n' stands for 1,2 or 3, can be prepared, e.g. in an analogous way as described above for the compounds of formula II, in which n' stands for 1 or 2, namely by reacting a compound of formula II, in which n' stands for 0 or 1, with compounds that differ from those of formula Illa and Illb by the presence of R instead of R, .

c b

Reactive functional derivatives of the aldehyde of the formula IV used as starting material in method variant b), as well as of formyl groups in general, are among others the corresponding acetals, such as dilower alkyl-, e.g. dimethyl or diethyl acetals, acyls such as dilave-alkanoylacyls, e.g. diacetylacylal, or especially the corresponding dihalomethyl compounds, e.g. dichloromethyl or dibromomethyl compounds, further addition compounds such as those with water or an alkali metal hydrogen sulphite, e.g. potassium hydrogen sulphite.

A variant of this method consists in 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 that it formed an intermediate with the formula Va

after its isolation or without isolating it is allowed to react with a compound of the formula VI.

Starting products with formulas IV and VI are known, and further starting substances can be prepared analogously to the known ones. The starting material with the formula V can be extracted in a manner known per se, e.g. by reacting a compound with the formula III, e.g. with diketenes according to Pharm. Acta. Hooray. 38, 616 (1963).

Usually, the starting materials of the formula VII used in method variant c) are formed in situ and the ring closure according to the method takes place under the reaction conditions for the preparation of the starting material. Thus, one can obtain starting substances with the formula VII and, under the reaction conditions, usually also the corresponding end products with the formula I, by approx.) reacting a compound with the formula IV or an above-defined reactive functional derivative thereof with a compound with the formula

of a compound of the formula V and a compound of the formula R^-NH2(X) , or cb) reacts a compound of the formula IV or a reactive functional derivative thereof, with a compound of the formula and a compound of the formula VIb or VI, or cc) reacts a compound of the formula X with a compound of the formula and a compound of the formula V, or cd) reacts a compound of the formula X with a compound of the formula Va and a compound of the formula Vb or VI, or ce) reacts a compound of the formula X with a compound of the formula or cf) reacts a compound of the formula VI with a compound of the formula Va or the formula or cg) reacts a compound of the formula Vb with a compound of the formula Via or with a compound of the formula

With the exception of the compounds with the formulas IV and X, the compounds with the formulas V, Va-c, VI, Vla-c,

VII and XI in the form of tautomers or in the form of tautomer mixtures, starting substances with the above-mentioned formulas with salt-forming properties can also be used in the form of salts. Furthermore, in the above-mentioned compounds the symbols n, Ar, Ac, R 1 , R 2 , R 3 , R 4 , R 6 and 2 have the meaning given under formula 1.

A compound with the formula X can also be used in the form of

an agent which releases these compounds in situ, e.g. ammonia in the form of an ammonium salt, such as ammonium acetate or ammonium bicarbonate, or a light metal compound, e.g. alkali metal compounds, such as sodium amide or

lithium N-methylamide.

In the ring closure reaction c), as well as the condensation reactions ca) to cg) for the production of the starting materials usually formed in situ for the ring closure reaction, as well as in process variant b), these are variants of the dihydropyridine synthesis according to Hantzsch. In the variant ca) a total of three molecules of water are separated, in further variants an addition reaction takes place in part instead of the water separation, i.e. the water separation already takes place during the production of one or two starting substances. In the reaction of the 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) further to respectively instead of water, a compound with the formula X cleaved off.

If according to variant c) compounds of formula I are to be prepared, unwanted by-products can be formed, e.g. of the type of 1,4-dihydro-pyridine-3,5-dicarboxylic acid derivs., as corresponding diesters. By non-simultaneous supply of reaction participants, however, the formation of such by-products can be reduced, as one promotes a specific reaction course which proceeds in situ according to a different variant, then according to the dosed addition of the reaction components, e.g. first a compound of the general formula VI or of the formula Vb can be formed.

Looping or the condensation reactions according to the method are carried out in a manner known per se, if necessary, in the presence of a condensation agent, especially a basic condensation agent, as an excess of a basic reaction component or a further, e.g. organic base, such as piperidine or ethyl diisopropylamine, or a metal alkoxide, such as an alkali metal lower alcohol alkoxide, 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 a organic carboxylic acid, e.g. acetic acid, and/or a suitable dehydrating or water absorbing agent, further usually in the presence of an inert organic solvent and at reaction temperatures in the range from about room temperature to about 150°C, especially at the boiling temperature of the solvent. If necessary, the turnover takes place in an inert gas atmosphere, e.g. nitrogen atmosphere, and/or e.g. by 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 according to processes known per se. Thus, for example, a compound with the formula Va can be prepared from each of a compound with the formula V and

CV, a compound of the formula Via can be prepared from each of the formulas VIb and IV, a compound of the formula Vb can be prepared from each of the formulas V and X, a compound of the formula Vc can be prepared from each of a of formulas Vb and IV, a compound of formula VIc can be prepared from each of formulas VI and IV

and one such with the formula XI can be prepared from each one with the formulas VIb and Va.

Method variant d) is carried out in a manner known per se. Reactive functional derivatives of aldehyde with the formula IV are described above. The reaction is carried out in the absence, preferably in the presence of a solvent or diluent or a similar mixture and/or in the presence of a condensing agent, whereby one works under cooling, at room temperature, or preferably under heating, e.g. in a temperature range from approx. 0°C to approx. 200°C, preferably from approx. 40°C to approx. 150°, and if necessary in a closed vessel, possibly under pressure and/or under an inert gas atmosphere.

The starting material with the formula VIII can be prepared in a manner known per se, for example, by reacting a compound of the formula V, preferably one in which Z is different from a hydroxy group, with a compound of the formula VI, the starting material with the formula can be directly obtained

VIII.

The starting materials with the formula IX used in the method variant e) corresponding to the residue Acq contained in the starting materials can for example be carboxylic acids (Acq is carboxy), carboxylic anhydrides, especially mixed anhydrides, such as acid halides, e.g. acid chlorides or acid bromides (Acq is halocarbonyl, e.g. chlorine or bromocarbonyl), further activated esters, e.g. cyanomethyl or pentachlorophenyl ester (Acq is cyanomethoxycarbonyl or pentachlorophenyloxycarbonyl). Such starting materials can be converted, optionally in the presence of condensation agents, by treatment with an alcohol, such as an unsubstituted or substituted lower alkanol, or a reactive derivative thereof, e.g. a corresponding alcoholate, such as alkali metal alcoholate, free carboxylic acids can also be converted by reaction with suitable diazo compounds, such as unsubstituted or substituted diazone lower alkanes,

in compounds of formula I, in which Ac means the acyl residue of a monoester of the carboxylic acid. Such compounds can also be obtained when starting materials with the formula IX use salts, especially alkali metal or alkaline earth metal salts of the free carboxylic acid and treat these with reactive esters of alcohols, such as unsubstituted or substituted lower alkanols, such as corresponding halides, e.g. chlorides, bromides or iodides, or organic sulphonic acid esters, e.g. lower alkanesulphonic acid or arenesulphonic acid esters, such as methanesulphonic acid or p-toluenesulfonic acid esters, or when one hydrolyzes corresponding hydrolyzable iminoesters, such as corresponding imino-lower alkyl esters, to the esters.

The reaction of free carboxylic acids with alcohols, such as unsubstituted or substituted lower alkanols, takes place advantageously in the presence of an acidic, water-splitting catalyst, such as a protonic acid, e.g. hydrochloric, hydrobromic, sulphurous, phosphoric or boric acid, benzenesulphonic or toluenesulphonic acid, or a Lewis acid, e.g. boron trifluoride etherate, in an excess of the alcohol used and/or in an inert solvent, if necessary under distillation, e.g. azeotrope, removal of the water released by the reaction. Furthermore, the reaction can also be carried out in the presence of a water-binding condensing agent, such as suitable substituted carbodiimides, e.g. N,N<1->diethyl-, N,N'-dicyclohexyl- or N-ethyl-N<1->(3-dimethylaminopropyl)-carbodiimide, optionally in inert organic solvents. Mixed anhydrides, especially acid halides, react for example in the presence of acid binding agents, e.g. organic, especially tertiary nitrogen bases, such as triethylamine, ethyl diisopropylamine or pyridine or also in the presence of inorganic bases, e.g. of alkali metal or alkaline earth metal hydroxides or carbonates, such as sodium, potassium or calcium hydroxide or -carbonate, with alcohols or with alcoholates, e.g. alkali metal alkoxides.

The turnover of reactive esters, e.g. cyanomethyl or pentachlorophenyl esters, with alcohols is carried out, for example, in a solvent inert to the reaction participants and in the temperature range from approx. 0°C to approx. 120°C, preferably at room temperature up to approx. 60°C.

The hydrolysis of the iminoester starting material, especially imino-lower alkyl ester starting materials, takes place for example with the help of water-containing mineral acids, such as hydrochloric acid or sulfuric acid, whereby e.g. as by the addition of hydrogen chloride to nitriles and reaction with anhydrous alcohols, especially unsubstituted or substituted lower alkanols formed iminoester salts, e.g. -hydrochlorides, after adding water directly, can hydrolyse to the corresponding esters. One can e.g. also from a mixture of nitrile starting material, an alcohol and sulfuric acid with a suitable water content, without isolation of the iminoester formed in situ obtain the desired ester compound with the formula I.

Compounds of formula I, in which the radical Ac produces the acyl radical of a carboxylic acid monoamide, can be obtained from compounds of formula IX, in which Ac stands for a carboxy group, an acid anhydride group, such as halocarbonyl, e.g. chlorocarbonyl, or an activated ester group, such as cyanomethoxycarbonyl or pentachlorophenyloxycarbonyl, reacting such starting materials, optionally in the presence of a suitable condensing agent, with ammonia or an ammonia-releasing agent or an N-mono- or N,N-disubstituted amine.

These conversions of carboxy groups and suitable functionally converted reactive carboxy groups into optionally N-mono- or N,N-disubstituted carbamoyl groups can be carried out in a manner known per se, e.g. according to the methods described for the formation of the ester groups.

Compounds with the formula I, in which the group Ac stands for carbamoyl, can likewise be obtained starting from compounds with the formula IX, in which the radical Ac o produces cy 2an.

Such starting materials can be transferred hydrolytically, preferably

show under acidic or basic conditions, e.g. in the presence of an alkali metal such as sodium hydroxide, and, if desired, of hydrogen peroxide, in an aqueous-alcoholic solvent, such as aqueous ethanol, in the desired compound of formula I with a carbamoyl group Ac.

The reactions stated above and below can be carried out under known reaction conditions in the absence or usually in the presence of a solvent or diluent,

depending on the nature of the reaction and/or reaction participant at a lowered or elevated temperature, e.g. in the temperature range from approx. -10°C to approx. 150°C, below atmospheric

pressure or in a closed vessel, possibly under pressure, and/or in an inert atmosphere, e.g. under a nitrogen atmosphere.

Starting substances of formula IX with free carboxyl groups Acq can be obtained, e.g. by preparing the corresponding 2-cyano-ethyl ester and cleaving this under mild conditions, e.g. using aqueous or aqueous-lower alkanol l-n. sodium hydroxide at room temperature to the free carboxylic acid. The 2-cyanoethyl ester itself can be obtained, e.g. by reacting a compound of formula IV with a compound of formula VI, in which Ac stands for a 2-cyano-ethyloxycarbonyl group, and a compound of formula V. The in the starting material of formula IX present

free carboxy group, can, if necessary, be transferred in a manner known per se in the desired reactive, functionally converted form.

The nitrile compounds with the formula IX which are also taken into consideration as starting materials for the method variant e) can be prepared, e.g. analogously to the above-mentioned 2-cyano-ethyl ester compounds, using intermediates which contain a cyano group instead of the residue Ac.

Compounds of formula I, in which formyl is functionally converted, can be prepared, e.g. according to method b)

of a compound of the formula V, in which R 1 means functionally converted formyl, e.g. a dilave alkyl acetal, and a compound of the formulas IV and VI (cf; also European patent application 107,203).

Compounds of formula I, in which R^ is functionally converted formyl, can be converted in a manner known per se into compounds of formula I, wherein R^ is formyl, which in turn can be transferred in a manner known per se into other compounds of formula I, in which R^means e.g. hydroxymethyl, hydroxyimino or cyan, (cf. Belgian patent 879,263). Likewise, it is possible, e.g. analogous procedure b) to

prepared from a compound of formula V, in which n = 0,

R^ means functionally converted formyl and Z preferably means a group -OR^, in which R^ stands for example for an acid protecting group, such as 2-cyanoethyl or carbamoyl-methyl, and each of a compound of the formulas IV and VI first a compound with formula II, in which n = 0 and R₂ means functionally converted formyl. In the latter case, the residue R^ can again be transferred as indicated above, e.g. in formyl, hydroxymethyl, hydroxyimino or cyano. The mentioned compounds of formula II can be transferred according to method a) into compounds of formula I.

In an analogous manner, compounds of formula I can also be obtained, in which R 1 is functionally formyl, namely, e.g. according to method cb) by reacting each of a compound of the formula VIb) with a compound of the formula VIb, in which R^ means functionally converted formyl. Such compounds of formula I can again be transferred in a manner known per se into other compounds of formula I, in which R 1 means e.g. formyl, hydroxymethyl, hydroxyimino or cyano.

Compounds with formula II-analogously also formula I - , in which R^means amino, can be prepared, e.g. according to method c), especially according to the variant cb), of a compound of the formula Vb<1>, which is completely analogous to a compound of the formula Vb, in which R^ means amino and n stands for e.g. 0,

and each of a compound with formulas IV and VIb (cf. Liebigs Ann. Chem. 1977, 1895-1908). Starting compounds

with the formula Vb' is obtainable according to the usual amidine syntheses, e.g. by transfer of a compound 'NC-CH2-COZ in the corresponding iminoether, e.g. using methanol and HCl,

and treatment of the latter, e.g. with ammonia.

In the same way, it is also possible to prepare compounds of formula I, in which R~ means amino, namely, e.g. according to method b) of each of a compound of the formula IV and V with a compound of the formula VI, wherein R 2 means amino.

Compounds of formula I, in which Ac means an acyl residue of cyclic carboxylic acid derivatives and/or R 2 means a carbocyclic or heterocyclic aryl residue, can be prepared e.g. according to method b), whereby the starting compounds of the formula VI are obtainable, e.g. analogous to the method described in US patent 4,414,213.

Compounds of formula I, in which R₂ means unsubstituted or substituted lower alkyl, can be obtained, e.g. by N-alkylation of corresponding compounds of formula I, in which R^ is hydrogen, (cf. US patent 4,258,042).

Compounds of formula I, in which R^ means e.g. hydroxy,

can be produced, e.g. according to method c), especially according to variant ce), of a compound of formula XI and hydroxylamine (cf. European patent application 93 945). From such compounds of formula I, in which R 1 is hydroxy, compounds of formula I, in which R 1 is etherified or esterified hydroxy, are obtained according to methods known per se by O-alkylation and O-acylation.

Compounds of formula I, in which R 1 and R 2 together mean unsubstituted or substituted lower alkylene, in which a carbon atom is optionally replaced by a heteroatom, can be prepared, e.g. according to method b') cf.

Liebgs Ann. Chem. 1977, 1888-1894). Completely analogous are compounds of formula I, in which R^ and R^ together mean unsubstituted or substituted lower alkylene, in which a carbon atom is optionally replaced by a heteroatom, obtainable e.g. by a reaction of a compound of the formula Via with a compound of the formula Vb according to method cg).

Compounds of the formula I in which R is hydrogen are obtainable e.g. by reacting a compound of the formula Via with a compound of the formula Vb, in which R 1 means dilower alkylamino or lower alkyleneamino.

3,4-dihydropyridine is first formed, which leads by hydration, for example in glacial acetic acid over PtO^/in an addition-elimination reaction to the desired compounds [cf. Angew. Chem. 93, 755-763 (1981). Compounds of formula I, in which R 2 is hydrogen, are obtainable completely analogously to a compound of formula Va and a compound of formula VI, in which R 2 is dilower alkylamino or lower alkyleneamino.

There are numerous literature references to the preparation of 4-aryl-1,4-dihydropyridines, e.g. in Angew.

Chem. 93, 755-763 (1981), Liebig's Ann. Chem. 1977, 1888-1894 and 1895-1908, BE 879 263, DE-A-3 207 982, in the European patent applications 26 317, 60 897, 93 945 and 107 203, as well as in the US patents 4 258 042 and 4 414 213 .

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

Thus, one can e.g. in compounds of formula I, in which R^ stands for hydrogen, by treatment with a reactive ester of an alcohol with the formula R^-OH (XII) introduce an organic residue R^ and thus obtain compounds of formula I, in which R^ is different from hydrogen.

Reactive esters of compounds of formula XII, e.g. of unsubstituted or substituted lower alkanols, are those of strong, inorganic or organic acids, for example the corresponding halides, especially chlorides, bromides or iodides, further sulphates, further lower alkanesulphonic acid or arenesulphonic acid esters come into consideration, e.g. methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid esters. The turnover is carried out, if necessary, during cooling or heating, e.g. in a temperature range from approx. 0°C to approx. 100°C, in the presence of a suitable basic condensing agent, e.g. an alkali metal, alkali metal amide or hydride, or in the presence of an alkali metal lower alkoxide, such as sodium or potassium methoxide, -ethoxide or -tert-butoxide, in the presence or absence of a solvent or diluent, at reduced or elevated temperature, e.g. in a temperature range from approx.

0°C to approx. 100°C, and/or under atmospheric pressure or in a closed vessel.

Preferably used in such N-substitution reactions

primarily compounds of the formula I, which do not contain other primary or secondary amino groups as substituents, as these may also react with the reactive ester of an alcohol of the formula XII.

Compounds of formula I, wherein Z represents the residue

NRgRg or for 0R?, whereby R7 is optionally substituted lower alkyl, can be converted in the same way as described above for compounds with the formula IIa, in which Rc means 2r a functionally converted carboxy group, e.g. by hydrolysis in an alkaline or acidic medium, in a compound of the formula I, in which Z stands for hydroxide. Conversely, compounds of formula I, in which Z is hydroxy, allow in a manner known per se according to the usual 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, is transferred in a compound of the formula I, in which Z means 0R? and R 2 means optionally substituted lower alkyl. Analogously, compounds with the formula I, in which Z means hydroxy, can also according to the usual methods by amide formation, e.g. by reaction with ammonia or a primary or secondary amine, possibly during removal of the water formed by the reaction, 1 compounds of formula I are transferred, in which Z means the group NRgRg.

Compounds of the formula I, in which n stands for 1 or

2 and Z is hydroxy, is identical to compounds of the formula II, in which n' stands for 1 or 2 and Rfa means carboxy. According to method a) by reaction with a compound of the formula III, they can be transferred into other compounds of the formula I, in which n stands for 2 or 3.

Compounds of formula I wherein Z is 0R? and R^ is benzyl can be converted, e.g. by hydrogenolysis in other compounds of the formula I, in which Z stands for hydroxy.

Furthermore, according to the invention obtainable compounds

with formula I, substituents present are converted into other substituents. Thus, one can transfer e.g. esterified carboxy groups such as corresponding groups Ac and/or C(=0)-OR7, by transesterification in other esters. In this way, one preferably uses corresponding alcohol compounds which exhibit a boiling point that is clearly above that of the alcohol in the esterified group in the compound with the formula I to be converted, and one carries out the reaction e.g. in an excess of the hydroxy compound and/or in an inert organic, preferably likewise clearly above the alcohol in the esterified group, boiling solvent, preferably in the presence of a catalyst, e.g.

an alkali metal lower alkoxide, such as sodium or potassium methoxide or ethoxide, or an orthotitanic acid lower alkyl ester, such as orthotitanic acid isopropyl ester, by heating and usually during distillation of the liberated alcohol.

Esterified carboxy groups, e.g. corresponding residues Ac or preferably a residue Z = C(=0)-OR7 can e.g. is also thereby transferred into other esters by first e.g. pre-soap these acidic or preferably alkaline and transfer the formed acid in a manner known per se into another ester.

Compounds of the formula I with esterified carboxy groups, such as lower alkoxycarbonyl groups, especially corresponding groups Ac or the residue C(=0)-OR7, can be converted into those with corresponding carbamoyl groups, e.g. with treatment with ammonia, further with mono- or di-substituted amines, if necessary under elevated temperature and/or in a closed vessel.

Suitable substituents for an aromatic residue, e.g. halogen atoms, especially fluorine atoms, can be exchanged for other substituents, e.g. an optionally substituted amino group, (e.g. by treatment with a primary or secondary amine, e.g. a compound of the formula X).

All starting materials mentioned in the described methods and post-operations, which contain one or more optically active carbon atoms, can be used as racemate mixtures, racemates, optical isomers or mixtures of optical isomers in the corresponding reactions and usually give compounds of formula I, in which on the corresponding carbon atoms have the same configuration or configurations as in the starting product.

Depending on the reaction conditions, the compounds can

formula I is available in free form or in the form of salts.

Formed acid addition salts can be known per se

way is converted 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. Formed free compounds with salt-forming properties, e.g. with corresponding basic groups, can be converted, e.g. by treatment with acids or equivalent anion exchangers in their salts.

Due to the close relationship between the compounds of formula I in free form and in the form of salts, above and below free compounds or their salts shall, where appropriate, also mean the corresponding salts,

respectively free connections.

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

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

Formed racemate mixtures can be split up due to physical-chemical differences of the racemates in a known manner into the pure racemates or diastereomers, for example by chromatography and/or fractional crystallization.

Racemates can be cleaved according to methods known per se in the optical antipodes, for example by recrystallization of an optically active solvent, with the help of suitable microorganisms or by reaction of 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 thus obtained mixtures of salts, e.g. because of their different solubilities, in the diastereomeric salts,

of which the antipodes, e.g. by treatment with a base, can be released.

Optical antipodes of neutral compounds of formula I

can you also get e.g. according to method e) using an optically active acid with the formula IX, whereby one can form these e.g. of the corresponding racemic acid in the usual way, e.g. by salt formation with an optically active base, separation of the diastereomeric salts and liberation of the optically active acid, or using a reactive functional derivative of an optically active acid.

Furthermore, one can transpose, e.g. compounds of formula I,

containing an esterified carboxy group, e.g. a corresponding group Ac, using an optically active alcohol according to the method described above and splitting the diastereomer mixture thus obtained into the antipodes, e.g. using fractional crystallization.

Advantageously, one isolates from a diastereomer mixture or racemate the pharmacologically more active isomer or the more active antipodes. The pharmacological activity is usually particularly high when the following configuration is present on the C4 carbon atom of the 1,4-dihydro-pyridine molecule: 4R, when according to the rule of Cahn, Ingold and Prelog the substituent is in the 5-position, i.e. the amino acid side chain , has less priority than the residue Ac in the 3-position in the dihydropyridine shell and higher priority than the residue Ar. Conversely 4S, when the residue Ac has a lower priority than the amino acid side chain and a higher priority than the residue Ar. The following configuration on the C4 carbon atom is therefore preferred,

in which the carbon atoms C3, C4 and C5 lie in the plane of the paper,

residues Ar above and the hydrogen atom behind the paper plane:

The invention also relates to such embodiments of the method after which one starts from any step of the method as an intermediate obtainable compound and carries out the missing steps or uses a starting substance in the form of a derivative, e.g. salt, and/or its racemate or antipodes or form a starting substance under the reaction conditions.

In the method according to the present invention, such starting materials are preferably used, which lead to the above as particularly valuable compounds. New starting materials and methods for their production likewise form an object of the present invention. The invention also relates to new intermediate products, which are obtained by the method as well as methods for their production.

The invention likewise relates to the use of compounds of formula I or of pharmaceutically usable salts of such compounds with salt-forming properties, especially as pharmacological, primarily as coronary dilator and/or antihypertensive usable compounds. Hereby one can use these, preferably in the form of pharmaceutical preparations, in a method for prophylactic and/or therapeutic treatment of the animal or human body, especially for the treatment of angina pectoris, hypertension and other cardiovascular diseases.

The dosage of the active substance that is administered alone or together with the usual carrier and auxiliary material depends on the species to be treated, the age and the individual condition as well as the method of administration. The daily doses are for mammals with a body weight of approx. 70 kg,

depending on the nature of the disease, individual condition and age, preferably between 1 and 100 mg and especially between 2 and 20 mg.

The invention also relates to pharmaceutical preparations, which contain the compounds of formula I or pharmaceutically usable salts of such compounds with salt-forming properties as active substances, as well as methods for their preparation.

The pharmaceutical preparations according to the invention are those for enteral, such as peroral or rectal, also for sublingual, as well as for parenteral administration to warm-blooded creatures. Corresponding dosage unit forms, especially for peroral and/or sublingual administration, e.g. herbs, tablets or capsules, preferably contain from approx. 0.5 to approx. 100 mg, especially from approx. 5 to approx. 50 mg of a compound of the formula I or a pharmaceutically acceptable salt of a corresponding compound suitable for salt formation together with pharmaceutically usable carriers.

Suitable carriers are especially fillers such as sugar,

e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders,

as starch adhesives using e.g. corn, wheat, rice or potato starch, gelatins, tragacanth, methylcellulose and/or polyvinylpyrrolidone and/or if desired explosives, such as the above-mentioned starches,

further carboxymethyl starch, cross-linked polyvinylpyrrolidone, Agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily viscosity-regulating agents and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof, such as magnesium

or calcium stearate and/or polyethylene glycol. Dragon-

cores can be provided with suitable, possibly gastric-juice-resistant coatings, whereby one uses, among other things, concentrated sugar solutions, which possibly contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or varnish solutions in suitable organic solvents or solvent mixtures or for production of gastric juice-resistant coatings, solutions of suitable cellulose preparations,

such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragé coatings may have added dyes or pigments, e.g. for identification or for characterizing different doses of active substance.

Further orally usable pharmaceutical preparations are injectable capsules of gelatins, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerin or sorbitol. The capsules may contain active substances in the form of

a granule, e.g. in a mixture with fillers such as lactose, binders such as starch and/or lubricants such as talc or magnesium stearate and possibly stabilizers. IN

soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, whereby stabilizers may possibly be added. Among other things, capsules that can be easily bitten into pieces in the event of signs of an attack of angina pectoris are preferred when the active substance is taken sublingually in order to achieve the fastest possible effect and that can also be swallowed whole.

As rectally applicable pharmaceutical preparations come into consideration e.g. suppositories consisting of a combination of the active substance with a suppository base.

As suppository bases, e.g. natural

or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used, which contain a combination of the active substance with a base mass.

As base material comes into question e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration, aqueous solutions of an active substance in water-soluble form are primarily suitable, e.g. a water-soluble salt, further suspensions of the active substance, such as corresponding oily injection suspensions, whereby suitable lyophilic solvents or carriers, such as fatty oils, e.g. sesame oil or synthetic fatty acid esters, e.g. ethyl oleate, or triglycerides, or aqueous injection suspensions, which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and optionally stabilizers.

The pharmaceutical preparations according to the present invention can be prepared in a manner known per se,

e.g. using conventional mixing, granulation, dragee, dissolution or lyophilization methods. Thus, pharmaceutical preparations for oral use can be obtained by combining the active substance with solid carriers, possibly granulating a formed mixture and processing the mixture, respectively. the granulate, if desired or necessary, after the addition of suitable excipients, into tablets or dragé cores.

The following examples a) to c) shall illustrate the production of some typical forms of application, but in no way represent the only embodiments of such.

a) Tablets containing 25 mg of active substance,

can be produced as follows:

The active substance is mixed with 60 g of corn starch and the lactose is kneaded with a paste made from 10 g of corn starch and water. The moist mass is granulated, dried and mixed with the crystalline cellulose and the magnesium stearate. The homogeneous mixture is pressed into tablets of 250 mg (with a breaking drill), these have a diameter of 9 mm. b) Capsules containing 10 mg of active substance can be prepared as follows:

The active substance is thoroughly mixed with talc and colloidal silicic acid, the mixture is passed through a sieve with a mesh size of 0.5 mm and this is filled in portions of 11 mg each in hard gelatin capsules of a suitable size.

c) A sterile solution of 5.0 g of active substance in 5000 ml of distilled water is filled in ampoules of 5 ml, as in

5 ml of solution contains 5 mg of active substance.

The following examples illustrate the preparation of the new compounds of formula I, but shall not limit the scope of the invention in any way. Temperatures are given in degrees Celsius.

Example 1

A mixture of 9.6 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-methyl ester, 3 .6 g of L-valine ethyl ester hydrochloride and 2.5 ml of N-ethylmorpholine in 90 ml of anhydrous dimethylformamide are stirred

for 16 hours at 80°C under a nitrogen atmosphere. The yellow reaction mixture is added under ice-water cooling with 300 ml of ice water. It is then stirred for a further 1 hour in the ice bath at 0-5°C, whereby 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 thus obtainable 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.

To separate the diastereomers, the crude product is added to 30 ml of diisopropyl ether and stirred for 1 hour at 0-5°C, whereby (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-( 3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-ethoxycarbonyl-2-methyl-1-propyl]amide crystallizes in the form of pale yellow crystals. The first diastereomer of these is configurationally uniform, it melts at 198-200°C and the specific rotation is [ct]^° = + 75° (c = 0.6, ethanol).

To isolate the second diastereomer, the mother liquor is evaporated under reduced pressure. The residue is purified by chromatography on the approx. 100 times the quantity of silica gel (elution with a 7:3 mixture of hexane and acetic acid ethyl ester) and crystallizes the crude second diastereomer by stirring in 20 ml of diethyl ether at o-5°C. The thus obtainable (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(S)-1- ethoxy-carbonyl-2-methyl-1-propyl]-amide melts at 147-148°C. The crude product is further purified by recrystallization from acetone.

The light yellow, fine-leaf-like needles thus formed melt at 156-157°C, whereby at the same time as new crystal modification

deep yellow rhombic crystals of the melt begin to grow,

remelting takes place at 171-172°C. This crystalline second diastereomer is configurationally uniform and exhibits a specific rotation of [α]D = -34.9° (c = 1.0, ethanol).

The starting material can be prepared as follows:

A solution of 6.7 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid monomethyl ester [see European patent application 11,706], 3.4 g of 1-hydroxybenzotriazole and 4.6 g of N,N<1->dicyclohexylcarbodiimide in 100 ml of anhydrous dimethylformamide are allowed to stand for 16 hours at 0-5°C under a nitrogen atmosphere. The crystallized N,N<1->dicyclohexylurea is filtered off. The yellow filtrate is added while cooling in an ice bath with 300 ml of water and stirred for a further 1 hour at 0-5°C, whereby the amorphous crude product is separated. It is filtered off, the filter residue is washed with 400 ml of water and dried in a vacuum. For further purification, the crude product is dissolved in 40 ml ethyl acetate and stirred for 1 hour at 0-5°C. The crystallized N,N'-dicyclohexylurea is then removed by filtration and the filtrate is evaporated under reduced pressure, whereby 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid is obtained 3-(1-Benzotriazolyl)-ester 5-methyl ester as highly viscous foam in quantitative yield: 250 MHz FT-<1>H-NMR (CDCl 3 ): 2.46 (2s,6H, dihydropyridyl-CH 3 ); 3.70 (s, 3H, -COCH 3 ); 5.44 (s, 1H, 4-dihydropyridyl-H); 6.78 (s, 1H, N-H); 6.92, 7.39, 8.04 (3m, 4H, benzotriazolyl-H); 6.48, 7.79, 8.14, 8.24 (4m, 4H, phenyl-H).

Example 2

A mixture of 12.5 g of (S)-N-acetoacetyl-α-amino-isovaleric acid ethyl ester [prepared analogously to Pharm. Acta Heiv. 3( 3, 616

(1963)], 6.2 g of 3-aminocrotonic acid methyl ester and 8.2 g of 3-nitrobenzaldehyde in 100 ml of ethanol are stirred for 16 hours at 80°C 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 each time. The organic phase is dried with sodium sulphate, filtered and the filtrate evaporated under reduced pressure. The residue is purified by chromatography on the approx. 100 times the amount of silica gel (elution with a 7:3 mixture of hexane and ethyl acetate). The thus obtainable resinous crude product is a 1:1 diastereomixture of (4R)- and (4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitro-phenyl)-pyridine -5-carboxylic acid-N-[(1S)-1-ethoxycarbonyl-2-methyl-1-propyl]amide. The separation of the diastereomers takes place as described in example 1.

Example 3

To a solution of 3.5 g of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid chloride [see Chem. Pharm. Bull. 28, 2809 (1980)] and 1.3 ml of N-ethylmorpholine in 30 ml of anhydrous tetrahydrofuran, a solution of 1.8 g of L-valine ethyl ester hydrochloride in 30 ml of anhydrous tetrahydrofuran is added dropwise at 0-10°C. After completion of the addition, it is allowed to warm to room temperature. The reaction mixture is evaporated under reduced pressure. The residue is dissolved in 100 ml of dichloromethane and washed several times with water. The organic phase is dried with sodium sulphate, filtered and the filtrate evaporated under reduced pressure. The residue is purified by chromatography on

the approx. 100 times the amount of silica gel (elution with a 3:7 mixture of ethyl acetate and hexane). The thus obtainable crude product 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-ethoxy-carbonyl-2-methyl-1-propyl]-amide. The separation of the diastereomers takes place as described in example 1.

Example 4

Analogous to the method described in example 1, one obtains

of a mixture of 42 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-methyl ester, 16 g of D-valine ethyl ester hydrochloride and 11 ml of N-ethylmorpholine in 350 ml of anhydrous dimethylformamide (-)-(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 which after recrystallization from a mixture of acetone and diisopropyl ether melts at 199-200°C. This diastereomer is configurationally uniform and shows a specific drinning of [a]^° -75° (c = 0.7, ethanol).

Analogous to the method described in example 1, (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N is isolated from the mother liquor -[(IR)-1-ethoxycarbonyl-2-methyl-1-propyl]amide. Upon comminution of the amorphous crude product with diethyl ether, this diastereomer crystallizes in configurationally uniform form, it melts at 144-145°C and shows a specific rotation of [a]D = +30°

(c= 0.4, ethanol).

Example 5

Analogous to the method described in example 1, one obtains

a mixture of 10.2 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid 3-(1-benzotriazolyl)-5-isopropyl ester, 3 .5 g of L-valine ethyl ester hydrochloride and 2.5 ml of N-ethylmorpholine in 90 ml of anhydrous dimethylformamide (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4-( 3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-ethoxycarbonyl-2-methyl-1-propyl)-amide, which after recrystallization from acetic acid ethyl ester melts at 178-179°C. The specific rotation of this configurationally uniform diastereomer is [a] ^= -28^

(c = 0.9, ethanol).

Analogous to the method described in example 1, (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-isopropoxy-carbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid is isolated from the mother liquor -N-[(IS)-1-ethoxycarbonyl-2-methyl-1-propyl]-amide in amorphous form. The specific rotation of this amorphous diastereomer is [α]^° = +46° (c = 0.45, ethanol), it still contains approx. 20% of (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(1S)-1- ethoxycarbonyl-2-methyl-1-propyl]amide. The starting material can be obtained as follows. Analogously to the method described in example 1, a mixture of 16.2 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid monoisopropyl ester is obtained [see European patent -application 11,706], 7.6 g of 1-hydroxybenzotriazole and 10.2 g of N,N<1->dicyclohexylcarbodiimide in 225 ml of anhydrous dimethylformamide 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)- pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-isopropyl ester as amorphous product.

250 mHz FT-<1>H-NMR (CDCl 3 ): 1.13, 1.30 (2d, 6H, Isopropyl-CH 3 ); 2.44, 2.46 (2s, 6H, dihydropyridyl-CH 3 ); 5.00 (m, 1H, -O-CH-); 5.40 (s, 1H, 4-dihydropyridyl-H); 6.28 (s, 1H, -NH-); 6.89, 7.40, 8.05 (3m, 4H, benzotriazolyl-H); 7.49, 7.79, 8.15, 8.25 (4m, 4H, phenyl-H).

Example 6

Analogous to the method described in example 1, one obtains

of a mixture of 30 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-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-Nitrophenyl)-pyridine-5-carboxylic acid-N-[(IR)-1-ethoxycarbonyl-2-methyl-1-propyl]-amide. This configurationally uniform diastereomer melts at 176-177°C and shows a specific rotation of [a]p° = +24 (c = 0.53, ethanol).

Analogous to the method described in example 1, (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-isopropoxy-carbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid is isolated from the mother liquor -N[(IR)-1-ethoxycarbonyl-2-methyl-1-propyl]amide in amorphous form. The specific rotation of this amorphous diastereomer is [ct]^°=

and 1

-47 (c = 0.65, ethanol), according to the H-NMR spectrum it still contains approx. 5% of (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IR)-1- ethoxycarbonyl-2-methyl-1-propyl]-amide.

Example 7

Analogous to the method described in example 1, one obtains

of a mixture of 42 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-isopropyl ester, 14 g of L-Leucine methyl ester hydrochloride and 9.6 ml of N-ethylmorpholine in 250 ml of anhydrous dimethylformamide (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4-(3 -nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-methoxycarbonyl-3-methyl-1-butyl]-amide, which after recrystallization from acetic acid ethyl ester melts at 176-177°C. This crystalline diastereomer is configurationally uniform and exhibits a specific rotation of [a]^ = + 106° (c = 0.48, ethanol).

The mother liquor is isolated analogously to the method described in example 1 (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid N-[(1S)-1-methoxycarbonyl-3-methyl-1-butyl]-amide. Upon fine distribution of the amorphous crude product with diethyl ether, this diastereomer crystallizes in configurationally uniform form, it melts at 154-155°C and shows a specific rotation of [a]p<0>= -55° (c = 0.78, ethanol) .

Example 8

Analogous to the method described in example 1, one obtains

of a mixture of 21 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-isopropyl ester, 6.9 g D-leucine methyl ester hydrochloride and 4.8 ml N-ethylmorpholine in 120 ml anhydrous dimethylformamide

(-)-(4R)-1,4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IR)-1-methoxycarbonyl-3 -methyl-1-butyl]-amide, which after recrystallization from acetic acid ethyl ester melts at 175-176°C. This configurationally uniform diastereomer exhibits a specific rotation of

[α]^° -109° (c = 0.28, ethanol).

From the mother liquor, analogously to the method described in example 1, (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-isopropoxy-carbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid is isolated N-[(IR)-1-methoxycarbonyl-3-methyl-1-butyl]-amide in amorphous, though configurationally uniform form. The specific rotation of this diastereomer is [ct]^° = + 48° (c = 0.79, ethanol).

Example 9

Analogous to the method described in example 1, one obtains

of a mixture of 23 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-methyl ester, 9.3 g D-leucine ethyl ester hydrochloride and 3.5 ml N-ethylmorpholine in 150 ml anhydrous dimethylformamide (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IR)-1-ethoxycarbonyl-3-methyl-1-butyl]-amide, which after recrystallization from a mixture of ethyl acetate and diisopropyl ether melts at 207-209° C. This diastereomer is configurationally uniform, the specific rotation is [ct]D= -116° (c = 0.76, ethanol).

Analogous to the method described in example 1, (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N is isolated from the mother liquor -[(IR)-1-ethoxycarbonyl-3-methyl-1-butyl]-amide. After recrystallization of the crude product from a mixture of diethyl ether and hexane, a crystalline product is obtained which melts at 112-114°C and whose specific rotation is [a]^° =+21° (c = 0.5, ethanol). This crystalline form still contains 5-10% (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl) )-pyridine-5-carboxylic acid-N-[(IR)-1-ethoxycarbonyl-3-methyl-1-butyl]amide.

Example 10

Analogous to the method described in example 1, a mixture of 19.2 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-(1- benzotriazolyl) ester 3-methyl ester, 7.8 g L-leucine ethyl ester hydrochloride and 2.9 ml N-ethylmorpholine in 120 ml anhydrous dimethylformamide

(+)-(4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N[(IS)-1-ethoxycarbonyl-3- methyl-1-butyl]-amide, which after recrystallization from a mixture of acetic acid ethyl ester and diisopropyl ether melts at 206-207°C. This crystalline form is configurationally uniform, the specific rotation is [a] = + 105° (c =

0.26, ethanol).

Analogously to the method described in example 1, (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N is isolated from the mother liquor -[(IS)-1-ethoxycarbonyl-3-methyl-1-butyl]-amide as crude product. Recrystallization of a mixture of diethyl ether and hexane yields a crystalline product that melts at 118-120°C

and whose specific rotation is [a]<2>^ = -23° (c = 0.7,

ethanol). According to the<1>H-NMR spectrum, this crystalline form still contains approx. 20% (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-ethoxycarbonyl -3-methyl-1-butyl]-

amide.

Example li

Analogous to the method described in example 1, one obtains

of a mixture of 25 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-methyl ester, 8.6 g L-proline methyl ester hydrochloride and 6.6 ml N-ethylmorpholine in 120 ml anhydrous dimethylformamide (+)-(4S)-5-[(2S)-2-methoxycarbonyl-pyrrolidin-1-yl-carbonyl ]-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine, which after recrystallization from a mixture of ethyl acetate and hexane melts at 180-181°C. This crystalline diastereomer is configurationally uniform, the specific rotation is [a]<20>^+104° (c =0.7,ethanol).

The mother liquor is isolated analogously to the method described in example 1 (-)-(4R)-5-[(2S)-2-methoxycarbonyl-pyrrolidin-1-yl-carbonyl]-1,4-dihydro-2,6-dimethyl- 3-methoxycarbonyl-4-

(3-nitrophenyl)-pyridine which, after recrystallization from a mixture of acetic acid ethyl ester and diisopropyl ether, melts at 118-119°C. This configurationally uniform diastereomer shows a specific rotation of [ct]D= -59° (c = 0.5, ethanol.

Example 12

Analogous to the method described in example 1, one obtains

of a mixture of 23 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-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-pyrrolidin-1-yl-carbonyl] -1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine, which after recrystallization from a mixture of acetone and diisopropyl ether melts at 180-181°C. This crystalline diastereomer is configurationally uniform and exhibits a specific rotation of [α]20 = -97° (c = 0.97, ethanol).

The mother liquor is isolated analogously to the method described in example 1 (+)-(4S)-5-[(2R)-2methoxycarbonyl-pyrrolidin-1-yl-carbonyl]-1,4-dihydro-2,6-dimethyl-3- methoxycarbonyl-4-(3-nitrophenyl)pyridine, which after recrystallization from a mixture of acetone and diethyl ether melts at 120-122°C.

This configurationally uniform diastereomer shows a

specific rotation of [a] = +56° (c = 0.55, ethanol).

Example 13

Analogous to the method described in example 1, one obtains

of a mixture of 18 g of 1,4 dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-methyl ester, 4 .7 g glycine methyl ester hydrochloride and 4.7 ml N-ethylmorpholine in 150 ml anhydrous dimethylformamide racemic 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5- carboxylic acid N-(methoxycarbonylmethyl)amide in amorphous form.

250 MHz FT-<1>H-NMR (CDCl 3 ): 2.32, 2.35 (2s, 6H, dihydropyridyl-CH 3 ); 3.67, 3.73 (2s, 6H, -C00CH3); 4.00 (d, 2H, -N-CH 2 ); 4.96 (s, 1H, 4-dihydropyridyl-H); 5.75 (s, 1H, 1-dihydropyridyl-H); 5.90 (t, 1H, -CONH); 7.4-8.18 (m, 4H, phenyl-H).

Example 14

Analogous to the method described in example 1, one obtains

of a mixture of 15 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-methyl ester, 5.2 g α-aminoisobutyric acid ethyl ester hydrochloride and 3.6 ml N-ethylmorpholine in 100 ml anhydrous

r

dimethylformamide racemic 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitro-phenyl)-pyridine-5-carboxylic acid-N-(1-ethoxycarbonyl-1-methyl-1-ethyl)- amide, which after recrystallization from a mixture of acetic acid ethyl ester and diethyl ether melts at 160-161°C.

Example 15

Analogous to the method described in example 1, one obtains

of a mixture of 18.5 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-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)-1,4-dihydro-2,6-dimethyl-3 -methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-ethoxycarbonyl-1-ethyl]-amide which after recrystallization from a mixture of acetic acid ethyl ester and diisopropyl ether melts at 134-135° C.

Example 16

Analogous to the method described in example 1, one obtains

of a mixture of 21.7 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5- methyl ester and 8.2 g of L-tyrosine methyl ester in 100 ml of anhydrous dimethylformamide a 1:1 diastereomer mixture of (4R)-

and (4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitro-phenyl)-pyridine-5-carboxylic acid-N-[(1S)-1-methoxycarbonyl-2-

(4-hydroxyphenyl)-1-ethyl]amide in amorphous form. 250 MHz FT """H-NMR (CDCl 3 ) : 2.18, 2.21, 2.30, 2.32 (4s, 6H, dihydropyridyl-CH 3 ); 2.80-3.10 (m, 2H, phenyl-CH2); 3.65, 3.75 (2s,

6H, -C00CH3); 4.74-4.94 (m, 1H, -CON-CH-); 4.83 (s, 1H, 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

Analogous to the method described in example 1, a mixture of 20 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1- benzotriazolyl) ester 5-methyl ester, 11.5 g of D,L-α-phenylglycine benzyl ester hydrochloride and 5.2 ml of N-ethylmorpholine in 90 ml of anhydrous dimethylformamide a racemic 1:1 diastereomer mixture of 1,4-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-<1>H-NMR (CDC13 /: 2.23, 2.26, 2.32, 2.33 (4s, 6H, dihydropyridyl-H); 3.63, 2.67 (2s,

3H, -C00CH3); 4.96, 5.09 (2s, 2H, -C00CH2); 5.15, 5.16

(2s, 1H, 4-dihydropyridyl-H); 5.5 (m, 1H, -N-CH-); 5,6,

5.65 (2s, 1H, 1-dihydropyridyl-H); 6.32, 6.40 (2d, 1H,

-CONH-); 7.04-8.12 (m, 14H, phenyl-H).

Example 18

Analogous to the method described in example 1, a mixture of 20 g of 4-(2-difluoromethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-(1-benzotriazolyl)-ester is obtained -5-methyl ester, 7 g of L-valine ethyl ester hydrochloride and 4.9 ml of N-ethylmorpholine in 150 ml of anhydrous dimethylformamide a 1:1 diastereomer mixture of (4R)- and (4S)-4-(2-difluoromethoxy-phenyl) )-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-pyridine-5-carboxylic acid-N-[(IS)-1-ethoxycarbonyl-2-methyl-1-propyl]-amide, which after recrystallization from one of a mixture of a mixture of diethyl ether and diisopropyl ether melts at 98-99°C.

The starting material can be obtained as follows:

Analogous to the method described in example 1, a mixture of 17 g of 4-(2-difluoromethoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid monomethyl ester is obtained [Production analogously to EP 11,706; Temp. 150-152°C], 8 g of 1-hydroxybenzotriazole and 11 g of N,N<1->dicyclohexylcarbodiimide in 150 ml of anhydrous dimethylformamide 4-(2-difluoromethoxy-phenyl)-1,4-dihydro-2,6-dimethyl- pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-methyl ester as crude product in amorphous form which is used without further purification in the following reaction.

Example 19

Analogous to the method described in example 1, one obtains

of a mixture of 20 g of 1,4-dihydro-2,-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-methyl ester, 8 .9 g L-α-phenylglycine ethyl ester hydrochloride and 5.2 ml N-ethylmorpholine in 150 ml anhydrous dimethylformamide 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-[(IS)-1-ethoxycarbonyl-1-benzyl]-amide as resinous crude product.

For the separation of the diastereomers, the crude product is added to a mixture of acetic acid ethyl ester and diisopropyl ether and stirred for 1 hour at 0-5°C, whereby a first diastereomer crystallizes. This configurationally uniform diastereomer melts at 193-194°C and shows a specific rotation of [α]43g -66° (c = 0.7, ethanol).

To isolate the second diastereomer, the mother liquor is evaporated under reduced pressure and the residue is purified by chromatography on the approx. 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 thus obtainable melts at 139-140°C and shows a specific rotation of

[a] = + 46 (c = 0.8, ethanol): this crystalline form

1

is, according to the H-NMR spectrum, still contaminated with approx. 20% of the first diastereomer.

Example 20

Analogous to the method described in example 1, one obtains

of a mixture of 20 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-methyl ester, 8.9 g D-α-phenylglycine ethyl ester hydrochloride and 5.2 ml N-ethylmorpholine in 150 ml anhydrous dimethylformamide 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-[IR)-1-ethoxycarbonyl-1-benzyl]-amide as highly viscous crude product.

To separate the diastereomers, the crude product is added to a mixture of acetic acid ethyl ester and diisopropyl ether and left for 16 hours at 0-5°C, whereby a first diastereomer crystallizes. The crystals are filtered off and recrystallized from ethyl alcohol. The thus obtainable diastereomer is configurationally uniform; it melts at 196-197°C and shows a specific rotation of [al^g = +61°

(c = 0.34, ethanol).

For isolation of the second diastereomer, the mother liquor is evaporated under reduced pressure and the residue is purified by chromatography on the approx. 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 twice from a mixture of acetic acid ethyl ester and diethyl ether.

The thus obtainable second diastereomer melts at 134-135°C and shows a specific rotation of [a]n = -45°1

(c = 0.7, ethanol); this crystalline form is, according to the H-NMR spectrum, contaminated with approx. 15% of the first diastereomer.

Example 21

A mixture of 5.9 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-isopropyl ester, 5 .34 g of L-phenylalanyl-L-phenylalanine-0-(2-trimethylsilyl-ethyl)-ester hydrochloride and 1.5 ml of N-ethylmorpholine in 90 ml of anhydrous dimethylformamide are stirred for 15 hours at 80°C in a nitrogen atmosphere. The reaction mixture is added under ice-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 the approx. 100 times the amount of silica gel (elution with a 1:1 mixture of chloroform and methanol).

The amorphous product thus obtainable is a 1:1 diastereomer mixture of N-[1,4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4-(3-nitrophenyl)-5-pyridoyl]-L-phenylalanyl- L-phenylalanine O-(2-trimethyl-ethyl)-ester; It exhibits 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 is stirred in 34 ml of a 0.7 M solution of tetraethylammonium fluoride in dimethyl sulfoxide for 20 minutes at 20°C. The clear reaction solution is cooled in the ice bath and 24 ml IN hydrochloric acid and 150 ml water are added. The separated precipitate is filtered off, the filter residue is 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. When the viscous residue is finely divided with diisopropyl ether, amorphous N-[1,4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4-(3-nitrophenyl)-5-pyridoyl]-L-phenylalanyl-L-phenylalanine is obtained as diastereomer mixture; it exhibits 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-trimethylsilyl-ethyl)-ester hydrochloride in 125 ml of anhydrous dichloromethane is added at 0°C with 3.50 ml of N -ethylmorpholine and 6.7 g of N,N-dicyclohexylcarbodiimide. It is stirred for 1 hour at 0°C and then for a further 15 hours at room temperature. The reaction mixture is filtered and the filtrate diluted with 80 ml of dichloromethane. The dichloromethane solution is washed with 1 N citric acid, 1 N sodium bicarbonate and water. The organic phase is dried over sodium sulphate, filtered and the filtrate evaporated under reduced pressure. The residue crystallizes from a mixture of acetic acid ethyl ester and petroleum ether. The thus obtainable N-benzyloxycarbonyl-L-phenylalanyl-L-phenylalanine-O-(2-trimethylsilyl-ethyl)-ester melts at 89-90°C.

1.80 g of this intermediate is subjected to 20 ml of methanol in the presence of 180 mg of 10% palladium-charcoal hydrogenolysis, whereby the pH of the reaction mixture is 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, where L-phenylalanyl-L-phenylalanine-0-(2-trimethylsilyl-ethyl)-ester hydrochloride is obtained as a white foam. The product exhibits a thin-layer chromatographic Rf value of

0.75 in the elution system chloroform-methanol 8:2.

Example 22

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

[α]^° -8.1° (c = 0.87, ethanol).

Example 23

In a completely analogous way to example 22, however starting from (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylstyrene-N -[(IS)-1-ethoxycarbonyl-2-methyl-1-propyl]-amide gives (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3 -nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-l-carboxy-2-methyl-l-propyl]-amide which melts at 198-202°C during decomposition and whose specific rotation is [a]2 <0>= +84.1° (c = 1.0, ethanol).

Example 24

47 g (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-carboxy -2-methyl-1-propyl]-amide is heated with 30.5 g of 0-n-butyl-N,N<1->dicyclohexyl-isourea [preparation according to Chem. Pray. _99, 1479 (1966) in 400 ml of acetic acid ethyl ester for 15 hours under nitrogen at 80°C. The initial suspension becomes clear and after one hour N,N<1->cicyclohexylurea begins to separate. The urea is filtered off, washed with acetic acid ethyl ester and the filtrate evaporated. The residue is chromatographed on a 1050 g flash column in a mixture of ethyl acetate/hexane 3:7 as solvent. The thus purified product (51 g) is recrystallized from 60 ml abs. ether and washed with a mixture of ether/hexane 95:5. The thus formed (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)pyridine-5-carboxylic acid-N-[(IS)-1- (n-butoxycarbonyl)-2-methyl-1-propyl]-amide has a melting point of 69-70°C { [a]<20>= -22° (c = 0.6 ethanol).

Example 25

In a completely analogous way to example 24, however outgoing

from (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-carboxy- 2-methyl-1-propyl]-amide, one obtains (+)-(4S)-1,4-dihydro-2,6-

Dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-(n-butoxycarbonyl)-2-methyl-1-propyl]-amide with m.p. 144-145°C; [a]2° = + 66° (c = 1.0, ethanol)

Example 26

In a completely analogous way to example 24, however starting from the corresponding O-substituted N,N'-dicyclohexyl-urea substances [pentyl according to Chem. Pray. 99_ ,1479 (1966) as well as Liebig's Ann. Chemie 597, 235 (1956)], the following compounds are obtained in configurationally uniform form: a) (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-(n-hexyloxycarbonyl)-2-methyl-1-propyl]-amide; ^ a^ i) 0 = 15.7

+ 3.2° (c 0.31, ethanol).

b) (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-( benzyloxycarbonyl)-2-methyl-1-propyl]amide; [α]^<0>= 15.5° (c = 0.9, ethanol). c) (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N- ^(1S)-1-[ 3-(4-methyl-1-piperazinyl)-1-propoxy]carbonyl-2-methyl-1-propyl}-amide; [α]<20>= -10.0° (c - 0.93, ethanol). d) (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-\(1S)-1-[ 3-(4-benzyl-1-piperazinyl)-1-propoxy]carbonyl-2-methyl-1-propyl)-amide; [α]<20>= -12.7° (c = 0.6, ethanol).

Example 27

In a completely analogous way to example 24, however starting from 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-[(IS)-1-carboxy-2-methyl-1-propyl]-amide as well as the corresponding O-substituted N,N<1->dicyclohexyl-ureas give the subsequently listed compounds as amorphous 1:1 diastereomer mixtures: a) (4R)- and (4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N- [(1S)-1-(2-Dimethylamino-1-ethoxy)-carbonyl-2-methyl-1-propyl]-amide.

250 MHz FT-<1>H-NMR (CDCl 3 ): 0.75 (m, 6H, -CH-j); 2.1 (m, 1H,

-CH); 2.3 (m, 12H, dihydropyridyl - CH 3 ; -N-CH 3 ); 2.55, 4.20

(2m, 4H, -O-CH2-CH2-N); 3.65 (2s, 3H, CO0CH3); 4.55 (m, 1H,

-CON-CH); 5.0 (2s, 1H, 4-dihydropyridyl-H); 5.65 (2s, 1H, 1-dihydropyridyl-H); 5.85 (2d, 1H, -CONH); 7.4-8.2 (m, 4H, phenyl-H). b) (4R)- and (4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1- (3-Dimethylamino-1-propoxy)-carbonyl-2-methyl-1-propyl]amide. 250MHz FT-<1>H-NMR (CDCl 3 ): 0.75 (m, 6H, -CH 3 ); 1.8 (m, 2H,

-CH2~); 2.1 (m, 1H, -CH-); 2,2-2,4 (m, 15H, dihydropyridyl-

CH3; -CH2-N-CH3); 3.65 (2s, 6H, CO0CH3); 4.15 (m, 2H,

C00CH2); 4.5 (m, 1H, -CON-CH); 5.0 (2s, 1H, 4-dihydropyridyl-

H); 5.6 (2s, 1H, 1-dihydropyridyl-H); 5.8 (2d, 1H, -CONH); 7.4-8.2 (m, 4H, phenyl-H). c) (4R)- and (4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-( (1S)-1- [2-(4-morpholino)-1-ethoxy]-carbonyl-2-methyl-1-propyl]'-amide 250 MHz FT-<1>H-NMR (CDCl 3 ): 0.75 (m, 6H, -CH 3 ); 2.1 (m, 1H,

-CH-); 2.3 (m, 6H, dihydropyridyl-CH 3 ); 2.4-2.65 (m, 6H,

-N-CH 2 ); 3.7 (m, 7H, -CO0CH3; -O-CH2"); 4.05-4.4 (m, 2H,

C00CH2); 4.55 (m, 1H, CON-CH-); 5.0 (2s, 1H, 4-dihydropyridyl-H), 5.62 (2s, 1H, 1-dihydropyridyl-H); 5.8 (2d,

1H, -CONH); 7.4-8.2 (m, 4H, phenyl-H).

d) (4R)- and (4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1- (2-Methoxy-letoxy)-carbonyl-2-methyl-1-propyl]-amide. 250 MHz FT-<1>H-NMR (CDCl 3 ): 0.75 (m, 6H, -CH-j); 2.1 (m,1H, -CH-); 2.2-2.36 (4s, 6H, dihydropyridyl-CH 3 ); 3.36 (2s, 3H, -OHCH3); 3.55 (in, 2H, -OCH2") ; 3.62 (2s, 3H, -COOCCH3); 4.25

(m, 2H, -CO0CH2-); 4.60 (m, 1H, -CON-CH-); 4.98 (2s, 1H, 4-dihydropyridyl-H); 5.6 (2s, 1H, 1-dihydropyridyl-H); 5.8

(2d, 1H, -CONH-); 7.4-8.2 (m, 4H, phenyl-H).

Example 28

Analogous to the method described in example 1, one obtains

of a mixture of 54.5 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5- methyl ester, 31 g of D,L-phenylglyein-carbamoyl methyl ester hydrochloride [prepared analogously to Tetrahedron Lett. 24, 5219

(1983)] and 16.2 ml N-ethylmorpholine in 300 ml anhydrous dimethylformamide a racemic 1:1 diastereomer mixture of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine -5-carboxylic acid-N-[1-(carbamoyl-methoxycarbonyl)-1-phenyl-methyl]*amide as resinous intermediate. 16 g of the above-mentioned intermediate product are stirred in a mixture of 67 ml of 0.5 N caustic soda and 50 ml of N-dimethylformamide for 2 hours at room temperature. The dark reaction solution is then evaporated to dryness under reduced pressure. The dark residue is dissolved in 100 ml of 0.02 N caustic soda, washed several times with acetic acid ethyl ester, further treated with activated charcoal, filtered and the filtrate acidified with 2 N hydrochloric acid. The precipitated acid is filtered off, the filter residue is washed several times with water and dried for 12 hours at 50°C in a high vacuum. The thus obtained racemic 1:1 diastereomer mixture of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-(1-carboxy-1-phenyl) -methyl)-amide melts at 126-128°C.

Example 2 9

a) 4 g of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-carboxylic acid-N-(1-carboxy-l-phenyl-methyl)-amide (racemic 1 :1-diastereomer mixture) is heated with 2.6 g of O-(2-dimethylamino-ethyl)-N,N'-dicyclohexyl-iso-urea [preparation analogous to Liebig's Ann. Chem. 597, 235

(1956) in 60 ml ethyl acetate for 15 hours under a nitrogen atmosphere at 80°C. The precipitated urea is filtered off and the filtrate is evaporated under reduced pressure. The residue is purified by chromatography on the approx. 100 times the amount of silica gel (elution with a 9:1 mixture of methylene chloride and methanol). 1 equivalent of 1.7 N alcoholic hydrochloric acid is added to the crude base thus formed and the solution is evaporated under reduced pressure. The resinous residue is stirred in a mixture of 20 ml of acetic acid ethyl ester and 50 ml of diethyl ether in an ice bath, whereby 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid The N-[1-(2-dimethylamino-1-ethoxy)-carbonyl-1-phenyl-methyl]-amide hydrochloride crystallizes. This 1:1 diastereomer mixture melts at 100 - 112°C with decomposition.

b) In a completely analogous way to a), but starting from 0-(2-morpholino-ethyl)-N,N'-dicyclohexyl-isourea

[production analogLiebig's Ann. Chem. 597, 235 (1956) one obtains 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitro-phenyl)-pyridine-5-carboxylic acid-N-^1-[2-(4 -morpholino)-1-ethoxy]-carbonyl-1-phenyl-methyl^-amide hydrochloride as 1:1 diastereomer mixture melting at 127-129°C.

Example 30

a) Analogous to the method described in example 1, a mixture of 50 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-(1- benzotriazolyl) ester 5-methyl ester, 20.4 g L-isoleucine ethyl ester hydrochloride and 12.2 ml N-ethylmorpholine in 300 ml anhydrous dimethylformamide (+)-(4S)-1,4-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 acetic acid methyl ester and diisopropyl ether melts at 170-171°C. This diastereomer α is configurationally uniform and exhibits a specific rotation of

[α]20 = + 93° (c = 0.44, ethanol).

Analogous to the method described in example 1, (4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS , 2S)-ethoxy-carbonyl-2-methyl-1-butyl]-amide. When the amorphous crude product is finely divided with diethyl ether, this diastereomer 0 crystallizes, which after further recrystallization from a mixture of acetic acid ethyl ester and n-hexane melts at 117-118 C. The specific rotation is [a]D 2 0= +5 (c = 0 ,91, ethanol), this 3-diastereomer still contains, according to the H-NMR spectrum, approx. 25% of the above-mentioned α-diastereomer.

b) In a completely analogous way to a), but starting from L-isoleucine methyl ester hydrochloride, one gets 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-[(IS ,2S)-1-methoxycarbonyl-2-methyl-1-butyl]-amide with m.p. 139-140°C

Example 31

Analogous to the method described in example 2, you get

of a mixture of 9.4 g of N-acetoacetyl-α-amino-cyclohexylcarboxylic acid ethyl ester [prepared analogously to Pharm. Acta Heiv. _38, 616 (1963)], 4.1 g of 3-aminocrotonic acid methyl ester and 5.5 g of 3-nitrobenzaldehyde in 70 ml of ethanol amorphous 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4- (3-nitrophenyl)-pyridine-5-carboxylic acid-N-(ethoxycarbonyl-1-cyclohexyl)-amide, which crystallizes on stirring with diethyl ether, m.p. 166-168°C.

Example 32

Analogous to the method described in example 2, you get

of a mixture of 8.1 g of N-acetoacetyl-α,α-diphenylglycine ethyl ester [prepared analogously Pharm. Acta Heiv. 3_8, 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-diphenyl-methyl)-amide.

250MHz FT-<1>H-NMR (CDCl 3 ): 1.15 (t, 3H, -COO-C-CH 3 ); 2.18, 2.30 (2s, 6H, dihydropyridyl-H); 3.61 (s, 3H, -COCH 3 ); 4.19 (q, 2H, -CO0-CH2-); 5.05 (s, 1H, 4-dihydropyridyl-H); 5.72 (s, 1H, 1-dihydropyridyl-H); 6.96 (s, 1H, -CONH-); 7.1-8.18 (m, 14H, phenyl-H).

Example 33

Analogous to the method described in example 1, one obtains

of 7.9 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-methyl ester and 5 g of D ,L-α-[2-(N-tert-butoxycarbonyl-amino)-4-thiazolyl]-glycine ethyl ester in 30 ml anhydrous dimethylformamide racemic 1,4-dihydro-2,6-dimethyl-3- methoxycarbonyl-4-(3- nitrof enyl)-pyridine-5-carboxylic acid-N- \_1- [2-(N-tert.-butoxycarbonyl-amino)-4-thiazolyl]-1-ethoxycarbonyl-methylj-amide as resinous intermediate.

This is dissolved in 40 ml of saturated hydrochloric acid, ice-cold glacial acetic acid and stirred for 1.5 hours at 0°C. The cold reaction solution is then neutralized with 2N caustic soda and the crude product is extracted several times with acetic acid ethyl ester. The combined organic extracts are evaporated under reduced pressure, whereby 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[1-(2-amino- 4-thiazolyl)-1-ethoxycarbonyl-methyl]-amide

remains as amorphous 1:1 diastereomer mixture.

250 MHz FT- 1 H-NMR (CDCl 3 ): 1.2 (2 h, 3H, -COO-C-CH 3 ); 2.32 (2d, 6H, dihydropyridyl-CH 3 ); 2.65 (2s, 3H, -C00CH3); 4.15 (2m, 2H, -CO0-CH2~); 5.0 (2s, 1H, 4-dihydropyridyl-H);

5.06 (s, 1H, -NH2); 5.40 (2s, 1H, -N-CH-); 5.60 (2s, 1H, 1-dihydropyridyl-H); 6.42 (2s, 1H, thiazolyl-H); 6.50, 6.65 (2d, 1H, -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

[manufactured analogously to EP 11.706, m.p. 228-229°C, 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°C under a nitrogen atmosphere. The crystallized N,N<1->dicyclohexylurea is filtered off. Man to-

put the yellow filtrate with 4 g of L-valine ethyl ester hydrochloride and 2.8 ml of N-ethylmorpholine and stir for 16 hours at 80°C under a nitrogen atmosphere. 250 ml of ice water is added to the yellow reaction mixture under ice water cooling and stirred for a further 1 hour at 0-5°C, whereby the crude product crystallizes. It is filtered off, the filter residue is washed with 1 1 water and dried in a vacuum. The thus obtainable 1:1 diastereomer mixture of (4R)- and (4S)-1,4-dihydro-2,6-dimethyl-3-methylsulfonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N- [(1S)-1-ethoxycarbonyl-2-methyl-1-propyl]-amide melts after the recrystallization from acetic acid ethyl ester at 191-192°C. b) In a completely analogous way to a), but starting from D-valine ethyl ester hydrochloride, a 1:1 diastereomer mixture of (4R)- and (4S)-1,4-dihydro-2,6-dimethyl is obtained -3-methylsulfonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IR)-1-ethoxycarbonyl-2-methyl-1-propyl]-amide melting at 188-191°C.

Example 3 5

A mixture of 44.6 g of (S)-N-(3-nitrobenzylidene-acetoacetyl)-α-amino-isovaleric acid ethyl ester and 14.1 g of 3-amino-crotonic acid methyl ester in 350 ml of ethanol is stirred for 16 hours at 80 °C under nitrogen atmosphere. The yellow reaction mixture is evaporated under reduced pressure and the residue purified by chromatography on the approx. 100 times the amount of silica gel (elution with a 7:3 mixture of n-hexane and ethyl acetate). The resinous crude product thus obtainable 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.

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-α-amino-isovaleric acid ethyl ester [prepared analogously Pharm. Acta Heiv. 38, 616 (1963)] in 140 ml of anhydrous toluene is introduced HCl gas for 2 hours at 5-15°C.

The mixture is then stirred for a further 2 hours at room temperature and the reaction mixture is evaporated under reduced pressure. The residue is stirred for 4 hours at 80°C under a water jet vacuum, whereby hydrochloric acid is split off. The thus obtainable crude (S)-N-(3-nitrobenzylidene-acetoacetyl)-ct-amino-isovaleric acid ethyl ester melts after the recrystallization of a mixture of 24 ml of tetrahydrofuran and 180 ml of diethyl ether at 114-116°C.

Example 36

In a completely analogous way to example 35, however outgoing

from 2-nitrobenzaldehyde, one first obtains (S)-N-(2-nitrobenzylidene-acetoacetyl)-α-amino-isovaleric acid ethyl ester [m.p. 106-107°C] as an intermediate and from this by condensation with 3-amino-crotonic acid methyl ester a resinous diastereomer mixture of (4R)- and (4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4 -(2-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-ethoxycarbonyl-2-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 a is obtained, whose specific rotation is [a]D =

-363.5-6.4° (c = 0.15, ethanol) and which melts at 179-180°C.

From the mother liquor, the amorphous diastereomer 3 is isolated which, according to the H-NMR spectrum, further contains approx. 15% of the above indicated cx diastereomer.

250 MHz FT-<1>H-NMR (CDC13) spectrum of diastereomer 3:

0.52, 0.6 (2d, 6H, -CH.j); 1.3 (t, 3H, -O-CH2"); 1.98 (m,

1H, -CH-); 2.28, 2.48 (2s, 6H, dihydropyridyl-CH 3 ); 3.55

(s, 3H, -C00CH3); 4.12 (m, 2H, -CO0CH2"); 4.6 (m, 1H, -CON-CH-); 5.7, 5.83 (2s, 2H, 1- or 4-dihydropyridyl-H) ;

7.25-7.8 (m, 4H, phenyl-H).

Example 37

Analogous to the method described in example 1, one obtains

of 18.7 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-(1-benzotriazolyl)-ester-5-methyl ester and 6.7 g L-valinamide in 100 ml anhydrous dimethylformamide 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-[(IS)-1-carbamoyl-2-methyl-1-propyl]-amide which after recrystallization from a mixture of acetone and diethyl-

ether melts at 190-191°C.

Example

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, 1.9 ml of chloroformate isobutyl ester is added dropwise over 10 minutes while cooling so that the temperature does not exceed - 15°C. The mixture is then stirred for a further 10 minutes at -20 to -15°C and then 2.8 ml of 2-(2-aminoethyl)pyridine is added dropwise while cooling, so that the temperature does not exceed -10°C. After the addition is complete, the reaction mixture is allowed to warm to room temperature and stirred for a further 3 hours, after which it is evaporated

under reduced pressure. The resinous residue is purified by chromatography on the approx. 100 times the amount of silica gel (elution with a 95:5 mixture of methylene chloride and methanol). The thus obtainable resinous 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-\l-[2-(2-pyridyl)-1- ethylamino]-carbonyl-2-methyl-1-propyl}-amide crystallizes from a mixture of methylene chloride and diethyl ether as a 1:4 diastereomer mixture with m.p. 158-160°C. b) In a completely analogous way to a), but starting from N-methyl-benzylamine, a 1:4-diastereomer mixture of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitro) is obtained -phenyl )-pyridine-5-carboxylic acid-N-[1-(N-benzylmethylamino)-carbonyl-2-methyl-1-propyl]-amide with m.p. 94-95°C. c) In a completely analogous way 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-[1-(4-benzyl-1-piperazinyl)-carbonyl-2-methyl-1-propyl]-amide.

250MHz FT-<1>H-NMR(CDCl 3 ): 0.6-0.85 (m,6H, -CH 3 ); 1.85 (m,

1H, -CH-), 2.2-2.35 (4s, 6H, dihydropyridyl-CH3); 2.4 (m,

4H, -N-CH2); 3.44-3.66 (m, 9H, N-CH 2 , -CO 0 CH 3 ); 4.85 (m,lH,

-CON-CH-); 5.0 (2s, 1H, 4-dihydropyridyl-H); 5.55, 5.6

(2s, 1H, 1-dihydropyridyl-H): 6.15, 6.30 (2d, 1H, -CONH); 7.25-8.18 (m, 9H, phenyl-H).

d) In a completely analogous way to a), but starting from N-diphenylmethyl-piperazine, an amorphous 3:7 is obtained

diastereomer mixture of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[1-(4-diphenylmethyl-1-piperazinyl)-carbonyl-2 -methyl-1-propyl]-amide.

250 MHz FT-<1>H-NMR (CDC13>: 0.55-0.9 (m, 6H, -CH-j); 1.8 (m, 1H, -CH-); 2.15-2 .45 (4s, 10H, dihydropyridyl-CH3, -N-CH2~);

3.4-3.6 (m, 4H,

3.55, 3.65 (2s, 3H, -COOCH 3 );

4.2 (2s, 1H, -CHPh2; 4.8 (m, 1H, -CON-CH); 4.98 (2s, 1H, 4-dihydropyridyl-H); 5.45, 5.55 (2S, 1H, 1-dihydropyridyl-H); 6.1, 6.28 (2d, 1H, -CONH-); 7.15-8.15 (m, 14H, phenyl-H).

e) In a completely analogous way to a), but starting from n-butylamine, an amorphous 1:2 diastereomer mixture is obtained

of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[1-(n-butylaminocarbonyl)-2-methyl-1-propyl] -amide.

250 MHz FT-<1>H-NMR (CDCl-j) : 0.65-0.98 (m, 9H, -CH3> ; 1.25-155 (m, 4H, -CH2-CH2-); 1 .95 (m, 1H, -CH-); 2.18-2.38 (4s, 6H, dihydropyridyl-CH3); 3.22 (m, 2H, -CON-CH2~); 3.65 (2s, 3H,

-C00CH3); 4.15 (m, 1H, -CON-CH-); 4.98 (2s, 1H, 4-dihydropyridyl-H); 5.55, 5.65 (2s, 1H, 1-dihydropyridyl-H); 5.8

6.05 (2m, 2H, -CONH); 7.4-8.15 (m, 4H, phenyl-H).

f) In a completely analogous way to a), but starting from N-n-heptyl-methylamine, an amorphous 1:1 diastereomer mixture of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3- nitrophenyl)-pyridine-5-carboxylic acid-N-[1_(N-methyl-n-heptylaminocarbonyl)-2-methyl-1-propyl]-amide.

250 MHz FT-<1>H-NMR (CDCl-j): 0.63-0.98 (m, 9H, -CH3)j 1.2-1.6 (m, 10H, -CH2-); 1.9 (m, 1H, -CH-); 2,15,2,35 (2d, 6H, dihydropyridyl-CH3); 2.89, 3.02 (2d, 3H, N-CH 3 ); 3.1-3.55 (m, 2H, N-CH 2 ); 3.6, 3.65 (2s, 3H, CO0CH3); 4.8 (m, 1H, -CON-CH-); 5.0 (2s, 1H, 4-dihydropyridyl-H); 5.52, 5.62 (2s, 1H, 1-dihydropyridyl-H); 6.08-6.30 (m, 1H, -CONH); 7.38-8.18 (m,4H-phenyl-H).

Example 39

In a completely analogous way to example 22, however 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-prop-1]-amide gives (+)-(4S)-1,4-dihydro-2,6-dimethyl-3methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid N-[(IR)-1-carboxy-2-methyl-1-propyl]-amide which melts at 216-218°C and whose specific rotation is [a]<20>= + 8.0°

(c = 1.0, ethanol).

Example 40

In a completely analogous way to example 22, however outgoing

from (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IR)-1-ethoxy- carbonyl-2-methyl-1-propyl]-amide, one obtains (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5 -carboxylic acid-N-[(IR)-1-carboxy-2-methyl-1-propyl]-amide which melts at 121-122° during cleavage and whose specific rotation is [a]Q = -77.0° (c = 1.0 ethanol).

Example 41

In a completely analogous way to example 24, however outgoing

from (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IR)-1-carboxy- 2-methyl-1-propyl]-amide, one obtains (+)-(4S)-1,4-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°C and has a specific rotation of [α]<20>=^21° (c = 1.0, ethanol).

Example 42

In a completely analogous way to example 24, however outgoing

from (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IR)-1-carboxy- 2-methyl-1-propyl]-amide, one obtains (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid -N-[(IR)-1-(n-butoxycarbonyl)-2-methyl-1-propylramide;.'which melts at 143-144°C and whose specific rotation is [a]D = -65° (c = 1.0, ethanol).

Example 4 3

In a completely analogous way to example 35, however outgoing

from 3-aminocrotonic acid ethyl ester, you get an approx. 1:1 diastereomer mixture as resinous crude product. Crystallization of a 2:1 mixture of acetic acid ethyl ester and diisopropyl ether gives crystalline (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-ethoxycarbonyl-4-(3-nitrophenyl)-pyridine- 5-carboxylic acid-N-[(IS)-1-ethoxycarbonyl-2-methyl-1-propyl]-amide in configurational unitary form. It melts at 169-170°C. Its specific rotation is [a]<20>= -46.6°

(c = 0.476, ethanol). Crystalline (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-ethoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1 is isolated from the mother liquor -ethoxycarbonyl-2-methyl-1-propyl]-amide; m.p. 135-136°; [α]<20>= +40.6° (c = 0.94, ethanol).

Example 4 4

In a completely analogous way to example 35, but starting from 3-aminocrotonic acid (n-propyl)-ester, you get an approx. 1:1 diastereomer mixture as resinous crude product. Crystallization of a 2:1 mixture of acetic acid ethyl ester and diisopropyl ether gives crystalline (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-(n-propyloxycarbonyl)-4-(3-nitrophenyl) )-pyridine-5-carboxylic acid-N-[(1S)-1-ethoxycarbonyl-2-methyl-1-propyl]-amide in configurational uniform form. It melts at 148-149°C. Its specific rotation is [a]<20>= -19.9°

(c = 0.55, ethanol). Crystalline (+)-(4S)-1,4-dihydro-2,6-dimethyl-3-(n-propyloxycarbonyl)-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[( 1S)-1-ethoxycarbonyl-2-methyl-1-propyl]-amide; m.p. 119-121°;

[α]<20>+ 70.9° (c = 0.67, ethanol).

Example 45

2.4 g of (S)-N-(3-nitrobenzylidene-acetoacetyl)-α-aminoisovaleric acid butyl ester and 0.92 g of amidinoacetic acid methyl ester hydrochloride [see Ann. Chem. 1977, 1895] dissolve in 6 ml abs. methanol and added dropwise under reflux with a

of 140 mg sodium and 6 ml abs. methanol prepared sodium methylate solution and heated for a further hour at reflux. The precipitated sodium chloride is filtered off, the filtrate evaporated under reduced pressure and the residue chromatographed on a medium pressure column in a 1:1 mixture of hexane and ethyl acetate. The amorphous 2-amino-1,4-dihydro-6-methyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-(n-butoxycarbonyl) thus formed )-2-methyl-1-propyl]-amide is an S,

4R: S, 4S diastereomer mixture and exhibits the following NMR data: 250 MHz FT-<1>H-NMR (CDCl 2 ) : 0.80 (2m, 6H, isopropyl-CH 3 ); 0.95 (2t, 3H, -C00-C-C-C-CH3); 1.34, 1.60 (2m, 4H, -COO-O CH 2 -CH 2 -C); 2.06 (m, 1H 1 -CHC 2 ); 2.10, 2.18 (2s, 6H, dihydropyridyl-CH 3 ); 2.62 (2s, 6H, -COOCH3); 4.1 (m, 2H,

-C00CH2-C-); 4.46 (m, 1H, -OOC-CH-N-CO-); 4.80, 4.86

(2s, 1H, 4-dihydropyridyl-H); 5.84, 5.98 (2d, 1H, -NH-); 6.35 (ls, 2H, -NH 2 ); 6.76, 6.90 (2d, 1H, -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:

Analogous to the method described in example 35, a mixture of 14.0 g of (S)-N-acetoacetyl-α-amino-isovaleric acid butyl ester, prepared analogously to Pharm. Acta Heiv. 38, 616 (1963), and 8.2 g of 3-nitrobenzaldehyde in 50 ml of toluene (S)-N-(3-nitrobenzylidene-acetoacetyl)-α-aminoisovaleric acid butyl ester.

Example 4 6

26.5 g 3-ethoxycarbonyl-2-diethoxymethyl-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-ethoxy-carbonyl-2 -methyl-1-propyl]-amide is dissolved in 160 ml of acetone and 26.5 ml of 6N hydrochloric acid is added. It is stirred for 1 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.

ester. The thus obtainable amorphous 3-ethoxycarbonyl-1,4-dihydro-2-formyl-6-methyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-ethoxycarbonyl-2-methyl -1-propyl]-amide is an S,4R : S,4S diastereomer mixture and shows the following NMR data: 250 MHz FT-<1>H-NMR (CDCl 3 ): 0.80 (2m, 6H, -C(CH 3 )2); 1.26 (2m, 6H, -CO0-C-CH3); 2.06 (m, 1H, -CHC2); 2.28, 2.36 (2s, 3H, dihydropyridyl-CH 3 ); 4.18 (m, 4H, -CO0-CH2-C); 4.53 (m, 1H, -OOC-CH-N-CO-); 5.00, 5.16 (2s, 1H, 4-dihydropyridyl-H); 5.72, 5.88 (2d, 1H, -NH-); 6.83, 6.90 (2s, 1H, -CO-NH-); 7.47, 7.70, 8.10, 8.18 (t, m, m, m, 4H, phenyl-H).

The starting material can be synthesized as follows:

A mixture of 29.0 g of (S)-N-(3-nitrobenzylidene-acetoacetyl)-α-amino-isovaleric acid ethyl ester (see Example 35), 17.4 g of 3-amino-4,4-diethoxy-crotonic acid- ethyl ester, 50 g molecular sieve (Union Carbide 3Å) and 160 ml abs. alcohol is heated 40 hours under reflux. 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-methyl- 1-propyl]-amide is immediately further reacted.

Example 4 7

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

acetic acid ethyl ester. The thus formed amorphous 3-ethoxy-carbonyl-1,4-dihydro-2-hydroxymethyl-6-methyl-4-(3-nitro-phenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-ethoxycarbonyl -2-methyl-1-propyl]-amide is an S,4R : S,4S diastereomer-

mixture and exhibits the following NMR data:

250 MHz FT-<1>H_NMR (CDCl-j): 0.74 (2m, 6H, -C(CH3)2); 1.28

(2m, 6H, -CO0-C-CH3); 2.06 (m, 1H, -CHC2); 2.26, 2.32 (2s,

3H, dihydropyridyl-CHJ -J ; 2.76, 2.96 (2m, 1H, -0H); 4.1

(m, 4H, -CO0-CH2-C-); 4.50 (m, 1H, -OC-CH-N-CO-); 4.68,

4.84 (2m, 2H, -CH2~O); 4.98, 5.02, (2s, 1H, 4-dihydropyridyl-H); 5.72, 5.98 (2d, 1H, -NH-); 6.96, 7.12 (2s, 1H, -CO-NH-); 7.46, 7.67, 8.05, 8.16 (t,t,m,m, 4H, phenyl-H).

Example 48

A mixture of 12.0 g of 3-ethoxycarbonyl-1,4-dihydro-2-formyl-6-methyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-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 2.5 hours at room temperature. It is then evaporated under reduced pressure and the residue is distributed between water and ethyl acetate. The organic phase is dried, evaporated and the oxime formed is reacted immediately further.

A mixture of 12.5 g of 3-ethoxycarbonyl-1,4-dihydro-2-hydroxy-iminomethyl-6-methyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1- ethoxycarbonyl-2-methyl-1-propyl]-amide,

12.9 g of N,N-dicyclohexylcarbodiimide and 50 ml of abs. pyridine is heated for 5 hours under reflux. The solution is then evaporated under reduced pressure, the residue is distributed between 1N hydrochloric acid and acetic acid ethyl ester and filtered off from the precipitated urea. The organic phase is washed with water and saline, dried and evaporated. The residue is chromatographed on a medium pressure column in a mixture of hexane and ethyl acetate. The thus formed amorphous 3-ethoxycarbonyl-2-cyano-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-ethoxycarbonyl-2-methyl -1-propyl]amide is an S,4R:S,4S diastereomer mixture and

exhibits the following NMR data:

250 MHz FT-<1>H-NMR (CDCl 3 ): 0.74 (2m, 6H, -C(CH 3 ) 2 ); 1.26 (m, 6H, -CO0-C-CH3); 2.05 (m, 1H, -CHC2); 2.24, 2.32 (2s, 3H, dihydropyridyl-CH 3 ); 4.2 (m, 4H, -CO0-CH2-C-); 4.50 (m, 1H, -OC-CH-N-CO-); 5.06, 5.10 (2s, 1H, 4-dihydropyridyl-H); 5.74, 5.86 (2d, 1H, -NH-); 6.26, 6.38 (2s, 1H, -CO-NH-); 7.50, 7.70, 8.14 (t, m, m, 4H, phenyl-H).

Example 4 9

In a completely analogous manner to example 26, the following compounds are also obtained in configurationally uniform form: a) (-)-([R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3- nitrophenyl)-pyridine-5-carboxylic acid-N-[(1S)-1-(2-furyl-methoxycarbonyl)-2-methyl-1-propyl]-amide; [alp0 = -38.4°

(c = 0.91, ethanol); m.p. 76-78°C.

b) (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-20 isopropyloxycarbonyl-2-methyl-1-propyl]-amide; [α]^ = -18.5 (c = 0.56, ethanol); m.p. 166-167°C. c) (4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylic acid-N-[(IS)-1-(tert-butyloxycarbonyl) -2-methyl-1-propyl]-amide; m.p. 163-164°C.

Claims (10)

1. Process for the preparation of compounds of formula I in which n stands for 1, 2 or 3, Ar means a carbocyclic or heterocyclic aryl residue, Ac means the acyl residue of an acid, Z stands for a residue -OR^ or -NRgRg, R^ means hydrogen, unsubstituted or substituted lower alkyl, a carbocyclic or heterocyclic aryl residue or free, etherified or esterified hydroxide, R2 and R^ independently of each other stand for hydrogen, unsubstituted or substituted lower alkyl, formyl or functionally converted formyl, carboxy or functionally converted carboxy, a carbocyclic or heterocyclic aryl residue or unsubstituted, mono- or disubstituted amino, R^ means hydrogen or lower alkyl, Rc and R, independently mean hydrogen, unsubstituted or substituted lower alkyl or a carbocyclic or heterocyclic aryl residue, R^, Rg and Rg independently mean hydrogen, unsubstituted or substituted alkyl or a carbocyclic or heterocyclic aryl radical, in which R 1 and R 2 together or R 1 and R 2 together can mean unsubstituted or substituted unsaturated lower alkylene, in which a carbon atom is optionally replaced by a heteroatom, in which R4 and R< . together, in the same way as R^ and R^ together and/or Rg and Rg together may mean, independently of each other, unsubstituted or substituted lower alkylene, in which one carbon atom may be replaced by a heteroatom, optical isomers of compounds of the formula I, mixtures of these optical isomers and salts of such compounds containing a salt-forming group, characterized in that mana) reacts with a compound of the formula II in which n<1> stands for 0, 1 or 2 and Rfa means an optionally activated carboxy group, with the proviso that R, differs from a residue C(=0)-Z, when n' stands for 1 or 2, with a connection with the formula III in which n" stands for 1, 2 or 3, and R|, R^ and R^ have the meaning given under formula I for R4, R^ and R^, may, however, be different from the residues R^, R^ or R ^ in formula II, with the proviso that the sum of n' and n" is not greater than 3, ora') in a connection with formula Ila where n! stands for 1, 2 or 3 and R is a transferable group in the residue C(=0)-Z, transfers this in the residue C(=0)-Z, or b) reacts 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 with formula VI, b <1> ) reacts completely analogously to method b) a compound of the formula Va with a compound of the formula VI, c) ring-closes a compound of formula VII in which one of the residues X and Y stands for the group with the formula -NH-R^ and the other is hydroxy or both means the group of the formula -NH-R^, or a tautomer thereof or a corresponding tautomer mixture, or d) reacts a compound with the formula Ar-CHO (IV) or a reactive functional derivative thereof with a compound with the formula VIII or a tautomer thereof or a corresponding tautomer mixture, oré) in a compound with the formula IX in which Acq means a residue in the group Ac transferable, this transfers in the group Ac, whereby in the above-mentioned starting substances with the formulas II to IX, Ila and Va, , which, provided they have salt-forming properties, can also be used in the form of their salts, the symbols n, Ar, Ac, , R2 , R^ , R4 / R^ , Rg and Z have the meanings given under formula I, and, if desired, converts a formed compound of formula I into another compound of formula I, and/or if desired, converts a formed salt into the free compound or into another salt, and/or, if desired, converts a formed free compound of formula I with salt-forming properties into a salt, and/or, if desired, splits a formed mixture of isomers or racemates into the individual isomers or racemates, and/or, if desired, resolve the formed racemates into the optical antipodes. 2. Method according to claim 1, characterized in that compounds with the formula I are prepared, in which n stands for 1, 2 or 3, Ar stands for a mono- or bicyclic, carbocyclic aryl residue or for a five- or six-membered, one to four ring nitrogen atoms, a ring oxygen or ring sulfur atom, or one or two ring nitrogen atoms together with a ring oxygen atom or a ring sulfur atom as a ring member containing, monocyclic heteroaryl residue , which optionally contains a fused benzo ring, and means in particular phenyl, naphthyl, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazolyte, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl , indolyl, isoindolyl, benzoxadiazolyl, benzthiadiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolinyl or isoquinolinyl, whereby in these residues ring nitrogen atoms may optionally be substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, cycloalkyl, phenyl, phenyl-lower alkyl, phenyl lower alkyl and/or phenyl lower alkylthio , whereby lower alkyl, phenyl, phenyl lower alkyl l, phenyl lower alkyl thio and/or phenyl lower alkylthio may optionally contain hydroxy, lower alkoxy, halogen lower alkyl oxy, lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl and/or cyan, the cyclic residues may also contain lower alkyl, which in turn may be substituted as indicated, as substituents, and/or may be substituted with hydroxy, lower alkyloxy, halolower alkyloxy, lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy, lower alkanoyloxy, halogen, nitro, amino, lower alkylamino, dilower alkylamino, N-lower alkyl-N-phenyl lower alkylamino, lower alkylene amino, oxal lower alkylenamino, thial lower alkylenamino and/or aza lower alkylenamino, in which the azanite nitrogen atom may be substituted with lower alkyl, phenyl or phenyl lower alkyl, whereby these substituents may contain hydroxy, lower alkoxy, halogen lower oxy, lower alkenyloxy, lower arealkynyloxy, lower alkylenedioxy, loweralkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-diloweralkylcarbamoyl and/or cyan as substituents, and/or may be substituted with loweralkanoylamino, azido, carboxy, lower alkoxycarbonyl, carbamoyl, N -lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl, cyan, sulfo, aminosulfonyl, lower alkylthio, lower alkylsulfinyl and/or lower alkylsulfonyl, and/or ring nitrogen atoms may optionally be substituted with lower alkoxycarbonyl or with lower alkyl, which may optionally contain as substituents hydroxy, lower alkoxy, halo-lower-alkoxy, lower-alkenyloxy, lower-alkynyloxy, lower-alkylenedioxy, lower-alkanoyloxy, halogen, carboxy, lower-alkoxycarbonyl, carbamoyl, N-lower-alkylcarbamoyl, N,N-di-lower-alkyl-carbamoyl or cyan, or may be substituted with hydroxy or oxido, the residue Ac stands for lower-alkanoyl, unsubstituted or with lower alkyl, lower alkoxy, nitro and/or r halogen substituted benzoyl, lower alkylsulfonyl, unsubstituted or with lower alkyl, lower alkoxy, nitro and/or halogen substituted phenylsulfonyl, lower alkoxycarbonyl, hydroxyl lower real oxycarbonyl, lower alkoxy lower real oxycarbonyl, amino lower real oxycarbonyl, lower alkylamino lower real oxycarbonyl, N,N-di-lower alkylamino lower real oxycarbonyl, N-lower alkyl-N-phenyl lower alkyl-amino lower real oxycarbonyl, N,N-lower alkyleneamino-lower oxycarbonyl, morpholino lower oxycarbonyl, thiomorpholino lower oxycarbonyl, piperazino-lower oxycarbonyl, 4-lower alkyl-piperazino-lower oxycarbonyl, unsubstituted or with lower alkyl, lower alkoxy, nitro and/or halogen substituted phenyl, thienyl, furyl, pyrryl or pyridyl -lower alkyloxycarbonyl, lower alkenyloxy or lower alkynyloxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-diloweralkylcarbamoyl, N-hydroxycarbamoyl, N,N-lower alkylenecarbamoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazinocarbonyl, 4-la verealkyl-piperazinocarbonyl, 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 means a residue -OR^ or -NRgR^ , R^ means hydrogen; lower alkyl, which is optionally substituted with lower alkylamino, dilower alkylamino, lower alkyleneamino, morpholino, thiomorpholino, piperazino, which on a nitrogen atom optionally carries lower alkyl or lower alkanoyl as substituents, carboxy, functionally converted carboxy, lower alkoxy, lower alkoxy-lower alkoxy, or phenyl, which in turn optionally contains lower alkyl, lower alkoxy, halogen and/or nitro as substituents, or is substituted with N-pyrrolyl, N-imidazolyl, N-pyrazolyl, N-indolyl or N-isoindolyl; phenyl, which is optionally substituted as a phenyl lower alkyl radical R 1 ; hydroxy, lower alkoxy or phenyl lower alkyl, R,> - and R^ independently of each other mean hydrogen, lower alkyl, which is optionally substituted by hydroxy, lower alkoxy, which optionally contains amino, lower alkylamino, dilower alkylamino or acylamino as substituents, acyloxy or phenyl, means formyl, dilower alkyl acetal or -dithioacetal, lower alkylene acetal or -dithioacetal, functionally converted carboxy; phenyl, optionally containing lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, halogen, nitro, amino, lower alkylamino, dilower alkylamino, lower alkanoylamino, carboxy, functionally converted carboxy and/or lower alkylthio as substituents; pyrryl, furyl, thienyl or pyridyl, whereby these residues are optionally substituted as a phenyl residue R 2 or R 2 ; amino, lower alkylamino or dilower alkylamino, R^ means hydrogen or lower alkyl, R^ means hydrogen, unsubstituted or with free or etherified hydroxy, free or etherified mercapto, which may optionally be oxidized, with carboxy, functionally converted carboxy, with amino, which optionally on its side may contain lower alkyl, carboxy, functionally converted carboxy or acyl as substituents, with a mono- or bicyclic carbocyclic aryl residue or a five- or six-membered heteroaryl residue according to the above definition of Ar substituted lower alkyl, unsubstituted or with free or etherified hydroxy , lower alkyl, nitro, amino., lower alkylamino, dilower alkylamino, lower alkanoylamino and/or halogen substituted phenyl or means an optionally similarly substituted monocyclic five- or six-membered heteroaryl radical according to the definition given above for Ar, R^ means hydrogen, lower alkyl, unsubstituted or with free or etherified hydroxy, lower alkyl, nitro, ami no, lower alkylamino, dilower alkylamino, lower alkanoylamino and/or halogen substituted phenyl lower alkyl, unsubstituted or as a phenyl lower alkyl radical R^ substituted phenyl or an optionally similarly substituted monocyclic five- or six-membered heteroaryl radical, and R_, RQ and Rn independently mean lol y of each other hydrogen; alkyl, which is optionally substituted with amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, oxa-, thia- or azalower alkyleneamino, in which the aza nitrogen optionally carries lower alkyl or lower alkanoyl as substituents, acylamino, free or etherified hydroxy or a carbocyclic aryl residue or heteroaryl residue as defined above for the group Ar; or means a carbocyclic aryl radical or heteroaryl radical as defined above for the group Ar, in which R 1 and R 2 together or R 2 and R 2 together can mean C 1 -C 2 -lower alkylene, in which with C2- or The C6 carbon atom of the 1,4-dihydropyridine ring directly bonded carbon atom is optionally replaced by an oxygen, sulfur or nitrogen atom, which is substituted by hydrogen or lower alkyl, in which R^ and R^ together may mean unsubstituted or with free or etherified hydroxy . these residues are optionally substituted on carbon atoms with free or etherified hydroxy, amino, lower alkylamino, dilower alkylamino, halogen, carboxy and/or functionally converted carboxy and on the aza nitrogen optionally substituted with lower alkyl, and in which Rg and Rg together can mean the lower alkylene, aza- , oxa- or thilower alkylene, whereby these residues are optionally substituted on carbon atoms with free or etherified hydroxy, amino, lower alkylamino, dilower alkylamino, halogen, carboxy, functionally converted carboxy or a five- or six-membered monoaza-, diaza- or triaza-heteroaryl residue, which is optionally fully or partially saturated and optionally substituted on the carbon atoms with oxo and on the azanite nitrogen atoms optionally with lower alkyl or phenyl, which in turn may contain lower alkyl, halogen, lower alkoxy and/or nitro as substituents; and is substituted on the aza nitrogen optionally with lower alkyl, which in turn optionally contains a carbocyclic aryl residue or heteroaryl residue as defined above for groups Ar and/or contains free or etherified hydroxy, acyloxy, amino, lower alkylamino and/or dilower alkylamino as substituents; with 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. 3. Method according to claim 1, characterized in that compounds of formula 1 are prepared, in which n stands for 1, 2 or 3, Ar means phenyl, which is optionally substituted with lower alkyl, phenyl, phenyl lower alkyl, phenyl lower alkyl oxy and/or phenyl lower alkyl thio, whereby such residues in turn may contain hydroxy, lower alkoxy, lower alkylene dioxy, halogen, carboxy, lower alkoxy carbonyl and/or cyan, the cyclic residues may also contain lower alkyl as substituents . lower alkylsulfonyl, or means pyrryl, furyl, thienyl, pyridyl, benzoxadiazolyl or benzthiadiazolyl, whereby these residues are optionally substituted as a phenyl residue Ar, and contains in particular lower alkyl, lower alkoxy, halogen and/or optionally with lower alkyl, lower alkoxy, halogen and/or nitro substituted phenyl as substituents, the residue Ac stands for low eralkanoyl, loweralkylsulfonyl, loweralkoxycarbonyl, hydroxy-loweralkoxycarbonyl, loweralkoxyloweralkoxycarbonyl, N,N-diloweralkylamino-loweralkoxycarbonyl, N-loweralkyl-N-phenyl-loweralkylamino- loweralkoxycarbonyl, N,N-loweralkyleneamino-loweralkoxycarbonyl, (4-morpholino)-loweralkoxy- • carbonyl, lower alkenyloxy or lower alkynyloxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-diloweralkylcarbamoyl, N,N-loweralkylenecarbamoyl, 4-morpholinocarbonyl or 4-loweralkyl-1-piperazinocarbonyl, Z means a residue -OR^ or -NRgR^ , R^ stands for hydrogen, lower alkyl, dilower alkylaminolower alkyl, lower alkylene-amino lower alkyl, (4-morpholino)-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or lower alkoxy lower real oxy-lower alkyl, whereby di lower alkylamino, lower alkyleneamino respectively. 4-morpholino is separated by at least two carbon atoms from the ring nitrogen atom, or stands for phenyl-lower alkyl, phenyl, hydroxy or lower alkoxy, R2 and R^ independently mean lower alkyl, which is optionally substituted with hydroxy, lower alkoxy, which optionally contains amino, lower alkylamino or dilower alkylamino as substituents, lower alkanoyloxy or phenyl, formyl, dilower alkyl acetal or -dithioacetal, lower alkylene acetal or -dithioacetal, cyan, phenyl, thienyl or amino, R^ means hydrogen or lower alkyl, R^ means hydrogen, unsubstituted or with hydroxy, lower alkoxy, mercapto, lower alkylthio, carboxy, carbamoyl, amino, lower alkanoylamino, carbamoylamino, guanidino, with phenyl, which in turn may be substituted with hydroxy and/or halogen, imidazolyl or indolyl substituted lower alkyl, unsubstituted or with hydroxy, lower alkoxy, lower alkyl, nitro, amino, lower alkylamino, dilower alkylamino and/or halogen substituted phenyl or unsubstituted ert or in the same way as stated for a phenyl residue R< - substituted. pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, R^ means hydrogen, lower alkyl, phenyl lower alkyl, unsubstituted or with hydroxy, lower alkoxy, lower alkyl, nitro, amino, lower alkylamino, dilower alkylamino and/or halogen substituted phenyl lower alkyl or means an unsubstituted or in the same way as indicated for a phenyl lower alkyl residue Rg substituted residue of the group phenyl, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl , furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, and , Rg and Rg independently represent hydrogen, lower alkyl or with amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, oxa -, thia- or aza-lower alkyleneamino, in which the aza-nitrogen is optionally substituted with lower alkyl, lower alkanoy lamino, hydroxy, lower alkoxy or with phenyl, which may be unsubstituted or in turn substituted with amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, hydroxy, lower alkoxy, halogen and/or nitro, or means with pyrryl, furyl, thienyl or pyridyl, whereby these groups can be substituted in the same way as phenyl, substituted lower alkyl or phenyl, pyrryl, furyl, thienyl or pyridyl, whereby these groups can be substituted in the same way as a phenyl lower alkyl residue R_, RQ or R~, in which R and R ^ together or R^ and R^ together can mean C^ -C^ -lower alkylene, in which with C2 or The C6 carbon atom of the 1,4-dihydropyridine ring directly bonded carbon atom is optionally replaced by an oxygen, sulfur or nitrogen atom, which is substituted by hydrogen or lower alkyl, in which R4 and R^ together can mean unsubstituted or hydroxy-substituted C^ -C^ -lower alkylene, C-j-C^ -oxa-or C^C^ -thialower alkylene, in which Rj- and R^ together can mean lower alkylene with 2 to 5 chain carbon atoms or aza lower alkylene with 3 or 4 chain carbon atoms, whereby these residues can be unsubstituted or substituted with hydroxy, lower alkoxy, amino, lower alkyleneamino or dilower alkylamino, and in which Rg and Rg together can mean C2 -C.y -lower alkylene, C.sub.2 -C.sub.2 -aza-, C.sub.2 -C.sub.2 -oxa- or C.sub.2 -C.sub.3 -thial lower alkylene, whereby this residue optionally on carbon atoms is substituted with hydroxy, lower alkoxy, amino, lower alkylamino, dilower alkylamino or five- or six-membered monoaza- or diazaheterocyclyl, which is optionally substituted on carbon atoms with oxo and on azanitrogen- atoms optionally substituted with lower alkyl or phenyl, which in turn may contain lower alkyl, halogen, lower alkoxy and/or nitro as substituents, and is substituted on the azanite nitrogen optionally with lower alkyl, which in turn may be substituted with phenyl, pyrryl, furyl, thienyl and/or pyridyl, whereby these residues themselves may optionally contain lower alkyl, hydroxy, lower alkoxy', halogen and/or nitro as substituents, and/or may be substituted with hydroxy , lower alkoxy, lower alkanoyloxy, amino, lower alkylamino and/or dilower alkylamino; with 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 the formula I, mixtures of these optical isomers and salts of such compounds with salt-forming groups. Method according to claim 1, characterized in that compounds of the formula I are prepared, in which n stands for 1 or 2, Ar stands for phenyl, thienyl, furyl or benzoxadiazolyl, whereby these groups are optionally mono-, di- or tri-substituted with lower alkyl , lower alkoxy, halolower alkyl, phenyl lower alkyl thio, lower alkylenedioxy, halogen, trifluoromethyl, nitro, lower alkanoylamino and/or cyan, the residue Ac means lower alkanoyl, lower alkylsulfonyl, lower alkoxycarbonyl, 2-lower alkyl-lower oxycarbonyl, N,N-dilower alkylamino-lower alkyl, N-lower alkyl- N-phenylloweralkylamino-loweralkyloxycarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-dilaverealkylcarbamoyl, N,N-loweralkylenecarbamoyl or 4-morpholinocarbonyl, Z stands for a residue -OR7 or -NRgRg, R^ means hydrogen, lower alkyl, 2-(dilower alkylamino)-lower alkyl, 2-(lower alkyleneamino)-lower alkyl, 2-(4-morpholino)-lower alkyl, carboxy lower alkyl or lower alkoxy lower alkyl -lower alkyl, R2 and R^ independently of each other mean lower alkyl, hydroxylower alkyl, cyan or amino, R. means hydrogen or lower alkyl, R,, means hydrogen, unsubstituted or with hydroxy, lower alkoxy, mercapto, lower alkylthio, carboxy, carbamoyl, amino, carbamoylamino , guanidino, phenyl, which in turn may be substituted with hydroxy, or imidazol-4-yl or indol-3-yl substituted lower alkyl or phenyl, thiazolyl, imidazolyl, furyl, thienyl, pyridyl or pyrimidinyl, whereby these residues may optionally be substituted with hydroxy, lower alkoxy and/or amino, Rfi means hydrogen, lower alkyl . and R_ means independent o /city of each other hydrogen or unsubstituted or with amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, oxa- or azalower alkyleneamino, in which the aza nitrogen is optionally substituted with lower alkyl, hydroxy, lower alkoxy, phenyl, which may be unsubstituted or in turn substituted with amino, hydroxy, lower alkoxy and/or halogen, or with thienyl or pyridyl, whereby these groups may be substituted in the same way as phenyl, substituted lower alkyl, in which R 4 and R 1 can together mean the C 1 -C 2 -lower alkylene, in which R 1 - and R ^ together may mean C 2 -C 1 -lower alkylene or C 2 -aza lower alkylene and in which Rg and Rg together may mean C 2 -C 3 -lower alkylene, which is optionally substituted with 2-imidazolidinon-1-yl, which in the 3-position may contain phenyl or lower alkyl as substituents, the C₁ -oxa- or C₁ -aza lower alkylene, whereby the aza nitrogen may be substituted with lower alkyl, which in turn is unsubstituted or mono- or disubstituted with phenyl, which can n contain lower alkyl, lower alkoxy, halogen and/or nitro as substituents, thienyl and/or pyridyl, or may be substituted with benzoyl, furanylcarbonyl, phenyl or lower alkoxyphenyl, optical isomers of compounds of formula I, mixtures of these optical / isomers and pharmaceutically usable salts of such compounds with salt-forming groups. 5. Method according to claim 1, characterized in that compounds with the formula I are prepared, in which n stands for 1 or 2, Ar stands for unsubstituted or with lower alkyl, lower alkoxy, halolower oxy, benzyloxy, benzylthio, halogen, trifluoromethyl, nitro and/or cyano mono- or disubstituted phenyl, 2-or 3-thienyl or 2,1,3-benzoxadiazol-4-yl, the residue Ac means lower alkylsulfonyl or lower alkoxycarbonyl, Z stands for a residue -OR^ or -NRgRg, R^ means hydrogen, further 2-(4-morpholino)-ethyl, R2 means lower alkyl, hydroxymethyl, cyan or amino, R^ stands for lower alkyl, R^ means hydrogen or lower alkyl, R,- means hydrogen, unsubstituted or with phenyl, which in turn may be substituted with hydroxy, substituted lower alkyl, phenyl or unsubstituted or amine-substituted thiazolyl, Rg means hydrogen, lower alkyl or phenyl, stands for hydrogen, lower alkyl or lower alkyl substituted with phenyl, amino, lower alkylamino, dilower alkylamino, 4-morpholino, 1-piperazino, which in turn may contain lower alkyl as substituents on the 4-nitrogen, or lower alkoxy, Rg and Rg independently mean hydrogen , unsubstituted or with lower alkoxy, phenyl or pyridyl substituted lower alkyl, in which R^ and R,- together can represent 1,3-propylene, in which R,- and Rg together can stand for 1,5-pentylene, and in which Rg and Rg together can mean 1,5-pentylene, 3-(3-phenyl-2-imidazolidinon-1-yl)-1,5-pentylene, 3-(2-imidazolidinon-1-yl)-1,5-pentylene or 3- oxa- or 3-aza-1,5-pentylene, whereby the aza nitrogen is optionally substituted with lower alkyl, benz yl, diphenylmethyl, whereby the residues 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 usable salts of such compounds with salt-forming groups. 6. Process according to claim 1, characterized in that compounds of formula I are prepared, in which n stands for 1, Ar means 2- or 3-nitro-phenyl, 2- or 3-difluoromethoxy-phenyl, 2- or 3-methyl-phenyl, 2- or 3-trifluoromethyl-phenyl, 2,3-dimethyl-phenyl, 2,3-dichlorophenyl, 2- or 3-benzyloxy-phenyl or 2- or 3-benzylthiophenyl, Ac means lower alkoxycarbonyl, Z stands for a residue -OR^ or -NRgRg, R1 is hydrogen, R2 and R^ independently mean lower alkyl, R^ is hydrogen, R^ means lower alkyl or phenyl, Rg means hydrogen, R^ means unsubstituted or with 4-morpholino, 1-piperazino or 4- lower alkyl-1-piperazino substituted lower alkyl, Rg and Rg stand independently of each other for hydrogen, unsubstituted or with phenyl or pyridyl substituted lower alkyl, and in which Rg and Rg together can mean 3-aza-1,5-pentylene, in which the aza nitrogen is optionally substituted with benzyl or diphenylmethyl, optical isomers of compounds with formal, mixtures of these optical isomers and pharmaceutically usable salts of such compounds with salt-forming groups. 7. Method according to claim 1, characterized in that one prepares (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5 -carboxylic acid-N-[(IS)-1-ethoxycarbonyl-2-methyl-1-propyl]-amide or pharmaceutically acceptable salts thereof. Process according to claim 1, characterized in that one prepares (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-isopropoxycarbonyl-4-(3-nitro-phenyl)-pyridine -5-carboxylic acid-N-[(IS)-1-ethoxycarbonyl-2-methyl-1-propyl)-amide or pharmaceutically acceptable salts thereof. 9. Process according to claim I, characterized in that one prepares (-)-(4R)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxy -N-[(1S)-1-(n-butoxycarbonyl)-2-methyl-1-propyl]-amide or pharmaceutically acceptable salts thereof. 10. Process for the production of pharmaceutical preparations, characterized in that a compound of formula I obtained according to the method according to claim 1 or a pharmaceutically usable salt of such a compound is mixed with a pharmaceutically usable carrier material.