WO1985000169A1 - 1,4-dihydropyridine derivatives, production thereof and pharmaceutical preparations containing them - Google Patents

Abstract

1,4-dihydropyridine-3,5-dicarbonic acid esters having the formula (I), wherein R1? is hydrogen, a cyclo-alkyl comprising from 3 to 7 atoms of carbon or optionally a substituted alkyl comprising from 1 to 6 atoms of carbon; R2? and R5? represent independently from each other a hydrogen or an alkyl comprising from 1 to 6 atoms of carbon; R3? is an alkyl comprising from 1 to 12 atoms of carbon or independently -AR4? described hereunder, proportion included; R4? is a hydroxy, an alkoxy comprising from 1 to 12 atoms of carbon, -OCOR6?, -NR7?R8? or -NB?; A is an alkylene comprising from 2 to 14 atoms of carbon; Q is an annulate fully unsaturated ring system, comprising at least 2 different ring hetero atoms, and having an aromatic character. Production thereof and pharmaceutical preparations containing them.

Description

 1,4-DIHYDROPYRIDINE OERIVATES, THEIR PRODUCTION AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME

The present invention relates to 1,4-dihydropyridine derivatives, their preparation and pharmaceutical preparations containing them.

The invention relates in particular to the compounds of the formula I.

wherein

R _{1 is} hydrogen, cycloalkyl of 3 to 7 carbon atoms; or optionally substituted alkyl having 1 to 6 carbon atoms;

R ₂ and R ₅ independently of one another are hydrogen or alkyl having 1 to 6 carbon atoms;

R ₃ for alkyl having 1 to 12 carbon atoms or independently has the meaning given below for -AR ₄ , including the proviso; R ₄ stands for: hydroxy; Alkoxy of 1 to 12 carbon atoms; -OCOR ₆ ; -NR ₇ R ₈ ; or -N _B ; wherein

R _{6 represents} : alkyl having 1 to 6 carbon atoms; Phenyl, phenylalkyl with 7 to 12 carbon atoms or bisphenylalkyl with 13 to 18 carbon atoms, these three

Residues optionally in the phenyl rings are mono- or identical or different di- or identical or different trisubstituted by alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, hydroxyl or halogen with an atomic number from 9 to 53; a 5-membered heteroaryl radical with 1 heteroatom from the series nitrogen, oxygen and sulfur or 2 heteroatoms from the series nitrogen and either nitrogen, oxygen or sulfur; or a 6-membered heteroaryl radical with 1 to 4 nitrogen atoms;

R _{7 represents} hydrogen or has the meaning given above for R ₆ ;

Ring, der gegebenenfalls, falls er gesättigt und 6- oder 7-gliedrig ist, ein weiteres Heteroglied aus der Reihe Sauerstoff, Schwefel und =NR₁₀ enthält, worin R₁₀ entweder Wasserstoff bedeutet oder die oben fürR ₈ stands for: hydrogen; Alkyl of 1 to 6 carbon atoms; or -COR ₉ , in which R _{9 has} the meaning given above for R ₆ ; means: a 5-, 6- or 7-membered heterocyclic

Ring which, if it is saturated and 6 or 7-membered, contains a further hetero member from the series oxygen, sulfur and = NR ₁₀ , in which R _{10 is} either hydrogen or the above for

R ₆ has the meaning given;

A represents alkylene of 2 to 14 carbon atoms; and

'₇R'₈ bedeutet, worinQ represents a fused, completely unsaturated ring system with at least 2 different ring heteroatoms in total and with an aromatic character; with the proviso that if R _{4 is} hydroxy; Alkoxy of 1 to 5 carbon atoms; as defined above or -NR

' ₇ R' ₈ means where

R ₇ 'represents: hydrogen, alkyl having 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and

R _{8 represents} hydrogen or alkyl of 1 to 6 carbon atoms; then A stands for alkylene with 7 to 14 carbon atoms. and their ammonium salts in which R _{4 is} one of the tertiary amino groups defined above for R ₄ and is quaternized with a group of the formula AlkY, in which Alk is alkyl having 1 to 4 carbon atoms and Y is the rest of an acid.

These compounds are hereinafter referred to briefly as "the compounds according to the invention".

Some of the compounds according to the invention fall under the very general disclosure of Bayer EP 42089.

Some of the compounds according to the invention also fall under the very general disclosure of Bayer EP 88276 and Takeda

EP 94159. These publications took place in September 1983 and November 1983 respectively, ie on a date later than that claimed for the compounds according to the invention. Priority date, namely June 21, 1983, However, none of the compounds specifically disclosed in the above-mentioned European publications fall within the scope of the present invention.

Weather disclosures relating to compounds related to the compounds of the invention provide e.g. represents:

Sandoz EP 150 Sandoz DOS 29 49 464 Sandoz DOS 29 49 491 Sandoz BE 890 311 Bayer EP 7T 819 Fisons EP 80 220 Sandoz DOS 33 20 616.

The publications mentioned above do not suggest any specific compounds similar to the compounds according to the invention. The compounds according to the invention have a particularly interesting pharmacological profile.

A preferred group of compounds according to the invention consists of the compounds of the formula Ia

worin

wherein

R stands for: hydrogen; Alkyl of 1 to 4 carbon atoms; Alkoxy of 1 to 4 carbon atoms; Alkylthio of 1 to 4 carbon atoms; Alkylsulfonyl of 1 to 4 carbon atoms; Halogen with an atomic number from 9 to 35; Trifluoromethyl; Nitro; or hydroxy; means: hydrogen; Alkyl of 1 to 6 carbon atoms; Alkenyl having 3 to 6 carbon atoms, the double bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the double bond; Alkynyl having 3 to 6 carbon atoms, the triple bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the triple bond; Cycloalkyl of 3 to 7 carbon atoms; Cycloalkylalkyl of 4 to 8 carbon atoms; Hydroxyalkyl of 2 to 6 carbon atoms, the hydroxy part being separated from the nitrogen atom by at least 2 carbon atoms; Alkoxyalkyl of 2 to 6 carbon atoms; or phenylalkyl with 7 to 9 carbon atoms or phenyl alkenyl with 9 to 12 carbon atoms, the double bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the double bond, and the two latter radicals optionally being mono- or identical or different in the phenyl ring or are trisubstituted identically or differently, by independently of one another alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halogen having an atomic number of 9 to 35 or hydroxy; Alkylcarbonyloxyalkyl having 2 to 6 carbon atoms in the alkylcarbonyl and in the alkylene part, and wherein oxygen is separated from the nitrogen atom by at least 2 carbon atoms; Dialkylaminoalkyl with independently 1 to 6 carbon atoms in the alkyl part and with 2 to 6 carbon atoms in the alkyl part, and wherein the amino group through at least 2 carbon atoms are separated from the nitrogen atom; or morpholinoalkyl having 2 to 6 carbon atoms in the alkylene part, the morpholino part being separated from the nitrogen atom by at least 2 carbon atoms;

angegebene Bedeutung besitzt; steht für: Hydroxy; Alkoxy mit 1 bis 12 Kohle

nstoffatomen;

; oder wie oben definiertes worin

und

die oben für R₇, R₇ bzw. R₈ angegebene Bedeutung besitzen;R ₂ and R _{5 have} the meaning given above; for alkyl with 1 to 12 carbon atoms or independently those below for

has the meaning given; stands for: hydroxy; Alkoxy with 1 to 12 carbon

natom atoms;

; or as defined above wherein

and

have the meaning given above for R ₇ , R ₇ or R ₈ ;

A ^a denotes alkylene with 2 to 14 carbon atoms; and

Hydroxy oder wie oben definiertes bedeutet,

dann A^a für Alkylen mit 7 bis 14 Kohlenstoffatomen steht, und b) falls

f xy mit 1 bis 12 Kohlenstoffatomen oder -

steht, worin ι

bedeutet: Wasserstoff; Alkyl mit 1 bis 6 Kohlenstoffatomen; unsubstituiertes Phenyl; oder unsubstituiertes Phenylalkyl mit 7 bis 10 Kohlenstoffatomen; und für Wasserstoff oder Alkyl mit 1 bis 6 Kohlen

stoffatomen steht, dann A^a Alkylen mit 9 bis 14 Kohlenstoffatomen bedeutet; und ihre Ammoniumsalze, in denen für. eine der oben für

definierten tertiären Aminogruppen steht und quaternisiert ist mit einer wie oben definierten Gruppe der Formel AlkY.X represents oxygen or sulfur; with the provisos that, a) if

Hydroxy or as defined above means

then A ^{a stands} for alkylene with 7 to 14 carbon atoms, and b) if

f xy with 1 to 12 carbon atoms or -

is where ι

means: hydrogen; Alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and for hydrogen or alkyl with 1 to 6 carbons

is atoms, then A ^{a is} alkylene having 9 to 14 carbon atoms; and their ammonium salts, in which for. one of the above for

defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.

nicht für Alkoxy. In einer anderen U ruppe bedeuten oder wie oben definiertes

In a subgroup of compounds of the formula Ia, A ^a denotes alkylene with 9 to 14 carbon atoms. Another subgroup says

not for alkoxy. Mean in another group or as defined above

A preferred group of compounds of the formula Ia consists of the compounds of the formula Iaa

wherein

, R₂, R_e und X die oben angegebene Bedeutung besitzen, für Alkyl mit 1 bis 6 Kohlenstoffatomen steht; die oben für

angegebene Bedeutung besitzt; und

Alkylen mit 2 bis 14 Kohlenstoffatomen bedeutet; mit den Massgaben, dass a) falls

tydroxy oder wie oben definiertes bedeutet,

dann A^aa für Alkylen mit 7 bis 14 Kohlenstoffatomen steht; und b) falls für Alkoxy mit 1 bis 12 Kohlenstoffatomen oder

R,

, R ₂ , R _e and X have the meaning given above, represents alkyl having 1 to 6 carbon atoms; the above for

has the meaning given; and

Alkylene having 2 to 14 carbon atoms; with the provisos that a) if

tydroxy or as defined above means

then A ^{aa represents} alkylene with 7 to 14 carbon atoms; and b) if for alkoxy having 1 to 12 carbon atoms or

und obige Bedeutung besitzen, dann A^aa Alkylen mit 9 bis 14 Kohlenstoffatomen bedeutet; und ihre Ammoniumsalze, in denen

für eine der oben für

definierten tertiären Aminogruppen steht und quaternisiert ist mit einer wie oben definierten Gruppe der Formel AlkY.- 'stands in what

and have the above meaning, then A ^aa denotes alkylene having 9 to 14 carbon atoms; and their ammonium salts, in which

for one of the above for

defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.

In a subset of compounds of formula Iaa means

A ^aa alkylene with 9 to 14 carbon atoms. In another

nicht für Alkoxy. In einer anderen Untergruppe steht für - oder wie oben definiertes

Subgroup stands.

not for alkoxy. Another subgroup stands for - or as defined above

Another preferred group of compounds of the formula Ia consists of the compounds of the formula lab

wherein

R, R ₂ , R ₅ and X have the above meaning.

hängig die hierunter für

angegebene Bedeutung besitzt; steht für: Hydroxy Alkoxy mit 1 bis 12 Kohlenstoffatomen;

-OCOR ., oder ; worin

obige Bedeutung besitzen; undAlkyl with 1 to 12 carbon atoms means or unab¬

pending the below for

has the meaning given; stands for: hydroxy alkoxy with 1 to 12 carbon atoms;

-OCOR., Or; wherein

have the above meaning; and

Hydroxy bedeutet, dann A für Alkylen mit 7 bis 14 Kohlenstoffatomen steht; und b) falls

für Alkoxy mit 1 bis 12 Kohlenstoffatomen oder

steht, worin und ' obige Bedeutung

besitzen, dann A^ab Alkylen mit 9 bis 14 Kohlenstoffatomen bedeutet; und ihre Ammoniumsalze, in denen

für eine der oben für

definierten tertiären Aminogruppen steht und quaternisiert ist mit einer wie oben definierten Gruppe der Formel AlkY.A ^{ab is} alkylene of 2 to 14 carbon atoms; with the provisos that a) if

Is hydroxy, then A is alkylene of 7 to 14 carbon atoms; and b) if

for alkoxy with 1 to 12 carbon atoms or

stands in what and 'meaning above

hold, then A represents alkylene having ^from 9 to 14 carbon atoms; and their ammonium salts, in which

for one of the above for

defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.

nicht für Alkoxy. In einer anderen Untergruppe . bedeuten

und

wie oben definiertes

.In a subgroup of compounds of formula lab A represents alkylene having ^from 9 to 14 carbon atoms. Another subgroup says

not for alkoxy. In another subgroup. mean

and

as defined above

,

Another preferred group of compounds of the formula Ia consists of the compounds of the formula Iaaa

worin

wherein

Alkyl mit 1 bis 6 Kohlenstoffatomen bedeutet;R ₁ , R ₂ , R ₅ and X have the above meaning,

Means alkyl of 1 to 6 carbon atoms;

oder worin obige Bedeutung

besitzen? unR ₄ ^aa for: hydroxy; Alkox hydrocarbon atoms;

or where the above meaning

have? U.N

Hydroxy bedeutet, dann A^aaa für Alkylen mit 7 bis 14 Kohlenstoffatomen steht; und b) falls für Alkoxy mit 1 bis 12 Kohlenstoffatomen oder

steht, worin

obige Bedeutung besitzen, dann A^aaa Alkylen mit 9 bis 14 Kohlenstoffatomen bedeutet; und ihre Ammoniumsalze, in denen

für eine der oben für definierten tertiären Aminogruppen steht und quaternisiert ist mit einer wie oben definierten Gruppe der Formel AlkY.A ^{aaa is} alkylene of 2 to 14 carbon atoms; with the provisos that a) if

Is hydroxy, then A ^{aaa is} alkylene of 7 to 14 carbon atoms; and b) if for alkoxy having 1 to 12 carbon atoms or

stands in what

have the above meaning, then A ^{aaa is} alkylene having 9 to 14 carbon atoms; and their ammonium salts, in which

stands for one of the tertiary amino groups defined above and is quaternized with a group of the formula AlkY as defined above.

nicht für Alkoxy, In anderen Unter

gruppe bedeutet

wie ohen definiertes .In a subgroup of compounds of the formula Iaaa, A ^{aaa means} alkylene having 9 to 14 carbon atoms. Another subgroup says

not for alkoxy, in other sub

group means

as defined above.

Wasserstoff oder Alkyl mit 1 bis 4 Kohlenstoffatomen, vorzugsweise Wasserstoff oder Methyl, insbesondere Wasserstoff bedeutet; diejenigen, in denen R₂ und R₅ Wasserstoff oder Alkyl mit 1 bis 4 Kohlenstoffatomen bedeuten, insbesondere Methyl; diejenigen, in denen R für Wasserstoff steht; und diejenigen, tn denen X für Sauerstoff steht; und deren Kombinationen;Further groups and subgroups of compounds according to the invention are the compounds of the formula Ia, laa, lab and Iaaa in which

Is hydrogen or alkyl having 1 to 4 carbon atoms, preferably hydrogen or methyl, in particular hydrogen; those in which R ₂ and R _{5 are} hydrogen or alkyl with 1 to 4 carbon atoms, in particular methyl; those in which R is hydrogen; and those where X is oxygen; and their combinations;

and optionally their corresponding quaternary salts as defined above.

Another preferred group of compounds according to the invention consists of the compounds of the formula Ib

worin

wherein

Alkyl mit 1 bis 12 Kohlenstoffatomen bedeutet oder unabhängig die hierunter für

angegebene Bedeutung besitzt;

steht für: Hydroxy; Alkoxy mit 1 bis 12 Kohlenstoffatomen;

oder wie oben definiertes

worin

die oben für R₆, R₇ bzw. R₈ angegebene Bedeutung besitzen; undR ₁ , R ₂ , R ₅ and Q have the above meaning;

Alkyl with 1 to 12 carbon atoms means or independently the below for

has the meaning given;

stands for: hydroxy; Alkoxy of 1 to 12 carbon atoms;

or as defined above

wherein

have the meaning given above for R ₆ , R ₇ or R ₈ ; and

definierten tertiären Aminogruppen steht und quaternisiert ist mit einer wie oben definierten Gruppe der Formel AlkY. In einer Untergruppe von Verbindungen der Formel Ib steht

nicht für Alkoxy, In einer anderen Untergruppe bedeuten

und

oder wie oben definiertes

A represents alkylene of 9 to 14 carbon atoms; and their ammonium salts, in which for one of the above for

defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above. In a subset of compounds of formula Ib

not for alkoxy, mean in another subgroup

and

or as defined above

A preferred group of compounds of the formula Ib consists of the compounds of the formula Iba

wherein

, R₅, A^b und Q obige Bedeutung besitzen und Alkyl mit 1 bis 6 Kohlenstoffatomen bedeutet; und ihre Ammoniumsalze, in denen

für eine der oben für

definierten tertiären Aminogruppen steht und quaternisiert ist mit einer wie oben definierten Gruppe der Formel AlkY.R ₁ , R ₂ ,

, R ₅ , A ^b and Q are as defined above and are alkyl having 1 to 6 carbon atoms; and their ammonium salts, in which

for one of the above for

defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.

nicht für Alkoxy. In einer weiteren Untergruppe bedeutet

oder wie oben definiertes

Eine weitere bevorzugte Gruppe von Verbindungen der Formel Ib besteht aus den Verbindungen der Formel IbbIn a subset of compounds of the formula Iba

not for alkoxy. In another sub-group means

or as defined above

Another preferred group of compounds of the formula Ib consists of the compounds of the formula Ibb

worin

wherein

angegebene Bedeutung besitzt; bedeutet: Hydroxy; Alkoxy mit 1 bis 12 Kohlenstoffatomen; oder - worin

obige Bedeutung besitzen; und ihre Ammoniumsalze, in denen für eine der oben für

definierten tertiären Aminogruppen steht und quaternisiert ist mit einer wie oben definierten Gruppe der Formel AlkY.R ₁ , R ₂ , R ₅ , A ^b and Q have the above meaning; stands for alkyl with 1 bohlenstoffatomen or independently below

has the meaning given; means: hydroxy; Alkoxy of 1 to 12 carbon atoms; or - in what

have the above meaning; and their ammonium salts, in which for one of the above for

defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.

nicht für Alkoxy. In einer anderen Untergruppe bedeuten

und

wie oben definiertes

In a subset of compounds of the formula Ibb

not for alkoxy. Mean in another subgroup

and

as defined above

Another preferred group of compounds of the formula Ib consists of the compounds of the formula Ibaa

wherein

, R₅, A und Q obige Bedeutung besitzen; und ihre Ammoniumsalze, in denen

für eine der oben für

definierten tertiären Aminogruppen steht und quaternisiert ist mit einer wie oben definierten Gruppe der Formel AlkY. In einer Untergruppe von Verbindungen der Formel Ibaa s

nicht für Alkoxy. In einer anderen Untergruppe bedeutet wie oben definiertes

R ₁ , R ₂ ,

, R ₅ , A and Q have the above meaning; and their ammonium salts, in which

for one of the above for

defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above. In a subset of compounds of the formula Ibaa s

not for alkoxy. In another sub-group means as defined above

steht, insbesondere für Wasserstoff oder Alkyl, vorzugsweise Wasserstoff oder Methyl, insbesondere Wasserstoff; diejenigen, in denen R₂ und R₅ Wasserstoff oder Alkyl mit 1 bis 4 Kohlenstoffatomen bedeuten, insbesondere Methyl; diejenigen, in denen Q für eine Gruppe der Formel worin R und X obige Bedeutung besitzen,

steht, insbesondere diejenigen, in denen R Wasserstoff bedeutet; und diejenigen, in denen X Sauerstoff bedeutet; und deren Kombinationen; und gegebenenfalls ihre entsprechenden, wie oben definierten quaternären Salze.Further groups and subgroups of compounds according to the invention consist of the compounds of the formula Ib, Iba, Ibb and Ibaa in which R _{1 is} as defined above

stands, in particular for hydrogen or alkyl, preferably hydrogen or methyl, in particular hydrogen; those in which R ₂ and R _{5 are} hydrogen or alkyl having 1 to 4 carbon atoms, especially methyl; those in which Q is a group of the formula in which R and X are as defined above,

stands, in particular those in which R is hydrogen; and those where X is oxygen; and their combinations; and optionally their corresponding quaternary salts as defined above.

Another group of compounds according to the invention consists of the compounds of the formula Ip

worin Wasserstoff oder Alkyl mit 1 bis 4 Kohlenstoffatomen bedeutet; und

unabhängig voneinander für Alkyl mit 1 bis 4 Kohlenstoffatomen stehen; Alkyl mit 1 bis 6 Kohlenstoffatomen bedeutet oder unabhängig die hierunter für -A^PR₄ ^P angegebene Bedeutung besitzt; bedeutet: Hydroxy; Alkoxy mit 1 bis 6 Kohlenstoffatomen;

worin

steht für: Alkyl mit 1 bis 6 Kohlenstoffatomen; Phenyl,

Phenylalkyl mit 7 bis 10 Kohlenstoffatomen oder Bisphenylalkyl mit 13 bis 16 Kohlenstoffatomen, wobei diese drei Reste gegebenenfalls in den Phenyl ringen mono- oder gleich oder verschieden di- oder gleich oder verschieden trisubstituiert sind durch Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Hydroxy oder Halogen mit einer Ordnungszahl von 9 bis 53; ein 5-gliedriger Heteroarylrest mit 1 Heteroatom aus der Reihe Stickstoff, Sauerstoff und Schwefel oder 2 Heteroatomen aus der Reihe Stickstoff und entweder Stickstoff, Sauerstoff oder Schwefel; oder ein 6-gliedriger Heteroaryl rest mit 1 bis 4 Stickstoffatomen;

bedeutet: Wasserstoff; Alkyl mit 1 bis 4 Kohlenstoffatomen; oder mit der Ausnahme von Alkyl mit 1 bis 6 Kohlenstoffatomen die oben für

angegebene Bedeutung besitzt; steht für: Wasserstoff oder Alkyl mit 1 bis 6 Kohlenstoff

atomen; oder bedeutet

, worin

die oben für

angegebene Bedeutung Besitzt; bedeutet: ein 5-, 6- oder 7-gliedriger, gesättigter

heterocycnscher Ring, der gegebenenfalls, falls er 6- oder 7-gliedrig ist, ein weiteres Heteroglied aus der Reihe Sauerstoff, Schwefel und

enthält, worin entweder Wasserstoff bedeutet oder die oben

für

angegebene Bedeutung besitzt;

wherein represents hydrogen or alkyl of 1 to 4 carbon atoms; and

independently represent alkyl of 1 to 4 carbon atoms; Alkyl with 1 to 6 carbon atoms means or independently has the meaning given below for -A ^P R ₄ ^P ; means: hydroxy; Alkoxy of 1 to 6 carbon atoms;

wherein

represents: alkyl of 1 to 6 carbon atoms; Phenyl,

Phenylalkyl with 7 to 10 carbon atoms or bisphenylalkyl with 13 to 16 carbon atoms, these three radicals optionally in the phenyl rings being mono- or identical or differently di- or identical or differently trisubstituted by alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 Carbon atoms, hydroxy or halogen with an atomic number of 9 to 53; a 5-membered heteroaryl radical with 1 heteroatom from the series nitrogen, oxygen and sulfur or 2 heteroatoms from the series nitrogen and either nitrogen, oxygen or sulfur; or a 6-membered heteroaryl radical with 1 to 4 nitrogen atoms;

means: hydrogen; Alkyl of 1 to 4 carbon atoms; or with the exception of alkyl of 1 to 6 carbon atoms the above for

has the meaning given; stands for: hydrogen or alkyl with 1 to 6 carbon

atoms; or means

, in which

the above for

given meaning Possesses; means: a 5-, 6- or 7-membered, saturated

heterocyclic ring which, if it is 6- or 7-membered, is a further hetero-member from the series oxygen, sulfur and

contains, where either means hydrogen or the above

For

has the meaning given;

A represents unbranched alkylene of 2 to 14 carbon atoms; and Q ^{P stands} for a fused, completely unsaturated two-ring system with at least 2 different ring heteroatoms in total and with at least one aromatic ring;

Hydroxy; Alkoxy mit 1 bis 6 Kohlenstoffatomen; wie oben definiertes ; oder -NRy ^PR₃ P bedeutet; worin

with the proviso that if

Hydroxy; Alkoxy of 1 to 6 carbon atoms; as defined above; or -NRy ^P R ₃ P; wherein

R ₇ ^'P stands for: hydrogen; Alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and

für eine der oben für defi

nierten tertiären Aminogruppen steht und quaternisiert ist mit einer wie oben definierten Gruppe der Formel AlkY.R ₈ ^{'P represents} hydrogen or alkyl of 1 to 6 carbon atoms; then A ^{p represents} unbranched alkylene of 7 to 14 carbon atoms; and their ammonium salts, in which

for one of the above for defi

is tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.

Alkyl mit 1 bis 6 Kohlenstoffatomen; in einer anderen Untergruppe steht es für Alkyl mit 1 Bis 3 Kohlenstoffatomen; in einer anderen Untergruppe bedeutet es - , worin A^P und

obige Bedeutung besitzen; in einer anderen Untergruppe steht

nicht für Alkoxy; in einer anderen Untergruppe bedeutet A^p unverzweigtes Alkylen mit 7 Bis 14 Kohlenstoffatomen; in einer anderen Untergruppe steht A^p für unverzweigtes Alkylen mit 9 bis 14 Kohlenstoffatomen; in einer anderen Untergruppe bedeutet R₄ Hydroxy; Alkoxy mit 1 bis 6 Kohlenstoffatomen; obige

Bedeutung besitzen; und ihre Kombinationen, und gegebenenfalls ihre entsprechenden,wie oben definierten quaternären Salze.In a subset of compounds of formula Ip

Alkyl of 1 to 6 carbon atoms; in another subgroup it stands for alkyl with 1 to 3 carbon atoms; in another subgroup it means -, where A ^P and

meaning above have; is in a different subgroup

not for alkoxy; in another subgroup A ^{p represents} unbranched alkylene of 7 to 14 carbon atoms; in another subgroup A ^p stands for unbranched alkylene with 9 to 14 carbon atoms; in another subgroup, R _{4 is} hydroxy; Alkoxy of 1 to 6 carbon atoms; above

Have meaning; and their combinations, and optionally their corresponding quaternary salts as defined above.

Another group of compounds according to the invention consists of the compounds of the formula Is

Is

stoffatomen stehen; Alkyl mit 1 bis 12 Kohlenstoffatomen bedeutet; steht für: Hydroxy; Alkoxy mit 1 bis 4 Kohlenstoffatomen;

worin Alkyl mit 1 bis 4 Kohlenstoffatomen oder Phenyl bedeutet;

steht für: Wasserstoff; Alkyl mit 1 bis 4 Kohlenstoffatomen; gegebenenfalls im Phenylring durch Alkoxy mit 1 Bis 4 Kohlenstoffatomen oder Halogen mit einer Ordnungszahl von 9 bis 53 mono- oder gleich oder verschieden disuBstituiertes Phenylalkyl mit 7 bis 10 Kohlenstoffatomen;

, worin

Alkyl mit 1 bis 4 Kohlenstoffatomen bedeutet; oder gegebenenfalls im Phenyl ring durch Alkoxy mit 1 bis 4 Kohlenstoffatomen, Hydroxy oder Halogen mit einer Ordnungszahl von 9 bis 53 mono- oder gleich oder verschieden di substituiertes Phenyl oder Phenylalkyl mit 7 bis 10 Kohlenstoffatomen; Wasserstoff oder Alkyl mit 1 bis 4 Kohlenstoffatomen be

deutet; für Piperidin oder Pioerazin, beide in 4-Stellung sub

stituiert durch Methyl,

oder beiden Phenyl ringen durch Halogen mit einer Ordnungszahl von 9 bis 53 oder Alkoxy mit 1 bis 4 Kohlenstoff- atomen mono- oder gleich oder verschieden disubstituiertes Bisphenylmethyl ,

A^s für Alkylen mit 2 bis 14 Kohlenstoffatomen steht; mit der Massgabe, dass falls bedeutet: Hydroxy; Alkoxy mit 1 bis 4 Kohlenstoffatomen;

wie oben definiertes ; oder , worin

für Wasserstoff, Alkyl mit 1 bis 4 Kohlenstoffatomen; oder unsubstituiertes Phenylalkyl mit 7 bis 10wherein independently for alkyl with 1 to 4 carbons

atoms of matter stand; Means alkyl of 1 to 12 carbon atoms; stands for: hydroxy; Alkoxy of 1 to 4 carbon atoms;

wherein Is alkyl of 1 to 4 carbon atoms or phenyl;

stands for: hydrogen; Alkyl of 1 to 4 carbon atoms; optionally in the phenyl ring by alkoxy having 1 to 4 carbon atoms or halogen having an atomic number of 9 to 53 mono- or identically or differently disubstituted phenylalkyl having 7 to 10 carbon atoms;

, in which

Means alkyl of 1 to 4 carbon atoms; or optionally in the phenyl ring by alkoxy with 1 to 4 carbon atoms, hydroxy or halogen with an atomic number from 9 to 53 mono- or identically or differently di-substituted phenyl or phenylalkyl with 7 to 10 carbon atoms; Be hydrogen or alkyl having 1 to 4 carbon atoms

indicates; for piperidine or pioerazine, both in the 4-position sub

substituted by methyl,

or both phenyl rings through halogen with an atomic number from 9 to 53 or alkoxy with 1 to 4 carbon atoms mono- or identically or differently disubstituted bisphenylmethyl,

A ^{s represents} alkylene with 2 to 14 carbon atoms; with the proviso that if means: hydroxy; Alkoxy of 1 to 4 carbon atoms;

as defined above; or, in what

for hydrogen, alkyl with 1 to 4 carbon atoms; or unsubstituted phenylalkyl with 7 to 10

dann A Alkylen mit 7 bis 14 Kohlenstoffatomen bedeutet; und ihre Ammoniumsalze, in denen für eine der oben für

definierten tertiären Aminogruppen steht und quaternisiert ist mit einer wie oben definierten Gruppe der Formel AlkY.Carbon atoms; and has the above meaning;

then A represents alkylene of 7 to 14 carbon atoms; and their ammonium salts, in which for one of the above for

defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.

In a subgroup of compounds of the formula Is, A ^s denotes alkylene having 7 to 14 carbon atoms; in another subgroup it stands for alkylene with 9 to 14 carbon atoms; it is unbranched in another subgroup.

In a further subgroup of compounds according to the invention, R ₆ , R ₇ and / or R _{8 are} substituted phenyl, substituted phenylalkyl or substituted bisphenyl alkyl.

; in einer weiteren Untergruppe bedeutet A unverzweigtes Alkylen und besitzt R₄ die oben für angegebene Bedeutung, einschliesslich der entsprechenden

Massgabe in einer weiteren Untergruppe besitzen R₆, R₇ bzw. R₈ die oben für

bzw.

angegebene Bedeutung; in einer weiteren Untergruppe besitzt die oben für angegebene Bedeutung;

in einer weiteren Untergruppe ist Q bicyclisch; in einer weiteren Untergruppe steht R₄ für Alkoxy mit 1 bis 6 Kohlenstoffatomen; in einer weiteren Untergruppe enthalten substituiertes oder unsubstituiertes Phenylalkyl 7 bis 10 Kohlenstoffatome im Phenylalkylgerüst und substituiertes oder unsubstituiertes Bisphenyl alkyl 13 bis 16 Kohlenstoffatome im Bisphenylalkylgerüst; in einer

weiteren Untergruppe besitzt R₇ die oben für angegebene Bedeutung.

In einer weiteren Untergruppe sind sämtliche nicht-annellierten Phenylringe substituiert. R₁ besitzt vorzugsweise die oben für angegebene Bedeutung.

bedeutet vorzugsweise Wasserstoff. Falls es nicht für Wasserstoff steht, bedeutet es vorzugsweise unsubstituiertes Alkyl, Cycloalkyl alkyl, gegebenenfalls substituiertes Phenylalkyl, Alkoxyalkyl oder Morphol ino, vorzugsweise unsubstituiertes Alkyl oderIn a further subgroup, R _{1 is} hydrogen or alkyl having 1 to 5 carbon atoms; in a further subgroup, R ₂ and R ₅ independently of one another represent alkyl having 1 to 4 carbon atoms; in a further subgroup, R _{3 represents} alkyl having 1 to 6 carbon atoms; in another subgroup, R _{3 is} as defined above

; in a further subgroup, A denotes unbranched alkylene and R _{4 has} the meaning given above, including the corresponding meaning

In another subgroup, R ₆ , R ₇ and R _{8 have} the above for

respectively.

given meaning; in another subgroup has the meaning given above;

in another subgroup, Q is bicyclic; in a further subgroup R _{4 represents} alkoxy having 1 to 6 carbon atoms; in a further subgroup, substituted or unsubstituted phenylalkyl contain 7 to 10 carbon atoms in the phenylalkyl skeleton and substituted or unsubstituted bisphenyl alkyl contain 13 to 16 carbon atoms in the bisphenylalkyl skeleton; in a

another subgroup, R _{7 has} the meaning given above.

In a further subgroup, all non-fused phenyl rings are substituted. R ₁ preferably has the meaning given above.

preferably means hydrogen. If it is not hydrogen, it preferably means unsubstituted alkyl, cycloalkyl alkyl, optionally substituted phenylalkyl, alkoxyalkyl or morphol ino, preferably unsubstituted alkyl or

bedeutet, ist der Alkoxyteil vom Stickstoffatom vorzugsweise durch mindestens 2 Kohlenstoffatome getrennt.Alkoxyalkyl, preferably unsubstituted alkyl. If alkoxyalkyl

means, the alkoxy part is preferably separated from the nitrogen atom by at least 2 carbon atoms.

R ₂ and / or R _{5 are} preferably alkyl. R3 preferably represents alkyl. If it has the meaning given above for -AR ₄ , it is preferably identical to -AR ₄ .

R ₄ preferably represents hydroxy, -OCOR ₆ , -NR ₇ R ₈ or.

Q preferably has at least 3 heteroatoms in total, in particular 3 heteroatoms. It preferably represents a bicyclic ring system. Preferred groups Q represent 2,1,3-benzoxadiazolyl and 2,1,3-benzothiadiazolyl, in particular 2,1,3-benzoxadiazolyl. If Q represents a ring system which contains a benzene ring component , the 1,4-dihydropyridinyl radical is preferably bound to this benzene ring component, preferably in one

Position of the benzene ring component that is adjacent to other ring components.

A is preferably straightforward. It preferably has 7 to 14, preferably 9 to 14, in particular 10 carbon atoms,

Alk preferably means methyl.

Y preferably represents the remainder of an inorganic acid, for example mesyl or halogen, in particular iodine. R ₆ preferably denotes alkyl, phenyl, phenylalkyl or bisphenylalkyl, in particular phenyl,

R ₇ preferably represents hydrogen, alkyl, phenylalkyl or bisphenylalkyl.

R ₈ is preferably hydrogen, alkyl or -COR ₉ .

R ₇ and R ₈ are preferably either hydrogen, or one of R ₇ and R ₈ is alkyl and the other is alkyl, optionally substituted phenylalkyl or optionally substituted bisphenylal kyl.

R ₉ preferably represents alkyl, optionally substituted

Phenyl, optionally substituted phenylalkyl or optionally substituted bisphenylal kyl.

vorzugsweise 6-gliedrig.Es bedeutet vorzugsweise 1-Piperazinyl. Falls es 6- oder 7-gliedrig ist, enthält es vorzugsweise ein weiteres Heteroglied =NR₁₀. R₁₀ besitzt vorzugsweise eine andere Bedeutung als Wasserstoff. Es bedeutet vorzugsweise Alkyl, gegebenenfalls substituiertes Phenylalkyl oder gegebenenfalls substituiertes Bisphenylalkyl.As defined above, it is preferably saturated. It is

preferably 6-membered. It preferably means 1-piperazinyl. If it is 6 or 7-membered, it preferably contains a further hetero-link = NR ₁₀ . R ₁₀ preferably has a meaning other than hydrogen. It preferably means alkyl, optionally substituted phenylalkyl or optionally substituted bisphenylalkyl.

X preferably represents oxygen. R is preferably hydrogen.

The rest are preferably in his

4-position bound to the 4-position of the 1,4-dihydropyridinyl radical. Cycloalkyl with 3 to 7 carbon atoms preferably contains 3, 5 or 6, in particular 5 or 6, carbon atoms.

Alkyl having 1 to 12 carbon atoms and / or alkoxy having 1 to 12 carbon atoms preferably contain 1 to 6, in particular 1 to 4, carbon atoms, and are preferably methyl, ethyl or isopropyl. Alkyl with 1 to 6 carbon atoms preferably contains 1 to 4, in particular 1 or 2, carbon atom (s), it means in particular methyl. If alkyl with 1 to 6 or with 1 to 4 carbon atoms represents a phenyl ring or amino substituent, it preferably contains 1 or 2 carbon atoms and in particular means methyl. If alkoxy having 1 to 4 carbon atoms represents a phenyl ring substituent, it preferably contains 1 or 2 carbon atoms and in particular means methoxy. If halogen with an atomic number of 9 to 53 represents a phenyl ring substituent, it preferably means chlorine, bromine or iodine, in particular chlorine or iodine. Alkenyl and / or alkynyl preferably contain 3 carbon atoms. The cycloalkyl part of cycloalkylalkyl preferably contains 3.5 or 6, in particular 5 or 6, carbon atoms. The alkyl part of cycloalkylalkyl and / or of phenylalkyl preferably contains 1 or 2 carbon atoms, it means in particular methylene. The alkenylene portion of phenylalkenyl preferably contains 3 carbon atoms. The alkyl part of hydroxyalkyl with 2 to 6 carbon atoms and / or of alkoxyalkyl with 2 to 6 carbon atoms preferably contains 2 or 3, in particular 2, carbon atoms. The hydroxy portion of hydroxyalkyl and / or of hydroxyalkoxyalkyl and / or the amino portion of aminoalkyl are preferably attached to the most distant, end-chain carbon atom.

If a phenyl ring occurs in a substituent, it is preferably unsubstituted. If it is substituted, it is preferably monosubstituted, preferably in the para position, If it is disubstituted, it is preferably substituted in the ortho or meta and in the para position. If it is trisubstituted, it is preferably substituted in the meta, meta and para position. Alkoxy and / or halogen are preferred substituents of a phenyl ring substituent. If a phenyl ring is polysubstituted, the substituents are preferably identical.

The amino part of aminoalkyl is preferably substituted, in particular disubstituted. Preferred substituents of the amino part of aminoalkyl are alkyl and / or optionally substituted phenylalkyl. The amino part of aminoalkyl is preferably disubstituted by alkyl and optionally substituted phenylalkyl.

In bisphenylalkyl, the two phenyl rings can be attached to the same or different carbon atoms. They are preferably attached to the same carbon atom. Bisphenylalkyl preferably means bisphenylmethyl.

A 5-membered heteroaryl radical as defined above preferably means pyrrolyl, furyl or thienyl. A 6-membered heteroaryl radical as defined above preferably represents pyridinyl, in particular 4-pyridinyl.

Phenylalkyl preferably contains 7 to 10 carbon atoms. Bisphenylalkyl preferably contains 13 to 16 carbon atoms,

Halogen with an atomic number from 9 to 53 preferably means bromine or iodine, halogen with an atomic number from 9 to 35 preferably means chlorine. The compounds according to the invention are obtained by a process which is characterized in that corresponding compounds of the formula II

wherein R ₁ , R ₂ , R ₅ and Q have the above meaning, Z represents a reactive group and

Z 'either represents a reactive group or has the meaning given above for -OR ₃ , appropriately converted.

The method according to the invention can be carried out analogously to known methods.

The choice of the most suitable process variant naturally depends on the nature of, for example, de.n substituents -AR ₃ and R ₃ .

A process variant can represent an esterification, for example. A suitable reactive group Z or Z 'in this case is, for example, IH-imidazol-1-yl. This process variant is suitable, for example, for conversion into a hydroxyalkyl, amidoalkyl, alkoxyalkyl, acyloxyalkyl or substituted or unsubstituted aminoalkyl substituent. So a corresponding compound of formula II with a corresponding diol, amido / alcohol, ester / alcohol or implemented amino alcohol. Suitable solvents are, for example, dioxane or an excess of the reactant.

A further process variant can be an amination, for example. This process variant is suitable, for example, for conversion into an aminoalkyl substituent. A reactive group Z or Z 'represents, for example, a group -OA-Z'', in which A is as defined above and Z "is chlorine, bromine or a group R _z -SO ₂ -O, in which R _{z is} phenyl, tolyl or lower alkyl Z "preferably denotes mesyloxy. The amination can be immediate, ie the reaction is carried out directly with an amine which contains the substituent to be introduced, or indirectly, for introducing a primary amino group, by reaction in a corresponding phthalimidoalkyl derivative, for example by Reaction with sodium or potassium phthalimide and subsequent reaction with hydrazine of the phthalimidoalkyl derivative thus obtained The indirect method is preferred if the substituent to be introduced represents a primary aminoalkyl group.

Another process variant can e.g. represent an acylation of a primary or secondary amine. A reactive group Z or V then represents e.g. represents the corresponding primary or secondary aminoalkoxy group. A corresponding compound of formula II is thus treated with a corresponding acyl derivative, e.g. an N-hydroxysuccinimide ester. Suitable solvents are e.g. Dioxane.

Another process variant can be, for example, an acylation of an alcohol. A reactive group Z or Z 'then represents, for example, the corresponding hydroxyalkoxy group. Thus, a corresponding compound of the formula II with a corresponding one Acyl derivative, such as an acyl halide, implemented. The reaction is preferably carried out in the presence of a strong base, such as N-ethyldiisopropylamine. A suitable solvent is, for example, methylene chloride.

Another process variant can e.g. to represent etherification. A reactive group Z or Z 'then represents e.g. represents a group -O-A-Z ", in which A and Z" have the above meaning. The reaction is preferably carried out under strongly alkaline conditions.

If in the starting material V stands for a reactive group, a group -AR ₄ can arise simultaneously in the 3- or 5-position of the 1,4-dihydropyridinyl skeleton.

Quaternary ammonium salts can be prepared analogously to known methods, e.g. by reaction with corresponding (lower) -alkyl iodides. Suitable as a solvent is e.g. an alcohol like methanol.

If there are potentially reactive groups, such as hydroxyl or primary or secondary amino, it may be appropriate to carry out the process according to the invention with these groups in a protected form, for example for phenolic hydroxyl in the form of a benzyloxy group, or for aliphatic hydroxyl in the form of a tetrahydropyranyloxy group , or for amino in the form of an acylamino or phthalimido group, and then converting the protected groups into the desired substituents, for example benzyloxy in hydroxy, for example, hydrogenolytically; Tetranydro-pyranyloxy in hydroxy, for example by acid hydrolysis; and protected amino in unprotected amino, for example by acid hydrolysis or hydrazinolysis. The compounds according to the invention can be isolated and purified from the reaction mixture in a known manner.

The compounds according to the invention can be in free form or optionally in salt form. The free forms are normally neutral, unless there are ionizable substituents. Salt forms can exist, e.g. if ionizable substituents, such as amino or phenolic hydroxy, are present. Salt forms can be obtained in a known manner from the compounds in free form and vice versa. Suitable acids for the formation of acid addition salts are e.g. Hydrogen chloride, malonic, p-toluenesulfonic and methanesulfonic acid. Suitable bases for the formation of anionic salts are e.g. Sodium and potassium hydroxide.

If the radicals in positions 2 and 6 and / or in positions 3 and 5 of the 1,4-dihydropyridinyl radical are different, the carbon atom in the 4-position is asymmetrically substituted. The corresponding compounds according to the invention can therefore occur in racemic form or in the form of the individual enantiomers.

The individual enantiomers can be obtained analogously to known methods.

The starting products can be obtained analogously to known methods, e.g. by direct cyclization to the 1,4-dihydropyridinyl skeleton.

Insofar as the production of the required starting materials is not described, they are known or by known methods or can be produced analogously to the methods described here or analogously to methods known per se. In the following examples, all temperatures are given in degrees Celsius without corrections.

In game 1: 4- (2, 1, 3-benzoxadiazol-4-yl) -1, 4-dihydro-5-isopropoxycarbonyl 1-2, 6-dimethy1-3-pyridinecarboxylic acid (10-hydroxydecyl) ester

(Esterification of imidazolide with alcohol)

A mixture of 5.2 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5 (1H-imidazol-1-ylcarbonyl) -2,6-dimethy1-3-pyridinecarboxylic acid isopropyl and 44.5 g of decane-1,10-diol is heated to 120 ° oil bath temperature for 2 hours. After cooling, ether is added. The excess decane-1,10-diol crystallizes out. After filtering and evaporating the ether in vacuo, the product is chromatographed on silica gel under light pressure, using methylene chloride / ether as the eluent. The title compound (oil) is obtained.

NMR spectrum (CDCl ₃ ) δ (ppm) - 0.97 (3H, d, J = 6Hz), 1.22 (3H, d, J = 6Hz), 1.15-1.65 (16H, m) , approx. 2.32 (6H, 2s), 3.63

(2H, t, J = 6Hz), 3.99 (2H, m), 4.91 (lH, m, J = 6Hz), 5.48 (lH, s), 5.92 (lH, s), 7.3 (2H, m), 7.62 (1H, m).

Example 2: 4- (2, 1, 3-Benzoxadiazo1-4-y1) -1, 4-dihydro-5-isopropoxycarbony1-2, 6-dimethy1-3-pyridinecarboxylic acid [10- (N-benzylmethylamino) decyl] ester

(direct amination of the masylate)

4.6g 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl2,6-dimethy1-3-pyridinecarboxylic acid (10-methanesulfonyloxydecyl) ester and 2.2ml N-benzylmethylamine are dissolved in 50 ml of ether, the mixture is evaporated in vacuo and the product is heated at 80 ° for 3 hours. The semish is then dissolved in ether, the solution washed with cold IN sodium hydroxide, the ether phase dried over magnesium sulfate and evaporated in vacuo. The product is purified by chromatography on silica gel using methylene chloride / ethanol 19: 1 as the eluent. The title compound is obtained (free base: oil; hydrochloride: amorphous).

Nuclear Magnetic Resonance Spectrum of the free base (CDCl ₃ ) δ (ppm): 0.98

(3H, d, J = 6Hz), 1.25 (3H, d, J = 6Hz), 1.15-1.8 (16H, m), 2.2 (3H, s), 2.34 (6H , s), 2.25-2.45 (2H, m), 3.5 (2H, s), 4.0 (2H, t, J = 6Hz), 4.92 (lH, m, J = 6Hz ), 5.48 (1H, s), 5.98 (1H, s), 7.2-7.7 (8H, m).

The mesylate used as the starting product is obtained by reacting 4.3 g of the title compound of Example 1 and 4.3 ml of N-ethyldiisoprαpylamine in 90 ml of methylene chloride at 0 ° with 1.0 ml of methanesulfonic acid chloride, and the mixture is stirred for 90 minutes in an ice bath, The solution is then washed with cold 2N hydrochloric acid solution and the organic phase is dried over magnesium sulfate and evaporated in vacuo. Example 3: 4- (2, 1, 3-Benzoxadiazo1-4-y1) -1, 4-dihydro-5-isopropoxycarbony1-2, 6-dimethy1-3-pyridinecarboxylic acid (10-aminodecyl) ester

(Amination of the mesylate via phthalimido derivative)

2.2 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-oihydro-5-isopropoxycarbonyl2,6-dimethyl-3-pyridinecarboxylic acid (10-methanesulfonyloxydecyl) ester are dissolved in 44 ml of dimethylformamide, 2.2 g of potassium phthalimide are added and the mixture is stirred for 3 hours at 80 ° bath temperature, the solution is then cooled, filtered, washed with 100 ml of methylene chloride and the filtrate is purified by shaking 8 times with cold 2N hydrochloric acid solution and then evaporated in vacuo. The product is chromatographed on silica gel with light pressure using ether as the eluent.

The 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl -2,6-dimethyl-3-pyridinecarboxylic acid (10-phthalimidodecyl) ester (oil) obtained is dissolved in 40 ml of ethanol dissolved, 1.0 ml of hydrazine hydrate is added and the solution is heated to boiling temperature under reflux for 30 minutes. After filtering off and washing with methylene chloride, the solution is extracted with ice-cold water and the organic phase is evaporated in vacuo. The product is chromatographed under gentle pressure on silica gel using methylene chloride / methanol (containing ammonia) 9: 1 as the eluent. The title compound (mp, 102 ° - from ether) is obtained. Example 4: 4- (2, 1, 3-Benzoxadiazo1-4-y1) -1, 4-dihydro-5-isopropoxycarbony1-2, 6-dimethy1-3-pyridinecarboxylic acid [10- [3- (4-hydroxy-3 -iodphenyl) -1-oxo-propylamino] decyl] ester (amidation of the amine)

A solution of 0.5 g of 4- (2, 1, 3-benzoxadiazol-4-yl) -1, 4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (10-aminodecyl) ester and 0, 4 g of 3- (4-hydroxy-3-iodophenyl) propionic acid N-hydroxysuccinimide ester in 15 ml of dioxane is heated to 120 ° bath temperature for 30 minutes, the solution is cooled, diluted with methylene chloride and extracted with cold saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, evaporated in vacuo and the product is chromatographed on silica gel under gentle pressure and using 49: 1 methylene chloride / ethanol as eluent. You get the title connection (amorphous).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ (ppm): 0.99 (3H, d, J = 6Hz), 1.1-1.9 (19H, m), 2.35 (6H, s), 2.43 (2H, t, J = 7Hz), 2.9 (2H, t, J = 7Hz), 3.23 (2H, q, J = 5Hz), 4.02 (2H, t, J = 6Hz), 4 , 96 (1H, m, J = 6Hz), 5.53 (1H, s), approx.5.62 (1H, broad), approx.6.55 (2H, broad),

6.9 (1H, d, J = 8Hz), 7.1 (1H, 2d, J = 8Hz and 2Hz), 7.25-7.75 (4H, m).

Example 5: 4- (2, 1, 3-Benzoxadiazo1-4-y1) -1, 4-dihydro-5-isopropoxycarbony1-2, 6-dimethy1-3-pyridinecarboxylic acid (10-benzoyloxydecyl) ester

(Alcohol acylation)

1.2 g of benzoyl chloride are added at 20 ° to a solution of 2.2 g of the title compound of Example 1 and 1.3 g of N-ethyldiisopropylamine in 30 ml of methylene chloride, and the solution is stirred at 40 ° for 1 hour. The reaction clay mixture is then diluted with ether and washed successively with water, 1N sodium hydroxide and 1N hydrochloric acid solution, dried over magnesium sulfate and evaporated in vacuo. The product is purified by chromatography on silica gel using methylene chloride / ether 9: 1 as the eluent. The title connection (amorphous) is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ (ppm): 0.99 (3H, d, J = 6Hz), 1.02-1.9 (19H, m), 2.35 (6H, s), 3.99 (2H, t, J = 6Hz), 4.33 (2H, t, J = 6Hz), 4.93 (1H, m, J = 6Hz), 5.5 (1H, s), 6.08 (1H , s), 7.15 - 8.15 (8H, m).

Example 6: 4- (2, 1, 3-Benzoxadiazo1-4-y1) -1, 4-dihydro-5-isopropoxycarbonyl 1-2, 6-dimethy1-3-pyridinecarboxylic acid [10- (N-benzylmethylamino) decyl] ester

(Esterification of the imidazolide with amino alcohol) A solution of 4 g of 4- (2, 1, 3-benzoxadidol-4-yl) -1,4-dihydro-5 (1H-imidazol-1-ylcarbonyl) -2,6-dimethyl Isopropyl -3-pyridinecarboxylic acid and 7.0 g of 10- (N-methylbenzylamino) decan-1-ol in 150 ml of dioxane are heated to reflux temperature for 16 hours. The mixture is then evaporated in vacuo and the product heated to 80 ° for 3 hours. The product is purified by chromatography on silica gel using methylene chloride / ethanol 19: 1 as the eluent. The title compound is obtained (free base: oil; hydrochloride: amorphous).

NMR spectrum: see Example 2. The amino alcohol used as the starting product is obtained as follows: a) One is at 30 ° to a solution of 20 g of decane-1,10-diol and 20 ml of N-ethyldiisopropylamine in 800 ml of methylene chloride and 100 ml of acetone Solution of 4.5 ml of methanesulfonic acid chloride in 60 ml of methylene chloride is added dropwise and the mixture is stirred at room temperature for 1 hour. The methanesulfonic acid (10-hydroxydecyl) ester (mp 48 ° - from ether, after chromatography on silica gel using methylene chloride / ether 2: 1 as the eluent) is obtained. b) A mixture of 8.5 g of the mesylate obtained as described above under a) and 12.3 g of N-methylbenzylamine is heated to 80 ° for 2 hours. The 10- (N-methylbenzylamino) decan-1-ol (oil; after chromatography on silica gel using ether as eluent) is obtained. Example 7: 4- (2, 1, 3-Benzoxadiazo1-4-y1) -1, 4-dihydro-5-isopropoxycarbony1-2, 6-dimethy1-3-pyridinecarboxylic acid (10-methoxydecyl) ester

(Etherification of the mesylate)

2.3 g of 4- (2, 1, 3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (10-methanesulfonyloxydecyl) ester in 30 ml of methanol reacted with 0.5 g of potassium methylate and the mixture is heated to reflux temperature for 4 hours. After evaporation in vacuo, the product is dissolved in ether, the solution is washed with 1N hydrochloric acid solution, the organic phase is dried over magnesium sulfate and evaporated. The product is purified by chromatography on silica gel using ether / hexane 1: 1 as the eluent. The title compound (oil) is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ (ppm): 0.98 (3H, d, J = 6Hz), 1.1 - 1.9 (19H, m), 2.32 (H, s), 3.35 (3H, s), 3.39 (2H, t, j = 6Hz), 4.0 (2H, t, J = 6Hz), 4.95 (1H, m, J = 6Hz), 5.5 (1H , s), 6.3 (1H, s), 7.27.8 (3H, m).

The compounds according to the invention in free form or, if appropriate, in the form of their physiologically tolerable salts are distinguished by interesting pharmacodynamic properties. They can be used as medicaments.

They show typical effects for calcium antagonists. They have a pronounced muscle-relaxing effect, particularly on smooth muscles, as can be seen from the determination of vasodilating and hypotensive activity in standard tests. So they effect e.g. in the anesthetized cat test using "tracer" microspheres (R. Hof et al., Basic Res. Cardiol. 75J1980] 747-756 and 76 (1981) 630-638; R. Hof et al., J. Cardiovasc. Pharmacol. 4 [1982] 352-362) coronary vasodilation, an increase in blood flow in the skeletal muscles and a decrease in blood pressure after intravenous administration of about 3 to about 300 μg / kg, for example from about 10 to about 100 µg / kq.

A decrease in blood pressure is also seen in the awake, spontaneously hypertensive rat (method of Gerold and Tschirki, drug research 18 [1968] 1285) after administration of about 1 to about 10 mg / kg p.o. detected. The compounds are longer-acting than known standard compounds, e.g. for once-daily administration. The compounds are also particularly well absorbed orally,

They are therefore suitable as calcium antagonists for the prophylaxis and therapy of

Coronary insufficiency, e.g. Angina pectoris;

- further circulation disorders, e.g. in the limbs, such as intermittent limping and spasms, e.g. cholic;

Asthma, e.g. exertional asthma; and

- hypertension. They also have a vasodilating effect on the capillary blood vessels in the carotid area; the vasoconstrictive effect of serotonin is suppressed and the associated dysregulation inhibited. They are therefore suitable for the prophylaxis and treatment of migraines and vascular headaches, such as "cluster headache", in particular for interval treatment (prevention) of migraines. Preferred in this indication are those compounds which have a relatively modest effect on blood pressure and peripheral blood vessels.

For the above-mentioned uses as medicaments, the dose to be used naturally varies depending on the substance used, the mode of administration and the desired treatment. In general, however, satisfactory results are achieved with a daily dose of approximately 1 mg to approximately 200 mg; if necessary, it can be administered in 1 to 3 portions or as a slow-release form. Suitable dosage forms for e.g. oral or non-oral administration generally contain from about 0.3 mg to about 200 mg in addition to solid or liquid carriers. A suitable daily dose is e.g. about 5 mg to about 50 mg.

The title compounds of Examples 2, 5, 14, 29 and 41, in particular Examples 2 and 14, are preferred.

Preferred in the prophylaxis and treatment of migraines and vascular headaches are those compounds in which Q represents a 2,1,3-benzothiadiazplyl residue.

The compounds according to the invention in free form or optionally in the form of their physiologically tolerable salts, preferably acid addition salts, can be used alone or in a suitable manner Dosage form are administered. The pharmaceutical forms, for example a capsule suitable for, for example, sublingual administration, or a tablet, can be prepared analogously to known methods. The invention therefore also relates to pharmaceutical preparations which contain the compounds according to the invention in free form or, if appropriate, in the form of their physiologically tolerable salts, and to the preparation of these pharmaceutical preparations in a manner known per se. The auxiliaries and carriers customary in pharmacy can be used for their production.

Claims

1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PRODUCTION AND THEIR PHARMACEUTICAL PREPARATIONS CONTAINING THEM 1. The compounds of formula I.

wherein R _{1 is} hydrogen; Cycloalkyl of 3 to 7 carbon atoms; or optionally substituted alkyl having 1 to 6 carbon atoms; R ₂ and R _{5 are} independently hydrogen or alkyl of 1 to 6 carbon atoms; R ₃ for alkyl having T to 12 carbon atoms or independently has the meaning given below for -AR ₄ , including the massgae; R ₄ stands for: hydroxy; Alkoxy of 1 to 12 carbon atoms; -OCOR ₆ ; -NR ₇ R ₈ ; or in what

R _{6 represents} : alkyl having 1 to 6 carbon atoms; Phenyl, phenylalkyl with 7 to 12 carbon atoms or bisphenylalkyl with 13 to 18 carbon atoms, these three radicals optionally being mono- or identical or differently di- or identical or differently trisubstituted by alkyl having 1 to 4 carbon atoms, alkoxy with 1 up to 4 carbon atoms, hydroxy or halogen with an atomic number from 9 to 53; a 5-membered heteroaryl radical with 1 heteroatom from the series nitrogen, oxygen and sulfur or 2 heteroatoms from the series Nitrogen and either nitrogen, oxygen or sulfur; or a 6-membered heteroaryl radical with 1 to 4 nitrogen atoms; R _{7 represents} hydrogen or has the meaning given above for R ₆ ; R ₈ represents: hydrogen, alkyl having 1 to 6 carbon atoms; or -COR ₉ , in which R _{9 has} the meaning given above for R ₆ ; means: a 5-, 6- or 7-membered heterocyclic

Ring, if any, if saturated and 6- or Is 7-membered, contains a further hetero-member from the series oxygen, sulfur and = NR ₁₀ , wherein R _{10 is} either hydrogen or the above for R ₆ has the meaning given; A represents alkylene of 2 to 14 carbon atoms; and Q denotes a fused, completely unsaturated ring system with at least 2 different ring heteroatoms in total and with an aromatic character; with the proviso that if R _{4 is} hydroxy; Alkoxy of 1 to 6 carbon atoms; as defined or means above; wherein

stands for: hydrogen; Alkyl with 1 to 6 carbons

atoms of matter; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and hydrogen or alkyl of 1 to 6 carbon atoms

means; then A stands for alkylene with 7 to 14 carbon atoms. and their ammonium salts in which R _{4 represents} one of the tertiary amino groups defined above for R ₄ and is quaternized with a group of the formula AlkY, in which Alk is alkyl having 1 to 4 carbon atoms and Y is the residue of an acid, in free form or optionally in salt form. 2. Compound according to claim 1, characterized in that it is the 4- (2, 1, 3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl¬ 2,6-dimethyl-3-pyridine-carboxylic acid [10- (N-benzylmethylamino) decyl] ester, in free form or in salt form. 3. The compounds defined in claim 1 in free form or, optionally, in the form of their physiologically acceptable salts, for use as a medicament. 4. A process for the preparation of the compounds defined in claim 1, characterized in that corresponding Compounds of formula II

where R ₁ , R ₂ , R ₅ and Q are as defined above, Z stands for a reactive group and Z 'is either a reactive group or has the meaning given above for -OR ₃ , appropriately converted, and the compounds thus obtained are obtained in free form or, if appropriate, in salt form. 5. Use of the compounds defined in claim 1 in free form or optionally in the form of their physiologically tolerable salts as medicaments. 6. Pharmaceutical preparations containing the compounds defined in claim 1 in free form or optionally in the form of their physiologically tolerable salts.