GB2142021A - 1 4-dihydropyridine derivatives their preparation and pharmaceutical compositions 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, -NR7R8 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

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

In particular the invention provides compounds of formula I,

wherein R, is hydrogen; cycloalkyl of 3 to 7 carbon atoms; or optionally substituted alkyl of 1 to 6 carbon atoms; R2 and R5 independently are hydrogen or alkyl of 1 to 6 carbon atoms; R3 is alkyl of 1 to 1 2 carbon atoms or independently has the significance indicated below for -AR4, including the proviso thereto; R4 is: hydroxy; alkoxy of 1 to 1 2 carbon atoms; -OCOR6; -NR7R8; or -N6; wherein Re is: alkyl of 1 to 6 carbon atoms; phenyl, phenylalkyl of 7 to 1 2 carbon atoms or bisphenylalkyl of 1 3 to 18 carbon atoms, the last three substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur; or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; R7 is hydrogen or has the significance indicated above for Re; R8 is: hydrogen; or alkyl of 1 to 6 carbon atoms; or is -COR9 wherein R9 has the significance indicated above for R6; N8 > is: a 5-, 6- or 7-membered heterocyclic ring which may optionally contain, when it is saturated and 6- or 7-membered, a further heteromember selected from oxygen, sulfur and = NR10, wherein R10 either is hydrogen or has the significance indicated above for Re; A is alkylene of 2 to 14 carbon atoms; and O is a condensed, fully unsaturated ring system having at least 2 different ring heteroatoms overall and having aromatic character; with the proviso that, when R4 is: hydroxy; alkoxy of 1 to 6 carbon atoms; -N8) as defined above; or -R7'R8'; wherein R7' is: hydrogen, alkyl of 1 to 6 carbon atoms: unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and R8' is hydrogen or alkyl of 1 to 6 carbon atoms; then A is alkylene of 7 to 14 carbon atoms, and their ammonium salts wherein R4 is selected from one of the tertiary amino groups defined above for R4 and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid, hereinafter referred to as "the compounds of the invention".

Some of the compounds of the invention fall under the very broad disclosure of Bayer EP 42 089.

Some of the compounds of the invention also fall under the very broad disclosure of Bayer EP 88 276 and of Takeda EP 94 1 59. These publications took place in September 1983 and November 1983, respectively, i.e. at a date later than the priority date claimed for the compounds of the invention, namely June 21, 1983.

None of the compounds specifically disclosed in the above-mentioned European publictions, however, falls under the scope of the present invention.

Further disclosures reiating to compounds similar to the compounds of the invention are e.g.: Sandoz EP 1 50 Sandoz DOS 29 49 464 Sandoz DOS 29 49 491 Sandoz BE 890 311 Bayer EP 71819 Fisons EP 80 220 Sandoz DOS 33 20 616.

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

A preferred group of compounds of the invention is the compounds of formula la,

wherein R is: 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 of atomic number of from 9 to 35; trifluoromethyl; nitro; or hydroxy; R1 is: hydrogen; alkyl of 1 to 6 carbon atoms; alkenyl of 3 to 6 carbon atoms wherein the double bond is separated from the nitrogen atom by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 6 carbon atoms wherein the triple bond is separated from the nitrogen atom by at least 1 carbon atom not participating 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 wherein the hydroxy part is separated from the nitrogen atom by at least 2 carbon atoms; alkoxyalkyl of 2 to 6 carbon atoms; or phenylalkyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 1 2 carbon atoms wherein the double bond is separated from the nitrogen atom by at least 1 carbon atom not participating in the double bond, the last two substituents optionally being independently mono-, di- or trisubstituted in the phenyl ring by independently alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen of atomic number of from 9 to 35 or hydroxy; alkylcarbonyloxyalkyl of 2 to 6 carbon atoms in the alkylcarbonyl and alkylene moieties thereof and wherein oxygen is separated from the nitrogen atom by at least 2 carbon atoms; dialkylaminoalkyl independently of 1 to 6 carbon atoms in the alkyl moieties and of 2 to 6 carbon atoms in the alkylene moiety thereof and wherein the amino group is separated from the nitrogen atom by at least 2 carbon atoms; or morpholinoalkyl of 2 to 6 carbon atoms in the alkylene moiety thereof and wherein the morpholino moiety is separated from the nitrogen atom by at least 2 carbon atoms; R2 and RB are as defined above; R3 is alkyl of 1 to 1 2 carbon atoms or independently has the significance indicated below for AaR4; R84 is: hydroxy; alkoxy of 1 to 1 2 carbon atoms; -OCORa6; -NRa7Ra8; or -NB) as defined above; wherein Ra6, R57 and R58 have the significance indicated above for R6, R7 and R8, respectively; Aa is alkylene of 2 to 14 carbon atoms; and X is oxygen or sulfur; with the proviso that, a) when R4 is hydroxy or -NB) as defined above, then Aa is alkylene of 7 to 14 carbon atoms; and b) when R84 is alkoxy of 1 to 12 carbon atoms or -NRa7'Ra6' wherein Ra7' is hydrogen; alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and R88 is hydrogen or alkyl of 1 to 6 carbon atoms, then Aa is alkyle ne of 9 to 14 carbon atoms, and their ammonium salts wherein R4 is selected from one of the tertiary amino groups defined above for R84 and quaternized with a group of formula AlkY as defined above.

In a subgroup of compounds of formula la Aa is alkylene of 9 to 14 carbon atoms. In another subgroup R84 is other than alkoxy. In another subgroup R3 and R84 are -NRa7Ra8 or -NB) as defined above.

A preferred group of compounds of formula la is the compounds of formula laa,

wherein R, R'1, R2, R5 and X are as defined above; R838 is alkyl of 1 to 6 carbon atoms; Rt has the significance indicated above for R4a; and Aaa is alkylene of 2 to 14 carbon atoms; with the provisos that a) when R4aa is hydroxy or -NB) as defined above, then Aaa is alkylene of 7 to 14 carbon atoms; and b) when R4aa is alkoxy of 1 to 12 carbon atoms or -NR7a' R8a' wherein R7a' and R8a' are as defined above, then Aaa is alkylene of 9 to 14 carbon atoms, and their ammonium salts wherein R4aa is selected from one of the tertiary amino groups defined above for R4aa and quaternized with a group of formula ALKY as defined above.

In a subgroup of compounds of formula laa Aaa is alkylene of 9 to 14 carbon atoms. In another subgroup R4aa is other than alkoxy. In another subgroup R4aa is -NR7aR8a or -NB) as defined above.

A further preferred group of compounds of formula la is the compounds of formula lab,

wherein R,R1a,R2,R5 and X are as defined above, R3ab is alkyl of 1 to 12 carbon atoms or independently has the significance indicated below for -AabR4ab; R4ab is: hydroxy; alkoxy of 1 to 12 carbon atoms; -OCOR6a; or -NR7aR8a; wherein R86, R7 and R89 are as defined above; and Aab is alkylene of 2 to 14 carbon atoms; with the provisos that a) when R4ab is hydroxy, then Aab is alkylene of 7 to 14 carbon atoms; and b) when R4ab is alkoxy of 1 to 12 carbon atoms or -NR7a'R8a' are as defined above, then Aab is alkylene of 9 to 14 carbon atoms, and their ammonium salts wherein R84b is selected from one of the tertiary amino groups defined above for R4ab and quaternized with a group of formu Alky as defined above.

In a subgroup of compounds of formula lab Aab is alkylene of 9 to 14 carbon atoms. In another subgroup R4ab is other than alkoxy. In another subgroup R3ab and R4ab are -NR7aR8a as defined above.

A further preferred group of compounds of formula la is the compounds of formula laaa,

wherein R, Rat, R2, R5 and X are as defined above; R3aaa is alkyl of 1 to 6 atoms; R4aaa is: hydroxy; alkoxy of 1 to 12 carbon atoms; -OCOR6a or -NR7aR8a wherein R89, R87 and R89 are as defined above; and A"8 is alkylene of 2 to 14 carbon atoms; with the provisos that a) when R"48 is hydroxy, then Aaaa is alkylene of 7 to 14 carbon atoms; and b) when R4aaa is alkoxy of 1 to 12 carbon atoms or -NR7a'R8a' wherein R7a' and R8a' are as defined above, then Aaaa is alkylene of 9 to 14 carbon atoms and their ammonium salts wherein R4aaa is selected from one of the tertiary amino groups defined above for R4aaa and quaternized with a group of formula ALKY as defined above.

In a subgroup of compounds of formula laaa A""" is alkylene of 9 to 14 carbon atoms. In another subgroup R4aaa is other than alkoxy. In another subgroup RT is -NR7aR8a as defined above.

Further groups and subgroups of compounds of the invention are those of formulae la, laa, lab and laaa wherein R1a is hydrogen or alkyl of 1 to 4 carbon atoms, particularly hydrogen or methyl, especially hydrogen; those wherein R2 and R5 are hydrogen or alkyl of 1 to 4 carbon atoms, particularly methyl; those wherein R is hydrogen; and those wherein X is oxygen; and combinations thereof; and where appropriate their corresponding quaternary salts as defined above.

Another preferred group of compounds of the invention is the compounds of formula Ib,

wherein Rl, R2, R5 and Q are as defined above; Rb3 is alkyl of 1 to 12 carbon atoms or independently has the significance indicated below for AbRb4; R4b is: hydroxy; alkoxy of 1 to 12 carbon atoms; -OCOR6b; -NR7bR8b; or -NB) as defined above; wherein R6b, R7b and R8b have the significance indicated above for R6, R7 and R8, respectively; and Ab is alkylene of 9 to 14 carbon atoms; and their ammonium salts wherein Rb4 is selected from one of the tertiary amino groups defined above for Rb4 and quaternized with a group of formula AlkY as defined above.

In a subgroup of compounds of fromula ib R4b is other than alkoxy. In another subgroup R3b and R4b are -NR7bR8b or -NB) as defined above.

A preferred group of compounds of formula Ib is the compounds of formula Iba,

wherein R1,R2,R4b,R5,Ab and Q are as defined above and R3ba is alkyl of 1 to 6 carbon atoms; and their ammonium salts wherein Rb4 is selected from one of the tertiary amino groups defined above for Rb4 and quaternized with a group of formula AlkY as defined above.

In a subgroup of compounds of formula lba R4b is other than alkoxy. In another subgroup R4b is -NR7bR8b or -NB) as defined above.

A further preferred group of compounds of formula Ib is the compounds of the formula Ibb,

wherein R1, R2, R5, Ab and Q are as defined above; Rb3b is alkyl of 1 to 1 2 carbon atoms or independently has the significance indicated below for -AbR4bb; R4bb is: hydroxy; alkoxy of 1 to 12 carbon atoms; -OCOR6b; or -NR7bR8b; wherein R8b, Rb7 and R8b are as defined above; and their ammonium salts wherein R4b is selected from one of the tertiary amino groups defined above for Riband quaternized with a group of formula AlkY as defined above.

In a subgroup of compounds of formula lbb R4bb is other than alkoxy. In another subgroup R3bb and R4bb are -NR7bR8b as defined above.

A further preferred group of compounds of formula lb is the compounds of formula lbaa,

wherein R1,R2,R3ba,R4bb,R5,Ab and O are as defined above; and their ammonium salts wherein R4bb is selected from one of the tertiary amino groups defined above for R4bb and quaternized with a group of formula AlKY as defined above.

In a subgroup of compounds of formula lbaa R4bb is other than alkoxy. In another subgroup R4bb is NRb7Rb9 as defined above.

Further groups and subgroups of compounds of the invention on those of formule Ib, Iba, Ibb and Ibaa wherein R1 is Rat as defined above, particularly hydrogen or alkyl, especially hydrogen or methyl, in particular hydrogen; those wherein R2 and R6 are hydrogen or alkyl of 1 to 4 carbon atoms, particularly methyl; those wherein Q is a group of formula

wherein R and X are as defined above, particularly those wherein R is hydrogen; and those wherein X is oxygen; and combinations thereof; and where appropriate their corresponding quaternary salts as defined above.

Another group of compounds of the invention is the compounds of formula Ip

wherein RP1 is hydrogen or alkyl of 1 to 6 carbon atoms; RP2 and RP5 independently are alkyl of 1 to 4 carbon atoms; RP3 is alkyl of 1 to 6 carbon atoms or independently has the significance indicated below for -ApR4p; R4p is: hydroxy; alkoxy of 1 to 6 carbon atoms: -OCOR6p; -NR7pR8p; or -NB)p; wherein R6p is: alkyl of 1 to 6 carbon atoms; phenyl, phenylalkyl of 7 to 10 carbon atoms or bis phenylalkyl of 13 to 16 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur; or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; R7p is: hydrogen: alkyl of 1 to 4 carbon atoms; or with the exception of alkyl of 1 to 6 carbon atoms has the significance indicated above for R6p; R8p is: hydrogen; or alkyl of 1 to 6 carbon atoms; or is -COR9p wherein R9p has the signigicance indicated above for R6p; -NB)P is: a 5-, 6- or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6- or 7-membered, a further heteromember selected from oxygen, sulfur and = wherein RP10 either is hydrogen or has the significance indicated above for RP7; AP is unbranched alkylene of 2 to 14 carbon atoms; and Qp is a condensed, fully unsaturated bicyclic ring system having at least 2 different ring heteroatoms overall and having at least one aromatic ring; with the proviso that when R4p is: hydroxy; alkoxy of 1 to 6 carbon atoms; -NB)p as defined above; or NR7p R8'p wherein R7'p is: hydrogen; a lkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and R8'p is hydrogen or alkyl of 1 to 6 carbon atoms; the Ap is unbranched alkylene of 7 to 14 carbon atoms; and their ammonium salts wherein R4p is selected from one of the tertiary amino groups defined above for R4p and quaternized with a group of formula AlKY wherein AlK is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.

In a subgroup of compounds of formula Ip RP3 is alkyl of 1 to 6 carbon atoms; in another subgroup it is alkyl of 1 to 3 carbon atoms; in another subgroup it is -ApR4p wherein Ap and R4p are as defined above; in another subgroup R4p is other than alkoxy; in another subgroup Ap is unbranched alkylene of 7 to 14 carbon atoms; in another subgroup Ap is unbranched alkylene of 9 to 14 carbon atoms; in another subgroup R4p is: hydroxy; alkoxy of 1 to 6 carbon atoms; -OCOR6p; or NR7pR8p wherein R6p, R7p and R8p are as defined above; and combinations thereof; and where appropriate their corresponding quaternary salts as defined above.

Another group of compounds of the invention is the compounds of formula Is,

wherein R2s and R5s independently are alkyl of 1 to 4 carbon atoms; R3s is alkyl of 1 to 12 carbon atoms; R4s is: hydroxy; alkoxy of 1 to 4 carbon atoms; -OCOR6s; -NR7sR8s; or -NB)s; wherein R6s is alkyl of 1 to 4 carbon atoms or phenyl; R75 is: hydrogen; alkyl of 1 to 4 carbon atoms; phenylalkyl of 7 to 10 carbon atoms optionally mono- or independently disubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 53; -CORgs wherein R95 is alkyl of 1 to 4 carbon atoms; or phenyl or phenylalkyl of 7 to 10 carbon atoms both optionally mono- or independently disubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; R85 is: hydrogen or alkyl of 1 to 4 carbon atoms; -NB)S is piperidine or piperazine both substituted in the 4 position by methyl, benzyl, or bisphenylmethyl optionally mono- or independently disubstituted in the phenyl ring(s) by halogen of atomic number of from 9 to 53 or alkoxy of 1 to 4 carbon atoms: As is alkylene of 2 to 14 carbon atoms; with the proviso that, when R4s is hydroxy; alkoxy of 1 to 4 carbon atoms; -NB)s as defined above; or -NR7s'R8s' wherein R7s' is: hydrogen; alkyl of 1 to 4 carbon atoms; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and R95 is as defined above; then A is alkylene of 7 to 14 carbon atoms; and their ammonium salts wherein R45 is selected from one of the tertiary amino groups defined above for R45 and quaternized with a group of formula AlkY as defined above.

In a subgroup of compounds of formula Is As is alkylene of 7 to 1 4 carbon atoms; in another subgroup it is alkylene of 9 to 14 carbon atoms; in another subgroup it is unbranched.

In a further subgroup of compounds of the invention RB, R7 and/or R8 is substituted phenyl, substituted phenylalkyl or substituted bis-phenylalkyl.

In a further subgroup R, is hydrogen or alkyl of 1 to 6 carbon atoms; in a further subgroup R2 and R5 independently are alkyl of 1 to 4 carbon atoms; in a further subgroup R3 is alkyl of 1 to 6 carbon atoms; in a further subgroup R3 is -APR4P as defined above; in a further subgroup A is unbranched alkylene and R4 has the significance indicated above for R4, including the proviso thereto; in a further subgroup R6, R7 and/or R9 have the significance indicated above for R6P, R7P and/or R9, respectively; in a further subgroup -NB) has the significance indicated above for -N 9)P in a further subgroup Q is bicyclic; in a further subgroup R4 is alkoxy of 1 to 6 carbon atoms; in a further subgroup substituted or unsubstituted phenylalkyl is of 7 to 10 carbon atoms in the phenylalkyl moiety, and substituted or unsubstituted bis-phenylalkyl is of 1 3 to 1 6 carbon atoms in the bis-phenylalkyl moiety; in a further subgroup R7 has the significance indicated above for R7. In a further subgroup all uncondensed phenyl rings are substituted.

R1 preferably has the significance indicated above for R,a.R,a preferably is hydrogen. When it is other than hydrogen it preferably is unsubstituted alkyl, cycloalkylalkyl, optionally substituted phenylalkyl, alkoxyalkyl or morpholino, preferably unsubstituted alkyl or alkoxyalkyl, preferably unsubstituted alkyl. When R18 is alkoxyalkyl the alkoxy part thereof preferably is separated from the nitrogen atom by at least 2 carbon atoms.

R2 and/or R5 preferably are alkyl.

R3 preferably is alkyl. When it has the significance indicated for -AR4 it preferably is identical to -AR4.

R4 preferably is hydroxy, -OCOR6, -NR7R8 or -NB)- 0 preferably has at least 3 heteroatoms overall, in particular 3. It preferably is a bicyclic system. Preferred groups Q are 2,1,3-benzoxadiazolyl and 2,1,3-benzothiadiazolyl, in particular 2,1 ,3-benzoxadiazolyl. When Q is a ring system having a benzene ring component the 1,4dihydropyridinyl moiety preferably is bound to that ring component, preferably at a position on the benzene ring component which is adjacent to further ring component(s).

A preferably is unbranched. It preferably has 7 to 14, especially 9 to 14, particularly 10 carbon atoms.

Alk preferably is methyl.

Y preferably is the rest of an anorganic acid, e.g. mesyl or halogen, particularly iodine.

R6 preferably is alkyl, phenyl, phenylalkyl or bis-phenylalkyl, particularly phenyl.

R7 preferably is hydrogen, alkyl, phenylalkyl or bisphenylalkyl.

R8 preferably is hydrogen, alkyl or -CORg.

Preferably either both R7 and R9 are hydrogen, or one of R7 and R9 is alkyl and the other is alkyl, optionally substituted phenylalkyl or optionally substituted bis-phenylalkyl.

R9 preferably is alkyl, optionally substituted phenyl, optionally substituted phenylalkyl or optionally substituted bisphenylalkyl.

-NB) as defined above preferably is saturated. It preferably is 6-membered. It preferably is 1piperazinyl. When it is 6- or 7-membered it preferably has a further heteromember = No,,. R,o preferably is other than hydrogen. It preferably is alkyl, optionally substituted phenylalkyl or optionally substituted bis-phenylalkyl.

X preferably is oxygen.

R preferably is hydrogen.

The moiety

preferably is bound at its 4 position with the 4 position on the 1,4-dihydropyridinyl moiety.

Cycloalkyl of 3 to 7 carbon atoms preferably is of 3,5 or 6, especially of 5 or 6 carbon atoms.

Alkyl of 1 to 1 2 carbon atoms and/or alkoxy of 1 to 1 2 carbon atoms preferably are of 1 to 6 carbon atoms, especially of 1 to 4 carbon atoms, it particularly is methyl, ethyl or isopropyl.

Alkyl of 1 to 6 carbon atoms preferably is of 1 to 4, especially of 1 or 2 carbon atoms, it particularly is methyl. When alkyl of 1 to 6 or of 1 to 4 carbon atoms is a phenyl ring or amino substituent is preferably is of 1 or 2 carbon atoms, it especially is methyl. When alkoxy of 1 to 4 carbon atoms is a phenyl ring substituent it preferably is of 1 or 2 carbon atoms, it especially is methoxy. Alkenyl and/or alkinyl preferably are of 3 carbon atoms. The cycloalkyl part of cycloalkylalkyl preferably are of 3,5 or 6 carbon atoms, especially of 5 or 6 carbon atoms. The alkylene part of cycloalkylalkyl and/or of phenylalkyl preferably is of 1 or 2 carbon atoms, it especially is methylene. The alkenylene part of phenylalkenyl preferably is of 3 carbon atoms.

The alkylene part of hydroxyalkyl of 2 to 6 carbon atoms and/or of alkoxyalkyl of 2 to 6 carbon atoms preferably is of 2 or 3 carbon atoms, especially of 2 carbon atoms. The hydroxy part of hydroxyalkyl and/or of hydroxyalkoxyalkyl and/or the amino part of aminoalkyl preferably is attached to the distal terminal carbon atom.

Where a phenyl ring is present in a substituent, it is preferably unsubstituted. When it is substituted it preferably is monosubstituted, preferably in the para position. When it is disubstituted it preferably is substituted in the ortho or meta and in the para positions. When it is trisubstituted it preferably is substituted in the meta, meta and para positions. Alkoxy and/or halogen are preferred as substituents on a phenyl ring substituent. When a phenyl ring is polysubstituted the substituents preferably are indentical.

The amino part of aminoalkyl preferably is substituted, especially disubstitutelil. Preferred substituents of the amino part of aminoalkyl are alkyl and/or optionally substituted phenylalkyl.

Preferably the amino part of aminoalkyl is disubstituted by alkyl and optionally substituted phenylalkyl.

In bis-phenylalkyl the two phenyl rings may be attached to the same or to different carbon atoms. They are preferably attached to the same carbon atom. Bis-phenylalkyl preferably is bisphenylmethyl.

A 5-membered heteroaryl moiety as defined above preferably is pyrrolyl, furyl or thienyl. A 6membered heteroaryl moiety as defined above preferably is pyridinyl, especially 4-pyridinyl.

Phenylalkyl preferably is of 7 to 10 carbon atoms. Bisphenylalkyl preferably is of 1 3 to 1 6 carbon atoms.

Halogen of atomic number of from 9 to 53 preferably is bromine or iodine. Halogen of atomic number of from 9 to 35 preferably is chlorine.

A compound of the invention may be obtained by a process comprising appropriately converting a corresponding compound of formula II,

wherein R1, R2, R5 and Q are as defined above, Z is a reactive group and Z' either is a reactive group or has the significance indicated above for -OR3.

The process of the invention may be effected in a manner analogous to known processes.

The choice of the most appropriate process variant depends of course on the nature of e.g.

the substituents -AR4 and R3.

A process variant may e.g. be an esterification. A reactive group Z or Z' is then conveniently a 1 H-imidazol-1-yI. This process variant is indicated e.g. for converting into a hydroxyalkyl, amidoalkyl, alkoxyalkyl, acyloxyalkyl or substituted or unsubstituted aminoalkyl substituent. A corresponding compound of formula II is thus reacted with a corresponding diol, amido/alcohol, ester/alcohol or aminoalcohol. As a solvent dioxane or an excess of the reaction partner may conveniently be used.

A further process variant may e.g. be an amination. This variant is indicated e.g. for converting into an aminoalkyl substituent. A reactive group Z or Z' is then conveniently a group -O-A-Z" wherein A is as defined above and Z" is chlorine, bromine or a group Rz-SO2-O- wherein Rz is phenyl, tolyl or lower alkyl. Z" preferably is mesyloxy. The amination may be direct, i.e. reaction takes place directly with an amine having the substituent to be introduced, or indirect, e.g., for introducing a primary amino group, by first converting into a corresponding phthalimidoalkyl derivative, e.g. by reaction with sodium or potassium phthalimide and subsequently reacting the resultant phthalimidoalkyl derivative with hydrazine. The indirect method is preferred when the substituent it is desired to introduce is a primary aminoalkyl group.

A further process variant may e.g. be an acylation of a primary or secondary amine. A reactive group Z or Z' is then conveniently the corresponding primary or secondary amino alkoxy group.

A corresponding compound of formula II is thus reacted with a corresponding acyl derivative, e.g. an N-hydroxysuccinimide ester. A suitable solvent is e.g. dioxane.

A further process variant may e.g. be an acylation of an alcohol. A reactive group Z or Z' is then conveniently the corresponding hydroxyalkoxy group. A corresponding compound of formula II is thus reacted with a corresponding acyl derivative, e.g. an acyl halide. The reaction preferably is effected in the presence of a strong base such as N-ethyldiisopropylamine. A suitable solvent is e.g. methylene chloride.

A further process variant may e.g. be an etherification. A reactive group Z or Z' is then conveniently a group -O-A-Z" wherein A and Z" are as defined above. The reaction preferably is effected under strongly alkaline conditions.

When in the starting material Z' is a reactive group then a group -AR4 may simultaneously be formed at both the 3- and 5- position of the 1 4-dihydropyridinyl moiety.

A quaternary ammonium salt may also be produced in a manner analogous to known methods, e.g. by reaction with a corresponding (lower) alkyl iodide. A suitable solvent is e.g. an alcohol, such as methanol.

When potentially reactive groups such as hydroxy or primary or secondary amino are present it may be indicated to effect the process of the invention with these groups in protected form, e.g. for phenolic hydroxy in the form of a benzyloxy group, or for aliphatic hydroxy in the form of a tetrahydropyranyloxy moiety, or for amino in the form of an acylamino or a phthalimido group and to convert thereafter any protecting group present as such into the desired substituent, e.g. benzyloxy to hydroxy, e.g. hydrogenolytically; tetrahydropyranyloxy to hydroxy, e.g. by acid hydrolysis; and protected amino to deprotected amino, e.g. by acid hydrolysis or hydrazinolysis.

A compound of the invention may be isolated from the reaction mixture and purified in a manner analogous to known methods.

A compound of the invention may exist in free form or where appropriate in salt form. A free form of a compound normally is neutral unless substituted by an ionizable substituent. A salt form may exist e.g. when an ionizable substituent is present, such as amino or phenolic hydroxy. A free form may be converted into a salt form in conventional manner and vice-versa.

Suitable acids for acid addition salt formation include hydrochloric, malonic, p-toluene sulfonic and methanesulfonic acid. Suitable bases for anionic salt formation include sodium and potassium hydroxide.

When the substituents in the 2 and 6 positions and/or in the 3 and 5 positions of the 1,4dihydropyridinyl moiety are different the carbon atom in the 4 position is asymmetrically substituted. A corresponding compound of the invention may thus exist in the racemic form or in individual enantiomer form.

Individual optical isomer forms may be obtained in conventional manner.

A compound used as a starting material may be obtained in conventional manner, e.g. by cyclisation to a 1 ,4-dihydropyridinyl moiety.

Insofar as the preparation of any particular starting material is not particularly described, this may be effected in conventional manner or in analogous manner to that described herein.

In the following Examples all temperatures are in degrees Centigrade and are uncorrected.

Example 1: 4-(2, 1, 3-Benzoxadiazol-4-yl)- 1, 4-dihydro-5-isopropoxycarbonyl-2, 6-dimethyl-3-pyridine-carboxylic acid-( 1 O-hydroxydecyl)ester (esterification of imidazolide with alcohol) A mixture of 5.2 g 4-(2,1. 3-benzoxadiazol-4-yl)-1 ,4-di-hydro-5-(l H-imidazol-l -ylcarbonyl)-2,6- dimethyl-3-pyridine carboxylic acid isopropyl ester and 44.5 g of decan-1,10-diol are heated for 2 hours at 120 oil bath temperature. After cooling ether is added to the mixture. The excess decan-1,10-diol crystallizes out. After filtration and evaporation of the ether under vacuum the product is chromatographed over silicagel under moderate pressure using methylene chloride/ ether as an eluent. The title compound is obtained (oil).

NMR-spectrum (CDCl3) S(ppm): 0.97(3H,d,J = 6Hz), 1,22(3H,d,J = 6Hz), 1,15-1,65 (16H,m), ca. 2.32(6H,2s), 3.63(2H,t,J = 6Hz),3,99(2H,m), 4,91(1H,m,J = 6Hz), 5,48(1H,s), 5,92(1H,s), 7,3(2H,m), 7,62(1H,m).

Example 2: 4-(2, 1, 3-Benzoxadiazol-4-yl)- 1, 4-dihydro-5-isopropoxycarbonyl-2, 6-dimeth yl-3-pyri- dine-carboxylic acid [1 O-(N-benzylmeth ylam in o)decyl]ester (direct amination of mesylate) 4.6 g 4-(2,1,3-benzoxad iazol-4-yl)- 1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyrid ine carboxylic acid-(10-methanesulfonyloxydecyl)ester and 2.2 ml N-benzylmethylamine are dissolved in 50 ml ether, the solution is evaporated to dryness in vacuo and the residue heated to 80 for 3 hours. The reaction mixture is then dissolved in ether, the solution washed with cold 1 N sodium hydroxide, the ethereal phase dried over magnesium sulfate and evaporated to dryness in vacuo. The product is purified cy chromatography over silicagel using methylene chloride/ethanol 1 9:1 as an eluent. The title compound is obtained (free base: oil; hydrochlo ride: amorphous).

NMR-spectrum of the base form (CDCI3) 6(pom): 0,98(3H,d,J =6Hz),1,25(3H,d,J = 6Hz), 1,15-1,8(1 6H,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(1 H,m,J = 6Hz), 5,48(1H,s), 5,98(1H,s), 7,2-7,7(8H,m).

The mesylate used as a starting material is obtained by reacting 4.3 g of the title compound of Example 1 and 4.3 ml of N-ethyldiisopropylamine in 90 ml methylene chloride at 0" with 1.0 ml of methanesulfonic acid chloride added dropwise and agitating the resultant mixture 90 minutes in an ice bath. The solution is then washed with cold 2N hydrochloric acid solution, the organic phase dried over magnesium sulfate and evaporated in vacuo.

Example 3: 4-(2, 1, 3-Benzoxadiazol-4-yl)- 1, 4-dihydro-5-isopropoxycarbonyl-2, 6-dimeth yl-3-pyri- dine carboxylic acid-( 1 O-aminodecyl)ester (amination of mesylate over phthalimido derivative) 2.2 g 4-(2, 1, 3-benzoxadiazol-4-yI)- 1, 4-dihydro-5-isopropoxycarbonyl-2, 6-dimethyl-3-pyridine carboxylic acid-(10-methanesulfonyloxydecyl)ester are dissolved in 44 ml of dimethylformamide, 2.2 g potassium phthalimide are added and the mixture is stirred for 3 hours at 80 bath temperature. The solution is then cooled off, filtered, washed with 100 ml of methylene chloride, the filtrate purified by extracting 8 times with cold 2N hydrochloric acid solution and then evaporated to dryness in vacuo.The product is chromatographed over silicagel under slight pressure using ether as diluent.

The resultant 4-(2,1,3-benzoxadiazol-4-yl)- 1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3- pyridine carboxylic acid-(10-phthalimidodecyl)ester (oil) is dissolved in 40 ml of ethanol, 1.0 ml hydrazine hydrate is added and the solution heated to boiling temperature under refluxing for 30 minutes. After filtration and washing with methylene chloride the solution is extracted with ice-cold water and the organic phase evaporated to dryness in vacuo.

The product is chromatographed under slight pressure over silicagel using methylene chloride/methanol (containing ammonia) 9:1 as an eluent. The title compound is obtained (M.P.

102'from ether).

Example 4: 4-(2, 1, 3-Benzoxadiazol-4-yl)- 1, 4-dihydro-S4sopropoxycarbonyl-2, 6-dimethyl-3-pyridine carboxylic acid-[10-[3-(4-hydroxy-3-iodophenyl)-1-oxo-propylamino]decyl]ester (Amidation of amine) A solution of 0.5g 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid-(10-aminodecyl)ester and 0.4g 3-(4-hydroxy-3-iodophenyl)propionic acid-N-hydroxysuccinimid ester in 15 ml dioxane are heated for 30 minutes to 120 bath temperature, the solution is then cooled off, diluted with methylene chloride and extracted with cold saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, evaporated to dryness in vacuo and the product is chromatographed over silicagel under slight pressure using methylene chloride/ethanol 49:1 as an eluent.The title compound is obtained (amorphous).

NMR-spectrum (CDCl3) #(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(1 H,m,J = 6Hz), 5,53(1 H,s), ca. 5.62(1H, broad), ca. 6,55(2H, broad), 6,9(1 H,d,J = 8Hz), 7.1(1 H,2d,J = 8Hz and 2Hz), 7,25-7,75(4H,m).

Example 5: 4-(2, 1, 3-Benzoxadiazol-4-yl)- 1, 4-dihydro-5-isopropoxycarbonyl-2, 6-dimethyl-3-pyridine-carboxylic acid-( 1 O-benzoyloxydecyl)ester (acylation of alcohol) To a solution of 2.2 g of the title compound of Example 1 and 1.3 g N-ethyldiisopropylamine in 30 ml methylene chloride is added at 20 1.2 9 benzoyl chloride and the solution stirred for 1 hour at 40 . The reaction mixture is then diluted with ether, washed successively with water, 1 N sodium hydroxide and 1 N hydrochloric acid solution, dried over magnesium sulfate and evaporated in vacuo. The produce is purified by chromatography over silicagel using methylene chloride/ether 9: 1 as an eluent.The title compound is obtained (amorphous) NMR-spectrum (CDCl3) 3(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(1 H,m,J = 6Hz), 5,5(1 H,s), 6.08(1 H,s), 7,15-8,15(8H,m).

Example 6: 4-(2, 1, 3-Benzoxadiazol-4-yl)- 1, 4-dihydro-5-isopropoxycarbon yl-2, 6-dimeth yl-3-pyri- dine-carboxylic acid [I O-(N-benzylmethylamino)decyl]esfer (esterification of imidazolide with aminoalcohol) A solution of 4 9 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-(1 H-imidazol-1 -ylcarbonyl)-2,6dimethyl-3-pyridine carboxylic acid isopropyl ester and 7.0 g 10-(N-methylbenzylamino)decan-1ol in 150 ml dioxane is heated for 16 hours at reflux temperature. The reaction mixture is then evaporated to dryness in vacuo and the residue heated for 3 hours at 80". The product is purified by chromatography over silicagel using methylene-chloride/ethanol 1 9:1 as an eluent.

The title compound is obtained (free base: oil; hydrochloride:amorphous).

NMR-spectrum: see Example 2.

The aminoalcohol used as a starting material is obtained as follows: a) To a solution of 20 g decan-1,10-diol and 20 ml N-ethyldiisopropylamine in 800 ml methylene chloride and 100 ml acetone is added dropwise at 30" a solution of 4.5 ml methanesulfonic acid chloride in 60 ml methylene chloride and the mixture is stirred for 1 hour at room temperature. Methanesulfonic acid-(10-hydroxydecyl)ester is obtained (M.P.: 48"from ether, after chromatography over silicagel using methylene chloride/ether 2:1 as an eluent).

b) A mixture of 8.5 g of the mesylate obtained as described under a) above and 12.3 g of Nmethylbenzylamine is heated for 2 hours to 80". 10-(N-Methylbenzylamino)decan-1-ol is obtained (oil; after chromatography over silicagel using ether as an eluent).

Example 7: 4-(2, 1, 3-Benzoxadiazol-4-yl)- 1, 4-dihydro-5-isopropoxycarbon yl-2, 6-dimethyl-3-pyridine carboxylic acid-( 1 O-methoxydecyl)ester (etherification of mesylate) 2.3 g of 4-(2, 1, 3-benzoxadiazol-4-yl)-1 ,4-dihydro-5-isopropoxycarbonyl-2, 6-dimethyl-3-pyri- dine carboxylic acid-(10-methanesulfonyloxydecyl)ester in 30 ml methanol are reacted with 0.5 g potassium methylate and the mixture is heated for 4 hours at reflux temperature. After evaporation to dryness in vacuo the product is dissolved in ether, the solution washed over with 1 N hydrochloric acid solution, the organic phase dried over magnesium sulfate and evaporated to dryness. The product is then purified by chromatography over silicagel using ether/hexane 1:1 as an eluent. The title compound is obtained (oil).

NMR-spectrum (CDCl3) 8(pom): 0,98(3H,d,J = 6Hz), 1,1-1,9(19H, m), 2,32(6H,s), 3,35(3H,s), 3,39(2H,t,J = 6Hz), 4,0(2H,t,J = 6Hz), 4,95(1 H,m,J = 6Hz), 5,5(1 H,s), 6,3(1 H,s), 7,2-7,8(3H,m).

The following compounds of formula I are obtained in analogous manner from the corresponding starting materials:

Example Analogous Q R1 R2 R3 AR4 R5 Configuration No. to at 4 position Example of 1,4-dihy N0. dropyridinyl moiety 8 1 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10OH Me (+)(R) 9 1 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10OH Me (-)(S) 10 1 2,1,3-benzoxadiazol-4-yl H Me Me -(CH2)10OH Me (R,S) 11 1 2,1,3-benzoxadiazol-4-yl H Me -(CH2)9Me -(CH2)10OH Me (R,S) 11a 1 2,1,3-benzoxadiazol-4-yl H Me Et -(CH2)10OH Me (R,S) 12 22):6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10N(Me)Bz Me (-)(S) 13 21)::6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10N(Me)Bz Me (+)(R) 14 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10#-CH(Phe)2 Me (R,S) 15 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10N(Me)Bu Me (R,S) 16 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10N(Me)CH2CH2PHe Me (R,S) 17 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10NMe2 Me (R,S) 18 23);6 2,1,3-benzoxadiazol-4-yl H Me Me -(CH2)10N(Me)Bz Me (R,S) 19 24);6 2,1,3-benzoxadiazol-4-yl H Me Et -(CH2)10N(Me)Bz Me (R,S) 20 2;;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10N(Me)CH2# Me (R,S)

Example Analogous Q R1 R2 R3 AR4 R5 Configuration No. to at 4 position Example of 1,4-dihy N0. dropyridinyl moiety 21 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10N(Me)CH2CH2# Me (R,S) 22 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10#-CH(p-F-Phe)2 Me (R,S) 23 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)5N(Me)CH2# Me (R,S) 24 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)5N(Me)CH2CH2# Me (R,S) 25 22);6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10#-CHPhe2 Me (-)(S) 26 21);6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10#-CHPhe2 Me (+)(R) 26a 2;6;;-10) 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10NHME Me (R,S) 26b 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10#-Me Me (R,S) 26c 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10-#-(o-MeO)Phe Me (R,S) 26d 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10-#-CH(Phe)2 Me (R,S) 26 e 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10-#-Bz Me (R,S) 27 35);21);6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10NH2 Me (+)(R) 28 35);22);6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10NH2 Me (-)(S) 29 33)6);23);;6 2,1,3-benzoxadiazol-4-yl H Me Me -(CH2)10NH2 Me (R,S) 30 2;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10NH2 Me (R,S)

Example Analogous Q R1 R2 R3 AR4 R5 Configuration No. to at 4 position Example of 1,4-dihy N0. dropyridinyl moiety 31 4;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)2NHCOCH2CH2#-OH Me (R,S) 32 4;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)5NHCOCH2CH2#-OH Me (R,S) 33 4;6 2,1,3-benzoxadiazol-4-yl H Me Me -(CH2)10NHCOCH2CH2#-OH Me (R,S) 34 4;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10NHCOCH2#-OH Me (R,S) 35 4;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10NHCOCH2CH2#-OH Me (-)(S) 36 4;6 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10NHCOCH2CH2#-OH Me (+)(S) 37 4;;17) 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10NHCOMe Me (R,S) 38 4;17) 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10NHCOtBu Me (R,S) 39 4;17) 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10NHCOPhe Me (R,S)

Example Analogous Q R1 R2 R3 AR4 R5 Configuration No. to at 4 position Example of 1,4-dihy N0. dropyridinyl moiety 40 5;18) 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10OCOtBu Me (R,S) 41 18) 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10OCOPhe Me (R,S) 41a 1 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10OMe Me (R,S) 42 ~9) 2,1,3-benzoxadiazol-4-yl H Me iPr -(CH2)10N(+)Me3i(-) Me (R,S) Bu = n-butyl iPr = isopropyl tBu = tert-butyl Bz = benzyl Me = methyl (R,S) = in racemic form Et = ethyl Phe = phenyl 1) The (+)-(4R)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridine car boxylic acid-(10-methanesulfonyloxydecyl)ester used as a startin material is obtained as an oil starting from the alcohol of Example 8, as described in Example 2 for the corresponding racemate.

2) The (-)-(4S)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridine car boxylic acid-(10-methanesulfonyloxydecyl)ester used as a starting material is obtained as an oil starting from the alcohol of Example 9, as described in Example 2 for the corresponding racemate.

3) The 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid (10-methanesulfonyloxydecyl)ester used as a starting material is obtained starting from the compound of Example 10, as described in Example 2 for the corresponding 5-isopropoxycarbonyl compound.

4) The 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-ethoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid (10--methanesulfonyloxydecyl)ester used as a starting material is obtained from the compound of Example lla, as described in Example 2 for the corresponding 5-isopropoxycarbonyl compound.

5) The (+)-(4R)- and, respectively, (-)(4S)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl 2,6-dimethyl-3-pyridine carboxylic acid-(10-phthalimidodecyl)ester are obtained as an oil starting from the mesylate of footnote 1) or, respectively, footnote 2), as described in Example 3 for the corresponding racemate.

6) The 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid (10-phthalimidodecyl)ester used as a starting material is obtained from the mesylate compound des cribed in footnote 3), as described in Example 3 for the corresponding 5-isopropoxycarbonyl compound.

7) The amidoalcohol used as a starting material is obtained by reacting the corresponding aminoal cohol with the appropriate acylating agent.

8) The alcohol/ester used as a starting material is obtained by reacting an excess of the corresponding diol with the corresponding acylating agent.

9) Starting from 1.4g of the compound of Example 17 in free base form dissolved in 20 ml methanol, by re acting with 0.21 ml methyl iodide at room temperature for 4 hours.

10)Analogous to Example 2, but by splitting off the benzyl protecting group from the compound of Example 2 with hydrogen over palladium 10% on carbon in methanol as a last step.

Physical characterization data for the compounds in the above table are as follows:

Example M.P. [αD20 [α]D546 No.

8 n oil + 20 + 28 (c = 1 g/dl in ethanol) 9 n oil - 20 - 28 (c = 1 g/dl in ethanol) 10 n oil - - 11 n oil - - 11a n oil - - 12 ch amorphous - 14 - 19 (c = 0.9 g/dl in ethanol) 13 ch amorphous + 13 + 19 (c = 0.9 g/dl in ethanol) 14 fu 130 - - 15 b oil - - 16 b oil - - 17 fu 95 - - 18 ch amorphous - - 19 ch amorphous - - 20 ch amorphous - - 21 ch amorphous - - 22 ch amorphous - - 23 ch amorphous - - 24 ch amorphous - - 25 fu 130 - 12 - 16 (c = 0.5 g/dl in ethanol) 26 fu 130 + 12 + 18 (c = 0.7 g/dl in ethanol) 26a ch amorphous - - 26b b oil; ch amorphous - - 26c b oil ;; ch amorphous - - 26d b oil; ch amorphous - - 26e b oil; ch amorphous - -

Example M.P. [αD20 [α]D546 No.

27 b 84 + 24 + 33 (c = 0.8 g/dl in ethanol) 28 b 83 - 24 - 33 (c = 0.6 g/dl in ethanol) 29 b 105 - - 30 b 102 - - 31 n amorphous - - 32 n amorphous - - 33 n amorphous - - 34 n amorphous - - 35 n amorphous - 13 - 18 (c = 0.5 g/dl in ethanol) 36 n amorphous + 13 + 20 (c = 0.5 g/dl in ethanol) 37 n oil - - 38 n amorphous - - 39 n amorphous - - 40 n oil - - 41 (see Example 5) 41a (see Example 7) 42 - 98 - - b = in free base form ch = in hydrochloric acid addition salt form fu = in fumaric acid addition salt form n = in free neutral form.

The compounds of the invention possess pharmacological activity.

The compounds exhibit effects typical of calcium antagonists. They exhibit a pronounced muscle-relaxing effect, particularly on smooth muscle, as evidenced by vasodilating and blood pressure lowering activity in standard tests. For example in the anaesthetized cat test using tracer microspheres (R. Hof et al., Basic Res. Cardiol. 75 [1980] 747-756 and 76 [1981] 630-638; R. Hof et al., J. Cardiovasc. Pharmacol. 4 [1 982] 352-362) coronary vasodilation, an increase in skelettal muscle blood flow and a fall in blood pressure are observed upon intravenous administration of from about 3 to about 300 yg/kg, e.g. of from about 10 to about 100 yg/kg.

A fall in blood pressure is also observed in the conscious spontaneously hypertensive rat (method of Gerold und Tschirki, Arzneimittelforsch. 18 [1968] 1285) upon- administration of from about 1 to about 10 mg/kg p.o. of the compounds. Thus, the title compound of Example 2 causes a fall in blood pressure of 40% after administration of 3 mg/kg p.o. The compounds are longer acting than known standard compounds, they are suitable e.g. for once-a-day administration. The compounds are also particularly well-absorbed orally.

The compounds are therefore indicated for use as calcium antagonists for the prevention and treatment of coronary insufficiency, e.g. Angina pectoris; -other disturbances in circulation e.g. in limbs such as intermittent claudication and spasms, e.g. cholic; asthma, e.g. exertion-related asthma; -hypertension; The compounds also have a vasodilating activity on capillary vessels of the carotid area; the vasoconstrictor effect of serotonin is thereby antagonized and the associated dysregulation inhibited. This makes the compounds indicated for the prevention and treatment of migraine and vascular headache such as cluster headache, especially for the interval treatment (prevention) of migraine.Preferred in this indication are the compounds having a relatively moderate effect on blood pressure and peripheral blood vessels.

An indicated daily dosage is from about 1 mg to about 200 mg, suitably administered, e.g.

orally, in divided dosages of from about 0.3 mg to about 200 mg of the compounds 1 to 3 times a day, or in sustained release form. An example of a daily dosage is from about 5 mg to about 50 mg.

Preferred are the title compounds of Examples 2,5,14,29 and 41, especially of Examples 2 and 14.

Preferred for the prevention and treatment of migraine and vascular headache are the compounds wherein Q is a 2,1 ,3-benzothiadiazolyl moiety.

The compounds of the invention may be administered in free form or where appropriate in pharmaceutically acceptable salt form, preferably acid addition salt form. Such salt forms exhibit the same order of activity as the free forms and are readily prepared in conventional manner.

The present invention also provides a pharmaceutical composition comprising a compound of the invention in free form or where appropriate in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a capsule suitable e.g. for sublingual administration, or a tablet.

Claims (1)

1. A process for the production of a compound of formula I,

wherein R, is hydrogen; cycloalkyl of 3 to 7 carbon atoms; or optionally substituted alkyl of 1 to 6 carbon atoms; R2 and R5 independently are hydrogen or alkyl of 1 to 6 carbon atoms; R3 is alkyl of 1 to 1 2 carbon atoms or independently has the significance indicated below for -AR4, including the proviso thereto; R4 is: hydroxy; alkoxy of 1 to 12 carbon atoms; -OCOR5; -NR7R8; or -NB); wherein R6 is: alkyl of 1 to 6 carbon atoms; phenyl, phenylalkyl of 7 to 1 2 carbon atoms or bisphenylalkyl of 1 3 to 1 8 carbon atoms, the last three substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 hetroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur; or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; R7 is hydrogen or has the significance indicated above for R6; R8 is: hydrogen; or alkyl of 1 to 6 carbon atoms; or is -COR9 wherein R9 has the significance indicated above for R6; -NB; is: a 5-, 6- or 7-membered heterocyclic ring which may optionally contain, when it is saturated and 6- or 7-membered, a further heteromember selected from oxygen, sulfur and = NRro, wherein R,o either is hydrogen or has the significance indicated above for R6; A is alkylene of 2 to 14 carbon atoms; and Q is a condensed, fully unsaturated ring system having at least 2 different ring heteroatoms overall and having aromatic character; with the proviso that, when R4 is: hydroxy; alkoxy of 1 to 6 carbon atoms; -N B) as defined above; or F -NR7, Rub'; wherein R7, is: hydrogen; alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and R9, is hydrogen or alkyl of 1 to 6 carbon atoms; then A is alkylene of 7 to 14 carbon atoms, and their ammonium salts wherein R4 is selected from one of the tertiary amino groups defined above for R4 and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid, which comprises appropriately converting a corresponding compound of formula 11,

wherein R1, R2, R5 and Q are as defined above, Z is a reactive group and Z' either is a reactive group or has the significance indicated above for -OR3 and where appropriate recovering a resultant compound wherein R4 is selected from one of the tertiary amino groups defined above for R4 in quaternary ammonium salt form with a compound of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.

2. A process for the production of a compound of formula I as defined in claim 1 or where appropriate a quaternary ammonium salt thereof as defined in claim 1, substantially as hereinbefore described with reference to any one of the Examples.

3. A compound of formula I as defined in claim 1 or where appropriate a quaternary ammonium salt thereof as defined in claim 1, whenever produced by a process according to claim 1.

4. A compound of formula I as defined in claim 1 or where appropriate a quaternary ammonium salt thereof as defined in claim 1.

5. A compound of claim 4 wherein Q is a 2,1,3-benzoxadiazolyl moiety.

6. A compound of claim 4 of formula Ia,

wherein R is: 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 of atomic number of from 9 to 35; trifluoromethyl; nitro; or hydroxy; R1a is; hydrogen; alkyl of 1 to 6 carbon atoms; alkenyl of 3 to 6 carbon atoms wherein the double bond is separated from the nitrogen atom by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 6 carbon atoms wherein the triple bond is separated from the nitrogen atom by at least 1 carbon atom not participating 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 wherein the hydroxy part is separated from the nitrogen atom by at least 2 carbon atoms; alkoxyalkyl of 2 to 6 carbon atoms; or phenylalkyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms wherein the double bond is separated from the nitrogen atom by at least 1 carbon atom not participating in the double bond, the last two substituents optionally being independently mono-, di- or trisubstituted in the phenyl ring by independently alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen of atomic number of from 9 to 35 or hydroxy; alkylcarbonyloxyalkyl of 2 to 6 carbon atoms in the alkylcarbonyl and alkylene moieties thereof and wherein oxygen is separated from the nitrogen atom by at least 2 carbon atoms; dialkylaminoalkyl independently of 1 to 6 carbon atoms in the alkyl moieties and of 2 to 6 carbon atoms in the alkylene moiety thereof and wherein the amino group is separated from the nitrogen atom by at least 2 carbon atoms; or morpholinoalkyl of 2 to 6 carbon atoms in the alkylene moiety thereof and wherein the morpholino moiety is separated from the nitrogen atom by at least 2 carbon atoms; R2 and RB are as defined in claim 1; Ra3 is alkyl of 1 to 12 carbon atoms or independently has the significance indicated below for -Aa R4a; R4a is: hydroxy; alkoxy of 1 to 12 carbon atoms; -OCOR6a; or -N8) as defined in claim 1; wherein R6,, R7a and R8a have the significance indicated in claim 1 for R6, R7 and R8, respectively; Aa is alkylene of 2 to 14 carbon atoms; and X is oxygen or sulfur; with the proviso that, a) when R4 is hydroxy or -NB) as defined in claim 1, then Aa is alkylene of 7 to 14 carbon atoms; and b) when R4a is alkoxy of 1 to 12 carbon atoms or -NR:'P"wherein R7a' is hydrogen; alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and R8' is hydrogen or alkyl of 1 to 6 carbon atoms, thn Aa is alkylen of 9 to 14 carbon atoms; and their ammonium salts wherein R4 is selected from one of the tertiary amino groups defined in this claim for R84 and quaternized with a group of formula AlkY as defined in claim 1.

7. A compound of claim 6 wherein Aa is alkylene of 9 to 14 carbon atoms.

8. A compound of claim 6 wherein R4a is other than alkoxy.

9. A compound of claim 6 wherein R3, and R4a are -NR3R8 as defined in claim 6 or -NB) as defined in claim 1.

10. A compound of claim 6 of formula laa,

wherein R, R3 and R5 are as defined in claim 1; X is as defined in claim 6; Ra3a is alkyl of 1 to 6 carbon atoms; R'4, has the significance indicated in claim 6 for R4a and A" is alkylene of 2 to 14 carbon atoms; with the provisos that a) when R? is hydroxy or -NB) as defined in claim 1, then A" is alkylene of 7 to 14 carbon atoms; and b) when Ra4 is alkoxy of 1 to 12 carbon atoms or -NR7a' RB' wherein R7' and RB' are as defined in claim 6, then Aaa is alkylene of 9 to 14 carbon atoms; and their ammonium salts wherein 4aa is selected from one of the tertiary amino groups defined in this claim for R'4, and quaternaized with a group of formula AlkY as defined in claim 1.

11. A compound of claim 10 wherein A" is alkylene of 9 to 14 carbon atoms.

12 A compound of claim 10 wherein R4aa is other than alkoxy.

13. A compound of claim 10 wherein R4aa is -NRaR8a as defined in claim 6 or -NB) as defined in claim 1.

14. A compound of claim 6 of formula lab,

wherein R, R2 and R5 are as defined in claim 1, R1a and X are as defined in claim 6, R3ab is alkyl of 1 to 12 carbon atoms or independently has the significance indicated in this claim for -AabR4ab, R4ab is: hydroxy; alkoxy of 1 to 12 carbon atoms; -OCOR6a; or -NR7aR8a; wherein R6a, R7a and R8a are as defined in claim 6; and Aab is alkylene of 2 to 14 carbon atoms; with the provisos that a) when R4bis hydroxy, then Aab is alkylene of 7 to 14 carbon atoms; and b) when R4abis alkoxy of 1 to 12 carbon atoms or -NR7a' RR8a' wherein R7a'and R8a' are as defined in claim 6, then Aab is alkylene of 9 to 14 carbon atoms; and their ammonium salts where Rris selected from one of the tertiary amino groups defined in this claim for Riband quaternized with a group of formula AlkY as defined in claim 1.

15. A compound of claim 14 wherein Aab is alkylene of 9 to 14 carbon atoms.

16. A compound of claim 14 wherein Rap is other than alkoxy.

17. A compound of claim 14 wherein Ra3band R4ab are m -NRaR8a as defined in claim 6.

18. A compound of claim 6 of formula laaa,

wherein R R2 and R@ are as defined in claim 1; R@ and X are as defined in claim 6; R3aaa is alkyl of 1 to 6 carbon atoms; R4aaa is: hydroxy; alkoxy of 1 to 12 cabon atoms; -OCOR6a or -NR7aR8a, wherein, R6a, R7a and R8a are as defined in claim 6; and Aaaa is alkylene of 2 to 14 carbon atoms; with the provisos that a) when RT is hydroxy, then Aaaa is alkylene of 7 to 14 carbon atoms; and b) when R4aaa is alkoxy of 1 to 12 carbon atoms or -NR7aR8a' wherein R7a' and R8a' are as defined in claim 6, then Aaaa is alkylene of 9 to 14 carbon atoms; and their ammonium salts wherein R4aaa is selected from one of the tertiary amino groups defined in this claim for R4aaa and quaternized with a group of formula AlkY as defined in claim 1.

19. A compound of claim 18 wherein Aaaa is alkylene of 9 to 14 carbon toms.

20. A compound of claim 18 wherein R4aaa is other than alkoxy.

21. A compound of claim 18 wherein r4aaa is -NR7aR8a as defined in claim 6.

22. A compound of any one of claims 6 to 21 wherein R1a is hydrogen or alkyl of 1 to 4 carbon atoms.

23. A compound of claim 22 wherein R,a is hydrogen.

24. A compound of any one of claims 6 to 21 wherein R2 and R9 are hydrogen or alkyl of 1 to 4 carbon atoms.

25. A compound of claim 24 wherein R2 and R5 are methyl.

26. A compound of any one of claims 6 to 21 wherein R is hydrogen.

27. A compound of any one of claims 6 to 21 wherein X is oxygen.

28. A compound of claim 4 of formula Ib,

wherein R1, R2, R5 and Q are as defined in claim 1; R3b is alkyl of 1 to 12 carbon atoms or independently has the significance indicated in this claim for -AR4b; R4b is: hydroxy; alkoxy of 1 to 12 carbon atoms; -OCOR6b; -NR7bR8b; or -NB) as defined in claim 1; wherein R6b, R7b and F have the signifcance indicated in claim 6 for R6, R7 and R8, respectively; and Ab is alkylene of 9 to 14 carbon atoms; and their ammonium salts wherein R4b is selected from one of the tertiary amino groups defined in this claim for R4b and quaternized with a group of formula AlkY as defined in claim 1.

29. A compound of claim 28 wherein R4b is other than alkoxy.

30. A compound of claim 28 wherein R3b and R4b are -NB) as defined in claim 1 or -NR7bR8b as defined in claim 28.

31. A compound of claim 28 of formula Iba,

wherein R1, R2, R5 and Q are as defined in claim 1, R,b and Ab. are as defined in claim 28 and R,bRs alkyl of 1 to 6 carbon atoms; and their ammonium salts wherein R4b is selected from one of the tertiary amino groups defined in this claim for R4b and quaternized with a group of formula AlkY as defined in claim 1.

32. A compound of claim 31 wherein R4b is other than alkoxy.

33. A compound of claim 31 wherein R4b is -NB) as defined in claim 1 or -NR7bR8b as defined in claim 28.

34. A compound of claim 28 of formula Ibb,

wherein R1,R2,R5 and Q are as defined in claim 1; Ab is as defined in claim 28; Rb3bis alkyl of 1 to 12 carbon atoms or independently has the significance indicated in this claim for AbR4bb; Rb4b is: hydroxy; alkoxy of 1 to 12 carbon atoms; -OCOR6b; or -NR7bR8b; wherein R6b, R7b and R8b are as defined in claim 28; and their ammonium salts wherein R4bb is selected from one of the tertiary amino groups defined in this claim for R4bb and quaternized with a group of formula AlkY as defined in claim 1.

35. A compound of claim 34 wherein R4bb is other than alkoxy.

36. A compound of claim 34 wherein R3bb and R4bb are -NR7bR8b as defined n claim 28.

37. A compound of claim 28 of formula Ibaa,

wherein R1, R2, R6 and Q are as defined in claim 1; Ab is as defined in claim 28; R3bais as defined in claim 31; and R4bbis as defined in claim 34; and their ammonium salts wherein R4b is selected from one of the tertiary amino groups defined in this claim for Riband quaternized with a group of formula AlkY as defined in claim 1.

38. A compound of claim 37 wherein Rb4bis other than alkoxy.

39. A compound of claim 37 wherein R4bb is -NR7bR8b as defined in claim 28.

40. A compound of any one of claims 28 to 39 wherein R1 is R1a as defined in claim 6.

41. A compound of claim 40 wherein R1 is hydrogen or alkyl of 1 to 4 carbon atoms.

42. A compound of claim 40 wherein R1 is hydrogen.

43. A compound of any one of claims 28 or 39 wherein R2 and R5 are hydrogen or alkyl of 1 to r carbon atoms.

44. A compound of claim 43 wherein R2 and R5 are methyl.

45. A compound of any one of claims 28 to 39 wherein Q is a group of formula

wherein R and X are as defined in claim 6.

46. A compound of claim 45 wherein R is hydrogen.

47. A compound of claim 45 wherein X is oxygen.

48. A compound of claim 4 of formula Ip

wherein R1P is hydrogen or alkyl of 1 to 6 carbon atoms; R2P and R5p independently are alkyl of 1 to 4 carbon atoms; R3p is alkyl or 1 to 6 carbon toms or independently has the signiticance indicated in this claim for-ApR4p; R4p is: hydroxy; alkoxy of 1 to 6 carbon atoms; -OCOR6p; -NR7pR3p; wherein R6p is: alkyl of 1 to 6 carbon atoms; phenyl, phenylalkyl of 7 to 10 carbon atoms or bisphenylalkyl of 13 to 16 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring (s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur; or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; R7p is: hydrogen; alkyl of 1 to 4 carbon atoms; or with the exception of alkyl of 1 to 6 carbon atoms has the significance indicated in this claim for R6p; R8p is: hydrogen; or alkyl of 1 to 6 carbon atoms; or is -COR9p wherein R9p has the significance indicated in this claim for R6p; -NB)P is: a 5-, 6- or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6- or 7-membered, a further heteromember selected form oxygen, sulfur and = NR10p wherein R10p either is hydrogen or has the significance indicated in this claim for R7p; Ap is unbranched alkylene of 2 to 14 carbon atoms; and Qp is a condensed, fully unsaturated bicyclic ring system having at least 2 different ring heteroatoms overall and having at least one aromatic ring;

49. A compound of claim 48 wherein R3p is alkyl of 1 to 6 carbon atoms.

50. A compound of claim 48 wherein R3p is -ApR4p wherein Ap and R4p are as defined in claim 48.

52. A compound of claim 48 wherein R4P is other than alkoxy.

53. A compound of claim 48 wherein AP is unbranched alkylene of 7 to 14 carbon atoms.

54. A compound of claim 48 wherein AP is unbranched alkylene of 9 to 14 carbon atoms.

55. A compound of claim 48 wherein R4P is: hydroxy; alkoxy of 1 to 6 carbon atoms; -OCOP' or -NR7pR8p wherein 8p, Rp and R8p are as defined in claim 48; with the proviso that when R4p is: hydroxy; alkoxy of 1 to 6 carbon atoms; -NB)p as defined in this claim; or NR7'pR8'p wherein R7'p is: hydrogen; alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and RB'P is hydrogen or alkyl of 1 to 6 carbon atoms; then AP is unbranched alkylene of 7 to 14 carbon atoms; and their ammonium salts wherein R4P is selected from one of the tertiary amino groups defined in this claim for R4P and quaternized with a group of formula AlkY as defined in claim 1.

56. A compound of claim 4 of formula Is,

wherein R2s and R5s independently are alkyl of 1 to 4 carbon atoms; R3s is alkyl of 1 to 12 carbon atoms; R4s is: hydroxy; alkoxy of 1 to 4 carbon atoms; -OCOR6s; -NR73R85; or -N wherein R6s is alkyl of 1 to 4 carbon atoms or phenyl; R7s is: hydrogen; alkyl of 1 to 4 carbon atoms; phenylalkyl of 7 to 10 carbon atoms optionally mono- or independently disubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 53; -COR9 wherein R9s is alkyl of 1 to 4 carbon atoms; or phenyl or phenylalkyl of 7 to 10 carbon atoms both optionally mono- or independently disubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; R8s is: hydrogen or alkyl of 1 to 4 carbon atoms; -NB)s is piperidine or piperazine both substituted in the 4 position by methyl, benzyl, or bisphenylmethyl optionally mono- or independently disubstituted in the phenyl ring(s) by halogen of atomic number of from 9 to 53 or alkoxy of 1 to 4 carbon atoms; As is alkylene of 2 to 14 carbon atoms; with the proviso that when R4s is hydroxy; alkoxy of 1 to 4 carbon atoms; -NB)s as defined in this claim; or -NR7s' R8s wherein R7s' is: hydrogen; alkyl of 1 to 4 carbon atoms; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and R8s is as defined in this claim; then A is alkylene of 7 to 14 carbon atoms; and their ammonium salts wherein R4s is selected frm one of the tertiary amino groups defined in this claim for R4s and quaternized with a group of formula AlkY as defined in claim 1.

57. A compound of claim 56 wherein As is alkylene of 7 to 14 carbon atoms.

58. A compound of claim 56 wherein As is alkylene of 9 to 14 carbon atoms.

59. A compound of claim 56 wherein As is unbranched alkylene.

60. A compound of claim 4 wherein RB, R7 and/or R9 are substituted phenyl, substituted phenylalkyl or substituted bis-phenylalkyl.

61. A compound of claim 4 wherein R1 is alkyl of 1 to 6 carbon atoms.

62. A compound of claim 4 wherein R2 and R9 independently are alkyl of 1 to 4 carbon atoms,

63. A compound of claim 4 wherein R3 is alkyl of 1 to 6 carbon atoms.

64. A compound of claim 4 wherein R3 is -ApR4p as defined in claim 48.

65. A compound of claim 4 wherein A is unbranched alkylene and R4 has the significance indicated in claim 48 for R4P, including the proviso thereto.

66. A compound of claim 4 wherein RB, R7 and/or RB have the significance indicated in claim 48 for R6p, RP and/or R8P, respectively.

67. A compound of claim 4 wherein -NB) has the significance indicated in claim 48 for NB) -

68. A compound of claim 4 wherein Q is bicyclic.

69. A compound of claim 4 wherein R4 is alkoxy of 1 to 6 carbon atoms.

70. A compound of claim 4 wherein substituted or unsubstituted phenylalkyl is of 7 to 10 carbon atoms in the phenylalkyl moiety and substituted or unsubstituted bis-phenylalkyl is of 12 to 16 carbon atoms in the bis-phenylalkyl moiety.

71. A compound of claim 4 wherein R7 has the significance indicated in claim 48 for RP.

72. A compound of claim 4 wherein all uncondensed phenyl rings are substituted.

73. A compound of claim 4 wherein R3 is alkyl.

74. A compound of claim 4 wherein R3 is identical to -AR4.

75. A compound of claim 4 wherein A is unbranched.

76. A compound of claim 4 wherein A has 7 to 14 carbon atoms.

77. A compound of claim 4 wherein A has 9 to 14 carbon atoms.

78. A compound of claim 4 wherein A has 10 carbon atoms.

79. A compound of claim 4 wherein Alk is methyl.

80. A compound of claim 4 wherein Y is iodine.

81. A compound of claim 4 wherein -NB) is saturated.

82. A compound of claim 4 wherein -NB; is 6-membered.

83. A compound of claim 4 wherein -NB) is 1-piperazinyl.

84. A compound of claim 4 wherein bis-phenylalkyl is optionally substituted bis-phenylmethyl.

85. The compound of claim 4 which is 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropox- ycarbonyl-2,6-dimethyl-3-pyridine-carboxylic acid-(10-hydroxydecyl)ester.

86. The compound of claim 4 which is 4-(2,1,3-benzoxadiazol-4-yI)-1,4-dihydro-5-isopropox- ycarbonyl-2,6-dimethyl-3-pyridine-carboxylic acid [10-(N-benzylmethylamino)decyl]ester

87. The compound of claim 4 which is 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropox- ycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid-( 1 0-aminodecyl)ester.

88. The compound of claim 4 which is 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2, 6-dimethyl-3-pyridine carboxylic acid-[10-[3-(4-hydroxy-3-iodophenyl)-1 -oxo-propy lamino]decyl]ester.

89. The compound of claim 4 which is 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropox- ycarbonyl-2,6-dimethyl-3-pyridine-carboxylic acid-(10-benzoyloxydecyl)ester.

90. The compound of claim 4 which is 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropox- ycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid-( 1 O-methoxydecyl)ester.

91. A compound of claim 4 wherein Cl is 2,1 ,3-benzoxadiazol-4-yl, R, is hydrogen and R2 and R5 are methyl.

92. A compound of claim 91 wherein the configuration at the 4 position of the 1,4dihydropyridinyl moiety is racemic.

93. A compound of claim 91 wherein the configuration at the 4 position of the 1,4dihydropyridinyl moiety is (+ )(R).

94. A compound of claim 91 wherein the configuration at the 4 position of the 1,4- dihydropyridinyl moiety is (-

95. The compound of claim 92 wherein R3 and AR4 are, respectively, Me and -(CH2),00H.

96. The compound of claim 92 wherein R3 and AR4 are, respectively, -(CH2)9Me and -(CH2)10OH.

97. The compound of claim 92 wherein R3 and AR4 are, respectively, Et and -(CH2)toOH.

98. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and

99. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and -(CH2),0N(Me)Bu.

100. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and -(CH2),0N(Me)CH2CH2Phe.

101. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and -(CH2),0NMe2-

102. The compound of claim 92 wherein R3 and AR4 are, respectively, Me and -(CH2),0N(Me)Bz.

103. The compound of claim 92 wherein R3 and AR4 are, respectively, Et and -(CH2),0N(Me)Bz.

104. The compound of claim 92 wherein R3 and AR4 are, respectively, Pr and

105. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and

106. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and

107. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and

108. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and

109. The compound of claim 92 wherein R3 and AR4 are, respectively, Pr and -(CH2),0NHMe.

110. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and

111. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and

112. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and

113. The compound of claim 92 wherein R3 and AR4 are, respectively, Pr and

114. The compound of claim 92 wherein R3 and AR4 are, respectively, Me and -(CH2)10NH2.

115. The compound of claim 92 wherein R3 and AR4 are. respectively, iPr and

116. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and

117. The compound of claim 92 wherein R3 and AR4 are, respectively, Me and

118. The compound of claim 92 wherein R3 and AR4 are, respectively, Pr and

119. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and -(CH2)tONHCOMe.

120. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and -(CH2)10 NHCOtBu.

121. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and -(CH2),0NHCOPhe.

122. The compound of claim 92 wherein R3 and AR4 are, respectively, iPr and -(CH2),00COtBu .

123. The compound of claim 93 wherein R3 and AR4 are, respectively, iPr and -(CH2)10OH.

124. The compound of claim 93 wherein R3 and AR4 are, respectively, iPr and -(CH2)10NMEBZ.

125. The compound of claim 93 wherein R3 and AR4 are respectively, iPr and

126. The compound of claim 93 wherein R3 and AR4 are, respectively, iPr and -(CH2)10NH2 127. The compound of claim 93 wherein R3 and AR4 are, respectively, iPr and

128. The compound of claim 94 wherein R3 and AR4 are, respectively, iPr and -(CH2),00H.

129. The compound of claim 94 wherein R3 and AR4 are, respectively, iPr and -(CH2),0N MeBz.

130. The compound of claim 94 wherein R3 and AR4 are, respectively, Pr and

131. The compound of claim 94 wherein R3 and AR4 are, respectively, iPr and -(CH2)10NH2 132. The compound of claim 94 wherein R3 and AR4 are, respectively, iPr and

133. The compound of claim 92 wherein R3 is isopropyl and AR4 is -(CH2)10NMe2 quaternized with methyl iodide.

134 A compound of claim 4 wherein the substituents in the 2 and 6 positions and/or in the 3 and 5 positions of the 1 ,4-dihydropyridinyl moiety are different, in racemic form.

1 35. A compound of claim 4 wherein the substituents in the 2 and 6 positions and/or in the 3 and 5 positions of the 1 ,4-dihydropyridinyl moiety are different, in enantiomer form.

1 36. A compound of claim 4 wherein the substituents in the 2 and 6 positions and/or in the 3 and 5 positions of the 1 4-dihydropyridinyl moiety are different, in (R)-enantiomer form.

1 37. A compound of claim 4 wherein the substituents in the 2 and 6 positions and/or in the 3 and 5 positions of the 1 ,4-dihydropyridinyl moiety are different, in (S)-enantiomer form.

1 38. A compound according to any one of claims 4 to 1 37 in free form.

1 39. A compound according to any one of claims 4 to 1 37 where appropriate in neutral form.

140. A compound according to any one of claims 4 to 1 37 where appropriate in salt form.

141. A compound according to any one of claims 4 to 1 37 where appropriate in acid addition salt form.

142. A compound according to any one of claims 4 to 1 37 in free form or where appropriate in pharmaceutically acceptable salt form, for use as a pharmaceutical.

143. A compound according to claim 142 for use as a calcium antagonist.

144. A compound according to claim 142 for use for the prevention or treatment of coronary insufficiency; -:listurbances in peripheral circulation; asthma; -hypertension; migraine and vascular headache.

145. A compound according to claim 142 for use for the prevention and treatment of Angina pectoris.

146. A compound according to claim 142 for use for the prevention and treatment of hypertension.

147. A compound according to claim 142 for use for the prevention and treatment of migraine and vascular headache.

148. A pharmaceutical composition comprising a compound of any one of claims 4 to 137 in free form or where appropriate in pharmaceutically acceptable salt form in association with a pharmaceutical carrier or diluent.

149. A method of preventing or treating coronaryl insufficiency, disturbances in peripheral circulation, asthma, hypertension or migraine and vascular headache which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of claim 4.

150. A compound according to claim 4 substantially as hereinbefore described wit reference to any one of the Examples.

151. The steps, features, compositions and compounds referred to or indicated in the specification and/or claims of this application, individually or collectively, and any and all combinations of any two or more of said steps or features.