IT8448415A1 - 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND USE AS MEDICINES - Google Patents

Description

DESCRIPTION of the industrial invention entitled: "Derivatives of 1,4-dihydropyridine, their preparation and their use as medicinal products".

SUMMARY OF THE INVENTION

The invention relates to derivatives of 1,4-dihydropyridine of formula I

(I)

R3OOC COO-AR/

in which

R-| stands for hydrogen, cycloalkyl or alkyl, R^ and R5 represent hydrogen or alkyl,

R^ means alkyl,

R^ represents hydroxy, alkoxy, acyloxy or an amine moiety,

A means alkylene, and

Q represents a heterocyclic system.

These compounds can be used as medicines.

The present invention relates to 1,4-dihydropyridine derivatives, their preparation and their therapeutic use as active ingredients in medicinal products.

The invention relates in particular to 1,4-dihydropyridine derivatives of formula I

(I) R^OOC? ??^ ^'??? COO-AR,

and N 1

1 R?

?n CUI

R1 represents hydrogen, a cycloalkyl group in C^-C^ or an alkyl group in C-j-Cg possibly substituted,

and Rbc each represent, independently of each other, hydrogen or an alkyl group at C^-Cg, represents an alkyl group at C^-C^ 0 has, independently of -AR^, one of the meanings given below for -AR^ including the conditions that concern it,

R4 represents a hydroxy or alkoxy group in C^-C^2 or an -OCQRg, -NR7Rg or -Ngj rest, in which

Rg means an alkyl group in C-j-Cg, a phenyl, phenylalkyl group in Z-j-C?^ or bis-phenylalkyl in Cj;3~C-]8? 1^ 01 benzene nuclei of these last three groups which may optionally carry one, two or three substituents selected from the halogens having an atomic number between 9 and 53 and the hydroxy, alkyl groups in C-j-C^ and alkoxy in Cj-C^, a 5-chain heteroaryl residue containing 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms of which one is nitrogen and the other is nitrogen, oxygen or sulfur, or a 6-chain heteroaryl residue containing from 1 to 4 nitrogen atoms,

R-j means hydrogen or has one of the meanings given above for Rg,

Rg means hydrogen, an alkyl group in C-j-Cg or a -CORg remainder where Rg has the meaning given above for Rg,

N means a 5, 6 or 7 chain heterocycle which may optionally contain, when saturated and 6 or 7 chained, another heteroatom chosen from oxygen, sulfur and =NR^Q where R^Q means hydrogen or has one of the meanings indicated above for Rg,

represents an alkylene group in Cg-C.^ , and

Q represents a totally unsaturated condensed cyclic system of aromatic character having in total at least 2 different cyclic heteroatoms,

A being to represent an alkylene group on C^-C^ when it means a hydroxy group, an alkoxy group on C-j-Cg, a -Ngj remainder as defined above, or a -NR^Rg remainder where R^ means hydrogen, an alkyl group on C-|-Cg, an unsubstituted phenyl group, or an unsubstituted phenylalkyl group on C-j-Cg, and Rg means hydrogen or an alkyl group on C-j-Cg,

and the ammonium salts of compounds in which R^ is one of the tertiary amino groups defined above for R^ and quaternized with a group of formula AlkY where A1k means an alkyl group on C-j-C^ and Y the remainder of an acid.

For the sake of simplification, the compounds of formula I and their ammonium salts will be referred to in this specification as "the compounds of the invention".

Certain compounds of the invention fall under the very general description of European patent application No. 42 089.

Certain compounds of the invention also fall under the very general description of European patent applications Nos. 88276 and 94159. These applications were published in September 1983 and November 1983, respectively, i.e., at a date later than the priority date claimed for the compounds of the present invention, i.e., June 21, 1983.

None of the compounds specifically described in the above-mentioned European patent applications fall within the scope of the present invention.

Other publications concerning compounds related to the compounds of the invention are for example European patent applications Nos. 150, 71819 and 80 220, German DOS patent applications Nos. 2949 464, 2949 491 and 3320 616 and Belgian patent No.

890 311.

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

A preferred group of compounds of the invention comprises the compounds of formula I.

(the) C00-Aan a

I X 4

N ^ R

p to R5

R1

in which

R represents hydrogen, a halogen having an atomic number from 9 to 35, or a hydroxy, nitro, trifluoromethyl, C^-C^ alkyl, C^-C^ alkoxy, C^-C^ alkylthio, or C^-C^ alkylsulfonic group,

R-j represents hydrogen, an alkyl group on C-|-Cg, an alkenyl group on Cg-Cg in which the double bond is separated from the nitrogen atom by at least one carbon atom not part of the double bond, an alkyl group on Cg-Cg in which the triple bond is separated from the nitrogen atom by at least one carbon atom not part of the double bond, separated from the nitrogen atom by at least one carbon atom not forming part of the triple bond, a cycloalkyl group in Cg-C^, a cycloalkylalkyl group in C^-Cg, a hydroxyalkyl group in C2"Cg in which the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms, an alkoxyalkyl group in a phenylalkyl group in C^-Cg or phenylalkenyl in Cg-C^ in which the double bond is separated from the nitrogen atom by at least one carbon atom not forming part of the double bond, the benzene nucleus of these last two groups possibly being able to carry one, two or three substituents selected from the halogens having an atomic number from 9 to 35 and the hydroxy, alkyl groups in C-j-C^ and alkoxy in C-j-C^, a alkylcarbonyloxyalkyl group containing from 2 to 6 carbon atoms in each alkylcarbonyl and alkylene residue and in which the oxygen is separated from the nitrogen atom by at least two carbon atoms, a dialkylaminoalkyl group containing independently from 1 to 6 carbon atoms in each alkyl residue and from 2 to 6 carbon atoms in the alkylene residue and whose amino group is separated from the nitrogen atom by at least two carbon atoms, or a morpholinoalkyl group containing from 2 to 6 carbon atoms in the alkylene residue and whose morpholino residue is separated from the nitrogen atom by at least two carbon atoms,

R^ and Rj- have the meanings indicated above, R3 represents an alkyl group in C-j-C^ or possesses, ana

regardless of -A ?, one of the meanings ina?a

indicated below for -A 4'

a

4 represents a hydroxy or alkoxy group at C -C12 or a -OCORg, -NR.^a^Rga, or -Ng^ residue as defined above cl 3 d

where Rc, R, and R? have the meanings given above for Rg, R^, and Rg, respectively,

Aa represents an alkylene group in e

X represents oxygen or sulfur,

- Aa having to represent an alkylene group in C^-C^ when R^ means a hydroxy group or a -??^ group as defined above, and

- Aa having to represent an alkylene group in Cg-C14 when R)j means an alkoxy group in or a ? ^ 3^

remainder -NR^ Rg in which

R7 means hydrogen, a C^-Cg alkyl group, an unsubstituted phenyl group or an unsubstituted C^-C^ phenylalkyl group, and

Rg means hydrogen 0 an alkyl group in C-j-Cg

and the ammonium salts of compounds where R^ means ? one of the tertiary amino groups defined above and quaternized with a group of formula AlkY as defined above.

In one subgroup of compounds of formula 1a, Aa means an alkylene group in Cg-C|^. In another subgroup, R^ has a meaning other than an alkoxy group. In another subgroup, Ra and Ra mean -NRaRg 0 as defined above.

A preferred group of compounds of the formula includes the compounds of the formula Iaa

(Iaa) N

R^OOC fr C00-AaaR!a

, 4

2

1n cui ?? Ja R5

1

.a

R, R-j? R2> R5 and X have the meanings indicated above,

R.a^a represents an alkyl group in C-|-Cg,

33 has the meaning given above for R^3, and Aaa represents an alkylene group at C^-C?]^,

- Aaa having to represent an alkylene group in C^-C^

when R^33 means a hydroxy group or an -N^ residue as defined above, and

- Aaa having to represent an alkylene group in C9"C14 when R^33 means an alkoxy group in C^-C^ 0 un a * ?J g I gl

remainder -NRy Rg where R^ and Rg have the meanings indicated above,

and ammonium salts? compounds where R,a)ja? means one of the tertiary amino groups defined above for R^ and quaternized with an A1kY group as defined above.

In one subgroup of compounds of the formula Iaa, A represents an alkylene group in Cg-C-j^. In another subgroup, Raa has a meaning other than an alkoxy group. In yet another subgroup, R^33 represents a -NRaRa or -N|^ residue as defined above.

Another favorite group of compounds of the formula la includes the compounds of the formula lab

R

u. N (lab) RfoOC. A/C00-Aab-Rab

? ?

in which

R, R,a-j, R ,.Rg and X have the meanings indicated above,

Rgb represents an alkyl group in C-j-C^ 0 and has, independently of -AabRab, one of the meanings given below for -AabR^b,

R,a^b represents a hydroxy or alkoxy group in C-j-C?^

0 a remainder -OCORg or -NRaRg where Rg, Ra and Rg have 1 meanings given above and

Aab represents an alkylene group in

from

A having to represent an alkylene group at C7'C14 when R,^ab means a hydroxy group, and

- A,ab having to represent an alkylene group in Cg-C-j^ ab

when A^ means an alkoxy group in C-|-C?^ or a remainder -NR,a^'Rag' where R^ and Rg have the meanings indicated above,

and the ammonium salts of compounds where R^b means one of the tertiary amino groups defined above for R^b and quaternized with an AlkY group as defined above.

In one subgroup of compounds with the formula lab, Aab means an alkylene group in Cg-C^. In another subgroup, Rab has a meaning other than an alkoxy group. In another subgroup, Rab and Rab represent a -NRaR? residue as defined above.

Another preferred group of compounds of the formula includes the compounds of the formula Iaaa

(Yaaa)

Rg^OOC COO-AaaaDaaa

R4

in which

R, Ra, R^, Rj and li have the meanings indicated above.

fearfully,

R3gd6l represents an alkyl group in C-j-Cg,

,aaa

4 represents a hydroxy or alkoxy group in

0 a remainder -OCORg or -NRaRg where Rg, Ra and Rg have

1 meanings given above, and

aaa represents an alkylene group in

aaa

- A having to represent an alkylene group at C^-C14

when ,aaa means a hydroxy group and

aaa having to represent an alkylene group in Cg-C-j^

when R3^33 means an alkoxy group in C-j-C^

I I I

a remainder -NR^ RQ where R7 and Rg have the meanings-

you indicated previously,

333

and the ammonium salts of compounds where R^ means one

of the tertiary amino groups defined above for Raaa and qua-

ternarized with an A1kY group as defined above.

In a subgroup of compounds of formula Iaaa, Aaaa means an alkylene group at C^-C14

In another subgroup, aaa has a meaning other than an alkoxy group. In another subgroup, R^aaa means a -NR^Rg residue as defined above.

Other groups and subgroups of compounds of the invention include those of formulae Ia, Iaa, a

lab and Iaaa where R^ means hydrogen or an alkyl group on C-j-C^, especially hydrogen or a methyl group, especially hydrogen, those where R? and Rg mean hydrogen or an alkyl group on C-|-C^, especially a methyl group, those where R means hydrogen, and those where X represents oxygen, as well as those comprising a combination of these meanings, and possibly their corresponding quaternary salts as defined above.

Another preferred group of compounds of the invention comprises the compounds of formula Ib.

R3OOC C00-AbRb

IJC (Ib)

N-

I

?

in which

R-j, R2, Rj and I] have the meanings indicated above,

represents an alkyl group in C-j-C^ 0 has, independently of -Ab?R^b, one of the meanings given below for -AbR^,

Rb represents a hydroxy or alkoxy group in CrCl 2 or a remainder -0C0Rgb, -NRb?Rgb or -Ng?^ as defined above, where R0b, Rb/ and Rbo have the meanings given above for Rg, R^ and Rg, respectively, and

A represents an alkylene group in Cg-C-j^,

and ammonium salts of compounds in which represents one of the tertiary amino groups defined above for Rb and quaternized with an AlkY group as defined above.

In one subgroup of compounds of formula Ib, Rb has a meaning other than an alkoxy group. In another subgroup, Rb and Rb mean a residue -NRbRb or -N|j as defined above.

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

(Iba) ,b3a?Y C00-AbRb

N

I

Rri

in which

R1> Rb j Rg, Ab and Q have the meanings indicated above,

Rba represents an alkyl group in C-j-Cg,

and the ammonium salts of compounds in which represents one of the tertiary amino groups defined above for Rb and quaternized with an AlkY group as defined above.

In a subgroup of compounds of formula Iba, Rb has a meaning other than an alkoxy group. In another subgroup, Rb represents a -NRbRg or -N^ residue as defined above.

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

bb

Rgb00Cx!r. COO-A-R (Ibb)

1

in which

R<l, R2, Rg, A and Q have the meanings indicated above,

Rb^b represents an alkyl group in 0 has, independently of - A^R^ , one of the meanings in? hfa

indicated below for -A R^

hK

^ represents a hydroxy or alkoxy group at C^-C12 a residue -0C0Rb or -NRbRb, where Rb, Rb and Rg have the meanings indicated above,

and the ammonium salts of compounds where Rbb represents one of the tertiary amino groups defined above for Rb^b and quaternary with an AlkY group as defined above.

In a subgroup of compounds with the formula Ibb, Rbb has a meaning other than an alkoxy group. In another subgroup, Rbb and Rbb mean a residue -NR^bRgb as defined above.

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

Rba00C C00-AbRbb

4 (Ibaa)

N

1

in which

R1, R2, Rba, *lb, R5 A and Q have the meanings indicated above,

and the ammonium salts of compounds where Rb^b represents one of the tertiary amino groups defined above for R^b and quaternized with an AlkY group as defined above.

In a subgroup of compounds with the formula Ibaa, Rbb has a meaning other than an alkoxy group. In another subgroup, R^b means a -NRbRg residue as defined above.

Other groups and subgroups of compounds of the invention include those of formulae Ib, Iba, Ibb and Ibaa where R-| means Ra as defined above, in particular hydrogen or an alkyl group, especially hydrogen or a methyl group, in particular hydrogen, those where R? and Rg represent hydrogen or a C^-C^ alkyl group, in particular a methyl group, those where Q represents a group of formula

where R and X have the meanings indicated above, in particular those where R means hydrogen, and those where X represents oxygen, as well as those comprising a combination of these meanings, and possibly their corresponding quaternary salts as defined above.

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

C00-APR? (ip)

in which

Rp represents hydrogen or an alkyl group at C^-Cg, Rp and Rp represent, independently of each other, an alkyl group at C^-C^,

R^ represents an alkyl group in -Cg or has, independently of -A^Rjjj, one of the meanings given below for -APRP,

represents a hydroxy or alkoxy group in Ci-C^ or an -OCORg, -NR^R^ or -?^ rest, in which

Rg means an alkyl group on C^-Cg, a phenyl group, a phenylalkyl on C7-C10 or a bis-phenylalkyl on C^3*C^g, the benzene nucleus(es) of these last 3 groups possibly carrying one, two or three substituents selected from the halogens having an atomic number from 9 to 53 and the hydroxy, alkyl on C-1-C^ and alkoxy on C-|-C^ groups, a 5-chain heteroaryl residue containing a heteroatom selected from nitrogen, oxygen and sulphur or 2 heteroatoms of which one is nitrogen and the other is nitrogen, oxygen or sulphur, or a 6-chain heteroaryl residue containing from 1 to 4 nitrogen atoms,

R^ means hydrogen, an alkyl group at C-|-C^, or has one of the meanings given above for Rg except an alkyl group at C-j-Cg,

Rg means hydrogen, an alkyl group in C^-Cg ? a remainder -CORg where R^ has one of the meanings given for Rg,

Njp means a saturated heterocycle with 5, 6 or 7 chains which can optionally contain, when it has 6 or 7 chains, another heteroatom chosen from oxygen, sulphur and =NRf0 where

R^Q means hydrogen or has one of the meanings given above for R^,

A*3 represents an unbranched alkylene group in

C2"C14 and

Qp represents a totally unsaturated condensed bicyclic system of aromatic character containing in total at least 2 different cyclic heteroatmospheres,

A*3 being required to represent an unbranched alkylene group at C7-Cj4 when RP means a hydroxy group, an alkoxy group at C-j-Cg, an -N^ residue as defined above, or an NRpRg residue where

Rp means hydrogen, a C-j-Cg alkyl group, an unsubstituted phenyl group, or an unsubstituted C7-C1Q phenylalkyl group, and

Rg means hydrogen or an alkyl group at C^-Cg, and the ammonium salts of compounds where Rp represents one of the tertiary amino groups defined above for Rp and quaternized with an AlkY group where Alk means an alkyl group at and Y the remainder of an acid.

In one subgroup of compounds of formula Ip, R^ means an alkyl group on C^-Cg; in another subgroup, it means an alkyl group on C^-Cg*; in another subgroup, it means -APRP where AP and Rp have the meanings indicated above; in another subgroup, Rp has a meaning other than an alkoxy group; in another subgroup, Ap means an unbranched alkylene group on C7-C-j^; in another subgroup, it means an unbranched alkylene group on Cg-C-j4; in another subgroup, it means a hydroxy or alkoxy group on -Cg or a remainder -OCORg or NR^Rg where Rg, R^, and Rg have the meanings indicated above, as well as combinations of these meanings, and possibly their corresponding quaternary salts as defined above.

Another group of compounds of the invention comprises the compounds of formula Is

(Is)

R *00C C00-ASR4S

in which

s s

R^ and Rg each represent, independently of each other, an alkyl group at C^-C^, represents an alkyl group at C^-C^ ?

R* represents a hydroxy or alkoxy group in an -OCORg, -NR^Rg or residue in which

Rg means an alkyl group in C-|-C^ or phenyl, R^ means hydrogen, an alkyl group in

a phenylalkyl group at C^-C?^ in which the benzene nucleus may optionally carry one or two substituents selected from the halogens having an atomic number from 9 to 53 and the alkoxy groups at C-j-C^, a -CORg residue in which the Rg residue signifies an alkyl group at C-j-C^, or a phenyl or phenylalkyl group at C^-C?^ in which the benzene nucleus may optionally carry one or two substituents selected from the halogens having an atomic number from 9 to 53 and the hydroxy and alkoxy groups at C-j-C^,

Rg means hydrogen or an alkyl group in

-N^ means a piperidine or piperazine ring substituted at position 4 with a methyl group, with a benzyl group or with a bis-phenylmethyl group in which the benzene ring(s) may optionally carry one or two substituents chosen from the halogens having an atomic number from 9 to 53 and the alkoxy groups in AS represents an alkylene group in

A being to represent a C-,-C^ alkylene group when R^ means a hydroxy group, an alkoxy group in a -Nsg?^ residue as defined above or a -NRs^Rsg residue where R^ means hydrogen,, a C-j-C^ alkyl group or an unsubstituted C^-C^g phenylalkyl group and Rg has the meaning given above,

and the ammonium salts of compounds where R^ represents one of the tertiary amino groups defined above and quaternized with an A1kY group as defined above.

In one subgroup of compounds of formula Is, As means an alkylene group in Cg-C-j^; in another subgroup, it means an alkylene group in Cg-C-j^; in another subgroup, it is unbranched.

In another subgroup of compounds of the invention, Rg, R^ and/or Rg mean a substituted phenyl, substituted phenylalkyl or substituted bis-phenylalkyl group.

In another subgroup, R-j means hydrogen or an alkyl group at C-j-Cg; in another subgroup, R-j and R^ each mean, independently of each other, an alkyl group at . In another subgroup, Rg means an alkyl group at C-j-Cg; in another subgroup, Rg means a -A^R^ remainder as defined above; in another subgroup, A means an unbranched alkylene group and R^ has the meaning given above for R^, including the conditions pertaining thereto; in another subgroup, Rg, R^ and/or Rg have the meanings given above for Rg and/or R^, respectively; in another subgroup, -N^ has the meaning given above for -Ng-j; in another subgroup, Q is a bicyclic system; in another subgroup, R^ means an alkoxy group at C-j-Cg; in

another subgroup, the substituted or unsubstituted phenylalkyl group ? at C^-C^Q and the substituted or unsubstituted bis-phenylalkyl group ? at C,13_-C,1c6; in another subgroup, it has one of the meanings given above for R^. In another subgroup, all uncondensed phenyl rings are substituted.

R-j preferably has the meaning indicated for Ri. Preferably, Ri means hydrogen. When it does not mean hydrogen, it preferably represents an unsubstituted alkyl, cycloalkylalkyl, possibly substituted phenylalkyl, alkoxyalkyl, or morpholino group, preferably an unsubstituted alkyl or alkoxyalkyl group, more preferably an unsubstituted alkyl group. When R^ means an alkoxyalkyl group, the alkoxy remainder is preferably separated from the nitrogen atom by at least 2 carbon atoms.

R2 and/or Rg preferably mean an alkyl group.

Rg preferably means an alkyl group. When it has the meaning indicated for -AR^, it is preferably identical to -AR^.

R^ preferably means a hydroxy group or a -OCORg, -NR^R^, or -Nj^ moiety. Q preferably contains a total of at least 3 heteroatoms, particularly 3 heteroatoms. It is preferably a bicyclic system. Q preferably means a 2,1,3-benzoxadiazolyl or 2,1,3-benzothiadiazolyl group, particularly a 2,1,3-benzoxadiazolyl group. When Q is a cyclic system comprising a benzene ring, the 1,4-dihydropyridinyl moiety is preferably bonded to this benzene ring, preferably at a position on the benzene ring that is adjacent to a ring junction.

A ? preferably unbranched and preferably contains 7 to 14 carbon atoms, especially 9 to 14 carbon atoms, especially 10 carbon atoms.

Alk preferably means a methyl group. Y preferably means the remainder of a mineral acid, for example a mesyl residue or a halogen, especially iodine.

Rg preferably means an alkyl, phenyl, phenylalkyl or bis-phenylalkyl group, especially a phenyl group.

preferably means hydrogen or an alkyl, phenylalkyl or bis-phenylalkyl group.

Rg preferably means hydrogen, an alkyl group, or a -CORg residue.

Preferably, R^ and Rg both mean hydrogen or one of the R7 substituents and Rg means an alkyl group and the other an alkyl group, possibly substituted phenylalkyl or possibly substituted bisphenylalkyl.

Rg preferably means an alkyl group, an optionally substituted phenyl group, an optionally substituted phenylalkyl group, or an optionally substituted bisphenylalkyl group. -Ng^ as defined above is preferably saturated. It is preferably a 6-chain ring, especially a 1-piperazine group. When 6 or 7-chain, it preferably contains another heteroatom =NR-|o? R10 is preferably other than hydrogen. It preferably means an alkyl group, an optionally substituted phenylalkyl group, or an optionally substituted bisphenylalkyl group. X preferably means oxygen. R preferably means hydrogen.

The rest

TV

? preferably bonded via its 4-position to the 4-position of the rest.1,4-dihydropyridines. The cycloalkyl groups at C^-C^ preferably contain 3, 5 or 6 carbon atoms, especially 5 or 6 carbon atoms. The alkyl and/or alkoxy groups at C^-C^ preferably contain 1 to 6 carbon atoms, especially 1 to 4 carbon atoms, and mean in particular a methyl, ethyl or isopropyl group. The alkyl groups at C^-C^ preferably contain 1 to 4 carbon atoms, especially 1 or 2 carbon atoms, and mean in particular a methyl group. When the alkyl groups at C^-C^ or C^-C^ are substituents of a benzene nucleus or an amino group, they preferably contain 1 or 2 carbon atoms and mean in particular a methyl group. When the C1-C2 alkoxy groups are substituents of a benzene ring, they preferably contain 1 or 2 carbon atoms and in particular mean a methoxy group. The alkenyl and/or alkynyl groups preferably contain 3 carbon atoms. The cycloalkyl residue of cycloalkylalkyl groups preferably contains 3, 5 or 6 carbon atoms, especially 5 or 6 carbon atoms. The alkylene residue of cycloalkylalkyl groups and/or phenylalkyl groups preferably contains 1 or 2 carbon atoms and in particular mean a methylene residue. The alkenylene residue of phenylalkenyl groups preferably contains 3 carbon atoms. The alkylene residue of hydroxyalkyl groups on C2~C8 and/or alkyl groups on C2~C8 preferably contains 2 or 3 carbon atoms, in particular 2 carbon atoms. The hydroxy group of hydroxyalkyl and/or hydroxyalkoxyalkyl groups and/or the amino group of aminoalkyl groups are preferably attached to the most distant terminal carbon atom.

When a benzene nucleus is present in a substituent, it is preferably unsubstituted. When substituted, it is preferably monosubstituted, preferably in the para position. When disubstituted, it is preferably substituted in the para and ortho or meta positions. When trisubstituted, it is preferably substituted in the meta, meta, and para positions. When a benzene nucleus is present in a substituent, it is preferably substituted with halogens and/or alkoxy groups. When a benzene nucleus is polysubstituted, the substituents are preferably identical. The amino group of aminoalkyl groups is preferably substituted, especially disubstituted. The preferred substituents of the amino group are alkyl and/or phenylalkyl groups, possibly substituted. This amino group is preferably disubstituted with alkyl and phenylalkyl groups, possibly substituted. In bis-phenylalkyl groups, the two benzene nuclei can be bonded to the same carbon atom or to different carbon atoms. They are preferably bonded to the same carbon atom. The bis-phenylalkyl group preferably means a bis-phenylmethyl group. A five-chain heteroaryl moiety as defined above preferably means a pyrrolyl, furyl, or thienyl group.

A six-chain heteroaryl moiety as defined above preferably means a pyridyl group, especially 4-pyridyl. Phenylalkyl groups preferably contain 7 to 10 carbon atoms. Bis-phenylalkyl groups preferably contain 13 to 16 carbon atoms. A halogen having an atomic number of 9 to 53 preferably means bromine or iodine. A halogen having an atomic number of 9 to 35 preferably means chlorine.

The invention also comprises a process for the preparation of the compounds of the invention, a process according to which a corresponding compound of formula II is appropriately transformed

(II) Z -OC?

I

in which

R1* R2? R5 and Q have the meanings indicated above,

Z means a reactive group and

Z' means a reactive group or has one of the meanings given above for -0R3<

The process of the invention can be carried out in a manner similar to known processes.

The choice of the most appropriate procedure variant naturally depends on the nature of, for example, the substituents -AR^ and R^.

A process variant may be, for example, an esterification. A suitable reactive group Z or Z' is, in this case, for example, a 1H-imidazole-1-yl group. This process variant is suitable, for example, for a transformation into a substituted or unsubstituted hydroxyalkyl, amidoalkyl, alkoxyalkyl, acyloxyalkyl, or aminoalkyl substituent. To this end, the corresponding compound of formula II is reacted with a diol, an amidoalcohol, an ester alcohol, or a corresponding aminoalcohol. Dioxane or an excess of the reaction product can advantageously be used as the solvent.

Another variant of the process could be, for example, an amination. This variant is suitable, for example, for the transformation into an aminoalkyl substituent. In this case, the reactive group Z or Z' is advantageously a -O-A-Z" group, where A has the meaning indicated above and Z" means chlorine, bromine, or an R^ SOg-O- group, where Rz means a phenyl, tolyl, or lower alkyl group. Z" preferably means a mesyloxy group. Amination may be direct, that is, the reaction takes place directly with an amine containing the substituent to be introduced, or indirect, for example by first converting the compound to the corresponding phthalimidoalkyl derivative to introduce a primary amino group, for example by reacting with sodium or potassium phthalimide, and then reacting the resulting phthalimidoalkyl derivative with hydrazine. The indirect method is preferred when the substituent to be introduced is a primary aminoalkyl group.

Another variant of the procedure could be, for example, the acylation of a primary or secondary amine. A reactive group Z or Z' is then advantageously the corresponding primary or secondary aminoalkoxy group. In this case, the corresponding compound of formula II is reacted with a corresponding acyl derivative, for example an ester of N-hydroxysuccinimide. A suitable solvent is, for example, dioxane.

Another variant of the procedure could be, for example, the acylation of an alcohol. The reactive group Z or Z' is then advantageously the corresponding hydroxyalkoxy group. In this case, the corresponding compound of formula II is reacted with the corresponding acyl derivative, for example an acyl halide. The reaction is preferably carried out in the presence of a strong base such as N-ethyldiisopropylene amine. A suitable solvent is, for example, methylene chloride.

Another variant of the procedure could be, for example, etherification. The reactive group Z or Z' is then advantageously an -O-A-Z" group in which A and Z" have the meanings indicated above. The reaction is preferably carried out under strongly alkaline conditions.

When Zl is a reactive group in the starting product, an -AR^ group can in this case be formed simultaneously at both positions 3 and 5 of the 1,4-dihydropyridines1e remnant.

Quaternary ammonium salts can be prepared similarly to known methods, for example by reaction with a corresponding (lower) alkyl iodide. An alcohol such as methanol can be considered as a suitable solvent.

When potentially reactive groups are present, such as hydroxy groups or primary or secondary amino groups, it may be appropriate to carry out the process of the invention with starting products in which these groups are in a protected form, for example for a phenolic hydroxy group in the form of a benzyloxy group, for an aliphatic hydroxy group in the form of a tetrahydropyranyloxy moiety and for an amiro group in the form of an acylamino or phthalimido group, and to subsequently convert any protected groups present into the desired substituent, for example the benzyloxy group into a hydroxy group, for example by hydrogenolysis, the tetrahydropyranyloxy group into a hydroxy group, for example by hydrolysis, and a protected amino group into a free amino group, for example by acid hydrolysis or by hydrazinolysis.

Starting from the reaction mixture, the compounds of the invention thus obtained can be isolated and purified according to known methods.

The compounds of the invention may exist in free form or, optionally, as a salt. Free forms are normally neutral, except when ionizable substituents are present.

Compounds can exist as salts, for example, when they include an ionizable substituent such as an amino or phenolic hydroxy group. Free-form compounds can be converted into salts by known methods, and vice versa. Suitable acids for the formation of acid addition salts include hydrochloric acid, malic acid, p-toluenesulfonic acid, and methanesulfonic acid. Suitable bases for the formation of anionic salts include sodium or potassium hydroxide.

When the substituents at positions 2 and 6 and/or at positions 3 and 5 of the 1,4-dihydropyridines remnant are different, the carbon atom at position 4 is asymmetric. Such a compound can therefore exist as a racemic compound or as individual enantiomers.

Individual optical isomers can be obtained by known methods.

The starting products can be obtained by known methods, for example by direct cyclization into 1,4-dihydropyridine.

Where the preparation of a particular starting product is not described in detail, it is a compound that is known or can be prepared by known processes or in a manner analogous to those described in this application.

The following examples illustrate the present invention without limiting its scope in any way. All temperatures are given in degrees Celsius and are uncorrected.

Example 1: 10-hydroxydeci1e 4-(2,T,3-benzoxadiazo1-4--yl)-1,4-dihydro-5-isO-propoxy carbonyl-2,6-dimetripyridin-3-carbossylate (esterification of the imidazolide with alcohol)

A mixture of 5.2 g of isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-(1H-imidazol-1-ylcarbonyl)-2,6-dimethylpyridin-3-carboxylate and 44.5 g of 1,10-decanediol is heated for 2 hours at an oil bath temperature of 120°C. After cooling, ether is added to the reaction mixture; the excess 1,10-decanediol separates by crystallization.

After filtration and evaporation of the ether under reduced pressure, the product is chromatographed on silica gel under low pressure using a mixture of methylene chloride and ether as the eluent. This yields the title compound in the form of an oil.

NMR spectrum (CDC13)?(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(IH.m.J = 6Hz), 5.48(lH,s), 5.92(lH,s), 7.3(2H,m), 7.62(lH,m).

Example 2: 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxy carbonyl-2,6-dimethylamino)-decyl e ...xycarbonyl-2,6-dimethylamino)-decyl e 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydroxycarbonyl-2,6-dimethylamino)-decyl e 4-(2,1,3-be

In 50 ml of ether, 4.6 g of 10-meta.nesulfoniloxydecyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethylpyridine-n-3-carboxylate and 2.2 ml of N-benzimethylamine are dissolved, the solution is evaporated to dryness under pressure, and the residue is heated for 3 hours at 80°C. The reaction mixture is then dissolved in ether, the solution is washed with cold sodium hydroxide, the ether phase is dried over magnesium sulfate, and it is evaporated to dryness under reduced pressure. The resulting product is purified by silica gel chromatography using, as the eluent, a 19:1 mixture of methylene chloride and ethanol. This gives: the title compound (free base: in the form of an oil; hydrochloride: in the amorphous form).

NMR spectrum of the free base (CDC13)&(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(lH,s), 5.98(lH,s), 7.2-7.7(8H,m).

The mesylate, used as a starting product, is prepared by reacting 0.4 g of the compound from Example 1 and 4.3 ml of N-ethyldiisopropylamine in 90 ml of methylene chloride with 1.0 ml of methanesulfonyl chloride added dropwise and stirring the resulting mixture for 90 minutes in an ice bath. The solution is then washed with cold 2N hydrochloric acid, and the organic phase is dried over magnesium sulfate and evaporated under reduced pressure.

Example 3: TO-aminodecyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethylpyridin-3-carboxylate (amination of the mesylate via the phthalimido derivative) In 44 ml of dimethylformamide, 2.2 g of 10-methanesulfonioxydecyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethylpyridin-3-carboxylate are dissolved, 2.2 g of potassium phthalimide is added, and the mixture is stirred for 3 hours at a bath temperature of 80°C. The solution is then cooled, filtered, washed with 100 ml of methylene chloride, purified by eight extractions with a cold 2N hydrochloric acid solution, and evaporated to dryness under reduced pressure. The product is chromatographed on silica gel under low pressure, using ether as the eluent.

The resulting 10-phthalimidodecyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethylpyridin-3-carboxylate (obtained as an oil) is dissolved in 40 ml of ethanol, 1.0 ml of hydrazine hydrate is added, and the solution is heated to boiling under reflux for 30 minutes. After filtration and washing with methylene chloride, the solution is extracted with ice-cold water, and the organic phase is evaporated to dryness under reduced pressure.

The product is chromatographed under low pressure on silica gel using, as the eluent, a 9:1 mixture of methylene chloride and methanol (containing ammonia). This gives the title compound (m.p. = 102? after crystallization in ether).

Example 4: 10-[3-(4-hydroxy-3-iodophenyl)-1-oxopropylamino]decyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-1,2,6-dimethylpyridin-3-carboxylate (amine amidation) A solution of 0.5 g of 10-aminodecyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-1,2,6-dimethylpyridin-3-carboxylate and 0.4 g of N-hydroxysuccinimide 3-(4-hydroxy-3-iodophenyl)-propionate in 15 ml of dioxane is heated for 30 minutes at a bath temperature of 120°C. The solution is then cooled, diluted with methylene chloride, and extracted with a cold, saturated aqueous solution of sodium bicarbonate. The organic phase is dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the product is chromatographed on silica gel under low pressure, using a 49:1 mixture of methylene chloride and ethanol as the eluent. This yields the title compound (amorphous product).

NMR spectrum (CDC13)&(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(lH,m,J = 6Hz), 5.53(1H,s),ca.5.62(lH,wide), ca.6.55(2H,wide), 6.9(lH,d,J = 8Hz), 7,l(lH,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-dimethylpyridin-3-carboxylate of 10-benzoyloxyde {alcohol acylation)

To a solution of 2.2 g of the compound of Example 1 and 1.3 g of N-ethyldiisopropylamine in 30 ml of methylene chloride, 1.2 g of benzoyl chloride are added at 20°C and the solution is stirred for 1 hour at 40°C. The reaction mixture is then diluted with ether, washed with water, 1N sodium hydroxide, and 1N hydrochloric acid, dried over magnesium sulfate, and evaporated under reduced pressure. The product is chromatographed on silica gel using a 9:1 mixture of methylene chloride and ether as the eluent. This yields the title compound (amorphous product).

NMR spectrum (CDC13)f>(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(lH,m,J = 6Hz), 5.5 <lH,s), 6.08(lH,s), 7.15 - 8.15(8H,m).

Example 6: 10-(N-benzimethylanimino)-decyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isoprooxycarbonyl-2,6-dimethylpyridin-3-carboxylate (esterification of 11imidazolide with 11-amminoalcool)

A solution of 4 g of isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-(1H-imidazol-1-ylcarbonyl)-2,6-dimethylpyridin-3-carboxylate and 7.0 g of 10-(N-methylbenzylamino)decan-1-ol in 150 ml of dioxane is heated under reflux for 16 hours. The reaction mixture is then evaporated under reduced pressure and the residue is heated for 3 hours at 80°C. The product is purified by silica gel chromatography using a 19:1 mixture of methylene chloride and ethanol as the eluent. This gives the title compound (free base: oil; hydrochloride: amorphous product).

NMR spectrum: see example 2.

The aminoalcohol, used as a starting product, is obtained as follows:

a) To a solution of 20 g of decanediol-1,10 and 20 ml of N-ethyldiisopropylamine in 800 ml of methylene chloride and 100 ml of acetone, a solution of 4.5 ml of methanesulfonyl chloride in 60 ml of methylene chloride is added dropwise to 30°C and the mixture is stirred for 1 hour at room temperature. 10-hydroxydecyl methanesulfonate is obtained (m.p. = 48°C, after chromatography on silica gel using, as eluent, a 2:1 mixture of methylene chloride and ether and crystallization in the ether).

b) A mixture of 8.5 g of the mesylate obtained under (a) above and 12.3 g of N-methylbenzilammine is heated to 80°C for 2 hours. This yields 10-(N-methylbenzilamino)decan-1-ol (oil; after chromatography on silica gel using ether as the eluent). Example 7: 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethylpyridin-3-carboxylate of 10-methoxydecyl e (etherification of the mesylate)

2.3 g of 10-methanesulfonyloxyde 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethylpyridin-3-carboxylate are reacted in 30 ml of methanol with 0.5 g of potassium methylate and the mixture is heated for 4 hours at reflux temperature. After evaporation to dryness under reduced pressure, the product is dissolved in ether, the solution is washed with 1N hydrochloric acid, the organic phase is dried over magnesium sulfate and evaporated to dryness. The product is then purified by silica gel chromatography using, as the eluent, a mixture of equal parts ether and hexane. This gives the title compound (oil).

NMR spectrum (CDCl3)fe(ppm): 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(lH,m,J = 6Hz), 5.5(lH,s), 6.3(lH,s), 7.2 -7.8(3H,m).

The following compounds of formula I are obtained in a similar manner from corresponding starting products:

?

Physicochemical properties of the compounds in the previous tables:

*Example P.F. Ca]20 [a]546

8 n oil 20? 28? (e = 1 g/dl in ethanol) 9 n oil -20? -28? (e = 1 g/dl in ethanol) 10 n oil

! 11 n oil

! Ila n oil

i 12 eh amorphous -14? -19? (e = 0.9 g/dl in ethanol) I eh amorphous 13? 19? (e = 0.9 g/dl in ethanol) I 1143 fu 130?

15 b oil

16 b oil

17 was 95?

18 eh amorphous

19 eh amorphous

20 eh amorphous

21 eh amorphous

22 eh amorphous

23 eh amorphous

24 eh amorphous

25 was 130? -12? -16? (e = 0.5 g/dl in ethanol) 26 was 130? 12? 18? (e = 0.7 g/dl in ethanol) 26a eh amorphous

26b b oil;

eh amorphous

| 26c b oil;

eh amorphous

j 26d b oil;

eh amorphous

26e b oil;

eh amorphous

Example P.F. [?]?U0 [?]?U46

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 r

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) I 37 n oil

? 38 n amorphous

39 n amorphous

40 n oil

41 (see example 5)

41a (see example 7)

42 98?

b = free base

eh = hydrochloride

fu = fumarate

n = in neutral free form

The compounds of the invention are distinguished by interesting pharmacological properties and can consequently be used in therapeutics as medicines.

The compounds of the invention exert effects characteristic of calcium antagonists. They exert a pronounced myorelaxant effect, particularly on smooth muscles, as demonstrated by vasodilation and lowering of blood pressure in classical tests. This is the case, for example, in the microsphere test performed on anesthetized cats according to the method described by R. Hof and co-workers in Basic Res. Cardici. 5, 747-756 (1980) and 7_6, 630-638 (1981) and by R. Hof and co-workers in J. Cardiovasc. Pharmacol. ?, 352-362 (1982), a dilation of the coronary vessels, an increase in blood flow in skeletal muscles and a lowering of blood pressure are observed, after administration of the compounds of the invention intravenously at doses ranging from about 3 to about 300 ug/kg, for example from about 10 to about 100 ug/kg.

A reduction in blood pressure is also observed in spontaneously hypertensive rats according to the method described by M. Gerold and colleagues in Arzneimittelforschung'1_8, 1285 (1968), after oral administration of the compounds of the invention at doses ranging from about 1 to about 10 mg/kg. Thus, the compound of Example 2 causes a 40% reduction in blood pressure after oral administration at a dose of 3 mg/kg. The compounds have a longer duration of action than the known reference substances and are suitable, for example, for once-daily administration. The compounds are also particularly well absorbed orally.

Thanks to these properties, the compounds of the invention can be used in therapeutics as calcium antagonists for the prevention and treatment of coronary insufficiencies, for example angina pectoris,

- circulatory disorders, for example in the limbs, such as intermittent claudication and spasms, for example of the colon muscles,

- asthma, for example asthma following exertion,

- of hypertension.

The compounds of the invention also exert a vasodilatory effect on the capillary vessels of the carotid region; this results in an antagonistic effect on the vasoconstrictor effect exerted by serotonin and an inhibition of the resulting disorders. Thanks to this property, the compounds of the invention can be used therapeutically for the prophylaxis and treatment of migraines and vascular headaches such as vascular pain of the face, especially for the interval therapeutic treatment (prevention) of migraines.

For this indication, the preferred compounds are those having a relatively moderate effect on blood pressure and peripheral blood vessels.

For the above-mentioned therapeutic uses, the compounds of the invention will be administered at a daily dose of between about 1 mg and about 200 mg. Advantageously, for example, administered orally, in divided doses once to three times daily, in the form of single doses, each comprising between about 0.3 mg and about 200 mg of active substance, or in a prolonged-action form. An example of a daily dose is between about 5 mg and about 50 mg.

The compounds of Examples 2, 5, 14, 29 and 41 are preferred, especially those of Examples 2 and 14.

For the prophylaxis and treatment of migraine and vascular headaches, the preferred compounds are those in which Q represents a 2,1,3-benzothiadiazo1?1e moiety.

The compounds of the invention can be administered in free form or, optionally, in the form of a pharmaceutically acceptable salt, preferably an acid addition salt. These salts exhibit the same order of activity as the free forms and are prepared according to conventional methods.

The invention therefore comprises a compound of the invention, in free form or optionally in the form of a pharmaceutically acceptable salt, for use as a medicament, especially for use as a calcium antagonist.

The invention also includes a medicament containing, as an active ingredient, a compound of the invention in free form or possibly in the form of a pharmaceutically acceptable salt.

As medicaments, the compounds of the invention can be used in the form of pharmaceutical compositions containing a compound of the invention in free form or, optionally, in the form of a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable diluent or carrier. Such pharmaceutical compositions, which are also part of the present invention, can be prepared according to conventional methods and presented, for example, in the form of capsules, suitable for sublingual administration, or tablets.

Claims (8)

C a i n s 1) The 1,4-dihydropyridines corresponding to formula I (n R^OOC? ? COO-AR^ in which R.| represents hydrogen, a cycloalkyl group at C3~C7 or an alkyl group at C-j-Cg possibly substituted, R2 and each represent, independently of each other, hydrogen or an alkyl group at C-j-Cg, represents an alkyl group at C-]-C-|2 or has, independently of -AR^, one of the meanings given below for -AR^ including the conditions relating thereto, R^ represents a hydroxy or alkoxy group at C.j-C-|2 or a -0C0RK, -NR^Rg or -NR?^ residue, in which Rg means an alkyl group on C^-C^g, a phenyl, phenylalkyl group on C^-2 or bis-phenylalkyl on C^3-C^g, the benzene nucleus(es) of these last three groups possibly bearing one, two or three substituents selected from the halogens having an atomic number between 9 and 53 and the hydroxy, alkyl groups on C-j-C^ and alkoxy groups on Cj-C^, a 5-chain heteroaryl residue containing 1 heteroatom selected from nitrogen, oxygen and sulphur or 2 heteroatoms of which one is nitrogen and the other is nitrogen, oxygen or sulphur, or a 6-chain heteroaryl residue containing from 1 to 4 nitrogen atoms, R^ means hydrogen or has one of the meanings given above for Rg, Rg means hydrogen, an alkyl group in C-|-Cg or a remainder -C0Rg where Rg has the meaning given above for Rg, Nj^means a 5, 6 or 7 chain heterocycle which may optionally contain, when saturated and 6 or 7 chained, another heteroatom chosen from oxygen, sulfur and =NR^Q where R^g means hydrogen or has one of the meanings indicated above for Rg, A represents an alkylene group at C2?C^ , and Q represents a totally unsaturated condensed cyclic system of aromatic character having in total at least 2 different cyclic heteroatoms, A being to represent an alkylene group at C7~C?4 when it means a hydroxy group, an alkoxy group at Cj-Cgt a -Ng^ residue as defined above or a -NRjRg residue where RJ means hydrogen, an alkyl group at C-j-Cg, an unsubstituted phenyl group or an unsubstituted phenylalkyl group at C7-C-jQ and R8p means hydrogen or an alkyl group at C^-Cg, and the ammonium salts of compounds in which R^ is one of the tertiary amino groups defined above for R^ and quaternized with a group of formula A1kY where Alk means an alkyl group on C-j-C^ and Y the remainder of an acid. in free form or possibly in the form of a salt. 2) 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethylpyridin-3-carboxylate of 10-(N-benzylmethylamino)-decyl, in free form or possibly in the form of a salt. 3) 10-C 4-(diphenylmethyl)piperazini]decyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethylpyridin-3-carboxylate, in free form or possibly in the form of a salt. 4) Process for the preparation of the 1,4-dihydropyridines defined in claim 1, characterized in that a compound corresponding to the formula II is appropriately transformed. 9 (II) Z'-OC? r in which R-|, R2, R5 and Q have the meanings indicated in claim 1, Z represents a reactive group and Z' represents a reactive group or has one of the meanings indicated in claim 1 for -ORg, and the compounds thus obtained are recovered in free form or possibly in the form of a salt. 5) The 1,4-dihydropyridines specified in any of claims 1 to 3 in free form or optionally in the form of a pharmaceutically acceptable salt, for use as medicaments. 6) The 1,4-dihydropyridines specified in any of claims 1 to 3 in free form or optionally in the form of a pharmaceutically acceptable salt, for use as calcium antagonists. 7) A medicament, characterised in that it contains, as an active substance, a 1,4-dihydropyridine as specified in any of claims 1 to 3 in free form or optionally in the form of a pharmaceutically acceptable salt. 8) A pharmaceutical composition, characterised in that it contains a 1,4-dihydropyridine as specified in any of claims 1 to 3 in free form or optionally in the form of a pharmaceutically acceptable salt, in association with a pharmaceutically acceptable diluent or vehicle.