LU85423A1 - NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Description

I *! *

The present invention relates to new derivatives of 1, 4-dihydropyridine, their prepa-tion and their use in therapy, as active principles of drugs.

% *.

5 The invention relates in particular to

^ 1,4-dihydropyridine derivatives of formula I

Q

1 R300c — ίΓ ^ Ίτ "coo ~ ar4 (1}? C R1 L in which 15 represents hydrogen, a C ^ -C7 cycloalkyl group or an optionally substituted C- | -Cg alkyl group, R„ and R each represents, independently of one another, hydrogen or a C1-C6 alkyl group, R ^ represents a C1-C12 alkyl group or has, independently of -AR ^, the one of the meanings ^ indicated below for -AR ^ including the conditions relating thereto, _ î R ^ represents a hydroxy or C 1 -C 4 alkoxy group, -η 25 or a residue -OCORg, -NR ^ Rg or -N0, in which

Rg signifies a C 1 -C 6 alkyl group, a phenyl, phenyl-C 1 -C 4 alkyl or bis-phenyl-alkyl group in the benzene ring (s) of these last three groups which may optionally carry one, two or three chosen substituents among the halogens having an atomic number of 9 to 53 and the hydroxy, C 1 -C alkyl and C 1 -C 4 alkoxy groups, a 5-membered heteroaryl radical containing 2 \ * ι, i 1 heteroatom chosen from nitrogen, oxygen and sulfur or 2 heteroatoms, one of which is nitrogen and the other is T nitrogen, T oxygen or * sulfur, or a 6-membered heteroaryl residue containing 1 to 4 nitrogen atoms, e R7 signifies hydrogen or has one of the meanings indicated above for Rg,

Rg signifies hydrogen, a C 1 -C 6 alkyl group or a residue -CORg where Rg has the meaning given above for R,., B signifies a 5, 6, or 7-membered heterocycle which may optionally contain , when it is saturated and 6 or 7-membered, another hetero atom chosen from oxygen, sulfur and = NR-jQ; Where R 1q signifies hydrogen or has one of the meanings given above for R 1, A represents a C 2 -C 14 alkylene group, and Q represents a fully unsaturated condensed ring system of aromatic character having a total of at least 20 2 different cyclic heteroatoms, A having to represent a C 1 -C 4 alkylene group. When R 4 signifies a hydroxy group, a C 4 -C 6 alkoxy group, _ a residue -Ng 4 as defined above or a residue -NR ^ Rg where Ry signifies hydrogen, an alkyl group 25 at 0, -0, -, an unsubstituted phenyl group or a Λ 16 phenylalkyl group C7-C1Q unsubstituted and Rg signifies hydrogen or a group C 1 -C 6 alkyl, and the ammonium salts of the compounds in which is one of the tertiary amino groups defined above for R4 and quaternized by a group of formula A1kY where A1k signifies a C -C4 alkyl group and Y the remainder of an acid.

For reasons of simplification, the 3 | In the present description, 9 compounds of formula I and their ammonium salts will be designated "the compounds of the invention".

Certain compounds of the invention fall * 5 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 88 886 and 94 94 59. These applications 10 were published respectively in September 1983 and November 1983, that is to say say at a date after the priority date claimed for the ί compounds of the present invention, namely June 21, 1983.

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

Other publications relating to compounds related to the compounds of the invention are for example European patent applications No. 150, No. 71 819 and 20 No. 80 220, German patent applications DOS No. 29 49 464, No. 29 49 491 and No. 33 20 616 and Belgian Patent No. 890 31 1.

The publications mentioned above do not suggest any specific compound 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 comprises the compounds of formula la

FT

I ψ I * * i i 4

Vy \

, X

(Ia) * 5 R3a00C COO-AaR.a

Ti i ** X> h K1 10 in which R represents hydrogen, a halogen having an atomic number of 9 to 35, or a hydroxy, ^ nitro, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 6 alkoxy group , CjC ^ alkylthio or alkylsu! fonyl - j C, -C-, 9. 'represents hydrogen, a Cj-Cg alkyl group, a Cg-Cg alkenyl group in which the double bond is separated from l nitrogen atom by at least one carbon atom not being part of the double bond, a C 1 -C 6 alkynyl group in which the triple bond is separated from the nitrogen atom by at least one atom carbon not being part of the triple bond, a C 1 -C 4 cycloalkyl group, a C 1 -C 4 cycloalkylalkyl group, a C 6 -C 4 hydroxyalkyl group in which 4 oco the hydroxy group is separated the nitrogen atom by at least 2 carbon atoms, a C2-C6 alkoxy-alkyl group, a C 1 -C 6 phenylalkyl group or a C 1 -C 12 phenylalkenyl group in which the double bond is separated from 1 1 atom of az ote with at least one carbon atom which is not part of the double bond, the benzene nucleus of these latter two groups possibly optionally bearing one, two or three substituents chosen from halogens having an atomic number: 5 9 from 9 to 35 and hydroxy groups, C 1 -C 4 alkyl and C 4 alkoxy, an alkylcarbonyloxy-alkyl group containing from 2 to 6 carbon atoms in each cha-, * which remains at 1 ky 1 carbony 1 e and alkylene and of which 5 is oxygen separated from the nitrogen atom by at least two carbon atoms, a dialkylaminoalkyl group independently containing from 1 to 6 carbon atoms in each alkyl residue and from 2 to 6 carbon atoms in the alkylene residue and the amino group is separated from the nitrogen atom by at least two carbon atoms, or a morpholinoalky1e group containing from 2 to 6 carbon atoms in the alkylene residue and whose morpholino residue is separated from the nitrogen atom by 15 at least two carbon atoms, R ^ and Rg have the significant previously given,

Ra represents an alkyl group in or P ° ssède, independently of -AaR ^, one of the meanings indicated below for -A, Ra represents a hydroxy or alkoxy group in ^ i-Ci 2 or a residue -OCORg, -NRaRg, or -N ^ as defined above, in which Ra, Ra and Ra have respectively the meanings indicated above for

Rg, R7 and Rg, Aa represents a C 1 -C 4 alkylene group, and X represents oxygen or sulfur, * - Aa must represent a C 7 -C 14 alkylene group when Ra signifies a hydroxy group or a -Nçj group as defined above, and 30 - Aa "must represent a C9 alkylene group" C14 when R ^ signifies a Ο, -Ο, ρ alkoxy group or ^ a 'a1 reads a residue -NR, R0 in which a '/ o R7 signifies hydrogen, a C 1 -C 6 alkyl group, 6 * an unsubstituted phenyl group or an unsubstituted phenyl-C 1 -C 4 alkyl group and "Ra signifies hydrogen or a C 1 -C 6 alkyl group, f and the ammonium salts of the compounds in which '5 R® signifies one of the tertiary amino groups defined <5î above for R ^ and quaternized by a group of formula ΑΊ k Y as defined above.

In a subgroup of compounds of formula la,

Aa signifies a Cg - C -j ^ alkylene group. In another subgroup, R ^ has a meaning other than an alkoxy group. In another subgroup, R ° and R. mean â â ^ _ -NR? R8 or -N0 as defined above.

A preferred group of compounds of formula la comprises the compounds of formula Iaa, 15 W \ N7 (Iaa) 20 R “° 0C 'V'O C00-AaaRaa T i

RZ 'aH

ù R] 5 λ 25 in which R, Ra, Rg, Rg and X have the meanings given ΐ previously,

Raa represents an aikyle group in

Raa has the meaning given above for R ^> and 30 aa A represents an alkylene group at ^ 2 ”C14 'aa - Aaa must represent an alkylene group at C ^ -C ^ 1 when R ^ signifies a hydroxy group or a residue -Nq as defined above, and 5 7 ί ^ - Aaa must represent a C9'C14 alkylene group when Raa signifies a CjC ^ alkoxy group or a residue -NR ^ Rq 'in which Ra' and Ra have the meanings given above, 9. 5 and the ammonium salts of the compounds in which

Raa means one of the defined tertiary amino groups

above for R ^ a and quaternized by a group A1kY

as defined above.

In a subgroup of compounds of formula Iaa, Aaa represents a Cg-C14 alkylene group.

In another subgroup, R ^ a has a meaning other than a alkoxy group. In another subgroup, R ^ 'represents a residue -NRaRg or -Nq as defined above.

L 15 Another preferred group of compounds of formula la comprises the compounds of formula Iab R v 20 γΧ l / R3b ° 0C / C00-Aab-Rjb Y Y 4 (Iab) R / 'R- 2 (a 5

R

* * 25 1 in which R, Ra, R2> r5 and X have the meanings given above, 30,

Rab represents a C-C alkyl group, Q or has, 3 a h λ h * \ ά independently of -A R ^, one of the meanings given below for -AabR ^ b, 8 P * ^ ΐ, 3

Rab represents a hydroxy or alkoxy group in CrC12 or a residue -OC 0 Rg or - N in which »R®, Ra and Ra have the meanings given! previously and 5 5 Aab represents a C2-C4 alkylene group, - Aab must represent a C7'C14 alkylene group when Rab signifies a hydroxy group, and - Aab must represent a Cq-C alkylene group, 4 ah “7 ! when A ^ signifies a C 1 -C 12 alkoxy group or 10 a residue -NRa Ra in which Ra and Ra have the meanings given above, and the ammonium salts of the compounds in which Rab signifies one of the tertiary amino groups defined ci above for Rab and quaternized by an AlkY 15 group as defined above.

In a subgroup of compounds of formula Iab, Aab signifies a Cg-C14 alkylene group. In another subgroup, Rab has a meaning other than an alkoxy group. In another subgroup, Rgb and R ^ 20 represent a residue -NRaRa as defined above.

Another preferred group of compounds of formula la comprises the compounds of formula Iaaa '- W ·', (Iaaa) 'Rfa00C \ C00-AaaaRaaa

T T

* 2 30 R1 ^ * 9 3 in which R, Ra, Rg and X have the meanings given above, "â â â R3 represents a C 1 -C 6 alkyl group, * aaa 3 5 represents a hydroxy or C1 alkoxy group" e! 2 or a remainder -OCOR ^ or -NR ^ Rq in which Ra, -, 0/0 0

Ra and Ra have the meanings given above, and cl â 3l A represents a C 1 -C 4 alkylene group., Â. cl d, * * 10 - A must represent a C7-C14 alkylene group when R ^ aa signifies a hydroxy group and â cl 3.

- A must represent a Cg-C ^ 3 3 3 alkylene group when R ^ signifies an alkoxy group in ci-c, 2 OR ~ a residue -NRa Ra in which Ra and Ra have the meanings given above, and the ammonium salts of the compounds in which 4 ia signifies one of the tertiary amino groups defined above for R ^ aa and quaternized by an A1 kY group as defined above.

20 In a subgroup of compounds of formula

Iaaa, Aaaa means a C 9 "C14 alkylene group * α o a

In another subgroup, R ^ has a meaning other than an alkoxy group. In another subgroup, - R ^ aa signifies a -NRaRg residue as defined above.

Other groups and subgroups of compounds of the invention include those of formulas la, Iaa,

Iab and Iaaa in which R ^ signifies hydrogen or a C 1 -C 4 alkyl group, in particular hydrogen or a methyl group, especially hydrogen, those in which R2 and Rg signify hydrogen or a C1-6 alkyl group, in particular a methyl group, those in which R represents hydrogen, those in which X represents oxygen, as well as those comprising a combination of these meanings, and optionally their corresponding quaternary salts such as defined above.

Another preferred group of compounds of the invention includes the compounds of formula Ib b 9 hh (Ib) 10 □ ^ Nxk R2 1 r5 R1 1 15 in which FL, FL, FL and Q have the meanings given above - 1 Z b demment,

Rb represents a C 1 -C 4 alkyl group? or has, ο hb island 20 independently of -A ° R °, one of the meanings * bb indicated below for -A ° R °, L ^ R “represents a hydroxy or alkoxy group in C]" ci2 or * a residue -0C0Rb, -NRbRb or -Ng as defined above, in which R ^, Rb and Rb have the * - 25 meanings given above respectively for Rg, R ^ and Rg, and - Ab represents a group Cg-C ^ alkylene, and the ammonium salts of the compounds in which Rb represents one of the tertiary amino groups defined above for Rb and quaternized by an AlkY group as defined above.

In a subgroup of compounds of formula Ib, Rb has a meaning other than an alkoxy group.

* η

K K

In another subgroup, R? and R. mean a

LL to T

remains -NR ° Rg or -N ^ as defined above.

A preferred group of compounds of formula Ib 'includes compounds of formula Iba £ 5

Q

, R ^ a00Cx Λ / COO-A ^ R ^ (Iba) R ^ N ^ n 2 I R5 10 R1 in which

K K

15 R ·], Rg> R ^ j Rgs Ad and Q have the meanings given above and R ^ a represents a C 1 -C 6 alkyl group, and the ammonium salts of the compounds in which R ^ represents one of the defined tertiary amino groups

Τ 'L

20 above for R 1 and quaternized by an A1 kY group as defined above.

In a subgroup of compounds of formula Iba, R *? has a meaning other than an alkoxy group.

In another subgroup, R ^ represents a residue -NR ^ Rg 25 or -Ng ^ as defined above.

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

Rjjb00CNJL / C00-Ab-R $ b

30 TT

(ibb) R1 12 Γ in which R., R_, R_, Ab and Q have the meanings given I c b î previously,

h K

- R ° represents an alkyl group in or has, O K K K \ \ l.

5 independently of -ADR °, one of the meanings • b b b. data below for -A R? , K K ** r ° d represents a hydroxy or C 1 -C 19 alkoxy group or

4 L k k I L I £ L

a remainder -OCORg or -NR ^ Rg, in which Rg, R ^ and Rb have the meanings given above,

O

10 and the ammonium salts of the compounds in which R ^ k represents one of the tertiary amino groups

4 LL

defined above for R ^ j and quaternized by a group A1k Y as defined above.

In a subgroup of compounds of formula Ibb,

~ K K

R ° has a meaning other than an alkoxy group.

^ r> bb „bb. . ...

In another subgroup, R., and R. signify an h h h 3 remain -NR ^ Rq as defined above.

Another preferred group of compounds of formula Ib includes compounds of formula Ibaa 20? R3a00CvA ^ ° »Abb (Ibaa)

II

R2? R5 25 R1 s in which R1S R2, Rba, Rbb, Rg, Ab and Q have the meanings given above, and the ammonium salts of the compounds in which Rbb represents one of the tertiary amino groups 4 L · L · defined above for R ° and quaternized by an AlkY group as defined above.

5 13

In a subgroup of compounds of formula Ibaa, has a meaning other than an alkoxy group.

In another subgroup, means a remainder b b ^ -NR ° Rg as defined above.

* 5 Other groups and subgroups of compounds of the invention include those of formulas Ib, Iba,

Ibb and Ibaa in which means as defined above, in particular hydrogen or an alkyl group, especially hydrogen or a methyl group, in particular hydrogen, those in which and Rg represent hydrogen or a C 1 -C 4 alkyl group, in particular a methyl group, those in which Q represents a group of formula - "ÇÛ in which R and X have the meanings given above, in particular those in which R signifies hydrogen, and those in which X 20 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 * includes the compounds of formula Ip

NOT

Qp φχ. 1 .C00-APR? , xc R2 I n R5 14 s in which RP represents hydrogen or a C -C 16 alkyl group 6 'i Rp and Rp represent, independently of one another, a C- alkyl group | C ^, R ^ represents a C 1 -C alkyl group or has, independently of -APR ^, one of the meanings given below for -APRP, RP represents a hydroxy or C 1 -C 6 alkoxy group or 10 a remainder -0C0RP, -NRPR ^ or -It ^ p, in which

Rg signifies a C ^-C alk alkyl group, a phenyl, phenyl-Ciq alkyl or bis-phenyl-C en-Cg alkyl group, the benzene ring (s) of these last 3 groups possibly optionally having one, two or three substituents chosen from halogens having an atomic number of 9 to 53 and hydroxy, C 1 -C 4 alkyl and C 1 -C 4 alkoxy groups, a 5-membered heteroaryl radical comprising a heteroatom chosen from nitrogen, oxygen 20 and sulfur or 2 heteroatoms, one of which is nitrogen and the other is nitrogen, oxygen or sulfur, or a 6-membered heteroaryl radical containing from 1 to 4 nitrogen atoms,

Rp signifies hydrogen, a CjC ^ 25 alkyl group or has one of the meanings given above for Rg except a Cj-Cg alkyl group, RP signifies hydrogen, a C 1 -C alkyl group | or a residue -COR ^ in which R ^ has one of the meanings given above for Rg, 30 - N signifies a saturated 5, 6 or 7-membered heterocycle which may optionally contain, when it is 6 or 7 links, another heteroatom chosen from oxygen, sulfur and = NRPq where 3 15

Rp signifies hydrogen or has one of the si-I u p gnifications i ndicated above for Ry,

Ap represents an unbranched C 1 -C 4 alkylene group and

Qp represents a totally ~ 5 unsaturated condensed bicyclic system of aromatic character containing in total at least 2 different cyclic heteroatoms,

Ap having to represent an unbranched alkylene group at C7-C- | 4 when R ^ signifies a hydroxy group, an alkoxy group at C ^ -Cg, a residue -N ^ p as defined above-] 0 or a residue- NRp Rg in which RP signifies hydrogen, a C1-C6 alkyl group, an unsubstituted phenyl group or an unsubstituted phenylalkyl group C 1 -C ^ and RP signifies hydrogen or a C1-alkyl group -Cg,] 5 and the ammonium salts of the compounds in which

Rp represents one of the defined tertiary amino groups

above for R ^ and quaternized by an AlkY group

in which A1k signifies a C 1 -C 4 alkyl group and Y the remainder of an acid.

2o In a subgroup of compounds of formula Ip, RP signifies a C 1 -C 6 alkyl group in another subgroup, it signifies a C 1 -C 3 alkyl group; in another subgroup, it means -APR ^ in which AP and Rp have the meanings given above; In another subgroup, Rp has a meaning other than an alkoxy group; in another subgroup, Ap means an unbranched alkylene group at Cy-C ^; in another subgroup, Ap means an unbranched Cg-Cl4 alkylene group; in another subgroup, RP represents a hydroxy or alkoxy group in Cj-Cg or a residue -0C0Rp or NRPRP in which Rg »Rp and Rp have the meanings given above, as well as the combinations of these meanings, and possibly their corresponding quaternary salts 16 as defined above.

Another group of compounds of the invention comprises the compounds of formula Is) 5 J ^ N / (Is) r.sooc - / y coo-asr, s 3 I | 4 R S N R s 10 K2, K5

H

in which R ^ and Rg each represent, independently of one another, an alkyl group in Rg represents a alkyl group in C1_C125 represents a hydroxy or alkoxy group in CjC ^ or a residue -OCORg, -NR ^ Rg or -NOS, in which Rg signifies a C ^-alkyl or phenyl group, R R signifies hydrogen, a C ^-C ^ alkyl group, a C ^-C ^ phenylalkyl group in which the benzene nucleus may optionally carry one or two substituents chosen from »25 halogens having an atomic number of 9 to Ξ 53 and C 1 - alkoxy groups, a residue - -CORg in which the residue Rg signifies a C 1 -C 4 alkyl group, or a phenyl or phenyl-C 7 -C 10 alkyl group in which the benzene ring may optionally carry one or two substituents chosen from halogens having an atomic number of 9 to 53.317 and hydroxy and C 1 -C 4 alkoxy groups,

Ro means hydrogen or an alkyl group

O

, in C.J -, ND \ S means a pi per di ne or piperazine cycle

sr D J

5 substituted in position 4 by a methyl group, by a benzyl group or by a bis-phenylmethyl group in which the benzene ring (s) may optionally bear one or two substituents chosen from halogens having an atomic number from 9 to 53 and the C] -C ^ alkoxy groups,

As represents a Cg-C-j ^ alkylene group, A having to represent a Cy-C14 alkylene group g when denotes a hydroxy group, a grouse alkoxy in

15 C -, - C,, a residue -N ^ \ S as defined above or a remainder 1 ς 4c V

- N R7 Rg in which

Ry signifies hydrogen, a C 1 -C 4 alkyl group or an unsubstituted C 1 -C 4 phenylalkyl group and Rg has the meaning given above, and the ammonium salts of the compounds in which R 1 represents one of the tertiary amino groups defined above for and quaternized by an A1kY group as defined above.

In a subgroup of compounds of formula Is, c * 25 A signifies a Cy-C4 alkylene group; in another subgroup, it signifies a Cg-C ^ alkylene group; w in another subgroup, it is unbranched.

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

In another subgroup, R-j signifies hydrogen or a C 1 -C 6 alkyl group; in another subgroup, R2 and R5 each mean, independently of one another, a C 1 -C 4 alkyl group; in another subgroup, R3 signifies a C ^ alkyl group;

in another subgroup, R3 means a remainder -APR ^ P

* "5 as defined above; in another subgroup, A means an unbranched alkylene group and R ^ a la.

meaning given above for R ^, including the conditions relating to it; in another subgroup, R., R., and / or Rq have the meanings given above respectively for R ^, Rp and / or Rg, in another subgroup, -N-rx has the meaning given above n Λ for -Ngy; in another subgroup, Q is a bicyclic system w; in another subgroup, R ^ signifies a C 1-6 alkoxy group; in another subgroup, w the substituted or unsubstituted phenylalkyl group is in Cy-C 1 and the substituted or unsubstituted bis-phenylalkyl group is in in another subgroup,

Ry has one of the meanings given previously for RP. In another subgroup, all of the uncondensed phenyl rings are substituted.

Ri preferably has the meaning given for R ^. Preferably, R * signifies hydrogen. When it does not mean hydrogen, it preferably represents an unsubstituted alkyl, cyalkylalkyl, optionally substituted phenylalkyl, alkoxyalkyl or morpholino group, preferably an unsubstituted alkyl or alkoxyalkyl group, more preferably an unsubstituted alkyl group. . When R-j signifies an alkoxyalkyl group, the alkoxy residue is preferably separated from the nitrogen atom by at least 2 carbon atoms.

R2 and / or R5 preferably signify an alkyl group.

R. preferably means an alkyl group.

O

When it has the meaning given for -AR ^, it is preferably i identical to -AR ^.

R ^ preferably signifies a hydroxy group or. 5 a residue -OCORg, -NRyRg or -Νβ ^. Q preferably contains a total of at least 3 heteroatoms, in particular 3 heteroatoms. It is preferably a bicyclic system. Q preferably signifies a 2,1,3-benzoxadiazolyl or 2,1,3-benzothiadiazolyl group, in particular a 2,1,3-benzoxadiazolyl group. When Q is a ring system comprising a benzene ring, the remainder 1,4-dihydropyri diny1e is preferably linked * · to this benzene ring, preferably in a position of the benzene ring which is adjacent to a junction of 15 rings.

A is preferably unbranched and preferably contains from 7 to 14 carbon atoms, especially from 9 to 14 carbon atoms, in particular 10 carbon atoms.

A1k preferably means a methyl group.

Y preferably means the residue of a mineral acid, for example a methyl residue or a halogen, in particular iodine.

R6 preferably signifies an alkyl, ς * phenyl, phenylalkyl or bis-phenylalkyl group, in particular a phenyl group.

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

R0 preferably means hydrogen, a

O

30 alkyl group or a residue -CORg.

Preferably, Ry and Rg both signify hydrogen or one of the substituents Ry and R_ signifies an alkyl group and the other an alkyl group,

O

optionally substituted phenylalkyl or optionally substituted bis-phenylalkyl 20Γ.

Rg preferably means an alkyl group, an optionally substituted phenyl group, an optionally substituted phenylalkyl group or an optionally substituted bi s-phenylalkyl group. -N ^ as defined above is preferably saturated. It is preferably a 6-membered ring, especially a 1-pi perazi nyl e group. When it is 6 or 7 members, it preferably contains another hetero-10 atom = NR ^ q. is preferably other than hydrogen. It preferably means an optionally substituted alkyl, phenylalkyl or optionally substituted bisphenylalkyl group. X preferably means oxygen. R preferably signifies hydrogen.

The remainder jpcj is preferably linked by its position 4 to position 20 4 of the remainder 1,4-dihydropyridinyl. C6-C6 cycloalkyl groups preferably contain 3.5 or 6 carbon atoms, especially 5 or 6 carbon atoms. C 1 -C 2 alkyl and / or C 1 -C 2 alkoxy groups preferably contain from 1 to 6 atoms; * 25 carbon, especially from 1 to 4 carbon atoms, and c- signify in particular a methyl, ethyl or isopropyl group. The C 1 -C 6 alkyl groups preferably contain from 1 to 4 carbon atoms, especially 1 or 2 carbon atoms, and signify in particular a methyl group. When the C 1 -C 6 or C 6 alkyl groups are substituents of a benzene ring or of an amino group, they preferably contain 1 or 2 carbon atoms and signify in particular a methyl group. When the alkoxy groups at C- | -C ^ are substituents of a benzene ring, they preferably contain 1 or 2 carbon atoms and r signify in particular a methoxy group. The alkenyl and / or alkynyl groups preferably contain 3 carbon atoms. The cycloalkyl residue of the cycloalkylalkyl groups preferably contains 3.5 or 6 carbon atoms, especially 5 or 6 carbon atoms. The alkylene residue of the cycloalkylalkyl groups and / or of the phenylalkyl groups preferably contains 1 or 2 carbon atoms and signifies in particular a methylene residue. The alkenylene residue of the phenylalkenyl groups preferably contains 3 carbon atoms.

The alkylene residue of the C 1 -C 20 hydroxyl groups and / or the C 1 -C 6 alkoxyalkyl groups preferably contains 2 or 3 carbon atoms, in particular 2 carbon atoms. The hydroxy group of the hydro-xyalkyl and / or hydroxyal coxyalkyl groups and / or the amino group of the aminoalkyl groups are preferably attached to the most distant terminal carbon atom.

When a benzene ring is present in a substituent, it is preferably unsubstituted. When substituted, it is preferably mono-substituted, preferably in the para position. When it is disubstituted, it is preferably substituted for the para and ortho or meta positions. When it is tri substituted, it is Dreference substituted in the meta, meta and para positions. When a benzene ring is present in a substituent, it is preferably substituted by halogens and / or alkoxy groups. When a benzene nucleus is polysubstituted, the substituents are preferably 22 Γ identical. The amino group of the aminoalkyl groups i 'is preferably substituted, in particular disubstituted. Preferred amino group substituents are optionally substituted alkyl and / or phenylalkyl T * 5. This amino group is preferably disubstituted by alkyl groups and optionally substituted phenylalkyl. In bis-phenylalkyl groups, the two benzene rings can be linked to the same carbon atom or to different carbon atoms. They are preferably linked to the same carbon atom. The bis-phenylalkyl group preferably means a bis-phenylmethyl group. A 5-membered heteroaryl radical as defined above preferably means a pyrrolyl, furyl or thienyl group.

A 6-membered heteroaryl radical as defined above preferably means a pyridyl group, in particular 4-pyridyl. The phenylalkyl groups preferably contain from 7 to 10 carbon atoms. Bisphenylalkyl groups preferably contain from 13 to 16 carbon atoms. By halogen having an atomic number of 9 to 53, is preferably meant bromine or iodine. By halogen having an atomic number of 9 to 35, is preferably meant chlorine.

The invention also includes a process for "preparing the compounds of the invention, a process in which a compound is suitably transformed

correspondent of formula II

0

30 Z'-0ClVZ

* 2, AR5 <">

Ri 5 i * * 23 in which, R ,, and Q have the meanings given above, Z signifies a reactive group and ~ 5 Z 'signifies a reactive group or has one of the meanings given above for -0R3.

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

The choice of the most suitable process variant obviously depends on the nature, for example, of the substituents -AR ^ and R ^.

A variant of the process can for example be a teri fi cati on. A suitable reactive group Z or Z 'is, in this case, for example a group 1 H-imidazole-1 -yle. This process variant is indicated, for example, for conversion to hydroxyalkyl, amidoalkyl, alkoxyalkyl, acyloxyalkyl or substituted or unsubstituted aminoalkyl. For this purpose, the corresponding compound of formula II is reacted with a diol, an amidoalcohol, an ester alcohol or a corresponding amino alcohol. As solvent, it is advantageous to use dioxane or an excess of the product * participating in the reaction.

Another variant of the process can be, for example, an amination. This variant is indicated, for example, for conversion to an aminoalkyl substituent. In this case, the reactive group Z or Z ′ is advantageously a group -0-AZ "in which A has the meaning given above and Z" signifies chlorine, bromine or a group Rz-S02 ~ 0- where Rz signifies a phenyl, tolyl or lower alkyl group. Z "preferably signifies a mesyloxy group. The amination can be direct, that is to say that reaction 24 takes place directly with an amine comprising the substituent to be introduced, or indirect, for example by trans-forming. introduce a primary amino group, first the corresponding phthalimidoalkyl derivative compound ~. 5, for example by reaction with sodium or potassium phthalimide, and then reacting the resulting phthalimidoalkyl derivative with hydrazine. preferred when the substituent to be introduced is a primary aminoalkyl group.

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

Another variant of the process can be, for example, an 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 -ëthyldiisopropylami ne.

A suitable solvent is, for example, methylene chloride.

Another variant of the process can be, for example, etherification. The reactive group Z or Z1 is then advantageously a group -0-A-Z "in which A and Z" have the meanings given above. The reaction is preferably carried out under strongly alkaline conditions.

25 r

When Z ′ is a reactive group in the starting product, it can in this case simultaneously form an -AR ^ group at the two positions 3 and 5 of the 1,4-dihydropyridinyl residue.

The quaternary ammonium salts can be prepared analogously to known methods, for example by reaction with a corresponding (lower) alkyl iodide. As suitable solvent, there may be mentioned for example an alcohol such as methanol. When potentially reactive groups are present, such as hydroxy groups or primary or secondary amino groups, it may be advisable to carry out the process of the invention with starting materials in which these groups are; In 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 tetrahydropyrannyloxy residue and for an amino group in the form of an acylamino or phthalimido group, and of trans-20 then form any protected group optionally present by substituting the desired substituent, for example the benzyloxy group in the hydroxy group, for example by hydro-, genolysis, the tetrahydropyrannyloxy group in the hydroxy group, for example by hydrolysis, and a group - · 25 amino protected in the group free amino, for example iti by acid hydrolysis or by hydrazinolysis.

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 can exist in free form or optionally in the form of a salt. Normally, the free forms are neutral, unless ionizable substituents are present. The compounds 26 can exist in the form of salts, for example when they contain an ionizable substituent such as a friend group no or phenolic hydroxy. The compounds in free form can be converted into salts according to known methods and vice versa. Acids suitable for the formation of acid addition salts include hydrochloric acid, malonic acid, p-tuuenesulfonic acid and methanesulfonic acid.

Appropriate bases for the formation of salts of salts include sodium or potassium hydroxide.

When the substituents in positions 2 and 6 and / or in positions 3 and 5 of the 1,4-dihydropyridinyl radical are different, the carbon atom in position 4 is asymmetric. Such a compound can therefore exist in the form of a raceme or in the form of individual enantiomers.

The individual optical isomers can be obtained according to known methods.

The starting materials can be obtained according to known methods, for example by direct cyclization to 1,4-dihydropyridine.

When the preparation of a particular starting material is not described in detail, it will be a known compound or one which can be prepared according to known methods or in a similar manner to those described in the present application. .

The following examples illustrate the present invention without in any way limiting its scope. All temperatures are given in degrees Celsius and 30 are uncorrected.

27

Example 1 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-di hydro-5-i so-propoxy-carbony1-2,6-dimethyl-pyridine-3-carboxy-10-hydroxydecylate (esterification of Γimidazolide with 5 have it cool)

A mixture of 5.2 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5- (1H) is heated for 2 hours at an oil bath temperature of 120 °. -imidazο1 -1-ylcarbonyl) -2,6-dimethylpyridine-3-carboxyate of iso-10 propyl and 44.5 g of decan-diol-1,10. After re-cooling, ether is added to the reaction mixture; the excess of dëcanediol-1,10 is separated by? crystallization. After filtration and evaporation of the ether under reduced pressure, the product is chroma-15 tographed on silica gel under low pressure using a mixture of methylene chloride and ether as eluent. The title compound is thus obtained in the form of an oil.

NMR spectrum: (CDCl ^) 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 __ · 2 5 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-iso-propoxycarbonyl-2,6-dimethylpyridine-3-carboxylate 10- (N-benzylmethylamino ) -decyl (direct amination of mesylate)

4.6 g of 4- (2,1,3-30 benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-pyridine-3-carboxylate are dissolved in 50 ml of ether. 10-methanesulfo-nyloxydecyl and 2.2 ml of N-benzylmethylamine, the solution is evaporated to dryness under reduced pressure 28 and the residue is heated for 3 hours at 80 °.

The reaction mixture is then dissolved in. ether, wash the solution with cold IN sodium hydroxide, dry the ethereal phase over 5 magnesium sulfate and evaporate to dryness under reduced pressure. The resulting product is purified by chromatography on silica gel using a 19: 1 mixture of methylene chloride and ethanol as eluent. The title compound is thus obtained (free base: in the form of an oil; hydrochloride: in amorphous form).

Base NMR spectrum (CDCl3) £ (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 15 4.92 (1H, m, J = 6Hz), 5.48 (1H, s), 5.98 (1H, s), 7.2-7.7 (8H, m) .

The mesylate, used as starting material, is obtained by reacting at 0 ° 4.3 g of the compound of Example 1 and 4.3 ml of N-ethyl diisopropylamine in 90 ml of methylene chloride with 1.0 ml fonyl methanesul chl orure added dropwise and stirring the resulting mixture for 90 minutes in an ice bath.

The solution is then washed with a cold solution of 2N hydrochloric acid and the organic phase is dried over magnesium sulfate and evaporated under reduced pressure.

Example 3 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxy-carbonyl-2,6-di methylpyri di ne-3-carboxylate 30Q-aminodecyl (amination of mesylate via the phthalimido derivative)

2.2 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-29 5-isopropoxycarbony1-2,6-dimethylpyridine-3-carboxy- are dissolved in 44 ml of dimethylformamide late of 10-methanesulfonyloxydecyl, 2.2 g of potassium phthalimide are added and the mixture is stirred for 3 hours at a bath temperature of 80 °.

The solution is then cooled, filtered, washed with 100 ml of methylene chloride, the filtrate is purified by 8 extractions with a cold solution of 2N hydrochloric acid and evaporated to dryness under reduced pressure. The product is chromatographed on silica gel under slight pressure using ether as the eluent.

Dissolve 10-phta 4- (2,1,3- “benzoxadiazol-4-y1) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethylpyridine-3-carboxylate in 40 ml of ethanol ! imido-15 decyle resulting (obtained in the form of an oil), 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 water cooled with ice and the organic phase is evaporated to dryness under reduced pressure.

The product is chromatographed under light pressure on silica gel using a 9: 1 mixture of methylene chloride and methanol (containing ammonia) as eluent. The title compound r is thus obtained (F = 102 ° after crystallization from 11 ether).

Example 4 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-i sopropoxy-carbonyl-2,6-dimethylpyri di ne-3-carboxylate of 10- [3- ( 4-hydroxy-3-i odophenyl) -1-oxo-propylaminoldecyl (amine friend)

A solution of 0.5 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5- is heated for 30 minutes at a bath temperature of 120 °. 10-aminodecyl isopropoxycarbonyl-2,6-dimethylpyridine-3-carboxylate and 0.4 g of N-hydroxysuccinimide 3- (4-hydroxy-3-iodophenyl) -propionate in 15 ml of dioxane. The solution is then cooled, diluted with methylene chloride and extracted with a cold aqueous solution, saturated with sodium bicarbonate.

The organic phase is dried over magnesium sulphate, 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 eluent.

This gives the title compound (amorphous product). ï 15 NMR spectrum (CDClj) S (ppm): 0.99 (3H, d, J = 6Hz), 1.1-1.9 (19H, m), 2.35 (6H, s), 2.43 (2H, t, J = 7Hz), 2.9 (2H, t, J = 7Hz), 3.23 (2H, q, J = 5Hz), 4.02 (2H, t, J = 6Hz), 4 , 96 (1H, m, d = 6Hz), 5.53 (1H, s), ca. 5.62 (1H, large), ca. 6.55 (2H, wide), 6.9 (1H, d, J = 8Hz), 7.1, (1H, 2d, J = 8Hz and 2Hz), 7.25 - 7.75 (4H, m) .

Example 5 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-i sopropoxycarbonyl -2,6-dimethylpyri dine-3-carboxyla te de 10-ben- * zoyloxydecyl (acylation alcohol) To a solution of 2.2 g of the compound; r 'of Example 1 and 1.3 g of N-ethyl 1 di i sopropyl ami ne ^ in 30 ml of methylene chloride, 1.2 g of benzoyl chloride are added at 20 ° and the solution is stirred for 1 hour at 40 °. The reaction mixture is then diluted with ether, washed successively with water, 1N sodium hydroxide and 1N hydrochloric acid, dried over magnesium sulfate and evaporated under reduced pressure . The product is purified by chromatography on silica gel using a 9: 1 mixture of methylene chloride and 331 of ether as eluent. This gives the title compound (amorphous product).

NMR spectrum (CDC13) fc "(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), *. 5 4.93 (1H, m, J = 6Hz), 5.5 (1H.s), 6.08 (1H, s), 7.15 - 8.15 (8H, m).

Example 6 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxy-carbony1-2,6-dimethylpyridine-3-carboxylate of 10- (N-benzylmethylamino) -decyl ( esterification of imida-10 zolid with amino alcohol)

A solution of 4 g of 4- (2,1,3-benzoxadiazol-4-yl) - 1,4-di hydro-5- (1H-i mi dazol-1-y1carbony1) is heated for 16 hours at reflux. ) -2,6-di methyl-pyridine-3-isopropyl carboxylate and 7.0 g of 10- (N-methylbenzylami no) decane-1-ol in 150 ml of dioxane. The reaction mixture is then evaporated to dryness under reduced pressure and the residue is heated for 3 hours at 80 °. The product is purified by chromatography on silica gel using a 19: 1 mixture of methylene chloride and ethanol as eluent. The title compound is thus obtained (free base: oil; hydrochloride: amorphous product). NMR spreader: see example 2.

The amino alcohol, used as starting material, is obtained as follows: a) In 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 at 30 ° and the mixture is stirred for 1 hour at room temperature. 10-hydroxydecyl methanesulfonate is obtained (F = 48 °, after chromatography 32 on silica gel using a 2: 1 mixture of methylene chloride and ether as eluent, and crystallization from ether).

b) A mixture of 5 8.5 g of the mesylate obtained under a) above and 12.3 g of N-methylbenzylami is heated at 80 ° for 2 hours. 10- (N-methylbenzylamino) decane-1-ol (oil; after chromatography on silica gel using ether as eluent) is thus obtained.

Example 7 4- (2, 1,3-benzoxadiazol-4-yl) -1,4-di hydro-5-i sopropoxy-carbonyl-2,6-dimethyl-pyridine-3-carboxylate of 10-methoxy-decyl (etherification mesylate)

2.3 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-pyridine-3-carboxylate of 10-methanesulfonyloxydecyl 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 IN hydrochloric acid, the organic phase is dried over magnesium sulfate and evaporated to dryness. The product is then purified by chromatography on silica gel using an equal parts mixture of ether and hexane as eluent. The title compound (oil) is thus obtained.

NMR spectrum (CDC13) i> (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 30 (2H, t, J = 6Hz), 4.95 (1H, m, J = 6Hz), 5.5 (1H , s), 6.3 (1H, s), 7.2 - 7.8 (3H, m).

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READ

40 t

The compounds of the invention are indicated by * interesting pharmacological properties and can therefore be used in therapy as medicaments.

The compounds of the invention exert effects characteristic of calcium antagonists.

They exert a pronounced muscle relaxant effect, in particular on smooth muscles, as is apparent from vasodilation and the drop in blood pressure in conventional tests. For example, in the microsphere test carried out in anesthetized cats according to the method described by R. Hof et al!, In Basic Res. Cardiol 75, 747-756 (1980) and Tb_ 630-638 (1981) and by R. Hof et al !. in J. Cardiovasc. Phar-15 macol. 4, 352-362 (1982), dilation of the coronary vessels, an increase in blood flow in the skeletal muscles and a drop in blood pressure are observed, after administration of the compounds of the invention by the intravenous route. at doses of from about 3 to about 300 µg / kg, for example from about 10 to about 100 pq / kg.

A drop in blood pressure is also observed in the spontaneously hypertensive awake rat according to the method described by M. Gerold et al. in w 25 Arznei mi ttel forschung Jjî, 1285 (1968) after administration of the compounds of the invention by the oral route at doses of between about 1 and about 10 mg / kg. Thus, the compound of Example 2 causes a drop in blood pressure of 40% after administration by the oral route 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 a single daily administration. The compounds are also particularly well absorbed orally.

Thanks to these properties, the compounds of "the invention can be used in therapy * * 5 as calcium antagonists for the prevention and treatment of - coronary insufficiencies, for example angina pectoris, - disorders of the circulation, for example in the limbs, such as intermittent claudication and spasms, for example of the muscles of the colon, - asthma, for example post-exercise asthma.

"- hypertension.

The compounds of the invention also exert a vasodilating action 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 disorders which are associated with it. Thanks to this property, the compounds of the invention can be used in therapy for the prophylaxis and treatment of migraines * and of vascular headaches such as cluster headaches, especially for the treatment of interval therapy (prevention ) migraine.

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

For the therapeutic uses indicated above, the compounds of the invention will be administered at a daily dose of between approximately 1 mg and approximately 200 mg, advantageously administered, for example by the oral route, in divided doses 42 1 to 3 times per day in the form of unit doses each comprising between approximately 0.3 mg and approximately 200 mg of active substance, or in a delayed-release form. An example of daily dose 4.> 5 is between approximately 5 mg and * approximately 50 mg.

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

For the prophylaxis and treatment of migraine and vascular headache, the preferred compounds are those in which Q represents a 2,1,3-benzothiadiazolyl residue.

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. Such salts exert the same order of activity as the free forms and are prepared according to the usual 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, in particular for the use as a calcium antagonist.

The invention also includes a drug> _ containing, as active ingredient, a compound of the invention in free form or optionally 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 vehicle - £ 43 table. Such pharmaceutical compositions, which also form part of the present invention, can be prepared according to the usual methods

AT

and be presented, for example, in the form of capsules, u e 5 suitable for example for subliminal administration, or tablets.

y s * t λ w

V

Claims (6)

44 1.- The 1,4-dihydropyridines corresponding to the formula I * if5 Q A (I) C00-AR4 4 î 'R1 10 in 1aquel1e û. represents hydrogen, a cycloalkyl group in Cg- ς 15 Cj or an alkyl group in C- | -Cg optionally substituted, R9 and R represent each one, independently one of the other, hydrogen or an alkyl group Cj-Cg, R ^ represents a C1_C12 alkyl group or has, independently of -AR ^, one of the meanings indicated below for -AR ^ including the conditions concerning it,. R ^ represents a hydroxy or C1 ~ C12 alkoxy group or a residue -OCORg, -NR ^ Rg or -Nq, in which j, "25 signifies a C 1 -C 6 alkyl group, a phenyl group, phenylalkyl in or bis-phenyl-C1-C6-alkyl C-jg. the benzene rings or nuclei of these last three groups may optionally bear one, two or three substituents chosen from halogens having an atomic number of 9 to 53 and hydroxy groups , alkyl and alkoxy to a 5-membered heteroaryl radical containing 45 1 heteroatom chosen from nitrogen, oxygen and sulfur or 2 heteroatoms of which one is nitrogen and the other is T nitrogen, T oxygen or * sulfur, or a 6-membered heteroaryl res e 5 containing 1 to 4 nitrogen atoms, ^ * ^ means hydrogen or has one of the meanings indicated above for Rg, Rg signifies hydrogen, a C ^ -Cg alkyl group or a residue -CORg where Rg has the meaning given above 10 for Rg, signifies a heterocycle at 5, 6, or 7 chain links which may optionally contain, when it is saturated and with 6 or 7 chain links, another hetero atom selected from oxygen, sulfur and = NR ^ g where R, "signifies hydrogen or has one of the w IJ meanings indicated above for Rg, A represents an alkylene group in ^ "Cj ^ and Q represents a fully unsaturated condensed ring system with aromatic character having in total 20 at least 2 different cyclic heteroatoms, A having to represent an alkylene group at when R ^ signifies a hydroxy group, a C 1 -C 6 alkoxy group, a residue as defined above or a residue * -NR ^ R ^ ° where R7 signifies hydrogen, an alkyl group * In 0, -0 ,,, an unsubstituted phenyl group or an unsubstituted C7-C10 phenylalkyl group and, Rg signifies hydrogen or a C- | -Cg alkyl group and the ammonium salts of compounds in which R ^ is one of the tertiary amino groups defined above for R ^ and quaternized by a group of formula AlkY o ù Alk signifies an alkyl group and Y the remainder of an acid, in free form or optionally in the form of a salt. * A. F! 46 2.- 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-hydro-5-i sopropoxycarbony1-2,6-dimethy1pyridi ne-3-carboxylate of 10- (N-benzylmethylamino) - decyle, in free form or optionally in the form of a salt. b, 5 3.- 4- (2,1,3-Benzoxadiazol-4-yl) -1,4> di hydro-5-i sopropoxycarbonyl-2,6-dimethylpyri di ne-3- X carboxylate of 10 - [4- (diphenylmethyl) piperazinyl)] decyl, in free form or optionally in the form of a salt. 4. Process for the preparation of the 1,4-dihydropyridines defined in claim 1, characterized in that an appropriate compound of formula II k Q ζ, '0ε_ίιΓ0'ζ (ii) “1 is transformed. In which, R ^, Rg and Q have the meanings given in * claim 1, $ 1 represents a reactive group and / * * Z 'represents a reactive group or has one of the v meanings given in claim 1 for -or3. and the compounds thus obtained are recovered in free form or optionally in the form of a salt. 5. The 1,4-dihydropyridines specified in any one 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 one of claims 1 to 3 in free form or optionally in the form of a pharmaceutically acceptable salt, for use as an anti- ·. calcium gonists. 7. A medicament, characterized in that it contains, as active substance, a 1,4-dihydropyridine as specified in any one of claims 1 to 3 in free form or optionally in the form of a pharmaceutically salt acceptable. 8. A pharmaceutical composition, charac- {. tërisëe in that it contains a 1,4-di hydropyri di as as specified in any one of claims 15 113 in free form or optionally in the form of a pharmaceutically acceptable salt, in association with a pharmaceutically acceptable diluent or vehicle table. 9. Products and processes in substance as described above with reference to the examples cited. Λ '4