FR2554109A1 - NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND USE IN THERAPEUTICS AS MEDICAMENTS - Google Patents

Abstract

THE INVENTION CONCERNS 1,4-DIHYDROPYRIDINES OF FORMULA: (CF DRAWING IN BOPI) IN WHICH R MEANS HYDROGEN OR A CYCLOALKYL OR ALKYL GROUP, R AND R MEAN HYDROGEN OR AN ALKYL GROUP, R MEANS HYDROGEN OR AN ALKYL, NO, CF, CN, COOR, COR OR S (O) R OR R, R AND R GROUP ARE VARIOUS RADICALS, N MEANS 0, 1 OR 2 AND Q MEANS A COMPLETELY UNSATURE CYCLIC SYSTEM. THESE COMPOUNDS MAY BE USED AS MEDICINAL PRODUCTS, ESPECIALLY AS ANTAGONISTS OF CALCIUM.

Description

The subject of the present invention is new derivatives of 1,4-

  dihydropyridine, their preparation and their use in

  therapeutic, as active ingredients of drugs.

  The invention relates in particular to the compounds of formula I

R3 NO2 (I)

R2 N R4

  Wherein R 1 represents hydrogen, a C 3 -C 7 cycloalkyl group or an optionally substituted C 1 -C 6 alkyl group, R 2 and R 4 are each, independently of one another, hydrogen or an alkyl group; C1-C6,

  R3 represents hydrogen, a C1-C25 alkyl group, nitro, tri-

  fluoromethyl, cyano, -COOR5, -COR6 or -S (O) nR7, wherein -COOR5 represents a carboxyl group or an ester group, R6 represents a C1-C25 alkyl group; C2-C24 hydroxyalkyl wherein hydroxy is separated from the group to which R6 is bonded by at least 2 carbon atoms; C1-C24 alkoxyalkyl in the alkoxy residue and C2-C24 in the alkylene residue, the alkoxy residue being separated from the group to which R6 is bound by at least 2 carbon atoms; C3-C25 alkenyl wherein the double bond is separated from the group to which R6 is bound by at least 1 carbon atom not forming part of the double bond; C3-C25 alkynyl in which the triple bond is separated

2554 1 0 9

  the group to which R6 is bound by at least 1 carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl residue and C1-C24 in the alkylene residue; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy residue and C2-C24 in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which R6 is linked by at least 2 carbon atoms and the hydroxyl being separated from the oxygen atom alkoxy residue with at least 2 carbon atoms; phenyl; C 7 -C 30 phenylalkyl or C 13 -C 36 bis-phenylalkyl, the last three substituents possibly being able to carry in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C 1 -C 4 alkyl and C 1 -C 4 alkoxy groups; -C4 and hydroxy and halogens having an atomic number of 9 to 53; a heteroaryl residue having 5 members with 1 heteroatom selected from nitrogen, oxygen and sulfur or two heteroatoms, one of which is nitrogen and the other is nitrogen, oxygen or sulfur, or a 6-membered heteroaryl residue having from 1 to 4 nitrogen atoms, the last two substituents being optionally bonded to the remainder of the molecule via a C1-C24 alkylene radical or a residue of formula -AOCOR8; -ANRgRlo; or -AN wherein R8 is a C1-C25 alkyl group; phenyl, C 7 -C 30 phenylalkyl or C 13 -C 36 bis-phenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C 1 -C 4 alkyl, alkoxy C1-C4 and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl residue with a heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms, one of which is nitrogen and the other is nitrogen, oxygen or sulfur, or a 6-membered heteroaryl residue having 1 to 4 nitrogen atoms; a C2-C24 hydroxyalkyl group in which the hydroxy is separated from the group to which R8Est is bound by at least 2 carbon atoms; C 1 -C 24 alkoxyalkyl in the alkoxy residue and C 2 -C 24 in the alkylene residue, the alkoxy residue being separated from the group to which R 8 is bonded by at least 2 carbon atoms; C3-C25 alkenyl wherein the double bond is separated from the group to which R8 is bound by at least 1 carbon atom not forming part of the double bond; C3-C25 alkynyl wherein the triple bond is separated from the group to which R8 is bound by at least 1 carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl residue and C1-C24 in the alkylene residue; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy and C2-C24 residue in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which R8 is bonded by at least 2 carbon atoms and the hydroxyl being separated from the oxygen atom alkoxy residue with at least 2 carbon atoms; C2-C24 aminoalkyl wherein the nitrogen atom is separated from the group to which R8 is bound by at least 2 carbon atoms and the amino residue optionally carries one or independently two substituents selected from C1-C6 alkyl, phenyl, phenylalkyl C7-C12 or C13-C18 bis-phenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C1-C4 alkyl, C1-C4 alkoxy and hydroxy and halogens having an atomic number of 9 to 53, R9 represents hydrogen or has the meaning indicated above for R8, R10 represents hydrogen or has the meaning indicated above for R8 or represents -COR11 in which R11 has the meaning indicated above for R8, -NB represents a saturated 5-, 6- or 7-membered heterocycle which may optionally contain, when it is 6 or 7-membered, another heteroatom selected among oxygen, sulfur and = NR12 wherein R12 is hydrogen or has the meaning indicated above for R8 and A is a C2-C24 alkylene group separating the group to which R6 is bound by at least 2 carbon atoms; carbon, R7 has the meaning indicated above for R6, n is 0, 1 or 2, Q represents a totally unsaturated condensed ring system of aromatic character having in total at least 2 different cyclic heteroatoms, and the ammonium salts of these compounds wherein R 3 is selected from one of the tertiary amino groups defined above for R 3 and quaternized with a group of the formula AlkY o Alk is C 1 -C 4 alkyl and Y is the residue of an acid, The compounds of formula I and their ammonium salts will be

  designated in the present description the "compounds of the invention".

  Some compounds of the invention fall under the description

  very general of European Patent Application No. 71,819. None of the compounds specifically described in the European patent application

  mentioned above does not fall within the scope of the present invention.

  Compounds similar to the compounds of the invention are also described for example in the European patent application

No. 208.

  The aforementioned publications do not suggest any specific compound similar to the compounds of the invention. The

  compounds of the invention possess a pharmacological profile parti-

interestingly.

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  The compounds of the invention are preferably

in non-quaternized form.

  R5 preferably has the meaning indicated above

for R6.

  R1 preferably means hydrogen. When it has a meaning other than hydrogen, it preferably has one of the meanings given below for Re, especially unsubstituted alkyl, cycloalkylalkyl, optionally substituted phenylalkyl, alkoxyalkyl or morpholino; preferably an unsubstituted alkyl or alkoxyalkyl group; preferably unsubstituted alkyl. When it is alkoxyalkyl, the alkoxy moiety is preferably separated from the nitrogen atom by at least 2 carbon atoms. R2 and R4 are preferably alkyl, especially methyl. R3 is preferably nitro, trifluoromethyl, -COOR5 or -COR6, especially -COOR5. R5 and / or R7 preferably means alkyl, hydroxyalkyl, alkoxyalkyl, -AOCOR8, -ANRgR1O or -ANB, especially -ORRgRlo or -AN-. R6 is preferably as defined above for R5 and / or R7 or means a 5-membered heteroaryl residue containing 2 nitrogen heteroatoms. R8 is preferably an optionally substituted alkyl or phenyl, phenylalkyl or bis-phenylalkyl group, in particular phenyl, Rg and R10 are preferably hydrogen or an optionally substituted alkyl or phenyl, phenylalkyl or bis-phenylalkyl group. Preferably, R 1 and R 10 are each hydrogen or one of R 8 and R 10 is alkyl and the other is alkyl, optionally substituted phenylalkyl or bisphenylalkyl.

  optionally substituted. -N preferably means a hetero

  saturated 6-membered ring containing another heteroatom. R11 preferably means an alkyl group, phenyl optionally

2554 1 0 9

  substituted, optionally substituted phenylalkyl or bis-phenylalkyl

  optionally substituted. R12 preferably has another meaning

  cation than hydrogen, and preferably means an alkyl group,

  optionally substituted phenylalkyl or bis-phenylalkyl

  substituted. A preferably contains 2 carbon atoms or 7 to 24 carbon atoms, especially 9 to 18 carbon atoms, especially 9 to 14 carbon atoms, especially 10 carbon atoms. It is preferably unbranched. n means of

  preferably at least 3 hetero atoms, in particular

  bind 3 and is preferably a bicyclic system. Q represents

  2,1,3-benzoxadiazolyl and 2,1,3-benzothiazole

  diazolyl, especially 2,1,3-benzoxadiazolyl. When Q is a ring system having a benzene ring, the 1,4-dihydropyridinyl moiety is preferably bonded to that ring, especially at a position of the benzene ring adjacent to a ring junction. 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.

  The C 3 -C 7 cycloalkyl group preferably contains 3, 5 or 6 carbon atoms, especially 5 carbon atoms. The optionally substituted C1-C6 alkyl group preferably has one of the meanings given below for Ra with the exception of hydrogen, and especially means a methyl group. The C1-C6 alkyl group preferably contains 1 to 4 carbon atoms, and especially means a methyl group. The C 1 -C 25 alkyl group preferably contains from 1 to 6 carbon atoms, such as methyl, ethyl or isopropyl, or from 9 to 19 carbon atoms, especially from 9 to 19, in particular 10 carbon atoms. The C2-C24 hydroxyalkyl group preferably contains

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  from 2 to 6 or from 9 to 18 carbon atoms, especially from 9 to 18 carbon atoms. The C 1 -C 24 alkoxyalkyl group in the alkoxy residue and C 2 -C 24 in the alkylene residue preferably contains 1 to 6 or 9 to 19 carbon atoms, especially 9 to 19 carbon atoms in the alkoxy residue and preferably 2 to 6 or 9 to 18 carbon atoms, especially 9 to 18 carbon atoms in the alkylene radical. C3-C25 alkenyl and / or C3-C25 alkynyl preferably contain 3 or 7 to 25 carbon atoms, especially 9 to 18 carbon atoms. The C 3 -C 7 cycloalkyl group and the C 3 -C 7 cycloalkyl residue of the cycloalkylalkyl group preferably contain 3, 5 or 6, especially 5 or 6 carbon atoms. The C1-C24 alkylene radical of the cycloalkylalkyl group

  preferably contains 1 or 7 to 24 carbon atoms, especially

  from 9 to 18 carbon atoms. The C2-C24 hydroxyalkoxy residue of the hydroxyalkoxyalkyl group preferably contains 2 or 7 to 24 carbon atoms, especially 9 to 18 carbon atoms. The C2-C24alkylene moiety of the hydroxyalkoxyalkyl group preferably contains 2 or 7 to 24 carbon atoms, especially 9 to 18 carbon atoms. The alkylene radical of the C 7 -C 30 phenylalkyl or C 13 -C 36 bis-phenylalkyl group preferably contains 1 or 2 or 7 to 24 carbon atoms, especially 9 to 18 carbon atoms. The C1-C4 alkyl and / or C1-C4 alkoxy groups preferably contain 1 or 2 carbon atoms, especially 1 carbon atom. Halogen having an atomic number of 9 to 53

  is preferably fluorine or bromine, especially bromine.

  Halogen having an atomic number of 9 to 35 is preferably fluorine or chlorine, especially fluorine. The heteroaryl residue defined above is preferably 5-membered and preferably contains 1 or 2 nitrogen heteroatoms, especially 2; it's about

  particular of the imidazolyl group, especially 1H-imidazole-1

  yl. When it is 6-membered, it preferably contains 1 or 2

255 4 1 0 9

  nitrogen heteroatoms, and it means a pyridinyl group. The C1-C24 alkylene residue optionally linking a heteroaryl residue to the remainder of the molecule preferably contains 1 or 7 to 24 carbon atoms, especially 9 to 18 carbon atoms. The C2-C24 alkylene residue of the aminoalkyl group preferably contains 2 or 7 to 24 carbon atoms, especially 9 to 18 carbon atoms. The amino residue of the aminoalkyl group is preferably substituted, especially disubstituted. The substituents of the amino residue of the aminoalkyl group are preferably optionally substituted alkyl and / or phenylalkyl groups. The amino residue of the aminoalkyl group is preferably disubstituted with optionally substituted alkyl and phenylalkyl groups. The saturated 5-, 6- or 7-membered heterocycle as defined above is preferably 6-membered. It is preferably 1-piperazinyl group. When it's 6 or 7

  links, it preferably contains another heteroatom = NR12.

  The hydroxyl of the hydroxyalkyl and / or hydroxyalkoxyalkyl group and / or the amino residue of the aminoalkyl group are preferably attached to the furthest terminal carbon atom. When a phenyl cycle

  is present in a substituent, it is preferably unsubstituted.

  When substituted, it is preferably monosubstituted, preferably in para position. When disubstituted, it is

  preferably substituted in the ortho or meta position and in the para position.

  When trisubstituted it is preferably substituted in meta, meta and para position. Alkoxy groups and / or halogens are preferred as substituents of the phenyl ring. When a phenyl ring is polysubstituted, the substituents are preferably the same. In the bis-phenylalkyl group, the two phenyl rings are preferably attached to the same carbon atom. The group

  bis-phenylalkyl preferably means a bis-phenylmethyl group.

  A group of compounds of the invention comprises the compounds of formula Ia (see formula on the following page) R N N '3 0N2 (Ia)

R2 R

  Wherein R2 and R4 are as defined above, Ra is hydrogen; a C1-C6 alkyl group; C3-C6 alkenyl wherein the double bond is separated from the nitrogen atom by at least 1 carbon atom not forming part of the double bond; C3-C6 alkynyl wherein the triple bond is separated from the nitrogen atom by at least 1 carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; C4-C8 cycloalkylalkyl; C2-C6 hydroxyalkyl wherein hydroxy is separated from the nitrogen atom by at least 2 carbon atoms; C2-C6 alkoxyalkyl; or C 7 -C 9 phenylalkyl or C 8 -C 12 phenylalkenyl in which the double bond is separated from the nitrogen atom by at least 1 carbon atom not forming part of the double bond, the last two substituents optionally bearing in the phenyl ring one, two or three substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy and hydroxy and

  halogens having an atomic number of 9 to 35; alkylcarbonyl

  C2-C6 oxyalkyl in the alkylcarbonyl and alkylene radicals and in which the oxygen atom is separated from the nitrogen atom

  by at least 2 carbon atoms; dialkylaminoalkyl independently

  C1-C6 in the alkyl and C2-C6 radicals in the alkylene radical and in which the amino group is separated from the nitrogen atom by at least 2 carbon atoms; or C 2 -C 6 morpholinoalkyl in the alkylene residue and wherein the morpholino residue is separated from the nitrogen atom by at least 2 carbon atoms,

  Ra represents hydrogen; a C1-C6 alkyl group; nitro; sorting-

  fluoromethyl; cyano; --COORa; -COR; or -S (O) nR; wherein

  Ra represents hydrogen; a C1-C6 alkyl group; hydroxy

  C2-C6 alkyl wherein hydroxy is separated from the group to which Ra is bonded by at least 2 carbon atoms; C1-C6 alkoxyalkyl in the alkoxy residue and C2-C6 in the alkylene radical, the alkoxy radical being separated from the group to which Ra is bound by at least 2 carbon atoms; C3-C6 alkenyl wherein the double bond is separated from the group to which Ra is bound by at least one carbon atom not forming part of the double bond; C3-C6 alkynyl in which the triple bond is separated from the group to which Ra is bound by at least 1 carbon atom not

  part of the triple bond; C3-C7 cycloalkyl; cyclohexane

  C3-C7 alkylalkyl in the cycloalkyl residue and C1-C6 in the alkylene residue; C2-C6 hydroxyalkoxyalkyl in the alkoxy residue and C2-C6 in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which Ra is bound by at least 2 carbon atoms and the hydroxy being separated from the oxygen atom of the alkoxy residue with at least 2 carbon atoms; phenyl, C 7 -C 12 phenylalkyl or bis-phenylalkyl

  at C13-C18, the last three substituents,

  in the phenyl ring (s) one, or independently of two, or independently three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and hydroxy groups and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl radical having a heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms, one of which is nitrogen and the other of which is nitrogen, oxygen or sulfur, or 6-membered heteroaryl residue containing 1 to 4 nitrogen atoms, the last two substituents being optionally bonded to the remainder of the molecule by

255 4 1 0 9

  via a C1-C6 alkylene radical; -AaOCORa; -AaNRRo; or Aa or (a;

8 9 10

wherein

  Ra represents a C1-C6 alkyl group; phenyl, phenyl

  C 7 -C 12 alkyl or C 13 -C 18 bis-phenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy C4 and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl radical comprising a heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms, one of which is nitrogen and the other of which is nitrogen, oxygen or sulfur, or 6-membered heteroaryl residue having 1 to 4 nitrogen atoms; C2-C6 hydroxyalkyl wherein hydroxy is separated from the group to which Ra is bonded by at least 2 carbon atoms; C1-C6 alkoxyalkyl in the alkoxy residue and C2-C6 in the alkylene radical, the alkoxy radical being separated from the group to which Ra is bound by at least 2 carbon atoms; C3-C6 alkenyl wherein the double bond is separated from the group to which Ra is bonded by at least one carbon atom not forming part of the double bond; C3-C6 alkynyl wherein the triple bond is separated from the group to which Ra is bonded by at least one carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl residue and C1-C6 in the remainder

  alkylene; C2-C6 hydroxyalkoxyalkyl in the hydroxyl radical

  alkoxy and C2-C6 in the alkylene radical, the hydroxyl radical

  alkoxy being separated from the group to which Ra is bound by at least 2 carbon atoms and the hydroxyl being separated from the oxygen atom of the alkoxy residue by at least 2 carbon atoms; C2-C6 aminoalkyl wherein the nitrogen atom is separated from the group to which Ra is bound by at least 2 carbon atoms and the amino residue optionally carries one or independently two substituents selected from groups

  C 1 -C 6 alkyl, phenyl, C 7 -C 12 phenylalkyl and

  C13-C18 phenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents

  selected from C1-C4 alkyl, C1-C4 alkoxy and.

  hydroxy and halogens having an atomic number of 9 to 53,

  Rg represents hydrogen or has the meaning indicated below

  above for Rg, Rf0 represents hydrogen or has the meaning indicated above for Rg or represents -CORf6 in which Rf1 has the meaning indicated above for Rg, -N. B a represents a 5-, 6- or 7-membered saturated heterocycle which may optionally contain, when it is 6 or 7-membered, another heteroatom selected from oxygen, sulfur and NRa 2 in which Rf 2 represents hydrogen or the meaning indicated above for Ra, and Aa represents a C2-C6 alkylene group separating the group to which Rg is bound by at least 2 carbon atoms, R6a and Ra, with the exception of hydrogen, have the meaning indicated higher for Ra, and n is as defined above, X represents oxygen or sulfur and R represents hydrogen, a halogen having an atomic number of 9 to 35 or a C 1 -C 4 alkyl group, C 1 alkoxy -C4, C1-C4 alkylthio, C1-C4 alkylsulfonyl, trifluoromethyl, nitro or hydroxy, and their ammonium salts wherein Rg is selected from one of

2554 109

  tertiary amino groups defined above for Ra and quaternized by a group of formula AlkY in which Alk represents a group

  C1-C4 alkyl and Y represents the residue of an acid.

  X is preferably oxygen. R is preferably hydrogen. The rest]> is preferably

  linked by its position 4 to position 4 of the remaining 1,4-dihydropyridine

  dinyle. Another group of compounds of the invention comprises the compounds of formula Iaa R x aa R3 NO2 (Iaa) R2 aa R4 Ri wherein R, R2, R4 and X are as defined above, Raa represents hydrogen or a hydrogen atom. C1-C6 alkyl group and

  Raa represents hydrogen; a C1-C6 alkyl group; nitro; sorting-

  fluoromethyl; cyano; -COORaa; -CORa or -S (O) nRa; wherein

  Raa represents hydrogen; a C1-C6 alkyl group; hydroxy

  C2-C6 alkyl wherein hydroxy is separated from the group to which Rga is bound by at least 2 carbon atoms; C1-C6 alkoxyalkyl in the alkoxy residue and C2-C6 in the alkylene residue, the alkoxy residue being separated from the group to which Raa is bound by at least 2 carbon atoms; a 5-membered heteroaryl residue containing 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms one of which is nitrogen and the other is nitrogen, oxygen or sulfur or a radical 6-membered heteroaryl

  containing from 1 to 4 nitrogen atoms; -AaaOCORaa; -AaaNRaaRaa-

  ## STR1 ## or AaaN Baa; wherein Raa is a C1-C6 alkyl group; phenyl, phenyl-C 7 -C 12 alkyl or C 13 -C 18 bis-phenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C 1 -C 4 alkyl, alkoxy C1-C4 and hydroxy and

  halogens having an atomic number of 9 to 53; hydro-

  C2-C6 xyalkyl wherein hydroxy is separated from the group to which R8a is bonded by at least 2 carbon atoms; C1-C6 alkoxyalkyl in the alkoxy residue and C2-C6 in the alkylene residue, the alkoxy residue being separated from the group to which Raa is bound by at least 2 carbon atoms, Raa represents hydrogen or has the meaning indicated above for Raa 8 'Rlaa represents hydrogen or has the meaning indicated above for Raa or means -CORaa in which Ra has the meaning indicated above for Rua, -N_ aa represents a saturated 5-, 6- or 7-membered heterocycle which may optionally containing, when it is 6 or 7 chain members, another heteroatom selected from oxygen, sulfur and NRa wherein Ra represents hydrogen or has the meaning indicated above for Raa, and

255 4 1 09

  Aaa represents a C2-C6 alkylene group separating the group to which Raa is bound by at least 2 carbon atoms, Rga and Rga, with the exception of hydrogen, have the meaning indicated above for Raa, and n is as defined above, and their ammonium salts in which Raa is selected from one of

  tertiary amino groups defined above for Raa and quater-

  nized by a group of formula AlkY in which Alk represents a

  C1-C4 alkyl group and Y represents the residue of an acid.

  Another group of compounds of the invention comprises the compounds of formula Iaaa N R5aa NO2 (Iaaa)

R2 N R

  Wherein R2, R4 and X are as defined above and Raaa is hydrogen or a nitro group; trifluoromethyl; cyano; COORaa; or -COR6aa in which Raa and Raa are as defined above, and their ammonium salts wherein R aa is selected from one of

  tertiary amino groups defined above for R aa and quater-

  nized by a group of formula AlkY in which Alk represents a

  C1-C4 alkyl group and Y represents the residue of an acid.

  In a subgroup of compounds of formula Iaa or Iaaa and

  their corresponding ammonium salts, Rfa represents hydrogen.

  In another subgroup, R2 and R4 represent a methyl group.

  In another subgroup, X represents oxygen. In another subgroup X represents sulfur. In another subgroup, R aa represents a group -COORga in which R a is as defined above. In a subgroup of compounds of formula Iaa and their salts

  corresponding ammonium salts, R represents hydrogen.

  A preferred group of compounds of the invention comprises the compounds of formula Ib

R N

x

NOT

Rb NO2 (Ib)

3 -NO2

  Wherein R, Rf, R2, R4 and X are as defined above and Rb is hydrogen or C7-C25 alkyl; nitro; trifluoromethyl; cyano; -COORb; -CORb; or -S (O) nRb; in '6' or 7 () Rdn which

  Rb is hydrogen; a C 7 -C 25 alkyl group; hydroxy

  C 7 -C 24 alkyl wherein hydroxy is separated from the group to which R b is linked by at least 2 carbon atoms; C1-C24alkoxyalkyl in the C2-C24alkoxy residue in the alkylene residue, the alkoxy residue being separated from the group to which Rb is bound by at least 2 carbon atoms, at least one of the alkoxy and / or alkylene radicals to have at least one of minus 7 carbon atoms; C7-C25 alkenyl wherein the double bond is separated from the group to which Rb is bound by at least 1 carbon atom not forming part of the double bond; C7-C25 alkynyl wherein the triple bond is separated from the group to which Rb is bound by at least one

2554 '0 9

  1 carbon atom not part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl residue and C7-C24 in the alkylene residue; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy and C2-C24 residue in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which Rb is linked by at least 2 carbon atoms and the hydroxy being separated from the oxygen atom of the alkoxy residue with at least 2 carbon atoms, at least one of the hydroxyalkoxy and / or alkylene radicals having at least 7 atoms

  of carbon; phenyl, C13-C30 phenylalkyl or bis-

  C19-C36 phenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C1-C4 alkyl, C1-C4 alkoxy and hydroxy and halogens having a atomic number from 9 to

  53; a 5-membered heteroaryl residue containing 1 heteroaryl

  atom selected from nitrogen, oxygen and sulfur or 2 heteroatoms one of which is nitrogen and the other is nitrogen, oxygen or sulfur or a 6-membered heteroaryl residue containing from 1 to 4 nitrogen atoms, the last two substituents being optionally bonded to the rest of the molecule through a C 7 -C 24 alkylene radical; -AbOCOR; - AbNRbRbo; or -AbNB b; wherein Rb is C 1 -C 25 alkyl with the proviso that it is C 7 -C 25 when Ab contains less than 7 carbon atoms; phenyl, C 7 -C 30 phenylalkyl with the proviso that it is C 13 -C 30 when Ab contains less than 7 carbon atoms, or C 13 -C 36 bis-phenylalkyl with the proviso that it is C 19 -C 36 when Ab contains less than 7 carbon atoms, the last three substituents

  possibly in the phenyl ring (s) one, or independently

  two, or independently, three chosen substituents

255 4 1 0 9

  from C1-C4alkyl, C1-C4alkoxy, and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl residue containing 1 heteroatom

  chosen from nitrogen, oxygen or sulfur or 2 hetero-

  atoms, one of which is nitrogen and the other is oxygen or sulfur, or a 6-membered heteroaryl radical containing from 1 to 4 nitrogen atoms; C2-C24 hydroxyalkyl wherein hydroxy is separated from the group to which Rb is bound by at least 2 carbon atoms, with the proviso that it is C7-C24 when Ab contains less than 7 carbon atoms; C1-C24 alkoxyalkyl in the alkoxy residue and C2-C24 in the alkylene residue, the alkoxy residue being separated from the group to which Rb is bound by at least 2 carbon atoms, with the proviso that when Ab contains less than 7 carbon atoms, carbon at least one of the alkoxy and / or alkylene radicals contains at least 7 carbon atoms; C3-C25 alkenyl wherein the double bond is separated from the group to which Rb is bound by at least one carbon atom not forming part of the double bond, with the proviso that it is C7-C25 when Ab contains less than 7 carbon atoms; C3-C25 alkynyl wherein the triple bond is separated from the group to which Rb is bound by at least one carbon atom not forming part of the triple bond, with the proviso that it is C7-C25 when Ab contains less than 7 carbon atoms; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl and C1-C24 residue in the alkylene moiety, with the proviso that it is C7-C24 in the alkylene moiety when Ab contains less than 7 carbon atoms; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy and C2-C24 residue in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which Rb is linked by at least 2 carbon atoms and the hydroxyl being separated from the oxygen atom of the alkoxy residue by at least 2 carbon atoms, with the proviso that when Ab contains less than 7 carbon atoms at least one of the hydroxyalkoxy and / or alkylene radicals contains at least 7 carbon atoms; C2-C24 aminoalkyl with the proviso that it is C7-C24 when Ab contains less than 7 carbon atoms, wherein the nitrogen atom is separated from the group to which Rb is bound by at least 2 carbon atoms and the amino residue optionally carries one or independently two substituents selected from C 1 -C 6 alkyl, phenyl, C 7 -C 12 phenylalkyl and bis-phenylalkyl groups;

  C13-C18, the last three substituents, possibly

  in the phenyl ring (s) one, or independently two, or independently three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and hydroxy and halogens having an atomic number of 9 to 53, R b is hydrogen or has the meaning indicated above for Rb, RbO represents hydrogen or has the meaning indicated above for Rb or represents a group -CORb in which Rb has the meaning indicated above for Rb il 8 '-iN @b represents a saturated 5-, 6- or 7-membered heterocycle which may optionally contain, when it is 6 or 7-membered, another heteroatom selected from oxygen, sulfur and NRb 2 wherein Rb 2 represents hydrogen or has the meaning indicated higher for Rb, and 8 'Ab represents a C2-C24 alkylene group separating the group to which Rb is bound by at least 2 carbon atoms, Rb and Rb, with the exception of hydrogen, have the meaning

6 7

  indicated above for Rb, and n is as defined above, and their ammonium salts wherein Rb is selected from one of the tertiary amino groups defined above for Rb and quaternized with a group of formula AlkY in which Al.k represents a group

  C1-C4 alkyl and Y represents the residue of an acid.

  Another preferred group of compounds of the invention comprises the compounds of formula Iba

R N

RE <2 (Iba)

R2 N R4

  Raa. Wherein R, Rf, R2, R4 and X are as defined above and Rba is C7-C25 alkyl, -COORba, -CORba, or S (O) nRba, wherein Rba is an alkyl group; C7-C25; C7-C24 hydroxyalkyl wherein the hydroxy is separated from the group to which Rba is bound by at least 2 carbon atoms; C1-C24 alkoxyalkyl in the alkoxy residue and C2-C24 in the alkylene residue, the alkoxy residue being separated from the group to which Rba is bound by at least 2 carbon atoms, with the proviso that at least one of the alkoxy residues and / or alkylene contains at least 7 carbon atoms; C7-C25 alkenyl wherein the double bond is separated from the group to which Rba is bound by at least one carbon atom not forming part of the double bond; C7-C25 alkynyl wherein the triple bond is separated from the group to which Rba is bound by at least 1 carbon atom not forming part of the triple bond; C3-C7 cycloalkylalkyl in the cycloalkyl residue and C7-C24 in the alkylene residue; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy and C2-C24 residue in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which Rba is bound by at least 2 carbon atoms and the hydroxyl being separated from the oxygen atom alkoxy with at least 2 carbon atoms, with the proviso that at least one of the hydroxyalkoxy and / or alkylene radicals contains at least 7 carbon atoms; C 13 -C 30 phenylalkyl or C 18 -C 36 bis-phenylalkyl, the last two substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy C4 and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl residue containing a heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms one of which is nitrogen and the other is nitrogen, oxygen or sulfur, or a a 6-membered heteroaryl residue containing from 1 to 4 nitrogen atoms, the last two substituents being bound to the remainder of the molecule through a C 7 -C 24 alkylene radical; - AbaOCORba, -AbaNRbaRba, or -AbaN. ba, in

8 '9 10' D

  which Rba is C1-C25 alkyl, with the proviso that it is C7-C25 when Aba contains less than 7 carbon atoms; phenyl, C7-C30 phenylalkyl with the proviso that it is C13-C30 when Aba contains less than 7 carbon atoms, or bis-phenyl-C13-C36 with the proviso that it is C19-C36 when Aba contains less than 7 carbon atoms, the last three substituents optionally bearing in the phenyl ring or rings one, or independently two, or independently three substituents selected from C1-C4 alkyl, C1-C4 alkoxy and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl residue containing 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms one of which is nitrogen and the other is nitrogen, oxygen or sulfur, or a remain heteroaryl

  6-membered ring containing 1 to 4 nitrogen atoms; hydroxy

  C2-C24alkyl wherein hydroxy is separated from the group to which R a is linked by at least 2 carbon atoms, with the proviso that it is C7-C24 when Aba contains less than 7 carbon atoms; C1-C24 alkoxyalkyl in the alkoxy residue and C2-C24 in the alkylene residue, the alkoxy residue being separated from the group to which Rba is bound by at least 2 carbon atoms, with the proviso that when Aba contains less than 7 carbon atoms at least one of the alkoxy and / or alkylene radicals contains at least 7 carbon atoms; C3-C25 alkenyl wherein the double bond is separated from the group to which Rba is bound by the at least 1 carbon atom not forming part of the double bond, with the proviso that it is C7-C25 when Aba contains less 7 carbon atoms; C3-C25 alkynyl in which the triple bond is separated from the group to which Rba is bound by at least 1 carbon atom not forming part of the triple bond, with the proviso that it is C7-C25 when Aba contains less than 7 carbon atoms; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl residue and C1-C24 in the alkylene residue, with the proviso that it is C7-C24 in the alkylene radical

4 1 0 9

  when Aba contains less than 7 carbon atoms; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy moiety

  and C2-C24 in the alkylbne radical, the hydroxyl residue

  alkoxy being separated from the group to which Rba is bound by at least 2 carbon atoms and the hydroxy being separated from the oxygen atom of the alkoxy residue by at least 2 carbon atoms, with the proviso that when Aba contains less than 7 carbon atoms, at least one of the hydroxyalkoxy and / or alkylene radicals contains at least 7 carbon atoms; C2-C24 aminoalkyl with the proviso that it is C7-C24 when Aba contains less than 7 carbon atoms, wherein the nitrogen atom is separated from the group to which Rba is bound by at least 2 carbon atoms and the amino residue optionally carries one or independently two substituents selected from C 1 -C 6 alkyl, phenyl, C 7 -C 12 phenylalkyl and C 13 -C 18 bisphenylalkyl groups, the last three substituents optionally bearing in the phenyl ring or rings, or independently two, or independently, three substituents selected from C1-C4 alkyl, C1-C4 alkoxy and hydroxy and halogens having an atomic number of 9-53, Rba represents hydrogen or has the meaning indicated above for Rba, R1R represents hydrogen or has the meaning indicated above for R8a or respresent -CORp in which Rb has the meaning indicated above for Rb a, 8 '-NB ba represents a saturated heterocycle with 5, 6 or 7 members ns which may optionally contain, when it is 6 or 7-membered, another heteroatom selected from oxygen, sulfur and NRC wherein RC represents hydrogen or has the meaning indicated above for Rba, and 8 'Aba represents a C2-C24 alkylene group separating the group to which Rba is bound by at least 2 carbon atoms, Rba and Rba, with the exception of hydrogen, have the meaning 6 7, indicated above for Rba, and n is as defined above, and their ammonium salts in which R a is selected from one of the tertiary amino groups defined above for Rba and quaternized by a group of formula AlkY in which Alk represents a group

  C1-C4 alkyl and Y represents the residue of an acid.

  Another preferred group of compounds of the invention comprises the compounds of formula Ibaa N Rbaa (Ibaa) R3NO

R N R

R2 i 4

R 4

  Wherein R2, R4 and X are as defined above and Raa represents a group -COORgaa or -CORgaa, in which

2554 I'0

  Rbaa represents a C8-C19 alkyl group; C8-C18 hydroxyalkyl wherein the hydroxy is separated from the group to which Rbaa is bound by at least 2 carbon atoms; C 1 -C 18 alkoxyalkyl in the alkoxy residue and C 2 -C 18 in the alkylene residue, the alkoxy residue being separated from the group to which Rbaa is bound by at least 2 carbon atoms, with the proviso that at least one of the alkoxy radicals and / or alkylene contains at least 9 carbon atoms; C2-C18 hydroxyalkoxyalkyl in the hydroxyalkoxy and C2-C18 residue in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which Rbaa is bound by at least 2 carbon atoms and the hydroxyl being separated from the oxygen atom alkoxy with at least 2 carbon atoms, with the proviso that at least one of the hydroxyalkoxy and / or alkylene radicals contains at least 9 carbon atoms; -AbaaOCORbaa; AbaaNRbaaRbaa; or _AbaaN (<\ baa, in

8 '9 10

  which Rbaa represents a C1-C18 alkyl group with the proviso that it is C9-Clg when Abaa contains less than 9 carbon atoms; phenyl, C 7 -C 24 phenylalkyl with the proviso that it is C15-C24 when Abaa contains less than 9 carbon atoms, or bis-phenylC1-C30 alkyl with the proviso that it is C21-C30 when Abaa contains less than 9 carbon atoms, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and hydroxy groups and halogens having an atomic number of 9 to 53; C2-C18 hydroxyalkyl wherein hydroxy is separated from the group to which Rbaa is bound by at least 2 carbon atoms, with the proviso that it is C9-C18 when Abaa contains less than 9 carbon atoms; C1-C18 alkoxyalkyl in the alkoxy residue and C2C18 in the alkylene residue, the alkoxy residue being separated from the group to which Rbaa is bound by at least 2 carbon atoms, Rbaa represents hydrogen or has the meaning indicated above for Rbaa Rbaa represents hydrogen or has the meaning indicated above for Rbaa or represents -CORpa in which Rfa has the meaning indicated above for Rbaa, -N baa represents a saturated 5-, 6- or 7-membered heterocycle which may optionally contain when it is 6 or 7-membered, another heteroatom selected from oxygen, sulfur and NRba wherein Rbaa represents hydrogen or has the meaning indicated above for Rbaa, and Abaa represents a C2-C18 alkylene group separating the group to which Rgaa is bound by at least 2 carbon atoms, Rbaa with the exception of hydrogen has the meaning indicated above for Rbaa, and n is as defined above,

2554 'I09

  and their ammonium salts in which Rbaa is selected from one of the tertiary amino groups defined above for Rbaa and quaternized by a group of formula AlkY in which Alk represents

  a C1-C4 alkyl group and Y represents the residue of an acid.

  Another group of compounds of the invention comprises the compounds of formula Ic R N x c (Ic)

R3 NO2

R2 R4

  Wherein R, Ra, R2, R4 and X are as defined above and R3 is hydrogen or nitro; trifluoromethyl; cyano; COORc; -CORc; or-S (O) nRc; in which Rc is hydrogen; a C3-C7 cycloalkyl group; phenyl optionally bearing, one or independently two, or independently three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl residue containing 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms one of which is nitrogen and the other is nitrogen, oxygen or sulfur, or a 6-membered heteroaryl residue containing from 1 to 4 nitrogen atoms, Rc and Rc, with the exception of hydrogen, have the meaning indicated above for Rc, and

n is as defined above.

  Another group of compounds of the invention comprises the compounds of formula Ica N

NIO

Ra N2 (Ica)

R3 NO2

R2 N R4

  Wherein R2, R4 and X are as defined above and Rca is hydrogen or nitro; trifluoromethyl; cyano; COORca; or -CORa, wherein R a is hydrogen or a heteroaryl heteroaryl containing one heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms one of which is nitrogen and the other is nitrogen, oxygen or sulfur, and Rca with the exception of hydrogen has the meaning indicated U

higher for Rca.

  Another group of compounds of the invention comprises the compounds of formula Id d RdH

3 2

R dt (Id)

R2 R

  Rd in which Rd to Rd and Qd have the meanings given above for R1 to R4 and Q respectively, the substituents in position 2 and 6 and / or 3 and 5 of the 1,4-dihydropyridinyl residue to be different, and their salts of wherein Rd is selected from one of the tertiary amino groups defined above for Rd and quaternized by a group of formula AlkY in which Alk represents

  a C1-C4 alkyl group and Y represents the residue of an acid.

  Another group of compounds of the invention comprises the compounds of formula Ie e) Re Re Re (Ie)

2 4

  in which Re to Re and Qe have the meaning indicated above for R1 and R4, respectively, and the substituents in position 2 and 6 and / or 3 and 5 of the 1,4-dihydropyridinyl radical to be different, and their salts; wherein Re is selected from one of the tertiary amino groups defined above for Re and quaternized by a group of formula AlkY in which Alk is a group

  C1-C4 alkyl and Y represents the residue of an acid.

  In subgroups of compounds of formula Id and Ie and their corresponding ammonium salts, the substituents respectively have the meanings indicated above for the

  compounds of formula Ia, Iaa, Iaa, Ib, Iba, Ibaa, Ic and Ica.

  Another group of compounds of the invention comprises the compounds of formula Ip N; 0 RPOOC 2 (Ip)

H3C N CH3

H S4109 in which

-COOR9 represents an ester group.

  Other groups of compounds of the invention include compounds of formula Ip wherein Rg respectively means: a) a C4-C6 cycloalkyl group, b) a C1-C12 alkyl group or C1-C10 alkoxyalkyl group in the alkoxy residue and C2-C11 in the alkylene residue, the alkoxy residue being separated from the group to which R6 is bound by at least 2 carbon atoms, the alkoxy and alkylene radicals having in total less than 13 carbon atoms, and c) a group - APNRRîo; or -APNB) P; in which RU is hydrogen; a C1-C4 alkyl group; phenyl, C7-C10 phenylalkyl or C13-C16 bisphenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C1-C4 alkyl, alkoxy group and C1-C4 and hydroxy and halogens having an atomic number of 9 to 53, RO represents hydrogen or a C1-C4 alkyl group, -NP represents a saturated 5-, 6- or 7-membered heterocycle which may optionally contain, when it is 6 or 7-membered, another heteroatom selected from oxygen, sulfur and = NR 2, wherein R 2 has the meaning indicated above for R, and AP represents a C 2 -C 12 alkylene chain right separating the group to which Rg is bound by at least 2 atoms

of carbon.

2554 10 9

  In a subgroup of group a) compounds of formula Ip, R D is cyclopentyl or cyclohexyl. In a subgroup of group b) compounds of formula Ip, RP represents

a C1-C8 alkyl group.

  Another group of compounds of the invention comprises the compounds of formula Is x R NsX (Is) R4

3 2 NO2

RS N RS

2 4 4

  wherein X is as defined above, Rs and Rs each represent, independently of one another, a

2 4

  C1-C4 alkyl group and R5 is hydrogen or nitro, trifluoromethyl; cyano; -COORS; or -CORS; wherein

  Rs represents hydrogen; a C1-C12 alkyl group; hydroxy

  C2-C6 alkyl wherein hydroxy is separated from the group to which Rs is bonded by at least 2 carbon atoms; -AsNRsRso; or -AsN B 5; in which Rs and RsO each represent, independently of one another, hydrogen; a C1-C4 alkyl group; C7-C10 phenylalkyl optionally bearing in the phenyl ring one or independently two substituents selected from C1-C4 alkoxy groups and halogens having an atomic number of 9 to 53, -NGB s represents a piperidinyl or piperazinyl group, both of which may be substituted in the 4-position by a methyl, benzyl or bis-phenylmethyl group, the last two substituents optionally bearing in the phenyl ring or rings, or independently, two substituents chosen from C1-C4 alkoxy groups and halogens having an atomic number of 9 to 53, and As is a C 2 -C 14 alkylene group separating the group to which R 8 is bonded by at least 2 carbon atoms, R 8 is an imidazolyl group, and their ammonium salts in which R 8 is selected from one of tertiary amino groups defined above for Rs and quaternized by a group of formula AlkY in which Alk represents a group

  C1-C4 alkyl and Y represents the residue of an acid.

  Other groups of compounds of the invention are those of formula I, Ia, Iaa, Iaaa, Ib, Iba, Ibaa, Ic, Ica, Id, Ie and Is in which, R3, Ra, Raa, Raaa, Rb, Rba, Rbaa, Rc,

3 '3 3 3' 3 3 3 '

  Rca, Rd, Re and Rs are respectively ester groups as defined above under the corresponding formulas, and, as the case may be, their corresponding ammonium salts as defined

upper.

  Other groups of compounds of the invention are the compounds of formula Ia, Iaa, Iaa, Ib, Iba, Ibaa, Ic, Ica and Is in which X represents sulfur and, depending on the case, their salts.

  corresponding ammonium salts as defined above.

  The invention also comprises a process for the preparation of the compounds of the invention, according to which process

  a) is appropriately condensed to form a 1,4-dihydro-

pyridine, a corresponding compound of formula II

(II)

& Ho

2554 '109

  in which Q is as defined above, a corresponding compound of formula III

R3 (III)

R2 0

  wherein R2 and R3 are as defined above, a corresponding compound of formula IV

NO2

  (IV) R4 wherein R4 is as defined above, and a corresponding compound of formula V

H2N (V)

  R 1 in which R 1 is as defined above, or a partial condensation product of these compounds, or b) for the preparation of a compound of formula I '

(I ')

R2 R4

  in which R1, R2, R4 and Q are as defined above and R'3 represents hydrogen, -COOR5 or -COR6 in which R5 and R6 are as defined above,

2554 1 0 9

  a corresponding compound of formula VI X-02 is suitably converted

X 02 (VI)

R2 N R4 (I

  R1 in which R1, R2, R4 and Q are as defined above and X

is a reactive group.

  The method of the invention can be carried out

analogous to known methods.

  The choice of the most appropriate variant of the process naturally depends on the nature of, for example, the substituents R 1 and R 3. Variant a) of the process can be carried out for example according to the Hantzsch synthesis. The reaction can be carried out advantageously in solution. A suitable solvent is water, ethanol, dioxane, dimethylformamide, dimethylsulfoxide,

  pyridine or glacial acetic acid.

  Suitable reaction temperatures are included

  between 20 and 1600C, preferably between 60 and 120C.

  Variant b) of the process can also be carried out according to the usual methods. The choice of the variant of the most appropriate method naturally depends first and foremost on the nature of the R'3 groups. When R'3 represents hydrogen, X may then represent, for example, a carboxy group and the conversion reaction is a decarboxylation. When R'3 represents a -COR6 group, X may then represent, for example, a carboxy group

  and the transformation reaction is then a substitute

  tution. When R'3 represents a carboxy group, X may then represent, for example, an easily cleavable ester group such as an ammonium salt and the transformation reaction is

then hydrolysis.

  When R'3 represents an ester group, X may then represent, for example, a -COX 'group in which X' represents a suitable reactive group for the preparation of an ester. The ester-producing transformation may be, for example, an esterification reaction. X 'is then advantageously a 1H-imidazol-1-yl group. This variant of the process is indicated, for example, for the conversion to unsubstituted or substituted hydroxyalkyl, amidoalkyl, alkoxyalkyl, acyloxyalkyl or aminoalkyl ester. A corresponding compound of formula VI

  wherein X is, for example, 1H-imidazol-1-yl-

  The carbonyl is thus reacted with a corresponding diol, amido-alcohol, ester-alcohol or aminoalcohol. As the solvent can be advantageously used dioxane or an excess of one of the products involved in the reaction. Another transformation producing an ester may be, for example, amination. This variant is indicated for example for the conversion to aminoalkyl ester. A reactive group X is then advantageously for example a group -COOAX "in which A is as defined above and X" means chlorine, bromine or a group Rz-SO 2 -On which R 1 is a phenyl, tolyl or alkyl group. inferior. X "preferably means a mesyloxy group The amination may be direct, ie the reaction proceeds directly with an amine having the substituent to be introduced, or indirectly, for example for the introduction of an amino group by first converting the compound to the corresponding phthalimidoalkyl derivative, for example by reaction with sodium phthalimide

  or potassium, and then reacting the phthalimino derivative

  resulting alkylation with hydrazine. The indirect method is preferred when the substituent which one wishes to introduce

2554 1 09

  is a primary aminoalkyl group. Another transformation producing an ester may be for example the acylation of an amine

  primary or secondary. A reactive group X is then advantageously

  the primary or secondary aminoalkoxycarbonyl group. A corresponding compound of formula VI is thus reacted with the

  corresponding acyl derivative, for example an ester of N-hydroxy-

  succinimide. A suitable solvent is, for example, dioxane. Another transformation producing an ester may be for example

  the acylation of an alcohol. A reactive group X is then advantageously the corresponding hydroxyalkoxycarbonyl group. A compound

  The corresponding formula VI is thus 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-ethyldiisopropylamine. As an appropriate solvent

  for example, methylene chloride. Another transformation

  The ester-producing composition may be, for example, an ether

  cation. A reactive group X is then advantageously a -COOAX "group in which A and X" are as defined above. The reaction is preferably carried out under strongly

alkaline.

  The quaternary ammonium salts can also be prepared analogously to known methods, for example by reaction with a lower alkyl iodide. As an appropriate solvent

  for example an alcohol such as methanol.

  When potentially reactive groups are present such as primary or secondary hydroxy or amino groups, it may be appropriate to carry out the process of the invention with these groups in protected form, for example for a phenolic hydroxy group as a benzyloxy group, or for an aliphatic hydroxy group in the form of a tetrahydropyranyloxy residue, or for an amino group in the form of an acylamino or phthalimino group, and then to convert any protected group present into a desired substituent, for example, the benzyloxy group in the hydroxy group, for example by hydrogenolysis, the tetrahydropyranyloxy group in the hydroxy group, for example by acid hydrolysis, and an amino group protected as a free amino group, for example by acid hydrolysis or hydrazinolysis. The compounds of the invention can be isolated from the reaction mixture and purified analogously to known methods. The compounds of the invention may exist in free form or optionally in the form of a salt. A free form of the compound is generally neutral unless ionizable substituents are present. The compounds may exist as salts, for example when an ionizable substituent is present such as an amino group or a phenolic hydroxy group. Compounds in free form can be converted into salts according to the usual methods and vice versa. Suitable acids for the formation of acid addition salts include hydrochloric acid,

  malonic acid, p-toluenesulphonic acid and methane-

  sulfonic acid. As suitable bases for salt formation

  anionic include sodium hydroxide or potassium hydroxide.

  When the substituents at positions 2 and 6 and / or positions 3 and 5 of the 1,4-dihydropyridinyl moiety are different, the carbon atom at the 4-position is asymmetric. Such a compound can therefore exist in racemic form or in the form of individual enantiomers. The individual optical isomers can be obtained according to the usual methods, for example by fractional crystallization, for example from optically active diastereoisomeric salts, or by transesterification of optically pure esters containing an easily cleavable ester group, preferably a

  basic ester group, such as the dimethylaminoethoxycarbonyl residue.

23541 09

  When the preparation of a starting material is not described, it will be a known compound or which may be prepared according to known methods or in a manner analogous to those described in

this application.

  The following examples illustrate the present invention in no way limit its scope. In these examples,

  temperatures are given in degrees Celsius and are uncorrected.

  EXAMPLE 1 4- (2,1,3-Benzoxadiazol-4-yl) Acid Ethyl Ester

  1,4-dihydro-2,6-dimethyl-5-nitro-pyridine-3-carboxylic acid [variant a) of the process; condensation of the condensation product of the compounds of formula II and IV with the condensation product of the compounds of formula III and V] is heated under reflux for 6 hours 3.5 g of 1- (2,1,3-benzoxadiazole-4yl) -2-nitro-1-butene-3-one and 1.95 g of ethyl ester of 3-aminocrotonic acid in 50 ml of

  dioxane. The mixture is then evaporated to dryness and chromatographed.

  The product is chromatographed on silica gel using a methylene chloride / ether mixture as eluent. We obtain the title compound

(F = 197 in ether).

  The starting material is obtained by refluxing

  for 35 hours a mixture of 44 g of 2,1,3-benzoxadiazole-4-

  carboxaldehyde, 30.6 g of nitroacetone, 1.26 g of piperidine and 1.78 g of acetic acid in 700 ml of benzene. After further purification by chromatography on silica gel with eluent

  methylene chloride, 1- (2,1,3-benzoxadiazole) is obtained.

  4-yl) -2-nitro-1-butene-3-one (F = 105 in ether).

  The title compound of Example 1 is also obtained according to variant (a) of the process using the following starting materials for the condensation of starting materials (compounds of formula as indicated or their example condensation products) 2 2,1,3benzoxadiazole-4-carbaldehyde (II) + ethyl acetoacetate (III) + nitroacetone (IV) + ammonia (V) 3 2-acetyl-3- (2,1,3-benzoxadiazol-4-yl) ) Ethyl 2-propenoate (II + III) + nitroacetone (IV) + ammonia (V) 4 1 (2,1,3-benzoxadiazol-4-yl) -2-nitro-1-butene-3-one ( II + IV) + ethyl acetoacetate (III) + ammonia (V) 2,1,3-benzoxadiazole-4-carbaldehyde (II) + ethyl 3-aminocrotonate (III) + V) + nitroacetone (IV)

  2,1,3-benzoxadiazole-4-carbaldehyde (II) + ethyl acetoacetate (III) + 2-

  ethyl 2-acetyl-3- (2,1,3-benzoxadiazol-4-yl) -2-propenoic acid ethyl (1-amino) -1-nitro-1-propene (IV + V) + 2-amino- 1-nitro-1-propene (IV + V)

23S4109

  EXAMPLE 8 4- (2,1,3-Benzoxadiazol-4-yl) Acid Ethyl Ester

  1,4-dihydro-2,6-dimethyl-5-nitro-pyridine-3-carboxylic acid [variant b) of the process; transformation of the imidazolide] A mixture of 1.5 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-3- (1H-imidazole) was heated to boiling for 8 hours. 1-yl-carbonyl) -2,6-dimethyl-5-nitropyridine and 30 ml of ethanol. The mixture is evaporated to dryness and the residue is chromatographed on silica gel using ether as eluent. We get the

  composed of the title (F = 195 in ether).

  The following compounds of formula I are obtained analogously from the corresponding starting materials: Ex. Prepared QR1 R2 R R4 Configuration in F

ex. n remains 1,4-dihydro-

  pyridinyl 9 1-7; 2,1,3-benzoxal H -COOH Me (R, S) n 146 8 'diazol-4-yl 1-7; 2,1,3-benzoxal H -COO (CH 2) 7 CH 3 Me (R, S) n 131 8 diazol-4-yl

11 to 7; 2,1,3-benzoxa-

  8 diazol-4-yl H Me -COOMe Me (R, S) n 205

12 i to 7; 2,1,3-benzoxa-

  8 diazol-4-yl H 2 O -COO (CH 2) 2 N Me 2 Me (R, S); C 275 B 128 13 1-7; 2, 1,3-benzothia H Me -COO (CH 2) 2 N Me 2 Me (R, S) n amorph 8 diazol-4-yl

14 to 7; 2,1,3-benzothia-

  8 diazol-4-yl Me -COOiPr Me (R, S) n 151-154

1-7; 2,1,3-benzoxa-

  810 diazol-4-yl H Me -COO (CH2) 10NMeBz Me (R, S) ch amorphous

16- 1 7

16 7; 2,1,3-benzoxa-

  diazol e-4-yl H Me -COO (CH 2) 10 N Me Me (R, S) ch amorphous MeO - CH 2) 2 17 1 to 7; 2,1,3-benzoxane-α, diazol e-4-yl H 2 Me -COO (CH 2) 10 N 3 -CH 2 Me (R, S) from 125-127 to 1-7; 2,1,3-benzoxa-HM 8 diazol-4-yl H 2 Me -COO (CH 2) 1OH Me (R, S) n 117-121 8 Wb di azol e-4-yl 2) Ex Preparing R1 R2 R3 R4 Configuration in F no according to position 4 of

ex. n .reste 1,4-dihydro-

  pyridinyl 19 to 7; 2,1,3-benzoxal H-1H-imidazol-1-Me (R, S) n 190 8k) diazol-4-yl-ylcarbonyl

1 to 7 2,1,3-benzothiazole

  81) diazol-4-yl H Me 1H-imidazol-1-Me (R, S) n amorphous ylcarbolyl

21 to 7; 2,1,3-benzoxa-

  n) diazol-4-yl H Me -COOH Me (R, S) n 227 22 1 to 7; 2,1,3-Benzothiazide-MeOH-CoOH (R, S) n Amorphous) diazol-4-yl; 1 e 23 P) 2,1,3-benzoxa H Me COO (CH 2) diazol e- 4-yl He-COH 2) 2N "e3 eMe (R, S) 246 24 q) 2.1.3benzothiazole-H Me -COO (CH2) 2Me3Ie1

diazol-4-yl Me (R, S) - amorphous.

  at. 7; 2,1,3-benzoxal H -H Me (R, S) n 201-202 8m) diazol e-4-yl 26 1 to 7 2,1,3-benzothiazole-MeCN Me (R. S) n 236-237 diazol-4-yl e 27 1 to 7 2, 1,3-benzoxa-MeCN Me (R, S) n 198-200c diazol-4-yl e 28 1 to 7 2, 1,3benzoxal H -NO 2 Me (R, S) n 217-219c diazol-4-yl e 28m1 7 2.1.3-. benzoxa-c LX. Prepared Q R1 R2 R3 R4 Configuration in F no according to position 4 of the

ex. n remains 1,4-dihydro-

  Fyridinyl n 1720 29 8) 2,1,3-benzoxa H Me -COOiPr Me (+) (S) [a] O = 6; a 0+ 9 diazol-4-yl 54 (MeOH, c = 0.53 g / dl) 8b-8u> 2,1.3-benzoxa H Me -COOiPr Me (-) (R) n 172 0

diazole-4-yl e 2a] 2-

i [a] 20.-57 [a2 = 96o

D 546

  (MeOH, c = 0.53 g / l) 31 8b) 2.1.3-benzoxa H Me -COOMe Me (-) (R) n 1880 diazol-4-yl [a] 20-9α] 20.147o

D 546

  (MeOH, c-0.5 g / dl) 328a) 2,1.3-benzoxa H Me -COOMe Me (+) (S) n 188 diazol-4-yl [a] 20 + 910o [a] 20. 146

D 546

  (MeOH, c = 0.5 g / dl) ro / n Ex. Prepared Q R1 R2 R3 R4 onfiguration e F

n we are, 4d-

noselon 1 2 3 4 iosition 4 of

ex. n0 remains 1,4-di-

  __ _ E x _ _ __. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ydropyri di nyl e 33 8c) 2,1,3-benzoxa- H Me 1H-imidazole-1-fe (-) (S) n 1900 diazole- 4 -ylcarbonyl [a] 20 = -170; [a] 20 = -20

D 546

  (MeOH, c = 0.5 g / dl) 34 8d) 2,1,3-benzoxalpha-1H-imidazol-1-Me (+) (R) n, 190 diazob-4-yl-ylcarbonyl [a] 20 + 17 at [a] 546 = + 20o (MeOH; c = 0.5 g / dl) 2,1,3-benzoxa- H Me -COOH Me (+) (S) n 200 di azol e- 4-yl e [a] 20 = + 126o; [α] 21 + 570 0 546 (MeOH, c = 0.5 g / dl) 36 8f) 2,1,3-benzoxal H-MeOH Me (-) (R) (n 200 diazol-4-yl) α2On 1260; [aJ2O0157 @ <tMeH cO 546 (MeOH, c "0.5 g / dl) br Ex. Prepared Q R1 R2 R3 R4 Configuration in F according to position 4 of the example n remains 1,4-dihydro

P y r i d i n i l e _ _ _ _ _ _ _ ..

  (MeOH; c = 0.5 g / dl) 38) 2,1,3-benzoxa-HMe -COO (CH2) 2 Me3 () Me (-) (116 diazol-4-yl (a) -HCO ((a 2.108 (MeOH, c = 0.5 g / dgl) 8.2.1,3-benzoxaHMe -COO (CH2) 2NMe2Me (<) () b 16 diazol-4-yl e 23210, 2014 [a] 0 +80; [a] 2l1 8

ILD 546 + 0

  (MeOH, c = 0.5 g / dl) | > 2,1,3-bis-oxo-HMe-COO (CH 2) 2 N Me 2 Me (+) (S) b 20 161 2 diazol-4-yl] a] 2121,; [aJ2 = 140

D 546

  (MeOH, c = 0.5 g / dl) J) 2,1,3-benzoxa-HMe-COO (CH 2) 2 NMe 2 Me +) (R) b 16 diazol-4-yl [ae + 1; 4

D 546

  (MeOH, c = 0.5 g / dl) Bz = benzyl Bz = benzyl b = in free base form Me = methyl ch = in the form of hydrochloride Phe = phenyl fu = in the form of fumarate n = in neutral free form or Acid a) Using the compound of Example 33 as starting material b) Using the compound of Example 34 as starting material C) Using the compound of Example 35 as starting material, by reaction with the

  1-carbonyl diimidazole in dioxane and subsequent purification by chromato-

  Silica gel graphite using methylene chloride / ethanol (19: 1) as eluent. d) Using the compound of Example 36 as starting material, as described under c) e) Using the compound of Example 37 as starting material, by hydrolysis with a

  2N sodium hydroxide solution at room temperature.

  f) Using the compound of Example 38 as starting material, as described under e).

  9) Using the compound of Example 39 as starting material, by quaternization of the

  free base with methyl iodide in acetone at room temperature.

  h) Using the compound of Example 40 as starting material, as described under g).

  i) Using the compound of Example 12 as free base as starting material,

  by fractionation with (-) - di-O, O'-p-toluoyl-L-tartaric acid in methanol.

  J) as described under i), by fractionation with (+) - di-O, O'-ptoluoyl-D-tartaric acid.

  k) Using the compound of Example 21 as starting material, as described under c).

  1) Using the compound of Example 22 as starting material, as described under c).

  m) Decarboxylation of the compound of Example 21 by heating with traces of acid

sulfuric acid in ethanol.

  n) Using the compound of Example 23 as starting material, as described under e).

   ) Using the compound of Example 24 as starting material, as described under e).

  P) Using the compound of Example 12 as starting material, as described under g).

  q) Using the compound of Example 13 as starting material, as described under g).

  r) Using the compound of Example 18 as starting material, by reaction with the

  methanesulfonyl chloride in methylene chloride in the presence of ethyl

  diisopropylamine at 0 and then reacting the resulting mesylate (oil) with

N-methylbenzylamine at 150.

  S) As described under r) but by reacting the resulting mesylate with N-methyl-

  homovératrylamine instead of N-methylbenzylamine.

  (t) As described under (r) but by reacting the resulting mesylate with benzhydryl

  piperazine instead of N-methylbenzylamine.

  U) Using the compound of Example 19 as starting material, by reaction with a

  excess of 1,10-decanediol in dioxane at 100.

  The compounds of the invention are distinguished by interesting pharmacological properties and can by

  therefore be used therapeutically as drugs.

  The compounds of the invention exert characteristic effects of calcium antagonists. They exert a pronounced muscle relaxant effect, especially on smooth muscles, as evidenced by vasodilation and lowering of blood pressure in conventional tests. For example, in the microsphere test performed in the anesthetized cat according to the method described by R. Hof et al., In Basic Res. Cardiol 75, 747-756 (1980) and 76630-638 (1981) and by R. Hof et al. in J. Cardiovasc. Pharmacol. 4, 352-362 (1982), dilation of the coronary vessels, increase of blood flow in skeletal muscle and decrease of blood pressure after administration of the compounds of the invention intravenously at doses between about 30 and 1000 μg / kg, for example

from about 100 to about 500 mg / kg.

  There is also a decrease in blood pressure in spontaneously hypertensive awake rats according to the method described by Gerold and Tschirki in Arzneimittelforsch. 18, 1285 (1968), after administration of the compounds of the invention orally to

  doses of from about 1 to about 10 mg / kg.

  Thanks to these properties, the compounds of the invention can be used in therapeutics as calcium antagonists for the prevention and the treatment - coronary insufficiency, for example angina pectoris, - other disorders of peripheral circulation, by example in the limbs, such as intermittent claudication and spasms, for example of the colon muscles, - asthma, for example, asthma following exercise, - hypertension, - cardiac insufficiency, for example, ischemic heart attack. The compounds of the invention also exert an action

  vasodilator on the capillary vessels of the carotid zone

  dian; this results in an antagonistic effect on the vaso

  constrictor exerted by serotonin and an inhibition of the disorders associated therewith. Thanks to this property, the compounds of

  the invention can be used therapeutically for prophylaxis.

  laxia and the treatment of migraines and vascular headaches such as vascular pain of the face, especially

  interval therapeutic treatment (prevention) of migraine.

  They are more powerful and more active than flunarizine. For this indication, the preferred compounds are those having a relatively moderate effect on blood pressure and vessels

peripheral blood.

  In addition, the compounds exert a very low negative inotropic activity. They are therefore not cardio-depressive and even exercise some cardiostimulant activity. If necessary, it is therefore possible to use relatively high daily doses even in patients for whom the administration of calcium antagonists is generally contraindicated, for example

  example in those who had a heart attack.

  In these asymmetrically substituted compounds in the 4-position of 1,4dihydropyridinyl, this absence of cardiodepression may occur to varying degrees in one or other of the enantiomeric forms. For the therapeutic uses indicated above, the compounds of the invention will be administered at a daily dose of between about 10 mg and about 1600 mg, advantageously administered, for example orally, in divided doses i to 3 times per day under unit dose form each comprising between about 2.5 mg and about 800 mg of

  active substance, or in delayed release form.

  Preferred indications are coronary and cardiac insufficiency, particularly ischemic heart attack. For the prophylaxis and treatment of migraine and vascular headaches, the preferred compounds are those in

  which Q represents a 2,1,3-benzothiadiazolyl residue.

  The compounds of the invention may 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, especially for

  use as a calcium antagonist.

  The invention also comprises a medicament containing, as active principle, 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 or possible form

  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, may be prepared according to the usual methods and may for example be in the form of tablets for oral administration or in the form of oral tablets for sublingual administration, or in the form of injectable solutions or suspensions for parenteral administration. Sublingual administration

is preferred.

25541 G 9

Claims (13)

  1. 1,4-Dihydropyridines of Formula I q R 3 AN 2 (I) R2 R4   Wherein R 1 represents hydrogen, a C 3 -C 7 cycloalkyl group or an optionally substituted C 1 -C 6 alkyl group, R 2 and R 4 are each, independently of one another, hydrogen or an alkyl group; C1-C6,   R3 represents hydrogen, a C1-C25 alkyl group, nitro, tri-   fluoromethyl, cyano, -COOR5, -COR6 or -S (O) nR7, wherein -COOR5 represents a carboxyl group or an ester group, R6 represents a C1-C25 alkyl group; C2-C24 hydroxyalkyl wherein hydroxy is separated from the group to which R6 is bonded by at least 2 carbon atoms; C1-C24 alkoxyalkyl in the alkoxy residue and C2-C24 in the alkylene residue, the alkoxy residue being separated from the group to which R6 is bound by at least 2 carbon atoms; C3-C25 alkenyl wherein the double bond is separated from the group to which R6 is bound by at least 1 carbon atom not forming part of the double bond; C3-C25 alkynyl wherein the triple bond is separated from the group to which R6 is bound by at least one carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl residue and C1-C24 in the alkylene residue; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy residue and C2-C24 in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which R6 is linked by at least 2 carbon atoms and the hydroxyl being separated from the oxygen atom alkoxy residue with at least 2 carbon atoms; phenyl; C 7 -C 30 phenylalkyl or C 13 -C 36 bis-phenylalkyl, the last three substituents possibly being able to carry in the phenyl ring (s) one, or independently two, or independently, three substituents chosen from C 1 -C 4 alkyl and C 1 -C 4 alkoxy groups; -C4 and hydroxy and halogens having an atomic number of 9 to 53; a heteroaryl residue having 5 members with 1 heteroatom selected from nitrogen, oxygen and sulfur or two heteroatoms, one of which is nitrogen and the other is nitrogen, oxygen or sulfur, or a a 6-membered heteroaryl residue having from 1 to 4 nitrogen atoms, the last two substituents being optionally bonded to the remainder of the molecule via a C1-C24 alkylene radical or a residue of the formula -AOCOR8; -ANRgR1o; or -AN 3 wherein R 8 is C 1 -C 25 alkyl; phenyl, C 7 -C 30 phenylalkyl or C 13 -C 36 bis-phenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C 1 -C 4 alkyl, alkoxy C1-C4 and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl residue with a heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms, one of which is nitrogen and the other is nitrogen, oxygen or sulfur, or a 6-membered heteroaryl residue having 1 to 4 nitrogen atoms; a C2-C24 hydroxyalkyl group in which the hydroxy is separated from the group to which R8st 2'5 4 1 0 9   bound by at least 2 carbon atoms; C1-C24 alkoxyalkyl in the alkoxy residue and C2-C24 in the alkylene residue, the alkoxy residue being separated from the group to which R8 is bonded by at least 2 carbon atoms; C3-C25 alkenyl wherein the double bond is separated from the group to which R8 is bound by at least 1 carbon atom not forming part of the double bond; C3-C25 alkynyl wherein the triple bond is separated from the group to which R8 is bound by at least 1 carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl and Cl-C24 residue in the alkylene residue; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy and C2-C24 residue in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which R8 is bonded by at least 2 carbon atoms and the hydroxyl being separated from the oxygen atom alkoxy residue with at least 2 carbon atoms; C2-C24 aminoalkyl wherein the nitrogen atom is separated from the group to which R8 is bonded by at least 2 carbon atoms and the amino residue optionally carries one or independently two substituents selected from C1-C6 alkyl, phenyl , C 7 -C 18 phenylalkyl or C 13 -C 18 bisphenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and hydroxy and halogens having an atomic number of 9 to 53, R 9 represents hydrogen or has the meaning indicated above for R 8, R 10 represents hydrogen or has the meaning indicated above for R 8 or represents -COR 11 in which R 11 has the meaning indicated above for R8, -Ns represents a saturated 5-, 6- or 7-membered heterocycle which may optionally contain, when it is 6 or 7-membered, another heteroatom selected among oxygen, sulfur and = NR12 wherein R12 is hydrogen or has the meaning indicated above for R8 and A represents a C2-C24 alkylene group separating the group to which R6 is bound by at least 2 carbon atoms R7 has the meaning indicated above for R6, n is 0, 1 or 2, Q is a fully unsaturated condensed ring system of aromatic character having in total at least 2 different cyclic heteroatoms, and the ammonium salts of these compounds, wherein R3 is selected from one of the tertiary amino groups defined above for R3 and quaternized by a group of the formula AlkYub Alk means a group   C1-C4 alkyl and Y the remainder of an acid.   2. 1,4-Dihydropyridines of Formula Ia R R N 2 a 3 NO 2 (Ia) R2N R4   wherein R 2 and R 4 are as defined in claim 1, R f is hydrogen; a C1-C6 alkyl group; C3C6 alkenyl wherein the double bond is separated from the nitrogen atom by at least 1 carbon atom not forming part of the double bond; C3-C6 alkynyl wherein the triple bond is separated from the nitrogen atom by at least 1 carbon atom not forming part of the triple bond; cycloalkyl 2554 1 G0 9   C3-C7; C4-C8 cycloalkylalkyl; C2-C6 hydroxyalkyl wherein hydroxy is separated from the nitrogen atom by at least 2 carbon atoms; C2-C6 alkoxyalkyl; or C 7 -C 8 phenylalkyl or C 8 -C 12 phenylalkenyl in which the double bond is separated from the nitrogen atom by at least 1 carbon atom not forming part of the double bond, the last two substituents optionally bearing in the phenyl ring one, two or three substituents independently selected from C1-C4alkyl, C1-C4alkoxy and hydroxy and   halogens having an atomic number of 9 to 35; alkylcarbonyl   C2-C6 oxyalkyl in the alkylcarbonyl and alkylene radicals and in which the oxygen atom is separated from the nitrogen atom   by at least 2 carbon atoms; dialkylaminoalkyl independently   C1-C6 in the alkyl and C2-C6 radicals in the alkylene radical and in which the amino group is separated from the nitrogen atom by at least 2 carbon atoms; or C 2 -C 6 morpholinoalkyl in the alkylene residue and wherein the morpholino residue is separated from the nitrogen atom by at least 2 carbon atoms,   Ra represents hydrogen; a C1-C6 alkyl group; nitro; sorting-   fluoromethyl; cyano; -COORg; -COR; or -S (O) nR; wherein   Rg is hydrogen; a C1-C6 alkyl group; hydroxy   C2-C6 alkyl wherein hydroxy is separated from the group to which Ra is bonded by at least 2 carbon atoms; C1-C6 alkoxyalkyl in the alkoxy residue and C2-C6 in the alkylene radical, the alkoxy radical being separated from the group to which Ra is bound by at least 2 carbon atoms; C3-C6 alkenyl wherein the double bond is separated from the group to which Rg is bound by at least one carbon atom not forming part of the double bond; C3-C6 alkynyl in which the triple bond is separated from the group to which Rg is bound by at least 1 non-carbon atom   part of the triple bond; C3-C7 cycloalkyl; cyclohexane   C3-C7 alkylalkyl in the cycloalkyl residue and C1-C6 in the alkylene residue; C2-C6 hydroxyalkoxyalkyl in the alkoxy residue and C2-C6 in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which Ra is bound by at least 2 carbon atoms and the hydroxy being separated from the oxygen atom of the alkoxy residue with at least 2 carbon atoms; phenyl, C 7 -C 12 phenylalkyl or bis-phenylalkyl   in Cj3-C18, the last three substituents, possibly   in the phenyl ring (s) one, or independently of two, or independently three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and hydroxy groups and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl radical having a heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms, one of which is nitrogen and the other of which is nitrogen, oxygen or sulfur, or a 6-membered heteroaryl residue having 1 to 4 nitrogen atoms, the last two substituents being optionally bonded to the remainder of the molecule via a C1-C6 alkylene radical; -AaOCORa; -AaNRaRao; or Aa N a; wherein   R8 represents a C1-C6 alkyl group; phenyl, phenyl   C 7 -C 12 alkyl or C 13 -C 18 bis-phenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy C4 and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl radical comprising a heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms, one of which is nitrogen and the other of which is nitrogen, oxygen or sulfur, or 6-membered heteroaryl residue having 1 to 4 nitrogen atoms; hydroxyalkyl 2554 I 9   C2-C6 wherein hydroxy is separated from the group to which Ra is bound by at least 2 carbon atoms; C1-C6 alkoxyalkyl in the alkoxy residue and C2-C6 in the alkylene residue, the alkoxy residue being separated from the group to which Rt is linked by at least 2 carbon atoms; C3-C6 alkenyl wherein the double bond is separated from the group to which Ra is bonded by at least 1 carbon atom not forming part of the double bond; C3-C6 alkynyl wherein the triple bond is separated from the group to which Ra is bonded by at least 1 carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl residue and C1-C6 in the remainder   alkylene; C2-C6 hydroxyalkoxyalkyl in the hydroxyl radical   alkoxy and C2-C6 in the alkylene radical, the hydroxyl radical   alkoxy being separated from the group to which R8 is bound by at least 2 carbon atoms and the hydroxyl being separated from the oxygen atom of the alkoxy residue by at least 2 carbon atoms; C2-C6 aminoalkyl wherein the nitrogen atom is separated from the group to which Ra is bound by at least 2 carbon atoms and the amino residue optionally carries one or independently two substituents selected from groups   C 1 -C 6 alkyl, phenyl, C 7 -C 12 phenylalkyl and   C13-C18 phenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy and halogens having a atomic number from 9 to 53,   Rg represents hydrogen or has the meaning indicated below   above for Rg, Rf0 represents hydrogen or has the meaning indicated above for Rg or represents -CORfi in which Rfi has the meaning indicated above for RE, 255 4 1 0 9   -N.) A represents a saturated 5-, 6- or 7-membered heterocycle which may optionally contain, when it is a 6- or 7-membered ring, another heteroatom selected from oxygen, sulfur and NRa 2 in which R 2 represents l hydrogen or has the meaning indicated above for Ra, and Aa represents a C2-C6 alkylene group separating the group to which Rg is bound by at least 2 carbon atoms, Ra and Ra, with the exception of hydrogen, have the meaning indicated above for Ra, and n is as defined in claim 1, X represents oxygen or sulfur and R represents hydrogen, a halogen having an atomic number of 9 to 35 or an alkyl group of C1-C4, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfonyl, trifluoromethyl, nitro or hydroxy, and their ammonium salts in which Ra is selected from one of the tertiary amino groups defined above for R and quaternized by a group of formula AlkY in which Alk represents a group e   C1-C4 alkyl and Y represents the residue of an acid.   3. 1,4-Dihydropyridines of Formula Ib R N \ x Rb (lb) 3 NO2 R ô R R.   wherein R 2 and R 4 are as defined in claim 1, R, R,   and X are as defined in claim 2, and -   Rb is hydrogen or C7-C25 alkyl; nitro; sorting-   fluoromethyl; cyano; -COORb; -HORN; or -S (O) nRb; in 255 4 1 0 9 which   Rb is hydrogen; a C 7 -C 25 alkyl group; hydroxy   C 7 -C 24 alkyl wherein hydroxy is separated from the group to which R b is linked by at least 2 carbon atoms; C 1 -C 24 alkoxyalkyl in the alkoxy residue and C 2 -C 24 in the alkylene residue, the alkoxy residue being separated from the group to which Rb is bound by at least 2 carbon atoms, at least one of the alkoxy and / or alkylene radicals to have at least 7 carbon atoms; C7-C25 alkenyl wherein the double bond is separated from the group to which Rb is bound by at least 1 carbon atom not forming part of the double bond; C7-C25 alkynyl wherein the triple bond is separated from the group to which Rb is bound by at least one carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl residue and C7-C24 in the alkylene residue; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy radical and C2-C24 in the alkylene radical, the hydroxyalkoxy radical being separated from the group to which Rg is bound by at least 2 carbon atoms and the hydroxyl being separated from the oxygen atom of the alkoxy residue by at least 2 carbon atoms, at least one of the hydroxyalkoxy and / or alkylene radicals having at least 7 atoms   of carbon; phenyl, C13-C30 phenylalkyl or bis-   C19-C36 phenylalkyl, the last three substituents optionally bearing in the phenyl ring (s) one, or independently two, or independently three substituents selected from C1-C4 alkyl, C1-C4 alkoxy and hydroxy groups and halogens having a atomic number from 9 to   53; a heteroaryl residue containing 5-membered heteroaryl   atom selected from nitrogen, oxygen and sulfur or 2 heteroatoms one of which is nitrogen and the other is nitrogen, oxygen or sulfur or a 6-membered heteroaryl residue containing from 1 to 4 nitrogen atoms, the last two substituents being optionally bonded to the rest of the molecule through a C 7 -C 24 alkylene radical; -AbOCOR9; - AbNRRbo; or -AbN Bb; wherein Rb is C 1 -C 25 alkyl with the proviso that it is C 7 -C 25 when Ab contains less than 7 carbon atoms; phenyl, C 7 -C 30 phenylalkyl with the proviso that it is C 13 -C 30 when Ab contains less than 7 carbon atoms, or C 13 -C 36 bis-phenylalkyl with the proviso that it is C 18 -C 36 when Ab contains less than 7 carbon atoms, the last three substituents   possibly in the phenyl ring (s) one, or independently   alternatively two, or independently, three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl residue containing 1 heteroatom   chosen from nitrogen, oxygen or sulfur or 2 hetero-   atoms, one of which is nitrogen and the other is oxygen or sulfur, or a six-membered heteroaryl radical containing from 1 to 4 nitrogen atoms; C2-C24 hydroxyalkyl wherein hydroxy is separated from the group to which R8 is bound by at least 2 carbon atoms, with the proviso that it is C7-C24 when Ab contains less than 7 carbon atoms; C1-C24 alkoxyalkyl in the alkoxy residue and C2-C24 in the alkylene residue, the alkoxy residue being separated from the group to which Rb is bound by at least 2 carbon atoms, with the proviso that when Ab contains less than 7 carbon atoms, carbon at least one of the alkoxy and / or alkylene radicals contains at least 7 carbon atoms; C3-C25 alkenyl wherein the double bond is separated from the group to which Rb is bound by at least 1 carbon atom not forming part of the double bond, with the proviso that it is C7-C25 when Ab contains less 7 carbon atoms; C3-C25 alkynyl wherein the triple bond is separated from the group to which Rb is bound by at least 1 carbon atom not forming part of the triple bond, with the proviso that it is C7-C25 when Ab contains less than 7 carbon atoms; C3-C7cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl and C1-C24 residue in the alkylene moiety, with the proviso that it is C7-C24 in the alkylene moiety when Ab contains less than 7 carbon atoms; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy and C2-C24 residue in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which Rb is linked by at least 2 carbon atoms and the hydroxyl being separated from the oxygen atom of the alkoxy residue by at least 2 carbon atoms, with the proviso that when Ab contains less than 7 carbon atoms at least one of the hydroxyalkoxy and / or alkylene radicals contains at least 7 carbon atoms; C2-C24 aminoalkyl with the proviso that it is C7-C24 when Ab contains less than 7 carbon atoms, wherein the nitrogen atom is separated from the group to which Rb is bound by at least 2 carbon atoms and the amino residue optionally carries one or independently two substituents selected from C 1 -C 6 alkyl, phenyl, C 7 -C 12 phenylalkyl and bis-phenylalkyl groups;   C13-Cl8, the last three substituents, possibly   in the phenyl ring (s) one, or independently two, or independently three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and hydroxy and halogens having an atomic number of 9 to 53, R b is hydrogen or has the meaning indicated above for Rb 8 'Rb represents hydrogen or has the meaning indicated above for R8b or represents a group -CORi in which Rb has the meaning indicated above for Rb il 8' 255410 9   MN b represents a saturated 5-, 6- or 7-membered heterocycle which may optionally contain, when it is 6 or 7-membered, another heteroatom selected from oxygen, sulfur and NR12 wherein R2 represents hydrogen or a the meaning indicated above for Rb, and 8 'Ab represents a C2-C24 alkylene group separating the group to which Rb is bound by at least 2 carbon atoms, Rg and R9, with the exception of hydrogen, have the the meaning indicated above for Rg, and n is as defined in claim 1, and their ammonium salts wherein Rb is selected from one of the tertiary amino groups defined above for Rb and quaternized with a group of formula AlkY in which Alk represents a group   C1-C4 alkyl and Y represents the residue of an acid.   4. 1,4-Dihydropyridines of Formula Ic R NX x Rc. - (Ic) 2   R 2 to R 4 R 1 wherein R 2 and R 4 are as defined in claim 1, R, Ra and X are as defined in claim 2, and R 1 is hydrogen or nitro; trifluoromethyl; cyano; -COORc; -CORc; or-S (O) n R 5; in which Rc is hydrogen; a C3-C7 cycloalkyl group; phenyl optionally bearing, one or independently two, or independently three substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl residue containing 1 selected heteroatom 2554 1 0 9   from nitrogen, oxygen 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, RC and RC, with the exception of hydrogen, have the meaning 6 7 ' indicated above for Rg, and   n is as defined in claim 1.   5. 1,4-dihydropyridines of formula Ip N, R5POOC O2 (Ip) H in which -COORs represents an ester group.   6. 1,4-Dihydropyridines of Formula Is x NsX (Is) R3 NO2 Rs N Rs 2 R4   wherein X is as defined in claim 2, R and Rs are each, independently of each other, a C1-C4 alkyl group and R1 is hydrogen or a nitro, trifluoromethyl group; cyano; -COORS; or -CORS; wherein 6 '   Rg is hydrogen; a C1-C12 alkyl group; hydroxy   C2-C6 alkyl wherein hydroxy is separated from the group to which Rs is bonded by at least 2 carbon atoms; -ASNR8RSO; or -ASNK S; wherein 2554 1 0 9   Rg and RIo each represent, independently of each other, hydrogen; a C1-C4 alkyl group; C7-C10 phenylalkyl optionally bearing in the phenyl ring one or independently two substituents selected from C1-C4 alkoxy groups and halogens having an atomic number of 9 to 53, -N s represents a piperidinyl or piperazinyl group, both of which may be substituted in the 4-position by a methyl, benzyl or bis-phenylmethyl group, the last two substituents optionally bearing in the phenyl ring or rings, or independently, two substituents chosen from C1-C4 alkoxy groups and halogens having an atomic number of 9 to 53, and AS represents a C 2 -C 14 alkylene group separating the group to which R is bonded by at least 2 carbon atoms, R 8 represents an imidazolyl group, and their ammonium salts in which R 5 is chosen from one of tertiary amino groups defined above for R) and quaternized by a group of formula AlkY in which Alk represents a group   C1-C4 alkyl and Y represents the residue of an acid.   7. 1,4-Dihydropyridines according to any one of   Claims 1 to 6, in which the substituents in position 2 and   6 and / or in position 3 and 5 of the rest 1,4-dihydropyridine are different,   in the form of racemates or enantiomers.   8. (R, S) -, (+) (S) - and (-) (S) -4- (2,1,3-benzoxamide)   diazol-1-yl) -1,4-dihydro-2,6-dimethyl-5-nitro-piridine-3-carboxylic acid isopropyl ester. 9. A 1,4-dihydropyridine according to any one of   Claims 1 to 8, in free form or in the form of a salt.   23541 i A process for the preparation of a 1,4-dihydropyridine of the formula I according to claim 1, characterized in that   a) is appropriately condensed to form a 1,4-dihydro-   pyridine, a corresponding compound of formula II XH4O (II)   in which Q is as defined in claim 1, a corresponding compound of formula III R3 (III) (III) R2 0   wherein R2 and R3 are as defined in claim 1, a corresponding compound of formula IV No2 (IV) R4 wherein R4 is as defined in claim 1, and a corresponding compound of formula V H2N (v) 1   wherein R 1 is as defined in claim 1, or a partial condensation product of these compounds, or b) for the preparation of a compound of formula I 2554 R 'R'3 [r2 (1I') R2 N R4   wherein R1, R2, R4 and Q are as defined in claim 1 and R'3 is hydrogen, -COOR5 or -COR6 wherein R5 and R6 are as defined in claim 1, suitably processed a corresponding compound of formula VI (VI) R2 K R.   Wherein R1, R2, R4 and Q are as defined in claim 1 and X is a reactive group and, as appropriate, recovering a resulting compound wherein R3 is   selected from one of the tertiary amino groups defined in the   claim 1 for R3, in the form of a quaternary ammonium salt with a compound of formula AlkY in which Alk represents an alkyl group   C1-C4 and Y represents the residue of an acid.   11. A 1,4-dihydropyridine according to any one of   1 to 8, in free form or in the form of a pharmaceutical salt.   ceutically acceptable for use as a medicament.   12. A medicament, characterized in that it contains, as active ingredient, a 1,4-dihydropyridine according to any one of   Claims 1 to 8, in free form or in the form of a salt pharmaceutically acceptable.   13. A pharmaceutical composition, characterized in that it contains a 1,4-dihydropyridine according to any one of 255 4 1 0 9   Claims 1 to 8, in free form or in the form of a salt   pharmaceutically acceptable, in combination with a diluent or   pharmaceutically acceptable vehicle.