LU85621A1 - NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE AS MEDICAMENTS - Google Patents

Description

* * * *

The subject of the present invention is new derivatives of> 1,4-dihydropyridine, their preparation and their use in therapy, as active principles of medicaments.

'' The invention relates in particular to the compounds of

5 formula I

Q

R3nfYN ° 2 (η 10 R4 R1 in which

R1 represents hydrogen, a C3-C7 cycloalkyl group or an optionally substituted (4-Cß) alkyl group, R2 and R4 each represent, independently of one another, hydrogen or a C-alkyl group - [- Cß, R3 represents hydrogen, a C1-025 alkyl group, nitro, tri-fluoromethyl, cyano, -COOR5, -C0R6 or -S (0) nR7, in which * -COOR5 represents a carboxyl group or an ester group, R5 represents a C1-C25 alkyl group; C2-C24 hydroxyalkyl in which the hydroxy is separated from the group to which Rβ is linked by at least 2 carbon atoms; C1-C24 alkoxyalkyl in the remainder alkoxy and C2-C24 in the alkylene residue, the alkoxy residue being separated from the group to which Rß is linked by at least 2 carbon atoms; C3-C25 alkenyl in which the double bond is separated from the group to which Rß is linked by to minus 1 carbon atom not part of the double bond; C3-C25 alkynyl in which the triple bond is separated

* "V

2 K- of the group to which Rβ is linked by at least 1 carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl radical and in C1-C24 ^ "in the alkylene remainder; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy residue and in C2-C24 in the alkylene remainder, the hydroxyalkoxy residue being separated from the group to which Rß 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; phenyl; phenyl C 7 -C 30 or bis-phenyl C 13 -C 36, 10 the last three substituents possibly optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C1-C4 alkyl, C1-C4 alkoxy and hydroxy and halogens having an atomic number of 9 a 53; a 5 15-membered heteroaryl radical with 1 heteroatom chosen 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 1 to 4 nitrogen atoms, both the latter substituents being optionally linked to the remainder of the molecule via a C1-C24 alkylene residue, or a residue of formula -A0C0R8; -ANR9R10; or -AN ^ ET in which R8 represents a C1-C25 alkyl group; phenyl, phenyl C7-C30 or bis-phenylalkyl C13-C36> the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from alkyl groups (4-C4, C1-C4 alkoxy and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl radical with a heteroatom chosen from nitrogen, oxygen and sulfur or 2 P 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 of the group to which Rs is "3 Μ" * · linked by at least 2 carbon atoms; alkoxyalkyl in (4-C24 in the alkoxy residue and in C2-C24 in the alkylene residue, the alkoxy residue being separated from the group to which Rg is linked by at least 2 carbon atoms; C3-C25 alkenyl in which the double bond is separated from the group to which R8 is linked by at least 1 carbon atom not forming part of the double bond; C3-C25 alkynyl in which the triple bond is separated from the group to which R8 is linked by at least 1 carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl and C1-C24 alkyl 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 R8 is linked by at least 2 carbon atoms and the hydroxy being separated from the atom 15 of oxygen from the alkoxy residue with at least 2 carbon atoms; C2-C24 aminoalkyl in which the nitrogen atom is separated from the group to which R8 is linked by at least 2 carbon atoms and the amino residue optionally carries one or independently two substituents chosen from (4-C6) alkyl groups, phenyl, C7-C12 phenylalkyl or C13-C18 bis-phenylalkyl, the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C1-C4 alkyl groups , C1-C4 alkoxy and hydroxy and the halogens having an atomic number of 9 to 53,

Rg represents hydrogen or has the meaning indicated above for R8,

R10 represents hydrogen or has the meaning indicated above for Rg or represents -CORn in which Ru has the meaning indicated above for Rs> 4 • m -NJÎ) represents a 5, 6 or 7-membered saturated heterocycle which can optionally contain, when it is 6 or 7-membered, another heteroatom chosen from oxygen, sulfur and = NRi2 jé; in which R12 represents hydrogen or has the meaning indicated above for R8 and A represents a C2-C24 alkylene group separating the group to which Rβ is linked by at least 2 carbon atoms, R7 has the meaning indicated above for Rß, 10 n means 0, 1 or 2, Q represents 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, in which R3 is chosen from l 'one of the tertiary amino groups defined above for R3 and quaternized by a group of formula AlkY where Alk signifies an alkyl group in (4-C4 and Y the remainder of an acid.

The compounds of formula I and their ammonium salts will be designated in the present description the "compounds of the invention". Certain compounds of the invention fall under the very general description of European patent application No. 71,819. None of the compounds specifically described in the above-mentioned European patent application fall within the scope of the present invention.

Compounds similar to the compounds of the invention are also described, for example, in European patent application No. 2,208.

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.

4 5

AT

*

The compounds of the invention are preferably in non-quaternized form.

R5 preferably has the meaning indicated above Pour ’For Rß.

5 R1 preferably means hydrogen. When it has a meaning other than hydrogen, it preferably has one of the meanings indicated below for R1, especially an unsubstituted alkyl, cycloalkylalkyl, optionally substituted phenylalkyl, alkoxyalkyl or morpholino group; preferably an unsubstituted alkyl or alkoxyalkyl group; preferably unsubstituted alkyl. When it signifies an alkoxyalkyl group, the alkoxy residue is preferably separated from the nitrogen atom by at least 2 carbon atoms. R2 and R4 preferably signify an alkyl group, especially methyl. R3 preferably means a nitro, trifluoromethyl, -COOR5 or -CORß, especially-COORß, group. R5 and / or R7 preferably signify an alkyl, hydroxyalkyl, alkoxyalkyl, -AOCORs, -ANR9R10 or -AN ^ group, especially -ANRgRio or -AN ^ i. Rβ is preferably as defined above for R5 and / or R7 or signifies a 5-membered heteroaryl radical containing 2 nitrogen heteroatoms. Rg preferably means an optionally substituted alkyl or phenyl, phenylalkyl or bis-phenylalkyl group, in particular phenyl, Rg and Rio preferably mean hydrogen or an optionally substituted alkyl or phenyl, phenylalkyl or bis-phenylalkyl group. Preferably, Rg and Rio both signify hydrogen or one of Rg and Rio signifies an alkyl group and the other signifies an alkyl, optionally substituted phenylalkyl or optionally substituted bis-phenylalkyl group. preferably means a saturated 6-membered hetero ring containing another hetero atom. Ru 30 preferably means an alkyl group, optionally substituted phenyl> 6, optionally substituted phenylalkyl or optionally substituted bis-phenylalkyl. R12 preferably has a different meaning than hydrogen, and preferably signifies an alkyl, optionally substituted phenylalkyl or optionally substituted bisphenylalkyl. A preferably contains 2 carbon atoms or from 7 to 24 carbon atoms, especially from 9 to 18 carbon atoms, in particular from 9 to 14 carbon atoms, especially 10 carbon atoms. It is preferably unbranched, n preferably means 1 or 2. Q has in total at least 3 heteroatoms, in particular 3 and is preferably a bicyclic system. Q preferably represents the 2,1,3-benzoxadiazolyle and 2,1,3-benzothia-diazolyle groups, in particular 2,1,3-benzoxadiazolyle. When Q is a ring system having a benzene ring, the 1,4-dihydropyridinyl residue is preferably linked to this ring, especially at a position of the benzene ring adjacent to a ring junction. Alk preferably means a methyl group. Y preferably means the residue of a mineral acid, for example a mesyl residue or a halogen, in particular iodine.

The C3-C7 cycloalkyl group preferably contains 3, 5 or 6 carbon atoms, especially 5 carbon atoms. The optionally substituted Οχ-Οβ alkyl group preferably has

One of the meanings given below for Rj * except hydrogen, and especially means a methyl group. The C1-C6 alkyl group preferably contains from 1 to 4 carbon atoms, and especially means a methyl group. The (4-C25) alkyl group preferably contains from 1 to 6 carbon atoms, such as the methyl, ethyl or isopropyl group, or from 9 to 19 carbon atoms, especially from 9 to 19, in particular 10 carbon atoms. The C2-C24 hydroxyalkyl group preferably contains "7" from 2 to 6 or from 9 to 18 carbon atoms, especially from 9 to 18 carbon atoms. The C1-C24 alkoxyalkyl group in the alkoxy and C2 radicals -C24 in the alkylene residue preferably contains from 1 to 6 or from 9 to 19 carbon atoms, especially from 9 to 19 carbon atoms in the alkoxy residue and preferably from 2 to 6 or from 9 to 18 carbon atoms , especially from 9 to 18 carbon atoms in the alkylene radical. The C3-C25 alkenyl and / or C3-C25 alkynyl group preferably contain 3 or from 7 to 25 carbon atoms, especially from 9 to 18 carbon atoms The C3-C7 cycloalkyl group and the C3-C7 cycloalkyl group of the cycloalkylalkyl group preferably contain 3, 5 or 6, especially 5 or 6 carbon atoms. The C1-C24 alkylene residue of the cycloalkylalkyl group preferably contains 1 or from 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 from 7 to 24 carbon atoms, especially from 9 to 18 carbon atoms. The C2-C24 alkylene residue of the hydroxyalkoxyalkyl group preferably contains 2 or from 7 to 24 carbon atoms, especially from 9 to 18 carbon atoms. The alkylene residue of the C7-C30 phenylalkyl group or the C13-C36 bisphenylalkyl group preferably contains 1 or 2 or from 7 to 24 carbon atoms, especially from 9 to 18 carbon atoms. C1-C4 alkyl and / or C1-C4 alkoxy groups preferably contain 1 or 2 carbon atoms, especially 1 carbon atom. The halogen having an atomic number of 9 to 53 is preferably fluorine or bromine, especially bromine.

The 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 is in particular the imidazolyl group, especially 1H-imidazole-1-T yl. When it is 6-link, it preferably contains 1 or 2 8

AT

nitrogen heteroatoms, and it means a pyridinyl group. The residue - C1-C24 alkylene optionally linking a heteroaryl residue to the rest of the molecule preferably contains 1 or from 7 to 24 carbon atoms, especially from 9 to 18 carbon atoms. The C2-C24 alkylene residue of the aminoalkyl group preferably contains 2 or from 7 to 24 carbon atoms, especially from 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 by alkyl and optionally substituted phenylalkyl groups. The 5, 6 or 7-membered saturated heterocycle as defined above is preferably 6-membered. It is preferably the 1-piperazinyl group. When it is 6 or 7 membered, it preferably contains another heteroatom = NRi2- The hydroxyl of the hydroxyalkyl and / or hydroxyalkoxyalkyl group and / or the amino residue of the aminoalkyl group are preferably attached to the carbon atom furthest terminal. When a phenyl ring is present in a substituent, it is preferably unsubstituted. When substituted, it is preferably monosubstituted, preferably in the para position. When it is disubstituted, it is preferably substituted in the ortho or meta position and in the para position. When it is tri substituted it is preferably substituted in the meta, meta and para position. Alkoxy groups and / or halogens are preferred as substituents on the phenyl ring. When a phenyl ring is polysubstituted, the substituents are preferably identical. In the bis-phenylalkyl group, the two phenyl rings are preferably attached to the same carbon atom. The bis-phenylalkyl group preferably means a bis-phenylmethyl group. A group of compounds of the invention includes? compounds of formula la (see formula on next page) / 9 »

R

5 * 3 ^ Ι ^ Ι | Γ "02 (Ia) ** T," "R * in which R2 and R4 are as defined above, 10 R £ represents hydrogen; a en-Οβΐ alkenyl C3-C6 alkyl group in which 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 in which 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 in which the hydroxy is separated from the nitrogen atom by at least 2 carbon atoms; C2-C6 alkoxyalkyl; or C7-C9 phenylalkyl or C9-C12 phenylalkenyl in which the double bond 20 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; C2-C6 alkylcarbonyloxyalkyl in alkylcarbonyl and alkylene radicals and in which the oxygen atom is separated from the nitrogen atom by at least 2 carbon atoms; C1-C6 dialkylaminoalkyl independently in the alkyl radicals and C2-C6 in the alkylene radical and in which the friend group no is separated from the nitrogen atom by at least 2 carbon atoms; or C2-C6 morpholinoalkyl in the alkylene residue and in which the morpholino residue is separated from the nitrogen atom by at least 2 carbon atoms,! ► 10 R | represents hydrogen; a C1-C6 alkyl group; nitro; tri-, fluoromethyl; cyano; -COOR ^; -CORg; or -S (0) nR ^; wherein

Ra represents hydrogen; a (4-Cß) alkyl group; hydroxy-Cp-Cß alkyl in which the hydroxy is separated from the * 5 group to which R | is linked by at least 2 carbon atoms; C1-C6 alkoxyalkyl in the alkoxy residue and C2-Cβ in the alkylene residue, the alkoxy residue being separated from the group to which R | is linked by at least 2 carbon atoms; Cβ-Cβ alkenyl in which the double bond is separated from the group to which R ^ is linked by at least one carbon atom which is not part of the double bond; Cß-Cß alkynyl in which the triple bond is separated from the group to which R | is linked by at least 1 carbon atom which is not part of the triple bond; C3-C7 cycloalkyl; C3-C7 cyclo-alkylalkyl in the cycloalkyl and C1-C6 alkyl in the alkylene residue; C2-C6 hydroxyalkoxyalkyl in the alkoxy residue and C2-Cß in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which R | is linked by r minus 2 carbon atoms and the hydroxy being separated from the oxygen atom of remains alkoxy with at least 2 carbon atoms; phenyl, C7-C12 phenylalkyl or C13-C18 bis-phenylalkyl * the last three substituents optionally carrying in the phenyl ring (s) one, or independently and two, or independently three substituents chosen from alkyl groups (4-C4, C1-C4 alkoxy and hydroxy and the halogens having an atomic number of 9 to 53; a 5-membered heteroaryl radical comprising a heteroatom chosen 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, the last two substituents being optionally linked to the rest of the molecule by t 11 ”Through a C1-C6 alkylene residue; -AaOCOR |; -AaNRaRaQ; or Aa M) a; in which Ä R | represents a C 1 -C 6 alkyl group; phenyl, phenyl-C7-C12 alkyl or bis-phenylalkyl C13-C18, the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C1-C4 alkyl groups , C1-C4 alkoxy and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl radical comprising a heteroatom chosen from nitrogen, oxygen and sulfur or 2 heteroatoms of which one is nitrogen and the other is nitrogen, oxygen or sulfur, or a 6-membered heteroaryl radical comprising 1 to 4 nitrogen atoms; C 6 -C 6 hydroxyalkyl in which the hydroxy is separated from the group to which

Ra is linked by at least 2 carbon atoms; C1-C6 alkoxyalkyl in the alkoxy radical and C2-C6 in the alkylene radical, the alkoxy radical being separated from the group to which R | is linked by at least 2 carbon atoms; C3-C6 alkenyl in which the double bond is separated from the group * to which R | is linked by at least 1 carbon atom which is not part of the double bond; C3-C6 alkynyl in which the triple bond is separated from the group to which R | is linked by at least 1 carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; C 3 -C 7 cycloalkylalkyl in the cycloalkyl radical and C 1 -C 6 in the alkylene residue; C2-C6 hydroxyalkoxyalkyl in the hydroxy-alkoxy radical and C2-C6 in the alkylene radical, the hydroxy-alkoxy radical being separated from the group to which is bonded by at least 2 carbon atoms and the hydroxy being separated from the oxygen atom c of the alkoxy residue with at least 2 carbon atoms; C2-C6 aminoalkyl in which the nitrogen atom is separated from the group to which R | is linked by at least 2 carbon atoms and the friendly residue optionally carries one or independently two substituents chosen from (4-C6 alkyl, phenyl, C7-C12 phenylalkyl and C13-C18 bis-phenylalkyl) groups last three substituents

V

5 optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C1-C4 alkyl, C1-C4alkoxy and. hydroxy and halogens having an atomic number of 9 to 53, represents hydrogen or has the meaning indicated above for RJ, RJ0 represents hydrogen or has the meaning indicated above for Rg or represents -COR ^ in which Rj ^ has the meaning indicated above for R ^, -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 chosen from oxygen, sulfur and NRj * 2 in which Rj ^ represents hydrogen or has the meaning indicated above for Ra, and Aa represents a C2-C6 alkylene group separating the group in which R | is linked by at least 2 carbon atoms, Λ R | and R ^, with the exception of hydrogen, have the meaning given above for RJ, and n is as defined above, X represents oxygen or sulfur and R represents hydrogen, a halogen having an atomic number from 9 to 35 or a C1-C4 alkyl, C1-C4 alkoxy, (4-C4) alkylthio, C1-C4 alkylsulfonyl, trifluoromethyl, nitro or hydroxy, and their ammonium salts in which R | is chosen from one of the S · 13 tertiary friend groups defined above for R | and quaternized by a group of formula AlkY in which Alk represents a C1-C4 alkyl group and Y represents the remainder of an acid.

X preferably represents oxygen. R represents 5 I ^ V \ preferably hydrogen. The residue L I t is preferably linked by its position 4 to position 4 of the 1,4-dihydropyri-dinyl residue.

Another group of compounds of the invention includes the compounds of formula Iaa, r 15 aa R3N ^ N ^ no? daa) .XX.

c R2 Ua ”4 K1 20 * in which R, R2, R4 and X are as defined above, R £ a represents hydrogen or a (C 4 -C 6) alkyl group and R | a represents hydrogen; (4-C6) alkyl group; nitro; tri-fluoromethyl; cyano; -C00R | a; -C0R | a or -S (0) nR ^ a; in which

Raa represents hydrogen; a C1-C6 alkyl group; hydroxy C2-C6 alkyl in which the hydroxy is separated from the group to which R ^ a is linked by at least 2 carbon atoms; (4-C6 alkoxyalkyl in the alkoxy radical and C2-C6 in the alkylene radical, the alkoxy radical being separated from the group to which R | a is linked by at least 2 carbon atoms; a 5-membered heteroaryl radical containing 1 hetero atom chosen from nitrogen, oxygen and sulfur or 2 hetero atoms, one of which is nitrogen and the other is nitrogen, 14 oxygen or sulfur or a 6-membered heteroaryl residue containing 1 to 4 nitrogen atoms; -Aaa0C0R ^ a; -AaaNR | aRj ^; or AaaN ^ B) aa; wherein 5 R | a represents a C1-C6 alkyl group; phenyl, phenyl-C7-C12 alkyl or bis-phenylalkyl-C13-C18, the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from 10 C1-C4 alkyl groups , C1-C4 alkoxy and hydroxy and halogens having an atomic number of 9 to 53; C2-C6 hydro-xyalkyl wherein the hydroxy is separated from the group to which R | a is linked by at least 2 carbon atoms; C1-C6 alkoxyalkyl in the alkoxy radical and in C2-C5 in the alkylene radical, the alkoxy radical being separated from the group to which R | a is linked by at least 2 carbon atoms, R | a represents hydrogen or a the meaning indicated - above for Raa, 20 represents hydrogen or has the meaning indicated above for Raa or means -COR ^ in which R ^ has the meaning indicated above for R | a, -NJ ^ I aa represents a 5, 6 or 7-membered saturated heterocycle which may optionally contain, when 6 or 7-membered, another heteroatom selected from oxygen, sulfur and NRjM} in which R £ | represents hydrogen or has the meaning given above for R | a, and 15

Aaa represents a C2-C6 alkylene group separating the ~ group to which R | a is linked by at least 2 carbon atoms, R | a and R ^ a, with the exception of hydrogen, have the meaning indicated more high for R | a, and n is as defined above, and their ammonium salts in which R | a is chosen from one of the tertiary friend groups defined above for R | a and quater-nized by a group of formula AlkY in which Alk represents a C1-C4 alkyl group and Y represents the remainder of an acid.

Another group of compounds of the invention comprises the compounds of formula Iaaa R3M (Iaaa) R2? R4

H

Wherein R2, R4 and X are as defined above and a R | aa represents hydrogen or a nitro group; trifluoromethyl; cyano; -C00R | a; or -C0R | a in which R | a and R | a are as defined above, and their ammonium salts in which R | aa is chosen from one of the tertiary friend 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 remainder of an acid.

In a subgroup of compounds of formula Iaa or Iaaa and their corresponding ammonium salts, Rj * a represents hydrogen.

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

- In another subgroup, X represents oxygen. In another 16 subgroup X represents sulfur. In another subgroup, R | aa represents a group -C00R ^ a in which Raa is as defined above. In a subgroup of compounds of formula Iaa and their corresponding ammonium salts, R represents hydrogen.

A preferred group of compounds of the invention comprises the compounds of formula Ib 10 R ^ Yr No. 2 (Ib) R2 U R4 K1 in which R, Rj1, R2, R4 and X are as defined above and R ^ represents hydrogen or a C7-C25 alkyl group; nitro; trifluoromethyl; cyano; -COORj ?; -CORj ?; or -S (0) nR ^; in which 20 Rj? represents hydrogen; a C7-C25 alkyl group; hydroxy-, C7-C24 alkyl in which hydroxy is separated from the group to which Rj? is linked by at least 2 carbon atoms; C1-C24 alkoxyalkyl in the alkoxy radical and C2-C24 in the alkylene radical, the alkoxy radical being separated from the group to which Rj? is linked by at least 2 carbon atoms, at least one of the alkoxy and / or alkylene radicals having to have at least 7 carbon atoms; C7-C25 alkenyl in which the double bond is separated from the group to which Rj? is linked by at least 1 carbon atom not forming part of the double bond; C7-C25 alkynyl in which the triple bond is separated from the group to which Rj? is linked by at least 17 1 carbon atom not forming part of the triple r bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl and C7-C24 alkyl in the t alkylene residue; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy and C2-C24 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 atom oxygen of the alkoxy residue with at least 2 carbon atoms, at least one of the hydroxyalkoxy and / or alkylene radicals having to have at least 7 carbon atoms; phenyl, C13-C30 phenylalkyl or C19-C36 bis-phenylalkyl, the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C1-C4 alkyl, alkoxy groups C1-C4 and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl residue containing 1 hetero atom chosen from nitrogen, oxygen and sulfur or 2; hetero atoms of which one 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 linked to the rest of the molecule via a C7-C24 alkylene residue; -AboCOR ^; -AbNR ^ R ^; or -AbN ^ B) b; in which R ^ represents a (C-C25) alkyl group with the condition that it is C7-C25 when Ab contains less than 7 carbon atoms; phenyl, phenyl C7-C30alkyl with the condition that it is in (43-C30 when Ab contains less than 7 carbon atoms, or bis-phenylalkyl in C3.3-C36 with the condition that it is in C19-C36 when Ab contains less than 7 carbon atoms, the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen 18 from (4-C4 alkyl, C1-C4 alkoxy, and hydroxy and halogens 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-5 atoms, one of which is nitrogen and the other is oxygen or sulfur, or a residue 6-membered heteroaryl containing from 1 to 4 nitrogen atoms; C2-C24 hydroxyalkyl in which the hydroxy is separated from the group l Rb is linked by at least 2 carbon atoms, with the condition that it is in 10 in C7-C24 when Ab contains less than 7 carbon atoms; C1-C24 alkoxyalkyl in the alkoxy residue and C2-C24 alkylene in the alkylene residue, the alkoxy residue being separated from the group to which is bonded by at least 2 carbon atoms, with the proviso that when Ab contains less than 7 atoms of carbon at least one of the alkoxy and / or alkylene radicals contains at least 7 carbon atoms; C3-C25 alkenyl in which the double bond is separated from the group to which Rb is linked by at least 1 carbon atom not forming part of the double bond, with the proviso that it is in C7-C25 when Ab contains less 7 carbon atoms; C3-C25 alkynyl in which the triple bond is separated from the group to which Rj ^ is linked by at least 1 carbon atom not forming part of the triple bond, with the condition that it is C7-C25 when Ab contains less 25 to 7 carbon atoms; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl radical and C1-C24 in the alkylene radical, with the condition that it is C7-C24 in the alkylene radical when Ab contains less than 7 carbon atoms; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy and C2-C24 in the alkylene residue, the remainder 19 hydroxyalkoxy being separated from the group to which R | j is bonded 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, with the proviso that when Ab contains 5 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 condition that it is C7-C24 when Ab contains less than 7 carbon atoms, in which the nitrogen atom is separated from the group 10 to which Rb is linked by at least 2 carbon atoms and the remaining friend no optionally carries one or independently two substituents chosen from C4-C6 alkyl, phenyl, C7-C12 phenylalkyl and C13-C18 bis-phenylalkyl "the last three substituents optionally bearing in 15 or phenyl rings one, or independently two, or independently three substituents chosen from C1-C4 alkyl, C1-C4 alkoxy and hydroxy groups and halogens having an atomic number of 9 to 53,

Rb represents hydrogen or has the meaning indicated above for Rb,

Rj> 0 represents hydrogen or has the meaning indicated above for R ^ or represents a group -COR ^ in which has the meaning indicated above for R ^, represents a 5, 6 or 7-membered saturated heterocycle which can optionally contain, when it is 6 or 7-membered, another heteroatom chosen from oxygen, sulfur and NRjj2 in which Rj2 represents hydrogen or has the meaning indicated above for R ^, and Ab represents an alkylene group in C2-C24 separating the group 30 to which Rj? is bound by at least 2 carbon atoms, 20

Rj3 and RÉJ, with the exception of hydrogen, have the meaning: indicated above for RjJ, and n is as defined above, „and their ammonium salts in which is chosen from one of the 5 groups tertiary amino defined above for Rb and quaternized with a group of formula AlkY in which Alk represents a (4-C4) alkyl group and Y represents the remainder of an acid.

Another preferred group of compounds of the invention includes the compounds of formula Iba 10 R

(Iba) iaa.

R1 in which R, R ^ a, R2, R4 and X are as defined above and Rba represents a C7-C25 alkyl group, -COORba, -COR ^ a, or 20 -S (0) nRj ^ a, in which s R ^ a represents a C7-C25 alkyl group; C7-C24 hydroxyalkyl in which the hydroxy is separated from the group to which R ^ a is linked by at least 2 carbon atoms; (4-C24 alkoxyalkyl in the alkoxy residue and in C2-C24 in the alkylene residue, the alkoxy residue being separated from the group to which R ^ a is linked by at least 2 carbon atoms, with the condition that at least one alkoxy and / or alkylene radicals contains at least 7 carbon atoms; C7-C25 alkenyl in which the double bond 30 is separated from the group to which Rba is linked by at least b 21 1 carbon atom not forming part of the double bond; C7-C25 alkynyl in which the triple bond is separated from the group to which Rjîa is linked by at least 1 carbon atom not forming part of the triple bond; 5 C3-C7 cycloalkylalkyl in the cycloalkyl and C7- residue C24 in the alkylene radical; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy radical and C2-C24 in the alkylene radical, the hydroxyalkoxy radical being separated from the group to which Rj? A is linked by at least 2 carbon atoms 10 and the hydroxy being separated from the oxygen atom of the alkoxy residue by at least 2 atoms of c arbone, with the condition that at least one of the hydroxyalkoxy and / or alkylene radicals contains at least 7 carbon atoms; C 13 -C 30 phenylalkyl or C19-C36 bis-phenylalkyl "the last two substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from (4-C4 alkyl, alkoxy C1-C4 and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl residue containing a heteroatom chosen 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 linked to the rest of the molecule via d '' a C7-C24 alkylene residue; -AbaocORba, -AbaNRbaRba, or -Aba ^ ba, in which

Rba represents a (4-C25) alkyl group, with the condition that it is in C7-C25 when A ^ a contains less than 7 30 carbon atoms; phenyl, phenylalkyl in C7-C30 with the condition that it is (43-C30 when A ^ a contains less than 7 carbon atoms, or bis-phenylalkyl in C13-C36 with the condition that it is in C19-C36 when A ^ a contains less than 7 carbon atoms, the three 35 last substituents optionally carrying 22 in the phenyl ring (s) one, or independently two, or independently three substituents chosen from (4-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 chosen 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; hydroxy-10 C2-C24 alkyl in which the hydroxy is separated from the group which el R ^ a is linked by at least 2 carbon atoms, with the condition that it is C7-C24 when Aba contains less than 7 carbon atoms; (4-C24 alkoxyalkyl in the alkoxy residue and in C2-C24 in the alkylene residue, the alkoxy residue being separated from the group to which R ^ a is linked by at least 2 carbon atoms, with the condition that when Aba contains less of 7 carbon atoms at least one of the alkoxy and / or alkylene radicals contains at least 7 carbon atoms; C3-C25 alkenyl in which the double bond is separated from the group to which R ^ a is linked by at least 1 atom of carbon not forming part of the double bond, with the proviso that it is C7-C25 when Aba contains less than 7 carbon atoms; alkynyl C3-C25 in which the triple bond is separated from the group to which R ^ a is linked by at least 1 carbon atom not forming part of the triple bond, with the condition that it is C7-C25 when Aba contains less than 7 carbon atoms; C3-C7 cycloalkyl; C3 cycloalkylalkyl -C7 in the cycloalkyl radical and in (4-C24 in the alkylene radical, with the condition that it is in C7-C24 in the alkylene residue 23 when A ^ a contains less than 7 carbon atoms; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy residue and C2-C24 in the alkylene residue, the hydroxyal coxy residue being separated from the group to which Rba is linked by at least 2 carbon atoms and the hydroxy being separated from the atom d oxygen of the alkoxy residue with at least 2 carbon atoms, with the proviso that when A ^ a contains less than 7 carbon atoms at least one of the hydroxyalkoxy and / or alkylene radicals contains at least 7 10 carbon atoms; C2-C24 aminoalkyl with the condition that it is C7-C24 when A ^ a contains less than 7 carbon atoms, in which the nitrogen atom is separated from the group to which R ^ a is linked by at least 2 carbon atoms and the amino residue optionally carries one or independently two substituents chosen from C 1 -C 6 alkyl phenyl, phenyl C 7 -C 12 alkyl and bis-phenyl C 13 -C 18 alkyl, the last three substituents optionally bearing in the phenyl rings one, or independently two, or independently three substituents selected from alkyl groups (4-C4, alkoxy C1-C4 and hydroxy and halogens having an atomic number of 9 to 53, pba represents hydrogen or a the meaning indicated above for Rj> a, 25 represents hydrogen or has the meaning indicated above for R | ja or represents -CORlj ^ in which Rjj> £ has the meaning indicated above for R ^, 24 -Njj ^ ba represents a 5, 6 or 7-membered saturated heterocycle which may possibly only contain, when it is 6 or 7-membered, another heteroatom chosen from oxygen, sulfur and NR ^ in which 5 represents hydrogen or has the meaning indicated above for R ^ a, and

Aba represents a C2-C24 alkylene group separating the group to which R ^ a is linked by at least 2 carbon atoms, Rj2a and REja, with the exception of hydrogen, have the meaning indicated above for R ^ a , and n is as defined above, and their ammonium salts in which Rjjja is chosen from one of the tertiary amino groups defined above for R ^ a and quaternized by a group of formula AlkY in which Alk represents a alkyl group in (4-C4 and Y represents the remainder of an acid.

Another preferred group of compounds of the invention comprises the compounds of formula Ibaa .bu lIbaa> 3 yV ° 2 25 ^ R, H * in which R2, R4 and X are as defined above and R ^ aa represents a group -CÛ0R ^ aa or -C0Rj2aa, in which 25

Rbaa represents a Cg-Cig alkyl group; C9-C18 hydroxyalkyl in which the hydroxy is separated from the group to which Rj? aa is linked by at least 2 carbon atoms; C1-CI8 alkoxyalkyl in the alkoxy residue and C2-C185 in the alkylene residue, the alkoxy residue being separated from the group to which Rj? aa is linked by at least 2 carbon atoms, with the condition that at least one of alkoxy and / or alkylene radicals contains at least 9 carbon atoms; C2-C18 hydroxyalkoxyalkyl in the hydroxyalkoxy and C2-C18 in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which

Rbaa is linked 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 at least one of the hydroxyalkoxy and / or alkylene residues contains at least 9 carbon atoms; -Abaa0C0Rbaa; -AbaaNRbaaRbaa; or -AbaalTß \ baas in o y iu / which

Rbaa represents a C1-C19 alkyl group with the condition that it is C9-C19 when Abaa contains less than 9 carbon atoms; phenyl, phenyl C7-C24 with the condition that it is C15-C24 when Abaa contains less than 9 carbon atoms, or bis-phenylalkyl C13-C30 with the condition that it is C21-C30 when Abaa contains less than 9 carbon atoms, the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C 26 alkyl groups

C1-C4, C1-C4 alkoxy and hydroxy and halogens: having an atomic number of 9 to 53; C2-C18 hydroxyalkyl in which the hydroxy is separated from the group to which R ^ aa is bound by at least 2 carbon atoms, with the proviso that it is Cg-Cis when Abaa contains less than 9 carbon atoms; C1-C6 alkoxyalkyl in the alkoxy radical and C2-C18 in the alkylene radical, the alkoxy radical being separated from the group to which R ^ aa is linked by at least 2 10 carbon atoms, R ^ aa represents hydrogen or a the meaning indicated above for R ^ aa,

Rbaâ represents hydrogen or has the meaning indicated above for R ^ aa or represents 15 -COR ^ j13 in which Rij ^ 3 has the meaning indicated above for R ^ aa, -t (j3) baa represents a heterocycle saturated with 5, 6 or 7-membered which may optionally contain, when it is 6 or 7-membered, another heteroatom chosen from oxygen, sulfur and NR ^ a in which Rjj> | a represents hydrogen or a meaning indicated above for R ^ aa, and

Abaa represents a C2-C18 alkylene group separating the group to which Rj? Aa is linked by at least 2 carbon atoms,

Rjîaa with the exception of hydrogen has the meaning indicated above for R ^ aa, and n is as defined above, 27 and their ammonium salts in which R ^ aa is chosen from one of the friend groups tertiary no 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 remainder of an acid.

Another group of compounds of the invention comprises the compounds of formula le 10 c (Ic) R3 'γΛγ' N02 2 Aa R4 R1 15 in which R, Rj1, R2, R4 and X are as defined above and RÇj represents hydrogen or a nitro group; trifluoromethyl; cyano; -COORg; -CORg; or-S (0) nRC; in which rc represents T hydrogen; a C3-C7 cycloalkyl group; phenyl optionally carrying one or independently two, or independently three substituents selected from (4-C4 alkyl, C1-C4 alkoxy and hydroxy) and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl radical containing 1 heteroatom chosen from nitrogen, oxygen and sulfur or 2 hetero atoms 25 one of which is T nitrogen and the other is nitrogen, oxygen or sulfur, or a 6-membered heteroaryl residue containing from 1 to 4 nitrogen atoms, RC and R ^, with the exception of hydrogen, have the meaning indicated above for R £, and 30 n is as defined above.

* »28

Another group of compounds of the invention comprises the compounds of formula Ica 0ca JL (Ica) R3 ^ llV ^ N02 rrR4

H

Wherein R2, R4 and X are as defined above and Rca represents hydrogen or a nitro group; trifluoromethyl; cyano; -C00R ^ a; or -C0Rj * a, in which

Rca represents hydrogen or a 5-membered heteroaryl residue containing a heteroatom chosen from nitrogen, oxygen and sulfur or 2 heteroatoms of which one is nitrogen and the other is nitrogen, the oxygen or sulfur, and RCa with the exception of hydrogen has the meaning given above for R ^ a.

Another group of compounds of the invention comprises the compounds of formula Id gd R3 25. Jl JL. (Id) pd Rd K2 "'K4

Rd in which R ^ to and Qd have the meanings indicated above respectively for R1 to R4 and Q, the substituents in positions 2 and 6 and / or 3 and 5 of the 1,4-dihydropyridinyl radical must be different, 29 "r and their ammonium salts in which R | j is chosen from one of the tertiary amino groups defined above for and quaternized by a group of formula AlkY in which Alk represents a C1-C4 alkyl group and Y represents the remainder of an acid.

Another group of compounds of the invention comprises the compounds of formula K1 in which a R | and Qe have the meanings indicated above respectively for R] to R4 and Q, the substituents in positions 2 and 6 and / or 3 and 5 of the 1,4-dihydropyridinyl radical must be different, and their ammonium salts in which R | is chosen from one of the tertiary amino groups defined above for R | and quaternized by a group of formula AlkY in which Alk represents a (4-C4) alkyl group and Y represents the remainder of an acid.

In subgroups of compounds of formula Id and Ia and their corresponding ammonium salts, the substituents have the meanings indicated above respectively for the compounds of formula Ia, Iaa, Iaaa, Ib, Iba, Ibaa, le and Ica.

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

30 R500C

h3c ^ Î ^ c «3

H

30 in which -C00RJ? represents an ester group.

Other groups of compounds of the invention include the compounds of formula Ip in which RJ3 signifies respectively: a) a C4-C6 cycloalkyl group, b) a C1-C12 alkyl or C1-C10 alkoxyalkyl group in the remains alkoxy and C2-C11 in the alkylene residue, the alkoxy residue being separated from the group to which Rj? is linked by at least 2 carbon atoms, the alkoxy and alkylene radicals must in total contain less than 13 carbon atoms, and c) a group -APNRjjRlj ^; or -APN B) P; in which R ^ represents hydrogen; a C1-C4 alkyl group; phenyl, C7-C10 phenylalkyl or C13-CI6 bisphenylalkyl "the last three substituents optionally carrying in the 15 or the phenyl rings one, or independently two, or independently three substituents chosen from C1-C4 alkyl, alkoxy groups in C1-C4 and hydroxy and the halogens having an atomic number of 9 to 53, RJg represents hydrogen or a C1-C4 alkyl group, 20 -l | S) P represents a saturated heterocycle with 5, 6 or 7 members which may optionally contain, when it has 6 or 7 members, another heteroatom chosen from oxygen, sulfur and = NR ^ 2> in which RÇ2 has the meaning indicated above for R ^, and 25 AP represents a C2-C12 straight chain alkylene group separating the group to which RJ? is linked by at least 2 carbon atoms.

\ v 31

In a subgroup of group a) of the compounds of formula Ip, R 2 represents a cyclopentyl or cyclohexyl group. In a subgroup of group b) of compounds of formula Ip, R |? represents a C1-C5 alkyl group. Another group of compounds of the invention comprises the compounds of formula Is 10 S (Is) 3 YV®! rsxAnJ <rs 2 fi 4 15 in which X is as defined above, RS and RS each represent, independently of one another, a C1-C4 alkyl group and RS represents hydrogen or a nitro group, trifluoromethyl; cyano; -C00R |; or -C0R |; in which 20 R | represents hydrogen; a C1-C12 alkyl group; hydroxy-C2-C6 alkyl in which hydroxy is separated from the group to which R | is linked by at least 2 carbon atoms; -AsNR | R | q; or -AsN ^ B / is; in which RS and R | q each represent, independently of one another, hydrogen; a C1-C4 alkyl group; C7-C10 phenylalkyl optionally carrying in the phenyl ring one or independently two substituents chosen from C1-C4 alkoxy groups and halogens having an atomic number of 9 to 53, 30 - | {jb) s represents a group pi per di nyl e or piperazinyl both optionally substituted in position 4 * 32 "- by a methyl, benzyl or bis-phenylmethyl group, the last two substituents optionally carrying in the ΐ or phenyl rings one, or independently two substituents chosen from the groups C1-C4 alkoxy and _ 5 halogens having an atomic number of 9 to 53, and

As represents a C2-C14 alkylene group separating the group to which RJ is linked by at least 2 carbon atoms, RJ represents an imidazolyl group, 10 and their ammonium salts in which RJ is chosen from one of the tertiary amino groups defined above for RJ and quaternized by a group of formula AlkY in which Alk represents a (C 4 -C 4) alkyl group and Y represents the remainder of an acid.

Other groups of compounds of the invention are those of formula I "la, Iaa, Iaaa, Ib, Iba, Ibaa, le, Ica, Id, le and Is in which, R3, RJ, RJa, RJaa, Rj , Rja, Rbja, RJ,

Rja, Rj, RJ and RJ are respectively ester groups as defined above under the corresponding formulas, and as the case may be their corresponding ammonium salts as defined above.

Other groups of compounds of the invention are the compounds of formula la, Iaa, Iaaa, Ib, Iba, Ibaa, le, Ica and Is in which X represents sulfur and, where appropriate, their corresponding ammonium salts as defined upper.

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

a) condensing, in an appropriate manner to form a 1,4-dihydro-pyridine, a corresponding compound of formula II

30 ? (II)

CHO

v> 33 - in which Q is as defined above,

a corresponding compound of formula III

(III) 5 R2 ^ Sû

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

10 ^ n02 Γ (IV) in which R4 is as defined above,

15 and a corresponding compound of formula V

y (v) R1 20 in which Ri is as defined above, or a partial condensation product of these compounds, or b) for the preparation of a compound of formula Γ "Λ” '<· k 4 K1 in which Ri, R2, R4 and Q are as defined above and R'3 represents hydrogen, -COOR5 or -CORß in which R5 and 30 Rß are as defined above, 9 34 - a compound is suitably transformed correspondent of

formula VI

AL (VI) R1 in which R] _, R2, R4 and Q are as defined above and X 10 is a reactive group.

The process of the invention can be carried out analogously to known processes.

The choice of the most suitable variant of the process naturally depends on the nature, for example, of 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 advantageously be carried out in solution. A suitable solvent is water, ethanol, dioxane, dimethylformamide, dimethylsulfoxide, pyridine or glacial acetic acid.

Suitable reaction temperatures are between 20 and 160 ° C, preferably between 60 and 120 ° C.

Variant b) of the process can also be carried out according to the usual methods. The choice of the most suitable variant of the process naturally depends first of all on the nature of the R13 groups. When R'3 represents hydrogen, X can then represent for example a carboxy group and the transformation reaction is a decarboxylation. When R'3 represents a -CORö group, X can then represent for example a carboxy group and the transformation reaction is then a substitution. When R13 represents a carboxy group, X can then represent, for example, an easily cleavable ester group f? 35 such as an ammonium salt and the transformation reaction is then a hydrolysis.

When R'3 represents an ester group, X can then represent, for example, a group -COX 'in which X1 represents a reactive group suitable for the preparation of an ester.

The ester-producing transformation can be, for example, an esterification reaction. X 'is then advantageously an 1H-imidazole-1-yl group. This variant of the process is indicated, for example, for conversion to an unsubstituted or substituted hydroxyalkyl, amidoalkyl, alkoxyalkyl, acyloxyalkyl or aminoalkyl ester. A corresponding compound of formula VI in which X represents for example a 1H-imidazole-1-yl-carbonyl group is thus reacted with a corresponding diol, amido-alcohol, ester-alcohol or amino-alcohol. As solvent, it is advantageous to use dioxane or an excess of one of the products participating in the reaction. Another transformation producing an ester can be for example an amination. This variant is indicated, for example, for the transformation into an aminoalkyl ester. A reactive group X is then advantageously for example a group -C00AX "in which A is as defined above and X" signifies chlorine, bromine or a group Rz-SO2-0- in which Rz signifies a phenyl group, tolyl or lower alkyl. X "preferably signifies a mesyloxy group. The amination can be direct, that is to say that the reaction takes place directly with an amine comprising the substituent to be introduced, or indirect, for example for the introduction of a primary amino group, first transforming the compound into the corresponding phthalimidoalkyl derivative, for example by reaction with sodium or potassium phthalimide, and then reacting the resulting phthaliminoalkyl derivative with hydrazine. The indirect method is preferred when the substituent which it is desired to introduce 36 "is a primary aminoalkyl group. Another transformation producing an ester can 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 can be, for example, the acylation of an alcohol. A reactive group X is then advantageously the corresponding hydroxyalkoxycarbonyl group. A corresponding compound of 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-ethyl-diisopropylamine. Mention may be made, as suitable solvent, for example, of methylene chloride. Another transformation producing an ester can be, for example, etherification. A reactive group X is then advantageously a group -C00AX “in which A and X" are as defined above. The reaction is preferably carried out under strongly alkaline conditions.

The quaternary ammonium salts can also be prepared analogously to the known methods, for example by reaction with a 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 the 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 in the form of a benzyloxy group. , or for an aliphatic hydroxy group in the form of a tetrahydro-pyrannyloxy residue, or for an amino group in the form of an acylamino or phthalimino group, and then transform any protected group present into the desired substituent, for example the benzyloxy group in hydroxy group, for example by hydrogenolysis, tetrahydropyrannyloxy group in hydroxy group, for example by acid hydrolysis, and an unprotected friend group. 5 in non-free friend group, for example by acid hydrolysis or hydrazinolysis.

The compounds of the invention can be isolated from the reaction mixture and purified in a manner analogous to the 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 can exist as salts, for example when an ionizable substituent is present such as an amino group or a phenolic hydroxy group. The compounds in free form can be converted into salts according to the usual methods and vice versa. Acids suitable for the formation of acid addition salts include T hydrochloric acid, malonic acid, T p-toluene sulfonic acid and T methane-20 sulfonic acid. As suitable bases for the formation of anionic salts, mention may be made of 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 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 than the remainder dimethylaminoethoxycarbonyl.

b 38 * When the preparation of a starting product is not described, it will be a known compound or 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. In these examples the temperatures are indicated in degrees Celsius and are not corrected. Example 1: Ethyl ester of 4- (2,1,3-benzoxacHazole-4-yl) - 1,4-dihydro-2,6-dimethyl-5-nitro-pyridine-3-carboxylic acid 10 [Variant a ) 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] 3.5 g of 1- (2,1,3-benzoxadiazole-4- are heated at reflux for 6 hours yl) -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 the product is chromatographed on silica gel using a methylene chloride / ether mixture as eluent. The title compound is obtained (F = 197 ° in ether).

The starting material is obtained by heating at reflux 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 acetic acid in 700 ml of benzene. After further purification by chromatography on silica gel using methylene chloride as eluent, l- (2,1,3-benzoxadiazole-4-yl) -2-nitro-1-butene-3-one (F = 105e in ether).

39 (Λ £ ν

-P

c fÖ <Λ r->

· .- <D

-P -P +

= 3 1X3 I

-P ^ Oü C + \ Q) l-H -f Φ 4 * (J »—i + (0 NH c—> \ CU I — I O --- ^ N-1

“Ο I — H * —I -P t-H t-H

\ φ H-H> - »\ φ QJ I — I HH

CJ H ~ t Ol- NH

o - + ">, - + Ο. W a> i — i 4- 4-> CU i — i Ε i— · Η-1 \ 0 i— I — i 3 3> 5 Ό CD -E;> Ό J = i— + -> OJ η- I + -> 0)> 10 d— 0 10 r— (0 3 - >> + P - >>

O Ό .Ε 10 Ό £ Z

0 + -> <—i C p P 10 0 10 I — IO 0 10 E 3 + -> - - <PP - fO CT ιΟ Ό O 10 Ό • r- · γ- + -> 0 E p E Ό 10 0 CO t0 0

10 Ε E OP O O UP

> ο · γ- <o ro i c ra ro • f- ο ο oo · ι- ο o

10 P 0 PC I E P C

i— 10 E 10 10 0 10 '0 10 in E O O. C I U Q_

ECO 0 O / 0 00 ro O

O 0 O E P E

ι— Ό +0.3 + + 0.

0 C I _Q I

(ΛΟ0 ·> - 'CM I «- ·" -> CVJ

Ol l-ι I | I — I I — 1 | 3 3 i — i. I i — i t — i .— C IO E —h r— O --- ι- Ο r— E>, E >>

P O 0 I P 0 0 I

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in Ό Ό O I ^ Ό Ό O

in V) r— N “-”> i— ι— + N> 3-M w ro o ro oi— -—- ro ro ro i — i 10 E '0 -O 10 -r- (O >> JE -QP * t- --- id in Ε * ι— Ό * / “IE Eh-ι Ό

p> o— 'rocrocro-oro ro —-roo I

W -r- Q.E ooxoiroo o Xe I

03 EO ΙΕΟΕ0 · 1-Ι 100/0 ui o-i- ro · ε n E i— c ro- ro- c n o.

t— o p irocroooi i / o Eo

m - ro 0 0 niE0 0Q.0E

OP in i— + JE + 10Ei— i— 0-0 0.

| - c -PC o I · Γ- ro o> ο E I | 0.10 E 0 N -— ”OO '—- Ό Ni — ι N Q. 00 ι— Ε ό ΐΟΌ ro>» >> ro + ro -—- ro ι “i 0 C O. E” 1— H-1 1— HH X · (- 'I— I- | - o XO 10 O Ό --- H --- O Ό 0 Ό I «<Ε 0 o_ ό o ro oo NH-irocroocro-p

“In X 0 '- 0 C η-ι X Ο X E --- τι— 0 00 OCIC0H-lO-POPlE

Ε Ό Ό NOOOOJE '- N 10 N -1- OO I

0 E E P I P I c ο c c ι γ- Ό o inin 0i0i— i0OO00ro0ii— ι O -P-P GAME>, 0 * ι— JD OJE, -> -) o

0 -Ι-T- J ro P ro r—> 5 I Ε I I P £ T

E + J 33 OOO10O *> -E CO P 00 Ο 10 -r- P Ε ΌΌ Λ Ε Ο E CM -P ”-i- - EO £ • i — ro oo ι— Pro-p * - · 10 ι— cr— ro ro

Po. EE »T- l ·! - I - H *> £ 11

'0 D-O. CMECVICi— OOJ + CSlfOCNOJ

3 Ό Ό _____-........... - "<u 0 10 Ό H“ in o.

Ο in E

Q. P 0 0

E -r- Ό X

0 3 0

Ο Ό O

O El— 00 00 ro- LT) Ό Oh 0 E __________ —J Q.

40 · * Example 8: Ethyl ester of 4- (2, l, 3-benzoxadiazole-4-yl) - l, 4-dihydro-2,6-dimeth.yl-5-nitro-pyridine-3- acid carboxylic [Variant b) of the process; transformation of imidazolide] A mixture of 1.5 g of 4- (2,1,3-benzoxadiazole-4-yl) -1,4-dihydro-3- (1H) is boiled for 8 hours -imidazole-1-yl-carbonyl) -2,6-dimethyl-5-nitropyridine and 30 ml of ethanol. The mixture is evaporated to dryness, the residue is chromatographed on silica gel using ether as an eluent. The title compound is obtained (F = 195 ° in ether).

/ ------ ------ - -. ----. __ 0 --- 41 * -P m 0 0 "JL ° ° ® i- Ü" a "cü ο Ό r" LO LO CO Q, r— - __ _

, 5t * 3- "o o r-. cm 5-7 a q. q. i T

a - - ^ - 0 - u vT 10 ri.

ai U. ns § §

Ό "J" J

-pcccc: .c je 3 • g ^ c υ o "* - c -σ -------" '- "" "-" ................ i ...

0 1

N / A

Q- C i- aj -a 01 >> ω c 3 £ τι o -a · <- • r · -a i ~ -M "d- I 0) • r— CO" vf r— ^

S- 3 O r— C l / l CO CO OO (/ i LO CO CO CO CO

rü CTI * 1— · 1— mm m m Λ mm m mm

Q. · £ -P OJTJ OC Q £ OC OC £ χ Q £ OC QC CK OC

110 E ΙΛ 1/1 S.

O O CU>, ai u aca 3 -Mil — llll -------- - -............

DI <Ü Ο Σ · - * t ωωαιαίΛία) «« a> gûi Σ Σ Σ Σ g r Σ Σ ^ CM Σ ίο .e a.

ai x

J- CM O

'01 Μ -. I

CQ CM

Ç CM CM 0) <U X

“CO ω φ Σ s: _ ^ 0 LJ _ E x X 2Ë z z -— '• r zr x aj SL z ο o JL <u ο oo

-O -C '^ LT

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The compounds of the invention are distinguished by interesting pharmacological properties and can therefore be used therapeutically 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 evident from vasodilation and the drop in blood pressure in conventional tests. Thus, for example, in the microsphere test carried out in the anesthetized cat according to the method described by R. Hof et al 1., in Basic Res. Cardiol 75_, 747-756 (1980) and 76 630-638 (1981) and by R. Hof et al !. in 0. Cardiovasc. Pharmacol. £, 352-362 (1982), dilation of the coronary vessels, increased blood flow in skeletal muscles and decreased blood pressure is observed after administration of the compounds of the invention intravenously at doses included between about 30 and 1000 pg / kg, for example from about 100 to about 500 pg / kg.

A drop in blood pressure is also observed in the spontaneously hypertensive awake rat according to the method described by Gerold and Tschirki in Arzneimittelforsch. 18, 1285 (1968), after administration of the compounds of the invention by the oral route at doses of between approximately 1 and approximately 10 mg / kg.

Thanks to these properties, the compounds of the invention can be used therapeutically as calcium antagonists for the prevention and treatment of - coronary insufficiencies, for example angina pectoris, - other peripheral circulation disorders, 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, „- heart failure, for example ischemic heart attack.

The compounds of the invention also exert a vasodilatory 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 associated therewith. Thanks to this property, the compounds of the invention can be used in therapy for the prophylaxis and treatment of migraines and vascular headaches such as cluster headaches, especially for the therapeutic interval treatment (prevention) of the migraine.

4 10 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 on peripheral blood vessels.

In addition, the compounds exert very low negative inotropic activity. They are therefore not cardiodepressive and even exert a certain cardiostimulatory 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 in those who have had a heart attack.

In these asymmetrically substituted compounds in position 4 of the 1,4-dihydropyridinyl residue, this absence of cardiodepression can appear to varying degrees in either of the enantiomeric forms.

For the therapeutic uses indicated above, the compounds of the invention will be administered at a daily dose of between approximately 10 mg and approximately 1600 mg, advantageously administered, for example by the oral route, in divided doses 1 to 3 times per day. as unit doses each comprising between about 2.5 mg and about 800 mg of active substance, or in a delayed release form.

50 ^ Preferred indications are coronary and heart failure, in particular ischemic heart attack.

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 use as a calcium antagonist.

The invention also includes 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 form or optionally in the form of a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable diluent or vehicle . Such pharmaceutical compositions, which also form part of the present invention, can be prepared according to the usual methods and can be presented, for example, in the form of tablets for oral administration or in the form of oral tablets for sublingual administration, or as injectables or suspensions for parenteral administration. Sublingual administration is preferred.

** »

Claims (19)

51 1. The 1,4-dihydropyridines of formula IQ β3ηΛ-Ν0 * (η ri ig in which R1 represents hydrogen, a C3-C7 cycloalkyl group or an optionally substituted C1-Cß alkyl group, R2 and R4 each represent independently of one another, hydrogen or a C1-C6 alkyl group, R3 represents hydrogen, a C1-C25 alkyl group "nitro, tri-fluoromethyl, cyano, -COOR5, -CORe or -S (0) nR7 "in which -COOR5 represents a carboxyl group or an ester group, v Rß represents a C1-C25 alkyl group; hydroxy-C2-C24 alkyl in which the hydroxy is separated from the group to which Rç is linked by at least 2 carbon atoms; C1-C24 alkoxyalkyl in the alkoxy radical and in C2-C24 alkylene in the alkylene radical, the alkoxy radical being separated from the group to which Rß is linked by at least 2 carbon atoms; C3- alkenyl C25 in which the double bond is separated from the group to which Rβ is linked by at least 1 carbon atom not forming part of the double bond; alkyny C3-C25 in which the triple bond is separated 52 from the group to which Rg is linked by at least 1 carbon atom not forming part of the triple bond; C3-C7 cycloalkyl; ^ C3-C7 cycloalkylalkyl in the cycloalkyl radical and C1-C24 in the alkylene residue; C2-C24 hydroxyalkoxyalkyl in the 1 5 hydroxyalkoxy residue and C2-C24 in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which Rg is linked by at least 2 carbon atoms and the hydroxy being separated from the atom d oxygen of the alkoxy residue with at least 2 carbon atoms; phenyl; C7-C30 phenylalkyl or C13-C36 bis-phenylalkyl, the last three substituents possibly optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C1-C4 alkyl, alkoxy C1-C4 and hydroxy and halogens having an atomic number of 9 to 53; a 5 15-membered heteroaryl radical with 1 heteroatom chosen from nitrogen, oxygen and sulfur or two heteroatoms of which one is nitrogen and the other is nitrogen, oxygen or sulfur, or a 6-membered heteroaryl radical having from 1 to 4 nitrogen atoms, the last two substituents being optionally linked to the remainder of molecule 20 via a C1-C24 alkylene residue; or a residue of formula -AOCORs ; -ANR9R10; or -In which R8 represents a C1-C25 alkyl group; phenyl, C7-C30 phenylalkyl or C13-C36 bis-phenylalkyl "the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C1-C4 alkyl, alkoxy groups C1-C4 and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl radical with a heteroatom chosen 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 Rsest 53 is linked by at least 2 carbon atoms; alkoxyalkyl (4-C24 in the alkoxy residue and C2-C24 in the alkylene residue, the remainder \ alkoxy being separated from the group to which Rg is linked by at least 2 carbon atoms; alkenyl C3-C25 in which the double 5 bond is separated from the group to which Rß is linked by at least 1 carbon atom not forming part of the double bond; C 3 -C 25 alkynyl in which the triple bond is separated from the group to which Rß is linked by at least 1 carbon atom not part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl and C1-C24 in the alkylene residue; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy and C2-C24 in the alkylene residue, the hydroxyalkoxy residue being separated from the group to which Rβ is bonded 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; -C24 in which the nitrogen atom is separated from the group to which Rg is linked by at least 2 carbon atoms and the friendly residue no optionally carries one or independently two substituents chosen from C1-C6 alkyl, phenyl, C7-C12 phenylalkyl or C13-C18 bis-phenylalkyl, the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen 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 above for Rg, RjO represents hydrogen or has the meaning indicated above for Rg or represents -COR3.1 in which Ru has the meaning indicated above for Rß, 54 -NjT ) represents a 5, 6 or 7-membered saturated heterocycle which may optionally contain, when it is 6 or 7-membered, another ^ other heteroatom chosen from oxygen, sulfur and = NR ^ 2 in which 5 R12 represents hydrogen or has the meaning indicated above for Rs and A represents a C2-C24 alkylene group separating the group to which Rß is linked by at least 2 carbon atoms, R7 has the meaning indicated above for Rß, 10. means 0, 1 or 2, Q represents 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, in which R3 is chosen from one tertiary friend groups defined above for R3 and quaternized by a group of formula AlkY where Alk signifies a C1-C4 alkyl group and Y the remainder of an acid. 2. The 1,4-dihydropyridines of formula la R \ ^ "20 R3 \ ^ V", Y (T 2 Ia 25 R2 f. "4 Rî in which Rg and R4 are as defined in claim 1, Rj * represents hydrogen; a C1-C6alkyl C3-C6 alkenyl group in which the double bond is separated from the nitrogen atom by at least 1 carbon atom not being part of the double bond; C3-C6 alkynyl in which the triple bond is separated from the nitrogen atom by at least 1 carbon atom not forming part of the triple bond; cycloalkyl 55 ~ C3-C7; C4-C8 cycloalkylalkyl; C2-C6 hydroxyalkyl in which the hydroxy is separated from the nitrogen atom by at least 2; carbon atoms; C2-C6 alkoxyalkyl; or C7-C9 phenylalkyl or C9-C12 phenylalkenyl in which the double bond f 5 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 chosen independently from (4-C4 alkyl, C1-C4 alkoxy and hydroxy groups and halogens having an atomic number of 9 to 35; C2-C6 alkylcarbonyl-oxyalkyl in alkylcarbonyl and alkylene radicals and in which the oxygen atom is separated from the nitrogen atom by at least 2 carbon atoms; independently C1-C6 dialkylaminoalkyl in the alkyl radicals and in C2-C6 in the balance alkylene and in which the friend group no is separated from the nitrogen atom by at least 2 carbon atoms; or C2-C6 morpholinoalkyl in the alkylene residue and in which the morpholino residue is separated from the nitrogen atom by at least 2 carbon atoms, 20 R | represents hydrogen; a Ο ^ -Οβ alkyl group; nitro; tri-fluoromethyl; cyano; -C00R £; -CORg; or -S (0) nR ^; in which R | represents hydrogen; a (4-C6) alkyl; C2-C6 hydroxyalkyl in which the hydroxy is separated from the group to which R | is linked by at least 2 carbon atoms; C1-C6 alkoxyalkyl in the alkoxy and C2- C6 in the alkylene residue, the alkoxy residue being separated from the group to which R | is linked by at least 2 carbon atoms; C3-C6 alkenyl in which the double bond is separated from the group to which R | is linked by at least one atom of carbon 30 not forming part of the double bond; C 3 -C 6 alkynyl in which the triple bond is separated from the group to which R 1 is linked by at least 1 carbon atom not forming part of the triple bond; cycloalkyl in C3-C7; C3-C7 cycloalkylalkyl in the cycloalkyl and C1-C6 alkyl 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 R | is linked by at least 2 carbon atoms and the hydroxy being separated from the oxygen atom the remainder alkoxy with at least 2 carbon atoms; phenyl, phenyl C7-C12 or bis-phenylalkyl C13-C18 "the last three substituents optionally carrying-10 in the ring (s) phenyl one, or independently and two, or independently three substituents chosen from alkyl groups C1-C4 , C1-C4 alkoxy and hydroxy and halogens having an atomic number of 9 to 53; a 5-membered heteroaryl radical comprising a heteroatom chosen from nitrogen, oxygen and sulfur or 2 heteroatoms of which one is nitrogen and the other is nitrogen, oxygen or sulfur, or a 6-membered heteroaryl radical containing 1 to 4 nitrogen atoms, the last two substituents being i optionally linked to the rest of the molecule via a Οχ-Οβ alkylene residue; -Aa0C0R |; -AaNRaRaQ; or Aa ^ a; in which represents a C 1 -C 6 alkyl group; phenyl, C7-C12 phenylalkyl or C13-C18 bis-phenylalkyl, the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C1-C4 alkyl, alkoxy groups in (4-C4 and hydroxy and the halogens having an atomic number of 9 to 53; a 5-membered heteroaryl residue comprising a heteroatom chosen from nitrogen, oxygen and ... sulfur or 2 heteroatoms including one is nitrogen and the other is nitrogen, oxygen or sulfur, or a 6-membered heteroaryl residue having 1 to 4 nitrogen atoms; C2-C6 hydroxyalkyl 57 ** in which hydroxy is separated of the group to which R | is linked by at least 2 carbon atoms; alkoxyalkyl s, C1-C6 in the alkoxy residue and C2-C6 in the alkylene residue, the alkoxy residue being separated from the group to which F 5 R ^ is linked by at least 2 carbon atoms; C3-C6 alkenyl in which the double bond is separated from the group to which R | is bound by at least 1 carbon atom not forming part of the double bond; C3-C6 alkynyl in which the triple bond is separated from the group to which R | is linked by at least 1 carbon atom not being part of the triple bond; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl and C1-C6 alkyl in the alkylene residue; C 6 -C 6 hydroxyalkoxyalkyl in the hydroxy-alkoxy residue and C 2 -C 6 in the alkylene residue, the hydroxy-alkoxy residue being separated from the group to which R | is linked by at least 2 carbon atoms and Hydroxy being separated from the oxygen atom of the alkoxy residue by at least 2 carbon atoms; C2-C6 aminoalkyl in which the nitrogen atom is separated from the group to which R £ is linked by at least 2 carbon atoms and the friendly moiety optionally carries one or independently two substituents selected from alkyl groups C1-C6, phenyl, phenylalkyl in C7-C12 and bis-phenylalkyl in C13-C18 "the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen among the alkyl groups in ( 4-C4, C1-C4 alkoxy, hydroxy and halogens having an atomic number of 9 to 53, R | represents hydrogen or has the meaning indicated above for R |, 30 RJo represents hydrogen or has the meaning indicated above for Rg or represents -CORj ^ in which Rj ^ has the meaning indicated above for Râ, * NO 58 -NJi) a represents a saturated heterocycle at 5, 6 or 7 chain links which may optionally contain, when it is 6 or 7 \ chain links, another heteroatom chosen from oxygen, sulfur and NR ^ in which Rj ^ represents hydrogen 5 or has the meaning indicated above for R | , and Aa represents a C2-C6 alkylene group separating the group to which R | is bound by at least 2 carbon atoms, R | and R ^, with the exception of hydrogen, have the meaning indicated above for R |, and 10 n is as defined in claim 1, X represents oxygen or sulfur and R represents hydrogen, halogen having an atomic number of 9 to 35 or a C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfonyl, trifluoromethyl, nitro or 15 hydroxy, and their ammonium salts in which R | is chosen from one of the tertiary friend groups defined above for R | and quaternized by a group of formula AlkY in which Alk represents a C1-C4 alkyl group and Y represents the remainder of an acid. 3. The 1,4-dihydropyridines of formula Ib R3 Nj ^ Sj ^ N02 R2 ü "" 4 in which R2 and R4 are as defined in claim!, R, R | 33 and X are as defined in claim 2, and l represents hydrogen or a C7-C25 alkyl group; nitro; tri-fluoromethyl; cyano; -COORj ?; -CORj ?; or -S (0) nR ^; in 59 # which Rb represents l hydrogen; a C7-C25 alkyl group; hydroxy- C7-C24 alkyl in which the hydroxy is separated from the group to which Rj? is linked by at least 2 carbon atoms;> 5 C1-C24 alkoxyalkyl in the alkoxy and C2-C24 radicals in the alkylene radical, the alkoxy radical being separated from the group to which Rj? is linked by at least 2 carbon atoms, at least one of the alkoxy and / or alkylene radicals must have at least 7 carbon atoms ; C7-C25 alkenyl in which the double bond is separated from the group to which Rj? is linked by at least 1 carbon atom not forming part of the double bond; C7-C25 alkynyl in which the triple bond we are separated from the group to which Rj? 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 C7-C24 alkyl 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 R 1? 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, at least one of the hydroxyalkoxy and / or alkylene radicals having to have at least 7 atoms carbon; phenyl, phenyl C1-C30 or bis-25 phenylalkyl (49-C36, the last three substituents optionally carrying in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C1-C4 alkyl groups, C1-C4 alkoxy and hydroxy and the halogens having an atomic number of 9 to 30 53; a 5-membered heteroaryl radical containing 1 heteroatom chosen 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 1 to 4 nitrogen atoms, the last two 35 substituents being optionally linked to the rest of the% 60 _ molecule via an alkylene residue in 07-024; -A ^ OCOR ^; -aNr ^ R ^ qî or -Α ^ Γβ) * 3; in which T. Rjj represents a (C-C25) alkyl group with the condition> that it is in C7-C25 when $ contains less than 7 carbon atoms> 5; phenyl, phenylalkyl in C7-C30 with the condition that it is in (43-C30 when A13 contains less than 7 carbon atoms, or bis-phenylalkyl in C13-C36 with the condition that it is in (49-036 when A & contains less than 7 carbon atoms, the last three substituents optionally carrying 10 in the phenyl ring (s) one, or independently two, or independently three substituents chosen from (4-C4 alkyl, C1-C4 alkoxy, and hydroxy and halogens having an atomic number of 9 a 53; a 5-membered heteroaryl radical containing 1 heteroatom chosen from nitrogen, oxygen or sulfur or 2 hetero atoms, one of which is nitrogen and the other of which is oxygen or sulfur, or a 6-membered heteroaryl radical containing 1 to 4 nitrogen atoms; C2-C24 hydroxyalkyl in which the hydroxy is separated from the g group to which is linked by at least 2 carbon atoms, with the condition that it is in C7-C24 when βP contains less than 7 carbon atoms; C1-C24 alkoxyalkyl in the alkoxy residue and C2-C24 alkoxy in the alkylene residue, the alkoxy residue being separated from the group to which Rjj is linked by at least 2 carbon atoms, with the proviso that when A & contains less than 7 atoms carbon at least one of the alkoxy and / or alkylene radicals contains at least 7 carbon atoms; C3-C25 alkenyl in which the double bond is separated from the group to which Rj3 is linked by at least 1 carbon atom not forming part of the double bond, with the proviso that it is C7-C25 when Pfi contains less 7 carbon atoms; ^ C3-C25 alkynyl in which the triple bond is separated from the group to which Rjjj is linked by at least 1 carbon atom not forming part of the triple bond, with / 61 - provided that it is C7-C25 when Ab contains less than 7 carbon atoms; C3-C7 cycloalkyl; C3-C7 cycloalkylalkyl in the cycloalkyl radical and C1-C24 in the alkylene residue, with the proviso that it is C7-C24 in ^ the alkylene residue when Ab contains less than 7 carbon atoms; C2-C24 hydroxyalkoxyalkyl in the hydroxyalkoxy residue and C2-C24 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 atom oxygen of the alkoxy residue by at least 2 carbon atoms, with the condition 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 condition that it is C7-C24 when Ab contains less than 7 carbon atoms, in which the nitrogen atom is separated from the group to which Rb is linked by at least 2 carbon atoms and the remainder friend optionally carries one or independently two substituents chosen from C 1 -C 6 alkyl, phenyl, C 7 -C 12 phenylalkyl and C 13 -C 18 bis-phenylalkyl, the last three substituents optionally bearing-1 Lement in the phenyl ring (s) one, or independently two, or independently three substituents chosen from C1-C4 alkyl, C1-C4 alkoxy and hydroxy and the halogens having an atomic number from 9 to 53, R ^ represents hydrogen or has the meaning indicated above for Rj, Rj> 0 represents hydrogen or has the meaning indicated above for R ^ or represents a group -CORjj ^ in which Rfj has U meaning indicated above for R ^ , 62 w represents a 5, 6 or 7-membered saturated heterocycle s which may possibly contain, when it is 6 or 7 ^ members, another heteroatom chosen from oxygen, the? sulfur and NRj> 2 in which Rj2 represents hydrogen f? 5 or has the meaning indicated above for R ^, and Ab represents a C2-C24 alkylene group separating the group to which Rj? is linked by at least 2 carbon atoms, Rjî and Riÿ, with the exception of hydrogen, have the meaning indicated above for Rjî, and # 10 n is as defined in claim 1, and their salts ammonium in which R ^ is chosen from one of the tertiary amino groups defined above for Rb and quaternized with a group of formula AlkY in which Alk represents a C1-C4 alkyl group and Y represents the remainder of an acid. 4. The 1,4-dihydropyridines of formula le> 20 "'W Γ R * R4 K1 in which R £ and R ^ are as defined in claim 1, R, R | and X are as defined in claim 2, and R ^ represents hydrogen or a nitro group; trifluoromethyl; cyano; -COOR ^; -CORg; or - $ (0) nR ^; in which represents hydrogen; a C3-C7 cycloalkyl group; phenyl optionally carrying 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 chosen 63 "" from T nitrogen, oxygen and sulfur or 2 heteroatoms of which one is nitrogen and the other is nitrogen, oxygen or sulfur, or a heteroaryl residue a 6 links containing from 1 to 4 nitrogen atoms, w 5 RC and RÇ, with the exception of hydrogen, have the meaning indicated above for RJ, and n is as defined in the claim n 1. 5. The 1,4-dihydropyridines of formula Ip ^ γγ ™ (lp) H3C-AnAch H 15 in which -COOR ^ represents an ester group. 6. The 1,4-dihydropyridines of formula Is f 20 0s <is) 3 YV "° 2 Ü ** 25 wherein X is as defined in claim 2, R | and R | each represent, independently of one another, a C1-C4 alkyl group and RJ represents the hydrogen or a nitro or trifluoromethyl group; cyano; -C00RJ; or -C0RJ; in which 30 RJ represents hydrogen; a C1-C12 alkyl group; hydroxy- ^ C2-C6 alkyl in which the hydroxy is separated from the group to which RJ is linked by at least 2 carbon atoms; -ASNR | R | 0; or -AsNjj) s; in which 64 ^ R | and Rf0 each represent, independently of Tun from the other, hydrogen; a group C1-C4 alkyl; C7-C10 phenylalkyl optionally carrying in the phenyl ring one or independently two substituents chosen from C1-C4 alkoxy groups and halogens having an atomic number of 9 to 53, -N ^ b) s represents a piperidinyl or piperazinyl group both optionally substituted in position 4 by a methyl, benzyl or bis-phenylmethyl group, the last two • 10 bstituents optionally carrying in the phenyl ring (s) one, or independently two substituents chosen from C1-C4 alkoxy groups and halogens having an atomic number of 9 to 53, and As represents a C2-C14 alkylene group separating the group to which R | is bound by at least 2 carbon atoms, R | represents an imidazolyl group, and their ammonium salts in which is chosen from Tun tertiary amino groups defined above for R 1 and quaternized v. 20 by a group of formula AlkY in which Alk represents a (J 4 -C 4) alkyl group and Y represents the remainder of an acid. Γ 7. The 1,4-dihydropyridines according to any one of claims 1 to 6, in which the substituents in positions 2 and 6 and / or in positions 3 and 5 of the 1,4-dihydropyridine residue are different, in the form of racemates or of enantiomers. 8. (R, S) -, (+) (S) - and (-) (5) -4- (2,1,3-benzoxa-diazole-l-yl) -l, 4-dihydro -2,6-dimethyl-5-nitn> isopropyl piridine-3-carboxylate. 9. A 1,4-dihydropyridine according to any one of claims 1 to 8, in free form or in the form of a salt. A 65 ^ 10. A process for the preparation of a 1,4-dihydropyridine of formula I according to claim I, characterized in that ^ a) is condensed, suitably to form a 1,4-dihydro- J * pyridine, a corresponding compound of formula II 1. L in which Q is as defined in claim 1, a corresponding compound of formula III R3X ",, jL (iii) r2 ^ o wherein R2 and R3 are as defined in claim 1, 15 a corresponding compound of formula IV. No. 2 I (IV) (T ^ R4% 20 * in which R4 is as defined in claim 1, and a corresponding compound of formula V "2" (V) 25 * 1 in which Ri is as defined in claim 1, or a partial condensation product of these compounds, or b ) for the preparation of a compound of formula Γ »66; rfx “'“ ·. Jr, R2 ^ N '"x'R4' R, 5 in which R-]" R2, R4 and Q are as defined in claim 1 and R13 represents hydrogen, -COOR5 or -CORß in which R5 and Rß are as defined in claim 1, a corresponding compound of formula VI is appropriately transformed q * IV! <vi> R 2 fc, 4 in which Rj, R £, R4 and Q are as defined in claim 1 and X is a reactive group and, depending on the case, a resulting compound is recovered in which R3 is chosen from one of the tertiary amino groups defined in FIG. 1 - claim 1 for R3, in the form of a salt d quaternary ammonium with a compound of the formula AlkY in which Alk represents a C 1 -C 4 alkyl group and Y represents the remainder of an acid. 11. A 1,4-dihydropyridine according to any one of claims 1 to 8, in free form or in the form of a pharmaceutically acceptable salt, for use as a medicament. 12. A medicament, characterized in that it contains, as active principle, a 1,4-dihydropyridine according to any one of claims 1 to 8, in free form or in the form of a pharmaceutically acceptable salt. 13. A pharmaceutical composition, characterized in that it contains a 1,4-dihydropyridine according to any one of the 4? ta 67 claims 1 to 8, in free form or in the form of a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable diluent or vehicle. ~ 14. Products and processes in substance as above 5 described with reference to the examples cited. ►> "'N Λ C ~