WO1985001940A1 - Derives de 1,4-dihydropyridine, leur preparation et les compositions pharmaceutiques les contenant - Google Patents

Derives de 1,4-dihydropyridine, leur preparation et les compositions pharmaceutiques les contenant Download PDF

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Publication number
WO1985001940A1
WO1985001940A1 PCT/CH1984/000170 CH8400170W WO8501940A1 WO 1985001940 A1 WO1985001940 A1 WO 1985001940A1 CH 8400170 W CH8400170 W CH 8400170W WO 8501940 A1 WO8501940 A1 WO 8501940A1
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carbon atoms
group
separated
alkyl
alkoxy
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PCT/CH1984/000170
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German (de)
English (en)
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Arnold Vogel
Gerhard Bormann
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Sandoz Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to 1,4-dihydropyridine derivatives, their preparation and pharmaceutical preparations containing them.
  • the invention relates to the compounds of formula I.
  • R 1 is hydrogen; Cycloalkyl of 3 to 7 carbon atoms; or optionally substituted alkyl having 1 to 6 carbon atoms;
  • R 2 and R 4 are independently hydrogen or alkyl of 1 to 6 carbon atoms
  • R 3 means: hydrogen; Alkyl of 1 to 25 carbon atoms; Nitro; Trifluoromethyl; Cyan; -COOR 5 ; -COR 6 ; or -S (O) n R 7 ; wherein
  • -COOR 5 represents carboxyl or an ester group
  • R 6 means; Alkyl of 1 to 25 carbon atoms; Hydroxyalkyl of 2 to 24 carbon atoms, wherein the hydroxy portion is separated from the group to which R 6 is attached by at least 2 carbon atoms; Alkoxyalkyl with 1 to 24 carbon atoms in the alkoxy part and with 2 to 24
  • R 8 is bound by at least 2 carbon atoms
  • Alkoxyalkyl having 1 to 24 carbon atoms in the alkoxy part and having 2 to 24 carbon atoms in the alkylene part, the alkoxy part being separated from the group to which R 8 is bonded by at least 2 carbon atoms; Alkenyl having 3 to 25 carbon atoms, the double bond being separated from the group to which R 8 is bonded, by at least 1 carbon atom not involved in the double bond; Alkynyl of 3 to 25 carbon atoms.
  • triple bond is separated from the group to which R 8 is bonded by at least 1 carbon atom not involved in the triple bond; Cycloalkyl of 3 to 7 carbon atoms; Cycloalkylalkyl with 3 to 7 carbon atoms in the cycloalkyl part and with 1 to 24
  • R 9 represents hydrogen or has the meaning given above for R 8 ;
  • R 12 is either hydrogen or has the meaning given above for R 8 and
  • A represents alkylene of 2 to 24 carbon atoms, which separates the group to which R 6 is attached by at least 2 carbon atoms;
  • R 7 mutatis mutandis has the meaning given above for R 6 , n stands for 0, 1 or 2;
  • Q represents a fused, completely unsaturated ring system with at least 2 different ring heteroatoms in total and with an aromatic character; and their ammonium salts in which R 3 is one of the tertiary amino groups defined above for R 3 and is quaternized with a group of the formula alky, in which alk is alkyl having 1 to 4 carbon atoms and Y is the rest of an acid.
  • the compounds according to the invention are preferably in unquaternized form.
  • R 5 preferably has mutatis mutandis the meaning given above for R 6 .
  • R 1 is preferably hydrogen. If it is not hydrogen, it preferably has one of the meanings given for R 1 a , in particular unsubstituted alkyl, cycloalkylalkyl, optionally substituted phenylalkyl, alkoxyalkyl or morpholino; preferably unsubstituted alkyl or alkoxyalkyl; especially unsubstituted alkyl. If it means alkoxyalkyl, its alkoxy part is preferably separated from the nitrogen atom by at least 2 carbon atoms. R 2 and R 4 are preferably alkyl, especially methyl.
  • R 3 is preferably nitro, trifluoromethyl, -COOR 5 or -COR 6 , in particular -COOR 5 , R 5 and / or R 7 are preferably alkyl, hydroxyalkyl, alkoxyalkyl, -AOCOR 8 , -ANR 9 R 10 or -ANB , in particular -ANR 9 R 10 or -ANB.
  • R 6 preferably has the meaning given above for R 5 and / or R 7 or preferably represents a 5-membered heteroaryl radical with 2 nitrogen heteroatoms.
  • R 8 preferably denotes alkyl, or optionally substituted phenyl, phenylalkyl or bisphenylalkyl, in particular phenyl.
  • R 9 and R 10 are preferably represents hydrogen or alkyl or optionally substituted phenyl, phenylalkyl or bis-phenylalkyl, preferably either both R 9 and R 10 are hydrogen or one of R 9 and R 10 is alkyl and the other is alkyl, optionally substituted phenylalkyl or optionally substituted bis -phenylalkyl.
  • -NB preferably represents a 6-membered saturated heterocyclic ring which contains a further hetero member.
  • R 11 preferably represents alkyl, optionally substituted phenyl, optionally substituted phenylalkyl or optionally substituted bis-phenylalkyl,
  • R 12 preferably does not represent hydrogen, it preferably means alkyl, optionally substituted phenylalkyl or optionally substituted bis-phenylalkyl.
  • A preferably contains 2 carbon atoms or 7 to 24 carbon atoms, in particular 9 to 18 carbon atoms, in particular 9 to 14 carbon atoms, in particular 10 carbon atoms. It is preferably unbranched.
  • n is preferably the number 1 or 2.
  • Q preferably has at least 3 heteroatoms in total, in particular 3 heteroatoms. It is preferably a bicyclic system.
  • Preferred groups Q are 2,1,3-benzoxadiazolyl and 2,1,3-benzothiadiazolyl, in particular 2,1,3-benzoxadiazolyl.
  • the 1,4-dihydropyridinyl radical is preferably bound to this benzene ring component, preferably in a position of the benzene ring component which is adjacent to other ring components.
  • Alk preferably means methyl
  • Y preferably stands for the remainder of an inorganic acid, for example mesyl or halogen, in particular iodine.
  • Cycloalkyl with 3 to 7 carbon atoms preferably contains 3, 5 or 6, in particular 5 carbon atoms.
  • Optionally substituted alkyl with 1 to 6 carbon atoms preferably has with the exception of hydrogen one of the meanings given below for R a 1 , it stands in particular for methyl, alkyl having 1 to 5 carbon atoms preferably contains 1 to 4 carbon atoms, it means in particular methyl.
  • Alkyl with 1 to 25 carbon atoms preferably contains 1 to 6 carbon atoms, it then preferably means methyl, ethyl or isooropvl, or 9 to 19 carbon atoms; especially 9 to 19 carbon atoms, especially 10 carbon atoms.
  • Hydroxyalkyl with 2 to 24 carbon atoms preferably contains 2 to 6 or 9 to 18 carbon atoms, in particular 9 to 18 carbon atoms
  • alkoxyalkyl with 1 to 24 carbon atoms in the alkoxy part and with 2 to 24 carbon atoms in the alkylene part preferably contains 1 to 6 or 9 to 19, in particular 9 to 19 carbon atoms in the alkoxy part and preferably 2 to 6 or 9 to 18, in particular 9 to 18 carbon atoms in the alkylene part.
  • Alkenyl with 3 to 25 carbon atoms and / or alkynyl with 3 to 25 carbon atoms preferably contain 3 or 7 to 25 carbon atoms, in particular 9 to 18 carbon atoms.
  • Cycloalkyl with 3 to 7 carbon atoms and the cycloalkyl part of cycloalkylalkyl with 3 to 7 carbon atoms in the cycloalkyl part preferably contain 3, 5 or 6, in particular 5 or 6, carbon atoms.
  • the alkylene part of cycloalkylalkyl having 1 to 24 carbon atoms in the alkylene part preferably contains 1 carbon atom or 7 to 24, in particular 9 to 13 carbon atoms.
  • the hydroxyalkoxy part of hydroxyalkoxyalkyl having 2 to 24 carbon atoms in the hydroxyalkoxy part preferably contains 2
  • the alkylene part of hydroxyalkoxyalkyl having 2 to 24 carbon atoms in the alkylene part preferably contains 2 carbon atoms or 7 to 24, in particular 9 to 18 carbon atoms.
  • the alkylene part of phenylalkyl having 7 to 30 carbon atoms or bis-phenylalkyl having 13 to 36 carbon atoms preferably contains wise 1 or 2 carbon atoms or 7 to 24, especially 9 to 18 carbon atoms, alkyl with 1 to 4 carbon atoms and / or alkoxy with 1 to 4 carbon atoms preferably contain 1 or 2, in particular 1 carbon atom (s).
  • Halogen with an atomic number from 9 to 53 preferably represents fluorine or bromine, in particular bromine.
  • Halogen with an atomic number of 9 to 35 preferably means fluorine or chlorine, in particular fluorine.
  • a heteroaryl radical as defined above is preferably 5-membered, it preferably contains 1 or 2 nitrogen heteroatoms, in particular 2 and in particular means imidazolyl, in particular 1H-imidazol-1-yl, if it is 6-membered it preferably contains 1 or 2 nitrogen heteroatoms and means in particular pyridinyl.
  • the alkylene radical having 1 to 24 carbon atoms, which optionally connects a heteroaryl radical to the rest of the molecule, preferably contains 1 carbon atom or 7 to 24, in particular 9 to 18, carbon atoms.
  • the alkylene part of aminoalkyl having 2 to 24 carbon atoms preferably contains 2 carbon atoms or 7 to 24, in particular 9 to 18 carbon atoms.
  • the amino part of aminoalkyl is preferably substituted, in particular disubstituted.
  • Preferred substituents of the amino part of aminoalkyl are alkyl and / or optionally substituted phenylalkyl.
  • the amino part of aminoalkyl is preferably disubstituted by alkyl and optionally substituted phenylalkyl.
  • hydroxy portion of hydroxyalkyl and / or of hydroxyalkoxyalkyl and / or the amino portion of aminoalkyl are preferably attached to the most distant, end-chain carbon atom. If one Phenyl ring occurs in a substituent, it is preferably unsubstituted. If it is substituted, it is preferably monosubstituted, preferably in the para position. If it is disubstituted, it is preferably substituted in the ortho or meta and in the para position. If it is trisubstituted, it is preferably substituted in the meta, meta and para positions. Alkoxy and / or halogen are preferred substituents of a phenyl ring substituent.
  • a phenyl ring is polysubstituted, the substituents are preferably identical.
  • bis-phenylalkyl both phenyl rings are preferably attached to the same carbon atom.
  • Bis-phenylalkyl preferably means bis-phenylmethyl.
  • a group of compounds according to the invention consists of the compounds of the formula Ia
  • R a 1 means: hydrogen; Alkyl of 1 to 6 carbon atoms; Alkenyl having 3 to 6 carbon atoms, the double bond being separated from the nitrogen atom by at least 1 carbon atom not involved in the double bond; Alkynyl having 3 to 6 carbon atoms, the triple bond being separated from the nitrogen atom by at least 1 carbon atom not involved in the triple bond; Cycloalkyl of 3 to 7 carbon atoms; Cycloalkylalkyl of 4 to 8 carbon atoms; Hydroxyalkyl with 2 to 6 carbon atoms, the hydroxy part being separated from the nitrogen atom by at least 2 carbon atoms; Alkoxyalkyl of 2 to 6 carbon atoms; or phenylalkyl with 7 to 9 carbon atoms or phenylalkenyl with 9 to 12 carbon atoms, the double bond being separated from the nitrogen atom by at least 1 carbon atom not involved in the double bond, the latter two substituents optionally being mono- or identical or differently di- or identical or differently
  • R a5 means: hydrogen; Alkyl of 1 to 6 carbon atoms; Hydroxyalkyl with 2 to 6 carbon atoms, the hydroxy part being separated from the group to which R a 5 is bound by at least 2 carbon atoms; Alkoxyalkyl having 1 to 6 carbon atoms in the alkoxy part and having 2 to 6 carbon atoms in the alkylene part, the alkoxy part being separated from the group to which R a 5 is bonded by at least 2 carbon atoms;
  • the hydroxyalkoxy part is separated from the group to which R 8 a is bonded by at least 2 carbon atoms and the hydroxy part is separated from the oxygen atom of the alkoxy part by at least 2 carbon atoms; Aminoalkyl having 2 to 6 carbon atoms, the
  • Nitrogen atom is separated from the group to which R 8 a is bonded by at least 2 carbon atoms and the amino part is optionally mono- or identical or differently disubstituted by alkyl having 1 to 6 carbon atoms, phenyl, phenylalkyl having 7 to 12 carbon atoms or bis- phenylalkyl having 13 to 18 carbon atoms, the three last-mentioned substituents optionally being mono- or identical or different di or identical or different tri-substituted in the phenyl rings by alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, hydroxy or halogen with an atomic number of 9 to 53;
  • R 9 a represents hydrogen or has the meaning given above for R 8 a ;
  • R a 10 is either hydrogen or has the meaning given above for R 8 a or -COR a 11 , where R a 11 has the meaning given above for R 8 a ;
  • NB a stands for: a 5-, 6- or 7-membered saturated heterocyclic ring which, if it is 6- or 7-membered, can optionally contain a further hetero member from the series consisting of oxygen, sulfur and NR a 12 , wherein R a 12 is either hydrogen or has the meaning given above for R 8 a ; and
  • a a represents alkylene having 2 to 6 carbon atoms, which separates the group to which R 5 a is bonded by at least 2 carbon atoms;
  • R 6 a and R 7 a with the exception of hydrogen have the meaning given above for R 5 a ; and n has the meaning given above;
  • X represents oxygen or sulfur
  • R means: hydrogen; Alkyl of 1 to 4 carbon atoms; Alkoxy of 1 to 4 carbon atoms; Alkylthio of 1 to 4 carbon atoms; Alkylsulfonyl of 1 to 4 carbon atoms; Halogen with an atomic number from 9 to 35; Trifluoromethyl; Nitro; or hydroxy;
  • R 3 a is one of the tertiary amino groups defined above for R 3 a and is quaternized with a group of the formula alky, in which alk is alkyl having 1 to 4 carbon atoms and Y is the residue of an acid.
  • X preferably represents oxygen.
  • R is preferably hydrogen.
  • the rest is preferably bound with its 4-position to the 4-position of the 1,4-dihydropyridinyl radical.
  • Another group of compounds according to the invention consists of the compounds of the formula Iaa
  • R 1 aa represents hydrogen or alkyl having 1 to 6 carbon atoms and R a 3 a means: hydrogen; Alkyl of 1 to 6 carbon atoms; Nitro; Trifluoromethyl; Cyan; -COOR 5 aa ; -COR 6 aa ; or -S (O) n R 7 aa ; wherein R 5 represents aa : hydrogen; Alkyl of 1 to 6 carbon atoms; Hydroxyalkyl with 2 to 6 carbon atoms, the hydroxy part being separated from the group to which R 5 aa is bonded by at least 2 carbon atoms; Alkoxyalkyl having 1 to 6 carbon atoms in the alkoxy part and having 2 to 6 carbon atoms in the alkylene part, the alkoxy part being separated from the group to which R 5 aa is bonded by at least 2 carbon atoms; a 5-membered heteroaryl radical with 1 heteroatom from the
  • R 8 aa means: alkyl having 1 to 6 carbon atoms; Phenyl, phenylalkyl with 7 to 12 carbon atoms or bis-phenylalkyl with 13 to 18 carbon atoms, the three last-mentioned substituents optionally being mono- or identical or different di- or identical or different trisubstituted in the phenyl rings by alkyl having 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy or halogen with an atomic number of 9 to 53; Hydroxyalkyl with 2 to 6 carbon atoms, the hydroxy part being separated from the group to which R 8 aa is bonded by at least 2 carbon atoms; Alkoxyalky!
  • R 9 aa is hydrogen or has the meaning given above for R 8 aa
  • R 1 a 0 a is either hydrogen or has the meaning given above for R 8 aa or represents -COR a 1 a 1, in which R a 11 a has the meaning given above for R a 8 a ;
  • -NB aa stands for: a 5-, 6- or 7-membered saturated heterocyclic ring, which, if it is 6- or 7-membered, can optionally contain a further hetero member from the series oxygen, sulfur and NR a 12 a , wherein R a12 a is either hydrogen or has the meaning given above for R 8 aa ; and A aa represents alkylene with 2 to 6 carbon atoms, which separates the group to which R 5 aa is bonded by at least 2 carbon atoms; R 6 aa and R 7 aa with the exception of hydrogen have the meaning given above for R 5 aa and n has the meaning indicated above;
  • R 3 aa represents one of the tertiary amino groups defined above for R 3 aa and is quaternized with a group of the formula Alky, in which Alk is alkyl having 1 to 4 carbon atoms and Y is the residue of an acid.
  • Another group of compounds according to the invention consists of the compounds of the form! Iaaa
  • Ra 3 aa stands for: hydrogen; Nitro; Trifluoromethyl; Cyan; -COOR a aa 5 a ; or -COR 6 aa ; wherein R 5 and R 6 aa have the meaning given above, and their ammonium salts, in which R 3 aaa represents one of the tertiary amino groups defined above for R 3 aaa and is quaternized with a group of the formula Alky as defined above.
  • R 1 aa represents hydrogen
  • R 2 and R 4 are methyl.
  • X stands for oxygen.
  • X means sulfur.
  • R 3 aaa represents -COOR 5 aa , in which R 5 aa has the meaning given above.
  • R represents hydrogen.
  • a preferred group of compounds according to the invention consists of the compounds of the formula Ib
  • R, R 1 a , R 2 , R 4 and X have the meaning given above and R 3 b means: hydrogen; Alkyl of 7 to 25 carbon atoms; Nitro; Trifluoromethyl; Cyan; -COOR 5 b ; -COR 6 b ; or -S (O) n R 7 b ; wherein R 5 b means: hydrogen, alkyl having 7 to 25 carbon atoms; Hydroxyalkyl with 7 to 24 carbon atoms, the hydroxy part being separated from the group to which R 5 b is bonded by at least 2 carbon atoms; Alkoxyalkyl having 1 to 24 carbon atoms in the alkoxy part and 2 to 24 carbon atoms in the alkylene part, the alkoxy part being separated from the group to which R 5 b is bonded by at least 2 carbon atoms, with the proviso that at least one of the alkoxy and / or contains alkylene parts at least 7 carbon atoms; Alkenyl having 7 to 25 carbon
  • At least one of the hydroxyalkoxy and / or alkylene parts contains at least 7 carbon atoms; Phenyl, phenylalkyl with 13 to 30 carbon atoms or bis-phenylalkyl with 19 to 36 carbon atoms, the three last-mentioned substituents optionally being mono- or identical or different di- or identical or different trisubstituted in the phenyl rings by Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen with an atomic number of 9 to 53; a 5-membered heteroaryl radical with 1 heteroatom from the series nitrogen, oxygen and sulfur or 2 heteroatoms from the series nitrogen and either nitrogen, oxygen or sulfur, or one
  • 6-membered heteroaryl radical having 1 to 4 nitrogen atoms, the two latter substituents optionally being connected to the rest of the molecule via an alkylene radical having 7 to 24 carbon atoms; -A b OCOR 8 b ;
  • R 8 b is: alkyl of 1 to 25 carbon atoms, with the proviso that if A b contains less than 7 carbon atoms, it contains 7 to 25 carbon atoms; Phenyl, phenylalkyl with 7 to 30 carbon atoms with the proviso that it contains 13 to 30 carbon atoms if A b contains less than 7 carbon atoms, or bis-phenylalkyl with 13 to 36 carbon atoms with the proviso that it contains 19 to 36 carbon atoms, if A b contains less than 7 carbon atoms, the three last-mentioned substituents optionally being mono- or identical or different di- or identical or different trisubstituted in the phenyl rings by alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, hydroxyl or halogen with an atomic number from 9 to 53;
  • R 9 b represents hydrogen or has the meaning given above for R 8 b ;
  • R b 10 is either hydrogen or has the meaning given above for R 8 b or represents -COR b 11 , in which Rb 11 has the meaning given above for R 8 b ;
  • -NB b means: a 5-, 6- or 7-membered saturated heterocyclic ring, which may optionally contain, if it is 6- or 7-membered, a further hetero member from the series oxygen, sulfur and NR b 12 , wherein R b 12 is either hydrogen or has the meaning given above for R 8 b ; and
  • a b represents alkylene with 2 to 24 carbon atoms, which separates the group to which R 5 b is bonded by at least 2 carbon atoms,
  • R 6 b and R 7 b with the exception of hydrogen have the meaning given above for R 5 b ; and n has the meaning given above;
  • R 3 b represents one of the tertiary amino groups defined above for R 3 b and is quaternized with a group of the formula alky, in which alk is alkyl having 1 to 4 carbon atoms and Y is the residue of an acid.
  • Another preferred group of compounds according to the invention consists of the compounds of the formula Iba
  • R, R 1 aa , R 2 , R 4 and X have the meaning given above and R 3 ba means: alkyl having 7 to 25 carbon atoms; -COOR 5 ba ; -COR 6 ba ; or -S (O) n R 7 ba ; wherein R 5 ba means: alkyl having 7 to 25 carbon atoms; Hydroxyalkyl of 7 to 24 carbon atoms, the hydroxy part being separated from the group to which R 5 ba is bonded by at least 2 carbon atoms; Alkoxyalkyl having 1 to 24 carbon atoms in the alkoxy part and 2 to 24 carbon atoms in the alkylene part, the alkoxy part being separated from the group to which R 5 ba is bonded by at least 2 carbon atoms, with the proviso that at least one of the alkoxy and / or contains alkylene parts at least 7 carbon atoms; Alkenyl having 7 to 25 carbon atoms, the double bond being separated from the group to which R 5 ba is bonded by
  • the hydroxyalkoxy part is separated from the group to which R 5 ba is bonded by at least 2 carbon atoms and the hydroxy part is separated from the oxygen atom of the alkoxy part by at least 2 carbon atoms, with the proviso that at least one of the hydroxyalkoxy and / or alkylene parts has at least 7 carbon atoms contains; Phenylalkyl with 13 to 30 carbon atoms or bis-phenylalkyl with 19 to 36 carbon atoms, the two latter substituents optionally being mono- or identical or differently di- or identical or differently trisubstituted in the phenyl rings by alkyl with
  • Carbon atoms the hydroxy part being separated from the group to which R 8 ba is attached by at least 2 carbon atoms, with the proviso that it contains 7 to 24 carbon atoms if A ba contains less than 7 carbon atoms;
  • Alkoxyalkyl with 1 to 24 carbon atoms in the alkoxy part and with 2 to 24 carbon atoms in the alkylene part, the alkoxy part being separated from the group to which R 8 ba is bonded by at least
  • Carbon atoms in the alkylene part with the proviso that there are - - - - - 7 to 24 carbon atoms in the alkylene contains part if A ba contains less than 7 carbon atoms; Hydroxyalkoxyalkyl with 2 to 24 carbon atoms in the hydroxyalkoxy part and with 2 to 24 carbon atoms in the alkylene part, the hydroxyalkoxy part being separated from the group to which R 8 ba is bonded by at least 2 carbon atoms and the hydroxy part being separated from the oxygen atom of the alkoxy part by at least 2 Carbon atoms, with the proviso that if A ba contains less than 7 carbon atoms then at least one of the hydroxyalkoxy and / or alkylene parts contains at least 7 carbon atoms; Aminoalkyl of 2 to 24 carbon atoms, with the proviso that if A ba contains less than 7 carbon atoms, it contains 7 to 24 carbon atoms, the oxygen atom being separated from the group to which R 8 ba
  • R 9 ba represents hydrogen or has the meaning given above for R 8 ba
  • R 1 b 0 a is either hydrogen and has the meaning given above for R 8 ba or -COR b 11 a , in which R1 ba 1 has the meaning given above for R 8 ba
  • -NB ba means: a 5-, 6- or 7-membered saturated heterocyclic ring which, if it is 6- or 7-membered, may contain a further hetero-member from the series oxygen, sulfur and NR b 1 a 2 where R 1 ba 2 is either hydrogen or has the meaning given above for R 8 ba ; and
  • a ba represents alkylene with 2 to 24 carbon atoms, which separates the group to which R 9 ba is bonded by at least 2 carbon atoms;
  • R 6 ba and R 7 ba with the exception of hydrogen have the meaning given above for R 5 ba ; and
  • n has the meaning given above;
  • R 3 ba stands for one of the tertiary amino groups defined above for R 3 ba and is quaternized with a group of the formula Alky, in which Alk is alkyl with 1 to 4 carbon atoms and Y is the residue of an acid.
  • Another preferred group of compounds according to the invention consists of the compounds of the formula Ibaa
  • R 2 , R 4 and X have the meaning given above and R 3 baa stands for: -COOR 5 baa or -COR 6 baa ; wherein R 5 is baa : alkyl of 9 to 19 carbon atoms; Hydroxyalkyl with 9 to 18 carbon atoms, the hydroxy part being separated from the group to which R 5 baa is bonded by at least 2 carbon atoms; Alkoxyalkyl with
  • R 8 baa means: alkyl having 1 to 19 carbon atoms, with the proviso that if A baa contains less than 9 carbon atoms it contains 9 to 19 carbon atoms; Phenyl, phenylalkyl with 7 to
  • a baa contains less than 9 carbon atoms;
  • Alkoxyalkyl having 1 to 18 carbon atoms in the alkoxy part and having 2 to 18 carbon atoms in the alkylene part, the alkoxy part being separated from the group to which R 8 ba a is bonded by at least 2 carbon atoms;
  • R 9 ba a is hydrogen or has the meaning given above for R 8 ba a ;
  • R b 10 aa is either hydrogen or has the meaning given above for R 8 ba a or -COR b 11 aa , wherein R b 11 aa has the meaning given above for R 8 ba a ;
  • -N B baa means: a 5-, 6- or 7-membered saturated heterocyclic ring which, if it is 6- or 7-membered, can optionally contain a further hetero member from the series oxygen, sulfur and NR b 12 aa , wherein R b 12 aa is either hydrogen or has the meaning given above for R 8 ba a ; and
  • a baa represents alkylene having 2 to 18 carbon atoms, which separates the group to which R 5 ba a is bonded by at least 2 carbon atoms;
  • R 6 ba a with the exception of hydrogen, the ba has a meaning given above for R 5; and n has the meaning given above;
  • R 3 ba a represents one of the tertiary amino groups defined above for R 3 ba a and is quaternized with a group of the formula Alky, in which Alk is alkyl having 1 to 4 carbon atoms and Y is the residue of an acid.
  • Another group of compounds according to the invention consists of the compounds of the formula Ic
  • R, R 1 a , R 2 , R 4 and X have the meaning given above and R 3 c represents: hydrogen, nitro; Trifluoromethyl; Cyan; -COOR 5 c ; -COR 6 c ; or -S (O) n R 7 c ; wherein R 5 c means: hydrogen, cycloalkyl having 3 to 7 carbon atoms; optionally by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy or halogen with an atomic number from 9 to 53 mono- or identical or different di- or identical or different trisubstituted phenyl; a 5-membered heteroaryl radical with 1 heteroatom from the series nitrogen, oxygen and sulfur or 2 heteroatoms from the series nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl radical with 1 to 4 nitrogen atoms;
  • R 6 c and R 7 c with the exception of hydrogen have the meaning given above for R 5 c ;
  • n has the meaning given above.
  • Another group of compounds according to the invention consists of the compounds of the formula Ica
  • R 2 , R 4 and X have the meaning given above and R 3 ca stands for: hydrogen; Nitro; Trifluoromethyl; Cyan; -COOR 5 ca ; or -CO R 6 ca ; wherein
  • R 5 ca means: hydrogen or a 5-membered heteroaryl radical with 1 hetero atom from the series nitrogen, oxygen and sulfur or 2 hetero atoms from the series nitrogen and either nitrogen, oxygen or sulfur;
  • R 6 ca with the exception of hydrogen has the meaning given above for R 5 ca.
  • Another group of compounds according to the invention consists of the compounds of the formula Id
  • R 1 d to R 4 d and Q d have the meaning given above for R 1 to R 4 and Q, with the proviso that the substituents in the 2- and 6-positions and / or in the 3- and 5 Positions of the 1,4-dihydropyridinyl radical are different,
  • R 3 d is one of the tertiary amino groups defined above for R 3 d and is quaternized with a group of the formula AlkY as defined above.
  • Another group of compounds according to the invention consists of the compounds of the formula Ie
  • R 1 e to R 4 e and Q e have the meaning given above for R 1 to R 4 and Q, with the proviso that the substituents in the 2- and 6-positions and / or in the 3- and 5 Positions of the 1,4-dihydropyridinyl radical are different,
  • R 3 e represents one of the tertiary amino groups defined above for R 3 e and is quaternized with a group of the formula AlkY as defined above.
  • Another group of compounds according to the invention consists of the compounds of the formula Ip
  • R 5 denotes p : a) cycloalkyl having 4 to 6 carbon atoms; b) alkyl having 1 to 12 carbon atoms or alkoxyalkyl having 1 to 10 carbon atoms in the alkoxy part and having 2 to 11 carbon atoms in the alkylene part, the alkoxy part being separated from the group to which R 5 p is bonded by at least 2 carbon atoms and with the Provided that the alkoxy and alkylene parts together contain fewer than 13 carbon atoms; and
  • R 9 p stands for: hydrogen; Alkyl of 1 to 4 carbon atoms; Phenyl, phenylalkyl with 7 to 10 carbon atoms or bisphenylalkyl with 13 to 16 carbon atoms, the three latter substituents in the phenyl rings optionally being alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy or halogen with an atomic number of 9 up to 53 are mono- or identical or different di- or identical or different trisubstituted; R p 10 represents hydrogen or alkyl of 1 to 4 carbon atoms;
  • -N-B p stands for: a 5-, 6- or 7-membered saturated heterocyclic ring which may optionally contain, if it is 6- or 7-membered, another hetero member from the series oxygen, sulfur and NR p 12 wherein R p 12 has the meaning given above for R 9 p ; and A p represents straight-chain alkylene with 2 to 12 carbon atoms, which separates the group to which R 5 p is bound by at least 2 carbon atoms.
  • R 5 p denotes cyclopentyl or cyclohexyl.
  • R 5 p represents alkyl having 1 to 8 carbon atoms.
  • Another group of compounds according to the invention consists of the compounds of the formula Is
  • R 2 s and R 4 s independently represent alkyl of 1 to 4 carbon atoms and R 3 s represents: hydrogen; Nitro; Trifluoromethyl; Cyan; -COOR 5 s ; or -COR 6 s ; wherein R 5 s means: hydrogen; Alkyl of 1 to 12 carbon atoms; Hydroxyalkyl of 2 to 6 carbon atoms, the hydroxy part being separated from the group to which R 5 s is bonded by at least 2 carbon atoms; -A s NR 9 s R 1 s 0; or -A s NB s ; wherein R 9 s and R s 10 independently represent: hydrogen; Alkyl of 1 to 4 carbon atoms; optionally in the phenyl rings by alkoxy having 1 to 4 carbon atoms or halogen having an atomic number of 9 to 53 mono- or identically or differently disubstituted phenylalkyl having 7 to 10 carbon atoms;
  • -N-B s means: piperidinyl or piperazinyl or piperidinyl or piperazinyl which is substituted in the 4-position by methyl, benzyl or bis-phenylmethyl, the two latter substituents optionally in the phenyl rings by alkoxy having 1 to 4 carbon atoms or halogen with an atomic number of 9 to 53 are disubstituted mono- or identical or different; and
  • a s means: alkylene with 2 to 14 carbon atoms, the group to which R 5 s is bonded by at least 2
  • R 6 s represents imidazolyl
  • R 3 s is one of the tertiary amino groups defined above for R 3 s and is quaternized with a group of the formula AlkY as defined above.
  • R 3 ca , R 3 d , R 3 e and R 3 s represent ester groups as defined above under the corresponding formula, and optionally their corresponding ammonium salts as defined above.
  • Further groups of compounds according to the invention consist of the compounds of the formulas Ia, Iaa, Iaaa, Ib, Iba, Ibaa, Ic, Ica and Is, in which X is sulfur, and, if appropriate, their corresponding ammonium salts as defined above.
  • R 1 has the meaning given above, or their partial condensation products, advantageously condensed to 1,4-dihydropyridines, or
  • R 1 , R 2 , R 4 and Q have the meaning given above and R ⁇ is hydrogen, -COOR 5 or -COR 6 , wherein R 5 and R 6 have the meaning given above.
  • R 1 , R 2 , R 4 and Q have the above meaning and X represents a reactive group, appropriately converted.
  • the method according to the invention can be carried out analogously to known methods.
  • Process variant a) can be carried out, for example, according to Hantzsch.
  • the implementation can take place, for example, in solution.
  • Suitable solvents are water, ethanol, dioxane, dimethylformamide, dimethyl sulfoxide, pyridine or glacial acetic acid.
  • Suitable reaction temperatures are about 20 to 160 ° C, preferably 60 to 120 ° C.
  • Process variant b) can also be carried out in a known manner.
  • the choice of the most suitable reaction conditions depends, of course, primarily on the nature of the group R 3 ' . If R 3 'is hydrogen, then X can be carboxyl, for example, and the conversion is decarboxylation. If R 3 'is -COR 6 , then X can represent carboxyl, for example, and the conversion is a substitution. If R 3 'is carboxyl, then X means, for example, an easily cleavable ester group, such as an ammonium ester group, and the conversion is then hydrolysis.
  • X means, for example, a group -COX', where X 'represents a reactive group suitable for producing an ester group.
  • the ester-resulting conversion can be, for example, an esterification.
  • X ' is then expediently 1H-imidazol-1-yl.
  • This process variant is suitable, for example, for conversion into a hydroxyalkyl; Amidoalkyl; Alkoxyalkyl; Acyloxyalkyl or substituted or unsubstituted aminoalkyl ester substituents.
  • a suitable solvent is dioxane or a Excess of the reactant can be used.
  • a further ester-yielding conversion can, for example, be an amination.
  • This variant is suitable, for example, for conversion into an aminoalkyl ester substituent.
  • a reactive group X represents, for example, a group -COOAX ", in which A has the meaning given above and X" represents chlorine, bromine or a group -R z -SO 2 -O-, in which R z is phenyl, tolyl or lower alkylene .
  • X '' preferably means mesyloxy.
  • the amination can be immediate, ie the reaction takes place directly with an amine which carries the substituent to be introduced, or indirectly, for example to introduce a primary amino group, by first converting it into a corresponding phthalimidoalkyl derivative, for example by reaction with sodium or potassium phthalimide, and then reacting the phthalimidoalkyl derivative thus obtained with hydrazine.
  • the indirect method is preferred if the substituent to be introduced is a primary one
  • Another ester-yielding conversion is e.g. is an acylation of a primary or secondary amine.
  • a reactive group X is then expediently the corresponding primary or secondary aminoalkoxycarbonyl group.
  • a corresponding compound of formula VI is thus combined with a corresponding one
  • Acyl derivative such as an N-hydroxysuccinimide ester implemented.
  • a suitable solvent is, for example, dioxane.
  • a further ester-yielding conversion can be, for example, an acylation of an alcohol.
  • a reactive group X is then expediently the corresponding hydroxyalkoxycarbonyl group.
  • a corresponding compound of formula VI is thus reacted with a 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.
  • a suitable solvent is, for example, methylene chloride.
  • Another ester-yielding conversion can be etherification, for example.
  • a reactive group X is then expediently a group -COOAX ′′, in which A and X ′′ have the above meaning.
  • the reaction is preferably carried out under strongly alkaline conditions.
  • Quaternary ammonium salts can also be prepared analogously to known methods, for example by reaction with corresponding lower alkyl iodides.
  • An alcohol such as methanol is suitable as a solvent.
  • the compounds according to the invention can be isolated and purified from the reaction mixture in a known manner.
  • the compounds according to the invention can be in free form or optionally in salt form.
  • the free forms are normally neutral, unless there are ionizable substituents.
  • Salt forms can exist, for example, if ionizable substituents, such as amino or phenolic hydroxy, are present. Salt forms can be obtained in a known manner from the compounds in free form and vice versa.
  • Suitable acids for the formation of acid addition salts are, for example, hydrogen chloride, malone, p-toluenesulfonic acid and methanesulfonic acid.
  • Suitable bases for the formation of anionic salts are, for example, sodium and potassium hydroxide.
  • the individual enantiomers can be obtained analogously to known methods, e.g. by fractional crystallization, e.g. of optically active diastereoisomeric salts, or by transesterification of optically pure esters which are substituted by easily cleavable, preferably basic ester groups, such as dimethylaminoethoxycarbonyl.
  • Example 1 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-5-nitro-pyridine-3-carboxylic acid ethyl ester
  • the starting product is obtained by heating under reflux for 35 hours of 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
  • Example 8 4- (2,1,3-Benzoxadiazol-4-yl) -1, 4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxylic acid ethyl ester
  • the compounds according to the invention in free form or, if appropriate, in the form of their physiologically tolerable salts are distinguished by interesting pharmacological properties. they can be used as medicines.
  • a decrease in blood pressure is also seen in the awake, spontaneously hypertensive rat (method of Gerold and Tschirki, drug research 1S [1968] 1285) after administration of about 1 to about 10 mg / kg p.o. detected.
  • the compounds also have very little negative inotropic activity. They are therefore not cardio-depressive and even have a certain cardiosimulatory effect. It is therefore possible to use relatively high daily doses if desired, even in patients for whom the administration of calcium channel blockers is generally contraindicated, e.g. in patients with heart failure.
  • the dose to be used naturally varies depending on the substance used, the mode of administration and the desired treatment. In general, however, satisfactory results are achieved with a daily dose of approximately 10 mg to approximately 1600 mg; if necessary, it can be administered in 1 to 3 portions or as a slow-release form.
  • Suitable dosage forms for, for example, oral or non-oral administration generally contain from about 2.5 mg to about 800 mg in addition to solid or liquid carriers.
  • the preferred indications are coronary insufficiency and cardiac insufficiency, especially ischemic heart failure.
  • Preferred for the prophylaxis and treatment of migraines and vascular headaches are those compounds in which Q represents a 2,1,3-benzothiadiazolyl radical.
  • the compounds according to the invention in free form or, if appropriate, in the form of their physiologically tolerable salts, preferably acid addition salts, can be administered alone or in a suitable dosage form.
  • the invention also relates to pharmaceutical preparations which contain the compounds according to the invention in free form or, if appropriate, in the form of their physiologically tolerable salts, and to the preparation of these pharmaceutical preparations in a manner known per se.
  • the auxiliaries and carriers customary in pharmacy can be used for their production. You can e.g. for use in enteral, preferably oral, administration e.g. as tablets, or in particular for sublingual administration, e.g. as buccal tablets, or for parenteral administration, e.g. as injectable solutions or suspensions. Sublingual administration is preferred.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Composés de formule (I) dans laquelle R1 représente l'hydrogène, cycloalkyle avec 3 à 7 atomes de carbone, alkyle éventuellement substitué avec 1 à 6 atomes de carbone; R2 et R4, indépendamment l'un de l'autre représentent l'hydrogène ou alkyle avec 1 à 6 atomes de carbone; R3, signifie l'hydrogène, alkyle avec 1 à 25 atomes de carbone, nitro, trifluorméthyl, cyane, -COOR5, -COR6 ou -S(O)nR7; Q, représente un système annulaire complètement insaturé avec en tout au moins 2 hétéro atomes différents, de caractère aromatique. Les dérivés sont utilisés comme antagonistes du calcium.
PCT/CH1984/000170 1983-11-01 1984-10-23 Derives de 1,4-dihydropyridine, leur preparation et les compositions pharmaceutiques les contenant WO1985001940A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
CH589383 1983-11-01
CH5895/83-0 1983-11-01
CH589583 1983-11-01
CH5893/83-6 1983-11-01
CH5891/83-2 1983-11-01
CH589183 1983-11-01
CH357884 1984-07-24
CH3578/84-6 1984-07-24
CH358084 1984-07-24
CH3580/84-4 1984-07-24

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BE (1) BE900874A (fr)
DE (1) DE3438884A1 (fr)
DK (1) DK517484A (fr)
FR (1) FR2554109A1 (fr)
GB (1) GB2148895A (fr)
IL (1) IL73363A0 (fr)
IT (1) IT1199214B (fr)
LU (1) LU85621A1 (fr)
NL (1) NL8403302A (fr)
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WO (1) WO1985001940A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0164010A2 (fr) * 1984-06-04 1985-12-11 Bayer Ag 3-Nitro-dihydropyridines, leur procédé de préparation et leur application comme médicaments

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0000150A1 (fr) * 1977-06-20 1979-01-10 Sandoz Ag Dérivés de dihydropyridine, leur préparation et leur application dans des compositions pharmaceutiques.
EP0002208A1 (fr) * 1977-11-26 1979-06-13 Bayer Ag Nitro dihydro-1,4 pyridines, médicaments les contenant et leur procédé de préparation
DE2949464A1 (de) * 1978-12-18 1980-06-26 Sandoz Ag Benzoxadiazole und benzothiadiazole, ihre herstellung und verwendung
EP0071819B1 (fr) * 1981-07-30 1987-04-22 Bayer Ag Dihydropyridines, douées d'une activité inotrope positive, leur application comme médicaments, et leurs procédés de préparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0000150A1 (fr) * 1977-06-20 1979-01-10 Sandoz Ag Dérivés de dihydropyridine, leur préparation et leur application dans des compositions pharmaceutiques.
EP0002208A1 (fr) * 1977-11-26 1979-06-13 Bayer Ag Nitro dihydro-1,4 pyridines, médicaments les contenant et leur procédé de préparation
DE2949464A1 (de) * 1978-12-18 1980-06-26 Sandoz Ag Benzoxadiazole und benzothiadiazole, ihre herstellung und verwendung
EP0071819B1 (fr) * 1981-07-30 1987-04-22 Bayer Ag Dihydropyridines, douées d'une activité inotrope positive, leur application comme médicaments, et leurs procédés de préparation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0164010A2 (fr) * 1984-06-04 1985-12-11 Bayer Ag 3-Nitro-dihydropyridines, leur procédé de préparation et leur application comme médicaments
EP0164010A3 (en) * 1984-06-04 1987-08-05 Bayer Ag 3-nitro-dihydropyridines, process for their preparation and their pharmaceutical use

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SE8405450D0 (sv) 1984-10-31
BE900874A (fr) 1985-04-23
IL73363A0 (en) 1985-01-31
DK517484D0 (da) 1984-10-30
NL8403302A (nl) 1985-06-03
DK517484A (da) 1985-05-02
IT8449079A0 (it) 1984-10-29
AU3486884A (en) 1985-05-09
GB2148895A (en) 1985-06-05
LU85621A1 (fr) 1985-07-17
DE3438884A1 (de) 1985-05-09
FR2554109A1 (fr) 1985-05-03
SE8405450L (sv) 1985-06-10
GB8427443D0 (en) 1984-12-05
IT1199214B (it) 1988-12-30
IT8449079A1 (it) 1986-04-29

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