GB2148895A - 1, 4-dihydropyridine derivatives their preparation and pharmaceutical compositions containing them - Google Patents

1, 4-dihydropyridine derivatives their preparation and pharmaceutical compositions containing them Download PDF

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GB2148895A
GB2148895A GB08427443A GB8427443A GB2148895A GB 2148895 A GB2148895 A GB 2148895A GB 08427443 A GB08427443 A GB 08427443A GB 8427443 A GB8427443 A GB 8427443A GB 2148895 A GB2148895 A GB 2148895A
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Dr Arnold Vogel
Gerhard Bormann
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Sandoz AG
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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

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

Abstract

Compounds having the formula (I), wherein R1 is hydrogen, cycloalkyl with 3 to 7 atoms of carbon, optionally substituted alkyl with 1 to 6 atoms of carbon; R2 and R4, independently from each other, represent hydrogen or alkyl with 1 to 6 atoms of carbon; R3 is hydrogen, alkyl with 1 to 25 atoms of carbon, nitro, trifluoromethyl, cyan, -COOR5, - COR6 or -S(O)nR7; Q is a completely insaturated ring system with at least 2 different ring hetero atoms of aromatic character. The derivatives are used as calcium antagonists.

Description

SPECIFICATION 1,4-Dihydropyridine derivatives, their preparation and pharmaceutical compositions containing them The invention relates to 1,4-dihydropyridine derivatives, their preparation and pharmaceutical compositions containing them.
In particular the invention provides compounds of formula I
wherein R1 is hydrogen; cycloalkyl of 3 to 7 carbon atoms; or optionally substituted alkyl of 1 to 6 carbon atoms; R2 and R4 independently are hydrogen or alkyl of 1 to 6 carbon atoms; R3 is hydrogen; alkyl of 1 to 25 carbon atoms; nitro; trifluoromethyl; cyano; -COOR5; -COR6; or -S(O),R7; wherein -COOR5 is carboxyl or an ester group; R6 is alkyl of 1 to 25 carbon atoms; hydroxyalkyl of 2 to 24 carbon atoms wherein the hydroxy part is separated from the group to which R6 is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and 2 to 24 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which R6 is bound by at least 2 carbon atoms; alkenyl of 3 to 25 carbon atoms wherein the double bond is separated from the group to which R6 is bound by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 25 carbon atoms wherein the triple bond is separated from the group to which Re is bound by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 24 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which Re is bound 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; phenyl, phenylalkyl of 7 to 30 carbon atoms or bis-phenylalkyl of 13 to 36 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl rings(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms, the last 2 substituents optionally being bound to the rest of the molecule over an alkylene moiety of 1 to 24 carbon atoms; -AOCOR8; -ANRgR10; or wherein R8 is alkyl of 1 to 25 carbon atoms; phenyl, phenylalkyl of 7 to 30 carbon atoms or bis-phenylalkyl of 13 to 36 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; hydroxyalkyl of 2 to 24 carbon atoms wherein the hydroxy part is separated from the group to which Re is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which Re is bound by at least 2 carbon atoms; alkenyl of 3 to 25 carbon atoms wherein the double bond is separated from the group to which Re is bound by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 25 carbon atoms wherein the triple bond is separated from the group to which Re is bound by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 24 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which Re is bound 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 of 2 to 24 carbon atoms wherein the nitrogen atom is separated from the group to which Re is bound by at least 2 carbon atoms and the amino part is optionally mono- or independently di-substituted by alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; Rg is hydrogen or has the significance indicated above for Rg;; Rlo either is hydrogen or has the significance indicated above for Re or is -COR11 wherein R11 has the significance indicated above for R8; -N & is a 5-,6- or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6-or 7-membered, a further heteromember selected from oxygen, sulfur and = NR12 wherein R12 either is hydrogen or has the significance indicated above for R5 and A is alkylene of 2 to 24 carbon atoms separating the group to which R5 is bound by at least 2 carbon atoms; R7 mutatis mutandis has the significance indicated above for R6; nisO,1 or2;; o is a condensed, fully unsaturated ring system having at least 2 different ring heteroatoms overall and having aromatic character; and their ammonium salts wherein R3 is selected from one of the tertiary amino groups defined above for R3 and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid, hereinafter referred to as "the compound of the invention".
Some of the compounds of the invention fall under the very broad disclosure of Bayer EP 71 819.
None of the compound specifically disclosed in the above-mentioned European publication, however, falls under the scope of the present invention.
A further disclosure relating to compounds similar to the compounds of the invention is e.g.: Bayer EP 2 208.
The above-mentioned publications do not suggest any specific compounds similar to the compounds of the invention. The compounds of the invention have a particularly interesting pharmacological profile.
The compounds of the invention preferably are in unquaternized form.
R5 preferably has mutatis mutandis the significance indicated above for R5.
R1 preferably is hydrogen. When it is other than hydrogen it preferably has one of the significances indicated below for R1, especially unsubstituted alkyl, cycloalkylalkyl, optionally substituted phenylalkyl, alkoxyalkyl or morpholino; preferably unsubstituted alkyl or alkoxyalkyl; preferably unsubstituted alkyl.
When it is alkoxyalkyl the alkoxy part thereof preferably is separated from the nitrogen atom by at least 2 carbon atoms. R2 and R4 preferably are alkyl, especially methyl. R3 preferably is nitro, trifluoromethyl, -COOR5 or -COR6, especially -COOR5. R5 andxor R7 preferably are alkyl, hydroxyalkyl, alkoxyalkyl, -AOCOR5, -ANRgR10 or -AN, , especially -ANRgRlo or -ANos . R6 preferably is as defined above for R5 and/or R7 or is a 5-memberedketeroaryl moiety with 2 nitrogen heteroatoms. R5 preferably is alkyl, or optionally substituted phenyl, phenylalkyl or bis-phenylalkyl, particularly phenyl, Rg and Rao preferably are hydrogen or alkyl, or optionally substituted phenyl, phenylalkyl or bis-phenylalkyl.Preferably either both Rg and Rlo are hydrogen, or one of Rg and Rio is alkyl and the other is alkyl, optionally substituted phenylalkyl or optionally substituted bis-phenylalkyl. - N;ss)preferably is a 6-membered saturated heterocyclic ring containing a further hetero-member. R11 preferably is alkyl, optionally substituted phenyl, optionally substituted phenylalkyl or optionally substituted bis-phenylalkyl. R12 preferably is other than hydrogen, it preferably is alkyl, optionally substituted phenylalkyl or optionally substituted bis-phenylalkyl. A preferably is of 2 carbon atoms or of 7 to 24, especially of 9 to 18 carbon atoms, particularly of 9 to 14 carbon atoms, especially of 10 carbon atoms.It preferably is unbranched, n preferably is 1 or 2. 0 preferably has at least 3 heteroatoms overall, in particular 3. It preferably is a bicyclic system. Preferred groups Q are 2,1,3benzoxadiazolyl and 2,1,3-benzothiadiazolyl, in particular 2,1,3-benzoxadiazolyl. When O is a ring system having a benzene ring component the 1,4-dihydropyridinyl moiety preferably is bound to that ring component, preferably at a position on the benzene ring component which is adjacent to further ring component(s). Alk preferably is methyl. Y preferably is the rest of an anorganic acid, e.g. mesyl or halogen, particularly iodine.
Cycloalkyl of 3 to 7 carbon atoms preferably is of 3,5 or 6, especially of 5 carbon atoms. Optionally substituted alkyl of 1 to 6 carbon atoms preferably has one of the significances indicated below for R2a except hydrogen, it especially is methyl. Alkyl of 1 to 6 carbon atoms preferably is of 1 to 4 carbon atoms, it especially is methyl. Alkyl of 1 to 25 carbon atoms preferably is of 1 to 6 carbon atoms, e.g. methyl, ethyl or isopropyl, or of 9 to 19 carbon atoms; especially of 9 to 19, particularly of 10 carbon atoms. Hydroxyalkyl of 2 to 24 carbon atoms preferably is of 2 to 6 or of 9 to 18 carbon atoms, especially of 9 to 18 carbon atoms.
Alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and 2 to 24 carbon atoms in the alkylene part preferably is of 1 to 6 or 9 to 19, especially of 9 to 19 carbon atoms in the alkoxy part and preferably of 2 to 6 or of 9 to 18, especially of 9 to 18 carbon atoms in the alkylene part. Alkenyl of 3 to 25 carbon atoms andlor alkinyl of 3 to 25 carbon atoms preferably are of 3 carbon atoms or of 7 to 25, especially of 9 to 18 carbon atoms. Cycloalkyl of 3 to 7 carbon atoms and the cycloalkyl part of cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part preferably are of 3,5 or 6, especially of 5 or 6 carbon atoms. The alkylene part of cycloalkylalkyl of 1 to 24 carbon atoms in the alkylene part preferably is of 1 carbon atom or of 7 to 24, especially of 9 to 18 carbon atoms. The hydroxyalkoxy part of hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part preferably is of 2 carbon atoms or of 7 to 24, especially of 9 to 18 carbon atoms. The alkylene part of hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the alkylene part preferably is of 2 carbon atoms or of 7 to 24, especially of 9 to 18 carbon atoms. The alkylene part of phenylalkyl of 7 to 30 carbon atoms or of bis-phenylalkyl of 13 to 36 carbon atoms preferably is of 1 or 2 carbon atoms or of 7 to 24, especially of 9 to 18 carbon atoms. Alkyl of 1 to 4 carbon atoms and/or alkoxy of 1 to 4 carbon atoms preferably are of 1 or 2, especially 1 carbon atom(s). Halogen of atomic number of from 9 to 53 preferably is fluorine or bromine, especially bromine. Halogen of atomic number of from 9 to 35 preferably is fluorine or chlorine, especially fluorine.A heteroaryl moiety as defined above preferably is 5-membered, it preferably has 1 or 2 nitrogen heteroatoms, especially 2; it particularly is imidazolyl, especially 1 H-imidazol-1 -yl. When it is 6-membered it preferably has 1 or 2 nitrogen heteroatoms, it especially is pyridinyl. The alkylene moiety of 1 to 24 carbon atoms optionally binding a heteroaryl moiety to the rest of the molecule preferably is of 1 or of 7 to 24, especially of 9 to 18 carbon atoms. The alkylene part of aminoalkyl of 2 to 24 carbon atoms preferably is of 2 or of 7 to 24, especially of 9 to 18 carbon atoms. The amino part of aminoalkyl preferably is substituted, especially disubstituted. Preferably substituents of the amino part of aminoalkyl are alkyl and/or optionally substituted phenylalkyl.Preferably the amino part of aminoalkyl is disubstituted by alkyl and optionally substituted phenylalkyl. A 5-, or 7-membered saturated heterocyclic ring as defined above preferably is 6-membered. It preferably is 1-piperazinyl. When it is 6- or7-membered it preferably has a further heteromember -NR12.
The hydroxy part of hydroxyalkyl and/or of hydroxyalkoxyalkyl and/or the amino part of aminoalkyl preferably is attached to the distal terminal carbon atom. Where a phenyl ring is present in a substituent, it is preferably unsubstituted. When it is substituted it preferably is monosubstituted, preferably in the para position. When it is disubstituted it preferably is substituted in the ortho or meta and in the para positions.
When it is trisubstituted it preferably is substituted in the meta, meta and para positions. Alkoxy and/or halogen are preferred as substituents on a phenyl ring substituent. When a phenyl ring is polysubstituted the substituents preferably are identical. In bis-phenylalkyl the two phenyl rings preferably are attached to the same carbon atom. Bis-phenylalkyl preferably is bis-phenylmethyl.
One group of compounds of the invention is the compounds of formula la
wherein R2 and R4 are as defined above, R is hydrogen; alkyl of 1 to 6 carbon atoms; alkenyl of 3 to 6 carbon atoms wherein the double bond is separated from the nitrogen atom by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 6 carbon atoms wherein the triple bond is separated from the nitrogen atom by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 4 to 8 carbon atoms; hydroxyalkyl of 2 to 6 carbon atoms wherein the hydroxy part is separated from the nitrogen atom by at least 2 carbon atoms; alkoxyalkyl of 2 to 6 carbon atoms; or phenylalkyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms wherein the double bond is separated from the nitrogen atom by at least 1 carbon atom not participating in the double bond, the last two substituents optionally being independently mono-, di- or trisubstituted in the phenyl ring by independently alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen of atomic number of from 9 to 35 or hydroxy; alkylcarbonyloxyalkyl of 2 to 6 carbon atoms in the alkylcarbonyl and alkylene moieties thereof and wherein oxygen is separated from the nitrogen atom by at least 2 carbon atoms; dialkylaminoalkyl independently of 1 to 6 carbon atoms in the alkyl moieties and of 2 to 6 carbon atoms in the alkylene moiety thereof and wherein the amino group is separated from the nitrogen atom by at least 2 carbon atoms; or morpholinoalkyl of 2 to 6 carbon atoms in the alkylene moiety thereof and wherein the morpholino moiety is separated from the nitrogen atom by at least 2 carbon atoms; Ra is hydrogen; alkyl of 1 to 6 carbon atoms; nitro; trifluoromethyl; cyano; -COOR5; -CORa6; or -S(O)nR7; wherein Ra is hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 2 to 6 carbon atoms wherein the hydroxy part is separated from the group to which Rs is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy part and of 2 to 6 carbon atoms in the alkylene part, wherein the alkylene part is separated from the group to which Ra is bound by at least 2 carbon atoms; alkenyl of 3 to 6 carbon atoms wherein the double bond is separated from the group to which Ra is bound by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 6 carbon atoms wherein the triple bond is separated from the group to which Ra is bound by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 6 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 6 carbon atoms in the alkoxy part and of 2 to 6 carbon atoms in the alkylene part, where the hydroxyalkoxy part is separated from the group to which R5 is bound 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; phenyi, phenylalkyl of to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms, the last 2 substituents optionally being bound to the rest of the molecule over an alkylne moiety of 1 to 6 carbon atoms; -AaOCOR8a; -AaNR9aR10a; or AaN#a; wherein R8a is alkyl of 1 to 6 carbon atoms; phenyl, phenylalkyl of 7 to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently tri-substituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; hydroxyalkyl of 2 to 6 carbon atoms wherein the hydroxy part is separated from the group to which Ra is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy part and of 2 to 6 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which Ra is bound by at least 2 carbon atoms; alkenyl of 3 to 6 carbon atoms wherein the double bond is separated from the group to which R8is bound by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 6 carbon atoms wherein the triple bond is separated from the group to which Ra is bound by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 6 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 6 carbon atoms in the hydroxyalkoxy part and of 2 to 6 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which Ra is bound 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 of 2 to 6 carbon atoms wherein the nitrogen atom is separated from the group to which Ra is bound by at least 2 carbon atoms and the amino part is optionally mono- or independently disubstituted by alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently dior independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; Rg is hydrogen or has the significance indicated above for R8; R10a either is hydrogen or has the significance indicated above for R8a or is -COR11a wherein R11a has the significance indicated above for R8a;; -N#a is a 5-, 6- or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6- or 7-membered, a further herteromember selected from oxygen, sulfur and NR12a either is hydrogen or has the significance indicated above for R8a; and Aa is alkylene of 2 to 6 carbon atoms separating the group to which Ras is bound by at least 2 carbon atoms; Ra6 and Ra with the exception of hydrogen have the significance indicated above for Rs; and n is as defined above; X is oxygen or sulfur and R is 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 of atomic number of from 9 to 35; trifluoromethyl; nitro; or hydroxy; and their ammonium salts wherein Ra is selected from one of the tertiary amino groups defined above for Ra3 and quarternized with a group of formula Alkywherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
X preferably is oxygen. R preferably is hydrogen. The moiety
preferably is bound at its 4 position with the 4 position on the 1 4-dihydropyridinyl moiety.
A further group of compounds of the invention is the compounds of formula laa
wherein R, R2, R4 and X are as defined above, R,aa is hydrogen or alkyl of 1 to 6 carbon atoms and R3aa is hydrogen; alkyl of 1 to 6 carbon atoms; nitro; trifluoromethyl; cyano; -COORasa; -CORa3a; or -S(O)nR7aa; wherein R5a is hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 2 to 6 carbon atoms where;n the hydroxy part is separated from the group to which Ra is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy part and of 2 to 6 carbon atoms in thp alkylene part, wherein the alkylene part is separated from the group to which R5a is bound by at least 2 carbon atoms; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; -AaaOCOR8aa; -AaaNR9aaR10aa or AaaN#aa; wherein R8a is alkyl of 1 to 6 carbon atoms; phenyl, phenylalkyl of 7 to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; hydroxyalkyl of 2 to 6 carbon atoms wherein the hydroxy part is separated from the group to which Ra5a is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy part and of 2 to 6 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which Ra5a is bound by at least 2 carbon atoms; R9a is hydrogen or has the significance indicated above for R3a; R1ao either is hydrogen or has the significance indicated above for R3a or is -COR1aaa wherein R11aa has the significance indicated above for R3a; - B aa is a 5-, or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6-or 7-membered, a further heteromember selected from oxygen, sulfur and NR12aa wherein Ra12a either is hydrogen or has the significance indicated above for R3a;; and Aaa is alkylene of 2 to 6 carbon atoms separating the group to which R5aa is bound by at least 2 carbon atoms; R8a and R7a with the exception of hydrogen have the significance indicated above for R6a, and n is as defined above; and their ammonium salts wherein R3aa is selected from one of the tertiary amino groups defined above for R3a and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
A further group of compound of the invention is the compounds of formula laaa
wherein R2, R4 and X are as defined above and R3aa is hydrogen; nitro; trifluoromethyl; cyano; -COOR5aa; or -COR6aa wherein R5a and R6a are as defined above, and their ammonium salts wherein R3aaa is selected from one of the tertiary amino groups defined above for R3aa and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
In a subgroup of compounds of formula laa or laaa and their corresponding ammonium salts R,aa is hydrogen. In another subgroup R2 and R4 are methyl. In another subgroup Xis oxygen. In another subgroup Xis sulfur. In another subgroup R3aaa is -COOR5aa wherein Rasta is as defined above. In a subgroup of compounds offormula laa and their corresponding ammonium salts R is hydrogen.
A preferrred group of compounds of the invention is the compounds of formula Ib
wherein R, R1 R2, R4 and X are as defined above and Rb is hydrogen; alkyl of 7 to 25 carbon atoms; nitro; trifluoromethyl; cyano; -COOR5b; -COR6b; or -S(O)nR7b; wherein Rb is hydrogen; alkyl of 7 to 25 carbon atoms; hydroxyalkyl of 7 to 24 carbon atoms wherein the hydroxy part is separated from the group to which Rs is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and 2 to 24 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which R5b is bound by at least 2 carbon atoms, with the proviso that at least one of the alkoxy and 'or alkylene parts is of at least 7 carbon atoms; alkenyl of 7 to 25 carbon atoms wherein the double bond is separated from the group to which R5b is bound by at least 1 carbon atom not participating in the double bond; alkinyl of 7 to 25 carbon atoms wherein the triple bond is separated from the group to which Rb is bound by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 7 to 24 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which Rb is bound 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 andlor alkylene parts is of at least 7 carbon atoms; phenyl, phenylalkyl of 13 to 30 carbon atoms or bis-phenylalkyl of 19 to 36 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms, the last 2 substituents optionally being bound to the rest of the molecule over an alkylene moiety of 7 to 24 carbon atoms; -AbOCOR8b; -AbNRgbR10b; or -AbNS b; wherein R8b is alkyl of 1 to 25 carbon atoms with the proviso that it is of 7 to 25 carbon atoms when Ab is of less than 7 carbon atoms; phenyl, phenylalkyl of 7 to 30 carbon atoms with the proviso that it is of 13 to 30 carbon atoms when Ab is of less than 7 carbon atoms, or bis-phenylalkyl of 13 to 36 carbon atoms with the proviso that it is of 19 to 36 carbon atoms when Ab is of less than 7 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independentlytrisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; hydroxyalkyl of 2 to 24 carbon atoms wherein the hydroxy part is separated from the group to which R8b is bound by at least 2 carbon atoms, with the proviso that it is of 7 to 24 carbon atoms when Ab is of less than 7 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which Rb3 is bound by at least 2 carbon atoms, with the proviso that when Ab is of less than 7 carbon atoms then at least one of the alkoxy and/or alkylene parts is of at least 7 carbon atoms; alkenyl of 3 to 25 carbon atoms wherein the double bond is separated from the group to which Rb3 is bound by at least 1 carbon atom not participating in the double bond, with the proviso that it is of 7 to 25 carbon atoms when Ab is of less than 7 carbon atoms; alkinyl of 3 to 25 carbon atoms wherein the triple bond is separated from the group to which R8b is bound by at least 1 carbon atom not participating in the triple bond, with the proviso that it is of 7 to 25 carbon atoms when Ab is of less than 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 24 carbon atoms in the alkylene part, with the proviso that it is of 7 to 24 carbon atoms in the alkylene part when Ab is of less than 7 carbon atoms; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which R3b is bound 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 when Ab is of less than 7 carbon atoms then at least one of the hydroxyalkoxy and/or alkylene parts is of at least 7 carbon atoms; aminoalkyl of 2 to 24 carbon atoms with the proviso that it is of 7 to 24 carbon atoms when Ab is of less than 7 carbon atoms, wherein the nitrogen atom is separated from the group to which R5b is bound by at least 2 carbon atoms and the amino part is optionally mono- or independently disubstituted by alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently dior independentlytrisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; Rbg is hydrogen or has the significance above for Rb.
R1b0 either is hydrogen or has the significance indicated abovefor Rb or is -COR1abwherein Ra,b hasthe significance indicated above for Rub5; NDBb is a 5-, 6- 7-membered saturated heterocyclic ring which may optionally contain, when it is 6-or 7-membered, a further heteromember selected from oxygen, sulfur and Nub12 wherein Rb either is hydrogen or has the significance indicated above for Rb. and Ab is alkylene of 2 to 24 carbon atoms separating the group to which Rb is bound by at least 2 carbon atoms; ; Rb and Rb with the exception of hydrogen have the significance indicated above for Rb. and n is as defined above; and their ammonium salts wherein Rb is selected from one of the tertiary amino groups defined above for Rb and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
A further preferred group of compounds of the invention is the compounds of formula Iba
wherein R, Ra1a, R2, R4 and X are as defined above and Rba is alkyl of 7 to 25 carbon atoms; -COOR5ba; -CORba; or -S(O)nR7ba; wherein R5a is alkyl of 7 to 25 carbon atoms; hydroxyalkyl of 7 to 24 carbon atoms wherein the hydroxy part is separated from the group to which R5ba is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and 2 to 24 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which R5ba is bound by at least 2 carbon atoms ,with the proviso that at least one of the alkoxy and/or alkylene parts is of at least 7 carbon atoms; alkenyl of 7 to 25 carbon atoms wherein the double bond is separated from the group to which Rb5a is bound by at least 1 carbon atom not participating in the double bond; alkinyl of 7 to 25 carbon atoms wherein the triple bond is separated from the group to which R5ba is bound by at least 1 carbon atom not participating in the triple bond; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 7 to 24 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which R5ba is bound 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 andlor alkylene parts is of at least 7 carbon atoms; phenylalkyl of 13 to 30 carbon atoms or bis-phenylalkyl of 19 to 36 carbon atoms, the last 2 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms, the last 2 substituents being bound to the rest of the molecule over an alkylene moiety of 7 to 24 carbon atoms; AbaOCOR5ba;AbaNR5baR%a; or AbaN5B ba; wherein Rba is alkyl of 1 to 25 carbon atoms with the proviso that it is of 7 to 25 carbon atoms when Aba is of less than 7 carbon atoms; phenyl, phenylalkyl of 7 to 30 carbon atoms with the proviso that it is of 13 to 30 carbon atoms when Aba is of less than 7 carbon atoms, or bis-phenylalkyl of 13 to 36 carbon atoms with the proviso that it is of 19 to 36 carbon atoms when Aba is of less than 7 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; hydroxyalkyl of 2 tc 24 carbon atoms wherein the hydroxy part is separated from the group to which R8ba is bound by at least 2 carbon atoms, with the proviso that is of 7 to 24 carbon atoms when Aba is of less than 7 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which R8ba is bound by at least 2 carbon atoms, with the proviso that when Aba is of less than 7 carbon atoms then at least one of the alkoxy and/or alkylene parts is of at least 7 carbon atoms; alkenyl of 3 to 25 carbon atoms wherein the double bond is separated from the group to which R8ba is bound by at least 1 carbon atom not participating in the double bond, with the proviso that it is of 7 to 25 carbon atoms when Aba is of less than 7 carbon atoms; alkinyl of 3 to 25 carbon atoms wherein the triple bond is separated from the group to which R8ba is bound by at least 1 carbon atom not participating in the triple bond, with the proviso that it is of 7 to 25 carbon atoms when Aba is of less than 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 24 carbon atoms in the alkylene part, with the proviso that it is of 7 to 24 carbon atoms in the alkylene part when Aba is of less than 7 carbon atoms; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which Rb5a is bound 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 when Aba is of less than 7 carbon atoms then at least one of the hydroxyalkoxy and/or alkylene parts is of at least 7 carbon atoms; aminoalkyl of 2 to 24 carbon atoms with the proviso that it is of 7 to 24 carbon atoms when Aba is of less than 7 carbon atoms, wherein the nitrogen atom is separated from the group to which R5ba is bound by at least 2 carbon atoms and the amino part is optionally mono- or independently disubstituted by alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently dior independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; R9ba is hydrogen or has the significance indicated above for R8ba;; R10ba either is hydrogen or has the significance indicated above for R8ba or is -COR11ba wherein R11ba has the significance indicated above for R8ba; -N#ba is a 5-, 6- or 7-membered saturated heteovyclic ring which may optionally contain, when it is 6- or 7-membered, a further heteromember selected from oxygen, sulfur and NR12ba wherein R12ba either is hydrogen or has the significance indicated above for Rb and Aba is alkylene of 2 to 24 carbon atoms separating the group to which Rb5a is bound by at least 2 carbon atoms; R6ba and R7ba with the exception of hydrogen have the significance indicated above for Rb5a; and n is as defined above; and their ammonium salts wherein R3ba is selected from one of the tertiary amino groups defined above for R2ba and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
A further preferred groups of compounds of the invention is the compounds of formula Ibaa
wherein R2, R4 and X are as defined above and R3baa is -COOR5baa or -COR6baa; wherein R5baa is alkyl of 9 to 19 carbon atoms; hydroxyalkyl of 9 to 18 carbon atoms wherein the hydroxy part is separated from the group to which R5baa is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 18 carbon atoms in the alkoxy part and 2 to 18 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which Rb5aa is bound by at least 2 carbon atoms, with the proviso that at least one of the alkoxy and/or alkylene parts is of at least 9 carbon atoms; hydroxyalkoxyalkyl of 2 to 18 carbon atoms in the hydroxyalkoxy part and of 2 to 18 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which R5baa is bound 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 andior alkylene parts is of at least 9 carbon atoms; -AbaaOCOR8baa; AbaaNRb5aaRb1a5a; or -AbaaN# baa; wherein R5baa is alkyl of 1 to 19 carbon atoms with the proviso that it is of 9 to 19 carbon atoms when Abaa is of less than 9 carbon atoms; phenyl, phenylalkyl of 7 to 24 carbon atoms with the proviso that it is of 15 to 24 carbon atoms when Abaa is of less than 9 carbon atoms, or bis-phenylalkyl of 13 to 30 carbon atoms with the proviso that it is of 21 to 30 carbon atoms when Abaa is of less than 9 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; hydroxyalkyl of 2 to 18 carbon atoms wherein the hydroxy part is separated from the group to which R8baa is bound by at least 2 carbon atoms, with the proviso that is is of 9 to 18 carbon atoms when Abaa is of less than 9 carbon atoms; alkoxy-alkyl of 1 to 18 carbon atoms in the alkoxy part and of 2 to 18 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which R8baa is bound by at least 2 carbon atoms, R9baa is hydrogen or has the significance indicated above for R8baa; R10baa either is hydrogen or has the significance indicated above for R8baa or is -COR11baa eherein R11baa has the significance indicated above for R8baa; -N#baa is a 5-, 6- or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6or 7-membered, a further heteromember selected from oxygen, sulfur and NR12baa wherein R12baa either is hydrogen or has the significance indicated above for R8baa; and Abaa is alkylene of 2 to 18 carbon atoms separating the group to which R5baa is bound by at least 2 carbon atoms; R5baa with the exception of hydrogen has the significance indicated above for Rb5aa; and n is as defined above; and their ammonium salts wherein R3baa is selected from one of the tertiary amino groups defined above for R3baa and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
A further group of compounds of the invention is the compounds of formula Ic
wherein R, R1, R2, R4 and X are as defined above and R3 is hydrogen; nitro; trifluoromethyl; cyano; -COOR5c; -COR6c; or -S(O)R07; wherein R5C is hydrogen; cycloalkyl of 3 to 7 carbon atoms; phenyl optionally mono- or independently di- or independently trisubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; R6c and R7C with the exception of hydrogen have the significance indicated above for R5C; and n is as defined above.
A further group of compounds of the invention is the compounds of formula Ica
wherein R2, R4 and X are as defined above and R3a is hydrogen; nitro; trifluoromethyl; cyano; -COOR5ca; or -COR6a; wherein R5a is hydrogen or a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur; and R6a with the exception of hydrogen has the significance indicated above for R5a.
Afurther group of compounds of the invention is the compounds of formula Id
wherein R,d to R4 and Qd have the significance indicated above for R1 to R4 and 0, respectively, with the proviso that the substituents at the 2- and 6-positions and/or at the 3- and 5-positions of the 1,4-dihydropyridinyl moiety are different, and their ammonium salts wherein Rd is selected from one of the tertiary amino groups defined above for Rd3 and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
A further group of compounds of the invention is the compounds of formula le
wherein Re to Re and Oe have the significance indicated above for R1 to R4 and Q, respectively, with the proviso that the substituents at the 2- and 6-positions and/or at the 3- and 5- positions of the 1,4-dihydropyridinyl moiety are different, and their ammonium salts wherein Re is selected from one of the tertiary amino groups defined above for R3e and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
In subgroups of compounds of formula Id and le and their corresponding ammonium salts the substituents have the significances indicated above for the compounds of formula la, laa, laaa, Ib, Iba, Ibaa, Ic and Ica, respectively.
A further group of compounds of the invention is the compounds of formula Ip
wherein -COOR5P is an ester group.
Further groups of compounds of the invention are the compounds of formula lp wherein R5 is, respectively: a) cycloalkyl of 4to 6 carbon atoms; b) alkyl of 1 to 12 carbon atoms or alkoxyalkyl of 1 to 10 carbon atoms in the alkoxy part and 2 to 11 carbon atoms in the alkylene part wherein the alkoxy part is separated from the group to which R5 is bound by at least 2 carbon atoms and with the proviso that the alkoxy and alkylene parts together are of less than 13 carbon atoms; and c) -APNRP9R%; or -ApN#p; wherein R9p is hydrogen; alkyl of 1 to 4 carbon atoms; phenyl, phenylalkyl of 7 to 10 carbon atoms or bis-phenylalkyl of 13 to 16 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; R10p is hydrogen or alkyl of 1 to 4 carbon atoms; -NQB P its a 5-, 6- or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6-or 7-membered, a further heteromember selected from oxygen, sulfur and = NR1P2 wherein R12 has the significance indicated above for R9p; and AP is straight-chained alkylene of 2 to 12 carbon atoms separating the group to which R5 is bound by at least 2 carbon atoms.
In a subgroup from group a) of compounds of formula Ip R5 is cyclopentyl or cyclohexyl. In a subgroup from group b) of compounds of formula Ip R5P is alkyl of 1 to 8 carbon atoms.
A further group of compounds of the invention is the compounds of formula Is
wherein X is as defined above; R2 and R4 independently are alkyl of 1 to 4 carbon atoms and R3 is hydrogen; nitro; trifluoromethyl; cyano; -COOR5s; or -COR5; wherein R5 is hydrogen; alkyl of 1 to 12 carbon atoms; hydroxyalkyl of 2 to 6 carbon atoms wherein the hydroxy part is separated from the group to which R55 is bound by at least 2 carbon atoms; -SsNR9sR10s; or -AsN B S; wherein R9s and Re independently are hydrogen; alkyl of 1 to 4 carbon atoms; phenylalkyl of 7 to 10 carbon atoms optionally mono- or independently disubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms or halogen of atom number of from 9 to 53; -NOB5 is piperidinyl or piperazinyl both optionally substituted in the 4 position by methyl, benzyl or bis-phenylmethyl, the last 2 substituents optionally being mono- or independently disubstituted in the phenyl ring(s) by alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 53; and As is alkylene of 2 to 14 carbon atoms separating the group to which R5 is bound by at least 2 carbon atoms; R55 is imidazolyl; and their ammonium salts wherein R35 is selected from one of the tertiary amino groups defined above R3s and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
Further groups of compounds of the invention are the compounds of formula I, la, laa, laaa, Ib, Iba, Ibaa, Ic, Ica, Id, le and Is wherein R3, R35, R3a, R3555, R3b, R3ba, Rb3aa, R3, R3a, Rd3, R3e and R35 are respectively ester groups as defined above under the corresponding formula, and where appropriate their corresponding ammonium salts as defined above.
Further groups of compounds of the invention are the compounds of formula la, 1aa, laaa, lb, Iba, Ibaa, Ic, Ica and Is wherein Xis sulfur and where appropriate their corresponding ammonium salts as defined above.
A compound of the invention may be obtained by a process comprising a) appropriately condensing to a 1,4-dihydropyridine a corresponding compound of formula II
wherein Q is as defined above, a corresponding compound of formula Ill
wherein R2 and R3 are as defined above, a corresponding compound of formula IV
wherein R4 is as defined above, and a corresponding compound of formula V
wherein R1 is as defined above, or a partial condensation product thereof, or b) for the production of a compound of formula I'
wherein R1, R2, R4 and 0 are as defined above and R3 is hydrogen, -COOR5 or -COR6) wherein R5 and R6 are as defined above, appropriately converting a corresponding compound offormula VI
wherein R1, R2, R4 and Q are as defined above and Xis a reactive group.
The process of the invention may be effected in a manner analogous to known processes.
The choice of the most appropriate process conditions depends of course on the nature of e.g.
substituents R1 and R3.
Process variant a) may be effected e.g. according to Hantzsch. The reaction may be effected conveniently in solution. A suitable solvent is water, ethanol, dioxane, dimethyl formamide, dimethyl sulfoxide, pyridine or glacial acetic acid.
Suitable reaction temperatures may be from 20 to 160"C, preferably from 60 to 120-C.
Process variant b) may also be effected in conventional manner. The choice of the most appropriate reaction conditions depends of course primarily on the nature of group R3. When R3 is hydrogen then X may e.g. be a carboxyl group and the conversion reaction is a decarboxylation. When R3 is -COR6 then X may e.g.
be carboxyl and the conversion reaction is then a substitution. When R3 is a carboxyl group then X may e.g.
be an easily splittable ester group such as an ammonium ester group and the conversion reaction is then a hydrolysis.
When R3 is an ester group then X may e.g. be a group -COX wherein X' is a reactive group suitable for producing an ester.
The ester-producing conversion may e.g. be an esterification reaction. X' is then conveniently 1 H-imidazol-1-yl This process variant is indicated e.g. for converting into a hydroxyalkyl, amidoalkyl, alkoxyalkyl, acyloxyalkyl or substituted or unsubstituted aminoalkyl ester substituent. A corresponding compound of formula VI wherein X is e.g. 1 H-imidazol-1-yl-carbonyl is thus reacted with a corresponding diol, amidolalcohol, esterfalcohol or aminoalcohol. As a solvent dioxane or an excess of the reaction partner may conveniently be used. Afurther ester-producing conversion may e.g. be an amination. This variant is indicated e.g. for converting into an aminoalkyl ester substituent.A reactive group X is then conveniently e.g. a group -COOAX" wherein A is as defined above and X" is chlorine, bromine or a group Rz-SO2-O- wherein Rz is phenyl, tolyl or lower alkyl. X" preferably is mesyloxy. The amination may be direct, i.e.
reaction takes place directly with an amine having the substituent to be introduced, or indirect, e.g. for introducing a primary amino group, by first converting into a corresponding pthalimidoalkyl derivative, e.g.
by reaction with sodium or potassium phthalimide and subsequently reacting the resultant phthalimidoalkyl derivative with hydrazine. The indirect method is preferred when the substituent it is desired to introduce is a primary aminoalkyl group. A further ester-producing conversion may e.g. be an acylation of a primary or secondary amine. A reactive group X is then conveniently the corresponding primary or secondary amino alkoxy carbonyl group. A corresponding compound of formula VI is thus reacted with a corresponding acyl derivative, e.g. an N-hydroxysuccinimid-ester. A suitable solvent is e.g. dioxane. A further ester-producing conversion may e.g. be an acylation of an alcohol. A reactive group X is then conveniently the corresponding hydroxyalkoxycarbonyl group. A corresponding compound of formula VI is thus reacted with a corresponding acyl derivative, e.g. an acyl halide.The reaction preferably is effected in the presence of a strong base such as N-ethyldiisopropylamine. A suitable solvent is e.g. methylene chloride. A further ester-producing conversion may e.g. be an etherification. A reactive group X is then conveniently a group -COOAX" wherein A and X" are as defined above. The reaction preferably is effected under strongly alkaline conditions.
A quaternary ammonium salt may also be obtained in a manner analogous to known methods, e.g. by reaction with a corresponding (lower) alkyl iodide. A suitable solvent is e.g. an alcohol, such as methanol.
When potentially reactive groups such as hydroxy or primary or secondary amino are present it may be indicated to effect the process of the invention with these groups in protected form, e.g. for phenolic hydroxy in the form of a benzyloxy group, or for aliphatic hydroxy in the form of a tetrahydropyranyloxy moiety, or for amino in the form of an acylamino or a phthalimido group and to convert thereafter any protecting group present as such into the desired substituent, e.g. benzyloxyto hydroxy, e.g. hydrogenolytically; tetrahydropyranyloxy to hydroxy, e.g. by acid hydrolysis; and protected amino to deprotected amino, e.g. by acid hydrolysis or hydrazinolysis.
A compound of the invention may be isolated from the reaction mixture and purified in a manner analogous to known methods.
A compound of the invention may exist in free form or where appropriate in salt form. A free form of a compound normally is neutral unless substituted by an ionizable substituent. A salt form may exist e.g.
when an ionizable substituent is present, such as amino or phenolic hydroxy. A free form may be converted into a salt form in conventional manner and vice-versa. Suitable acids for acid addition salt formation include hydrochloric, malonic, p-toluene sulfonic and methanesulfonic acid. Suitable bases for anionic salt formation include sodium and potassium hydroxide.
When the substituents in the 2 and 6 positions and/or in the 3 and 5 positions of the 1,4-dihydropyridinyl moiety are different the carbon atom in the 4 position is asymmetrically substituted. A corresponding compound of the invention may thus exist in the racemic form or in individuai enantiomerform.
Individual optical isomer forms may be obtained in conventional manner, e.g. by fractional crystallization, e.g. of optically active diastereoisomeric salts or by transesterification of optically pure esters having an easily splittable, preferably basic ester group such as dimethylaminoethoxycarbonyl.
Insofar as the preparation of any particular starting material is not particularly described, this may be effected in conventional manner or in analogous manner to that described herein.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected.
Example 1: 4-(2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2,6-dimethyl-5-nitro-pyridine-3-carboxylic acid ethyl ester [process variant a); condensation of the condensation product of compounds offormula 'II and IV with the ---- condensation product of compounds of formula III and V] 3.5 g of 1-(2,1,3-benzoxadiazol-4-yl)-2-nitro-1-buten-3-one and 1.95 g of 3-aminocrotonic acid ethyl ester are heated under refluxing in 50 ml dioxane for 6 hours. The mixture is then evaporated to dryness and the product chromatographed over silicagel using methylene chloride/ether as an eluent. The title compound is obtained (M.P. 197 -from ether).
The starting material is obtained by heating under refluxing for 35 hours a mixture of 44 g of 2,1,3-benzoxadiazol-4-carboxaldehyde, 30.6 g nitroacetone, 1.26 g piperidine and 1.78 g acetic acid in 700 ml benzene. After subsequent chromatographic purification over silicagel using methylene chloride as an eluant 1-(2,1,3-Benzoxadiazol-4-yl)-2-nitro-1-buten-3-one (M.P. 1 CS - from ether) is obtained.
The title compound of Example 1 is also obtained according to process variant a) using the following corresponding starting materials for the condensation to a 1 ,4-dihydropyridine: Example Starting materials (compounds of formula -- as indicated below or No. condensation products thereof ------- as indicated below) 2 2,1,3-benzoxadiazol-4-aldehyde (II) + acetoacetic acid ethyl ester (III) + nitroacetone (IV) + ammonia (V) 3 2-acetyl-3-(2,1 ,3-benzoxadiazol-4-yl)-2-propenic acid ethyl ester (II + III) + nitroacetone (IV) + ammonia (V) 4 1-(2,1,3-tenzoxadiazol-4-yl)-2-nitro-1-buten-3-on(II+IV)+acetoacetic acid ethyl ester (III) + ammonia (V) 5 2,1,3-benzoxadiazol-4-aldehyde (II) + 3-aminocrotonic acid ethyl ester (Ill + V) + nitroacetone (IV) 6 2,1 ,3-benzoxadiazol-4-aldehyde (II) + acetoacetic acid ethyl ester (III) + 2-amino-1-nitro-1-propene (IV + V) 7 2-acetyl-3-(2,1,3-benzoxadiazol-4-yl)-2-propenic acid ethyl ester (II + III) + 2-amino-1-nitro-1-propene (IV t V) Example 8: 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-pyridine-3-carboxylic acid ethyl ester [process variant b); conversion of imidazolide] A mixture of 1.5 g 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-3-(1 H-imidazol-1 -ylcarbonyl)-2,6-dimethyl-5nitropyridine and 30 ml ethanol are heated to boiling for 8 hours.The mixture is evaporated to dryness, the residue is chromatographed over silicagel using ether as an eluant. The title compound is obtained (M.P.
195 -from ether).
The following compounds of formula are obtained in alalogous manner from the corresponding starting materials:
Exam Analogous Q R1 R2 R3 R4 Konfiguratio Melting point ple to the 4-positio No. Example 1,4-dihydro No. nyl moiety 9 1 to 7;8 2,1,3-benzoxa- H Me -COOiPr Me (R,S) n 146 diazol-4-yl 10 1 to 7;8 2,1,3-benzoxa- H Me -COO(CH2)7CH3 Me (R,S) n 131 diazol-4-yl 11 1 to 7;8 2,1,3-benzoxa- H Me -COOMe Me (R,S) n 205 diazol-4-yl 12 1 to 7;8 2,1,3-benzoxa- H Me -COO(CH2)2NMe2 Me (R,S) ch 275 diazol-4-yl {b 128 13 1 to 7;8 2,1,3-benzoxa- H Me -COO(CH2)2NMe2 Me (R,S) n amorphous diazol-4-yl 14 1 to 7;;8 2,1,3-benzoxa- H Me -COOiPr Me (R,S) n 151-154 diazol-4-yl 15 1 to 7;8r) 2,1,3-benzoxa- H Me -COO(CH2)10NMeBz Me (R,S) ch amorphous diazol-4-yl 16 1 to 7;8s) 2,1,3-benzoxa- H Me -COO(CH2)10 N(Me)(#H2)2 Me (R,S) ch amorphous diazol-4-yl 17 1 to 7;8t) 2,1,3-benzoxa- H Me -COO(CH2)10 #-CHPhe2- Me (R,S) fu 125-127 diazol-4-yl 18 1 to 7;8u) 2,1,3-benzoxa- H Me -COO(CH2)10OH Me (R,S) n 117-121 diazol-4-yl 19 1 to 7;;8k) 2,1,3-benzoxa- H Me 1H-imidazol-1- Me (R,S) n 190 diazol-4-yl ylcarbonyl
20 1 to 7;8l) 2,1,3-benzothia diazol-4-yl H Me 1H-imidazol-1- Me (R,S) n amorphous ylcarbonyl 21 1 to 7;8l) 2,1,3-benzothia diazol-4-yl H Me -COOH (R,S) n 227 22 1 to 7;;8l) 2,1,3-benzothia diazol-4-yl H Me -COOH Me (R,S) n amorphous 23 p) 2,1,3-benzothia- (1) diazol-4-yl H Me -COO(CH2)2 NMe3l(-) Me (R,S) - 246 24 q) 2,1,3-benzothia- (+) diazol-4-yl H Me -COO(CH2)2 NMe3l(-) Me (R,S) - amorphous 25 1 to 7;;8l)m) 2,1,3-benzothia diazol-4-yl H Me -H Me (R,S) n 201-202 26 1 to 7 2,1,3-benzothia diazol-4-yl H Me -CN Me (R,S) n 236-237 27 1 to 7 2,1,3-benzothia diazol-4-yl H Me -CN Me (R,S) n 198-200 28 1 to 7 2,1,3-benzothia diazol-4-yl H Me -NO2 Me (R,S) n 217-219 29 8a) 2,1,3-benzothia- n 172 diazol-4-yl H Me -COOiPr Me (+) (S) [α]=56 ;[α ;]546=+95 (MeOH,c=0.53 g/dl) 30 8b) 2,1,3-benzothia diazol-4-yl H Me -COOiPr Me (-) (R) n 172 [#] [α]D20=-57 ;[α]546=-96 31 8b) 2,1,3-benzothia diazol-4-yl H Me -COOMe Me (-) (R) n 188 [α]D20=-91 ;[α]546=-147 (MeOH,c=0.5 g/dl) 32 8a) 2,1,3-benzothia diazol-4-yl H Me -COOMe Me (+) (S) n 188 [αD20=+91 ;[α]546=+146 (MeOH, c=0.5g/dl)
33 8a) 2,1,3-banzoxa- H Me 1H-imidazol-1- Me (-) (S) n 190 diazol-4-yl ylcarbonyl [α]D20=17 ;;[α]546=-20 (MeOH; c=0.5 g/dl) 34 8d) 2,1,3-banzoxa- H Me 1H-imidazol-1- Me (+) (R) n 190 diazol-4-yl ylcarbonyl [α]D20=17 ;[α]546=+20 (MeOH; c=0.5 g/dl) 35 8e) 2,1,3-banzoxa- H Me -COOH Me (+) (S) N 200 diazol-4-yl [α]D20=+126 ;[α]546=+157 (MeOH, c=0.5 g/dl) 36 8f) 2,1,3-banzoxa- H Me -COOH Me (-) (R) n 200 diazol-4-yl [α]D20=-126 ;[α;]546=-157 (+) (MeOH, c=0.5 g/dl) 37 g) 2,1,3-banzoxa- H Me -COO(CH2)2NMe3 I(-)Me (-) (S) - 116 diazol-4-yl [α]D20-80 ;[α]546=-108 (+) (MeOH;c=0.5g/dl) 38 h) 2,1,3-banzoxa- H Me -COO(CH2)2NMe3 I(-)Me (+) (R) - 116 diazol-4-yl [α]D20=+80 ;[α546=+108 (MeOH,c=0.5 g/dgl) 39 i) 2,1,3-banzoxa- H Me -COO(CH2)2NMe2 Me (-) (S) b 161 diazol-4-yl [α]D20=+21 ;;[#]546=-14 (MeOH,c=0.5g/dl) 40 j) 2,1,3-banzoxa- H Me -COO(CH2)2NMe2 Me (+) (R) b 161 diazol-4-yl [α]D20=+21 ;[#]546=+14 (MeOH,c=0.5g/dl) Bz = benzyl Me = methyl Phe = phenyl b = in free base form ch = in hydrochloric acid addition salt form fu = in fumaric acid addition salt form n = in free neutral or acidic form a) using the compound of Example 33 as a starting material b) using the compound of Example 34 as a starting material C) using the compound of Example 35 as a starting material, by reaction with 1,1 '-carbonyl-diimidazole in dioxane and subsequent chromatographic purification over silicagel using methylene chloride/ethanol (19:1) as an eluant.
d) using the compound of Example 36 as a starting material, as described under c) e) using the compound of Example 37 as a starting material, by hydrolysis with 2N sodium hydroxide solution at room temperature.
fl using the compound of Example 38 as a starting material, as described bye).
9) using the compound of Example 39 as a starting material, by quaternisation of the free base form with methyl iodide in acetone at room temperature.
h) using the compound of Example 40 as a starting material, as described under g).
using the compound of Example 12 in free base as a starting material, by fractionation with (- )-di-O,O'-p-toluoyl-L-tartaric acid in methanol.
as as described under i), by fractionation with (+ )-di,-O,O'-p-toluoyl-D-tartaric acid.
k) using the compound of Example 21 as a starting material as described under c).
using the compound of Example 22 as a starting material, as described under c).
m) by decarboxylation of the compound of Example 21 by heating with traces of sulfuric acid in ethanol.
n) using the compound of Example 23 as a starting material, as described under e).
) using the compound of Example as a starting material, as described under e).
P using the compound of Example 12 as a starting material, as described under g).
q) using the compound of Example 13 as a starting material, as described under g).
r) using the compound of Example 18 as a starting material, by reaction with methanesulfonic acid chloride in methylene chloride in the presence of ethyl-diisopropylamine at 0" and then reacting the resultant mesylate (oil) with N-methyl benzylamine at 150'.
as as described under r) but reacting the resultant mesylate with N-methylhomoveratrylamine instead of with N-methylbenzylamine.
as as described r) but reacting the resultant mesylate with benzhydrylpiperazine instead of with N-methylbenzylamine.
u) using the compound of Example 19 as a starting material, by reacting with an excess of 1,10-decandiol in dioxane at 100 .
The compounds of the invention possess pharmacological activity.
The compounds exhibit effects typical of calcium antagonists. They exhibit a pronounced muscle-relaxing effect, particularly on smooth muscle, as evidenced by vasodilating and blood pressure lowering activity in standard tests. For example in the anaesthetized cat test using tracer microspheres (R: Hof et al., Basic Res.
Cardiol. 75 [1980] 747-756 and 76 [1981] 630-638; R. Hof et al., J. Cardiovasc. Pharmacol. 4[1982]352-362) coronary vasodilation, an increase in skelettal muscle blood flow and a fall in blood pressure are observed upon intravenous administration of from about 30 to about 1000 ug/kg, e.g. of from about 100 to about 500 -lg/kg.
Afall in blood pressure is also observed in the conscious spontaneously hypertensive rat (method of Gerold and Tschirki,Arzneimittelforsch. 18 [1968] 1285) upon administration of from about 1 to about 10 mg/kg p.o. of the compounds.
The compounds are therefore indicated for use as calcium antagonists for the prevention and treatment of - coronary insufficiency, e.g. Angina pectoris; - other disturbances in peripheral circulation e.g. in limbs such as intermittent claudication and spasms, e.g.
cholic; - asthma, e.g. exertion-related asthma; - hypertension; - heart insufficiency, e.g. ischaemic heart failure.
The compounds also have a vasodilating activity on capillary vessels of the carotid area; the vasoconstrictor effect of serotonin is thereby antagonized and the associated dysregulation inhibited. This makes the compounds indicated for the prevention and treatment of migraine and vascular headache such as cluster headache, especially for the interval treatment (prevention) of migraine. They are more potent and effective than flunarizine. Preferred in this indication are the compounds having a relatively moderate effect on blood pressure and peripheral blood vessels.
Further, the compounds have very little negative-inotropic activity. They are therefore not cardiodepressant and even possess some degree of cardiostimulant activity. Thus if desired it is possible to use relatively large daily dosages even in patients for whom the administration of calcium antagonists is generally contra-indicated, such as patients with cardiac failure.
In those compounds asymmetrically substituted at the 4-position of the 1,4-di 1 ,4-dihydropyridinyl moiety this lacks of cardiodepression may appear to a varying degree in one or the other enantiomeric form.
An indicated daily dosage is from about 10 mg to about 1600 mg, suitably administered, e.g. orally, in divided dosages of from about 2.5 mg to about 800 mg of the compounds 1 to 3 times a day, or in sustained release form.
The preferred indications are coronary insufficiency and heart insufficiency, particularly ischaemic heart failure.
Preferred for the prevention and treatment of migraine and vascular headache are the compounds wherein Qis a 2,1 ,3-benzothiadiazolyl moiety.
The compounds ofthe invention may be administered in free form or where appropriate in pharmaceutically acceptable salt form, preferably acid addition salt form. Such salt forms exhibit the same order of activity as the free forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of the invention in free form or where appropriate in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent.
Such compositions may be formulated to be used for enteral, preferably oral, administration, e.g. tablets, or parenteral administration, e.g. injectable solutions or suspensions. Sublingual administration is preferred.

Claims (85)

1. A process for the production of a compound of formula I
wherein R1 is hydrogen; cycloalkyl of 3 to 7 carbon atoms; or optionally substituted alkyl of 1 to 6 carbon atoms; R2 and R4 independently are hydrogen or alkyl of 1 to 6 carbon atoms; R3 is hydrogen; alkyl of 1 to 25 carbon atoms; nitro; trifluoromethyl; cyano; -COOR5; -COR6; or -S(O)nR7; wherein -COORs is carboxyl or an ester group; R5 is alkyl of 1 to 25 carbon atoms; hydroxyalkyl of 2 to 24 carbon atoms wherein the hydroxy part is separated from the group to which R5 is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and 2 to 24 atoms in the alkylene part, wherein the alkoxy part is separated from the group to which Re is bound by at least 2 carbon atoms; alkenyl of 3 to 25 carbon atoms wherein the double bond is separated from the group to which R5 is bound by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 25 carbon atoms wherein the triple bond is separated from the group to which R5 is bound by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkyalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 24 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which R5 is bound 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; phenyl, phenylalkyl of 7 to 30 carbon atoms or bis-phenylalkyl of 13 to 36 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independentlytrisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms, the last 2 substituents optionally being bound to the rest of the molecule over an alkylene moiety of 1 to 24 carbon atoms; -AOCOR5; -ANRgR10; or -ANs :wherein R5 is alkyl of 1 to 25 carbon atoms; phenyl, phenylalkyl of 7 to 30 carbon atoms or bis-phenylalkyl of 13 to 36 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; hydroxyalkyl of 2 to 24 carbon atoms wherein the hydroxy part is separated from the group to which R8 is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which R8 is bound by at least 2 carbon atoms; alkenyl of 3 to 25 carbon atoms wherein the double bond is separated from the group to which R8 is bound by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 25 carbon atoms wherein the triple bond is separated from the group to which R5 is bound by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 24 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which R5 is bound 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 of 2 to 24 carbon atoms wherein the nitrogen atom is separated from the group to which R5 is bound by at least 2 carbon atoms and the amino part is optionally mono- or independently disubstituted by alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; Rg is hydrogen or has the significance indicated in this claim for R8;; Ro either is hydrogen or has the significance indicated in this claim for R8 or is -COR11 wherein R11 has the significance indicated in this claim for R8; - í9) is a 5-, 6- or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6-or 7-membered, a further heteromember selected from oxygen, sulfur and = NR12 wherein R12 either is hydrogen or has the significance indicated in this claim for R5 and A is alkylene of 2 to 24 carbon atoms separating the group to which Re is bound by at least 2 carbon atoms; R7 mutatis mutandis has the significance indicated in this claim for Rg; nits0,1 or2;; o is a condensed, fully unsaturated ring system having at least 2 different ring heteroatoms overall and having aromatic character; and its ammonium salts wherein R3 is selected from one of the tertiary amino groups defined in this claim for R3 and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid, which comprises a) appropriately condensing to a 1,4-dihydropyridine a corresponding compound of formula 11
wherein Q is as defined in this claim, a corresponding compound of formula Ill
wherein R2 and R3 are as defined in this claim, a corresponding compound of formula IV
wherein R4 is as defined in this claim, and a corresponding compound of formula V
wherein R1 is as defined in this claim, or a partial condensation product thereof or b) for the production of a compound of formula I'
wherein R1, R2, R4 and 0 are as defined in this claim and R'3 is hydrogen, -COOR5 or -COR6 wherein R5 und R5 are as defined in this claim, appropriately converting a corresponding compound of formula VI
wherein R1, R2, R4 and 0 are as defined in this claim and X is a reactive group and where appropriate recovering a resultant compound wherein R3 is selected from one of the tertiary amino groups defined in this claim for R3 is quaternary ammonium salt form with a compound of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
2. A process for the production of a compound of formula I as defined in claim 1 or where appropriate a quaternary ammonium salt thereof as defined in claim 1, substantially as hereinbefore described with reference to any one of the Examples.
3. A compound of formula las defined in claim 1 or where appropriate a quaternary ammonium salt thereof as defined in claim 1, whenever produced by a process according to claim 1.
4. A compound of formula I as defined in claim 1 or where appropriate a quaternary ammonium salt thereof as defined in claim 1.
5. A compound of claim 4 in unquaternized form.
6. A compound of claim 4 wherein R5 has mutatis mutandis the significance indicated in claim 1 for R5.
7. A compound of claim 4 wherein R1 is hydrogen.
8. A compound of claim 4 wherein R2 and R4 are alkyl.
9. A compound of claim 4 wherein R3 is nitro, trifluoromethyl, -COOR5 or -COR6.
10. Acompound of claim 4wherein Qis a bicyclicsystem.
11. A compound of claim 4 wherein Q is 2,1 ,3-benzoxadiazolyl.
12. Acompound of claim 4wherein Qis 2,1,3-benzothiadiazolyl.
13. A compound of claim 4 wherein Y is halogen.
14. A compound of claim 4 of formula la
wherein R2 and R4 are as defined in claim 1, R1a is hydrogen; alkyl of 1 to 6 carbon atoms; alkenyl of 3 to 6 carbon atoms wherein the double bond is separated from the nitrogen atom by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 6 carbon atoms wherein the triple bond is separated from the nitrogen by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 4 to 8 carbon atoms; hydroxyalkyl of 2 to 6 carbon atoms wherein the hydroxy part is separated from the nitrogen atom by at least 2 carbon atoms; alkoxyalkyl of 2 to 6 carbon atoms; or phenylalkyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms wherein the double bond is separated from the nitrogen atom by at least 1 carbon atom not participating in the double bond, the last two substituents optionally being independently mono-, di- or trisubstituted in the phenyl ring by independently alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen of atomic number of from 9 to 35 or hydroxy; alkylcarbonyloxyalkyl of 2 to 6 carbon atoms in the alkylcarbonyl and alkylene moieties thereof and wherein oxygen is separated from the nitrogen atom by at least 2 carbon atoms; dialkylaminoalkyl independently of 1 to 6 carbon atoms in the alkyl moieties of 2 to 6 carbon atoms in the alkylene moiety thereof and wherein the amino group is separated from the nitrogen atom by at least 2 carbon atoms; or morpholinoalkyl of 2 to 6 carbon atoms in the alkylene moiety thereof and wherein the morpholino moiety is separated from the nitrogen atom by at least 2 carbon atoms; R3 is hydrogen; alkyl of 1 to 6 carbon atoms; nitro; trifluoromethyl; cyano; -COOR5; -COR55;or -S(O)R75; wherein R5 is hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 2 to 6 carbon atoms wherein the hydroxy part is separated from the group of which Ra is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy part and of 2 to 6 carbon atoms in the alkylene part, wherein the alkylene part is separated from the group to which R55 is bound by at least 2 carbon atoms; alkenyl of 3 to 6 carbon atoms wherein the double bond is separated from the group to which R5 is bound by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 6 carbon atoms wherein the triple bond is separated from the group to which Ra is bound by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 6 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 6 carbon atoms in the alkoxy part and of 2 to 6 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which Ra is bound 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; phenyl, phenylalkyl of 7 to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms, the last 2 substituents optionally being bound to the rest of the molecule over an alkylene moiety of 1 to 6 carbon atoms; -AaOCOR8; -AaNRgR1ao; orAaNi) a; wherein R8 is alkyl of 1 to 6 carbon atoms; phenyl, phenylalkyl of 7 to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with a heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; hydroxyalkyl of 2 to 6 carbon atoms wherein the hydroxy part is separated from the group to which R8 is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy part and of 2 to 6 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which R8 is bound by at least 2 carbon atoms; alkenyl of 3 to 6 carbon atoms wherein the double bond is separated from the group to which R3 is bound by at least 1 carbon atom not participating in the double bond; alkinyl of 3 to 6 carbon atoms wherein the triple bond is separated from the group to which R3 is bound by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 6 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 6 carbon atoms in the hydroxyalkoxy part and of 2 to 6 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group of which R8a is bound by at least 2 carbon atoms and hydroxy part is separated from the oxygen atom of the alkoxy part by at least 2 carbon atoms; aminoalkyl of 2 to 6 carbon atoms wherein the nitrogen atom is separated from the group to which R8 is bound by at least 2 carbon atoms and the amino part is optionally mono- or independently disu bstituted by alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; Rg is hydrogen or has the significance indicated in this claim for Ra.
R1ao either is hydrogen of has the significance indicated in this claim for R3 or is -COR1a1 wherein R511 has the significance indicated in this claim for R3; -N#a is a 5-, 6- or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6- or 7-membered, a further heteromember selected from oxygen, sulfur and NR1a2 wherein Ra either is hydrogen or has the significance indicated in this claim for R3; and Aa is alkylene of 2 to 6 carbon atoms separating the group to which Ra is bound by at least 2 carbon atoms;; R6 and Ra with the exception of hydrogen have the significance indicated in this claim for Rsa; and n is as defined in claim 1; Xis oxygen or sulfur and R is 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 of atomic number of from 9 to 35; trifluoromethyl; nitro; or hydroxy; and its ammonium salts wherein R3 is selected from one of the tertiary amino groups defined in this claim for R3 and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
15. A compound of claim 4 of formula laa
wherein R2 and R4 are as defined in claim 1, R and X are as defined in claim 14, R515 is hydrogen or alkyl of 1 to 6 carbon atoms and R3aa is hydrogen; alkyl of 1 to 6 carbon atoms; nitro; trifluoromethyl; cyano; -COOR5aa; -COR6aa; or -S(O)R575; wherein R5a is hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 2 to 6 carbon atoms wherein the hydroxy part is separated from the group to which R5 is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy part and of 2 to 6 carbon atoms in the alkylene part, wherein the alkylene part is separated from the group to which R5a is bound by at least 2 carbon atoms; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; -AaaOCOR8aa; -AaaNR9aaR10aa; orAaaN B aa; wherein R555 is alkyl of 1 to 6 carbon atoms; phenyl, phenylalkyl of to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; hydroxyalkyl of 2 to 6 carbon atoms wherein the hydroxy part is separated from the group to which R8a is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy part and of 2 to 6 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which R8a is bound by at least 2 carbon atoms; Raga is hydrogen or has the significance indicated in this claim for R8a; R5105 either is hydrogen or has the significance indicated in this claim for R8a or is -COR1a1a wherein R1a1a the significance indicated in this claim for R8a;; -N#a is a 5-, 6- or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6- or 7-membered, a further heteromember selected from oxygen, sulfur and NR11aa wherein R12aa either is hydrogen or has the significance indicated in this claim for R8a; and Aaa is alkylene of 2 to 6 carbon atoms separating the group to which R555 is bound by at least 2 carbon atoms; R6a and R575 with the exception of hydrogen have the significance indicated in this claim for R5a; and n is as defined in claim 1; and their ammonium salts wherein Ra3a is selected from one of the tertiary amino groups defined in this claim for R535 and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
16. A compound of claim 4 of formula laaa
wherein R2 and R4 are as defined in claim 1,X is as defined in claim 14 and R3aaa is hydrogen; nitro; trifluoromethyl; cyano; -COOR5aa; or -COR6aa; wherein R5aa and R6aa are as defined in claim 15, and its ammonium salts wherein Ra3aa is selected from one of the tertiary amino groups defined in this claim for R5355 and quarternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid, in free form or where appropriate in pharmaceutically acceptable salt form.
17. A compound of claim 4 of formula Ib
wherein R2 and R4 are as defined in claim 1, R, R1a and X are as defined in claim 14 and R3@ is hydrogen; alkyl of 7 to 25 carbon atoms; nitro; trilfuoromethyl; cyano; -COOR5b; -COR6b; or S(O)nR7b; wherein Rb is hydrogen; alkyl of 7 to 25 carbon atoms; hydroxyalkyl of 7 to 24 carbon atoms wherein the hydroxy part is separated from the group to which Rb is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and 2 to 24 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which Rb is bound by at least 2 carbon atoms, with the proviso that at least one of the alkoxy and/or alkylene parts is of at least 7 carbon atoms; alkenyl of 7 to 25 carbon atoms wherein the doubel bond is separated from the group to which R5b is bound by at least 1 carbon atom not participating in the double bond; alkinyl or 7 to 25 carbon atoms wherein the triple bond is separated from the group to which Rb is bound by at least 1 carbon atom not participating in the triple bond; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 7 to 24 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which Rb is bound 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 is of at least 7 carbon atoms; phenyl, phenylalkyl of 13 to 30 carbon atoms or bis-phenylalkyl of 19 to 36 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with a heteroatom selected from nitrogen, oxygen and sulfur o4 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms, the last 2 substituents optionally being bound to the rest of the molecule over an alkylene moiety of 7 to 24 carbon atoms; -AbOCOR8b; -AbNRgbR1bo; or -AbN) b; wherein R8b is alkyl of 1 to 25 carbon atoms with the proviso that it is of 7 to 25 carbon atoms when Ab is of less than 7 carbon atoms; phenyl, phenylalkyl of 7 to 30 carbon atoms with the proviso that it is of 13 to 30 carbon atoms when Ab iS of less than 7 carbon atoms, or bis-phenylalkyl of 13 to 36 carbon atoms with the proviso that it is of 9 to 36 carbon atoms when Ab is of less than 7 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independentlytrisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moeity with 1 to 4 nitrogen atoms; hydroxyalkyl of 2 to 24 carbon atoms wherein the hydroxy part is separated from the group to which R8b is bound by at least 2 carbon atoms, with the proviso that it is of 7 to 24 carbon atoms when Ab is of less than 7 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which R3b is bound by at least 2 carbon atoms, with the proviso that when Ab is of less than 7 carbon atoms then at least one of the alkoxy and/or alkylene parts is of at least 7 carbon atoms; alkenyl of 3 to 25 carbon atoms wherein the double bond is separated from the group of which R3b is bound by at least 1 carbon atom not participating in the double bond, with the proviso that it is of 7 to 25 carbon atoms when Ab is of less than 7 carbon atoms; alkinyl of 3 to 25 carbon atoms wherein the triple bond is separated from the group to which R8b is bound by at least 1 carbon atom not participating in the triple bond, with the proviso that it is of 7 to 25 carbon atoms when Ab is of less than 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 24 carbon atoms in the alkylene part, with the proviso that it is of 7 to 24 carbon atoms in the alkylene part when Ab is of less than 7 carbon atoms; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which R3b is bound 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 when Ab is of less than 7 carbon atoms then at least one of the hydroxyalkoxy and/or alkylene parts is of at least 7 carbon atoms; aminoalkyl of 2 to 24 carbon atoms with the proviso that it is of 7 to 24 carbon atoms when Ab is of less than 7 carbon atoms, wherein the nitrogen atom is separated from the group to which R8b is bound by at least 2 carbon atoms and the amino is optionally mono- or independently disubstituted by alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; Rb is hydrogen or has the significance indicated in this claim for R8b;; R10 either is hydrogen or has the significance indicated in this claim for R5b or is - CO Rb11 wherein Rb11 has the significance indicated in this claim for -NOB b iS a 5-, or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6-or 7-membered, a further heteromember selected from oxygen, sulfur and NR12 wherein R,2 either is hydrogen or has the significance indicated in this claim for Rub5; and Ab is alkylene of 2 to 24 carbon atoms separating the group to which R5b is bound at least 2 carbon atoms;; R8b and R7b with the exception of hydrogen have the significance indicated in this claim for Rb5; and n is as defined in claim 1; and its ammonium salts wherein R3b is selected from one of the tertiary amino groups defined in this claim for Rb and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
18. A compound of claim 4 of formula Iba
wherein R2 and R4 are as defined in claim 1, Rand X are as defined in claim 14, R,aa is as defined in claim 15 and Rba is alkyl of 7 to 25 carbon atoms; -COORb5a; -CO Rb5a; or -S(O)nR7ba; wherein is is alkyl of 7 to 25 carbon atoms; hydroxyalkyl of 7 to 24 carbon atoms wherein the hydroxy part is separated from the group to which R5ba is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and 2 to 24 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which R5ba is bound by at least 2 carbon atoms, with the proviso that at least one of the alkoxy andfor alkylene parts is of at least 7 carbon atoms; alkenyl of 7 to 25 carbon atoms wherein the double bond is separated from the group to which Rb5a is bound by at least 1 carbon atom not participating in the double bond; alkinyl of 7 to 25 carbon atoms wherein the triple bond is separated from the group in which R5ba is bound by at least 1 carbon atom not participating in the triple bond; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 7 to 24 carbon atoms in the alkylene part; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which R5ba is bound 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 is of at least 7 carbon atoms; phenylalkyl of 13 to 30 carbon atoms or bis-phenylalkyl of 19 to 36 carbon atoms, the last 2 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms, the last 2 substituents being bound to the rest of the molecule over an alkylene moiety of 7 to 24 carbon atoms; -AbaOCOR8ba; -AbaNR9baR10ba; or -AbaN#ba; wherein R8ba is alkyl of 1 to 25 carbon atoms with the proviso that it is of 7 to 25 carbon atoms when Aba is of less than 7 carbon atoms; phenyl, phenylalkyl of 7 to 30 carbon atoms with the proviso that it is of 13 to 30 carbon atoms when Aba is of less than 7 carbon atoms, or bis-phenylalkyl of 13 to 36 carbon atoms with the proviso that it is of 19 to 36 carbon atoms when Aba is of less than 7 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; hydroxyalkyl of 2 to 24 carbon atoms wherein the hydroxy part is separated from the group to which R8ba is bound by at least 2 carbon atoms, with the proviso that it is of 7 to 24 carbon atoms when Aba is of less than 7 carbon atoms; alkoxyalkyl of 1 to 24 carbon atoms in the alkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which Rb8a is bound by at least 2 carbon atoms, with the proviso that when Aba is of less than 7 carbon atoms then at least one of the alkoxy andlor alkylene parts is of at least 7 carbon atoms; alkenyl of 3 to 25 carbon atoms wherein the double bond is separated from the group to which R8ba is bound by at least 1 carbon atom not participating in the double bond, with the proviso that it is of 7 to 25 carbon atoms when Aba is of less than 7 carbon atoms; alkinyl of 3 to 25 carbon atoms wherein the triple bond is separated from the group to which Rb5a is bound by at least 1 carbon atom not participating in the triple bond, with the proviso that it is of 7 to 25 carbon atoms when Aba is of less than 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl part and of 1 to 24 carbon atoms in the alkylene part, with the proviso that it is of 7 to 24 carbon atoms in the alkylene part when Aba is of less than 7 carbon atoms; hydroxyalkoxyalkyl of 2 to 24 carbon atoms in the hydroxyalkoxy part and of 2 to 24 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which Rb8a is bound 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 when Aba is of less than 7 carbon atoms then at least one of the hydroxyalkoxy andlor alkylene parts if of at least 7 carbon atoms; aminoalkyl of 2 to 24 carbon atoms with the proviso that it is of 7 to 24 carbon atoms when Aba is of less than 7 carbon atoms, wherein the nitrogen atom is separated from the group to which R8ba is bound by at least 2 carbon atoms and the amino part is optionally mono- or independently disubstituted by alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms or bis-phenylalkyl of 13 to 18 carbon atoms, the last 3 substituents optionally being mono- or independently dior independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; is is hydrogen or has the significance indicated in this claim for Rba;; R105 is hydrogen or has the significance indicated in this claim for R8ba or is -CO wherein Rrbaa has the significance indicated in this claim for R8ba; -N0B ba iS a 5-, or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6- or 7-membered, a further heteromember selected from oxygen, sulfur and NR,b2 wherein Rnb2 either is hydrogen or has the significance indicated in this claim for R8ba; and Aba is alkylene of 2 to 24 carbon atoms separating the group to which Rb8a is bound by at least 2 carbon atoms;; R5ba and R7ba with the exception of hydrogen have the significance indicated in this claim for R5ba; and n is as defined in claim 1; and its ammonium salts wherein R3ba is selected from one of the tertiary amino groups defined in this claim for R3ba and quaternized with a group offormula AlkYwherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
19. A compound of claim 4 of formula Ibaa
wherein R2 and R4 are as defined in claim 1, Xis as defined in claim 14 and Rbaa is -COOR5baa or CORb8aa,wherein R5aa is alkyl of 9 to 19 carbon atoms; hydroxyalkyl of 9 to 18 carbon atoms wherein the hydroxy part is separated from the group to which Rb8aa is bound by at least 2 carbon atoms; alkoxyalkyl of 1 to 18 carbon atoms in the alkoxy part and 2 and 18 carbon atoms in the alkylene part, wherein the alkoxy part is separated from the group to which R5baa is bound by at least 2 carbon atoms, with the proviso that at least one of the alkoxy and/or alkylene parts is of at least 9 carbon atoms; hydroxyalkoxyalkyl of 2 to 18 carbon atoms in the hydroxyalkoxy part and of 2 to 18 carbon atoms in the alkylene part, wherein the hydroxyalkoxy part is separated from the group to which R5baa is bound 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 is of at least 9 carbon atoms; -AbaaOCOR8baa; -AbaaNR9baaR10baa; or -AbaaN#baa; wherein R8baa is alkyl of 1 to 19 carbon atoms with the proviso that it is of 9 to 19 carbon atoms when Abaa is of less than 9 carbon atoms; phenyl, phenylalkyl of 7 to 24 carbon atoms with the proviso that it is of 15 to 24 carbon atoms when Abaa is of less than 9 carbon atoms, or bis-phenylalkyl of 13 to 30 carbon atoms with the proviso that it is of 21 to 30 carbon atoms when Abaa is of less than 9 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; hydroxyalkyl of 2 to 18 carbon atoms wherein the hydroxy part is separated from the group to which R8baa is bound by at least 2 carbon atoms, with the proviso that it is of 9 to 18 carbon atoms when Abaa is of less than 9 carbon atoms; alkoxyalkyl of 1 to 18 carbon atoms in the alkoxy part and or 2 to 18 carbon atoms in the slkylene part, wherein the alkoxy part is separated from the group to which R8baa is bound by at least 2 carbon atoms; Rbaa is hydrogen of has the significance indicated in this claim for R3baa; R10baa either is hydrogen or has the significance indicated in this claim for R8baa or is -COR11baa wherein R11baa has the significance indicated in this claim for R8baa; N#baa is a 5-, 6- or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6or 7-membered, a further heteromember selected from oxygen, sulfur and NR1b2a wherein R,b2a either is hydrogen or has the significance indicated in this claim for R8baa;; and Abaa is alkylene of 2 to 18 carbon atoms separating the group to which R5baa is bound by at least 2 carbon atoms; Rb8aa with the exception of hydrogen has the significance indicated in this claim for R5baa; and n is as defined in claim 1; and its ammonium salts wherein Rbaa is selected from one of the tertiary amino groups defined in this claim for Rbaa and quaternized with a for R3baa and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
20. A compound of claim 4 of formula 1c
wherein R, R1a, R2 and R4 are as defined in claim 1, Xis as defined in claim 14 and R3c is hydrogen, nitro; trifluoromethyl; cyano; -COOR5c; -COR6c; or -S(O)nR7c; wherein R051s hydrogen; cycloalkyl of 3 to 7 carbon atoms; phenyl optionally mono- or independently di- or independently trisubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy or halogen of atomic number of from 9 to 53; a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur, or a 6-membered heteroaryl moiety with 1 to 4 nitrogen atoms; R8c and R7 with the exception of hydrogen have the significance indicated in this claim for R5; and n is as defined in claim 1.
21. Acompound of claim 4forformula Ica
wherein R2 and R4 are as defined in claim 1, X is as defined in claim 14 and R3ca is hydrogen; nitro; trifluoromethyl; cyano; -COOR5a; or -COR6Ca; wherein R5a is hydrogen or a 5-membered heteroaryl moiety with 1 heteroatom selected from nitrogen, oxygen and sulfur or 2 heteroatoms selected from nitrogen and either nitrogen, oxygen or sulfur; and R6a with the exception of hydrogen has the significance indicated in this claim for Rc5a.
22. A compound of claim 4 of formula Id
wherein R,d to R4 and Qd have the significance indicated in claim 1 for R1 to R4 and 0, respectively, with the proviso that the substituents at the 2- and 6-positions and/or at the 3- and 5-positions of the 1,4-dihydropyridinyl moiety are different, and its ammonium salts wherein Rd3 is selected from one of the tertiary amino groups defined in this claim for R3d and quaternized with a group of a formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
23. A compound of claim 4 of formula le
wherein R1e to R4e and Qe have the significance indicated in claim 1 for R1 to R4 and Q, respectively, with the proviso that the substituents at the 2- and 6-positions and/or at the 3- and 5-positins of the 1,4-dihydropyridinyl moiety are different, and its ammonium salts wherein Re is selected from one of the tertiary amino groups defined in this claim for R3e and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest ofan acid.
24. Acompound of claim 4 of formula Ip
wherein -COOR is an ester group.
25. A compound of claim 4 of formula Ip as defined in claim 24, wherein R5p is cycloalkyl of 4 to 6 carbon atoms.
26. A compound of claim 4 of formula Ip as defined in claim 24, wherein R5p is alkyl of 1 to 12 carbon atoms or alkoxyalkyl of 1 to 10 carbon atoms in the alkoxy part and 2 to 11 carbon atoms in the alkylene part wherein the alkoxy part is separated from the group to which R5 is bound by at least 2 carbon atoms and with the proviso that the alkoxy and alkylene parts together are of less than 13 carbon atoms.
27. A compound of claim 4 of formula Ip as defined in claim 24, wherein R5 is -ApNR9pR10p or -ApN# P wherein RgP is hydrogen; alkyl of 1 to 4 carbon atoms; phenyl, phenylalkyl of 7 to 10 carbon atoms or bis-phenylalkyl of 13 to 16 carbon atoms, the last 3 substituents optionally being mono- or independently di- or independently trisubstituted in the phenyl ring(s) by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy of halogen of atomic number of from 9 to 53; R, is hvdroaen or alkvl of 1 to 4 carbon atoms;; -N P is a 5-6-or 7-membered saturated heterocyclic ring which may optionally contain, when it is 6or 7-membered, a further heteromember selected from oxygen, sulfur and = NR12 wherein R12 has the significance indicated in this claim for RgP; and AP is straight-chained alkylene of 2 to 12 carbon atoms separating the group to which R5 is bound by at least 2 carbon atoms.
28. A compound of claim 4 offormula is
wherein Xis as defined in claim 14; R25 and 545 independently are alkyl of 1 to 4 carbon atoms and R35 is hydrogen; nitro; trifluoromethyl; cyano; -COORs5; or -COR6; wherein R5is hydrogen; alkyl of 1 to 12 carbon atoms; hydroxyalkyl of 2 to 6 carbon atoms wherein the hydroxy part is separated from the group to which R5s is bound by at least 2 carbon atoms;; -AsNR9sR10s; or -AsN#s; wherein R9s and R10s independently are hydrogen; alkyl of 1 to 4 carbon atoms; phenylalkyl of 7 to 10 carbon atoms optionally mono-or independently disubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 53; -N B S is piperidine or piperazine both optionally substituted in the 4 position by methyl, benzyl or bis-phenylmethyl, the last 2 substituents optionally being mono- or independently disubstituted in the phenyl ring(s) by alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 53; and As is alkylene of 2 to 14 carbon atoms separating the group to which R55 is bound by at least 2 carbon atoms; R55 is imidazolyl; and its ammonium salts wherein R5is selected from one of the tertiary amino groups defined in this claim for R3 and quaternized with a group of formula AlkY wherein Alk is alkyl of 1 to 4 carbon atoms and Y is the rest of an acid.
29. A compound of claim 4 wherein R3 is -COORs wherein -COOR5 is an ester group.
30. A compound of claim 14 wherein X is sulfur.
31. A compound of claim 4 of formula I wherein R1 is hydrogen, R2 and R4 are methyl and Qis 2,1 ,3-benzoxadiazol-4-yI, in racemic form.
32. A compound of claim 4 of formula I wherein R1 is hydrogen, R2 and R4 are methyl and Qis 2,1 ,3-benzothiadiazol-4-yl, in racemic form.
33. The compound of claim 31 wherein R3 is ethoxycarbonyl.
34. The compound of claim 31 wherein R3 is -COOiPr.
35. The compound of claim 31 wherein R3 is -COO(CH2)7CH3.
36. The compound of claim 31 wherein R3 is -COOMe.
37. The compound of claim 31 wherein R3 is -COO(CH2)2NMe2.
38. The compound of claim 32 wherein R3 is -COO(CH2)2NMe2.
39. The compound of claim 32 wherein R3 is -COOiPr.
40. The compound of claim 31 wherein Rg is -COO(CH2)10NMeBz.
41. The compound of claim 31 wherein R3 is
42. The compound of claim 31 wherein R3 is
43. The compound of claim 31 wherein R3 is -COO(CH2)10OH.
44. The compound of claim 31 wherein R3 is 1 H-imidazol-1 -ylcarbonyl.
45. The compound of claim 32 wherein R3 is 1H-imidazol-1-ylcarbonyl.
46. The compound of claim 31 wherein R3 is -COOH.
47. The compound of claim 32 wherein R3 is -COOH.
48. The compound of claim 31 wherein R3 is -COO(CH2)2NMe2 and is quaternized with a group Mel.
49. The compound of claim 32 wherein R3 is -COO(CH2)2NMe2 and is quaternized with a group Mel.
50. The compound of claim 31 wherein R2 is-H.
51. The compound of claim 32 wherein R3 is -CN.
52. The compound of claim 31 wherein R3 is -CN.
53. The compound of claim 31 wherein R3 is -NO2.
54. A compound of claim 4 of formula I wherein R1 is hydrogen, R2 and R4 are methyl and Qis 2,1 ,3-benzoxadiazol-4-yI, in optically active form having the S configuration at the 4 position of the 1,4-dihydropyridinyl moiety.
55. A compound of claim 4 of formula I wherein R1 is hydrogen, R2 and R4 are methyl and Qis 2,1 ,3-benzoxadiazol-4-yI, in optically active form having the R configuration at the 4 position of the 1,4-dihyropyridinyl moiety.
56. The compound of claim 54 wherein R3 is -COOiPr.
57. The compound of claim 55 wherein R3 is -COOiPr.
58. The compound of claim 55 wherein R3 is -COOMe.
59. The compound of claim 54 wherein R3 is -COOMe.
60. The compound of claim 54 wherein R3 is 1H-imidazol-1-ylcarbonyl.
61. The compound of claim 55 wherein R3 is 1 H-imidazol-1 -ylcarbonyl.
62. The compound of claim 54 wherein R3 is -COOH.
63. The compound of claim 55 wherein R3 is -COOH.
64. The compound of claim 54 wherein R3 is -COO(CH2)2NMe2 and is quaternized with a group Mel.
65. The compound of claim 55 wherein R3 is -COO(CH2)2NMe2 and is quaternized with a group Mel.
66. The compound of claim 54 wherein R3 is -COO(CH2)2NMe2.
67. The compound of claim 55 wherein R3 is -COO(CH2)2NMe2.
68. A compound of claim 4 wherein the substituents in the 2 and 6 positions and/or in the 3 and 5 positions of the 1 ,4-dihydropyridinyl moiety are different, in racemic form.
69. A compound of claim 4 wherein the substituents in the 2 and 6 positions andlor in the 3 and 5 positions of the 1,4-dihydropyridinyl moiety are different, in enantiomerform.
70. A compound of claim 4wherein the substituents in the 2 and 6 positions and/or in the 3 and 5 positions of the 1,4-dihydropyridinyl moiety are different, in (R)-enantiomerform.
71. A compound of claim 4wherein the substituents in the 2 and 6 positions andlor in the 3 and 5 positions of the 1,4-dihydropyridinyl moiety are different, in (S)-enantiomer form.
72. Acompound according to any one of claims 4to 71 in free form.
73. A compound according to any one of claims 4 to 71 where appropriate in neutral form.
74. A compound according to any one of claims 4 to 71 where appropriate in salt form.
75. Acompound according to any one of claims 4to 71 where appropriate in acid addition salt form.
76. A compound according to any one of claims 4to 71 in free form or where appropriate in pharmaceutically acceptable salt form, for use as a pharmaceutical.
77. A compound according to claim 76 for use as a calcium antagonist.
78. A compound according to claim 76 for use for the prevention or treatment of - coronary insufficiency; - disturbances in peripheral circulation; - asthma; - hypertension; - heart insufficiency; - migraine and vascular headache.
79. A compound according to claim 76 for use for the prevention and treatment of coronary insufficiency.
80. A compound according to claim 76 for use for the prevention and treatment of heart insufficiency.
81. A compound according to claim 76 for use for the prevention and treatment of hypertension.
82. A pharmaceutical composition comprising a compound of any one of claims 4 to 71 in free form or where appropriate in pharmaceutically acceptable salt form in association with a pharmaceutical carrier or diluent.
83. A method of preventing or treating coronary insufficiency, disturbances in peripheral circulation, asthma, hypertension, heart insufficiency or migraine and vascular headache which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 4.
84. A compound according to claim 4 substantially as hereinbefore described with reference to any one of the Examples.
85. The steps, features, compositions and compounds referred to or indicated in the specification and/or claims of this application, individually or collectively, and any and all combinations of any two or more of said steps or features.
GB08427443A 1983-11-01 1984-10-30 1, 4-dihydropyridine derivatives their preparation and pharmaceutical compositions containing them Withdrawn GB2148895A (en)

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IT1199214B (en) 1988-12-30
IT8449079A1 (en) 1986-04-29

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