CA1340798C - Disubstituted pyridines - Google Patents

Disubstituted pyridines

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Publication number
CA1340798C
CA1340798C CA000588502A CA588502A CA1340798C CA 1340798 C CA1340798 C CA 1340798C CA 000588502 A CA000588502 A CA 000588502A CA 588502 A CA588502 A CA 588502A CA 1340798 C CA1340798 C CA 1340798C
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Prior art keywords
methyl
phenyl
butyl
stands
tert
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CA000588502A
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French (fr)
Inventor
Rolf Angerbauer
Peter Fey
Walter Hubsch
Thomas Philipps
Hilmar Bischoff
Dieter Petzinna
Delf Schmidt
Gunter Thomas
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FATZAUN BEATE
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Bayer AG
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Priority claimed from DE3801406A external-priority patent/DE3801406A1/en
Priority claimed from IT8821317A external-priority patent/IT8821317A0/en
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07F7/0803—Compounds with Si-C or Si-Si linkages
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    • C07F7/1804—Compounds having Si-O-C linkages

Abstract

New substituted pyridines can be prepared by reduction of pyridines which are substituted by a ketone radical, and subsequent hydrolysis, cyclization or hydrogenation. The new compounds can be used as active compounds in medicaments, particularly for inhibiting HMG-CoA reductase, for inhibiting cholesterol biosynthesis or for the treatment of hyperlipoproteinaemia, lipoproteinaemia or arteriosclerosis.

Description

The invention relates to substituted pyridines, -intermediates for their preparation, their preparation and their use in medicaments.
It is known that lactone derivatives isolated from fungal cultures are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase) [mevinolin, EP-A
22,478; US 4,231,938]. Moreover, certain indole derivatives or pyrazole derivatives are also inhibitors of HMG-CoA reductase [EP-A 1,114,027; US Patent 4,613,610].

E' .,.,.
Substituted pyridines of the formula H
D X-R D -R
(Ia) (Ib) E -~ H . E _.
in which A stands for thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimid~rl, pyrazinvl, pyrida-zinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, each of which can be mono-substituted or disubstituted by identical or different fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or C1-C6-alkoxy-carbonyl, or A stands for phenyl or naphthyl, each of which can be monosubstituted to tetrasubstituted by identical or different C1-C6-alkyl, C1-C6-hydro:c~ralkyl, Cl-C6-alkoxy-Cl-C6-alkyl, C1-C6-alkoxy, Cl-C6-alkylthio, Cl-C6-alkylsulphonyl, phenyl, phenyloxy, phenylthio, phenylsulphonyl, benzyl, benzyloxy, benzylthio, benzylsulphonyl, phenethyl, phenyl-ethoxy, phenylethylthio, phenylethylsulphonyl, fluorine, chlorine, bromine, or cyano, or A stands for methyl, ethyl, propyl, isopropyl, butyl or tert.butyl;
E

13~~'~~~
B stands for cyclopropyl, cyclopentyl or cyclohexyl, or H stands for Cl-C6-alkyl which can be substituted by fluorine, chlorine, bromine, cyano, Cl-C6-alkoxy, Cl-C6-alkyl-thio, Cl-C6-alkylsulphonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulphonyl, C1-C6-alkoxycarbonyl, benzoyl, Cl-C6-alkylcarbonyl, or by a group of the formula -DTR1R2, Wherein R1 and R2 are identical or different and denote Cl-C6-alkyl, phenyl, benzyl, acetyl, benzoyl, phenylsulphonyl or Cl-C6-alkylsulphonyl, or B stands for C1-C6-alkyl which can be substituted by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenyl-sulphonyl, benzyloxy, benzylthio, benzylsulphonyl, phenylethoxy, phenylethylthio or phenylethylsulphonyl, where the heteroaryl and aryl radicals mentioned can be monosubstituted or disubstituted by identical or different fluorine, chlorine, bromine, Cl-C6-alkyl, Cl-C6-alkoxy, trifluoromethyl or.
trifluorvmethoxy;
E stands for unsubstituted straight-chain or branched C1-C6-alkyl; or D and E are identical or different and stand for cyclopropyl, cyclopentyl or cyclohexyl, or D and E stand fvr straight-chain or branched C1-C6-alkyl which is substituted by azido, fluorine, chlorine, bromine, cyano, hydroxyl, Cl-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylsulphonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulphonyl, Cl-C6-alkoxy-carbonyl, benzoyl or Cl-C6-alkylcarbonyl, or by a group of the formula -NR1R2 wherein R1 and R2 have the abovementioned meaning, or D and E stand for straight-chain or branched;Cl-C6-alkyl which is substituted by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl~,,~thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyloxy, benzylthio, benzyl-sulphonyl, phenylethcxy, phenylethylthio or phenylethyl-sulphonyl, where the heteroaryl and aryl radicals mentioned can be moncsubstituted or disubstituted by identical or different fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-alkoxy, trifluoromethyl or trifluoromethoxy, or D and E stand for thienyl, furyl, thiazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, iscindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzcthiazolyl, benzoxazolyl or benzimidazolyl, each of which can be monosubstituted or disubstituted by identical or different fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-alkoxy, phenyl, phenoxy, trifluoro-methyl, trifluoromethoxy or C1-C6-alkoxycarbonyl, or D and E
stand for naphthyl which can be monosubstituted to tetra-substituted by identical or different C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, Cl-C6-alkylsulphonyl, phenyl, phenyloxy, phenylthio, phenylsulphonyl, benzyl, benzyloxy, benzylthio, benzyl-sulphonyl, phenylethyl, phenylethoxy, phenylethylthio, phenyl-ethylsulphonyl, fluorine, chlorine, bromine, cyano, trifluoro-methyl, trifluoromethoxy, trifluoromethylthio, Cl-C6-alkoxy-carbonyl or by a group of the formula -NR1R2 wherein R1 and R2 1340r~~~
have the abovementioned meanings, or D and E stand for a group of the formula -CR11R12-Y, wherein R11 and R12 can be identical or different and stand for hydrogen, or stand for C1-G6-alkyl which can optionally be substituted by hydroxyl, fluorine, chlorine, Cl-C6-alkoxy or C1-C6-alkvxycarbonyl, or R11 and R12 stand for cyclopropyl, cyclopentyl or cyclohexyl, or R11 and R12 together form a saturated or unsaturated carbocyclic or heterocyclic ring having up to 6 carbon atoms, Y denotes a group of the formula -NR13R14, _COR15, -S-R16, SO-R16, -SOZR16, -OR1~ or N3 wherein R13 and R14 are identical or different and stand for hydrogen, C1-C6-alkyl, phenyl or benzyl,, where the radicals mentioned can be substituted by fluorine, chlorine, bromine, C1-C6-alkyl, Cl-C6-alkoxy or trifluoromethyl, or R13 and R14 stand for a group of the formula -COR15 or -S02R16, or R13 and R14 together form an alkylene chain which can be interrupted by O, N, S, r1-Cl-C6-alkyl, N-benzyl, N-phenyl, N-carbarnoyl or N-C1-C6-alkoxycarbonyl, R15 denotes a group -NR1aR19, or R15 denotes C1-C6-alkyl or C1-C6-alkoxy, or R15 denotes phenyl, benzyl, benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl which are optionally substituted by C1-C6-alkyl, C1-C6-alkoxy, fluorine, chlorine, bromine, trifluoro-methyl, dimethylamino or diethylamino, R16 denotes cyclopropyl, cyclopentyl, cyclohexyl, or R16 denotes straight-chain or branched C1-C6-alkyl which is -E

1340~~~~
optionally substituted by cyano, fluorine, chlorine, bromine, trifluoromethyl or C1-C6-alkoxycarbonyl, or R16 denotes~phenyl, naphthyl, benzyl, thienyl, furyl, pyrimidyl, pyridyl, quinclyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl,~oxazolyl, iscxazolyl or isothiazolyl which are optionally monosubstituted or polysubstituted by identical or different Cl-C6-alkyl, C1-C6-alkoxy, fluorine, chlorine, bromine, trifluoromethyl, dimethylamino or diethylamino, or R16 denotes trimethylsilyl or dimethylethylsilyl, or R16 denotes a group -NR9R1~ wherein R9 and Rl~ are identical or different and denote hydrogen, C1-C6-alkyl or phenyl, or R9 and Rl~ denote a heterocyclic ring from the series comprising pyrrolidine, piperidine, piperazine, N-alkylpiperazine, N-arylpiperazine, N-benzylpiperazine, N-carbamoylpiperazine or T1-alkoxycarbonylpiperazine, R1~ stands for hydrogen, cyclcpropyl, cyclcpentyl or cyclohexyl, or Rl~ stands for Cl-C6-alkyl which can be substituted by fluorine, chlorine, bromine, cyano, Cl-C6-alkoxy, C1-C6-alkylthio, Cl-C6-alkylsulphonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulphonyl, C1-C6-alkoxy-carbonyl, benzoyl, C1-C6-alkylcarbonyl, or by a group of the formula -NR1R2 wherein R1 and R2 have the abovementioned meaning, or R1~ stands for C1-C6-alkyl which can be substituted by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, iso-quinclyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenyl-sulphonyl, benzyloxy, benzylthio, benzylsulphonyl, phenyl-ethoxy, phenylethylthio or phenylethylsulphonyl, where the ~~3~~"~l ~~
heteroaryl and aryl radicals mentioned can be monosubstituted or disubstituted by identical or different fluorine, chlorine, bromine, Cl-C6-alkyl, C1-C6-alkoxy, trifluoromethyl or trifluoromethoxy, or R1~ stands for thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, iso-quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, each of which can be monosubstituted or disubstituted by identical or different fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-alkoxy, phenyl, phenyloxy, trifluoromethyl, trifluoromethoxy or C1-C6-alkoxycarbonyl, or R1~ stands for benzyl, phenyl or naphthyl, each of which can be monosubstituted to tetra-substituted by identical or different C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylsulphonyl, phenyl, phenyloxy, phenylthio, phenylsulphonyl, benzyl, benzyloxy, benzylthio, benzylsulphonyl, phenylethyl, phenylethcxy, phenylethylthio, phenylethylsulphonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluorcmethylthio, C1-C6-alkoxycarbonyl or by a group of the formula -NR1R2 wherein Rl and R2 have the abovementioned meaning, or R1~ stands for 2,5-dioxo-tetrahydropyrryl, tetrahydropyranyl, dimethyl-tert.-butylsilyl, tripropylsilyl or tributylsilyl, or Rl~ denotes a group of the formula COR16 wherein R16 has the abovementiored meaning, and R1$ and R19 are identical or different and denote hydrogen, or R18 and R19 denote C1-C6-alkyl which is optionally 7 _ i3~fl ~9~
substituted by cyano, fluorine, chlorine or bromine, or R18 and R19 denote phenyl, benzyl, thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or~isothiazolyl which are optionally substituted by C1-C6-alkyl, C1-C6-alkoxy, fluorine, chlorine, bromine, trifluoromethyl, dimethylamino or diethyl-amino, or D and E together form a ring of the formula If W/
c or Z (CH2)m Z
(CHZ)m R13 ~R14 wherein W stands for a group of the formula C=O or stands for CH-OH, m stands for a number 1 or 2, Z stands for 0, CHZ or NHR20, R13 and Rla have the abovementioned meaning, and R2~ stands for hydrogen, C1-C6-alkyl, phenyl,. benzyl, carbamoyl or Cl-C6-alkoxycarbonyl,~
X stands for a group of the formula -CH=CH-, R stands for a group of the formula R21 "21 -iH-CH2-~-CHZ-COOR22 or OH OH
- g _ E

j3~D l~'~
wherein R21 denotes hydrogen or Cl-C6-alkyl, and R22 denotes hydrogen, C1-C6-alkyl, phenyl or benzyl, or denotes a cation, and their oxidation products have now been found.
Among the oxidation products of the compounds of the general formulae (Ia) and (Ib) according to the invention, there are understood the corresponding compounds of the pyridine~N-oxide.
Surprisingly, the substituted pyridines according to the invention show a superior inhibitory action on HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl coenzyme A reductase).
Cycloalkyl in general stands for a cyclic hydrocarbon radical having 3 to 8 carbon atoms. The cyclopropyl, cyclopentyl and cyclohexyl ring is preferred. Examples which may be mentioned are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Alkyl in general stands for a straight-chain or branched hydrocarbon radical. Lower alkyl having 1 to about 6 carbon atoms is preferred.
Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.
Alkoxy in general stands for a straight-chain or branched hydrocarbon radical which is bonded via an oxygen atom. Lower alkoxy having 1 to about 6 carbon atoms is preferred. An alkoxy radi-cal having 1 to 4 carbon atoms is particularly prefer-red. Examples which may be mentioned are methoxy, eth-oxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.
Alkylthio in general stands for a straight-chain or Le A 25 747 E

....
branched hydrocarbon radical vhich is bonded via a sulphur atom. Lower alkylthio having 1 to about 6 carbon atoms is preferred. An alkyl-thio radical having 1 to 4 carbon atoms is particularly preferred. Examples vhich may be mentioned are methyl-thio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio, hexylthio, iso-hexylthio, heptylthio, isoheptylthio, octylthio or iso-octylthio.
Alkylsulphonyl in general stands for a straight-chain or branched hydrocarbon radical which is bonded m a an S02 group. Lower alkyl-sulphonyl having 1 to about 6 carbon atoms is preferred.
Examples which may be mentioned are: methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl, isobutylsulphonyl, pentylsulphonyl, iso-pentylsulphonyl, hexylsulphonyl, isohexylsulphonyl.
Sulphamoyl (aminosulphonyl) stands for the group -S02-NHZ.
Aryl in general stands for an aromatic radical having 6 to about 12 Carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
Aryloxy in general stands for an aromatic radical having 6 to about 12 carbon atoms which is bonded via an oxygen atom. Preferred aryloxy radicals are phenoxy or naph-thyloxy.
Arylthio in general stands for an aromatic radical hav-ing 6 to about 12 carbon atoms Which is bonded via a sulphur atom. Preferred arylthio radicals are phenyl-thio or naphthylthio.
Arylsulphonyl in general stands for an aromatic radical having 6 to about 12 carbon atoms which is bonded via an S02 group. Examples which may be mentioned are:
phenylsulphonyl, naphthylsulphonyl and biphenylsulphonyl.
Aralkyl in general stands for an aryl radical having 7 to 14 carbon atoms which is bonded via an alkylene chain.
Aralkyl radicals having 1 to 6 carbon atoms in the Le A 25 747 E

aliphatic moiety and 6 to 12 carbon atoms in the aromatic moiety are preferred. Examples which may be mentioned are the following alkyl radicals: benzyl, naphthylmethyl, phenethyl and phenylpropyl, Ara~ in general stands for an aralkyl radical having 7 to 14 carbon atoms, the alkylene chain being bonded via an oxygen atom. Aralkoxy radicals having 1 to 6 carbon atoms in the aliphatic moiety and 6 to 12 carbon atoms in the aromatic moiety are preferred. Examples which may be mentioned are the following aralkoxy radi-cals: benzyloxy, naphthylmethoxy, phenethoxy and phenyl-propoxy.
Aralkylthio in general stands for an aralkyl radical having 7 to about 14 carbon atoms, the alkyl chain being bonded via a sulphur atom. Aralkylthio radicals having 1 to 6 carbon atoms in the aliphatic moiety and 6 to 12 carbon atoms in the aromatic moiety are preferred. Exam-ples which may be mentioned are the following aralkyl-thio radicals: benzylthio, naphthylmethylthio, phenethyl-thio and phenylpropylthio, Aralkylsulphonyl in general stands for an aralkyl radi-cal having 7 to about 14 carbon atoms, the alkyl radical being bonded via an S02 link. Aralkylsulphonyl radicals having 1 to 6 carbon atoms in the aliphatic moiety and 6 to 12 carbon atoms in the aromatic moiety are preferred.
Examples Which may be mentioned are the following aralkyl-sulphonyl radicals: benzylsulphonyl, naphthylmethylsul-phonyl, phenethylsulphonyl and phenylpropylsulphonyl.
Alkoxycarbonyl can be represented, for example, by the formula -iI-OAlkyl O
In this connection, alkyl stands for a straight-chain or branched hydrocarbon radical.
Lower alkoxycarbonyl having 1 to about 6 carbon atoms in Le A 25 747 _ 11 _ the alkyl moiety is preferred. An alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety is particularly preferred. Examples which may be mentioned are the ~fol-lowing alkoxycarbonyl radicals: methoxycarbonyl, ethoxy-carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy-carbonyl or isobutoxycarbonyl.
Acyl in general stands for phenyl or straight-chain or -branched lower alkyl having 1 to about 6 carbon atoms which are bonded via a carbonyl group. Phenyl and alkyl radicals having up to 4 carbon atoms are preferred.
Examples which may be mentioned are: benzoyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butyl-carbonyl and isobutylcarbonyl.
Halogen in general stands for fluorine, chlorine, bromine or iodine, preferably for fluorine, chlorine or bromine.
Particularly preferably, halogen stands for fluorine or chlorine.
Heteroaryl in general stands for a 5- to 6-membered aromatic ring which can contain oxygen, sulphur and/or nitrogen as hetero atoms and onto which can be fused further aromatic rings. 5- and 6-membered aromatic rings which contain one oxygen, one sulphur and/or up to 2 nitrogen atoms and which are optionally fused to ben-zene are preferred. Heteroaryl radicals which may be mentioned as particularly preferred are: thienyl, furyl, pyrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyri-dazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolyl, thiazolyl, benzothiazolyl, iso-thiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imida-zolyl, benzimidazolyl, pyrazolyl, indolyl and isoindolyl.
If R22 stands for an ester radical, then a physiol-ogically tolerable ester radical is preferably meant by this, which is easily hydrolyzed in vivo to a free carboxyl group and a corresponding physiologically tolerable alcohol.
These include, for example, alkyl esters (C1 to C4) and aralkyl esters (C7 to C10), preferably lower alkyl Le A 25 747 _ 12 _ E

I340~~a esters and benzyl esters. Moreover, the following ester radicals may be mentioned: methyl esters, ethyl esters, propyl esters, benzyl esters.
If R22 stands for a cation then a physiologically tolerable metal cation or ammonium cation is preferably meant. In this connection, alkali metal cations or alkal-ine earth metal cations such as, for example, sodium cations, potassium cations, magnesium cations or calcium cations, and also aluminium cations or ammonium cations, and also non-toxic substituted ammonium cations from amines such as dilower alkylamines, trilower alkylamines, procain, dibenzylamine, N,N'-dibenzylethylenediamine, N-benzyl-B-phenylethylamine, N-methylmorpholine or N-ethylmorpholine, 1-ephenamine, dihydroabietylamine, N,N'-bis-dihydroabietyl-ethylenediamine, N-loser alkylpiperidine and other amines which can be used for the formation of salts are preferred.

E

~3~0-(~~
Preferred compounds are those of the general formulae (Ia) and (Ib) above, wherein A stands for thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinvlyl, each of which can be substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or A
stands for phenyl which can be monosubstituted, disubstituted or trisubstituted by identical or different methyl, hydroxy-methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, butyl, isobutyl, methoxymethyl, ethoxymethyl, propoxymethyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine or cyano, or A stands for methyl, ethyl, propyl, isopropyl, butyl or tert.butyl, B stands for cyclopropyl, cyclopentyl or cyclohexyl, or B stands for methyl, ethyl, propyl, isopropyl, butyl, E

~34~ ~~8 sec.butyl or tert.butyl, each of which can be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropvxy, butoxy, sec.butoxy, tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulphonyl, ethyl-sulphonyl, prvpylsulphonyl, isopropylsulphonyl, trifluoromethyl, trifluoromethoxy, methoxycarbcnyl, ethoxycarbonyl, butoxy-carbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl,,thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyloxy, benzylthio or benzyl-sulphonyl, E stands for unsubstituted straight-chain or branched CZ-C6-alkyl; or E

D and E are identical or different and stand for cyclopropyl, cyclopentyl or cyclohexyl, or D and E stand for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, each of which is substituted by azido, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, methoxy, ethoxy, propoxy, ispropoxy, butoxy, isobutoxy, tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl, isobutylsulphonyl, tert.butylsulphonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl, or by a group -NR1R2 wherein R1 and R2 are identical or different and denote methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, phenyl, benzyl, acetyl, E

~~40~
methylsulphonyl, ethylsulphvnyl, propylsulphonyl, isopropyl-sulphonyl or phenylsulphonyl, or D and E stand for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl; pentyl, isopentyl, hexyl or isohexyl which is substituted by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isa-quinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyloxy, benzylthio or benzylsulphonyl, where the heteroaryl and aryl radicals mentioned can be substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, isobutyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, trifluoromethyl or trifluoromethvxy,~or D and E stand for thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, tetrazolyl, pyridazinyl, E

13~~'~~~
oxazolyl, iscoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, ben2imidazolyl or benzthiazolyl, where the radicals mentioned can be substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, iscbutyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, phenyl, phenoxy, trifLuoro:~;ethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, iscpropoxy-carbonyl, propoxycarbonyl, butoxycarbonyl, iscbutoxycarbonyl or tert.butoxycarbonyl, or D and E stand for E

13~0~~
a group of the formula -CR11R12-Y wherein Rll and R12 are, identical or different and stand for hydrogen, or R11 and R12 stand for methyl, ethyl, propyl or isopropyl which can ' optionally be substituted by hydroxyl, fluorine, chlorine, methoxy, ethoxy, methoxycarbonyl or ethoxycarbonyl, or R11 and R12 stand for cyclopropyl, cyclonentyl or cyclohe:cyl, or R11 and R12 together stand for cyclopropyl, cyclopentyl or cyclo-hexyl, and E

~3~~~9 Y denotes a group of the formula -NR13R14, _COR15~
-SR16, -SO-R16, -S02R16, -OR1~ or -N3, wherein R13 and R14 are identical or different, and stand for hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or R13 and R14 stand for phenyl which is optionally substituted by fluorine, chlorine, methyl or methoxy, or R13 and R14 stand for a group -COR15 or -SOZR16, or R13 and R14 together with the nitrogen E

m~o~~~~
atom form a ring from the series comprising piperidine, piperazine, morpholine, morpholine-N-oxide, N-lower alkyl-piperazine, benzylpiperazine or phenylpiperazine, ~' R15 denotes a group -rIRl8R19, or R15 denotes methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, or R15 denotes phenyl, benzyl, benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl which are option-ally substituted by methyl, methoxy, fluorine or chlorine, R16 denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl or isopentyl which are optionally substituted by fluorine, chlorine, methoxycarbonyl, ethoxycarbonyl, propoxy-carbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxy-carbonyl, or R16 denotes benzyl, phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or iscquinolyl which are optionally monosubstituted or polysubstituted by identical or different methyl, ethyl, propyl, isopropyl, methoxy, fluorine or chlorine, or R16 denotes trimethylsilyl or dimethylethylsilyl, or R16 denotes a group -NR9R1~ wherein R9 and R1~ are identical or different and denote hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or phenyl, or R9 and R1~ denote a heterocyclic ring of the series comprising piperidine, N-methylpiperazine, N-ethylpiperazine or N-benzylpiperazine, E

R1~ stands for hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or R1~ stands for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, each of which can be substituted by, fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, methylthiti;
ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio, methylsulphonyl, ethylsulphonyl, propyl-sulphvnyl, isvpropylsulphonyl, butylsulphonyl, isobutyl-sulphonyl, tert.butylsulphonyl, trifluoromethyl, trifluoro-methoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 13~0'~~~
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl, or by a group -NR1R2 wherein R1 and R2 are identical or different and denote methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, phenyl, benzyl, acetyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl or phenylsulphonyl, or R1~ stands for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl which can be substituted by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyloxy, benzylthio or benzylsulphonyl, where the heteroaryl and aryl radicals mentioned can be substituted by fluorine, chlorine, methyl, 'E

I34 0'~~~
ethyl, propyl, isopropyl, isobutyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, trifluoromethyl or trifluoromethoxy, or Rl~ stands for thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzthiazolyl, where the radicals mentioned can be substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, te~t.butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, phenyl, phenvxy, trifluoromethyl, trif luoromethoxy, methoxycarbonyl, ethvxycarbonyl, isopropoxycarbonyl, propoxy-carbonyl, butoxycarbonyl, isobutoxycarbonyl or tert.butoxy-carbonyl, or R1~ stands for benzyl or phenyl, each of which can be monosubstituted, disubstituted or trisubstituted by identical or different methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, E

l3~On~~~
tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butyl-sulphonyl, isobutylsulphonyl, tert.butylsulphonyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyl, benzyloxy, benzylthio, benzylsulphonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy-carbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxy-carbonyl or by a group -NR1R2 wherein R1 and R2 have the abovementioned meaning, or Rl~ stands for 2,5-dioxo-tetra-hydropyrryl, tetrahydropyranyl, dimethyl tert.butylsilyl or trimethylsilyl, or R1~ denotes a group -COR16, wherein R16 has the abovementioned meaning, and E

l3~Orl~~
R1$ and R19 are identical or different and denote hydrogen, or R18 and R19 denote methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl or isohexyl Which are optionally substituted by fluorine or chlorine, or Rl8 and R19 denote phenyl which can optionally be substituted by fluorine, chlorine, methyl or methoxy, or E

~~~0 <~
D and E together form a ring of the formula O O O O

~,/ , , ~ o r wherein R20 stands for hydrogen, methyl, ethyl, propyl, isopropyl, carbamoyl, methoxycarbonyl or ethoxycarbonyl, X stands for a group of the formula -CH=CH-, R stands for a group of the formula -;H-CH2-i-CH2-COOR22 or HO
OH OH
wherein E

13~0~~~
R21 denotes hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl or tert.butyl, and R22 denotes hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert.butyl or benzyl, or a sodium, potassium, calcium, or magnesium or ammonium ion, and their oxidation products.

E

Z340~~8 Particularly preferred compounds are those of the general formulae (Ia) and (Ib) in which A stands for thienyl or furyl, or A stands for phenyl which can be monosubstituted or disubstituted by identical or different methyl, hydroxymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, phenoxy, benzyloxy, fluorine, chlorine or trifluoromethyl, or A stands for methyl, ethyl, propyl or isopropyl, B stands for cyclopropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.butyl, each of which can be substituted by fluorine, chlorine, methoxy, phenyl or phenoxy, E stands for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, or D and E are identical or different and stand for cyclopropyl, cyclopentyl or cyclohexyl, or D and E stand for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, each of which is substituted by azido, fluorine, chlorine, iodine, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, methylsulphonyl, ethylsulphonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or by a group of the formula NR1R2, where Rl and R2 are identical or different and 'E

13~~~~~
stand for methyl, ethyl, propyl, isopropyl, phenyl or benzyl, or by pyridyl, pyrimidyl, quinolyl, thienyl, furyl, phenyl, phenoxy, phenylsulphonyl or benzyloxy which are optionally substituted by fluorine, chlorine, methyl, methoxy, trifluoromethyl or trifluoromethoxy, or D and E stand for thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzoxazolyl, tetrazolyl, benzthiazolyl or benzimidazolyl which are optionally substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, phenyl, methoxycarbonyl or ethoxycarbonyl, or D and E stand for a group of the formula -CR11R12-Y
wherein R11 and R12 denote hydrogen, methyl or ethyl, and Y denotes a group of the formula -NR13R14, -COR15, -S-R16_ -SO-R16, -S02R16 or -OR1~, where R13 and R14 are identical or different, and stand for hydrogen, methyl, ethyl, propyl, or stand for a group -COR15 or -S02R16 or R13 and R14, together with the nitrogen atom, form a ring from the series comprising morpholine or morpholine N-oxide, and R15 denotes a group -NR18R19, or R15 denotes methyl, ethyl, propyl, methoxy or ethoxy, E

...~ 13~0'"l~~
R16 denotes trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl or benzyl, or R16 denotes phenyl or naphthyl which is optionally substituted by one or more methyl or chlorine, or R16 denotes trimethylsilyl or dimethylethylsilyl, or R16 denotes a group -NR9R10, where R9 and R1~ are identical or different and denote hydrogen, methyl, ethyl, propyl or phenyl, Rl~ stands for hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or R1~ stands for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, each of which can be substituted by fluorine, chlorine, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, methylsulphonyl, ethylsulphonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or by a group of the formula NR1R2, where R1 and R2 are identical or different and stand for methyl, ethyl, propyl, isopropyl, phenyl or benzyl, or Rl~ stands for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, each of which is substituted by pyridyl, pyrimidyl, quinolyl, thienyl, furyl, phenyl, phenoxy, phenylsulphonyl or benzyloxy, E

130 ~9~
,~hich are optionally substituted by fluorine, chlorine, methyl, methoxy, trifluoromethyl or trifluoromethoxy, or R1~ stands for thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzoxazolyl, benzthiazolyl or benzimidazolyl which are optionally substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, phenyl, methoxycarbonyl or ethoxycarbonyl, or R1~ stands for benzyl or phenyl, each of which can be monosubstituted or disubstituted by identical or different methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butoxy, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, methylsulphonyl, ethylsulphonyl, phenyl, phenoxy, phenylsulphonyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl or a group of the formula -NR1R2, where Rl and R2 have the abovementioned meaning, or R1~ stands for 2,5-dioxo-tetrahydropyrryl, tetrahydro-pyranyl, dimethyl-tert.butylsilyl or trimethylsilyl, or R1~ denotes a group -COR16, where R16 has the abovementioned meaning, and R18 and R19 are identical or different and denote hydrogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, or phenyl, or E

D and E together form a ring of the formula O
O
X stands for a group of the formula \ (E-configuration) and R stands for a group of the formula Rz t R2 t O
-CH-CHZ- i -CHZ-COORzz or HO
OH OH
wherein R21 denotes hydrogen and R22 denotes hydrogen, methyl or ethyl, or a sodium or potassium ion and their oxidation products.
Particularly preferred also are substituted pyridines of the formula F

E

E

i34~~1~~
in which B and E are Cl-3alkyl or one of B and E is cyclo-propyl, y-Q- is CH30-, (H3C)3C(CH3)2-Si-O-. ~ CH2-O-, ~ C2H5-p-O, CH3i-O-, ~CHZ-S-, C2H50-, C3H~0-, O ~0 z-C3H70-, C4H90 ' C5H11 ' C6H130 or ~CH2-O-, F
and R22 is hydrogen, lower alkyl, phenyl, benzyl or a physiologically tolerable metal or ammonium cation.
The substituted pyridines of the general formulae (Ia) and (Ib) according to the invention have several asymmetric carbon atoms and can therefore exist in various stereo-chemical forms.
The invention relates both to the individual isomers and to their mixtures.
Depending on the meaning of the group X or the radical R, different stereoisomers result, which are more closely illustrated in the following:
(a) As the group -X- stands for a group of the formula -CH=CH-, the compounds according to the invention exist in two stereoisomeric forms which can have the E configuration (II) or the Z configuration (III) on the double bond:
E

1~~~~~

., (II) E form E
B A
w R (III) Z form E
(A, B, D, E and R have the abovementioned meaning).
Preferred compounds are those of the general formula (I) which have the E configuration (II).
b) If the radical -R- stands for a group of the formula -CH-CH2-~-CH2-COOR22 OH OH
then the compounds of the general formula (I) possess at least two asymmetric carbon atoms, namely the two carbon atoms to which the hydroxyl groups are bonded. Depending on the relative position of these hydroxyl groups to one another, the compounds according to the invention can be present in the erythro configuration (IV) or in the threo configuration (V).

0 OH erythro form (IV) E

g A
-CH~CHZ-C~CHZ-COOR2~ threo form (V) " ._ _ OH
OH
E
Two enantiomers in each case again exist of the compounds in the erythro and the threo configuration, Le A 25 747 13~0'l~8 namely the 3R, SS-isomer or the 3S, SR-isomer (erythro form) and the 3R, SR-isomer and the 3S, SS-isomer (threo form).
In this case, the isomers having the erythro con-s figuration are preferred, particularly preferably the 3R, SS-isomer and the 3R, SS-3S, SR-racemate.
c) If the radical -R- stands for a group of the formula R 21 ~>~/'0 Ho then the substituted pyridines possess at least two asymmetric carbon atoms, namely the carbon atom to which the hydroxyl group is bonded and the carbon atom to which the radical of the formula B A
E
is bonded. Depending on the position of the hydroxyl group to the free valency on the lactone ring, the sub-stituted pyridines can be present as the cis-lactone (VI) or as the traps-lactone (VII).
HO ..yZ 1 B A
' ~ ~0~ cis-lactone (VI) E
traps-lactone (VII>
E
Le A 25 747 ~0~

13~0~1~
TWO isomers in each case again exist of the cis-lactone and the traps-lactone, namely the 4R,6R-isomer or the 4S,6S-isomer (cis-lactone), and the 4R,6S-isomer or the 4S,6R-isomer (traps-lactone). Preferred isomer are the traps-lactones. Particularly preferred in this connection is the 4R,6S-isomer (traps) and the 4R,6S-4S, 6R-racemate.
For example, the following isomeric forms of the substituted pyridines may be mentioned:
H 0 \\\R 21 ~B
21 .v;~H

E~B
HO ,~~R21 A
.. D I \ ( I ~ ~~ 0 E/~,~8 Le A 25 747 _. -A OH OH
CH-CH2-CR~1-CH2-COOR22 E~g A OH OH

E~g A OH OH

E~.3 A OH OH

E~B
HO ,~~R21 ..
D ~\ ~~ ~ 0 E~A
Le A 25 747 i34~'~~~
H0 ~~~ Z i B
0-~0 i ii E~A
R21 .~~~H
B
II ~ ~~~,~0~
E~A
B OH OH
r .r i- I) ~ CH-CH2-CRZ1-CHZ-COOR22 E~A
B OH OH
__ -E~A
B OH OH
r I- II ~ CH-CH2-CR21-CH2-COOR22 E~A
OH OH

E~A
Le A 25 747 I3~O~l In addition, a process for the preparation of the substituted pyridines of the general formula (I) R (I) E
in which A, B, D, E, X and R have the abovementioned meaning, has been found, characterized in that ketones of the general formula (VIII) - B ~' (~X./CH=CH-CH-CHZ-C-CH2-COOR23 (VIII) OH
E
in which A, 8, D and E have the abovementioned meaning, and R23 - stands for alkyl.
are reduced, in the case of the preparation of the acids the esters are hydrolyzed, in the case of the preparation of the lactones, the carboxylic acids are cyclized, in the case of the preparation of the salts either the esters or the lactones are hydrolyzed, in the case of the preparation of the ethylene compounds (X = -CH2-CH2-) the ethene compounds (X - -CH=CH-) are hydrogenated by customary methods, and, if appropriate, isomers are resolved.
The process according to the invention can be illustrated by the following reaction scheme:
Le A 25 747 134~~~9~
F

.i w H
W
Reduction F

;OO~NaE
_.. , I \ i H .
COON
v ~ ~ I/ v OOH
cyclization F
~H

Le A 25 747 hydroly s i s F
OH

1340~'~~
The reduction can be carried out using the cus-tomary reductants, preferably using those which are suitable for the reduction of ketones to hydroxyl com-pounds. Particularly suitable in this case is reduction using metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkyl borane. The reduction is preferably carried out using complex metal hydrides such as, for example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkyl borohydride, sodium trialkyl borohydrides, sodium cyanoborohydride or lithium aluminium hydride. The reduction is very parti-cularly preferably carried out using sodium borohydride in the presence of triethylborane.
Suitable solvents in this connection are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as, for example, diethyl ether, dioxane, tetrahydro-furan or dimethoxyethane, or halogenated hydrocarbons such as, for example, dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, or hydrocarbons such as, for example, benzene, toluene or xylene. Like-wise, it is possible to employ mixtures of the solvents mentioned.
The reduction of the ketone group to the hydroxyl group is particularly preferably carried out under condi-tions in which the remaining functional groups such as, Le A 25 747 ~34p~~ ~~
for example, the alkoxycarbonyl group are not changed.
The use of sodium borohydride as a reductant, in the presence of triethyl borane in inert solvents such as, preferably, ethers, is particularly suitable for this.
The reduction in general takes place in a tem-perature range from -80°C to +30°C, preferably from -78°C to 0°C.
The process according to the invention is in general carried out at normal pressure. However, it is also possible to carry out the process at underpressure or at overpressure (for example in a range from 0.5 to 5 bar).
In general, the reductant is employed in an amount from 1 to 2 moles, preferably from 1 to 1.5 moles, 75 relative to 1 mole of the keto compound.
Under the abovementioned reaction conditions, the carbonyl group is in general reduced to the hydroxyl group, without reduction of the double bond to a single bond taking place.
To prepare compounds of the general formula (I), in which X stands for an ethylene grouping, the reduction of the ketones (III) can be carried out under those con-ditions under which both the carbonyl group and the double bond are reduced.
Moreover, it is also possible to carry out the reduction of the carbonyl group and the reduction of the double bond in two separate steps.
The carboxylic acids in the context of the general formula (I) correspond to the formula (Ic) I -iH-CH2-i-CHZ-COON (Ic) OH OH
E
in which A, B, D, E and R20 have the abovementioned Le A 25 747 134~'~~~
meaning.
The carboxylic acid esters in the context of the general formula (I) correspond to the formula (Id>

(Id) ~-iH-CH2-j-CH2-COOR23 OH OH
E
in which A, B, D, E and R21 have the abovementioned meaning, and R23 - stands for alkyl.
70 The salts of the compounds according to the invention in the context of the general formula (I) correspond to the formula (Ie) $ A
_ -CH-CH2-C-CH2-C00-~ Mn' (Ie) I I I
OH OH
E
n in which A, B, D, E and R21 have the abovementioned meaning, and Mn+ stands for a cation, where n indicates the valency.
The lactones in the context of the general formula (I) correspond to the formula (If) (If>
E
Le A 25 747 1~~0~~3 in which A, 8, D, E and R2~ have the abovementioned meaning.
To prepare the carboxylic acids of the genera l formula (Ic) according to the invention, the carboxylic acid esters of the general formula (Id) or the lactones of the general formula (If> are in general hydrolyzed by customary methods. The hydrolysis in general takes place by treating the esters or the lactones in inert solvents with customary bases, by means of which in general the salts of the general formula (Ie) are first formed, which can subsequently then be converted in a second step into the free acids of the general formula (Ic) by treating with ac id.
Bases suitable for the hydrolysis are the cus-tomary bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate or sodium hydro-gen carbonate, or alkali metal alkoxides such as sodium ethoxide, sodium methoxide, potassium methoxide, potas-sium ethoxide or potassium tert.butoxide. Sodium hydroxide or potassium hydroxide are particularly pre-ferred.
Suitable solvents for the hydrolysis are water or the organic solvents which are customary for hydroly-sis. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used.
Likewise, it is possible to employ mixtures of the sol-vents mentioned.
The hydrolysis is in general carried out in a temperature range from 0°C to +100°C, preferably from Le A 25 747 1~~~~~~
+20°c to +80°c.
In general, the hydrolysis is carried out at normal pressure. However, it is also possible to work at underpressure or at overpressure (for example from 0.5 to 5 bar).
When carrying out the hydrolysis, the base is in general employed in an amount from 1 to 3 moles, prefer-ably from 1 to 1.5 moles, relative to 1 mole of the ester or the lactone. Molar amounts of the reactants are par-ticularly preferably used.
When carrying out the reaction, the salts of the compounds according to the invention (Ie), are formed in the first step, as intermediates which can be isolated.
The acids according to the invention (Ic) are obtained by treating the salts (Ie) with customary inorganic acids.
These preferably include mineral acids such as, for ex-ample, hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid. In this connection, it has proved advantageous in the preparation of the carboxylic acids (Ic) to acidify the basic reaction mixture from the hydrolysis in a second step without isolation of the salts. The acids can then be isolated in a customary manner.
To prepare the lactones of the formula (If) according to the invention, the carboxylic acids accord-ing to the invention (Ic) are in general cyclized by customary methods, for example by heating the corres-ponding acids in inert organic solvents, if appropriate in the presence of molecular sieve.
Suitable solvents in this connection are hydro-carbons such as benzene, toluene, xylene, mineral oil fractions, or tetralin or diglyme or triglyme. Benzene, toluene or xylene are preferably employed. Likewise, it is possible to employ mixtures of the solvents mentioned.
Hydrocarbons, in particular toluene, are particularly preferably used in the presence of molecular sieve.
Le A 25 747 ~.3~0'~~3.
The cyclization is in general carried out in a temperature range from -40°C to +200°C, preferably from -25°C to +50°C.
The cyclization is in general carried out at normal pressure, but it is also possible to carry out the process at underpressure or at overpressure (for example in a range from 0.5 to 5 bar).
Moreover, the cyclization is also carried out in inert organic solvents, with the aid of cyclizing or water-eliminating agents. In this connection, carbodi-imides are preferably used as water-eliminating agents.
N,N'-Dicyclohexylcarbodiimide paratoluenesulphonate, N-cyclohexyl-N'-C2-(N " -methylmorpholinium)ethylJcarbodi-imide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride are preferably employed as carbodiimides.
Suitable solvents in this connection are the cus-tomary organic solvents. These preferably include ethers such as diethyl ether, tetrahydrofuran or dioxane, or chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xylene or mineral oil fractions.
Chlorinated hydrocarbons such as, for example, methylene chloride, chloroform or carbon tetrachloride, or hydro-carbons such as benzene, toluene, xylene or mineral oil fractions are particularly preferred. Chlorinated hydro-carbons such as, for example, methylene chloride, chloro-form or carbon tetrachloride are particularly preferably employed.
The reaction is in general carried out in a tem-perature range from 0°C to +80°C, preferably from +10°C to +50°C.
When carrying out the cyclization, it has proved advantageous to employ the cyclization methods with the aid of carbodiimides as dehydrating agents.
The resolution of the isomers into the homogene-ous stereoisomeric constituents in general takes place by Le A 25 747 customary methods such as, for example, are described by E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962. In this case, the resolution of the isomers from the racemic ester step is preferred. Particularly preferably in this connection, the racemic mixture of the traps-lactones (VII) is converted by customary methods by treating either with D-(+)-or L-(-)-a-methylbenzyl-amine into the diastereomeric dihydroxyamides (Ig) B ~ ~HZ CONH-#H-C6H5 ~OH (Ig) E
which can subsequently be resolved, as customary, into the individual diastereomers by chromatography or crystallization. Subsequent hydrolysis of the pure diastereomeric amides by customary methods, for example by treating the diastereomeric amides with inorganic bases such as sodium hydroxide or potassium hydroxide in water and/or organic solvents such as alcohols, for example methanol, ethanol, propanol or isopropanol, yields the corresponding pure enantiomeric dihydroxy acids (Ic> which can be converted into the,pure enantio-merit lactones by cyclization as described above. In general, it applies that, for the preparation of the compounds of the general formula (I) according to the invention in pure enantiomeric form, the configuration of the final products according to the method described above is dependent on the configuration of the starting materials.
The resolution of isomers is illustrated, for example, in the following scheme:
Le A 25 747 thro-Rac emate + H2N-CH-C6H5 Diastereomeric Mixture 1) Diastereomeric resolution 2) hydrolysis 3) lactonisation F
F OH

'CHZ-CO-NH- ~ H-C6H5 OH
F OH F OH
E

The ketones (VIII) employed as starting materials are new.
A process for the preparation of the ketones of the general formula (VIII) according to the invention B A I, 23 (VIII) I CH=CH-iH-CH2-C-CHZ-COOR
OH
E
in which A, B, 0, E and R23 have the abovementioned meaning, has been found, which is characterized in that aldehydes of the general formula (IX) (IX) E
in which A, 8, D and E have the abovementioned meaning, are reacted in inert solvents with acetoacetates of the general formula (X) O
(X) in which R23 has the abovementioned meaning, in the presence of bases.
The process according to the invention can, for example, be illustrated by the following reaction scheme:
Le A 25 747 ~3~D l9~
F

~H
O

W
Base Suitable bases in this connection are the custom-ary strong basic compounds. These preferably include organolithium compounds such as, for example, N-butyl-lithium, sec.butyllithium, tert.butyllithium or phenyl-lithium, or amides such as, for example, lithium diiso-propylamide, sodium amide or potassium amide, or lithium hexamethyldisilylamide, or alkali metal hydrides such as sodium hydride or potassium hydride. Likewise, it is possible to employ mixtures of the bases mentioned. N-Butyllithium or sodium hydride or a mixture thereof are particularly preferably employed.
Suitable solvents in this connection are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, tetrahydrofuran, dioxane or di-methoxyethane, or hydrocarbons such as benzene, toluene, xylene, cyclohexane, hexane or mineral oil fractions.
Likewise, it is possible to employ mixtures of the sol-vents mentioned. Ethers such as diethyl ether or tetra-Le A 25 747 F O

."- ~.3~~~1 ~
hydrofuran are particularly preferably used.
The reaction is in general carried out in a tem-perature range from -80°C to +50°C, preferably from -20oC to room temperature.
The process is in general carried out at normal pressure, but it is also possible to carry out the pro-cess at underpressure or at overpressure, for example in a range from 0.5 to 5 bar.
When carrying out the process, the acetoacetate 70 is in general employed in an amount of 1 to 2, preferably of 1 to 1.5 moles, relative to 1 mole of the aldehyde.
The acetoacetates of the formula (X) employed as starting materials are known or can be prepared by known methods CBeilstein's Handbuch der organischen Chemie (8eilstein's Handbook of Organic Chemistry) III, 632;
438J.
Acetoacetates which may be mentioned for the process according to the invention, are, for example:
methyl acetoacetate, ethyl acetoacetate, propyl aceto-acetate, isopropyl acetoacetate.
The preparation of the aldehydes of the general formula (IX) employed as starting materials is illustra-ted by way of example for the compounds of the type (Ia>
A A
D (~ COOR24 [ 1 7 D~/~/CHZOH
E~8 E~.B
tX) tXI) A H~/C H 0 [~ I ~ ~ CHO [ 3 ] D w H
E Tr '8 E
IXII) cIX) Le A 25 747 1340~10~
In this connection, according to scheme A, pyri-dines of the formula (X) in which R24 stands for an alkyl radical having up to 4 carbon atoms are reduced in the first step C1J to the hydroxymethyl compounds (XI) in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or dioxane, preferably tetrahydrofuran, using metal hydrides as reductants, for example lithium aluminium hydride, sodium cyanoborohydride, sodium aluminium hydride, diisobutylaluminium hydride or sodium 1D bis-(2-methoxyethoxy)-dihydroaluminate, in temperature ranges from -70°C to +100°C, preferably from -70°C to room temperature, or from room temperature to 70°C, depending on the reductant used. Preferably, the reduc-tion is carried out using lithium aluminium hydride in tetrahydrofuran in a temperature range from room tempera-ture to 80°C. The hydroxymethyl compounds (XI) are oxi-dized in a second step C2J by customary methods to the aldehydes (VII>. The oxidation can, for example, be car-ried out using pyridinium chlorochromate, if appropriate in the presence of aluminium, in inert solvents such as chlorinated hydrocarbons, preferably methylene chloride, in a temperature range from 0°C to 60°C, preferably at room temperature, or else can be carried out using trifluoro-acetic acid/dimethyl sulphoxide by the customary methods of Swern oxidation. The aldehydes (XII) are reacted in a third step C3J to give the aldehydes (IX) using diethyl 2-(cyclohexylamino)-vinylphosphonate in the presence of sod-ium hydride in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or dioxane, preferably in tetrahydrofuran, in a temperature range from -20°C to +40°C, preferably from -5°C to room temperature.
The pyridines of the formula (X) employed as starting materials in this connection are in this case in general obtained according to scheme B by oxidation of dihydropyridines (XIII) which again, depending on the meaning of the radical D, have been obtained by variation Le A 25 747 134~'~9~
of the corresponding functional groups. The dihydropyri-dines employed as starting materials in this connection are known or can be prepared by known methods CEP-A
88,276, DE-A 2,847,236J. The oxidation of the dihydro-pyridines (XIII) to the pyridines (X) can be carried out, for example, using chromic oxide in glacial acetic acid in a temperature range from -20oC to +150°C, preferably at reflux temperature, or using 2,3-dichloro-5,6-dicyano-p-benzoquinone as an oxidant in inert solvents such as chlorinated hydrocarbons, preferably n~ethylene chloride, in a temperature range from 0oC to +100oC, preferably at room temperature.
(8) D ~ COOR24 COOR
N E ~ 8 H
tXIII) tX) The variation of the radical D is illustrated by some examples in the following reaction equations:
CC) A A
...
NC-HZC-HZC-OOC~COOR24 HOOC'~/'~,/COOR24 E~tJ
H E~N~B
H
tXIV) tXV) A A
HOOC~/\/COOR2a H~%\/COOR24 ELI N ~~ ESN~8 H H
tXV) tXVI) Le A 25 747 1~40~1~~

HOOC~COOR24 N-C~/~/COORZ4 E~N~B R' E~N~B
H H
(XV) (XVII) The dihydropyridines (XIV) can be hydrolyzed to the dihydropyridinecarboxylic acids (XV>, for example by reaction with an alkali metal hydroxide in dimethoxy-ethane at room temperature. The dihydropyridinecarboxy-lic acids (XV) can be decarboxylated to the dihydropyri-dines (XVI), for example, by heating to 200oC in di-ethylene glycol. In addition, the dihydropyridinecar-boxylic acids (XV) can be reacted to give the dihydro-pyridinecarboxylic acid amides (XVII) by known methods, for example by reaction with dicyclohexylcarbodiimide.
A A
RZ4 ~ OOC\/~/COOR24 H3C~/~/COOR24 E~N~B
H E~N~8 H
cXVIII) (XIX) The dihydropyridines (XVIII) can be reduced to the dihydropyridines (XIX) using customary reductants, for example by reaction of lithium aluminium hydride in tetrahydrofuran, at room temperature or at boiling point.
A A
R24 ~OOC~/~/COOR24 H I~ COOR24 ~~B
(XX) (XXI) Le A 25 747 A A
I i E~B
tXXII (XXIIf The pyridines (XX), which can be prepared from the dihydropyridines (XVIII) by oxidation as des-cribed above, can be reduced to the pyridines (XXI) by suitable reductants, such as, for example, lithium aluminium hydride, diisobutylaluminium hydride or sodium bis-(2-methoxyethoxy)-dihydroaluminate in inert solvents, such as, for example, tetrahydrofuran.
The pyridines (XXI) can be reacted to give the pyridines (XXII) by known methods, for example by reac-tion with an alkyl or benzyl halide in the presence of a base, such as, for example, sodium hydride or for example by reaction with a trialkylsilyl halide or an acid halide in the presence of a base such as imidazole, pyridine or triethylamine. The hydroxyl group of the pyridines (XXI) can be converted into a leaving group by known methods, for example by reaction with trifluoromethane-sulphonic anhydride, thionyl chloride or methanesulphonyl chloride in the presence of a base. The leaving group can then be exchanged for a nucleophile by known methods.
The compounds of the general formula (I> accord-ing to the invention possess useful pharmacological pro-perties and can be employed in medicaments. In particu-lar, they are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HGM-CoA) reductase and are consequently in-hibitors of cholesterol biosynthesis. They can therefore be employed for the treatment of hyperlipoproteinaemia, lipoproteinaemia or arteriosclerosis. The active compounds according to the invention additionally cause a lowering of the cholesterol content in the blood.
Le A 25 747 The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. In this connection, the therapeutically active compound should in each case be present in a con-centration from about 0.5 to 98% by weight, preferably 1 to 90% by weight, of the total mixture, i.e. in amounts which are sufficient to achieve the dosage range indica-ted.
The formulations are prepared, for example, by extending the active compounds using solvents and/or excipients, if appropriate using emulsifiers and/or dis-persants, where, for example, in the case of the use of water as a diluent, if appropriate organic solvents can be used as auxiliary solvents.
Auxiliary solvents which may be mentioned as examples are: water, non-toxic organic solvents, such as paraffins (for example mineral oil fractions>, vege-table oils (for example groundnut/sesame oil), alcohols (for example: ethyl alcohol, glycerol), excipients, such as for example ground natural minerals (for example kaolins, argillaceous earths, talc, chalk), ground syn-thetic minerals (for example highly disperse silica, silicates), sugars (for example sucrose, lactose and dextrose>, emulsifiers (for example polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulphonates and aryl sulphonates), dispersants (for example lignin sulphite waste liquors, methylcellulose, starch and polyvinylpyrrolidone> and lubricants (for example magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
The administration takes place in a customary manner, preferably orally, parenterally, perlingually or intravenously. In the case of oral use, tablets can, of Le A 25 747 1340~1~~
course, also contain additions, such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatine and the like in addition to the excipi-ents mentioned. Furthermore, lubricants, such as mag-nesium stearate, sodium lauryl sulphate and talc can additionally be used for tabletting. In the case of aqueous suspensions, various flavour improvers or colour-ants can be added to the active compounds in addition to the auxiliaries mentioned above.
In the case of parenteral use, solutions of the active compounds can be employed using suitable liquid excipients.
In general, it has proved advantageous on intra-venous administration to administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight to attain effective results, and on oral administration the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.
In spite of this, it can be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on individual behaviour towards the medicament, the manner of its formulation and ._ the point in time or interval at which administration takes place.
Thus, in some cases it may be sufficient to manage with less than the minimum amount previously mentioned, whereas in other cases the upper limit mentioned must be exceeded. In the case of the administration of larger amounts, it can be advisable to divide these into several individual doses over the day.
Le A 25 747 ~~~o~~~
The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for the use thereof for treatment of hyperlipoproteinaemia, lipoproteinaemia or arteriosclerosis.
The invention is illustrated in the following examples. Examples 33, 42, 51, 58, 96, 99, 100, 103, 129 and 130 are reference examples and are not within the scope of claim 1.
59a E

1340~~9~
Preparation Examples Example 1 (E/Z)-4-Carboxyethyl-5-(4-fluorophenyl)-2-methyl-pent-4-en-3-one F
w COOC2N5 Oi 62 g (0.5 mol) of 4-fluorobenzaldehyde and 79 g (0.5 mol) of ethyl isobutyrylacetate are initially intro-duced into 300 ml of isopropanol and a mixture of 2.81 ml (28 mmol) of piperidine and 1.66 ml (29 mmol> of acetic acid in 40 ml of isopropanol is added. The mixture is allowed to stir for 48 hours at room temperature and is concentrated in vacuo, and the residue is distilled in a high vacuum.
8.p. 0.5 mm: 127oC
Yield: 108.7 g (82.3% of theory) Example 2 °w Diethyl 1,4-dihydro-2,6-diisopropyl-4-(4-fluorophenyl>-pyridine-3,5-dicarboxylate F

98 g <0.371 ~nol> of the compound from Example 1 are heated to reflux for 18 h with 58.3 g (0.371 mol) of ethyl 3-amino-4-methyl-pent-2-enoate in 300 ml of Le A 25 747 ethanol. The mixture is cooled to room temperature, the solvent is evaporated off in vacuo and the unreacted starting materials are distilled off in a high vacuum at 130oC. The remaining syrup is stirred with n-hexane and the deposited precipitate is filtered off with suc-tion, washed with n-hexane and dried in a desiccator.
Yield: 35 g (23.4% of theory) 1H-NMR (CDCl3): - 1.1 - 1.3 (m, 18H); 4.05 - 4.25 (m, 6H>; 5.0 (s, 1H); b.13 (s, 1H); 6.88 (m, 2H); 7.2 (m, 2H) ppm.
Example 3 Diethyl 2,6-diisopropyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate F

3.8 g (16.4 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone are added to a solution of 6.6 g (16.4 mmol) of the compound from Example 2 in 200 ml of methylene chloride p.a. and the mixture is stirred for 1 h at room temperature. It is then filtered pith suction over kieselguhr, and the methylene chloride phase is extracted three times with 100 ml of water each time and dried over magnesium sulphate. After concentrating in vacuo, the residue is chromatographed on a column (100 g of silica gel 70-230 mesh, 3.5 cm, using ethyl acetate/petroleum ether 1:9).
Yield: 5.8 g (87.9% of theory) 1H-NMR (CDCl3): - 0.98 (t, 6H); 1.41 (d, 12H); 3.1 (m, 2H); 4.11 (q, 4H); 7.04 (m, 2H>;
Le A 25 747 13~~'~~
7.25 (m, 2H> ppm.
Example 4 Ethyl 2,6-diisopropyl-4-(4-fluorophenyl>-5-hydroxymethyl-pyridine-3-carboxylate F
HO-HZC~COOC2H5 21 ml (80.5 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 9.2 g (23 mmol) of the compound from Example 3 in 100 ml of dry tetra-hydrofuran at -10°C to -5°C and the mixture is stirred for 5 h at room temperature. After cooling to OoC, 100 ml of water are cautiously added dropwise and the mixture is extracted three times using 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The residue is chromatographed on a column (200 g of silica gel 70-230 mesh, 4.5 cm, using ethyl acetate/petroleum ether 3:7).
Yield: 7.2 g (87.2% of theory) 1H-NMR (CDCl3): - 0.95 (t, 3H); 1.31 (m, 12H>; 3.05 (m, 1H>; 3.48 (m, 1H), 3.95 (q, 2H); 4.93 (d, 2H); 7.D5 - 7.31 (m, 4H) ppm.
Example S
Ethyl 5-(tert.butyldimethylsilyloxymethyl)-2,6-diiso-propyl-4-(4-fluorophenyl)-pyridine-3-carboxylate Le A 25 747 13~~'7~~
F

tH3C)3C-Si-0-H OC2H5 2.1 g (13.8 mmol) of tert.butyldimethylsilyl chloride, 1.8 g (27.5 mmol) of imidazole and 0.05 g of 4-dimethylaminopyridine are added at room temperature to a solution of 4.5 g (12.5 mmol) of the compound from Example 4 in 50 ml of dimethylformamide. The mixture is stirred overnight at room temperature, 200 ml of water are added and the mixture is adjusted to pH 3 using 1 N
hydrochloric acid. The mixture is extracted three times using 100 ml of ether each time, and the combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (150 g of silica gel, 70-230 mesh, 4 cm, using ethyl acetate/petroleum ether 1:9).
Yield: 4.2 g (73.7% of theory) 1H-NMR (CDCl3): - 0.0 (s, 6H); 0.9 (s, 9H); 1.02 (t, 3H); 1.35 (m, 12H>; 3.1 (m, 1H);
3.47 (m, 1H); 4.03 (q, 2H>; 4.4 (s, 2H>; 7.05 - 7.40 (m, 4H> ppm.
Example 6 3-(tent.Butyldimethylsilyloxymethyl)-2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxy~nethyl-pyridine Le A 25 747 134~~~~~
F

(H3C)3C-Si-0-H 2-OH

9.2 ml (32.2 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 4.2 g (9.2 mmol) of the compound from Example 5 in 100 ml of dry tetrahydrofuran at 0°C and the mixture is stirred over-night at room temperature. After cooling to 0°C, 100 ml of eater are cautiously added dropuise and the mixture is extracted three times using 100 ml of ethyl acetate each time. The combined organic phases are Washed once with saturated sodium chloride solution, dried over mag-nesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, 3.5 cm, using ethyl acetate/petroleum ether 2:8).
Yield: 2.4 g (60% of theory) 1H-NMR (CDCl3): - 0.2 (s, 6H); 1.11 (s, 9H); 1.6 (m, 12H); 3.7 (m, 2H); 4.55 (s, 2H);
4.65 (d, 2H>; 7.35 - 7.55 (m, 4H) ppm.
Example 7 5-(tert.Butyldimethylsilyloxymethyl)-2,6-diisopropyl>-4-(4-fluorophenyl)-pyridine-3-carbaldehyde i a a ~S 7~7 F

(H3C)3C-Si-0-HZC ~ CHO

1.24 g (12.4 inmol) of neutral alumina and 2.7 g (12.4 ~amol) of pyridinium chlorochromate are added to a solution of 2.7 g (6.2 mmol) of the compound from Example 6 in 50 ml of methylene chloride and the mixture is stirred for 1 h at room temperature. It is filtered over kieselguhr and washed with 200 ml of methylene chloride.
The methylene chloride phase is concentrated in vacuo and the residue is chromatographed on a column (100 g of silica gel 70-230 mesh, 3.5 cm, using ethyl acetate/
petroleum ether 1:9).
Yield: 2 g (77% of theory) 1H-NMR (CDCl3): - 0.0 (s, 6H); 0.9 (s, 9H); 1.35 (m, 12H); 3.5 (m, 1H); 3.9 (m, 1H>;
4.38 (s, 2H); 7.15 - 7.35 (m, 4H>;
9.8 (s, 1H) ppm.
Example 8 (E)-3-CS-tent.Butyldimethylsilyloxymethyl-2,6-diisopro-pyl-4-(4-fluorophenyl)-pyrid-3-yl7-prop-2-enal F

(H3C>3C-Si-0-H

1.b g (6 mmol) of diethyl 2-(cyclohexylamino>-vinylphosphonate dissolved in 30 ml of dry tetrahydro-Le A 25 747 ~.3~a'~~o furan are added dropwise under nitrogen to a suspension of 180 mg (6 mmol) of 80% strength sodium hydride in 15 ml of dry tetrahydrofuran at -5°C. After 30 min, 2 g (4.7 mmol) of the compound from Example 7 in 40 ml of dry tetrahydrofuran are added dropwise at the same temperature and the mixture is warmed to reflux for 30 min. After cooling to room temperature, the batch is added to 200 ml of ice-cold water and extracted three times using 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulphate. After concentrating in vacuo, the residue is taken up in 70 ml of toluene, a solution of 0.9 g (7 mmol> of oxalic acid dehydrate in 30 ml of water is added and the mixture is heated to reflux for 30 min. After cooling to room temperature, the phases are separated, and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh 3.5 cm, using ethyl acetate/-petroleum ether 1:9>.
Yield: 2 g (95% of theory) 1H-NMR (CDCl3): - 0.0 (s, 6H); 0.9 (s, 9H); 1.38 (m, 12H>; 3.36 (m, 1H); 3.48 (m, 1H);
4.48 (s, 2H); 6.03 (dd, 1H); 7.12 -7.35 (m, 5H); 9.45 (d, 1H) ppm.
Example 9 Methyl (E)-7-C5-tert.butyldimethylsilyloxymethyl-2,6-di-isopropyl-4-(4-fluorophenyl)-pyrid-3-ylJ-5-hydroxy-3-oxo-hept-6-enoate ~/COOCH3 tH3C)3C-Si~0~H

Le A 25 747 I3~0 ~9~
1.02 g (8.8 mmol) of methyl acetate in 5 ml of dry tetrahydrofuran are added dropwise under nitrogen to a suspension of 330 mg (11 mmol) of 80% strength sodium hydride in 30 ml of dry tetrahydrofuran at -SoC. After 15 min, 5.5 ml (8.8 mmol) of 15% strength butyllithium in n-hexane are added dropwise at the same temperature and the mixture is stirred for 15 min. Subsequently, 2 g (4.4 mmol) of the compound from Example 8 dissolved in 20 ml of dry tetrahydrofuran are added dropwise and the mixture is stirred for 30 min at -SoC. 3 ml of 50%
strength acetic acid are cautiously added to the reaction solution, and the mixture is diluted using 100 ml of water and extracted three times using 100 ml of ether each time. The combined organic phases are washed twice with saturated sodium hydrogen carbonate solution and once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The resi-due is chromatographed on a column (100 g of silica gel 70-230 mesh, 3 cm, using ethyl acetate/petroleum ether 3:7).
lrield: 1.9 g (84.4% of theory) 1H-NMR (CDCl3): - 0.0 (s, 6H); 0.9 (s, 9H); 1.35 (m, 12H); 2.5 (m, 2H); 3.32 (m, 1H);
3.45 (m, 1H); 3.48 (s, 2H>; 3.81 (s, 3H); 4.35 (s, 2H); 4.55 (m, 1H);
5.32 (dd, 1H); 6.42 (d, 1H); 7.15 (m, 4H) ppm.
Example 10 Methyl erythro-(E)-7-C5-tert.butyldimethylsilyloxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyrid-3-ylJ-3,5-di-hydroxy-hept-6-enoate Le A 25 747 ~~~Ol~g iH3 (H3C>3C-Si-0-H

4.5 ml (4.5 mmol) of 1 M triethylborane solution in tetrahydrofuran are added at room temperature to a solution of 1.9 g (3.7 mmol) of the compound from Example 9 in 40 ml of dry tetrahydrofuran, air is passed through the solution for 5 min and it is cooled to an internal temperature of -30oC. 160 mg (4.5 mmol) of sodium borohydride and, slowly, 3 ml of methanol are added, the mixture is stirred for 30 min at -30°C and a mixture of 12 ml of 30% strength hydrogen peroxide and 25 ml of water is then added. The temperature is allowed to rise to 0°C during the course of this and the mixture is stirred for 30 min more. The mixture is extracted three times using 70 ml of ethyl acetate each time, and the combined organic phases are washed once each with satura-ted sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromato-graphed on a column (80 g of silica gel 230-400 mesh, 2.5 cm, using ethyl acetate/petroleum ether 4:6>.
Yield: 1.5 g (78.9% of theory) 1H-NMR (CDCl3>: - 0.0 (s, 6H); 0.9 (s, 9H); 1.35 (m, 12H); 1.5 (m, 2H); 2.5 (m, 2H>;
3.35 (m, 1H); 3.45 (m, 1H); 3.8 (s, 3H); 4.15 (m, 1H>; 4.45 (m, 3H); 5.32 (dd, 1H>; 6.38 (d, 1H>;
7.05 - 7.25 (m, 4H) ppm.
Le A 25 747 F OH

~340~~~~
Example 11 Methyl erythro-(E)-7-C2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-pyrid-3-yl7-3,5-dihydroxy-hept-b-enoate HO-H
15 ml of 0.1 N hydrochloric acid are added to 8.4 g (14.6 mmol) of the compoundfrom Example 10 dis-solved in 135 ml of methanol and the mixture stirred is for 4 days at room temperature. The mixture concen-is trated in vacuo, and the residue is taken up dichloro-in methane and washed several times with saturatedsodium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate and concentrated in uo, and vac the residue is chromatographed a column (sil ica gel on 70-230 mesh, using ethyl acetate/petroleum ether 4:6).

Yield: 3.5 g (52.5% of theory) 1H-NMR (CDCl3>: - 1.25 (m, 6H); 1.33 (d, bH); 1.40 (m, 2H); 2.41 (m, 2H); 3.30 (m, 1H>;

3.45 (m, 1H); 3.71 (s, 3H); 4.07 (m, 1H); 4.28 (m, 1H); 4.39 (d, 2H);

5.25 (dd, 1H>; 6.30 (d, 1H); 7.08 (m, 4H) ppm.

Example 12 Ethyl 5-benzyloxymethyl-2,6-diisopropyl-4-(4-fluoro-phenyl)-pyridine-3-carboxylate Le A 25 747 OH

~~~~r~~~
F
OCZH~
4.5 g (12.5 mmol) of the compound from Example 4 in 50 ml of dimethylformamide are added dropwise under nitrogen to a suspension of 414 mg (13.8 mmol) of 80%
strength sodium hydride in 20 ml of dimethylformamide at 0°C and the mixture is stirred for 30 min at the same temperature. Subsequently, 1.65 ml (13.8 mmol) of benzyl bromide in 20 ml of dimethylformamide are added dropwise and the mixture is stirred for a further 3 h at room temperature. The mixture is poured into 300 ml of water at 0°C and extracted three times using 150 ml of ether each time. The combined organic phases are washed once with saturated sodium chloride solution, dried over mag-nesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, 3.5 cm, using ethyl acetate/petroleum ether 1:10>.
Yield: 2.6 g (46.4% of theory) 1H-NMR (CDCl3): - 0.95 (t, 3H>; 1.3 (m, 12H); 3.05 (m, 1H); 3.38 (m, 1H); 3.97 (q, 2H>; 4.2 (s, 2H>; 4.38 (s, 2H>;
7.02 (m, 2H); 7.25 (m, 7H) ppm.
Example 13 3-Benzyloxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-pyridine Le A 25 747 F
ZOH
2.5 g (5.5 mmol) of the compound from Example 12 are reacted analogously to Example 6.
Yield: 1.5 g (68% of theory) 1H-NMR CCDCl3): - 1.3 (m, 12H); 3.35 (m, 1H); 3.45 (m, 1H); 4.13 (s, 2H); 4.35 (m, 4H); 7.08 (m, 2H); 7.25 (m, 7H) ppm.
Example 14 5-Benzyloxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyridine-3-carbaldehyde F

1.5 g (3.6 mmol) of the compound from Example 13 are reacted analogously to Example 7.
Yield: 1.1 g (75.9X of theory) 1H-NMR (CDCl3): - 1.3 (m, 12H); 3.4 (m, 1H); 3.85 (m, 1H); 4.18 (s, 2H); 4.38 (s, 2H); 7.05 - 7.35 (m, 9H); 9.75 (s, 1H) ppm.
Le A 25 747 ... ~3~~ l9 Example 15 (E)-3-C5-Benzyloxymethyl-2,6-diisopropyl-4-(4-fluoro-phenyl)-pyrid-3-yl7-prop-2-enal F
ECHO
n 1.1 g (2.7 mmol) of the compound from Example 14 are reacted analogously to Example 8.
Yield: 450 mg (38.8% of theory) 1H-NMR (CDCl3): - 1.35 (m, 12H); 3.35 (m, 1H); 3.42 (m, 1H); 4.21 (s, 2H>; 4.41 (s, 2H); 6.0 (dd, 1H); 7.05 - 7.4 (m, 10H); 9.38 (d, 1H) ppm.
Example 16 Methyl (E)-7-C5-benzyloxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyrid-3-ylJ-5-hydroxy-3-oxo-kept-6-enoate ... OOCH3 431 mg (1 mmol) of the compound from Example 15 are reacted analogously to Example 9.
Yield: 300 mg (54.8% of theory) Le A 25 747 _ 72 _ 13~~'~~~
Example 17 Methyl erythro-(E)-7-C3-benzyloxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyrid-5-ylJ-3,5-dihydroxy-hept-6-enoate F OH
~COOCH3 v ~ OOH
,. , _ 300 mg (0.55 mmol) of the compound from Example 16 are reacted analogously to Example 10.
Yield: 180 mg (59.6% of theory) 1H-NMR (CDCl3>: - 1.2 - 1.35 (m, 12H>; 1.4 (m, 2H>;
2.41 (m, 2H); 3.3 (m, 2H); 3.73 (s, 3H); 4.05 (m, 1H); 4.15 (s, 2H); 4.28 (m, 1H); 4.35 (s, 2H);
5.25 (dd, 1H); 6.3 (d, 1H); 6.95 -7.35 (m, 9H) ppm.
Example 18 3-Ethyl 5-methyl 1,4-dihydro-4-(4-fluorophenyl)-2-iso-propyl-6-methylpyridine-3,5-dicarboxylate F

15 g (56.8 mmol) of the compound from Example 1 and 6.5 g (56.8 mol> of methyl 3-aminocrotonate are heated at reflux for 20 h in 150 ml of ethanol. The mix-ture is cooled, filtered and concentrated in vacuo. The Le A 25 747 residue is chromatographed on a column (250 g of silica gel 70-230 mesh, 6 4.5 cm, using ethyl acetate/petroleum ether 3:7).
Yield: 13.6 g (66.3% of theory) 1H-NMR (CDCl3): - 1.2 (m, 9H); 2.35 (s, 3H>; 3.65 (s, 3H); 4.12 (m, 3H); 4.98 (s, 1H); 5.75 (s, 1H); 6.88 (m, 2H);
7.25 (m, 2H) ppm.
Example 19 3-Ethyl 5-methyl 4-(4-fluorophenyl)-2-isopropyl-b-methyl-pyridine-3,5-dicarboxylate F
H3COOC~COOC2H5 13.5 g (37.4 mmol) of the compound from Example 18 are reacted analogously to Example 3.
Yield: 9.5 g (70.9% of theory) 1H-NMR (CDCl3): - 0.98 (t, 3H); 1.31 (d, 6H); 2.6 (s, 3H); 3.11 (m, 1H); 3.56 (s, 3H); 4.03 (q, 2H); 7.07 (m, 2H);
7.25 (m, 2H) ppm.
Example 20 Ethyl 4-(4-fluorophenyl)-5-hydroxymethyl-2-isopropyl-6-methylpyridine-3-carboxylate F

Le A 25 747 26.5 ml (92.75 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 9.5 g (26.5 mmol) of the compound from Example 19 in 200 ml of abso-lute tetrahydrofuran at 0°C and the mixture is stirred for 30 min at room temperature. After cooling again to OoC, 200 ml of water are cautiously added dropwise and the mixture is extracted three times using 150 ml of ethyl acetate each time. The combined organic phases are washed once vith saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo.
The residue is chromatographed on a column (200 g of silica gel 70-230 mesh, 4.5 cm, using ethyl acetate/
petroleum ether 2:8).
Yield: 4.2 g (48.2% of theory) 1H-NMR (CDCl3): - 0.98 (t, 3H); 1.3 (d, 6H); 2.73 (s, 3H); 3.05 (m, 1H); 3.98 (q, 2H); 4.45 (d, 2H>; 7.1 (m, 2H);
7.25 (m, 2H> ppm.
Example 21 (E/Z)-4-Carboxyethyl-5-(4-fluoro-3-phenoxyphenyl)-2-methyl-pent-4-en-3-one F

49 g (0.31 mol> of ethyl isobutyrylacetate and 67 g (0.31 mol) of 3-phenoxy-4-fluorobenzaldehyde are initially introduced in 300 ml of isopropanol and a mix-ture of 1.81 ml (18 mmol) of piperidine and 1.06 ml (18.6 mmol) of acetic acid in 30 ml of isopropanol is added. The mixture is stirred overnight at room tempera-te A 25 747 .
~~~o r~~
ture, then concentrated in vacuo and dried in a high vacuum.
Yield: 110 g (was employed without further purification in Example 22>.
Example 22 Diethyl 1,4-dihydro-2,6-diisopropyl-4-(4-fluoro-3-phen-oxy-phenyl)-pyridine-3,5-dicarboxylate F
HSC200C I~COOCZHS
H
30 g (84.3 mmol> of the compound from Example 21 and 13.2 g (84.3 mmol) of ethyl 3-amino-4-methyl-pent-2-enoate are heated to reflux in 150 ml of ethanol over-night. The mixture is cooled to 0°C, and the deposited precipitate is filtered off, gashed with petroleum ether and dried in a desiccator.
Yield: 18.4 g (44.2X of theory) 1H-NMR (CDCl3>: b - 1.05 - 1.25 (m, 18H); 4.05 - 4.2 (m, 6H); 4.95 (s, 1H>; 6.03 (s, 1H>; 6.85 - 7.1 (m, 6H); 7.3 (m, 2H) ppm.
Example 23 Diethyl 2,6-diisopropyl-4-(4-fluoro-3-phenoxyphenyl)-pyridine-3,5-dicarboxylate F
HSC200C IwC00C2H5 Le A 25 747 18.4 g (37.2 mmol) of the compound from Example 22 are reacted analogously to Example 3.
Yield: 17.6 g (96% of theory) 1H-NMR (CDCl3): - 1.05 (t, 6H); 1.29 (d, 12H); 3.08 (m, 2H); 4.05 (q, 4H>; 6.95 - 7.35 (m, 8H) ppm.
Example 24 Ethyl 2,6-diisopropyl-4-(4-fluoro-3-phenoxy-phenyl)-5-hydroxymethyl-pyridine-3-carboxylate F
.._ HO-HZC'~/~/COOCZHS
10 g (20.3 mmol> of the compound from Example 23 are reacted analogously to Example 4.
Yield: 4.9 g (59.0% of theory) 1H-NMR (CDCl3): - 1.07 (t, 3H); 1.3 (m, 12H>; 3.04 (m, 1H); 3.47 (m, 1H); 4.05 (m, 2H); 4.45 (s, 2H); 6.95 - 7.4 (m, 8H) ppm.
Example 25 Methyl 2-cyanoethyl 1,4-dihydro-2,6-dimethyl-4-(4-fluoro-phenyl)-pyridine-3,5-dicarboxylate F

H
15.4 g (0.1 mol) of 2-cyanoethyl 3-aminocrotonate, Le A 25 747 _ 77 _ .. ~3~O~~~b 12.4 g (0.1 mol) of p-fluorobenzaldehyde and 11.6 g of methyl acetoacetate are heated overnight under reflux in 150 ml of ethanol. After removing the solvent on a rotary evaporator, the residue is taken up in ethyl ace-s tate, washed with water, dried and 33.8 g of crude pro-duct are obtained after removing the solvent in vacuo.
Crude yield: 94.4% of theory 1H-NMR (DMSO): - 1.15 (tr, 3H, CH3); 2.3 (m, 6H, CH3);
2.75 (m, 2H, CH2CN); 3.55 (s, 3H, OCH3); 4.15 (m, 2H, OCH2); 4.9 (m, 1H, p-FC6H4-CH); 6.9 - 7.3 (m, 4H, aromatic -H>; 8.8, 9.0 (2s, 1H, NH) ppm.
Example 26 Methyl 1,4-dihydro-2,6-dimethyl-4-(4-fluorophenyl)-pyri-dine-3,5-dicarboxylate F
p I ~ O

H3C~N~CH3 H
33.8 g of crude product from Example 25 are added to a solution of 12 g (0.3 mol) of sodium hydroxide in 300 ml of water/150 ml of 1,2-dimethoxyethane. The sus-pension warms and forms a clear solution. After stirring at 25oC overnight, 100 ml of water are added, and the mixture is washed three times with dichloromethane, adjusted to pH 1 using dilute hydrochloric acid and the tacky deposited product is extracted using dichloro-methane. After drying and concentrating the solvent in vacuo, 25.8 g of crude product are obtained.
Crude yield: 84.5X of theory 1H-NMR (DM50): - 2.25 (s, 6H, CH3); 3.55 (s, 3H, OCH3); 4.85 (broad s, 1H, FC6H4-i a a ~c _ - ~~ ..
CH); 6.9 - 7.3 (m, 4H, aromatic-H);
8.85 (broad s, 1H, NH>; 1.7 (broad, 1H, COOH) ppm.
Example 27 Methyt 1,4-dihydro-2,6-dimethyl-4-(4-fluorophenyl)-pyri-dine-3-carboxylate F

H3C/''wN 1/~CH3 H
12.5 g (41 mmol) of crude product from Example 26 are suspended in 90 ml of bis-(2-hydroxyethyl)-ether-(diglycol> and the mixture is heated to a bath tempera-ture of 200°C, a vigorous evolution of gas taking place.
After evolution of gas is complete, the now clear solu-tion is quickly cooled and washed with 500 ml of eater/
500 ml of ether, the aqueous phase is washed trice with ether and the combined ether phases are crashed with ,. water, 1 N sodium hydroxide solution and water and dried.
After removing the solvent on a rotary evaporator, 8.7 g of crude product are obtained.
Crude yield: 81.2X of theory Example 28 Methyl 2,6-d iethyl-4-(4-fluorophenyl>-pyridine-3-carboxylate O

H3C~~H3 le A 25 747 _. 13~~~~~
8.6 g (33 mmol> of crude product from Example 27 and 3.3 g of chromium(VI) oxide are heated under reflux for 1 hour in 90 ml of glacial acetic acid. The solvent is then removed on the rotary evaporator, ethyl acetate/
petroleum ether 1:1 is added to the residue and undis-solved material is filtered off with suction. The mother liquor is concentrated in vacuo and chromatographed over 500 g of silica gel using ethyl acetate/petroleum ether 1:1.
Yield: 1.45 g (16.3% of theory) 1H-NMR (cocl3): - 2.6 (s, bH, cH3); 3.b5 (s, 3H, OCH3); 7.0 (s, 1H, pyridine-H);
7.1 - 7.4 (m, 4H, aromatic-H) ppm.
Example 29 2,b-Dimethyl-4-(4-fluorophenyl)-3-hydroxymethyl-pyridine F
I
N I
I I
N3C ~ N3 5.3 ml (5.3 mmol> of diisobutylaluminium hydride (1 M in toluene) are added under nitrogen at -78°C to 1.35 g (5.2 mmol) of the compound from Example 28 in 25 ml of absolute tetrahydrofuran and, after warming to 25°C, the mixture is hydrolyzed using 20% strength potassium hydroxide solution. The aqueous phase is washed with ethyl acetate and the combined organic phases are dried. After evaporating in vacuo, 1.12 g of crude product are obtained.
Yield: 93% of theory) 1H-NMR (CD30D): - 2.5 (s, 3H, CH3); 2.7 (s, 3H, CH3); 4.5 (s, 2H, CH20H); 4.6 (s, OH); 7.0 (s, 1H, pyridine-H); 7.1 Le A 25 747 1340~19~
- 7.6 (m, 4H, aromatic-H) ppm.
Example 30 2,6-Dimethyl-4-(4-fluorophenyl)-pyridine-3-carbaldehyde F

1.5 g (7 mmol) of pyridinium dichromate are added in portions to 1.0 g (4.3 mmol) of the compound from Example 29 in 20 ml of dichloromethane, the mixture is stirred for 2 h at 25°C, after concentrating chromato-graphed over 150 g of silica gel using dichloromethane/
methanol 10:1 and 0.71 g of product are obtained.
Yield: 72% of theory 1H-NMR (DMSO): - 2.5 (s, 3H, CH3); 2.7 (s, 3H, CH3);
7.2 (s, 1H, pyridine-H); 7.3 - 7.6 (m, 4H, aromatic-H); 9.95 (s, 1H, CHO) ppm.
Example 31 (E>-3-C2,6-Dimethyl-4-(4-fluorophenyl)-pyrid-3-ylJ-prop-2-enal F

778 mg (3.2 mmol> of diethyl C2-(cyclohexylamino)-vinylJ-phosphate in 3 ml of tetrahydrofuran are added under a nitrogen atmosphere to 75.5 mg (3.2 mmol) of Le A 25 747 1340 ~~8 sodium hydride in 3 ml of absolute tetrahydrofuran during the course of 15 min at 0°C, the mixture is stirred for 15 min at 0°C and a solution of 0.6 g (2.6 mmol> of the compound from Example 30 in 3 ml of acetonitrile/3 ml of dimethylformamide is added dropwise. After stirring for 1 h at 0°C and 30 min at 25°C, the mixture is hydro-lyzed using 50 ml of water, washed with ether (3 x 50 ml), and the organic phase; is dried, concentrated in vacuo, taken up in 8 ml of toluene and stirred with 1.2 g (13.5 mmol> of oxalic acid/20 ml of water for 1.5 h at 60°C - 80°C under a nitrogen atmosphere. After cooling, the mixture is adjusted to pH 10 using 2 N sodium hydrox-ide solution and washed four times with ether, and the ether phase is dried, concentrated in vacuo and chromatographed over 100 g of silica gel using dichloro-methane/methanol 30:1.
Yield: 0.3 g (45% of theory) 1H-NMR (CDCl3>: - 2.6 (s, 6H, CH3); 6.2 (dd, 1H, CH-CHO); 6.9 - 7.4 (m, SH, aroma-tic-H); 7.45 (d, 1H, CH=CH-CHO);
9.5 (d, 1H, CHO) ppm.
Example 32 Methyl (E)-7-C2,6-dimethyl-4-(4-fluorophenyl)-pyrid-3-yl7-5-hydroxy-3-oxo-hept-6-enoate F
~ OH 0 0 H3C~~H3 82.2 ul (0.76 mmol> of methyl acetoacetate are added dropwise at 0°C under a nitrogen atmosphere to 18.5 mg (0.8 mmol) of sodium hydride in 1 ml of tetra-hydrofuran. After 15 min, 0.55 ml (0.77 mmol) of n-Le A 25 747 1340r~ ~~
butyllithium (1.5 M in hexane) is added dropwise at OoC, the mixture is stirred for 15 min at 0°C and 180 mg (0.7 mmol) of the compound from Example 31 are added dropwise in 3 ml of tetrahydrofuran. After 1 h, the mixture is hydrolyzed using saturated ammonium chloride solution and washed three times using dichloromethane, and the organic phases are dried and 0.25 g of oil are obtained after removing the solvent in vacuo.
Crude yield: 95.5% of theory 1H-NMR (CDCl3): - 2.55, 2.58 (2s, 6H, CH3); 2.6 (2H, CH2); 3.45 (s, 2H, CH2C02>;
3.75 (s, 3H, OCH3); 4.6 (m, 1H, CHOH); 5.45 (dd, 1H, CH-CHOH); 6.5 (d, 1H, CH=CH-CHOH); 6.9 (s, 1H, pyridine-H); 7.0 - 7.4 (m, 4H, aromatic-H) ppm.
Example 33 Methyl erythro-(E)-7-C2,6-dimethyl-4-(4-fluorophenyl>-pyridin-3-ylJ-3,5-dihydroxy-hept-6-enoate F
I ~ OH OH 0 I wI w CH3 H3C~~H3 Air is blown through a solution of 0.25 g (0.67 mmol> of the compound from Example 32 and 0.81 ml (0.81 mmol) of triethylborane (1M in tetrahydrofuran) for 5 min, 30.6 mg (0.81 mol) of sodium borohydride and, slowly, 0.55 ml of methanol are added at -30oC, the mixture is stirred for 30 min at -30°C, a mixture of 4.7 ml of water and 2.16 ml of 30% strength hydrogen peroxide solu-tion is added in such a way that the temperature does not exceed OoC, the mixture is diluted after 30 min using Le A 25 747 ~3~0 ~~~
eater, gashed three times vith ethyl acetate, the organic phase is washed with sodium hydrogen carbonate solution and dried, the solvent is removed in vacuo, the residue is chromatographed over 75 g of silica gel using ethy l acetate and 0.11 g of product is obtained.
Yield: 43.7X of theory 1H-NMR (CDCl3): a = 2.45 (m, 2H, CH2C02); 2.5, 2.58 (2s, 6H, CH3); 3.75 (s, 3H, OCH3>;
4.2, 4.4 (2m, 2H, CHOH); 5.45 (dd, 1H, CH-tHOH); 6.55 (d, 1H, CH=CH-OH); 6.4 (s, 1H, pyridine-H); 7.0 - 7.4 (m, 4H, aromatic-H) ppm.
fxample 34 5-(2-Cyanoethyl)-3-ethyl-1,4-dihydro-2-(4-fluorophenyl)-4-isopropyl-6-methyl-pyridine-3,5-dicarboxylate EL CN
.. H/~C H 3 F
Analogously to Example 25, 32.6 g of crude pro-duct are obtained from 2.75 g (0.1 mol) of ethyl iso-propylidene-4-fluoro-benzoylacetate and 15.4 g (0.1 mol) of 2-cyanoethyl 3-aminocrotonate.
Crude yield: 93.6X of theory 1H-NMR (CDCl3): a = 0.7 - 1.3 (m, 9H, CH3); 2.3, 2.35 (2s, 3H, CH3); 2.75 (m, 2H, CH2CN); 3.9 - 4.4 (m, SH, CHCH3, CH20); 5.6, 5.7, 6.1, 6.2 (4s, 1H, CH); 7.0 - 8.0 (m, 4H, aromatic-H) ppm.
Le A 25 747 134~~~~~
Example 35 3-Ethyl 1,4-dihydro-2-(4-fluorophenyl)-4-isopropyl-6-methyl-pyridine-3,5-dicarboxylate 0 '~~,/
Et COON
y'~CH3 F I H
Analogously to Example 26, 7.17 g of crude pro-duct are obtained from 36 g (93.2 mmol) of the compound from Example 34.
Crude yield: 22.2% of theory 1H-NMR (DMSO): - 0.8 (m, 9H, CH3); 1.6 (m, 1H, CHCH3); 2.2, 2.25 (2s, 3H, CH3);
3.8 (m, 3H, CH20, CH); 7.2 - 7.5 (m, 4H, aromatic-H) ppm.
Example 36 Ethyl 1,4-dihydro-2-(4-fluorophenyl)-4-isopropyl-6-methyl-pyridine-3-carboxylate E t 0~'~, .. _ 'N~'~CH3 H
F
Analogously to Example 27, 7.15 g of crude pro-duct are obtained from 11.3 g (32.6 mmol) of Example 35.
Crude yield: 7.25% of theory 1H-NMR (CDCl3): - 0.8 - 1.3 (m, 9H, CH3); 2.5, 2.6 (2s, 3H, CH3); 3.1 (m, 1H, CHCH3); 3.8 - 4.2 (m, 2H, CH20);
4.55, 5.2 (br, 1H, CH>; 6.8 (s, 1H, CH); 6.9 - 8.0 (m, 4H, aromatic-H) ppm.
Le A 25 747 1340~1~~
Example 37 Ethyl 2-(4-fluorophenyl)-4-isopropyl-6-methyl-pyridine-3-carboxylate Analogously to Example 28, 2.82 g are obtained after chromatography (silica gel, toluene/ethanol 95:5) from 6.95 g (22.9 mmol) of the compound from Example 36.
Yield: 41% of theory 1H-NMR (CDCl3): - 1.0 (tr, 3H, CH3); 1.3 (d, 6H, CH3CH); 2.6 (5, 3H, CH3); 3.1 (sept, 1H, CH); 4.1 (q, 2H, CH20);
7.0 (s, 1H, pyridine-H); 7.1 -7.6 (m, 4H, aromatic-H) ppm.
Example 38 2-(4-Fluorophenyl)-3-hydroxymethyl-4-isopropyl-6-methyl-pyridine ~H
ilI _ 5.5 g (18.3 mmol) of the compound from Example 37 are reacted analogously to Example 29. After drying in a desiccator, 4.24 g of crude product are obtained.
Yield: 89% of theory 1H-NMR (CDCl3): - 1.3 (d, 6H); 2.55 (s, 3H); 3.36 (m, 1H); 4.49 (s, 2H); 7.09 (m, 3H); 7.53 (m, 2H) ppm.
Le A 25 747 1340~~~
Example 39 2-(4-Fluorophenyl)-4-isopropyl-6-methyl-pyridine-3-carbaldehyde MHO
i 4.1 g (15.85 mmol) of the compound from Example 38 are reacted analogously to Example 30.
Yield: 2.23 g (54.7% of theory) 1H-NMR (CDCl3): - 1.3 (d, 6H); 2.65 (s, 3H); 3.91 (m, 1H>; 7.10 - 7.28 (m, 3H>;
7.5 (m, 2H>; 9.91 (s, 1H> ppm.
Example 40 (E)-3-C2-(4-Fluorophenyl)-4-isopropyl-6-methyl-pyrid-3-ylJ-prop-2-enal CHO
I 1 ~ I
II

2.13 g (8.3 mmol) of the compound from Example 39 are reacted analogously to Example 8.
Yield: 1.34 g of crude product (57% of theory) 1H-NMR (CDCl3): - 12.8 (d, 6H); 2.6 ts, 3H); 3.27 (m, 1H>; 6.11 tdd, 1H); 7.05 -7.55 (m, 6H); 9.55 td, 1H) ppm.
Le A 25 747 1~~~~~
Example 41 Methyl (E)-7-C2-(4-fluorophenyl)-4-isopropyl-6-methyl-pyrid-3-yl7-5-hydroxy-3-oxo-hept-6-enoate HO
i il li °cH
II ; ~ I ° °
i r~I

1.07 g (3.78 mmol) of the compound from Example 40 are reacted analogously to Example 32.
Yield: 0.34 g of crude product (22.5% of theory) 1H-NMR (CDCl3): - 1.25 (d, 6H); 2.5 (m, 2H); 2.57 (s, 3H); 3.2 (m, 1H); 3.42 (s, 2H>; 3.75 (s, 3H); 4.45 (m, 1H);
5.3 (dd, 1H); 6.6 (d, 1H>; 7.05 (m, 3H); 7.43 (m, 2H) ppm.
Example 42 Methyl erythro-(E)-7-C2-(4-fluorophenyl)-2-isopropyl-6-methyl-pyrid-3-yl7-3,5-dihydroxy-hept-6-enoate F

200 mg (0.5 ~nmol) of the compound from Example 41 are reacted analogously to Example 33.
Yield: 21.5 mg (10.7% of theory) 1H-NMR (COCl3): - 1.23 (d, 6H); 1.5 (m, 2H>; 2.45 (m, 2H); 2.58 (s, 3H); 3.21 (m, 1H); 3.72 (s, 3H); 4.11 (m, 1H>;
4.38 (m, 1H); 5.31 (dd, 1H); 6.55 Le A 25 747 _ _ ~ ~~ ".
~.~4a'~~~
(d, 1H); 7.05 (m, 3H); 7.4 (m, 2H) ppm.
Example 43 5-(2-Cyanoethyl)-3-ethyl-1,4-dihydro-4-(4-fluorophenyl)-2-isopropyl-b-methyl-pyridine-3,5-dicarboxylate F
Ei Analogously to Example 25, 44.6 g of crude pro-duct are obtained from 26.4 g (0.1 mol) of ethyl 4-fluorobenzylidene-2-butanoylacetate and 15.4 g (0.1 mol) of 2-cyanoethyl 3-aminocrotonate.
Crude yield: 100X of theory 1H-NMR (DMSO): a = 1.15 (m, 9H, CH3-CH2, CH3-CH-CH3);
2.3 (s, 3H, CH3); 2.45 (m, 2H, CH2-CN); 4.0 (q, 2H, CH20); 4.1 (m, 75 1H, CHCH3); 4.15 (m, 2H, CH20);
4.4 (s, 1H, p-FC6H4CH); 6.9 - 7.3 (m, 4H, aromatic-H); $.3 (s, 1H, NH) ppm.
Example 44 3-Ethyl-1,4-dihydro-4-(4-fluorophenyl)-2-isopropyl-b-methyl-pyridine-3,5-dicarboxylate F
0 ~ 0 Et H
~hCH
H
Le A 25 747 Analogously to Example 26, 8.5 g of crude product are obtained from 10.2 g (25.6 mmol) of the compound from Example 43.
Crude yield: 95% of theory 1H-NMR (DMSO): - 1.15 (m, 9H, CH3CH2, CH3CHCH3);
2.25, 2.3 (2s, 3H, CH3); 4.0 (m, 3H, CH20, CH3CH); 4:85, 6.3 (2s, 1H, FC6H4-CH>; 6.9 - 7.3 (m, 4H, aromatic-H); 8.1 (s, 1H, NH>; 10.9 (s, 1H, COOH) ppm.
Example 45 Ethyl 1,4-dihydro-4-(4-fluorophenyl)-2-isopropyl-6-methyl-pyridine-3-carboxylate F

Et IBC H
N
Analogously to Example 27, 5.6 g of crude product are obtained from 8.35 g (24 mmol) of the compound from Example 44.
Crude yield: 77.5% of theory 1H-NMR (CDCl3): - 1.2 (m, 9H, _CH3CH2, CH3CH_CH3);
2.6 (s, 3H, CH3); 4.1 (m, CHCH3, CH20); 4.5, 4.6 (2d, 1H, FC6H4CH); 5.3 (s, 1H, NH);
6.9 - 7.4 (m, >5H, aromatic-H) ppm.
Example 46 Ethyl 4-(4-fluorophenyl)-2-isopropyl-6-methyl-pyridine-3-carboxylate Le A 25 747 F

J
Et Analogously to Example 37, 2.9 g of red oil are obtained after chromatography over silica gel (dichloro-methane) from 5.5 g (18.2 mmol) of the compound from Example 45.
Yield: 53% of theory 1H-NMR (CDCl3): - 1.05 (tr, 3H, CH3CH2); 1.35 (d, 6H, CH3CH); 2.6 (s, 3H, CH3>;
3.15 (sept., 1H, CH>; 4.1 (q, 2H, CH2); 6.95 (s, 1H, pyridine-H);
7.1 - 7.4 (m, 4H, aromatic-H) ppm.
Example 47 4-(4-Fluorophenyl)-3-hydroxymethyl-2-isopropyl-b-methyl-pyridine ~, Analogously to Example 29, 2.19 g of product are obtained from 2.8 g (9.3 mmol) of the compound from Example 46.
Yield: 91% of theory 1H-NMR (CDCl3): - 1.3 (d, 6H, CH3CH); 1.5 (br, 1H, OH); 2.5 (s, 3H, CH3>; 3.5 (sept., 1H, CH); 4.6 (s, 2H, CH2); 6.9 (s, 1H, pyridine-H); 7.1 - 7.5 (m, 4H, aromatic-H) ppm.
Le A 25 747 134o~r~~
Example 48 4-(4-Fluorophenyl)-2-isopropyl-6-methyl-pyridine-3-carbaldehyde ~ iH0 i Analogously to Example 30, 0.56 g of product is obtained from 2.0 g (7.7 mmol) of the compound from Example 47.
Yield: 28.3% of theory 1H-NMR (CDCl3): - 1.3 (d, 6H, CH3CH); 2.6 (s, 3H, CH3); 3.6 (sept, 1H, CH); /,0 (s, 1H, pyridine-H); 7.1 - 7.4 (m, 4H, aromatic-H); 10.0 (s, 1H, CHO) ppm.
Example 49 (E>-3-C4-(4-Fluorophenyl)-2-isopropyl-6-methyl-pyrid-3-ylJ-prop-2-enal CHO
i ~ .
...
I

Analogously to Example 31, 0.48 g is obtained from 0.51 g (1.99 mmol) of the compound from Example 48.
Yield: 85.5% of theory 1H-NMR (CDCl3): - 1.2 (d, 6H, CH3CH>; 2.5 (s, 3H, CH3); 3.3 (sept, 1H, CH); 6.0 (dd, 1H, CHCHO); 6.9 (s, 1H, pyridine-H); 7.0 - 7.3 (m, 4H, aromatic-H>; 7.5 (d, 1H,CH); 9.5 (d, 1H, CHO) ppm.
Le A 25 747 13~0'~9~
Example 50 Methyl (E)-7-C4-(4-fluorophenyl)-2-isopropyl-6-methyl-pyrid-3-ylJ-5-hydroxy-3-oxo-hept-6-enoate Analogously to Example 32, 0.22 g is obtained from 0.41 g (1.44 mmol) of the compound from Example 49.
Yield: 38.2% of theory 1H-NMR (CDCl3): - 1.3 (d, 6H, CH3CH>; 2.5 (s, 3H, CH3); 3.3 (sept, 1H, CH); 3.5 (s, 2H, CH2); 3.25 (s, 3H, OCH3>; 4.6 (m, 1H; CHOH); 5.3 (dd, 1H, CH); 6.6 (d, 1H, CH);
6.9 (s, 1H, pyridine-H>; 7.0 -7.3 (m, 4H, aromatic-H) ppm.
Example 51 Methyl erythro-(E)-7-C4-(4-fluorophenyl)-2-isopropyl-6-methyl-pyrid-3-ylJ-3,5-dihydroxy-hept-6-enoate F

1.2 g (3.01 mmol) of the compound from Example 50 are reacted analogously to Example 33.
Yield: 320 mg (26.6% of theory) 1H-NMR (CDCl3): - 1.28 (d, 6H); 1.40 (m, 2H); 2.45 Le A 25 747 13~0'l~8 (m, 2H); 2.55 (s, 3H); 3.35 (m, 1H); 3.72 (s, 3H); 4.15 (m, 1H);
4.39 (m, 1H); 5.30 (dd, 1H); 6.55 (d, 1H>; 6.88 (s, 1H); 7.0 - 7.30 (m, 4H) ppm.
Example 52 Methyl 1,4-dihydro-2,6-dimethyl-4-(4-fluo-rophenyl)-5-phenyl-pyridine-3-car;boxylate H

24.0 g (0.1 mol> of 1-(4-fluorophenyl)-2-phenyl-buten-3-one, 23 g (0.2 mol) of methyl 3-amino-crotonate and 6 ml (0.1 mol) of glacial acetic acid are heated under reflux overnight in 150 ml of ethanol, heated under reflux for 18 h after addition of 11.5 g (0.1 mol) of methyl 3-aminocrotonate and 3 ml of glacial acetic acid and heated under reflux for 18 h once more after repeated addition of 11.5 g (0.1 mol) of methyl 3-aminocrotonate and 3 ml of glacial acetic acid. The solvent is removed in vacuo, 80 ml of methanol are added to the residue, undissolved material is filtered off with suction, the methanolic solution is concentrated in vacuo and excess aminocrotonate is distilled off from the residue at 73oC - 90oC/18 mbar and subsequently at 60oC - 70oC/
0.2 mbar. 37.5 g of crude product are obtained as a brittle fused mass.
Crude yield: >100% of theory 1H-NMR (CDCl3): - 1.85 (s, 3H, CH3); 2.85 (s, 3H, CH3); 3.6 (s, 3H, CH3); 4.65, 5.4 (2br, s, 1H, CH); 6.7 - 7.4 (m, 9H, aromatic-H) ppm.
Le A 25 747 I3~0'~9 Example 53 Methyl-2,6-dimethyl-4-(4-fluorophenyl)-5-phenyl-pyridine-3-carboxylate i C)ZCH3 Analogously to Example 37, 20.4 g of solid are obtained from 37.3 g (0.1 mol, crude) of the compound from Example 52.
Yield: 49.4X of theory 1H-NMR (CDCl3): a = 2,45 (s, 3H, CH3); 2.6 (s, 3H, _ CH3>; 3.5 (s, 3H, CH3); b.7 - _ 7.4 (m, 9H, aromatic-H) ppm.
Example 54 2,6-Dimethyl-4-(4-fluorophenyl)-3-hydroxymethyl-5-phenyl-pyridine _' Analogously to Example 29, 12.4 g of crude pro=
duct are obtained from 20.2 g (60 mmol) of the compound from Example 53.
Yield: 67X of theory 1H-NMR (CDCl3): d ~ 2.0 (br, S, 1H, OH); 2.3 (s, 3H, CH3); 2.75 (s, 3H, CH3>; 4.45 (s, 2H, CH2); 6.8 - 7.3 (m, 9H, aromatic-H) ppm.
le A 25 747 1340r~98 Example 55 2,6-Dimethyl-4-(4-fluorophenyl)-5-phenyl-pyridine-3-carbaldehyde I ~ MHO

Analogously to Example 30, 3.8 g of solid are obtained after chromatography over silica gel (dichloro-methane) from 6.0 g (19.5 mmol) of the compound from Example 54.
Yield: 64% of theory 1H-NMR (CDCl3): - 2.4 (s, 3H,CH3>; 2.9 (s, 3H, CH3); 6.8 - 7.3 (m, 9H, aroma-tic-H) 9.8 (s, 1H, CHO) ppm.
Example 56 (E)-3-C2,6-Dimethyl-4-(4-fluorophenyl)-5-phenyl-pyrid-3-yl7-prop-2-enal CHO

Analogously to Example 31, 2.0 g of crude product are obtained from 3.1 g (10 mmol) of the compound from Example 55.
Yield: 60X of theory 1H-NMR (CDCl3): - 2.4 (s, 3H, CH3>; 2.75 (s, 3H, CH3); 6.15 (dd, 1H, CHCHO); 6.85 (d, 1H, CH>; 6.9 - 7.3 (m, 9H, aromatic-H>; 9.4 (d, 1H, CHO) ppm.
Le A 25 747 13~0~1~
Example 57 Methyl (E)-7-C2,6-dimethyl-4-(4-fluorophenyl)-5-phenyl-pyrid-3-yl7-5-hydroxy-3-oxo-kept-6-enoate F
_ ' ~ H ~~

H3C~~H3 Analogously to Example 32, 2.4 g of crude product are obtained from 2.0 g (6 mmol> of the compound from Example 56.
Crude yield: 89% of theory 1H-NMR (CDCl3): - 2.3 (s, 3H, CH3>; 2.6 (s, 3H, CH3>; 2.7 (m, 2H, CH2); 3.45 (d, 2H, CH2); 3.75 (2s, 3H, OCH3); 4.5 (m, 1H, CH>; 5.4 (dd, 1H, CHCHO); 6.3 (2d, 1H, CH);
6.7 - 7.3 (m, 9H, aromatic-H) ppm.
Example 58 Methyl erythro-(E)-7-C2,6-dimethyl-4-(4-fluorophenyl)-5-phenyl-pyrid-3-ylJ-3,5-dihydroxy-hept-6-enoate F

Analogously to Example 33, 550 mg of product are obtained after chromatography over silica gel (ethyl acetate) from 2.4 g (5.3 mmol) of the compound from Example 57.
Yield: 23.1% of theory 1H-NMR (CDCl3): - 1.7 (br, s, 2H, OH); 2.3 (s, 3H, Le A 25 747 1340~~~~
CH3); 2.4 - 2.6 (m, 2H, CH2);
2.65 (s, 3H, CH3>; 3.7 (s, 3H, OCH3>; 4.1 (m, 1H, CHOH); 4.45 (m, 1H, CHOH); 5.4 (dd, 1H, CHCHOH); 6.3 (d, 1H, CH); 6.7 -7.3 (m 9H, aromatic-H) ppm.
Example 59 Ethyl 2,6-diisopropyl-4-(4-fluorophenyl>-5-methoxymethyl-pyridine-3-carboxylate F
H3C, I~ y COOC2H5 0.57 ml (9.2 mmol) of methyl iodide and, at -50°C, 327 mg (10.9 mmol) of 80% strength sodium hydride are added under a nitrogen atmosphere to 3 g (8.4 mmol) of the compound from Example 4 in 100 ml of dry tetra-hydrofuran. The mixture is stirred for 2 hours and the temperature is allowed to rise to 25oC in the course of this. Water is cautiously added to the mixture and it is extracted several times using ether, and the organic phase is dried over sodium sulphate and concentrated in vacuo.
lrield: 2.9 g (92.7% of theory) 1H-NMR (CDCl3): - 0.97 (t, 3H); 1.3 (m, 12H>; 3.05 (m, 1H); 3.21 (s, 3H>; 3.38 (m, 1H>; 3.96 (q, 2H>; 4.1 (s, 2H>;
7.08 (m, 2H); 7.25 (m, 2H) ppm.
Le A 25 747 1~4~~~9~
Example 60 2,6-Diisopropyl-4-(4-fluorophenyl>-3-hydroxymethyl-5-~nethoxymethyl-pyridine F

2.85 g (7.6 mmol) of the compound from Example 59 dissolved in 30 ml of absolute tetrahydrofuran are added dropwise under a nitrogen atmosphere to 0.5 g (13.2 mmol) of lithium aluminium hydride in 20 ml of absolute tetra-hydrofuran at 60oC. The mixture is heated to reflux for 1 hour, subsequently cooled to 0°C and 1.5 ml of water and 0.3 ml of 15% strength potassium hydroxide solution are cautiously added dropwise. The solution is filtered from the deposited precipitate with suction and the latter is boiled several times with ether. The com-bined phases are dried over magnesium sulphate and con-centrated in vacuo. The residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/
petroleum ether 1:9>.
Yield: 1.9 g (74.8% of theory) 1H-NMR (CDCl3): - 1.3 (m, 12H); 3.17 (s, 3H>; 3.35 (m, 1H); 3.43 (m, 1H>; 4.02 (s, 2H); 4.35 (d, 2H); 7.12 (m, 2H);
7.25 (m, 2H) ppm.
Example 61 Methyl erythro-(E)-7-f2,6-diisopropyl-4-(4-fluorophenyl)-5-~nethoxymethyl-pyrid-3-ylJ-3,5-dihydroxy-hept-6-enoate Le A 25 747 13~~'~~~
F

Example 61 was prepared from the compound from Example 60, in analogy to the reactions of Examples 7, 8, 9 and 10.
1H-NMR (CDCl3): d = 1.23 (m, 6H); 1.32 (d, 6H); 1.40 (m, 2H); 2.43 (m, 2H); 3.18 (s, 3H); 3.32 tm, 2H); 3.73 (s, 3H);
4.05 (s, 2H>; 4.08 (m, 1H>; 4.29 _ (m, 1H); 5.23 (dd, 1H); 6.31 td, 1H); 7.0 - 7.20 (m, 4H) ppm.
Example 62 Methyl erythro-(E)-7-C5-tert.butyldimethylsilyloxymethyl-4-(4-fluorophenyl)-2-isopropyl-6-methyl-pyrid-3-yl7-3,5-dihydroxy-hept-6-enoate F
H3 i OOCH3 cH3C)3CwSi-The follo~ing compound vas synthesized from the compound from Example 20 in analogy to the reactions of Examples S, 6, 7, 8, 9, 10, 11 and 12.
1H-NMR (CDCl3): d - 0.0 (s, 6H); 0.82 ts, 9H); 1.22 (d, 6H); 1.40 (m, 2H); 2.42 (m, 2H); 2.65 (s, 3H); 3.28 tm, 1H);
3.70 (s, 3H); 4.08 (m, 1H); 4.26 Le A 25 747 ~3~p,r~~
(m, 1H); 4.29 (s, 2H); 5.22 (dd, 1H); 6.30 (d, 1H>; 7.0 - 7.20 (m, 4H) ppm.
Example 63 Methyl erythro-(E)-7-C4-(4-fluorophenyl)-5-hydroxymethyl-1-isopropyl-6-methyl-pyrid-3-yl7-3,5-dihydroxy-hept-6-enoate F
IH IH

.... H ~.~.~
H C II

The above compound was synthesized from the .
compound from Example 20 in analogy to the reactions from Examples 5, 6, 7, 8, 9, 10, 11 and 12.
1H-NMR (CDCl3): - 1.22 (d, 6H); 1.30 - 1.60 (m, 2H>;
2.43 (m, 2H); 2.69 (s, 3H); 3.32 (m, 1H); 3.72 (s, 3H>; 4.07 (m, 1H); 4.30 (m, 1H>; 4.41 (s, 2H);
5.25 (dd, 1H); 6.31 (d, 1H);
7.11 (m, 4H) ppm.
Example 64 Methyl erythro-(E)-7-C3-benzyloxymethyl-4-(4-fluoro-phenyl)-1-isopropyl-6-methyl-pyrid-5-ylJ-3,5-dihydroxy-hept-6-enoate F

Le A 25 747 134~~1~~
The above compound was synthesized from the compound from Example 20 in analogy to the reactions from Examples 5, 6, 7, 8, 9, 10, 11 and 12.
1H-NMR (CDCl3): - 1.23 (d, 6H); 1.40 (m, 2H>; 2.42 (m, 2H>; 2.63 (s, 3H); 3.30 (m, 1H); 3.72 (s, 3H>; 4.10 (m, 1H);
4.15 (s, 2H); 4.32 (m, 1H); 4.38 (S, 2H>; 5.20 (dd, 1H>; 6.31 (d, 1H); 7.0 - 7.40 (m, 9H) ppm.
Example 65 3-(tert.8utyldimethylsilyloxymethyl>-2,6-diisopropyl-5-(2,2-dimethyl-butyryloxymethyl)-4-(4-fluorophenyl>-pyridine F
0 ' iH3 HSC2-i-C- ~I ~ CHZ-0-ii-CtCH3)3 cH3C)2 ~ CH

865 mg (3.3 mmol) of triphenylphosphine, 0.41 ml (3.3 mmol> of 2,2-dimethylbutyric acid and 0.52 ml (3.3 _ mmol) of diethyl azodicarboxylate are added successively at 0oC to 1.29 g (3 mmol) of the compound from Example 6 in 50 ~nl of absolute tetrahydrofuran and the mixture is stirred overnight at room temperature. The mixture is concentrated in vacuo and the residue is chromato-graphed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 1:9>.
Yield: 1.32 g (87.4X of theory) 1H-NMR (CDCl3): - 0.01 (s, 6H); 0.86 (t, 3H); 0.91 (s, 9H); 1.2 (s, 6H>; 1.39 (m, 12H); 1.6 (q, 2H); 3.24 (m, 1H);
3.48 (m, 1H); 4.38 (s, 2H); 4.79 (s, 2H); 7.05 - 7.35 (m, 4H) ppm.
Le A 25 747 ~~~o~~
Example 66 2,6-Diisopropyl-3-(2,2-dimethyl-butyryloxymethyl)-4-(4-fluorophenyl)-5-hydroxymethyl-pyridine F

HSC2_C.C_ H
cH3C)Z
2.6 ml (2.6 ~nmol> of a 1 molar tetrabutylammonium fluoride solution in tetrahydrofuran are added to 1.3 g (2.6 mmol) of the compound from Example 65 dissolved in 20 ml of absolute tetrahydrofuran and the mixture is stirred for 1 hour at room temperature. Saturated sodium hydrogen carbonate solution is added to the mixture and it is extracted several times using dichloromethane. The organic phase is dried over magnesium sulphate and con-centrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/
petroleum ether 1:9) as eluent).
Yield: 1 g (95.2% of theory) 1H-NMR (CDCl3>: - 0.71 (t, 3H); 1.02 (s, 6H); 1.21 (d, 6H); 1.25 (d, 6H); 1.43 (q, 2H>; 3.09 (m, 1H); 3.38 (m, 1H>;
4.3 (d, 2H>; 4.61 (s, 2H); 6.95 -7.18 (m, 4H) ppm.
Example 67 2,6-Diisopropyl-5-(2,2-dimethyl-butyryloxymethyl)-4-(4-fluorophenyl)-pyridine-3-carbaldehyde Le A 25 747 13~0'~~~
F

HSCZ_i_C_ (H3C)2 1 g (2.5 ~nmol) of the compound from Example 66 is reacted analogously to Example 7.
Yield: 890 mg (86.4% of theory) S 1H-NMR (CDCl3): - 0.82 (t, 3H); 1.25 (s, 6H); 1.32 (m, 12H); 1.55 (q, 2H); 3.26 (m, 1H); 3.88 (m, 1H); 4.77 (s, 2H);
7.09 - 7.27 (m, 4H>; 9.77 (s, 1H>
ppm.
Example 68 (E>-3-C2,6-Diisopropyl-5-(2,2-dimethyl-butyryloxymethyl>-4-(4-fluorophenyl)-pyrid-3-ylJ-prop-2-enal F
0 ~ CHO
._ ~~
HSC2 ~ C
(H3C)2 860 mg (2.1 mol) of the compound from Example 67 are reacted analogously to Example 8.
Yield: 420 mg (45.6X of theory) 1H-NMR (CDCl3): - 0.82 (t, 3H); 1.14 (s, 6H); 1.31 (m, 12H>; 1.53 (q, 2H>; 3.22 (m, 1H>; 3.33 (m, 1H); 4.75 (s, 2H>;
5.99 (dd, 1H); 7.05 - 7.29 (m, SH); 9.4 (d, 1H) ppm.
Le A 25 747 Example 69 Methyl (E)-7-C2,6-diisopropyl-5-(2,2-dimethyl-butyryloxy-nethyl>-4-(4-fluorophenyl)-pyrid-3-ylJ-5-hydroxy-3-oxo-hept-6-enoate F
I w OH O
i II
li ( ( COOCH3 HSC2_C_C_ cH3C)Z ( I I
0.15 ml (1.4 mmol) of methyl acetoacetate in 2 ml of absolute tetrahydrofuran is added dropwise under nitro-gen to a suspension of 54.6 mg (1.82 mmol) of 80% strength sodium hydride in 5 ml of absolute tetrahydrofuran at - 5°C.
70 After 15 minutes, 0.89 ml (1.4 mmol) of 15% strength butyl-lithium in n-hexane is added dropwise at the same tempera-ture and after a further 15 minutes 408 mg (1.8 mmol) of dry zinc bromide in 5 ml of absolute tetrahydrofuran are added. The mixture is allowed to stir for a further 15 minutes at -5°C, 400 mg (0.91 mmol) of the compound from Example 68 dissolved in 10 ml of dry tetrahydrofuran are added and the mixture is stirred overnight. Saturated ammonium chloride solution is added to the mixture and it is extracted several times using ether. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 3:7).
Yield: 200 mg (38.5% of theory) 1H-NMR (CDCl3>: - 0.8 (t, 3H>; 1.12 (s, 6H); 1.27 (d, 6H>; 1.32 (d, 6H); 1.53 (q, 2H); 2.45 (m, 2H>; 3.18 (m, 1H>;
3.27 (m, 1H); 3.43 (s, 2H); 3.74 (s, 3H), 4.50 (m, 1H); 4.73 (s, Le A 25 747 I34U~~~
2H); 5.28 (dd, 1H); 6.38 (d, 1H);
7.0 - 7.10 (m, 4H> ppm.
Example 70 Methyl erythro-(E)-7-C2,6-diisopropyl-5-(2,2-dimethyl-butyryloxymethyl)-4-(4-fluorophenyl)-pyrid-3-yl7-3,5-dihydroxy-hept-6-enoate F

__ HgC2-C-C-tH3C)2 180 mg (0.32 mmol) of the compound from Example 69 are reacted analogously to Example 10.
Yield: 138 mg (77.5% of theory) 1H-NMR (CDCl3): - 0.81 (t, 3H); 1.12 (s, 6H); 1.28 (m, 6H); 1.40 (m, 2H); 1.53 (q, 2H); 2.43 (m, 2H); 3.17 (m, 1H);
3.32 (m, 1H>; 3.73 (s, 3H>; 4.08 (m, 1H); 4.31 (m, 1H); 4.75 (s, 2H>; 5.28 (dd, 1H); 6.32 (d, 1H);
7.0 - 7.1 (m, 4H) ppm.
Example 71 Methyl erythro-(E)-7-C5-benzyloxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyrid-3-ylJ-3,5-dihydroxy-hept-6-enoate F

Le A 25 747 134~'l~3 The above compound vas synthesized from the compound from Example 6 in analogy to the reactions of Examples 65, 66, 67, 68, 69 and 70.
1H-NMR (CDCl3>: - 1.31 (m, 6H); 1.40 (m, 2H); 2.43 (m, 2H); 3.32 (m, 2H>; 3.73 (s, 3H); 4.07 (m, 1H); 4.32 (m, 1H);
5.07 (s, 2H); 5.30 (dd, 1H);
6.32 (d, 1H); 6.90 - 7.20 (m, 4H);
7.42 (m, 2H>; 7.55 (m, 1H); 8.02 <m, 2H) ppm.
Example 72 Methyl erythro-(E)-7-C3-acetoxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyrid-S-yl7-3,5-dihydroxy-hept-b-enoate The above compound vas synthesized from the compound from Example 6 in analogy to the reactions from Examples 65, 66, 67, 68, 69 and 70.
1H-NMR (CDCl3>: - 1.25 (m, 12H); 1.40 (m, 2H); 2.02 (s, 3H); 2.43 (m, 3H); 3.20 (m, 1H); 3.32 (m, 1H); 3.72 (s, 3H>;
4.07 (m, 1H); 4.29 (m, 1H); 4.81 (S, 2H); 5.28 (dd, 1H); 6.30 (d, 1H); 7.0 - 7.1 (m, 4H) ppm.
Example 73 (E/Z)-3-Carboxymethyl-4-(4-fluorophenyl)but-3-en-2-one Le A 25 747 F
OH OH

1340~~~~
F
~COOCH3 O~H3 62 g (0.5 mol) of 4-fluorobenzaldehyde and 53.9 ml (0.5 mol) of methyl acetoacetate are initially intro-duced in 300 ml of isopropanol, a mixture of 2.81 ml (28 mmol) of piperidine and 1.66 ml (29 mmol) of acetic acid in 40 ml of isopropanol is added and the mixture is stirred for 48 h at room temperature. The mixture is concentrated in vacuo and the residue is distilled in a high vacuum.
8.p. 0.5 mm: 138oC
Yield: 50.5 g (45.5% of theory) Example 74 Dimethyl 1,4-dihydro-2,6-dimethyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate F
H3COOC~COOCH3 H 3 C~h1/~H3 H
33.3 g (0.15 mol) of the compound from Example 73 are heated under reflux for 4 h with 17.3 g (0.15 mol) of methyl 3-aminocrotonate in 150 ml of ethanol. The mixture is cooled to 0°C and the deposited precipitate is filtered off with suction, vashed with a little petroleum ether and dried in a desiccator.
Yield: 32 g (66.8% of theory) Le A 25 747 ._ 1340~~~
1H-NMR (CDCl3>: - 2.33 (s, 6H); 3.65 (s, 6H); 4.99 (s, 1H); 5.77 (s, 1H); 6.89 (m, 2H>; 7.22 (m, 2H) ppm.
Example 75 Dimethyl 2,6-dimethyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate F
H3COOC ~ COOCH3 H3C~~H3 32 g (0.1 mol) of the compound from Example 74 are reacted analogously to Example 3.
Yield: 27.2 g (87% of theory) 1H-NMR (CDCl3): - 2.59 (s, 6H); 3.56 (s, 6H); 7.08 (m, 2H); 7.25 (m, 2H) ppm.
Example 76 Methyl 2,6-dimethyl-4-(4-fluorophenyl)-5-hydroxy-methyl-pyridine-3-carboxylate F

40.3 ml (141 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy>-dihydroaluminate in toluene are added under nitrogen to a solution of 14.9 g (47 mmol>
of the compound from Example 75 in 300 ml of dry tetra-hydrofuran at -10°C to -5°C and the mixture is stirred for 30 minutes at room temperature. After cool-Le A 25 747 .. 1340~~9~
ing to OoC, 150 ml of water are cautiously added drop-wise and the mixture is extracted several times using ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over mag-nesium sulphate and concentrated in vacuo. The residue crystallizes using ether/petroleum ether. After drying in a desiccator, 7.5 g of substance (55.2% of theory) are obtained 1H-NMR (COCl3): - 2.52 (s, 3H); 2.7 (s, 3H); 3.52 (s, 3H); 4.45 (s, 2H); 7.05 - 7.3 (m, 4H) ppm.
Example 77 Methyl erythro-(E)-7-CS-tert.butyldimethylsilyloxymethyl 2,6-dimethyl-4-(4-fluorophenyl)pyrid-3-yl7-3,5-dihydroxy kept-6-enoate !r H3i OOCH3 (H3C)3C-Si-H3C H3C!~CH3 Example 77 was prepared from the compound of Example 76 in analogy to the reactions of Examples 5, 6, 7, 8, 9 and 10.
1H-NMR (CDCl3): - 0.01 (s, 6H); 0.92 (s, 9H>; 1.40 (m, 2H>; 2.49 (m, 2H); 2.62 (s, 3H); 2.71 (s, 3H); 3.80 (s, 3H);
4.17 (m, 1H); 4.36 (s, 2H); 4.38 (m, 1H); 5.42 (dd, 1H); 6.31 (d, 1H); 7.10 - 7.20 (m, 4H) ppm.
i a a ~S

134a ~~~
Example 78 Methyl erythro-(E>-7-C2,6-dimethyl-4-(4-fluorophenyl)-5-hydroxymethyl-pyrid-3-yl7-3,5-dihydroxy-hept-6-enoate F
I
iH OH
V \/COOCH3 I
H3C~~~H3 Example 78 was prepared analogously to Example 11 from the compound from Example 77.
Example 79 (E/Z>-2-Carboxyethyl-1-cyclopropyl-3-(4-fluorophenyl)-2-prop-2-en-1-one F
I
\VCOOC H
is 39 g (0.25 mol) of ethyl cyclopropylcarbonylace-tate and 31 g (0.25 mol) of 4-fluorobenzaldehyde are initially introduced in 150 ml of dry isopropanol and a mixture of 1.4 ml (14 mmol) of piperidine and 0.83 ml (14.5 mmol) of acetic acid in 20 ml of isopropanol is added. The mixture is stirred for 48 hours at room tem-perature and concentrated in vacuo, and the residue is distilled in a high vacuum.
B.p. 0.5 mm: 140°C
Yield: 52.3 g (79.8% of theory) le A 25 747 13~0~1~~
Example 80 Diethyl 1,4-dihydro-2-cyclopropyl-4-(4-fluorophenyl>-6-isopropyl-pyridine-3,5-dicarboxylate F
HSC20 ~OCZHs 39.3 g (0.15 mol) of the compound from Example 79 and 23.6 g (0.15 mol) of ethyl 3-amino-4-methyl-pent-2-enoate are heated under reflux overnight in 150 ml of ethylene glycol. After cooling to room temperature, the mixture is extracted several times using ether and the combined ether phases are washed three times with 10%
strength hydrochloric acid, once each with water and saturated sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated in vacuo. The resi-due is stirred With petroleum ether/ether, filtered off with suction and dried in a desiccator.
Yield: 22.8 g (37.8% of theory) 1H-NMR (CDCl3): - 0.65 (m, 2H); 1.03 (m, 2H); 1.15 (m, 13H>; 2.78 (m, 1H); 4.15 (m, 4H); 5.03 (s, 1H>; 5.72 (s, 1H);
6.90 (m, 2H); 7.22 (m, 2H) ppm.
Example 81 Diethyl 2-cyclopropyl-4-(4-fluorophenyl)-6-isopropyl-pyridine-3,5-dicarboxylate Le A 25 747 ~340'~~~
F
HSC2C ~pCZHs 19.1 g (47 mmol) of the compound from Example 80 are reacted analogously to Example 3.
Yield: 9.8 g (52.5% of theory) 1H-NMR (CDCl3): - 0.97 (m, 8H); 1.25 (m, 8H); 2.09 (m, 1H); 3.06 (m, 1h); 4.02 (m, 4H); 7.06 (m, 2H); 7.26 (m, 2H) ppm.
Example 82 Ethyl 6-cyclopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-2-isopropyl-pyridine-3-carboxylate F
Hp-H OCZHs 6 g (15 mmol) of the compound from Example 81 are reacted analogously to Example 4.
Yield: 3.1 g (57.9% of theory) 1H-NMR (CDCl3): - 0.97 (t, 3H); 1.03 (m, 2H); 1.22 (m, 8H>, 2.38 (m, 1H); 3.03 (m, 1H); 4.0 (q, 2H>; 4.58 (s, 2H);
7.1 (m, 2H>; 7.25 (m, 2H) ppm.
Le A 25 747 Example 83 Ethyl 6-cyclopropyl-4-(4-fluorophenyl>-2-isopropyl-5-methoxymethyl-pyridine-3-carboxylate H3C OCZHs 2.9 g (8 mmol) of the compound from Example 82 are reacted analogously to Example 59.
Yield: 2 g (67.4% of theory) 1H-NMR (CDCl3): - 0.93 (t, 3H>; 0.98 (m, 2H>; 1.22 (d, 6H); 1.24 (m, 2H); 2.32 (m, 1H); 3.03 (m, 1H); 3.28 (s, 3H);
3.97 (q, 2H); 4.25 (s, 2H>; 7.08 (m, 2H); 7.25 (m, 2H) ppm.
Example 84 6-Cyclopropyl-4-(4-fluorophenyl)-3-hydroxy-methyl-2-iso-propyl-5-methoxymethyl-pyridine 44.3 ml (15 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 1.9 g (5 mmol>
of the compound from Example 83 in 50 ml of dry tetra-hydrofuran and the mixture is stirred for 2 hours at room temperature and 1 hour under reflux. After cooling to Le A 25 747 1340~1~~
OoC, 50 ml of water are cautiously added dropwise and the mixture is extracted several times with ethyl acetate.
The ethyl acetate phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo.
Yield: 1.6 g (97% of theory) 1H-NMR (CDCl3>: - 0.89 (m, 2H), 1.17 (d, 6H); 1.19 (m, 2H); 2.20 (s, 1H); 3.13 (s, 3H>; 3.32 (m, 1H); 4.07 (s, 2H);
4.26 (s, 2H); 7.05 (m, 2H); 7.16 (m, 2H) ppm.
Example 85 Methyl erythro-(E>-7-C6-cyclopropyl-2-isopropyl-4-(4-fluorophenyl)-5-methoxymethyl-pyrid-3-yl7-3,5-dihydroxy-hept-6-enoate F
I
I w IH IH

I i H3c I I ~ I
i Example 85 was prepared from the compound from Example 84, in analogy to the reactions of Examples 7, 8, 9 and 10.
1H-NMR (CDCl3): - 0.95 (m, 2H); 1.17 (m, 6H); 1.22 (m, 2H); 1.40 (m, 2H); 2.25 (m, 1H>; 2.44 (m, 2H); 3.22 (s, 3H);
3.23 (m, 1H); 3.73 (s, 3H); 4.07 (m, 1H); 4.18 (s, 2H); 4.28 (m, 1H); 5.22 (dd, 1H); 6.30 (d, 1H);
7.0 - 7.20 (m, 4H) ppm.
Le A 25 747 1~~~~~~
Example 86 Ethyl 5-chloromethyl-2,b-diisopropyl-4-(4-fluorophenyl)-pyridine-3-carboxylate F
C1~HZC ~I ~I COOCZHS
1.69 ml (20.9 mmol) of pyridine and 1.5 ml (20.9 mmol) of thionyl chloride are added successively at -5°C to 5 g (13.9 mmol) of the compound from Example 4 dissolved in 100 ml of dry tetrahydrofuran and the mixture is stirred for 15 minutes at the same temperature. The mixture is diluted using ethyl acetate and extracted several times using saturated sodium hydrogen carbonate solution, and the organic phases are dried over magnesium sulphate and concentrated in vacuo. The residue is chro-matographed on a column (silica gel 70-230 mesh, in petro-leum ether/ethyl acetate 95:5).
Yield: 3.2 g (65.2% of theory) 1H-NMR (CDCl3): - 0.98 (t, 3H); 1.30 (d, 6H); 1.35 (d, 6H); 3.05 (m, 1H); 3.45 (m, 1H); 3.98 (q, 2H); 4.38 (s, 2H);
7.13 (m, 2H); 7.31 tm, 2H) ppm.
Example 87 Ethyl 2,b-diisopropyl-4-(4-fluorophenyl)-5-phenoxymethyl-pyridine-3-carboxylate Le A 25 747 13=~~'l~a F

3.22 g (9.1 mmol) of the compound from Example 86 dissolved in 50 ml of absolute tetrahydrofuran are added dropWise at 0°C to a solution of 2.11 g (18.2 mmol) of sodium phenoxide in 50 ml of absolute tetrahydrofuran and the mixture is heated to reflux for 4 days. After cool-ing to room temperature, the mixture is diluted using 150 ml of crater and extracted several times using ether.
The combined organic phases are dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using petroleum ether/ethyl acetate 95:5>.
Yield: 3.2 g (80.8% of theory) 1H-NMR (CDCl3): - 0.97 (t, 3H); 1.3 (d, 6H>; 1.33 (d, 6H); 3.1 (m, 1H); 3.32 (m, 1H); 4.0 (q, 2H>; 4.7 (s, 2H);
6.78 - 7.31 (m, 9H) ppm.
Example 88 2,6-Diisopropyl-4-(4-fluorophenyl>-5-hydroxymethyl-3-phenoxymethyl-pyridine F

3.25 g (7.5 mmol) of the compound from Example 87 Le A 25 747 are reacted analogously to Example 60.
Yield: 2.75 g (93.2% of theory) 1H-NMR (CDCl3): - 1.35 (m, 12H); 3.30 (m, 1H); 3.48 (m, 1H); 4.42 (d, 2H); 4.62 (s, 2H); 6.75 - 7.30 (m, 9H> ppm.
Example 89 Methyl erythro-(E)-7-C2,6-diisopropyl-4-U4-fluorophenyl)-5-phenoxymethyl-pyrid'-3-ylJ-3,5-dihydroxy-hept-6-enoate F

Example 89 was prepared from the compound of Example 88, in analogy to Examples 7, 8, 9 and 10.
1H-NMR (CDCl3>: - 1.28 (m, 6H); 1.31 (d, 6H>; 1.43 (m, 2H); 2.41 (m, 2H); 3.30 (m, 2H); 3.71 (s, 3H>; 4.08 (m, 1H);
4.30 (m, 1H); 4.65 (s, 2H); 5.28 (dd, 1H>; 6.35 (d, 1H); 6.75 -7.30 (m, 9H) ppm.
Example 90 Ethyl 2,6-diisopropyl-4-(4-fluorophenyl>-5-(tetrahydro-pyran-2-yl-oxymethyl)-pyridine-3-carboxylate f OCZHS
1.88 g (22.4 mmol) of dihydropyran and 0.525 g Le A 25 747 1340~1~~
(1.49 mmol) of pyridinium p-toluene-sulphonate are added to a solution of 5.36 g (14.9 mmol) of the compound from Example 4 in 100 ml of dry dichloromethane and the mix-ture is heated to reflux for 48 hours. After cooling to room temperature, the mixture is diluted using dichloro-methane and extracted several times using eater. The organic phase is dried over magnesium sulphate and con-centrated in vacuo, and the residue is ch~romatographed on a column (silica gel 70-230 mesh, using dichloro-methane).
Yield: 4.4 g (66.7% of theory) 1H-NMR (CDCl3): - 0.98 (t, 3H); 1.31 (m, 12H);
1.40 - 1.80 (m, 6H>; 3.05 (m, 1H);
3.43 (m, 2H>; 3.61 (m, 1H); 3.98 (q, 2H); 4.05 (d, 1H); 4.45 (m, 1H); 4.55 (d, 1H); 7.05 (m, 2H);
7.25 (m, 2H> ppm.
Example 91 2,b-Diisopropyl-4-(4-fluorophenyl)-3-hydroxymethyl-5-(tetrahydropyran-2-yl-oxymethyl)-pyridine F
2-0!i 4.4 g (9.9 mmol) of the compound from Example 90 are reacted analogously to Example 60.
Yield: 2.5 g (63.5% of theory) 1H-NMR (CDCl3): - 1.32 (m, 12H); 1.40 - 1.80 (m, 6H); 3.40 (m, 3H>; 3.57 (m, 1H);
3.95 (d, 1H); 4.35 (m, 3H>; 4.5 (d, 1H); 7.11 (m, 2H>; 7.25 (m, 2H) ppm.
Le A 25 747 134Q~1 Example 92 Methyl erythro-(E)-7-C2,6-diisopropyl-4-(4-fluorophenyl)-5-(tetrahydropyran-2-yl-oxymethyl)-pyrid-3-yl7-3,5-dihydroxy-hept-6-enoate F
OH OH

Example 92 was prepared from the compound from Example 91, in analogy to the reactions from Examples 7, 8,.
9 and 10.
1H-NMR (CDCl3): d - 1.20 - 1.80 (m, 20H); 2.43 (m, 2H); 3.32 (m, 1H); 3.41 (m, 2H);
3.58 (m, 1H>; 3.72 (s, 3H); 3.98 (d, 1H); 4.08 (m, 1H); 4.29 (m, 1H>; 4.43 (m, 1H); 4.54 (d, 1H);
5.28 (dd, 1H); 6.31 (d, 1H); 7.10 (m, 4H) ppm.
Example 93 2-(Trimethylsilyl)-ethyl 3-amino-4-methyl-pent-2-enoate ~H3 ~) iH3 CH3-Si-tCH2)2-0-C-CH=C-CH-CH3 3 g of p-toluenesulphonic acid are added to 150 g (0.65 mol) of 2-<trimethylsilyl)ethyl-isobuturyl-acetate in 700 ml of toluene and the mixture is saturated using ammonia gas at room temperature. It is allowed to stand overnight and subsequently heated to reflux for 8 hours, ammonia gas being introduced continuously. After cooling to room temperature, the mixture is filtered and the Le A 25 747 ~3~a~~~~
toluene solution is extracted several times with water, dried over magnesium sulphate and concentrated in vacuo.
Yield: 134 g (90% of theory) 1N-NMR (CDCl3): - 0.21 (s, 9H); 1.15 (m, 2H); 1.30 (m, 6H); 2.48 (m, 1H); 4.31 (m, 2H); 4.71 (s, 1H) ppm.
Example 94 5-Ethyl 3-(2-trimethylsilyl)-ethyl 1,4-dihydro-2,6-diiso-propyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate F
cH3C)35i 52.7 g (0.2 mol) of the compound from Example 1 are added to a solution of 45.8 g (0.2 mol) of the com-pound from Example 93 in 100 ml of ethylene glycol and the mixture is heated overnight to reflux. The mixture is cooled, 5 ml of conc. hydrochloric acid is added and it is again warmed to 100°C for 30 minutes. After cooling to room temperature, it is concentrated in vacuo and the residue is taken up in ethyl acetate and extrac-ted several times with dilute hydrochloric acid. The organic phase is subsequently gashed once each with saturated sodium hydrogen carbonate solution and sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (silica gel 70-230 mesh, using dichloro-methane).
Yield: 39.2 g (41.3% of theory) 1H-NMR (CDCl3): - 0.01 (s, 9H); 0.95 (m, 2H); 1.18 (m, 12H); 1.22 (t, 3H>; 4.10 (m, 6H); 4.97 (s, 1H); 6.10 (s, 1H);
Le A 25 747 1340'j~~
6.85 (m, 2H); 7.18 (m, 2H) ppm.
Example 95 3-Ethyl 1,4-dihydro-2,6-diisopropyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate 83.3 ml (83.3 mmol) of a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution of 38.9 g (81.8 mmol) of the compound from Example 94 in 300 ml of dry tetrahydrofuran and the mix-ture is stirred for 48 hours at room temperature. After concentrating in vacuo, the residue is taken up in ether and washed three times each with dilute sodium hydroxide solution and dilute sulphuric acid, and the organic phase is dried over magnesium sulphate and concentrated again in vacuo.
Yield: 29 g (94.5% of theory) 1H-NMR (CDCl3): - 1.09 - 1.3 (m, 15H); 4.02 (q, 2H>; 4.08 (m 2H); 4.18 (m, 1H>;
4.89 (s, 1H); 7.03 (m, 2H>; 7.12 (m, 2H) ppm.
Example 96 Methyl erythro-(E)-7-C2,6-diisopropyl-4-(4-fluorophenyl)-pyrid-3-ylJ-3,5-dihydroxy-hept-6-enoate Le A 25 747 I3~ ~ l9~
F

Example 96 was prepared from the compound from Example 95 in analogy to the reactions from Examples 27, 3, 29, 7, 8, 9 and 10.
1H-NMR (CDCl3): - 1.28 (m, 12H); 1.50 (m, 2H>;
2.47 (m, 2H); 3.05 (m, 1H); 3.35 (m, 1H>; 3.72 (s, 3H); 4.13 (m, 1H); 4.38 (m, 1H); 5.31 (dd, 1H);
6.55 (d, 1H); 6.85 (s, 1H); 7.05 (m, 2H>; 7.25 (m, 2H) ppm.
Example 97 1-(4-Fluorophenyl)-4-methyl-2-phenyl-penten-3-one F
0.9 ml of piperidine is added to 24.8 g (0.2 mol) of 4-fluorobenzaldehyde and 32.4 g (0.2 mol) of benzyl iso-propyl ketone in 150 ml of toluene and the mixture is heat-ed to reflux overnight. After cooling to room temperature, the mixture is extracted several times using water and the organic phase is dried over magnesium sulphate and concen-trated in vacuo. The residue is subjected to incipient dis-tillation up to a bath temperature of 150oC at 0.1 mbar in a high vacuum and 43.8 g of crude product are obtained in Le A 25 747 the distillation residue.
Yield: 81% of theory Example 98 Ethyl 1,4-dihydro-2,6-diisopropyl-4-(4-fluorophenyl)-5-phenyl-pyridine-3-carboxylate COOCZHS
I ~ -~H
2.86 ml (50 mmol) of glacial acetic acid are added to 13.45 g (50 mmol) of the compound from Example 97 and 17.4 g (100 ml) of ethyl 3-amino-4-methyl-pent-2-enoate in 80 ml of ethylene glycol and the mixture is heated to reflux overnight. After cooling to room tem-perature, it is concentrated in vacuo and the residue is dissolved in dichloromethane and extracted several times using water. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is taken up in ethyl acetate. After extracting using 10%
strength hydrochloric acid, water and saturated sodium hydrogen carbonate solution, the organic phase is dried again and concentrated, and the residue is chromato-graphed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether).
Yield: 2.3 g (11.3% of theory) 1H-NMR (CDCl3): - 1.1 (m, 9H>; 1.25 (m, 6H); 2.70 (m, 1H); 3.90 - 4.40 (m, 3H);
4.55 (s, 1H); 5.75 (s, 1H); 6.80 - 7.30 (m, 9H> ppm.
Le A 25 747 Example 99 Methyl erythro-(E)-7-~2,6-diisopropyl-4-(4-fluorophenyl)-S-phenyl-pyrid-3-ylJ-3,5-dihydroxy-kept-6-enoate F

Example 99 was prepared from the compound from Example 98 in analogy to the reactions of Examples 3, 29, 7, 8, 9 and 10.
1H-NMR (CDCl3): a - 1.18 (d, 6H); 1.32 (m, 6H); 1.42 _ (m, 2H); 2.40 (m, 2H>; 2.70 (d, 1H); 2.88 (m, 1H); 3.38 (m, 1H);
3.48 (d, 1H); 3.71 (s, 3H>; 4.05 (m, 1H>; 4.30 (m, 1H>; 5.30 (dd, 1H); 6.39 (d, 1H); 6.70 - 7.20 (m, 9H) ppm.
Example 100 Methyl erythro-(E)-7-C2,6-diisopropyl-4-(4-fluorophenyl)-5-carboxyethyl-pyrid-3-yJ-3,5-dihydroxy-hept-6-enoate F

HSCZ-Example 100 was prepared from the compound from Example 4 in analogy to the reactions of Examples 7, 8, 69 and 10.
1H-NMR (CDCl3): a = 0.98 (t, 3H); 1.25 (m, 6H ; 1.32 Le A 25 747 (d, 6H); 1.45 (m, 2H); 2,42 (m, 2H); 3.05 (m, 1H>; 3.32 (m, 1H>;
3.72 (s, 3H); 3.98 (q, 2H); 4.10 (m, 1H>: 4.32 (m, 1H); 5.29 (dd, 1H); 6.38 (d, 1H); 7.02 (m, 2H);
7.12 (m, 2H) ppm.
Example 101 Ethyl 1,4-dihydro-2,6-diisopropyl-4-(4-fluorophenyl)-5-~norpholinocarbonyl-pyridine-3-carboxylate F
C~ OC2H5 1.05 g (6.5 mmol) of N,N'-carbonylimida=ole are added under a nitrogen atmosphere to 1.875 g (5 mmol) of the compound from Example 95 dissolved in 20 ml of dry tetrahydrofuran and the mixture is stirred for 30 minutes at room temperature. It is subsequently heated to reflux for 30 minutes, a solution of 0.87 ml (10 mmol) of mor-pholine in 5 ml of dry tetrahydrofuran is added and it is heated to boiling for a further 2 hours. After cool-ing to room temperature, the mixture is concentrated in vacuo and the residue is taken up in dichloromethane and gashed successively vith 1 N hydrochloric acid, 1 N
sodium hydroxide solution and eater. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the crystalline residue is dried in a desiccator.
lrield: 1.96 g (88X of theory) . 1H-NMR (CDCl3): a - 1.0 - 1.28 (m, 15H); 3.20 - 4.40 (complex region, 12H>; 4.70 (s, 1H); 5.50 (s, 1H); 6.90 (m, 2H);
7.20 (m, 2H) ppm.
Le A 25 747 1340r~~~
Example 102 3-Ethyl 2,6-diisopropyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate 5-morpholide F
0~ OC2H5 9 g (21.5 mmol) of the compound from Example 101 are reacted analogously to Example 3.
Yield: 7.6 g (80% of theory) 1H-NMR (CDCl3>: - 0.95 (t, 3H>; 1.25 (m, 6H>; 1.35 (m, 6H); 2.70 - 3.80 (complex region, 10H); 4.0 (m, 2H); 7.0 -7.50 (m, 4H) ppm.
Example 103 Methyl erythro-(E)-7-C2,6-diisopropyl-4-(4-fluorophenyl>-5-morpholinocarbonyl-pyrid-3-ylJ-3,5-dihydroxy-hept-6-enoate F

a Example 103 was prepared from the compound from Example 102 in analogy to the reactions of Examples 29, 7, 8, 9 and 10.
1H-NMR (CDCl3>: - 1.10 - 1.50 (complex region, 14H); 2.40 (m, 2H); 2.80 - 3.65 (complex region, 10H); 3.75 (s, Le A 25 747 1340r1~~
3H); 4.10 (m, 1H); 4.35 (m, 1H>;
5.25 (m, 1H); 6.45 (dd, 1H);
6.95 - 7.50 (m, 4H) ppm.
Example 104 2,b-Diisopropyl-4-(4-fluorophenyl)-3-hydroxymethyl-5-morpholinomethyl-pyridine F
~~ ZOH
20.6 ml (31 mmol) of diisobutylaluminium hydride (1 M in toluene) are added under a nitrogen atmosphere at -78°C to 1.37 g (3.1 mmol) of the compound from Example 102 dissolved in 30 ml of dry toluene and the mixture is stirred for 1 hour at the same temperature.
The mixture is subsequently stirred for 48 hours at room temperature, hydrolyzed using 20% strength potassium hydroxide solution with ice-cooling and extracted several times with toluene. The organic phase is dried over mag-nesium sulphate, concentrated in vacuo and dried in a desiccator. Yield: 1.04 g (87% of theory) 1H-NMR (CDCl3): - 1.28 (d, 6H); 1.32 (d, 6H); 2.15 (m, 4H); 3.18 (s, 2H>; 3.45 (m, 2H); 3.52 (m, 4H); 4.32 (d, 2H);
7.05 - 7.20 (m, 4H) ppm.
Example 105 Methyl erythro-(E)-7-C2,6-diisopropyl-4-(4-fluorophenyl)-5-morpholinomethyl-pyrid-3-yl7-3,5-dihydroxy-hept-6-enoate Le A 25 747 13~0~1~~
F

a Example 105 was prepared from the compound from Example 104 in analogy to the reactions of Examples 7, 8, 9 and 10.
1H-NMR (CDCl3): - 1.25 (m, 12H>; 1.40 (m, 2H>; 2.20 (m, 4H); 2.45 (m, 2H>; 3.20 (s, 2H); 3.30 (m, 1H); 3.45 (m, 1H);
3.55 (m, 4H); 3.75 (s, 3H); 4.10 (m, 1H); 4.30 (m, 1H); 5.30 (dd, 1H); 6.25 (d, 1H); 7.0 - 7.20 (m, 4H) ppm.
Example 106 Methyl erythro-(E>-7-(2,6-diisopropyl)-4-(4-fluoro-phenyl>-5-iodomethyl-pyrid-3-ylJ-3,5-dihydroxy-hept-6-enoate F
I

80 mg (0.1514 mmol) of the compound from Example 105 are dissolved in 5 ml of methyl iodide and the mixture is stirred 3 hours at 30°C and overnight at 60°C with the exclusion of light. The mixture is concentrated in vacuo and dried in a desiccator over phosphorus pentoxide.
120 mg of crude product are obtained.
Le A 25 747 1340'~~'~
1H-NMR (CDCl3): - 1.20 - 1.70 (complex region, 14H);
2.45 (m, 2H); 3.30 (m, 2H); 3.75 (s, 3H); 4.05 (m, 1H); 4.20 (s, 2H); 4.30 (m, 1H); 5.30 (dd, 1H);
6.25 (d, 1H); 7.0 - 7.25 (m, 4H) ppm.
Example 107 Methyl erythro-(E)-7-~C2,6-diisopropyl-4-(4-fluorophenyl>-5-benzylthio-methyl-pyrid-3-ylJ-3,5-dihydroxy-kept-6-enoate F

22.3 ul (0.19 mmol> of benzyl mercaptan and 32.7 ul (0.237 mmol) of triethylamine are added successively under a nitrogen atmosphere to 90 mg (0.158 mmol) of the compound from Example 106 dissolved in 2 ml of dry di-chloromethane and the mixture is stirred overnight at room temperature. The mixture is diluted using dichloro-methane and extracted several times using water. After drying the organic phase over magnesium sulphate and concentrating in vacuo, the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/-petroleum ether 1:1>.
Yield: 20 mg (22.4X of theory) 1H-NMR (COCl3): - 1.23 (m, 12H); 1.4 (m, 2H); 2.40 (m, 2H); 3.20 (m, 2H); 3.28 (s, 2H); 3.55 (s, 2H>; 3.73 (s, 3H);
4.05 (m, 1H>; 4.25 (m, 1H); 5.25 (dd, 1H>; 6.25 (d, 1H); 6.90 -7.28 (m, 9H) ppm.
Le A 25 747 1340~t ~8 Example 108 4-~C5-(3,5-Dihydroxy-6-methoxycarbonylhex-1-enyl)-2,6-diisopropyl-4-(4-fluorophenyl7-pyrid-3-yl?methyl-morpho-line oxide F
iH OH
~ I COOCH3 O N~
52 mg (0.303 mmol) of m-chloroperbenzoic acid are added to 80 mg (0.1515 mmol) of the compound from Example 105 dissolved in 3 ml of dry dichloromethane and the mix-ture is stirred for 1 hour at room temperature. The mixture is then washed successively with potassium iodide solution, sodium thiosulphate solution and sodium hydrogen carbonate solution, and the organic phase is dried over magnesium sulphate and concentrated in vacuo.
Yield: 60 mg (73% of theory) 1H-NMR (CDCl3): - 1.10 - 1.55 (complex region, 14H); 2.45 (m, 2H); 2.70 - 3.70 (complex region, 10H); 3.75 (s, 3H); 4.0 (m, 1H); 4.10 (m, 1H);
4.30 (m, 2H); 5.25 (dd, 1H); 6.25 (d, 1H); 7.0 - 7.30 (m, 4H> ppm.
Example 109 Ethyl 2-(4-fluorobenzoyl)-4-methyl-pent-2-enoate \/
CH
() ~~-0~CHZ-CH3 A solution of 210 g (1 mol) of ethyl 4-fluoro-Le A 25 747 40r198 benzoylacetate and 144 g (2 mol) of 2-methylpropanal are stirred overnight at 50oC with 7 ml of piperidine and ail of acetic acid in 100 ml of isopropanol. After reaction is complete, the batch is concentrated at about 5 15 Torr and the crude product (270 g, about 85X) is reacted vithout further purification.
Example 110 3-Ethoxycarbonyl-2-(4-fluorophenyl)-1,4-dihydro-4-iso-propyl-6-methyl-5-~nethoxycarbonyl-pyridine H3C OZC I I C02 Et H3C~N
H II
62.9 g (0.2 mol> of the compound from Example 109 and 21.9 g (0.19 mol) of methyl 3-amino-crotonate are heated to reflux overnight in 200 ml of ethylene glycol.
The mixture is extracted three times using ether, the combined organic phases are extracted, using 2 N hydrochloric acid and saturated sodium chloride solution, dried over mag-nesium sulphate and concentrated to dryness. The residue (65 g> is chromatographed in two portions on 750 g of silica gel each time (230 - 400 mesh) in a column (7.5 cm ~) using petroleum ether/ethyl acetate 10:1 ->
5:1. ' lrield: 21.5 g (31X) of yello~ crystals M.p. : 109°C
Example 111 3-Ethoxycarbonyl-2-(4-fluorophenyl)-4-isopropyl-5-a~ethoxycarbonyl-6-methyl-pyridine H3C-02C~/'~C02-Et I I
H3C II w le A 25 747 i340r198 Analogously to Example 3, Example 111 was pre-pared from 14.9 g (14.5 mmol) of the compound from Example 110.
Yield: 15.2 g (102%> of crude product, a colourless oil which is reacted without further purification.
1H-NMR (CDCl3): - 1.02 (t, 3H, CH2CH3); 1.33 (d, 6H, CH(CH3)2); 2.55 (S, 3H, 6-CH3>; 3.15 (sept, 1H, CH(CH3)2);
3.95 (s, 3H, 0-CH3); 4.08 (q, 2H, CH2-CH3); 7.1 (m, 2H, 3'-H);
7.55 (m, 2H, 2'-H); ppm.
Example 112 3-Ethoxycarbonyl-2-(4-fluorophenyl)-5-hydroxymethyl-4-isopropyl-6-methyl-pyridine HO-HZ

Analogously to Example 4, Example 112 Was pre-pared from 10 g (27.8 mmol) of the compound from Example 111.
Yield: 4.53 g (49% of theory) of yellowish crystals M.p. . 113°C
Example 113 Methyl erythro-(E)-7-C5-tert.butyldimethyl-silyloxy-n~ethyl-2(4-fluorophenyl>-4-isopropyl-6-methyl-pyrid-3-ylJ-3,5-dihydroxy-hept-6-enoate (H3C)3C-ii-0-H2 Le A 25 747 ~3~o~r~~
Example 113 was prepared from the compound from Example 112 in analogy to the reactions from Examples S, 6, 7, 8, 9 and 10.
A colourless foam was obtained.
1H-NMR (CDCl3): a = 0.2 (s, 6H, Si(CH3)2); 9.13 (s, 9H, Si-C(CH3)3>;; 1.3 (m, 8H, CH(CH3)2 + CH(OH)-_CH2-CH(OH)); 2.4 (m, 2H, _CH2-COOCH3);
2.65 (s, 3H, 6'-CH3); 3.1 (b, 1H, OH); 3.65 (b, 1H, OH); 3.7 (s, 3H, 0-CH3); 4.1 (m, 1H, _CH-OH);
4.35 (m, 1H, CH-0H); 4.8 (s, 2H, 5'-CH2); 5.15 (dd, 1H, 6-H);
6.7 (d, 1H, 7-H); 7.0 (m, 2H, _ 3"-H); 7.35 (m, 2H, 2"-H) ppm. _ Example 114 Methyl erythro-(E)-7-C2-(4-fluorophenyl)-5-hydroxymethyl-4-isopropyl-6-methyl-pyrid-3-yl7-3,5-dihydroxy-hept-6-enoate OH OH
HO-HZC , ~ CH=CH-CH-CHZ-CH-CH2-C02-CH3 223 g (0.4 mmol) of the compound from Example 113 are stirred at room temperature for 2 days with 0.5 ml of 1 N hydrochloric acid in 5 ml of methanol. Concen-trating and column chromatography on 18 g of silica gel 230-400 mesh, 2 cm, chloroform/methanol 10:1, give 100 mg (57X of theory) of colorless foam.
1H-NMR (CDCl3): a = 1.2 - 1.45 (m, 8H, CH(CH3)2 +
CH(OH)-CH2-CH(OH)); 2.4 (m, 2H, _CH2-COOCH3); 2.7 (s, 3H, 6'-Ch3);
3.1 (b, 1H, OH>; 3.6 (m, 2H, CH(CH3)2 + OH); 3.7 (s, 3H, Le A 25 747 ~.3~0'l~~
0-CH3); 4.1 (m, 1H, CHOH); 4.35 (m, 1H, CH-OH); 4.88 (s, 2H, 5'-CH2); 5.18 (dd, 1H, 6'-H); 6.7 (d, 1H, 7-H); 7.03 (m, 2H, 3 " -H>; 7.38 (m, 2H, 2 " -H) ppm.
Example 115 Methyl erythro-(E)-7-C5-benzyloxymethyl-2-(4-fluoro-phenyl)-4-isopropyl-b-methyl-pyrid-3-ylJ-3,5-dihydroxy-hept-b-enoate F
I w iH iH
'H2C-0-H2C~/~/CHsCH-CH-CHZ-CH-CH -CO -CH
H3C I y, Example 115 was prepared from the compound from Example 112 in analogy to the reactions of Examples 12, 6, 7, 8, 9 and 10. A colourless foam was obtained.
1H-NMR (CDCl3): - 1.2 - 1.45 (m, 8H, CH(CH3)2 +
CH(OH)-CH2-CH(OH); 2.4 (m, 2H, CH2-COOCH3); 2.6 (s, 3H, 6'-CH3>; 3.05 (b, 1H, OH>; 3.5 (m, 2H, CH(CH3)2 + OH); 3.72 (s, 3H, 0-CH3); 4.1 (m, 1H, CH-OH);
4.35 (m, 1H, CHOH); 4.62 (s, 2H, 0-CH2>; 4.66 (s,2H,OCH2); 5.15 (dd, 7H, 6-H); 6.2 (d, 1H, 7-H);
7.12 (m, 2H, 3"-H); 7.3 - 7.45 (m, 7H, aromatic-H) ppm.
Example 116 Methyl erythro-(E)-7-C2-(4-fluorophenyl)-4-isopropyl-5-methoxymethyl-b-methyl-pyrid-3-ylJ-3,5-dihydroxy-hept-b-enoate Le A 25 747 1340'~~~
OH OH
H3C-0-H2C I ~ CH=CH-CH-CH2-CH-CH2-COZ-CH3 H3C ~ ~ w Example 116 was prepared from the compound from Example 112 in analogy to the reactions of Examples 59, b, 7, 8, 9 and 10. A~colourless foam was obtained.
S 1H-NMR (CDCl3): - 1.2 - 1.45 (m, 8H, CH(CH3)2 +
CH(OH)-CH2-CH(OH); 2.4 (m, 2H, CH2-COOCH3); 2.63 (s, 3H, 66'-CH3>; 3.15 (b, 1H, OH>; 3.5 (m, 4H, 0-CH3 + CH(CH3)2); 3.62 (b, 1H, OH); 3.71 (s, 3H, COOCH3);
4.1 (m, 1H, CH-OH); 4.35 (m, 1H, CH-OH); 4.55 (s, 2H, 0-CH2>; 5.15 (dd, 1H, 6-H>; 6.65 (d, 1H, 7-H);
7.0 (m, 2H, 3 " -H); 7.35 (m, 2H, 2"-H) ppm.
Example 117 3-Benzyloxymethyl-4-(4-fluorophenyl)-b-isopropyl-5-(methyl-erythro-(E)-3,5-dihydroxy-hept-b-enoat-7-yl)-pyridine N-oxide 0~
8b3 mg (4 mmol) of 80X strength meta-chloroper-oxybenzoic acid are added to 208.4 mg (0.4 mmol) of the compound from Example 64 dissolved in 10 ml of dichloro-methane and the mixture is stirred overnight at room Le A 25 747 ~.34U~1~~
temperature. After concentrating in vacuo, the residue is chromatographed on a column (silica gel 70-230 mesh, using dichloromethane/methanol 96:4).
Yield: 107 mg (50% of theory) 1H-NMR (CDCl3): - 1.20 - 1.60 (m, 2H); 1.45 (d, 6H>;
2.40 (m, 2H>; 2.58 (s, 3H); 3.62 (m, 1H); 3.72 (s, 3H); 4.08 (m, 1H); 4.12 (s, 2H); 4.30 (m, 1H);
4.38 (s, 2H); 5.23 (dd, 1H>; 6.28 (d, 1H); 7.00 - 7.40 (m, 9H) ppm.
_. Example 118 3-Amino-4'-fluoro-cinnamonitrile NC

F
A solution of 41 g (1 mol> of acetonitrile, 135 g (1.1 mol) of 4-fluorobenzonitrile and 7.4 g (0.1 mol) of tert.-butanol 300 ml of tetrahydrofuran are added in dropwise at room temperature with stirring to a suspen-sion of 30 g (1 mol) of sodium hydride in 300 ml of p.a.

tetrahydrofuran and the mixture is heated to about 30C

until the reacti on starts. The remainder is added drop-wise at 35 - 40 C with external cooling and the mixture is subsequently heated under reflux for 30 min. Then 500 ml of water are cautiously added dropwise, the aqueous phase extracted twice using ethyl acetate is and the combined organic phases are dried over sodium sulphate. After stripping off the solvent, a crop of crystals remains which is stirred with ether and filtered off with suction (65.1 g>. The filtrate is concentrated to dryness on rotary evaporator, filtered over 300 g a of silica gel using toluene and crystallized from ether as above (46.3 g).

Yield: 111.4 g 69% of theory) of colourless crystals ( Le A 25 747 M.p. . 108oC
Example 119 E/Z-4- Ethoxycarbonyl-2,6-dimethyl-hept-4-en-3-one ~COOCH2CH3 ~--CH = C

158 g (1 mol) of ethyl isobutyrylacetate, 108 g (1.5 mol) of isobutyraldehyde, 8.75 ml of piperidine and 6.25 ml of acetic acid are stirred at 50°C for 20 h in 400 ml of isopropanol. Volatile components are stripped off in a water pump vacuum and the residue is subse-quently distilled in a high vacuum.
Yield: 145 g (68X of theory) of col. oil, m.p. - 60oC, 0.2 mbar Example 120 3-Cyano-5-ethoxycarbonyl-2-(4-fluorophenyl)-1,4-dihydro-4,6-diisopropyl-pyridine Et0 26.7 g (165 mmol) of the compound~from Example 118 and 35 g (165 mmol) of E/Z-4-ethoxycarbonyl-2,6-dimethyl-hept-4-en-3-one from Example 119 are heated at a bath temperature of 200°C~for 4 h. A further 17 g (80 mmol) of the latter components is then added and the mixture is heated overnight. The residue is prepurified over 450 g of silica gel 1230-400 mesh) using 3 l of tolu-ene/petroleum ether (1:1), 3 l of toluene and 2 l of tolu-ene/ethyl acetate (10:1). 5.7 g (9.7X) of yellowish crys-tals (m. p:. 140oC) crystallize from ether from the concentra-ted filtrate. The filtrate is chromatographed once again on Le A 25 747 1340~r~~
750 g of silica gel using petroleum ether/ethyl acetate (10:1). Two zones are obtained:
1. 7.4 g (12.5%) of colourless crystals of m.p.: 141°C
(from ether/petroleum ether) and as a by-product 2. 3,5-bis-cyano-2,6-bis-4-fluorophenyl-1,4-dihydro-4-isopropyl-pyridine C2.2 g (3.7%) of yellowish crystals of m.p.: 227 - 228°C, from ether/petroleum etherJ.
Total yield: 13.1 g (22% of theory) 1H-NMR (CDCl3): - 0.93 (d, 3H); 1.02 (d, 3H); 1.2 (m, 6H>; 1.3 (t, 3H); 1.8 (m, 1H);
3.6 (d, 1H); 4.2 (m, 2H); 6.15 (b, 1H); 7.2 (t, 2H); 7.53 (m, 2H) ppm.
Example 121 3-Cyano-5-ethoxycarbonyl-2-(4-fluorophenyl)-4,6-diiso-propyl-pyridine EtC
The preparation takes place from 16.0 g (45 mmol) of the compound from Example 120 analogously to the instructions of Example 3.
Yield: 14.5 g (91% of theory) M.p. . 82oC
Example 122 2-(4-Fluorophenyl)-3-formyl-5-hydroxymethyl-4,6-diiso-propyl-pyridine HO~H
Le A 25 747 13~0~~~~
110 ml (165 mmol) of a 1.5 M solution of diiso-butylaluminium hydride in toluene are added dropwise under argon at -78°C to -75°C to a solution of 14.5 g (41 mmol) of the compound from Example 121 in 320 ml of toluene p.a. and the mixture is stirred for 2 h at this temperature and subsequently for 1 h at -20°C. 350 ml of water and 250 ml of ethyl acetate are then added drop-wise, the mixture is filtered with suction using kiesel-guhr and washed with ethyl acetate, and the aqueous phase is extracted using 300 ml of ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulphate and concentrated. Column chromatography on 500 g of silica gel (230-400 mesh) using petroleum ether/ethyl acetate (5:1) and recrystal-tization from ether/petroleum ether yields 5.4 g (42% of theory) of yellowish crystals of m.p.. 147°C.
Example 123 (E)-3-C2-(4-Fluorophenyl)-5-hydroxymethyl-4,6-diiso-propyl-pyridin-3-yl7-prop-2-enal HO-H
The preparation takes place analogously to Example 8 from 200 mg (6.6 mmol) of SOX pure sodium hydride, 0.86 g (3.3 mmol) of diethyl 2-(cyclohexylamino)-vinylphosphonate and 0.94 g (3 mmol) of the compound from Example 122.
lrield: 0.46 g (45% of theory) M.p. . 210°C
Le A 25 747 Example 124 Methyl (E)-7-C2-(4-fluorophenyl)-5-hydroxymethyl-4,6-diisopropyl-pyridin-3-ylJ-5-hydroxy-3-oxo-hept-b-enoate HO-H
0.5 ml (4.5 mmol> of methyl acetoacetate are added dropwise at 0oC - 5oC under argon to a suspension of 0.15 g (5 mmol) of 80% pure sodium hydride in 6.5 ml of tetrahydrofuran p.a. After 15 min. in each case, 3.65 ml (6 mmol) of 15% strength butyllithium in hexane are first added dropwise at 0°C during the course of 10 min. then a solution of 1.01 g (4.5 mmol) of dry zinc bromide in 4.5 ml of tetrahydrofuran and finally 0.51 g (1.5 mmol) of the compound from Example 123. The mixture is stirred overnight at room temperature, saturated ammonium chloride solution is added slowly, the aqueous phase is extracted using ethyl acetate, and the combined organic phases are washed using saturated sodium chloride solution, dried over sodium sulphate and concentrated.
After column chromatography ( 3 cm) on 20 g of silica gel (230-400 mesh) using petroleum ether-ethyl acetate (1:1), 0.17 g (25% of theory) of yellowish oil is obtained.
Rf = 0.35 (petroleum ether-ethyl acetate (1:1» .
Example 125 Methyl erythro-(E)-7-C2-(4-fluorophenyl)-5-hydroxymethyl-4,b-diisopropyl-pyridin-3-ylJ-3,5-dihydroxy-kept-b-enoate Le A 25 747 1~40~103 HO-H
The preparation takes place analogously to the instructions for Example 10 from 0.15 g (0.33 mmol) of the compound from Example 124.
Yield: 85 mg (56X of theory) 1H-NMR (CDCl3): d = 1.25 - 1.6 (m, 14H, CH(OH)-CH2-CH(OH) + CH(CH3)2); 2.45 (m, 2H, CH2-COOCH3); 3.1 (b, 1H, OH);
3.45 - 3.7 (m, 3H, _CH(CH3)2 +
OH); 3.7 (s, 3H, OCH3>; 4.1 (m, 1H, CH(OH); 4.35 (m, 1H, _CH(OH);
4.85 (s, 2H, CH2-OH); 5.7 (dd, 1H, 6-H); 6.25 (d, 1H, 7-H); 7.05 (t, 2H, 3"-H); 7.45 (m, 2H, 2"-H) ppm.
Example 126 5-Ethoxycarbonyl-2-(4-fluorophenyl)-3-formyl-4,6-diiso-propyl-pyridine Et0 The preparation takes place analogously to the process for Example 122 from 3.5 g (10 mmol) of the com-pound from Example 121 and 35 ml of a 1 M solution of diisobutylaluminum hydride in toluene, the temperature being kept at -75oC for 1.5 h, the mixture then being warned to -30oC before water is added.
Le A 25 747 Yield: 0.8 g (22% of theory) of colourless crystals M.p.: 88oC (from petroleum ether) Example 127 (E)-3-C5-Ethoxycarbonyl-2-(4-fluorophenyl)-4,6-diiso-propyl-pyridin-3-ylJ-prop-2-enal Et The preparation takes place analogously to the instructions for Example 8 from 1.25 g (3.5 mmol) of the compound from Example 126.
Yield: 0.17 g (72% of theory) of colourless oil Rf - 0.35 (petroleum ether-ethyl acetate (5:1 » .
fxample 128 Methyl (E>-7-C5-ethoxycarbonyl-2-(4-fluorophenyl>-4,6-diisopropyl-pyridin-3-ylJ-5-hydroxy-3-oxo-hept-6-enoate gt0 The preparation takes place analogously to the instructions for Example 123 from 0.95 g (2.48 mmol> of the compound from Example 127.
Yield: 0.83 g (67% of theory) of colourless oil Rf = 0.27 (petroleum ether-ethyl acetate (2:1)>
Example 129 Methyl erythro-(E)-7-C5-ethoxycarbonyl-2-(4-fluorophenyl>-4,6-diisopropyl-pyridin-3-ylJ-3,5-dihydroxy-hept-6-enoate Le A 25 747 ~3~0~'l9~

The preparation takes place analogously to the instructions for Example 10 from 0.89 g (1.66 mmol) of the compound from Example 128.
Yield: 0.65 g (78X of theory) of colorless oil 1H-NMR (CDCl3): d = 1.25 - 1.5 (m, 17H, CH(CH3)2 +
CH2-CH3 + CH(OH)-CH2); 2.42 (m, 2H, CH2-COOCH3); 2.95 (m, 1H, _CH(CH3)2); 3.15 (b, 1H, OH); 3.2 (m 1H, CH(CH3>2); 3.6 (b, 1H, OH); 3.7 (s, 3H, 0-CH3);
4.1 (m, 1H, CH-OH); 4.4 (m, 3H, CH-OH + 0-CH2-CH3); 5.2 (dd, 1H, 6-H); 6.75 (d, 1H, 7-H); 7.05 (t, 2H, 3"-H); 7.45 (m, 2H, 2"
H) oom.
Example 130 Methyl erythro-(E>-7-C2-(4-fluorophenyl)-4-isopropyl-5-methoxy-methyl-6-methyl-1- oxo -pyridin-3-ylJ-3,5-di-hydroxy-hept-6-enoate 67 mg (0.15 mmol) of the compound from Example 116 and 54 mg (0.17 mmol> of SSX strength metachloroper-Le A 25 747 1340 ~1~8 benzoic acid are stirred for 2 h at room temperature in 6 ml of dichloromethane. The solvent is stripped off, and the residue is taken up in 20 ml of ethyl acetate and washed with 20 ml of saturated sodium hydrogen carbonate solution. The aqueous phase is washed with 20 ml of ethyl acetate and the combined organic phases are dried over magnesium sulphate. The crude product is chromato-graphed on 10 g of silica gel (230-400 mesh) in a column ( 2 cm) using ethyl acetate and ethyl acetate/methanol (10:1>.
Yield: 57 mg (82% of theory) of amorphous solid 1H-NMR (CDCl3): - 1.1 - 1.3 (m, 2H, CH(OH)-CH2-CH(OH » ; 1.35 (d, 6H, CH(CH3)2);
2.38 (m, 2H, CH2-COOCH3>; 2.6 (s, 3H, 6'-CH3); 3.4 (b, 1H, OH);
3.5 (m, 4H, CH(CH3)2 + CH2-0-CH3>; 3.28 (b, 1H, OH); 3.72 (s, 3H, COOCH3); 4.05 (m, 1H, HO-C-H);
4.28 (m, 1H, HO-C-_H); 4.55 (s, 2H, 0-CH2); 5.12 (dd, 1H, 6-H); 6.38 (d, 1H, 7-H>; 7.05 - 7.25 (m, 4H, aromatic-H) ppm.
MS: m/e - 461 (9%), M+.
Exempla 131 2-(4-Fluorophenyl)-3-formyl-4,6-diisopropyl-5-methoxy-methyl-pyridine 3.15 g (96X of theory) of colourless crystals of m.p. 77oC (from MeOH> are obtained from 3.15 g (10 mmol) of the compound from Example 122 in analogy to the instructions from Example 59 Le A 25 747 ~~~0 ~~8 Example 132 Methyl erythro-(E)-7-C2-(4-fluorophenyl)-4,b-diisopropyl-5-methoxymethyl-pyridin-3-yl7-3,5-dihydroxy-hept-b-enoate Colorless crystals of m.p. 92°C (from ether/
petroleum ether) are obtained from the compound from Example 131 according to the instructions from Example 8, 9 and 10 1H-NMR (CDCl3>: d = 1,3 (m, 14H, CH(_CH3)2 + 4-H);
2.4 (m, 2H, 2-H); 3.05 (b, 1H, OH);
3.3-3.57 (m, SH, 0-CH3 +
CH(CH3)2>; 3. b2 (b, 1H, OH);
3.72 (s, 3H, COOCH3); 4.1 (m, 1H
CH-OH) 4.35 (m, 1H, CH-OH); 4.55 (s, 2H, 0-CH2); 5.15 (dd, 1H, b-H>; 6.75 (d, 1H, 7-H); 7.0 (t, 2H, 3"H>; 7.45 (m, 2H, 2"-H).
Example 133 5-Cyano-3-ethoxycarb,onyl-2-(4-fluorophenyl)-1,4-dihydro-4-isopropyl-b-Methyl-pyridine 17.4 g (0.2 mol) of 3-amino-crotonacidnitrile and 56 g (0.2 mol) of the compound from Example 109 are heated to reflux overnight in 800 ml of ethanol. The solvent is stripped off and the residue is chromatographed on silica Le A 25 747 - 14b -OH OH

130 ~~a gel using petroleum ether/ethyl acetate 20:1.
Yield: 14.9 g (21% of theory) 1H-NMR (CDCl3>: - 1.0 (m, 9H); 1.9 (m, 1H); 2.2 (m, 3H); 3.6 (d, 1H>; 3.9 (m, 2H);
5.75 (b, 1H); 7.1 (t, 2H); 7.25 (m, 2H).
Example 134 5-Cyano-3-ethoxycarbonyl-2-(4-fluorophenyl)-4-isopropyl-6-methyl-pyridine N ~ I OOCHZCH3 From 9.8 g (30 mmol) of the compound from Example 133 analogously to Example 3 Yield: 9.4 g (96% of theory>, m.p. 76°C.
Example 135 5-Cyano-2-(4-fluorophenyl)-3-hydroxymethyl-4-isopropyl-5-methyl-pyridine N ~ ( HZOH
H3C ' 50 ml (60 mmol> of a 1.2 M diisobutylaluminium hydride solution in toluene are added under argon during the course of 1.5 h to a solution of 9.8 g (30 mmol) of the compound from Example 134 in 150 ml of toluene p.a.
at -75oC and the mixture is stirred for a further 30 min.
280 ml of water are cautiously added dropwise at -30oC, and the mixture is filtered with suction using kieselguhr and washed with ethyl acetate. The aqueous phase is extracted three times using ethyl acetate and 1 o d 7S 7G7 1340~~0~
the combined organic phases are washed with satd.
sodium chloride solution, dried over sodium sulphate and concentrated. Column chromatography (400 g of silica gel, 230-400 mesh, 6 cm, petroleum ether/ethyl acetate 10/1 5/1) yields 3 zones:
1.
3-Ethoxycarbonyl-2-(4-fluorophenyl)-5-formyl-4-isopropyl-6-methyl-pyridine ... CH ~~~

2.6 g (26% of theory) of m.p. 53°C
2.
2.1 g (25% of theory) of the title compound (Example 135) m.p. 157°C from ether/petroleum ether.
3.
2-(4-Fluorophenyl)-5-formyl-3-hydroxymethyl)-4-isopropyl-6-methyl-pyridine OH ~ I HZOH
CHI ~
1.6 g (19% of theory), m.p. 150°C from ether/petroleum ether.
Example 136 5-Cyano-2-(4-fluorophenyl)-3-formyl-4-isopropyl-6-methyl-pyridine.
Le A 25 747 1340r~~8 N

2.2 g (10.5 mmol) of trifluoroacetic anhydride in 10 ml of methylene chloride are added dropwise at -75°C to 1.1 g (14 mmol) of DMSO in 8 ml of methylene chloride, the mixture is stirred for 10 min at -70°C, a solution of 2.0 g (7 mmol) of the compound from Example 135 in 50 ml of methylene chloride is then added dropwise and the mixture is stirred for 1 h at -70°C.
2.1 ml (21 mmol) of triethylamine are added drop-wise to the suspension now present and the mixture is stirred for 10 min at -65°C. After warming to room temperature, it is washed with satd. sodium chloride solution, dried over sodium sulphate and concentrated.
Crude yield: 2.0 g (100% of theory), m.p. 109°C
1H-NMR (CDCl3): - 1.52 (d, 6H, CH(CH3)2); 2.9 (s " 3H, 6-CH3); 4.0 (sept. 1H, CH(CH3>2); 7.2 (m, 2H, 3'-H>;
7.5 (m, 2H, 2'H); 9.95 (s, 1H, CHO).
Example 137 (E)-3-C5-Cyano-2-(4-fluorophenyl)-4-isopropyl-6-methyl-pyrid-3-yl7-prop-2-enal N

From 1.9 g of the compound from Example 136 analogously to Example 8 Yield: 0.6 g (28% of theory), m.p. 112°C (ether-petroleum Le A 25 747 I3~0 r~~
ether).
Example 138 Methyl (E)-7-CS-cyano-2-(4-fluorophenyl)-4-isopropyl-6-methyl-pyrid-3-ylJ-5-hydroxy-3-oxo-kept-6-enoate H.
From 0.52 g (1.7 mmol) of the compound from Example 137 analogously to Example 9 Yield: 0.32 g (44% of theory) of yellowish oil.
Example 139 Methyl erythro-(E)-7-CS-cyano-2-(4-fluorophenyl)-4-iso-propyl-6-methyl-pyrid-3-ylJ-3,5-dihydroxy-hept-6-enoate OH OH
OOCH
N ~ ( H~CH 3 From 0.32 g of the compound from Example 138 analogously to Example 10 Yield: 0.15 g (47% of theory) of yellowish oil.
1H-NMR (CDCl3): - 1.35 (m, 2H, CH(OH)CH2-CH(OH);
1.45 (d, 6H, CH(CH3)2); 2.42 (m, 2H, CH2-COOCH3); 2.7 (s, 3H, 6-CH3>;
3.55 (m, 2H, CH(CH3)2 + OH); 3.68 (b, 1H, OH); 3.72 (s, 3H, 0-CH3);
4.13 (m, 1H, CH(OH)), 4.4 (m, 1H, CH(OH)); 5.32, (dd, 1H, olefin-H); 6.6 (d, 1H, olefin-H>; 7.08 i a a ~c ~~ ~o~o~
(m, 2H, 3"-H); 7.45 (m, 2H, 2"-H).
Example 140 Ethyl 4-fluorobenzoylacetate ~CHZCH3 21.7 g (0.72 mol) of sodium hydride (80% strength, 20% mineral oil) are weighed into a litre of diethyl ether p.a. and 85.5 g (127 ml, 0.72 mol) of diethyl carbonate (VK 22-010) are subsequently added. A solution of 100 g (0.72 mol) of 4-fluoroacetophenone in 300 ml of diethyl ether are added dropwise to this solution at boiling heat over a period of 4 hours (vigorous, mechani-cal stirrer necessary; a viscous paste is formed). The mixture is then heated to reflux for a further hour, then cooled to about 5°C and a solution of 50 ml of acetic acid and 100 ml of Et20 is next added dropwise under N2 at this temperature. About S00 ml of H20 are subse-quently added dropwise and the organic phase is separated off. The aqueous phase is extracted once again using Et20 (2 x 400 ml), and the combined ethereal phases are washed with NaHC03 solution, dried over MgS04 and con-centrated. The residue is distilled over a short Vigreux column.
Yield: 93 g (60%) b.p. 0.4 mm 99-102°C
Example 141 S-Cyano-3-ethoxycarbonyl-4-(4-fluorophenyl)-1,4-dihydro-2-isopropyl-6-methyl-pyridine ~-0-CH2CH3 H3C~N
H
Le A 25 747 1340'~~8 52.8 g (0.2 mol) of the compound from Example 1 and 16.4 g (0.2 mol) of 3-amino-crotononitrile are heated to reflux for 2 h in 200 ml of ethylene glycol. After cooling, the deposited oil is taken off and extracted S another three times using ether. The ether phases are washed with eater, dried and concentrated. The residue and the initially isolated oil are crystallized from ether.
Yield: 31.4 g (48%), m.p. 168°C.
Example 142 5-Cyano-3-ethoxycarbonyl-4-(4-fluorophenyl)-2-isopropyl-6-methyl-pyridine 14.8 g (45 mmol> of the compound from Example 141 are reacted analogously to Example 3.
Yield: 13.7 g (93% of theory) of colourless crystals of m.p. 95°C.
Example 143 5-Cyano-4-(4-fluorophenyl)-3-hydroxymethyl-2-isopropyl-6-methyl-pyridine Compound 1 N ZOH

Le A 25 747 13~0~~~3 5-Cyano-4-(4-fluorophenyl)-5-hydroxyiminomethyl-3-hydroxymethyl-2-isopropyl-6-methyl-pyridine F
Compound 2 HO-N~ ZOH
H
83.3 ml (0.1 mol) of 1.2 h diisobutylaluminium hyride solution in toluene are added dropwise at -78°C
under argon during the course of 3 h to 16.3 g (50 mmol) of the compound from Example 142 in 240 ml of toluene p.A. so that the temperature remains under -75oC.
The mixture is stirred for a further 30 min at -75°C and allowed to warm to -30oC, and 300 ml of water and 160 ml of ethyl acetate are then added cautiously.
The mixture is filtered with suction over kiesel-guhr and washed with ethyl acetate. The aqueous phase is extracted three times using ethyl acetate, and the combined org. phases are washed with satd. sodium chlor-ide solution, dried over sodium sulphate and concentrated.
Column chromatography twice over silica gel using toluene/
ethyl acetate 5:1 or petroleum ether/ethyl acetate 5:1 yields 3.4 g of a fraction of Rf 0.2 (petroleum ether/
ethyl acetate 5:1) which is a mixture of 5-cyano-4-(4-fluorophenyl)-3-hydroxymethyl-2-isopropyl-6-methyl-pyridine and 4-(4-fluorophenyl)-5-formyl-3-hydroxy-2-iso-propyl-6-methyl-pyridine.
3.16 g of this mixture are dissolved in 10 ml of methanol and added to a solution of 1.22 g (17.6 mol) of hydroxylamine hydrochloride and 1.22 g (14.9 mmol) of sodium acetate in 10 ml of water. After stirring for 3 h at room temperature, the methanol is removed by rotary evaporation, some water is added and the mixture is Le A 25 747 1340~1~~
extracted three times using ethyl acetate. The org.

phases are gashed with satd. sodium chloride solution, dried over sodium sulphate and concentrated. The residue is chromatographed in a column (100 g of silica gel 230-400 mesh, 4 cm, petroleum ether/ethyl acetate 5:1).

Tao fractions are obtained:

Compound 1: 0.65 g (4.9%) of colourless crystals of m.p. 132oC

5-Cyano-4-(4-fluorophenyl)-3-hydroxymethyl-2-isopropyl-6-methyl-pyridine 1H-NMR (CDCl3): - 1.32 (d, 6H" CH(CH3)2); 1.6 (b, 1H, OH); 2.7 (s, 3H, 6-CH3>;

3.5 (sept, 1H, CH(CH3)2); 4.5 (d, 2H, CH2-OH); 7.15-7.35 (m, 4H, aromatic-H).

Compound 2: 2.15 g (15.3%) of amorphous solid 5-Cyano-4-(4-fluorophenyl)-5-hydroxyiminomethyl-3-hydroxy-methyl-2-isopropyl-6-methyl-pyridine 1H-NMR (CFCl3): - 1.33 (d, 6H, CH(CH3)2)%

1.4 (b, 1H, -OH);

rv_. 2.7 (s, 3H" 6-CH3>;

3.48 (m, 1H, CH(CH3)2);

4.4 (d, 2H, CH2-OH);

7.15 (m, 4H, aromatic H);

7.77 (s, 1H, CH=N-);

8.08 (s, 1H, =N-OH).

Example 144 5-Cyano-4-(4-fluorophenyl>-3-formyl-2-isopropyl-6-methyl-pyridine Le A 25 747 1310~t~~
F
D
H
A> 0.63 g (2.2 mmol) of compound 1 from Example 144 is reacted analogously to the process from Example 136.
Yield: 0.6 g (97%>.
B) 4.4 g (21 mmol> of trifluoroacEtic anhydride in ml of methylene chloride are added dropwise at -78oC
to 1.1 g (14 mmol) of DMSO in 8 ml of methylene chloride p.A. and the mixture is stirred for 10 min at -70°C.
2.1 g (7 mmol) of compound 2 from Example 143 are then 10 added in 50 ml of methylene chloride, the mixture is stirred for 1 h at -70°C, 5.8 ml (42 mmol) of triethyl-amine are noW added and the mixture is stirred for 4 h at room temperature. It is washed with satd. sodium chlor-ide solution, concentrated, chromatographed over 100 g of 15 silica gel (230-400 mesh, 4 cm, petroleum ether/ethyl acetate 10:1) and recrystallized from ethyl acetate/
petroleum ether.
Yield: 0.31 g (16%), m.p. 82oC
1H-NMR (CDCl3>: - 1.32 (d, 6H, CH(CH3)2); 2.78 (s, 3H, 6-CH3>; 3.77 (m, 1H, CH(CH3>2); 7.23 (m, 2H, 3'-H);
7.36 (m, 2H, 2'-H); 9.86 (s, 1H, CHO).
Example 145 Methyl erythro-(E)-7-C5-cyano-4-(4-fluorophenyl)-2-iso-propyl-6-methyl-pyrid-3-ylJ-3,5-dihydroxy-hept-6-enoate Le A 25 747 i F

NC

The reaction takes place from the compound from Example 144 in analogy to the reactions of Example 8, 9 and 10. colorless solid, m.p. 124°C.
1H-NMR (CDCl3): a - 1.3 (m, 8H, CH(CH3)2 + CH(OH)-CH2-CH(OH » ; 2.4 (m, 2H, CH2-COOCH3>; 2.75 (s, 3H, 6-CH3);
3.35 (m, 2H, CH(CH3) + OH); 3.6 (b, 1H, OH); 3.7 (s, 3H 0-CH3);
4.1 (m, 1H, CH-OH); 4.35 (m, 1H, CH-OH); 5.3 (dd, 1H, 6-H); 6.4 (d, 1H, 7-H); 7.05-7.3 (m, 4H, Ar-H).
Example 146 Ethyl 5-(tert.-butyldimethylsilyloxymethyl)-6-cyclo-propyl-4-(4-fluorophenyl)-2-isopropyl-pyridine-3-car-boxylate F
Et --~~5 i 15 g (42 mmol) of the compound from Example 82 are reacted analogously to Example 5.
lrield: 16.9 g (85.4X of theory) le A 25 747 1~~~~1~
Example 147 3-ltert.-Butyldimethylsilyloxymethyl)-2-cyclopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyridine -~3 i 16.9 g (35.8 mmol) of the compound from Example 146 are reacted analogously to Example 6.
Yield: 12.3 g (80.1X of theory).
Example 148 3-(tert.-8utyldimethylsilyloxymethyl)-2-cyclopropyl-4-(4-fluorophenyl)-6-isopropyl-5-methoxymethyl-pyridine F
CH30 S i'-~-5.5 g (12.8 mmol) of the compound from Example 147 are reacted analogously to Example 59.
lrield: 5.7 g of crude product.
Example 149 2-Cyclopropyl-4-(4-fluorophenyl)-3-hydroxymethyl-6-iso-propyl-5-methoxymethyl-pyridine Le A 25 747 c F

5.7 g (12.8 mmol) of the crude product from Example 148 are dissolved in absolute tetrahydrofuran.
After addition of 12.8 ml of tetrabutylammonium fluoride solution (1 M in THF) the mixture is stirred overnight at room temperature. 50 ml of saturated sodium hydrogen carbonate solution are then added and the mixture is extracted several times with methylene chloride. The combined organic phases are dried with sodium sulphate, concentrated and chromatographed over silica gel (eluent:
petroleum ether/ethyl acetate 7:3).
Yield: 3.9 g (94% of theory).
1H-NMR (CDCl3): - 0.0 (s, 6H); 0.87 (s, 9H); 0.8-1.0 (m, 2H>; 1.22 (d, 6H); 1.10-1.30 (m, 2H); 2.31 (m, 1H>; 3.12 (s, 3H); 3.30 (m, 1H); 3.98 (s, 2H); 4.47 (m, 2H); 7.0-7.3 (m, 4H) ppm.
Example 150 Methyl erythro-(E)-7-C2-cyclopropyl-4-(4-fluorophenyl)-6-isopropyl-5-methoxymethyl-pyrid-3-ylJ-3,5-dihydroxy-hept-6-enoate F

Le A Z5 74.
' - 158 -130?~
Example 150 was prepared from the compound from Example 149, in analogy to he actions f Examples7, t re o 8, 9 and 10.

1H-NMR (CJCl3): - 0.89 (m, 2H); 1.18 (m, 2H>; 1.26 (d, 6H); 1.40 (m, 2H>; 2.24(m, 1H>; 2.44 (m, 2H); 3.17 (s, 3H);

3.30 (m, 1H); 3.72(s, 3H); 4.03 (s, 2H); 4.12 (m, 1H); 4.32(m, 1H); 5.51 (d,d, ); 6.32 , 1H>;
1H (d 7.10 (m, 4H) ppm.

Example 151 Ethyl 3-amino-3-cyclopropyl-acrylate 1.1 g of p-toluenesulphonic acid are added to 49.9 g (0.32 mol> of ethyl cyclopropylcarbonylacetate in 200 ml of dry toluene and the mixture is saturated with ammonia gas at room temperature with stirring. After allowing to stand overnight, the mixture is heated under reflux for 8 h in a water separator, ammonia gas being .. 20 continuously introduced. The mixture is allowed to cool overnight and is filtered, and the toluene solution is con-centrated in vacuo and distilled from unreacted starting material in a high vacuum up to 65oC. The substance is subsequently found in the residue.
Yield: 11.9 g (24% of theory>.
Example 152 Diethyl 1,4-dihydro-2,6-dicyclopropyl-4-(4-fluorophenyl)-pyridine-3,5-dicarboxylate Le A 25 747 1340r1~~
HSC2 )C2H5 6.2 g (40 mmol) of the compound from Example 151 and 10.5 g (40 mmol) of the compound from Example 79 are dissolved in 100 ml of ethylene glycol and heated to 3 reflux overnight. After cooling to room temperature, the mixture is extracted several times using ether, and the organic phase is washed once each pith 10X strength hydrochloric acid, saturated sodium bicarbonate solution and water, dried over magnesium sulphate and concentrated in vacuo.
Yield: 10.4 g (65.1X of theory).
1H-NMR (CDCl3): d = 0.60 (m, 4H); 0.95 (m, 4H); 1.23 (t, 6H); 2.72 (m, 2H); 4.12 (m, 4H); 5.02 (s, 1H>; 5.40 (s, 1H);
6.88 (m, 2H); 7.20 (m, 2H) ppm.
Example 153 Methyl erythro-(E)-7-C2,6-dicyclopropyl-4-(4-fluoro-phenyl)-S-n~ethoxymethyl-pyrid-3-yl7-3,5-dihydroxy-hept-6-enoate CH3i Example 153 was prepared from the compound from fxample 152, in analogy to the reactions of Examples 3, le A 25 747 ~34~r1~~
4, 59, 60, 7, 8, 9 and 10.
1H-NMR (CDCl3): - 0.89 (m, 4H); 1.08 (m, 4H); 1.40 (m, 2H); 2.21 (m, 2H>; 2.43 (m, 2H>; 3.21 (s, 3H>; 3.72 (s, 3H>;
4.11 (m, 1H); 4.15 (s, 2H>; 4.30 (m, 1H); 5.47 (dd, 1H); 6.30 (d, 1H); 7.10 (m, 4H) ppm.
Example 154 Ethyl 2,b-diisopropyl-5-ethoxymethyl-4-(4-fluorophenyl)-pyridine-3-carboxylate 4.4 ml (76 mmol> of absol. ethanol are added dropwise at room temperature to a suspension of 2.29 g (76 mmol) of sodium hydride (80% strength) in 30 ml of absot. tetrahydrofuran and the mixture is stirred for 30 min. A solution of 2.7 g (7.6 mmol) of the compound from Example 86 are then added dropwise in 20 ml of absol. tetrahydrofuran and the mixture is heated over-night under reflux. The reaction batch is subsequently poured onto ice water and, after the pH has been adjusted to 8, extracted several times using ether. The organic phase is washed with sodium chloride solution, dried over sodium sulphate, concentrated and chromatographed over silica gel (eluent ethyl acetate/petroleum ether 5:95).
Yield: 1.07 g (36.4X of theory).
1H-NMR (COCl3): - 0.95 (t, 3H); 1.13 (t, 3H>; 1.31 (m, 6H); 3.05 (m, 1H>; 3.32 (q, 2H); 3.41 (m, 1H); 3.97 (q, 2H>;
4.18 (d, 2H>; 7.08 (m, 2H>; 7.27 Le A 25 747 ~3~0~~
m, 2H) ppm.
Examplr 155 Methyl erythro-(E)-7-C2,b-diisopropyl-5-ethoxymethyl-4-(4-fluorophenyl)-pyrid-3-ylJ-3,5-dihydroxy-hept-b-enoate F

Example 155 was obtained from the compound from Example 154, in analogy to the reactions from Examples 60, 7, 8, 9 and 10.
1H-NMR (CDCl3): d = 1.13 (t, 3H); 1.20-1.50 (m, 8H);
2.43 (m, 2H); 3.30 (m, 3H); 3.72 (s, 3H); 4.08 (m, 1H); 4.12 (s, 2H); 4.29 (m, 1H); 5.25 (dd, 1H);
6.30 (d, 1H); 7.0-7.2 (m, 4H) ppm.
The following compounds were obtained from . 15 Example 86 analogously to Example 155:
Example 156 Methyl erythro-(E)-(. 7-C2,6-diisopropyl-4-(4-fluorophenyl)-5-propyloxymethyl-pyrid-3-yl7-3,5-dihydroxy-hept-b-enoate.
Exaople 157 Methyl erythro-(E)-(7-C2,b-diisopropyl-4-(4-fluorophenyl>-5-isopropoxymethyl-pyrid-3-yl7-3,5-dihydroxy-hept-b-enoate.
Example 158 Methyl erythro-(E)-(7-L2,6-diisopropyl-4-(4-fluorophenyl)-5-butyloxymethyl-pyrid-3-yl7-3,5-dihydroxy-hept-b-enoate.
Example 159 Methyl erythro-(E)-(7-C2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyloxymethyl-pyrid-3-yl7-3,5-dihydroxy-kept-b-enoate.
Le A 25 747 1340~0~
Example 160 Methyl erythro~(E)-(7-C2,6-diisopropyl-4-(4-fluorophenyl)-5-hexyloxymethyl-pyrid-3-yl7-3,5-dihydroxy-kept-6-enoate.
Example 161 Sodium erythro-(E)-7-C2,6-diisopropyl-5-ethoxymethyl-4-(4-fluorophenyl)-pyrid-3-yl7-3,5-dihydroxy-hept-6-enoate F
-Nay 487 mg (1 mmol) of the compound from Example 155 are dissolved in 10 ml of tetrahydrofuran and 10 ml of 0.1 N sodium hydroxide solution are added. After 1 h, the tetrahydrofuran is stripped off in vacuo and the aqueous residue is freeze-dried.
Yield: 490 mg (99X of theory).

Le A 23 747 - 163 -~3401~~
Example 162 F OH
'~ 0 trans-(E)-6-[2-(3-benzyloxymethyl-2,6-diisopropyl-4-(4-fluoro-~5 phenyl)-pyrid-5-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one 5.5 g (10 mmol) of the product from example 17 was dissolved in 100 ml tetrahydrofuran and after adding 100 ml 0.1 N sodium-hydroxide solution was stirred for 1 hr at room temperature.
Subsequently, the solution was diluted with 100 ml water, adjusted to pH 4.4 using 1 N HC1 and extracted with methylene chloride. The methylene chloride phase was dried with sodium sulphate and concentrated under vacuum. The residue was dissolved in 100 ml absolute toluene, 40 g molecular sieve 4 Was added and heated under reflux over night. Subsequently it Was separated from the molecular filter, concentrated under vacuum, and the residue crystallised with petroleum ether.
Yield: 4.3 (83.2 % of the theoretical yield) Le A 25 747 1~~0~~9~

H-N~IR (CDC13): = 1.22 (d,6H); 1.32 (d,6H); 1.40-1.80 (m,2H);
2.45-2.70 (m,2H); 3.30 (m,2H); 4.12 (m,lH);
4.14 (s,2H); 4.45 (s,2H); 5.04 (m,lH); 5.28 (dd,lH); 6.39 (d,lH); 6.95-7,40 (m,9H) ppm.
Example 163 F OH

trans-(E)-6-(2-(2,6-diisopropyl-4-(4-fluorophenyl)-5-phenoxyme-thyl-pyrid-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one From 540 mg (1 mmol) of product 89 one receives 450 mg (89.4 %
of the theoretical yield) using a method analogous to example 162.

H-NMR (CDC13): = 1.25 (d,6H); 1.30 (d,6H); 1.40-1.70 (m,2H);
2.60 (m,2H); 3.30 (m,2H); 4.18 (m,lH); 4.65 (s,2H); 5.08 (m,lH); 5.30 (dd,lH); 6.42 (d,lH); 6.70-7.30 (m,9H) ppm.
Le A 25 747 13~~~r Example 164 Methyl-erythro-(E)-7-(3-azidomethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyrid-5-yl)-3,5-dihydroxy-hept-6-enoate 459 mg (1 mmol) of the product from example 11 and 320 mg (1.1 mmol) triphenylphosphine were dissolved in 10 ml absol. tetrahy-drofuran. After adding 3.2 ml of an 0.48 molar solution of HN
in.toluene, it was cooled in an ice-bath and then 173 ml (1.13 mmol) diethyl azodicarboxylate was added. Subsequently the solution was stirred at room temperature overnight and then - concentrated under vacuum. The residue was chromatographed over silica gel (mobile phase: ethyl acetate - petroleum ether 1:1) Yield: 260 mg (53.7 % of the theoretical yield) H-NMR (CDC13): = 1.30 (d,6H); 1.39 (d,6H); 1.25-1.60 (m,2H);
2.50 (m,2H); 3.37 (m,2H); 3.80 (s,3H); 4.15 (s,lH); 4.18 (s,2H); 4.36 (m,lH); 5.36 (dd,lH); 6.36 (d,lH); 7.15 (m,4H) ppm.
Le A 25 747 ~~40'l~~
Example 165 S
F

Methyl-erythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-~5 succinimidooxymethyl-pyrid-3-yl)-3,5-dihydroxy-hept-6-enoate The preparation was carried out by a method analogous to example 164 using the product from example 11 and N-hydroxysuccinimide.

H-N~IR (CDC13):? = 1.28 (d,6H); 1.37 (d,6H); 1.2-1.5 (m,2H};
2.43 (m,2H); 2.66 (s,4H); 3.32 (sept.,lH);
3.?2 (s,3H); 3.78 (sept.,lH); 4.08 (m,lH};
4.31 (m,lH); 4.86 (s,2H); 5.28 (dd,lH); 6.33 (d,lH); 7.0-7.4 (m,4H) ppm.
Le A 25 747 1340~1~b Example 166 S
F

' N

Methyl-erythro-{E)-7-(2,6-diisopropyl-4-(4-fluorophenyl)-5-succinimidomethyl-pyrid-3-yl)-3,5-dihydroxy-kept-6-enoate The preparation was carried by a method analogous to example 164 using the product from example 11 and succinimide.

H-NMR (CDC13):? = 1.23 (m,l2H); 1.25-1.50 (m,2H); 2.43 {m,2H);
2.51 (s,4H); 3.16 (m,lH); 3.28 (m,lH);3.73 (s,3H); 4.07 (m,lH); 4.26 (m,lH); 4.52 (s,2H); 5.25 (dd,lH); 6.20 (d,lH); 7.0-7.2 (m,4H) ppm.
Le A 25 747 1340~1~~
Example 167 _. w Methyl-erythro-(E)-7-[2,6-diisopropyl-3-(4-fluorobenzyloxy-methyl)-4-(4-fluorophenyl)-pyrid-5-yl)-3,5-dihydroxy-kept-6-enoate.
Example 166 was prepared from the product of example 4 and 20 4_fluorobenzylbromide according to methods analogous to examples 12 - 17 .
...
H-NMR (CDC13):

Le A 25 747 - 1.25 (m,6H); 1.32 (d,6H); 1.21-1.5 (m,2H);
2.42 (m,2H); 3.30 (m,2H); 3.72 (s,3H); 4.07 (m,lH); 4.13 (s,2H); 4.28 (m,lH); 4.30 (s,2H); 5.22 (dd,lH); 6.30 (d,lH); 6.90-7.30 (m,BH) ppm.

~3~0~~
Example 168 OH
'''. 0 F
trans-(E)-6-[2-(2,6-diisopropyl-3-(4-fluorobenzyloxymethyl)-4-(4-fluorophenyl)-pyrid-5-yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one.
The preparation was carried out by a method analogous to example Zp 164 using the product from example 167.

H-N~IR (CDC13): - 1.23 (d,6H); 1.32 (d,6H); 1.40-1.80 (m,2H);
2.40 (m,2H}; 3.30 (m,2H); 4.13 (s,2H); 4.16 25 (m.lH); 4.30 (s,2H); 5.05 (m,lH); 5.28 (dd,lH); 6.37 (d,lH); 6.9-7.3 (m,8H) ppm.
Le A 25 747 1340r1~~
Example 169 ~COOCHZCH3 CH=C' ~0 (E/Z)-2-Ethoxycarbonyl-4-methyl-1-(thiophen-2-yl)penten-3-one.
~5 The above mentioned product was produced from ethyl isobutyryl acetate and th;ophene-2-carbaldehyde by a method analogous to that for example 1.
20 Yuild: 86 ~ yellow oil, b p 145°C (1.5 mbar).
Example 170 ~COOCH2CH3 H=C

(E/Z)-2-Ethoxycarbonyl -1-(furan-2-yl)-4-methyl-penten-3-one.
~e A 25 747 1340 ~~~
Analogue procedure for example 1 the above mentioned compound is produced from furan-2-carbaldehyde and ethyl isobutyryl acetate.
Yield: 93 % yellow oil, bp: 130°C (0.5 mbar).
Example 171 S
CH3CH200C~COOCHZCH3 ~s il I
~N
H
Ethyl-2,6-diisopropyl-4-(thiopen-2-yl)-1,4-dihydropyridine-3,5-20 .bis-dicarboxylate.
g (0.28 mol) of the product from example 169 and 44 g (0.28 mol) ethyl-3-amino-4-methyl-pent-2-enoate were heated at 160°C
for 24 hrs. There after it was taken up in ethyl acetate, washed 25 three times with 6 N hydrochloric acid, twice with water and saturated sodium hydrogen carbonate solution, and the organic phase was dried over sodium sulphate, concentrated under vacuum, and the residue chromatographed on 400 g silica gel using petroleum ether - dichloromethane (2:1).
Yield: 50 g (46 %) colourless crystals having a melting point of 72°C (from N hexane).
Le A 25 747 . 1340~~~~
Example 172 _ S
OH OH
I ~,/~/COOCH3 H I
Methyl-erythro-(E)-7-(2,6-diisopropyl-5-methoxymethyl-4(thio-phen-2-yl)-pyridin-3-yl]-3,5-dihydroxy-kept-6-enoate.
The above mentioned product was prepared by methods analogous to examples 3, 4, 59, 6, 7, 8, 9 and 10, based on the products from example 171.
Colourless crystals, melting point: 94°C.
Example 173 HOCHZ ~ I CH20H
~N
4-(Furan-2-yl)-3.5-bis(hydroxyethyl)-2,6-diisopropyl-pyridine Le A 25 747 Based on the compound from example 170 and ethyl-3-amino-4-methyl-pent-2-enoate. The above mentioned product was prepared by methods analogous to the procedures for examples 171, 3 and 122.
Colourless crystals, melting point: 212°C.
Example 174 1 ''==''S l HOCH2~CH0 ~N
3-formyl-4-(furan-2-yl)-5-hydroxymethyl-2,6-diisopropyl-pyridine The synthesis was carried out by the method analogous to example 7 using 32 g (0.11 mol) of the product from 173 and 28.6 g (0.13 mol) pyridium chlorochromate.
Yield: 14.6 g (46 % colourless crystals, melting point: 113°C).
Example 175 HO-C
~e A 25 747 ,;,_. .
1340~r~~
Methyl-erythro-(E)-7-[4-(furan-2-ylj-5-hydroxymethyl-2,6-diiso-propyl-pyridin-3-yl]-3,5-dihydroxy-kept-6-enoate.
The a/m product was prepared by a method analogous to the procedures for examples 123, 124 and 125 on the basis of example 174.
Colourless crystals, melting point: 86 %
Example 176 Methyl-erythro-(E)-7-[2,4,6-triisopropyl-5-methoxymethyl-pyridin -3-yl]-3,5-dihydroxy-kept-6-enoate.
The a/m product was synthesised by a method analogous to the procedures from examples 171, 3, 4, 59, 6, 7, 8, 9 and 10. Using the product from 119 and ethyl-3-amino-4-methyl-pent-2-enoate.

Colourless oil Le A 25 747 OH OH

- . 1340~~

H-NMR (CDC13):? = 1.1-1.35 (m,l8H, isopropyl-H) 1.65-1.85 (m,2H, 4-H) 2.55 (d,2H,2-H), 3.2-3.45 (m,7H, isopropyl-H, OH, ~,H -0-CH2) 3,7 (m,4H, OH, COOC~~) 70 4.35 (m,lH, HO-~H) 4.45 (s,2H,CH -0-_CH ) 4.62 (m, 1H, HO-~H).5.55 (d~, 1H,6-H) 6.73 (3, 1H, 7-H) Use Example Example 177 The determination of enzyme activity was carried out as modified by G.C Ness et al., Archives of 8io-chemistry and Biophysics 197, 493 - 499 (1979). Male Rico rats (body weight 300 - 400 g) were treated for 11 days with Altromin pondered feed, to vhich 40 g of cole-styramine/kg of feed was added. After decapitation, the liver was removed from the animals and placed on ice.
The livers were comminuted and homogenized 3 times in a Potter-Elvejem hon~ogenizer in 3 volumes of 0.1 M sacc-harose, 0.05 M KCI, 0.04 M KxHy phosphate, 0.03 M
ethylenediaminetetraacetic acid, 0.002 M dithiothreitol (SPE) buffer pH T.2. The mixture gas subsequently cen-trifuged for 15 minutes at 15,000* g and the sediment rejected. The supernatant ryas sedimented for 75 minutes Le A 25 747 _~. 1340~1~~3 at 100,000 g. The pellet is taken up in 1/4 volume of SPE buffer, homogenizes once again and subsequently centrifuged again for 60 minutes at 100,000 g. The pellet is taken up using the 5-fold amount of its volume S of SPE buffer, homogenized and frozen and stored at -78°C (= enzyme solution).
For testing, the test compounds (or mevinolin as a reference substance) were dissolved in dimethylform-amide pith the addition of SX by volume of 1 N NaOH and employed in the enzyme test in various concentrations using 10 ul. The test vas started after preincubation of the compound vith the enzyme at 37cC for 20 minutes.
The test batch gas 0.380 ml and contained 4 umol of glucose-6-phosphate, 1.1 mg of bovine serum albumin, 2.1 umol of dithiothreitol, 0.35 umol of NADP, 1 unit of glucose-6-phosphate dehydrogenase 35 umol of KxHy phosphate PH 7.2, 20 ul of enzyme preparation and Sb nmol of 3x hydroxy-3-methyl-glutaryl conenzyme A (glutaryl-3-14C) 100,000 dpm.
After incubation for 60 minutes at 37°C, the batch gas centrifuged and 600 ul of the supernatant was applied to a 0.7 x 4 cm column filled with a 5-chloride 100-200 mesh (anion exchanger). It vas gashed with 2 ml of distilled water and 3 ml of a q a a s o l rr a r a a d d a d t o t h a runnings plus gashing grater and counted in the LKB scin-tillation counter. ICSO values sere determined by intrapolation by plotting the percentage inhibition against the concentration of the compound in the test.
To determine the relative inhibitory potency, the IC50 value of the reference substance mevinolin was set at 100 and compared pith the simultaneously determined IC50 value of the test compound.

For example the following relative activities have been found:
Example --_------_ - Rel. Activity (mevinolin = 100 ) 2nd Use Example Example 178 The subchronic action of the compounds according to the invention on the blood cholesterol values of dogs - 177a -~3~4p~9~
was tested in feeding experiments of several weeks dura-tion. For this, the substance to be investigated was given p.o. once daily in a capsule to healthy beagle dogs together with the feed over a period of time lasting several creeks. Colestyramine (4 g / 100 g of feed) as the gallic acid sequestrant was additionally admixed in the feed during the entire experimental period, i.e. before, during and after the administration period of the sub-stances to be investigated. Venous blood gas taken from the dogs twice meekly and the serum cholesterol was de-termined enrymatically using a commercial test kit. The ~- serum cholesterol values during the administration period were compared with the serum cholesterol values before the administration period (controls).
Thus, for example, a lowering of the serum cholesterol by about 66X resulted for the compound according to the invention Example No. 17 after adminis-tration of 8 mg/kg p.o. daily for 2 peeks.
It will be appreciated that the instant specification and claims are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of.the present invention.
Le A 25 747

Claims (33)

1. Substituted pyridines of the formula in which A stands for thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrida-zinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, each of which can be mono-substituted or disubstituted by identical or different fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or C1-C6-alkoxy-carbonyl, or A stands for phenyl or naphthyl, each of which can be monosubstituted to tetrasubstituted by identical or different C1-C6-alkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylsulphonyl, phenyl, phenyloxy, phenylthio, phenylsulphonyl, benzyl, benzyloxy, benzylthio, benzylsulphonyl, phenethyl, phenyl-ethoxy, phenylethylthio, phenylethylsulphonyl, fluorine, chlorine, bromine, or cyano, or A stands for methyl, ethyl, propyl, isopropyl, butyl or tert.butyl;

B stands for cyclopropyl, cyclopentyl or cyclohexyl, or B stands for C1-C6-alkyl which can be substituted by, fluorine, chlorine, bromine, cyano, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylsulphonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulphonyl, C1-C6-alkoxycarbonyl, benzoyl, C1-C6-alkylcarbonyl, or by a group of the formula -NR1R2, wherein R1 and R2 are identical or different and denote C1-C6-alkyl, phenyl, benzyl, acetyl, benzoyl, phenylsulphonyl or C1-C6-alkylsulphonyl, or B stands for C1-C6-alkyl which can be substituted by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyloxy, benzylthio, benzylsulphonyl, phenylethoxy, phenylethylthio or phenylethylsulphonyl, where the heteroaryl and aryl radicals mentioned can be monosubstituted or disubstituted by identical or different fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-alkoxy, trifluoromethyl or trifluoromethoxy;
E stands for unsubstituted straight-chain or branched C1-C6-alkyl; or D and E are identical or different and stand for cyclopropyl, cyclopentyl or cyclohexyl, or D and E stand for straight-chain or branched C1-C6-alkyl which is substituted by azido, fluorine, chlorine, bromine, cyano, hydroxyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylsulphonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulphonyl, C1-C6-alkoxycarbonyl, benzoyl or C1-C6-alkylcarbonyl, or by a group of the formula -NR1R2 wherein R1 and R2 have the abovementioned meaning, or D and E stand for straight-chain or branched C1-C6-alkyl which is substituted by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyloxy, benzylthio, benzylsulphonyl, phenylethoxy, phenylethylthio or phenylethyl-sulphonyl, where the heteroaryl and aryl radicals mentioned can be monosubstituted or disubstituted by identical or different fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-alkoxy, trifluoromethyl or trifluoromethoxy, or D and E stand for thienyl, furyl, thiazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, each of which can be monosubstituted or disubstituted by identical or different fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or C1-C6-alkoxycarbonyl, or D and E
stand for naphthyl which can be monosubstituted to tetra-substituted by identical or different C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylsulphonyl, phenyl, phenyloxy, phenylthio, phenylsulphonyl, benzyl, benzyloxy, benzylthio, benzylsulphonyl, phenylethyl, phenylethoxy, phenylethylthio, phenylethylsulphonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C1-C6-alkoxycarbonyl or by a group of the formula -NR1R2 wherein R1 and R2 have the abovementioned meanings, or D and E stand for a group of the formula -CR11R12-Y, wherein R11 and R12 can be identical or different and stand for hydrogen, or stand for C1-C6-alkyl which can optionally be substituted by hydroxyl, fluorine, chlorine, C1-C6-alkoxy or C1-C6-alkoxycarbonyl, or R11 and R12 stand for cyclopropyl, cyclopentyl or cyclohexyl, or R11 and R12 together form a saturated or unsaturated carbocyclic or heterocyclic ring having up to 6 carbon atoms, Y denotes a group of the formula -NR13R14, -COR15, -S-R16, SO-R16, -SO2R16, -OR17 or N3 wherein R13 and R14 are identical or different and stand for hydrogen, C1-C6-alkyl, phenyl or benzyl, where the radicals mentioned can be substituted by fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-alkoxy or trifluoromethyl, or R13 and R14 stand for a group of the formula -COR15 or -SO2R16, or R13 and R14 together form an alkylene chain which can be interrupted by O, N, S, N-C1-C6-alkyl, N-benzyl, N-phenyl, N-carbamoyl or N-C1-C6-alkoxycarbonyl, R15 denotes a group -NR18R19, or R15 denotes C1-C6-alkyl or C1-C6-alkoxy, or R15 denotes phenyl, benzyl, benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl which are optionally substituted by C1-C6-alkyl, C1-C6-alkoxy, fluorine, chlorine, bromine, trifluoro-methyl, dimethylamino or diethylamino, R16 denotes cyclopropyl, cyclopentyl, cyclohexyl, or R16 denotes straight-chain or branched C1-C6-alkyl which is optionally substituted by cyano, fluorine, chlorine, bromine, trifluoromethyl or C1-C6-alkoxycarbonyl, or R16 denotes phenyl, naphthyl, benzyl, thienyl, furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl which are optionally monosubstituted or polysubstituted by identical or different C1-C6-alkyl, C1-C6-alkoxy, fluorine, chlorine, bromine, trifluoromethyl, dimethylamino or diethylamino, or R16 denotes trimethylsilyl or dimethylethylsilyl, or R16 denotes a group -NR9R10 wherein R9 and R10 are identical or different and denote hydrogen, C1-C6-alkyl or phenyl, or R9 and R10 denote a heterocyclic ring from the series comprising pyrrolidine, piperidine, piperazine, N-alkylpiperazine, N-arylpiperazine, N-benzylpiperazine, N-carbamoylpiperazine or N-alkoxycarbonylpiperazine, R17 stands for hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or R17 stands for C1-C6-alkyl which can be substituted by fluorine, chlorine, bromine, cyano, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylsulphonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulphonyl, C1-C6-alkoxy-carbonyl, benzoyl, C1-C6-alkylcarbonyl, or by a group of the formula -NR1R2 wherein R1 and R2 have the abovementioned meaning, or R17 stands for C1-C6-alkyl which can be substituted by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, iso-quinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenyl-sulphonyl, benzyloxy, benzylthio, benzylsulphonyl, phenyl-ethoxy, phenylethylthio or phenylethylsulphonyl, where the heteroaryl and aryl radicals mentioned can be monosubstituted or disubstituted by identical or different fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-alkoxy, trifluoromethyl or trifluoromethoxy, or R17 stands for thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, iso-quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, each of which can be monosubstituted or disubstituted by identical or different fluorine, chlorine, bromine, C1-C6-alkyl, C1-C6-alkoxy, phenyl, phenyloxy, trifluoromethyl, trifluoromethoxy or C1-C6-alkoxycarbonyl, or R17 stands for benzyl, phenyl or naphthyl, each of which can be monosubstituted to tetrasubstituted by identical or different C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylsulphonyl, phenyl, phenyloxy, phenylthio, phenylsulphonyl, benzyl, benzyloxy, benzylthio, benzylsulphonyl, phenylethyl, phenylethoxy, phenylethylthio, phenylethylsulphonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C1-C6-alkoxycarbonyl or by a group of the formula -NR1R2 wherein R1 and R2 have the abovementioned meaning, or R17 stands for
2,5-dioxo-tetrahydropyrryl, tetrahydropyranyl, dimethyl-tert.-butylsilyl, tripropylsilyl or tributylsilyl, or R17 denotes a group of the formula COR16 wherein R16 has the abovementioned meaning, and R18 and R19 are identical or different and denote hydrogen, or R18 and R19 denote C1-C6-alkyl which is optionally substituted by cyano, fluorine, chlorine or bromine, or R18 and R19 denote phenyl, benzyl, thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl which are optionally substituted by C1-C6-alkyl, C1-C6-alkoxy, fluorine, chlorine, bromine, trifluoromethyl, dimethylamino or diethylamino, or D and E together form a ring of the formula wherein W stands for a group of the formula C=O or stands for CH-OH, m stands for a number 1 or 2, Z stands for O, CH2 or NHR20, R13 and R14 have the abovementioned meaning, and R20 stands for hydrogen, C1-C6-alkyl, phenyl, benzyl, carbamoyl or C1-C6-alkoxycarbonyl, X stands for a group of the formula -CH=CH-, R stands for a group of the formula wherein R21 denotes hydrogen or C1-C6-alkyl, and R22 denotes hydrogen, C1-C6-alkyl, phenyl or benzyl, or denotes a cation, and their oxidation products.
2. Substituted pyridines according to claim 1, wherein A stands for thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl, each of which can be substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or A
stands for phenyl which can be monosubstituted, disubstituted or trisubstituted by identical or different methyl, hydroxy-methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, butyl, isobutyl, methoxymethyl, ethoxymethyl, propoxymethyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, phenyl, phenoxy, benzyl, benzyloxy, fluorine, chlorine, bromine or cyano, or A stands for methyl, ethyl, propyl, isopropyl, butyl or tert.butyl, B stands for cyclopropyl, cyclopentyl or cyclohexyl, or B stands for methyl, ethyl, propyl, isopropyl, butyl, sec.butyl or tert.butyl, each of which can be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.butoxy, tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyloxy, benzylthio or benzylsulphonyl, E stands for unsubstituted straight-chain or branched C1-C6-alkyl; or D and E are identical or different and stand for cyclopropyl, cyclopentyl or cyclohexyl, or D and E stand for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, each of which is substituted by azido, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl, isobutylsulphonyl, tert.butylsulphonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl, or by a group -NR1R2 wherein R1 and R2 are identical or different and denote methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, phenyl, benzyl, acetyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropyl-sulphonyl or phenylsulphonyl, or D and E stand for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl which is substituted by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyloxy, benzylthio or benzylsulphonyl, where the heteroaryl and aryl radicals mentioned can be substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, isobutyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, trifluoromethyl or trifluoromethoxy, or D and E stand for thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, tetrazolyl, pyridazinyl, oxazolyl, iscoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzthiazolyl, where the radicals mentioned can be substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxy-carbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert.butoxycarbonyl, or D and E stand for a group of the formula -CR11R12-Y wherein R11 and R12 are identical or different and stand for hydrogen, or R11 and R12 stand for methyl, ethyl, propyl or isopropyl which can optionally be substituted by hydroxyl, fluorine, chlorine, methoxy, ethoxy, methoxycarbonyl or ethoxycarbonyl, or R11 and R12 stand for cyclopropyl, cyclopentyl or cyclohexyl, or R11 and R12 together stand for cyclopropyl, cyclopentyl or cyclo-hexyl, and Y denotes a group of the formula -NR13R14, -COR15, -SR16, -SO-R16, -SO2R16, -OR17 or -N3, wherein R13 and R14 are identical or different, and stand for hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or R13 and R14 stand for phenyl which is optionally substituted by fluorine, chlorine, methyl or methoxy, or R13 and R14 stand for a group -COR15 or -SO2R16, or R13 and R14 together with the nitrogen atom form a ring from the series comprising piperidine, piperazine, morpholine, morpholine-N-oxide, N-lower alkyl-piperazine, benzylpiperazine or phenylpiperazine, R15 denotes a group -NR18R19, or R15 denotes methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, or R15 denotes phenyl, benzyl, benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl which are optionally substituted by methyl, methoxy, fluorine or chlorine, R16 denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl or isopentyl which are optionally substituted by fluorine, chlorine, methoxycarbonyl, ethoxycarbonyl, propoxy-carbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxy-carbonyl, or R16 denotes benzyl, phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl which are optionally monosubstituted or polysubstituted by identical or different methyl, ethyl, propyl, isopropyl, methoxy, fluorine or chlorine, or R16 denotes trimethylsilyl or dimethylethylsilyl, or R16 denotes a group -NR9R10 wherein R9 and R10 are identical or different and denote hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or phenyl, or R9 and R10 denote a heterocyclic ring of the series comprising piperidine, N-methylpiperazine, N-ethylpiperazine or N-benzylpiperazine, R17 stands for hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or R17 stands for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, each of which can be substituted by fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, methylthio;
ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio, methylsulphonyl, ethylsulphonyl, propyl-sulphonyl, isopropylsulphonyl, butylsulphonyl, isobutyl-sulphonyl, tert.butylsulphonyl, trifluoromethyl, trifluoro-methoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.-butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl, or by a group -NR1R2 wherein R1 and R2 are identical or different and denote methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, phenyl, benzyl, acetyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl or phenylsulphonyl, or R17 stands for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl which can be substituted by pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyloxy, benzylthio or benzylsulphonyl, where the heteroaryl and aryl radicals mentioned can be substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, isobutyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, trifluoromethyl or trifluoromethoxy, or R17 stands for thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzthiazolyl, where the radicals mentioned can be substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxy-carbonyl, butoxycarbonyl, isobutoxycarbonyl or tert.butoxy-carbonyl, or R17 stands for benzyl or phenyl, each of which can be monosubstituted, disubstituted or trisubstituted by identical or different methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert.butylthio, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butyl-sulphonyl, isobutylsulphonyl, tert.butylsulphonyl, phenyl, phenoxy, phenylthio, phenylsulphonyl, benzyl, benzyloxy, benzylthio, benzylsulphonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy-carbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxy-carbonyl or by a group -NR1R2 wherein R1 and R2 have the abovementioned meaning, or R17 stands for 2,5-dioxo-tetra-hydropyrryl, tetrahydropyranyl, dimethyl tert.butylsilyl or trimethylsilyl, or R17 denotes a group -COR16, wherein R16 has the abovementioned meaning, and R18 and R19 are identical or different and denote hydrogen, or R18 and R19 denote methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl or isohexyl which are optionally substituted by fluorine or chlorine, or R18 and R19 denote phenyl which can optionally be substituted by fluorine, chlorine, methyl or methoxy, or D and E together form a ring of the formula wherein R20 stands for hydrogen, methyl, ethyl, propyl, isopropyl, carbamoyl, methoxycarbonyl or ethoxycarbonyl, X stands for a group of the formula -CH=CH-, R stands for a group of the formula wherein R21 denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.butyl, and R22 denotes hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl or benzyl, or a sodium, potassium, calcium, or magnesium or ammonium ion, and their oxidation products.
3. Substituted pyridines according to claim 1, wherein A stands for thienyl or furyl, or A stands for phenyl which can be monosubstituted or disubstituted by identical or different methyl, hydroxymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, methoxy, ethoxy, propoxy, isopropoxy, phenoxy, benzyloxy, fluorine, chlorine or trifluoromethyl, or A stands for methyl, ethyl, propyl or isopropyl, B stands for cyclopropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.butyl, each of which can be substituted by fluorine, chlorine, methoxy, phenyl or phenoxy, E stands for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, or D and E are identical or different and stand for cyclopropyl, cyclopentyl or cyclohexyl, or D and E stand for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, each of which is substituted by azido, fluorine, chlorine, iodine, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, methylsulphonyl, ethylsulphonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or by a group of the formula NR1R2, where R1 and R2 are identical or different and stand for methyl, ethyl, propyl, isopropyl, phenyl or benzyl, or by pyridyl, pyrimidyl, quinolyl, thienyl, furyl, phenyl, phenoxy, phenylsulphonyl or benzyloxy which are optionally substituted by fluorine, chlorine, methyl, methoxy, trifluoromethyl or trifluoromethoxy, or D and E stand for thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzoxazolyl, tetrazolyl, benzthiazolyl or benzimidazolyl which are optionally substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, phenyl, methoxycarbonyl or ethoxycarbonyl, or D and E stand for a group of the formula -CR11R12-y wherein R11 and R12 denote hydrogen, methyl or ethyl, and Y denotes a group of the formula -NR13R14, -COR15, -S-R16-, -SO-R16, -SO2R16 or -OR17, where R13 and R14 are identical or different, and stand for hydrogen, methyl, ethyl, propyl, or stand for a group -COR15 or -SO2R16 or R13 and R14, together with the nitrogen atom, form a ring from the series comprising morpholine or morpholine N-oxide, and R15 denotes a group -NR18R19, or R15 denotes methyl, ethyl, propyl, methoxy or ethoxy, R16 denotes trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl or benzyl, or R16 denotes phenyl or naphthyl which is optionally substituted by one or more methyl or chlorine, or R16 denotes trimethylsilyl or dimethylethylsilyl, or R16 denotes a group -NR9R10, where R9 and R10 are identical or different and denote hydrogen, methyl, ethyl, propyl or phenyl, R17 stands for hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or R17 stands for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, each of which can be substituted by fluorine, chlorine, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, methylsulphonyl, ethylsulphonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or by a group of the formula NR1R2, where R1 and R2 are identical or different and stand for methyl, ethyl, propyl, isopropyl, phenyl or benzyl, or R17 stands for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, hexyl or isohexyl, each of which is substituted by pyridyl, pyrimidyl, quinolyl, thienyl, furyl, phenyl, phenoxy, phenylsulphonyl or benzyloxy, which are optionally substituted by fluorine, chlorine, methyl, methoxy, trifluoromethyl or trifluoromethoxy, or R17 stands for thienyl, furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzoxazolyl, benzthiazolyl or benzimidazolyl which are optionally substituted by fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, phenyl, methoxycarbonyl or ethoxycarbonyl, or R17 stands for benzyl or phenyl, each of which can be monosubstituted or disubstituted by identical or different methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butoxy, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, methylsulphonyl, ethylsulphonyl, phenyl, phenoxy, phenylsulphonyl, benzyloxy, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl or a group of the formula -NR1R2, where R1 and R2 have the abovementioned meaning, or R17 stands for 2,5-dioxo-tetrahydropyrryl, tetrahydropyranyl, dimethyl-tert.butylsilyl or trimethylsilyl, or R17 denotes a group -COR16, where R16 has the abovementioned meaning, and R18 and R19 are identical or different and denote hydrogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, or phenyl, or D and E together form a ring of the formula X stands for a group of the formula and R stands for a group of the formula wherein R21 denotes hydrogen and R22 denotes hydrogen, methyl or ethyl, or a sodium or potassium ion and their oxidation products.
4. A substituted pyridine of the formula in which B and E are C1-3alkyl or one of B and E is cyclopropyl, Y-Q- is CH3O-, (H3C)3C(CH3)2-Si-O-, , C2H5O-, C3H7O-i-C3H7O-, C4H9O-, C5H11-, C6H13O- or and R22 is hydrogen, lower alkyl, phenyl, benzyl or a physiologically tolerable metal or ammonium cation.
5. The compound methyl erythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-methoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.
6. The compound methyl erythro-(E)-7-[5-tert.-butyl-dimethylsiloxymethyl-4-(4-fluorophenyl)-2-isopropyl-6-methyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.
7. The compound methyl erythro-(E)-7-[3-benzyloxymethyl-4-(4-fluorophenyl)-6-isopropyl-2-methyl-pyrid-5-yl]-3,5-dihydroxy-hept-6-enoate.
8. The compound methyl erythro-(E)-7-[5-tert.butyl-dimethylsilyloxymethyl-2,6-dimethyl-4-(4-fluorophenyl)-pyrid-3-yl)-3,5-dihydroxy-hept-6-enoate.
9. The compound methyl erythro-(E)-7-[6-cyclopropyl-2-isopropyl-4-(4-fluorophenyl)-5-methoxymethyl-pyrid-3-yl)-3,5-dihydroxy-hept-6-enoate.
10. The compound methyl erythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-phenoxymethyl-pyrid-3-yl)-3,5-dihydroxy-hept-6-enoate.
11. The compound methyl erythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-carboxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.
12. The compound methyl erythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-benzothiomethyl-pyrid-3-yl)-3,5-dihydroxy-hept-6-enoate.
13. The compound methyl erythro-(E)-7-[2,6-diisopropyl-5-ethoxymethyl -4-(4-fluorophenyl)-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.
14. The compound methyl erythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-propyloxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.
15. The compound methyl erythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-isopropoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.
16. The compound methyl erythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-butyloxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.
17. The compound methyl erythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyloxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.
18. The compound methyl erythro-(E)-7-[2,6-diisopropyl-4-(4-fluorophenyl)-5-hexyloxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.
19. The compound methyl erythro-(E)-7-[2,6-diisopropyl-3-(4-fluorobenzyloxymethyl)-4-(4-fluorophenyl)pyrid-5-yl]-3,5-dihydroxy-hept-6-enoate.
20. Substituted pyridines according to any one of claims 1 to 19, for therapeutic use for inhibiting HMG-CoA
reductase, for inhibiting cholesterol biosynthesis or for the treatment of hyperlipoproteinaemia, lipoproteinaemia or arteriosclerosis.
21. A process for the preparation of a substituted pyridine of the formula in which A, B, D, E, X and R are as defined in any one of claims 1 to 4, or an oxidation product thereof, characterized in that a ketone of general formula (VIII) in which A, B, D and E have the abovementioned meaning and R23 stands for alkyl, is reduced, in the case of the preparation of acids esters are hydrolyzed, in the case of the preparation of lactones carboxylic acids are cyclized, in the case of the preparation of salts either esters or lactones are hydrolyzed, in the case of the preparation of ethylene compounds (X = -CH2-CH2-) ethene compounds (X = -CH=CH-) are hydrogenated.
22. A process according to claim 21, characterized in that the reduction is carried out in the temperature range from -80°C to +30°C.
23. Ketones of the formula (VIII) in which A, H, D and E are as defined in claim 1 or 2, and R23 is alkyl, and their oxidation products.
24. Process for the preparation of ketones of the formula (VIII) in which A, B, D, E and R23 are as defined in claim 23, which is characterized in that an aldehyde of the general formula (IX) in which A, B, D and E have the abovementioned meaning, is reacted in inert solvent with an acetoacetate of the general formula (X) in which R23 has the abovementioned meaning, in the presence of a base.
25. Process according to claim 24, characterized in that the reaction is carried out in the temperature range from -80°C
to +50°C.
26. A medicament containing a substituted pyridine according to any one of claims 1 to 19, for inhibiting HMG-CoA
reductase, for inhibiting cholesterol biosynthesis or for the treatment of hyperlipoproteinaemia, lipoproteinaemia or arteriosclerosis.
27. A medicament according to claim 26, containing 0.5 to 98% by weight of substituted pyridine.
28. Use of a substituted pyridine according to any one of claims 1 to 19, for the preparation of a medicament for inhibiting HMG-CoA reductase, for inhibiting cholesterol biosynthesis or for the treatment of hyperlipoproteinaemia, lipoproteinaemia or arteriosclerosis.
29. Use according to claim 28, for the preparation of cholesterol biosynthesis inhibitors and HMG-CoA reductase inhibitors.
30. Use according to claim 29, for the treatment of hyperlipoproteinaemia, lipoproteinaemia cr arteriosclerosis.
31. Use of a substituted pyridine according to any one of claims 1 to 19, for inhibiting HMG-CoA reductase, for inhibiting cholesterol biosynthesis or for the treatment of hyperlipoproteinaemia, lipoproteinaemia or arteriosclerosis
32. A process for preparing a medicament for inhibiting HMG-CoA reductase, for inhibiting cholesterol biosynthesis or for the treatment of hyperlipoproteinaemia, lipoproteinaemia or arteriosclerosis, in ready-to-use drug form, which process comprises admixing a substituted pyridine according to any one of claims 1 to 19, with a suitable diluent or carrier.
33. A commercial package containing as active pharmaceutical ingredient, a substituted pyridine as defined in any one of claims 1 to 19, together with instructions for the use thereof for inhibiting HMG-CoA reductase, for inhibiting cholesterol biosynthesis or for the treatment of hyperlipoproteinaemia, lipoproteinaemia or arteriosclerosis.
CA000588502A 1988-01-20 1989-01-18 Disubstituted pyridines Expired - Fee Related CA1340798C (en)

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DE3801406A DE3801406A1 (en) 1988-01-20 1988-01-20 Substituted pyridines
DEP3801406.8 1988-01-20
IT8821317A IT8821317A0 (en) 1988-07-11 1988-07-11 SUBSTITUTED PYRIDINES.
IT21317/A88 1988-07-11

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