CA2304274A1 - Benzyl-biphenyls and analogous compounds and the application thereof in order to treat arteriosclerosis and dyslipidaemia - Google Patents
Benzyl-biphenyls and analogous compounds and the application thereof in order to treat arteriosclerosis and dyslipidaemia Download PDFInfo
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- 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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Abstract
The invention relates to benzyl-biphenyls and analogous compounds thereof which are produced first by reacting .alpha. and .beta.-unsaturated ketones to form corresponding substituted and conjugated dienes, and afterwards said dienes are cyclized with acetylene derivatives. The resulting cyclohexane dienes are oxidized to form aromatic compounds and/or are varied in available substituents through usual methods. The compounds are suited for additives in medicaments, especially in medicaments for treating arteriosclerosis and dyslipidaemia.
Description
Ix A 32 664-Forei Countries Sto/li/vos/NT
Benzvl-biphenvls and analogous compounds The present rove;ntion relates to benzyl-biphenyls and analogous compounds, to processes for their preparation and to their use in medicaments.
The publication US-5 169 857-A2 discloses 7-(polysubstituted pyridyl)-6-heptenoates for treating arteriosclerosis, lipoproteinaemia and hyperproteinaemia.
Moreover, the preparation of 7-(4-aryl-3-pyridyl)-3,5-dihydroxy-6-heptenoates is described in the publication EP-325 130-A2.
The present invention relates to benzyl-biphenyls and analogous compounds of the general formula (1_), A
p \ / Ri i \ I 2 (1), E R
in which A represents cycloalkyl having 3 to 8 carbon atoms, or represents aryl having 6 to 10 carbon atoms, or represents a 5- to 7-membered, saturated, partially unsaturated or unsaturated, optionally benzo-fused heterocycle having up to 4 heteroatoms from the group con<.~isting of S, N and O, where aryl and the abovementioned heterocyclic ring systems are optionally substituteCi up to 5 times by identical or different substituents from the group consisting of cyano, halogen, vitro, carboxyl, hydroxyl, trifluoromethyl, Le A 32 664-Foreign Countries trifluorom~ethoxy oar by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxyca~rbonyl, oxyalkoxycarbonyl or alkoxy having in each case up to 7 carbon atonns, or by a group of the formula -NR3R4 in which R3 and R4 are idlentical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, D represents a radical of the formula R~ Ra RS-k- , R6~~ or R9-T-V-X-in which R5, R6 and R9 independently of one another represent aryl having 6 to 10 carbon atoms or a 5- to 7-membered, optionally benzo-fused, saturated or unsaturated, mono-, bi- or tricyclic heaerocycle having up to 4 heteroatoms from the group consisting of S, N and O, where the cycles, optionally, in the case of the nitrogen-containing rin;~s also via the N function, are substituted up to 5 times by identical or different substituents from the group consisting of halogen, trifluoromethyl, vitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryl having in each case 6 to 10 carbon atoms or b:y an optionally benzo-fused, aromatic 5- to 7-membered Le A 32 664-Forei r~ountries heterocycle having up to 3 heteroatoms from the group consisting of S, :'V and O, ancUor by a group of the formula -ORS°, -SR~1, -SOZR~2 or -NR~3R'4, in which R'°, R'1 and R12 independently of one another represent aryl having to 10 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, halogen, or by straight-chain or branched alkyll having up to 6 carbon atoms, R'' and R14 are identical or different and have the meaning of R3 and R4 given above, or R5 andlor R6 represent a radical of the formula ~ ~ ~- O~ F
or , - \ ~ O F FsC O
R' represents hydrogen, halogen or methyl, and Rg represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromet:hoxy, straight-chain or branched alkoxy or alkyl having in each case up to 6 carbon atoms or a radical of the formula -NR~SR~6 Le A 32 664-Fore:i Countries in which R~~' and RAE' are identical or different and have the meaning of R3 and R4 given above, or R' and R$ together form a :radical of the formula =O or =NR1~
in which R" represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 6 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 8 carbon atoms which are optionally substituted up to 2 times by hydroxyl, T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 8 carbon atoms, or T or X represent a bond, V represents .an oxygen or sulphur atom or represents an -NR~B- group in which Le A 32 664-Fomign Countries R~g represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, E represents, cycloalhyl having 3 to 8 carbon atoms, or represents straight--chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or hydroxyl, or represents phenyl which is optionally substituted by halogen or trifluorom~ethyl, R1 represents straight-chain or branched alkyl having up to 6 carbon atoms which is substituted by hydroxyl or by a group of the formula --O O
RZ represents hydrogen or represents straight-chain or branched alkyl or alkenyl having in each case: up to 8 carbon atoms, which are optionally substituted by hydroxyl, halogen, phenyl, cycloalkyl having 3 to 6 carbon atoms or by a group of the formula O N O
-O-R ~ '~
O N O
or Le A 32 664-Fore:i Countries in which R'9 represents a radical of the formula -Si(CH3)2C(CH3)3, or represents straight-chain or branched alkyl having up to 6 carbon atoms, or represents a 5- to ;~-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, or represents phenyl or benzyl, where all ring systems listed under R19 are optionally substituted up to 2 times by identical or different substituents from the group consisting of trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or b;y straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, and their salts.
The compounds according, to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, preference is given to physiologically acceptable salts. F'hysiolog;ically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methaneaulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, malefic acid or benzoic acid.
Le A 32 664-Forei n~Countries Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
Particular preference, is given, for example, to sodium, potassium, magnesium of calcium salts, and also to ammonium salts, which are derived from ammonia, or organic amines, such as, for example, e;thylamine, di-or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The compounds according; to the invention can exist in stereoisomeric forms which are either like image and mirror image (enantiomers), or which are not like image and mirror image (diastereom~ers). The invention relates both to the enantiomers or diastereomers anci to their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform components IS in a manner known per se.
In the context of the invention, a heterocycle, optionally benzo-fused, generally represents a saturated, partially unsaturated or unsaturated 5- to 7-membered, preferably 5- to E.-membered, heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N and O. Examples which may be mentioned are:
indolyl, isoquinol:yl, quinolyl, benzo[b]thiophene, benzo[b]furanyl, pytidyl, thienyl, furyl, pyrrolyl, thi;izolyl, o:~cazolyl, imidazolyl, morpholinyl or piperidyl.
Preference is given to quinolyl, furyl, pyridyl and thienyl.
Preference is given to the: compounds of the general formula (I) according to the invention in which A represents napththyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or morpholinf; which are optionally substituted up to 2 times by identical or Le A 32 664-Fore:i Countries _g_ different substituents from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, or alkoxy having in each case up to 6 carbon atoms, D represents phenyl which is optionally substituted by nitro, fluorine, chlorine, bromine, pfienyl, trifluoromethyl or trifluoromethoxy, or represents a radical of the formula R~ Ra s R -L- ~ Rs'~ or R9-T-V-X- , in which R5, R~ and R9 independently of one another represent phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phe.noxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl, where the cycles, optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, are substituted by identical or different sul'~stituents from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifl.uoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alk:ylalkoxy., alkoxy or alkoxycarbonyl having in each case up to 4 c~~rbon atoms, triazolyl, tetrazolyl, bezoxathiazolyl, or trifluoromethyl-substituted phenyl or phenyl, and/or are substituted by a group of the formula -OR'°, -SR" or -SOZR' z Le A 32 664-Foreign Countries in which R1°, R" and R'2 are identical or different and represent phenyl which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, fluorine, chlorine, or by straight-chain or branched alkyl having up to 4 caJrbon atoms, or RS and/or R6 represent a radical of the formula ~O~F
/' or F3C p R' represents hydrogen, fluorine, chlorine or bromine, and R8 represents hydrogen, fluorine, chlorine, bromine, azido, trio uoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 5 carbon atoms or a radical of the formula -NR~SRIG
in which R~5 and R'6 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atones, Le A 32 664-Forei n Countries or R' and R8 togethe;r form a radical of the formula =O or =NR'7 in which R" represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 6 carbon atoms, which are optionally substituted up to 2 times by hydroxyl, T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 6 carbon atoms, or T or X represents a bond, V represents an oxy~;en or sulphur atom or represents a group of the formula -NR ~ g-in which R~8 represents Izydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or Le A 32 664-Forc:i Countries represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by cyclopropyl, -butyl, -hexyl, -pentyl, -heptyl or by hydroxyl, or represents phenyl which is optionally substituted by fluorine, chlorine, or trifluoromethyl, Rl represents a group of the formula -CHZOH or -CH2 O~ O~
RZ represents hydrogen or represents straight-chain or branched alkyl or alkenyl having in each case up to 6 carbon atoms which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohe:xylor by a group of the formula N
O O O N O
_O_Ri s~
O N O
or in which R'9 represents a radical of the formula -Si(CH3)ZC(CH3)3 or Le A 32 664-Fore~n Countries represents straight-chain or branched alkyl having up to S carbon atoms, or represents tetrahydropyranyl, pyridyl, phenyl or benzyl which are optionally substituted up to 2 times by identical or different substituents~ from the group consisting of trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl haring in each case up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl, and their salts.
Particular preference is given to compounds of the general formula (I) according to the invention in which A represents phenyl or pyridyl which are optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, D represents phenyl which is optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or represents a radical of the formula R~ Rs RS-L- , R6'' \ or R9-T-V-X- , in which Le A 32 664-Forei Countries R5, R6 and R9 independently of one another represent phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl, where the cycles, optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, are substituted by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl-substituted phenyl or phenyl ancl/or are substituted by a group of the formula -OR'°, -SR" or -St~zR' Z
in which R"', R" and R'z are identical or different and represent phenyl which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, fluorine, chlorine, or by straight-chain or branched alkyl having up to 3 carbon atoms, or RS and/or R6 represent a radical of the formula Le A 32 664-Forei,.nytries ,O
F or ~' O F FsC O
R' represents hydrogen or fluorine, and Rg represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain or branched allkoxy or alkyl having in each case up to 4 carbon atoms or a radical of 'the formula -NR~SR~~
in which R~5 and R~6 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or R' and Rg ~:ogether form a radical of the formula =O or =NR", in which R" represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 5 carbon atoms, which are optionally substituted up to 2 times by hydroxyl, Le A 32 664-Forei Countries T and X .are identical or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms, or S
T or X represents a bond, V represents an oxygen or sulphur atom or represents a group of the formula -NRIB
in which R~g represents hydrogen or straight-chain or branched alkyl having up t:o 3 carbon atoms, >; represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl which is optionally substituted by fluorine or trifluoromethyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, R' represents a group of the formula -CHZOH or -CH2 O~ O~
R2 represents hydrogen or represents straight-chain or branched alkyl or alk.enyl having in each case up to S carbon atoms which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine, bromine, T Le A 32 664-Foreign Countries cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or by a group of the fonmula O N O
-O-R~ '' O N O
or in vvhich R'9 represents straight-chain or branched alkyl having up to 4 carbon atoms, or represents a radical of the formula Si(CH3)ZC(CH3)3 or represents tetrahydropyranyl, pyridyl, phenyl or benzyl, which are optionally substituted up to 2 times by identical or different substituents from the group consisting of trifluoromethyl, fluorine, chlorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl and their salts.
Le A 32 664-Fore~i ngn Countries Very particular :preferen<:e is given to compounds of the general formula (I) according to the invention A represents phenyl, fluorine, chlorine, bromine, trifluoromethyl, D represents a radical of the formula R~ Rs R5-L- or Rs'~ , in which R5, R6 and R9 independently of one another represent phenyl, which is optionally substituted up to 3 times by identical or different substituents from the group consisting of fluorine, chlorine and trifluoromethyl, R' represents hydrogen or fluorine, and Rg rep~~esents hydrogen, fluorine, chlorine, bromine or alkyl having in each case up to 4 carbon atoms or R' and Rg Together form a radical of the formula =O or =NR"
Le A 32 664-Fore:i Countries in which Rr~ repre;sents hydrogen or straight-chain or branched alkyl, alkoxy or ac:yl having in each case up to 4 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 5 carbon atoms which are optionally substituted up to 2 times by hydroxyl, T and X aJ~e identical or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms, or T or X represent a frond, V represents an oxygen or sulphur atom or represents a group of the forrnula -NR;'g in which Rrg represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, E represents c;yclopropyl, cyclopentyl or cyclohexyl or phenyl which is optionally substituted by fluor7ne or tr-ifluoromethyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms, Rr represents a group of the formula -CHZOH or Le A 32 664-Foreign Countries -CH2 O ~O~
R2 represents hydroge;n or represents straight-chain or branched alkyl or alkenyl having in each case up to 5 carbon atoms which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobuty:l, cyclohc~xyl or by a group of the formula i O N O
_~~_R~s O N O
or in which R'9 represents straight-chain or branched alkyl having up to 4 carbon atoms, or represents a radical of the formula -Si(CH~)ZC(CH~)3, or represents tetrahydropyranyl, pyridyl, phenyl or benzyl, which are optionally substituted up to 2 times by identical or different substituenta from the group consisting of trifluoromethyl, fluorine, chlorine, vitro, hydroxyl, straight-chain or branched alkoxy or Le A 32 664-Foreign Countries alkoxycarbonyl having in each case up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl, and their salts.
Moreover, processes for prepar7ng the compounds of the general formula (I) according to the invention have been found, which are characterized in that compounds of the general formula (II) A
D
(II) E O
in which A, D and E are as defined above are, in the system (C6:H5)3PCH3Br/n-butyllithium, initially converted into the compounds of the: general formula (III) A
D
(III) E
in which A, D and E are as defined above, Le A 32 664-Fore:i ng-Countries subsequently, wit',h compounds of the general formula (N) or (IVa) R2°-02C C02R2° (IV) R2' C02R2°~~ (IVa) in which R2°, R2°~ and R2°~~ are identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms and RZ' represents hydrogen or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, phenyl, straight-chain or branched alkoxy having up to 6 carbon atoms, amino, alkyl-or dialkyla.mines having up to 4 carbon atoms in the alkyl moiety, converted into the compounds of the general formula (V) A
D C02R2°", ( E R2z in which A, D and E are as defined above, RZ°~" includes the abovementioned scope of the meaning of RZ° and RZOw, Ix A 32 664-Fore:i Countries and R22 either represents hydrogen or represents the radical -C02R2°", or includes the abovernentioned scope of the meaning of R2y by oxidation, the compounds of the general formula (VI) A
D ~ C02R2°"' (vl) I. ~ R22 to in which A, D, E, R2, RZ°"' and RzZ are as defined above are prepared, and subsequently ~.he carbomyl functions are reduced to the hydroxymethyl function, and derivatization on the s~abstituent R2 is carried out by, starting from compounds of the general formula (Ia) A
D CH-O OJ
w ~ z (la) E
in which Le A 32 664-Foreign Countries A, D and E are as defined above, reacting, depending on the abovementioned meaning of R2, in the system P(C6H5)3/ethyl diethylazo~dicarboxylate and the corresponding amines or alcohols defined under R~9, or carrying out an etherification by reaction with alkyl halides in the presence of a base, and subsequently eliminating in the two derivatizations the hydroxyl-protective group with acids, or, in the case where R2 = alkenyl, initially converting the compounds of the general formula (Ia) into the aldeh:ydes of the general formula (VII) A
D CH-O OJ
z i ~ (VII) E CHO
in which A, D and E are as defined .above and, in a further svtep, camping out a Wittig reaction according to customary methods, eliminating the hydroxyl-protective group as described above and subsequently, by hydrogenation in the presence of a catalyst, reducing to the corresponding alkyl compounds (RZ = alkyl).
Le A 32 664-Forei Countries The process according to the invention can be illustrated in an exemplary manner by the following scheme:
Ph3PCH3Br nBul_i, THF
FaC F
~C02CH3 H
xylene, 140°C
F
LiAIH4 OH
Le A 32 664-Foreign Countries 1. NaH, TBAI, Br-(CHZ)2CH(CH3)2 2. H+
1. PPh3, DEAD, C6H5( ' 2. H+
F
1. PPh3, DEAD, O
HN' ~O
2. H' PCC, AI203 O
F N
O
P 1. W ittig 2. PPTA, MeOH
F3C 1 FsC
H2, PUC
F
Le A 32 664-Forei Countries Suitable solvents for the reaction step (II) ~ (III) are ethers such as diethyl ether, dioxane, tetrahyd:rofuran, ,glycol dimethyl ether. It is also possible to use mixtures of the solvents mentioned. Preference is given to diethyl ether.
Suitable bases far the reaction step (II) -> (III) are the customary strongly basic compounds. These preferably include organolithium compounds such as, for example, N-butyillithium, sec-butyllithium, ten butyullithium or phenyllithium or amides such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithiurr~ hexameahylsilylamide, or alkali metal hydrides, such as sodium hydride or potassium hydride. Particular preference is given to N-butyllithium.
The base is generally employed in an amount of from 1 mol to 2 mol, preferably from 1.05 mol to 1.2 mol, based. on 1 mol of the compounds of the general formula (II).
The reaction generally proceeds at a temperature of from -30°C to room temperature, preferably from -20°C to 0~°C.
The reaction generally proceeds at atmospheric pressure; however, it is also possible to operate under elevated or reduced pressure.
Suitable solvents for prep~u-ing the compounds of the general formula (V) according to the invention a.re hydrocarbons such as benzene, toluene, xylene, chlorobenzene, ethyl benzoate, de~calin, be:nzonitrile, hexane, cyclohexane or mineral oil fractions. It is also possible t~~ use mixtures of the solvents mentioned. Preference is given to xylene.
The reaction can .also be carried out without solvent, or the solvent used can be the alkine.
The reaction generally proceeds at a temperature of from -30°C to +250, preferably of from 80°C to 1.80°C.
Le A 32 664-Foreign Countries The reaction generally proceeds at atmospheric pressure; however, it is also possible to operate under elevated or reduced pressure.
The reaction generally proceeds without catalyst; however, it is also possible to use Lewis acids as catalysts. Examples which may be mentioned are: BF3, BF3 x OEt2, A1C13, TiCl4, Al(CH3)3, A1(C2H5)3, (CzHs)2A1C1, MgCl2, ZnCl2 and BCl3.
Suitable solvents for the oxidation are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichloromethane:> tr~ichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene., chlorobenzene, ethyl acetate, dimethyl sulphoxide, dimethylformamide, hey;amethylphosphoric triamide, acetonitr-ile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned.
Preference is given to toluene.
Suitable oxidizing agents are, for example, potassium permanganate, bromine, cerium (IV) ammonium nitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate on basic alumina, osmium tetroxide, sodium acetate;/iodine and manganese dioxide. Preference is given to 2,3-dichloro-5,6-dicyano-benzoquinone.
The oxidizing agent is employed in an amount of from 1 mol to 10 mol, preferably from 2 mol to 5 mol, based on 1 mol of the compounds of the general formula (V).
The oxidation generally proceeds in a temperature range of from 0°C to +100°C, preferably from room temperature to 80°C.
The oxidiation generally proceeds at atmospheric pressure. However, it is also possible to carry out the o;Kidation under elevated or reduced pressure.
Le A 32 664-Fore:i~Qrr Countries Suitable solvents i~or the reduction are the hydrocarbons listed above, and preference is given to toluene.
The reduction of the compounds of the general formula (VI) is generally carried out using reducing agents, preferably those which are suitable for reducing alkoxycarbonyl to hydroxyl compounds. Particularly suitable here is the reduction with metal hydrid<a or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out using complex .
metal hydrides such as, 'for example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylborohydride, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is very particularly prefer~~bly carnied out using diisobutylaluminium hydride.
The reducing agent is generally employed in an amount of from 1 mol to 6 mol, preferably from 1 mol to 4 mol, based on 1 mol of the compounds to be reduced.
The reduction generally proceeds in a temperature range of from -78°C
to +50°C, preferably from -78°C to 0°C, particularly preferably at 78°C, in each case depending on the choice of the reducing agent and solvent.
The reduction generally proceeds at atmospheric pressure; however, it is also possible to operate under elevated or reduced pressure.
Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dirnethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, c.yclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethyl formamide, hexamethylphosphoric triamide, Le A 32 664-Forf:i Countries acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Preference is given to toluene and dichloromethane.
The protective group is gc,nerally cleaved off in one of the abovementioned alcohols and THF, preferably me;thanol/THF in the presence of hydrochloric acid in a temperature range of from 0°C to 50°C, preferably at room temperature, and atmospheric pressure. In particular cases, the protective group is preferably cleaved off using tetrabut:ylammonium fluoride (TBAF) in THF at room temperature.
The reaction of the compounds of the general formula (VI) is earned out in one of the abovementioned ethers, preferably in tetrahydrofuran under an atmosphere of protective gas in a temperature range of from -78°C to -10°C, preferably at -25°C.
The derivatization of the; hydroxyl function into the compounds of the general 1~ formula (VII) is earned out, for example, by oxidations, sulphonations, alkylations, hydrogenations, 1-ialogenation, Wittig/Grignard reactions, Aldol reactions, reductive amination and sulpho amidations.
Suitable bases for the indiividual steps are the customary strongly basic compounds.
These preferably include organolithium compounds such as, for example, n-butyllithium, sec-butyllithium, tertbutyllithium or phenyllithium, or amides such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides such as sodium hydride or potassium hydride. Particular preference is given to using N-butyllithium, sodium hydride or lithium diisopropylamide.
Suitable bases are furthermore the customary inorganic 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 Ix A 32 664-Fore:i.ng-Countries bicarbonate. Particular prE;ference is given to using sodium hydroxide or potassium hydroxide.
Suitable solvents for the individual reaction steps are also alcohols such as methanol, ethanol, propanol., butanol or tertbutanol. Preference is given to tertbutanol.
The alkylation with alkyl halides is generally carried out in inert solvents in the presence of a base:.
Suitable solvents here are, depending on the type of the alkylating agent, all inert organic solvents. These preferably include ethers such as diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene or xvlene, or dimethylformamide or he:~camethylphosphoric triamide, or mixtures of the solvents mentioned.
Suitable bases for the alkylation are the customary basic compounds. These preferably include: alkali metal hydrides such as sodium hydride, alkali metal amides such as sodium amide or lithium diisopropylamide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium terbutoxide, or organic amines such as trialkylamines, for example triethylamine, or organolithium compounds such as butyllithium or phenyllithium.
Preference is given to lithium diisopropylamide.
The alkylation is generally carried out in a temperature range of from -70°C to +110°C, preferably from 20°C to 80°C.
The alkylation is generally carried out under atmospheric pressure. However, it is also possible to carry out the process under reduced pressure or elevated pressure (for example in a range of from 0.5 to 5 bar).
Le A 32 664-Foreign Countries Some of the compounds oiF the general formula (II) are novel and can be prepared, for example, by reacting compounds of the general formula (VIII) D-(~HZ-CO-~CH(CH3)2 (VIII) in which D is as defined above with compounds of the general formula (IX) A-C:HO (IX) in which A is as defined above in the presence o;f lithium diisopropylamide to give the compounds of the general formula (X) A
(X) in which A and D are as defined above, Le A 32 664-Foreign Countries and subsequently, in two steps, stirring mesyl chloride/tr-iethylamine and diazabicycloundecane in tearahydrofuran into the system.
Some of the compounds of the general formula (VIII) are known or novel and can be prepared by reacting initially with N,N-dimethylhydrazine and finally with compounds of the general formula (XI) D-B r (XI) in which D is as defined above in inert solvents, in the presence of a base, finally followed by treatment with hydrochloric acid.
The reaction of the compounds of the general formula (XI) is carried out in ethers such as diethyl ether, dio~;ane, tetrahydrofuran, glycol dimethyl ether.
Preferably in tetrahydrofuran.
Suitable bases for the individual steps are the customary strongly basic compounds.
These preferably include organolithium compounds such as, for example, n-butyllithium, sec-butyllivthium, tent butyllithium or phenyllithium, or amides such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylarrride, or alkali metal hydrides such as sodium hydride or potassium hydride. Particular preference is given to using N-butyllithium, sodium hydride or lithium diisopre~pylamide.
The base is employed in an amount of from 0.1 mol to 10 mol, preferably from 1 mol to 5 mol, based in each case on 1 mol of the starting material.
Le A 32 664-Forei;~n Countries The reaction is generally carried out in a temperature range of from -10°C to +10°C, preferably from 5"C to 10"C and atmospheric pressure.
The reaction with the aldehydes of the general formula (IX) is carried out as follows:
Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol di:methyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichlorornethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlo:robenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, climethyl formamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Preference is given to tetrahydrofuran.
Suitable bases for the individual steps are the customary strongly basic compounds.
These preferably include organolithium compounds such as, for example, n-butyllithium, sec-butyllithium, tert butyllithium or phenyllithium, or amides such as, for example, lithium ~diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides such as sodium hydride or potassium hydride. Particular preference is given to using N-butyllithium, sodium hydride or lithium diisopropylamide.
The base is employed in an amount of from 0.1 mol to 10 mol, preferably from 1 mol to 5 mol, in each case based on 1 mol of the starting material.
The reaction is generally carried out in a temperature range of from -10°C to +10°C, preferably from 5"C to 10"C and atmospheric pressure.
The compounds of the general formula (XI) are known per se or can be prepared by customary methods.
Le A 32 664-Forei n Countries The compounds of the general formula (IX) are known per se or can be prepared by customary methods.
The compounds of the general formula (X) are novel and can be prepared as described above.
The compounds of the general formula (III), (V) and (VI) are novel and can be prepared as described above.
The compounds of the general formula (IV) are known per se or can be prepared by customary methods.
Most of the compounds oiF the general formula (VII) are novel and can be prepared as described above.
The compounds of the general formula (Ia) are novel and can be prepared as described above.
The compounds of the general formula (I) according to the invention have a pharmacological activity spectrum which could not have been foreseen.
The compounds of the general formula (I) according to the invention have useful pharmacological properties which are superior when compared to the prior art;
in particular, they ane highly effective inhibitors of the cholesterol ester transfer protein (CETP) and they stimulate the reverse cholesterol transport. The active compounds according to the invention effect a reduction of the LDL cholesterol level in the blood and simultaneously increa se the HDL cholesterol level. They can therefore be used for the treatment and prevention of hyperlipoproteinaemia, dyslipidaemias, hypertriglyceridaemias, hyperlipidaemias or arteriosclerosis.
Le A 32 664-Foreign Countries The pharmacological activity of the substances according to the invention was assessed using the following test:
CETP Inhibition test Preparation of CETP
CETP is obtained in partially purified form from human plasma by differential centrifugation and column chromatography and used for the test. For this purpose, human plasma is adjusted to a density of 1.21 g per ml using NaBr and centrifuged) at SO,OCIO rpm at 4°C for 18 h. The bottom fraction (d >
1.21 g/ml) is applied to a Sephadex~Phenyl-Sepharose 4B (Pharmacia) column, washed with 0.15 rn NaCI/0.001 m TrisHCl pH 7.4 and subsequently eluted using dist.
water. The: CETP-active fractions are pooled, dialysed against 50 mM Na-acetate pH 4.5 and applied to a CM-Sepharose~ (Pharmacia) column. Elution is subsequently carne~d out using a linear gradient (0-1 M NaCI). The pooled CETP fractions are dialysed against 10 mM TrisHCl pH 7.4 and subsequently purified further by chromatography over a Mono Q~ column (Pharmacia).
Preparation of radioactively labelled HDL
50 ml of fresh human EDTA plasma is adjusted to a density of 1.12 using NaBr and centrifisged at 4°C in a Ty 65 rotor at 50,000 rpm for 18 h. The upper phase is used to obtain cold LDL. The lower phase is dialysed against 3*41 of PDB
buffer (10 mM Tris/HCl pH 7.4, 0.15 mM NaCI, 1 mM EDTA, 0.02% NaN3).
Per 10 ml volume of retained material, 20 p,l of 3H-cholesterol (Dupont NET-725; 1 -p,Ci/~,1, dissolved in ethanol) are subsequently added, and the mixture is incubated at 37°C under NZ for 72 h.
The mixture is then adjusted to a density of 1.21 using NaBr and centrifuged in a Ty 65 rotor at 20°C and 50,000 rpm for 18 h. The upper phase is collected and Le A 32 664-Forf:i Countries the lipoprotein fractions are purified by gradient centrifugation. To this end, the isolated, labelled lipoprotein fraction is adjusted to a density of 1.26 using NaBr. In each case 4 ml of this solution are covered in centrifuge tubes (SW
rotor) with 4 ml of a solution of a density of 1.21 and 4.5 ml of a solution of 1.063 (density solutions of PDB buffer and NaBr), and the tubes are subsequently centrifuged in an SW 40 rotor at 38,000 rpm and 20°C for 24 h.
The intermediate layer which is found between a density of 1.063 and 1.21 and which contains the; labelled HDL is dialysed against 3*100 volume of PDB
buffer at 4°C.
The retained material contains radioactively labelled 3H-CE-HDL, which is used for the test adjusted to approximately Sx 106 cmp per ml.
CETP test To assess the CET'P activity, the transfer of 3H-cholesterol ester from human HD lipoproteins to biotinylated LD lipoproteins is measured.
The reaction is ternunated by addition of Streptavidin-SPA~ beads (Amersham) and the transferredl radioactivity is directly measured in a liquid scintillation counter.
In the ass;~y mixture, 10 p,l of HDL 3H-cholesterol ester (- 50,000 cpm) with 10 p l of Eeiotin-LDL (Amersham) in 50 mM Hepes/0.15 m NaCI/0.1% bovine serum albumin/0.05% NaN3 pH 7.4 are incubated with 10 p,l of CETP
(1 mg/ml) and 3 p,l of a solution of the substance to be tested (dissolved in 10%
DMSO/1°ro BSA) at 37°C for 18 h. 200 p.l of the SPA streptavidin bead solution (TRKQ 7005) are subsequently added, the mixture is incubated with shaking for another 1 h and subsequently measured in a scintillation counter. The controls used are corresponding incubations with lOp,l of buffer, lOp,l of CETP at 4°C and 10 p l of CETP at 37°C.
Le A 32 664-Forei Countries The activity which its transferred in the control experiments with CETP at 37°C
is taken to be 100% transfer. The substance concentration at which this transfer is reduced by half is. stated as the ICSo value.
do Table A below, the ICSO values (mol/1) for CETP inhibitors are given:
Table A:
Example lVo. ~ ICSO value (nmoUl) 2'.2 6000 Ex vivo activity o:f the compounds according to the invention Syrian gold hamsters, which have been bred in our own laboratory, are anaesthetized after 24 hours of fasting (0.8 mg/kg of atropine, 0.8 mg/kg of Ketavet~ s.c., 30' later 50 mg/kg of nembutal i.p.). The jugular vein is subsequently exposed and cannulated. The test substance is dissolved in a suitable solvent (usually adalate placebo solution: 60 g of glycerol, 100 ml of H20, ad 1C100 ml PEG-400) and administered to the animals via a PE catheter, which is introduced into the jugular vein. The same volume of solvent without test substance is administered to the control animals. The vein is subsequently tied off anti the wound is closed.
The test substances can also be administered p.o. by dissolving the substances in DMSO and suspending them in 0.5% tylose and administering them perorally using a pfiaryngeal tube. Identical volumes of solvent without test substance ~~re administered to the control animals.
Le A 32 664-Foreii, n~Countries At different intervalls - up to 24 hours after the administration - blood samples are taken from the: animals by puncture of the retro-orbital venous plexus (approximately 250 p.l). Coagulation is completed by incubation at 4°C
overnight, and the samples are subsequently centrifuged at 6000 x g for 10 minutes. The CET1P activity is determined in the resulting serum using the modified C'ETP test. The transfer of 3H-cholesterol ester from HD lipoproteins to biotinylated LD lipoproteins is measured as described above for the CETP
test.
The reaction is terminated by addition of Streptavidin-SPAR beads (Amersham), and the transferred radioactivity is directly deterniined in a liquid scintillation counter.
The test protocol is carried out as described under "CETP test". However, to test the serum, 10 p,l o~f CETP are replaced by 10 p l of the appropriate serum samples. C'.orresponding incubations of sera of untreated animals serve as controls.
The activity that is transferred in the control experiments using control sera is classified as 100% transfer. The substance concentration at which this transfer is reduced by half is stated as the EDSO value.
In vivo activity oi' the compounds according to the invention In experiments for assessing the oral activity on lipoproteins and triglycerides, test substance, dissolved in DMSO and suspended in 0.5% tylose, is administered perorally using a pharyngeal tube to Syrian gold hamsters which have been bred in our own laboratory. To determine the CETP activity, blood samples (approximately 250 p.l) are taken by retro-orbital puncture prior to the start of the experiment. The test substances are subsequently administered perorally using a pharyngeal tube. Identical volumes of solvent without test Le A 32 664-Forei n Countries substance are administered to the control animals. Subsequently, the animals have to fast and at different intervals - up to 24 hours after the administration of the substances - blood samples are taken by puncture of the retro-orbital venous plexus.
Coagulation is completed by incubation at 4°C overnight, and the samples are subsequently cenUrifuged at 6000 x g for 10 minutes. The content of cholesterol) and triglycerides in the resulting serum is assessed using modified commercially availlable enzyme tests (cholesterol enzymatic 14366 Merck, triglycerides 14364 Merck). Serum is diluted in a suitable manner with physiologi~:.al saline: solution.
100 p.l of serum dilution and 100 r~ 1 of test substance are transferred into 96-well plates and incubated at room temperature for 10 minutes. The optical density is subsequently determined at a wavelength of 492 nm using an automatic plate reader. The triglyceride and cholesterol concentrations of the samples are determined with the aid of a standard curve measured in parallel.
The determination of the HDL-cholesterol content is earned out after precipitation of the ApoB-containing lipoproteins using a reagent mixture (Sigma 35:?-4 HDL cholesterol reagent) in accordance with the instructions of the manufacturer.
In vivo activity in transgf~nic hCETP mice The substances to be tested were administered to transgenic mice, which were bred in our own laboratory (Dinchuck, Hart, Gonzalez, Karmann, Schmidt, Wirak; BE~A (1995~), 1295, 301), via the feed. Prior to the beginning of the experiment, blood samples were taken retro-orbitally from the mice to determine cholesterol and triglycerides in the serum. The serum was obtained as described above for hamsters by incubation at 4°C overnight and Le A 32 664-Forei.~n Countries subsequent centrifugation at 6000 x g. After one week, blood samples were again taken from the mice to determine lipoproteins and triglycerides. The change in the measured parameters are expressed as a change in per cent based on the initial value.
The invention fun:hermore relates to the combination of benzyl-biphenylenes of the general formula (1:) with a glucosidase and/or amylase inhibitor for the treatment of familial hyperlipidaemias, of obesity (adipositas) and of diabetes mellitus.
Glucosidase and/or amylase inhibitors in the context of the invention are, for example, acarbose, adipasine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose (MLiL-73945), tendamistate, AI-3688, trestatin, pradimicin-Q and salbostatin.
Preference is given to the .combination of acarbose, miglitol, emiglitate or voglibose with one of the abovementioned compounds of the general formulae (I) according to the invention.
Furthermore, the compounds according to the invention can be combined in combination with cholesterol-lowering vastatins or ApoB-lowering principles, in order to treat dyslipidaemias, combined hyperlipidaemias, hypercholesterolaemias or hypertriglyceridaemias.
The abovementicmed connbinations can also be used for primary or secondary prevention of coronary heart diseases (for example myocardial infarction).
Vastatins in the context of the invention are, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. ApoB-lowering agents are, for example, MTP inhibitors.
Le A 32 664-Foreign Cc>untries Preference is given to the combination of cerivastatin or ApoB inhibitors with one of the abovementioned compounds of the general formulae (I) and (Ia) according to the invention.
The novel 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 earners or solvents. In this case the therapeutically active compound should in each case be present in a concentration from approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds using solvents amj/or earners, if appropriate using emulsifiers and/or dispersants, it optionally being possible, for example, to use organic solvents as auxiliary solvents if the diluent used is water.
Administration i;~ carried out in a customary manner, intravenously, orally, parenterally or perlingually, in particular orally.
In the case of parenteral administration, solutions of the active compound can be used by employing suitable liquid earner materials.
In general, it has proved advantageous, in the case of intravenous administration, to administer amounts from approximately 0.001 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg, of body weight to achieve effective results, and in the case of oral administration th~~ dosage is approximately 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg, of body weight.
In spite of this, if appropriate it may be necessary to depart from the amounts mentioned, namely depending on the body weight or on the type of administration Le A 32 664-Fore:i~n Countries route, on individual reaction towards the medicament, the manner of its formulation and the time at or interval during which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amounts, while in other cases the upper limit mentioned has to be exceeded. In the S case of the administration of relatively large amounts, it may be advisable to divide these into several i~,ndividual doses over the course of the day ' Le A 32 664-Foreign Countries Starting materials Example I
4-Methyl-1-(4-trifluoromethyl-phenyl)-pentan-3-one O
At 0°C, 131 ml (0.328 mol) of a 2.SM solution of nBuLi in n-hexane are added dropwise over a period of 30 min to 40 g (0.312 mol) of N,N-dimethyl-N-{2-methyl-1-[2-(4-trifluorom~~thyl-phenyl)-ethyl]-propylidene}-hydrazine (S.D Sharma et al., J. Org. Chem. 1990, 55, 2196) in 400 ml of abs. THF, and the mixture is stirred at 15-20°C for 30 m,in. A solution of 67.9 g (0.284 mol) of 4-trifluoromethyl-benzyl bromide in 100 ml of al>s. THF is then added dropwise and the mixture is stirred at 20°C for 2 h. The reaction mixture is concentrated to about 80 ml and carefully hydrolysed using :?00 ml of H20. The mixture is extracted with ethyl acetate and the extract is washed with sat. NaCI solution, dried over Na2S04 and concentrated.
This gives 82 g of N,N-dimethyl-N-{ 2-methyl-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-propylidene}-hydrazine as a red oil.
The hydrazone is ~3issolved in 150 ml of THF and admixed with 170 ml of 2M
HCI, and the mixture is stirred at 20°C for 1 h. The mixture is extracted with EtOAc and the extract is washed with water and sat.. NaCI solution, dried over NaZS04 and concentrated. Distillation gives a colourless oil (b.p. 95-98°C/0.7 mbar).
Yield: 51.5 g (78 r~) Rf = 0.25 (EtOAc/PE 1:20) Le A 32 664-Foreign Countries _q.4_ Example II
1-(4-Fluoro-phenyl)-1-hydroxy-4-methyl-2-(4-trifluoromethyl-benzyl)-pentan-3-one H
F
At -70°C, 400 ml (0.791 mol) of a 2.OM solution of LDA in THF/heptane are added over a period of 50 min to 184 g (0.753 mol) of the compound from Example 1 in 1.2 I of abs. THF, and the mixture is stirred at -70°C for 60 min. 81 ml (0.753 mol) of 4-fluorobenzaldehyde are then added, and the mixture is stirred at -70°C for 60 min. The reaction is quenched with 100 ml of a 10% Nl-hCl solution, the mixture is allowed to warm to -10°C and a further 400 ml of a 10% NH4C1 solution are added. The phases are separated, the aqueous phase is extracted with EtOAc and the extract is washed with sat. NaCI solution dried over Na2S04 and concentrated.
The crude product is purified over silica gel 60 (EtOAc/PE 1:5).
Yield: 253 g (91%) Rf= 0.31 (EtOAc/PE 1:5) Example III
1-(4-Fluoro-pheny 1)-4-methyl-2-(4-trifluoromethyl-benzyl )-pent-1-en-3-one Le A 32 664-Forei,~n Countries F
At 0°C, 231 rnl (1.672 mol) of triethylamine and 118 ml (1.52 mol) of methanesulphonvl chloride are added to 279 g (0.76 mol) of the compound from Example II in 2.:p 1 of abs. CHZC12. The mixture is stirred at 20°C
overnight and, at -30°C, 456 ml (;5.04 mol) of DBU dissolved in 1 1 of abs. CH2Cl2 are added. After 90 min, the reaction is quenched with 500 ml of water. The phases are separated and the aqueous phase is extracted with CH2ClZ. The combined organic phases are washed with 0.5 M HC'.1, dried over Na~S04 and concentrated. The crude product is purified over silica gel 60 (cyclohexane/EtOAc 40:1 to 10:1).
Yield: 220 g (83~~0) R f = 0.27 (EtOAc;/PE 1:20).
Example IV
1-Fluoro-4-(3-isopropyl-2-(4-trifluoromethyl-benzyl)-buta-1,3-dienyl)-benzene F
Le A 32 664-Forei, ng-Countries At 0°C, 47.6 g ( l 14.2 mmol) of a mixture of methyl-triphenylphosphonium bromide and sodium amide in 200 ml of abs. ether are added to 20 g (5.71 mmol) of the compound from Example III in 100 ml of abs. ether. After 90 min, 300 ml of petroleum ether ;ire added and the mixture is filtered off with suction through a little silica gel. The silica gel is washed with 2 1 of PE and the filtrate is concentrated. The crude product is purified over silica gel 60 (cyclohexane/EtOAc 20:1 to 10:1).
Yield: 9.1 g (44°'0) Rf = 0.35 (PE).
Example V
Methyl 6-(4-fluoro-phenyl)-4-isopropyl-5-(4-trifluoromethyl-benzyl)-cyclohexa-1,4-dienecarbox~~late F
Benzvl-biphenvls and analogous compounds The present rove;ntion relates to benzyl-biphenyls and analogous compounds, to processes for their preparation and to their use in medicaments.
The publication US-5 169 857-A2 discloses 7-(polysubstituted pyridyl)-6-heptenoates for treating arteriosclerosis, lipoproteinaemia and hyperproteinaemia.
Moreover, the preparation of 7-(4-aryl-3-pyridyl)-3,5-dihydroxy-6-heptenoates is described in the publication EP-325 130-A2.
The present invention relates to benzyl-biphenyls and analogous compounds of the general formula (1_), A
p \ / Ri i \ I 2 (1), E R
in which A represents cycloalkyl having 3 to 8 carbon atoms, or represents aryl having 6 to 10 carbon atoms, or represents a 5- to 7-membered, saturated, partially unsaturated or unsaturated, optionally benzo-fused heterocycle having up to 4 heteroatoms from the group con<.~isting of S, N and O, where aryl and the abovementioned heterocyclic ring systems are optionally substituteCi up to 5 times by identical or different substituents from the group consisting of cyano, halogen, vitro, carboxyl, hydroxyl, trifluoromethyl, Le A 32 664-Foreign Countries trifluorom~ethoxy oar by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxyca~rbonyl, oxyalkoxycarbonyl or alkoxy having in each case up to 7 carbon atonns, or by a group of the formula -NR3R4 in which R3 and R4 are idlentical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, D represents a radical of the formula R~ Ra RS-k- , R6~~ or R9-T-V-X-in which R5, R6 and R9 independently of one another represent aryl having 6 to 10 carbon atoms or a 5- to 7-membered, optionally benzo-fused, saturated or unsaturated, mono-, bi- or tricyclic heaerocycle having up to 4 heteroatoms from the group consisting of S, N and O, where the cycles, optionally, in the case of the nitrogen-containing rin;~s also via the N function, are substituted up to 5 times by identical or different substituents from the group consisting of halogen, trifluoromethyl, vitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryl having in each case 6 to 10 carbon atoms or b:y an optionally benzo-fused, aromatic 5- to 7-membered Le A 32 664-Forei r~ountries heterocycle having up to 3 heteroatoms from the group consisting of S, :'V and O, ancUor by a group of the formula -ORS°, -SR~1, -SOZR~2 or -NR~3R'4, in which R'°, R'1 and R12 independently of one another represent aryl having to 10 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, halogen, or by straight-chain or branched alkyll having up to 6 carbon atoms, R'' and R14 are identical or different and have the meaning of R3 and R4 given above, or R5 andlor R6 represent a radical of the formula ~ ~ ~- O~ F
or , - \ ~ O F FsC O
R' represents hydrogen, halogen or methyl, and Rg represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromet:hoxy, straight-chain or branched alkoxy or alkyl having in each case up to 6 carbon atoms or a radical of the formula -NR~SR~6 Le A 32 664-Fore:i Countries in which R~~' and RAE' are identical or different and have the meaning of R3 and R4 given above, or R' and R$ together form a :radical of the formula =O or =NR1~
in which R" represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 6 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 8 carbon atoms which are optionally substituted up to 2 times by hydroxyl, T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 8 carbon atoms, or T or X represent a bond, V represents .an oxygen or sulphur atom or represents an -NR~B- group in which Le A 32 664-Fomign Countries R~g represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, E represents, cycloalhyl having 3 to 8 carbon atoms, or represents straight--chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or hydroxyl, or represents phenyl which is optionally substituted by halogen or trifluorom~ethyl, R1 represents straight-chain or branched alkyl having up to 6 carbon atoms which is substituted by hydroxyl or by a group of the formula --O O
RZ represents hydrogen or represents straight-chain or branched alkyl or alkenyl having in each case: up to 8 carbon atoms, which are optionally substituted by hydroxyl, halogen, phenyl, cycloalkyl having 3 to 6 carbon atoms or by a group of the formula O N O
-O-R ~ '~
O N O
or Le A 32 664-Fore:i Countries in which R'9 represents a radical of the formula -Si(CH3)2C(CH3)3, or represents straight-chain or branched alkyl having up to 6 carbon atoms, or represents a 5- to ;~-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, or represents phenyl or benzyl, where all ring systems listed under R19 are optionally substituted up to 2 times by identical or different substituents from the group consisting of trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or b;y straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, and their salts.
The compounds according, to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, preference is given to physiologically acceptable salts. F'hysiolog;ically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methaneaulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, malefic acid or benzoic acid.
Le A 32 664-Forei n~Countries Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
Particular preference, is given, for example, to sodium, potassium, magnesium of calcium salts, and also to ammonium salts, which are derived from ammonia, or organic amines, such as, for example, e;thylamine, di-or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The compounds according; to the invention can exist in stereoisomeric forms which are either like image and mirror image (enantiomers), or which are not like image and mirror image (diastereom~ers). The invention relates both to the enantiomers or diastereomers anci to their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform components IS in a manner known per se.
In the context of the invention, a heterocycle, optionally benzo-fused, generally represents a saturated, partially unsaturated or unsaturated 5- to 7-membered, preferably 5- to E.-membered, heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N and O. Examples which may be mentioned are:
indolyl, isoquinol:yl, quinolyl, benzo[b]thiophene, benzo[b]furanyl, pytidyl, thienyl, furyl, pyrrolyl, thi;izolyl, o:~cazolyl, imidazolyl, morpholinyl or piperidyl.
Preference is given to quinolyl, furyl, pyridyl and thienyl.
Preference is given to the: compounds of the general formula (I) according to the invention in which A represents napththyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or morpholinf; which are optionally substituted up to 2 times by identical or Le A 32 664-Fore:i Countries _g_ different substituents from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, or alkoxy having in each case up to 6 carbon atoms, D represents phenyl which is optionally substituted by nitro, fluorine, chlorine, bromine, pfienyl, trifluoromethyl or trifluoromethoxy, or represents a radical of the formula R~ Ra s R -L- ~ Rs'~ or R9-T-V-X- , in which R5, R~ and R9 independently of one another represent phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phe.noxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl, where the cycles, optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, are substituted by identical or different sul'~stituents from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifl.uoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alk:ylalkoxy., alkoxy or alkoxycarbonyl having in each case up to 4 c~~rbon atoms, triazolyl, tetrazolyl, bezoxathiazolyl, or trifluoromethyl-substituted phenyl or phenyl, and/or are substituted by a group of the formula -OR'°, -SR" or -SOZR' z Le A 32 664-Foreign Countries in which R1°, R" and R'2 are identical or different and represent phenyl which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, fluorine, chlorine, or by straight-chain or branched alkyl having up to 4 caJrbon atoms, or RS and/or R6 represent a radical of the formula ~O~F
/' or F3C p R' represents hydrogen, fluorine, chlorine or bromine, and R8 represents hydrogen, fluorine, chlorine, bromine, azido, trio uoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 5 carbon atoms or a radical of the formula -NR~SRIG
in which R~5 and R'6 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atones, Le A 32 664-Forei n Countries or R' and R8 togethe;r form a radical of the formula =O or =NR'7 in which R" represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 6 carbon atoms, which are optionally substituted up to 2 times by hydroxyl, T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 6 carbon atoms, or T or X represents a bond, V represents an oxy~;en or sulphur atom or represents a group of the formula -NR ~ g-in which R~8 represents Izydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or Le A 32 664-Forc:i Countries represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by cyclopropyl, -butyl, -hexyl, -pentyl, -heptyl or by hydroxyl, or represents phenyl which is optionally substituted by fluorine, chlorine, or trifluoromethyl, Rl represents a group of the formula -CHZOH or -CH2 O~ O~
RZ represents hydrogen or represents straight-chain or branched alkyl or alkenyl having in each case up to 6 carbon atoms which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohe:xylor by a group of the formula N
O O O N O
_O_Ri s~
O N O
or in which R'9 represents a radical of the formula -Si(CH3)ZC(CH3)3 or Le A 32 664-Fore~n Countries represents straight-chain or branched alkyl having up to S carbon atoms, or represents tetrahydropyranyl, pyridyl, phenyl or benzyl which are optionally substituted up to 2 times by identical or different substituents~ from the group consisting of trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl haring in each case up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl, and their salts.
Particular preference is given to compounds of the general formula (I) according to the invention in which A represents phenyl or pyridyl which are optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, D represents phenyl which is optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or represents a radical of the formula R~ Rs RS-L- , R6'' \ or R9-T-V-X- , in which Le A 32 664-Forei Countries R5, R6 and R9 independently of one another represent phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl, where the cycles, optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, are substituted by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl-substituted phenyl or phenyl ancl/or are substituted by a group of the formula -OR'°, -SR" or -St~zR' Z
in which R"', R" and R'z are identical or different and represent phenyl which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, fluorine, chlorine, or by straight-chain or branched alkyl having up to 3 carbon atoms, or RS and/or R6 represent a radical of the formula Le A 32 664-Forei,.nytries ,O
F or ~' O F FsC O
R' represents hydrogen or fluorine, and Rg represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain or branched allkoxy or alkyl having in each case up to 4 carbon atoms or a radical of 'the formula -NR~SR~~
in which R~5 and R~6 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or R' and Rg ~:ogether form a radical of the formula =O or =NR", in which R" represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 5 carbon atoms, which are optionally substituted up to 2 times by hydroxyl, Le A 32 664-Forei Countries T and X .are identical or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms, or S
T or X represents a bond, V represents an oxygen or sulphur atom or represents a group of the formula -NRIB
in which R~g represents hydrogen or straight-chain or branched alkyl having up t:o 3 carbon atoms, >; represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl which is optionally substituted by fluorine or trifluoromethyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, R' represents a group of the formula -CHZOH or -CH2 O~ O~
R2 represents hydrogen or represents straight-chain or branched alkyl or alk.enyl having in each case up to S carbon atoms which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine, bromine, T Le A 32 664-Foreign Countries cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or by a group of the fonmula O N O
-O-R~ '' O N O
or in vvhich R'9 represents straight-chain or branched alkyl having up to 4 carbon atoms, or represents a radical of the formula Si(CH3)ZC(CH3)3 or represents tetrahydropyranyl, pyridyl, phenyl or benzyl, which are optionally substituted up to 2 times by identical or different substituents from the group consisting of trifluoromethyl, fluorine, chlorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl and their salts.
Le A 32 664-Fore~i ngn Countries Very particular :preferen<:e is given to compounds of the general formula (I) according to the invention A represents phenyl, fluorine, chlorine, bromine, trifluoromethyl, D represents a radical of the formula R~ Rs R5-L- or Rs'~ , in which R5, R6 and R9 independently of one another represent phenyl, which is optionally substituted up to 3 times by identical or different substituents from the group consisting of fluorine, chlorine and trifluoromethyl, R' represents hydrogen or fluorine, and Rg rep~~esents hydrogen, fluorine, chlorine, bromine or alkyl having in each case up to 4 carbon atoms or R' and Rg Together form a radical of the formula =O or =NR"
Le A 32 664-Fore:i Countries in which Rr~ repre;sents hydrogen or straight-chain or branched alkyl, alkoxy or ac:yl having in each case up to 4 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 5 carbon atoms which are optionally substituted up to 2 times by hydroxyl, T and X aJ~e identical or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms, or T or X represent a frond, V represents an oxygen or sulphur atom or represents a group of the forrnula -NR;'g in which Rrg represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, E represents c;yclopropyl, cyclopentyl or cyclohexyl or phenyl which is optionally substituted by fluor7ne or tr-ifluoromethyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms, Rr represents a group of the formula -CHZOH or Le A 32 664-Foreign Countries -CH2 O ~O~
R2 represents hydroge;n or represents straight-chain or branched alkyl or alkenyl having in each case up to 5 carbon atoms which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobuty:l, cyclohc~xyl or by a group of the formula i O N O
_~~_R~s O N O
or in which R'9 represents straight-chain or branched alkyl having up to 4 carbon atoms, or represents a radical of the formula -Si(CH~)ZC(CH~)3, or represents tetrahydropyranyl, pyridyl, phenyl or benzyl, which are optionally substituted up to 2 times by identical or different substituenta from the group consisting of trifluoromethyl, fluorine, chlorine, vitro, hydroxyl, straight-chain or branched alkoxy or Le A 32 664-Foreign Countries alkoxycarbonyl having in each case up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl, and their salts.
Moreover, processes for prepar7ng the compounds of the general formula (I) according to the invention have been found, which are characterized in that compounds of the general formula (II) A
D
(II) E O
in which A, D and E are as defined above are, in the system (C6:H5)3PCH3Br/n-butyllithium, initially converted into the compounds of the: general formula (III) A
D
(III) E
in which A, D and E are as defined above, Le A 32 664-Fore:i ng-Countries subsequently, wit',h compounds of the general formula (N) or (IVa) R2°-02C C02R2° (IV) R2' C02R2°~~ (IVa) in which R2°, R2°~ and R2°~~ are identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms and RZ' represents hydrogen or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, phenyl, straight-chain or branched alkoxy having up to 6 carbon atoms, amino, alkyl-or dialkyla.mines having up to 4 carbon atoms in the alkyl moiety, converted into the compounds of the general formula (V) A
D C02R2°", ( E R2z in which A, D and E are as defined above, RZ°~" includes the abovementioned scope of the meaning of RZ° and RZOw, Ix A 32 664-Fore:i Countries and R22 either represents hydrogen or represents the radical -C02R2°", or includes the abovernentioned scope of the meaning of R2y by oxidation, the compounds of the general formula (VI) A
D ~ C02R2°"' (vl) I. ~ R22 to in which A, D, E, R2, RZ°"' and RzZ are as defined above are prepared, and subsequently ~.he carbomyl functions are reduced to the hydroxymethyl function, and derivatization on the s~abstituent R2 is carried out by, starting from compounds of the general formula (Ia) A
D CH-O OJ
w ~ z (la) E
in which Le A 32 664-Foreign Countries A, D and E are as defined above, reacting, depending on the abovementioned meaning of R2, in the system P(C6H5)3/ethyl diethylazo~dicarboxylate and the corresponding amines or alcohols defined under R~9, or carrying out an etherification by reaction with alkyl halides in the presence of a base, and subsequently eliminating in the two derivatizations the hydroxyl-protective group with acids, or, in the case where R2 = alkenyl, initially converting the compounds of the general formula (Ia) into the aldeh:ydes of the general formula (VII) A
D CH-O OJ
z i ~ (VII) E CHO
in which A, D and E are as defined .above and, in a further svtep, camping out a Wittig reaction according to customary methods, eliminating the hydroxyl-protective group as described above and subsequently, by hydrogenation in the presence of a catalyst, reducing to the corresponding alkyl compounds (RZ = alkyl).
Le A 32 664-Forei Countries The process according to the invention can be illustrated in an exemplary manner by the following scheme:
Ph3PCH3Br nBul_i, THF
FaC F
~C02CH3 H
xylene, 140°C
F
LiAIH4 OH
Le A 32 664-Foreign Countries 1. NaH, TBAI, Br-(CHZ)2CH(CH3)2 2. H+
1. PPh3, DEAD, C6H5( ' 2. H+
F
1. PPh3, DEAD, O
HN' ~O
2. H' PCC, AI203 O
F N
O
P 1. W ittig 2. PPTA, MeOH
F3C 1 FsC
H2, PUC
F
Le A 32 664-Forei Countries Suitable solvents for the reaction step (II) ~ (III) are ethers such as diethyl ether, dioxane, tetrahyd:rofuran, ,glycol dimethyl ether. It is also possible to use mixtures of the solvents mentioned. Preference is given to diethyl ether.
Suitable bases far the reaction step (II) -> (III) are the customary strongly basic compounds. These preferably include organolithium compounds such as, for example, N-butyillithium, sec-butyllithium, ten butyullithium or phenyllithium or amides such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithiurr~ hexameahylsilylamide, or alkali metal hydrides, such as sodium hydride or potassium hydride. Particular preference is given to N-butyllithium.
The base is generally employed in an amount of from 1 mol to 2 mol, preferably from 1.05 mol to 1.2 mol, based. on 1 mol of the compounds of the general formula (II).
The reaction generally proceeds at a temperature of from -30°C to room temperature, preferably from -20°C to 0~°C.
The reaction generally proceeds at atmospheric pressure; however, it is also possible to operate under elevated or reduced pressure.
Suitable solvents for prep~u-ing the compounds of the general formula (V) according to the invention a.re hydrocarbons such as benzene, toluene, xylene, chlorobenzene, ethyl benzoate, de~calin, be:nzonitrile, hexane, cyclohexane or mineral oil fractions. It is also possible t~~ use mixtures of the solvents mentioned. Preference is given to xylene.
The reaction can .also be carried out without solvent, or the solvent used can be the alkine.
The reaction generally proceeds at a temperature of from -30°C to +250, preferably of from 80°C to 1.80°C.
Le A 32 664-Foreign Countries The reaction generally proceeds at atmospheric pressure; however, it is also possible to operate under elevated or reduced pressure.
The reaction generally proceeds without catalyst; however, it is also possible to use Lewis acids as catalysts. Examples which may be mentioned are: BF3, BF3 x OEt2, A1C13, TiCl4, Al(CH3)3, A1(C2H5)3, (CzHs)2A1C1, MgCl2, ZnCl2 and BCl3.
Suitable solvents for the oxidation are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichloromethane:> tr~ichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene., chlorobenzene, ethyl acetate, dimethyl sulphoxide, dimethylformamide, hey;amethylphosphoric triamide, acetonitr-ile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned.
Preference is given to toluene.
Suitable oxidizing agents are, for example, potassium permanganate, bromine, cerium (IV) ammonium nitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate on basic alumina, osmium tetroxide, sodium acetate;/iodine and manganese dioxide. Preference is given to 2,3-dichloro-5,6-dicyano-benzoquinone.
The oxidizing agent is employed in an amount of from 1 mol to 10 mol, preferably from 2 mol to 5 mol, based on 1 mol of the compounds of the general formula (V).
The oxidation generally proceeds in a temperature range of from 0°C to +100°C, preferably from room temperature to 80°C.
The oxidiation generally proceeds at atmospheric pressure. However, it is also possible to carry out the o;Kidation under elevated or reduced pressure.
Le A 32 664-Fore:i~Qrr Countries Suitable solvents i~or the reduction are the hydrocarbons listed above, and preference is given to toluene.
The reduction of the compounds of the general formula (VI) is generally carried out using reducing agents, preferably those which are suitable for reducing alkoxycarbonyl to hydroxyl compounds. Particularly suitable here is the reduction with metal hydrid<a or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out using complex .
metal hydrides such as, 'for example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylborohydride, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is very particularly prefer~~bly carnied out using diisobutylaluminium hydride.
The reducing agent is generally employed in an amount of from 1 mol to 6 mol, preferably from 1 mol to 4 mol, based on 1 mol of the compounds to be reduced.
The reduction generally proceeds in a temperature range of from -78°C
to +50°C, preferably from -78°C to 0°C, particularly preferably at 78°C, in each case depending on the choice of the reducing agent and solvent.
The reduction generally proceeds at atmospheric pressure; however, it is also possible to operate under elevated or reduced pressure.
Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dirnethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, c.yclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethyl formamide, hexamethylphosphoric triamide, Le A 32 664-Forf:i Countries acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Preference is given to toluene and dichloromethane.
The protective group is gc,nerally cleaved off in one of the abovementioned alcohols and THF, preferably me;thanol/THF in the presence of hydrochloric acid in a temperature range of from 0°C to 50°C, preferably at room temperature, and atmospheric pressure. In particular cases, the protective group is preferably cleaved off using tetrabut:ylammonium fluoride (TBAF) in THF at room temperature.
The reaction of the compounds of the general formula (VI) is earned out in one of the abovementioned ethers, preferably in tetrahydrofuran under an atmosphere of protective gas in a temperature range of from -78°C to -10°C, preferably at -25°C.
The derivatization of the; hydroxyl function into the compounds of the general 1~ formula (VII) is earned out, for example, by oxidations, sulphonations, alkylations, hydrogenations, 1-ialogenation, Wittig/Grignard reactions, Aldol reactions, reductive amination and sulpho amidations.
Suitable bases for the indiividual steps are the customary strongly basic compounds.
These preferably include organolithium compounds such as, for example, n-butyllithium, sec-butyllithium, tertbutyllithium or phenyllithium, or amides such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides such as sodium hydride or potassium hydride. Particular preference is given to using N-butyllithium, sodium hydride or lithium diisopropylamide.
Suitable bases are furthermore the customary inorganic 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 Ix A 32 664-Fore:i.ng-Countries bicarbonate. Particular prE;ference is given to using sodium hydroxide or potassium hydroxide.
Suitable solvents for the individual reaction steps are also alcohols such as methanol, ethanol, propanol., butanol or tertbutanol. Preference is given to tertbutanol.
The alkylation with alkyl halides is generally carried out in inert solvents in the presence of a base:.
Suitable solvents here are, depending on the type of the alkylating agent, all inert organic solvents. These preferably include ethers such as diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene or xvlene, or dimethylformamide or he:~camethylphosphoric triamide, or mixtures of the solvents mentioned.
Suitable bases for the alkylation are the customary basic compounds. These preferably include: alkali metal hydrides such as sodium hydride, alkali metal amides such as sodium amide or lithium diisopropylamide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium terbutoxide, or organic amines such as trialkylamines, for example triethylamine, or organolithium compounds such as butyllithium or phenyllithium.
Preference is given to lithium diisopropylamide.
The alkylation is generally carried out in a temperature range of from -70°C to +110°C, preferably from 20°C to 80°C.
The alkylation is generally carried out under atmospheric pressure. However, it is also possible to carry out the process under reduced pressure or elevated pressure (for example in a range of from 0.5 to 5 bar).
Le A 32 664-Foreign Countries Some of the compounds oiF the general formula (II) are novel and can be prepared, for example, by reacting compounds of the general formula (VIII) D-(~HZ-CO-~CH(CH3)2 (VIII) in which D is as defined above with compounds of the general formula (IX) A-C:HO (IX) in which A is as defined above in the presence o;f lithium diisopropylamide to give the compounds of the general formula (X) A
(X) in which A and D are as defined above, Le A 32 664-Foreign Countries and subsequently, in two steps, stirring mesyl chloride/tr-iethylamine and diazabicycloundecane in tearahydrofuran into the system.
Some of the compounds of the general formula (VIII) are known or novel and can be prepared by reacting initially with N,N-dimethylhydrazine and finally with compounds of the general formula (XI) D-B r (XI) in which D is as defined above in inert solvents, in the presence of a base, finally followed by treatment with hydrochloric acid.
The reaction of the compounds of the general formula (XI) is carried out in ethers such as diethyl ether, dio~;ane, tetrahydrofuran, glycol dimethyl ether.
Preferably in tetrahydrofuran.
Suitable bases for the individual steps are the customary strongly basic compounds.
These preferably include organolithium compounds such as, for example, n-butyllithium, sec-butyllivthium, tent butyllithium or phenyllithium, or amides such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylarrride, or alkali metal hydrides such as sodium hydride or potassium hydride. Particular preference is given to using N-butyllithium, sodium hydride or lithium diisopre~pylamide.
The base is employed in an amount of from 0.1 mol to 10 mol, preferably from 1 mol to 5 mol, based in each case on 1 mol of the starting material.
Le A 32 664-Forei;~n Countries The reaction is generally carried out in a temperature range of from -10°C to +10°C, preferably from 5"C to 10"C and atmospheric pressure.
The reaction with the aldehydes of the general formula (IX) is carried out as follows:
Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol di:methyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichlorornethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlo:robenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, climethyl formamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Preference is given to tetrahydrofuran.
Suitable bases for the individual steps are the customary strongly basic compounds.
These preferably include organolithium compounds such as, for example, n-butyllithium, sec-butyllithium, tert butyllithium or phenyllithium, or amides such as, for example, lithium ~diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides such as sodium hydride or potassium hydride. Particular preference is given to using N-butyllithium, sodium hydride or lithium diisopropylamide.
The base is employed in an amount of from 0.1 mol to 10 mol, preferably from 1 mol to 5 mol, in each case based on 1 mol of the starting material.
The reaction is generally carried out in a temperature range of from -10°C to +10°C, preferably from 5"C to 10"C and atmospheric pressure.
The compounds of the general formula (XI) are known per se or can be prepared by customary methods.
Le A 32 664-Forei n Countries The compounds of the general formula (IX) are known per se or can be prepared by customary methods.
The compounds of the general formula (X) are novel and can be prepared as described above.
The compounds of the general formula (III), (V) and (VI) are novel and can be prepared as described above.
The compounds of the general formula (IV) are known per se or can be prepared by customary methods.
Most of the compounds oiF the general formula (VII) are novel and can be prepared as described above.
The compounds of the general formula (Ia) are novel and can be prepared as described above.
The compounds of the general formula (I) according to the invention have a pharmacological activity spectrum which could not have been foreseen.
The compounds of the general formula (I) according to the invention have useful pharmacological properties which are superior when compared to the prior art;
in particular, they ane highly effective inhibitors of the cholesterol ester transfer protein (CETP) and they stimulate the reverse cholesterol transport. The active compounds according to the invention effect a reduction of the LDL cholesterol level in the blood and simultaneously increa se the HDL cholesterol level. They can therefore be used for the treatment and prevention of hyperlipoproteinaemia, dyslipidaemias, hypertriglyceridaemias, hyperlipidaemias or arteriosclerosis.
Le A 32 664-Foreign Countries The pharmacological activity of the substances according to the invention was assessed using the following test:
CETP Inhibition test Preparation of CETP
CETP is obtained in partially purified form from human plasma by differential centrifugation and column chromatography and used for the test. For this purpose, human plasma is adjusted to a density of 1.21 g per ml using NaBr and centrifuged) at SO,OCIO rpm at 4°C for 18 h. The bottom fraction (d >
1.21 g/ml) is applied to a Sephadex~Phenyl-Sepharose 4B (Pharmacia) column, washed with 0.15 rn NaCI/0.001 m TrisHCl pH 7.4 and subsequently eluted using dist.
water. The: CETP-active fractions are pooled, dialysed against 50 mM Na-acetate pH 4.5 and applied to a CM-Sepharose~ (Pharmacia) column. Elution is subsequently carne~d out using a linear gradient (0-1 M NaCI). The pooled CETP fractions are dialysed against 10 mM TrisHCl pH 7.4 and subsequently purified further by chromatography over a Mono Q~ column (Pharmacia).
Preparation of radioactively labelled HDL
50 ml of fresh human EDTA plasma is adjusted to a density of 1.12 using NaBr and centrifisged at 4°C in a Ty 65 rotor at 50,000 rpm for 18 h. The upper phase is used to obtain cold LDL. The lower phase is dialysed against 3*41 of PDB
buffer (10 mM Tris/HCl pH 7.4, 0.15 mM NaCI, 1 mM EDTA, 0.02% NaN3).
Per 10 ml volume of retained material, 20 p,l of 3H-cholesterol (Dupont NET-725; 1 -p,Ci/~,1, dissolved in ethanol) are subsequently added, and the mixture is incubated at 37°C under NZ for 72 h.
The mixture is then adjusted to a density of 1.21 using NaBr and centrifuged in a Ty 65 rotor at 20°C and 50,000 rpm for 18 h. The upper phase is collected and Le A 32 664-Forf:i Countries the lipoprotein fractions are purified by gradient centrifugation. To this end, the isolated, labelled lipoprotein fraction is adjusted to a density of 1.26 using NaBr. In each case 4 ml of this solution are covered in centrifuge tubes (SW
rotor) with 4 ml of a solution of a density of 1.21 and 4.5 ml of a solution of 1.063 (density solutions of PDB buffer and NaBr), and the tubes are subsequently centrifuged in an SW 40 rotor at 38,000 rpm and 20°C for 24 h.
The intermediate layer which is found between a density of 1.063 and 1.21 and which contains the; labelled HDL is dialysed against 3*100 volume of PDB
buffer at 4°C.
The retained material contains radioactively labelled 3H-CE-HDL, which is used for the test adjusted to approximately Sx 106 cmp per ml.
CETP test To assess the CET'P activity, the transfer of 3H-cholesterol ester from human HD lipoproteins to biotinylated LD lipoproteins is measured.
The reaction is ternunated by addition of Streptavidin-SPA~ beads (Amersham) and the transferredl radioactivity is directly measured in a liquid scintillation counter.
In the ass;~y mixture, 10 p,l of HDL 3H-cholesterol ester (- 50,000 cpm) with 10 p l of Eeiotin-LDL (Amersham) in 50 mM Hepes/0.15 m NaCI/0.1% bovine serum albumin/0.05% NaN3 pH 7.4 are incubated with 10 p,l of CETP
(1 mg/ml) and 3 p,l of a solution of the substance to be tested (dissolved in 10%
DMSO/1°ro BSA) at 37°C for 18 h. 200 p.l of the SPA streptavidin bead solution (TRKQ 7005) are subsequently added, the mixture is incubated with shaking for another 1 h and subsequently measured in a scintillation counter. The controls used are corresponding incubations with lOp,l of buffer, lOp,l of CETP at 4°C and 10 p l of CETP at 37°C.
Le A 32 664-Forei Countries The activity which its transferred in the control experiments with CETP at 37°C
is taken to be 100% transfer. The substance concentration at which this transfer is reduced by half is. stated as the ICSo value.
do Table A below, the ICSO values (mol/1) for CETP inhibitors are given:
Table A:
Example lVo. ~ ICSO value (nmoUl) 2'.2 6000 Ex vivo activity o:f the compounds according to the invention Syrian gold hamsters, which have been bred in our own laboratory, are anaesthetized after 24 hours of fasting (0.8 mg/kg of atropine, 0.8 mg/kg of Ketavet~ s.c., 30' later 50 mg/kg of nembutal i.p.). The jugular vein is subsequently exposed and cannulated. The test substance is dissolved in a suitable solvent (usually adalate placebo solution: 60 g of glycerol, 100 ml of H20, ad 1C100 ml PEG-400) and administered to the animals via a PE catheter, which is introduced into the jugular vein. The same volume of solvent without test substance is administered to the control animals. The vein is subsequently tied off anti the wound is closed.
The test substances can also be administered p.o. by dissolving the substances in DMSO and suspending them in 0.5% tylose and administering them perorally using a pfiaryngeal tube. Identical volumes of solvent without test substance ~~re administered to the control animals.
Le A 32 664-Foreii, n~Countries At different intervalls - up to 24 hours after the administration - blood samples are taken from the: animals by puncture of the retro-orbital venous plexus (approximately 250 p.l). Coagulation is completed by incubation at 4°C
overnight, and the samples are subsequently centrifuged at 6000 x g for 10 minutes. The CET1P activity is determined in the resulting serum using the modified C'ETP test. The transfer of 3H-cholesterol ester from HD lipoproteins to biotinylated LD lipoproteins is measured as described above for the CETP
test.
The reaction is terminated by addition of Streptavidin-SPAR beads (Amersham), and the transferred radioactivity is directly deterniined in a liquid scintillation counter.
The test protocol is carried out as described under "CETP test". However, to test the serum, 10 p,l o~f CETP are replaced by 10 p l of the appropriate serum samples. C'.orresponding incubations of sera of untreated animals serve as controls.
The activity that is transferred in the control experiments using control sera is classified as 100% transfer. The substance concentration at which this transfer is reduced by half is stated as the EDSO value.
In vivo activity oi' the compounds according to the invention In experiments for assessing the oral activity on lipoproteins and triglycerides, test substance, dissolved in DMSO and suspended in 0.5% tylose, is administered perorally using a pharyngeal tube to Syrian gold hamsters which have been bred in our own laboratory. To determine the CETP activity, blood samples (approximately 250 p.l) are taken by retro-orbital puncture prior to the start of the experiment. The test substances are subsequently administered perorally using a pharyngeal tube. Identical volumes of solvent without test Le A 32 664-Forei n Countries substance are administered to the control animals. Subsequently, the animals have to fast and at different intervals - up to 24 hours after the administration of the substances - blood samples are taken by puncture of the retro-orbital venous plexus.
Coagulation is completed by incubation at 4°C overnight, and the samples are subsequently cenUrifuged at 6000 x g for 10 minutes. The content of cholesterol) and triglycerides in the resulting serum is assessed using modified commercially availlable enzyme tests (cholesterol enzymatic 14366 Merck, triglycerides 14364 Merck). Serum is diluted in a suitable manner with physiologi~:.al saline: solution.
100 p.l of serum dilution and 100 r~ 1 of test substance are transferred into 96-well plates and incubated at room temperature for 10 minutes. The optical density is subsequently determined at a wavelength of 492 nm using an automatic plate reader. The triglyceride and cholesterol concentrations of the samples are determined with the aid of a standard curve measured in parallel.
The determination of the HDL-cholesterol content is earned out after precipitation of the ApoB-containing lipoproteins using a reagent mixture (Sigma 35:?-4 HDL cholesterol reagent) in accordance with the instructions of the manufacturer.
In vivo activity in transgf~nic hCETP mice The substances to be tested were administered to transgenic mice, which were bred in our own laboratory (Dinchuck, Hart, Gonzalez, Karmann, Schmidt, Wirak; BE~A (1995~), 1295, 301), via the feed. Prior to the beginning of the experiment, blood samples were taken retro-orbitally from the mice to determine cholesterol and triglycerides in the serum. The serum was obtained as described above for hamsters by incubation at 4°C overnight and Le A 32 664-Forei.~n Countries subsequent centrifugation at 6000 x g. After one week, blood samples were again taken from the mice to determine lipoproteins and triglycerides. The change in the measured parameters are expressed as a change in per cent based on the initial value.
The invention fun:hermore relates to the combination of benzyl-biphenylenes of the general formula (1:) with a glucosidase and/or amylase inhibitor for the treatment of familial hyperlipidaemias, of obesity (adipositas) and of diabetes mellitus.
Glucosidase and/or amylase inhibitors in the context of the invention are, for example, acarbose, adipasine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose (MLiL-73945), tendamistate, AI-3688, trestatin, pradimicin-Q and salbostatin.
Preference is given to the .combination of acarbose, miglitol, emiglitate or voglibose with one of the abovementioned compounds of the general formulae (I) according to the invention.
Furthermore, the compounds according to the invention can be combined in combination with cholesterol-lowering vastatins or ApoB-lowering principles, in order to treat dyslipidaemias, combined hyperlipidaemias, hypercholesterolaemias or hypertriglyceridaemias.
The abovementicmed connbinations can also be used for primary or secondary prevention of coronary heart diseases (for example myocardial infarction).
Vastatins in the context of the invention are, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. ApoB-lowering agents are, for example, MTP inhibitors.
Le A 32 664-Foreign Cc>untries Preference is given to the combination of cerivastatin or ApoB inhibitors with one of the abovementioned compounds of the general formulae (I) and (Ia) according to the invention.
The novel 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 earners or solvents. In this case the therapeutically active compound should in each case be present in a concentration from approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds using solvents amj/or earners, if appropriate using emulsifiers and/or dispersants, it optionally being possible, for example, to use organic solvents as auxiliary solvents if the diluent used is water.
Administration i;~ carried out in a customary manner, intravenously, orally, parenterally or perlingually, in particular orally.
In the case of parenteral administration, solutions of the active compound can be used by employing suitable liquid earner materials.
In general, it has proved advantageous, in the case of intravenous administration, to administer amounts from approximately 0.001 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg, of body weight to achieve effective results, and in the case of oral administration th~~ dosage is approximately 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg, of body weight.
In spite of this, if appropriate it may be necessary to depart from the amounts mentioned, namely depending on the body weight or on the type of administration Le A 32 664-Fore:i~n Countries route, on individual reaction towards the medicament, the manner of its formulation and the time at or interval during which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amounts, while in other cases the upper limit mentioned has to be exceeded. In the S case of the administration of relatively large amounts, it may be advisable to divide these into several i~,ndividual doses over the course of the day ' Le A 32 664-Foreign Countries Starting materials Example I
4-Methyl-1-(4-trifluoromethyl-phenyl)-pentan-3-one O
At 0°C, 131 ml (0.328 mol) of a 2.SM solution of nBuLi in n-hexane are added dropwise over a period of 30 min to 40 g (0.312 mol) of N,N-dimethyl-N-{2-methyl-1-[2-(4-trifluorom~~thyl-phenyl)-ethyl]-propylidene}-hydrazine (S.D Sharma et al., J. Org. Chem. 1990, 55, 2196) in 400 ml of abs. THF, and the mixture is stirred at 15-20°C for 30 m,in. A solution of 67.9 g (0.284 mol) of 4-trifluoromethyl-benzyl bromide in 100 ml of al>s. THF is then added dropwise and the mixture is stirred at 20°C for 2 h. The reaction mixture is concentrated to about 80 ml and carefully hydrolysed using :?00 ml of H20. The mixture is extracted with ethyl acetate and the extract is washed with sat. NaCI solution, dried over Na2S04 and concentrated.
This gives 82 g of N,N-dimethyl-N-{ 2-methyl-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-propylidene}-hydrazine as a red oil.
The hydrazone is ~3issolved in 150 ml of THF and admixed with 170 ml of 2M
HCI, and the mixture is stirred at 20°C for 1 h. The mixture is extracted with EtOAc and the extract is washed with water and sat.. NaCI solution, dried over NaZS04 and concentrated. Distillation gives a colourless oil (b.p. 95-98°C/0.7 mbar).
Yield: 51.5 g (78 r~) Rf = 0.25 (EtOAc/PE 1:20) Le A 32 664-Foreign Countries _q.4_ Example II
1-(4-Fluoro-phenyl)-1-hydroxy-4-methyl-2-(4-trifluoromethyl-benzyl)-pentan-3-one H
F
At -70°C, 400 ml (0.791 mol) of a 2.OM solution of LDA in THF/heptane are added over a period of 50 min to 184 g (0.753 mol) of the compound from Example 1 in 1.2 I of abs. THF, and the mixture is stirred at -70°C for 60 min. 81 ml (0.753 mol) of 4-fluorobenzaldehyde are then added, and the mixture is stirred at -70°C for 60 min. The reaction is quenched with 100 ml of a 10% Nl-hCl solution, the mixture is allowed to warm to -10°C and a further 400 ml of a 10% NH4C1 solution are added. The phases are separated, the aqueous phase is extracted with EtOAc and the extract is washed with sat. NaCI solution dried over Na2S04 and concentrated.
The crude product is purified over silica gel 60 (EtOAc/PE 1:5).
Yield: 253 g (91%) Rf= 0.31 (EtOAc/PE 1:5) Example III
1-(4-Fluoro-pheny 1)-4-methyl-2-(4-trifluoromethyl-benzyl )-pent-1-en-3-one Le A 32 664-Forei,~n Countries F
At 0°C, 231 rnl (1.672 mol) of triethylamine and 118 ml (1.52 mol) of methanesulphonvl chloride are added to 279 g (0.76 mol) of the compound from Example II in 2.:p 1 of abs. CHZC12. The mixture is stirred at 20°C
overnight and, at -30°C, 456 ml (;5.04 mol) of DBU dissolved in 1 1 of abs. CH2Cl2 are added. After 90 min, the reaction is quenched with 500 ml of water. The phases are separated and the aqueous phase is extracted with CH2ClZ. The combined organic phases are washed with 0.5 M HC'.1, dried over Na~S04 and concentrated. The crude product is purified over silica gel 60 (cyclohexane/EtOAc 40:1 to 10:1).
Yield: 220 g (83~~0) R f = 0.27 (EtOAc;/PE 1:20).
Example IV
1-Fluoro-4-(3-isopropyl-2-(4-trifluoromethyl-benzyl)-buta-1,3-dienyl)-benzene F
Le A 32 664-Forei, ng-Countries At 0°C, 47.6 g ( l 14.2 mmol) of a mixture of methyl-triphenylphosphonium bromide and sodium amide in 200 ml of abs. ether are added to 20 g (5.71 mmol) of the compound from Example III in 100 ml of abs. ether. After 90 min, 300 ml of petroleum ether ;ire added and the mixture is filtered off with suction through a little silica gel. The silica gel is washed with 2 1 of PE and the filtrate is concentrated. The crude product is purified over silica gel 60 (cyclohexane/EtOAc 20:1 to 10:1).
Yield: 9.1 g (44°'0) Rf = 0.35 (PE).
Example V
Methyl 6-(4-fluoro-phenyl)-4-isopropyl-5-(4-trifluoromethyl-benzyl)-cyclohexa-1,4-dienecarbox~~late F
7.66 ml (86.1 mmol) of methyl propiolate are added to 3.0 g (8.61 mmol) of the compound from Example IV in 15 ml of abs. xylene, and the mixture is heated in a closed autoclave at 180°C for 20 h. The mixture is subsequently concentrated with silica gel under reduced pressure and purified over 80 g of silica gel (elution with cyclohexane and cyclohexane/EtOAc 20:1, 10:1) Yield: 2.68 g (70%) Rf = 0.36 (EtOAc:/PE 1:20) Example VI
Methyl4'-fluoro-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-carboxylate Le A 32 664-Fore:i ng-Cauntries F
149 mg (0.34 mol) of the compound from Example V and 472 mg (2.08 mmol) of DDQ are dissolved in 10 ml of toluene, and the mixture is refluxed overnight.
The mixture is concentrated and the residue is purified over silica gel (cyclohexane/EtO.Ac 20:1) Yield: 122 mg (82%) Rf = 0.22 (EtOAc/PE 1:20) Example VII
[4'-Fluoro-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol 46 mg (0.11 mmol) of the compound from Example VI are dissolved in 5 ml of abs.
toluene and, at -7f~°C, admixed with 600,1 (0.9 mmol) of a 1.SM
solution of DIBAH
in toluene. The mixture: is stirred at this temperature for 1 h, allowed to warm to room temperature and stirred for another hour. The reaction is quenched with water and the mixture is extracted with EtOAc. The combined organic phases are dried over Na2S04 and concentrated. The crude product is purified over silica gel 60 (petroleum ether/1=?tOAc 2:1).
Yield: 25 mg (58°r'o) Rf = 0.28 (EtOAc/petroleum ether 1:5).
Le A 32 664-Foreign Countries Example VIII
Dimethyl 3-(4-fluoro-phenyl)-5-isopropyl-4-(4-trifluoromethyl-benzyl)-cyclohexa-1,4-diene-1,2-dicarboxylate C02Me F3C C02Me 36.3 g (255 mural) of dimethyl acetylenedicarboxylate are added to 22.25 g (63.9 mmol) of the compound from Example IV in 400 ml of abs. toluene, and the mixture is refluxed for 48 h. The mixture is concentrated and excess dimethyl acetylenedicarboxylate is distilled off under reduced pressure. The crude product is subsequently purified over silica gel (CHZC12) Yield: 23.9 g (77°0) Rf = 0.39 (CHzCl2).
Example IX
Dimethyl 4'-fluoro-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2,3-dicar-boxylate C02Me F3 C02Me 23.9 g (50 mol) of the compound from Example VIII and 22.2 g (100 mmol) of DDQ
are dissolved in 250 ml of toluene, and the mixture is refluxed overnight. The mixture is concentrated and the product is purified over silica gel (CHZC12).
Yield: 19.9 g (81 ~'o) R f = 0.37 (CHZCI;;).
Le A 32 664-Foreign Countries Example X
[4'-Fluoro-5-isopropyl-2-(tetrahydro-pyran-2-yloxymethyl)-6-(4-trifluoromethyl-benzyl)-biphenyl-3-yl]-c;arbaldehyde P
830 mg of A1203 (neutral) and 1.31 g (6.11 mmol) of pyridinium chlorochromate are added in 3 portions over a period of 60 minutes to 2.10 g (4.06 mmol) of the compound from Example 2, dissolved in 100 ml of abs. CHZC12. After 1 h, the mixture is filtere~3 through A1Z03, and the A1203 is washed with CHZC12.
Further purification is carried out over silica gel 60 (CHzCIz).
Yield: 1.84 g (8770) Rf = 0.39 (EtOAc,~PE 1:5).
Le A 32 664-Fore i ~n Countries Preparation Examples Example 1 [4'-Fluoro-3-hydroxymethyl-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol FsC H
2.2 g (4.5 mmol) of the compound from Example TX are dissolved in 60 ml of abs.
toluene and, at -7.3°C, admixed with 60 ml (90 mmol) of a 1.SM solution of DIBAH
in toluene. The mixture is stirred at this temperature for 1, allowed to warm to room temperature and stirred for another hour. The mixture is poured onto ice and extracted with EtOAc. The combined organic phases are dried over Na2S04 and concentrated. The crude product is purified over silica gel 60 (CHZC12/MeOH
100:3).
Yield: 1.82 g (93~~0) Rf = 0.20 (CHZCI;/MeOH 100:3).
Example 2 [4'-Fluoro-5-isopropyl-2,-(tetrahydro-pyran-2-yloxymethyl)-6-(4-trifluoromethyl-benzyl)-biphenyl-3-yl]-methanol P
Le A 32 664-Foreign Countries 15.5 g (35.2 mrnol) of the compound from Example 1, 7.2 g (105 mmol) of imidazole and l:l ml (42 mmol) of tert-butyl-diphenyl-chlorosilane (TBDPS) are dissolved in 300 ml of CH2C12, and the mixture is stirred at room temperature for 90 min. The reaction is quenched with water, the mixture is extracted with and the extract is dried over Na2S04 and concentrated. The crude product is purified over silica gel 60 (cyclohexane/EtOAc 100:1 to 20:1). This gives 17.8 g (26.4 mmol, 75%) of [3- ten-butyl-diphenylsiloxymethyl-4'-fluoro-5-isopropyl-6-(4-trifluoro-methyl-benzyl)-biphenyl-2-ylJ-methanol (Rf = 0.52 in CH2C12).
This compound is dissolved in 220 ml of abs. CH2C12, and 3.32 g (13.2 mmol) of pyridinium p-tolu~~nesulphonate (PPTS) and 12.1 ml (132 mmol) of 3,4-dihydropyran are added. After 60 min at room temperature, water is added and the mixture is extracted with Cl-12C12. The combined organic phases are washed with sat.
NaHC03 solution and water, dried over Na2S04 and concentrated. This gives 19.6 g (26 mmol, 98%) of the THP-protected compound (Rf = 0.22 EtOAc/PE 1:20).
This compound is dissolved in 250 ml of abs. THF. 24.3 g (77 mmol) of tetra-n-butyl-ammonium fluoride trihydrate (TBAFx3Hz0) are added, and the mixture is stirred at room temperature for 90 min. Water is added and the mixture is extracted with EtOAc. The combined organic phases are washed with sat. NaHC03 solution and water, dried over Na2S04 and concentrated. Purification is carried out over silica gel 60 (cyclohexane/EtOAc 20:1 to 2:1).
Yield: 11.3 g (85~~0) Rf = 0.54 (EtOAc APE 1:2) Example 3 [3-Benzyloxymethyl-4'-fluoro-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol Le A 32 664-Foreign Countries F
12 mg (0.48 mmol) of sodium hydride and 8 mg of tetra-n-butyl-ammonium iodide are suspended in 3 ml of abs. THF, and a solution of 50 mg (0.1 mmol) of the compound from Example 2 in 1 ml of abs. THF is added dropwise. After 30 minutes, .
14 p,l (0.115 mrnol) of benzyl bromide are added, and the mixture is stirred overnight. Water is added, and the mixture is then extracted with EtOAc and the extract is dried over NaaS04 and concentrated. Purification is carned out over silica gel 60 (cyclohexan/EtOAc 5:1). This gives 70 mg of the THP-protected compound.
This is dissolved in methanol and mixed with 300 mg of pyridinium-p-toluenesulphonate (PPTS) After 2h of stirnng at room temperature, water is added, the mixture is e~;tracted with EtOAc and the extract is dried over Na2S04 and concentrated. The purification is carned out over silica gel 60 (cyclohexane/EtOAc 5:1).
Yield: 35 mg (58°'0) Rf = 0.56 (EtOAc/PE 1: '_>) Example 4 [4'-Fluoro-3-(4-fluoro-phenoxymethyl)-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol F
F
Le A 32 664-Fore i Qn Countries 150 mg (0.29 mrnol) of the compound from Example 2, 99 mg (0.38 mmol) of triphenylphosphine and 49 mg (0.435 mmol) of 4-fluorophenol are dissolved in 4 ml of ether/THF (3:1 ), and 59 ~,l (0.38 mmol) of diethyl azodicarboxylate are added dropwise over 15 minutes. After 30 minutes at room temperature, the mixture is concentrated under reduced pressure and the crude product is purified over silica gel 60 (cyclohexane/laOAc: 20:1). This gives 156 mg (83%) of the THP-protected compound. This i<,; dissolved in methanol and admixed with 300 mg of pyridinium-p-toluenesulphonate (PPT~S). After 2h of stirnng at room temperature, water is added, the mixture is e~;tracted with EtOAc and the extract is dried over Na2S04 and concentrated. Purification is carded out over silica gel 60 (cyclohexane/EtOAc 5:1).
Yield: 75 mg (79°~) R f = 0.40 (EtOAc/PE l :.'>) Example S
2-[4'-Fluoro-2-hydroxymethyl-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-3-ylmethyl]-isoindole-1,3-dione N
F
O
150 mg (0.29 mmol) of the compound from Example 2, 99 mg (0.38 mmol) of triphenylphosphine and 64 mg (0.435 mmol) of phthalimide are dissolved in 4 ml of ether/THF (3:1), and 59 ~,l (0.38 mmol) of diethylazodicarboxylate are added dropwise over 1_'~ minutes. After 30 minutes at room temperature, the mixture is concentrated under reduced pressure and the crude product is purified over silica gel 60 (cyclohexane/ EtOAc 5:1).This gives 134 mg (72%) of the THP-protected compound. This is dissolved in 12 ml of acetic acid/THF/water (4:2:1) and the Le A 32 664-Fore:i n~Countries mixture is stirred at 45°C for 18 h. The mixture is concentrated under reduced pressure and the crude product is purified over silica gel 60 (CH2C12/MeOH
100:3).
Yield: 74 mg (69°r'o) Rf = 0.39 (CH2C12/MeOH 100:3).
Example 6 [3-Cyclopentylidenemethyl-4'-fluoro-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol At 0°C, 0.63 ml ( 1.0 mrnol) of a 1.6M solution of n-BuLi in n-hexane is added to 480 mg (1.16 mm.ol) of methyl-triphenylphosphonium bromide in 40 ml of abs.
ether, and the mixture is stirred at 20°C for 2 h. 100 mg (0.19 mmol) of the compound from lJxample X, dissolved in 10 ml of abs. ether, are added. After 90 min, petroleum. ether is added and the mixture is filtered with suction through a little silica gel. The silica gel is washed with petroleum ether and the filtrate is concentrated. The crude product is purified over silica gel 60 (toluene). This gives 88 mg (80%), Rf == 0.42 (toluene) of the THP-protected compound. 70 mg of this are dissolved in meth~~nol and admixed with 300 mg of pyridinium-p-toluenesulphonate (PPTS). After 2 h of stirring at room temperature, water is added, the mixture is extracted with EI:OAc and the extract is dried over Na2S04 and concentrated.
Purification is carried out over silica gel 60 (cyclohexane/EtOAc 10:1).
Yield: 49 mg (81Q~) Rf = 0.19 (EtOAc/PE 1:1.0) Le A 32 664-Foreign Countries Example 7 [3-Cyclopentylmethyl-4'-fluoro-S-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol 20 mg of Pt/C (5°r'o) are added to 20 mg (0.04 mmol) of the compound from Example 6, dissolved in 5 ml of EtOAc, and the mixture is hydrogenated at atmospheric pressure in the presence of hydrogen for 5 h. The mixture is filtered through a membrane filter and concentrated. Further purification is carned out over silica gel 60 (EtOAc/Pe 1:1~~).
Yield: 19 mg (96°,0) Rf=0.20(EtOAciPE 1::L0) Le A 32 664-Forei ~n Countries The compounds listed in Table 1 are prepared analogously to the procedure of Examples 1-7:
Table 1:
Ex. No. ~~tructure R f 8 F 0.20 (CH2C12/MeOH = 100:3) / OH
\ /
/ \ ~ OH
f. F HaC
Methyl4'-fluoro-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-carboxylate Le A 32 664-Fore:i ng-Cauntries F
149 mg (0.34 mol) of the compound from Example V and 472 mg (2.08 mmol) of DDQ are dissolved in 10 ml of toluene, and the mixture is refluxed overnight.
The mixture is concentrated and the residue is purified over silica gel (cyclohexane/EtO.Ac 20:1) Yield: 122 mg (82%) Rf = 0.22 (EtOAc/PE 1:20) Example VII
[4'-Fluoro-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol 46 mg (0.11 mmol) of the compound from Example VI are dissolved in 5 ml of abs.
toluene and, at -7f~°C, admixed with 600,1 (0.9 mmol) of a 1.SM
solution of DIBAH
in toluene. The mixture: is stirred at this temperature for 1 h, allowed to warm to room temperature and stirred for another hour. The reaction is quenched with water and the mixture is extracted with EtOAc. The combined organic phases are dried over Na2S04 and concentrated. The crude product is purified over silica gel 60 (petroleum ether/1=?tOAc 2:1).
Yield: 25 mg (58°r'o) Rf = 0.28 (EtOAc/petroleum ether 1:5).
Le A 32 664-Foreign Countries Example VIII
Dimethyl 3-(4-fluoro-phenyl)-5-isopropyl-4-(4-trifluoromethyl-benzyl)-cyclohexa-1,4-diene-1,2-dicarboxylate C02Me F3C C02Me 36.3 g (255 mural) of dimethyl acetylenedicarboxylate are added to 22.25 g (63.9 mmol) of the compound from Example IV in 400 ml of abs. toluene, and the mixture is refluxed for 48 h. The mixture is concentrated and excess dimethyl acetylenedicarboxylate is distilled off under reduced pressure. The crude product is subsequently purified over silica gel (CHZC12) Yield: 23.9 g (77°0) Rf = 0.39 (CHzCl2).
Example IX
Dimethyl 4'-fluoro-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2,3-dicar-boxylate C02Me F3 C02Me 23.9 g (50 mol) of the compound from Example VIII and 22.2 g (100 mmol) of DDQ
are dissolved in 250 ml of toluene, and the mixture is refluxed overnight. The mixture is concentrated and the product is purified over silica gel (CHZC12).
Yield: 19.9 g (81 ~'o) R f = 0.37 (CHZCI;;).
Le A 32 664-Foreign Countries Example X
[4'-Fluoro-5-isopropyl-2-(tetrahydro-pyran-2-yloxymethyl)-6-(4-trifluoromethyl-benzyl)-biphenyl-3-yl]-c;arbaldehyde P
830 mg of A1203 (neutral) and 1.31 g (6.11 mmol) of pyridinium chlorochromate are added in 3 portions over a period of 60 minutes to 2.10 g (4.06 mmol) of the compound from Example 2, dissolved in 100 ml of abs. CHZC12. After 1 h, the mixture is filtere~3 through A1Z03, and the A1203 is washed with CHZC12.
Further purification is carried out over silica gel 60 (CHzCIz).
Yield: 1.84 g (8770) Rf = 0.39 (EtOAc,~PE 1:5).
Le A 32 664-Fore i ~n Countries Preparation Examples Example 1 [4'-Fluoro-3-hydroxymethyl-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol FsC H
2.2 g (4.5 mmol) of the compound from Example TX are dissolved in 60 ml of abs.
toluene and, at -7.3°C, admixed with 60 ml (90 mmol) of a 1.SM solution of DIBAH
in toluene. The mixture is stirred at this temperature for 1, allowed to warm to room temperature and stirred for another hour. The mixture is poured onto ice and extracted with EtOAc. The combined organic phases are dried over Na2S04 and concentrated. The crude product is purified over silica gel 60 (CHZC12/MeOH
100:3).
Yield: 1.82 g (93~~0) Rf = 0.20 (CHZCI;/MeOH 100:3).
Example 2 [4'-Fluoro-5-isopropyl-2,-(tetrahydro-pyran-2-yloxymethyl)-6-(4-trifluoromethyl-benzyl)-biphenyl-3-yl]-methanol P
Le A 32 664-Foreign Countries 15.5 g (35.2 mrnol) of the compound from Example 1, 7.2 g (105 mmol) of imidazole and l:l ml (42 mmol) of tert-butyl-diphenyl-chlorosilane (TBDPS) are dissolved in 300 ml of CH2C12, and the mixture is stirred at room temperature for 90 min. The reaction is quenched with water, the mixture is extracted with and the extract is dried over Na2S04 and concentrated. The crude product is purified over silica gel 60 (cyclohexane/EtOAc 100:1 to 20:1). This gives 17.8 g (26.4 mmol, 75%) of [3- ten-butyl-diphenylsiloxymethyl-4'-fluoro-5-isopropyl-6-(4-trifluoro-methyl-benzyl)-biphenyl-2-ylJ-methanol (Rf = 0.52 in CH2C12).
This compound is dissolved in 220 ml of abs. CH2C12, and 3.32 g (13.2 mmol) of pyridinium p-tolu~~nesulphonate (PPTS) and 12.1 ml (132 mmol) of 3,4-dihydropyran are added. After 60 min at room temperature, water is added and the mixture is extracted with Cl-12C12. The combined organic phases are washed with sat.
NaHC03 solution and water, dried over Na2S04 and concentrated. This gives 19.6 g (26 mmol, 98%) of the THP-protected compound (Rf = 0.22 EtOAc/PE 1:20).
This compound is dissolved in 250 ml of abs. THF. 24.3 g (77 mmol) of tetra-n-butyl-ammonium fluoride trihydrate (TBAFx3Hz0) are added, and the mixture is stirred at room temperature for 90 min. Water is added and the mixture is extracted with EtOAc. The combined organic phases are washed with sat. NaHC03 solution and water, dried over Na2S04 and concentrated. Purification is carried out over silica gel 60 (cyclohexane/EtOAc 20:1 to 2:1).
Yield: 11.3 g (85~~0) Rf = 0.54 (EtOAc APE 1:2) Example 3 [3-Benzyloxymethyl-4'-fluoro-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol Le A 32 664-Foreign Countries F
12 mg (0.48 mmol) of sodium hydride and 8 mg of tetra-n-butyl-ammonium iodide are suspended in 3 ml of abs. THF, and a solution of 50 mg (0.1 mmol) of the compound from Example 2 in 1 ml of abs. THF is added dropwise. After 30 minutes, .
14 p,l (0.115 mrnol) of benzyl bromide are added, and the mixture is stirred overnight. Water is added, and the mixture is then extracted with EtOAc and the extract is dried over NaaS04 and concentrated. Purification is carned out over silica gel 60 (cyclohexan/EtOAc 5:1). This gives 70 mg of the THP-protected compound.
This is dissolved in methanol and mixed with 300 mg of pyridinium-p-toluenesulphonate (PPTS) After 2h of stirnng at room temperature, water is added, the mixture is e~;tracted with EtOAc and the extract is dried over Na2S04 and concentrated. The purification is carned out over silica gel 60 (cyclohexane/EtOAc 5:1).
Yield: 35 mg (58°'0) Rf = 0.56 (EtOAc/PE 1: '_>) Example 4 [4'-Fluoro-3-(4-fluoro-phenoxymethyl)-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol F
F
Le A 32 664-Fore i Qn Countries 150 mg (0.29 mrnol) of the compound from Example 2, 99 mg (0.38 mmol) of triphenylphosphine and 49 mg (0.435 mmol) of 4-fluorophenol are dissolved in 4 ml of ether/THF (3:1 ), and 59 ~,l (0.38 mmol) of diethyl azodicarboxylate are added dropwise over 15 minutes. After 30 minutes at room temperature, the mixture is concentrated under reduced pressure and the crude product is purified over silica gel 60 (cyclohexane/laOAc: 20:1). This gives 156 mg (83%) of the THP-protected compound. This i<,; dissolved in methanol and admixed with 300 mg of pyridinium-p-toluenesulphonate (PPT~S). After 2h of stirnng at room temperature, water is added, the mixture is e~;tracted with EtOAc and the extract is dried over Na2S04 and concentrated. Purification is carded out over silica gel 60 (cyclohexane/EtOAc 5:1).
Yield: 75 mg (79°~) R f = 0.40 (EtOAc/PE l :.'>) Example S
2-[4'-Fluoro-2-hydroxymethyl-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-3-ylmethyl]-isoindole-1,3-dione N
F
O
150 mg (0.29 mmol) of the compound from Example 2, 99 mg (0.38 mmol) of triphenylphosphine and 64 mg (0.435 mmol) of phthalimide are dissolved in 4 ml of ether/THF (3:1), and 59 ~,l (0.38 mmol) of diethylazodicarboxylate are added dropwise over 1_'~ minutes. After 30 minutes at room temperature, the mixture is concentrated under reduced pressure and the crude product is purified over silica gel 60 (cyclohexane/ EtOAc 5:1).This gives 134 mg (72%) of the THP-protected compound. This is dissolved in 12 ml of acetic acid/THF/water (4:2:1) and the Le A 32 664-Fore:i n~Countries mixture is stirred at 45°C for 18 h. The mixture is concentrated under reduced pressure and the crude product is purified over silica gel 60 (CH2C12/MeOH
100:3).
Yield: 74 mg (69°r'o) Rf = 0.39 (CH2C12/MeOH 100:3).
Example 6 [3-Cyclopentylidenemethyl-4'-fluoro-5-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol At 0°C, 0.63 ml ( 1.0 mrnol) of a 1.6M solution of n-BuLi in n-hexane is added to 480 mg (1.16 mm.ol) of methyl-triphenylphosphonium bromide in 40 ml of abs.
ether, and the mixture is stirred at 20°C for 2 h. 100 mg (0.19 mmol) of the compound from lJxample X, dissolved in 10 ml of abs. ether, are added. After 90 min, petroleum. ether is added and the mixture is filtered with suction through a little silica gel. The silica gel is washed with petroleum ether and the filtrate is concentrated. The crude product is purified over silica gel 60 (toluene). This gives 88 mg (80%), Rf == 0.42 (toluene) of the THP-protected compound. 70 mg of this are dissolved in meth~~nol and admixed with 300 mg of pyridinium-p-toluenesulphonate (PPTS). After 2 h of stirring at room temperature, water is added, the mixture is extracted with EI:OAc and the extract is dried over Na2S04 and concentrated.
Purification is carried out over silica gel 60 (cyclohexane/EtOAc 10:1).
Yield: 49 mg (81Q~) Rf = 0.19 (EtOAc/PE 1:1.0) Le A 32 664-Foreign Countries Example 7 [3-Cyclopentylmethyl-4'-fluoro-S-isopropyl-6-(4-trifluoromethyl-benzyl)-biphenyl-2-yl]-methanol 20 mg of Pt/C (5°r'o) are added to 20 mg (0.04 mmol) of the compound from Example 6, dissolved in 5 ml of EtOAc, and the mixture is hydrogenated at atmospheric pressure in the presence of hydrogen for 5 h. The mixture is filtered through a membrane filter and concentrated. Further purification is carned out over silica gel 60 (EtOAc/Pe 1:1~~).
Yield: 19 mg (96°,0) Rf=0.20(EtOAciPE 1::L0) Le A 32 664-Forei ~n Countries The compounds listed in Table 1 are prepared analogously to the procedure of Examples 1-7:
Table 1:
Ex. No. ~~tructure R f 8 F 0.20 (CH2C12/MeOH = 100:3) / OH
\ /
/ \ ~ OH
f. F HaC
9 F 0.38 (EtOAc/petroleum ether =
1:5) \ \ ~OH
/ ( /
f. _H3C _ F 0.28 (EtOAc/petroleum ether =
/ I 1:5) \ \ ~OH
F ~ / ~ /
f. HsC _ Le A 32 664-Forei gn Countries Ex. No. Structure Rf 11 F 0.66 (CH2Cl2) o~
F
O~ ,CHa ' HaC ~
CH
F, a ~
F CH CH
CHa HaC
12 F 0.13 (EtOAc/petroleum ether =
1:5) \ o \ \
F ~ ~ ~ / OH
F H3C _ _ F CHs 13 F 0.20 (EtOAc/petroleum ether =
/
1:5) H
\ \
/ O O
w/
C
F
a F
14 F 0.60 (CH~C12) /
\
H
\ /
~
F:
~ \
F H3C v ~ 'CH3 Ix A 32 664-Foreign Countries Ex. No. Structure R~
1 S F 0.25(EtOAc/petroleumether =
/ I 1:S) \ OH
F: I / \ I O
v 16 F O.S6(EtOAclpetroleumether =
/
I la) \
OH
/ \
F \ I o \
C
17 F 0.28(EtOAc/petroleumether =
I 1:S) \
OH
F \ HI I / O i C CH
F 3 I 'O
3 \
N
b-18 F O.S4(EtOAc/petroleumether =
/
\ I OH 1:S) / \ ~O~CH~
I I
F I
o \ /
. I~C \
19 F 0.19(EtOAc/petroleumether =
/
I 1:S) \
OH
O O
I CHs I
\ O
/
/
F HsC I
F Hs \
Le A 32 664-Foreign Countries Ex. No. ~~tructure Rf 20 F 0.37 (EtOAc/petroleum ether =
1:5) OH
I- \ ( I / O /
F F HOC CHa \
21 F 0.39 (EtOAc/petroleum ether =
I 1:5) \
H
/ \
\ ~ ~ / O
F HsC /
Ha \ F
F
F
22 F 0.40 (EtOAc/petr~leum ether =
1:5) OH
/' \
E- ~ ~ ~ / O
F CH
a \
F
23 F 0.14 (EtOAc/petroleum ether =
/ I 1:10) OH
/ \
I I
\
/
f- F H3C CH3 Le A 32 664-Foreign Countries Ex. No. ~~tructure Rf 24 F 0.23 (EtOAc/petroleum ether =
/ ( 1:10) \ OH
/ \
_F \ H C I / i CHz 25 F 0.19 (EtOAc/petroleum ether =
1:10) \
OH
/ \
HsC CH3 26 F 0.39 (CHZCIz/methanol = 100:3) /I
\ OH
/ \
\I i/
"3~ v 1 Le A 32 664-Fore~n Countries Ex. No. Structure Rf 27 F 0.30 (CH2C12/methanol = 100:3) /I
\ OH
/ \
\ I I /
f. ~ H3C I
CH3 O~V~O
28 F 0.47 (CH2C12/methanol = 100:3) /I
H
\I I/ , ~Fi3C
f F CH3 O N O
29 F 0.89 (toluene) OH
\ IC ~ / /
v~ v v E F 3 CH3 \
Le A 32 664-Foreign Countries Ex. No. Structure Rf 30 F 0.18 (toluene) /
I
OH
/ \
F. \ I I /
-1-~3C
I
CH
/I
\
31 F 0.15 (EtOAc/petroleum ether =
/ I 1:10) \ H
\ /
F' / \ ~ CH3 I
32 F 0.28 (EtOAc/petroleum ether =
1:10) OH
/ \ ~ CH3 33 F 0.25 (EtOAc/petroleum ether =
/ I 1:10) \ OH
\ /
\
Le A 32 664-Foreign Countries Ex. No. Structure Rf 34 F 0.20 (EtOAc/petroleum ether =
1:10) \ OH
\ /
F ~ ~ \
v v /
F H'C
35 F 0.36 (CHZC12/methanol = 100:3) /
\ H
\ / OH
F. I / I~~O
F CH3 \
36 F 0.34 (EtOAc/petroleum ether =
/ 1:5) OH
\ /
\ ~ /
F: F HsC
1:5) \ \ ~OH
/ ( /
f. _H3C _ F 0.28 (EtOAc/petroleum ether =
/ I 1:5) \ \ ~OH
F ~ / ~ /
f. HsC _ Le A 32 664-Forei gn Countries Ex. No. Structure Rf 11 F 0.66 (CH2Cl2) o~
F
O~ ,CHa ' HaC ~
CH
F, a ~
F CH CH
CHa HaC
12 F 0.13 (EtOAc/petroleum ether =
1:5) \ o \ \
F ~ ~ ~ / OH
F H3C _ _ F CHs 13 F 0.20 (EtOAc/petroleum ether =
/
1:5) H
\ \
/ O O
w/
C
F
a F
14 F 0.60 (CH~C12) /
\
H
\ /
~
F:
~ \
F H3C v ~ 'CH3 Ix A 32 664-Foreign Countries Ex. No. Structure R~
1 S F 0.25(EtOAc/petroleumether =
/ I 1:S) \ OH
F: I / \ I O
v 16 F O.S6(EtOAclpetroleumether =
/
I la) \
OH
/ \
F \ I o \
C
17 F 0.28(EtOAc/petroleumether =
I 1:S) \
OH
F \ HI I / O i C CH
F 3 I 'O
3 \
N
b-18 F O.S4(EtOAc/petroleumether =
/
\ I OH 1:S) / \ ~O~CH~
I I
F I
o \ /
. I~C \
19 F 0.19(EtOAc/petroleumether =
/
I 1:S) \
OH
O O
I CHs I
\ O
/
/
F HsC I
F Hs \
Le A 32 664-Foreign Countries Ex. No. ~~tructure Rf 20 F 0.37 (EtOAc/petroleum ether =
1:5) OH
I- \ ( I / O /
F F HOC CHa \
21 F 0.39 (EtOAc/petroleum ether =
I 1:5) \
H
/ \
\ ~ ~ / O
F HsC /
Ha \ F
F
F
22 F 0.40 (EtOAc/petr~leum ether =
1:5) OH
/' \
E- ~ ~ ~ / O
F CH
a \
F
23 F 0.14 (EtOAc/petroleum ether =
/ I 1:10) OH
/ \
I I
\
/
f- F H3C CH3 Le A 32 664-Foreign Countries Ex. No. ~~tructure Rf 24 F 0.23 (EtOAc/petroleum ether =
/ ( 1:10) \ OH
/ \
_F \ H C I / i CHz 25 F 0.19 (EtOAc/petroleum ether =
1:10) \
OH
/ \
HsC CH3 26 F 0.39 (CHZCIz/methanol = 100:3) /I
\ OH
/ \
\I i/
"3~ v 1 Le A 32 664-Fore~n Countries Ex. No. Structure Rf 27 F 0.30 (CH2C12/methanol = 100:3) /I
\ OH
/ \
\ I I /
f. ~ H3C I
CH3 O~V~O
28 F 0.47 (CH2C12/methanol = 100:3) /I
H
\I I/ , ~Fi3C
f F CH3 O N O
29 F 0.89 (toluene) OH
\ IC ~ / /
v~ v v E F 3 CH3 \
Le A 32 664-Foreign Countries Ex. No. Structure Rf 30 F 0.18 (toluene) /
I
OH
/ \
F. \ I I /
-1-~3C
I
CH
/I
\
31 F 0.15 (EtOAc/petroleum ether =
/ I 1:10) \ H
\ /
F' / \ ~ CH3 I
32 F 0.28 (EtOAc/petroleum ether =
1:10) OH
/ \ ~ CH3 33 F 0.25 (EtOAc/petroleum ether =
/ I 1:10) \ OH
\ /
\
Le A 32 664-Foreign Countries Ex. No. Structure Rf 34 F 0.20 (EtOAc/petroleum ether =
1:10) \ OH
\ /
F ~ ~ \
v v /
F H'C
35 F 0.36 (CHZC12/methanol = 100:3) /
\ H
\ / OH
F. I / I~~O
F CH3 \
36 F 0.34 (EtOAc/petroleum ether =
/ 1:5) OH
\ /
\ ~ /
F: F HsC
Claims (11)
1. Compounds of the general formula (I) in which A represents cycloalkyl having 3 to 8 carbon atoms, or represents aryl having 6 to 10 carbon atoms, or represents a 5- to 7-membered, saturated, partially unsaturated or unsaturated, optionally benzo-fused heterocycle having up to 4 heteroatoms from the group consisting of S, N and O, where aryl and the abovementioned heterocyclic ring systems are optionally substituted up to 5 times by identical or different substituents from the group consisting of cyano, halogen, nitro, carboxyl, hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy having in each case up to 7 carbon atoms, or by a group of the formula -NR3R4 in which R3 and R4 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, D represents a radical of the formula in which R5, R6 and R9 independently of one another represent aryl having 6 to 10 carbon atoms or a 5- to 7-membered, optionally benzo-fused, saturated or unsaturated, mono-, bi- or tricyclic heterocycle having up to 4 heteroatoms from the group consisting of S, N and O, where the cycles, optionally, in the case of the nitrogen-containing rings also via the N function, are substituted up to 5 times by identical or different substituents from the group consisting of halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryl having in each case 6 to 10 carbon atoms or by an optionally benzo-fused, aromatic 5- to 7-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, and/or by a group of the formula -OR10, -SR11, -SO2R12 or -NR13R14, in which R10, R11 and R12 independently of one another represent aryl having 6 to 10 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, halogen, or by straight-chain or branched alkyl having up to 6 carbon atoms, R13 and R14 are identical or different and have the meaning of R3 and R4 given above, or R5 and/or R6 represent a radical of the formula R7 represents hydrogen, halogen or methyl, and R8 represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 6 carbon atoms or a radical of the formula -NR15R16 in which R15 and R16 are identical or different and have the meaning of R3 and R4 given above, or R7 and R8 together form a radical of the formula =O or =NR17 in which R17 represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 6 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 8 carbon atoms which are optionally substituted up to 2 times by hydroxyl, T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 8 carbon atoms, or T or X represent a bond, V represents an oxygen or sulphur atom or represents an -NR18- group in which R18 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, E represents cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or hydroxyl, or represents phenyl which is optionally substituted by halogen or trifluoromethyl, R1 represents straight-chain or branched alkyl having up to 6 carbon atoms which is substituted by hydroxyl or by a group of the formula R2 represents hydrogen or represents straight-chain or branched alkyl or alkenyl having in each case up to 8 carbon atoms, which are optionally substituted by hydroxy, halogen, phenyl, cycloalkyl having 3 to 6 carbon atoms or by a group of the formula in which R19 represents a radical of the formula -Si(CH3)2C(CH3)3, or represents straight-chain or branched alkyl having up to 6 carbon atoms, or represents a 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, or represents phenyl or benzyl, where all ring systems listed under R19 are optionally substituted up to 2 times by identical or different substituents from the group consisting of trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carton atoms or by straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, or and their salts.
2. Compounds of the formula (I) according to Claim 1 in which A represents napththyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or morpholine which are optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, or alkoxy having in each case up to 6 carbon atoms, D represents phenyl which is optionally substituted by nitro, fluorine, chlorine, bromine, phenyl, trifluoromethyl or trifluoromethoxy, or represents a radical of the formula in which R5, R6 and R9 independently of one another represent phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl, where the cycles, optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, are substituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl, or trifluoro-methyl-substituted phenyl or phenyl, and/or are substituted by a group of the formula -OR10, -SR11 or -SO2R12 in which R10, R11 and R12 are identical or different and represent phenyl which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, fluorine, chlorine, or by straight-chain or branched alkyl having up to 4 carbon atoms, or R5 and/or R6 represent a radical of the formula R7 represents hydrogen, fluorine, chlorine or bromine, and R8 represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 5 carbon atoms or a radical of the formula -NR15R16 in which R15 and R16 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, or R7 and R8 together form a radical of the formula =O or =NR17 in which R17 represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 6 carbon atoms, which are optionally substituted up to 2 times by hydroxyl, T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 6 carbon atoms, or T or X represents a bond, V represents an oxygen or sulphur atom or represents a group of the formula -NR18-in which R18 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by cyclopropyl, -butyl, -hexyl, -pentyl, -heptyl or by hydroxyl, or represents phenyl which is optionally substituted by fluorine, chlorine, or trifluoromethyl, R1 represents a group of the formula -CH2OH or R2 represents hydrogen or represents straight-chain or branched alkyl or alkenyl having in each case up to 6 carbon atoms which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexylor by a group of the formula -O-R19,~~ in which R19 represents a radical of the formula -Si(CH3)2C(CH3)3 or represents straight-chain or branched alkyl having up to 5 carbon atoms, or represents tetrahydropyranyl, pyridyl, phenyl or benzyl which are optionally substituted up to 2 times by identical or different substituents from the group consisting of trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl, and their salts.
3. Compounds of the formula (I) according to Claim 1 in which A represents phenyl or pyridyl which are optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, D represents phenyl which is optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or represents a radical of the formula R5-L-,~ or R9-T-V-X-, in which R5, R6 and R9 independently of one another represent phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl, where the cycles, optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, are substituted by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl-substituted phenyl or phenyl and/or are substituted by a group of the formula -OR10, -SR11 or -SO2R12 in which R10, R11 and R12 are identical or different and represent phenyl which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, fluorine, chlorine, or by straight-chain or branched alkyl having up to 3 carbon atoms, or R5 and/or R6 represent a radical of the formula R7 represents hydrogen or fluorine, and R8 represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain or branched alkoxy or alkyl having in each case up to 4 carbon atoms or a radical of the formula -NR15R16 in which R15 and R16 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or R7 and R8 together form a radical of the formula =O or =NR17, in which R17 represents hydrogen or straight-chain or branched alkyl, alkoxy or aryl having in each case up to 4 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 5 carbon atoms, which are optionally substituted up to 2 times by hydroxyl, T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms, or T or X represents a bond, V represents an oxygen or sulphur atom or represents a group of the formula -NR18 in which R18 represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl which is optionally substituted by fluorine or trifluoromethyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, R1 represents a group of the formula -CH2OH or R2 represents, hydrogen or represents straight-chain or branched alkyl or alkenyl having in each case up to 5 carbon atoms which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or by a group of the formula ~
in which R19 represents straight-chain or branched alkyl having up to 4 carbon atoms, or represents a radical of the formula Si(CH3)2C(CH3)3 or represents tetrahydropyranyl, pyridyl, phenyl or benzyl, which are optionally substituted up to 2 times by identical or different substituents from the group consisting of trifluoromethyl, fluorine, chlorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl and their salts.
in which R19 represents straight-chain or branched alkyl having up to 4 carbon atoms, or represents a radical of the formula Si(CH3)2C(CH3)3 or represents tetrahydropyranyl, pyridyl, phenyl or benzyl, which are optionally substituted up to 2 times by identical or different substituents from the group consisting of trifluoromethyl, fluorine, chlorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl and their salts.
4. Compounds of the formula (I) according to Claim 1 in which A represents phenyl or pyridyl which are optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, D represents phenyl which is optionally substituted by vitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or represents a radical of the formula R5-L-, or R9-T-V-X-, in which R5, R6 and R9 independently of one another represent phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl, where the cycles, optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, are substituted by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl-substituted phenyl or phenyl and/or are substituted by a group of the formula -OR10, -SR11 or -SO2R12 in which R10, R11 and R12 are identical or different and represent phenyl which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, fluorine, chlorine, or by straight-chain or branched alkyl having up to 3 carbon atoms, or R5 and/or R6 represent a radical of the formula, R7 represents hydrogen or fluorine, and R8 represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain or branched alkoxy or alkyl having in each case up to 4 carbon atoms or a radical of the formula -NR15R16 in which R15 and R16 are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or R7 and R8 together form a radical of the formula =O or =NR17 in which R17 represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms, L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 5 carbon atoms which are optionally substituted up to 2 times by hydroxyl, T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms, or T or X represent a bond, V represents an oxygen or sulphur atom or represents a group of the formula -NR18 in which R18 represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl which is optionally substituted by fluorine or trifluoromethyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, R1 represents a group of the formula -CH2OH or R2 represents hydrogen or represents straight-chain or branched alkyl or alkenyl having in each case up to 5 carbon atoms which is optionally substituted by hydroxyl, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or by a group of the formula in which R19 represents straight-chain or branched alkyl having up to 4 carbon atoms, or represents a radical of the formula -Si(CH3)2C(CH3)3, or represents tetrahydropyranyl, pyridyl, phenyl or benzyl, which are optionally substituted up to 2 times by identical or different substituents from the group consisting of trifluoromethyl, fluorine, chlorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl, and their salts.
5. Compounds according to Claim 1 for use in the control of diseases.
6. Process for preparing compounds according to Claim 1, characterized in that compounds of the general formula (II) in which A, D and E are as defined above are, in the system (C6H5)3PCH3Br/n-butyllithium, initially converted into the compounds of the general formula (III) in which A, D and E are as defined above, subsequently, with compounds of the general formula (IV) or (IVa) in which R20, R20' and R20'' are identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms and R21 represents hydrogen or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, phenyl, straight-chain or branched alkoxy having up to 6 carbon atoms, amino, alkyl- or dialkylamino having up to 4 carbon atoms in the alkyl moiety.
converted into the compounds of the general formula (V) in which A, D and E are as defined above, R20''' includes the abovementioned scope of the meaning of R20 and R20'', and R22 either represents hydrogen or represents the radical -CO2R20'', or includes the abovementioned scope of the meaning of R21, by oxidation, the compounds of the general formula (VI) in which A, D, E, R2, R20''' and R22 are as defined above are prepared, and subsequently the carbonyl functions are reduced to the hydroxymethyl function, and derivatization on the substituent R2 is carried out by, starting from compounds of the general formula (Ia) in which A, D and E are as defined above, reacting, depending on the abovementioned meaning of R2, in the system P(C6H5)3/ethyl diethylazodicarboxylate and the corresponding amines or alcohols defined under R19, or carrying out an etherification by reaction with alkyl halides in the presence of a base, and subsequently eliminating in the two derivatization the hydroxyl-protective group with acids, or, in the case where R2 = alkenyl, initially converting the compounds of the general formula (Ia) into the aldehydes of the general formula (VII) in which A, D and E are as defined above and, in a further step, carrying out a Wittig reaction according to customary methods, eliminating the hydroxyl-protective group as described above and subsequently, by hydrogenation in the presence of a catalyst, reducing to the corresponding alkyl compounds (R2 = alkyl).
converted into the compounds of the general formula (V) in which A, D and E are as defined above, R20''' includes the abovementioned scope of the meaning of R20 and R20'', and R22 either represents hydrogen or represents the radical -CO2R20'', or includes the abovementioned scope of the meaning of R21, by oxidation, the compounds of the general formula (VI) in which A, D, E, R2, R20''' and R22 are as defined above are prepared, and subsequently the carbonyl functions are reduced to the hydroxymethyl function, and derivatization on the substituent R2 is carried out by, starting from compounds of the general formula (Ia) in which A, D and E are as defined above, reacting, depending on the abovementioned meaning of R2, in the system P(C6H5)3/ethyl diethylazodicarboxylate and the corresponding amines or alcohols defined under R19, or carrying out an etherification by reaction with alkyl halides in the presence of a base, and subsequently eliminating in the two derivatization the hydroxyl-protective group with acids, or, in the case where R2 = alkenyl, initially converting the compounds of the general formula (Ia) into the aldehydes of the general formula (VII) in which A, D and E are as defined above and, in a further step, carrying out a Wittig reaction according to customary methods, eliminating the hydroxyl-protective group as described above and subsequently, by hydrogenation in the presence of a catalyst, reducing to the corresponding alkyl compounds (R2 = alkyl).
7. Medicaments, comprising at least one compound according to Claim 1 and pharmacologically acceptable formulation auxiliaries.
8. Medicaments according to Claim 7 for treating hyperlipoproteinaemia.
9. Medicaments according to Claim 7 for treating arteriosclerosis.
10. Use of compounds according to Claim 1 for preparing medicaments.
11. Use according to Claim 10 for preparing medicaments for treating arteriosclerosis, in particular dyslipidaemias.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19741400.1 | 1997-09-19 | ||
| DE19741400A DE19741400A1 (en) | 1997-09-19 | 1997-09-19 | New benzyl-biphenyl derivatives |
| PCT/EP1998/005731 WO1999015487A1 (en) | 1997-09-19 | 1998-09-09 | Benzyl-biphenyls and analogous compounds and the application thereof in order to treat arteriosclerosis and dyslipidaemia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2304274A1 true CA2304274A1 (en) | 1999-04-01 |
Family
ID=7842955
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002304274A Abandoned CA2304274A1 (en) | 1997-09-19 | 1998-09-09 | Benzyl-biphenyls and analogous compounds and the application thereof in order to treat arteriosclerosis and dyslipidaemia |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1017658A1 (en) |
| JP (1) | JP2001517646A (en) |
| AU (1) | AU1145899A (en) |
| CA (1) | CA2304274A1 (en) |
| DE (1) | DE19741400A1 (en) |
| WO (1) | WO1999015487A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102304096A (en) * | 2004-07-02 | 2012-01-04 | 默沙东公司 | CETP inhibitors |
| US11078192B2 (en) | 2016-07-05 | 2021-08-03 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Aromatic acetylene or aromatic ethylene compound, intermediate, preparation method, pharmaceutical composition and use thereof |
| US11384048B2 (en) | 2017-12-29 | 2022-07-12 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Aromatic vinyl or aromatic ethyl derivative, preparation method therefor, intermediate, pharmaceutical composition, and application |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4092203B2 (en) | 2000-12-21 | 2008-05-28 | ニトロメッド，インク． | Substituted aryl compounds, compositions, and methods of use as novel cyclooxygenase 2-selective inhibitors |
| ATE444060T1 (en) | 2001-06-22 | 2009-10-15 | Pfizer Prod Inc | PHARMACEUTICAL COMPOSITIONS CONTAINING DISPERSIONS OF MEDICINAL SUBSTANCES AND NEUTRAL POLYMERS |
| CZ20033456A3 (en) | 2001-06-22 | 2004-07-14 | Pfizer Products Inc. | Pharmaceutical compositions comprising adsorbates of amorphous drug |
| EP1469832B2 (en) | 2002-02-01 | 2016-10-26 | Bend Research, Inc. | Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials |
| BRPI0413277A (en) | 2003-08-04 | 2006-10-10 | Pfizer Prod Inc | pharmaceutical compositions of amorphous drug adsorbates and lipophilic microphase forming materials |
| CL2004001884A1 (en) | 2003-08-04 | 2005-06-03 | Pfizer Prod Inc | DRYING PROCEDURE FOR SPRAYING FOR THE FORMATION OF SOLID DISPERSIONS AMORPHES OF A PHARMACO AND POLYMERS. |
| WO2006082518A1 (en) | 2005-02-03 | 2006-08-10 | Pfizer Products Inc. | Pharmaceutical compositions with enhanced performance |
| WO2006098394A1 (en) * | 2005-03-14 | 2006-09-21 | Japan Tobacco Inc. | Method for inhibiting lipid absorption and lipid absorption inhibitor |
| JP5192392B2 (en) * | 2005-12-30 | 2013-05-08 | メルク・シャープ・エンド・ドーム・コーポレイション | Cholesteryl ester transfer protein inhibitor |
| US20130156720A1 (en) | 2010-08-27 | 2013-06-20 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
| KR102651062B1 (en) * | 2020-10-08 | 2024-03-25 | 재단법인 대구경북첨단의료산업진흥재단 | Aminoalcohol derivatives as PCSK9 inhibitor and pharmaceutical composition comprising the same for preventing or treating hypercholesterolemia |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5169857A (en) * | 1988-01-20 | 1992-12-08 | Bayer Aktiengesellschaft | 7-(polysubstituted pyridyl)-hept-6-endates useful for treating hyperproteinaemia, lipoproteinaemia or arteriosclerosis |
| DE3909378A1 (en) * | 1989-03-22 | 1990-09-27 | Bayer Ag | SUBSTITUTED BIPHENYLE |
| DE19704244A1 (en) * | 1997-02-05 | 1998-08-06 | Bayer Ag | 5-hydroxy-alkyl substituted phenyls |
-
1997
- 1997-09-19 DE DE19741400A patent/DE19741400A1/en not_active Withdrawn
-
1998
- 1998-09-09 WO PCT/EP1998/005731 patent/WO1999015487A1/en not_active Application Discontinuation
- 1998-09-09 CA CA002304274A patent/CA2304274A1/en not_active Abandoned
- 1998-09-09 AU AU11458/99A patent/AU1145899A/en not_active Abandoned
- 1998-09-09 JP JP2000512799A patent/JP2001517646A/en active Pending
- 1998-09-09 EP EP98954266A patent/EP1017658A1/en not_active Withdrawn
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102304096A (en) * | 2004-07-02 | 2012-01-04 | 默沙东公司 | CETP inhibitors |
| CN102311401A (en) * | 2004-07-02 | 2012-01-11 | 默沙东公司 | Cetp inhibitors |
| CN102304096B (en) * | 2004-07-02 | 2014-12-03 | 默沙东公司 | CETP inhibitors |
| CN102311401B (en) * | 2004-07-02 | 2014-12-03 | 默沙东公司 | CETP inhibitors |
| CN104557757A (en) * | 2004-07-02 | 2015-04-29 | 默沙东公司 | CETP inhibitors |
| US11078192B2 (en) | 2016-07-05 | 2021-08-03 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Aromatic acetylene or aromatic ethylene compound, intermediate, preparation method, pharmaceutical composition and use thereof |
| US11384048B2 (en) | 2017-12-29 | 2022-07-12 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Aromatic vinyl or aromatic ethyl derivative, preparation method therefor, intermediate, pharmaceutical composition, and application |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001517646A (en) | 2001-10-09 |
| AU1145899A (en) | 1999-04-12 |
| DE19741400A1 (en) | 1999-03-25 |
| WO1999015487A1 (en) | 1999-04-01 |
| EP1017658A1 (en) | 2000-07-12 |
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