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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,
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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
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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
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
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
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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
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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
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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.
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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
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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
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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,
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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
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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
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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
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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
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,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,
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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,
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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.
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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"
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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
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-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
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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,
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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,
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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
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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).
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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
H3 DDO
xylene, 140°C
F
C02CH3
LiAIH4 OH
F3C
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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
F3
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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.
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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.
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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,
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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
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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).
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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,
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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.
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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.
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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.
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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
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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
40
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.
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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)
14 900
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.
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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
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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
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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.
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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
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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
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Starting materials
Example I
4-Methyl-1-(4-trifluoromethyl-phenyl)-pentan-3-one
O
F3C
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)
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_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
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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
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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
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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
F3C
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).
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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;;).
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Example X
[4'-Fluoro-5-isopropyl-2-(tetrahydro-pyran-2-yloxymethyl)-6-(4-trifluoromethyl-
benzyl)-biphenyl-3-yl]-c;arbaldehyde
P
F3
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).
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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
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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
CH2C12
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
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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
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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
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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
F3C
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)
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Example 7
[3-Cyclopentylmethyl-4'-fluoro-S-isopropyl-6-(4-trifluoromethyl-benzyl)-
biphenyl-
2-yl]-methanol
F3C
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)
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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
CH3
9 F 0.38 (EtOAc/petroleum ether =
1:5)
\ \ ~OH
/ ( /
f. _H3C _
F CH3 CI
F 0.28 (EtOAc/petroleum ether =
/ I 1:5)
\ \ ~OH
F ~ / ~ /
f. HsC _
F CH3
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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
CH3
14 F 0.60 (CH~C12)
/
\
H
\ /
~
F:
~ \
F H3C v ~ 'CH3
F CH3
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Ex. No. Structure R~
1 S F 0.25(EtOAc/petroleumether
=
/ I 1:S)
\ OH
F: I / \ I O
v
F CH3
16 F O.S6(EtOAclpetroleumether
=
/
I la)
\
OH
/ \
F \ I o \
C
F F 3 CH3
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 \
F H3
19 F 0.19(EtOAc/petroleumether
=
/
I 1:S)
\
OH
O O
I CHs
I
\ O
/
/
F HsC I
F Hs \
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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 H3C /
F CH
a \
F
23 F 0.14 (EtOAc/petroleum
ether =
/ I 1:10)
OH
/ \
I I
\
/
f- F H3C CH3
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Ex. No. ~~tructure Rf
24 F 0.23 (EtOAc/petroleum ether =
/ ( 1:10)
\ OH
/ \
_F \ H C I / i CHz
E F 3 CH3
25 F 0.19 (EtOAc/petroleum ether =
1:10)
\
OH
/ \
HsC CH3
H3C
CH3
26 F 0.39 (CHZCIz/methanol = 100:3)
/I
\ OH
/ \
\I i/
"3~ v 1
CH3 O N O
H3C CH3
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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 \
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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
H3C
CH3
32 F 0.28 (EtOAc/petroleum
ether =
1:10)
OH
/ \ ~ CH3
F H3C1 I
F CH3 CH3
33 F 0.25 (EtOAc/petroleum
ether =
/ I 1:10)
\ OH
\ /
\
H3C
CH3
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Ex. No. Structure Rf
34 F 0.20 (EtOAc/petroleum ether =
1:10)
\ OH
\ /
F ~ ~ \
v v /
F H'C
CH3
35 F 0.36 (CHZC12/methanol = 100:3)
/
\ H
\ / OH
F. I / I~~O
F H3C /
F CH3 \
36 F 0.34 (EtOAc/petroleum ether =
/ 1:5)
OH
\ /
\ ~ /
F: F HsC
CH3
