Title of Invention

"HEXAFLUOROISOPROPANOL PHENYL ETHER COMPOUNDS"

Abstract The invention is concerned with hexafluoroisopropanol phenyl ether compounds of formula (I) wherein R1 to R3 are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds bind to LXR alpha and LXR beta and can be used as medicaments.
Full Text The invention is concerned with novel hexafluoroisopropanol substituted ether
derivatives of the formula (I)
(Figure Removed)
wherein
R1 is hydrogen, lower-alkyl, or halogen;
one of R2 and R3 is hydrogen, lower-alkyl, or halogen; and
the other of R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6;
R4 is hydrogen, lower-alkyl, aryl, aryl-lower-alkyl, heteroaryl, or heteroaryllower-
alkyl;
R5 is hydrogen or aryl;
R6 is phenyl or aryl-lower-alkyl, which phenyl or aryl-lower-alkyl is optionally
substituted with 1 to 3 substituents selected from the group consisting of
amino, halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl, R8-OC(
O)-, R9R'°NC(O)-, Rn-O-C(O)-lower-alkyl, R12Rl3NC(O)-lower-alkyl,
lower-alkoxy and aryl-lower-alkoxy;
or R6 is 5- to 6-membered monocyclic heteroaryl which is optionally
substituted with 1 to 3 substituents selected from the group consisting of
lower-alkyl, fluoro-lower-alkyl, halogen and aryl, which aryl is optionally
substituted with 1 to 3 substituents selected from the group consisting of
amino, halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl, R8-OC(
O)-, R9R'°NC(O)-, R"-O-C(O)-lower-alkyl, R12R13NC(O)-lower-alkyl,
lower-alkoxy and aryl-lower-alkoxy;
or R6 is 9-membered bicyclic heteroaryl which is optionally substituted with 1
to 3 substituents selected from the group consisting of lower-alkyl, fluorolower-
alkyl, halogen and aryl, which aryl is optionally substituted with 1 to 3
substituents selected from the group consisting of amino, halogen, lower-alkyl,
fluoro-lower-alkyl, hydroxy-lower-alkyl, R8-O-C(O)-, R9R10NC(O)-, Rn-OC(
O)-lower-alkyl, R12R13NC(O)-lower-alkyl, lower-alkoxy and aryl-loweralkoxy;
or R6 is heteroaryl-lower-alkyl which is optionally substituted with 1 to 3
substituents selected from the group consisting of lower-alkyl, fluoro-loweralkyl,
halogen and aryl, which aryl is optionally substituted with 1 to 3
substituents selected from the group consisting of amino, halogen, lower-alkyl,
fluoro-lower-alkyl, hydroxy-lower-alkyl, R8-O-C(O)-, RV°NC(O)-, R"-OC(
O)-lower-alkyl, Rl2R13NC(O)-lower-alkyl, lower-alkoxy and aryl-loweralkoxy;
or R6 is -O-R7 or lower-alkyl-OR7;
R7 is aryl which is optionally substituted with 1 to 3 substituents selected from
the group consisting of amino, halogen, lower-alkyl, fluoro-lower-alkyl,
hydroxy-lower-alkyl, R8-O-C(O)-, R9RIONC(O)-, Rn-O-C(O)-lower-alkyl,
R12R13NC(O)-lower-alkyl, lower-alkoxy and aryl-lower-alkoxy;
or R7 is heteroaryl which is optionally substituted with 1 to 3 substituents
selected from the group consisting of lower-alkyl, fluoro-lower-alkyl, halogen,
amino, hydroxy-lower-alkyl, R8-O-C(O)-, R9R10NC(O)-, Ru-O-C(O)-loweralkyl,
R12R13NC(O)-lower-alkyl, lower-alkoxy, aryl-lower-alkoxy and aryl,
which aryl is optionally substituted with 1 to 3 substituents selected from the
group consisting of lower-alkyl and halogen;
R8, R9, R10, R11, R12 and R13 independently from each other are hydrogen or loweralkyl;
m is 0 to 3;
n is 0 or 1;
and pharmaceutical ly acceptable salts and esters thereof.
Further, the invention is concerned with a process for the manufacture of the
above compounds, pharmaceutical preparations which contain such compounds as
well as the use of these compounds for the production of pharmaceutical preparations.
Liver-X-Receptors (LXRs) are members of the nuclear hormone receptor
superfamily. The LXRs are activated by endogenous oxysterols and regulate the
transcription of genes controlling multiple metabolic pathways. Two subtypes,
LXRalpha and LXRbeta, have been described (Willy et al., Genes Dev. 1995,
9:1033-45; Song et al., Proc Natl Acad Sci USA. 1994, 91:10809-13). LXRbeta is
ubiquitously expressed, while LXRalpha is predominantly expressed in cholesterol
metabolizing tissues such as the liver, adipose, intestine and macrophage. The LXRs
modulate a variety of physiological responses including regulation of cholesterol
absorption, cholesterol elimination (bile acid synthesis), and transport of cholesterol
from peripheral tissues via plasma lipoproteins to the liver. The LXRs are also
involved in glucose metabolism, cholesterol metabolism in the brain, cell
differentiation, and inflammation.
At present, approximately half of all patients with coronary artery disease have
low concentrations of plasma high-density lipoprotein cholesterol (HDL-C). The
atheroprotective function of HDL was first highlighted almost 25 years ago and
stimulated exploration of the genetic and environmental factors that influence HDL-C
levels (Miller NE., Lipids 1978,13:914-9). The protective function of HDL derives
from its role in a process termed reverse cholesterol transport. HDL mediates the
removal of cholesterol from cells in peripheral tissues, including macrophage foam
cells in the atherosclerotic lesions of the arterial wall. HDL delivers its cholesterol to
the liver and sterol-metabolizing organs for conversion to bile and elimination in
feces. Studies have shown that HDL-C levels are predictive of coronary artery
disease risk independently of low-density lipoprotein cholesterol (LDL-C) levels
(Gordon et al., Am J Med. 1977, 62:707-14).
At present, the estimated age-adjusted prevalence among Americans age 20
and older who have HDL-C of less than 35 mg/dl is 16% (males) and 5.7 % (females).
A substantial increase of HDL-C is currently achieved by treatment with niacin in
various formulations. However, the substantial unfavorable side-effects limit the
therapeutic potential of this approach.
It has been observed that as many as 90% of the 14 million diagnosed type 2
diabetic patients in the United States are overweight or obese, and a high proportion
of type 2 diabetic patients have abnormal concentrations of lipoproteins. Studies have
shown that the prevalence of total cholesterol 240 mg/dl is 37% in diabetic men and
44% in women. The rates for LDL-C 160 mg/dl are 31% and 44%, and for HDL-C
35 mg/dl are 28% and 11%, in diabetic men and women respectively. Diabetes is a
disease in which a patient's ability to control glucose levels in blood is decreased
because of partial impairment in response to the action of insulin. Type II diabetes
(T2D) is also called non-insulin dependent diabetes mellitus (NIDDM) and has been
shown to afflict 80-90 % of all diabetic patients in developed countries. In T2D, the
pancreatic Islets of Langerhans continue to produce insulin. However, the target
organs for insulin action, mainly muscle, liver and adipose tissue, exhibit a profound
resistance to insulin stimulation. The body continues to compensate by producing
unphysiologically high levels of insulin, which ultimately decreases in the later stages
of the disease, due to exhaustion and failure of pancreatic insulin-producing capacity.
Thus, T2D is a cardiovascular-metabolic syndrome associated with multiple comorbidities,
including insulin resistance, dyslipidemia, hypertension, endothelial
dysfunction and inflammatory atherosclerosis.
The first line of treatment for dyslipidemia and diabetes at present generally
involves a low-fat and low-glucose diet, exercise and weight loss. However,
compliance can be moderate, and as the disease progresses, treatment of the various
metabolic deficiencies becomes necessary with lipid-modulating agents such as
statins and fibrates for dyslipidemia, and hypoglycemic drugs, e.g. sulfonylureas,
metformin, or insulin sensitizers of the thiazolidinedione (TZD) .class of PPARyagonists,
for insulin resistance. Recent studies provide evidence that modulators of
LXRs would result in compounds with enhanced therapeutic potential, and as such,
modulators of LXRs should improve the plasma lipid profile, and raise HDL-C levels
(Lund et al., Arterioscler. Thromb. Vase. Biol. 2003, 23:1169-77). LXRs are also
known to control the efflux of cholesterol from the macrophage foam cell of the
atherosclerotic lesion, and agonists of LXRs have been shown to be atheroprotective
(Joseph and Tontonoz, Curr. Opin. Pharmacol. 2003, 3:192-7). Thus, modulators of
LXRs would be effective treatments for the atherosclerotic disease which underlies
the cardiovascular morbidity and mortality of stroke and heart disease. Recent
observations also suggest that there is an independent LXR mediated effect on
insulin-sensitization in addition to its role in atheroprotection (Cao et al., J Biol Chem.
2003, 278:1131-6). Thus LXR modulators can also show superior therapeutic
efficacy on HDL-raising and atheroprotection, with additional effects on diabetes,
compared to current therapies.
The novel compounds of the present invention have been found to bind to and
selectively activate LXR alpha and LXR beta or coactivate LXR alpha and LXR beta.
Consequently, cholesterol absorption is reduced, HDL cholesterol is increased, and
inflammatory atherosclerosis is reduced. Since multiple facets of combined
dyslipidemia and cholesterol homeostasis are addressed by LXR modulators, novel
compounds of the present invention have an enhanced therapeutic potential compared
to the compounds already known in the art. They can therefore ,be used in the
treatment and prophylaxis of diseases which are modulated by LXR alpha and/or
LXR beta agonists. Such diseases include increased lipid and cholesterol levels,
particularly low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases,
diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome,
dyslipidemia, Alzheimer's disease, sepsis, and inflammatory diseases such as colitis,
pancreatitis, cholestasis/fibrosis of the liver, psoriasis and other inflammatory diseases
of the skin, and diseases that have an inflammatory component such as Alzheimer's
disease or impaired/improvable cognitive function. Moreover, the novel compounds
of the present invention can be used for treatment and prophylaxis of age-related and
inherited (e.g. Stargardt's disease) forms of macular degeneration.
Other compounds that bind to and activate LXR alpha and LXR beta have
previously been suggested (e.g.: WO 03/099769). However, there is still a need for
new compounds with improved properties. The present invention provides the novel
compounds of formula (I) which bind to LXR alpha and/or LXR beta. The
compounds of the present invention unexpectedly exhibit improved pharmacological
properties compared to the compounds known in the art, concerning e.g. metabolic
stability, bioavailability and activity.
Unless otherwise indicated, the following definitions are set forth to illustrate
and define the meaning and scope of the various terms used to describe the invention
herein.
In this specification the term "lower" is used to mean a group consisting of one
to seven, preferably of one to four carbon atom(s).
The term "halogen" refers to fluorine, chlorine, bromine and iodine, with
fluorine, chlorine and bromine being preferred.
The term "alkyl", alone or in combination with other groups, refers to a
branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one
to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one
to ten carbon atoms. Lower-alkyl groups as described below also are preferred alkyl
groups.
The term "lower-alkyl", alone or in combination with other groups, refers to a
branched or straight-chain monovalent alkyl radical of one to seven carbon atoms,
preferably one to four carbon atoms. This term is further exemplified by such radicals
as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like. Loweralkyl
groups can optionally be substituted, e.g. by hydroxy. Such substituted loweralkyl-
groups are referred to as "hydroxy-lower-alkyl". Unsubstituted lower-alkyl
groups are preferred
The term "fluoro-lower-alkyl" refers to lower-alkyl groups which are mono- or
multiply substituted with fluorine. Examples of fluoro-lower-alkyl groups are e.g.
CFH2, CF2H, CF3, CF3CH2, CF3(CH2)2, (CF3)2CH and CF2H-CF2
The term "amino", alone or in combination, signifies a primary, secondary or
tertiary amino group bonded via the nitrogen atom, with the secondary amino group
carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two
similar or different alkyl or cycloalkyl substituents or the two nitrogen substitutents
together forming a ring, such as, for example, -NH2i methylamino, ethylamino,
dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino etc.,
preferably primary amino, dimethylamino and diethylamino and particularly
dimethylamino.
The term "cycloalkyl" refers to a monovalent carbocyclic radical of 3 to 10
carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl,
cyclopentyl, or cyclohexyl.
The term "alkoxy" refers to the group R'-O-, wherein R' is an alkyl. The term
"lower-alkoxy" refers to the group R'-O-, wherein R' is a lower-alkyl.
The term "fluoro-lower-alkoxy" refers to the group R"-O-, wherein R" is
fluoro-lower-alkyl. Examples of fluoro-lower-alkoxy groups are e.g. CFH2-O, CF2HO,
CF3-0, CF3CH2-0, CF3(CH2)rO, (CF3)2CH-O, and CF2H-CF2-O.
The term "alkylene" refers to a straight chain or branched divalent saturated
aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms,
more preferably up to 10 carbon atoms. Lower-alkylene groups as described below
also are preferred alkylene groups. The term "lower-alkylene" refers to a straight
chain or branched divalent saturated aliphatic hydrocarbon group of 1 to 7, preferably
1 to 6 or 3 to 6 carbon atoms. Straight chain alkylene or lower-alkylene groups are
preferred.
The term "aryl", alone or in combination, relates to the phenyl or naphthyl
group, preferably the phenyl group, which can optionally be substituted by 1 to 5 ,
preferably 1 to 3, substituents independently selected from the group consisting of
lower-alkyl, lower-alkoxy, halogen, hydroxy, CN, CF3, amino, aminocarbonyl,
carboxy, NO2, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), loweralkylsufonyl,
aminosulfonyl, lower-alkylcarbonyl, lower-alkylcarbonyloxy, loweralkylcarbonyl-
NH, lower-alkoxycarbonyl, fluoro-lower-alkyl, fluoro-lower-alkoxy,
cycloalkyl, phenyloxy and methyl-oxadiazolyl. Preferred substituents are halogen,
lower-alkyl, fluoro-lower-alkyl and CN. Furthermore, aryl groups can be substituted
as described in the description below.
The term "heteroaryl" refers to an aromatic 5 to 6 membered monocyclic ring
or 9 to 10 membered bicyclic ring which can comprise 1, 2 or 3 atoms selected from
nitrogen, oxygen and/or sulphur, such as furyl, pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl,
triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzoimidazolyl,
indolyl, indazolyl, benzoisothiazolyl, benzoxazolyl and benzoisoxazolyl. Preferred
heteroaryl groups are pyridinyl, pyrimidinyl, isoxazolyl, oxazolyl and triazolyl. A
heteroaryl group may have a substitution pattern as described earlier in connection
with the term "aryl". A heteroaryl may further be substituted as described in the
description below.
The term "5 to 6 membered monocyclic heteroaryl" refers to an aromatic 5 to
6 membered monocyclic ring as described above in context with the term
"heteroaryl", which can be substituted as described above or as described below in the
description. Examples of 5 to 6 membered monocyclic heteroaryl groups are furyl,
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl,
oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,
isothiazolyl and 1,2,3-thiadiazolyl. Prefered are oxazolyl, isoxazolyl and triazolyl. A 5
to 6 membered monocyclic heteroaryl group may have a substitution pattern e.g. as
described earlier in connection with the term "aryl". Preferably, a heteroaryl may
further be substituted as described in the description below.
The term "9 membered bicyclic heteroaryl" refers to an aromatic 9 membered
bicyclic ring which can comprise 1, 2 or 3 atoms selected from nitrogen, oxygen
and/or sulphur, as described above in context with the term "heteroaryl", which can be
substituted as described above or as described below in the description. Examples of 9
membered bicyclic heteroaryl groups are benzoimidazolyl, indolyl, indazolyl,
benzoisothiazolyl, benzoxazolyl and benzoisoxazolyl. Preferred 9 membered bicyclic
heteroaryl groups are benzoisothiazolyl and benzoisoxazolyl. A 9 membered bicyclic
heteroaryl group may have a substitution pattern e.g. as described earlier in
connection with the term "aryl". Preferably, a heteroaryl may further be substituted as
described in the description below.
The term "leaving group" refers to a group that may be displaced by a
nucleophile (e.g. a secondary amine). Typical leaving groups are e.g.: Cl, Br, I, OSO2-
lower-alkyl (wherein O-SO2-CH3 = OMs), O-SO2-lower-fluoroalkyl (wherein OSO2-
CF3 = OTf), O-SO2-aryl (wherein wherein O-SO2-ptolyl = OTs), O-(paranitrophenyl).
The term "protecting group" refers to groups which are used to protect
functional groups, particularly hydroxy groups, temporarily. Examples of protecting
groups are benzyl, p-methoxybenzyl, t-butyl-dimethylsilyl and t-butyl-diphenylsilyl.
Compounds of formula (I) can form pharmaceutically acceptable acid addition
salts. Examples of such pharmaceutically acceptable salts are salts of compounds of
formula (I) with physiologically compatible mineral acids, such as hydrochloric acid,
sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as
methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid,
trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid
or salicylic acid. The term "pharmaceutically acceptable salts" refers to such salts.
Compounds of formula (I) in which a COOH group is present can further form salts
with bases. Examples of such salts are alkaline, earth-alkaline and ammonium salts
such as e.g. Na-, K-, Ca- and trimethylammoniumsalt. The term "pharmaceutically
acceptable salts" also refers to such salts. Salts obtained by the addition of an acid are
preferred.The term "pharmaceutically acceptable esters" embraces derivatives of the
compounds of formula (I), in which a carboxy group has been converted to an ester.
Lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, amino-lower-alkyl,
mono- or di-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl, pyrrolidinolower-
alkyl, piperidino-lower-alkyl, piperazino-lower-alkyl, lower-alkyl-piperazinolower-
alkyl and aralkyl esters are examples of suitable esters. The methyl, ethyl,
propyl, butyl and benzyl esters are preferred esters. The methyl and ethyl esters are
especially preferred. The term "pharmaceutically acceptable esters" furthermore
embraces compounds of formula (I) in which hydroxy groups have been converted to
the corresponding esters with inorganic or organic acids such as, nitric acid, sulphuric
acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid,
tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are
non toxic to living organisms.
In detail, the present invention relates to compounds of formula (I)
(Figure Removed)
wherein
R1 is hydrogen, lower-alkyl, or halogen;
one of R2 and R3 is hydrogen, lower-alkyl, or halogen; and
the other of R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6;
R4 is hydrogen, lower-alkyl, aryl, aryl-lower-alkyl, heteroaryl, or heteroaryllower-
alkyl;
R5 is hydrogen or aryl;
R6 is phenyl or aryl-lower-alkyl, which phenyl or aryl-lower-alkyl is optionally
substituted with 1 to 3 substituents selected from the group consisting of
amino, halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl, R8-OC(
O)-, R9R10NC(O)-, Ru-O-C(O)-lower-alkyl, R12R13NC(O)-lower-alkyl,
lower-alkoxy and aryl-lower-alkoxy;
or R6 is 5- to 6-membered monocyclic heteroaryl which is optionally
substituted with 1 to 3 substituents selected from the group consisting of
lower-alkyl, fluoro-lower-alkyl, halogen and aryl, which aryl is optionally
substituted with 1 to 3 substituents selected from the group consisting of
amino, halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl, R8-O-
)-, R9R10NC(0)-, R"-0-C(O)-lower-alkyl, R12R13NC(O)-lower-alkyl,
lower-alkoxy and aryl-lower-alkoxy;
or R6 is 9-membered bicyclic heteroaryl which is optionally substituted with 1
to 3 substituents selected from the group consisting of lower-alkyl, fluorolower-
alkyl, halogen and aryl, which aryl is optionally substituted with 1 to 3
substituents selected from the group consisting of, amino, halogen, loweralkyl,
fluoro-lower-alkyl, hydroxy-lower-alkyl, R8-O-C(O)-, R9R10NC(O)-,
Ru-O-C(O)-lower-alkyl, R12R13NC(O)-lower-alkyl, lower-alkoxy and aryllower-
alkoxy;
or R6 is heteroaryl-lower-alkyl which is optionally substituted with 1 to 3
substituents selected from the group consisting of lower-alkyl, fluoro-loweralkyl,
halogen and aryl, which aryl is optionally substituted with 1 to 3
substituents selected from the group consisting of amino, halogen, lower-alkyl,
fluoro-lower-alkyl, hydroxy-lower-alkyl, R8-O-C(O)-, R9R10NC(O)-, RM-OC(
O)-lower-alkyl, R12R13NC(O)-lower-alkyl, lower-alkoxy and aryl-loweralkoxy;
or R6 is -O-R7 or lower-alkyl-OR7;
R7 is aryl which is optionally substituted with 1 to 3 substituents selected from
the group consisting of amino, halogen, lower-alkyl, fluoro-lower-alkyl,
hydroxy-lower-alkyl, R8-O-C(O)-, R9R10NC(O)-, Ru-O-C(O)-lower-alkyl,
R12R13NC(O)-lower-alkyl, lower-alkoxy and aryl-lower-alkoxy;
or R7 is heteroaryl which is optionally substituted with 1 to 3 substituents
selected from the group consisting of lower-alkyl, fluoro-lower-alkyl, halogen,
amino, hydroxy-lower-alkyl, R8-O-C(O)-, R9R10NC(O)-, Rn-O-C(O)-loweralkyl,
R12R13NC(O)-lower-alkyl, lower-alkoxy, aryl-lower-alkoxy and aryl,
which aryl is optionally substituted with 1 to 3 substituents selected from the
group consisting of lower-alkyl and halogen;
R8, R9, R10, R11, R12 and R13 independently from each other are hydrogen or loweralkyl;
m is 0 to 3;
n is 0 or 1;
and pharmaceutically acceptable salts and esters thereof.
Compounds of formula (I) are individually preferred and physiologically
acceptable salts thereof are individually preferred and pharmaceutical ly acceptable
esters thereof are individually preferred, with the compounds of formula (I) being
particularly preferred.
The compounds of formula (I) can have one or more asymmetric C atoms and
can therefore exist as an enantiomeric mixture, diastereomeric mixture or as optically
pure compounds.
Preferred compounds of formula (I) as described above are those, wherein R1
is hydrogen, chlorine or methyl. Hydrogen, chlorine and methyl individually
constitute preferred embodiments.
Other preferred compounds of formula (I) as described above are those,
wherein one of R2 and R3 is hydrogen or lower-alkyl, and the other of R2 and R3 is -
O-CHR4-(CH2)m-(CHR5)n-R6, wherein R4, R5, R6, m and n are as defined above. More
preferred are those compounds, wherein R2 is -O-CHR4-(CH2)m-(CHR5)n-R6, and R3
is hydrogen, wherein R4, R5, R6, m and n are as defined above.
Another preferred embodiment of the present invention relates to compounds
of formula (I) as described above, wherein R4 is hydrogen, lower-alkyl, aryl, or aryllower-
alkyl, more preferably wherein R4 is hydrogen, lower-alkyl, or aryl-loweralkyl,
most preferably wherein R4 is hydrogen, methyl or benzyl. Hydrogen, methyl
and benzyl individually constitute preferred embodiments.
Other preferred compounds of formula (I) as described above are those,
wherein n is 1 and R5 is aryl, especially wherein n is 1 and R5 is phenyl.
Compounds wherein R is phenyl which is optionally substituted with R -OC(
O)-, or R6 is 5- to 6-membered monocyclic heteroaryl which is optionally
substituted with 1 to 3 substituents selected from the group consisting of lower-alkyl
and aryl, which aryl is optionally substituted with 1 to 3 substituents selected from the
group consisting of halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl,
R8-O-C(O)- and R9R10NC(O)-, wherein R8, R9 and R10 are as defined above, are also
preferred. Particularly preferred are those compounds wherein R6 is phenyl, or R6 is
oxazolyl, which oxazolyl is substituted with lower-alkyl and phenyl, which phenyl is
substituted with halogen, fluoro-lower-alkyl or hydroxy-lower-alkyl. More
particularly preferred are those compounds wherein R6 is phenyl, 2-(3-chloro-phenyl)-
5-methyl-oxazol-4-yl, 5-methyl-2-(3-trifluoromethyl-phenyl)-oxazoI-4-yl, or 2-(3-
hydroxymethyl-phenyl)-5-methyl-oxazol-4-yl.
Another preferred embodiment of the present invention relates to compounds
of formula (I) as described above, wherein R6 is -O-R7, wherein R7 is phenyl which is
substituted with 1 substituent selected from the group consisting of hydroxy-loweralkyl,
Ru-O-C(O)-lower-alkyl and R12R13NC(O)-lower-alkyl, or R7 is heteroaryl
selected from the group consisting of benzo[d]isothiazolyl and benzo[d]isoxazolyl,
which heteroaryl is optionally substituted with 1 to 2 substituents selected from the
group consisting of lower-alkyl, fluoro-lower-alkyl and phenyl, which phenyl is
optionally substituted with halogen, wherein R11, R12 and R13 are as defined above.
Preferably, R7 is phenyl substituted with lower-alkoxy-carbonyl .or lower-alkoxycarbonyl-
lower-alkyl. More preferably, R7 is 3-methoxycarbonylmethyl-phenyl, 4-
methoxycarbonylmethyl-phenyl, or 4-methoxycarbonyl-phenyl.
Another preferred embodiment of the present invention relates to compounds
as defined above, wherein m is 0 to 2, particularly wherein m is 0 or 1. Compounds
wherein m is 0 and wherein m is 1 individually constitute preferred embodiments of
the present invention. Other preferred compounds are those, wherein n is 0.
In a preferred embodiment of the present invention, m is 0 to 2, more
preferably m is 0 or 1. Compounds of formula (I) as described above, wherein n is 0
also constitute a preferred embodiment of the present invention.
In particular, preferred compounds are the compounds of formula (I) described
in the examples as individual compounds as well as pharmaceutically acceptable salts
as well as pharmaceutically acceptable esters thereof.
Preferred compounds of formula (I) are those selected from the group consisting
of:2-(4-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propoxy}-phenyl)-
1,1,1,3,3,3-hexafluoro-propan-2-ol,
3-(3-{3-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-propionic acid ethyl ester,
rac (4-{ 1 -Phenyl-2-[3-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid methyl ester,
rac (4-{l-Phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid,
rac 4- {l-Phenyl-2-[4-(2,2,2-trifluoro-l -hydroxy- l-trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-benzole acid methyl ester,
4-{2-[4-(2,2,2-Trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-ethoxy} -
benzole acid methyl ester,
2-(4-Benzyloxy-3-chloro-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,
2-(4-Benzyloxy-3-methyl-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol,
2-(3-Benzyloxy-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol,
2-(4-Benzyloxy-3,5-dimethyl-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol,
2-(4-Benzyloxy-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol,
(4-{3-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
4-{3-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid methyl ester,
3-(4-{3-[2-Chloro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-propionic acid methyl ester,
(4-{3-[2-Chloro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
4-{3-[2-Chloro-4-(2,2,2-trifluoro-l -hydroxy- l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid methyl ester,
(4- {3-[2,6-Dimethyl-4-(2,2,2-trifluoro-l -hydroxy- l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
4-{3-[2,6-Dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid methyl ester,
4-{3-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzole acid,
(4-{3-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid,
(4-{3-[2,6-Dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid,
4- {3 -[2,6-Dimethyl-4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethy l-ethyl)-phenoxy] -
propoxy} -benzole acid,
4- {2-[2,6-Dimethyl-4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-benzole acid methyl ester,
3-(4-{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-3-phenyl-propoxy}-phenyl)-propionic acid methyl ester,
(4-{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
3-phenyl-propoxy}-phenyl)-acetic acid methyl ester,
4- {(S)-2-[2-Methyl-4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethy l-ethyl)-phenoxy] -
3-phenyl-propoxy}-benzole acid methyl ester,
(4-{ (S)-3-Phenyl-2-[4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
4-{(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid methyl ester,
(4-{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy|-
3-phenyl-propoxy}-phenyl)-acetic acid,
4-{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
3-phenyl-propoxy}-benzoic acid,
(4-{(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid,
4- {(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-l -hydroxy- l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid,
rac 1,1,1,3,3,3-Hexafluoro-2-{4-[2-(4-hydroxymethyl-phenoxy)-l-phenyl-ethoxy]-
phenyl} -propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-(3-methyl-4-phenethyloxy-phenyl)-propan-;2,-ol,
rac l,l,l,3,3,3-Hexafluoro-2-[3-methyl-4-(l-phenyl-ethoxy)-phenyl]-propan-2-ol,
2-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l, 1,1,3,3,3-
hexafluoro-propan-2-ol,
2-[4-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-
ol,
l,l,l,3,3,3-Hexafluoro-2-[4-(5-methyl-isoxazol-3-ylmethoxy)-phenyl]-propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-[4-(5-methyl-2-phenyl-2^-[l,2,3]triazol-4-ylmethoxy)-
phenyl]-propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-[4-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-phenyl]-
propan-2-ol,
3-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxymethyl]-benzoic
acid methyl ester,
4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-3-
phenyl-propoxy}-benzoic acid,
(4-{(S)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic . , acid,
3-(4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-phenyl)-propionic acid methyl ester,
(4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
4-{(R)-3-Phenyl-2-[4-(2,2,2-trifIuoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxyl-
propoxy}-benzoic acid methyl ester,
3-(4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-phenyl)-propionic acid,
(4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid,
4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid,
2-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-3-methyl-phenyl}-
1,1,1,3,3,3-hexafluoro-propan-2-ol,
2-{3-Chloro-4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2-(4-phenethyloxy-phenyl)-propan-2-ol,
2-(3,5-Dimethyl-4-phenethyloxy-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,
2-(3-Chloro-4-phenethyloxy-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol,
rac 1,1,1,3,3,3-Hexafluoro-2-[4-( 1 -phenyl-ethoxy)-phenyl]-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2-[3-methyl-4-(5-methyl-2-w-tolyl-oxazol-4-yltnethoxy)-
phenyl]-propan-2-ol,
2-{4-[2-(2-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-3-methyl-phenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2-[3-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-
phenyl]-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2-{3-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-
oxazol-4-ylmethoxy]-phenyl}-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2- {4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-
ylmethoxy]-3-methyl-phenyl}-propan-2-ol,
2-{3-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol,
2-[3-Chloro-4-(5-methyl-2-w-tolyl-oxazol-4-ylmethoxy)-phenyl]-l,1,1,3,3,3-
hexafluoro-propan-2-ol,
2-{3-Chloro-4-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol,
2-[3-Chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-1,1,1,3,3,3-
hexafluoro-propan-2-ol,
2-{3-Chloro-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-
1,1,1,3,3,3-hexafluoro-propan-2-ol,
2-{3-Chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-
phenyl} -1,1,1,3,3,3-hexafluoro-propan-2-ol,
2-{3-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l, 1,1,3,3,3-
hexafluoro-propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-[3-(5-methyl-2-o-tolyl-oxazol-4-ylmethox>;)-phenyl]-
propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-{3-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-
ylmethoxyj-phenyl} -propan-2-ol,
2-{3-[2-(2-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l, 1,1,3,3,3-
hexafluoro-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2-[3-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)-phenyl]-
propan-2-ol,
3-{4-[2-Chloro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxymethyl]-5-methyl-oxazol-2-yl}-benzoic acid methyl ester,
2-{3-Chloro-4-[2-(3-hydroxymethyl-phenyl)-5-tnethyl-oxazol-4-ylmethoxy]-phenyl}-
1,1,1,3,3,3-hexafluoro-propan-2-ol,
4-{5-Methyl-4-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxymethyl]-oxazol-2-yl}-benzoic acid methyl ester,
4-{5-Methyl-4-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxymethyl]-oxazol-2-yl}-benzoic acid,
N,N-Dimethyl-4-{5-methyl-4-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluor9methyl-ethyl)-
phenoxymethyl]-oxazol-2-yl}-benzamide,
(3-{2-[4-(2,2,2-Trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid methyl ester,
(4- {2-[4-(2,2,2-Trifluoro-l -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid methyl ester,
(3-{2-[3-(2,2,2-Trifluoro-l -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid methyl ester,
(3-{2-[4-(2,2,2-Trifluoro-l-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid,
(4-{2-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid,
rac (3-{ 1 -Phenyl-2-[3-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid methyl ester,
rac (3-{l-Phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid,
rac N,N-Dimethyl-2-(3-{l-phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethylethyl)-
phenoxy] -ethoxy} -phenyl)-acetamide,
2-(4-{2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethoxy}-phenyl)-
l,l,l,3,3,3-hexafluoro-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2-{4-[3-(7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-
yloxy)-propoxy]-phenyl} -propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2-{3-[3-(7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-
yloxy)-propoxy]-pheny 1} -propan-2-ol,
(4-{3-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-acetic acid methyl ester,
(3-{3-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-acetic acid methyl ester,
3-(4-{3-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-propionic acid methyl ester, and
3-(4- {3 -[3 -(2,2,2-Trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-propoxy} -
phenyl)-propionic • : acid,
and pharmaceutical ly acceptable salts and esters thereof.
Particularly preferred compounds of formula (I) are those selected from the
group consisting of
(3-{2-[4-(2,2,2-Trifluoro-l -hydroxy- l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid methyl ester,
rac 4-{l-Phenyl-2-[4-(2,2,2-trifluoro-l -hydroxy- l-trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-benzoic acid methyl ester,
2-(4-Benzyloxy-3-chloro-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol,
(4-{(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
l,l,l,3,3,3-Hexafluoro-2-(3-methyl-4-phenethyloxy-phenyl)-propan-2-ol,
rac l,l,l,3,3,3-Hexafluoro-2-[3-methyl-4-(l-phenyl-ethoxy)-phenyl]-propan-2-ol,
2-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l, 1,1,3,3,3-
hexafluoro-propan-2-ol,
(4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
2-{3-Chloro-4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-
1,1,1,3,3,3-hexafluoro-propan-2-ol,
2-(3-Chloro-4-phenethyloxy-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2-{3-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-
oxazol-4-ylmethoxy]-phenyl}-propan-2-ol,
2-{3-Chloro-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol, and
2- {3 -Chloro-4-[2-(3 -hydroxymethyl-phenyl)-5 -methy l-oxazol-4-ylmethoxy] -pheny 1} -
1,1,1,3,3,3-hexafluoro-propan-2-ol,
and pharmaceutically acceptable salts and esters thereof.
It will be appreciated that the compounds of general formula (I) in this
invention may be derivatised at functional groups to provide derivatives which are
capable of conversion back to the parent compound in vivo.The invention further
relates to a process for the manufacture of compounds of formula (I) as defined
above, which process comprises
a) reacting a compound of formula (II)
(Figure Removed)
with a compound HO-CHR4-(CH2)m-(CHR5)n-R6,
wherein R1, R4, R5, R6, m and n are as defined above, one of R2 and R3 is OH and the
other of R2 and R3 is hydrogen, lower-alkyl, or halogen, and A is hydrogen or a
protecting group
or
b) reacting a compound of formula (II)

(Figure Removed)
with a compound LG-CHR4-(CH2)m-(CHR5)n-R6
wherein R1, R4, R5, R6, m and n are as defined above, one of R2 and R3 is OH and the
other of R2 and R3 is hydrogen, lower-alkyl, or halogen, LG is a leaving group (such
as I, Br, Cl, OTf, OMs, OTs) and A is hydrogen or a protecting group.
The reaction of a compound of formula (II) with a compound HO-CHR -
(CH2)m-(CHR5)n-R6 or with LG-CHR4-(CH2)m-(CHR5)n-R6 and cleavage of the
protecting group A if necessary can be performed under reaction conditions well
known to the person skilled in the art. Such reactions of a phenol (II) can conveniently
be carried out either under Mitsunobu conditions with an alcohol HO-CHR4-(CH2)m-
(CHR5)n-R6 in the presence of DEAD or DIAD and Ph3P in a solvent such as THF at a
suitable temperature or with an alkylating agent LG-CHR4-(CH2)m-(CHR5)n-R6 with
bases such as Cs2CO3, K2CO3 optionally in the presence of KI or Nal in inert solvents
such as acetone, THF, DMF or DMA.
The present invention also relates to compounds of formula (I) as defined
above, when prepared by a process as described above.
The compounds of formula (I) can be prepared by methods known in the art or
as described below. Unless otherwise indicated, the substituents R1, R2, R3, R4, R5, R6,
R7, m, and n are as described above.
(Figure Removed)
The preparation of starting materials for the synthesis of compounds of formula (I) is
illustrated in schemes la/lb. Bromophenol derivatives la or Ib are transformed into the
suitably protected derivatives 2a or 2b by treatment with e.g. silylating agents such as t-
BuMe2SiCl or /-BuPh2SiCl in solvents such as DMF, or THF in the presence of a base
such as imidazole or triethylamine at temperatures between 0°C and room temperature
(step a). 2a or 2b may be converted to the derivatives 3a or 3b by treatment with «-BuLi
or r-BuLi in solvents such as THF or ether, followed by reaction with hexafluoro acetone
at low temperature, e.g. -78°C (step b). The compounds 3a or 3b may be O-protected by a
Mitsunobu reaction with reagents such as benzyl alcohol or 4-methoxybenzyl alcohol
(PMB-OH) in THF in the presence of triphenylphosphine and DEAD or DIAD to give 4a
or 4b, respectively (step c). Cleavage of the protecting group PG1 may be achieved by
treatment of the compound 3a, 3b, 4a or 4b with TBAF in THF or 48% aq. HBr, KF in
DMF to yield the desired building blocks 5a, 5b, 6a or 6b , respectively (step d).
Schemes 2a/2b depict the synthesis of the final products. Treatment of phenol 5a or 5b
with R2'-X or R3'-X (with R2' or R3' = CHR4-(CH2)m-(CHR5)n-R6) under Mitsunobu
conditions for X = OH with e.g. Ph^P, DEAD or DIAD in a solvent such as THF gives 7a
or 7b (step a). Alternatively, 5a or 5b may be treated with alkylating agents R2 -X or R3 -
X in which X is a leaving group such as Cl, Br, I, MsO, TsO, or TfO. These reactions are
performed in the presence of a base such as Cs2CO3 or K2COs in inert solvents such as
acetone, dioxane, DMF or DMA optionally in the presence of KI or Nal to give 7a or 7b
(step b). Cleavage of the protecting group PG2 may be accomplished by hydrogenation in
the presence of a catalyst such as Pd/C in a solvent such as EtOAc or alcohols (EtOH,
MeOH) for PG2 = Bn or PMB. An alternative method for cleavage of the PMB group may
be the treatment of 7a or 7b with DDQ in CH2C12 or dichloroethane in the presence of
H2O at temperatures between -20°C and reflux or the treatment with eerie ammonium
nitrate in acetonitrile/ water to give 8a (step c). In some cases the direct'conversion of 6a
or 6b (A=H) to 8a or 8b respectively, may be achieved under Mitsunobu conditions with
the alcohols R2'-X or R3'-X.
Alternatively, the final product may be assembled in several steps. Treatment of the
phenol 5a or 5b with Y-CHR4-(CH2)m-(CHR5)n-OH (Y = leaving group such as e.g. Cl,
Br, I, MsO, TsO, or TfO) in the presence of bases such as Cs2CO3 or K2CO3 in inert
solvents such as acetone, dioxane, DMF or DMA optionally in the presence of KI or Nal
gives alcohol 9a or 9b (step d). 9a or 9b can be converted to lOa or lOb by reaction with
aryl or heteroaryl derivative R7-OH using Mitsunobu conditions (PhsP, DEAD or DIAD)
in a solvent such as THF (step e). Alternatively, the alcohol 9a or 9b can be subjected to a
nucleophilic aromatic substitution reaction with R7-Z wherein Z is a leaving group such as
F, Br or I or to a transition metal catalysed coupling reaction with R7-Z wherein Z is Cl,
Br, I or OTf (step f). Deprotection to the final product lla or lib may be accomplished
as described above by hydrogenation (for PG2 = Bn or PMB) or by oxidative cleavage (for
PG2 = PMB) with DDQ in CH2C12 or dichloromethane, dichloroethane and water at
temperatures between -20°C and reflux or with eerie ammonium nitrate in acetonitrile and
water (step c).
Another procedure consists of the treatment of 5a or 5b with an ester of the formula XCHR4-(
CH2)m-CO2-B under Mitsunobu conditions for X = OH with Ph3P, DEAD or
DIAD in a solvent such as THF to give 12a or 12b (step g). Alternatively, 5a or 5b may
be treated with X-CHR4-(CH2)m-CO2-B under alkylating conditions for X = leaving group
such as e.g. Cl, Br, I, MsO, TsO, or TfO with bases such as Cs2CC>3 or K2CO3 in acetone,
dioxane, DMF or DMA in the presence of KI or Nal to give 12a or 12b (step h).
Reduction of the ester 12a or 12b with sodium borohydride in a solvent such as THF,
methanol or ethanol or mixtures thereof yields 9a or 9b (for R5 = H, step i). Alternatively,
the ester may be converted to derivative 9a or 9b (for R5 * H, step j) in two or three steps.
Reduction of the ester to an aldehyde can be accomplished directly by e.g. DIBAH or by a
reduction to the alcohol by e.g. LiAlH4 and subsequent reoxidation to the aldehyde. The
reaction of the aldehyde with a Grignard reagent R5-MgBr or R5-MgCl or organolithium
reagent R5-Li gives derivative 9a or 9b (for R5 * H, step j). 9a may be converted to lOa
and lla as described above (steps e,c or f,c).
If 5a or 5b is treated with a R4 substituted oxirane in a solvent such as dioxane, DMF or
DMA in the presence of bases such as Cs2CO3 or K2CC>3 under microwave conditions
(step k) alcohol 13a or 13b can be isolated. These alcohols 13a or 13b can be converted to
lOa or lOb and lla or lib (with m=0 and R5=H) respectively, using the reaction
conditions described previously for steps e and c or f and c.
A large number of compounds X-(CHR4)(CH2)m(CHR5)nR6, in which R4 to R6, m, n, and
X are defined as above, are commercially available. If not, they may be prepared from a
related commercially available starting material such as e.g. an alcohol HO-(CHR4)-
(CH2)m(CHR5)nR6, an ester alkylOOC-(CH2)m-(CHR5)nR6, or a carboxylic acid HOOC-
(CH2)m-(CHR5)nR6 according to standard literature procedures commonly known to those
skilled in the art. R4 substituted oxiranes may be prepared by treatment of R4CH=CH2
with a commonly used epoxidizing agent such as w-CPBA. Many of the X-
(CHR4)(CH2)m(CHR5)nR6 wherein R4, R5 = H, and R6 = heteroaryl may be prepared
according to literature procedures (e.g. Binggeli et al. WO2004031162, WO200292084
and WO97019311, Boehringer et al. WO2003037327, Bouillot et al. WO2004006922;
Morita et al., JP9095482; Cynkowski et al., J. Chem. Soc. Chem. Commun., 1995, 2335-
2336; Kodama et al., US6472386; Paul et al., Heterocycles, 2001, 55 (4), 689 - 704,
Ackermann et al. WO200236584, Adams et al. WO9728137).
After preparation of derivatives 7a,7b or 10a,10b according to the synthetic descriptions
above, functional groups present in R6 or R7 may be converted further prior to cleavage of
the protecting group A. Examples for typical transformations of such functional groups are
summarized below:
Ester moieties may be hydrolysed to the corresponding acids by treatment with LiOH,
NaOH or KOH in solvents such as THF, methanol or ethanol. The resulting acids may be
converted to amides by treatment with an amine NHRaRb in the presence of a coupling
reagent such as N,N-dicylohexylcarbo-diimide (DCC), N-(3-dimethylaminopropyl)-N'-
ethylcarbodiimide hydrochloride (EDCI) or O-(l,2-dihydro-2-oxo-l-pyridyl)-N,N,N,Ntetra-
methyluronium-tetrafluorborate (TPTU) and 1-hydroxybenzo-triazole (HOBT) and a
base such as Huenigs base, EtsN or NMM (N-methylmorpholine) in a solvent such as
THF, ether or dichloromethane. Reduction of the esters with reducing agents such as
NaBH4, LiAlH4 in solvents such as MeOH or THF may give the corresponding
hydroxyalkyl residues. Alternatively, the conversions may be carried out with the
unprotected derivatives 8a, 8b, lla or lib, respectively.
Prior to the derivatizations of the functional group on R6or R7, sensitive functional groups
may be suitably protected (e.g. silylation of a hydroxy group) and deprotected again when
desired or required (as described e.g. in "Protective Groups in Organic Synthesis" by T.W.
Greene and P.G.M. Wuts, 2nd Ed., 1991, Wiley N.Y.).
The conversion of a compound of formula (I) into a pharmaceutically acceptable
salt can be carried out by treatment of such a compound with an inorganic acid, for
example a hydrohalic acid, such as, for example, hydrochloric acid or hydrobromic acid,
or other inorganic acids such as sulfuric acid, nitric acid, phosphoric acid etc., or with an
organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid,
tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. The corresponding
carboxylate salts can also be prepared from the compounds of formula (I) by treatment
with physiologically compatible bases.
The conversion of compounds of formula (I) into pharmaceutically acceptable
esters can be carried out e.g. by treatment of suited amino or hydroxy groups present in the
molecules with an carboxylic acid such as acetic acid, with a condensating reagent such as
benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), N,N-
dicylohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (EDCI) or O-(l,2-dihydro-2-oxo-l-pyridyl)-N,N,N,N-tetra-methyluroniumtetrafluorborate
(TPTU) to produce the carboxylic ester or carboxylic amide.
Insofar as their preparation is not described in the examples, the compounds of
formula (I) as well as all intermediate products can be prepared according to analogous
methods or according to the methods set forth above. Starting materials are commercially
available or known in the art.
As described above, the novel compounds of the present invention have been found to
bind to and selectively activate LXR alpha and LXR beta or coactivate LXR alpha and
LXR beta. Consequently, cholesterol absorption is reduced, HDL cholesterol is increased,
and inflammatory atherosclerosis is reduced. They can therefore be used in the treatment
and prophylaxis of diseases which are modulated by LXR alpha and/or LXR beta agonists.
Such diseases include increased lipid and cholesterol levels, particularly low HDLcholesterol,
high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly noninsulin
dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's
disease, sepsis, and inflammatory diseases such as colitis, pancreatitis, cholestasis/fibrosis
of the liver, psoriasis and other inflammatory diseases of the skin, and diseases that have
an inflammatory component such as Alzheimer's disease or impaired/improvable
cognitive function. Moreover, the novel compounds of the present invention can be used
for treatment and prophylaxis of age-related and inherited (e.g. Stargardt's disease) forms
of macular degeneration.
The invention therefore also relates to pharmaceutical compositions comprising a
compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
The invention likewise embraces compounds as described above for use as
therapeutically active substances, especially as therapeutically active substances for the
treatment and/or prophylaxis of diseases which are modulated by LXR alpha and/or LXR
beta agonists, particularly as therapeutically active substances for the treatment and/or
prophylaxis of increased lipid levels, increased cholesterol levels, low HDL-cholesterol,
high LDL-cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes
mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseas.es, skin diseases,
colitis, pancreatitis, cholestasis of the liver, fibrosis of the liver, macular degeneration
and/or Alzheimer's disease.
In another preferred embodiment, the invention relates to a method for the
therapeutic and/or prophylactic treatment of diseases which are modulated by LXR alpha
and/or LXR beta agonists, particularly for the therapeutic and/or prophylactic treatment of
increased lipid levels, increased cholesterol levels, low HDL-cholesterol, high LDLcholesterol,
atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus,
metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis,
pancreatitis, cholestasis of the liver, fibrosis of the liver, macular degeneration and/or
Alzheimer's disease, which method comprises administering a compound as defined
above to a human being or animal.
The invention also embraces the use of compounds as defined above for the
therapeutic and/or prophylactic treatment of diseases which are modulated by LXR alpha
and/or LXR beta agonists, particularly for the therapeutic and/or prophylactic treatment of
increased lipid levels, increased cholesterol levels, low HDL-cholesterol, high LDLcholesterol,
atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus,
metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis,
pancreatitis, cholestasis of the liver, fibrosis of the liver, macular degeneration and/or
Alzheimer's disease.
The invention also relates to the use of compounds as described above for the
preparation of medicaments for the therapeutic and/or prophylactic treatment of diseases
which are modulated by LXR alpha and/or LXR beta agonists, particularly for the
therapeutic and/or prophylactic treatment of increased lipid levels, increased cholesterol
levels, low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes,
non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis,
inflammatory diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, fibrosis
of the liver, macular degeneration and/or Alzheimer's disease. Such medicaments
comprise a compound as described above.
Prevention and/or treatment of increased lipid levels, increased cholesterol levels,
atherosclerotic diseases, dyslipidemia, or diabetes is the preferred indication, particularly
prevention and/or treatment of increased lipid levels, increased cholesterol levels,
atherosclerotic diseases, or dyslipidemia, especially prevention and/or treatment of
atherosclerotic diseases or dyslipidemia.
The following tests were carried out in order to determine the activity of the
compounds of the present invention. Background information on the performed assays can
be found in: Nichols JS et al. "Development of a scintillation proximity assay for
peroxisome proliferator-activated receptor gamma ligand binding domain", Anal
Biochem. 1998,257: 112-119.
Mammalian expression vectors were constructed to express full-length human
LXR alpha and LXR beta. Bacterial expression vectors were constructed to produce
glutathione-s-transferase (GST) fused to the ligand binding domains (LBD) of human
LXR alpha (aa 164 to 447) and human LXR beta (aa 155 to 460). To accomplish this, the
portions of the sequences encoding the LBDs were amplified from full-length clones by
PCR and then subcloned into the plasmid vectors. Final clones were verified by DNA
sequence analysis (Willy et al., Genes Dev. 1995, 9:1033-45; Song et al., Proc Natl Acad
SciUSA.1994, 91:10809-13).
Induction, expression, and purification of GST-LBD fusion proteins were performed
in E. coli strain BL21(pLysS) cells by standard methods (Ref: Current Protocols in
Molecular Biology, Wiley Press, edited by Ausubel et al).
Radioligand Binding Assay
LXR alpha and LXR beta receptor binding were assayed in buffer consisting of 50
mM HEPES, pH 7.4, 10 mM NaCl, 5 mM MgCl2. For each 96-well reaction, 500 ng of
GST-LXR alpha-LBD or 700 ng of GST-LXR beta-LBD fusion proteins were bound to 80
Hg or 40 u.g SPA beads (Pharmacia Amersham) respectively, in a final volume of 50 |il by
shaking. The resulting slurry was incubated for 1 h at RT and centrifuged for 2 min at
1300 X g. The supernatant containing unbound protein was removed, and the semi-dry
pellet containing the receptor-coated beads was re-suspended in 50 p.1 of buffer.
Radioligand (eg. 100,000 dpm of (A^-(2,2,2-trifluoroethyl)-A^-[4-(2,2,2-trifluoro-lhydroxy-
l-trifluoromethylethyl)-phenyl]-benzenesulfonamide)) was added, and the
reaction incubated at RT for 1 h in the presence of test compounds, and then scintillation
proximity counting was performed. All binding assays were performed in 96-well plates
and the amount of bound ligand was measured on a Packard TopCount using OptiPlates
(Packard). Dose response curves were measured within a range of concentration from 10"'°
MtolO'4M.
Luciferase Transcriptional Reporter Gene Assays
Baby hamster kidney cells (BHK21 ATCC CCL10) were grown in DMEM medium
containing 10% FBS at 37°C in a 95%O2:5%CO2 atmosphere. Cells were seeded in 6-well
plates at a density of 105 Cells/well and then batch-transfected with either the full-length-
LXR alpha or full-length-LXR beta expression plasmids plus a reporter plasmid
expressing luceriferase under the control of LXR response elements . Transfection was
accomplished with the Fugene 6 reagent (Roche Molecular Biochemicals) according to the
suggested protocol. Six hours following transfection, the cells were harvested by
trypsinization and seeded in 96-well plates at a density of 104 cells/well. After 24 hours to
allow attachment of cells, the medium was removed and replaced with 100 jal of phenol
red-free medium containing the test substances or control ligands. (final DMSO
concentration: 0.1%). Following incubation of the cells for 24 hours with substances, 50 |il
of the supernatant was discarded and then 50 jal of Luciferase Constant-Light Reagent
(Roche Molecular Biochemicals) was added to lyse the cells and initiate the luciferase
reaction. Luminescence, as a measure of luciferase activity, was detected in a Packard
TopCount. Transcriptional activation in the presence of a test substance was expressed as
fold-change in luminescence compared to that of cells incubated in the absence of the
substance. EC$o values were calculated using the XLfit program (ID Business Solutions
Ltd. UK).
The compounds according to formula (I) have an activity in at least one of the above
assays (EC50 or IC50) of 1 nM to 100 pM, preferably 1 nM to 10 ^M, more preferably 1
nM to 1
For example, the following compounds showed the following IC50 values in the binding
assay:
LXRalpha Binding LXRbeta' Binding
XamP C IC50 [umol/1] IC50 [^imol/1]
11 0.093 0.014
13 0.237 0.236
57 0.033 0.0227
These results have been obtained by using the foregoing test.
The compounds of formula I and/or their pharmaceutically acceptable salts can be
used as medicaments, e.g. in the form of pharmaceutical preparations for enteral,
parenteral or topical administration. They can be administered, for example, perorally, e.g.
in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions,
emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in
the form of injection solutions or suspensions or infusion solutions, or topically, e.g. in the
form of ointments, creams or oils. Oral administration is preferred.
The production of the pharmaceutical preparations can be effected in a manner
which will be familiar to any person skilled in the art by bringing the described
compounds of formula I and/or their pharmaceutically acceptable salts, optionally in
combination with other therapeutically valuable substances, into a galenical administration
form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid
carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic
carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic
acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard
gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example,
vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of
the active ingredient no carriers might, however, be required in the case of soft gelatine
capsules). Suitable carrier materials for the production of solutions and syrups are, for
example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for
injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils.
Suitable carrier materials for suppositories are, for example, natural or hardened oils,
waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical
preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils,
liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and
cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistencyimproving
agents, flavour-improving agents, salts for varying the osmotic pressure, buffer
substances, solubilizers, colorants and masking agents and antioxidants come into
consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula I can vary within wide limits depending
on the disease to be controlled, the age and the individual condition of the patient and the
mode of administration, and will, of course, be fitted to the individual requirements in
each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially
about 1 to 300 mg, comes into consideration. Depending on severity of the disease and the
precise pharmacokinetic profile the compound could be administered with one or several
daily dosage units, e.g. in 1 to 3 dosage units.
The pharmaceutical preparations conveniently contain about 1-500 mg, preferably
1-100 mg, of a compound of formula I.
The following Examples serve to illustrate the present invention in more detail.
They are, however, not intended to limit its scope in any manner
Examples
Abbreviations:
n-BuLi = w-butyl lithium, CHjCb = dichloromethane, DDQ = 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone, DEAD = diethyl azodicarboxylate, DIAD = di-wopropyl
azodicarboxylate, DMF = dimethylformamide, EDCI = N-(3-dimethylaminopropyl)-N'-
ethylcarbodiimide hydrochloride, EtOAc = ethyl acetate, EtOH = ethanol, Et2O = diethyl
ether, MeOH = methanol, HOBT = 1 -hydroxybenzo-triazole, Huenigsbase = iP^NEt, Nethyldiisopropylamine,
NMM = N-metylmorpholine, TBAF = tetra «-butylammonium
fluoride, TBDMSC1 = fcrt-butyldimethylsilyl chloride, TFA = trifluoroacetic acid, THF =
tetrahydrofuran
General remarks
All reactions were performed under argon.
Example 1
4-[2,2,2-Trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyI-ethyl]-phenol
1.1
At 0°C, to 10 g (57.81 mmol) of 4-bromo-phenol in 100 ml of DMF were added 4.33 g
(63.6 mmol) of imidazole and 9.58 g (63.6 mmol) of TBDMSC1 in 30 ml of DMF. The
mixture was stirred at room temperature overnight. A saturated solution of NaHCCh was
added, and the product was extracted with diethyl ether (3x). The organic phase was
washed with water and brine, and dried (Na2SO4). After filtration and evaporation of the
solvent 16.57 g (99%) of (4-bromo-phenoxy)-tert-butyl-dimethyl-silane were isolated as a
colorless liquid, MS: 286 (M, lBr)+.
1.2
At -78 °C, a solution of 16.57 g (57.7 mmol) of (4-bromo-phenoxy)-fert-butyl-dimethylsilane
in 140 ml of THF was treated with 43.6 ml (69.8 mmol) of «-BuLi (ca 1.6 M in
hexane). After 30 min at this temperature hexafluoroacetone was bubbled into the solution
(very exothermic reaction). Stirring was continued for additional 30 min at -78°C, and a
solution of NH4C1 was added to the mixture. The phases were separated and the product
was extracted with EtOAc (3x). The combined organic phases were washed with brine,
dried (NaaSC^), filtered and evaporated. Purification by flash-chromatography on silica
gel («-heptane/EtOAc 97:3 to 9:1) gave 8.5 g (40%) of 2-[4-(teA7-butyl-dimethylsilanyloxy)-
phenyl]-l,l,l,3,3,3-hexafiuoro-propan-2-ol as a yellow liquid, MS: 374 (M)+.
1.3
To a solution of 4.1 g (29.6 mmol) of 4-methoxybenzyl alcohol in 100 mL of THF was
added 7.76 g (29.6 mmol) of triphenylphosphine and 8.53 g (22.8 mmol) of 2-[4-(tertbutyl-
dimethyl-silanyloxy)-phenyl]-l, 1,1,3,3,3-hexafluoro-propan-2-ol at room
temperature. The reaction mixture was cooled to 0 °C and 5.7 mL (29.6 mmol) of
diisopropylazo dicarboxylate were added. The solution was stirred at room temperature
overnight, a solution of NFUCl was added and the inorganic layer was extracted with ethyl
acetate. The combined layers were washed with brine, and dried (Na2SC>4), filtered and
evaporated. Column chromatography with ethyl acetate/«-heptane 1:99 as eluent yielded
8.39 g (74%) of ^^-butyl-dimethyl-{4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenoxy}-silane as a light yellow liquid, MS: 494 (M)+.
1.4
8.39 g (17.0 mmol) of ter/-butyl-dimethyl-{4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenoxy}-silane was dissolved in 70 mL of THF and 25.4 ml (25.4
mmol) of 1M TBAF solution in THF was added at 0°C. The mixture was stirred at room
temperature overnight, a 1M KHSCU solution was added and the product was extracted
with ethyl acetate (2x). The organic phase was washed with brine, dried (Na2SO4), filtered
and evaporated. Column chromatography on silica gel with H-heptane/ethyl acetate 5:1 as
eluent yielded 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenol
as a yellow liquid, MS: 379 (M-H)'.
Example 2
2-Methyl-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenol
In analogy to example 1.1-1.4, from 4-bromo-2-methylphenol was prepared 2-methyl-4-
[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenol as a white solid,
MS: 393 (M-H)'.
Example 3
2-Chloro-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenol
In analogy to example 1.1-1.4, from 4-bromo-2-chloro-phenol was prepared 2-chloro-4-
[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenol as an off-white
solid, MS: 414 (M, 1C1)+.
Example 4
2,6-Dimethyl-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyI-ethyl]-
phenol
In analogy to example 1.1-1.4, from 4-bromo-2,6-dimethyl-phenol was prepared 2,6-
dimethyl-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenol as a
yellow solid, MS: 407 (M-H)'.
Example 5
3-[2,2,2-Trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenol
In analogy to example 1.1-1.4, from 3-bromo-phenol was prepared 3-[2,2,2-trifluoro-l-(4-
methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenol as a white semisolid, MS: 380 (M)+.
Example 6
4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenol
In analogy to example 1.4, from 2-[4-(te/"f-butyl-dimethyl-silanyloxy)-phenyl]-l, 1,1,3,3,3-
hexafluoro-propan-2-ol (example 1.2) was prepared 4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenol as a white crystalline solid, MS: 259 (M-H)~.
Example 7
2-(4-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yIoxy]-propoxy}-phenyl)-
l,l,l,3,3,3-hexafluoro-propan-2-ol
100 mg (0.23 mmol) of 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-ol (CAS 423159-55-1,
prepared as described in WO 2002036584) in 2 ml of acetone were treated with 67 mg
(0.22 mmol) of 4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenol (example 6),
76 mg (0.2 mmol) of CS2CO3 and 8 mg (0.05 mmol) of potassium iodide. The reaction
mixture was stirred at ambient temperature for 2.5 d, at 45 °C for 4h, and then was diluted
with dichloromethane. The organic phase was washed with water and brine, dried
(Na2SO4) and evaporated. The crude product was purified by column chromatography on
silica gel to yield 40 mg (28%) 2-(4-{3-[3-(4-bromo-phenyl)-benzo[d]isQthiazol-6-yloxy]-
propoxy}-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol as a colorless solid, MS: 604 (M-H,
IBr)-.
Example 8
3-(3-{3-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-propionic acid ethyl ester
8.1
1.12 g (2.9 mmol) of 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-
phenol (example 5) in 20 ml of acetone were treated with 0.51 mL (5.9 mmol) of 3-
bromo-1-propanol in the presence of 1.9 g (5.9 mmol) Cs2COa and 245 mg (1.5 mmol) of
potassium iodide. The reaction mixture was stirred at 50°C overnight, filtered and
evaporated. The crude product was redissolved in EtOAc and a 1M KHSO4 solution, the
phases were separated and the inorganic one extracted with EtOAc. The combined organic
phases were washed with brine, dried (Na2SO4) and the solvent was evaporated. Column
chromatography on silica gel yielded 1.1 g (84 %) of 3-{3-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-propan-l-ol as a colorless liquid, MS: 438
8.2
150 mg (0.3 mmol) of 3-{3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethylethyl]-
phenoxy}-propan-l-ol and 73 mg (0.38 mmol) of 3-(3-hydroxy-phenyl)-propionic
acid ethyl ester (CAS 34708-60-6) in 4 mL of THF were treated with 1 17 mg (0.44 mmol)
of triphenylphosphine. The solution was cooled to 0°C and treated with 88 uL (0.44
mmol) of DIAD. The mixture was stirred at room temperature overnight, the solvent was
evaporated and the crude mixture was purified by column chromatography on silica gel
with a gradient of EtOAc/»-heptane 1:5 to 1:3 to yield 1 10 mg (52%) of 3-[3-(3-{3-[2,2,2-
trifluoro- 1 -(4-methoxy-benzyloxy)- 1 -trifluoromethyl-ethyl]-phenoxy } -propoxy)-phenyl]-
propionic acid ethyl ester as a colorless liquid, MS: 614 (M)+.
100 mg (0.16 mmol) of 3-[3-(3-{3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenoxy}-propoxy)-phenyl]-propionic acid ethyl ester in 10 mL of
EtOAc were hydrogenated in the presence of 60 mg of 10% Pd/C. After removal of the
catalyst and evaporation of the solvent, the residue was purified by column
chromatography on silica gel with a gradient of EtOAc/»-heptane 1:5 to 1:3 to yield 64 mg
(80%) of 3-(3-{3-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-propionic acid ethyl ester as a colorless oil, MS: 493 (M-H)".
Example 9
rac (4-{l-Phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyI-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid methyl ester
9.1
To 1 g (2.6 mmol) of 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethylethyl]-
phenol (example 5) in 8 mL of dioxane were added 1.0 mL (8.8 mmol) of 2-phenyloxirane.
The reaction was split in 2 portions. To each of those was added 4.28 g (13.1
mmol) of Cs2CC>3 and each reaction mixture was treated for 30 min at 130°C in the
microwave. The mixtures were combined and water and ether were added. The aqueous
phase was extracted with ether and the combined organic phases were washed with brine
and dried (Na2SC>4). After evaporation of the solvent the crude products were separated by
column chromatography to give 810 mg (62%) of rac l-phenyl-2-{3-[2,2,2-trifluoro-l-(4-
methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenoxy}-ethanol as light yellow oil, MS:
500 (M)+ , and 250 mg (19%) of rac 2-phenyl-2-{3-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-ethanol as light yellow oil, MS: 500 (M)+.
In analogy to example 8.2, from rac l-phenyl-2-{3-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-ethanol and methyl 4-hydroxyphenylacetate
was prepared rac [4-(l-phenyl-2-{3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenoxy}-ethoxy)-phenyl]-acetic acid methyl ester as a colorless
oil, MS: 648(M)+.
In analogy to example 8.3, from rac [4-(l-phenyl-2-{3-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-phenyl]-acetic acid methyl ester
was prepared rac (4-{l-phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-ethoxy}-phenyl)-acetic acid methyl ester as a colorless oil, MS: 527 (M-H)".
Example 10
rac (4-{l-Phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid
40 mg (0.08 mmol) of rac (4-{l-phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethylethyl)-
phenoxy]-ethoxy}-phenyl)-acetic acid methyl ester (example 9) in 1 mL of THF
were treated with 0.76 mL of 1M LiOH at room temperature for 2h. 1M KHSO4 solution
was added, the phases were separated, and the inorganic one was extracted with EtOAc.
The combined organic phases were washed with brine, dried (Na2SC>4) and evaporated.
The crude product was purified by column chromatography to give 29 mg (74%) of rac (4-
{l-phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid as a colorless oil, MS: 513 (M-H)~.
Example 11
rac 4-{l-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-benzoic acid methyl ester
11.1
In analogy to example 10.1, from 4-hydroxy-benzoic acid methyl ester arid rac 2-phenyloxirane
was prepared rac 4-(2-hydroxy-l-phenyl-ethoxy)-benzoic acid methyl ester, MS:
273 (M)+.
11.2
In analogy to example 8.2, from 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethylj-phenol and rac 4-(2-hydroxy-l-phenyl-ethoxy)-benzoic acid methyl
ester was prepared rac 4-(l-phenyl-2-{4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenoxy}-ethoxy)-benzoic acid methyl ester as a yellow oil, MS:
634 (M)+.
11.3
76 mg (0.12 mmol) of rac 4-(l-phenyl-2-{4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenoxy}-ethoxy)-benzoic acid methyl ester in 4 ml of a mixture of
acetonitrile:water (9:1) were treated with 250 mg (0.46 mmol) of eerie ammonium nitrate
at room temperature overnight. An additional 100 mg (0.18 mmol) of eerie ammonium
nitrate were added and stirring was continued for 3h. EtOAc and 1M KHSO4 were added
and the phases were separated. The inorganic one was extracted with EtOAc, the
combined organic phases were washed with brine and dried (Na2SO4) and evaporated.
Column chromatography on ISOLUTE Flash NH2 with a gradient of EtOAc/w-heptane to
EtOAc gave 30 mg (48%) of rac 4-{l-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-ethoxy}-benzoic acid methyl ester as a colorless oil, MS:
513(M-H)".
Example 12
4-{2-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
benzoic acid methyl ester
12.1
In analogy to example 8.1, from 4-hydroxy-benzoic acid methyl ester and 2-bromoethanol
was prepared 4-(2-hydroxy-ethoxy)-benzoic acid methyl ester as a colorless oil,
MS: 197(M+H)+.
12.2
In analogy to example 11.2 (8.2) and 11.3, from 4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol and 4-(2-hydroxy-ethoxy)-benzoic acid
methyl ester was prepared 4-{2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-ethoxy}-benzoic acid methyl ester as a white semisolid, MS: 437 (M-H)".
Example 13
2-(4-Ben/yloxy-3-chloro-phenyl)-l, 1,1,3,3,3-hexafluoro-propan-2-ol
13.1
100 mg (0.2 mmol) of 2-chloro-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 3) in 4 ml of acetone were treated with 47 mg (0.3
mmol) of benzyl bromide, 157 mg (0.5 mmol) of Cs2CO3 and 4 mg (0.025 mmol) of
potassium iodide. The reaction mixture was stirred at 50 °C overnight, cooled to room
temperature, filtered and the solvent was evaporated. The residue was dissolved in EtOAc
and water, the phases were separated and the inorganic one was extracted with EtOAc.
The combined organic phases were washed with brine, dried (Na2SO4) and evaporated to
give 82 mg (67%) of crude l-benzyloxy-2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
1 -trifluoromethyl-ethyl]-benzene.
13.2
82 mg (0.2 mmol) of crude l-benzyloxy-2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-benzene were treated with 3 mL 'of a mixture of
dichloromethane/ trifluoroacetic acid (1:3) at room temperature for 1 h. The solvent was
evaporated and the residue was redissolved in a mixture of diethyl ether and a solution of
3. The inorganic phase was extracted with diethyl ether and the combined organic
phases were washed with brine and dried (Na2SO4). After filtration and evaporation of the
solvent, the crude product was purified by column chromatography to give 7.3 mg (12%)
of 2-(4-benzyloxy-3-chloro-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol as a yellow gum,
MS: 383 (M-H, 1C1)'.
Example 14
2-(4-Benzyloxy-3-methyl-phenyl)-l,l,l53,3,3-hexafluoro-propan-2-ol
In analogy to example 13.1-13.2, from 2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 2) and benzyl bromide was prepared
2-(4-benzyloxy-3-methyl-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol as a light yellow
gum, MS: 363 (M-H)'.
Example 15
2-(3-Benzyloxy-phenyl)-l,l)l>3,3,3-hexafluoro-propan-2-ol
In analogy to example 13.1-13.2, from 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 5) and benzyl bromide was prepared 2-(3-
benzyloxy-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol as an off-white solid, MS: 349 (MH)-.
Example 16
2-(4-Benzyloxy-3,5-dimethyl-phenyl)-l,l»l»3,3,3-hexafluoro-propan-2-ol
In analogy to example 13.1-13.2, from 2,6-dimethyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 4) and benzyl bromide was prepared
2-(4-benzyloxy-3,5-dimethyl-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol as a light yellow
solid, MS: 377 (M-H)Example 17
2-(4-Benzyloxy-phenyl)-l,l»l?3,3,3-hexafluoro-propan-2-ol
In analogy to example 13.1-13.2, from 4-[2,2,2-trifluoro-l-(4-methoxy-benzyIoxy)-ltrifluoromethyl-
ethyl]-phenol (example 1) and benzyl bromide was prepared 2-(4-
benzyloxy-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol as an off-white solid, MS: 349 (MH)-.
Example 18
(4-{3-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy|-
propoxy}-phenyl)-acetic acid methyl ester
18.1
In analogy to example 8.1, from 2-methyl-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 2) and 3-bromo-l-propanol was prepared 3-{2-
methyl-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenoxy}-
propan-1-ol as white solid, MS: 452 (M)+.
18.2
In analogy to example 8.2-8.3, from 3-{2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
1 -trifluoromethyl-ethyl]-phenoxy} -propan-1 -ol and (4-hydroxy-phenyl)-acetic
acid methyl ester was prepared (4-{3-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid methyl ester as a yellow
oil, MS: 479 (M-Hy.
Example 19
4-{3-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxyj-benzoic acid methyl ester
In analogy to example 8.2-8.3, from 3-{2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-propan-l-ol and 4-hydroxy-benzoic acid
methyl ester was prepared 4-{3-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethylethyl)-
phenoxy]-propoxy}-benzoic acid methyl ester as a white solid, MS: 465 (M-H)".
Example 20
3-(4-{3-[2-Chloro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-propionic acid methyl ester
20.1
In analogy to example 8.1, from 2-chloro-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 3) and 3-bromo-l-propanol was prepared 3-{2-
chloro-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenoxy}-
propan-1-ol as a yellow oil, MS: 472 (M, 1C1)+.
20.2
In analogy to example 8.2-8.3, from 3-{2-chloro-4-[2,2,2-trifluoro-l-(4-methoxy-
benzyloxy)-1 -trifluoromethyl-ethylj-phenoxy} -propan-1 -ol and 3-(4-hydroxy-pheny 1)-
propionic acid methyl ester was prepared 3-(4-{3-[2-chloro-4-(2,2,2-trifluoro-l-hydroxyl-
trifluoromethyl-ethyl)-phenoxy]-propoxy}-phenyl)-propionic acid methyl ester as a
colorless oil, MS: 513 (M-H, 1C1)'.
Example 21
(4-{3-[2-Chloro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyI-ethyl)-phenoxyJpropoxy}-
phenyl)-acetic acid methyl ester
In analogy to example 8.2-8.3, from 3-{2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
1 -trifluoromethyl-ethylj-phenoxy} -propan-1 -ol and (4-hydroxy-phenyl)-acetic
acid methyl ester was prepared (4-{3-[2-chloro-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid methyl ester as a colorless
oil, MS: 499 (M-H, 1C1)-.
Example 22
4-{3-[2-ChIoro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyI)-phenoxy]-
propoxyj-benzoic acid methyl ester
In analogy to example 8.2-8.3, from 3-{2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-propan-l-ol and 4-hydroxy-benzoic acid
methyl ester was prepared 4-{3-[2-chloro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyIethyl)-
phenoxy]-propoxy}-benzoic acid methyl ester as a white solid, MS: 485 (M-H,
1C1)'.
Example 23
(4-{3-[2,6-Dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester
23.1
In analogy to example 8.1, from 2,6-dimethyl-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 4) and 3-bromo-l-propanol was prepared 3-
{2,6-dimethyl-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-
phenoxy}-propan-l-ol as a yellow oil, MS: 466 (M)+.
23.2
In analogy to example 8.2-8.3, from 3-{2,6-dimethyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
1 -trifluoromethyl-ethyl]-phenoxy}-propan-1 -ol and (4-hydroxy-phenyl)-acetic
acid methyl ester was prepared (4-{3-[2,6-dimethyl-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid methyl ester as a colorless
oil, MS: 493 (M-H)-.
Example 24
4-{3-[2,6-Dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxyj-benzoic acid methyl ester
In analogy to example 8.2-8.3, from 3-{2,6-dimethyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-propan-l-ol and 4-hydroxy-benzoic acid
methyl ester was prepared 4-{3-[2,6-dimethyl-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-benzoic acid methyl ester as 'a colorless oil,
MS: 479 (M-H)-.
Example 25
4-{3-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxyj-benzoic acid
94 mg (0.2 mmol) of 4-{3-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethylethyl)-
phenoxy]-propoxy}-benzoic acid methyl ester (example 19) in 2 mL of THF were
treated with 2 mL of 1M LiOH at room temperature overnight. 1M KHSO4 solution was
added, the phases were separated, and the inorganic one was extracted with EtOAc. The
combined organic phases were washed with brine, dried (Na2SC>4) and evaporated. The
crude product was purified by column chromatography with CH2Cl2/MeOH 95:5 to give
60 mg (65%) 4-{3-[2-methyl-4-(2)2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-benzoic acid as a light yellow solid, MS: 451 (M-H)".
Example 26 ' :
(4-{3-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid
In analogy to example 25, from (4-{3-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid methyl ester (example 18)
was prepared (4-{3-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluorornethyl-ethyl)-
phenoxy]-propoxy}-phenyl)-acetic acid as a colorless oil, MS: 435 (M-H)".
Example 27
(4-{3-[2,6-Dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid
In analogy to example 25, from (4-{3-[2,6-dimethyl-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid methyl ester (example 23)
was prepared (4-{3-[2,6-dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-phenyl)-acetic acid as a light brown oil, MS: 479 (M-H)~.
Example 28
4-{3-[2,6-Dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxyj-benzoic acid
In analogy to example 25, from 4-{3-[2,6-dirnethyl-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-benzoic acid methyl ester (example 24) was
prepared 4-{3-[2,6-dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-benzoic acid as a white solid, MS: 465 (M-H)".
Example 29
4-{2-[2,6-Dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
ethoxyj-benzoic acid methyl ester
29.1
In analogy to example 8.1, 2,6-dimethyl-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 4) and 2-bromo-ethanol was prepared 2- {2, 6-
dimethyl-4-[2,2,2-trifluoro- 1 -(4-methoxy-benzyloxy)- 1 -trifluoromethyl-ethylj-phenoxy } -
ethanol as a white solid, MS: 470
29.2
In analogy to example 8.2, from 2-{2,6-dimethyl-4-[2,2,2-trifluoro-l -(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy} -ethanol and 4-hydroxy-benzoic acid
methyl ester was prepared 4-(2-{2,6-dimethyl-4-[2,2,2-trifluoro-l -(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-benzoic acid methyl ester as a
colorless oil, MS: 604 (M+NH4)+.
29.3
To 105 mg (0.2 mmol) of 4-(2-{2,6-dimethyl-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-benzoic acid methyl ester in 5 mL of
dichloroethane 61 mg (0.3 mmol) of DDQ and a drop of water were added. The reaction
mixture was stirred at 70°C overnight, cooled to room temperature and was diluted with
dichloromethane and EtOAc, dried (Na2SC>4) and evaporated. Column chromatography on
ISOLUTE Flash NH2 with EtOAc/w-heptane 1:1 gave 21 mg (25%) of 4-{2-[2,6-dimethyl-
4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-benzoic acid
methyl ester as a light yellow solid, MS: 465 (M-H)".
Example 30
3-(4-{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
3-phenyl-propoxy}-phenyI)-propionic acid methyl ester
30.1
To 1.27 g (4.9 mmol) of (R)-2-hydroxy-3-phenyl-propionic acid benzyl ester in 10 mL of
THF were added 1.5 g (3.8 mmol) of 2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 2) and 1.3 g (4.9 mmol) of
triphenylphosphine. The mixture was cooled to 0°C, treated with 0.77 mL (4.9 mmol) of
DEAD and stirred at room temperature overnight. The solvent was evaporated and the
crude mixture was purified by column chromatography on silica ge,l with EtOAc/«-
heptane 1:4 to yield 1.7 g (71%) of (S)-2-{2-methyl-4-[2,2,2-trifluoro-l-(4-rnethoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-3-phenyl-propionic acid benzyl ester as a
light yellow oil, MS: 632 (M)+.
30.2
1.7 g (2.7 mmol) of (S)-2-{2-methyl-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenoxy}-3-phenyl-propionic acid benzyl ester was dissolved in a
mixture of 11 mL of methanol and 11 mL of THF and cooled to 0°C. To this solution 1.0
g (26.9 mmol) of NaBFLt were added in portions, and the mixture was slowly warmed to
room temperature overnight. Water was added, the phases were separated and the
inorganic one was extracted with dichloromethane. The combined organic phases were
washed with brine, dried (Na2SC>4), filtered and evaporated. Purification by column
chromatography with CH2Cl2/MeOH 95:5 yielded 960 mg (68%) (S)-2-{2-methyl-4-
[2,2,2-trifluoro-1 -(4-methoxy-benzyloxy)-1 -trifluoromethyl-ethyl]-phenoxy} -3 -pheny 1-
propan-1-ol as a light yellow oil, MS: 528 (M)+.
30.3
To 320 mg (0.6 mmol) of (S)-2-{2-methyl-4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-1 -
trifluoromethyl-ethyl]-phenoxy}-3-phenyl-propan-l-ol in 5 mL of THF were added 0.14 g
(0.8 mmol) of 3-(4-hydroxy-phenyl)-propionic acid methyl ester and 0.2 g (0.8 mmol) of
triphenylphosphine. The mixture was cooled to 0°, was treated with 0.12 mL (0.8 mmol)
of DEAD and was stirred at room temperature overnight. A solution of NH4C1 was added,
the phases were separated and the inorganic one was extracted with EtOAc. The combined
organic phases were washed with brine, dried (NaaSO.*), filtered and evaporated. The
crude product was purified by column chromatography on silica gel with EtOAc/rc-heptane
1:3 to yield 330 mg (79%) of 3-[4-((S)-2-{2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-3-phenyl-propoxy)-phenyl]-propionic acid
methyl ester as a yellow oil.
30.4
330 mg (0.5 mmol) of 3-[4-((S)-2-{2-methyl-4-[2,2,2-trifluoro-l-(4-meth6xy-benzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-3-phenyl-propoxy)-phenyl]-propionic acid methyl ester
in 10 mL of EtOAc were hydrogenated in the presence of 200 mg of 10% Pd/C. After
removal of the catalyst and evaporation of the solvent, the residue was purified by column
chromatography on silica gel with EtOAc/n-heptane 1:4 to yield 116 mg (42%) of 3-(4-
{(S)-2-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-3-
phenyl-propoxy}-phenyl)-propionic acid methyl ester as a light yellow oil,
MS: 569 (M-H)'.
Example 31
(4-{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyI)-phenoxy]-3-
phenyl-propoxy}-phenyl)-acetic acid methyl ester
In analogy to example 30.3-30.4, from (S)-2-{2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
1 -trifluoromethyl-ethylj-phenoxy} -3-pheny 1-propan-1 -ol and (4-hydroxyphenyl)-
acetic acid methyl ester was prepared (4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-lhydroxy-
1 -trifluoromethyl-ethyl)-phenoxy]-3-phenyl-propoxy} -phenyl)-acetic acid
methyl ester as a colorless oil, MS: 555 (M-H)".
Example 32
4-{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-3-
phenyl-propoxyj-benzoic acid methyl ester
In analogy to example 30.3-30.4, from (S)-2-{2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
1 -trifluoromethyl-ethy l]-phenoxy} -3 -phenyl-propan-1 -ol and 4-hydroxybenzoic
acid methyl ester was prepared 4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-l-hydroxyl-
trifluoromethyl-ethyl)-phenoxy]-3-phenyl-propoxy}-benzoic acid methyl ester as a light
yellow oil, MS: 541 (M-Hy.
Example 33
(4-{(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester
33.1
In analogy to example 30.1-30.2, from (R)-2-hydroxy-3-phenyl-propionic acid benzyl
ester and 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenol
(example 1) was prepared (S)-3-phenyl-2-{4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenoxy}-propan-l-ol as a light yellow oil, MS: 514 (M)+.
33.2
In analogy to example 30.3-30.4, from (S)-3-phenyl-2-{4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
1 -trifluoromethyl-ethylj-phenoxy}-propan-1 -ol and (4-hydroxy-phenyl)-acetic
acid methyl ester was prepared (4-{(S)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid methyl ester as a colorless
oil, MS: 541 (M-H)'.
Example 34
4-{(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyI)-phenoxy]-
propoxy}-benzoic acid methyl ester
In analogy to example 30.3-30.4, from (S)-3-phenyl-2-{4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-!-
trifluoromethyl-ethylj-phenoxy}-propan-l-ol and 4-hydroxy-benzoic acid
methyl ester was prepared 4-{(S)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-benzoic acid methyl ester as a colorless oil,
MS: 527 (M-H)'.
Example 35
(4-{(S)-2-[2-MethyI-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-3-
phenyl-propoxy}-phenyl)-aceticacid
In analogy to example 25, from (4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-3-phenyl-propoxy}-phenyl)-acetic acid methyl ester
(example 31) was prepared (4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-3-phenyl-propoxy}-phenyl)-acetic acid as a colorless oil,
MS: 541 (M-H)-.
Example 36
4-{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-3-
phenyl-propoxyj-benzoic acid
In analogy to example 25, from 4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-3-phenyl-propoxy}-benzoic acid methyl ester (example
32) was prepared 4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyIethyl)-
phenoxy]-3-phenyl-propoxy}-benzole acid as a colorless oil, MS: 527 (M-H)".
Example 37
(4-{(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid
In analogy to example 25, from (4-{(S)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid methyl ester (example 33)
was prepared (4-{(S)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-phenyl)-acetic acid as a colorless oil, MS: 527 (M-H)".
Example 38
4-{(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxyj-benzoic acid
In analogy to example 25, from 4-{(S)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-benzoic acid methyl ester (example 34) was
prepared 4-{(S)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-benzoic acid as a colorless oil, MS: 513 (M-H)".
Example 39
Rac l,l,l)3,3,3-Hexafluoro-2-{4-[2-(4-hydroxymethyl-phenoxy)-l-phenyl-ethoxy]-
phenyl}-propan-2-ol
39.1
In analogy to example 9.1, from rac 2-phenyl-oxirane and p-cresol was prepared rac 1-
phenyl-2-p-tolyloxy-ethanol, MS: 228 (M)+, and rac 2-phenyl-2-/?-tolyloxy-ethanol, MS:
228 (M)+.
39.2
In analogy to example 9.2, from 4-[2,2,2-trifluoro-l-(4-metnoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 1) and rac l-phenyl-2-p-tolyloxy-ethanol was
prepared rac l-(l-phenyl-2-p-tolyloxy-ethoxy)-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-benzene as yellow oil, MS: 590 (M)+.
39.3
90 mg (0.15 mmol) of rac l-(l-phenyl-2-p-tolyloxy-ethoxy)-4-[2,2,2-trifluoro-l-(4-
methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-benzene in 3 ml of a mixture of
acetonitrile:water (9:1) were treated with 100 mg (0.18 mmol) of eerie ammonium nitrate
at room temperature overnight. An additional 100 mg (0.18 mmol) of eerie ammonium
nitrate were added and stirring was continued. EtOAc and 1M KHSO4 were added and the
phases were separated. The inorganic one was extracted with EtOAC, the combined
organic phases were washed with brine, dried (Na2SO4) and evaporated. Column
chromatography on silica gel gave 44 mg (48%) of rac 4-(2-phenyl-2-{4-[2,2,2-trifluoro-
1 -(4-methoxy-benzyloxy)-1 -trifluoromethyl-ethylj-phenoxy} -ethoxy)-benzaldehyde, MS:
663 (M+OAc)-.
39.4
To 44 mg (0.07 mmol) of rac 4-(2-phenyl-2-{4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-benzaldehyde in 2 mL of dichloroethane 33
mg (0.15 mmol) of DDQ and a drop of water were added. The reaction mixture was stirred
at 70°C overnight, cooled to room temperature and was diluted with dichloromethane and
EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography on silica gel
with EtOAc/w-heptane 1:5 gave 22 mg (62%) of rac 4-{2-phenyl-2-[4-(2,2,2-trifluoro-lhydroxy-
l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-benzaldehyde, MS: 483 (M-H)~.
40 mg (0.08 mmol) of rac 4-{2-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethylethyl)-
phenoxy]-ethoxy}-benzaldehyde in 2 mL of a mixture of THF/EtOH (1:1) were
treated with 31 mg (0.8 mmol) of NaBHj at 0°C. The mixture was stirred at room
temperature, water and EtOAc were added, and the phases were separated. The inorganic
phase was extracted with EtOAc, and the combined organic ones were washed with brine,
dried (NajSC^), filtered and evaporated. Column chromatography on ISOLUTE Flash
NH2 with EtOAc yielded 24 mg (59%) of rac l,l,l,3,3,3-hexafluoro-2-{4-[2-(4-
hydroxymethyl-phenoxy)-l-phenyl-ethoxy]-phenyl}-propan-2-ol as a colorless oil, MS:
485 (M-Hy.
Example 40
l,l,l,3,3,3-Hexafluoro-2-(3-methyl-4-phenethyloxy-phenyl)-propan-2-oI
In analogy to example 13.1 and 29.3, from 2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 2) and phenethyl bromide was
prepared l,l,l,3,3,3-hexafluoro-2-(3-methyl-4-phenethyloxy-phenyl)-propan-2-ol as a
light yellow oil, MS: 377 (M-H)'.
Example 41
Rac l,l,l,3,3,3-Hexafluoro-2-[3-methyl-4-(l-phenyI-ethoxy)-phenyl]-propan-2-ol
In analogy to example 13.1 and 29.3, from 2-methyl-4-[2,2,2-trifiuoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 2) and rac (l-bromo-ethyl)-benzene
was prepared rac l,l,l,3,3,3-hexafluoro-2-[3-methyl-4-(l-phenyl-ethoxy)-phenyl]-propan-
2-ol as a colorless oil, MS: 377 (M-H)~.
Example 42
2-{4-[2-(3-ChIoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l,1,1,3,3,3-
hexafluoro-propan-2-ol
In analogy to example 13.1 and 29.3, from 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 1) and 4-chloromethyl-2-(3-chloro-phenyl)-5-
methyl-oxazole (CAS 475481-97-1, prepared according to WO2002092084) was prepared
2-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-1,1,1,3,3,3-hexafluoropropan-
2-ol as a white solid, MS: 464 (M-H, 1C1)".
Example 43
2-[4-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-phenyl]-l,l,l,3,3,3-hexafluoFo-propan-2-ol
In analogy to example 13.1 and 29.3, from 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethylj-phenol (example 1) and 4-chloromethyl-3,5-dimethyl-isoxazole
(CAS 19788-37-5) was prepared 2-[4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-phenyl]-
l,l,l,3,3,3-hexafluoro-propan-2-ol as a white solid, MS: 368 (M-H)'.
Example 44
l,l,l,3,3,3-Hexafluoro-2-[4-(5-methyl-isoxazol-3-ylmethoxy)-phenyl]-propan-2-ol
In analogy to example 13.1 and 29.3, from 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 1) and 3-chloromethyl-5-methyl-isoxazole (CAS
35166-37-1) was prepared l,lJ,3,3,3-hexafluoro-2-[4-(5-methyl-isoxazol-3-ylmethoxy)-
phenyl]-propan-2-ol as a white solid, MS: 354 (M-H)".
Example 45
l,l,l,3,3,3-Hexafluoro-2-[4-(5-methyI-2-phenyl-2^T-[l,2,3]triazol-4-ylinethoxy)-
phenyl]-propan-2-ol
In analogy to example 13.1 and 29.3, from 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 1) and 4-bromomethyl-5-methyl-2-phenyl-2//-
[l,2,3]triazole (CAS 13322-02-6) was prepared l,l,l,3,3,3-hexafluoro-2-[4-(5-methyl-2-
phenyl-2//-[l,2,3]triazol-4-ylmethoxy)-phenyl]-propan-2-ol as a colorless oil, MS: 430
(M-H)-.
Example 46
l,l5l»3,3,3-Hexafluoro-2-[4-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-phenyl]-
propan-2-ol
In analogy to example 13.1 and 29.3, from 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 1) and 4-bromomethyl-5-methyl-3-phenylisoxazole
(CAS 180597-83-5) was prepared l,l,l,3,3,3-hexafluoro-2-[4-(5-methyl-3-
phenyl-isoxazol-4-ylmethoxy)-phenyl]-propan-2-ol as a light yellow oil, MS: 430 (M-H)'.
Example 47
3-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxymethyl]-benzoic
acid methyl ester
In analogy to example 13.1 and 29.3, from 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 1) and 3-bromomethyl-benzoic acid methyl ester
(CAS 1129-28-8) was prepared 3-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxymethyl]-benzoic acid methyl ester as a white solid, MS: 407 (M-H)".
Example 48
Lithium 4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-3-phenyI-propoxy}-benzoate
20.2 mg (0.04 mmol) of 4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-3-phenyl-propoxy}-benzoic acid (example 36) in 3 mL of
THF were treated with 1 mg (0.04 mmol) of lithium hydroxide. The solvent was
evaporated to give 21 mg (quantitative) of lithium 4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-lhydroxy-
l-trifluoromethyl-ethyl)-phenoxy]-3-phenyl-propoxy}-benzoate as a light yellow
oil, MS: 527 (M-H)'.
Example 49
Lithium (4-{(S)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-phenyl)-acetate
In analogy to example 48, from (4-{(S)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid (example 37) was prepared
lithium (4-{(S)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-phenyl)-acetate as a light yellow oil, MS: 527 (M-H)~.
Example 50
3-(4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-phenyl)-propionic acid methyl ester
50.1
In analogy to example 30.1, from (S)-2-hydroxy-3-phenyl-propionic acid methyl ester and
4-[2,2,2-trifluoro- 1 -(4-methoxy-benzyloxy)- 1 -trifluoromethyl-ethyl]-phenol (example 1 )
was prepared (R)-3-phenyl-2-{4-[2,2,2-trifluoro-l -(4-methoxy-benzyloxy)- 1 -
trifluoromethyl-ethyl]-phenoxy}-propionic acid methyl ester as a yellow oil, MS: 676
50.2
In analogy to example 30.2, from (R)-3-pheny 1-2- {4-[2,2,2-trifluoro-l -(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-propionic acid methyl ester was prepared
(R)-3-phenyl-2-{4-[2,2,2-trifluoro-l -(4-methoxy-benzyloxy)- 1 -trifluoromethyl-ethyl]-
phenoxy}-propan-l-ol as a light yellow oil, MS: 514 (M)+.
50.3
In analogy to example 30.3 and 30.4, from (R)-3-phenyl-2-{4-[2,2,2-trifluoro-l-(4-
methoxy-benzyloxy)- 1 -trifluoromethyl-ethyl]-phenoxy} -propan- 1 -ol and 3-(4-hydroxyphenyl)-
propionic acid methyl ester was prepared 3-(4-{(R)-3-phenyl-2-[4-(2,2,2-
trifluoro- 1 -hydroxy- 1 -trifluoromethyl-ethyl)-phenoxy]-propoxy } -phenyl)-propionic acid
methyl ester as a colorless oil, MS: 555 (M-H)~.
Example 51
(4-{(R)-3-PhenyI-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxyJpropoxy}-
phenyl)-acetic acid methyl ester
In analogy to examples 30.3 and 30.4, from (R)-3-phenyl-2-{4-[2,2,2-trifluoro-l-(4-
methoxy-benzyloxy)-1 -trifluoromethyl-ethyl]-phenoxy} -propan-1 -ol and (4-hydroxyphenyl)-
acetic acid methyl ester was prepared (4-{(R)-3-phenyl-2-[4-(2,2,2-trifluoro-lhydroxy-
l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid methyl ester as
a colorless oil, MS: 541 (M-H)'. ' '
Example 52
4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid methyl ester
In analogy to examples 30.3 and 30.4, from (R)-3-phenyl-2-{4-[2,2,2-trifluoro-l-(4-
methoxy-benzyloxy)-1 -trifluoromethyl-ethyl]-phenoxy} -propan-1 -ol and 4-hydroxybenzoic
acid methyl ester was prepared 4-{(R)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxyl-
trifluoromethyl-ethyl)-phenoxy]-propoxy}-benzole acid methyl ester as a colorless oil,
MS: 527 (M-H)-.
Example 53
3-(4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy] -propoxy }-phenyl)-propionic acid
In analogy to example 25, from 3-(4-{(R)-3-phenyl-2-[4-(2,2,2-triflu'oro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-phenyl)-propionic acid methyl ester (example
50) was prepared 3-(4-{(R)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethylethyl)-
phenoxy]-propoxy}-phenyl)-propionic acid as a colorless oil, MS: 541 (M-H)".
Example 54
(4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid
In analogy to example 25, from (4-{(R)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid methyl ester (example 51)
was prepared (4-{(R)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-phenyl)-acetic acid as a colorless oil, MS: 527 (M-H)'.
Example 55
4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid
In analogy to example 25, from 4-{(R)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-benzoic acid methyl ester (example 52) was
prepared 4-{(R)-3-phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-benzoic acid as a colorless oil, MS: 514 (M-H)".
Example 56
2-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-3-methyl-phenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 2) and 4-chloromethyl-2-(3-chlorophenyl)-
5-methyl-oxazole (CAS 475481-97-1, prepared according to WO2002092084)
was prepared 2-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-3-methylphenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol as a light yellow solid, MS: 478 (M-H, 1C1)'.
Example 57
2-{3-Chloro-4-[2-(3-chloro-phenyI)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-
1,1,1,3,3,3-hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 3) and 4-chloromethyl-2-(3-chlorophenyl)-
5-methyl-oxazole (CAS 475481-97-1, prepared according to WO2002092084)
was prepared 2-{3-chloro-4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol as a white solid, MS: 498 (M-H, 2C1)~.
Example 58
l,14,3,3,3-Hexafluoro-2-(4-phenethyloxy-phenyl)-propan-2-ol
In analogy to examples 13.1 and 29.3, from 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 1) and phenethyl bromide was prepared
1,1,1,3,3,3-hexafluoro-2-(4-phenethyloxy-phenyl)-propan-2-ol as a light yellow oil, MS:
362 (M-H)'.
Example 59
2-(3,5-Dimethyl-4-phenethyIoxy-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2,6-dimethyl-4-[2,2,2-trifluoro-l-(4-rnethoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 4) and phenethyl bromide was
prepared 2-(3,5-dimethyl-4-phenethyloxy-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol as a
light yellow oil, MS: 391 (M-H)'.
Example 60
2-(3-Chloro-4-phenethyloxy-phenyl)-l,l»l»3,3,3-hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 3) and phenethyl bromide was
prepared 2-(3-chloro-4-phenethyloxy-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol as a
light yellow oil, MS: 397 (M-H, 1C1)'.
Example 61
Rac l,l,l,3,3,3-Hexafluoro-2-[4-(l-phenyl-ethoxy)-phenyl]-propan-2-ol
In analogy to examples 13.1 and 29.3, from 4-[2,2,2-trifiuoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethylj-phenol (example 1) and rac (l-bromo-ethyl)-benzene was prepared
rac l,l,l,3,3,3-hexafluoro-2-[4-(l-phenyl-ethoxy)-phenyl]-propan-2-ol as a light yellow
oil, MS: 363 (M-H)'.
Example 62
l,l,l»3,3,3-Hexafluoro-2-[3-methyl-4-(5-methyl-2-/M-tolyl-oxazol-4-ylmethoxy)-
phenyl] -propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 2) and 4-chloromethyl-5-methyl-2-
m-tolyl-oxazole (CAS 521266-92-2, prepared according to WO2003037327) was prepared
1,1,1,3,3,3-hexafluoro-2-[3-methyl-4-(5-methyl-2-w-tolyl-oxazol-4-ylmethoxy)-phenyl]-
propan-2-ol as a white solid, MS: 458 (M-H)".
Example 63
2-{4-[2-(2-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-3-methyl-phenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 2) and 4-chloromethyl-2-(2-chlorophenyl)-
5-methyl-oxazole (CAS 475481-96-0, prepared according to WO2002092084)
was prepared 2- {4-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-3-methylphenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol as a white solid, MS: 478 (M-H, 1C1)'.
Example 64
l,l,l»3,3,3-Hexafluoro-2-[3-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-
phenyl]-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 2) and 4-chloromethyl-5-methyl-2-
o-tolyl-oxazole (CAS 671215-81-9, prepared according to WO2004031162) was prepared
1,1,1,3,3,3-hexafluoro-2-[3-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-
propan-2-ol as a white solid, MS: 458 (M-H)".
Example 65
l,l,lj3,3,3-Hexafluoro-2-{3-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-
4-ylmethoxy]-phenyI}-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 2) and 4-chloromethyl-5-methyl-2-
(3-trifluoromethyl-phenyl)-oxazole (CAS 678164-78-8, prepared according to
WO2004031162) was prepared l,l,l,3,3,3-hexafluoro-2-{3-methyl-4-[5-methyl-2-(3-
trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propan-2-ol as a white solid, MS:
512 (M-H)-.
Example 66
l,l)l»3,3,3-Hexafluoro-2-{4-[2-(4-fluoro-3-methyl-phenyI)-5-methyl-oxazol-4-
ylmethoxy]-3-methyI-phenyl}-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-methyl-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 2) and 4-chloromethyl-2-(4-fluoro-
3-methyl-phenyl)-5-methyl-oxazole (CAS 475481-98-2, prepared1 \ according to
WO2002092084) was prepared l,l,l,3,3,3-hexafluoro-2-{4-[2-(4-fluoro-3-methylphenyl)-
5-methyl-oxazol-4-ylmethoxy]-3-methyl-phenyl}-propan-2-ol as a white solid,
MS: 476 (M-H)'.
Example 67
2-{3-ChIoro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyI}-
1,1,1,3,3,3-hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 3) and 4-chloromethyl-5-methyl-2-
(4-trifluoromethyl-phenyl)-oxazole (CAS 174258-39-0, prepared according to
WO2002092084) was prepared 2-{3-chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-
oxazol-4-ylmethoxy]-phenyl}-l,l,l,3,3,3-hexafluoro-propan-2-ol as a white solid, MS:
532 (M-H, 1C1)'.
Example 68
2-[3-Chloro-4-(5-methyl-2-w-tolyl-oxazol-4-ylmethoxy)-phenyl]-l,l»l»3,3,3-
hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 3) and 4-chloromethyl-5-methyl-2-
m-tolyl-oxazole (CAS 521266-92-2, prepared according to WO2003037327) was prepared
2-[3-chloro-4-(5-methyl-2-w-tolyl-oxazol-4-ylmethoxy)-phenyl]-1,1,1,3,3,3-hexafluoropropan-
2-ol as a white solid, MS: 478 (M-H, 1C1)".
Example 69
2-{3-Chloro-4-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-yImethoxy]-phenyl}-
1,1,1,3,3>3-hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 3) and 4-chloromethyl-2-(2-chlorophenyl)-
5-methyl-oxazole (CAS 475481-96-0, prepared according to WO2002092084)
was prepared 2-{3-chloro-4-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol as a white solid, MS: 498 (M-H, 2C1)~.
Example 70
2-[3-Chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-l,14»3v3,3-
hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 3) and 4-chloromethyl-5-methyl-2-
o-tolyl-oxazole (CAS 671215-81-9, prepared according to WO2004031162) was prepared
2-[3-chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-1,1,1,3,3,3-hexafluoropropan-
2-ol as a white solid, MS: 478 (M-H, 1C1)'.
Example 71
2-{3-Chloro-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-
l,l,l,3,3,3-hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 3) and 4-chloromethyl-5-methyl-2-
(3-trifluoromethyl-phenyl)-oxazole (CAS 678164-78-8, prepared according to
WO2004031162) was prepared 2-{3-chloro-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-
oxazol-4-ylmethoxy]-phenyl}-l,l,l,3,3,3-hexafluoro-propan-2-ol as a white solid, MS:
532 (M-H, ICiy.
Example 72
2-{3-Chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazoI-4-ylmethoxy]-phenyl}-
1,1,1,3,3,3-hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 3) and 4-chloromethyl-2-(4-fluoro-
3-methyl-phenyl)-5-methyl-oxazole (CAS 475481-98-2, prepared according to
WO2002092084) was prepared 2-{3-chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyloxazol-
4-ylmethoxy]-phenyl}-l,l,l,3,3,3-hexafluoro-propan-2-ol as a white solid, MS:
496 (M-H, ICiy.
Example 73
2-{3-[2-(3-Chloro-phenyI)-5-methyl-oxazoI-4-yImethoxy]-phenyl}-l,l,l»3,3,3-
hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifiuoromethyl-
ethylj-phenol (example 5) and 4-chloromethyl-5-methyl-2-(3-
trifluoromethyl-phenyl)-oxazole (CAS 678164-78-8, prepared according to
WO2004031162) was prepared 2-{3-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-
phenyl}-l,l,l,3,3,3-hexafluoro-propan-2-ol as a light yellow solid, MS: 464 (M-H, 1C1)".
Example 74
l,l,l,3,3,3-Hexafluoro-2-[3-(5-methyl-2-o-tolyI-oxazol-4-ylmethoxy)-phenyl]-propan-
2-oI
In analogy to examples 13.1 and 29.3, from 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethylj-phenol (example 5) and 4-chloromethyl-5-methyl-2-o-tolyl-oxazole
(CAS 671215-81-9, prepared according to WO2004031162) was prepared 1,1,1,3,3,3-
hexafluoro-2-[3-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propan-2-ol as a yellow
oil, MS: 444 (M-H)'.
Example 75
l,l,l,3,3,3-Hexafluoro-2-{3-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-
ylmethoxy]-phenyl}-propan-2-ol
In analogy to examples 13.1 and 29.3, from 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 5) and 4-chloromethyl-5-methyl-2-(3-
trifluoromethyl-phenyl)-oxazole (CAS 678164-78-8, prepared according to
WO2004031162) was prepared l,l,l,3,3,3-hexafluoro-2-{3-[5-rnethyl-2-(3-
trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propan-2-ol as a white solid, MS:
498 (M-H)'.
Example 76
2-{3-[2-(2-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l,l,l)3,3,3-
hexafluoro-propan-2-ol
In analogy to examples 13.1 and 29.3, from 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethylj-phenol (example 5) and 4-chloromethyl-2-(2-chloro-phenyl)-5-
methyl-oxazole (CAS 475481-96-0, prepared according to WO2002092084) was prepared
2-{3-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l,l,l,3,3,3-hexafluoropropan-
2-ol as an orange oil, MS: 464 (M-H, 1C1)".
Example 77
l,l»l»3,3,3-Hexafluoro-2-[3-(5-methyl-2-/M-tolyl-oxazol-4-ylmethoxy)-phenyl]-propan-
2-ol
In analogy to examples 13.1 and 29.3, from 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 5) and 4-chloromethyl-5-methyl-2-/w-tolyloxazole
(CAS 521266-92-2, prepared according to WO2003037327) was prepared
1,1,1,3,3,3-hexafluoro-2-[3-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)-phehyl]-propan-2-
ol as a yellow solid, MS: 444 (M-H)".
Example 78
3-{4-[2-Chloro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxymethyI]-5-methyI-oxazol-2-yl}-benzoic acid methyl ester
In analogy to examples 13.1 and 29.3, from 2-chloro-4-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenol (example 3) and 3-(4-chloromethyl-5-methyloxazol-
2-yl)-benzoic acid methyl ester (CAS 675148-35-3) was prepared 3-{4-[2-chloro-
4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxymethyl]-5-methyl-oxazol-2-
yl}-benzoic acid methyl ester as a light yellow solid, MS: 522 (M-H, 1C1)".
Example 79
2-{3-Chloro-4-[2-(3-hydroxymethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyI}-
l,l,l,3,3,3-hexafluoro-propan-2-ol > •
In analogy to example 30.2, from 3-{4-[2-chloro-4-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxymethyl]-5-methyl-oxazol-2-yl}-benzoic acid methyl ester
(example 78) was prepared 2-{3-chloro-4-[2-(3-hydroxymethyl-phenyl)-5-methyl-oxazol-
4-ylmethoxy]-phenyl}-l,l,l,3,3,3-hexafluoro-propan-2-ol as a white solid, MS: 494 (MH,
1 Cl)'.
Example 80
4-{5-Methyl-4-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyI)-
phenoxymethyl]-oxazol-2-y!}-benzoic acid methyl ester
In analogy to examples 13.1 and 29.3, from 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 5) and 4-(4-chloromethyl-5-methyl-oxazol-2-yl)-
benzoic acid methyl ester (CAS 675148-38-6, WO2004024705) was prepared 4-{5-
methyl-4-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxymethyl]-oxazol-
2-yl}-benzoic acid methyl ester as a light yellow solid, MS: 488 (M-H)". .
Example 81
4-{5-Methyl-4-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxymethyl]-oxazol-2-yl}-benzoic acid
In analogy to example 25, from 4-{5-methyl-4-[3-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxymethyl]-oxazol-2-yl}-benzoic acid methyl ester (example
80) was prepared 4-{5-methyl-4-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxymethyl]-oxazol-2-yl}-benzoic acid as a white solid, MS: 474 (M-H)".
Example 82
N,N-Dimethyl-4-{5-methyl-4-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxymethyl]-oxazol-2-yl}-benzamide
To 25 mg (0.05 mmol) of 4-{5-methyl-4-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethylethyl)-
phenoxymethyl]-oxazol-2-yl}-benzoic acid (example 81) in 1.5 ml of CfyCb were
added 8.6 mg (0.11 mol) of dimethylamine-HCl and 23 |il (0.11 mmol) of NMM. The
solution was cooled to 0°C and 13.1 mg (0.07 mmol, 1.3 eq) of EDCI and 1.4 mg (0.01
mmol) of HOBT were added. The mixture was stirred at room temperature overnight.
Water was added and the inorganic phase was extracted with EtOAc. The organic phase
was washed with brine, dried (Na2SO4), filtered and evaporated. Column chromatography
with CH2Cl2/MeOH 98:2 gave 22 mg (83%) N,N-dimethyl-4-{5-methyl-4-[3-(2,2,2-
trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxymethyl]-oxazol-2-yl}-benzamide as
a colorless oil, MS: 501 (M-H)'.
Example 83
(3-{2-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid methyl ester
83.1
In analogy to example 18.1, from 4-[2,2,2-trifIuoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 1) and 2-bromo-ethanol was prepared 2-{4-[2,2,2-
trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenoxy}-ethanol as a white
semisolid, MS: 424 (M)+.
In analogy to example 8.2 - 8.3, from 2-{4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenoxy}-ethanol and (3-hydroxy-phenyl)-acetic acid methyl ester
was prepared (3-{2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid methyl ester as a white powder, MS: 451 (M-H)".
Example 84
(4-{2-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid methyl ester
In analogy to example 8.2 - 8.3, from 2-{4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenoxy}-ethanol (example 83.1) and (4-hydroxy-phenyl)-acetic
acid methyl ester was prepared (4-{2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethylethyl)-
phenoxy]-ethoxy}-phenyl)-acetic acid methyl ester as a white powder, MS: 451 (MH)'.
Example 85 ' :
(3-{2-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid methyl ester
85.1
In analogy to example 18.1, from 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethylj-phenol (example 5) and 2-bromo-ethanol was prepared 2-{3-[2,2,2-
trifluoro-l-(4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenoxy}-ethanol as a
colorless oil, MS: 424 (M)+.
In analogy to example 8.2 - 8.3, from 2-{3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenoxy}-ethanol and (3-hydroxy-phenyl)-acetic acid methyl ester
was prepared (3-{2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid methyl ester as a white powder, MS: 451 (M-H)".
Example 86
(3-{2-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid
In analogy to example 25, from (3-{2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethylethyl)-
phenoxy]-ethoxy}-phenyl)-acetic acid methyl ester (example 83) was prepared (3-
{2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-phenyl)-
acetic acid as a white semisolid, MS: 437 (M-H)".
Example 87
(4-{2-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-
phenyl)-acetic acid
In analogy to example 25, from (4-{2-[4-(2,2,2-trifluoro-l-hydroxy-1-trifluorornethylethyl)-
phenoxy]-ethoxy}-phenyl)-acetic acid methyl ester (example 84) was prepared (4-
{2-[4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethy l)-phenoxy] -ethoxy} -pheny 1)-
acetic acid as a colorless solid, MS: 437 (M-H)~.
Example 88
rac (3-{l-Phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid methyl ester
In analogy to example 9.2, from rac l-phenyl-2-{3-[2,2,2-trifluoro-l-(4-methoxybenzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-ethanol (example 9.1) and (3-hydroxyphenyl)-
acetic acid methyl ester was prepared via rac [3-(l-phenyl-2-{3-[2,2,2-trifluorol-(
4-methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-phenyl]-acetic acid
methyl ester, which was deprotected according to example 13.2, to give rac (3-{l-phenyl-
2-[3-(2,2,2-trifluoro-l -hydroxy- l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-phenyl)-acetic
acid methyl ester as a colorless oil, MS: 527 (M-H)~.
Example 89
rac-(3-{l-Phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid
In analogy to example 25, from rac (3-{l-phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-ethoxy}-phenyl)-acetic acid methyl ester (example 88)
was prepared rac-(3-{l-phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-ethoxy}-phenyl)-acetic acid as a colorless oil, MS: 513 (M-H)~.
Example 90
rac N,N-DimethyI-2-(3-{l-phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethylethyl)-
phenoxy]-ethoxy}-phenyl)-acetamide
In analogy to examples 25, 82 and 13.2, from rac [3-(l-phenyl-2-{3-[2,2,2-trifluoro-l-(4-
methoxy-benzyloxy)-l-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-phenyl]-acetic acid
(example 91) and dimethylamine HC1 was prepared rac N,N-dimethyl-2-(3-{l-phenyl-2-
[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-phenyl)-
acetamide as an off-white powder, MS: 542 (M+H)+.
Example 91
2-(4-{2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethoxy}-phenyl)-l, 1,1,3,3,3-
hexafluoro-propan-2-ol
95.1
In analogy to example 8.1, from 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-ol (CAS
192443-17-7, prepared according to EP778271) and 2-bromo-ethanol was prepared 2-[3-
(4-bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethanol as a light yellow solid, MS: 350
(M+H,
95.2
In analogy to examples 8.2 and 29.3, from 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 1) and 2-[3-(4-bromo-phenyl)-benzo[d]isothiazol-
6-yloxy]-ethanol was prepared 2-(4-{2-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yIoxy]-
ethoxy}-phenyl)- 1,1,1, 3,3, 3-hexafluoro-propan-2-ol as a white solid, MS: 590 (M-H,lBr)~.
Example 92
l,l,l,3,3,3-Hexafluoro-2-{4-[3-(7-propyl-3-trifluoromethyl-benzo[d]iso'xazol-6-yloxy)-
propoxy]-phenyl}-propan-2-oI
In analogy to examples 8.1 and 8.3, from 4-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 1) and 6-(3-bromo-propoxy)-7-propyl-3-
trifluoromethyl-benzo[(/]isoxazole (CAS 194608-95-2, prepared according to
WO9728137) was prepared l,l,l,3,3,3-hexafluoro-2-{4-[3-(7-propyl-3-trifluoromethylbenzo[
d]isoxazol-6-yloxy)-propoxy]-phenyl}-propan-2-ol as a colorless oil, MS: 544 (MH)-.
Example 93
l,l,l,3,3,3-Hexafluoro-2-{3-[3-(7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-yloxy)-
propoxy]-phenyl}-propan-2-ol
In analogy to examples 8.1 and 8.3, from 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 5) and 6-(3-bromo-propoxy)-7-propyl-3-
trifluoromethyl-benzo[cf]isoxazole (CAS 194608-95-2, prepared • : according to
WO9728137) was prepared l,l,l,3,3,3-hexafIuoro-2-{3-[3-(7-propyl-3-trifluoromethylbenzo[
d]isoxazol-6-yloxy)-propoxy]-phenyl}-propan-2-ol as a colorless oil, MS: 544 (MH)-.
Example 94
(4-{3-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-acetic acid methyl ester
In analogy to examples 8.1 and 30.4, from 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 5) and [4-(3-bromo-propoxy)-phenyl]-acetic acid
methyl ester (CAS 203071-48-1) was prepared (4-{3-[3-(2,2,2-trifluoro-l-hydroxy-ltrifluoromethyl-
ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid methyl ester as a colorless
oil, MS: 465 (M-H)'.
Example 95
(3-{3-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-acetic acid methyl ester
95.1
In analogy to example 8.1, from 3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-ltrifluoromethyl-
ethyl]-phenol (example 5) and 3-bromo-l-propanol was prepared 3-{3-
[2,2,2-trifluoro-1 -(4-methoxy-benzyloxy)-1 -trifluoromethyl-ethylj-phenoxy} -propan-1 -ol
as a colorless liquid, MS: 438 (M)+.
95.2
In analogy to examples 8.2 and 30.4, from 3-{3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-
1-trifluoromethyl-ethylj-phenoxy}-propan-l-ol and (3-hydroxy-phenyl)-acetic acid methyl
ester was prepared (3-{3-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester as a colorless oil, MS: 465 (M-H)~.
Example 96
3-(4-{3-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-propionic acid methyl ester
In analogy to examples 8.2 and 30.4, from 3-{3-[2,2,2-trifluoro-l-(4-methoxy-benzyloxy)-
l-trifluoromethyl-ethyl]-phenoxy}-propan-l-ol and 3-(4-hydroxy-phenyl)-propionic acid
methyl ester was prepared 3-(4-{3-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-
phenoxy]-propoxy}-phenyl)-propionic acid methyl ester as a colorless oil, MS: 479 (MH)-.
Example 97
3-(4-{3-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-propionic acid
In analogy to example 25, from 3-(4-{3-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethylethyl)-
phenoxy]-propoxy}-phenyl)-propionic acid methyl ester (example 96) was prepared
3-(4-{3-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-propionic acid as a colorless oil, MS: 465 (M-H)~.
Example A
Film coated tablets containing the following ingredients can be manufactured in a
conventional manner:
Ingredients Per tablet
Kernel:
Compound of formula (I) lO.Omg 200.0 mg
Microcrystalline cellulose 23.5 mg 43.5 mg
Lactose hydrous 60.0 mg 70.0 mg
PovidoneK30 12.5 mg 15.0 mg
Sodium starch glycolate 12.5 mg 17.0mg
Magnesium stearate 1.5mg 4.5 mg
(Kernel Weight) 120.0 mg 350.0 mg
Film Coat:
Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg
Polyethylene glycol 6000 0.8 mg 1.6 mg
Talc 1.3 mg 2.6 mg
Iron oxyde (yellow) 0.8 mg 1.6mg
Titan dioxide 0.8 mg 1.6 mg
The active ingredient is sieved and mixed with microcristalline cellulose and the
mixture is granulated with a solution of polyvinylpyrrolidon in water. The granulate is
mixed with sodium starch glycolate and magesiumstearate and compressed to yield
kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous solution
/ suspension of the above mentioned film coat.
Example B
Capsules containing the following ingredients can be manufactured in a
conventional manner:
Ingredients Per capsule
Compound of formula (I) 25.0mg ' !
Lactose ISO.Omg
Maize starch 20.0 mg
Talc 5.0 mg
The components are sieved and mixed and filled into capsules of size 2.
Example C
Injection solutions can have the following composition:
Compound of formula (I) 3.0mg
Polyethylene Glycol 400 150.0 mg
Acetic Acid q.s. ad pH 5.0
Water for injection solutions ad 1.0 ml ' '
The active ingredient is dissolved in a mixture of Polyethylene Glycol 400 and water
for injection (part). The pH is adjusted to 5.0 by Acetic Acid. The volume is adjusted to
1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials
using an appropriate overage and sterilized.
Example D
Soft gelatin capsules containing the following ingredients can be manufactured in a
conventional manner:
Capsule contents
Compound of formula (I) 5.0 mg
Yellow wax 8.0 mg
Hydrogenated Soya bean oil 8.0 mg
Partially hydrogenated plant oils 34.0 mg
Soya bean oil HO.Omg
Weight of capsule contents 165.0 mg
Gelatin capsule
Gelatin 75.0 mg
Glycerol 85 % 32.0 mg
Karion 83 8.0 mg (dry matter)
Titan dioxide 0.4 mg
Iron oxide yellow 1.1 mg
The active ingredient is dissolved in a warm melting of the otheri ingredients and
the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin
capsules are treated according to the usual procedures.
Example E
Sachets containing the following ingredients can be manufactured in a
conventional manner:
Compound of formula (I) 50.0 mg
Lactose, fine powder 1015.0 mg
Microcristalline cellulose (AVICEL PH 102) 1400.0 mg
Sodium carboxymethyl cellulose 14.0 mg
Polyvinylpyrrolidon K 30 10.0 mg
Magnesiumstearate lO.Omg
Flavoring additives 1.0 mg . ,
The active ingredient is mixed with lactose, microcristalline cellulose and sodium
carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidon in water.
The granulate is mixed with magnesiumstearate and the flavouring additives and filled
into sachets.






We Claim:
1. Hexafluoroisopropanol-phenyl-ether compounds of formula (I)
(Formula Removed)
wherein
R1 is hydrogen, lower-alkyl, or halogen;
one of R2 and R3 is hydrogen, lower-alkyl, or halogen; and
the other of R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6;
R4 is hydrogen, lower-alkyl, phenyl or phenyl-lower-alkyl;
R5 is hydrogen or phenyl;
R6 is phenyl, which phenyl is optionally substituted with 1 to 3 substituents selected from the group consisting of R8-O-C(O)-, R11-O-C(O)-lower-alkyl, R12R13NC(O)-lower-alkyl;
or R6 is 5-membered monocyclic heteroaryl selected from the group consisting of isoxazolyl, triazolyl, oxazolyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of lower-alkyl and phenyl, which phenyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl, R8-O-C(O)-, R9R10NC(O)-;
or R6 is-O-R7;
R7 is phenyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy-lower-alkyl, R8-O-C(O)-, R11-O-C(O)-lower-alkyl, R12R13NC(O)-lower-alkyl;
or R7 is heteroaryl selected from the group consisting of benzo[d]isothiazolyl and benzo[d]isoxazolyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of lower-alkyl, fluoro-lower-alkyl and phenyl, which phenyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen;
R8, R9, R10, R11, R12 and R13 independently from each other are hydrogen or lower-alkyl;
m is 0 to 3;
n is 0 or 1;
and pharmaceutically acceptable salts and esters thereof.
2. The compounds as claimed in claim 1, wherein R1 is hydrogen, chlorine or methyl.
3. The compounds as claimed in any of claims 1 to 2, wherein one of R2 and R3 is hydrogen or lower-alkyl, and the other of R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6, wherein R4, R5, R6, m and n are as defined in claim 1.
4. The compounds as claimed in any of claims 1 to 3, wherein R2 is -O-CHR4-(CH2)m-(CHR5)n-R6, and R3 is hydrogen, wherein R4, R5, R6, m and n are as defined in claim 1.
5. The compounds as claimed in any of claims 1 to 4, wherein R4 is hydrogen, lower-alkyl, or phenyl-lower-alkyl.
6. The compounds as claimed in any of claims 1 to 5, wherein R4 is hydrogen, methyl or benzyl.
7. The compounds as claimed in any of claims 1 to 6, wherein n is 1 and R5 is phenyl.
8. The compounds as claimed in any of claims 1 to 7, wherein R6 is phenyl which is optionally substituted with R8-O-C(O)-, or R6 is 5-membered monocyclic heteroaryl selected from the group consisting of isoxazolyl, triazolyl, oxazolyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of
lower-alkyl and phenyl, which phenyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl, R8-O-C(O)- and R9R10NC(O)-, wherein R8, R9 and R10 are as defined in claim 1.
9. The compounds as claimed in any of claims 1 to 8, wherein R6 is phenyl, or R6 is oxazolyl, which oxazolyl is substituted with lower-alkyl and phenyl, which phenyl is substituted with halogen, fluoro-lower-alkyl or hydroxy-lower-alkyl.
10. The compounds as claimed in any of claims 1 to 9, wherein R6 is phenyl, 2-(3-chloro-phenyl)-5-methyl-oxazol-4-yl, 5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-yl, or 2-(3-hydroxymethyl-phenyl)-5-methyl-oxazol-4-yl.
11. The compounds as claimed in any of claims 1 to 7, wherein R6 is -O-R7, wherein R7 is phenyl which is substituted with 1 substituent selected from the group consisting of hydroxy-lower-alkyl, R11-O-C(O)-lower-alkyl and R12R13NC(O)-lower-alkyl, or R7 is heteroaryl selected from the group consisting of benzo[d]isothiazolyl and benzo[d]isoxazolyl, which heteroaryl is optionally substituted with 1 to 2 substituents selected from the group consisting of lower-alkyl, fluoro-lower-alkyl and phenyl, which phenyl is optionally substituted with halogen, wherein R11, R12 and R13 are as defined in claim 1.
12. The compounds as claimed in claim 11, wherein R7 is phenyl substituted with lower-alkoxy-carbonyl or lower-alkoxy-carbonyl-lower-alkyl.
13. The compounds as claimed in claim 12, wherein R7 is 3-methoxycarbonylmethyl-phenyl, 4-methoxycarbonylmethyl-phenyl, or 4-methoxycarbonyl-phenyl.
14. The compounds as claimed in any of claims 1 tol3, wherein m is 0 to 2.
15. The compounds as claimed in any of claims 1 to 14, wherein m is 0 or 1.
16. The compounds as claimed in any of claims 1 to 15, wherein n is 0.
17. The compounds as claimed in any of claims 1 to 16, selected from the group consisting of:
2-(4-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propoxy}-phenyl)-l,1,1,3,3,3-hexafluoro-propan-2-ol,
3-(3-{3-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-propionic acid ethyl ester,
rac (4- {1 -Phenyl-2-[3-(2,2,2-trifluoro-l -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid methyl ester,
rac (4- {1 -Phenyl-2-[3-(2,2,2-trifluoro-l -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid,
rac 4- {1 -Phenyl-2-[4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-benzoic acid methyl ester,
4-{2-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-benzoic
acid methyl ester,
2-(4-Benzyloxy-3 -chloro-phenyl)-1,1,1,3,3,3 -hexafluoro-propan-2-ol,
2-(4-Benzyloxy-3 -methyl-phenyl)-1,1,1,3,3,3 -hexafluoro-propan-2-ol,
2-(3 -Benzyloxy-phenyl)-1,1,1,3,3,3 -hexafluoro-propan-2-ol,
2-(4-Benzyloxy-3,5-dimethyl-phenyl)-1,1,1,3,3,3 -hexafluoro-propan-2-ol,
2-(4-Benzyloxy-phenyl)-1,1,1,3,3,3 -hexafluoro-propan-2-ol,
(4-{3-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
4-{3-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid methyl ester,
3-(4-{3-[2-Chloro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-propionic acid methyl ester,
(4-{3-[2-Chloro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
4-{3-[2-Chloro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid methyl ester,
(4-{3-[2,6-Dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
4-{3-[2,6-Dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid methyl ester,
4-{3-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid,
(4- {3-[2-Methyl-4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid,
(4-{3-[2,6-Dimethyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid,
4- {3-[2,6-Dimethyl-4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
propoxy} -benzoic acid,
4- {2-[2,6-Dimethyl-4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-benzoic acid methyl ester,
3.(4.{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-3-
phenyl-propoxy}-phenyl)-propionic acid methyl ester,
(4-{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-3-
phenyl-propoxy}-phenyl)-acetic acid methyl ester,
4- {(S)-2-[2-Methyl-4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-3-
phenyl-propoxy}-benzoic acid methyl ester,
(4- {(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
4-{(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid methyl ester,
(4-{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-3-
phenyl-propoxy} -phenyl)-acetic acid,
4-{(S)-2-[2-Methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-3-
phenyl-propoxy}-benzoic acid,
(4- {(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid,
4-{(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy} -benzoic acid,
rac 1,1,1,3,3,3-Hexafluoro-2- {4-[2-(4-hydroxymethyl-phenoxy)-1 -phenyl-ethoxy]-
phenyl} -propan-2-ol,
1,1,1,3,3,3 -Hexafluoro-2-(3 -methyl-4-phenethyloxy-phenyl)-propan-2-ol,
rac 1,1,1,3,3,3 -Hexafluoro-2-[3 -methyl-4-( 1 -phenyl-ethoxy)-phenyl] -propan-2-ol,
2-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l,1,1,3,3,3-
hexafluoro-propan-2-ol,
2-[4-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-phenyl]-l,l,l,3,3,3-hexafluoro-propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-[4-(5-methyl-isoxazol-3-ylmethoxy)-phenyl]-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2-[4-(5-methyl-2-phenyl-2H-[ 1,2,3]triazol-4-ylmethoxy)-phenyl]-
propan-2-ol,
1,1,1,3,3,3 -Hexafluoro-2- [4-(5-methyl-3 -phenyl-isoxazol-4-ylmethoxy)-phenyl] -propan-
2-ol,
3-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxymethyl]-benzoic acid methyl ester,
4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-3-
phenyl-propoxy}-benzoic acid,
(4. {(S)-3-phenyl-2-[4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid,
3-(4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-propionic acid methyl ester,
(4_ {(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid methyl ester,
3-(4-{(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-propionic acid,
(4- {(R)-3 -Phenyl-2-[4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid,
4- {(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
propoxy}-benzoic acid,
2-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-3-methyl-phenyl}-l,1,1,3,3,3-
hexafluoro-propan-2-ol,
2- {3 -Chloro-4- [2-(3 -chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy] -phenyl }-l,1,1,3,3,3-
hexafluoro-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2-(4-phenethyloxy-phenyl)-propan-2-ol,
2-(3,5-Dimethyl-4-phenethyloxy-phenyl)-l, 1,1,3,3,3-hexafluoro-propan-2-ol,
2-(3 -Chloro-4-phenethyloxy-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol,
rac 1,1,1,3,3,3-Hexafluoro-2-[4-(l -phenyl-ethoxy)-phenyl]-propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-[3-methyl-4-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)-phenyl]-
propan-2-ol,
2- {4-[2-(2-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-3-methyl-phenyl} -1,1,1,3,3,3-
hexafluoro-propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-[3-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-
propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-{3-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-
ylmethoxy]-phenyl}-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2- {4-[2-(4-fluoro-3 -methyl-phenyl)-5-methyl-oxazol-4-
ylmethoxy]-3-methyl-phenyl}-propan-2-ol,
2-{3-Chloro-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-
1,1,1,3,3,3-hexafluoro-propan-2-ol,
2-[3-Chloro-4-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)-phenyl]-l,l,l,3,3,3-hexafluoro-
propan-2-ol,
2-{3-Chloro-4-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l,1,1,3,3,3-
hexafluoro-propan-2-ol,
2-[3-Chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-l,l,l,3,3,3-hexafluoro-
propan-2-ol,
2-{3-Chloro-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-
1,1,1,3,3,3-hexafluoro-propan-2-ol,
2-{3-Chloro-4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-
1,1,1,3,3,3-hexafluoro-propan-2-ol,
2- {3-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-1,1,1,3,3,3-
hexafluoro-propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-[3-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propan-2-
ol,
1,1,1,3,3,3-Hexafluoro-2- {3-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-
ylmethoxy] -phenyl} -propan-2-ol,
2-{3-[2-(2-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l,1,1,3,3,3-
hexafluoro-propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-[3-(5-methyl-2-m-tolyl-oxazol-4-ylmethoxy)-phenyl]-propan-2-
ol,
3-{4-[2-Chloro-4-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxymethyl]-5-
methyl-oxazol-2-yl}-benzoic acid methyl ester,
2-{3-Chloro-4-[2-(3-hydroxymethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-
1,1,1,3,3,3 -hexafluoro-propan-2-ol,
4- {5-Methyl-4-[3-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxymethyl]-
oxazol-2-yl} -benzoic acid methyl ester,
4-{5-Methyl-4-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxymethyl]-
oxazol-2-yl}-benzoic acid,
N,N-Dimethyl-4- {5-methyl-4-[3-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-
phenoxymethyl] -oxazol-2-yl} -benzamide,
(3-{2-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-phenyl)-
acetic acid methyl ester,
(4- {2-[4-(2,2,2-Trifluoro-l -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-ethoxy}-phenyl)-acetic acid methyl ester,
(3-{2-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-phenyl)-acetic acid methyl ester, (3-{2-[4-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-phenyl)-
acetic acid,
(4. {2-[4-(2,2,2-Trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy] -ethoxy} -phenyl)-
acetic acid,
rac(3-{l-Phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid methyl ester,
rac (3- {1 -Phenyl-2-[3-(2,2,2-trifluoro-l -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
ethoxy}-phenyl)-acetic acid,
rac N,N-Dimethyl-2-(3-{l-phenyl-2-[3-(2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-
ethyl)-phenoxy] -ethoxy} -phenyl)-acetamide,
2-(4-{2-[3-(4-Bromo-phenyl)-benzo [d]isothiazol-6-yloxy]-ethoxy}-phenyl)-1,1,1,3,3,3 -
hexafluoro-propan-2-ol,
1,1,1,3,3,3-Hexafluoro-2- {4-[3-(7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-yloxy)-
propoxy] -phenyl} -propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-{3-[3-(7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-yloxy)-
propoxy] -phenyl} -propan-2-ol,
(4-{3-[3-(2,2,2-Trifluoro-l-hydroxy-l-trifluoromethyl-ethyl)-phenoxy]-propoxy}-
phenyl)-acetic acid methyl ester,
(3 - {3 - [3 -(2,2,2-Trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy] -propoxy} -
phenyl)-acetic acid methyl ester,
3-(4- {3 - [3 -(2,2,2-Trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy] -propoxy} -
phenyl)-propionic acid methyl ester, and
3 -(4- {3 -[3 -(2,2,2-Trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy] -propoxy} -
phenyl)-propionic acid,
and pharmaceutically acceptable salts and esters thereof.
18. The compounds as claimed in any of claims 1 to 17, further selected from the group consisting of
(3 - {2-[4-(2,2,2-Trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy] -ethoxy} -phenyl)-acetic acid methyl ester,
rac 4- {1 -Phenyl-2-[4-(2,2,2-trifluoro-l -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-ethoxy}-benzoic acid methyl ester,
2-(4-Benzyloxy-3-chloro-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, (4- {(S)-3-Phenyl-2-[4-(2,2,2-trifluoro-l -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-propoxy}-phenyl)-acetic acid methyl ester,
1,1,1,3,3,3 -Hexafluoro-2-(3 -methyl-4-phenethyloxy-phenyl)-propan-2-ol, rac 1,1,1,3,3,3 -Hexafluoro-2- [3 -methyl-4-( 1 -phenyl-ethoxy)-phenyl] -propan-2-ol,
2-{4-[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l, 1,1,3,3,3-
hexafluoro-propan-2-ol,
(4- {(R)-3-Phenyl-2-[4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl)-phenoxy]-
propoxy}-phenyl)-acetic acid methyl ester,
2-{3-Chloro-4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-l,1,1,3,3,3-
hexafluoro-propan-2-ol,
2-(3-Chloro-4-phenethyloxy-phenyl)-l,l,l,3,3,3-hexafluoro-propan-2-ol,
l,l,l,3,3,3-Hexafluoro-2-{3-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-
ylmethoxy]-phenyl} -propan-2-ol,
2-{3-Chloro-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-
1,1,1,3,3,3-hexafluoro-propan-2-ol, and
2-{3-Chloro-4-[2-(3-hydroxymethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-
1,1,1,3,3,3 -hexafluoro-propan-2-ol,
and pharmaceutically acceptable salts and esters thereof.
19. A process for the manufacture of compounds of formula (I) as defined in any of claims 1 to 18, which process comprises
a) reacting a compound of formula (II)
(Formula Removed)
with a compound HO-CHR4-(CH2)m-(CHR5)n-R6, in the presence of DEAD or DIAD and Ph3P in THF as solvent,
wherein R1, R4, R5, R6, m and n are as defined in any of claims 1-18, one of R2 and R3 is OH and the other of R2' and R3' is hydrogen, lower-alkyl, or halogen, and A is hydrogen or a protecting group,
or
b) reacting a compound of formula (II)
(Formula Removed)
with a compound LG-CHR4-(CH2)m-(CHR5)n-R6, in the presence of bases selected from CS2CO3 or K2CO3, optionally in the presence of KI or Nal, in acetone, THF, DMF or DMA as solvent,
wherein R1, R4, R5, R6, m and n are as defined in any of claims 1-18, one of R2 and R3 is OH and the other of R2 and R3 is hydrogen, lower-alkyl, or halogen, LG is a leaving group and A is hydrogen or a protecting group.
20. The compounds as claimed in any of claims 1 to 18, when manufactured by a process according to claim 19.
21. Pharmaceutical compositions comprising a compound as claimed in any of claims 1 to 18 and a pharmaceutically acceptable carrier and/or adjuvant.
22. The pharmaceutical compositions as claimed in claim 21 for the therapeutic and/or prophylactic treatment of increased lipid levels, increased cholesterol levels, low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, fibrosis of the liver, macular degeneration and/or Alzheimer's disease.

Documents:

2188-DELNP-2007-Abstract-(17-01-2012).pdf

2188-delnp-2007-abstract.pdf

2188-delnp-2007-assignment.pdf

2188-DELNP-2007-Claims-(17-01-2012).pdf

2188-delnp-2007-Claims-(22-06-2011).pdf

2188-delnp-2007-claims.pdf

2188-DELNP-2007-Correspondence Others-(17-01-2012).pdf

2188-delnp-2007-Correspondence Others-(22-06-2011).pdf

2188-DELNP-2007-Correspondence Others-(26-08-2011).pdf

2188-delnp-2007-correspondence-others-1.pdf

2188-delnp-2007-correspondence-others.pdf

2188-delnp-2007-description(complete).pdf

2188-delnp-2007-form-1.pdf

2188-delnp-2007-form-18.pdf

2188-DELNP-2007-Form-2-(17-01-2012).pdf

2188-delnp-2007-form-2.pdf

2188-delnp-2007-Form-3-(22-06-2011).pdf

2188-delnp-2007-form-3.pdf

2188-delnp-2007-form-5.pdf

2188-DELNP-2007-GPA-(17-01-2012).pdf

2188-delnp-2007-GPA-(22-06-2011).pdf

2188-delnp-2007-gpa.pdf

2188-delnp-2007-pct-210.pdf

2188-delnp-2007-pct-304.pdf

2188-delnp-2007-pct-409.pdf

abstract.jpg


Patent Number 251342
Indian Patent Application Number 2188/DELNP/2007
PG Journal Number 10/2012
Publication Date 09-Mar-2012
Grant Date 06-Mar-2012
Date of Filing 21-Mar-2007
Name of Patentee H.HOFFMANN-LA ROCHE AG
Applicant Address GRENZACHERSTRASSE 124 CH-4070 BASEL (SWITZERLAND)
Inventors:
# Inventor's Name Inventor's Address
1 HENRIETTA DEHMLOW RITTERSTRASSE 85, D-79639 GRENZACH-WYHLEN, GERMANY
2 KUHN, BERND SONNMATTWEG 42, CH-4410 LIESTAL, SWITZERLAND
3 PANDAY, NARENDRA PASSAUERSTRASSE 35, CH-81369 MUENCHEN, SWITZERLAND
4 RATNI, HASAN 4, RUE LOUIS PASTEUR, F-68440 HABSHEIM, FRANCE
5 WRIGHT, MATHEW BLAKE PFEFFINGERSTRASSE 16, CH-4053 BASEL, SWITZERLAND
PCT International Classification Number C07C 69/92
PCT International Application Number PCT/EP2005/010237
PCT International Filing date 2005-09-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 04104818.2 2004-10-01 EUROPEAN UNION