Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
' CA 02477031 2004-08-20
WO 03/072555 PCTIEP03101484
SUBSTITUTED 3-PHENYL-5-ALKOXY-1,3,4-OXDIAZOL-2-ONES, THE
PRODUCTION THEREOF AND THEIR USE IN MEDICAMENTS
Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, their preparation and
use in
medicaments
The invention relates to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones
which
have an inhibitory effect on pancreatic lipase, PL.
Certain 5-alkoxy-1,3,4-oxadiazol-2-ones with an ortho-substituted phenyl ring
as
substituent or with fused-on five- or six-membered rings have an anthelmintic
(DE-A 26 04 110) and insecticidal action (DE-A 26 03 877, EP-B 0 048 040,
EP-B 0 067 471 ).
Certain 5-phenoxy-1,3,4-oxadiazol-2-ones with an ortho-substituted phenyl ring
as
substituent show an endoparasiticidal action (EP-A 0 419 918).
Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones with an inhibitory effect
on
hormone-sensitive lipase are disclosed in WO 01117981 (HMR 19991L 052) and WO
01166531 (AVE-D 20001A 015K).
The object of the invention was to find compounds which show an inhibitory
effect on
pancreatic lipase, PL.
This was achieved with the substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-
ones of
the formula 1
R5
R4 r ~ ~ 1
.- N~ ~O
R3 ~ ~O
//O
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2
in which the meanings are:
R' C~-C~-alkyl; C4-C2o-alkoxy-, C6-Coo-aryl-, C6-C,o-aryloxy- or C4-C~2-alkoxy-
C2-C4-alkoxy-substituted CZ-C4-alkyl, where aryl may be a phenyl or naphthyi
radical which is substitued one or more times by halogen, C,-C4-alkyl, C~-C4-
alkyloxy, vitro or CF3; C~-CZo-alkenyl; 3~i-cholestan-3-yl; phenyl which is
substituted by C6-C~2-alkyl or by phenoxy;
R2, R3, R4 and R5 independently of one another hydrogen, halogen, vitro,
C,-C4-alkyl, C~-C9-alkyloxy, trifluoromethyl, trifluoromethoxy, or
Cs-Coo-aryl-C~-C4-alkyloxy, C6-Coo-aryloxy, C6-Coo-aryl, C3-Ce-cycloalkyl or
O-C3-C$-cycloalkyl, each of which may be substituted once, twice or three
times by halogen, trifluoromethyl, C,-C4-alkyloxy or C~-C4-alkyl;
and their pharmacologically acceptable salts and acid addition salts.
Said aryl radicals may optionally be substituted one or more times by C~-C9-
alkyl,
C~-Cs-alkyloxy, halogen, trifluoromethyl. Said cycloalkyl radicals may
optionally be
substituted one or more times by C~-C4-alkyl, Cs-Coo-aryl, and said alkyl
radicals may
be substituted by hydroxyl, di-C~-C4-alkylamino and fluorine. Halogen is
fluorine,
chlorine, bromine, preferably fluorine and chlorine. Alkyl, alkenyl, alkoxy
etc. may be
branched or unbranched.
Preferred compounds are those of the formula 1 in which R' is C7-C22-alkyl,
C7-C2o-alkenyl, 3~i-cholestan-3-yl or phenyl which is substitued by C6-C~z-
alkyl or by
phenoxy.
Further preferred compounds are those of the formula 1 in which the meanings
are:
RZ hydrogen, halogen, C~-C4-alkyl or C~-C9-alkyloxy;
and/or
R3 hydrogen, C~-C4-alkyl, trifluoromethoxy, C6-Coo-aryl-C~-C4-alkyioxy, which
may
optionally be substituted in the aryl moiety by halogen;
CA 02477031 2004-08-20
3
andlor
Ra hydrogen, trifluoromethoxy or chlorophenoxy;
andlor
R5 hydrogen.
Particularly preferred compounds of the formula 1 are those in which R' is
C$-C~6-alkyl.
Very particularly preferred compounds are those of the formula 1 in which the
meanings are:
R' C8-C~6-alkyl,
R2 hydrogen,
R3 hydrogen or trifluoromethyloxy,
R4 hydrogen, trifluoromethyloxy or 4-chlorophenoxy and
R5 hydrogen.
Additional very particularly preferred compounds of the formula 1 are those
which
are mentioned in Examples 1, 2, 3, 4, 5, 6 and 16.
The compounds according to the invention of the formula 1 have an inhibitory
effect
on pancreatic lipase, PL.
The invention relates to the use of compounds of the formula I in the form of
their
racemates, racemic mixtures and pure enantiomers, and to their diastereomers
and
mixtures thereof.
Pharmaceutically acceptable salts are particularly suitable for medical
applications
because of their greater solubility in water compared with the initial
compounds on
which they are based. These salts must have a pharmaceutically acceptable
anion
or cation. Suitable pharmaceutically acceptable acid addition salts of the
compounds
of the formula 1 are salts of inorganic acids such as hydrochloric acid,
hydrobromic
acid, phosphoric, metaphosphoric, nitric, sulfamic and sulfuric acids, and of
organic
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4
acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric,
ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic,
malefic,
malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and
trifluoroacetic acids.
It is particularly preferred to use the chloride salt and the tartaric acid
salt for medical
purposes. Suitable pharmaceutically acceptable basic salts are ammonium salts,
alkali metal salts (such as sodium and potassium salts) and alkaline earth
metal salts
(such as magnesium and calcium salts).
Salts.with a pharmaceutically unacceptable anion likewise fall within the
scope of the
invention as useful intermediates for preparing or purifying pharmaceutically
acceptable salts and/or for use in non-therapeutic, for example in vitro,
applications.
The term "physiologically functional derivative" used herein refers to any
physiologically tolerated derivative of a compound according to the invention,
for
example an ester, which is able on administration to a mammal, such as, for
example, to humans, to form (directly or indirectly) such a compound or an
active
metabolite thereof.
A further aspect of this invention is the use of prodrugs of compounds of the
formula
1. Such prodrugs can be metabolized in vivo to a compound of the formula 1.
These
prodrugs may themselves be active or not.
The compounds of the formula 1 may also exist in various polymorphous forms,
for
example as amorphous and crystalline polymorphous forms. All polymorphous
forms
of the compounds of the formula 1 fall within the scope of the invention and
are a
further aspect of the invention.
All references hereinafter to "compound(s) of the formula 1" refer to
compounds) of
the formula 1 as described above and to the salts, solvates and
physiologically
functional derivatives thereof as described herein.
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The amount of a compound of the formula 1 necessary to achieve the desired
biological effect depends on a number of factors, for example the specific
compound
chosen, the intended use, the mode of administration and the clinical
condition of the
patient. The daily dose is generally in the range from 0.3 mg to 100 mg
(typically
5 from 3 mg to 50 mg) per day and per kilogram of body weight, for example
3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3
mg
to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100
ng per
kilogram and per minute. Infusion solutions suitable for these purposes may
contain,
for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per
milliliter. Single
doses may contain, for example, from 1 mg to 10 g of the active ingredient.
Thus,
ampoules for injections may contain, for example, from 1 mg to 100 mg, and
single
dose formulations which can be administered orally, such as, for example,
tablets or
capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to
600 mg. In the case of pharmaceutically acceptable salts, the above weight
data are
based on the weight of the salt of the compound of the formula 1. The
compounds of
the formula 1 can be used for prophylaxis or therapy of the abovementioned
states
themselves as compound, but they are preferably in the form of a
pharmaceutical
composition with a compatible carrier. The carrier must, of course, be
compatible in
the sense of compatibility with other ingredients of the composition and not
be
harmful to the patient's health. The carrier may be a solid or a liquid or
both and is
preferably formulated with the compound as single dose, for example as tablet,
which may contain from 0.05% to 95% by weight of the active ingredient.
Further
pharmaceutically active substances may likewise be present, including further
compounds of the formula 1. The pharmaceutical compositions according to the
invention may be produced by one of the known pharmaceutical methods which
essentially consist of mixing the ingredients with pharmacologically
acceptable
carriers and/or excipients.
Pharmaceutical compositions according to the invention are those suitable for
oral,
rectal, topical, peroral (for example sublingual) and parenteral (for example
subcutaneous, intramuscular, intradermal or intravenous) administration,
although
the most suitable mode of administration depends in each individual case on
the
CA 02477031 2004-08-20
6
nature and severity of the condition to be treated and on the nature of the
compound
of the formula 1 used in each case. Coated formulations and coated slow-
release
formulations also fall within the scope of the invention. Acid- and gastric
fluid-
resistant formulations are preferred. Suitable gastric fluid-resistant
coatings comprise
cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl-
cellulose phthalate and anionic polymers of methacrylic acid and methyl
methacrylate.
Suitable pharmaceutical compounds for oral administration may be in the form
of
separate units such as, for example, capsules, cachets, pastilles or tablets,
each of
which contains a defined amount of the compound of the formula 1; as powder or
granules; as solution or suspension in an aqueous or nonaqueous liquid; or as
an oil-
in-water or water-in-oil emulsion. These compositions may, as already
mentioned, be
prepared by any suitable pharmaceutical method which includes a step in which
the
active ingredient and the carrier (which may consist of one or more additional
ingredients) are brought into contact. In general, the compositions are
produced by
uniform and homogeneous mixing of the active ingredient with a liquid and/or
finely
dispersed solid carrier, after which the product is shaped if necessary. Thus,
for
example, a tablet can be produced by compressing or shaping a powder or
granules
of the compound, where appropriate with one or more additional ingredients.
Compressed tablets may be produced by tabletting the compound in free-flowing
form, such as, for example, a powder or granules, where appropriate mixed with
a
binder, lubricant, inert diluent and/or one (or more) surface-
active/dispersing agents
in a suitable machine. Shaped tablets can be produced by shaping, in a
suitable
machine, the compound which is in powder form and has been moistened with an
inert liquid diluent.
Pharmaceutical compositions suitable for peroral (sublingual) administration
comprise suckable tablets which contain a compound of the formula 1 with a
flavoring, normally sucrose, and gum arabic or tragacanth, and pastilles which
contain the compound in an inert base such as gelatin and glycerol or sucrose
and
gum arabic.
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Suitable pharmaceutical compositions for parenteral administration comprise
preferably sterile aqueous preparations of a compound of the formula 1, which
are
preferably isotonic with the blood of the intended recipient. These
preparations are
preferably administered intravenously, although administration can also take
place
by subcutaneous, intramuscular or intradermal injection. These preparations
can
preferably be produced by mixing the compound with water and making the
resulting
solution sterile and isotonic with blood. Injectable compositions according to
the
invention generally contain from 0.1 to 5% by weight of the active compound.
Suitable pharmaceutical compositions for rectal administration are preferably
in the
form of single-dose suppositories. These can be produced by mixing a compound
of
the formula 1 with one or more conventional solid carriers, for example cocoa
butter,
and shaping the resulting mixture.
Suitable pharmaceutical compositions for topical use on the skin are
preferably in the
form of an ointment, cream, lotion, paste, spray, aerosol or oil. Carriers
which can be
used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations
of two
or more of these substances. The active ingredient is generally present in a
concentration of from 0.1 to 15% by weight of the composition, for example
from 0.5
to 2%.
Transdermal administration is also possible. Suitable pharmaceutical
compositions
for transdermal applications may be in the form of single plasters which are
suitable
for long-term close contact with the patient's epidermis. Plasters of this
type suitably
contain the active ingredient in an aqueous solution which is buffered where
appropriate, dissolved and/or dispersed in an adhesive or dispersed in a
polymer. A
suitable active ingredient concentration is about 1 % to 35%, preferably about
3% to
15%. As a particular option, the active ingredient can be released by
electrotransport
or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6):
318
(1986).
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The compounds according to the invention of the formula 1 can be prepared in
various ways by methods known per se.
R5 R5
r v H O-F 1 H
R4 N + O~ '~ R4 r ~ N O-R1
NH2 CI
R3 ~ R3 R2 O
3
4
R5 O R5
CI
R4 r ~ ~ O-R1 ~ R4 r . ~ N O
v v
N-~ N O~R1
R3 R2 H O R3 R2
1
5
For example, substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the
formula 1
can be prepared by reacting hydrazines of the formula 2 with chloroformic
esters of
the formula 3 or other reactive carbonic ester derivatives, in which R', R2,
R3, R4 and
RS are as defined above, to give the compounds of the formula 4, which are
acylated
with phosgene, carbonyldiimidazole, diphosgene or triphosgene, cyclized and
converted where appropriate by further chemical modification of the radicals
R2-R5,
such as, for example, by reduction of nitro to amino radicals by known
processes,
and subsequent acylation or alkylation, into compounds of the formula 1. Since
acids
are usually liberated in these reactions, promotion is advisable by adding
bases such
as pyridine, triethylamine, sodium hydroxide solution or alkali metal
carbonates. The
reactions can be carried out in wide temperature ranges. It has proved
advantageous as a rule to operate at 0°C to the boiling point of the
solvent used.
Examples of solvents employed are methylene chloride, THF, DMF, toluene, ethyl
acetate, n-heptane, dioxane, diethyl ether.
The hydrazines of the formula 2 can be prepared by known methods, for example
by
diazotization of the corresponding anilines and
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R5 R5
R4 ~ ~ hydrazine hydrate R4 ~ ~ H
NH2
R3 6 R2 R3 R2
- 2
subsequent reduction by known methods or by nucleophilic substitution of
suitably
substituted phenyl derivatives 6 (X = F, CI, Br, I, OS02CF3) with hydrazine
hydrate.
Such suitable phenyl derivatives may be vitro-substituted halobenzenes,
preferably
fluoro- and chloronitrobenzenes, from which the compounds according to the
invention can be prepared by known methods at a suitable point in the
synthetic
route by reduction and reaction with acylating or alkylating agents such as,
for
example, acid chlorides, anhydrides, isocyanates, chloroformic esters,
sulfonyl
chlorides or alkyl and arylalkyl halides, or by reductive alkylation with
aldehydes.
The effect of the compounds according to the invention of the formula 1 was
tested
using the following enzyme assay system:
The compounds of the formula 1 show an inhibitory effect on pancreatic lipase
(PL).
As PL inhibitors, they are able to prevent absorption of fat consumed with the
diet
and thus lead to a reduction in the fat uptake and the body weight or prevent
an
increase in body weight. The compounds of the formula 1 are particularly
suitable for
treating obesity but may also have a very beneficial effect in various
metabolic
derangements such as, for example, diabetes, and cardiovascular disorders such
as,
for example, hypertension and myocardial infarction.
The activity of the compounds was assayed as follows:
1. Preparation of the substrate:
80,u1 of tripalmitin (85 mM in chloroform) are mixed with 5 NI of glycerol
tri[9,10(n)-
3H]oleate (5 mCi/ml in toluene) in a 12 ml polypropylene vessel. Evaporation
in a
rotary evaporator (50°C) and addition of 4 ml of 200 mM Tris/HCl (pH
7.6), 0.8% TX-
100 are followed by ultrasound treatment of the mixture (Branson B-12
sonifier,
CA 02477031 2004-08-20
output level 4, 3 x 2 min with 1 min intervals on ice) until a homogeneous
milky
suspension is produced.
2. Assay:
5 Lipase buffer: 80 mM Tris/HCI (pH 7.6), 600 mM NaCI, 8 mM CaCl2, 8 mM
benzamidine, 2 mM Pefabloc (Roche Biochemicals) (add the inhibitors only on
the
day of the assay)
Pancreatic lipase: Enriched preparation from porcine pancreas (Sigma order No.
10 L-0382) dissolved in lipase buffer (100 000 units/500 NI)
Procedure:
5,u1 of test substance (in 100% DMSO) or DMSO (control) are mixed with 10 NI
of
substrate and 5,u1 of lipase (in this sequence) and incubated at 30°C
(Eppendorf
Thermomixer, 350 min-') for 30 min. After addition of 325 NI of
methanol/chloroform/n-heptane (1019/7) and 105 NI of 0.1 M K2C03, 0.1 M H3B03
(pH 10.5 adjusted with 1 M KOH) and vigorous mixing, the phases are separated
by
centrifugation (8000 rpm, Eppendorf centrifuge, 4°C). 140 NI portions
of the aqueous
supernatant (contains the liberated radiolabeled oleate; 70% recovery) are
transferred into 20 ml scintillation vials and mixed with 6 ml of
scintillation cocktail
(Beckman ReadySafe). After vigorously mixing and incubating at room
temperature
for 2 h, the radioactivity is measured in a liquid scintillation counter
(Beckman,
L8008, tritium channel with quench curve, measurement time 20 min).
Evaluation:
Substances are routinely tested in each concentration in three independent
incubation mixtures each with duplicate determination after phase separation
(SD <
0.02). Background values (reaction under the same conditions but without
lipase) are
subtracted from all values (corresponds predominantly to the content of
glycerol
trioleate or free oleate in the substrate preparation in the aqueous phase, <
5% of
the radioactivity employed). The inhibition of the pancreatic lipase enzymatic
activity
CA 02477031 2004-08-20
11
by a test substance is determined by comparison with an uninhibited control
reaction
(presence of lipase = 0% inhibition; absence of lipase 100% inhibition in each
case
after background correction). The ICSO is calculated from an inhibition plot
with up to
8 concentrations of the test substance. The software package GRAPHIT (Elsevier-
BIOSOFT) is used for curve fitting and ICSO determination.
The compounds showed the following effect in this assay:
Compound Example No.:ICSO (~rM)
__._
0.03
____.
_
2 0.25
3 0.35
4 2.5
5 2.0
6 0.9
0.6
10 The following examples illustrate the preparation methods in greater detail
without
restricting them.
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12
Examples:
Example 1:
5-Dodecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
0.43 ml of dodecyl chloroformate was cautiously added dropwise to a mixture
consisting of 0.84 g of 4-trifluoromethoxyphenylhydrazine, 15 ml of NMP and 2
ml of
pyridine while cooling in ice, and the mixture was then stirred for 2 hours
while slowly
warming to RT. After dilution with 50 ml of water, extraction by shaking was
carried
out with 30 ml of methylene chloride, the organic phase was dried with sodium
sulfate and, while stirring and cooling in ice, 5 ml of pyridine and 3 ml of a
20%
strength solution of phosgene in toluene were added dropwise. This mixture was
allowed to stand overnight at room temperature and was diluted with a further
10 ml
of methylene chloride and then washed 3 times with water. After drying over
sodium
sulfate, the mixture was concentrated in vacuo and the product was purified by
column chromatography (silica gel, solvents:methanol:methylene chloride = 2 :
98).
Yield : 0.85 g M.p.: 41 °C
The compounds of the following examples were prepared analagously:
Example 2:
5-Hexadecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 56°C
Example 3:
5-Octyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: oil
Example 4:
5-Hexadecyloxy-3-(3-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 53°C
Example 5:
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13
5-Hexadecyloxy-3-(4-(4-chlorophenoxy)-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 52°C
Example 6:
5-Octyioxy-3-phenyl-3H-(1,3,4)-oxadiazol-2-one
M.p.: 38°C
Example 7:
5-Octyloxy-3-(3-fl uoro-phenyl )-3H-( 1,3,4 )-oxad iazol-2-one
M.p.: oil
Example 8:
5-Hexadecyloxy-3-(3-fluoro-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 58°C
Example 9:
5-Hexadecyloxy-3-(3-benzyloxy-phenyl)-3H-( 1,3,4)-oxadiazol-2-one
M.p.: 65°C
Example 10:
5-Hexadecyloxy-3-phenyl-3H-(1,3;4)-oxadiazol-2-one
M.p.: 63°C
Example 11:
5-Hexadecyloxy-3-(4-vitro-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 72°C
Example 12:
5-Hexadecyloxy-3-(4-methoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 66°C
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14
Example 13:
5-Hexadecyloxy-3-(4-benzyloxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 73°C
Example 14:
5-Decyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: oil
Example 15:
5-Undecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 38°C
Example 16:
5-Tetradecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 46°C
Example 17:
5-Tridecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 50°C
Example 18:
5-(2-(2-Hexyloxy-ethoxy)-ethoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-
oxadiazol-
2-one
M.p.: oil
Example19:
5-((Z)-Octadec-9-enyloxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-
one
M.p.: oil
Example 20:
5-(Dodecyloxy-ethoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
CA 02477031 2004-08-20
M.p.: oil
Example 21:
5-(2-(4-Fluorophenyl)-ethoxyr3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-
oxadiazol-2-
5 one
M.p.: 60°C
Example 22:
5-((3~i-Cholestan-3-yl)-oxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4~oxadiazol-
2-one
10 M.p.: 127°C
Example 23:
5-(2-Butoxy-ethoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: resin
Example 24:
5-(7-Phenyl-heptyloxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-
one
M.p.: resin
Example 25:
5-(Docosyloxy-ethoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 71 °C
Example 26:
5-(2-(1-Naphthyloxy)-ethoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-
oxadiazol-2-
one
M.p.: resin
Example 27: .
5-(4-Octylphenoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: resin
CA 02477031 2004-08-20
16
Example 28:
5-(3-Phenoxy-phenoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: resin
Example 29:
5-(Dodecyloxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4roxadiazol-2-one
M.p.: 41 °C
Example 30:
5-(Dodecyloxy)-3-(3,4-dichloro-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 74°C
Example 31:
5-(Dodecyloxy)-3-(3,5-dichloro-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 48°C
Example 32:
5-(Dodecyloxy)-3-(3-methoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 51 °C
Example 33:
5-(Dodecyloxy)-3-(4-methoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 57°C
Example 34:
5-(Dodecyloxy)-3-(3-vitro-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 64°C
Example 35:
5-(Dodecyloxy)-3-(3-trifluoromethyl-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 43°C
CA 02477031 2004-08-20
17
Example 36:
5-(Dodecyloxy)-3-(3,5-bis-trifluoromethyl-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M:p.: oil
Example 37:
5-(Dodecyloxy)-3-(4-benzyloxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 65°C
Example 38:
5-(Dodecyloxy)-3-(3-fluoro-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 44°C
Example 39:
5-(Dodecyloxy)-3-(3-(4-fluorobenzyloxy)-4-vitro-phenyl)-3H-(1,3,4)-oxadiazol-2-
one
M.p.: 71 °C
Example 40:
5-(Dodecyloxy)-3-(2-methyl-4-vitro-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 63°C
Example 41:
5-(Dodecyloxy)-3-(3-methyl-4-vitro-phenyl)-3H-(1,3,4)-oxadiazol-2-one
M.p.: 62°C
