Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, their...

Details Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, their... Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, their...

2000-09-05

2003-07-22

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S144000

Reexamination Certificate

active

06596742

ABSTRACT:

The invention relates to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones which have an inhibitory effect on the hormone-sensitive lipase HSL.
Certain 5-alkoxy-1,3,4-oxadiazol-2-ones having an ortho-substituted phenyl ring as substituent or having fused-on five- or six-membered rings have 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 having an ortho-substituted phenyl ring as substituent have endoparasiticidal action (EP-A 0 419 918).
It is an object of the present invention to provide compounds having an inhibitory effect on the hormone-sensitive lipase HSL.
This object was achieved with the substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1,
in which
R
1
is C
1
-C
6
-alkyl or C
3
-C
9
-cycloalkyl, where both groups are unsubstituted or mono- or polysubstituted by O—C
1
-C
4
-alkyl, S—C
1
-C
4
-alkyl, N(C
1
-C
4
-alkyl)
2
and/or phenyl which for its part may be mono- or polysubstituted by halogen, C
1
-C
4
-alkyl, O—C
1
-C
4
-alkyl, nitro, CF
3
, and
R
2
and R
3
independently of one another are hydrogen, C
6
-C
10
-aryl, C
3
-C
8
-cycloalkyl, optionally C
1
-C
4
-alkyl-substituted C
6
-C
10
-aryloxymethyl, O—C
3
-C
8
-cycloalkyl, O—C
6
-C
10
-aryl or O-benzyl, unsubstituted or mono- or polysubstituted by halogen, CF
3
or C
1
-C
4
-alkyl, O—C
1
-C
6
-alkyl which is mono- or polysubstituted by fluorine, C
6
-C
10
-aryl or amino, where amino for its part may be mono- or polysubstituted by C
1
-C
4
-alkyl, are SO
2
—NH—C
1
-C
6
-alkyl, unsubstituted or substituted by N(C
1
-C
6
-alkyl)
2
, are SO
2
—NH-(2,2,6,6-tetramethylpiperidin4-yl), SO
2
—NH—C
3
-C
8
-cycloalkyl, unsubstituted or mono- or polysubstituted by C
1
-C
4
-alkyl, are SO
2
—N(C
1
-C
6
-alkyl)
2
or COX,
where X is O—C
1
-C
6
-alkyl, NH—C
1
-C
6
-alkyl, NH—C
3
-C
8
-cycloalkyl or N(C
1
-C
6
-alkyl)
2
, and
N(C
1
-C
6
-alkyl)
2
may also be pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino -which may be unsubstituted or substituted by C
1
-C
4
-alkyl, benzyl, C
6
-C
10
-aryl, CO—C
1
-C
4
-alkyl, CO—C
6
-C
10
-aryl, CO—O—C
1
-C
4
-alkyl, SO
2
—C
1
-C
4
-alkyl or SO
2
—C
6
-C
10
-aryl,
with the proviso that R
2
and R
3
are not simultaneously hydrogen, and their physiologically acceptable salts and optical isomers.
The aryl radicals mentioned can be unsubstituted or mono- or polysubstituted by C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, halogen, trifluoromethyl. The cycloalkyl radicals mentioned can be unsubstituted or mono- or polysubstituted by C
1
-C
4
-alkyl, and the alkyl radicals mentioned can be substituted by hydroxyl, di-C
1
-C
4
-alkylamino and fluorine. Halogen denotes fluorine, chlorine, bromine, preferably fluorine and chlorine.
Preference is given to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1, in which one of the radicals R
2
or R
3
is hydrogen.
Particular preference is given to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1, in which
R
1
is C
1
-C
6
-alkyl which may be unsubstituted or substituted by phenyl.
Particular preference is furthermore given to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1, in which
R
2
and R
3
independently of one another are hydrogen, C
6
-C
10
-aryl,
C
3
-C
8
-cycloalkyl, unsubstituted or C
1
-C
4
-alkyl-substituted C
6
-C
10
-aryloxymethyl, O—C
3
-C
8
-cycloalkyl, O—C
6
-C
10
-aryl or O-benzyl, unsubstituted or mono- or polysubstituted by C
1
-C
4
-alkyl or halogen, O—C
1
-C
6
-alkyl which is mono- or polysubstituted by fluorine, C
6
-C
10
-aryl or amino, where amino for its part may be mono- or polysubstituted by C
1
-C
4
-alkyl, are SO
2
—NH—C
1
-C
6
-alkyl, optionally substituted by N(C
1
-C
6
-alkyl)
2
, are SO
2
—NH—(2,2,6,6-tetramethylpiperidin4-yl), SO
2
—NH—C
3
-C
8
-cycloalkyl, substituted by C
1
-C
4
-alkyl, are SO
2
—N(C
1
-C
6
-alkyl)
2
or CO—N(C
1
-C
6
-alkyl)
2
, and N(C
1
-C
6
-alkyl)
2
may also be piperidino, morpholino or piperazino which can be unsubstituted or substituted by C
1
-C
4
-alkyl.
Very particular preference is also given to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1, in which
R
2
is hydrogen, C
6
-C
10
-aryl, O—C
6
-C
10
-aryl, unsubstituted or C
1
-C
4
-alkyl-substituted C
6
-C
10
-aryloxymethyl, O-benzyl, is O—C
1
-C
6
-alkyl which is mono- or polysubstituted by fluorine or amino, where amino for its part may be mono- or polysubstituted by C
1
-C
4
-alkyl, is O—C
3
-C
8
-cycloalkyl which is unsubstituted or mono- or polysubstituted by C
1
-C
4
-alkyl, and
R
3
is hydrogen, C
6
-C
10
-aryl, C
3
-C
8
-cycloalkyl, O—C
3
-C
8
-cycloalkyl or O—C
6
-C
10
-aryl which is unsubstituted or mono- or polysubstituted by C
1
-C
4
-alkyl or halogen, is O—C
1
-C
6
-alkyl which is mono- or polysubstituted by fluorine, is SO
2
—NH—C
1
-C
6
-alkyl, unsubstituted or substituted by N(C
1
-C
6
-alkyl)
2
, is SO
2
—NH-(2,2,6,6-tetramethylpiperidin-4-yl), SO
2
—NH—C
3
-C
8
-cycloalkyl, mono- or polysubstituted by C
1
-C
4
-alkyl, is SO
2
—N(C
1
-C
6
-alkyl)
2
or CO—N(C
1
-C
6
-alkyl)
2
, and
N(C
1
-C
6
-alkyl)
2
is also piperidino, morpholino or piperazino, which may be unsubstituted or substituted by C
1
-C
4
-alkyl.
Very particular preference is given to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1, in which
R
1
is methyl, ethyl, butyl, isopropyl or benzyl and
R
2
is hydrogen, trifluoromethoxy, trifluorobutoxy, 3,3,5,5-tetramethylcyclohexyloxy, benzyloxy, phenoxy, phenyl, 2-diethylaminoethyloxy or 3-methylphenoxymethyl, and
R
3
is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, 4-chlorophenoxy, cyclohexyl, phenyl, morpholinosulfonyl, 3,3,5-trimethylcyclohexylaminosulfonyl, 2,2,6,6-tetramethylpiperidin-4-yl-aminosulfonyl, 2-(diisopropylaminoethyl)aminosulfonyl, 4-methylpiperazin-1-yl-sulfonyl, 3,3-dimethylpiperidinocarbonyl or 3,5-dichlorophenoxy.
Very particular preference is furthermore given to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1, in which
R
1
is methyl, ethyl, butyl, isopropyl or benzyl and
R
2
is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, 3 benzyloxy or phenoxy and
R
3
is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, cyclohexyl, phenyl, morpholinosulfonyl or 3,3,5-trimethylcyclohexylaminosulfonyl.
The compounds of the formula 1 according to the invention have an unexpected inhibitory effect on the hormone-sensitive lipase HSL, an allosteric enzyme in adipocytes which is inhibited by insulin and responsible for the degradation of fats in fat cells and thus for the transfer of fat components into the bloodstream. Thus, an inhibition of this enzyme corresponds to an insulin-like effect of the compounds according to the invention which in the end results in a reduction of free fatty acids in the blood and of blood sugar. Accordingly, they can be used for metabolic disorders such as, for example, for non-insulin-dependent diabetes mellitus, for diabetic syndrome and in cases where the pancreas is damaged directly.
The compounds of the formula 1 according to the invention can be prepared by different routes using methods known per se.
For example, the 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 acid ester derivatives, in which R
1
, R
2
and R
3
are as defined above, to give compounds of the formula 4 which are acylated with phosgene, carbonyldiimidazole or diphosgene and cyclized to give the compounds of the formula 1. Since in general acids are liberated in these reactions, it is recommended to add bases such as pyridine, triethylamine, aqueous sodium hydroxide solution or alkali metal carbonates to accelerate the reaction. The reactions can be carried out in wide temperature ranges. In general, it has been found to be advantageous to carry out the reactions at from 0° C. to the boiling point of the solvent used. Suitable solvents are, for ex

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