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...

2001-03-06

2002-04-09

Gerstl, Robert (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

06369088

ABSTRACT:

This invention relates to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, which show an inhibitory effect on hormone-sensitive lipase (HSL), and their pharmaceutically acceptable salts or acid addition salts. The present invention further relates to processes for the preparation of 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, to the use of 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones and their pharmaceutically acceptable salts or acid addition salts as pharmaceuticals, including their use as inhibitors of HSL, and to pharmaceutical compositions comprising 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones and their pharmaceutically acceptable salts or acid addition salts, including their use in the treatment of non-insulin dependent diabetes mellitus and diabetic syndrome.
Certain 5-alkoxy-1,3,4-oxadiazol-2-ones substituted with an ortho-substituted phenyl ring or with fused-on five- or six-membered rings have anthelmintic (DE-A 26 04 110) and insecticidal effects (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 substituents show an endoparasiticidal effect (EP-A 0 419 918).
An aim of the invention was to find compounds which show an inhibitory effect on hormone-sensitive lipase, HSL.
The present invention relates 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, C
3
-C
9
-cycloalkyl, wherein both groups are optionally substituted one or more times by phenyl, C
1
-C
4
-alkyloxy, S—C
1
—C
4
-alkyl, N(C
1
-C
4
-alkyl)
2
, and wherein phenyl is optionally substituted one or more times by halogen, C
1
-C
4
-alkyl, C
1
-C
4
-alkyloxy, nitro, CF
3
; and
R
2
, R
3
, R
4
and R
5
independently of one another are hydrogen, halogen, nitro, C
1
-C
4
-alkyl, C
1
-C
9
-alkyloxy; C
6
-C
10
-aryl-C
1
-C
4
-alkyloxy, C
6
-C
10
-aryloxy, C
6
-C
10
-aryl, C
3
-C
8
-cycloalkyl or O—C
3
-C
8
-cycloalkyl, each of which is optionally substituted once, twice or three times by halogen, CF
3
, C
1
-C
4
-alkyloxy or C
1
-C
4
-alkyl; 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR
6
-A-R
7
, with the proviso that R
2
, R
3
, R
4
and R
5
are not simultaneously hydrogen, and at least one of the radicals R
2
, R
3
, R
4
or R
5
is the radical 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl, or NR
6
-A-R
7
, and wherein:
R
6
is hydrogen, C
1
-C
4
-alkyl or C
6
-C
10
-aryl-C
1
-C
4
-alkyl, wherein aryl may be substituted by halogen, CF
3
, C
1
-C
8
-alkyloxy or C
1
-C
4
-alkyl;
A is a single bond, CO
n
, SO
n
, or CONH;
n is 1 or 2;
R
7
is hydrogen, C
1
-C
18
-alkyl or C
2
-C
18
-alkenyl, wherein C
1
-C
18
-alkyl or C
2
-C
18
alkenyl are optionally substituted one to three times by C
1
-C
4
-alkyl, halogen, CF
3
, C
1
-C
4
-alkyloxy, N(C
1
-C
4
-alkyl)
2
, —COOH, C
1
-C
4
-alkyloxycarbonyl, C
6
-C
12
-aryl, C
6
-C
12
-aryloxy, C
6
-C
12
-arylcarbonyl, C
6
-C
10
-aryl-C
1
-C
4
-alkyloxy or oxo, wherein aryl is in turn optionally substituted by halogen, C
1
-C
4
-alkyl, aminosulfonyl or methylmercapto;
C
6
-C
10
-aryl-C
1
-C
4
-alkyl, C
5
-C
8
-cycloalkyl-C
1
-C
4
-alkyl, C
5
-C
8
-cycloalkyl, C
6
-C
10
-aryl-C
2
-C
6
-alkenyl, C
6
-C
10
-aryl, biphenylyl, biphenylyl-C
1
-C
4
-alkyl, indanyl, each of which is optionally substituted once or twice by C
1
-C
18
-alkyl, C
1
-C
1 8
-alkyloxy, C
3
-C
8
-cycloalkyl, COOH, hydroxyl, C
1
-C
4
-alkylcarbonyl, C
6
-C
10
-aryl-C
1
-C
4
-alkyl, C
6
-C
10
-aryl-C
1
-C
4
-alkyloxy, C
6
-C
10
-aryloxy, nitro, cyano, C
6
-C
10
-aryl, fluorosulfonyl, C
1
-C
6
-alkyloxycarbonyl, C
6
-C
10
-arylsulfonyloxy, pyridyl, NHSO
2
-C
6
-C
10
-aryl, halogen, CF
3
or OCF
3
, wherein alkyl is in turn optionally substituted by C
1
-C
4
-alkyloxycarbonyl, CF
3
or carboxyl, and aryl is also optionally substituted by halogen, CF
3
or C
1
-C
4
-alkyloxy;
or the group Het-(CH
2
)
r
—,
wherein r=0, 1, 2 or 3 and Het=a saturated or unsaturated 5-7-membered heterocycle, optionally benzo-fused and optionally substituted by C
1
-C
4
-alkyl, C
6
-C
10
-aryl, halogen, C
1
-C
4
-alkyloxy, C
1
-C
4
-alkyloxycarbonyl, C
6
-C
10
-aryl-C
1
-C
4
-alkyl, C
6
-C
10
-aryl-C
1
-C
4
-alkylmercapto or nitro, wherein the benzo-fused aryl is in turn optionally substituted by halogen, C
1
-C
4
-alkyloxy or CF
3
and the alkyl in arylalkyl is also optionally by methoxy and CF
3
,
and their pharmaceutically acceptable salts and acid addition salts.
Said aryl radicals are optionally substituted one or more times by C
1
-C
9
-alkyl, C
1
-C
8
-alkyloxy, halogen, and trifluoromethyl. Said cycloalkyl radicals are optionally substituted one or more times by C
1
-C
4
-alkyl, C
6
-C
10
-aryl, and said alkyl radicals are optionally substituted by hydroxyl, di-C
1
-C
4
-alkylamino and fluorine. Halogen is fluorine, chlorine, bromine, generally fluorine and chlorine. Alkyl, alkenyl, alkyloxy, etc. are branched or unbranched. The phrase “is optionally substituted” means that the relevant group is or is not substituted.
Pharmaceutically acceptable salts of compounds of the formula 1 include their organic and inorganic salts, as described in Remington's Pharmaceutical Sciences (A. R. Gennard Editor, Mack Publishing Co., Easton, Pa., USA, 17
th
Ed., p 1418, (1985)). Examples of acidic groups include, inter alia, sodium, potassium, calcium and ammonium salts. Examples of basic groups include, inter alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid, or of carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.
Typical compounds of the formula 1 are those in which:
R
1
is C
1
-C
4
-alkyl; and/or
R
5
is hydrogen; and/or
R
2
is hydrogen, halogen, C
1
-C
4
-alkyl, C
1
-C
9
-alkyloxy or amino.
Further examples of compounds of the formula 1 are those in which:
R
3
is hydrogen, C
1
-C
4
-alkyl, C
6
-C
10
-aryl-C
1
-C
4
-alkyloxy, which is optionally substituted in the aryl moiety by halogen, or is NR
6
-A-R
7
wherein
R
6
=hydrogen or benzyl,
A=single bond and
R
7
=C
6
-C
10
-aryl-C
1
-C
4
-alkyl, which is optionally substituted by halogen, CF
3
, cyano, phenyl-C
1
-C
4
-alkyloxy, CF
3
-phenoxy, C
5
-C
8
-cycloalkyl or fluorosulfonyloxy;
C
1
-C
12
-alkyl, which is optionally substituted by C
1
-C
4
-alkyloxy, phenyl, CF
3
or phenyl-C
1
-C
4
-alkyloxy; C
2
-C
12
-alkenyl;
or the group Het-(CH
2
)
r
—,
wherein r=0 or 1, and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally benzo-fused and optionally substituted by C
1
-C
4
-alkyl or halogen.
Additional compounds of the formula 1 are those in which:
R
4
is hydrogen, 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C
6
-C
10
-aryl-C
1
-C
4
-alkyloxy, which is optionally substituted by halogen, and/or: compounds of the formula 1 in which: R
4
is NR
6
-A-R
7
, wherein
R
6
=hydrogen or methyl,
A=single bond and
R
7
=hydrogen;
C
1
-C
12
-alky, which is optionally substituted once or twice by halogen;
C
2
-C
18
-alkenyl, which is optionally substituted once or twice by C
1
-C
4
-alkyl or C
1
-C
4
-alkyloxycarbonyl;
C
6
-C
10
-aryl-C
1
-C
4
-alky, which is optionally substituted by halogen, C
1
-C
6
-alkyloxy, CF
3
, cyano, C
5
-C
6
-cycloalkyl, C
1
-C
4
-alkyloxycarbonyl, C
6
-C
10
-aryl-C
1
-C
4
-alkyl, C
6
-C
10
-aryl-C
1
-C
4
-alkyloxy, wherein aryl is further optionally substituted by halogen or CF
3
;
C
5
-C
8
-cycloalkyl-C
1
-C
4
-alkyl;
or the group Het-(CH
2
)
r
—,
wherein r=1, 2 or 3 and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally substituted by halogen, C
1
-C
4
-alkyloxy or C
1
-C
4
-alkyloxycarbonyl, and/or compounds of the formula 1 in which:
R
4
is NR
6
-A-R
7
, wherein
R
6
=hydrogen,
A=—CO— and
R
7
=C
1
-C
18
-alkyl, which is optionally substituted by halogen, phenyl, phenoxy, phenylcarbonyl or C
1
-C
4
-alkyloxycarbonyl, wherein phenoxy is optionally substituted by methyl, halogen or methylmercapto;
C
2
-C
18
-alkenyl, which is optionally substit

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