Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-21
2004-09-21
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S415000, C514S227200, C514S339000, C514S369000, C514S381000, C514S391000, C548S469000, C548S504000, C548S510000, C548S467000, C548S250000, C548S252000, C548S312100, C548S181000, C546S277400, C544S054000
Reexamination Certificate
active
06794406
ABSTRACT:
The invention relates to new indole derivatives, processes for their preparation and their use in medicaments.
In EP-A-580 550, oxamic acid derivatives are described which have cholesterol-lowering properties in mammals. The reduction of plasma cholesterol, in particular of LDL cholesterol, is emphasized as a pharmacological property. Cholesterol-lowering actions are also described in EP-A-188 351 for certain diphenyl ethers having thyroid-hormone-like actions, which differ clearly in their chemical structure from the compounds according to the invention.
WO 00/51971 discloses oxamic acid derivatives having indole partial structure as thyroid receptor ligands for the treatment of various diseases.
Further indoles which are connected in the 5-position via a bridge member having a substituted phenyl ring are known (WO 94/14770; EP-A-674 619 A1 or WO 94/26737). No thyroid-hormone-like properties are described for these 5-substituted indoles.
WO 99/50268 discloses substituted indolealkanecarboxylic acids which are suitable for the treatment of chronic complications caused by diabetes mellitus.
WO 95/20588 discloses indole derivatives having action as 5-HT
1
agonists.
WO 98/11895 discloses the use of 5-HT
1
agonists for the treatment of migraine; indole derivatives are also indicated as suitable active compounds. In WO 98/06402, use for the treatment of coryza or rhinitis is described for the same structures.
EP-A-639 573 discloses benzo-fused 5-membered ring heterocycles and their use in medicaments and diagnostics. The disclosed compounds are inhibitors of the cellular sodium-proton antiporter (Na
+
/H
+
exchanger).
U.S. Pat. No. 5,468,899 relates to bicyclic aryl compounds having selective properties as LTB
4
antagonists.
EP-A-377 450 discloses substituted indole, benzofuran and benzothiophene derivatives having action as 5-lipoxygenase inhibitors.
JP-A-07145 147 discloses testosterone 5-alpha-reductase inhibitors derived from benzoic acid, which can be employed for the treatment of prostate cancer and certain hair loss disorders.
In GB-A-2 253 848, phenylindole ethers di-ortho-substituted in the phenyl moiety and having herbicidal action are described which can be employed as crop protection agents. Thyromimetic actions have hitherto not been published for these ortho-substituted indoles.
The object of the invention is the provision of new compounds having improved actions, in particular pharmaceutical actions.
It has now been found that compounds of the general formula (I)
in which
Z represents O, S, SO, SO
2
, CH
2
, CHF, CF
2
or represents NR
9
, in which R
9
denotes hydrogen or (C
1
-C
4
)-alkyl,
R
1
and R
2
are identical or different and represent hydrogen, halogen, cyano, (C
1
-C
6
)-alkyl, CF
3
, CHF
2
, CH
2
F, vinyl or (C
3
-C
7
)-cycloalkyl, where at least one of the two substituents is unequal to hydrogen and in the ortho position to the bridge bond,
R
3
represents a group of the formula
—A
m
—D
n
—E
o
—G
p
—L—R
10
,
in which
A represents O, S, NR
11
or represents the group —(CR
12
═CR
13
)—, in which R
11
denotes hydrogen or (C
1
-C
4
)-alkyl, and R
12
and R
13
are identical or different and denote hydrogen, cyano, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-alkoxy,
D represents a straight-chain (C
1
-C
3
)-alkylene group, which can be mono- or polysubstituted, identically or differently, by (C
1
-C
4
)-alkyl, hydroxyl, (C
1
-C
4
)-alkoxy, halogen, amino, mono-(C
1
-C
4
)-alkylamino, mono-(C
1
-C
4
)-acylamino or (C
1
-C
4
)-alkoxycarbonylamino,
E and L independently of one another represent a C(O) or SO
2
group,
G represents NR
14
, in which R
14
denotes hydrogen or (C
1
-C
4
)-alkyl, or represents a straight-chain (C
1
-C
3
)-alkylene group, which can be mono- or polysubstituted, identically or differently, by (C
1
-C
4
)-alkyl, hydroxyl, (C
1
-C
4
)-alkoxy, halogen, amino, mono- or di-(C
1
-C
4
)-alkylamino or mono-(C
1
-C
4
)-acylamino,
m, n, o and p independently of one another in each case represent the number 0 or 1, with the proviso that
in the case that L represents a C═O group, the sum (m+n+o+p) is unequal to the number 0,
and
in the case that m and o in each case represent the number 1, A represents the radical NR
11
and E and L in each case represent a C═O group, the sum (n+p) is unequal to the number 0,
and
R
10
represents OR
15
, NR
16
R
17
, (C
1
-C
10
)-alkyl, (C
3
-C
8
)-cycloalkyl, (C
2
-C
6
)-alkenyl, (C
6
-C
10
)-aryl, (C
6
-C
10
)-arylmethyl or represents a saturated, partly unsaturated or aromatic 5- to 10-membered heterocycle having up to four identical or different heteroatoms from the group consisting of N, O and/or S, where the abovementioned radicals are optionally substituted by one, two or three identical or different substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, nitro, amino, NR
18
R
19
, trifluoromethyl, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy optionally substituted by R
20
, (C
3
-C
8
)-cycloalkyl, (C
6
-C
10
)-aryl, which for its part is optionally substituted by halogen, (C
1
-C
4
)-alkyl, (C
1
-C
4
)-alkoxy, trifluoromethyl, nitro or cyano; —O—C(O)—R
21
, —C(O)—OR
22
, —C(O)—NR
23
R
24
, —SO
2
—NR
25
R
26
, —NH—C(O)—R
27
and —NH—C(O)—OR
28
, where
R
15
, R
16
, R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
24
, R
25
, R
26
, R
27
and R
28
are identical or different and in each case represent hydrogen, phenyl, benzyl, (C
1
-C
6
)-alkyl or (C
3
-C
8
)-cycloalkyl, which for their part are optionally mono- or polysubstituted, identically or differently, by halogen, hydroxyl, amino, carboxyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkoxycarbonyl, (C
1
-C
4
)-alkoxy-carbonyl-amino, (C
1
-C
5
)-alkanoyloxy, a heterocycle or phenyl which is optionally substituted by halogen or hydroxyl,
or the group
—L—R
10
represents a group of the formula
in which
R
29
denotes hydrogen or (C
1
-C
4
)-alkyl,
or
R
3
represents a group of the formula
in which
Q represents a 5- to 6-membered saturated, partly unsaturated or aromatic heterocycle having up to four identical or different heteroatoms from the group consisting of N, O and/or S, which for its part is optionally mono- to trisubstituted, identically or differently, by oxo (═O), thioxo (═S), hydroxyl, (C
1
-C
6
)-alkyl or phenyl,
r represents the number 0, 1 or 2,
and
the ring Het denotes a 5- to 6-membered saturated or partly unsaturated heterocycle having up to three identical or different heteroatoms from the group consisting of N, O and/or S, which is optionally mono- to trisubstituted, identically or differently, by oxo (═O), thioxo (═S), hydroxyl, (C
1
-C
6
)-alkyl or phenyl,
R
4
and R
5
are identical or different and in each case represent hydrogen, hydroxyl, halogen, cyano, nitro, (C
1
-C
4
)-alkyl or the radical of the formula NR
30
R
31
, where R
30
and R
31
have the meaning indicated for R
15
and independently of one another can be identical to or different from this substituent,
R
6
represents hydrogen, halogen or represents a group of the formula
—M
a
—R
32
,
in which
M represents a carbonyl group, a sulphonyl group or a methylene group,
a represents the number 0 or 1,
and
R
32
has the meaning of R
10
indicated above and can be identical to or different from this substituent,
R
7
represents hydrogen or represents an acyl group which can be removed under physiological conditions with formation of an NH function, preferably represents hydrogen or acetyl,
and
R
8
has the meaning of R
6
indicated above and can be identical to or different from this substituent,
and their pharmaceutically tolerable salts, solvates, hydrates and hydrates of the salts,
preferably the compounds which are trisubstituted, in particular tetrasubstituted, in the phenyl moiety and preferably in the 1-, 2-, 4- and 6-position and have a substituent in the 3-position in the indole ring,
exhibit a pharmacological action and can be used as medicaments or for the preparation of pharmaceutical formulations.
Heterocycles in the definition of R
6
, R
8
or R
10
which may preferab
Bischoff Hilmar
Faeste Christiane
Haning Helmut
Kretschmer Axel
Schmidt Gunter
Pellegrino Susan M.
Stockton Laura L.
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