Cyclopentabenzofuran derivatives and their use

Details Cyclopentabenzofuran derivatives and their use Cyclopentabenzofuran derivatives and their use

2001-03-26

2002-07-16

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S444000, C514S464000, C514S468000, C546S284100, C549S060000, C549S078000, C549S435000, C549S458000, C549S466000

Reexamination Certificate

active

06420393

ABSTRACT:

The invention relates to cyclopentabenzofuran derivatives, processes for their preparation, the use of cyclopentabenzofuran derivatives for the production of a medicament for the therapy of NF-&kgr;B-dependent diseases and medicaments which contain the cyclopentabenzofuran derivatives.
Extracts of the plant
Aglaia elliptifolia
exhibit antileukemic properties. The first active compound identified was a dihydrocyclopentabenzofuranol derivative called rocaglamide (J. Chem. Soc., Chem. Commun. 1982, 1150; U.S. Pat. No. 4,539,414). After this, several studies appeared on synthesis experiments which were finally also successful (J. Chem. Soc., Chem. Commun. 1991, 1137). Only 10 years after the isolation of rocaglamide were its insecticidal properties described (Pestic. Sci 36, 53 (1992) and Phytochemistry 32, 67 (1993)) and after that in another species,
Aglaia odorata
, another three derivatives only differing in one substituent were found (Phytochemistry 32, 307 (1993)). Later, for example, from the species
Aglaia roxburghiana
, the first four fused derivatives of rocaglamide were isolated (WO 96/04284), then numerous further new derivatives and their pharmacological properties were described (cf., for example, J. Nat. Prod. 59, 650 (1996); Tetrahedron 52, 6931 (1996); Phytochemistry 44, 1455 (1997); Phytochemistry 45 1579 (1997); Z. Naturforsch., C: Biosci. 52, Tetrahedron 52, 17625 (1997); B. W. Nugroho, Thesis, Bayer. Julius-Maximilian Univ. Würzburg, 1997); WO 97/08161 A1).
An important step in many inflammatory processes is the translocation of the protein “nuclear factor kappa B”, in brief NF-&kgr;B, into the cell nucleus and the stimulation of the expression of the genes caused thereby. whose products are responsible for inflammatory reactions (Trends Pharmacol. Sci. 18, 46 (1997)). For example, in asthma the nonbeneficial, excessive (non self-limiting) production of these proteins is responsible for the intensification and maintenance of the inflammatory process and the unpleasant to life-threatening symptoms of this disease associated therewith. Because the long-term treatment with glucocorticoids corresponding to the present state of the art is affected by some disadvantages, NF-&kgr;B is seen as a compelling target for the development of new antiinflammatory active compounds against asthma.
It has now been found that the cyclopentabenzofuran derivatives of the formula (I)
in which
R
1
and R
3
independently of one another in each case represent hydrogen, halogen or alkyl,
R
2
and R
4
independently of one another in each case represent halogen, alkyl or optionally substituted alkoxy,
R
5
represents hydroxyl, alkylamino or the radical —NR
12
—CHR
13
—COOR
14
, in which
R
12
represents hydrogen or alkyl,
R
13
represents one of the radicals of a natural or synthetic &agr;-amino acid, where functional groups can optionally be present in protected form, or
R
12
and R
13
together represent —(CH
2
)
3
— and —(CH
2
)
4
—, and
R
14
represents alkyl, benzyl or another C-terminal protective group,
R
6
represents hydrogen or
R
5
and R
6
together represent oxygen (oxo),
R
7
and R
8
in each case represent hydrogen,
R
9
represents optionally substituted phenyl or hetaryl,
R
10
represents hydrogen, halogen, alkyl or alkoxy and
R
11
represents hydrogen, halogen or alkyl,
and their salts
are suitable as inhibitors of nuclear factor kappa B (NF-&kgr;B)-mediated gene expression for the therapy of pathophysiological processes.
Depending on the nature of the substituents, the compounds of the formula (I) can also be present as geometrical and/or optical isomers or isomer mixtures, in different compositions, which can optionally be separated in a customary manner. Both the pure isomers and the isomer mixtures, their preparation and use, and compositions containing these are a subject of the present invention. Below, for the sake of simplicity, however, compounds of formula (I) are always referred to, although both the pure compounds and optionally also mixtures having different proportions of isomeric compounds are intended.
If, in a structural formula, the number of diastereomers is restricted by fixing the configuration on at least two chiral centers then, if not stated otherwise, in principle also the other enantiomers (mirror image) are intended.
The compounds according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acid or sulfonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Those particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts, which are derived from ammonia, or organic amines, such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
Formula (I) provides a general definition of the substances utilizable according to the invention. Preferred substituents or ranges of the radicals listed in the formulae above and below are explained in the following.
R
1
and R
3
independently of one another preferably in each case represent hydrogen, fluorine, chlorine, bromine or C
1
-C
6
-alkyl.
R
2
and R
4
independently of one another preferably in each case represent fluorine, chlorine, bromine, C
1
-C
6
-alkyl or C
1
-C
4
-alkoxy optionally substituted by fluorine or chlorine.
R
5
preferably represents hydroxyl, C
1
-C
4
-alkylamino or the radical —NR
12
—CHR
13
—COOR
14
.
R
6
preferably represents hydrogen.
R
5
and R
6
also preferably together represent oxygen (oxo).
R
7
and R
8
preferably in each case represent hydrogen.
R
9
preferably represents phenyl, methylenedioxyphenyl or 5- or 6-membered hetaryl having 1 or 2 heteroatoms from the series consisting of nitrogen, oxygen and sulfur which in each case can optionally be substituted up to four times by substituents of the group: halogen, C
1
-C
6
-alkyl, hydroxyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio, C
1
-C
4
-alkylcarbonyl, phenyl, phenoxy, hetaryl, hetaryloxy, C
1
-C
4
-alkyl substituted by fluorine or chlorine, C
1
-C
4
-alkoxy substituted by fluorine or chlorine, C
1
-C
4
-alkylthio substituted by fluorine or chlorine, C
1
-C
4
-alkylcarbonyl substituted by fluorine or chlorine.
R
10
preferably represents hydrogen, fluorine, chlorine, C
1
-C
6
-alkyl or C
1
-C
6
-alkoxy.
R
11
preferably represents for hydrogen, fluorine, chlorine, bromine or C
1
-C
6
-alkyl.
R
12
preferably represents hydrogen or C
1
-C
4
-alkyl.
R
13
preferably represents hydrogen, C
1
-C
4
-alkyl optionally substituted by amino or hydroxyl or represents mercaptomethyl, methylthioethyl, carboxmethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl or represents phenyl or benzyl optionally substituted by amino, nitro, halogen, hydroxyl or methoxy or represents naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, where functional groups can optionally be present in protected form.
R
12
and R
13
also preferably together represent —(CH
2
)
3
— or —(CH
2
)
4
—.
R
14
preferably represents C
1
-C
6
-alkyl, benzyl or another C-terminal protected group.
R
1
and R
3
independently of one another particularly preferably in each case represent hydrogen, fluorine, chlorine, bromine, methyl or ethyl.
R
2
and R
4
independently of on

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