Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-18
2003-02-11
Krass, Fredrick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S908000, C514S066000, C514S158000, C514S826000, C514S825000, C514S885000, C514S886000, C514S824000, C424S725000, C549S458000
Reexamination Certificate
active
06518274
ABSTRACT:
This application is a national stage application filed under 35 U.S.C. 371 of PCT/EP99/05426, filed Jul. 29, 1999.
The invention relates to the use of cyclopentabenzofuran derivatives for the production of a medicament for the therapy of NF-&kgr;B-dependent diseases.
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; US 4 539 414). After this, several studies appeared on synthesis experiments which were finally also successful. Only 10 years after the isolation of rocaglamide were its insecticidal properties described (Pestic. Sci. 36 53 (1992); 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 96/04 284), 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 97/08 161 A1, J. Nat. Prod. 61, 1482 (1998), Tetrahedron 53, 17625 (1997).).
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 anti-inflammatory active compounds against asthma.
It has now been found that the cyclopentabenzofuran derivatives of the formula (I):
in which
[A] R
1
represents hydrogen,
R
2
represents methoxy,
R
3
represents hydrogen or
R
2
and R
3
together represent —OCH
2
O—,
R
4
represents methoxy,
R
5
represents hydroxyl, OCHO or acetoxy,
R
6
and R
7
in each case represent hydrogen or
R
5
and R
6
together represent oxygen (oxo) or hydroxyimino,
R
8
represents —COOR
12
or —CONR
13
R
14
, in which
R
12
and R
13
represent hydrogen or methyl and
R
14
represents hydrogen, methyl, 4-hydroxybutyl or 2-tetrahydrofuryl,
or
R
8
represents a radical of the formula:
R
5
and R
8
together represent a group of the formulae (a) or (b):
where the linkage site adjacent to the N atom corresponds to R
5
and moreover R
6
and R
7
together represent a direct bond,
R
9
represents phenyl,
R
10
represents methoxy,
R
11
represents hydrogen, hydroxyl, 2-methoxy or 2-rhamnosyl, or
R
10
and R
11
are adjacent and together represent —OCH
2
O—, or
R
15
represents hydroxyl, methoxy or ethoxy,
R
16
represents hydrogen, hydroxyl or methoxy,
[B] R
1
, R
3
and R
8
in each case represent hydrogen,
R
2
and R
4
in each case represent methoxy,
R
5
represents hydroxyl,
R
6
and R
7
in each case represent hydrogen or
R
5
and R
6
together represent oxygen (oxo group),
R
9
represents phenyl,
R
10
represents methoxy,
R
11
represents 2-methoxy or 2-rhanmosyl, or
R
10
and R
11
are adjacent and together represent —OCH
2
O—,
are suitable as inhibitors of nuclear factor kappa B (NF-&kgr;B)-mediated gene expression for the therapy of pathophysiological processes.
The substances utilizable according to the invention are known from the above-mentioned literature.
Examples of the substances of the formula (I) utilizable according to the invention are the compounds (I-1) to (I-45), which are listed below.
TABLE 1
(I-n)
No.
(n)
R
2
R
3
R
5
R
6
R
8
R
10
R
11
1
OCH
3
H
OH
H
CON(CH
3
)
2
OCH
3
H
2
OCH
3
H
OH
H
CONHCH
3
OCH
3
H
3
OCH
3
H
OH
H
CO
2
CH
3
OCH
3
H
4
—OCH
2
O—
OH
H
CON(CH
3
)
2
OCH
3
H
5
—OCH
2
O—
OH
H
CON(CH
3
)
2
OCH
3
OCH
3
6
OCH
3
H
OH
H
CONH
2
OCH
3
H
7
OCH
3
H
OH
H
CO
2
H
OCH
3
H
8
OCH
3
H
OH
H
CON(CH
3
)
2
OCH
3
OH
9
OCH
3
H
OCOCH
3
H
CON(CH
3
)
2
OCH
3
OH
10
OCH
3
H
OH
H
CONH(CH
2
)
4
OH
OCH
3
H
11
OCH
3
H
OCOCH
3
H
CONH(CH
2
)
4
OH
OCH
3
H
12
OCH
3
H
OH
H
OCH
3
H
13
OCH
3
H
OH
H
OCH
3
H
14
OCH
3
H
OCOCH
3
H
CONHCH
3
OCH
3
OH
15
OCH
3
H
OH
H
CONH
2
OCH
3
OH
16
OCH
3
H
OCOCH
3
H
CO
2
CH
3
OCH
3
OH
17
OCH
3
H
OH
H
H
OCH
3
OCH
3
18
OCH
3
H
OH
H
H
OCH
3
O-rhamnosyl
19
OCH
3
H
OH
H
CON(CH
3
)
2
OCH
3
OCH
3
20
OCH
3
H
OH
H
CONHCH
3
OCH
3
OH
21
OCH
3
H
OH
H
CONHCH
3
OCH
3
OH
22
OCH
3
H
═NOH
CO
2
CH
3
OCH
3
OCH
3
23
OCH
3
H
OH
H
CO
2
CH
3
—OCH
2
O—
24
OCH
3
H
OH
H
H
—OCH
2
O—
25
OCH
3
H
═O
H
—OCH
2
O—
26
OCH
3
H
OCHO
H
CO
2
CH
3
—OCH
2
O—
(I-27)
(I-28)
(I-29)
TABLE 2
No.
R
5
R
8
R
11
R
15
30
OCOCH
3
CON(CH
3
)
2
H
OH
31
OCOCH
3
CONHCH
3
H
OH
32
OCOCH
3
CONH
2
H
OH
33
OH
COOCH
3
OH
OH
34
OH
COOCH
3
OCH
3
OH
35
OCOCH
3
COOCH
3
H
OH
36
OCHO
COOCH
3
H
OH
37
OCHO
COOCH
3
OH
OH
I-38
TABLE 3
No.
R
5
R
8
39*
═O(R
5
/R
6
)
H
40
OCOCH
3
COOCH
3
*Cui et al., Tetrahedron 53, 17625 (1997)
TABLE 4
No.
R
5
R
8
R
11
R
16
41
OH
CON(CH
3
)
2
OCH
3
OH
42
OH
COOCH
3
H
H
43
OCOCH
3
COOCH
3
H
H
44*
OH
COOCH
3
OCH
3
H
*Brader et al., J. Nat. Prod. 61, 1482 (1998).
I-45
Of the above-mentioned substances of the general formula (I), the compounds I-1, I-2, I-3, I-4, I-5, I-6, I-8, I-10, I-12, I-13, I-15, I-19, I-20, I-22, I-26, I-28, I-32, I-33, I-42 are preferred.
The substances utilizable according to the invention are low molecular weight inhibitors which selectively inhibit nuclear factor kappa B (NF-&kgr;B)-mediated pathophysiological processes. NF-&kgr;B-mediated processes occur in inflammatory diseases, immunological disorders, septic shock, transplant rejection, radiation damage, reperfusion injuries after ischemia, thromboses or in complex, chronic inflammatory disorders such as arteriosclerosis.
The Pharmacological Action of Inhibitors of Nuclear Factor Kappa B
Nuclear factor kappa B (NF-&kgr;B) is a dimeric protein complex occurring in many tissue cells and in particular in blood cells. NF-&kgr;B takes on a particular role in the control of the expression of genes which have an NF-&kgr;B binding sequence (5′-GGGPuNNPyPyCC-3′) in their promoter sequence. To this extent, NF-&kgr;B is a transcription factor. The physiological activity of NF-&kgr;B in the control of gene expression, however, is subject to a regulation principle, in which NF-&kgr;B is released from a complex with the protein I&kgr;B in order to be translocated as a transcription factor in the cell nucleus of gene activation. The regulation principle for the release of active NF-&kgr;B from a complex with the protein I&kgr;B is still not known in detail.
Likewise, it is not known how the formation of homodimeric and heterodimeric NF-&kgr;B protein complexes takes place. NF-&kgr;B acts on gene activation as a dimeric transcription factor. The dimerization can take place under the structurally related transcription factors Rel A, Rel B, c-Rel, p50 or p52, which form a family of transcription factor proteins. In the dimerization of the subunits to the NF-&kgr;B, there can also already be a regulation principle for the control of the genes later described in greater detail, which is still not known.
A crucial feature of NF-&kgr;B compared to other transcription factors is that NF-&kgr;B is a primary transcription factor. Primary transcription factors are already present in the cell in inactive (usually complex-bound) form and are released after an appropriate stimulus in
Antonicek Horst-Peter
Baumgarten Jörg
Bohnenstengel Frank
Gehling Matthias
Kretschmer Axel
Bayer Aktiengesellschaft
Connolly Bove & Lodge & Hutz LLP
Krass Fredrick
Ostrup Clinton
LandOfFree
Use of cyclopentabenzofuran-derivatives for combating... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of cyclopentabenzofuran-derivatives for combating..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of cyclopentabenzofuran-derivatives for combating... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3130577