Use of galiella lactone

Details Use of galiella lactone Use of galiella lactone

2001-06-29

2003-01-28

Henley, III, Raymond (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

Reexamination Certificate

active

06512007

ABSTRACT:

The invention relates to the use of the substance known under the name of
galiella lactone
as pharmaceutical, in particular for the treatment of inflammatory processes.
Inflammations are distinguished by a large number of changes even in organ systems which are not in the immediate vicinity of the site of the inflammation. All the systemic changes associated with an inflammation are embraced by the term “acute phase response”. This also applies to chronic inflammatory phenomena (
Perspect. Biol. Med.,
1993, 36: 611-22). The principal part is played in the development of acute phase response by the altered rate of synthesis of so-called acute phase proteins (AP proteins) in the liver (
N. Engl. J. Med.,
1999, 340: 448-54). The acute phase response occurs in infections, traumats, operations, burns, organ damage and advanced stages of malignant diseases. The main mediator of the acute phase response is interleukin-6 (IL-6) (
Proc. Natl. Acad. Sci. USA,
1987, 84: 7251-5).
IL-6 uses tyrosine kinases from the Janus Kinase (Jak) family and transcription factors from the signal transducer and acovator of transcription (Stat) family as the main mediators of intracellular signal transduction. IL-6 induces phosphorylation and thus activation of the transcription factors Stat3 and Stat1 (to a smaller extent) (
Science,
1994, 264: 1415-21:
Science,
1997, 277: 1630-5). After the activation. Stat3 and Stat1 are translocated into the cell nucleus and, after binding to their binding sites on the DNA, cause expression of the genes of AP proteins therein (
Biochem. J.,
1998, 334: 297-314).
Treatments of inflammatory processes corresponding to the current state of the art, for example with corticosteriods, are not without unwanted side effects. There is a need for therapeutic agents which reduce or suppress the unwanted or unwantedly strong expression of the IL-6 -induced AP proteins in the diseases mentioned above and below without at the same time intervening elsewhere in cellular metabolism. For this reason, Stat3 is regarded as a suitable target for developing novel active substances against a non-beneficial, excessive (not self-limiting) acute phase response as is present, for example, in the case of cirrhosis of the liver.
It has now been found, surprisingly, that the compound of the formula (I).
which is called
galiella lactone
is outstandingly suitable for the treatment of inflammatory processes induced by excessive expression of the IL-6-induced acute phase proteins. In this connection, the substance has a specific effect on IL-6 signal induction which has not previously been disclosed for any substance.
Galiella lactone
of the formula (I) is disclosed in
Z. Naturforsch.
1990, 45 c; 1093-8 (and the thesis by R. Hautzel, University of Kaiserslautem 1989) and can be isolated from the fungus
Galiella rufa
(subdivision
Ascomycotina,
class
Discomycotina,
order
Pezizales
, family
Sarcosomaraceae, genus Galiella
) as described therein or in the thesis by H. J. Knerr, University of Kaiserslaurem 1995. No report of its use as pharmaceutical has appeared to date.
Galiella rufa
is described, for example, in: Gary H. Lincoff, Carol Nehring,
The Audubon Society Field Guide to North American Mushrooms
, Alfred A. Knopf, N.Y. 1981.
Galiella lactone
has the physical and chemical properties described hereinafter.
Galiella lactone
forms white crystals which are readily soluble in polar solvents (methanol, pyridine, ethyl acetaze, acetonitrile, tert-butyl methyl ether (lMBE), tetrahydrofurn (THF) and water) and scarcely soluble in nonpolar solvents (cyclohexane, n-pentane, n-hexane). It was possible with the aid of the mass spectra (Table 1) to establish firstly the molecular weight of 194 Da and then the molecular formula of C
11
H
14
O
3
.
TABLE 1
Relative frequency of the peaks in the mass spectra of galiella
lactone. APCI (positive polantry, fragmenter voltage: 70 V, vaporizer
temperature: 400° C.);
CI
APCI
m/z
Intensity [%]
m/z
Intensity [%]
194.8
100 
195.1
69
(MH
+
)
(MH
+
)
177.0
70
177.1
100 
159.2
19
159.1
13
149.2
47
149.1
17
131.4
27
133.1
16
105.5
12
131.1
15
TABLE 2
1
H (500 MHz) (&dgr;/ppm; multiplicity) and
13
C (125 MHz)
(&dgr;/ppm) NMR data for galiella lactone in CDCl
3
.
The CHCl
3
/CDCl
3
signal was used as reference).
H/C No.
1
H data
13
C data
1
—
170.4
2
—
130.6
3
6.85; d
149.6
4
2.53; m
28.6
5
0.90; m; 2.13; m
32.7
6
2.32; m
42.7
7
1.02; m; 1.71; m
31.0
8
1.60; m; 1.95; m
31.0
9
4.64; m
90.0
10 
—
81.3
11 
1.05; m
20.5
The structure was elucidated by means of two-dimensional homonuclear and heteronuclear NMR spectroscopy (
1
H and
13
C). The assignment of the NMR signals to the respective nuclei can be found in Table 2. The UV spectrum of
galiella lactone
shows a maximum at 219 nm. The characteristic peaks in the IR spectrum and their assignment can be found in Table 3.
TABLE 3
Assignment of characteristics peaks in the IR spectrum of
galiella lactone to functional groups.
{overscore (v)}of peak [cm
−1
]
Assignment
3435
tert-alcohol (—OH stretching vibration)
2961-2933
═CH stretching vibration
1742
aliphatic ester (C═O stretching vibration)
1670
C═C stretching vibration
1460
—CH
3
and CH
2
deformation vibration
The invention also relates to pharmacologically active derivatives of
galiella lactone
and their use analogous to
galiella lactone.
In the 1930s, the inflammatory phenomena leading to changes in organ systems were investigated in detail for the first time. This led to the discovery of C-reactive protein (so-called because it reacts with the C polysaccharide of pneumococci) in the plasma of patients during the acute phase of pneumonia induced by pneumococci. Since then, all systemic changes associated with an inflammation are summarized by the term “acute phase response”, and this also applies to chronic inflammatory phenomena.
TABLE 4
Human AP proteins (N. Engl. J. Med. 1999, 340; 448-54)
Proteins whose plasma concentrations increase:
Complement system: C3, C4, C9, factor B, Cl inhibitor, C4b building
protein, mannose binding lectin
Coagulation and fibrinolytic system: fibrinogen, plasminogen, tissue
plasminogen activator, urokinase, protein S, vitronectin, plasminogen
activator inhibitor 1
Antiproteases: &agr;
1
-protease inhibitor, &agr;
1
-antichymotrypsin,
pancreatic secretory trypsin inhibitor, inter-&agr;-trypsin inhibitors
Transport proteins: ceruloplasmin, haptoglobin, hemopexin
Inflammatory system: secreted phospholipase A
2
, lipopolysaccharide
binding protein. IL-1 receptor antagonist, granulocyte-colony
stimulating factor
Others: C-reative protein, serum amyloid A, &agr;
1
-acid glycoprotein,
fibronectin, ferritin, angiotensinogen
Proteins whose plasma concentrations decrease:
albumin, transferrin, &agr;
2
-HS glycoprotein, &agr;-fetoprotein, thyroxine
binding globulin, insulin like growth factor I, factor XII
A rather arbitrary distinction is made between two aspects of the acute phase response: thus, on the one hand, changes in concentration of many proteins in the plasma, the so-called acute phase proteins (AP proteins), are observed (Table 4) and, on the other hand, changes occur in the behaviour and general physiological state (see Table 5). The latter are, of course, caused by the former. A protein is included by definition in the group of AP proteins if, during inflammatory disorders, its plasma concentration increases (positive AP proteins) or decreases (negative AP proteins) by at least 25% (ef., for example,
Ann. N.Y. Acad. Sci.
1982, 389: 406-18). The changes in concentrations of the AP proteins derive principally from their altered rate of synthesis in the liver.
TABLE 5
Phenomena occuring in the acute phase
Neuroendocrine changes: fever, insomnia, anorexia, increased secretion
of the following hormones: corticotropin-releasing hormone,
corticotropin, cortisol, vasopressin and catecholamines
Changes in haemasopoiesis; anaemia, leukocytosis, thrombocytosis
Metabolic changes: muscle atrophy and negative nitrogen balance
reduced glu

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