Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-03-10
2002-01-22
Fonda, Kathleen Kahler (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C560S128000
Reexamination Certificate
active
06340706
ABSTRACT:
The invention relates to new leukotriene-B
4
derivatives, process for their production and their use as pharmaceutical agents. The new compounds are optically active structural analogs of previously known leukotriene-B
4
antagonists, which contain a six-membered ring as a basic structural element (DE 39 17 597, DE 42 27 790, DE 42 42 390).
KEY
Arachidonsäure=arachidonic acid
Leukotrien A
4
(LTA
4
)=leukotriene A
4
(LTA
4
)
Glutathion-S-transferase=glutathione-S-transferase
Leukotrien B
4
(LTB
4
)=leukotriene B
4
(LTB
4
)
Leukotrien C
4
(LTC
4
)=leukotriene C
4
(LTC
4
)
Leukotriene B
4
(LTB
4
) was discovered by B. Samuelsson et al. as a metabolite of the arachidonic acid. In the biosynthesis, leukotriene A
4
is formed by the enzyme 5-lipoxygenase first as a central intermediate product, which then is converted by a specific hydrolase into the LTB
4
.
The nomenclature of the leukotrienes can be deduced from the following works:
a) B. Samuelsson et al., Prostaglandins 19, 654 (1980); 17, 785 (1979);
b) C. N. Serhan et al., Prostaglandins 34, 201 (1987).
The physiological and especially the pathophysiological importance of leukotriene B
4
is summarized in several more recent works: a) The Leukotrienes, Chemistry and Biology eds. L. W. Chakrin, D. M. Bailey, Academic Press 1984. b) J. W. Gillard et al., Drugs of the Future 12, 453 (1987). c) B. Samuelsson, Sciences 237, 1171 (1987). d) C. W. Parker, Drug Development Research 10, 277 (1987). e) W. R. Henderson, Annals of Internal Medicine 121, 684 (1994). It follows from the above that LTB
4
is an important inflammation mediator for inflammatory diseases, in which leukocytes invade the affected tissue.
The effects of LTB
4
are triggered on the cellular plane by the binding of LTB
4
to a specific receptor.
It is known concerning LTB
4
that it causes the adhesion of leukocytes to the blood vessel wall. LTB
4
is chemotactically active, i.e., it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration. Furthermore, it indirectly changes the vascular permeability based on its chemotactic activity, whereby a synergism with prostaglandin E
2
is observed. LTB
4
obviously plays a decisive role in inflammatory, allergic and immunological processes.
Leukotrienes and especially LTB
4
are involved in skin diseases, which are accompanied by inflammatory processes (increased vascular permeability and formation of edemas, cell infiltration), increased proliferation of skin cells and itching, such as, for example, in eczemas, erythemas, psoriasis, pruritus and acne. Pathologically increased leukotriene concentrations are involved either causally in the development of many dermatitides or there is a connection between the persistence of the dermatitides and the leukotrienes. Clearly increased leukotriene concentrations were measured, for example, in the skin of patients with psoriasis, atopic dermatitis, allergic contact dermatitis, bullous pemiphigoids, delayed duchurticaria and allergic vasculitis.
Leukotrienes and especially LTB
4
are also involved in the diseases of internal organs, for which an acute or chronic inflammatory component was described, e.g.: joint diseases (rheumatic arthritis); diseases of the respiratory tract (asthma and chronically obstructive lung diseases (OPD)); inflammatory intestinal diseases (ulcerous colitis and Crohn's disease); as well as reperfusion damages (to the heart, intestinal or renal tissues), which result by the temporary pathological obstruction of blood vessels, such as glomerulonephritis, NSAID gastropathies, multiple sclerosis, rhinitis and inflammatory eye diseases.
Further, leukotrienes and especially LTB
4
are involved in the disease of multiple sclerosis and in the clinical appearance of shock (triggered by infections, burns or in complications in kidney dialysis or other separately discussed perfusion techniques).
In addition, leukotrienes and especially LTB
4
have an effect on the formation of white blood cells in the bone marrow, on the growth of unstriped muscle cells, of keratinocytes and of B-lymphocytes. LTB
4
is therefore involved in diseases with inflammatory processes and in diseases with pathologically increased formation and growth of cells.
For example, leukemia or arteriosclerosis represent diseases with this clinical appearance.
Leukotrienes and especially LTB
4
and its derivatives are suitable for reducing elevated triglyceride levels and thus act in an anti-arteriosclerotic manner and against obesity.
By the antagonizing of the effects, especially by LTB
4
, the active ingredients and their forms for dispensing of this invention are specific medicines for diseases of humans and animals, in which especially leukotrienes play a pathological role.
Besides the therapeutic possibilities, which can be derived from an antagonizing of LTB
4
action with LTB
4
analogs, the usefulness and potential use of leukotriene-B
4
agonists for the treatment of fungus diseases of the skin were also able to be shown (H. Katayama, Prostaglandins 34, 797 (1988)).
The invention relates to leukotriene-B
4
derivatives of general formula I
in which
R
1
represents CH
2
OH, CH
3
, CF
3
, COOR
4
, CONR
5
R
6
and
R
2
represents H or an organic acid radical with 1-15 C atoms,
R
3
symbolizes H; C
1
-C
14
alkyl, C
3
-C
10
cycloalkyl optionally substituted in one or more places; C
6
-C
10
aryl radicals, independently of one another, optionally substituted in one or more places by halogen, phenyl, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carbonyl, carboxyl or hydroxy; or a 5- to 6-membered aromatic heterocyclic ring with at least 1 heteroatom,
R
4
means hydrogen, C
1
-C
10
alkyl, C
3
-C
10
cycloalkyl, C
6
-C
10
aryl radicals optionally substituted by 1-3 halogen, phenyl, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxyl or hydroxy; CH
2
—CO—(C
6
-C
10
) aryl or a 5- to 6-membered ring with at least 1 heteroatom;
A symbolizes a trans, trans—CH═CH—CH═CH, a —CH
2
CH
2
—CH═CH—or a tetramethylene group;
B symbolizes a C
1
-C
10
straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine or the group
D can mean a direct bond, oxygen, sulfur, —C≡C—, —CH═CR
7
or together with B can also mean a direct bond;
r
5
and R
6
are the same or different, and represent H or C
1
-C
4
alkyl optionally substituted by hydroxy groups, or R
6
represents H and R
5
represents C
1
-C
15
alkanoyl or R
8
SO
2
,
R
7
means H, C
1
-C
5
alkyl, chlorine, bromine,
R
8
has the same meaning as R
3
,
m means 1-3,
o means 0-5,
p means 0-5,
x is a direct bond, oxygen, sulfur,
y is a C
1
-C
8
alkyl optionally substituted in one or more places, C
3
-C
10
cycloalkyl, and
n is 2-5, and, if R
4
means hydrogen, their salts with physiologically compatible bases and their cyclodextrin clathrates.
The group OR
2
can be in &agr;- or &bgr;-position. Formula I comprises both racemates and the possible pure diastereomers and enantiomers.
As alkyl groups R
4
, straight-chain or branched-chain alkyl groups with 1-10 C atoms are considered, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl.
Alkyl groups R
4
can optionally be substituted in one or more places by halogen atoms, alkoxy groups, optionally substituted aryl or aroyl groups with 6-10 C atoms (relative to possible substituents, see under aryl R
4
), dialkylamino and trialkylammonium with 1-4 C atoms in the alkyl portion, whereby single substitution is to be preferred. As substituents, for example, fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, ethoxy can be mentioned. As preferred alkyl groups R
4
, those with 1-4 C atoms can be mentioned.
Cycloalkyl group R
4
can contain 3-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. For example, cyclopentyl, cyclohexyl, methylcyclohexyl ca
Buchmann Bernd
Frohlich Wolfgang
Giesen Claudia
Hennekes Hartwig
Jaroch Stefan
Fonda Kathleen Kahler
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
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