Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-22
2001-01-23
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S325000, C546S195000, C546S205000
Reexamination Certificate
active
06177448
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel alkene diamino substituted compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GRO&agr;, GRO&bgr;, GRO&ggr;, NAP-2 and ENA-78 mediated diseases.
BACKGROUND OF THE INVENTION
Many different names have been applied to Interleukin-8 (IL-8), such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1&agr;, IL-1&bgr; or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al,
J. Clin. Invest
. 84, 1045 (1989); J. Schroderet al,
J. Immunol
. 139,3474 (1987) and
J. Immunol
. 144, 2223 (1990); Strieter, et al,
Science
243, 1467 (1989) and
J. Biol. Chem
. 264, 10621 (1989); Cassatella et al,
J. Immunol
. 148, 3216 (1992).
GRO&agr;, GRO&bgr;, GRO&ggr; and NAP-2 also belong to the chemokine &agr; family. Like IL-8 these chemokines have also been referred to by different names. For instance GRO&agr;, &bgr;, &ggr; have been referred to as MGSA&agr;, &bgr; and &ggr; respectively (Melanoma Growth Stimulating Activity), see Richmond et al, J. Cell Physiology 129, 375 (1986) and Chang et al,
J. Immunol
148, 451 (1992). All of the chemokines of the &agr;-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor.
IL-8, GRO&agr;, GRO&bgr;, GRO&ggr; and NAP-2 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GRO&agr; have demonstrated T-lymphocytes, and basophiles chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals GRO-&agr; and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration. As IL-8, Gro&agr;, GRO&bgr;, GRO&ggr; and NAP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al,
FEBS Lett
. 307, 97 (1992); Miller et al,
Crit. Rev. Immunol
. 12, 17 (1992); Oppenheim et al,
Annu. Rev. Immunol
. 9, 617 (1991); Seitz et al.,
J. Clin. Invest
. 87, 463 (1991); Miller et al.,
Am. Rev. Respir. Dis
. 146, 427 (1992); Donnely et al.,
Lancet
341, 643 (1993). In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis. Strieter et al, Science 258, 1798 (1992).
In vitro, IL-8, GRO&agr;, GRO&bgr;, GRO&ggr; and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the B-receptor. Thomas et al.,
J. Biol. Chem
. 266, 14839 (1991); and Holmes et al.,
Science
253, 1278 (1991). The development of non-peptide small molecule antagonists for members of this receptor family has precedent For a review see R. Freidinger in:
Progress in Drug Research
, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8R&agr;, which binds only IL-8 with high affinity, and IL-8R&bgr;, which has high affinity for IL-8 as well as for GRO-&agr;, GRO&bgr;, GRO&ggr; and NAP-2. See Holmes et al., supra; Murphy et al.,
Science
253, 1280 (1991); Lee et al.,
J. Biol. Chem
. 267, 16283 (1992); LaRosa et al.,
J. Biol. Chem
. 267, 25402 (1992); and Gayle et al.,
J. Biol. Chem
. 268, 7283 (1993).
There remains a need for treatment, in this field, for compounds which are capable of binding to the IL-8 &agr; or &bgr; receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds which are inhibitors of IL-8 receptor binding.
SUMMARY OF THE INVENTION
This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 &agr; or &bgr; receptor, which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8.
This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
Another aspect of the present invention are the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
Compounds of Formula (I) useful in the present invention are represented by the structure:
wherein
Z is cyano, nitro, CF
3
, C(O)NR
15
R
16
, S(O)
2
NR
15
R
16
, or S(O)
2
R
17
;
R
18
is hydrogen, halogen, cyano, optionally substituted C
1-4
alkyl, halo substituted C
1-4
alkyl, C(O)NR
15
R
16
, optionally substituted aryl, optionally substituted aryl C
1-4
alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC
1-4
alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC
1-4
alkyl;
A is nitrogen, provided that only one or two of the A moieties are nitrogen and the remainder are carbon substituted by hydrogen or R
1
;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
R
1
is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C
1-10
alkyl; C
1-10
alkyl; C
2-10
alkenyl; C
1-10
alkoxy; halosubstituted C
1-10
alkoxy; azide; (CR
8
R
8
)q S(O)
t
R
4
; hydroxy; hydroxy C
1-4
alkyl; aryl; aryl C
1-4
alkyl; aryloxy; aryl C
1-4
alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C
1-4
alkyl; heteroaryl C
1-4
alkyloxy; aryl C
2-10
alkenyl; heteroaryl C
2-10
alkenyl; heterocyclic C
2-10
alkenyl; (CR
8
R
8
)qNR
4
R
5
; C
2-10
alkenyl C(O)NR
4
R
5
; (CR
8
R
8
)q C(O)NR
4
R
5
; (CR
8
R
8
)q C(O)NR
4
R
10
; S(O)
3
H; S(O)
3
R
8
; (CR
8
R
8
)q C(O)R
11
; C
2-10
alkenyl C(O)R
11
; C
2-10
alkenyl C(O)OR
11
(CR
8
R
8
)q C(O)OR
12
; (CR
8
R
8
)q OC(O)R
11
; (CR
8
R
8
)qNR
4
C(O)R
11
, (CR
8
R
8
)q NHS(O)
2
R
19
, (CR
8
R
8
)q S(O)
2
NR
4
R
5
; or two R
1
moieties together may form O—(CH
2
)
s
O— or a 5 to 6 membered unsaturated ring;
q is 0, or an integer having a value of 1 to 10;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
v is 0, or an integer having a value of 1 to 4;
R
4
and R
5
are independently hydrogen, optionally substituted C
1-4
alkyl, optionally substituted aryl, optionally substituted aryl C
1-4
alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C
1-4
alkyl, heterocyclic, heterocyclic C
1-4
alkyl, or R
4
and R
5
together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C
1-10
alkyl; C
1-10
alkyl; C
2-10
alkenyl; C
1-10
alkoxy; halosubstituted C
1-10
alkoxy; azide; (CR
8
R
8
)q S(O)
t
R
4
; hydroxy; hydroxyC
1-4
alkyl; aryl; aryl C
1-4
alkyl; aryloxy; arylC
1-4
alkyloxy; h
Gleason John Gerald
Widdowson Katherine L.
Dinner Dara L.
Kinzig Charles M.
Shah Mukund J.
Simon Soma G.
SmithKline Beecham Corporation
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