Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-09-10
2002-03-12
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06355683
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds which modulate binding of immunoglobulins to Fc receptors and uses thereof.
BACKGROUND OF THE INVENTION
Fc receptors (FcR) are a family of highly related receptors that are specific for the Fc portion of immunoglobulin (Ig). These receptors have major roles in normal immunity and resistance to infection and provide the humoral immune system with a cellular effector arm. Receptors have been defined for each of the immunoglobulin classes and as such are defined by the class of Ig of which they bind (i.e. Fc gamma receptor (Fc&ggr;R) bind gamma immunoglobulin (IgG), Fc epsilon receptor (Fc&ggr;R) bind epsilon immunoglobulin (IgE), Fc alpha receptor (Fc&agr;R) bind alpha immunoglobulin (IgA)). Among the Fc&ggr;R receptors, three subfamily members have been defined; Fc&ggr;RI, which is a high affinity receptor for IgG; Fc&ggr;RII, which are low affinity receptors for IgG that avidly bind to aggregates of immune complexes; and Fc&ggr;RIII, which are low affinity receptors that bind to immune complexes. These receptors are highly related structurally but perform different functions. The structure and function of Fc&ggr;RII is of interest because of its interaction with immune complexes and its association with disease.
Fc&ggr;R are expressed on most hematopoietic cells, and through the binding of IgG play a key role in homeostasis of the immune system and host protection against infection. Fc&ggr;RII is a low affinity receptor for IgG that essentially binds only to IgG immune complexes and is expressed on a variety of cell types including, for example monocytes, macrophages, neutrophils, eosinophils, platelets and B lymphocytes. Fc&ggr;RII is involved in various immune and inflammatory responses including antibody-dependent cell-mediated cytotoxicity, clearance of immune complexes, release of inflammatory mediators and regulation of antibody production. The binding of IgG to a Fc&ggr;R can lead to disease indications that involve regulation by Fc&ggr;R. For example, the autoimmune disease thrombocytopenia purpura involves tissue (platelet) damage resulting from Fc&ggr;R-dependent IgG immune complex activation of platelets or their destruction by Fc&ggr;R+ phagocytes. In addition, various inflammatory diseases are known to involve IgG immune complexes (e.g. rheumatoid arthritis, systemic lupus erythematosus), including type II and type III hypersensitivity reactions. Type II and type III hypersensitivity reactions are mediated by IgG, which can activate either complement-mediated or phagocytic effector mechanisms, leading to tissue damage.
Because FcR are involved in a variety of biological mechanisms, there is a need for compounds which affect the binding of immunoglobulins to FcR. There is also a need for using such compounds to treat a variety of illnesses.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition comprising:
(a) a compound selected from the group consisting of an aromatic compound of the formula:
a heteroaromatic compound of the formula:
a cyclic compound of the formula:
a bicyclic compound of the formula:
and an amino acid derivative of the formula:
or salts thereof,
wherein
each of W
1
and W
2
is independently CO
2
R
15
, C(═NH)NH(OH), SO
3
R
15
, C(═NH)NH
2
, OPO(OR
15
)
2
, C(═O) CF
3
or PO(OR
15
)
2
;
each of Ar
1
, Ar
2
, Ar
4
and Ar
5
is independently C
6
-C
20
aryl or C
1
-C
20
heteroaryl;
Ar
3
is C
1
-C
20
heteroaryl;
each of X
1
, X
2
, X
3
, X
4
, X
5
, X
6
, X
7
and X
8
is independently methylene, O, S or NR
16
;
each of R
1
and R
2
is independently a bond, C
1
-C
6
alkylene, or halogenated C
1
-C
6
alkylene;
each of R
3
and R
4
are independently halogen, —Z
1
or C
1
-C
6
alkyl;
each of X
9
, Y
1
and Z
1
is independently OR
17
, SR
17
or NR
7
R
18
;
each of R
5
and R
6
is independently amino acid side chain residue or a moiety of the formula —R
19
—W
3
;
each of R
8
, R
9
and R
11
is independently an amino acid side chain residue, provided R
11
is not H or CH
3
;
R
7
is OR
20
, NR
21
R
22
, or from about 1 to about 10 amino acids;
R
10
is C
1
-C
6
alkylene;
R
12
is C
1
-C
6
alkyl or C
6
-C
20
aralkyl;
W
3
is C(═O)X
10
;
X
10
is OR
23
or NR
24
R
25
;
each of R
13
, R
15
, R
17
, R
18
, R
20
, R
21
, R
23
and R
24
is independently hydrogen or C
1
-C
6
alkyl;
each R
16
is independently H, C
6
-C
20
aryl or an amide protecting group;
R
19
is C
1
-C
6
alkylene;
each of R
22
and R
25
is independently H, C
1
-C
6
alkyl or an amide protecting group;
R
14
is H, C
1
-C
6
alkyl or an amine protecting group;
L is a linker comprising from 1 to about 20 atoms; and
each of m and n is independently an integer from 0 to 2; and
(b) a pharmaceutically acceptable carrier.
The present invention also provides a method for using a compound selected from the group consisting of substituted or unsubstituted benzoic acids; nucleosides and analogs thereof; folic acid and its derivatives; peptides comprising from about 2 to about 10 amino acid residues or derivatives thereof, preferably tripeptides or hexapeptides; macrocyclic compounds containing a ring moiety which comprises from about 8 atoms to about 18 atoms, preferably cyclic peptides or derivatives thereof; and compounds of the above formulas to modulate, e.g., inhibit or enhance, binding of immunoglobulins to Fc receptors in a patient. In a particular embodiment of the present invention, this modulation of Fc receptors by the above identified compounds is used to treat a disease where aggregates of antibodies are produced or where immune complexes are produced by contact of antibody with intrinsic or extrinsic antigen. Modulation of Fc receptors by the above identified compounds can also be used to reduce IgG-mediated tissue damage, to reduce IgE-mediated response and/or to reduce inflammation in a patient.
REFERENCES:
patent: 4686282 (1987-08-01), Hahn
patent: 4752601 (1988-06-01), Hahn
patent: WO 86/01211 (1986-02-01), None
patent: WO 97/40033 (1997-10-01), None
patent: WO 99/40117 (1999-08-01), None
Tabata et al., Pharm. Res. (1993), 10(4), 487-96 (abstract).*
Chemical Abstracts CA:55:1138e (1955).
Baell Jonathan B.
Garrett Thomas P. J.
Hogarth P. Mark
Matthews Barry R.
McCarthy Thomas D.
Ilexus Pty Limited
Sheridan & Ross P.C.
Spivack Phyllis G.
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