Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-21
2002-04-23
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S617000, C514S646000, C514S728000, C548S250000, C548S252000, C564S170000, C564S174000, C568S636000, C568S638000, C568S643000
Reexamination Certificate
active
06376524
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to antagonists of interleukin-4 signaling. In particular, this invention relates to certain triphenyl compounds that antagonize interleukin-4 signaling, to methods of making them, to pharmaceutical compositions containing them, and to their uses.
2. Description of the Related Art
Interleukin-4 (IL-4) is a pleiotropic cytokine that is produced primarily by T helper type 2 lymphocytes (TH2 cells). The most clinically significant activity of this cytokine is the stimulation of immunoglobin class switching of the immune system's B-cells to IgE production. See P. Chomarat et al., “An update on interleukin-4 and its receptor”,
Eur. Cytokine Netw.,
8(4), 333-344 (1997); R. A. Pauwels et al., “Cytokines and their receptors as therapeutic targets in asthma”,
Clin. Exp. Allergy,
28(Suppl. 3), 1-5 (1998), and references discussed therein.
Ample evidence exists that antagonism of IL-4 can alleviate allergic responses. These include the correlation of allergy and asthma symptoms with IL-4 levels in both allergen immunotherapy and asthma patients, the reduction of spontaneous IgE production in lymphocytes following treatment with IL-4 antibodies, and the inability to induce asthma-associated eosinophilia in IL-4 gene knockout mice. Additional evidence exists correlating elevated levels of IL4 with osteoporosis, osteoarthritis, rheumatoid arthritis, and autoimmune and other inflammation related disorders. Antagonism of IL-4 might further prove useful for therapeutically desirable immunosuppression.
The attractiveness of developing a drug that antagonizes IL4 activity has not escaped the pharmaceutical industry. Immunex and Wyeth-Ayerst are developing a nebulized form of a soluble IL4 receptor for the treatment of moderate asthma. The drug, Nuvance, is now in Phase II clinical trials. Glaxo SmithKline is developing an IL-4 antibody that is currently in clinical trials for the treatment of asthma.
Small molecule IL-1 antagonists have been sought. See R. Sarabu, “Design and synthesis of small molecule interleukin-1 receptor antagonists based on a benzene template,
Drug Design Discovery,
15, 191-198 (1998).
It would be desirable to develop a small-molecule IL-4 antagonist.
SUMMARY OF THE INVENTION
In a first aspect, this invention provides compounds of formula I and formula II:
where:
A—B is selected from the group consisting of —CHR
X
—CHR
X
—, —CR
Y
═CR
Y
—, —CHR
Y
—O—, —O—CHR
Y
—, NR
1
—C(═O)—, —C(═O)—NR
1
, —S(O)
0-2
—CHR
X
—, —CHR
X
—S(O)
0-2
—, —SO
2
—NR
1
—, —NR
1
—SO
2
—,—C(═O)—CHR
X
—, —CHR
X
—C(═O)—, and cycloalkylene;
each R
X
is independently selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, aminoalkyl, guanidinoalkyl, alkoxy, amino, alkylamino, dialkylamino, cycloamino, alkylcarbonylamino, guanidino, carboxy, alkoxycarbonyl, and tetrazole;
each R
Y
is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, carboxy, and alkoxycarbonyl;
each R
1
is independently selected from the group consisting of hydrogen and lower alkyl;
R
2
is selected from the group consisting of hydrogen, halo, and hydroxy;
R
3
is selected from the group consisting of optionally fluorinated methoxy and optionally fluorinated ethoxy;
R
4
is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, dialkylamino, and cycloamino;
R
5
is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, alkoxy, amino, alkylcarbonylamino, alkylsulfonylamino, benzenesulfonylamino, toluenesulfonylamino, carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloaminocarbonyl, and alkoxycarbonyl;
R
6
is selected from the group consisting of hydrogen, halo, and hydroxy;
R
8
, R
9
, R
11
, R
12
, R
14
, R
15
, R
17
and R
18
are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, methoxy, and ethoxy;
R
16
is selected from the group consisting of hydrogen, hydroxy, halo, haloalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, carboxy, alkoxycarbonyl, —SO
2
NR
1
2
, and —NR
1
SO
2
R
1
;
R
19
is selected from the group consisting of hydrogen, hydroxy, halo, haloalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, carboxy, alkoxycarbonyl, —SO
2
NR
1
2
, and —NR
1
SO
2
R
1
;
and compounds of formula VI
where
X is selected from —CHR
X
—and —CH
2
—CHR
X
—;
A—B is selected from the group consisting of —CHR
X
—CHR
X
—, —CR
Y
═CR
Y
—, —CHR
Y
—O—, —O—CHR
Y
—, —NR
1
—C(═O)—, —C(═O)—NR
1
, —S(O)
0-2
—CHR
X
—, —CHR
X
—S(O)
0-2
—, —SO
2
—NR
1
—, —NR
1
—SO
2
—, —C(═O)—CHR
X
—, —CHR
X
—C(═O), and cycloalkylene;
each R
X
is independently selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, aminoalkyl, guanidinoalkyl, alkoxy, amino, alkylamino, dialkylamino, cycloamino, alkylcarbonylamino, guanidino, carboxy, alkoxycarbonyl, and tetrazole;
each R
Y
is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, carboxy, and alkoxycarbonyl;
each R
1
is independently selected from the group consisting of hydrogen and lower alkyl;
R
2
is selected from the group consisting of hydrogen, halo and hydroxy;
R
5
is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, alkoxy, amino, alkylcarbonylamino, alkylsulfonylamino, benzenesulfonylamino, toluenesulfonylamino, carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloaminocarbonyl, and alkoxycarbonyl;
R
6
is selected from the group consisting of hydrogen, halo, and hydroxy;
R
8
, R
9
, R
11
, R
12
, R
14
, R
15
, R
17
, and R
18
are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, methoxy, and ethoxy;
R
16
is selected from the group consisting of hydrogen, hydroxy, halo, haloalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, carboxy, alkoxycarbonyl, —SO
2
NR
1
2
, and —NR
1
SO
2
R
1
;
and the pharmaceutically acceptable salts of all these compounds.
In a third aspect, this invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of at least one compound of this invention. These compositions find particular use as anti-asthmatic and anti-allergenic agents; and in the treatment of osteoporosis, osteoarthritis, rheumatoid arthritis, and autoimmune and other inflammation related disorders, and for therapeutically desirable immunosuppression.
In a fourth aspect, this invention provides a method of treating an animal having a disease capable of treatment by administration of an IL-4 antagonist, comprising administration to that animal of a therapeutically effective amount of at least one compound of this invention, optionally in conjunction with at least one other conventional therapeutic agent for the disease being treated.
In a fifth aspect, this invention provides methods of preparing the compounds of this invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Definitions
“Alkyl” means a linear monovalent hydrocarbyl group having 1 to 5 carbon atoms, or a branched or cyclic hydrocarbyl group having 3 to 5 carbon atoms. Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, cyclopropylmethyl, and pentyl. “Alkoxy” means the group —O-alkyl, where “alkyl” is as defined immediately before.
“Cycloalkylene” means a cyclic hydrocarbyl group having 5 to 7 ring carbon atoms, bonded to an aryl group or other linker atom at both of two adjacent ring carbon atoms; such as 1,2-cyclohexylene. “Cycloalkylene also includes those compounds where the bond between the ring carbon atoms that are bonded to the aryl groups or other linker atoms is a double bond. “Cycloalkylene” specifically includes cyclic compounds as defined immediately before where 1 or 2 of the ring carbon atoms are replaced by O, S, NH, or N-alkyl; such as 2,3-piperidinylene and 3,4-tetrahydropyranylene.
“Cycloamino” means a cyclic amino group having 5 to 7 ring atoms of which at least one is nitrogen and the remainder may all be carbon (e.g. pyrrolidino, piperidi
Barr Kenneth J.
Cunningham Brian C.
Flanagan William Michael
Lu Wanli
Raimundo Brian C.
Heller Ehrman White & McAuliffe LLP
Powers Fiona T.
Sunesis Pharmaceuticals, Inc.
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