Source: {"pile_set_name": "USPTO Backgrounds"}

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., xe2x80x9cAn update on interleukin-4 and its receptorxe2x80x9d, Eur. Cytokine Netw., 8(4), 333-344 (1997); R. A. Pauwels et al., xe2x80x9cCytokines and their receptors as therapeutic targets in asthmaxe2x80x9d, 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, xe2x80x9cDesign 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.
In a first aspect, this invention provides compounds of formula I and formula II: 
where:
Axe2x80x94B is selected from the group consisting of xe2x80x94CHRXxe2x80x94CHRXxe2x80x94, xe2x80x94CRYxe2x95x90CRYxe2x80x94, xe2x80x94CHRYxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHRYxe2x80x94, NR1xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NR1, xe2x80x94S(O)0-2xe2x80x94CHRXxe2x80x94, xe2x80x94CHRXxe2x80x94S(O)0-2xe2x80x94, xe2x80x94SO2xe2x80x94NR1xe2x80x94, xe2x80x94NR1xe2x80x94SO2xe2x80x94,xe2x80x94C(xe2x95x90O)xe2x80x94CHRXxe2x80x94, xe2x80x94CHRXxe2x80x94C(xe2x95x90O)xe2x80x94, and cycloalkylene;
each RX 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 RY is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, carboxy, and alkoxycarbonyl;
each R1 is independently selected from the group consisting of hydrogen and lower alkyl;
R2 is selected from the group consisting of hydrogen, halo, and hydroxy;
R3 is selected from the group consisting of optionally fluorinated methoxy and optionally fluorinated ethoxy;
R4 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, dialkylamino, and cycloamino;
R5 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, alkoxy, amino, alkylcarbonylamino, alkylsulfonylamino, benzenesulfonylamino, toluenesulfonylamino, carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloaminocarbonyl, and alkoxycarbonyl;
R6 is selected from the group consisting of hydrogen, halo, and hydroxy;
R8, R9, R11, R12, R14, R15, R17 and R18 are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, methoxy, and ethoxy;
R16 is selected from the group consisting of hydrogen, hydroxy, halo, haloalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, carboxy, alkoxycarbonyl, xe2x80x94SO2NR12, and xe2x80x94NR1SO2R1;
R19 is selected from the group consisting of hydrogen, hydroxy, halo, haloalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, carboxy, alkoxycarbonyl, xe2x80x94SO2NR12, and xe2x80x94NR1SO2R1;
and compounds of formula VI 
where
X is selected from xe2x80x94CHRXxe2x80x94and xe2x80x94CH2xe2x80x94CHRXxe2x80x94;
Axe2x80x94B is selected from the group consisting of xe2x80x94CHRXxe2x80x94CHRXxe2x80x94, xe2x80x94CRYxe2x95x90CRYxe2x80x94, xe2x80x94CHRYxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHRYxe2x80x94, xe2x80x94NR1xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NR1, xe2x80x94S(O)0-2xe2x80x94CHRXxe2x80x94, xe2x80x94CHRXxe2x80x94S(O)0-2xe2x80x94, xe2x80x94SO2xe2x80x94NR1xe2x80x94, xe2x80x94NR1xe2x80x94SO2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94CHRXxe2x80x94, xe2x80x94CHRXxe2x80x94C(xe2x95x90O), and cycloalkylene;
each RX 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 RY is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, carboxy, and alkoxycarbonyl;
each R1 is independently selected from the group consisting of hydrogen and lower alkyl;
R2 is selected from the group consisting of hydrogen, halo and hydroxy;
R5 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, alkoxy, amino, alkylcarbonylamino, alkylsulfonylamino, benzenesulfonylamino, toluenesulfonylamino, carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloaminocarbonyl, and alkoxycarbonyl;
R6 is selected from the group consisting of hydrogen, halo, and hydroxy;
R8, R9, R11, R12, R14, R15, R17, and R18 are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, methoxy, and ethoxy;
R16 is selected from the group consisting of hydrogen, hydroxy, halo, haloalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, carboxy, alkoxycarbonyl, xe2x80x94SO2NR12, and xe2x80x94NR1SO2R1;
and the pharmaceutically acceptable salts of all these compounds.
In a