Preventing airway mucus production by administration of egf-r antagonists

A pharmaceutical formulation for treatment of airway mucus hypersecretion, comprising:

• an epidermal growth factor receptor (EGF-R) antagonist in an amount effective to reduce airway mucus hypersecretion;
• and
• a flowable formulation suitable for delivery by inhalation,
• wherein said EGF-R antagonist is a tyrosine kinase inhibitor of the formula:
• and pharmaceutically acceptable salts and prodrugs thereof,
• wherein m is 1, 2, or 3;
• each R1 is independently selected from hydrogen, halo, hydroxy, amino, hydroxyamino, carboxy, (C1-C4)alkoxycarbonyl, nitro, guanidino, ureido, carbamoyl, cyano, trifluoromethyl, (R6)2N-carbonyl, and phenyl-W-alkyl wherein W is selected from a single bond, O, S and NH;
• or each R1 is independently selected from cyano-(C1-C4)-alkyl and R9 wherein R9 is selected from the group consisting of R5, R50, (R6)2N, R7C(═O), R5ONH, A and R5Y;
• wherein R5 is (C1-C4)alkyl;
• R6 is hydrogen or R5 wherein the R5s are the same or different;
• R7 is R5, R5O or (R6)2N;
• A is selected from piperidino-, morpholino, pyrrolidino and 4-R6-piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, carboxy-(C1-C4)-alkyl, phenoxy, phenyl, phenylsulfanyl, (C2-C4)-alkenyl, (R6)2—N-carbonyl-(C1-C4)-alkyl;
• and Y is selected from S, SO, SO;
• the alkyl moieties in R5, R5O and (R6)2N are optionally substituted with halo or R9 wherein R9 is defined as above and wherein the resulting groups are optionally substituted with halo or R9 with the proviso that a nitrogen, oxygen or sulfur atom and another heteroatom can not be attached to the same carbon atom, and with the further proviso that no more than three “R9” units may comprise R1;
• or each R1 is independently selected from R5-sulfonylamino, phthalimido-(C1-C4)-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10—(C2-C4)-alkanoylamino wherein R10 is selected from halo, R6O, (C2-C4)-alkanoyloxy, R7C(═O), and (R6)2N;
• and wherein said benzamido or benzenesulfonylamino or phenyl or phenoxy or anilino or phenylsulfanyl substituent in R1 may optionally bear one or two halogens, (C1-C4)alkyl, cyano, methanesulfonyl or (C1-C4)-alkoxy substituents;
• or any two R's taken together with the carbons to which they are attached comprise a 5-8 membered ring comprising at least one or two heteroatoms selected from oxygen, sulfur or nitrogen;
• and wherein the alkyl groups and alkyl portions of the alkoxy or alkylamino groups may be straight chained or if comprised of at least three carbons may be branched or cyclic;
• R2 is selected from hydrogen and optionally substituted (C1-C6)-alkyl;
• n is 1 or 2 and each R3 is independently selected from hydrogen, optionally substituted (C1-C6)-alkyl, optionally substituted amino, halo, hydroxyl, optionally substituted hydroxyl;
• R4 is azido or R11-ethynyl wherein R11 is selected from hydrogen, optionally substituted (C1-C6)-alkyl wherein the substituents are selected from hydrogen, amino, hydroxy, R5O, R5NH, and (R5)2N.