Combination

A method of treating a patient suffering from a disease or condition which responds to dual EGFR and VEGF protein tyrosine kinase inhibition and either aromatase inhibition or inhibition of estrogen action comprising administering to the patient an effective amount of a dual EGFR and VEGF protein tyrosine kinase inhibitor of formula (I)

• wherein
• R1 and R2 are, each independently of the other hydrogen, unsubstituted or substituted alkyl or cycloalkyl, a heterocyclic radical bonded via a ring carbon atom, or a radical of the formula R4—Y—(C=Z)-,
• wherein
• R4 is unsubstituted, mono- or disubstituted amino or a heterocyclic radical;
• Y is either not present or lower alkyl;
• and
• Z is oxygen, sulfur or imino, with the proviso that R1 and R2 are not both hydrogen, or
• R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclic radical;
• R3 is a heterocyclic radical or an unsubstituted or substituted aromatic radical;
• G is C1-C7alkylene, —C(═O)— or C1-C6alkylene-C(═O)—, wherein the carbonyl group is attached to the NR1R2 moiety;
• Q is —NH— or —O—, with the proviso that Q is —O— if G is —C(═O)— or C1-C6-alkylene-C(═O)—;
• and
• X is either not present or C1-C7-alkylene, with the proviso that a heterocyclic radical R3 is bonded via a ring carbon atom if X is not present;
• or a pharmaceutically acceptable salt thereof or any hydrate thereof and an effective amount of either an aromatase inhibitor or estrogen receptor antagonist.

A package comprising a dual EGFR and VEGF protein tyrosine kinase inhibitor of formula (I)

• wherein
• R1 and R2 are, each independently of the other hydrogen, unsubstituted or substituted alkyl or cycloalkyl, a heterocyclic radical bonded via a ring carbon atom, or a radical of the formula R4—Y—(C=Z)-,
• wherein
• R4 is unsubstituted, mono- or disubstituted amino or a heterocyclic radical;
• Y is either not present or lower alkyl;
• and
• Z is oxygen, sulfur or imino, with the proviso that R1 and R2 are not both hydrogen, or
• R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclic radical;
• R3 is a heterocyclic radical or an unsubstituted or substituted aromatic radical;
• G is C1-C7alkylene, —C(═O)— or C1-C6alkylene-C(═O)—, wherein the carbonyl group is attached to the NR1R2 moiety;
• Q is —NH— or —O—, with the proviso that Q is —O— if G is —C(═O)— or C1-C6-alkylene-C(═O)—;
• and
• X is either not present or C1-C7-alkylene, with the proviso that a heterocyclic radical R3 is bonded via a ring-carbon atom if X is not present;
• or a pharmaceutically acceptable salt thereof or any hydrate thereof together with instructions for use in combination with either an aromatase inhibitor or estrogen receptor antagonist for treatment of a disease or condition which responds to dual EGFR and VEGF protein tyrosine kinase inhibition and either aromatase inhibition or inhibition of estrogen action.

A method of reducing cell proliferation in hormone receptor positive cells comprising administering to said patient an effective amount of a dual EGFR and VEGF protein tyrosine kinase inhibitor of formula (I)

• wherein
• R and R0, independently of one another, are each hydrogen or lower alkyl, or
• R and R0 at adjacent carbon atoms, together with the benzene ring to which they are bonded, form a naphthalene or tetrahydronaphthalene ring;
• R1 is hydrogen, lower alkyl, aryl, aryl-lower alkyl or lower alkenyl;
• R2 is hydrogen, lower alkyl, aryl, aryl-lower alkyl, (lower alkyl, aryl or aryl-lower alkyl)-thio or lower alkenyl, or
• R1 and R2, together, are lower alkylidene or C4-C6alkylene;
• W is 1-imidazolyl, 1-(1,2,4 or 1,3,4)-triazolyl, 3-pyridyl or one of the mentioned heterocyclic radicals substituted by lower alkyl and aryl within the context of the above definitions has the following meanings:
• phenyl that is unsubstituted or substituted by one or two substituents from the group lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, nitro, amino, halogen, trifluoromethyl, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, lower alkanoyl, benzoyl, lower alkylsulfonyl, sulfamoyl, N-lower alkylsulfamoyl and N,N-di-lower alkylsulfamoyl;
• also thienyl, indolyl, pyridyl or furyl, or one of the four last-mentioned heterocyclic radicals monosubstituted by lower alkyl, lower alkoxy, cyano or by halogen;
• or a pharmaceutically acceptable salt thereof and an effective amount of either an aromatase inhibitor or an estrogen receptor antagonist.