Combination of a 6-oxo-1,6-dihydro-pyridazine derivative having anti-cancer activity with an EGFR inhibitor

Abstract

A pharmaceutical composition of 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof in combination with N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

1 . A pharmaceutical composition or combination, comprising 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof and N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide. 
     
     
         2 . The pharmaceutical composition or combination according to  claim 1 , which comprises 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide. 
     
     
         3 - 9 . (canceled) 
     
     
         10 . The pharmaceutical composition or combination according to  claim 1 , wherein the 3 N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is present in an amount of 300 to 900 mg. 
     
     
         11 . The pharmaceutical composition or combination according to  claim 1 , wherein the 3 N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is present in an amount of 400 to 800 mg. 
     
     
         12 . The pharmaceutical composition or combination according to  claim 1 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof is present in an amount of 250 mg to 12500 mg. 
     
     
         13 . The pharmaceutical composition or combination according to  claim 1 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof is present in an amount of 800 mg to 8000 mg. 
     
     
         14 . The pharmaceutical composition or combination according to  claim 1 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof is present in an amount of 500 mg to 2000 mg. 
     
     
         15 . The pharmaceutical composition or combination according to  claim 2 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate is present in an amount of 250 mg to 12500 mg. 
     
     
         16 . The pharmaceutical composition or combination according to  claim 2 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate is present in an amount of 800 mg to 8000 mg. 
     
     
         17 . The pharmaceutical composition or combination according to  claim 2 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate is present in an amount of 500 mg to 2000 mg. 
     
     
         18 . The pharmaceutical composition or combination according to  claim 1 , which is in a form suitable for intravenous infusion. 
     
     
         19 . The pharmaceutical composition or combination according to  claim 2 , which is in a form suitable for intravenous infusion. 
     
     
         20 . The pharmaceutical composition or combination according to  claim 1 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof and the N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide are present in a synergistic amount. 
     
     
         21 . The pharmaceutical composition or combination according to  claim 2 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and the N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide are present in a synergistic amount. 
     
     
         22 . The pharmaceutical combination according to  claim 1 , which is in a kit comprising separate packages of the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof and of the N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide. 
     
     
         23 . The pharmaceutical combination according to  claim 22 , wherein the kit further comprises instructions to administer the contents of the kit to a subject for the treatment of a disease selected from the group consisting of cancer of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, and cancer, small cell lung cancer, non-small cell lung cancer, squamous cell cancer of the head and neck, and solid tumors and blood-borne tumors. 
     
     
         24 . The pharmaceutical combination according to  claim 1 , which is in a kit comprising separate packages of the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and of the N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide. 
     
     
         25 . The pharmaceutical combination according to  claim 24 , wherein the kit further comprises instructions to administer the contents of the kit to a subject for the treatment of a disease selected from the group consisting of cancer of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, and cancer, small cell lung cancer, non-small cell lung cancer, squamous cell cancer of the head and neck, and solid tumors and blood-borne tumors. 
     
     
         26 . The pharmaceutical composition according to  claim 1 , which comprises 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof and N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide. 
     
     
         27 . The pharmaceutical composition according to  claim 1 , which comprises 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.