US2019343836A1PendingUtilityA1

Pharmaceutical combination comprising an alk inhibitor and a shp2 inhibitor

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Assignee: NOVARTIS AGPriority: Jan 10, 2017Filed: Jan 8, 2018Published: Nov 14, 2019
Est. expiryJan 10, 2037(~10.5 yrs left)· nominal 20-yr term from priority
Inventors:Leila Dardaei AlghalandisJeffrey EngelmanHuaixiang HaoMatthew J. LamarcheFang LiHui-Qin Wang
A61P 35/00A61P 35/02A61P 43/00A61K 31/53A61K 31/506A61K 31/5377A61K 31/4545A61K 31/519A61K 31/497A61K 31/513A61K 31/5375A61K 45/06A61K 31/4353A61K 31/4439A61K 31/675A61K 31/4985A61K 2300/00
42
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Claims

Abstract

A pharmaceutical combination comprising an ALK inhibitor, in free form or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor, in free form or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, for simultaneous or sequential administration; the uses of such combination in the treatment of proliferative diseases; and methods of treating a subject suffering from a proliferative disease comprising administering a therapeutically effective amount of such combination.

Claims

exact text as granted — not AI-modified
1 . A pharmaceutical combination comprising:
 (i) an ALK inhibitor or a pharmaceutically acceptable salt thereof, and   (ii) a SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.   
     
     
         2 . The pharmaceutical combination of  claim 1 , further comprising at least one pharmaceutically acceptable carrier. 
     
     
         3 . A pharmaceutical composition comprising a pharmaceutical combination of  claim 1  and at least one pharmaceutically acceptable carrier. 
     
     
         4 . The pharmaceutical combination of  claim 1 , wherein the ALK inhibitor or pharmaceutically acceptable salt thereof and the SHP2 inhibitor or pharmaceutically acceptable salt thereof are provided in jointly therapeutically effective amounts for use in the treatment of cancer. 
     
     
         5 . The pharmaceutical combination of  claim 4 , wherein the ALK inhibitor or pharmaceutically acceptable salt thereof and the SHP2 inhibitor or pharmaceutically acceptable salt thereof are provided in synergistically effective amounts for use in the treatment of cancer. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The pharmaceutical combination  claim 4 , wherein the cancer is an ALK-positive cancer selected from anaplastic large-cell lymphoma, gastric cancer, breast cancers, oesophageal cancer, colorectal cancer, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer, pancreatic cancer and lung cancer. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The pharmaceutical combination of  claim 4 , wherein the cancer is an ALK-positive cancer resistant to an ALK inhibitor. 
     
     
         12 . (canceled) 
     
     
         13 . The pharmaceutical combination of  claim 4 , wherein the cancer is an ALK-positive cancer characterized by ALK-independent resistance to an ALK inhibitor. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . A method of treating a cancer in a subject, comprising administering to said subject a therapeutically effective amount of:
 (i) an ALK inhibitor or a pharmaceutically acceptable salt thereof, and   (ii) a SHP2 inhibitor or a pharmaceutically acceptable salt thereof.   
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 17 , wherein the cancer is an ALK-positive cancer selected from anaplastic large-cell lymphoma, gastric cancer, breast cancers, oesophageal cancer, colorectal cancer, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer, pancreatic cancer and lung cancer. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . The pharmaceutical combination of  claim 1 , wherein the ALK inhibitor is selected from 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine (ceritinib), (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (lorlatinib; PF-06463922), 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         26 . The pharmaceutical combination of  claim 1 , wherein the ALK inhibitor is 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine (ceritinib). 
     
     
         27 . The pharmaceutical combination of  claim 1 , wherein the SHP2 inhibitor is selected from:
 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine;   6-(4-(aminomethyl)-4-phenylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine;   6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine;   6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-3-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-amine;   (R)-8-(6-amino-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine;   (R)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine;   (3S,4S)-8-(6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine;   3-(2,3-dichlorophenyl)-6-(1,8-diazaspiro[4.5]decan-8-yl)pyrazin-2-amine;   (R)-8-(6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine;   (S)-8-(6-amino-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine;   (S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine;   (1R,3R)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine;   (2S,4R)-4-amino-8-(6-amino-5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-2-ol;   (2R,4R)-4-amino-8-(6-amino-5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-2-ol;   (1R)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-methyl-8-azaspiro[4.5]decan-1-amine;   (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine;   (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-y)thio)pyrazin-2-yl)-3-ethyl-2-oxa-8-azaspiro[4.5]decan-4-amine;   (2R,4R)-4-amino-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-2-ol;   (1R,3R)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine;   (1R)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-methyl-8-azaspiro[4.5]decan-1-amine;   (3S,4S)-8-(5-((6-amino-2,3-dichloropyridin-4-y)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine;   (3S,4S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine;   (R)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine;   (S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine;   6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-y)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one;   6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-y)-5-((3-chloro-2-methylpyridin-4-yl)thio)-3-methylpyrimidin-4(3H)-one;   6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-y)-5-((2,3-dichlorophenyl)thio)-3-methylpyrimidin-4(3-)-one;   6-amino-2-((1R,3R)-1-amino-3-methyl-8-azaspiro[4.5]decan-8-y)-3-methyl-5-((3-(trifluoromethyl)pyridin-4-yl)thio)pyrimidin-4(3H)-one;   6-amino-2-((1R,3R)-1-amino-3-methyl-8-azaspiro[4.5]decan-8-y)-5-(2,3-dichlorophenyl)-3-methylpyrimidin-4(31-)-one;   6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-y)-5-((2-chloro-3-methoxyphenyl)thio)-3-methylpyrimidin-4(31-)-one;   6-amino-2-((3S,4S)-4-amino-3-ethyl-2-oxa-8-azaspiro[4.5]decan-8-y)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one;   6-amino-5-((3-amino-2-(trifluoromethyl)phenyl)thio)-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4 0.5]decan-8-yl)-3-methylpyrimidin-4(3H)-one;   (R)-6-amino-2-(1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl)-5-((2-amino-3-chloropyridin-4-yl)thio)-3-methylpyrimidin-4(31-)-one;   6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-y)-3-methyl-5-((3-(trifluoromethyl)pyridin-4-yl)thio)pyrimidin-4(3H)-one;   6-amino-2-((1R,3R)-1-amino-3-methyl-8-azaspiro[4.5]decan-8-y)-5-(4-chlorophenyl)-3-methylpyrimidin-4(31-)-one;   6-amino-2-((1R,3R)-1-amino-3-methyl-8-azaspiro[4.5]decan-8-y)-3-methyl-5-phenylpyrimidin-4(31-)-one;   (R)-6-(1-amino-8-azaspiro[4.5]decan-8-y)-3-(2,3-dichlorophenyl)-5-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;   2-(4-(aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;   (3S,4S)-8-(3-(2,3-dichloropyridin-4-y)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine;   3-(6-amino-2-methylpyridin-3-y)-6-((1R,3R)-1-amino-3-methyl-8-azaspiro[4.5]decan-8-yl)-5-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;   (R)-3-(6-amino-2-methylpyridin-3-yl)-6-(1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl)-5-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;   6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(3-chloro-2-(cyclopropylamino)pyridin-4-yl)-5-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;   2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(3-chloro-2-methoxypyridin-4-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;   N-(3-((3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;   N-(3-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;   N-(3-((3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-4-hydroxy-2-oxo-1-phenyl-2,5-dihydro-1H-pyrrole-3-carboxamide;   (R)-N-(3-((3-amino-5-(1-amino-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;   N-(3-((3-amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;   (R)-N-(3-((3-amino-5-(1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;   N-(3-((3-amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;   N-(3-((3-amino-5-(4-amino-4-(fluoromethyl)piperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;   N-(3-((3-amino-5-(4-amino-4-(fluoromethyl)piperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;   (S)-N-(3-((3-amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide, and   N-(3-((3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-5-benzyl-4-hydroxy-1-methyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide.

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