Synergistic pharmaceutical combination for the treatment of squamous cell carcinoma of head and neck

Abstract

The present invention relates to a pharmaceutical combination for use in the treatment of squamous cell carcinoma, comprising a CDK inhibitor selected from the compounds of formula (I); or a pharmaceutically acceptable salt thereof and one or more antineoplastic agents selected from sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or cetuximab or a pharmaceutically acceptable salt thereof. The said pharmaceutical combination exhibits synergy when used in the treatment of squamous cell carcinoma of head and neck (SCCHN). The invention also relates to a pharmaceutical composition comprising the said combination and a method for the treatment of squamous cell carcinoma of head and neck (SCCHN), using a therapeutically effective amount of said combination.

1 . A pharmaceutical combination for use in the treatment of squamous cell carcinoma of head and neck, wherein said pharmaceutical combination comprises a CDK inhibitor selected from the compounds of formula I; 
       
         
           
           
               
               
           
         
         wherein Ar is a phenyl group, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from: halogen; nitro, cyano, C 1 -C 4 -alkyl, trifluoromethyl, hydroxyl or C 1 -C 4 -alkoxy; or a pharmaceutically acceptable salt or solvate thereof; and one or more antineoplastic agents selected from sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or cetuximab. 
       
     
     
         2 . The pharmaceutical combination for the use according to  claim 1 , wherein in the compound of formula I the phenyl group is substituted by 1, 2, or 3 identical or different substituents selected from: chlorine, bromine, fluorine or iodine, C1-C4-alkyl or trifluoromethyl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         3 . The pharmaceutical combination for the use according to  claim 2 , wherein in the compound of formula I the phenyl group is substituted by chlorine. 
     
     
         4 . The pharmaceutical combination for the use according to  claim 3 , wherein the compound of formula I is (+)-trans-2-(2-chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxy-methyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (Compound A). 
     
     
         5 . The pharmaceutical combination for the use according to  claim 2 , wherein in the compound of formula I the phenyl group is a substituted group substituted by 2 different substituents selected from chlorine and trifluoromethyl. 
     
     
         6 . The pharmaceutical combination for the use according to  claim 5 , wherein the compound of formula I is (+)-trans-3-[2[(2-chloro-4-trifluoromethyl-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (Compound B). 
     
     
         7 . The pharmaceutical combination for the use according to  claim 1 , wherein said antineoplastic agent is sorafenib. 
     
     
         8 . The pharmaceutical combination for the use according to  claim 1 , wherein said antineoplastic agent is lapatinib. 
     
     
         9 . The pharmaceutical combination for the use according to  claim 1 , wherein said antineoplastic agent is erlotinib. 
     
     
         10 . The pharmaceutical combination for the use according to  claim 1 , wherein said antineoplastic agents are cisplatin and 5-fluorouracil. 
     
     
         11 . The pharmaceutical combination for the use according to  claim 1 , wherein said pharmaceutical combination further comprising radiation. 
     
     
         12 . A pharmaceutical composition comprising a CDK inhibitor selected from the compounds of formula I or a pharmaceutically acceptable salt or solvate thereof and one or more antineoplastic agents selected from one or more of sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or cetuximab or pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier for the treatment of squamous cell carcinoma of head and neck. 
     
     
         13 . A method for the treatment of squamous cell carcinoma of head and neck in a subject comprising administering to said subject a therapeutically effective amount of a CDK inhibitor selected from the compounds of formula I; 
       
         
           
           
               
               
           
         
         wherein Ar is a phenyl group, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from: halogen, nitro, cyano, C1-C4-alkyl, trifluoromethyl, hydroxyl or C1-C4-alkoxy; or a pharmaceutically acceptable salt or solvate thereof; in combination with a therapeutically effective amount of one or more antineoplastic agents selected from sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or cetuximab. 
       
     
     
         14 . The method according to  claim 13 , wherein the compound of formula I is (+)-trans-2-(2-chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxy-methyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (Compound A). 
     
     
         15 . The method according to  claim 13 , wherein the compound of formula I is (+)-trans-3-[2[(2-chloro-4-trifluoromethyl-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (Compound B). 
     
     
         16 - 20 . (canceled) 
     
     
         21 . A pharmaceutical composition according to  claim 12  wherein a compound of formula I is (+)-trans-3-[2[(2-chloro-4-trifluoromethyl-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (Compound B). 
     
     
         22 . A pharmaceutical composition according to  claim 12  comprising (+)-trans-3-[2[(2-chloro-4-trifluoromethyl-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride (Compound B) and one or more antineoplastic agents selected from one or more of sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or cetuximab or pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier for the treatment of squamous cell carcinoma of head and neck.