Fgfr inhibitor for use in the treatment of hypophosphatemic disorders

Abstract

The present invention relates generally to 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl)-1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemia rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), tumor-induced osteomalacia, post-renal transplant hypophosphatemia, epidermal nevus syndrome, osteoglophonic dysplasia or McCune-Albright syndrome.

1 - 10 . (canceled) 
     
     
         11 . A method of treating a disease selected from the group comprising of X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), tumor-induced osteomalacia, post-renal transplant hypophosphatemia, epidermal nevus syndrome, osteoglophobic dysplasia and McCune-Albright syndrome with a therapeutically effective amount of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof. 
     
     
         12 . The method of  claim 11  wherein the disease is selected from the group comprising of X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR) and autosomal recessive hypophosphatemic rickets (ARHR). 
     
     
         13 . A method of increasing cortical bone volume or thickness when compared to a control or cortical bone volume or thickness before the beginning of the treatment with a therapeutically effective amount of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyramid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof. 
     
     
         14 . A method of inhibiting FGF23 expression in bone or inhibiting FGF23 activity in bone with a therapeutically effective amount of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof. 
     
     
         15 . The method according to  claim 11  wherein 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl]-1-methyl-urea is in the form of monophosphoric acid salt. 
     
     
         16 . The method according to  claim 11  wherein 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyramid-4-yl}-1-methyl-urea is in the form of a free base. 
     
     
         17 . The method of treatment according to  claim 11  further comprising a treatment that lasts at least 8 weeks and the dose is about 1-50 mg of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof. 
     
     
         18 . The method according to  claim 17  wherein the dose is about 0.5-100 mg, or about 1-50 mg, or about 1-25 mg, or about 1-10 mg. 
     
     
         19 . A Pharmaceutical composition comprising 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea for use according to  claim 14 , wherein the subject is human or a pharmaceutically acceptable salt, N-oxide or solvate thereof for use as defined in  claim 11 . 
     
     
         20 . The method according to  claim 11  wherein said 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof is in combination with another FGFR inhibitor, phosphate, calcium, osteopontin (OPN), parathyroid hormone or its analogue (PTH), vitamin D or vitamin D analogue. 
     
     
         21 . A Pharmaceutical composition comprising 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof for use as defined in  claim 11 . 
     
     
         22 . The Pharmaceutical composition of  claim 21  for oral administration, parenteral administration, or topical administration.