Isoquinolinyl triazolone complexes

Abstract

a stereoisomer thereof, or a tautomer of the compound of Formula 1 or stereoisomer thereof, and a cyclodextrin, in which the complex is an amorphous solid. This disclosure also relates to materials and methods for preparing the complex, to pharmaceutical compositions which contain the complex, and to the use of the complex to treat Type I hypersensitivity reactions, autoimmune diseases, inflammatory disorders, cancer, non-malignant proliferative disorders, and other conditions associated with BTK.

1 . A complex comprising a compound of Formula 1, 
       
         
           
           
               
               
           
         
         a stereoisomer thereof or a tautomer of the compound of Formula 1 or stereoisomer thereof, and a cyclodextrin, wherein the complex is an amorphous solid. 
       
     
     
         2 . The complex according to  claim 1 , wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one or a tautomer thereof. 
     
     
         3 . The complex according to  claim 1 , wherein the compound is (R)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one or a tautomer thereof. 
     
     
         4 . The complex according to  claim 1 , wherein the cyclodextrin is an unmodified β-cyclodextrin or a β-cyclodextrin derivative. 
     
     
         5 . The complex according to  claim 1 , wherein the cyclodextrin is a cyclodextrin derivative. 
     
     
         6 . The complex according to  claim 1 , wherein the cyclodextrin is selected from unmodified α-cyclodextrin, unmodified β-cyclodextrin, unmodified γ-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, trimethyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, randomly dimethylated-β-cyclodextrin, ethyl-β-cyclodextrin, diethyl-β-cyclodextrin, triethyl-β-cyclodextrin, (2-hydroxyethyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-γ-cyclodextrin, (β-hydroxypropyl)-β-cyclodextrin, (2,3-dihydroxypropyl)-β-cyclodextrin, (2-hydroxyisobutyl)-β-cyclodextrin, carboxymethyl-β-cyclodextrin, carboxymethyl ethyl-β-cyclodextrin, tributyryl-β-cyclodextrin, trivaleryl-β-cyclodextrin, dihexanoyl-β-cyclodextrin, sulfobutylether β-cyclodextrin, glucosyl-β-cyclodextrin, and maltosyl-β-cyclodextrin. 
     
     
         7 . The complex according to  claim 1 , wherein the cyclodextrin is selected from unmodified β-cyclodextrin, methyl-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-γ-cyclodextrin, and sulfobutylether β-cyclodextrin. 
     
     
         8 . The complex according to  claim 1 , wherein the cyclodextrin is a sulfobutylether-β-cyclodextrin or a (2-hydroxypropyl)-β-cyclodextrin. 
     
     
         9 . The complex according to  claim 1 , wherein the cyclodextrin is a sulfobutylether-β-cyclodextrin. 
     
     
         10 . The complex according to  claim 1 , wherein the cyclodextrin and the compound of Formula 1, stereoisomer or tautomer are present in a molar ratio of about 1:1 to about 10:1. 
     
     
         11 . The complex according to  claim 1 , wherein the cyclodextrin and the compound of Formula 1, stereoisomer or tautomer are present in a molar ratio of about 1:1 to about 5:1. 
     
     
         12 . The complex according to  claim 1 , wherein the cyclodextrin and the compound of Formula 1, stereoisomer or tautomer are present in a molar ratio of about 1:1. 
     
     
         13 . A pharmaceutical composition comprising a complex as defined in  claim 1 ; and a pharmaceutically acceptable excipient. 
     
     
         14 . A method of making a complex comprising the compound of Formula 1, 
       
         
           
           
               
               
           
         
         a stereoisomer thereof or a tautomer of the compound of Formula 1 or stereoisomer thereof, and a cyclodextrin, wherein the complex is an amorphous solid, the method comprising:
 atomizing a liquid solution into droplets, the liquid solution comprising the compound, stereoisomer, or tautomer of Formula 1, a cyclodextrin derivative, and water; and 
 removing at least a portion of the water from the droplets to form the complex. 
 
       
     
     
         15 . The method according to  claim 14 , wherein the liquid solution was obtained by dissolving the compound, stereoisomer or tautomer in water having a pH of about 12 or greater. 
     
     
         16 . The method according to  claim 15 , wherein the liquid solution was obtained by dissolving the compound, stereoisomer or tautomer in water having a pH of about 13 or greater. 
     
     
         17 . The method according to  claim 14 , wherein the pH of the liquid solution was adjusted to a pH of about 7 before atomizing the liquid solution into droplets. 
     
     
         18 . A complex as defined in  claim 1  for use as a medicament. 
     
     
         19 . A method for inhibiting BTK in a subject, the method comprising administering to the subject a complex as defined in  claim 1 . 
     
     
         20 . A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a complex as defined in  claim 1 , wherein the disease, disorder or condition is associated with BTK. 
     
     
         21 . A The method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a complex as defined in  claim 1 , wherein the disease, disorder or condition is selected from Type I hypersensitivity reactions, autoimmune diseases, inflammatory disorders, cancer, and non-malignant proliferative disorders. 
     
     
         22 . A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a complex as defined in  claim 1 , wherein the disease, disorder or condition is selected from allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstructive pulmonary disease, Sjögren's syndrome, ankylosing spondylitis, Behcet's disease, graft versus host disease, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, and thrombosis. 
     
     
         23 . A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a complex as defined in  claim 1 , wherein the disease, disorder or condition is selected from B-cell lymphoma, chronic lymphocytic leukemia, and multiple myeloma. 
     
     
         24 . A combination comprising an effective amount of a complex as defined in  claim 1 , and at least one additional pharmacologically active agent. 
     
     
         25 . The combination according to  claim 24 , wherein the additional pharmacologically active agent is a disease modifying antirheumatic drug (DMARD). 
     
     
         26 . The combination according to  claim 25 , wherein the DMARD is methotrexate.