Pharmaceutical compositions for preventing or treating inflammatory disease, autoimmune disease, or combination thereof, and method for using same

Abstract

Provided are a pharmaceutical composition for preventing or treating inflammatory disease, autoimmune disease, graft rejection responses, or combinations thereof, the pharmaceutical composition including a compound represented by Formula 1, or a stereoisomer, derivative, solvate, or pharmaceutically acceptable salt thereof, and a method using the pharmaceutical composition. The pharmaceutical composition and the method can be used to effectively prevent or treat inflammatory disease, autoimmune disease, graft rejection responses, or combinations thereof.

1 . A pharmaceutical composition for preventing or treating inflammatory disease, autoimmune disease, a graft rejection response, or combinations thereof, the pharmaceutical composition comprising a compound represented by Formula 1, or a stereoisomer, derivative, solvate, or pharmaceutically acceptable salt thereof. 
       
         
           
           
               
               
           
         
         wherein in Formula 1, 
         R 1  and R 2  form a 3 to 8-membered heterocyclic ring, together with nitrogen linked thereto, 
         n is an integer from 0 to 5, 
         when R 3  is one or more, R 3  are each independently selected from the group consisting of hydrogen, halogen, hydroxy, a C 1  to C 6  alkyl, a C 1  to C 6  alkoxy, a C 1  to C 6  alkylthio, amino, amide, sulfonamide, nitro, heteroaryl, cyano, sulfonic acid, and sulfamoyl, and 
         R 1 , R 2 , and R 3  are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxy, and a C 1  to C 6  alkyl. 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the heterocyclic ring is a 4-membered to 7-membered nitrogen-containing heterocyclic ring. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the heterocyclic ring is a 5-membered nitrogen-containing heterocyclic ring. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the heterocyclic ring is selected from the group consisting of pyrrolidine, azetidine, piperidine, morpholine, piperazine, azepanyl, and aziridine. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein n is an integer from 0 to 3, and
 when R 3  is one or more, R 3  are each independently selected from the group consisting of hydrogen, halogen, hydroxy, a C 1  to C 6  alkyl, a C 1  to C 6  alkoxy, and heteroaryl.   
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein R 3  is substituted with at least one selected from the group consisting of halogen, hydroxy, and a C 1  to C 6  alkyl. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula 1 is
 N1-piperidine-N5-(3-bromo)phenyl biguanide;   N1-piperidine-N5-phenyl biguanide;   N1-piperidine-N5-(3-methyl)phenyl biguanide;   N1-piperidine-N5-(3-ethyl)phenyl biguanide;   N1-piperidine-N5-(3-hydroxy)phenyl biguanide;   N1-piperidine-N5-(3-hydroxymethyl)phenyl biguanide;   N1-piperidine-N5-(3-methoxy)phenyl biguanide;   N1-piperidine-N5-(4-fluoro)phenyl biguanide;   N1-piperidine-N5-(2-fluoro)phenyl biguanide;   N1-piperidine-N5-(3-fluoro)phenyl biguanide;   N1-pyrrolidine-N5-(4-chloro)phenyl biguanide;   N1-piperidine-N5-(4-chloro)phenyl biguanide;   N1-pyrrolidine-N5-(3-chloro)phenyl biguanide;   N1-piperidine-N5-(3-chloro)phenyl biguanide;   N1-azepan-N5-(3-chloro)phenyl biguanide;   N1-morpholine-N5-(3-bromo)phenyl biguanide;   N1-pyrrolidine-N5-(3-trifluoromethyl)phenyl biguanide;   N1-piperidine-N5-(3-trifluoromethyl)phenyl biguanide;   N1-azetidine-N5-(4-trifluoromethyl)phenyl biguanide;   N1-pyrrolidine-N5-(4-trifluoromethyl)phenyl biguanide;   N1-piperidine-N5-(4-trifluoromethyl)phenyl biguanide;   N1-pyrrolidine-N5-(3-trifluoromethoxy)phenyl biguanide;   N1-piperidine-N5-(3-trifluoromethoxy)phenyl biguanide;   N1-piperidine-N5-(3-difluoromethoxy)phenyl biguanide;   N1-azetidine-N5-(4-trifluoromethoxy)phenyl biguanide;   N1-pyrrolidine-N5-(4-trifluoromethoxy)phenyl biguanide;   N1-piperidine-N5-(4-trifluoromethoxy)phenyl biguanide;   N1-morpholine-N5-(4-trifluoromethoxy)phenyl biguanide;   N1-(4-methyl)piperazine-N5-(4-trifluoromethoxy)phenyl biguanide;   N1-piperidine-N5-(3-amino)phenyl biguanide;   N1-piperidine-N5-(4-dimethylamino)phenyl biguanide;   N1-piperidine-N5-(4-acetamide)phenyl biguanide;   N1-piperidine-N5-(3-acetamide)phenyl biguanide;   N1-piperidine-N5-(4-(1H-tetrazole-5-yl))phenyl biguanide;   N1-piperidine-N5-(3-methylsulfonamide)phenyl biguanide;   N1-piperidine-N5-(4-sulfonic acid)phenyl biguanide;   N1-piperidine-N5-(4-methylthio)phenyl biguanide;   N1-piperidine-N5-(4-sulfamoyl)phenyl biguanide;   N1-piperidine-N5-(3,5-dimethoxy)phenyl biguanide;   N1-piperidine-N5-(4-fluoro-3-trifluoromethyl)phenyl biguanide;   N1-piperidine-N5-(4-chloro-3-trifluoromethyl)phenyl biguanide;   N1-pyrrolidine-N5-(3-fluoro-4-trifluoromethyl)phenyl biguanide;   N1-piperidine-N5-(3-fluoro-4-trifluoromethyl)phenyl biguanide;   N1-piperidine-N5-(4-fluoro-3-trifluoromethoxy)phenyl biguanide;   N1-piperidine-N5-(4-chloro-3-trifluoromethoxy)phenyl biguanide;   N1-azetidine-N5-(3-fluoro-4-trifluoromethoxy)phenyl biguanide;   N1-pyrrolidine-N5-(3-fluoro-4-trifluoromethoxy)phenyl biguanide;   N1-piperidine-N5-(3-fluoro-4-trifluoromethoxy)phenyl biguanide;   N1-azetidine-N5-(3-chloro-4-trifluoromethoxy)phenyl biguanide;   N1-pyrrolidine-N5-(3-chloro-4-trifluoromethoxy)phenyl biguanide;   N1-piperidine-N5-(3-chloro-4-trifluoromethoxy)phenyl biguanide;   N1-piperidine-N5-(2,4-difluoro)phenyl biguanide;   N1-piperidine-N5-(3,4-difluoro)phenyl biguanide;   N1-piperidine-N5-(3,5-difluoro)phenyl biguanide;   N1-piperidine-N5-(3,5-dichloro)phenyl biguanide;   N1-piperidine-N5-(2,4-dichloro)phenyl biguanide;   N1-pyrrolidine-N5-(3,4-dichloro)phenyl biguanide;   N1-piperidine-N5-(3,4-dichloro)phenyl biguanide;   N1-piperidine-N5-(3-chloro-5-trifluoromethoxy)phenyl biguanide;   N1-pyrrolidine-N5-(3-bromo-5-trifluoromethoxy)phenyl biguanide;   N1-piperidine-N5-(3-bromo-5-trifluoromethoxy)phenyl biguanide;   N1-piperidine-N5-(3,4,5-trifluoro)phenyl biguanide; or   N1-piperidine-N5-(2,4,6-trifluoro)phenyl biguanide.   
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula 1 is
 N1-pyrrolidine-N5-(4-trifluoromethoxy)phenyl biguanide, N1-pyrrolidine-N5-(4-trifluoromethyl)phenyl biguanide, N1-piperidine-N5-(4-fluoro)phenyl biguanide, N1-piperidine-N5-(4-(1H-tetrazole-5-yl))phenyl biguanide, N1-pyrrolidine-N5-(3,4-dichloro)phenyl biguanide, or N1-piperidine-N5-(3,5-dimethoxy)phenyl biguanide.   
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable salt is acetate or hydrochloride. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the inflammatory disease is selected from the group consisting of sepsis, gastritis, enteritis, nephritis, hepatitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, hypersensitivity colorectal syndrome, inflammatory pain, migraine, headaches, back pain, fibromyalgia, fascial disease, viral infection, bacterial infection, fungal infection, burns, wounds due to surgical or dental surgery, prostaglandin excessive syndrome, atherosclerosis, gout, Hodgkin's disease, pancreatitis, conjunctivitis, iritis, sclerotitis, uveitis, and eczema. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the autoimmune disease is selected from the group consisting of hemophagocytic lymphohistiocytosis, systemic lupus erythematosus, Kikuchi disease, vasculitis, adult onset Still's disease, rheumatoid arthritis, inflammatory myositis, Behcet disease, IgG4-related disease, Sjogren syndrome, giant cell arteritis, temporal arteritis, Type 1 diabetes, atopic dermatitis, Crohn's disease, systemic sclerosis, psoriasis, multiple sclerosis, and Graves hyperthyroidism. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula 1, and the stereoisomer, derivative, solvate, or pharmaceutically acceptable salt thereof inhibit the differentiation or proliferation of a memory T cell. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the memory T cell is a central memory T cell (T CM ) or an effector memory T cell (T EM ). 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula 1, and the stereoisomer, derivative, solvate, or pharmaceutically acceptable salt thereof promote the differentiation or proliferation of the effector T cell (T EFF ). 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition further comprises an immunosuppressive agent. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the immunosuppressive drug is rapamycin. 
     
     
         17 . The pharmaceutical composition of  claim 15 , wherein the pharmaceutical composition is a single composition or separate compositions. 
     
     
         18 . A method of preventing or treating inflammatory disease, autoimmune disease, graft rejection responses, or combinations thereof, the method including administering, to a subject, the compound of  claim 1 , or a stereoisomer, derivative, solvate, or pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 18 , wherein the subject is suffering from, or at risk of, inflammatory disease, autoimmune disease, graft rejection responses or combinations thereof.