Method for treating macrophage migration inhibitory factor (mif)-implicated diseases and conditions with iodo pyrimidine derivatives

Abstract

Compounds useful for the inhibition of macrophage migration inhibitory factor (MIF) are provided herein, having the Formula I: wherein A is selected from the group consisting of aromatic or non-aromatic rings, bicyclic rings, polycyclic rings, alkenes or alkynes; B is H, OH, OR, SR, NH 2 , NHR, or alkyl; R is H or alkyl, and X and Y are independently N or CH, but one of X and Y must be N. Also provided are pharmaceutical compositions that contain a Formula I compound and methods for the treatment of MIF-implicated diseases or conditions that include administering a safe and effective amount of a Formula I compound.

What is claimed is: 
     
         1 . A method for treating a macrophage migration inhibitory factor (MIF)-implicated disease or condition, comprising administering to a patient in need thereof a safe and effective amount of a migration inhibitory factor (MIF) inhibitory compound or its enantiomeric or diastereomeric form or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, said compound having the formula: 
       
         
           
           
               
               
           
         
         wherein:
 (i) A is selected from the group consisting of:
 (a) substituted or unsubstituted 5, 6, or 7-membered aromatic or nonaromatic rings having 0 or 1 to 4 heteroatoms selected from the group consisting of N, O, S, and combinations thereof; 
 (b) substituted or unsubstituted bicyclic ring; 
 (c) substituted or unsubstituted polycyclic rings; and 
 (d) substituted or unsubstituted alkenes and alkynes having 2 to 10 carbon atoms with 1 to 3 double or triple bonds; and 
 
  B is H, OH, OR, SR, NH 2 , NHR, or alkyl or substituted alkyl, wherein R is H, alkyl, or substituted alkyl of 2 to 20 carbon atoms; or 
 (ii) A is H or halo; and 
  B is selected from the group consisting of:
 (a) substituted or unsubstituted 5, 6, or 7-membered aromatic or nonaromatic rings having 0 or 1 to 4 heteroatoms selected from the group consisting of N, O, S, and combinations thereof; 
 (b) substituted or unsubstituted bicyclic ring; 
 (c) substituted or unsubstituted polycyclic rings; and 
 (d) substituted or unsubstituted alkenes and alkynes having 2 to 10 carbon atoms with 1 to 3 double or triple bonds; and 
 
 X and Y are independently N or CH, wherein at least one of X and Y is N. 
 
       
     
     
         2 . The method of  claim 1 , wherein the MIF-implicated disease is selected from the group consisting of inflammatory disease and cancer. 
     
     
         3 . The method of  claim 2 , wherein the inflammatory disease is selected from the group consisting of dermatitis, arthritis, rheumatoid arthritis, insulin-dependent diabetes, proliferative vascular disease, acute respiratory distress syndrome, sepsis, septic shock, psoriasis, asthma, cytokine related toxicity, lupus, multiple sclerosis, transplant-host response, and autoimmune disorders. 
     
     
         4 . The method of  claim 1 , wherein the MIF-implicated condition is caused by a MIF-producing pathogen. 
     
     
         5 . The method of  claim 4 , wherein the MIF-producing pathogen is selected from the group consisting of parasitic helminths, spirochetes, and plasmodium. 
     
     
         6 . The method of  claim 1 , wherein the MIF inhibitory compound is selected from the group consisting of:
 4-Iodo-6-(2,3-difluoro-4-methoxyphenyl)pyrimidine;   4-Iodo-6-(2-fluoro-4-methoxyphenyl)pyrimidine;   4-Iodo-6-(2-fluorophenyl)pyrimidine;   4-Iodo-6-(4-fluorophenyl)pyrimidine;   4-Iodo-6-(furan-3-yl)pyrimidine;   4-Iodo-6-(pyridin-3-yl)pyrimidine;   4-Iodo-6-(3-fluorophenyl)pyrimidine;   4-Iodo-6-(4-tert-butyloxymethylphenyl)pyrimidine;   4-Iodo-6-(2-fluoropyridin-3-yl)pyrimidine;   4-Iodo-6-(furan-2-yl)pyrimidine;   4-Iodo-6-(4-fluoropyrimidin-3-yl)pyrimidine;   4-Iodo-6-(3-fluoro-4-methoxyphenyl)pyrimidine;   4-Iodo-6-(2-chloropyridin-5-yl)pyrimidine;   4-Iodo-6-(2-hydroxyphenyl)pyrimidine;   4-Iodo-6-(2,4-difluorophenyl)pyrimidine;   4-Iodo-6-(2-fluoro-6-methoxyphenyl)pyrimidine;   4-Iodo-6-(2-chlorophenyl)pyrimidine;   4-Iodo-6-(3-acetylaminophenyl)pyrimidine;   4-Iodo-6-(thiophen-3-yl)pyrimidine;   4-Iodo-6-(3-hydroxymethylphenyl)pyrimidine;   4-Iodo-6-(isoquinolin-4-yl)pyrimidine;   4-Iodo-6-(2,4,5-trifluorophenyl)pyrimidine;   4-Iodo-6-(2,4-difluoropyridin-3-yl)pyrimidine;   4-Iodo-6-(4-methoxypyridin-3-yl)pyrimidine;   4-Iodo-6-(thiophen-2-yl)pyrimidine;   4-Iodo-6-(3,4-difluorophenyl)pyrimidine;   4-Iodo-6-(4-ethoxyphenyl)pyrimidine;   4-Iodo-6-(4-aminocarbonylphenyl)pyrimidine;   4-Iodo-6-(3-aminocarbonylphenyl)pyrimidine;   4-Iodo-6-(quinolin-4-yl)pyrimidine;   4-Iodo-6-(quinolin-8yl)pyrimidine;   4-Iodo-6-(quinolin-3-yl)pyrimidine;   4-Iodo-6-(isoquinolin-5-yl)pyrimidine;   2-Methylthio-4-iodo-6-phenylpyrimidine;   2-Ethylthio-4-iodo-6-phenylpyrimidine;   2-Isopropylthio-4-iodo-6-phenylpyrimidine;   2-n-Butylthio-4-iodo-6-phenylpyrimidine;   2-Methylamino-4-iodo-6-phenylpyrimidine;   2-Ethylamino-4-iodo-6-phenylpyrimidine;   2-Propylamino-4-iodo-6-phenylpyrimidine;   2-Isopropylamino-4-iodo-6-phenylpyrimidine;   2-n-Butylamino-4-iodo-6-phenylpyrimidine;   4-Iodo-6-(benzothiophen-2-yl)pyrimidine;   4-Iodo-6-(benzofuran-2-yl)pyrimidine;   4-Iodo-6-(4-hydroxybenzothiophen-2-yl)pyrimidine;   4-Iodo-6-(4-acetylaminobenzothiophen-2-yl)pyrimidine;   4-Iodo-6-(4-aminocarbonylbenzothiophen-2-yl)pyrimidine;   4-Iodo-6-(5-acetylaminopyridin-3-yl)pyrimidine;   4-Iodo-6-(5-aminocarbonylpyridin-3-yl)pyrimidine;   4-Iodo-6-(4-fluoropyridin-3-yl)pyrimidine;   4-Iodo-6-(4-acetylaminothiophen-2-yl)pyrimidine;   4-Iodo-6-(4-aminocarbonylthiophen-2-yl)pyrimidine; and   4-Iodo-6-(4-methoxythiophen-2-yl)pyrimidine.   
     
     
         7 . The method of  claim 1 , wherein:
 A is a substituted or unsubstituted bicyclic ring selected from the group consisting of a quinoline, an isoquinoline, a benzofuran, and a benzothiophene;   B is H;   X and Y are both N,   and further wherein the MIF inhibitory compound interacts with a MIF polypeptide present in the patient in need thereof to inhibit an enzymatic activity of the MIF polypeptide.   
     
     
         8 . The method of  claim 7 , wherein the MIF inhibitory compound is selected from the group consisting of:
 4-Iodo-6-(isoquinolin-4-yl)pyrimidine;   4-Iodo-6-(quinolin-4-yl)pyrimidine;   4-Iodo-6-(quinolin-8-yl)pyrimidine;   4-Iodo-6-(quinolin-3-yl)pyrimidine;   4-Iodo-6-(isoquinolin-5-yl)pyrimidine;   4-Iodo-6-(benzothiophen-2-yl)pyrimidine; and   4-Iodo-6-(benzofuran-2-yl)pyrimidine.   
     
     
         9 . The method of  claim 1 , wherein the administering is via oral administration, intravenous administration, intraperitoneal administration, or a combination thereof. 
     
     
         10 . A method for inhibiting proliferation, cell migration, metastasis, and/or invasion of a tumor cell, and/or angiogenesis associated with the presence of the tumor cell, the method comprising contacting the tumor cell with an effective amount of a MIF inhibitory compound or its enantiomeric or diastereomeric form or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, said compound having the formula: 
       
         
           
           
               
               
           
         
         wherein:
 (i) A is selected from the group consisting of:
 (a) substituted or unsubstituted 5, 6, or 7-membered aromatic or nonaromatic rings having 0 or 1 to 4 heteroatoms selected from the group consisting of N, O, S, and combinations thereof; 
 (b) substituted or unsubstituted bicyclic ring; 
 (c) substituted or unsubstituted polycyclic rings; and 
 (d) substituted or unsubstituted alkenes and alkynes having 2 to 10 carbon atoms with 1 to 3 double or triple bonds; and 
 
  B is H, OH, OR, SR, NH 2 , NHR, or alkyl or substituted alkyl, wherein R is H, alkyl, or substituted alkyl of 2 to 20 carbon atoms; or 
 (ii) A is H or halo; and 
  B is selected from the group consisting of:
 (a) substituted or unsubstituted 5, 6, or 7-membered aromatic or nonaromatic rings having 0 or 1 to 4 heteroatoms selected from the group consisting of N, O, S, and combinations thereof; 
 (b) substituted or unsubstituted bicyclic ring; 
 (c) substituted or unsubstituted polycyclic rings; and 
 (d) substituted or unsubstituted alkenes and alkynes having 2 to 10 carbon atoms with 1 to 3 double or triple bonds; and 
 
 X and Y are independently N or CH, wherein at least one of X and Y is N, whereby proliferation, cell migration, metastasis, and/or invasion of the tumor cell and/or angiogenesis associated with the presence of the tumor cell is inhibited. 
 
       
     
     
         11 . The method of  claim 10 , wherein the MIF inhibitory compound is selected from the group consisting of:
 4-Iodo-6-(2,3-difluoro-4-methoxyphenyl)pyrimidine;   4-Iodo-6-(2-fluoro-4-methoxyphenyl)pyrimidine;   4-Iodo-6-(2-fluorophenyl)pyrimidine;   4-Iodo-6-(4-fluorophenyl)pyrimidine;   4-Iodo-6-(furan-3-yl)pyrimidine;   4-Iodo-6-(pyridin-3-yl)pyrimidine;   4-Iodo-6-(3-fluorophenyl)pyrimidine;   4-Iodo-6-(4-tert-butyloxymethylphenyl)pyrimidine;   4-Iodo-6-(2-fluoropyridin-3-yl)pyrimidine;   4-Iodo-6-(furan-2-yl)pyrimidine;   4-Iodo-6-(4-fluoropyrimidin-3-yl)pyrimidine;   4-Iodo-6-(3-fluoro-4-methoxyphenyl)pyrimidine;   4-Iodo-6-(2-chloropyridin-5-yl)pyrimidine;   4-Iodo-6-(2-hydroxyphenyl)pyrimidine;   4-Iodo-6-(2,4-difluorophenyl)pyrimidine;   4-Iodo-6-(2-fluoro-6-methoxyphenyl)pyrimidine;   4-Iodo-6-(2-chlorophenyl)pyrimidine;   4-Iodo-6-(3-acetylaminophenyl)pyrimidine;   4-Iodo-6-(thiophen-3-yl)pyrimidine;   4-Iodo-6-(3-hydroxymethylphenyl)pyrimidine;   4-Iodo-6-(isoquinolin-4-yl)pyrimidine;   4-Iodo-6-(2,4,5-trifluorophenyl)pyrimidine;   4-Iodo-6-(2,4-difluoropyridin-3-yl)pyrimidine;   4-Iodo-6-(4-methoxypyridin-3-yl)pyrimidine;   4-Iodo-6-(thiophen-2-yl)pyrimidine;   4-Iodo-6-(3,4-difluorophenyl)pyrimidine;   4-Iodo-6-(4-ethoxyphenyl)pyrimidine;   4-Iodo-6-(4-aminocarbonylphenyl)pyrimidine;   4-Iodo-6-(3-aminocarbonylphenyl)pyrimidine;   4-Iodo-6-(quinolin-4-yl)pyrimidine;   4-Iodo-6-(quinolin-8yl)pyrimidine;   4-Iodo-6-(quinolin-3-yl)pyrimidine;   4-Iodo-6-(isoquinolin-5-yl)pyrimidine;   2-Methylthio-4-iodo-6-phenylpyrimidine;   2-Ethylthio-4-iodo-6-phenylpyrimidine;   2-Isopropylthio-4-iodo-6-phenylpyrimidine;   2-n-Butylthio-4-iodo-6-phenylpyrimidine;   2-Methylamino-4-iodo-6-phenylpyrimidine;   2-Ethylamino-4-iodo-6-phenylpyrimidine;   2-Propylamino-4-iodo-6-phenylpyrimidine;   2-Isopropylamino-4-iodo-6-phenylpyrimidine;   2-n-Butylamino-4-iodo-6-phenylpyrimidine;   4-Iodo-6-(benzothiophen-2-yl)pyrimidine;   4-Iodo-6-(benzofuran-2-yl)pyrimidine;   4-Iodo-6-(4-hydroxybenzothiophen-2-yl)pyrimidine;   4-Iodo-6-(4-acetylaminobenzothiophen-2-yl)pyrimidine;   4-Iodo-6-(4-aminocarbonylbenzothiophen-2-yl)pyrimidine;   4-Iodo-6-(5-acetylaminopyridin-3-yl)pyrimidine;   4-Iodo-6-(5-aminocarbonylpyridin-3-yl)pyrimidine;   4-Iodo-6-(4-fluoropyridin-3-yl)pyrimidine;   4-Iodo-6-(4-acetylaminothiophen-2-yl)pyrimidine;   4-Iodo-6-(4-aminocarbonylthiophen-2-yl)pyrimidine; and   4-Iodo-6-(4-methoxythiophen-2-yl)pyrimidine.   
     
     
         12 . The method of  claim 10 , wherein:
 A is a substituted or unsubstituted bicyclic ring selected from the group consisting of a quinoline, an isoquinoline, a benzofuran, and a benzothiophene;   B is H;   X and Y are both N,   and further wherein the MIF inhibitory compound interacts with a MIF polypeptide present in the patient in need thereof to inhibit an enzymatic activity of the MIF polypeptide.   
     
     
         13 . The method of  claim 12 , wherein the MIF inhibitory compound is selected from the group consisting of:
 4-Iodo-6-(isoquinolin-4-yl)pyrimidine;   4-Iodo-6-(quinolin-4-yl)pyrimidine;   4-Iodo-6-(quinolin-8-yl)pyrimidine;   4-Iodo-6-(quinolin-3-yl)pyrimidine;   4-Iodo-6-(isoquinolin-5-yl)pyrimidine;   4-Iodo-6-(benzothiophen-2-yl)pyrimidine; and   4-Iodo-6-(benzofuran-2-yl)pyrimidine.   
     
     
         14 . The method of  claim 10 , wherein the tumor cell is present within a subject and the contacting results from administering the MIF inhibitory compound or its enantiomeric or diastereomeric form, or the pharmaceutically acceptable salt, prodrug, or metabolite thereof to the subject orally, intravenously, intraperitoneally, or a combination thereof. 
     
     
         15 . The method of  claim 14 , wherein the MIF inhibitory compound or its enantiomeric or diastereomeric form, or the pharmaceutically acceptable salt, prodrug, or metabolite thereof is administered as part of a pharmaceutical composition comprising a safe and effective amount of the MIF inhibitory compound and one or more pharmaceutically acceptable excipients. 
     
     
         16 . The method of  claim 15 , wherein the pharmaceutical composition is pharmaceutically acceptable for use in a human. 
     
     
         17 . A method for inhibiting autoimmune-associated activation of a T cell, the method comprising contacting a T cell subject to autoimmune-associated activation with an effective amount of a MIF inhibitory compound or its enantiomeric or diastereomeric form or a pharmaceutically acceptable salt, prodrug, or metabolite thereof of  claim 1 , whereby autoimmune-associated activation of the T cell is inhibited. 
     
     
         18 . The method of  claim 18 , wherein the T cell subject to autoimmune-associated activation is present within a mammal. 
     
     
         19 . A compound selected from the group consisting of:
 4-Iodo-6-(2,3-difluoro-4-methoxyphenyl)pyrimidine;   4-Iodo-6-(2-fluoro-4-methoxyphenyl)pyrimidine;   4-Iodo-6-(4-fluorophenyl)pyrimidine;   4-Iodo-6-(furan-3-yl)pyrimidine;   4-Iodo-6-(pyridin-3-yl)pyrimidine;   4-Iodo-6-(3-fluorophenyl)pyrimidine;   4-Iodo-6-(4-tert-butyloxymethylphenyl)pyrimidine;   4-Iodo-6-(2-fluoropyridin-3-yl)pyrimidine;   4-Iodo-6-(furan-2-yl)pyrimidine;   4-Iodo-6-(4-fluoropyrimidin-3-yl)pyrimidine;   4-Iodo-6-(3-fluoro-4-methoxyphenyl)pyrimidine;   4-Iodo-6-(2-chloropyridin-5-yl)pyrimidine;   4-Iodo-6-(2-hydroxyphenyl)pyrimidine;   4-Iodo-6-(2,4-difluorophenyl)pyrimidine;   4-Iodo-6-(2-fluoro-6-methoxyphenyl)pyrimidine;   4-Iodo-6-(2-chlorophenyl)pyrimidine;   4-Iodo-6-(3-acetylaminophenyl)pyrimidine;   4-Iodo-6-(thiophen-3-yl)pyrimidine;   4-Iodo-6-(3-hydroxymethylphenyl)pyrimidine;   4-Iodo-6-(2,4,5-trifluorophenyl)pyrimidine;   4-Iodo-6-(2,4-difluoropyridin-3-yl)pyrimidine;   4-Iodo-6-(4-methoxypyridin-3-yl)pyrimidine;   4-Iodo-6-(thiophen-2-yl)pyrimidine;   4-Iodo-6-(3,4-difluorophenyl)pyrimidine;   4-Iodo-6-(4-ethoxyphenyl)pyrimidine;   4-Iodo-6-(4-aminocarbonylphenyl)pyrimidine;   4-Iodo-6-(3-aminocarbonylphenyl)pyrimidine;   2-Methylthio-4-iodo-6-phenylpyrimidine   2-Ethylthio-4-iodo-6-phenylpyrimidine;   2-Isopropylthio-4-iodo-6-phenylpyrimidine;   2-n-Butylthio-4-iodo-6-phenylpyrimidine;   2-Methylamino-4-iodo-6-phenylpyrimidine;   2-Ethylamino-4-iodo-6-phenylpyrimidine;   2-Propylamino-4-iodo-6-phenylpyrimidine;   2-Isopropylamino-4-iodo-6-phenylpyrimidine;   2-n-Butylamino-4-iodo-6-phenylpyrimidine;   4-Iodo-6-(4-hydroxybenzothiophen-2-yl)pyrimidine;   4-Iodo-6-(4-acetylaminobenzothiophen-2-yl)pyrimidine;   4-Iodo-6-(4-aminocarbonylbenzothiophen-2-yl)pyrimidine;   4-Iodo-6-(5-acetylaminopyridin-3-yl)pyrimidine;   4-Iodo-6-(5-aminocarbonylpyridin-3-yl)pyrimidine;   4-Iodo-6-(4-fluoropyridin-3-yl)pyrimidine;   4-Iodo-6-(4-acetylaminothiophen-2-yl)pyrimidine;   4-Iodo-6-(4-aminocarbonylthiophen-2-yl)pyrimidine; and   4-Iodo-6-(4-methoxythiophen-2-yl)pyrimidine.