Prostaglandin receptor ep2 antagonists, derivatives, compositions, and uses related thereto

Abstract

The disclosure relates to Prostaglandin receptor EP2 antagonists, derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to methods of treating or preventing conditions and diseases in which EP2 receptor activation has a physiological role, such as but not limited to, brain injury, inflammatory diseases, neuroinflamation after a seizure, pain, endometriosis, cancer, rheumatoid arthritis, skin inflammation, vascular inflammation, colitis, and neurological disorders by administering a pharmaceutical composition comprising a compound disclosed herein to a subject in need thereof.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a compound of Formula XIV, 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt or prodrug thereof, wherein:
 a broken line represents the presence of a single or double bond; 
 n is 1, 2, 3, or 4; 
 q is 0, 1 or 2; 
 if there is a double bond between U and the attached carbon, then U is C; or if there is a single bond between U and the attached carbon, then U is N; 
 if there is a double bond between W and the attached carbon, then W is CX 6 ; or if there is a single bond between W and the attached carbon, then W is NX 6 ; 
 V is a 5 or 6 membered heterocyclyl having at least one nitrogen heteroatom; 
 Z is a 5 to 7 membered carbocyclyl, aryl, or heterocyclyl optionally substituted; 
 R 1 , R 2 , R 4 , and R 5  are each, the same or different, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 , R 2 , R 4 , and R 5  are optionally substituted with one or more, the same or different, R 10 ; 
 R 10  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10  is optionally substituted with one or more, the same or different, R 11 ; 
 R 11  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11  is optionally substituted with one or more, the same or different, 102; 
 R 12  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; 
 R 30  is at each occurance, the same or different, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 30  is optionally substituted with one or more, the same or different, R 100 ; 
 R 100  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 100  is optionally substituted with one or more, the same or different, R 101 ; 
 R 101  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 101  is optionally substituted with one or more, the same or different, R 102 ; 
 R 102  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; 
 X 5  and X 6  are each, the same or different, hydrogen or alkyl, wherein X 5  and X 6  are optionally substituted with one or more, the same or different, X 10 ; 
 X 10  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X 10  is optionally substituted with one or more, the same or different, X 11 ; and 
 X 11  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein U is C and there is a double bond between U and the attached carbon. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein W is NX 6  and there is a single bond between W and the attached carbon. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein Z is a 6 membered aryl. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the compound has Formula XIVC, 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1 , X 2 , X 3 , and X 4  are each, the same or different, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X 1 , X 2 , X 3 , and X 4  are optionally substituted with one or more, the same or different, X 10 . 
 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the V ring is a diazolyl, triazolyl, or tetrazolyl. 
     
     
         7 . The pharmaceutical composition of  claim 5 , wherein R 1 , R 2 , R 3 , and R 4  are each hydrogen. 
     
     
         8 . The pharmaceutical composition of  claim 5 , wherein X 5  is CH 3 . 
     
     
         9 . The pharmaceutical composition of  claim 5 , wherein X 6  is hydrogen. 
     
     
         10 . The pharmaceutical composition of  claim 5 , wherein n is 2. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the compound has Formula XIVG, 
       
         
           
           
               
               
           
         
       
       wheren:
 X 1 , X 2 , X 3 , and X 4  are each, the same or different, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X 1 , X 2 , X 3 , and X 4  are optionally substituted with one or more, the same or different, X 10 . 
 
     
     
         12 . The pharmaceutical composition of  claim 1 , in the form of a tablet, capsule, bead, granule, particle, powder, lotion, cream, ointment, gel, or aerosol. 
     
     
         13 . The pharmaceutical composition of  claim 1 , further comprising a pharmaceutically acceptable excipient selected from lactose, sucrose, glucose, dextrose, mannitol, sorbitol. starch, cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and ethylcellulose. 
     
     
         14 . The pharmaceutical composition of  claim 1 , further comprising a pharmaceutically acceptable excipient selecrted from sodium chloride, dicalcium, phosphate dihydrate, calcium sulfate, kaolin, silicone dioxide, titanium oxide, magnesium aluminum silicate, magnesium stearate, calcium. stearate, stearic acid, glycerol behenate, polyethylene glycol, late, and mineral oil. 
     
     
         15 . A method of treating endometriosis comprising administering an effective amount of the pharmaceutical composition of  claim 1  to a subject in need thereof. 
     
     
         16 . A method of treating arthritis comprising administering an effective amount of the pharmaceutical composition of  claim 1  to a subject in need thereof. 
     
     
         17 . The method of  claim 16 , wherein the arthritis is rheumatoid arthritis, enthesitis-related arthritis, or psoriatic arthritis. 
     
     
         18 . A method of treating cancer comprising administering an effective amount of the pharmaceutical composition of  claim 1  to a subject in need thereof. 
     
     
         19 . The method of  claim 18 , wherein the cancer is skin cancer, blood vessel cancer, lung cancer, head cancer, neck cancer, prostate cancer, colon cancer, ovary cancer, breast cancer, or hepatocellular carcinoma.