Use of etodolac to treat hyperplasia

Abstract

The present invention provides a therapeutic method to treat non-malignant diseases characterized by the excessive tissue growth, e.g., hyperplastic diseases, comprising administering to a mammal (e.g., human) afflicted with excessive tissue growth, an effective amount of a derivative of an indole compound of formula (I):formula (I): wherein R 1 is lower alkyl, (hydroxy)lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, phenyl, benzyl or 2-thienyl; R 2 , R 3 , R 4 and R 5 are the same or different and are each hydrogen or lower alkyl; each R 6 is individually hydrogen, lower alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro or halo, R 7 is hydrogen, lower alkyl or lower alkenyl, X is oxy and thio, Y is carbonyl, —(CH 2 ) 1-3 —, —(C 1 -C 3 )alkyl(CO)—, or —(CH 2 ) 1-3 SO 2 —; Z is hydroxy, lower alkoxy, (C 2 -C 4 )acyloxy, —N(R 8 )(R 9 ), phenylamino, (ω-(4-pyridyl)(C 2 -C 4 alkoxy), (ω-((R 8 )(R 9 ) amino)(C 2 -C 4 alkoxy), an amino acid ester of (ω-(HO)(C 2 -C 4 ))alkoxy, —N(R 8 )CH(R 8 )CO 2 H, 1′-D-glucuronyloxy, —SO 3 H, —PO 4 H 2 , —N(NO)(OH), —SO 2 NH 2 , —PO(OH)(NH 2 ), —OCH 2 CH 2 N(CH 3 ) 3 + , or tetrazolyl; wherein R 8 and R 9 are each H, (C 1 -C 3 )alkyl or together with N are a 5- or 6-membered heterocyclic ring comprising 1-3 N(R 8 ), S or nonperoxide O; n is 0, 1, 2, or 3; wherein R 8 and R 9 are each H, (C 1 -C 3 )alkyl or together with N are a 5- or 6-membered heterocyclic ring comprising 1-3 N(R 8 ), S or nonperoxide O; each alkyl or phenyl group of R 1 , R 2 , R 3 , R 4 ,R 5 , R 6 , R 7 and Z is optionally substituted with 1, 2, or 3 (C 1 -C 4 )alkyl groups; or a pharmaceutically acceptable salt thereof.

1 . A therapeutic method for treatment of non-malignant diseases characterized by the excessive growth of tissue comprising administering to a patient in need of said therapy, an effective amount of a compound of formula (I):  
       
         
           
           
               
               
           
         
         wherein R 1  is lower alkyl, (hydroxy)lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, phenyl, benzyl or 2-thienyl;  
         R 2 , R 3 , R 4  and R 5  are the same or different and are each hydrogen or lower alkyl;  
         each R 6  is independently hydrogen, lower alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro or halo;  
         R 7  is hydrogen, lower alkyl or lower alkenyl, X is oxy and thio, Y is carbonyl, —(C 1 -C 3 )alkyl(CO)—, —(CH 2 ) 1-3 —, or —(CH 2 ) 1-3 SO 2 —;  
         Z is hydroxy, lower alkoxy, (C 2 -C 4 )acyloxy, —N(R 8 )(R 9 ), phenylamino, (ω-(4-pyridyl)(C 2 -C 4  alkoxy), (ω-((R 8 )(R 9 ) amino)(C 2 -C 4  alkoxy), an amino acid ester of (ω-(HO)(C 2 -C 4 ))alkoxy, —N(R 8 )CH(R 8 )CO 2 H, 1′-D-glucuronyloxy, —SO 3 H, —PO 4 H 2 , —N(NO)(OH), —SO 2 NH 2 , —PO(OH)(NH 2 ), —OCH 2 CH 2 N(CH 3 ) 3   + , or tetrazolyl;  
         wherein R 8  and R 9  are each H, (C 1 -C 3 )alkyl or together with N are a 5- or 6-membered heterocyclic ring comprising 1-3 N(R 8 ), S or nonperoxide O; n is 0, 1, 2, or 3; and  
         each alkyl or phenyl group of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and Z is optionally substituted with 1, 2, or 3 (C 1 -C 4 )alkyl groups;  
         or a pharmaceutically acceptable salt thereof;  
         wherein the disease comprises fibroplastic dysplasia of the breast or fibroplastic growth in the uterus or cervix or gastric hyperplastic polyposis.  
       
     
     
         2 . A therapeutic method for treatment of mammalian hyperplastic cells comprising administering to a patient in need of said therapy a chemotherapeutic agent in combination with an effective amount of a compound of formula (I):  
       
         
           
           
               
               
           
         
         wherein R 1  is lower alkyl, (hydroxy)lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, phenyl, benzyl or 2-thienyl;  
         R 2 , R 3 , R 4  and R 5  are the same or different and are each hydrogen or lower alkyl;  
         each R 6  is independently hydrogen, lower alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro or halo; and n is 1-3;  
         R 7  is hydrogen, lower alkyl or lower alkenyl, X is oxy and thio, Y is carbonyl, —(C 1 -C 3 )alkyl(CO)—, —(CH 2 ) 1-3 —, or —(CH 2 ) 1-3 SO 2 —;  
         Z is hydroxy, lower alkoxy, (C 2 -C 4 )acyloxy, —N(R 8 )(R 9 ), phenylamino, (ω-(4-pyridyl)(C 2 -C 4  alkoxy), (ω-((R 8 )(R 9 ) amino)(C 2 -C 4  alkoxy), an amino acid ester of (ω-(HO)(C 2 -C 4 ))alkoxy, —N(R 8 )CH(R 8 )CO 2 H, 1′-D-glucuronyloxy, —SO 3 H, —PO 4 H 2 , —N(NO)(OH), —SO 2 NH 2 , —PO(OH)(NH 2 ), —OCH 2 CH 2 N(CH 3 ) 3+ , or tetrazolyl;  
         wherein R 8  and R 9  are each H, (C 1 -C 3 )alkyl or together with N are a 5- or 6-membered heterocyclic ring comprising 1-3 N(R 8 ), S or nonperoxide O;  
         wherein each alkyl or phenyl group of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and Z is optionally substituted with 1, 2, or 3 (C 1 -C 4 )alkyl groups;  
         or a pharmaceutically acceptable salt thereof;  
         wherein the hyperplastic cells are associated with fibroplastic dysplasia of the breast or fibroplastic growth in the uterus or cervix or gastric hyperplastic polyposis.  
       
     
     
         3 . (canceled)  
     
     
         4 . (canceled)  
     
     
         5 . (canceled)  
     
     
         6 . The method of  claim 1  or  2 , wherein the compound of formula (I) is administered orally.  
     
     
         7 . The method of claims  1  or  2 , wherein the compound of formula (I) is administered in combination with an androgen inhibitor, or an α-1 adrenergic receptor blocker.  
     
     
         8 . The method of  claim 7 , wherein the androgen inhibitor is finasteride.  
     
     
         9 . The method of  claim 7 , wherein the α-1 adrenergic receptor blocker is phenoxybenzamine, prozosin, terazin, doxazosin, or tamsulosin.  
     
     
         10 . The method of  claim 1  or  2 , wherein Z is the L-valine or L-glycine ester of 2-hydroxyethoxy.  
     
     
         11 . The method of  claim 1  or  2 , wherein Z is N-morpholinoethoxy.  
     
     
         12 . The method of  claim 1  or  2 , wherein each R 8  is H, CH 3  or i-Pr.  
     
     
         13 . The method of  claim 1  or  2 , wherein Z is OCH 2 CH 2 N(CH 3 ) 3 .  
     
     
         14 . The method of  claim 1  or  2 , wherein the compound of formula (I) is etodolac.  
     
     
         15 . The method of  claim 1  or  2 , wherein the compound of formula (I) is the R(−)isomer.  
     
     
         16 . The method of  claim 1  or  2  wherein at least one R 6  is halo.  
     
     
         17 . The method of  claim 16  wherein at least one R 6  is bromo.  
     
     
         18 . The method of  claim 17  wherein n is 1.  
     
     
         19 . The method of  claim 1  or  2  wherein the compound of formula (I) is  
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 19  wherein X is O, R 1  is ethyl and Y-Z is —CH 2 CH 2 OH.  
     
     
         21 . The method of  claim 19  wherein R 2 , R 3 , R 4  and R 5  are hydrogen.  
     
     
         22 . The method of  claim 19  wherein the compound of formula (I) is the R-isomer.