Cyclourea Compounds as Calcium Channel Blockers

Abstract

The invention relates to cyclourea compounds of Formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 -R 3 and Z are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula I to treat, prevent or ameliorate a disorder responsive to the blockade of calcium channels, and particularly N-type calcium channels. Compounds of the present invention are especially useful for treating pain.

1 . A compound having the Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
         Z is Z 2 , wherein
 Z 2  is —CH 2 —(CH 2 ) n —R 8 ; 
 
         R 1  and R 2  are both hydrogen or R 1  and R 2 , together with the carbon atoms to which they are attached, form a fused cyclopropyl ring or a fused phenyl ring; 
         R 3  is selected from the group consisting of
 (i) hydrogen; 
 (ii) alkyl; 
 (iii) C 3-6  cycloalkyl; 
 (iv) —(C 2 ) p —Y; 
 
       
       
         
           
           
               
               
           
         
         R 8  is selected from the group consisting of
 phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino; 
 pyridyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, and alkoxy; and 
 thiazolyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, and haloalkyl; 
 
         R 9  and R 10  are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         R 11  and R 12  are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         wherein Y is a 3-7 membered saturated heterocyclic ring optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         n is 0, 1, or 2; 
         p is 0, 1, 2, 3, or 4; 
         q and s are each independently 0, 1, 2, 3, 4, or 5; 
         r is 0 or 1; 
         t is 0, 1, 2, 3, or 4; and 
         u is 0, 1, 2, 3, or 4; 
         with the provisos that 
         1) when R 1  and R 2  are both hydrogen and R 3  is (i) or (v), where r is 0 and R 9  and R 10  are each independently hydrogen or alkoxy, then R 8  is not phenyl or 3,4-dimethoxyphenyl; or 
         2) when R 1  and R 2  together form a fused phenyl ring and R 8  is an unsubstituted phenyl group, then R 3  is not alkyl. 
       
     
     
         2 . The compound of  claim 1 , having the
 a) Formula II:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein R 3  and Z are as defined in  claim 1 ; or
 b) Formula III: 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof; wherein R 3  and Z are as defined in  claim 1 ; or
 c) Formula IV: 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein R 3  and Z are as defined in  claim 1 . 
     
     
         3 .- 4 . (canceled) 
     
     
         5 . The compound of  claim 2 ,
 wherein R 3  is
 a) selected from the group consisting of (i) hydrogen, (ii) alkyl, and (iii) C 3-6  cycloalkyl; or 
 b) (iv) —(CH 2 ) p —Y, wherein Y is a 3-7 membered saturated heterocyclic ring optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl, and p is 0, 1, 2, 3, or 4; or 
   
       c) 
       
         
           
           
               
               
           
         
         wherein R 9  and R 10  are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl, r is 0 or 1, and q and s are each independently 0, 1, 2, 3, 4, or 5, or 
       
       
         
           
           
               
               
           
         
         
           d) 
         
         wherein R 9  and R 10  are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl, and t is 0, 1, 2, 3, or 4; or
 e) 
 
       
       
         
           
           
               
               
           
         
         wherein R 11  and R 12  are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl, and u is 0, 1, 2, 3, or 4. 
       
     
     
         6 .- 8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein said compound has an IC 50  of about 100 μM or less for N-type calcium channel blocking activity in a calcium mobilization and/or electrophysiological assay. 
     
     
         10 . A pharmaceutical composition, comprising the compound as claimed in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         11 . A method of treating, preventing or ameliorating a disorder responsive to the blockade of calcium channels in a mammal suffering from excess activity of said channels, comprising administering to a mammal in need of such treatment, prevention or amelioration an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
         Z is wherein
 Z 2  is —-CH 2 —(CH 2 ) n —R 8 ; 
 
         R 1  and R 2  are both hydrogen or R 1  and R 2 , together with the carbon atoms to which they are attached, form a fused cyclopropyl ring or a fused phenyl ring; 
         R 3  is selected from the group consisting of
 (i) hydrogen; 
 (ii) alkyl; 
 (iii) C 3-6  cycloalkyl; 
 (iv) —(CH 2 ) p   —Y ; 
 
       
       
         
           
           
               
               
           
         
         R 8  is selected from the group consisting of
 phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino; 
 pyridyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, and alkoxy; and 
 thiazolyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, and haloalkyl; 
 
         R 9  and R 10  are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         R 11  and R 12  are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         wherein Y is a 3-7 membered saturated heterocyclic ring optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         n is 0, 1, or 2; 
         p is 0, 1, 2, 3, or 4; 
         q and s are each independently 0, 1, 2, 3, 4, or 5; 
         r is 0 or 1; 
         t is 0, 1, 2, 3, or 4; and 
         u is 0, 1, 2, 3, or 4. 
       
     
     
         12 . The method of  claim 11 , wherein a disorder responsive to the blockade of N-type calcium channels is treated, prevented or ameliorated. 
     
     
         13 . A method of treating, preventing or ameliorating stroke, head trauma, epilepsy, pain, migraine, a mood disorder, schizophrenia, a neurodegenerative disorder, depression, anxiety, a psychosis, hypertension, or cardiac arrhythmia in a mammal, comprising administering an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
         Z is Z 2 , wherein
 Z 2  is —CH 2 —(CH 2 ) n —R 8 ; 
 
         R 1  and R 2  are both hydrogen or R 1  and R 2 , together with the carbon atoms to which they are attached, form a fused cyclopropyl ring or a fused phenyl ring; 
         R 3  is selected from the group consisting of
 (i) hydrogen; 
 (ii) alkyl; 
 (iii) C 3-6  cycloalkyl; 
 (iv) —(CH 2 ) p —Y; 
 
       
       
         
           
           
               
               
           
         
         R 8  is selected from the group consisting of
 phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino; 
 pyridyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, and alkoxy; and 
 thiazolyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, and haloalkyl; 
 
         R 9  and R 10  are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         R 11  and R 12  are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         wherein Y is a 3-7 membered saturated heterocyclic ring optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         n is 0, 1, or 2; 
         p is 0, 1, 2, 3, or 4; 
         q and s are each independently 0, 1, 2, 3, 4, or 5; 
         r is 0 or 1; 
         t is 0, 1, 2, 3, or 4; and 
         u is 0, 1, 2, 3, or 4; 
       
       to a mammal in need of such treatment, prevention or amelioration. 
     
     
         14 . The method of  claim 13 , wherein the method is of treating, preventing or ameliorating pain. 
     
     
         15 . A method of modulating calcium channels in a mammal, comprising administering to the mammal at least one compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
         Z is Z 2 , wherein
 Z 2  is —CH 2 —(CH 2 ) n —R 8 ; 
 
         R 1  and R 2  are both hydrogen or R 1  and R 2 , together with the carbon atoms to which they are attached, form a fused cyclopropyl ring or a fused phenyl ring; 
         R 3  is selected from the group consisting of
 (i) hydrogen; 
 (ii) alkyl; 
 (iii) C 3-6  cycloalkyl; 
 (iv) —(CH 2 ) p —Y; 
 
       
       
         
           
           
               
               
           
         
         R 8  is selected from the group consisting of
 phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, and dialkylamino; 
 pyridyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, haloalkoxy, and alkoxy; and 
 thiazolyl optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, and haloalkyl; 
 
         R 9  and R 10  are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         R 11  and R 12  are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         wherein Y is a 3-7 membered saturated heterocyclic ring optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl; 
         n is 0, 1, or 2; 
         p is 0, 1, 2, 3, or 4; 
         q and s are each independently 0, 1, 2, 3, 4, or 5; 
         r is 0 or 1; 
         t is 0.1, 2, 3, or 4; and 
         u is 0, 1, 2, 3, or 4. 
       
     
     
         16 . A compound having the Formula I as claimed in  claim 1 , wherein the compound is  3 H or  14 C radiolabeled. 
     
     
         17 . A method for screening a candidate compound for the ability to bind to a receptor using a radiolabeled compound of  claim 16 , comprising:
 a) introducing a fixed concentration of the radiolabeled compound to the receptor to form a mixture;   b) titrating the mixture with the candidate compound; and   c) determining the binding of the candidate compound to said receptor.   
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 14 , wherein said pain is acute pain, chronic pain or surgical pain. 
     
     
         20 . The method of  claim 20 , wherein said pain is chronic pain. 
     
     
         21 . The method of  claim 15 , wherein N-type calcium channels are modulated. 
     
     
         22 . The compound of  claim 2 , wherein R 8  is phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluorine, trifluoromethyl, trifluoromethoxy, and dimethylamino. 
     
     
         23 . The compound of  claim 2 , wherein R 8  is pyridyl optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy. 
     
     
         24 . The compound of  claim 2 , wherein R 8  is thiazolyl optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl, isopropyl, methoxy, ethoxy, fluorine, and trifluoromethyl. 
     
     
         25 . The compound of  claim 1 , wherein n is 0 or 1. 
     
     
         26 . The compound of  claim 5 , wherein R 3  is 
       (iii) C 3-6  cycloalkyl; 
       (iv) —(CH 2 ) p —Y, wherein Y is 
       
         
           
           
               
               
           
         
       
       wherein R 13  and R 14  are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, and hydroxyalkyl, and w is 0, 1, 2, or 3, and p is 0, 1, 2, or 3; or 
       
         
           
           
               
               
           
         
       
       wherein R 11  and R 12  are each independently selected from the group consisting of hydrogen, C 1-4  alkyl, C 1-4  alkoxy, halogen, halo(C 1-3 )alkyl, halo(C 1-3 )alkoxy, cyano, hydroxy, and hydroxy(C 1-4 )alkyl; and u is 0, 1, 2, or 3.