Dual-action inhbitors and methods of using same

Abstract

Provided are compounds, compositions, and methods for treating diseases and conditions wherein an inhibitor of a kinase, such as rho kinase (ROCK), and an inhibitor of one or more of the monoamine transporters, such as NET or SERT, act in concert to improve the condition.

1 . A compound comprising a monoamine transport inhibitor and a kinase inhibitor. 
     
     
         2 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein each X is independently selected from hydrogen, amino, lower alkyl, halogen, carbonyl, nitrile, hydroxyl, and alkoxy; 
         Z is selected from substituted monovalent hydrocarbon groups, substituted heterogeneous groups, substituted heterocyclic groups, substituted heteroaromatic groups, substituted carbocyclic groups, substituted aromatic groups, heterogeneous groups, heterocyclic groups, heteroaromatic groups, carbocyclic groups, and aromatic groups; 
         R is selected from guanidino or —N(R 5 ) 2 ; 
         R 5  is independently selected from H, methyl, or ethyl groups; 
         B is C═O, C═S, or —CH 2 —; 
         n and m are independently selected from the integers 0, 1, 2 or 3 and represent an independently variable number of substituted or unsubstituted methylene units in the alkyl chain; and 
         pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof. 
       
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . A compound of Formula III: 
       
         
           
           
               
               
           
         
         wherein X 1  and X 2  are independently selected from hydrogen, amino, lower alkyl, halogen, carbonyl, nitrile, hydroxyl, and alkoxy; 
         Z is selected from substituted monovalent hydrocarbon groups, substituted heterogeneous groups, substituted heterocyclic groups, substituted heteroaromatic groups, substituted carbocyclic groups, substituted aromatic groups, heterogeneous groups, heterocyclic groups, heteroaromatic groups, carbocyclic groups, and aromatic groups; 
         R is selected from guanidino or —N(R 5 ) 2 ; 
         R 5  is independently selected from H, methyl, or ethyl groups; 
         B is C═O, C═S, or —CH 2 —; 
         n and m are independently selected from the integers 0, 1, 2 or 3 and represent an independently variable number of substituted or unsubstituted methylene units in the alkyl chain; and 
         pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof. 
       
     
     
         6 . (canceled) 
     
     
         7 . A compound of Formula IV: 
       
         
           
           
               
               
           
         
         wherein each X 1  and X 2  are independently selected from hydrogen, amino, lower alkyl, halogen, carbonyl, nitrile, hydroxyl, and alkoxy; 
         Z is selected from substituted monovalent hydrocarbon groups, substituted heterogeneous groups, substituted heterocyclic groups, substituted heteroaromatic groups, substituted carbocyclic groups, substituted aromatic groups, heterogeneous groups, heterocyclic groups, heteroaromatic groups, carbocyclic groups, and aromatic groups; 
         R is selected from guanidino or —N(R 5 ) 2 ; 
         R 5  is independently selected from H, methyl, and ethyl groups; 
         B is C═O, C═S, or —CH 2 —; 
         n and m are independently selected from the integers 0, 1, 2 or 3 and represent an independently variable number of substituted or unsubstituted methylene units in the alkyl chain; and 
         pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof. 
       
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . A compound of Formula V: 
       
         
           
           
               
               
           
         
         wherein X 1  and X 2  are independently selected from hydrogen, amino, lower alkyl, halogen, carbonyl, nitrile, and hydroxyl; 
         Z is selected from substituted monovalent hydrocarbon groups, substituted heterogeneous groups, substituted heterocyclic groups, substituted heteroaromatic groups, substituted carbocyclic groups, substituted aromatic groups, heterogeneous groups, heterocyclic groups, heteroaromatic groups, carbocyclic groups, and aromatic groups; 
         R is selected from guanidino or —N(R 5 ) 2 ; 
         R 5  is independently selected from H, methyl, or ethyl groups; 
         R 2  is H or methyl group; 
         B is C═O, C═S, or —CH 2 —; 
         n and m are independently selected from the integers 0, 1, 2 or 3 and represent an independently variable number of substituted or unsubstituted methylene units in the alkyl chain; and 
         pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof. 
       
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . A compound of Formula VI: 
       
         
           
           
               
               
           
         
         wherein each X is independently selected from hydrogen, amino, hydroxy, alkoxy, lower alkyl, halogen, carbonyl, and nitrile; 
         R 1  and R 2  are each independently selected from substituted monovalent hydrocarbon groups, substituted heterogeneous groups, substituted heterocyclic groups, substituted heteroaromatic groups, substituted carbocyclic groups, substituted aromatic groups, heterogeneous groups, heterocyclic groups, heteroaromatic groups, carbocyclic groups, and aromatic groups; 
         R is selected from guanidino and —N(R 5 ) 2 ; 
         R 5  is selected from H, methyl group, and ethyl group; 
         A is —NR 4 —, —S(O) 2 —NH—, —NH—S(O) 2 —, C═O, or lower alkylene; 
         B is C═O, C═S, —CH 2 —, or NR 4 ; 
         R 4  is H, methyl group, or ethyl group; 
         n 1  and n 2  are independently selected from the integers 0, 1, and 2 and represent a variable number of carbon units in the alkyl chain; and 
         pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof. 
       
     
     
         14 . The compound of  claim 13 , wherein each X is independently selected from hydrogen, amino, hydroxy, and alkoxy;
 R is —N(R 5 ) 2 ;   R 5  is selected from H and methyl group; and   R 4  is H or methyl group.   
     
     
         15 . A compound of Formula VII: 
       
         
           
           
               
               
           
         
         wherein X 7  is a —O— or —NH—; 
         A is a NET inhibitor; and 
         B is a rho kinase inhibitor. 
       
     
     
         16 . (canceled) 
     
     
         17 . A composition comprising:
 (a) a compound according  claim 13 ; and   (b) a carrier.   
     
     
         18 . The composition of  claim 17 , further comprising (c) one or more activity enhancers. 
     
     
         19 . A method for treating a disease or condition, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to  claim 13 . 
     
     
         20 . The method of  claim 19 , wherein the compound inhibits a kinase and monoamine transport in concert to alleviate the symptoms associated with the disease or condition. 
     
     
         21 . The method of  claim 19 , wherein the disease or condition comprises at least one of eye disease, bone disorder, obesity, heart disease, hepatic disease, renal disease, pancreatitis, cancer, myocardial infarct, gastric disturbance, hypertension, fertility control, disorders of hair growth, nasal congestion, neurogenic bladder disorder, gastrointestinal disorder, and dermatological disorder. 
     
     
         22 . The method of  claim 21 , wherein the disease or condition comprises an eye disease. 
     
     
         23 . The method of  claim 22 , wherein the eye disease comprises glaucoma. 
     
     
         24 . A method of reducing intraocular pressure comprising contacting a cell with an effective amount of a compound according to  claim 13 . 
     
     
         25 . A method for treating cardiac indications comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 13 . 
     
     
         26 . A method of treating a respiratory disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 13 . 
     
     
         27 . A method of treating a renal disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 13 . 
     
     
         28 . A method of treating upper respiratory indications comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 13 . 
     
     
         29 . A method of treating inflammatory disease, inflammation in response to injury, or rheumatoid arthritis comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 13 . 
     
     
         30 . A method for modulating the action of a kinase and a monoamine transporter in a cell comprising contacting the cell with a compound according to  claim 13  in an amount effective to modulate the action of a kinase and a monoamine transporter in a cell. 
     
     
         31 . The method of  claim 19 , wherein the compound is administered in conjunction with one or more additional therapeutic agents. 
     
     
         32 . The method of  claim 31 , wherein the additional therapeutic agent is selected from the group consisting of beta blockers, alpha-agonists, carbonic anhydrase inhibitors, prostaglandin-like compounds, miotic or cholinergic agents, and epinephrine compounds.