Novel prostamides for the treatment of glaucoma and related diseases

Abstract

Disclosed herein are compositions comprising an amide related to a prostaglandin and an amine wherein the amine is selected from the group consisting of epinephrine, dopamine, serotonin, and analogs or prodrugs thereof. Also disclosed are certain chemical compounds, pharmaceutical compositions, and methods of treating glaucoma.

1 . A composition comprising an amide related to 
 a. a prostaglandin; and    b. an amine selected from the group consisting of epinephrine, dopamine, diacetyl dopamine and serotonin.    
   
   
       2 . The composition of  claim 1  wherein the prostaglandin is a natural prostaglandin selected from the group consisting of prostaglandin E, prostaglandin E 2 , prostaglandin F, prostaglandin F 2α,  and prostaglandin D 2 , or is an analog thereof.  
   
   
       3 . The composition of  claim 1  wherein the prostaglandin is prostaglandin F 2α  or an analog thereof.  
   
   
       4 . The composition of  claim 1  wherein the prostaglandin is prostaglandin E 2  or an analog thereof.  
   
   
       5 . The composition of  claim 1  wherein the prostaglandin comprises from 0 to 2 double covalent bonds connecting two carbon atoms.  
   
   
       6 . The composition of  claim 1  wherein the prostaglandin comprises two double covalent bonds connecting two carbon atoms.  
   
   
       7 . The composition of  claim 1  wherein the prostaglandin comprises from 1 to 3 heteroatoms, wherein said heteroatoms comprise S or O, said heteroatoms replacing carbon atoms which are present in prostaglandin E 2 , prostaglandin F 2 , or prostaglandin D 2 .  
   
   
       8 . The composition of  claim 1  wherein the prostaglandin comprises a moiety which replaces from 2 to 5 carbon atoms on the terminal end of a ω chain of a natural prostaglandin, said moiety comprising phenyl, naphthyl, benzothienyl, furanyl, or thienyl.  
   
   
       9 . The composition of  claim 1  wherein the prostaglandin is prostaglandin F 2α  and the amine is dopamine.  
   
   
       10 . The composition of  claim 1  wherein the prostaglandin is prostaglandin F 2α  and the amine is diacetyl dopamine.  
   
   
       11 . The composition of  claim 1  wherein the prostaglandin is prostaglandin F 2α  and the amine is serotonin.  
   
   
       12 . A compound comprising  
     
       
         
         
             
             
         
       
       or a salt, ester, or prodrug thereof,  
       wherein  
       said compound is not naturally occurring;  
       the hatched wedge indicates an (x configuration and the solid wedge indicates a β configuration;  
       the dashed line indicates the presence or absence of a double bond;  
       A and B are both CHOH, or A is CHOH and B is C═O, or B is CHOH and A is C═O;  
       R 1  is phenyl, indolyl, or monohydroxy or dihydroxy derivatives of phenyl or indolyl;  
       R 2  is OH or H;  
       R 3  is n-butyl, n-pentyl, or n-hexyl; cyclohexyl, Ar, or W—Ar;  
       wherein Ar is phenyl, naphthyl, thienyl, furanyl, or benzothienyl, or a substituted derivative of phenyl, naphthyl, thienyl, furanyl, or benzothienyl, wherein from 1 to 3 hydrogen atoms are substituted with halogen, methyl, or trifluoromethyl; and  
       W is N, S, O, or CH 2 ; and  
       R 4  is hydrogen, methyl, ethyl, iso-propyl, or n-propyl.  
     
   
   
       13 . The compound of  claim 12  wherein R 3  is n-butyl, Ar, or W—Ar, wherein Ar is phenyl, naphthyl, or benzothienyl.  
   
   
       14 . The compound of  claim 12  wherein R 3  is n-butyl, Ar, or W—Ar, wherein Ar is phenyl.  
   
   
       15 . The compound of  claim 12  wherein R 3  is n-butyl or W—Ar, wherein W is o or CH 2 , and Ar is phenyl.  
   
   
       16 . The compound of  claim 12  wherein R 1  is 3,4-dihydroxyphenyl and R 2  is OH.  
   
   
       17 . The compound of  claim 12  wherein R 1  is 3,4-dihydroxyphenyl, R 2  is OH, and R 4  is methyl.  
   
   
       18 . The compound of  claim 12  wherein R 1  is 3,4-dihydroxyphenyl, R 2  is H, and R 4  is hydrogen.  
   
   
       19 . The compound of  claim 12  wherein R 1  is 5-hydroxyindolyl, R 2  is H, and R 4  is hydrogen.  
   
   
       20 . The compound of  claim 12  comprising  
     
       
         
         
             
             
         
       
     
   
   
       21 . The compound of  claim 12  comprising  
     
       
         
         
             
             
         
       
     
   
   
       22 . The compound of  claim 12  comprising  
     
       
         
         
             
             
         
       
     
   
   
       23 . The compound of  claim 12  comprising  
     
       
         
         
             
             
         
       
     
   
   
       24 . An ophthalmic composition comprising a therapeutically active agent or a prodrug thereof, 
 said therapeutically active agent comprising an amide functional group,    wherein    selective hydrolysis of said amide functional group of the therapeutically active agent produces:    a compound having agonist activity at a prostaglandin receptor and a compound selected from the group consisting of serotonin and analogs thereof, dopamine and analogs thereof, and epinephrine and analogs thereof.    
   
   
       25 . The composition of  claim 24  wherein said prostaglandin receptor is selected from the group consisting of an FP receptor, an EP 1  receptor, an EP 2  receptor, an EP 4  receptor, a DP receptor, and combinations thereof.  
   
   
       26 . The composition of  claim 24  wherein said compound having agonist activity at a prostaglandin receptor is prostaglandin E, prostaglandin E 2 , prostaglandin F, prostaglandin F 2α  or prostaglandin D 2 .  
   
   
       27 . The composition of  claim 24  wherein said compound having agonist activity at a prostaglandin receptor is prostaglandin F 2α .  
   
   
       28 . The composition of  claim 24  wherein selective hydrolysis of said amide functional group produces epinephrine, dopamine, or serotonin.  
   
   
       29 . The composition of  claim 24  wherein the therapeutically active agent or said prodrug thereof is selected from the group consisting of 
 (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopentyl]-hept-5-enoic acid [2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide;    Acetic acid 2-acetoxy-5-(2-{(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopenyl]-hept-5 -enoylamino}-ethyl)-phenyl ester; and    (Z)-7-[(1R,2R,3R,5S)-3,5 -Dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopentyl]-hept-5-enoic acid [2-(3,4-dihydroxy-phenyl)-ethyl]-amide.    
   
   
       30 . A method of treating glaucoma comprising administering to a mammal suffering from glaucoma an effective amount of a therapeutically active agent or a pharmaceutically acceptable salt or a prodrug thereof, said therapeutically active agent consisting of a prostaglandin and a 2-aryl-1-ethylamine coupled by an amide bond.  
   
   
       31 . The method of  claim 30  wherein the 2-aryl-1-ethylamine comprises from 1 to 3 hydroxy or acetyloxy moieties.  
   
   
       32 . The method of  claim 30  wherein said prostaglandin is an FP-related prostaglandin.  
   
   
       33 . The method of  claim 30  wherein said prostaglandin is an EP 2 -related prostaglandin.  
   
   
       34 . The method of  claim 30  wherein said prostaglandin is an EP 4 -related prostaglandin.  
   
   
       35 . The method of  claim 30  wherein said prostaglandin is a DP-related prostaglandin.  
   
   
       36 . The method of  claim 30  wherein said prostaglandin is prostaglandin prostaglandin F 2α .  
   
   
       37 . The method of  claim 36  wherein said amine is epinephrine, dopamine, or serotonin.  
   
   
       38 . The composition of  claim 1  wherein the prostaglandin is prostaglandin F 2α  and the amine is epinephrine.  
   
   
       39 . The method of  claim 30  wherein said prostaglandin is EP 1 -related.