EP4 receptor agonist, compositions and methods thereof

Abstract

This invention relates to potent selective agonists of the EP 4 subtype of prostaglandin E2 receptors, their use or a formulation thereof in the treatment of glaucoma and other conditions which are related to elevated intraocular pressure in the eye of a patient. This invention further relates to the use of the compounds of this invention for mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts.

1 . A compound having the structural formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein, 
 X is O or S;  
 Y 1  is 
 1) CH 2 CH 2 ,  
 2) CHCH, or  
 3)  
                     
 
 Y is C(O) or CH(OH);  
 A and W are independently selected from the group consisting of 
 1) a bond, and  
 2) C 1-6  alkylene, unsubstituted or substituted with 1, 2, 3, or 4 halogen atoms;  
 
 Z is 
 1) O,  
 2) S,  
 3)  
                     
 7) a disubstituted aryl or heteroaryl ring, wherein one ring atom of the ring is attached to the moiety  
                     
 and another ring atom is attached to the moiety  
                     
 with the proviso that when Z is O or S, then A and W are independently selected from the group consisting of C 1-6  alkylene, unsubstituted or substituted with 1, 2, 3, or 4 halogen atoms;  
 
 R 1  is 
 COR 5 ,  
 OH,  
 CN,  
 (CH 2 ) 1-3  CO 2 R 6 ,  
 (CH 2 ) 0-4 SO 3 R 6 ,  
 CF 2 SO 2 NH 2 ,  
 SO 2 NH 2 ,  
 SO 2 NHCOR 8 ,  
 PO(OH) 2 ,  
 C 1-4  alkoxy,  
 hydroxymethylketone,  
 (CH 2 ) 0-4  heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with 1 to 3 groups of R a , or  
 tetrazole;  
 
 R 2  is 
 1) C 1-6 alkyl, provided that R 2  is not n-pentyl,  
 2) (CH 2 ) 0-8 C 6-10 aryl,  
 3) (CH 2 ) 0-8 C 5-10 heteroaryl,  
 4) (CH 2 ) 0-8 C 3-10 heterocycloalkyl,  
 5) (CH 2 ) 0-8 C 3-8 cycloalkyl,  
 6) O—C 1-10 alkyl,  
 7) O—C 6-10 aryl,  
 8) O—C 5-10 heteroaryl,  
 9) O—C 5-10 heterocycloalkyl,  
 10) O—C 3-10 cycloalkyl  
 wherein aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with 1-3 groups of R b ;  
 
 R 3  and R 4  are independently selected from the group consisting of 
 1) hydrogen,  
 2) halogen, and  
 3) C 1-6  alkyl, or  
 
 R 3  and R 4 , together with the carbon atom to which they are attached, form a C 3-7  cycloalkyl ring;  
 R 5  is 
 1) hydrogen,  
 2) OH,  
 3) CH 2 OH,  
 4) C 1-6  alkoxy,  
 5) NHPO 2 R 6 ,  
 6) NHR 9 ,  
 7) NHSO 2 R 8 , or  
 8) NR 6 R 7 ;  
 
 R 6  and R 7  are independently selected from the group consisting of hydrogen and C 1-6  alkyl;  
 R 8  is selected from the group consisting of hydrogen, C 6-10 aryl, and C 1-4 alkyl;  
 R 9  is acyl or sulfonyl; and  
 R a  and R b  are independently selected from the group consisting of 
 1) C 1-6 alkoxy,  
 2) C 1-6 alkyl, unsubstituted or substituted with 
 a) C 1-6  alkoxy,  
 b) C 1-6  alkylthio,  
 c) CN,  
 d) OH, or  
 e) CF 3 ,  
 
 3) CF 3 ,  
 4) nitro,  
 5) amino,  
 6) cyano,  
 7) C 1-6 alkylamino,  
 8) halogen  
 9) OR c ,  
 10) OCH 2 R c , and  
 11) CH 2 OR c ;  
 
 R c  is 
 1) C 6-10 aryl,  
 2) C 5-10 heteroaryl,  
 3) C 3-10 heterocycloalkyl, or  
 4) C 3-8 cycloalkyl.  
 
 
   
   
       2 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is 
 1) cyclohexyl,    2) unsubstituted aryl, or    3) aryl substituted with 
 a) unsubstituted C 1-6  alkyl,  
 b) C 1-6  alkyl substituted with C 1-6  alkoxy  
 c) halogen, or  
 d) CF 3 .  
   
   
   
       3 . A compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1  is tetrazole or COR 5 , wherein R 5  is CH 2 OH or OH.  
   
   
       4 . A compound of  claim 3 , or a pharmaceutically acceptable salt thereof, wherein A is a bond, (CH 2 ) 1-4 , or (CH 2 ) 1-5 CF 2 , and W is a bond or (CH 2 ) 1-6 .  
   
   
       5 . A compound of  claim 4 , or a pharmaceutically acceptable salt thereof, wherein Z is 
 4) O,    5) S,                          7) disubstituted thiophene,    8) disubstituted furan, or    9) disubstituted benzene; and    R 3  and R 4  are independently selected from the group consisting of hydrogen and F, or R 3  and R 4 , together with the carbon atom to which they are attached, formn a cyclopropyl or cyclohexyl ring.    
   
   
       6 . A compound of  claim 5  selected from the group consisting of 
 4-[2-(2,2-difluoro-1-hydroxy-2-phenylethyl)cyclopropyl]-3-[6-(1H-tetraazol-5-yl)hexyl]-1,3-thiazolidin-2-one,    4-[2-(1-hydroxy-2-phenylethyl)cyclopropyl]-3-[6-(1H-tetraazol-5-yl)hexyl]-1,3-thiazolidin-2-one,    4-[2-(1-hydroxy-2-phenylethyl)cyclopropyl]-3-[6-(1H-tetraazol-5-yl)hexyl]-1,3-thiazolidin-2-one,    5-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-3-yl}propyl)thiophene-2-carboxylic acid,    5-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-3-yl}propyl)-2-furoic acid,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{3-[5-(1H-tetraazol-5-yl)-2-furyl]propyl}-1,3-thiazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{3-[5-(1H-tetraazol-5-yl)thien-2-yl]propyl}-1,3-thiazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{(2E)-3-[5-(1H-tetraazol-5-yl)thien-2-yl]prop-2-enyl}-1,3-thiazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{(2E)-3-[5-(1H-tetraazol-5-yl)-2-furyl]prop-2-enyl}-1,3-thiazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{(2Z)-3-[5-(1H-tetraazol-5-yl)thien-2-yl]prop-2-enyl}-1,3-thiazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{(2Z)-3-[5-(1H-tetraazol-5-yl)-2-furyl]prop-2-enyl}-1,3-thiazolidin-2-one,    3-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-3-yl}propyl)benzoic acid,    4-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-3-yl}propyl)benzoic acid,    2-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-3-yl}propyl)benzoic acid,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{3-[3-(1H-tetraazol-5-yl)phenyl]propyl}-1,3-thiazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{3-[2-(1H-tetraazol-5-yl)phenyl]propyl}-1,3-thiazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{3-[4-(1H-tetraazol-5-yl)phenyl]propyl}-1,3-thiazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{2-[3-(1H-tetraazol-5-ylmethyl)phenyl]ethyl}-1,3-thiazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{2-[4-(1H-tetraazol-5-ylmethyl)phenyl]ethyl)}-1,3-thiazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{2-[2-(1H-tetraazol-5-ylmethyl)phenyl]ethyl}-1,3-thiazolidin-2-one,    4-(2-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-3-yl}ethoxy)butanoic acid,    3-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-3-yl}propoxy)propanoic acid,    (4-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-3-yl}butoxy)acetic acid,    [(4-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-3-yl}butyl)thio]acetic acid,    3-[(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-3-yl}propyl)thio]propanoic acid,    4-[(2-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazolidin-3-yl}ethyl)thio]butanoic acid,    4-[2-(2,2-difluoro-1-hydroxy-2-phenylethyl)cyclopropyl]-3-[6-(1H-tetraazol-5-yl)hexyl]-1,3-oxazolidin-2-one,    4-[2-(1-hydroxy-2-phenylethyl)cyclopropyl]-3-[6-(1H-tetraazol-5-yl)hexyl]-1,3-oxazolidin-2-one,    4-[2-(1-hydroxy-2-phenylethyl)cyclopropyl]-3-[6-(1H-tetraazol-5-yl)hexyl]-1,3-oxazolidin-2-one,    5-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazolidin-3-yl}propyl)thiophene-2-carboxylic acid,    5-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazolidin-3-yl}propyl)-2-furoic acid,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{3-[5-(1H-tetraazol-5-yl)-2-furyl]propyl}-1,3-oxazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{3-[5-(1H-tetraazol-5-yl)thien-2-yl]propyl}-1,3-oxazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{(2E)-3-[5-(1H-tetraazol-5-yl)thien-2-yl]prop-2-enyl}-1,3-oxazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{(2E)-3-[5-(1H-tetraazol-5-yl)-2-furyl]prop-2-enyl}-1,3-oxazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{(2Z)-3-[5-(1H-tetraazol-5-yl)thien-2-yl]prop-2-enyl}-1,3-oxazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{(2Z)-3-[5-(1H-tetraazol-5-yl)-2-furyl]prop-2-enyl}-1,3-oxazolidin-2-one,    3-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazolidin-3-yl}propyl)benzoic acid,    4-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazolidin-3-yl}propyl)benzoic acid,    2-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazolidin-3-yl}propyl)benzoic acid,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{3-[3-(1H-tetraazol-5-yl)phenyl]propyl}-1,3-oxazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{3-[2-(1H-tetraazol-5-yl)phenyl]propyl}-1,3-oxazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{3-[4-(1H-tetraazol-5-yl)phenyl]propyl}-1,3-oxazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{2-[3-(1H-tetraazol-5-ylmethyl)phenyl]ethyl}-1,3-oxazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{2-[4-(1H-tetraazol-5-ylmethyl)phenyl]ethyl}-1,3-oxazolidin-2-one,    4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-{2-[2-(1H-tetraazol-5-ylmethyl)phenyl]ethyl}-1,3-oxazolidin-2-one,    4-(2-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazolidin-3-yl}ethoxy)butanoic acid,    3-(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazolidin-3-yl}propoxy)propanoic acid,    (4-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazolidin-3-yl}butoxy)acetic acid,    [(4-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazolidin-3-yl}butyl)thio]acetic acid,    3-[(3-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazolidin-3-yl}propyl)thio]propanoic acid,    4-[(2-{4-[(1E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazolidin-3-yl}ethyl)thio]butanoic acid,    or a pharmaceutically acceptable salt thereof.    
   
   
       7 . A method for treating disorders related to elevated intraocular pressure by: treating ocular hypertension, treating glaucoma, treating macular edema, treating macular degeneration, increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve tension, providing a neuroprotective effect or treating dry eyes, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of therapeutically effective amount of a compound of  claim 1 .  
   
   
       8 . A method according to  claim 7  wherein the topical formulation optionally contains xanthan gum or gellan gum.  
   
   
       9 . A method according to  claim 8  wherein the topical formulation is a solution or suspension.  
   
   
       10 . A method according to  claim 7  further comprising administering to the patient an active ingredient selected from the group consisting of a β-adrenergic blocking agent, a parasympatho-mimetic agent, a sympathomimetic agent, a carbonic anhydrase inhibitor, a prostaglandin, a hypotensive lipid, a neuroprotectant, and a 5-HT2 receptor agonist, is added to the formulation.  
   
   
       11 . A method according to  claim 10  wherein the β-adrenergic blocking agent is timolol, betaxolol, levobetaxolol, carteolol, or levobunolol; the parasympathomimetic agent is pilocarpine; the sympathomimetic agent is epinephrine, brimonidine, iopidine, clonidine, or para-aminoclonidine; the carbonic anhydrase inhibitor is dorzolamide, acetazolamide, metazolamide or brinzolamide; the prostaglandin is latanoprost, travaprost, unoprostone, rescula, or S1033; the hypotensive lipid is lumigan; the neuroprotectant is eliprodil, R-eliprodil or memantine; and the 5-HT2 receptor agonist is 1-(2-aminopropyl)-3-methyl-1H-imdazol-6-ol fumarate or 2-(3-chloro-6-methoxy-indazol-1-yl)-1-methyl-ethylamine.  
   
   
       12 . A pharmaceutical composition which is comprised of a compound in accordance with  claim 1  and a pharmaceutically acceptable carrier.