Inhibitors of the gastric h+, k+-atpase with enhanced therapeutic properties

Abstract

Chemical syntheses and medical uses of novel inhibitors of the gastric H + , K + -ATPase for the treatment and/or management of duodenal ulcers, heartburn, acid reflux, other conditions mediated by gastric acid secretion and/or psoriasis are described.

1 - 23 . (canceled) 
     
     
         24 . A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H + , K + -ATPase inhibitor comprising a compound of Formula 1 wherein said amount of said gastric H + , K + -ATPase inhibitor affects a less pronounced increase in gastrin levels in mammalian subjects during treatment of gastric acid related diseases as compared to the non-isotopically enriched compound;
 wherein said compound of Formula 1 has the structure   
       
         
           
           
               
               
           
         
         or a single enantiomer, a mixture of enantiomers, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt thereof, wherein: 
         R 1 , R 4 , R 9  and R 10  are each independently hydrogen or deuterium; 
         R 2 , R 3 , R 6 , and R 8  are each independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6  alkyl, and C 1 -C 6  alkyloxy; 
         R 5  is selected from the group consisting of —CH 2 —, —CHD- and —CD 2 -; and 
         R 7  is selected from the group consisting of hydrogen, deuterium, —NO 2 , C 1 -C 6  alkyl, and C 1 -C 6  alkyloxy; 
         provided that said compound of Formula 1 contains at least one deuterium atom; and 
         provided that deuterium enrichment in said compound of Formula 1 is at least about 1%. 
       
     
     
         25 . A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H + , K + -ATPase inhibitor comprising a compound of Formula 1 wherein said amount of said gastric H + , K + -ATPase inhibitor affects a decreased inhibition of at least one cytochrome P 450  isoform in mammalian subjects during treatment of gastric acid related diseases as compared to the non-isotopically enriched compound;
 wherein said compound of Formula 1 has the structure   
       
         
           
           
               
               
           
         
         or a single enantiomer, a mixture of enantiomers, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt thereof, wherein: 
         R 1 , R 4 , R 9  and R 10  are each independently hydrogen or deuterium; 
         R 2 , R 3 , R 6 , and R 8  are each independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6  alkyl, and C 1 -C 6  alkyloxy; 
         R 5  is selected from the group consisting of —CH 2 —, —CHD- and —CD 2 -; and 
         R 7  is selected from the group consisting of hydrogen, deuterium, —NO 2 , C 1 -C 6  alkyl, and C 1 -C 6  alkyloxy; 
         provided that said compound of Formula 1 contains at least one deuterium atom; and 
         provided that deuterium enrichment in said compound of Formula 1 is at least about 1%. 
       
     
     
         26 . The method of  claim 25 , wherein said cytochrome P 450  isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP1B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51, 
     
     
         27 . A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H + , K + -ATPase inhibitor comprising a compound of Formula 1 so as to elicit an improved antisecretory effect during the treatment of gastric acid related diseases as compared to the non-isotopically enriched compound;
 wherein said compound of Formula 1 has the structure   
       
         
           
           
               
               
           
         
         or a single enantiomer, a mixture of enantiomers, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt thereof, wherein: 
         R 1 , R 4 , R 9  and R 10  are each independently hydrogen or deuterium; 
         R 2 , R 3 , R 6 , and R 8  are each independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6  alkyl, and C 1 -C 6  alkyloxy; 
         R 5  is selected from the group consisting of —CH 2 —, —CHD- and —CD 2 -; and 
         R 7  is selected from the group consisting of hydrogen, deuterium, —NO 2 , C 1 -C 6  alkyl, and C 1 -C 6  alkyloxy; 
         provided that said compound of Formula 1 contains at least one deuterium atom; and 
         provided that deuterium enrichment in said compound of Formula 1 is at least about 1%. 
       
     
     
         28 . A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H + , K + -ATPase inhibitor comprising a compound of Formula 1 wherein said amount of said gastric H + , K + -ATPase inhibitor elicits an improved clinical effect comprising accelerated rate of healing and accelerated rate of symptom relief during the treatment of gastric related diseases as compared to the non-isotopically enriched compound;
 wherein said compound of Formula 1 has the structure   
       
         
           
           
               
               
           
         
         or a single enantiomer, a mixture of enantiomers, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt thereof, wherein: 
         R 1 , R 4 , R 9  and R 10  are each independently hydrogen or deuterium; 
         R 2 , R 3 , R 6 , and R 8  are each independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6  alkyl, and C 1 -C 6  alkyloxy; 
         R 5  is selected from the group consisting of —CH 2 —, —CHD- and —CD 2 -; and 
         R 7  is selected from the group consisting of hydrogen, deuterium, —NO 2 , C 1 -C 6  alkyl, and C 1 -C 6  alkyloxy; 
         provided that said compound of Formula 1 contains at least one deuterium atom; and 
         provided that deuterium enrichment in said compound of Formula 1 is at least about 1%. 
       
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising administering to a mammalian subject in need of treatment a therapeutically effective amount of a gastric H + , K + -ATPase inhibitor comprising a compound of Formula 1 wherein said compound of Formula 1 has the structure 
       
         
           
           
               
               
           
         
         or a single enantiomer, a mixture of enantiomers, an individual diastereomer, a mixture of diastereomers, or a pharmaceutically acceptable salt thereof, wherein: 
         R 1 , R 4 , R 9  and R 10  are each independently hydrogen or deuterium; 
         R 2 , R 3 , R 6 , and R 8  are each independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6  alkyl, and C 1 -C 6  alkyloxy; 
         R 5  is selected from the group consisting of —CH 2 —, —CHD- and —CD 2 -; and 
         R 7  is selected from the group consisting of hydrogen, deuterium, —NO 2 , C 1 -C 6  alkyl, and C 1 -C 6  alkyloxy; 
         provided that said compound of Formula 1 contains at least one deuterium atom; and 
         provided that deuterium enrichment in said compound of Formula 1 is at least about 1%. 
       
     
     
         32 - 35 . (canceled) 
     
     
         36 . The method as recited in  claim 31 , said compound having a structural formula wherein:
 if R 1 , R 3 , and R 4  are deuterium, R 2  is —OCH 3 , R 6  is —CH 3 , R 7  is —OCH 3 , R 8  is —CH 3 , then at least one of R 5  and R 9  has deuterium enrichment of at least about 1%;   if R 1 , R 3 , and R 4  are deuterium, R 2  is —OCH 3 , R 6  is —CH 3 , R 7  is —OCH 3 , and R 8  is —CH 3 , then at least one of R 5 , R 9 , and R 10  has deuterium enrichment of at least about 1%;   if R 1 , R 2 , R 3 , and R 4  are deuterium, R 6  is —CH 3 , and R 7  is —OCH 2 CF 3 , then at least one of R 8 , R 9 , and R 10  has deuterium enrichment of at least about 1%;   provided that if R 2  is hydrogen or C 1 -C 4  alkyloxy, R 6  is C 1 -C 4  alkyl or C 1 -C 4  alkyloxy, R 7  is C 1 -C 4  alkyl, C 1 -C 4  alkyloxy, or C 2 -C 8  alkyloxyalkyloxy, and R 8  is hydrogen or C 1 -C 4  alkyl, and at least one of the hydrogen atoms of R 2 , R 6 , R 7 , and R S  is replaced with deuterium, then at least one of R 1 , R 3 , R 4 , R 5 , R 9 , and R 10  has deuterium enrichment of at least about 1%; and provided that if R 2  is —OCHF 2 , R 6  is —OCH 3 , and R 7  is —OCH 3 , and at least one of the hydrogen atoms of R 2 , R 6 , and R 7  is replaced with deuterium, then at least one of R 1 , R 3 , R 4 , R 5 , R 8 , R 9 , and R 10  has deuterium enrichment of at least about 1%.   
     
     
         37 . The method of  claim 31 , wherein said compound contains about 90% or more by weight of the (R)-enantiomer of said compound and about 10% or less by weight of (S)-enantiomer of said compound. 
     
     
         38 . The method of  claim 31 , wherein said compound contains about 90% or more by weight of the (S)-enantiomer of said compound and about 10% or less by weight of (R)-enantiomer of said compound. 
     
     
         39 . The method of  claim 31 , wherein said alkyl is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and tert-butyl. 
     
     
         40 . The method of  claim 31 , wherein said alkyloxy is selected from the group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, and tert-butoxy. 
     
     
         41 . The method of  claim 31 , wherein said compound has a structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a single enantiomer, a mixture of enantiomers, or a pharmaceutically acceptable salt thereof. 
       
     
     
         42 . The method of  claim 31 , wherein said compound has a structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a single enantiomer, a mixture of enantiomers, or a pharmaceutically acceptable salt thereof. 
       
     
     
         43 . The method of  claim 42 , wherein said compound contains about 90% or more by weight of the (R)-enantiomer of said compound and about 10% or less by weight of (S)-enantiomer of said compound. 
     
     
         44 . The method of  claim 42 , wherein said compound contains about 90% or more by weight of the (S)-enantiomer of said compound and about 10% or less by weight of (R)-enantiomer of said compound.