Secondary phosphoric acid esters

Abstract

Novel symmetrical secondary phosphoric acid esters having the general formula ##STR1## wherein the substituent R is positioned in meta or para position relative to the phosphoric acid ester group; processes for the preparation of said esters; and compositions containing said esters. The esters are i.a. useful as selective inhibitors of prostaglandins and compounds with prostaglandin activities. They also selectively antagonize the slow reacting substance (SRS).

What we claim is: 
     
       1. A symmetrical secondary phosphoric acid ester compound of the general formula ##STR17## wherein R is positioned in m- or p-position relative to the phosphoric acid ester group and is ##STR18## wherein X is selected from the group consisting of ##STR19## wherein Y is a straight hydrocarbon chain having 2 or 3 carbon atoms, said chain being saturated or containing one double bond and having at most 2 substituents selected from the group consisting of lower alkyl, phenyl, phenyl substituted in p-position by lower alkyl, lower alkoxy or halogen (F, Cl, Br), benzyl and benzyl substituted in p-position by lower alkyl, lower alkoxy or halogen (F, Cl, Br); R 3 , R 4 , R 5 , R 6 , and R 7  are same or different and are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, hydroxy, OCOR 8 , F, Cl, Br, CF 3 , NO 2 , COOR 9 , CH 2  COOR 9 , OCH 2  COOR 9 , CONR 2   8 , CH 2  CONR 2   8 , OCH 2  CONR 2   8 , .Iadd.NR 2   8 , .Iaddend.NR 8  COR 8 , CH 2  NR 2   8  and CH 2  NR 8  COR 8 , wherein R 8  is selected from the group consisting of hydrogen and lower alkyl, and wherein R 9  is selected from the group consisting of hydrogen, lower alkyl and M, where M is selected from the group consisting of H, Na, K,1/2 Ca and a pharmaceutically acceptable amine with the proviso that one of said substituents R 3  -R 7  is selected from the group consisting of COOR 9 , CH 2  COOR 9 , OCH 2  COOR 9 , CONR 2   8 , CH 2  CONR 2   8  and OCH 2  CONR 2   8 , or selected from the group consisting of NR 2   8 , NR 8  COR 8 , CH 2  NR 2   8 , and CH 2  NR 8  COR 8 , wherein R 8  and R 9  have the above meaning. 
     
     
       2. A compound according to claim 1, wherein at least two of substituents R 3 , R 4 , R 5 , R 6  and R 7  are hydrogen. 
     
     
       3. A compound according to claim 2, wherein Y contains one substituent selected from the group consisting of phenyl, phenyl substituted in p-positions, benzyl and benzyl substituted in p-position. 
     
     
       4. A compound according to claim 3, wherein Y is a straight substituted hydrocarbon chain having two carbon atoms. 
     
     
       5. A compound according to claim 4, wherein one of substituents R 3 , R 4 , R 5 , R 6 , R 7  is selected from the group consisting of NR 2   8 , NR 8  COR 8 , CH 2  NR 2   8 , and CH 2  NR 8  COR 8 , wherein R 8  has the above meaning, said one substituent being in o-position relative to the keto-group of X. 
     
     
       6. A compound according to claim 4, wherein at least one of substituents R 3 , R 4 , R 5 , R 6 , R 7  is selected from the group consisting of hydroxy, alkoxy, and OCOR 8 , wherein R 8  has the above meaning, said substituent being in o-position relative to the keto-group of X. 
     
     
       7. A compound according to claim 4, wherein at least one of substituents R 3 , R 4 , R 5 , R 6 , R 7  is selected from the group consisting of hydroxy, alkoxy, and OCOR 8 , wherein R 8  has the .Iadd.above meaning..Iaddend. 
     
     
       8. A compound according to claim 2, wherein Y is a straight hydrocarbon chain having two or three carbon atoms, said chain being saturated or containing one double bond and having at most two substitutents being lower alkyl. 
     
     
       9. A compound according to claim 8, wherein Y is a straight substituted or unsubstituted hydrocarbon chain having two carbon atoms. 
     
     
       10. A compound according to claim 9, wherein at least one of substituents R 3 , R 4 , R 5 , R 6 , R 7  is selected from the group consisting of hydroxy, alkoxy, and OCOR 8 , wherein R 8  has the above meaning, said substituent being in o-position relative to the keto-group of X. 
     
     
       11. A compound according to claim 9, wherein one of substitutents R 3 , R 4 , R 5 , R 6 , R 7  is selected from the group consisting of NR 2   8 , NR 8  COR 8 , CH 2  NR 2   8 , and CH 2  NR 8  COR 8 , wherein R 8  has the above meaning, said one substitutent being in o-position relative to the keto-group of X. 
     
     
       12. A compound according to claim 8, wherein Y is a straight substituted or unsubstituted hydrocarbon chain having three carbon atoms. 
     
     
       13. A compound according to claim 9, wherein in the presence of substituents R 3 , R 4 , R 5 , R 6 , R 7  selected from the group consisting of hydroxy, loweralkoxy, OCOR 8  such substituents are positioned in m- and p-positions relative to the keto-group of X. 
     
     
       14. A compound according to claim 9, wherein X is ##STR20## where Y has the above meaning. 
     
     
       15. A compound according to claim 9, wherein X is ##STR21## where Y has the above meaning. 
     
     
       16. A compound according to claim 14, wherein R is positioned in p-position relative to the phosphoric acid ester group. 
     
     
       17. A compound according to claim 14, wherein R is positioned in m-position relative to the phosphoric acid ester group. 
     
     
       18. A compound according to claim 16, wherein Y is a straight unsubstituted hydrocarbon chain having two carbon atoms, said chain being saturated or containing one double bond. 
     
     
       19. A compound according to claim 16, wherein Y is a straight hydrocarbon chain having two carbon atoms and having at most two hydrogen atoms of the carbon atom adjacent to the keto-group substituted by lower alkyl. 
     
     
       20. A compound according to claim 1, wherein M is selected from the group consisting of Na, K, 1/2 Ca, diethanolamine, dimethylaminoethanol and N-methylglucamine. 
     
     
       21. A compound according to claim 6, which is sodium bis(4-(3-(4-diethylaminophenyl)-2-(4-methylphenyl) acryloyl)-3-methoxyphenyl) phosphate. 
     
     
       22. A compound according to claim 6, which is trisodium bis(4-(3-(4-carboxylatophenyl)-2-(4-methoxy-phenyl)-acryloyl)-3-methoxyphenyl) phosphate. 
     
     
       23. A compound according to claim 9, which is trisodium bis(4-(3-(3-(carboxylatomethoxy)phenyl)-3-oxopropyl)-phenyl) phosphate. 
     
     
       24. A compound according to claim 9, which is sodium bis (4-(3-(4-ethoxycarbonylphenyl)propionyl-2-methoxyphenyl) phosphate. 
     
     
       25. A compound according to claim 9, which is sodium bis(4-(3-(4-aminophenyl)-3-oxopropyl) phenyl) phosphate. 
     
     
       26. A compound according to claim 9, which is sodium bis(4-(3-(4-diethylaminophenyl)propionyl)-2,6-dimethylphenyl) phosphate. 
     
     
       27. A compound according to claim 9, which is trisodium bis(3-(3-(4-carboxylatomethylphenyl)-3-oxopropyl)phenyl) phosphate. 
     
     
       28. A compound according to claim 9, which is sodium bis(3-(3-(4-(N,N-dimethylcarbamoylmethyl) phenyl)-3-oxopropyl)phenyl) phosphate. 
     
     
       29. A compound according to claim 9, which is sodium bis(3-(3-(4-diethylaminophenyl)propionyl) phenyl) phosphate. 
     
     
       30. A compound according to claim 9, which is trisodium bis(3-(3-(4-carboxylatophenyl) propionyl)phenyl) phosphate. 
     
     
       31. A compound according to claim 9, which is sodium bis(3-(3-(3-dimethylaminomethyl-4-methoxyphenyl)propionyl) phenyl) phosphate. 
     
     
       32. A compound according to claim 10, which is sodium bis(4-(3-(4-aminophenyl)propionyl)-3-methoxyphenyl) phosphate. 
     
     
       33. A compound according to claim 11, which is sodium bis(4-(3-(2-aminophenyl)-3-oxopropyl) phenyl) phosphate. 
     
     
       34. A compound according to claim 11, which is sodium bis(3-(3-(2-aminophenyl)-3-oxopropyl) phenyl) phosphate.