Method for treating central nervous system disorders

Abstract

The present invention provides a method for treating a central nervous system disorder in a mammalian subject, which comprises administering an effective amount of a 11-deoxy-prostaglandin compound to a subject in need thereof. The invention also provide novel 11-deoxy-prostaglandin compound.

1 . A method for protecting cerebrovascular endothelial cells in a mammalian subject, which comprises administering an effective amount of an 11-deoxyprostaglandin compound represented by the formula (III): 
       
         
           
           
               
               
           
         
         wherein L is hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein the five-membered ring may optionally have at least one double bond; 
         A is —CH 3 , —CH 2 OH, —COCH 2 OH, —COOH or a functional derivative thereof; 
         B is single bond, —CH 2 —CH 2 —, —CH—CH—, —C≡C—, —CH 2 —CH 2 —CH 2 —, —CH═CH—CH 2 —, —CH 2 —CH═CH—, —C≡C—CH 2 — or —CH 2 —C≡C—; 
         C═Z is 
       
       
         
           
           
               
               
           
         
         wherein R 4  and R 5  are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R 4  and R 5  are not hydroxy and lower alkoxy at the same time; 
         X 1  and X 2  are hydrogen, lower alkyl, or halogen; 
         R 1  is a saturated or unsaturated bivalent lower or medium aliphatic hydrocarbon, which is unsubstituted or substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; and 
         R 2  is a single bond or lower alkylene; and 
         R 3  is lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-oxy group, and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur, 
         provided that one of X 1  and X 2  is substituted by halogen and/or C═Z is C═O; to a subject in need thereof. 
       
     
     
         2 . The method described in  claim 1 , wherein the cerebrovascular endothelial cell is that of a Blood-brain barrier. 
     
     
         3 . A compound represented by the formula (IV): 
       
         
           
           
               
               
           
         
         wherein L is hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein the five-membered ring may optionally have at least one double bond; 
         A is —CH 3 , —CH 2 OH, —COCH 2 OH, —COOH or a functional derivative thereof; 
         B is single bond, —CH 2 —CH 2 —, —CH═CH—, —C≡C—, —CH 2 —CH 2 —CH 2 —, —CH═CH—CH 2 —, —CH 2 —CH═CH—, —C≡C—CH 2 — or —CH 2 —C≡C—; 
         C═Z is 
       
       
         
           
           
               
               
           
         
         wherein R 4  and R 5  are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R 4  and R 5  are not hydroxy and lower alkoxy at the same time; 
         X 1 ′ and X 2 ′ are same or different halogen atoms; 
         R 1  is a saturated or unsaturated bivalent lower or medium aliphatic hydrocarbon, which is unsubstituted or substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; and 
         R 2  is a single bond or lower alkylene; and 
         R 3  is lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-oxy group, and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur; 
         provided that the compound is not 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE 1 . 
       
     
     
         4 . The compound as described in  claim 3  selected from the group consisting of: 11-deoxy-13,14-dihydro-16,16-difluoro-PGE 1 , 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE 1  isopropyl ester, 2-decarboxy-2-(2-carboxyethyl)-11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE 1  isopropyl ester, 2-decarboxy-2-(2-carboxyethyl)-11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE 1 , 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGE 1  isopropyl ester, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGE 1 , 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-ethyl-PGE 1 , 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGE 1  methyl ester, 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-20-ethyl-PGE 1  isopropyl ester and 11-deoxy-13,14-dihydro-15-keto-16,16-difluoro-PGF 1α  isopropyl ester.