Use of Sphingosine-1-Phosphate (S1P) Receptor Agonists For the Treatment of Brain Degenerative Diseases

Abstract

Disclosed is the use of sphingosine-1-phosphate (S1P) receptor agonists, preferably 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in the treatment of progressive dementia or brain degenerative diseases.

1 - 3 . (canceled) 
     
     
         4 . A pharmaceutical composition for use in treating progressive dementia or brain degeneration, R-amyloid-related inflammatory diseases or disorders or for reducing or inhibiting loss of cognitive abilities comprising a sphingosine-1-phosphate (S1P) receptor agonist or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable diluents or carriers therefore. 
     
     
         5 . A pharmaceutical combination comprising a) a first agent which is a S1P receptor agonist or a pharmaceutically acceptable salt thereof and b) a co-agent useful in the alleviation or treatment of brain degenerative diseases or progressive dementia. 
     
     
         6 . A combination according to  claim 5 , wherein co-agent b) is selected from an AMPA receptor agonist, a noortropic or anti-inflammatory agent or a painkiller. 
     
     
         7 . A method for treating progressive dementia or brain degeneration or β-amyloid-related inflammatory diseases or disorders or for reducing or inhibiting loss of cognitive abilities in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a sphingosine-1-phosphate (S1P) receptor agonist or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A method according to  claim 7  comprising co-administration, e.g. concomitantly or in sequence, of b) a co-agent useful in the alleviation or treatment of brain degenerative diseases or progressive dementia. 
     
     
         9 . A composition, according to  claim 4 , wherein the S1P receptor agonist is compound of formula I 
       
         
           
           
               
               
           
         
         wherein R 1  is straight- or branched (C 12-22 )carbon chain
 which may have in the claim a bond or a hetero atom selected from a double bond, a triple bond, O, S, NR 6 , wherein R 6  is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or 
 which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxyl or carboxy; or 
 
         R 1  is
 a phenylalkyl wherein alkyl is a straight- or branched (C 6-20 )carbon chain; or 
 a phenylalkyl wherein alkyl is a straight- or branched (C 1-30 )carbon chain wherein said phenylalkyl is substituted by 
 a straight- or branched (C 6-20 )carbon chain optionally substituted by halogen, 
 a straight- or branched (C 6-20 )alkoxy chain optionally substituted by halogen, 
 a straight- or branched (C 6-20 )alkenyloxy, 
 phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, 
 cycloalkylalkyl substituted by C 6-20 alkyl, 
 heteroarylalkyl substituted by C 6-20 alkyl, 
 heterocyclic C 6-20 alkyl or 
 heterocyclic alkyl substituted by C 6-20 alkyl, 
 
       
       and wherein
 the alkyl moiety may have
 in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR 6 , wherein R 6  is as defined above, and 
 as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyl or carboxy, and 
 
 each of R 2 , R 3 , R 4  and R 5 , independently, is H, C 1-4 alkyl or acyl 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . A composition, according to  claim 9 , wherein the S1P receptor agonist is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form. 
     
     
         11 . A combination according to  claim 5 , wherein the S1P receptor agonist is compound of formula I 
       
         
           
           
               
               
           
         
         wherein R 1  is straight- or branched (C 12-22 )carbon chain
 which may have in the cain a bond or a hetero atom selected from a double bond, a triple bond, O, S, NR 6 , wherein R 6  is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or 
 which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxyl or carboxy; or 
 
         R 1  is
 a phenylalkyl wherein alkyl is a straight- or branched (C 6-20 )carbon chain; or 
 a phenylalkyl wherein alkyl is a straight- or branched (C 1-30 )carbon chain wherein said phenylalkyl is substituted by 
 a straight- or branched (C 6-20 )carbon chain optionally substituted by halogen, 
 a straight- or branched (C 6-20 )alkoxy chain optionally substituted by halogen, 
 a straight- or branched (C 6-20 )alkenyloxy, 
 phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, 
 cycloalkylalkyl substituted by C 6-20 alkyl, 
 heteroarylalkyl substituted by C 6-20 alkyl, 
 heterocyclic C 6-20 alkyl or 
 heterocyclic alkyl substituted by C 6-20 alkyl, 
 
       
       and wherein
 the alkyl moiety may have
 in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR 6 , wherein R 6  is as defined above, and 
 as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyl or carboxy, and 
 
 each of R 2 , R 3 , R 4  and R 5 , independently, is H, C 1-4 alkyl or acyl 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A method according to  claim 7 , wherein the S1P receptor agonist is compound of formula I 
       
         
           
           
               
               
           
         
         wherein R 1  is straight- or branched (C 12-22 )carbon chain
 which may have in the cain a bond or a hetero atom selected from a double bond, a triple bond, O, S, NR 6 , wherein R 6  is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or 
 which may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxyl or carboxy; or 
 
         R 1  is
 a phenylalkyl wherein alkyl is a straight- or branched (C 6-20 )carbon chain; or 
 a phenylalkyl wherein alkyl is a straight- or branched (C 1-30 )carbon chain wherein said phenylalkyl is substituted by 
 a straight- or branched (C 6-20 )carbon chain optionally substituted by halogen, 
 a straight- or branched (C 6-20 )alkoxy chain optionally substituted by halogen, 
 a straight- or branched (C 6-20 )alkenyloxy, 
 phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, 
 cycloalkylalkyl substituted by C 6-20 alkyl, 
 heteroarylalkyl substituted by C 6-20 alkyl, 
 heterocyclic C 6-20 alkyl or 
 heterocyclic alkyl substituted by C 6-20 alkyl, 
 
       
       and wherein
 the alkyl moiety may have
 in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR 6 , wherein R 6  is as defined above, and 
 as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyl or carboxy, and 
 
 each of R 2 , R 3 , R 4  and R 5 , independently, is H, C 1-4 alkyl or acyl 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A combination according to  claim 11 , wherein the S1P receptor agonist is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form. 
     
     
         14 . A method according to  claim 12 , wherein the S1P receptor agonist is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form.