Use of s1p receptor modulator

Abstract

Use of an S1P receptor modulator in the treatment or prevention of a disease or condirion dependent on brain-derived neurotrophic factor (BDNF) expression.

1 . A method for preventing, inhibiting or treating a condition effected by brain-derived neurotrophic factor, production, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an sphingosine-1 phosphate receptor modulator other than 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof, wherein said S1P receptor modulator is selected from:
 (a) Compounds of the formula I   
       
         
           
           
               
               
           
         
         wherein X is O, S, SO or SO 2 ; 
         R 1  is halogen, trihalomethyl, OH, C 1-7 alkyl, C 1-4 alkoxy, trifluoromethoxy, phenoxy, cyclohexylmethyloxy, pyridylmethoxy, cinnamyloxy, naphthylmethoxy, phenoxymethyl, CH 2 —OH, CH 2 —CH 2 —OH, C 1-4 alkylsulfonyl, benzylthio, acetyl, nitro or cyano, or phenyl, phenylC 1-4 alkyl or phenyl-C 1-4 alkoxy each phenyl group thereof being optionally substituted by halogen, CF 3 , C 1-4 alkyl or C 1-4 alkoxy; 
         R 2  is H, halogen, trihalomethyl, C 1-4 alkoxy, C 1-7 alkyl, phenethyl or benzyloxy; 
         R 3 H, halogen, CF 3 , OH, C 1-7 alkyl, C 1-4 alkoxy, benzyloxy, phenyl or C 1-4 alkoxymethyl; 
         each of R 4  and R 5 , independently is H or a residue of formula (a) 
       
       
         
           
           
               
               
           
         
         wherein each of R 8  and R 9 , independently, is H or C 1-4 alkyl optionally substituted by halogen; and 
         n is an integer from 1 to 4; 
         (b) Compounds of formula II 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1a  is halogen, trihalomethyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl-sulfonyl, aralkyl, optionally substituted phenoxy or aralkyloxy; 
         R 2a  is H, halogen, trihalomethyl, C 1-4 alkyl, C 1-4 alkoxy, aralkyl or aralkyloxy; 
         R 3a  is H, halogen, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio or benzyloxy; 
         R 4a  is H, C 1 -Alkyl, phenyl, optionally substituted benzyl or benzoyl, or lower aliphatic C 1-5 acyl; 
         R 5a  is H, monohalomethyl, C 1-4 alkyl, C 1-4 alkoxy-methyl, C 1-4 alkyl-thiomethyl, hydroxyethyl, hydroxypropyl, phenyl, aralkyl, C 2-4 alkenyl or -alkynyl; 
         R 6a  is H or C 1-4 alkyl; 
         R 7a  is H, C 1-4 alkyl or a residue of formula (a) as defined above, 
         X, is O, S, SO or SO 2 ; and 
         n a  is an integer of 1 to 4; 
         (c) Compounds of the formula III 
       
       
         
           
           
               
               
           
         
         wherein R 1  is a straight- or branched (C 12-22 )chain
 which may have in the chain a bond or a hetero atom selected from a double bond, a triple bond, O, S, NR 6 , wherein R 6  is H, C 1-4 alkyl, aryl-C 1-4 alkyl, acyl or (C 1-4 alkoxy)carbonyl, and carbonyl, and/or
 which may have as a substituent C 1-4 alkoxy, C 2-4 alkenyloxy, C 2-4 alkynyloxy, arylC 1-4 alkyl-oxy, acyl, C 1-4 alkylamino, C 1-4 alkylthio, acylamino, (C 1-4 alkoxy)carbonyl, (C 1-4 alkoxy)-carbonylamino, acyloxy, (C 1-4 alkyl)carbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy 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, 
 phenyl-C 1-14 alkoxy, halophenyl-C 1-4 alkoxy, phenyl-C 1-14 alkoxy-C 1-14 alkyl, phenoxy-C 1-4 alkoxy or phenoxy-C 1-4 alkyl, 
 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 2-20 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 C 1-4 alkoxy, C 2-4 alkenyloxy, C 2-4 alkynyloxy, arylC 1-4 alkyloxy, acyl, C 1-4 alkyl-amino, C 1-4 alkylthio, acylamino, (C 1-4 alkoxy)carbonyl, (C 1-4 alkoxy)carbonylamino, acyloxy, (C 1-4 alkyl)carbamoyl, nitro, halogen, amino, hydroxy or carboxy, and 
 
         each of R 2 , R 3 , R 4  and R 5 , independently, is H, C 1-4  alkyl or acyl; 
         (d) Compounds of the formula IV 
       
       
         
           
           
               
               
           
         
         wherein m is 1 to 9 and each of R′ 2 , R′ 3 , R′ 4  and R′ 5 , independently, is H, C 1-6 alkyl or acyl; 
         (e) Compounds of the formula V 
       
       
         
           
           
               
               
           
         
         wherein W is H; C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; unsubstituted or by OH substituted phenyl; R″ 4 O(CH 2 ) n ; or C 1-6 alkyl substituted by 1 to 3 substituents selected from the group consisting of halogen, C 3-8 cycloalkyl, phenyl and phenyl substituted by OH; 
         X is H or unsubstituted or substituted straight chain alkyl having a number p of carbon atoms or unsubstituted or substituted straight chain alkoxy having a number (p-1) of carbon atoms, e.g. substituted by 1 to 3 substitutents selected from the group consisting of C 1-6 alkyl, OH, C 1-6 alkoxy, acyloxy, amino, C 1-6 alkylamino, acylamino, oxo, haloC 1-6 alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1 to 3 substituents selected from the group consisting of C 1-6 alkyl, OH, C 1-6 alkoxy, acyl, acyloxy, amino, C 1-6 alkylamino, acylamino, haloC 1-6 alkyl and halogen; Y is H, C 1-6 alkyl, OH, C 1-6 alkoxy, acyl, acyloxy, amino, C 1-6 alkylamino, acylamino, haloC 1-6 alkyl or halogen, Z 2  is a single bond or a straight chain alkylene having a number or carbon atoms of q, 
         each of p and q, independently, is an integer of 1 to 20, with the proviso of 6≦p+q≦23, m′ is 1, 2 or 3, n is 2 or 3, 
         each of R″ 1 , R″ 2 , R″ 3  and R″ 4 , independently, is H, C 1-4 alkyl or acyl; 
         (f) Compounds of the formula VIa or VIb 
       
       
         
           
           
               
               
           
         
         wherein X a  is O, S, NR 1s  or a group —(CH 2 ) na —, which group is unsubstituted or substituted by 1 to 4 halogen; n, is 1 or 2, R 1s  is H or (C 1-4 )alkyl, which alkyl is unsubstituted or substituted by halogen; R 1a  is H, OH, (C 1-4 )alkyl or O(C 1-4 )alkyl wherein alkyl is unsubstituted or substituted by 1 to 3 halogen; R 1b  is H, OH or (C 1-4 )alkyl, wherein alkyl is unsubstituted or substituted by halogen; each R 2a  is independently selected from H or (C 1-4 )alkyl, which alkyl is unsubstituted or substituted by halogen; R 3a  is H, OH, halogen or O(C 1-4 )alkyl wherein alkyl is unsubstituted or substituted by halogen; and R 3b  is H, OH, halogen, (C 1-4 )alkyl wherein alkyl is unsubstituted or substituted by hydroxy, or O(C 1-4 )alkyl wherein alkyl is unsubstituted or substituted by halogen; Y a  is —CH 2 —, —C(O)—, —CH(OH)—, —C(═NOH)—, O or S, and R 4a  is (C 4-14 )alkyl or (C 4-14 )alkenyl; 
         (g) Compounds of the formula VII 
       
       
         
           
           
               
               
           
         
         wherein each of R 1d  and R 2d , independently, is H or an amino-protecting group; 
         R 3d  is hydrogen, a hydroxy-protecting group or a residue of formula 
       
       
         
           
           
               
               
           
         
         R 4d  is C 1-4 alkyl; 
         n d  is an integer of 1 to 6; 
         X d  is ethylene, vinylene, ethynylene, a group having a formula -D-CH 2 — (wherein D is carbonyl, —CH(OH)—, O, S or N), aryl or aryl substituted by up to three substitutents selected from group a as defined hereinafter; 
         Y d  is single bond, C 1-10 alkylene, C 1-10 alkylene which is substituted by up to three substitutents selected from groups a and b, C 1-10 alkylene having O or S in the middle or end of the carbon chain, or C 1-10 alkylene having O or S in the middle or end of the carbon chain which is substituted by up to three substituents selected from groups a and b; 
         R 5d  is hydrogen, C 3-6 cycloalkyl, aryl, heterocyclic group, C 3-6 cycloalkyl substituted by up to three substituents selected from groups a and b, aryl substituted by up to three substituents selected from groups a and b, or heterocyclic group substituted by up to three substituents selected from groups a and b; 
         each of R 6d  and R 7d , independently, is H or a substituent selected from group a; 
         each of R 8d  and R 9d , independently, is H or C 1-4 alkyl optionally substituted by halogen; 
         <group a> is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, lower alkylthio, carboxyl, lower alkoxycarbonyl, hydroxy, lower aliphatic acyl, amino, mono-lower alkylamino, di-C 1-4 alkylamino, acylamino, cyano or nitro; and 
         <group b> is C 3-6 cycloalkyl, aryl or heterocyclic group, each being optionally substituted by up to three substituents selected from group a; 
         with the proviso that when R 5d  is hydrogen, Y d  is a either a single bond or linear C 1-10 alkylene; 
         (h) Compounds of the formula VIII 
       
       
         
           
           
               
               
           
         
         wherein R 1e , R 2e , R 3e , R 4e , R 5e , R 6e , R 7e , n e , X e  and Y e  are as disclosed in JP-14316985; 
         or a pharmacologically acceptable salt, ester or hydrate thereof; 
         (i) compounds of the formula IX 
       
       
         
           
           
               
               
           
         
         wherein 
         Ar is phenyl or naphthyl; each of m g  and n g  independently is 0 or 1; A is selected from COOH, PO 3 H 2 , PO 2 H, SO 3 H, PO(C 1-3 alkyl)OH and 1H-tetrazol-5-yl; each of R 1g  and R 2g  independently is H, halogen, OH, COOH or C 1-4 alkyl optionally substituted by halogen; R 3g  is H or C 1-4 alkyl optionally substituted by halogen or OH; each R 4g  independently is halogen, or optionally halogen substituted C 1-4 alkyl or C 1-3 alkoxy; and each of R g  and M has one of the significances as indicated for B and C, respectively, in WO03/062252A1; 
         (j) Compound of the formula X 
       
       
         
           
           
               
               
           
         
         wherein Ar is phenyl or naphthyl; n is 2, 3 or 4; A is COOH, 1H-tetrazol-5-yl, PO 3 H 2 , PO 2 H 2 , —SO 3 H or PO(R 5h )OH wherein R 5h  is selected from C 1-4 alkyl, hydroxyC 1-4 alkyl, phenyl, —CO—C 1-3 alkoxy and —CH(OH)-phenyl wherein said phenyl or phenyl moiety is optionally substituted; each of R 1h  and R 2h  independently is H, halogen, OH, COOH, or optionally halogeno substituted C 1-6 alkyl or phenyl; R 3h  is H or C 1-4 alkyl optionally substituted by halogen or OH; each R 4h  independently is halogen, OH, COOH, C 1-4 alkyl, S(O) 0,1 or 2 O 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkoxy, aryl or aralkoxy, wherein the alkyl portions may optionally be substituted by 1-3 halogens; and each of R h  and M has one of the significances as indicated for B and C, respectively, in WO03/062248A2; 
         (k) Compounds of the formula XIa or XIb 
       
       
         
           
           
               
               
           
         
         wherein 
         A k  is COOR 5k , OPO(OR 5k ) 2 , PO(OR 5k ) 2 , SO 2 OR 5k , POR 5k OR 5k  or 1H-tetrazol-5-yl, R 5k  being H or C 1-6 alkyl; 
         W k  is a bond, C 1-3 alkylene or C 2-3 alkenylene; 
         Y k  is C 6-10 aryl or C 3-9 heteroaryl, optionally substituted by 1 to 3 radicals selected from halogene, OH, NO 2 , C 1-6 alkoxy; halo-substituted C 1-6 alkyl and halo-substituted C 1-6 alkoxy; 
         Z k  is a heterocyclic group as indicated in WO 04/103306A, e.g., azetidine; 
         R 1k  is C 6-10 aryl or C 3-9 heteroaryl, optionally substituted by C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, C 3-9 heteroaryl, C 3-9 heteroarylC 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-4 alkyl, 
         C 3-8 heterocycloalkyl or C 3-8 heterocycloalkylC 1-4 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 1k  may be substituted by 1 to 5 groups selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and halo substituted-C 1-6 alkyl or —C 1-6 alkoxy; 
         R 2k  is H, C 1-6 alkyl, halo substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl: and 
         each of R 3k  or R 4k , independently, is H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy or halo substituted C 1-6 alkyl or C 1-6 alkoxy; 
         and the N-oxide derivatives thereof or prodrugs thereof; 
         and the pharmacologically acceptable salts, solvates and hydrates of compounds of the formulae I, II, III, IV, V, VIa, VIb, VII, VIII, IX, X, XIa and XIb. 
       
     
     
         2 . The method of  claim 1 , where the condition affected by BDNF production is selected from one or more of diabetes, nervous system injured by wound, congenital conditions, neurodegenerative diseases, sensory nerve dysfunction, obesity, cognitive impairment, attention deficit disorders, sleep disorders or depressive disorders. 
     
     
         3 . A method according to  claim 2 , wherein the condition affected by BDNF production is depression. 
     
     
         4 . A method according to  claim 1  comprising co-administration, concomitantly or in sequence, of a therapeutically effective non-toxic amount of a S1P receptor modulator and a second therapeutic substance. 
     
     
         5 . A method according to  claim 1 , wherein the condition affected by BDNF production is diabetes mellitus, obesity, inherited convulsive paraplegia associated with retina degeneration, Kjelin syndrome, Barnard-Scholz syndrome, retinitis pigmentosa, Stargardt disease, Usher syndromes and Refsum syndrome. 
     
     
         6 . A method according to  claim 1 , wherein the S1P receptor modulator that is administered is BAF312. 
     
     
         7 . A method according to  claim 1 , wherein the S1P receptor modulator that is administered is KRP203.