Neuroprotective polyphenol analogs

Abstract

The present invention provides neuroprotective polyphenol compounds, which can be synthetic analogs of fisetin, baicalein or chlorogenic acid, that maintain neuroprotective, anti-inflammatory, glutathione promoting, and/or antioxidant properties. The neuroprotective polyphenol compounds are useful for promoting, enhancing and/or increasing neuron protection, growth and/or regeneration. The polyphenol compounds further find use for increasing and or maintaining intracellular glutathione (GSH) levels. The polyphenol compounds are also useful for treating, preventing, mitigating and/or delaying neurodegenerative conditions, including diabetes, Parkinson's disease, Huntington's disease, Alzheimer's disease, non-Alzheimer's dementias, multiple sclerosis, traumatic brain injury, spinal cord injury or ALS.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Z is N or O, when Z is N then 
 
       
         
           
           
               
               
           
         
         when Z is O, then 
       
       
         
           
           
               
               
           
         
         each of R 1  and R 2 , independent of the other, is H, optionally substituted C 1-6 alkyl, —OR a , —NO 2  or —N(R c ) 2 ; when both R 1  and R 2  are —OR a , then, optionally, they combine to form a 5-6 membered ring of formula 
       
       
         
           
           
               
               
           
         
       
       where z is 1 or 2;
 R 3  is H, optionally substituted C 1-6 alkyl or —OR a ; 
 R 4 , when present, is R a ; 
 each of R 5  and R 6  is, independently for each occurrence, H, R e , R b , R e  substituted with one or more of the same or different R a  and/or R b , —OR e  substituted with one or more of the same or different R a  and/or R b , —SR e  substituted with one or more of the same or different R a  and/or R b , —C(O)R e  substituted with one or more of the same or different R a  and/or R b , —N(R a )R e  where R e  is substituted with one or more of the same or different R a  and/or R b , —(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —R b , —S—(C(R a ) 2 ) m —R b ,
 —O—(C(R b ) 2 ) m —R a , —N(R a )—(C(R a ) 2 ) m —R b , —O—(CH 2 ) m —CH((CH 2 ) m R b )R b , —C(O)N(R a )—(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N((C(R a ) 2 ) m R b ) 2 , —S—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—(C(R a ) 2 ) m —C(R a )(R b ) 2  or —N(R a )—(C(R a ) 2 ) m —C(O)—N(R a )—(C(R a ) 2 ) m —R b ; 
 
 each R a  is independently for each occurrence H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl; 
 each R b  is independently for each occurrence ═O, ═S, —OR a , —O—(C(R a ) 2 ), —OR a , —SR a , ═NR a , ═NOR a , —N(R c ) 2 , halo, —CF 3 , —CN, —NO 2 , —S(O)R a , —S(O) 2 R a , —SO 3 R a , —S(O) 2 N(R c ) 2 ,
 —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —OC(O)N(R c ) 2 , —[N(R a )C(O)] n R a , —[N(R a )C(O)] n OR a  or —[N(R a )C(O)] n N(R c ) 2 ; 
 
 each R c  is independently for each occurrence R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form a 3 to 10-membered heteroalicyclyl or a 5-10 membered heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which is optionally substituted with one or more of the same or different R a  and/or R d  groups; 
 each R d  is ═O, —OR a , haloC 1-3 alkyloxy, C 1-6 alkyl, ═S, —SR a , —N(R a ) 2 , halo, —CF 3 , —CN, —NO 2 , —S(O)R a , —S(O 2 )R a , —SO 3 R a , —S(O) 2 N(R a ) 2 ,
 —C(O)R a , —CO 2 R a , —C(O)N(R a ) 2 , —OC(O)N(R a ) 2 , —[N(R a )C(O)] n R a , —(C(R a ) 2 ) n —OR a , —C(O)—C 1-6 haloalkyl, —OC(O)R a , —O(C(R a ) 2 ) m —OR a , —S(C(R a ) 2 ) m —OR a , —N(R a )—(C(R a ) 2 ) m —OR a , —[N(R a )C(O)] n OR a , —[N(R a )C(O)] n N(R a ) 2  or —N(R a )C(O)C 1-6 haloalkyl; two R d , taken together with the atom or atoms to which they are attached, combine to form a 3-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a ; 
 
 each R e  is independently for each occurrence C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11  cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl; 
 two of R 5 , and independently, two of R 6 , together with the vicinal carbons to which they are attached, combine to form a 4-10 membered unsaturated, partially saturated or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a  and/or R b ; 
 each m is 1, 2 or 3; 
 each n is 0, 1, 2 or 3; 
 x is 0, 1, 2, 3 or 4; and 
 y is 0, 1, 2 or 3, 
 provided the compound is not Fisetin, Baicalein, PM-001, PM-002, PM-003, PM-004, PM-008 or PM-014. 
 
     
     
         2 . The compound of  claim 1 , according to Formula IIA or IIA, 
       
         
           
           
               
               
           
         
         wherein each of R 1  and R 2 , independent of the other, is H, optionally substituted C 1-6 alkyl, —OR a  or —N(R c ) 2 ; R 3  is H, optionally substituted C 1-6 alkyl or —OR a ; R 4  is C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl or C 7-16 arylalkyl; and each of R 5  and R 6  is independently for each occurrence H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11  cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, —OR a , —O—(C(R a ) 2 ) m —OR a , —SR a , —N(R c ) 2 , halo, —CF 3 , —CO 2 R a , —C(O)N(R c ) 2 ; and optionally, two of R 5 , together with the vicinal carbons to which they are attached, combine to form a 6-membered unsaturated aryl ring, said 6-membered aryl ring optionally substituted with one or more R a  and/or R b . 
       
     
     
         3 . The compound of  claim 2 , wherein:
 (a) the compound is of Formula II, and wherein each of R 1  and R 2 , independent of the other, is —OR a ; R 3  is H or optionally substituted C 1-6 alkyl; and R 4  is C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl or C 7-16 arylalkyl;   (b) the compound is of Formula IIIA, and wherein each of R 1  and R 2 , independent of the other, is —OR a ; R 3  is H, C 1-6 alkyl or —OR a ;   (c) the compound is Formula IIA, and wherein one of R 1  and R 2  is optionally substituted C 1-6 alkyl and the other of R 1  and R 2  is H, —OR a  or —N(R c ) 2 ; R 3  is H or optionally substituted C 1-6 alkyl; and R 4  is C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl or C 7-16 arylalkyl;   (d) the compound is of Formula IIIA, and wherein one of R 1  and R 2  is optionally substituted C 1-6 alkyl and the other of R 1  and R 2  is H, —OR a  or —N(R c ) 2 ; and R 3  is H, C 1-6 alkyl or —OR a ;   (e) The compound is of Formula IIA, and wherein one of R 1  and R 2  is H or —OR a  and the other of R 1  and R 2  is H or —N(R c ) 2 , provided at least one of R 1  and R 2  is not H; R 3  is H or optionally substituted C 1-6 alkyl; and R 4  is C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl or C 7-16 arylalkyl; or   (f) the compound is of Formula IIIA, and wherein one of R 1  and R 2  is H or —OR a  and the other of R 1  and R 2  is H or —N(R c ) 2 , provided at least one of R 1  and R 2  is not H; and R 3  is H, C 1-6 alkyl or —OR a .   
     
     
         4 . The compound of  claim 2 , according to:
 (a) Formula IIB,   
       
         
           
           
               
               
           
         
       
       wherein R a  is H or C 1-6 alkyl; R 3  is H or C 1-6 alkyl; R 4  is C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl or C 7-16 arylalkyl; each of R 5  and R 6  is independently for each occurrence H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11  cycloalkylalkyl, —OR a , —O—(C(R a ) 2 ) m —OR a , —SR a , —N(R c ) 2 , halo, —CF 3 , —CO 2 R a  or —C(O)N(R c ) 2 ; and each R c  is independently for each occurrence R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form a 3 to 7-membered heteroalicyclyl;
 (b) Formula IIIB, 
 
       
         
           
           
               
               
           
         
       
       wherein each R a  is H or C 1-6 alkyl; R 3  is H, —OH, —OC 1-6 alkyl or C 1-6 alkyl; each of R 5  and R 6  is, independently for each occurrence H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11  cycloalkylalkyl, —OR a , —O—(C(R a ) 2 ) m —OR a , —SR a , —N(R c ) 2 , halo, —CF 3 , —CO 2 R a  or —C(O)N(R c ) 2 ; and each R c  is independently for each occurrence R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form a 3 to 7-membered heteroalicyclyl, and optionally, two of R 5 , together with the vicinal carbons to which they are attached, combine to form a 6-membered unsaturated aryl ring, said 6-membered aryl ring optionally substituted with one or more R a  and/or R b ; or
 (c) Formula IIIF, 
 
       
         
           
           
               
               
           
         
       
       wherein R 2  is H or —OR a ; R 3  is H, C 1-6 alkyl or —OR a ; and each of R 5  and R 6  is independently for each occurrence H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11  cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, —OR a , —O—(C(R a ) 2 ) m , —OR a , —SR a , 
       —N(R c ) 2 , halo, —CF 3 , —CO 2 R a , —C(O)N(R c ) 2 ; and optionally, two of R 5 , together with the vicinal carbons to which they are attached, combine to form a 6-membered unsaturated aryl ring, said 6-membered aryl ring optionally substituted with one or more R a  and/or R. 
     
     
         5 . The compound of  claim 4 , according to
 (a) Formula IIIC or IIID,   
       
         
           
           
               
               
           
         
       
       wherein each R a  is H or C 1-6 alkyl; R 3  is H, —OH, —OC 1-6 alkyl or C 1-6 alkyl; each of R 6  is, independently for each occurrence H, C 1-6 alkyl, —OR a , —SR a , —N(R c ) 2 , or halo; each R c  is independently for each occurrence R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form a 3 to 7-membered heteroalicyclyl; and R 7  is independently for each occurrence H, C 1-6 alkyl, —OR a , —SR a , —N(R c ) 2 , or halo;
 (b) Formula IIIE, 
 
       
         
           
           
               
               
           
         
       
       wherein each R a  is H or C 1-6 alkyl; R 3  is H, —OH or C 1-6 alkyl; each of R 5a  and R 5b  is independently H or C 1-6 alkyl; and R 6  is independently for each occurrence H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11  cycloalkylalkyl, —OR a , —N(R c ) 2 , halo, —CF 3 , —CO 2 R a  or —C(O)N(R c ) 2 ;
 (c) Formula IIIG, 
 
       
         
           
           
               
               
           
         
       
       wherein R 2  is H or —OR a ; R 3  is H, C 1-6 alkyl or —OR a ; each of R 5a  and R 5b  is independently H or C 1-6 alkyl; and each R c  is independently for each occurrence R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form an optionally substituted 3- to 7-membered heteroalicyclyl; or
 (d) Formula IIIH or IIIJ, 
 
       
         
           
           
               
               
           
         
       
       wherein R 2  is H or —OR a ; R 3  is H, —OH, —OC 1-6 alkyl or C 1-6 alkyl; each of R 6  is, independently for each occurrence H, C 1-6 alkyl, —OR a , —SR a  or halo; each R c  is independently for each occurrence R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form an optionally substituted 3- to 7-membered heteroalicyclyl; and R 7  is independently for each occurrence H, C 1-6 alkyl, —OR a , —SR a , —N(R c ) 2 , or halo. 
     
     
         6 . A compound of Formula IVA, 
       
         
           
           
               
               
           
         
         wherein each of R 1  and R 2 , independent of the other, is H, optionally substituted C 1-6 alkyl, —OR a  or —N(R c ) 2 ; R 3  is H, optionally substituted C 1-6 alkyl or —OR a ; and each of R 5  and R 6  is independently for each occurrence H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11  cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, —OR a , 
       
       —O—(C(R a ) 2 ) m —OR a , —SR a , —N(R c ) 2 , halo, —CF 3 , —CO 2 R a , —C(O)N(R c ) 2 ; and optionally, two of R 5 , together with the vicinal carbons to which they are attached, combine to form a 6-membered unsaturated aryl ring, said 6-membered aryl ring optionally substituted with one or more R a  and/or R b , provided the compound is not chlorogenic acid. 
     
     
         7 . The compound of  claim 6 , according to
 (a) Formula IVB,   
       
         
           
           
               
               
           
         
       
       wherein each R a  is H or C 1-6 alkyl; R 3  is H, —OH, —OC 1-6 alkyl or C 1-6 alkyl; each of R 5  and R 6  is, independently for each occurrence H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11  cycloalkylalkyl, —OR a , —O—(C(R a ) 2 ) m —OR a , —SR a , —N(R c ) 2 , halo, —CF 3 , —CO 2 R a  or —C(O)N(R c ) 2 ; and each R c  is independently for each occurrence R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form a 3 to 7-membered heteroalicyclyl, and optionally, two of R 5 , together with the vicinal carbons to which they are attached, combine to form a 6-membered unsaturated aryl ring, said 6-membered aryl ring optionally substituted with one or more R a  and/or R b ; or
 (b) Formula IVF, 
 
       
         
           
           
               
               
           
         
       
       wherein R 2  is H or —OR a ; and R 3  is H, C 1-6 alkyl or —OR a . 
     
     
         8 . The compound of  claim 7 , according to
 (a) Formula IVC or IVD,   
       
         
           
           
               
               
           
         
       
       wherein each R a  is H or C 1-6 alkyl; R 3  is H, —OH, —OC 1-6 alkyl or C 1-6 alkyl; each of R 6  is, independently for each occurrence H, C 1-6 alkyl, —OR a , —SR a , —N(R c ) 2 , or halo; each R c  is independently for each occurrence R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form a 3 to 7-membered heteroalicyclyl; and R 7  is independently for each occurrence H, C 1-6 alkyl, —OR a , —SR a , —N(R c ) 2 , or halo;
 (b) Formula IVE, 
 
       
         
           
           
               
               
           
         
       
       wherein each of R 5a  and R 5b  is independently H or C 1-6 alkyl;
 (c) Formula IVG, 
 
       
         
           
           
               
               
           
         
       
       wherein each of R 5a  and R 5b  is independently H or C 1-6 alkyl; and each R c  is independently for each occurrence R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form an optionally substituted 3- to 7-membered heteroalicyclyl; or
 (d) Formula IVH or IVJ, 
 
       
         
           
           
               
               
           
         
       
       wherein R 3  is H, —OH, —OC 1-6 alkyl or C 1-6 alkyl; each of R 6  is, independently for each occurrence H, C 1-6 alkyl, —OR a , —SR a  or halo; each R c  is independently for each occurrence R a , or, alternatively, two R c  are taken together with the nitrogen atom to which they are bonded to form an optionally substituted 3- to 7-membered heteroalicyclyl; and R 7  is independently for each occurrence H, C 1-6 alkyl, —OR a , —SR a , —N(R c ) 2 , or halo. 
     
     
         9 . The compound according to  claim 1 , wherein the compound is:
 4-methoxy-2-(3,4-dihydroxyphenyl)quinoline (CMS-007);   4-ethoxy-2-(3,4-dihydroxyphenyl)quinoline (CMS-023);   4-isopropoxy-2-(3,4-dihydroxyphenyl)quinoline (CMS-024);   4-isopropoxy-2-(2,4-dihydroxyphenyl)quinoline (CMS-084);   4-cyclopentyloxy-2-(3,4-dihydroxyphenyl)quinoline (CMS-121);   4-methoxy-2-(3-hydroxy,4-methoxyphenyl)quinoline (CMS-001);   4-methoxy-2-(3,4-diethoxyphenyl)quinoline (CMS-004);   4-methoxy-2-(4-hydroxy,3-methoxyphenyl)quinoline (CMS-017);   4-methoxy-2-phenylquinoline (CMS-021);   4-methoxy-2-(4-hydroxyphenyl)quinoline (CMS-022);   4-methoxy-2-(2,4-dihydroxyphenyl)quinoline (CMS-083);   4-methoxy-2-(4-dimethylaminophenyl)quinoline (CMS-109);   4-methoxy-2-(4-(pyrrolidin-1-yl)phenyl)quinoline (CMS-110);   4-methoxy-2-(3-hydroxy-4-nitrophenyl)quinoline (CMS-111);   4-isopropoxy-2-(4-dimethylaminophenyl)quinoline (CMS-112); 4-isopropoxy-2-(4-(pyrrolidin-1-yl)phenyl)quinoline (CMS-113);   2-(3,4-dihydroxyphenyl)-3-hydroxy-6-methyl-4H-chromen-4-one (PM-010);   2-(3,4-dihydroxyphenyl)-6-ethyl-3-hydroxy-4H-chromen-4-one (PM-013);   2-(3,4-dihydroxyphenyl)-3-hydroxy-6-propyl-4H-chromen-4-one (PM-012);   2-(3,4-dihydroxyphenyl)-3-hydroxy-4H-benzo[h]chromen-4-one (CMS-040);   3-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one (CMS-069);   2-(4-(benzyloxy)-3-methoxyphenyl)-3-hydroxy-4H-benzo[h]chromen-4-one (CMS-065);   2-(4-hydroxy-3-methoxyphenyl)-3-methyl-4H-benzo[h]chromen-4-one (CMS-072);   2-(4-(benzyloxy)-3-methoxyphenyl)-3-hydroxy-6,7-dimethyl-4H-chromen-4-one (CMS-059);   2-(4-hydroxy-3-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one (CMS-064);   2-(4-(chloromethyl)-3-methoxyphenyl)-3-hydroxy-6,7-dimethyl-4H-chromen-4-one (CMS-078);   3-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one (CMS-092);   2-(4-(dimethylamino)phenyl)-3-hydroxy-6,7-dimethyl-4H-chromen-4-one (CMS-117);   3-hydroxy-2-(4-(pyrrolidin-1-yl)phenyl)-4H-benzo[h]chromen-4-one (CMS-114);   2-(4-(dimethylamino)phenyl)-3-hydroxy-4H-benzo[h]chromen-4-one (CMS-118);   3-hydroxy-2-(3-methoxy-4-(pyrrolidin-1-yl)phenyl)-4H-benzo[h]chromen-4-one (CMS-139);   3-hydroxy-2-(3-hydroxy-4-(pyrrolidin-1-yl)phenyl)-4H-benzo[h]chromen-4-one (CMS-140);   2-(3,4-diethoxyphenyl)-6,7-dimethyl-4H-chromen-4-one (CMS-018);   2-(3,4-diethoxyphenyl)-3-hydroxy-6,7-dimethyl-4H-chromen-4-one (CMS-025);   2-(3,4-dihydroxyphenyl)-3-hydroxy-6,7-dimethyl-4H-chromen-4-one (CMS-027);   2-(3,4-dihydroxyphenyl)-6,7-dimethyl-4H-chromen-4-one (CMS-028);   2-(3,4-diethoxyphenyl)-3-hydroxy-4H-benzo[h]chromen-4-one (CMS-036);   2-(3,4-diethoxyphenyl)-4H-benzo[h]chromen-4-one (CMS-038);   3-(3,4-dihydroxyphenyl)-2-hydroxy-1H-benzo[f]chromen-1-one (CMS-041);   2-(4-(benzyloxy)-3-methoxyphenyl)-6,7-dimethyl-4H-chromen-4-one (CMS-058);   2-(2,4-dihydroxyphenyl)-3-hydroxy-6,7-dimethyl-4H-chromen-4-one (CMS-093);   2-(2,4-dihydroxyphenyl)-6,7-dimethyl-4H-chromen-4-one (CMS-094);   3-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-4H-benzo[h]chromen-4-one (CMS-070);   2-(4-(pyrrolidin-1-yl)phenyl)-4H-benzo[h]chromen-4-one (CMS-115);   6,7-dimethyl-2-(4-(pyrrolidin-1-yl)phenyl)-4H-chromen-4-one (CMS-116);   2-(4-(dimethylamino)phenyl)-6,7-dimethyl-4H-chromen-4-one (CMS-119);   2-(4-(dimethylamino)phenyl)-4H-benzo[h]chromen-4-one (CMS-120); or   3-hydroxy-6,7-dimethyl-2-(4-(pyrrolidin-1-yl)phenyl)-4H-chromen-4-one (CMS-122).   
     
     
         10 . The compound according to  claim 6 , wherein the compound is:
 (E)-3-(3,4-dihydroxyphenyl)-1-(2-hydroxy-4,5-dimethylphenyl)prop-2-en-1-one (CMS-011);   (E)-3-(3,4-dihydroxyphenyl)-1-(1-hydroxynaphthalen-2-yl)prop-2-en-1-one (CMS-034);   (E)-3-(3-hydroxy-4-(pyrrolidin-1-yl)phenyl)-1-(1-hydroxynaphthalen-2-yl)prop-2-en-1-one (CMS-138);   (E)-1-(1-hydroxynaphthalen-2-yl)-3-(3-methoxy-4-(pyrrolidin-1-yl)phenyl)prop-2-en-1-one (CMS-137);   (E)-3-(3,4-dihydroxyphenyl)-1-(2-hydroxy-5-isopropylphenyl)prop-2-en-1-one (CMS-129);   (E)-3-(3,4-diethoxyphenyl)-1-(2-hydroxy-4,5-dimethylphenyl)prop-2-en-1-one (CMS-013);   (E)-3-(3,4-diethoxyphenyl)-1-(1-hydroxynaphthalen-2-yl)prop-2-en-1-one (CMS-032);   (E)-3-(4-(benzyloxy)-3-methoxyphenyl)-1-(1-hydroxynaphthalen-2-yl)prop-2-en-1-one (CMS-063);   (E)-3-(3-(benzyloxy)-4-methoxyphenyl)-1-(2-hydroxy-4,5-dimethylphenyl)prop-2-en-1-one (CMS-086);   (E)-3-(2,4-dihydroxyphenyl)-1-(2-hydroxy-4,5-dimethylphenyl)prop-2-en-1-one (CMS-087); or   (E)-1-(2-hydroxy-4,5-dimethylphenyl)-3-(3-hydroxy-4-methoxyphenyl)prop-2-en-1-one (CMS-088).   
     
     
         11 . A pharmaceutical composition comprising one or more compounds of  claim 1 , and a pharmaceutically acceptable carrier, excipient or vehicle. 
     
     
         12 . A method of:
 promoting, increasing, and/or enhancing the protection, growth and/or regeneration of neurons in a patient in need thereof, or   treating, reducing, mitigating or preventing a condition comprising diabetes, Parkinson's disease, Huntington's disease, Alzheimer's disease, non-Alzheimer's dementia, multiple sclerosis, traumatic brain injury, spinal cord injury, or ALS,   comprising administering to the patient an effective amount of one or more compounds of  claim 1 , thereby promoting, increasing, and/or enhancing the protection, growth and/or regeneration of neurons in a patient in need thereof, or treating, reducing, mitigating or preventing a condition comprising diabetes, Parkinson's disease, Huntington's disease, Alzheimer's disease, non-Alzheimer's dementia, multiple sclerosis, traumatic brain injury, spinal cord injury, or ALS.   
     
     
         13 . The method of  claim 12  wherein the method maintains glutathione levels in the patient. 
     
     
         14 . The method of  claim 12 , wherein:
 the compound is administered over a period of one to three weeks;   the compound administered orally, intravenously, inhalationally, transdermally or subcutaneously;   the patient is experiencing or is at risk of experiencing sepsis, trauma and/or shock;   the compound is co-administered with a thromolytic agent; or   the compound is co-administered with a thromolytic agent and the thrombolytic agent is co-administered in a subtherapeutic dose or amount.   
     
     
         15 . The method of  claim 14 , wherein the thrombolytic agent comprises tissue plasminogen activator, tenecteplase, urokinase, desmoteplase, reteplase, alteplase, anistreplase, streptokinase, or combinations thereof. 
     
     
         16 . A pharmaceutical composition comprising one or more compounds of  claim 6 , and a pharmaceutically acceptable carrier, excipient or vehicle. 
     
     
         17 . A method of:
 promoting, increasing, and/or enhancing the protection, growth and/or regeneration of neurons in a patient in need thereof, or   treating, reducing, mitigating or preventing a condition comprising diabetes, Parkinson's disease, Huntington's disease, Alzheimer's disease, non-Alzheimer's dementia, multiple sclerosis, traumatic brain injury, spinal cord injury, or ALS,   comprising administering to the patient an effective amount of one or more compounds of  claim 6 , thereby promoting, increasing, and/or enhancing the protection, growth and/or regeneration of neurons in a patient in need thereof, or treating, reducing, mitigating or preventing a condition comprising diabetes, Parkinson's disease, Huntington's disease, Alzheimer's disease, non-Alzheimer's dementia, multiple sclerosis, traumatic brain injury, spinal cord injury, or ALS.   
     
     
         18 . The method of  claim 17  wherein the method maintains glutathione levels in the patient. 
     
     
         19 . The method of  claim 17 , wherein:
 the compound is administered over a period of one to three weeks;   the compound administered orally, intravenously, inhalationally, transdermally or subcutaneously;   the patient is experiencing or is at risk of experiencing sepsis, trauma and/or shock;   the compound is co-administered with a thrombolytic agent; or   the compound is co-administered with a thrombolytic agent and the thrombolytic agent is co-administered in a subtherapeutic dose or amount.   
     
     
         20 . The method of  claim 19 , wherein the thrombolytic agent comprises tissue plasminogen activator, tenecteplase, urokinase, desmoteplase, reteplase, alteplase, anistreplase, streptokinase, or combinations thereof.