Compounds useful for treating neurodegenerative disorders

Abstract

As described herein, the present invention provides compounds useful for treating or lessening the severity of a neurodegenerative disorder. The present invention also provides methods of treating or lessening the severity of such disorders wherein said method comprises administering to a patient a compound of the present invention, or composition thereof. Said method is useful for treating or lessening the severity of, for example, Alzheimer's disease.

1 - 39 . (canceled) 
     
     
         40 . A method of inhibiting amyloid-beta production in a patient wherein said method comprises administering a composition comprising a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         each of Ring A, Ring B, Ring C, Ring D, and Ring E is independently saturated, partially unsaturated or aromatic; 
         G is S, CH 2 , NR, or O; 
         R 1  and R 2  are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N(R) 2 , or a suitably protected amino group, or R 1  and R 2  are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         each R is independently hydrogen, an optionally substituted C 1-6  aliphatic group, or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein: 
         two R on the same nitrogen atom are optionally taken together with said nitrogen atom to form a 3-8 membered saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         n is 0-2; 
         R 3 , R 4 , R 7 , and R 8  are each independently selected from halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ; 
         m is 0-2; 
         R 5  is T-C(R’) 3 , T-C(R′) 2 C(R″) 3 , R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 , or: 
         when R 5  is T-C(R′) 3  or T-C(R′) 2 C(R″) 3 , then R 6  and an R′ group on R 5  are optionally taken together to form a 3-8 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         each T is independently a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C 1-6  alkylidene chain wherein up to two methylene units of T are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —S(O)—, or —S(O) 2 —; 
         each R′ and R″ is independently selected from R, OR, SR, SO 2 R, OSO 2 R, N(R) 2 , NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ; 
         R 6  is halogen, R, OR, SR, SO 2 R, OSO 2 R, N(R) 2 , NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ; 
         R 9  and R 9 ′ are each independently selected from halogen, R, OR, SR, or N(R) 2 , or R 1  and R 2  are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         Q is a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C 1-6  alkylidene chain wherein up to two methylene units of Q are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —S(O)—, or —S(O) 2 —; and 
         R 10  is R, a suitably protected hydroxyl group, a suitably protected thiol group, a suitably protected amino group, an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a detectable moiety, a polymer residue, a peptide, or a sugar-containing or sugar-like moiety 
       
     
     
         41 . The method according to  claim 40 , wherein:
 G is 0; and   R 1  and R 2  are each independently R or OR.   
     
     
         42 . The method according to  claim 40 , wherein R 1  and R 2  are each independently R wherein R is hydrogen or an optionally substituted C 1-6  aliphatic group. 
     
     
         43 . The method according to  claim 40 , wherein R 1  and R 2  are taken together to form a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         44 . The method according to  claim 40 , wherein:
 R 5  is T-C(R′) 3  or T-C(R′) 2 C(R″) 3 ;   each T is independently a valence bond or a straight or branched C 1-4  alkylidene chain wherein one methylene unit of T is optionally replaced by —O—, —N(R)—, or —S—; and   each R′ and R″ is independently R, OR, OC(O)R, SR, or N(R) 2 .   
     
     
         45 . The method according to  claim 40 , wherein:
 Q is a an optionally substituted straight or branched, saturated or unsaturated, C 1-2  alkylidene chain wherein up to one methylene unit of Q is optionally replaced by —O—, —N(R)—, or —S—; and   R 10  is a glycoside.   
     
     
         46 . The method according to  claim 45 , wherein Q is —O— and R 10  is an arabinopyranoside or a xylopyranoside. 
     
     
         47 . The method according to  claim 40 , wherein said compound is of formula I-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         48 . The method according to  claim 40 , wherein said compound is of formula I-b or I-c: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         49 . The method according to  claim 40  wherein said compound is of formula II or II-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof 
       
     
     
         50 . The method according to  claim 40 , wherein the amyloid-beta peptide is amyloid-beta (1-42). 
     
     
         51 . The method according to  claim 50 , wherein amyloid-beta (1-42) peptide levels are reduced and amyloid-beta (1-40) peptide levels are not substantially reduced. 
     
     
         52 . The method according to  claim 50 , wherein the level of at least one of amyloid-beta (1-37) and amyloid-beta (1-39) is increased. 
     
     
         53 . The method according to  claim 40 , wherein the ratio of amyloid-beta (1-42) peptide to amyloid-beta (1-40) peptide in a patient is reduced. 
     
     
         54 . The method of  claim 53 , wherein the ratio is reduced from a range of about 0.1 to about 0.4 to a range of about 0.05 to about 0.08. 
     
     
         55 . A method for reducing the ratio of amyloid-beta (1-42) peptide to amyloid-beta (1-40) peptide in a cell, comprising contacting the cell with a compound of formula I of  claim 40 . 
     
     
         56 . A method for treating or lessening the severity of a disorder associated with amyloid-beta (1-42) peptide, wherein said method comprises administering to a patient a composition comprising a compound of Formula I and a pharmaceutically acceptable carrier. 
     
     
         57 . The method according to  claim 56 , wherein said disorder is Alzheimer's disease or Parkinson's disease. 
     
     
         58 . A method for reducing amyloid-beta (1-42) peptide levels in a cell, comprising contacting said cell with a compound of Formula I of  claim 40 . 
     
     
         59 . The method according to  claim 40 , further comprising the step of administering one or more additional therapeutic agents useful for treating neurodegenerative disorders, wherein the step of administering the one or more additional therapeutic agents occurs prior to, concurrent with, or subsequent to the step of administering a composition comprising a compound of Formula I. 
     
     
         60 . The method according to  claim 59 , wherein the one or more additional therapeutic agents are useful for treating Alzheimer's disease or Parkinson's Disease (PD). 
     
     
         61 . The method according to  claim 60 , wherein the one or more additional therapeutic agents are selected from the group consisting of acetylcholinesterase inhibitors, beta-secretase inhibitors, gamma-secretase inhibitors, aggregation inhibitors, metal chelators, antioxidants, NMDA inhibitors, and neuroprotectants. 
     
     
         62 . The method according to  claim 59 , wherein the one or more additional therapeutic agents are selected from the group consisting of donepezil, memantine, Exelon®, L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine.