Methods for treating or preventing neuroinflammation or autoimmune diseases

Abstract

Disclosed herein are ribonucleotide reductase inhibitors, compositions comprising ribonucleotide reductase inhibitors, and methods for treating and/or preventing autoimmune diseases and neuroinflammatory diseases with the ribonucleotide reductase inhibitors.

What is claimed is: 
     
         1 . A method for preventing or treating a neuroinflammatory, an autoimmune disease, or a lipid storage disease in a subject, comprising administering to a subject an effective amount of one or more ribonucleotide reductase inhibitors, or a pharmaceutically acceptable salt thereof, having the formula: 
       
         
           
           
               
               
           
         
       
       wherein the index n is 0 or 1; 
       X is N or CR; 
       R is chosen from hydrogen and hydroxyl; 
       Y is a unit having the formula: 
       
         
           
           
               
               
           
         
       
       R 4  is chosen from:
 i) O; 
 ii) S; or 
 iii) NR 7 : 
 R 7  is chosen from: 
 i) hydrogen; 
 ii) hydroxy; 
 iii) amino 
 iv) cyano; 
 v) substituted or unsubstituted C 1 -C 4  linear or branched alkyl; 
 vi) substituted or unsubstituted C 1 -C 4  linear or branched alkoxy; or 
 vii) NR 8 R 9 ; R 8  and R 9  are each independently chosen from hydrogen, hydroxy, amino, C 1 -C 4  linear or branched alkyl, C 1 -C 4  linear or branched alkoxy, or C(═R 10 )R 11 ; R 10  is chosen from O, S, or NR 12 ; R 12  is hydrogen, hydroxyl, or amino; is chosen from hydrogen, hydroxyl, amino, cyano, C 1 -C 4  linear or branched alkyl, or C 1 -C 4  linear or branched alkoxy; 
 
       R 5  is chosen from:
 i) hydrogen; 
 ii) hydroxy; 
 iii) cyano; 
 iv) substituted or unsubstituted C 1 -C 10  linear or branched alkyl; 
 v) substituted or unsubstituted C 1 -C 10  linear or branched alkoxy; 
 vi) substituted or unsubstituted phenoxy; or 
 vii) NR 14 ; R 13  and R 14  are each independently chosen from hydrogen, hydroxy, amino, C 1 -C 4  linear or branched alkyl, C 1 -C 4  linear or branched alkoxy, or C(═R 15 )R 16 ; R 15  is chosen from O, S, or NR 17 ; R 17  is hydrogen, hydroxyl, or amino; R 16  is chosen from hydrogen, hydroxyl, amino, cyano, C 1 -C 4  linear or branched alkyl, or C 1 -C 4  linear or branched alkoxy; 
 
       R 6a  and R 6b  are each independently hydrogen, hydroxy, amino, C 1 -C 4  linear or branched alkyl, or C 1 -C 4  linear or branched alkoxy; 
       the index x is 0 or 1; 
       Z is chosen from:
 i) hydrogen; 
 ii) hydroxyl; 
 iii) NR 18a R 18b ; R 18a  and R 18b  are each independently chosen from hydrogen, hydroxy, amino, C 1 -C 6  linear or branched alkyl, C 1 -C 6  linear or branched alkoxy, or C(═R 21 )R 22 ; R 21  is chosen from O, S, or NR 23 ; R 23  is hydrogen, hydroxyl, or amino; R 22  is chosen from hydrogen, hydroxyl, amino, cyano, C 1 -C 6  linear or branched alkyl, or C 1 -C 6  linear or branched alkoxy; 
 iv) NR 19 NR 20a R 20b ; R 19 , R 20a , and R 20b  are each independently chosen from hydrogen, hydroxy, amino, C 1 -C 6  linear or branched alkyl, C 1 -C 6  linear or branched alkoxy, or C(═R 21 )R 22 ; R 21  is chosen from O, S, or NR 23 ; R 23  is hydrogen, hydroxyl, or amino; R 22  is chosen from hydrogen, hydroxyl, amino, cyano, C 1 -C 6  linear or branched alkyl, or C 1 -C 6  linear or branched alkoxy; 
 v) substituted or unsubstituted C 1 -C 6  linear or branched alkyl; 
 vi) substituted or unsubstituted C 1 -C 6  linear or branched alkoxy; 
 vii) —C(O)OR 24 ; R 24  is hydrogen, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted phenyl; 
 viii) —OC(O)R 25 ; R 25  is substituted or unsubstituted C 1 -C 6  alkyl or substituted or unsubstituted phenyl; 
 ix) substituted or unsubstituted C 6  or C 10  aryl; 
 x) substituted or unsubstituted C 1 -C 9  heterocyclic; 
 xi) substituted or unsubstituted C 1 -C 9  heteroaryl; and 
 
       R 1 , R 2 , and R 3  are each independently chosen from:
 i) hydrogen; 
 ii) hydroxyl; 
 iii) amino; 
 iv) halogen; 
 v) substituted or unsubstituted C 1 -C 3  alkyl; 
 vi) substituted or unsubstituted C 1 -C 3  alkoxy; 
 vii) —C(O)OR 26 ; R 26  is hydrogen, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted phenyl; 
 viii) —OC(O)R 27 ; R 27  is substituted or unsubstituted C 1 -C 6  alkyl or substituted or unsubstituted phenyl; 
 ix) —NR 28 NR 29 R 30 ; R 28  is hydrogen or C 1 -C 3  alkyl, R 29  and R 30  are each independently chosen from hydrogen or C 1 -C 3  alkyl; or 
 x) R 1  and R 2  can be taken together to form a substituted or unsubstituted 6-member aryl ring. 
 
     
     
         2 . The method according to  claim 1 , wherein the ribonucleotide reductase inhibitor has a formula chosen from: 
       
         
           
           
               
               
           
         
       
       wherein R 31 , R 32  R 33 , and R 34  are each independently chosen from substitution independently chosen from:
 i) hydrogen; 
 ii) C 1 -C 12  linear, branched, or cyclic alkyl, alkenyl, and alkynyl; 
 iii) substituted or unsubstituted C 6  or C 10  aryl; 
 iv) substituted or unsubstituted C 6  or C 10  alkylenearyl; 
 v) substituted or unsubstituted C 1 -C 9  heterocyclic rings; 
 vi) substituted or unsubstituted C 1 -C 9  heteroaryl rings; 
 vii) —(CR 102a R 102a ) z OR 101 ; 
 viii) —(CR 102a R 102b ) z C(O)R 101 ; 
 ix) —(CR 102a R 102b ) z C(O)OR 101 ; 
 x) —(CR 102a R 102b ) z C(O)N(R 101 ) 2 ; 
 xi) halogen; 
 xii) —(CR 102a R 102b ) z CN; 
 xiii) —(CR 102a R 102b ) z NO 2 ; 
 xiv) —CH j X k ; wherein X is halogen, j is from 0 to 2, j+k=3; 
 xv) —(CR 102a R 102b ) z SR 101 ; 
 xvi) —(CR 102a R 102b ) z SO 2 R 101 ; and 
 xvii) —(CR 102a R 102b ) z SO 3 R 101 ; 
 
       wherein each R 101  is independently hydrogen, substituted or unsubstituted C 1 -C 4  linear. branched, or cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R 101  units can be taken together to form a ring comprising 3-7 atoms; R 102a  and R 102b  are each independently hydrogen or C 1 -C 4  linear or branched alkyl; the index z is from 0 to 4. 
     
     
         3 . The method according to  claim 2 , wherein the ribonucleic reductase inhibitor has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 4  is chosen from:
 i) O; 
 ii) NH; or 
 iii) NOH; 
 
       R 5  is chosen from:
 i) OH; 
 ii) C 1 -C 4  linear or branched alkyl; 
 iii) NH 2 ; 
 iv) NHOH; or 
 v) NHNH 2 ; and 
 
       Z, R, R 1 , R 2 , and R 3  are each independently hydrogen or hydroxyl. 
     
     
         4 . The method according to  claim 2 , wherein the ribonucleic reductase inhibitor has a formula chosen from: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method according to  claim 2 , wherein the ribonucleotide reductase inhibitor has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 3  is each independently chosen from:
 i) hydrogen; 
 ii) methyl; 
 ii) methoxy; 
 iii) ethoxy; 
 iv) hydroxy; 
 v) acetate; 
 vi) fluoro; 
 vii) chloro; or 
 viii) carboxy; 
 
       R 5  is hydrogen or methyl, R 8  is hydrogen or methyl, R 10  is S, and R 11  is NH 2 . 
     
     
         6 . The method according to  claim 2 , wherein the ribonucleotide reductase inhibitor has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 5  is hydrogen or methyl, R 8  is hydrogen or methyl, R 10  is S, R 11  is NH 2 , and R 3 , R 31 , R 32  R 33 , and R 34  are each independently chosen from:
 i) hydrogen; 
 ii) methyl; 
 iii) methoxy; 
 iv) ethoxy; 
 v) hydroxy; 
 vi) cyano; 
 vii) acetate; 
 viii) fluoro; 
 ix) chloro; and 
 x) carboxy. 
 
     
     
         7 . The method according to  claim 2 , wherein the ribonucleotide reductase inhibitor has the formula:
   Z—Y;
   
       wherein Z is chosen from:
 i) hydrogen; 
 ii) NH 2 ; 
 iii) NHNH 2 ; 
 iv) NHOH; 
 viii) NOHR 18b ; R 18b  is chosen from substituted or unsubstituted C 1 -C 6  linear or branched alkyl, C 1 -C 6  linear or branched alkoxy, or C(═O)R 22 ; R 22  is C 1 -C 6  linear or branched alkyl; 
 ix) substituted or unsubstituted C 1 -C 6  linear or branched alkyl; 
 x) phenyl; 
 xi) naphthyl; 
 xii) pyridinyl; 
 xiii) pyrimidinyl; or 
 xiv) thienyl; and 
 
       Y has the formula: 
       
         
           
           
               
               
           
         
       
       R 4  is chosen from:
 i) O; 
 ii) S; or 
 iii) NHR 7 ; R 7  is chosen from hydrogen, hydroxy, amino, substituted or unsubstituted C 1 -C 4  linear or branched alkyl; or substituted or unsubstituted C 1 -C 4  linear or branched alkoxy; and 
 
       R 5  is NH 2 . 
     
     
         8 . A method for preventing or treating a neuroinflammatory or autoimmune disease in a subject, comprising administering to a subject an effective amount of one or more ribonucleotide reductase inhibitors chosen from:
 i) hydroxyurea;   ii) methoxyurea;   iii) 1-methoxy-1-methylurea;   iv) N-ethylhydroxyurea;   v) N-acetylhydroxyurea;   vi) 3-phenyl-1-hydroxyurea;   vii) dihydroxyurea   viii) hydroxylamine;   ix) methoxyamine;   x) N-methylhydroxylamine;   xi) O,N-dimethylhydroxylamine;   xii) formamidoxime;   xiii) N-hydroxyglycine;   xiv) N-hydroxyglycine amide;   xv) acetohydroxamic acid;   xvi) N-methylacetohydroxamic acid;   xvii) N-hydroxyurethane;   xviii) N-hydroxyguanidine;   xix) guanidine; and   xx) 3-phenyl-1-hydroxy-2-thiourea.   
     
     
         9 . A method according to  claim 1 , wherein the neurological inflammatory disease is chosen from Alzheimer's disease, multiple sclerosis, Parkinson's disease, traumatic brain injury, ataxia telangiectasia, Coackayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, spinocerebellare ataxia type 3, neuroborreliosis, primary lateral sclerosis, progressive supranuclear palsy, Schilder's disease, subacute combined degeneration of spinal cord secondary to pernicious anaemia, drug-induced demyelination, radiation induced demyelination, spinal muscular atrophy, tabes dorsales, spinal cord injury, chronic inflammatory demyelinating neuropathy, a congenital metabolic disorder, polymyositis, temporal arteritis, vasculitis, autism, and interstitial cystitis, Hurler's Syndrome, Scheie's Syndrome, Hunter's Syndrome, San Fillipo's Syndrome, Maroteaux-Lany Syndrome, Sly Syndrome, Fucosidosis, Alpha-mannosidosis, Beta-mannosidosis, Schindler's Disease, Pompeii's Disease, Woman's Disease, and Infantile Neuronal Ceroid Lipofuscinosis. 
     
     
         10 . A method according to  claim 1 , wherein the autoimmune disease is chosen from multiple sclerosis, rheumatoid arthritis, insulin dependent diabetes mellitus, systemic lupus, inflammatory bowel disease, Crohn's disease, psoriasis, sarcoidosis, asthma, Addison's disease, myasthenia gravis, celiac disease, autoimmune hepatitis, Ankylosing spondylitis, Sjögren's syndrome, Wegener's granulomatosis, lupus erythematosus, scleroderma, autoimmune thyroid disease, ultra-violet induced dermatomyositis, Graves' disease, juvenile idiopathic arthritis, neuropathy with abnormal myelination, a hereditary demyelinating condition, a prion-induced demyelination, and encephalitis-induced demyelination, and autoimmune hemolytic anemia. 
     
     
         11 . A method according to  claim 1 , wherein the storage disease is chosen from Tay-Sachs disease, Fabry's disease, GM1 gangliosidoses, GM2 gangliosidoses, Gaucher's disease, Krabbe's disease, metachromatic leukodystrophy, Niemann-Pick disease, Alexander's disease, Refsum's disease, Sandhoff's disease, acute disseminated encephalomyelitis, Prion disease, Lewy body dementia, and Spielmeyer-Vogt-Sjorgen-Batten disease. 
     
     
         12 . A method according to  claim 1 , wherein the disease is chosen from stroke, antiphospholipid antibody syndrome, bullous pemphigoid, Goodpature's syndrome, Guillain-Barré syndrome, Hashimoto's disease, ideopathic thrombocytopenic purpura, myasthenia gravis, pemphigus vulgaris, alcoholism, Canavan disease, spinal cerebellar ataxia, Kennedy's disease, and Huntington's disease. 
     
     
         13 . A composition comprising:
 a) effective amount of one or more ribonucleotide reductase inhibitors, or a pharmaceutically acceptable salt thereof, having the formula:   
       
         
           
           
               
               
           
         
          wherein the index n is 0 or 1; 
         X is N or CR; 
         R is chosen from hydrogen and hydroxyl; 
         Y is a unit having the formula: 
       
       
         
           
           
               
               
           
         
          R 4  is chosen from:
 i) O; 
 ii) S; or 
 iii) NR 7 : 
 R 7  is chosen from: 
 i) hydrogen; 
 ii) hydroxy; 
 iii) amino 
 iv) cyano; 
 v) substituted or unsubstituted C 1 -C 4  linear or branched alkyl; 
 vi) substituted or unsubstituted C 1 -C 4  linear or branched alkoxy; or 
 vii) NR 8 R 9 ; R 8  and R 9  are each independently chosen from hydrogen, hydroxy, amino, C 1 -C 4  linear or branched alkyl, C 1 -C 4  linear or branched alkoxy, or C(═R 10 )R 11 ; R 10  is chosen from O, S, or NR 12 ; R 12  is hydrogen, hydroxyl, or amino; R 11  is chosen from hydrogen, hydroxyl, amino, cyano, C 1 -C 4  linear or branched alkyl, or C 1 -C 4  linear or branched alkoxy; 
 
         R 5  is chosen from:
 viii) hydrogen; 
 ix) hydroxy; 
 x) cyano; 
 xi) substituted or unsubstituted C 1 -C 10  linear or branched alkyl; 
 xii) substituted or unsubstituted C 1 -C 10  linear or branched alkoxy; 
 xiii) substituted or unsubstituted phenoxy; or 
 xiv) NR 13 R 14 ; R 13  and R 14  are each independently chosen from hydrogen, hydroxy, amino, C 1 -C 4  linear or branched alkyl, C 1 -C 4  linear or branched alkoxy, or C(═R 15 )R 16 ; R 15  is chosen from O, S, or NR 17 ; R 17  is hydrogen, hydroxyl, or amino; R 16  is chosen from hydrogen, hydroxyl, amino, cyano, C 1 -C 4  linear or branched alkyl, or C 1 -C 4  linear or branched alkoxy; 
 R 6a  and R 6b  are each independently hydrogen, hydroxy, amino, C 1 -C 4  linear or branched alkyl, or C 1 -C 4  linear or branched alkoxy; 
 the index x is 0 or 1; 
 Z is chosen from: 
 xii) hydrogen; 
 xiii) hydroxyl; 
 xiv) NR 18a R 18b ; R 18a  and R 18b  are each independently chosen from hydrogen, hydroxy, amino, C 1 -C 6  linear or branched alkyl, C 1 -C 6  linear or branched alkoxy, or C(═R 21 )R 22 ; R 21  is chosen from O, S, or NR 23 ; R 23  is hydrogen, hydroxyl, or amino; R 22  is chosen from hydrogen, hydroxyl, amino, cyano, C 1 -C 6  linear or branched alkyl, or C 1 -C 6  linear or branched alkoxy; 
 xv) NR 19 NR 20a R 20b ; R 19 , R 20a , and R 20b  are each independently chosen from hydrogen, hydroxy, amino, C 1 -C 6  linear or branched alkyl, C 1 -C 6  linear or branched alkoxy, or C(═R 21 )R 22 ; R 22  is chosen from O, S, or NR 23 ; R 23  is hydrogen, hydroxyl, or amino; R 22  is chosen from hydrogen, hydroxyl, amino, cyano, C 1 -C 6  linear or branched alkyl, or C 1 -C 6  linear or branched alkoxy; 
 xvi) substituted or unsubstituted C 1 -C 6  linear or branched alkyl; 
 xvii) substituted or unsubstituted C 1 -C 6  linear or branched alkoxy; 
 xviii) —C(O)OR 24 ; R 24  is hydrogen, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted phenyl; 
 xix) —OC(O)R 25 ; R 25  is substituted or unsubstituted C 1 -C 6  alkyl or substituted or unsubstituted phenyl; 
 xx) substituted or unsubstituted C 6  or C 10  aryl; 
 xxi) substituted or unsubstituted C 1 -C 9  heterocyclic; 
 xxii) substituted or unsubstituted C 1 -C 9  heteroaryl; and 
 R 1 , R 2 , and R 3  are each independently chosen from: 
 xi) hydrogen; 
 xii) hydroxyl; 
 xiii) amino; 
 xiv) halogen; 
 xv) substituted or unsubstituted C 1 -C 3  alkyl; 
 xvi) substituted or unsubstituted C 1 -C 3  alkoxy; 
 xvii) —C(O)OR 26 ; R 26  is hydrogen, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted phenyl; 
 xviii) —OC(O)R 27 ; R 27  is substituted or unsubstituted C 1 -C 6  alkyl or substituted or unsubstituted phenyl; 
 xix) —NR 28 NR 29 R 30 ; R 28  is hydrogen or C 1 -C 3  alkyl, R 29  and R 30  are each independently chosen from hydrogen or C 1 -C 3  alkyl; or 
 R 1  and R 2  can be taken together to form a substituted or unsubstituted 6-member aryl ring; and 
 
         b) a pharmaceutically acceptable carrier. 
       
     
     
         14 . A composition according to  claim 13 , further comprising one or more compounds chosen from glatiramer acetate, mitoxantrone, tysabri, interferon β1-a, interferon β 1-b, interferon α, methylprednisolone, prednisone, cyclophosphamide, methotrexate, azathioprine, cladribine cyclosporine, FTY-720 (fingolimod), MBP8298 (dirucotide), liquinimod, 4-aminopyridine (4AP), lovastatin, and pravastatin. 
     
     
         15 . A method for preventing or treating a neuroinflammatory, an autoimmune disease, or a lipid storage disease in a subject, comprising administering to a subject an effective amount of one or more ribonucleotide reductase inhibitors, or a pharmaceutically acceptable salt thereof, chosen from:
 i) ribonucleotide reductase inhibitors having the formula II:   
       
         
           
           
               
               
           
         
          wherein n is from 2 to 5 and P can be COOH or the pharmaceutically-acceptable salt or ester thereof, CN, C 1 -C 8  alkyl, aryl-substituted C 1 -C 8  alkyl, acylamino, HOC 2 H 4 —NH—CH 2 —C(═O)—, C 1 -C 2 H 4 —NCH 3 —CH 2 —C(═O)—, C(S)OC 2 H 5 , C(O)—NH—C 1-3  alkyl, C(═NH)—N(OH)—C 1-3  alkyl and substituted variants thereof; 
         ii) ribonucleotide reductase inhibitors having the formula R 31 Z, wherein R 31  can be H, NH 2 , NH 2 —NH, NHOH, NOH—R 36 , C 1 -C 6  alkyl, OC 1-6  alkyl, aryl-substituted with C 1 -C 6  alkyl, phenyl, naphthyl, pyridyl, pyrimidyl or thienyl, and wherein Z can be C(═O)NOH—R 34 , C(═S)—NOH—R 34 , C(═NH)—NOH—R 34 , C(═NOH)—C 1 -C 3  alkyl, C(=NOH)—R 34  and C(═NOH)—R 35 , wherein R 34  can be H, C 1 -C 6  alkyl and substituted C 1 -C 6  alkyl, wherein R 34  can be substituted with hydroxy, alkoxy, amino or halo, and wherein R 35  is NH 2  or NHOH, wherein R 36  is C 1-6  acyl, alkyl and substituted C, alkyl substituted with hydroxyl, alkoxy, amino or halo; and 
         iii) ribonucleotide reductase inhibitors having the Formulae III and IV: 
       
       
         
           
           
               
               
           
         
          wherein Formula III represents pyridine-type compounds and Formula IV represents isoquinoline-semithiocarbazones, where X 1  can be H or CH 3 , X 2  can be H, OH, NH 2 , F, CF 3 , C 1-3  alkyl, OX 3 , NHX 3 N(X 3 ) 2 , and O(O═C)X 4 , in which X 3  denotes C 1-3  alkyl and X 4  can be aryl, C 1-6  alkyl including substitutions on the alkyl chain of the carboxylic acid with C alkoxy, C 1-3  mono- or di-alkylamino, aryloxy, also those in which the aryl ring is substituted with one or more hydroxy, amino or chloro groups; including both E and Z isomers of the compounds and their mixtures. 
       
     
     
         16 . A method according to  claim 15 , wherein the ribonucleotide reductase inhibitors are chosen from 2-formylpyridine and 2-acetylpyridine thiosemicarbazone substituted with 3-hydroxy, 3-amino, 3-methyl, 3-methoxy, 3-acetoxy, 3-ethoxy, 3-fluoro, 5-hydroxy, 5-amino, 5-fluoro, 5-trifluoromethyl, 5-methoxy, 5-ethoxy, 5-dimethylamino, 5-pivaloyloxy, 5-phenoxyacetoxy, 5-N, N-dimethylaminoacetoxy, and 3,4-dihydroxybenzoyloxy as ring substituents. 
     
     
         17 . A method according to  claim 15 , wherein the ribonucleotide reductase inhibitors are chosen from 1-formylisoquinoline and 1-acetylisoquinoline thiosemicarbazone derivatives substituted with 4-hydroxy, 4-methyl, 4-amino, 5-fluoro, 5-trifluoromethyl, 5-amino and 5-acetylamino as ring substituents.