Compounds and methods for the treatment of neurodegenerative diseases

Abstract

Novel compounds of formula (II) are disclosed. Compounds of formula (II) comprise ornithine derivatives or compounds that can metabolize under physiological conditions to ornithine. The pH and plasma stability of compounds of formula (II) is also described. Also disclosed are methods for the treatment of neurodegenerative diseases such as Alzheimer's Disease using compounds of formula (II).

What is claimed is: 
     
         1 . A prodrug of difluoromethylornithine. 
     
     
         2 . A compound of formula (II): 
       
         
           
           
               
               
           
         
       
       wherein one or more of Q 1 , Q 2 , Q 3 , Q 4  and Q 5  is a moiety which is cleavable in vivo to hydrogen and the remainder are hydrogen. 
     
     
         3 . The compound of  claim 2 , wherein at least one of Q 1 , Q 2 , Q 3 , Q 4  and Q 5  is cleavable to hydrogen and is cleavable by an esterase. 
     
     
         4 . A compound selected from the group consisting of
 a) an N-acyloxyalkoxy carbonyl derivative of,   b) a (phosphoryloxy)methyl carbamate of,   c) a redox based system derivative of,   d) a beta-aminoketone based derivative of,   e) a Schiff base derivative of,   f) an N-Mannich base of,   g) an (oxodioxolenyl)methyl carbamate of,   h) a trimethyl lock system based derivative of,   i) an intramolecular bonded derivative of,   j) a tetrahydrothiadiazine-2-thione derivative of, and   k) a sulfonamide derivative of difluoromethylornithine or a pharmaceutically acceptable salt thereof.   
     
     
         5 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         R x  is alkyl of 1-30 carbons, substituted or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of 5 to 9 carbons, substituted or unsubstituted; 
         R 2  and R 2 , are independently hydrogen, alkyl of 1-30 carbons, substituted or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of 5 to 9 carbons, substituted or unsubstituted; 
         R 3  is hydrogen or
 (a) C 1 -C 30 -alkyl, 
 (b) C 2 -C 5 -alkenyl, 
 (c) C 2 -C 5 -alkynyl, (d) (CH 2 ) p NR 12 R 13 , 
 (e) (CH 2 ) s CH(R 7 ) (CH 2 ) s O 2 CR 8 , 
 (f) 
 
       
       
         
           
           
               
               
           
         
         
           (g) —(CH 2 ) p CO 2 R 10 , 
           (h) 
         
       
       
         
           
           
               
               
           
         
         
           (i) C 1 -C 5  alkyl substituted by one or more F; 
         
         R is independently a hydrogen, a cation or alkyl of 1-30 carbons, substituted or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of 5 to 9 carbons, substituted or unsubstituted; 
         R 4  is hydrogen, alkyl of 1-30 carbons, substituted with one or more F, or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of 5 to 9 carbons, substituted or unsubstituted; 
         R 5  is alkyl of 1-30 carbons, substituted, substituted with one or more F, or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of about 5 to 9 carbons, substituted or unsubstituted; 
         R 6  is alkyl of about 1-30 carbons, substituted with one or more F, or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of 5 to 9 carbons, substituted or unsubstituted; 
         R 7  is H or C 1 -C 4 -alkyl, unsubstituted or substituted by one or more F; 
         R 8  is
 (a) H, 
 (b) C 1 -C 5 -alkoxy, 
 (c) C 1 -C 5 -alkyl optionally substituted with a group consisting of:
 i) C 1 -C 5 -alkoxy, 
 ii) aryl, wherein aryl is phenyl or napthyl optionally substituted with one or two substituents selected from the group consisting of halo (F, Cl, Br, I), C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, —NO 2 , —S(O) r (C 1 -C 5 -alkyl), —OH, —NR 12 R 13 , —CO 2 R 15 , and —C v F w  where v=1 to 3 and w=1 to (2v+1), or 
 iii) one or more F; 
 
 
         R 9  is
 (a) C 1 -C 5 -alkyl, 
 (b) —C v F w  where v=1 to 3 and w=1 to (2v+1), or 
 (c) C 1 -C 5 -alkyl optionally substituted with a group consisting of:
 i) C 1 -C 5 -alkoxy, 
 ii) phenyl or phenyl substituted with at least one substituent selected from the group consisting of halo (F, Cl, Br, I), C 2 -C 4 -alkyl, C 1 -C 4 -alkoxy, —NO 2 , —S(O) r (C 1 -C 4 -alkyl), —OH, —NR 12 R 13 , —CO 2 R 5 , and —C v F w  where v=1 to 3 and w=1 to (2v+1), or 
 
 iii) benzyl or benzyl substituted with at least one substituent selected from the group consisting of halo (F, Cl, Br, I), C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, —NO 2 , —S(O) r (C 1 -C 4 -alkyl), —OH, —NR 12 R 13 , —CO 2 R 15 , and —C v F w  where v=1 to 3 and w=1 to (2v+1); 
 
         R 10  is
 (a) phenyl or phenyl substituted with at least one substituent selected from the group consisting of halo (F, Cl, Br, I), C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, —NO 2 , —S(O) r (C 1 -C 4 -alkyl), —OH, —NR 12 R 13 , —CO 2 R 15 , and —C v F w  where v=1 to 3 and w=1 to (2v+1), or 
 (b) benzyl or benzyl substituted with at least one substituent selected from the group consisting of halo (F, Cl, Br, I), C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, —NO 2 , —S(O) r (C 1 -C 4 -alkyl), —OH, —NR 12 R 13 , —CO 2 R 15 , and —C v F w  where v=1 to 3 and w=1 to (2v+1); 
 
         R 11  is H, C 1 -C 5 -alkyl or benzyl; 
         R 12  and R 13  are independently H, C 1 -C 5 -alkyl, phenyl or benzyl; 
         R 15  is H, C 1 -C 5 -alkyl, or NR 12 R 13 ; 
         p is 1-5; 
         r is 0-2; 
         s and s′ are 0-5; 
         t is 0 or 1; 
         R 8  is independently a value of R 8  other than (a) H and (b) C 1 -C 5 -alkoxy; and 
         R 10  is —SR; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The prodrug of any one of  claims 1 - 5 , which is in the R configuration corresponding to R-ornithine. 
     
     
         7 . The prodrug of any one of  claims 1 - 5 , which is in the S configuration corresponding to S-ornithine. 
     
     
         8 . The prodrug of any of  claims 1  to  5 , wherein R x  is a C 9-20  alkyl. 
     
     
         9 . A method of treating a neurodegenerative disorder, comprising administering to a patient in need there of an effective amount of a prodrug according to any one of  claims 1 - 8 . 
     
     
         10 . The method of  claim 9 , wherein the neurodegenerative disorder is Alzheimer's disease. 
     
     
         11 . The method of  claim 9 , wherein the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS). 
     
     
         12 . A method of treating cancer in humans, comprising administering to a patient in need thereof an effective amount of a prodrug according to any one of  claims 1 - 8 . 
     
     
         13 . The method of  claim 12 , wherein the method further comprises administering at least one other anti-cancer agent.