Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid

Abstract

The invention relates to methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid (3APS) in a subject, preferably a human subject. The invention encompasses compound that will yield or generate 3APS, either in vitro or in vivo. Preferred compounds include amino acid prodrugs of 3APS for use, including but not limited to the prevention and treatment of Alzheimer's disease

1 . A compound selected from the group consisting of:
 a) a compound of Formula I:
   B-L-A   (I)
 
   
       wherein
 B is a pharmacokinetic modulating moiety, which is optionally also bonded to A directly or indirectly through a further linking group L; 
 A is a 3-amino-1-propanesulfonic acid moiety; and 
 L is a cleavable linkage for covalently and dissociably coupling B to A via the NH 2  group, whereby L can be a direct bond or additional chemical structure providing a cleavable linkage, or a pharmaceutically acceptable salt thereof; 
 
       b) a compound of Formula I-A: 
       
         
           
           
               
               
           
         
       
       wherein,
 R x  and R y  are independently selected from hydrogen and a protecting group, wherein R x  and R y  are not both hydrogen; and 
 L 1  and L 2  are each a cleavable linkage; wherein when R x  is H, L 1  is absent, and when R y  is H, then L 2  is absent, or a pharmaceutically acceptable salt thereof; 
 
       c) a compound of Formula VII: 
       
         
           
           
               
               
           
         
       
       wherein, 
       f) a compound of Formula X: 
       
         
           
           
               
               
           
         
         wherein, 
         R 10  is a residue of a carbohydrate, a carbohydrate derivative or a carbohydrate-derived polyol, e.g., a C 5-6  saturated or partially or completely unsaturated cycloalkyl group, optionally and preferably containing an —O— group, which is substituted by 3 to 5 substituents, each independently selected from —OH, —OAc, —CH 2 OH, —OCH 3 , —CH 2 OAc and ═O. 
         L is a linking moiety or is absent, e.g., an alkyl group, which may be saturated or unsaturated, preferably a lower alkyl group, which is optionally interrupted by one or more —O— and/or —NH— groups, and is optionally substituted by one or more ═O, —OH, and/or —NH 2  groups, or a pharmaceutically acceptable salt thereof; 
       
       g) a compound of Formula XI: 
       
         
           
           
               
               
           
         
         wherein, 
         R 11  is a hydrogen or a substituted or unsubstituted group selected from C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 15  cycloalkyl, C 3 -C 15  heterocycloalkyl, C 6 -C 15  aryl, C 5 -C 15  heteroaryl, C(O)R 12 , and C(O)OR 13 ; and 
         R 12  and R 13  are independently selected from substituted or unsubstituted C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 15  cycloalkyl, C 3 -C 15  heterocycloalkyl, C 6 -C 15  aryl, and C 5 -C 15  heteroaryl, or a pharmaceutically acceptable salt thereof; 
       
       h) a compound of Formula XII: 
       
         
           
           
               
               
           
         
         wherein, 
         D is a carbonyl, an amino acid residue, or a substituted methylene group; and 
         R 5  is a substituted or unsubstituted group selected from C 1 -C 12 alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 15  cycloalkyl, C 3 -C 15  heterocycloalkyl, C 6 -C 15  aryl, C 5 -C 15  heteroaryl, NH(C 1 -C 6  alkyl), N(C 1 -C 6  alkyl) 2 , and C(O)(C 1 -C 6  alkyl); 
         R 6  is a hydrogen or a substituted or unsubstituted group selected from C(O)NH 2 , C(O)NH(C 1 -C 6  alkyl), C(O)N(C 1 -C 6  alkyl) 2 , and C(O)(C 1 -C 6  alkyl); or R 5  and R 6  are taken together with the adjacent carbon atom to form a substituted or unsubstituted C 3 -C 12  heterocycloalkyl; 
         M is selected from the group consisting of oxygen, sulfur, nitrogen or absent, or a pharmaceutically acceptable salt thereof; 
       
       d) a compound of Formula VIII: 
       
         
           
           
               
               
           
         
         wherein, 
         R 7  is a substituted or unsubstituted group selected from C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 15  cycloalkyl, C 3 -C 15  heterocycloalkyl, C 6 -C 15  aryl, C 5 -C 15  heteroaryl, C 7 -C 12  arylalkyl, C 7 -C 12  heteroarylalkyl, and combinations thereof, or a pharmaceutically acceptable salt thereof; 
       
       e) a compound of Formula IX: 
       
         
           
           
               
               
           
         
         wherein, 
         R 8  is a substituted or unsubstituted group selected from C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 15  cycloalkyl, C 3 -C 15  heterocycloalkyl, C 6 -C 15  aryl, C 5 -C 15  heteroaryl; and 
         R 9  is a hydrogen or a substituted or unsubstituted C(O)(C 1 -C 6  alkyl), C(O)NH 2 , C(O)NH(C 1 -C 6  alkyl), or C(O)N(C 1 -C 6  alkyl) 2 ; or R 8  and R 9  are taken together with the adjacent carbon atom to form a substituted or unsubstituted C 3 -C 12  heterocycloalkyl, or a pharmaceutically acceptable salt thereof; 
         X is selected from O, NH, and S, or a pharmaceutically acceptable salt thereof; 
       
       i) a compound of Formula XIII: 
       
         
           
           
               
               
           
         
         wherein, 
         R 15  and R 16  are independently selected from a hydrogen or a substituted or unsubstituted group selected from C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 15  cycloalkyl, C 3 -C 15  heterocycloalkyl, C 6 -C 15  aryl, and C 5 -C 15  heteroaryl, or a pharmaceutically acceptable salt thereof; and 
       
       j) a compound of Formula I-P:
   A-(L x -A) p -L x -A   (I-P)
 
 
       wherein:
 A is 3-amino-1-propanesulfonic acid moiety; 
 L x  is a cleavable linkage for covalently and dissociably coupling together two adjacent 3APS moieties, and 
 p is 0, or an integer number which may vary from 1 to 5, e.g. 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound of Formula XII is a compound of Formula XII-A: 
       
         
           
           
               
               
           
         
       
       wherein,
 R 14  is a substituted or unsubstituted group selected from C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 3 -C 15  cycloalkyl, C 3 -C 15  heterocycloalkyl, C 6 -C 15  aryl, C 5 -C 15  heteroaryl, or a pharmaceutically acceptable salt thereof. 
 
     
     
         3 . The compound of  claim 1 , wherein said compound of Formula I-P is selected from the group consisting of: 
       a) a compound of Formula I-P2:
   L y (A) m    (I-P2)
 
 
       wherein,
 m is an integer from 2 to 5; 
 A is 3-amino-1-propanesulfonic acid moiety; 
 L y  is a multivalent carrier moiety for covalently and dissociably coupling from two to five A moieties, either at the amino or sulfonic acid end of A, or a pharmaceutically acceptable salt thereof; 
 
       b) a compound of Formula I-C: 
       
         
           
           
               
               
           
         
       
       wherein,
 L 3  is bivalent linker which connects two molecules of 3APS at their amino groups either using the same or different linkages as defined herein, including, but not limited to, amide linkage and carbamate linkage, or a pharmaceutically acceptable salt thereof; 
 
       c) a compound of Formula I-D: 
       
         
           
           
               
               
           
         
       
       wherein,
 L 4  is a bivalent linker which connects two molecules of 3APS at their sulfonic acid groups either using the same or different linkages as defined herein, including, but not limited to, ester linkage or anhydride linkage where X is oxygen, or sulfonamide linkage where X is nitrogen (NH, or NR), or thiosulfonate linkage where X is sulfur, P is hydrogen or a N-protecting group, or a pharmaceutically acceptable salt thereof; and 
 
       d) a compound of Formula I-E: 
       
         
           
           
               
               
           
         
       
       wherein,
 L 5  is a bivalent linker which connects two molecules of 3APS, at amino group in one 3APS using a linkage as defined in Formula I-C, and at sulfonic acid group in the other 3APS using a linkage as defined in Formula I-D, P is hydrogen or a N-protecting group as defined herein, or a pharmaceutically acceptable salt thereof. 
 
     
     
         4 . The compound of  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A method for treating Alzheimer's disease, mild cognitive impairment, Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, a degenerative dementia, a dementia of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease, comprising administering a therapeutically effective amount of a compound of  claim 1  to a human subject in need thereof. 
     
     
         6 . The method of  claim 5 , which is for treating Alzheimer's disease, mild cognitive impairment, cerebral amyloid angiopathy, or degenerative dementia. 
     
     
         7 . The method of  claim 6 , which is for treating Alzheimer's disease. 
     
     
         8 . The method of  claim 5  wherein the compound is administered intratracheally, intranasally, ontologically, rectally, vaginally, or orally. 
     
     
         9 . A pharmaceutical composition comprising a compound of  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
         10 . The pharmaceutical composition of  claim 9  which is suitable for oral administration. 
     
     
         11 . The pharmaceutical composition of  claim 9 , which is in the form of a hard shell gelatin capsule, soft shell gelatin capsule, cachet, pill, tablet, lozenge, powder, granule, pellet, dragee, which is optionally enteric coated, a solution, an aqueous liquid suspension, a non-aqueous liquid suspension, an oil-in-water liquid emulsion, a water-in-oil liquid emulsion, an elixir, a syrup, or a pastille. 
     
     
         12 . A process for converting a compound of  claims 1  to 3-amino-1-propanesulfonic acid (3APS) comprising contacting said compound with plasma, blood and/or brain cells whereby said compound is metabolized to 3APS.