Amino acid conjugates providing for sustained systemic concentrations of GABA analogues

Abstract

This invention is directed to compounds that provide for sustained systemic concentrations of GABA analogs following administration to animals. This invention is also directed to pharmaceutical compositions including and methods using such compounds.

What is claimed is:  
     
         1 . A GABA analog derivative comprising a compound of Formula (I):  
       H—I i -J j -D-K k —OH   (I)  
       wherein: 
 H is hydrogen;  
 I is —[NR 50 —(CR 51 R 52 ) a —(CR 53 R 54 ) b —C(O)]—;  
 J is —[NR 55 —(CR 56 R 57 ) c —(CR 58 R 59 ) d —C(O)]—;  
 K is —[NR 60 —(CR 61 R 62 ) e —(CR 63 R 64 ) f —C(O)]—;  
 wherein a, b, c, d, e and f are independently 0 or 1, provided that at least one of a and b is 1, at least one of c and d is 1, and at least one of e and f is 1;  
 and wherein i, j and k are independently 0 or 1, provided that at least one of i, j and k is 1;  
 D is a moiety derived from a GABA analog having the following structure:  
                     
 wherein:  
 R 3  is a covalent bond linking the GABA analog moiety to J j ;  
 R 4  is hydrogen, or R 4  and R 9  together with the atoms to which they are attached form an azetidine, substituted azetidine, pyrrolidine or substituted pyrrolidine ring;  
 R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;  
 R 7  and R 8  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, or R 7  and R 8  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic ring;  
 R 9  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;  
 R 10  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;  
 R 11  is C(O)R 12 , wherein R 12  is a covalent bond linking the moiety derived from a GABA analog to K k ;  
 R 50  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 50  and R 51  together with the atoms to which they are attached form a heterocyclyl ring;  
 R 51  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 51  and R 52  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R 51  and R 53  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 52  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 53  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 53  and R 54  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 54  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 55  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 55  and R 56 , together with the atoms to which they are attached form a heterocyclyl ring;  
 R 56  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 56  and R 57  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R 56  and R 58  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 57  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 58  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 58  and R 59  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 59  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 60  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 60  and R 61 , together with the atoms to which they are attached form a heterocyclyl ring;  
 R 61  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 61  and R 62  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R 61  and R 63  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 62  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 63  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 63  and R 64  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 64  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 and pharmaceutically acceptable salts, hydrates and solvates thereof,  
 provided that if k is 0 then neither I nor J is derived from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or phenylglycine;  
 and provided that when R 5 , R 6 , R 9  and R 10  are each hydrogen, then R 7  and R 8  are neither both hydrogen nor both methyl;  
 and yet further provided that when D is either of the following moieties  
                     
 neither I nor J are selected from the group of moieties consisting of: H 2 NCH 2 C(O)—, H 2 NCH(CH 3 )C(O)—, NH 2 CH 2 CH 2 C(O)— and  
                     
 
     
     
         2 . The compound according to  claim 1 , wherein i and k are 0, and j is 1.  
     
     
         3 . The compound according to  claim 1 , wherein k is 0, and i and j are 1.  
     
     
         4 . The compound according to  claim 1 , wherein i is 0, and j and k are 1.  
     
     
         5 . The compound according to  claim 1 , wherein a and c are 1, and b and d are 0.  
     
     
         6 . The compound according to  claim 1 , wherein I, J and K are not derived from natural amino acids.  
     
     
         7 . The compound according to  claim 1 , wherein at least one of I, J and K are derived from the group consisting of O-phosphoserine and O-phosphotyrosine.  
     
     
         8 . The compound according to  claim 5 , wherein i and k are 0, and j is 1.  
     
     
         9 . The compound of  claim 1 , wherein D is a moiety selected from the group consisting of the following GABA analog moieties:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The compound of claims  1 , wherein D is a moiety selected from the group consisting of the following GABA analog moieties:  
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 9 , wherein i and k are 0, j is 1, c is 1, and d is 0.  
     
     
         12 . The compound of  claim 11 , wherein 
 R 55  is hydrogen;    R 57  is hydrogen; and    R 56  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.    
     
     
         13 . The compound of  claim 12 , wherein R 56  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl and heteroaryl.  
     
     
         14 . The compound of  claim 11 , wherein 
 R 57  is hydrogen; and    R 55  and R 56  together with the atoms to which they are attached form a heterocyclyl or substituted heterocyclyl ring.    
     
     
         15 . The compound of  claim 14 , wherein R 55  and R 56  together with the atoms to which they are attached form an azetidine, 4-substituted pyrrolidine, piperidine or substituted piperidine ring.  
     
     
         16 . The compound of  claim 11 , wherein 
 R 55  is hydrogen; and    R 56  and R 57  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring.    
     
     
         17 . The compound of  claim 16 , wherein R 56  and R 57  together with the atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, substituted cyclopentyl cyclohexyl, substituted cyclohexyl, piperidinyl or substituted piperidinyl ring.  
     
     
         18 . The compound of  claim 12 , wherein R 56  is substituted alkyl.  
     
     
         19 . The compound of  claim 18 , wherein R 56  is selected from the group consisting of arylalkyl, substituted arylalkyl, heteroarylalkyl and substituted heteroarylalkyl.  
     
     
         20 . The compound of  claim 19 , wherein R 56  is selected from the group consisting of substituted benzyl, s-naphthylmethyl, substituted s-naphthylmethyl, t-pyridylmethyl, substituted t-pyridylmethyl, t-quinolylmethyl, substituted t-quinolylmethyl, u-furanylmethyl, substituted u-furanylmethyl, u-benzofuranylmethyl, substituted u-benzofuranylmethyl, u-thienylmethyl, substituted u-thienylmethyl, u-benzothienylmethyl, substituted u-benzothienylmethyl, u-pyrrolylmethyl, substituted u-pyrrolylmethyl, substituted u-indolylmethyl, u-pyrazinylmethyl, substituted u-pyrazinylmethyl, substituted v-imidazolylmethyl, v-oxazolylmethyl, substituted v-oxazolylmethyl, v-thiazolylmethyl and substituted v-thiazolylmethyl; and wherein 
 s is 1 or 2;    t is 2, 3 or 4;    u is 2or 3; and    .v is 2, 4 or 5.    
     
     
         21 . The compound of  claim 20 , wherein R 56  is selected from the group consisting of 2-methylphenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 2-methoxyphenylmethyl, 3-methoxyphenylmethyl, 4-methoxyphenylmethyl, 2-trifluoromethylphenylmethyl, 3-trifluoromethylphenylmethyl, 4-trifluoromethylphenylmethyl, 2-cyanophenylmethyl, 3-cyanophenylmethyl, 4-cyanophenylmethyl, 2-fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluorophenylmethyl, 2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenylmethyl, 2-bromophenylmethyl, 3-bromophenylmethyl, 4-bromophenylmethyl, 2-iodophenylmethyl, 3-iodophenylmethyl, 4-iodophenylmethyl, 2,3-difluorophenylmethyl, 2,4-difluorophenylmethyl, 2,5-difluorophenylmethyl, 2,6-difluorophenylmethyl, 3,4-difluorophenylmethyl, 3,5-difluorophenylmethyl, 2,3-dichlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,5-dichlorophenylmethyl, 2,6-dichlorophenylmethyl, 3,4-dichlorophenylmethyl, 3,5-dichlorophenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-quinolylmethyl, 3-quinolylmethyl, 4-quinolylmethyl, 2-furanylmethyl, 3-furanylmethyl, 3-benzofuranylmethyl, 2-thienylmethyl, 3-thienylmethyl, 3-benzothienylmethyl, 5-hydroxyindol-3-ylmethyl, 5-alkoxyindol-3-ylmethyl, 5-acyloxyindol-3-ylmethyl, 2-oxazolylmethyl, 4-oxazolylmethyl 2-thiazolylmethyl and 4-thiazolylmethyl.  
     
     
         22 . The compound of  claim 18 , wherein R 56  is selected from the group consisting of —(CH 2 ) n C(O)XR 13  and —CH 2 [4-C 6 H 4 —OC(O)R 15 ]; and wherein: 
 n is 1 or 2;  
 X is 0 or NR 14 ;  
 R 13  and R 14  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, or R 13  and R 14  together with the atoms to which they are attached form a heterocyclyl or substituted heterocyclyl ring; and  
 R 15  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, alkynyloxy, substituted alkynyloxy, cycloalkoxy, substituted cycloalkoxy, heterocyclyloxy, substituted heterocyclyloxy, aryloxy, substituted aryloxy, heteroaryloxy and substituted heteroaryloxy;  
 provided that when X is O, then R 13  is not hydrogen; and when X is NR 14 , then R 13  and R 14  are not both hydrogen.  
 
     
     
         23 . A GABA analog derivative comprising a compound selected from the group consisting of L-1-Naphthylalanine-Gabapentin, L-2-Naphthylalanine-Gabapentin, L-2-Quinoylalanine-Gabapentin, L-(2-Quinoylalanine N-Oxide)-Gabapentin, L-2-Pyridylalanine-Gabapentin, L-3-Pyridylalanine-Gabapentin, L-(4-Pyridylalanine N-Oxide)-Gabapentin, L-2-Thienylalanine-Gabapentin, L-3-Thienylalanine-Gabapentin, L-3-Benzothienylalanine-Gabapentin, L-4-Thiazolylalanine-Gabapentin, L-2-Methylphenylalanine-Gabapentin, L-4-Methylphenylalanine-Gabapentin, L-2-Trifluoromethylphenylalanine-Gabapentin, L-3-Trifluoromethylphenylalanine-Gabapentin, L-4-Trifluoromethylphenylalanine-Gabapentin, L-2-Fluorophenylalanine-Gabapentin, L-3-Fluorophenylalanine-Gabapentin, L-4-Fluorophenylalanine-Gabapentin, L-2-Chlorophenylalanine-Gabapentin, L-3-Chlorophenylalanine-Gabapentin, L-4-Chlorophenylalanine-Gabapentin, L-4-Bromophenylalanine-Gabapentin, L-4-Iodophenylalanine-Gabapentin, L-2-Methoxyphenylalanine-Gabapentin, L-4-Methoxyphenylalanine-Gabapentin, L-4-Ethoxyphenylalanine-Gabapentin, L-3-Cyanophenylalanine-Gabapentin, L-4-Cyanophenylalanine-Gabapentin, L-3,4-Difluorophenylalanine-Gabapentin, L-3,5-Difluorophenylalanine-Gabapentin, D, L-2,4-Difluorophenylalanine-Gabapentin, D, L-2,6-Difluorophenylalanine-Gabapentin, L-2,4-Dichlorophenylalanine-Gabapentin, L-3,4-Dichlorophenylalanine-Gabapentin, L-Pipecolyl-Gabapentin, L-tert-Butylglycine-Gabapentin, L-2,3-Diaminopropionyl-Gabapentin, L-Norvaline-Gabapentin, L-Penicillamine-Gabapentin, 1-Aminocyclopropane-1-Carbonyl-Gabapentin, 1-Aminocyclohexane-1-Carbonyl-Gabapentin, L-Homophenylalanine-Gabapentin, L-Aspartyl-β-(Pyrrolidinyl)-Gabapentin, L-Aspartyl-β-(Butylamido)-Gabapentin, L-Aspartyl-β-(2-Methoxyethylamido)-Gabapentin, L-Aspartyl-β-(Piperidinyl)-Gabapentin, L-Aspartyl-β-(3-Methylbutylamido)-Gabapentin, L-Aspartyl-β-(Cyclohexylamido)-Gabapentin, L-Aspartyl-β-(4-Amidomethylpyridine)-Gabapentin, L-Aspartyl-β-(3-Amidomethylpyridine)-Gabapentin, L-Aspartyl-β-(Heptylamido)-Gabapentin, L-Aspartyl-β-(3,4-Dimethoxyphenethylamido)-Gabapentin, L-Aspartyl-β-(O-Cyclohexyl ester)-Gabapentin, L-Aspartyl-β-(O-Benzyl ester)-Gabapentin, L-Tyrosine-(O-2,6-Dimethylbenzoyl)-Gabapentin, L-Tyrosine-(O-2,6-Dimethoxybenzoyl)-Gabapentin, L-Tyrosine-(O-2-Methylbenzoyl)-Gabapentin and L-Tyrosine-(O-2-Bromobenzyloxycarbonyl)-Gabapentin.  
     
     
         24 . A GABA analog derivative comprising a compound selected from the group consisting of L-1-Naphthylalanine-Pregabalin, L-2-Naphthylalanine-Pregabalin, L-2-Quinoylalanine-Pregabalin, L-(2-Quinoylalanine N-Oxide)-Pregabalin, L-2-Pyridylalanine-Pregabalin, L-3-Pyridylalanine-Pregabalin, L-(4-Pyridylalanine N-Oxide)-Pregabalin, L-2-Thienylalanine-Pregabalin, L-3-Thienylalanine-Pregabalin, L-3-Benzothienylalanine-Pregabalin, L-4-Thiazolylalanine-Pregabalin, L-2-Methylphenylalanine-Pregabalin, L-4-Methylphenylalanine-Pregabalin, L-2-Trifluoromethylphenylalanine-Pregabalin, L-3-Trifluoromethylphenylalanine-Pregabalin, L-4-Trifluoromethylphenylalanine-Pregabalin, L-2-Fluorophenylalanine-Pregabalin, L-3-Fluorophenylalanine-Pregabalin, L-4-Fluorophenylalanine-Pregabalin, L-2-Chlorophenylalanine-Pregabalin, L-3-Chlorophenylalanine-Pregabalin, L-4-Chlorophenylalanine-Pregabalin, L-4-Bromophenylalanine-Pregabalin, L-4-Iodophenylalanine-Pregabalin, L-2-Methoxyphenylalanine-Pregabalin, L-4-Methoxyphenylalanine-Pregabalin, L-4-Ethoxyphenylalanine-Pregabalin, L-3-Cyanophenylalanine-Pregabalin, L-4-Cyanophenylalanine-Pregabalin, L-3,4-Difluorophenylalanine-Pregabalin, L-3,5-Difluorophenylalanine-Pregabalin, D, L-2,4-Difluorophenylalanine-Pregabalin, D, L-2,6-Difluorophenylalanine-Pregabalin, L-2,4-Dichlorophenylalanine-Pregabalin, L-3,4-Dichlorophenylalanine-Pregabalin, L-Pipecolyl-Pregabalin, L-tert-Butylglycine-Pregabalin, L-2,3-Diaminopropionyl-Pregabalin, L-Norvaline-Pregabalin, L-Penicillamine-Pregabalin, 1-Aminocyclopropane-1-Carbonyl-Pregabalin, 1-Aminocyclohexane-1-Carbonyl-Pregabalin, L-Homophenylalanine-Pregabalin, L-Aspartyl-β-(Pyrrolidinyl)-Pregabalin, L-Aspartyl-β-(Butylamido)-Pregabalin, L-Aspartyl-β-(2-Methoxyethylamido)-Pregabalin, L-Aspartyl-β-(Piperidinyl)-Pregabalin, L-Aspartyl-β-(3-Methylbutylamido)-Pregabalin, L-Aspartyl-β-(Cyclohexylamido)-Pregabalin, L-Aspartyl-β-(4-Amidomethylpyridine)-Pregabalin, L-Aspartyl-β-(3-Amidomethylpyridine)-Pregabalin, L-Aspartyl-β-(Heptylamido)-Pregabalin, L-Aspartyl-β-(3,4-Dimethoxyphenethylamido)-Pregabalin, L-Aspartyl-β-(O-Cyclohexyl ester)-Pregabalin, L-Aspartyl-β-(O-Benzyl ester)-Pregabalin, L-Tyrosine-(O-2,6-Dimethylbenzoyl)-Pregabalin, L-Tyrosine-(O-2,6-Dimethoxybenzoyl)-Pregabalin, L-Tyrosine-(O-2-Methylbenzoyl)-Pregabalin and L-Tyrosine-(O-2-Bromobenzyloxycarbonyl)-Pregabalin.  
     
     
         25 . A GABA analog derivative comprising a compound of Formula (Ia):  
       H—I i -J j -D-K k —OH   (Ia)  
       wherein: 
 H is hydrogen;  
 I is —[NR 50 —(CR 51 R 52 ) a —(CR 53 R 54 ) b —C(O)]—;  
 J is —[NR 55 —(CR 56 R 57 ) c —(CR 58 R 59 ) d —C(O)]—;  
 K is —[NR 60 —(CR 61 R 62 ) e —(CR 63 R 64 ) f —C(O)]—;  
 wherein a, b, c, d, e and f are independently 0 or 1, provided that at least one of a and b is 1, at least one of c and d is 1, and at least one of e and f is 1;  
 and wherein i, j and k are independently 0 or 1, provided that at least one of i, j and k is 1;  
 D is a moiety derived from a GABA analog having the following structure:  
                     
 wherein:  
 R 3  is a covalent bond linking the GABA analog moiety to J j ;  
 R 4  is hydrogen, or R 4  and R 9  together with the atoms to which they are attached form an azetidine, substituted azetidine, pyrrolidine or substituted pyrrolidine ring;  
 R 5  and R 6  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;  
 R 7  and R 8  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, or R 7  and R 8  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic ring;  
 R 9  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;  
 R 10  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;  
 R 11  is C(O)R 12 , wherein R 12  is a covalent bond linking the moiety derived from a GABA analog to K k ;  
 R 50  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 50  and R 51  together with the atoms to which they are attached form a heterocyclyl ring;  
 R 51  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 51  and R 52  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R 51  and R 53  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 52  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 53  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 53  and R 54  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 54  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 55  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 55  and R 56 , together with the atoms to which they are attached form a heterocyclyl ring;  
 R 56  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 56  and R 57  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R 56  and R 58  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 57  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 58  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 58  and R 59  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 59  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 60  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 60  and R 61 , together with the atoms to which they are attached form a heterocyclyl ring;  
 R 61  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 61  and R 62  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R 61  and R 63  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 62  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 R 63  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R 63  and R 64  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;  
 R 64  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 and pharmaceutically acceptable salts, hydrates and solvates thereof,  
 and provided that the compound of Formula (Ia) has a half-life of at least 1 hour when incubated in vitro at 37° C. at a concentration of 5 μM with an S9 fraction of Caco-2 cell homogenate at a protein concentration of 0.5 mg/mL;  
 and provided that if k is 0 then neither I nor J is derived from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or phenylglycine;  
 and provided that when R 5 , R 6 , R 9  and R 10  are each hydrogen, then R 7  and R 8  are neither both hydrogen nor both methyl;  
 and yet further provided that when D is either of the following moieties  
                     
 neither I nor J are selected from the group of moieties consisting of: H 2 NCH 2 C(O)—, H 2 NCH(CH 3 )C(O)—, NH 2 CH 2 CH 2 C(O)— and  
                     
 
     
     
         26 . A compound of  claim 1 , which upon oral administration of a dose of GABA analog to a patient in need of therapy, provides therapeutically efficacious levels of a GABA analog in the plasma of the patient, where the GABA analog in the plasma of the patient has a concentration which over time provides a curve of concentration of the GABA analog in the plasma over time, the curve having an area under the curve (AUC) which is substantially more proportional to the dose of GABA analog administered, as compared to the proportionality achieved following oral administration of the GABA analog itself.  
     
     
         27 . A compound of  claim 1 , which upon oral administration of a dose of GABA analog to a patient in need of therapy, provides therapeutically efficacious levels of a GABA analog in the plasma of a patient, where the GABA analog in the plasma of the patient has a concentration which over time provides a curve of concentration of the GABA analog in the plasma over time, the curve having a maximum plasma concentration (C max ) which is substantially more proportional to the dose of GABA analog administered, as compared to the proportionality achieved following oral administration of the GABA analog itself.  
     
     
         28 . A compound of  claim 1  which is metabolized to produce a GABA analog at a sufficient rate in vivo, upon colonic administration to rats, to produce a C max  of the GABA analog in plasma of at least 200% of the C max  of the GABA analog in plasma achieved by colonically administering an equimolar dose of the GABA analog itself.  
     
     
         29 . A compound of  claim 1  which is metabolized to produce a GABA analog at a sufficient rate in vivo, upon colonic administration to rats, to produce a C max  of the GABA analog in plasma of at least 1000% of the C max  of the GABA analog in plasma achieved by colonically administering an equimolar dose of the GABA analog itself.  
     
     
         30 . A compound of  claim 1  which is metabolized to produce a GABA analog at a sufficient rate in vivo, upon colonic administration to rats, to produce an AUC of the GABA analog in plasma of at least 200% of the AUC of the GABA analog in plasma achieved by colonically administering an equimolar dose of the GABA analog itself.  
     
     
         31 . A compound of  claim 1  which is metabolized to produce a GABA analog at a sufficient rate in vivo, upon colonic administration to rats, to produce an AUC of the GABA analog in plasma of at least 500% of the AUC of the GABA analog in plasma achieved by colonically administering an equimolar dose of the GABA analog itself.  
     
     
         32 . A method for treating or preventing epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain, inflammatory disease, insomnia, gastrointestinal disorders or ethanol withdrawal syndrome in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         33 . A method for treating or preventing neuropathic pain, muscular pain or skeletal pain in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         34 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         35 . A method for treating or preventing epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain, inflammatory disease, insomnia, gastrointestinal disorders or ethanol withdrawal syndrome in a patient, comprising administering to a patient in need of such treatment a pharmaceutical composition according to  claim 34 .  
     
     
         36 . A method for treating or preventing neuropathic pain, muscular pain or skeletal pain in a patient, comprising administering to a patient in need of such treatment a pharmaceutical composition according to  claim 34 .  
     
     
         37 . An oral dosage form of a GABA analog derivative, comprising: 
 a sustained release oral dosage form containing a compound of  claim 1 , the dosage form being adapted for oral delivery to a patient;    the dosage form further being adapted to release the compound gradually into the intestinal lumen of the patient over a period after oral administration.    
     
     
         38 . The dosage form of  claim 37 , wherein the period comprises at least about 6 hours.  
     
     
         39 . The dosage form of  claim 37 , wherein the period comprises at least about 8 hours.  
     
     
         40 . The dosage form of  claim 37 , wherein the period comprises at least about 12 hours.  
     
     
         41 . The dosage form of  claim 37 , wherein the dosage form releases from 0 to 20% of the compound in 0 to 2 hours, from 20 to 50% of the compound in 2 to 12 hours, from 50 to 85% of the compound in 3 to 20 hours and greater than 75% of the compound in 5 to 18 hours.  
     
     
         42 . The dosage form of  claim 37 , wherein the dosage form comprises an osmotic dosage form.  
     
     
         43 . The dosage form of  claim 37 , wherein the dosage form comprises a compound-releasing polymer.  
     
     
         44 . The dosage form of  claim 37 , wherein the dosage form comprises a compound-releasing lipid.  
     
     
         45 . The dosage form of  claim 37 , wherein the dosage form comprises a compound-releasing wax.  
     
     
         46 . The dosage form of  claim 37 , wherein the dosage form comprises tiny timed-release pills.  
     
     
         47 . The dosage form of  claim 37 , wherein the dosage form comprises compound-releasing beads.  
     
     
         48 . A method for achieving sustained release of a GABA analog in a patient in need of therapy, comprising orally administering to the patient a sustained release dosage form containing a therapeutically effective amount of a compound of  claim 1 .  
     
     
         49 . The method of  claim 48 , wherein the sustained release dosage form further contains a pharmaceutically acceptable carrier.  
     
     
         50 . A compound of  claim 25 , which upon oral administration of a dose of GABA analog to a patient in need of therapy, provides therapeutically efficacious levels of a GABA analog in the plasma of the patient, where the GABA analog in the plasma of the patient has a concentration which over time provides a curve of concentration of the GABA analog in the plasma over time, the curve having an area under the curve (AUC) which is substantially more proportional to the dose of GABA analog administered, as compared to the proportionality achieved following oral administration of the GABA analog itself.  
     
     
         51 . A compound of  claim 25 , which upon oral administration of a dose of GABA analog to a patient in need of therapy, provides therapeutically efficacious levels of a GABA analog in the plasma of a patient, where the GABA analog in the plasma of the patient has a concentration which over time provides a curve of concentration of the GABA analog in the plasma over time, the curve having a maximum plasma concentration (C max ) which is substantially more proportional to the dose of GABA analog administered, as compared to the proportionality achieved following oral administration of the GABA analog itself.  
     
     
         52 . A compound of  claim 25  which is metabolized to produce a GABA analog at a sufficient rate in vivo, upon colonic administration to rats, to produce a C max  of the GABA analog in plasma of at least 200% of the C max  of the GABA analog in plasma achieved by colonically administering an equimolar dose of the GABA analog itself.  
     
     
         53 . A compound of  claim 25  which is metabolized to produce a GABA analog at a sufficient rate in vivo, upon colonic administration to rats, to produce a C max  of the GABA analog in plasma of at least 1000% of the C max  of the GABA analog in plasma achieved by colonically administering an equimolar dose of the GABA analog itself.  
     
     
         54 . A compound of  claim 25  which is metabolized to produce a GABA analog at a sufficient rate in vivo, upon colonic administration to rats, to produce an AUC of the GABA analog in plasma of at least 200% of the AUC of the GABA analog in plasma achieved by colonically administering an equimolar dose of the GABA analog itself.  
     
     
         55 . A compound of  claim 25  which is metabolized to produce a GABA analog at a sufficient rate in vivo, upon colonic administration to rats, to produce an AUC of the GABA analog in plasma of at least 500% of the AUC of the GABA analog in plasma achieved by colonically administering an equimolar dose of the GABA analog itself.