Bile acid recycling inhibitors for treatment of obesity and diabetes

Abstract

Provided herein are methods of utilizing bile acid transport inhibitors for the treatment of obesity and diabetes.

1 .- 21 . (canceled) 
     
     
         22 . A method for increasing the concentration of bile acid in the distal gastrointestinal tract of an individual comprising non-systemically administering to the distal ileum, the colon, or the rectum of the individual, a therapeutically effective amount of an Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI), wherein the ASBTI is a compound that is less than 10% systemically absorbed or is formulated to be less than 10% systemically absorbed. 
     
     
         23 . A method for inhibiting bile acid reuptake or bile acid recycling in the distal gastrointestinal tract of an individual comprising non-systemically administering to the distal ileum, the colon, or the rectum of the individual, a therapeutically effective amount of an Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI), wherein the ASBTI is a compound that is less than 10% systemically absorbed or is formulated to be less than 10% systemically absorbed. 
     
     
         24 . The method of  claim 22  or  23 , wherein the ASBTI is a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is a straight chained C 1-6  alkyl group; 
         R 2  is a straight chained C 1-6  alkyl group; 
         R 3  is hydrogen or a group OR 11  in which R 11  is hydrogen, optionally substituted C 1-6  alkyl or a C 1-6  alkylcarbonyl group; 
         R 4  is pyridyl or optionally substituted phenyl or -L z -K z ; wherein z is 1, 2 or 3; each L is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; each K is a moiety that prevents systemic absorption; 
         R 5 , R 6 , R 7  and R 8  are the same or different and each is selected from hydrogen, halogen, cyano, R 5 -acetylide, OR 15 , optionally substituted C 1-6  alkyl, COR 15 , CH(OH)R 15 , S(O) n R 15 , P(O)(OR 15 ) 2 , OCOR 15 , OCF3, OCN, SCN, NHCN, CH 2 OR 15 , CHO, (CH 2 ) p CN, CONR 12 R 13 , (CH 2 ) p CO 2 R 15 , (CH 2 ) p NR 12 R 13 , CO 2 R 15 , NHCOCF 3 , NHSO 2 R 15 , OCH 2 OR 15 , OCH═CHR 15 , O(CH 2 CH 2 O) n R 15 , O(CH 2 ) p SO 3 R 15 , O(CH 2 ) p NR 12 R 13 , O(CH 2 ) p N + R 12 R 13 R 14  and —W—R 31 , wherein W is O or NH and R 31  is selected from 
       
       
         
           
           
               
               
           
         
         wherein p is an integer from 1-4, n is an integer from 0-3 and, R 12 , R 13 , R 14  and R 15  are independently selected from hydrogen and optionally substituted C 1-6  alkyl; or 
         R 6  and R 7  are linked to form a group 
       
       
         
           
           
               
               
           
         
         
           wherein R 12  and R 13  are as hereinbefore defined and m is 1 or 2; and 
         
         R 9  and R 10  are the same or different and each is selected from hydrogen or C 1-6  alkyl; and 
         salts, solvates and physiologically functional derivatives thereof. 
       
     
     
         25 . The method of  claim 22  or  23 , wherein the ASBTI is a compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein:
 q is an integer from 1 to 4; 
 n is an integer from 0 to 2; 
 R 1  and R 2  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, 
 wherein alkyl, alkenyl, alkynyl, halo alkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR 9 , NR 9 R 10 , N + R 9 R 10 R w A − , SR 9 , S + R 9 R 10 A − , P + R 9 R 10 R 11 A − , S(O)R 9 , SO 2 R 9 , SO 3 R 9 , CO 2 R 9 , CN, halogen, oxo, and CONR 9 R 10 , 
 wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR 9 , N + R 9 R 10 A − , S, SO, SO 2 , S + R 9 A − , P + R 9 R 10 A − , or phenylene, 
 wherein R 9 , R 10 , and R w  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; or 
 R 1  and R 2  taken together with the carbon to which they are attached form C 3 -C 10  cycloalkyl; 
 R 3  and R 4  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 , NR 9 R 10 , SR 9 , S(O)R 9 , SO 2 R 9 , and SO 3 R 9 , wherein R 9  and R 10  are as defined above; or 
 R 3  and R 4  together ═O, ═NOR 11 , ═S, ═NNR 11 R 12 , ═NR 9 , or ═CR 11 R 12 , 
 wherein R 11  and R 12  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 , NR 9 R 10 , SR 9 , S(O)R 9 , SO 2 R 9 , SO 3 R 9 , CO 2 R 9 , CN, halogen, oxo, and CONR 9 R 10 , wherein R 9  and R 10  are as defined above, provided that both R 3  and R 4  cannot be OH, NH 2 , and SH, or 
 R 11  and R 12  together with the nitrogen or carbon atom to which they are attached form a cyclic ring; 
 R 5  and R 6  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, quarternary heteroaryl, OR 9 , SR 9 , S(O)R 9 , SO 2 R 9 , SO 3 R 9 , and -L z -K z ; 
 wherein z is 1, 2 or 3; each L is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; each K is a moiety that prevents systemic absorption; 
 wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13 , NR 13 R 14 , SR 13 , S(O)R 13 , SO 2 R 13 , SO 3 R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , NO 2 , CO 2 R 13 , CN, OM, SO 2 OM, SO 2 NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, CR 13 , P(O)R 13 R 14 , P + R 13 R 14 R 15 A − , P(OR 13 )OR 14 , S + R 13 R 14 A − , and N + R 9 R 11 R 12 A − , 
 
         wherein:
 A −  is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR 7 , NR 7 R 8 , S(O)R 7 , SO 2 R 7 , SO 3 R 7 , CO 2 R 7 , CN, oxo, CONR 7 R 8 , N + R 7 R 8 R 9 A − , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 , P + R 7 R 8 R 9 A − , and P(O)(OR 7 ) OR 8  and 
 wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR 7 , N + R 7 R 8 A − , S, SO, SO 2 , S + R 7 A − , PR 7 , P(O)R 7 , P + R 7 R 8 A − , or phenylene, and R 13 , R 14 , and R 15  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl, 
 wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR 9 , N + R 9 R 10 A − , S, SO, SO 2 , S + R 9 A − , PR, P + R 9 R 10 A − , P(O)R 9 , phenylene, carbohydrate, amino acid, peptide, or polypeptide, and 
 R 13 , R 14  and R 15  are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR 9 , NR 9 R 10 , N + R 9 R 11 R 12 A − , SR 9 , S(O)R 9 , SO 2 R 9 , SO 3 R 9 , oxo, CO 2 R 9 , CN, halogen, CONR 9 R 10 , SO 2 OM, SO 2 NR 9 R 10 , PO(OR 16 )OR 17 , P + R 9 R 10 R 11 A − , S + R 9 R 10 A − , and C(O)OM, 
 wherein R 16  and R 17  are independently selected from the substituents constituting R 9  and M; or 
 R 14  and R 15 , together with the nitrogen atom to which they are attached, form a cyclic ring; and 
 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; and 
 R 7  and R 8  are independently selected from the group consisting of hydrogen and alkyl; and 
 one or more R x  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR 13 , NR 13 R 14 , SR 13 , S(O)R 13 , S(O) 2 R 13 , SO 3 R 13 , S + R 13 R 14 A − , NR 13 OR 14 , NR 13 NR 14 R 15 , NO 2 , CO 2 R 13 , CN, OM, SO 2 OM, SO 2 NR 13 R 14 , NR 14 C(O)R 13 , C(O)NR 13 R 14 , NR 14 C(O)R 13 , C(O)OM, COR 13 , OR 18 , S(O) n  NR 18 , NR 13 R 18 , NR 18 R 14 , N + R 9 R 11 R 12 A − , P + R 9 R 11 R 12 A − , amino acid, peptide, polypeptide, and carbohydrate, 
 wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR 9 , NR 9 R 10 , N + R 9 R 11 R 12 A − , SR 9 , S(O)R 9 , SO 2 R 9 , SO 3 R 9 , oxo, CO 2 R 9 , CN, halogen, CONR 9 R 10 , SO 2 OM, SO 2 NR 9 R 10 , PO(OR 16 )OR 17 , P + R 9 R 11 R 12 A − , S + R 9 R 10 A − , or C(O)M, and 
 wherein W is O or NH, R 31  is selected from 
 wherein R 18  is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, 
 wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR 9 , NR 9 R 10 , N + R 9 R 11 R 12 A − , SR 9 , S(O)R 9 , SO 2 R 9 , SO 3 R 9 , oxo, CO 3 R 9 , CN, halogen, CONR 9 R 10 , SO 3 R 9 , SO 2 OM, SO 2 NR 9 R 10 , PO(OR 16 )OR 17 , and C(O)OM, 
 wherein in R x , one or more carbons are optionally replaced by O, NR 13 , N + R 13 R 14 A − , S, SO, SO 2 , S + R 13 A − , PR 13 , P(O)R 13 , P + R 13 R 14 A − , phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, 
 wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR 9 , R 9 R 10 A − , S, SO, SO 2 , S + R 9 A − , PR 9 , P + R 9 R 10 A − , or P(O)R 9 ; 
 wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 , NR 13 R 14 , SR 13 , S(O)R 13 , SO 2 R 13 , SO 3 R 13 , NR 13 OR 14 , NR 13 NR 14 R 15 , NO 2 , CO 2 R 13 , CN, OM, SO 2 OM, SO 2 NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, COR 13 , P(O)R 13 R 14 , P + R 13 R 14 R 15 A − , P(OR 13 )OR 14 , S + R 13 R 14 A − , and N + R 9 R 11 R 12 A − , 
 provided that both R 5  and R 6  cannot be hydrogen or SH; 
 provided that when R 5  or R 6  is phenyl, only one of R 1  or R 2  is H; 
 provided that when q=1 and R x  is styryl, anilido, or anilinocarbonyl, only one of R 5  or R 6  is alkyl; 
 or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
 
       
     
     
         26 . The method of  claim 22  or  23 , wherein the ASBTI is a compound of Formula III: 
       
         
           
           
               
               
           
         
         wherein:
 each R 1 , R 2  is independently H, hydroxy, alkyl, alkoxy, —C(═X)YR 8 , —YC(═X)R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K; or R 1  and R 2  together with the nitrogen to which they are attached form a 3-8-membered ring that is optionally substituted with R 8 ; 
 each R 3 , R 4  is independently H, hydroxy, alkyl, alkoxy, —C(═X)YR 8 , —YC(═X)R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K; 
 R 5  is H, hydroxy, alkyl, alkoxy, —C(═X)YR 8 , —YC(═X)R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, 
 each R 6 , R 7  is independently H, hydroxy, alkyl, alkoxy, —C(═X)YR 8 , —YC(═X)R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K; or R 6  and R 7  taken together form a bond; 
 each X is independently NH, S, or O; 
 each Y is independently NH, S, or O; 
 R 8  is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K; 
 L is A n , wherein
 each A is independently NR 1 , S(O) m , O, C(═X)Y, Y(C═X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; wherein each m is independently 0-2; 
 n is 0-7; 
 
 K is a moiety that prevents systemic absorption; 
 provided that at least one of R 1 , R 2 , R 3  or R 4  is -L-K; 
 or a pharmaceutically acceptable prodrug thereof. 
 
       
     
     
         27 . The method of  claim 22  or  23 , wherein the ASBTI is a compound of Formula IV: 
       
         
           
           
               
               
           
         
         wherein
 R 1  is a straight chain C 1-6  alkyl group; 
 R 2  is a straight chain C 1-6  alkyl group; 
 R 3  is hydrogen or a group OR 11  in which R 11  is hydrogen, optionally substituted C 1-6  alkyl or a C 1-6  alkylcarbonyl group; 
 R 4  is pyridyl or an optionally substituted phenyl; 
 R 5 , R 6  and R 8  are the same or different and each is selected from:
 hydrogen, halogen, cyano, R 15 -acetylide, OR 15 , optionally substituted C 1-6  alkyl, COR 15 , CH(OH)R 15 , S(O) n R 15 , P(O)(OR 15 ) 2 , OCOR 15 , OCF 3 , OCN, SCN, NHCN, CH 2 OR 15 , CHO, (CH 2 ) p CN, CONR 12 R 13 , (CH 2 ) p CO 2 R 15 , (CH 2 ) p NR 12 R 13 , CO 2 R 15 , NHCOCF 3 , NHSO 2 R 15 , OCH 2 OR 15 , OCH═CHR 15 , O(CH 2 CH 2 O) n R 15 , O(CH 2 ) p SO 3 R 15 , O(CH 2 ) p NR 12 R 13  and O(CH 2 ) p N + R 12 R 13 R 14  wherein 
 
 p is an integer from 1-4, 
 n is an integer from 0-3 and 
 R 12 , R 13 , R 14  and R 15  are independently selected from hydrogen and optionally substituted C 1-6  alkyl; 
 R 7  is a group of the formula 
 
       
       
         
           
           
               
               
           
         
         
           wherein the hydroxyl groups may be substituted by acetyl, benzyl,
 or —(C 1 -C 6 )-alkyl-R 17 , 
 
           wherein the alkyl group may be substituted with one or more hydroxyl groups; 
           R 16  is —COOH, —CH 2 —OH, —CH 2 —O-Acetyl, —COOMe or —COOEt; 
           R 17  is H, —OH, —NH 2 , —COOH or COOR 18 ; 
           R 18  is (C 1 -C 4 )-alkyl or —NH—(C 1 -C 4 )-alkyl; 
           X is —NH— or —O—; and 
           R 9  and R 10  are the same or different and each is hydrogen or C 1 -C 6  alkyl; and salts thereof. 
         
       
     
     
         28 . The method of  claim 22  or  23 , wherein the ASBTI is a compound of Formula V: 
       
         
           
           
               
               
           
         
         wherein:
 R v  is selected from hydrogen or C 1-6 alkyl; 
 One of R 1  and R 2  are selected from hydrogen or C 1-6 alkyl and the other is selected from C 1-6  alkyl; 
 R x  and R y  are independently selected from hydrogen, hydroxy, amino, mercapto, C 1-6 alkyl, C 1-6 alkoxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkylS(O) a  wherein a is 0 to 2; 
 R z  is selected from halo, nitr, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 -alkyl)sulphamoyl and N,N—(C 1-6 alkyl) 2 sulphamoyl; 
 n is 0-5; 
 one of R 4  and R 5  is a group of formula (VA): 
 
       
       
         
           
           
               
               
           
         
         
           R 3  and R 6  and the other of R 4  and R 5  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl and N,N—(C 1-6 alkyl) 2 sulphamoyl; 
           wherein R 3  and R 6  and the other of R 4  and R 5  may be optionally substituted on carbon by one or more R 17 ; 
           X is —O—, —N(R a )—, —S(O) b — or —CH(R a )—;
 wherein R a  is hydrogen or C 1-6 alkyl and b is 0-2; 
 
           Ring A is aryl or heteroaryl;
 wherein Ring A is optionally substituted on carbon by one or more substituents selected from R 18 ; 
 
           R 7  is hydrogen, C 1-6 alkyl, carbocyclyl or heterocyclyl;
 wherein R 7  is optionally substituted on carbon by one or more substituents selected from R 19 ; and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R 20 ; 
 
           R 8  is hydrogen or C 1-6 -alkyl; 
           R 9  is hydrogen or C 1-6 alkyl; 
           R 10  is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C 1-10 alkyl, C 2-10 alkynyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkanoyl, C 1-10 alkanoyloxy, N—(C 1-10 alkyl)amino, N,N—(C 1-10 alkyl) 2 amino, N,N,N—(C 1-10 alkyl) 3 ammonio, C 1-10 alkanoylamino, N—(C 1-10 alkyl)carbamoyl, N,N—(C 1-10 alkyl) 2 carbamoyl, C 1-10 alkylS(O) a  wherein a is 0 to 2, N—(C 1-10 alkyl)sulphamoyl, N,N—(C 1-10 alkyl) 2 sulphamoyl, N—(C 1-10 alkyl)sulphamoylamino, N,N—(C 1-10 alkyl) 2 sulphamoylamino, C 1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC 1-10 alkyl, heterocyclyl, heterocyclylC 1-10 alkyl, carbocyclyl-(C 1-10 alkylene) p -R 21 —(C 1-10 alkylene) q - or heterocyclyl-(C 1-10 alkylene) r -R 22 —(C 1-10 alkylene) s -; wherein R 10  is optionally substituted on carbon by one or more substituents selected from R 23 ; and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R 24 ; or R 10  is a group of formula (VB): 
         
       
       
         
           
           
               
               
           
         
         
           wherein: 
           R 11  is hydrogen or C 1-6 -alkyl; 
           R 12  and R 13  are independently selected from hydrogen, halo, carbamoyl, sulphamoyl, C 1-10 alkyl, C 2-10 alkynyl, C 2-10 alkynyl, C 1-10 alkanoyl, N—(C 1-10 alkyl)carbamoyl, N,N—(C 1-10 alkyl) 2 carbamoyl, C 1-10 alkylS(O) a  wherein a is 0 to 2, N—(C 1-10 alkyl)sulphamoyl, N,N—(C 1-10 -alkyl) 2 sulphamoyl, N—(C 1-10 alkyl)sulphamoylamino, N,N—(C 1-10 alkyl) 2 sulphamoylamino, carbocyclyl or heterocyclyl; wherein R 12  and R 13  may be independently optionally substituted on carbon by one or more substituents selected from R 25 ; and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R 26 ; 
           R 14  is selected from hydrogen, halo, carbamoyl, sulphamoyl, hydroxyaminocarbonyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkanoyl, N—(C 1-10 alkyl)carbamoyl, N,N—(C 1-10 alkyl) 2 carbamoyl, C 1-10 alkylS(O) a  wherein a is 0 to 2, N—(C 1-10 alkyl)sulphamoyl, N,N—(C 1-10 alkyl) 2 sulphamoyl, N—(C 1-10 alkyl)sulphamoylamino, N,N—(C 1-10 alkyl) 2 sulphamoylamino, carbocyclyl, carbocyclylC 1-10 alkyl, heterocyclyl, heterocyclylC 1-10 alkyl, carbocyclyl-(C 1-10 alkylene) p -R 27 —(C 1-10 alkylene) q - or heterocyclyl-(C 1-10 alkylene) r -R 28 —(C 1-10 alkylene) s -; wherein R 14  may be optionally substituted on carbon by one or more substituents selected from R 29 ; and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R 30 ; or R 14  is a group of formula (VC): 
         
       
       
         
           
           
               
               
           
         
         
           R 15  is hydrogen or C 1-6 alkyl; and R 16  is hydrogen or C 1-6 alkyl; wherein R 16  may be optionally substituted on carbon by one or more groups selected from R 31 ; 
           or R 15  and R 16  together with the nitrogen to which they are attached form a heterocyclyl; wherein said heterocyclyl may be optionally substituted on carbon by one or more R 37 ; and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R 38 ; 
           m is 1-3; wherein the values of R 7  may be the same or different; 
           R 17 , R 18 , R 19 , R 23 , R 25 , R 29 , R 31  and R 37  are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 -alkoxy, C 1-10 alkanoyl, C 1-10 alkanoyloxy, N—(C 1-10 alkyl)amino, N,N—(C 1-10 alkyl) 2 amino, N,N,N—(C 1-10 alkyl) 3 ammonio, C 1-10 alkanoylamino, N—(C 1-10 alkyl)carbamoyl, N,N—(C 1-10 alkyl) 2 carbamoyl, C 1-10 alkylS(O) a  wherein a is 0 to 2, N—(C 1-10 alkyl)sulphamoyl, N,N—(C 1-10 alkyl) 2 sulphamoyl, N—(C 1-10 alkyl)sulphamoylamino, N,N—(C 1-10 alkyl) 2 sulphamoylamino, C 1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC 1-10 alkyl, heterocyclyl, heterocyclylC 1-10 alkyl, carbocyclyl-(C 1-10 alkylene) p -R 32 —(C 1-10 alkylene) q - or heterocyclyl-(C 1-10 alkylene) r -R 33 —(C 1-10 alkylene) s -; wherein R 17 , R 18 , R 19 , R 23 , R 25 , R 29 , R 31  and R 37  may be independently optionally substituted on carbon by one or more R 34 ; and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R 35 ; 
           R 21 , R 22 , R 27 , R 28 , R 32  or R 33  are independently selected from —O—, —NR 36 —, —S(O) x —, —NR 36 C(O)NR 36 —, —NR 36 C(S)NR 36 —, —OC(O)N═C—, —NR 36 C(O)— or —C(O)NR 36 —; wherein R 36  is selected from hydrogen or C 1-6 alkyl, and x is 0-2; 
           p, q, r and s are independently selected from 0-2; 
           R 34  is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino and N,N-dimethylsulphamoylamino; 
           R 20 , R 24 , R 26 , R 30 , R 35  and R 38  are independently selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulphonyl, C 1-6 alkoxycarbonyl, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; and 
           wherein a “heteroaryl” is a totally unsaturated, mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur and oxygen, which heteroaryl may, unless otherwise specified, be carbon or nitrogen linked; 
           wherein a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur and oxygen, which heterocyclyl may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH 2 — group can optionally be replaced by a —C(O)— group, and a ring sulphur atom may be optionally oxidised to form an S-oxide; and 
           wherein a “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a —CH 2 — group can optionally be replaced by a —C(O) group; 
           or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide formed on an available carboxy or hydroxy group thereof. 
         
       
     
     
         29 . The method of  claim 22  or  23 , wherein the ASBTI is a compound of Formula VI: 
       
         
           
           
               
               
           
         
         wherein:
 R v  and R w  are independently selected from hydrogen or C 1-6 alkyl; 
 one of R 1  and R 2  is selected from hydrogen or C 1-6 alkyl and the other is selected from C 1-6 alkyl; 
 R x  and R y  are independently selected from hydrogen or C 1-6 alkyl, or one of R x  and R y  is hydrogen or C 1-6 alkyl and the other is hydroxy or C 1-6 alkoxy; 
 R z  is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl and N,N—(C 1-6 alkyl) 2 sulphamoyl; 
 n is 0-5; 
 one of R 4  and R 5  is a group of formula (VIA): 
 
       
       
         
           
           
               
               
           
         
         
           R 3  and R 6  and the other of R 4  and R 5  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 -alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl and N,N—(C 1-6 alkyl) 2 sulphamoyl; wherein R 3  and R 6  and the other of R 4  and R 5  may be optionally substituted on carbon by one or more R 17 ; 
           X is —O—, —N(R a )—, —S(O) b — or —CH(R a )—; wherein R a  is hydrogen or C 1-6 alkyl and b is 0-2; 
           Ring A is aryl or heteroaryl; wherein Ring A is optionally substituted on carbon by one or more substituents selected from R 18 ; 
           R 7  is hydrogen, C 1-6 alkyl, carbocyclyl or heterocyclyl; wherein R 7  is optionally substituted on carbon by one or more substituents selected from R 19 ; and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R 20 ; 
           R 8  is hydrogen or C 1-6 alkyl; 
           R 9  is hydrogen or C 1-6 alkyl; 
           R 10  is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkanoyl, C 1-10 alkanoyloxy, N—(C 1-10 alkyl)amino, N,N—(C 1-10 alkyl) 2 amino, N,N,N—(C 1-10 alkyl) 3 ammonio, C 1-10 alkanoylamino, N—(C 1-10 alkyl)carbamoyl, N,N—(C 1-10 alkyl) 2 carbamoyl, C 1-10 alkylS(O) a  wherein a is 0 to 2, N—(C 1-10 alkyl)sulphamoyl, N,N—(C 1-10 alkyl) 2 sulphamoyl, N—(C 1-10 alkyl)sulphamoylamino, N,N—(C 1-10 alkyl) 2 sulphamoylamino, C 1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC 1-10 alkyl, heterocyclyl, heterocyclylC 1-10 alkyl, carbocyclyl-(C 1-10 alkylene) p -R 21 —(C 1-10 alkylene) q - or heterocyclyl-(C 10 alkylene) r -R 22 —(C 1-10 alkylene) s -; wherein R 10  is optionally substituted on carbon by one or more substituents selected from R 23 ; and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R 24 ; or R 10  is a group of formula (VIB): 
         
       
       
         
           
           
               
               
           
         
         wherein:
 R 11  is hydrogen or C 1-6 alkyl; 
 R 12  and R 13  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkanoyl, C 1-10 alkanoyloxy, N—(C 1-10 alkyl)amino, N,N—(C 1-10 alkyl) 2 amino, C 1-10 alkanoylamino, N—(C 1-10 alkyl)carbamoyl, N,N—(C 1-10 alkyl) 2 carbamoyl, C 1-10 alkylS(O) a  wherein a is 0 to 2, N—(C 1-10 alkyl)sulphamoyl, N,N—(C 1-10 alkyl) 2 sulphamoyl, N—(C 1-10 alkyl)sulphamoylamino, N,N—(C 1-10 alkyl) 2 sulphamoylamino, carbocyclyl or heterocyclyl; wherein R 12  and R 13  may be independently optionally substituted on carbon by one or more substituents selected from R 25 ; and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R 26 ; 
 R 14  is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkanoyl, C 1-10 alkanoyloxy, N—(C 1-10 alkyl)amino, N,N—(C 1-10 alkyl) 2 amino, N,N,N—(C 1-10 alkyl) 3 ammonio, C 1-10 alkanoylamino, N—(C 1-10 alkyl)carbamoyl, N,N—(C 1-10 alkyl) 2 carbamoyl, C 1-10 alkylS(O) a  wherein a is 0 to 2, N—(C 1-10 alkyl)sulphamoyl, N,N—(C 1-10 alkyl) 2 sulphamoyl, N—(C 1-10 alkyl)sulphamoylamino, N,N—(C 1-10 alkyl) 2 sulphamoylamino, C 1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC 1-10 alkyl, heterocyclyl, heterocyclylC 1-10 alkyl, carbocyclyl-(C 1-10 alkylene) p -R 27 —(C 1-10 alkylene) q - or heterocyclyl-(C 1-10 alkylene) r -R 28 —(C 1-10 alkylene) s -; wherein R 14  may be optionally substituted on carbon by one or more substituents selected from R 29 ; and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R 30 ; or R 14  is a group of formula (VIC): 
 
       
       
         
           
           
               
               
           
         
         
           R 15  is hydrogen or C 1-6 alkyl; 
           R 16  is hydrogen or C 1-6 alkyl; wherein R 16  may be optionally substituted on carbon by one or more groups selected from R 31 ; 
           n is 1-3; wherein the values of R 7  may be the same or different; 
           R 17 , R 18 , R 19 , R 23 , R 25 , R 29  or R 31  are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, amidino, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkanoyl, C 1-10 alkanoyloxy, (C 1-10 alkyl) 3 silyl, N—(C 1-10 alkyl)amino, N,N—(C 1-10 alkyl) 2 amino, N,N,N—(C 1-10 alkyl) 3 ammonio, C 1-10 alkanoylamino, N—(C 1-10 alkyl)carbamoyl, N,N—(C 1-10 alkyl) 2 carbamoyl, C 1-10 alkylS(O) a  wherein a is 0 to 2, N—(C 1-10 alkyl)sulphamoyl, N,N—(C 1-10 alkyl) 2 sulphamoyl, N—(C 1-10 alkyl)sulphamoylamino, N,N—(C 1-10 alkyl) 2 sulphamoylamino, C 1-10 alkoxycarbonylamino, carbocyclyl, carbocyclylC 1-10 alkyl, heterocyclyl, heterocyclylC 1-10 alkyl, carbocyclyl-(C 1-10 alkylene) p -R 32 —(C 1-10 alkylene) q - or heterocyclyl-(C 1-10 alkylene) r -R 33 —(C 1-10 alkylene) s -; wherein R 17 , R 18 , R 19 , R 23 , R 25 , R 29  or R 31  may be independently optionally substituted on carbon by one or more R 34 ; and wherein if said heterocyclyl contains an —NH— group, that nitrogen may be optionally substituted by a group selected from R 35 ; 
           R 21 , R 22 , R 27 , R 28 , R 32  or R 33  are independently selected from —O—, —NR 36 —, —S(O) x —, —NR 36 C(O)NR 36 —, —NR 36 C(S)NR 36 —, —OC(O)N═C—, —NR 36 C(O)— or —C(O)NR 36 —; wherein R 36  is selected from hydrogen or C 1-6 alkyl, and x is 0-2; 
           p, q, r and s are independently selected from 0-2; 
           R 34  is selected from halo, hydroxy, cyano, carbamoyl, ureide, amino, nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl, N-methylsulphamoylamino and N,N-dimethylsulphamoylamino; 
           R 20 , R 24 , R 26 , R 30  or R 35  are independently selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulphonyl, C 1-6 alkoxycarbonyl, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; 
           or a pharmaceutically acceptable salt, solvate or solvate of such a salt, or an in vivo hydrolysable ester formed on an available carboxy or hydroxy thereof, or an in vivo hydrolysable amide formed on an available carboxy thereof. 
         
       
     
     
         30 . The method of  claim 24 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
       
     
     
         31 . The method of  claim 25 , wherein the compound of Formula II is 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         32 . The method of  claim 25 , wherein the compound of Formula II is 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 25 , wherein the compound of Formula II is 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         34 . The method of  claim 25 , wherein the compound of Formula II is 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method of  claim 25 , wherein the compound of Formula II is 
       
         
           
           
               
               
           
         
       
     
     
         36 . The method of  claim 28 , wherein the compound of Formula V is 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-[(R)-α[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-[(R)-α[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; or 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-[(R)-α[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine.