Colchinol derivatives as vascular damaging agents

Abstract

The invention relates to the use of compounds of formula (I): wherein X is —C(O)—, —C(S)—, —C═NOH, or —CH(R 7 )— wherein R 7 is hydrogen, hydroxy, C 1-7 alkoxy, —OR 8 or —NR 8 R 9 (wherein R 8 is a group —Y 1 R 10 (wherein Y 1 is a direct bond, —C(O)—, —C(S)—, —S—, —C(O)O—, —C(O)NR 11 —, —SO 2 — or —SO 2 NR 12 — (wherein R 11 and R 12 , which may be the same or different, each independently represents hydrogen; C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 10 is as defined herein, R 9 includes hydrogen; R 11 , R 12 and R 13 are as defined herein and are preferably methyl; R 4 , R 5 and R 6 are as defined herein with the proviso that R 5 is not hydroxy, alkoxy, substituted alkoxy, —OPO 3 H 2 , —O—C 1-7 alkanoyl or benzyloxy; and salts thereof in the manufacture of a medicament for use in the production of a vascular damaging effect in warm-blooded animals such as humans. The present invention further relates to compounds of the formula (I), pharmaceutical compositions containing them, processes for their preparation and to a method of treatment using the compounds to produce a vascular damaging effect in a warm-blooded animal such as a human. The compounds of formula (I) and the pharmaceutically acceptable salts thereof may be useful in the treatment of a number of disease states including cancer and rheumatoid arthritis.

1 . (canceled)  
     
     
         2 . A compound of the formula IIa:  
       
         
           
           
               
               
           
         
       
       wherein 
 X is —C(O)—, —C(S)—, —C═NOH  
 R 1 , R 2  and R 3  are each independently hydrogen, PO 3 H 2 , sulphate, C 3-7 cycloalkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 1-7 alkanoyl, a group R 20 C 1-7 alkyl (wherein R 20  is phenyl which may bear one or more substituents selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 aminoalkyl and C 1-4 hydroxyalkoxy), C 1-7 alkyl or C 1-7 alkylsulphonyl, which alkyl or alkylsulphonyl group may bear one or more substituents selected from: 
 halogeno, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, C 1-4 alkoxy, C 1-4 alkylsulphanyl, C 1-4 alkylsulphonyl, C 1-4 alkoxycarbonylamino, C 1-4 alkanoyl, carboxy, phenyl, nitro, sulphate, phosphate and a group —Y 2 R 21 , wherein 
 Y 2  is —NR 22 C(O)— or —O—C(O)—, wherein R 22  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and  
 R 21  is C 1-7 alkyl, C 3-7 cycloalkyl or a group R 23  wherein R 23  is a phenyl group or a 5-10-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-4 heteroatoms selected independently from O, N and S, which phenyl or aromatic heterocyclic group may bear one or more substituents selected from hydroxy, nitro, halogeno, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxyalkoxy, carboxy, cyano, —CONR 24 R 25  and —NR 26 COR 27  (wherein R 24 , R 25 , R 26  and R 27 , which may be the same or different, each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl);  
 
 with the proviso that at least two of R 1 , R 2  and R 3  are C 1-7 alkyl;  
 
 R 4  is hydrogen, cyano, halogeno, nitro, amino, hydroxy, C 1-7 alkoxy, C 1-7 thioalkoxy, C 1-7 alkanoyl or C 1-7 alkyl, (which alkyl group may bear one or more substituents selected from: 
 halogeno, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, C 1-4 alkoxy, C 1-4 alkylsulphanyl, C 1-4 alkylsulphonyl, C 1-4 alkoxycarbonylamino, C 1-4 alkanoyl, carboxy, phenyl, nitro, sulphate, phosphate and a group —Y 3 R 28 , wherein 
 Y 3  is —NR 29 C(O)— or —O—C(O)— (wherein R 29  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and  
 R 28  is C 1-7 alkyl, C 3-7 cycloalkyl or a group R 30  wherein R 30  is a phenyl group or a 5-10-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-4 heteroatoms selected independently from O, N and S, which phenyl or aromatic heterocyclic group may bear one or more substituents selected from hydroxy, nitro, halogeno, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxyalkoxy, carboxy, cyano, —CONR 31 R 32  and —NR 31 COR 32  (wherein R 31 , R 32 , R 33  and R 34 , which may be the same or different, each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl);  
 
 
 R 5  and R 6  are each independently selected from hydrogen, —OPO 3 H 2 , phosphonate, cyano, halogeno, nitro, amino, carboxy, carbamoyl, hydroxy, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 thioalkoxy, C 1-7 alkyl, (which alkyl group may bear one or more substituents selected from: 
 halogeno, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, C 1-4 alkoxy, C 1-4 alkylsulphanyl, C 1-4 alkylsulphonyl, C 1-4 alkoxycarbonylamino, C 1-4 alkanoyl, carboxy, phenyl, sulphate, phosphate and a group —Y 3 R 28 , wherein Y 3  is —NR 29 C(O)— or —O—C(O)— (wherein R 29  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 28  is C 1-7 alkyl, C 3-7 cycloalkyl or a group R 30  wherein R 30  is a phenyl group or a 5-10-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-4 heteroatoms selected independently from O, N and S, which phenyl or aromatic heterocyclic group may bear one or more substituents selected from hydroxy, nitro, halogeno, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxyalkoxy, carboxy, cyano, —CONR 31 R 32  and —NR 31 COR 32  (wherein R 31 , R 32 , R 33  and R 34 , which may be the same or different, each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl), and  
 
 a group —Y 4 R 35 , wherein 
 Y 4  is —C(O)—, —OC(O)—, —O—, —SO—, —SO 2 —, —OSO 2 —, —NR 36 —, —C 1-4 alkylNR 36 —, —C 1-4 alkylC(O)—, —NR 37 C(O)—, —OC(O)O—, —C(O)NR 38 — or —NR 39 C(O)O— (wherein R 36 , R 37 , R 33  and R 39 , which may be the same or different, each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and  
 R 35  is a sugar moiety, a mono-peptide, a di-peptide, a tri-peptide, a tetra-peptide, sulphate, hydroxy, amino, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkylamino, di(C 1-7 alkyl)amino, aminoC 1-7 alkylamino, C 1-7 alkylaminoC 1-7 alkylamino, C 1-7 alkanoylaminoC 1-7 alkyl, di(C 1-7 alkyl)aminoC 1-7 alkylamino, C 1-7 alkylphosphate, C 1-7 alkylphosphonate, C 1-7 alkylcarbamoylC 1-7 alkyl, which alkyl, alkoxy, alkanoyl, alkylamino, dialkylamino, aminoalkylamino, alkylaminoalkylamino, alkanoylaminoalkyl, dialkylaminoalkylamino, alkylphosphate, alkylphosphonate or alkylcarbamoylalkyl, may bear one or more substituents selected from: 
 halogeno, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkylsulphanyl, C 1-4 alkylsulphonyl, C 1-4 alkoxycarbonylamino, C 1-4 alkanoyl, carboxy, phenyl, nitro, sulphate, phosphate and a group —Y 5 R 40 , wherein Y 5  is —NR 41 C(O)—, —C(O)NR 42 —, —C(O)—O— or —O—C(O)— (wherein R 41  and R 42  which may be the same or different each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 40  is C 1-7 alkyl, C 3-7 cycloalkyl, carboxyC 1-7 alkyl or a group R 43  wherein R 43  is a phenyl group, a benzyl group or a 5-10-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-4 heteroatoms selected independently from O, N and S, which phenyl, benzyl or aromatic heterocyclic group may bear one or more substituents selected from hydroxy, nitro, halogeno, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxyalkoxy, carboxy, cyano, —CONR 44 R 45  and —NR 46 COR 47  (wherein R 44 , R 45 , R 46  and R 47 , which may be the same or different, each represents hydrogen, C 1-3 alkyl or  
 
 
 R 48 , wherein R 48  is a phenyl group, a benzyl group or a 5-10-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-4 heteroatoms selected independently from O, N and S, which phenyl, benzyl or aromatic heterocyclic group may bear one or more substituents selected from hydroxy, nitro, halogeno, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, di(C 1-4 alkyl)aminoC 1-4 alkyl, di(C 1-4 hydroxyalkyl)aminoC 1-4 alkyl, di(C 1-4 aminoalkyl)aminoC 1-4 alkyl, C 1-4 hydroxyalkoxy, carboxy, C 1-4 carboxyalkyl, phenyl, cyano, —CONR 49 R 50 , —NR 51 COR 52  (wherein R 49 , R 50 , R 51  and R 52 , which may be the same or different, each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and C 1-4 alkylR 53  (wherein R 53  is as defined herein),  
 C 1-7 alkylR 48  (wherein R 48  is as defined herein),  
 R 53 , wherein R 53  is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from 
 oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 carboxyalkyl, C 1-4 aminoalkyl, di(C 1-4 alkyl)aminoC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylsulphonylC 1-4 alkyl and R 54 , wherein R 54  is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from 
 oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, 
 C 1-4 alkoxyC 1-4 alkyl and C 1-4 alkylsulphonylC 1-4 alkyl or  
 
 
 
 (CH 2 ) a Y 6 (CH 2 ) b R 53 , wherein R 53  is as defined herein, a is 0, or an integer 1-4, b is 0 or an integer 1-4 and Y 6  represents a direct bond, —O—, —C(O)—, —NR 51 —, —NR 56 C(O)— or —C(O)NR 57 — (wherein R 55 , R 56 , and R 57 , which may be the same or different, each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl), and wherein one or more of the (CH 2 ) a  or (CH 2 ) b  groups may bear one or more substituents selected from hydroxy, amino and halozeno;  
 with the proviso that R 5  is not hydroxy, alkoxy, substituted alkoxy (wherein R 5 is Y 4 R 35  and Y 4  is —O— and R 35  is C 1-7 alkyl bearing one or more substituents selected from the list given herein), —OPO 3 H 2 , —O—C 1-7 alkanoyl or benzyloxy;  
 with the further proviso that at least one of R 5  or R 6  is a group —Y 4 R 35  (wherein Y 4  and R 35  are as defined herein) but with the further provisos that when R 5  is —Y 4 R 35  and R 6  is hydrogen, hydroxy, methoxy or methoxycarbonyl, —Y 4 R 35  is not selected from cases wherein: 
 Y 4  is —C(O)—, —OC(O)—, —O—, —SO—, —OSO 2 —, —NR 36 —, —NR 37 C(O)— or —C(O)NR 38 — (wherein R 36 , R 37  and R 38 , which may be the same or different, each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and  
 R 35  is a glycine, valine or lysine group, a dipeptide of glycine and valine groups, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, (which alkyl, alkoxy or alkanoyl may bear one or more substituents selected from: 
 halogeno, hydroxy, and a group —Y 5 R 40  (wherein Y 5  is —O—C(O)— and R 40  is C 1-7 alkyl) or R 48 , wherein R 48  is a tetrazolyl group (which may or may not be substituted as herein defined), a phenyl group or a benzyl group which phenyl or benzyl group may bear one or more substituents selected from C 1-4 alkyl); and  
 
 
 that when R 6  is —Y 4 R 35  and R 5  is hydrogen, methoxy or methoxycarbonyl, —Y 4 R 35  is not selected from cases wherein: 
 Y 4 is —C(O)—, —O— or —OSO 2 — and  
 R 35  is C 1-7 alkyl, C 1-7 alkoxy (which alkyl, alkoxy or alkanoyl may bear one or more substituents selected from: halogeno), R 48  (wherein R 48  is a benzyl group which benzyl group may bear one or more substituents selected from C 1-4 alkyl), or R 53  (wherein R 53  is piperidinyl);  
 
 or a salt thereof.  
 
     
     
         3 - 4 . (canceled)  
     
     
         5 . A compound according to  claim 2  wherein R 1 , R 2  and R 3  are each methyl.  
     
     
         6 . A compound according to  claim 2  wherein R 4  is hydrogen.  
     
     
         7 . A compound according to  claim 2  wherein R 6  is hydrogen, halogeno, amino, carboxy, hydroxy, C 1-7 alkoxy or a group Y 4 R 35 , wherein 
 Y 4  is —C(O)—, —O— or —OSO 2 — and    R 35  is C 1-7 alkyl, C 1-7 alkoxy (which alkyl or alkoxy may bear one or more substituents selected from halogeno), R 48  (wherein R 48  is a benzyl group) or R 53  (wherein R 53  is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms selected independently from O, S and N).    
     
     
         8 . A compound according to  claim 2  wherein R 6  is hydrogen, C(O)OCH 3  or methoxy.  
     
     
         9 . A compound according to  claim 2  wherein 
 R 5  is hydrogen, halogeno, amino, carboxy, carbamoyl, C 1-7 alkanoyl, C 1-7 thioalkoxy, or a group —Y 4 R 35 , wherein 
 Y 4  is —C(O)—, —OC(O)—, —O—, —SO—, —OSO 2 —, —NR 36 —, —NR 37 C(O)— or —C(O)NR 38 — (wherein R 36 , R 37  and R 38 , which may be the same or different, each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and  
 R 35  is a sugar moiety, a mono-peptide, a di-peptide, a tri-peptide, a tetra-peptide, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkanoyl, C 1-7 alkanoylaminoC 1-7 alkyl, which alkyl, alkoxy, alkanoyl, alkanoylaminoalkyl may bear one or more substituents selected from: halogeno, amino, hydroxy, carboxy, and a group —Y 5 R 40 , wherein 
 Y 5 is —C(O)—O— or —O—C(O)— and  
 R 40  is C 1-7 alkyl or a group R 43  wherein R 43  is a benzyl group,  
 
 R 48 , wherein R 48  is a phenyl group, a benzyl group or a 5-10-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-4 heteroatoms selected independently from O, N and S, which phenyl, benzyl or aromatic heterocyclic group may bear one or more substituents selected from hydroxy, fluoro, amino, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, di(C 1-4 alkyl)aminoC 1-4 alkyl, di(C 1-4 hydroxyalkyl)aminoC 1-4 alkyl, di(C 1-4 aminoalkyl)aminoC 1-4 alkyl, C 1-4 hydroxyalkoxy, carboxy, C 1-4 carboxyalkyl, cyano, —CONR 49 R 50 , —NR 51 COR 52  (wherein R 49 , R 50 , R 51  and R 52 , which may be the same or different, each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and C 1-4 alkylR 53  (wherein R 53  is as defined herein), C 1-7 alkylR 48  (wherein R 48  is as defined herein), R 53 , wherein R 53  is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from 
 oxo, hydroxy, fluoro, chloro, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 carboxyalkyl, C 1-4 aminoalkyl, di(C 1-4 alkyl)aminoC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 alkylsulphonylC 1-4 alkyl and R 54 , wherein R 54  is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, 
 C 1-4 alkoxyC 1-4 alkyl and C 1-4 alkylsulphonylC 1-4 alkyl, or  
 
 
 (CH 2 ) a Y 6 (CH 2 ) b R 53 , wherein R 53  is as defined herein, a is 0, or an integer 1-4, b is 0 or an integer 1-4 and Y 6  represents a direct bond, —O—, —C(O)—, —NR 55 —, —NR 56 C(O)— or —C(O)NR 57 — (wherein R 55 , R 56 , and R 57 , which may be the same or different, each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl), and wherein one or more of the (CH 2 ) a  or (CH 2 ) b  groups may bear one or more substituents selected from hydroxy, amino and halogeno;  
 with the proviso that R 5  is not alkoxy, substituted alkoxy (wherein R 5  is Y 4 R 35  and Y 4  is —O— and R 35  is C 1-7 alkyl bearing one or more substituents selected from the list given herein), —O—C 1-7 alkanoyl or benzyloxy.  
   
     
     
         10 - 12 . (canceled)  
     
     
         13 . A process for the manufacture of a compound of formula IIa as defined in  claim 2  which comprises: 
 (a) for the preparation of compounds of formula IIa and salts thereof in which R 5  or R 6  is a group Y 4 R 35  (wherein R 35  is as defined in  claim 2  and Y 4  is a group —OC(O)— or —NHC(O)—), the reaction of a compound of formula III or IV:                        (wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  are as defined in  claim 2  and Y 7 is —O— or —NH—), by acylation or coupling reactions;      (b) for the preparation of compounds of formula Iha and salts thereof in which R 5  or R 6  is a group Y 4 R 35  (wherein R 35  is C 1-7 alkoxy which may be substituted as defined in  claim 2  and Y 4  is a group —OC(O)— or —NHC(O)—), the reaction of a compound of formula III and IV, by acylation reactions;    (c) for the preparation of compounds of formula IIa and salts thereof in which R 5  or R 6  is a group Y 4 R 35  (wherein R 35  is aminoC 1-7 alkylamino, C 1-7 alkylaminoC 1-7 alkylamino, di(C 1-7 alkyl)aminoC 1-7 alkylamino and may be substituted as defined in  claim 2 , or is R 53  (wherein R 53  is as defined in  claim 2)  and Y 4  is a group —OC(O)— or —NHC(O)—), can be prepared by the reaction of a compound of formula III or IV, acylation reactions;    (d) for the preparation of compounds of formula IIa and salts thereof in which R 5  or R 6  is a group Y 4 R 35  (wherein R 35  is a sugar moiety and Y 4  is a group —O— or —NH—), the reaction of a compound of formula III or IV by glycosylation reactions;    (e) for the preparation of compounds of formula IIa and salts thereof in which R 5  or R 6  is a group Y 4 R 35  (wherein R 35  is sulphate and Y 4  is a group —O— or —NH—), the reaction of a compound of formula III or IV, by sulphonylation reactions;    (f) for the preparation of compounds of formula IIa and salts thereof in which R 5  or R 6  is a group Y 4 R 35  (wherein R 35  is C 1-7 alkylphosphate and may be substituted as defined in  claim 2  and Y 4  is a group —O— or —NH—), the reaction of a compound of formula III or IV, by phosphorylation reactions;    (g) for the preparation of compounds of formula IIa and salts thereof in which R 5  is amino the reaction of a carboxylic acid of formula V:                        (wherein X, R 1 , R 2 , R 3 , R 4  and R 6  are as defined in  claim 2)  via Curtius rearrangement and hydrolysis; and      (h) for the preparation of compounds of formula IIa and salts thereof in which R 5  or R 6  is chloro the reaction of a compound of formula III or IV by the Sandmeyer reaction;    and when a pharmaceutically acceptable salt of a compound of formula IIa is required, reaction of the compound obtained with an acid or base whereby to obtain the desired pharmaceutically acceptable salt.    
     
     
         14 . A pharmaceutical composition which comprises as active ingredient a compound of formula IIa as defined in  claim 2  or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient or carrier.  
     
     
         15 . (canceled)  
     
     
         16 . A compound according to  claim 2  selected from: 
 methyl 2,9,10,11-tetramethoxy-5-oxo-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl carbonate; and    5-(hydroxyimino)-2,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl methyl carbonate;    and salts thereof.    
     
     
         17 . A method of reducing neovascularization by selectively damaging newly formed vascular endothelium in a warm-blooded animal in need thereof which comprises administering to said animal an effective amount of a compound of formula IIa or a pharmaceutically acceptable salt thereof as defined in any one of claims  2 ,  4 ,  5 ,  6 ,  7 ,  8 ,  9 ,  10 ,  11  and  12 .