Pyrrolo[3,4-d]pyrimidinone derivatives and their use as medicaments

Abstract

The invention provides certain novel 5-substituted pyrrolo[3,4-d]pyrimidine-2,4-diones, processes for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and methods of treatment involving their use.

1 . A compound according to the general formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 W represents —CH 2 — or a bond; Q represents Ar 1  or Ar 2 ; in the case where W represents —CH 2 —, Q represents an aryl group Ar 1  wherein Ar 1  represents naphthyl, phenyl, quinolyl, isoquinolyl, indolyl, benzofuranyl or benzothienyl; in the case where W represents a bond, Q represents an aryl group Ar 2  wherein Ar 2  represents acenaphthenyl, fluorenyl or indanyl; wherein the ring systems which Ar 1  and Ar 2  represent may all be optionally substituted by one or more substituents selected from C 1-4  alkyl, C 1-4  alkoxy, halogen, or trifluoromethyl; R 10  represents X—(A) p —Y; X represents S(O) n , C≡C, (CH 2 ) 2 , CH═CH or CH 2 CH═CH; n represents 0, 1 or 2; A represents C 1-6  alkylene; p is 0 or 1; Y represents CN, OR 11 , CO 2 R 12 , CONR 13 R 14 , NR 15 R 16 , NHSO 2 R 17 , NHCOR 18  or an optionally substituted aryl or heteroaryl group, provided that when X represents S(O) n  and Y is other than an optionally substituted aryl or heteroaryl group, then p is 1 and also provided that when X represents S(O) n , p is 1 and Y represents OH, then n is not 0; R 13  and R 14  independently represent H, C 1-5  alkyl or phenyl, which latter group may be substituted by one or more substituents selected from C 1-4  alkyl, C 1-4  alkoxy, halogen, or CO 2 R 21 ; and R 1 , R 2 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18  and R 21  independently represent H or C 1-5  alkyl; or a pharmaceutically acceptable derivative thereof.  
 
     
     
         2 . A compound according to  claim 1 , wherein in formula (I), W represents —CH 2 — and Q represents an aryl group Ar 1  wherein Ar 1  represents a naphthyl or phenyl group, each of which may be optionally substituted by one or more substituents selected from C 1-4  alkyl, C 1-4  alkoxy, halogen or trifluoromethyl.  
     
     
         3 . A compound according to  claim 1 , wherein, in formula (I), W represents a bond and Q represents an aryl group Ar 2  wherein Ar 2  represents an indanyl group which may be optionally substituted by one or more substituents selected from C 1-4  alkyl, C 1-4  alkoxy, halogen or trifluoromethyl.  
     
     
         4 . A compound according to any one of  claims 1  to  3 , wherein, in formula (I), X represents S(O) n  wherein n is 0, 1 or 2, C≡C, (CH 2 ) 2  or CH 2 CH═CH.  
     
     
         5 . A compound according to any one of  claims 1  to  4 , wherein, in formula (I), X represents S(O) n  wherein n is 0, 1 or 2.  
     
     
         6 . A compound according to any one of  claims 1  to  5 , wherein in formula (I), A represents C 1-4  alkylene.  
     
     
         7 . A compound according to any one of  claims 1  to  6 , wherein, in formula (I), each of groups R 1 , R 2 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18  and R 21  represents H or a C 1-4  alkyl group.  
     
     
         8 . A compound according to any one of  claims 1  to  7 , wherein, in formula (I), each of groups R 13  and R 14  represents H, C 1-3  alkyl or phenyl, which latter group may be substituted by one or more substituents selected from C 1-4  alkyl, C 1-4  alkoxy, halogen or CO 2 R 21 .  
     
     
         9 . A compound according to  claim 1 , wherein, in formula (I), W represents —CH 2 — or a bond; Q represents Ar 1  or Ar 2 ; in the case where W represents —CH 2 —, Q represents an aryl group Ar 1  wherein Ar 1  represents naphthyl or phenyl; in the case where W represents a bond, Q represents an aryl group Ar 2 wherein Ar 2  represents indanyl; wherein the ring systems which Ar 1  and Ar 2  represent may all be optionally substituted by one or more, e.g. one, two, three or four, substituents selected from C 1-4  alkyl, C 1-4  alkoxy, halogen, or trifluoromethyl; R 10  represents X—(A) p —Y; X represents S(O) n , C≡C, (CH 2 ) 2  or CH 2 CH═CH; n represents 0, 1 or 2; A represents C 1-6  alkylene; p is 0 or 1; Y represents CN, OR 11 , CO 2 R 12 , CONR 13 R 14 , NR 15 R 16  or an optionally substituted phenyl, pyridyl or tetrazolyl group, provided that when X represents S(O) n  and Y is other than an optionally substituted aryl or heteroaryl group, the p is 1 and also provided that when X represents S(O) n , p is 1 and Y represents OH, then n is not 0; R 13  and R 14  independently represent H, C 1-5  alkyl or phenyl, which latter group may be substituted by one or more substituents selected from C 1-4  alkyl, C 1-4  alkoxy, halogen, or CO 2 R 21 ; and R 1 , R 2 , R 11 , R 12 , R 15 , R 16  and R 21  independently represent H or C 1-5  alkyl.  
     
     
         10 . A compound according to  claim 1 , wherein, in formula (I), W represents —CH 2 — or a bond; Q represents Ar 1  or Ar 2 ; in the case where W represents —CH 2 —, Q represents an aryl group Ar 1  wherein Ar 1  represents naphthyl; in the case where W represents a bond, Q represents an aryl group Ar 2  wherein Ar 2  represents indanyl; R 10  represents X—(A) p —Y; X represents S(O) n , C≡C, (CH 2 ) 2  or CH 2 CH═CH; n represents 0, 1 or 2; A represents C 1-3  alkylene; p is 0 or 1; Y represents CN, OR 11 , CO 2 R 12 , CONR 13 R 14 , NR 15 R 16  or a phenyl, pyridyl or tetrazolyl group optionally substituted by a hydroxyl or methoxy group, provided that when X represents S(O) n  and Y is other than an optionally substituted aryl or heteroaryl group, then p is 1 and also provided that when X represents S(O) n , p is 1 and Y represents OH, then n is not 0; R 13  and R 14  independently represent H; and R 1 , R 2 , R 11 , R 12 , R 15  and R 16  independently represent H or C 1-4  alkyl.  
     
     
         11 . A compound according to  claim 1  being: 
 5-[(3-hydroxypropyl)sulphinyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or  
 5-[(3-hydroxypropyl)sulphonyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or  
 methyl 4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoate; or  
 5-[(3-methoxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or  
 5-[(2-hydroxyethyl)sulphinyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or  
 4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoic acid; or  
 4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl-6-(1-naphthalenylmethyl-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoic acid, sodium salt; or  
 5-[(2-dimethylaminoethyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or  
 6-(2,3-dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)sulphinyl]-3-methyl-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or  
 6-(2,3-dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)sulphonyl]-3-methyl-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or  
 5-[(3-hydroxypropyl)sulphinyl]-3-methyl-1-(1-methylethyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4-(3H, 6H)-dione; or  
 4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanamide; or  
 5-(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)pent-3-enoic acid; or  
 5-(5-hydroyxpent-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,3-(3H,6H)-dione; or  
 5-(5-hydroxypentyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or  
 5-(4-hydroxybut-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4-(3H,6H)-dione; or  
 5-(4-hydroxybutyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4-(3H,6H)-dione;  
 5-(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidine-5-yl)pentanoic acid;  
 4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidine-5-yl)thio]butanenitrile;  
 5-[(3-{1H-tetrazol-5-yl}propyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;  
 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-pyridinyl)thio]-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;  
 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-pyridinyl)sulphinyl]-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;  
 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(4-pyridinyl)thio]-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;  
 5-([3-methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;  
 5-([3-hydroxyphenyl]thio)-3-methyl-1(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;  
 5-([4-methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione;  
 5-([4-hydroxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4-(3H,6H)-dione;  
 5-([2-methoxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione; or  
 5-([2-hydroxyphenyl]thio)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione.  
 
     
     
         12 . A process for the preparation of a compound of formula (I) as defied in  claim 1 , which comprises: 
 (a) when X represents S(O) n  and n is 1 or 2, oxidising a compound of general formula                           wherein R 1 , R 2 , A, p, Y, W and Q are as defined in  claim 1  including the provisos;    (b) when Y represents OR 11  and R 11  represents C 1-5  alkyl, reacting a corresponding compound of formula (I) in which Y represents OH, with an alkyl halide of general formula    R 11a Hal  (III)     R 11a  represents C 1-5  alkyl and Hal represents a halogen atom;    (c) when Y represents CO 2 R 12  and R 12  represents C 1-5  alkyl, esterifying a corresponding compound of formula (I) in which Y represents CO 2 H with an alcohol of general formula    R 12a OH  (IV)     wherein R 12a  represents C 1-5  alkyl;    (d) when Y represents CONR 13 R 14 , reacting a corresponding compound of formula (I) in which Y represents CO 2 H with an amine of general formula    R 13 R 14 NH  (V)     wherein R 13  and R 14  are as defined in  claim 1;     (e) when Y represents CO 2 H, hydrolysing a corresponding compound of formula (I) in which Y represents CO 2 R 12  and R 12  represents C 1-5  alkyl;    (f) when X represents S, A represents a C 1-6  alkylene group, Y represents CO 2 R 12  and R 12  represents C 1-5  alkyl, reacting a compound of general formula                           in which R 1 , R 2 , W and Q are as defined in  claim 1 , with a compound of general formula    L—S—A—C(OR 12 ) 3   (VII)     wherein L is a leaving group and A and R 12  are as defined in  claim 1 , followed by hydrolysis of the resulting ortho ester;    (g) when X represents S, A represents a C 2-6  alkylene group, Y represents NR 15 R 16  and R 15  and R 16  are as defined in  claim 1 , reducing a corresponding compound of formula (II) as hereinbefore defined in which A represents a C 1-5  alkylene group, Y represents CONR 13 R 14  and R 13  and R 14  are respectively equal to R 15  and R 16 ;    (h) when X represents S, A represents a C 1-6  alkylene group, Y represents NR 15 R 16  and R 15  and R 16  are defined in  claim 1 , reacting a corresponding compound of general formula                           wherein L′ represents a leaving group and R 1 , R 2 , A, W and Q are as defined in  claim 1 , with a compound of formula (V) wherein R 13  and R 14  are respectively equal to R 15  and R 16 ;    (j) when X represents C≡C, CH═CH or CH 2  CH═CH, reacting a compound of general formula                           in which Hal represents a halogen atom and R 1 , R 2 , W and Q are as defined in  claim 1 , with a compound of general formula (X), H—X′—(A) p —Y, in which X′ represents C≡C, CH═CH or CH═CHCH 2  and A, p and Y are as defined in  claim 1 , in the presence of a palladium catalyst, and optionally hydrogenating the compound of formula (I) obtained wherein X represents C≡C or CH═CH in the presence of a palladium on carbon catalyst to produce a further compound of formula (I) wherein X represents (CH 2 ) 2 ;    (k) when X represents S, A represents a C 1-6  alkylene group and Y represents CN, reacting a compound of formula (VIII) as hereinbefore defined with sodium cyanide;    (l) when W represents S, A represents a C 1-6  alkylene group and Y represents NHSO 2 R 17 , reacting a corresponding compound of formula (I) in which Y represents NH 2  with a compound of general formula (XI), R 17 SO 2 Cl, wherein R 17  is as defined in  claim 1;     (m) when X represents S, A represents a C 1-6  alkylene group and Y represents NHCOR 18 , reacting a corresponding compound of formula (I) in which Y represents NH 2  with a compound of general formula (XII), R 18 COCl, wherein R 18  is as defined in  claim 1;     (n) when X represents S and Y represents an optionally substituted aryl or heteroaryl group, reacting a compound of formula (VI) as hereinbefore defined with a compound of general formula    Y′—(A) p —S—S—(A) p —Y′  (XIII)     wherein Y′ represents an optionally substituted aryl or heteroaryl group and p and A are as defined in  claim 1;  or    (p) when X represents S, A represents a C 1-6  alkylene group and Y represents a tetrazolyl group, reacting a compound of formula (I) in which X represents S, A represents a C 1-6  alkylene group and Y represents CN, with trialkyltin azide;    and optionally forming a pharmaceutically acceptable derivative thereof.    
     
     
         13 . A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in  claim 1 , in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.  
     
     
         14 . A process for the preparation of a pharmaceutical composition according to  claim 13 , which comprises admixing a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in  claim 1 , with a pharmaceutically acceptable adjuvant, diluent or carrier.  
     
     
         15 . A compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in  claim 1  for use in therapy.  
     
     
         16 . Use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in  claim 1  in the manufacture of a medicament for use in therapy.  
     
     
         17 . A method of effecting immunosuppression which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in  claim 1 .  
     
     
         18 . A method of treating, or reducing the risk of, a reversible obstructive airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in  claim 1.