Purine derivatives

Abstract

The present invention relates to compounds of formula 1 or pharmaceutically acceptable salts thereof, wherein one of R 1 and R 2 is methyl, ethyl or isopropyl, and the other is H; R 3 and R 4 are each independently H, branched or unbranched C 1 -C 6 alkyl, or aryl, and wherein at least one of R 3 and R 4 is other than H; R 5 is a branched or unbranched C 1 -C 5 alkyl group or a C 1 -C 6 cycloalkyl group, each of which may be optionally substituted with one or more OH groups; R 6 , R 7 , R 8 and R 9 are each independently H, halogen, NO 2 , OH, OMe, CN, NH 2 , COOH, CONH 2 , or SO 2 NH 2 . A further aspect of the invention relates to pharmaceutical compositions comprising compounds of formula 1, and the use of said compounds in treating proliferative disorders, viral disorders, CNS disorders, diabetes, stroke, alopecia or neurodegenerative disorders.

1 . A compound of formula 1 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein
 one of R 1  and R 2  is methyl, ethyl or isopropyl, and the other is H; 
 R 3  and R 4  are each independently H, branched or unbranched C 1 -C 6  alkyl, or aryl, and wherein at least one of R 3  and R 4  is other than H; 
 R 5  is a branched or unbranched C 1 -C 5  alkyl group or a C 1 -C 6  cycloalkyl, each of which may be optionally substituted with one or more OH groups; 
 R 6 , R 7 , R 8  and R 9  are each independently H, halogen, NO 2 , OH, OMe, CN, NH 2 , COOH, CONH 2 , or SO 2 NH 2 . 
 
   
   
       2 . A compound according to  claim 1 , wherein one of R 1  and R 2  is ethyl or isopropyl, and the other is H; 
   
   
       3 . A compound according to  claim 1 , wherein R 5  is isopropyl or cyclopentyl. 
   
   
       4 . A compound according to  claim 1 , wherein R 6 , R 7 , R 8  and R 9  are all H. 
   
   
       5 . A compound according to  claim 1 , wherein one of R 1  and R 2  is ethyl and the other is H. 
   
   
       6 . A compound according to  claim 1 , wherein R 3  and R 4  are each independently H, methyl, ethyl, isopropyl, n-butyl, s-butyl, t-butyl or phenyl. 
   
   
       7 . A compound according to  claim 1 , wherein R 3  and R 4  are each independently H, methyl, ethyl, isopropyl, n-propyl, n-butyl, s-butyl or t-butyl. 
   
   
       8 . A compound according to  claim 7 , wherein R 3  and R 4  are each independently H, methyl, ethyl, isopropyl or t-butyl. 
   
   
       9 . A compound according to  claim 1  selected from the following: 
     (2S3R)-3-{9-Isopropyl-6-[(pyridin-2-ylmethyl)-amino]-9H-purin-2-ylamino}-pentan-2-ol; 
     (2R3S)-3-{9-Isopropyl-6-[(pyridin-2-Amethyl)-amino]-9H-purin-2-ylamino}-pentan-2-ol; 
     (3RS,4R)-4-{9-Isopropyl-6-[(pyridin-2-ylmethyl)-amino]-9H-purin-2-ylamino}-hexan-3-ol; 
     (3RS,4S)-4-{9-Isopropyl-6-[(pyridin-2-ylmethyl)-amino]-9H-purin-2-ylamino}-hexan-3-ol; 
     (3RS,4R)-4-{9-Isopropyl-6-1 (pyridin-2-ylmethylyamino-J-9H-purin-2-ylamino}-2-methyl-hexan-3-ol; 
     (3RS,4S)-4-{9-Isopropyl-6-[(pyridin-2-ylmethyl)-amino]-911-purin-2-ylamino}-2-methyl-hexan-3-ol; 
     (3RS,4R)-4-{9-Isopropyl-6-[(pyridin-2-ylmethyl)-amino]-9H-purin-2-ylamino}-2,2-dimethyl-hexan-3-01; 
     (3RS,4S)-4-{9-Isopropyl-6-[(pyridin-2-ylmethyl)-amino]-9H-purin-2-ylamino}-2,2-dimethyl-hexan-3-ol; 
     (3R)-3-{9-Isopropyl-6-[(pyridin-2-ylmethyl)-amino]-9H-purin-2-ylamino}-2-methylpentan-2-ol; and 
     (3S)-3-{9-Isopropyl-6-[(pyridin-2-ylmethyl)-amino]-9H-purin-2-ylamino}-2-methyl-pentan-2-ol. 
   
   
       10 . A compound according to  claim 1  which is (2R3S)-3-{9-Isopropyl-6-[(pyridin-2-ylmethyl)-amino]-911-purin-2-ylamino}-pentan-2-o 1. 
   
   
       11 . A pharmaceutical composition comprising a compound according to  claim 1  admixed with a pharmaceutically acceptable diluent, excipient or carrier, or a mixture thereof. 
   
   
       12 . A method of treating a proliferative disorder, said method comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 , such that said proliferative disorder is treated. 
   
   
       13 . A method according to  claim 12 , wherein said proliferative disorder is cancer or leukaemia. 
   
   
       14 . A method according to  claim 12 , wherein the proliferative disorder is glomerulonephritis, rheumatoid arthritis, psoriasis or chronic obstructive pulmonary disorder. 
   
   
       15 . A method of treating a viral disorder, said method comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 , such that said viral disorder is treated. 
   
   
       16 . A method according to  claim 15 , wherein the viral disorder is selected from human cytotnegalovirus (HCMV), herpes simplex virus type 1 (HSV-1), human immunodeficiency virus type 1 (HIV-1), and varicella zoster virus (VZV). 
   
   
       17 . A method of treating a CNS disorder, said method comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 , such that said CNS disorder is treated. 
   
   
       18 . A method according to  claim 17  wherein the CNS disorder is Alzheimer's disease or bipolar disorder. 
   
   
       19 . A method of treating alopecia, said method comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 , such that alopecia is treated. 
   
   
       20 . A method of treating a stroke, said method comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 , such that a stroke is treated. 
   
   
       21 . A method according to  claim 12  wherein the compound is administered in an amount sufficient to inhibit at least one PLK enzyme. 
   
   
       22 . The method according to  claim 21  wherein the PLK enzyme is PLK1. 
   
   
       23 . The method according to  claim 12  wherein the compound is administered in an amount sufficient to inhibit at least one CDK enzyme. 
   
   
       24 . The method according to  claim 23  wherein the CDK enzyme is CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and/or CDK9. 
   
   
       25 . The method according to  claim 12  wherein the compound is administered in an amount sufficient to inhibit aurora kinase. 
   
   
       26 . A method of treating diabetes, said method comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 , such that diabetes is treated. 
   
   
       27 . A method according to  claim 26  wherein the diabetes is Type II diabetes. 
   
   
       28 . A method according to  claim 26  wherein the compound is administered in an amount sufficient to inhibit GSK. 
   
   
       29 . A method according to  claim 28  wherein the compound is administered in an amount sufficient to inhibit GSK3β. 
   
   
       30 . A compound according to  claim 1 , wherein said compound is an anti-mitotic agent. 
   
   
       31 . A method of treating a neurodegenerative disorder, said method comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 , such that said neurodegenerative disorder is treated. 
   
   
       32 . A method according to  claim 31 , wherein the neurodegenerative disorder is neuronal apoptosis. 
   
   
       33 . A method of inhibiting a protein kinase, comprising contacting said protein kinase with a compound according to  claim 1 , such that said protein kinase is inhibited. 
   
   
       34 . A method according to  claim 33  wherein said protein kinase is a cyclin dependent kinase. 
   
   
       35 . A method according to  claim 34  wherein said cyclin dependent kinase is CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and/or CDK9. 
   
   
       36 . A method according to  claim 12 , wherein said compound is administered orally. 
   
   
       37 . A process for preparing a compound of formula I as defined in  claim 1 , said process comprising reacting a compound of formula V with a compound of formula VI 
     
       
         
         
             
             
         
       
     
     wherein R 1-9  are as defined in  claim 1  and X is Cl or F. 
   
   
       38 . A process according to  claim 37  wherein said compound of formula V is prepared by the following steps: 
     
       
         
         
             
             
         
       
       (i) reacting a compound of formula II with a compound of formula III to form a compound of formula IV; 
       (ii) alkylating said compound of formula IV with an alkyl halide, R 5 —X′, to form a compound of formula V. 
     
   
   
       39 . A process according to  claim 38  wherein said compound of formula VI is prepared by the following steps: 
     
       
         
         
             
             
         
       
       (i) oxidising a compound of formula VIII, wherein PG is a protecting group, to form a compound of formula IX; 
       (ii) alkylating said compound of formula IX to form a compound of formula X; 
       (iii) removing protecting group PG from said compound of formula X; or 
       (i) oxidising a compound of formula VIII, wherein PG is a protecting group, to form a compound of formula IX; 
       (ii) alkylating said compound of formula IX to form a compound of formula X; 
       (iii) oxidising said compound of formula X to form a compound of formula XII; 
       (iv) alkylating said compound of formula XII to form a compound of formula XIII; 
       (v) removing protecting group PG from said compound of formula XIII.