US2007203217A1PendingUtilityA1

Substituted stilbenes and their reactions

Individually held — no corporate assignee on recordPriority: Dec 21, 2000Filed: May 4, 2007Published: Aug 30, 2007

Est. expiryDec 21, 2020(expired)· nominal 20-yr term from priority

Inventors:John Anthony Hadfield Alan Mcgown Stephen Patrick Mayalarp Edward John Land Ian Hamblett Keira Gaukroger Nicholas J. Lawrence Lucy Annette Hepworth John Butler

A61P 35/00A61P 27/02C07F 7/1804A61P 17/06C07C 205/44C07C 43/215C07D 213/68A61P 15/00C07C 43/23C07C 205/37C07C 205/35C07C 50/30C07C 46/06C07C 271/22

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References

Claims

Abstract

The present invention relates to stilbene and quinine compounds related to combretastatin A-4 and their use as anticancer compounds and prodrugs. The compounds include those with an alkyl group on the double bond of cis or trans-stilbenes, compounds with one or more (and preferably 2 or 3) alkyl group substituents on the stilbene a ring, compounds with an alkoxy group other than methoxy at position 3, 4 and/or 5 of the stilbene A ring, compounds (or prodrugs) in which BOC amino acid esters are formed with the phenolic hydroxyl at the 3-position of the B ring and compounds (or prodrugs) based on a benzoquinone B ring. The present invention further relates to the photochemical reactions of stilbene compounds, either the above compounds disclosed for the first time herein or compounds based on prior art stilbenes. These reactions include the photochemical release of an active form of the compound from a prodrug conjugate and the photochemical isomerisation of the compounds, especially from a trans to cis form of compounds. The reactions can be used alone or in combination to convert inactive or comparatively less active forms of the compounds to more active forms, thereby allowing the compounds to be selectively targeted, e.g., activating them at the site of a tumour.

Claims

exact text as granted — not AI-modified

1 . A compound represented by the structural formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 the zigzag line indicates that the compound can be cis or trans;  
 R a  is selected from the groups consisting of:  
                     
 X is selected from hydroxyl, nitro, amino, aryl, heteroaryl, alkyl, alkoxy, CHO, COR, haloalkyl, NH 2 , NHR, NRR′, SR, CONH 2 , CONHR, CONHRR′, O-aryl, O-heteroaryl or O-ester;  
 R 1 , R 2  and R 3  are independently selected from hydrogen, alkyl, CHO, COR, alkoxy, hydroxyl, NH 2 , NHR, NRR′, SR, haloalkyl or halogen;  
 R 4  and R 5  are independently selected from hydrogen, alkyl, CH 2 NHCOR″ or CH 2 CONHR″; and,  
 R 6 , R 7  and R 8  are independently selected from alkyl or alkoxy;  
 wherein R and R′ are independently selected from C- 1-10  alkyl groups and R″ is a C 1-10  alkyl group, aryl group or heteroaryl group;  
 or a salt, an ester, a free acid or base or a hydrate thereof.  
 
   
   
       2 . A compound according to  claim 1  represented by the structural formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 the zigzag line indicates that the compound can be cis or trans;  
 X is selected from hydroxyl, nitro, amino, aryl, heteroaryl, alkyl, alkoxy, CHO, COR, haloalkyl, NH 2 , NHR, NRR′, SR, CONH 2 , CONHR, CONHRR′, O-aryl, O-heteroaryl or O-ester;  
 R 1  is selected from alkyl, CHO, alkoxy, NH 2 , NHR, NRR′, SR, CF 3  or halogen;  
 R 2  and R 3  are independently selected from hydrogen, alkyl, alkoxy, hydroxyl, NH 2 , NHR, NRR′, SR, haloalkyl or halogen;  
 R 4  and R 5  are independently selected from hydrogen, alkyl, CH 2 NHCOR″ or CH 2 CONHR″; and,  
 R 6 , R 7  and R 8  are independently selected from alkyl or alkoxy;  
 wherein at least one of the substituents R 4  and R 5  is an alkyl group; and  
 wherein R and R′ are independently selected from C 1-10  alkyl groups and R″ is a C 1-10  alkyl group, aryl group or heteroaryl group;  
 or a salt, an ester, a free acid or base or a hydrate thereof.  
 
   
   
       3 . The compound of  claim 2  which is the cis or Z-isomer.  
   
   
       4 . The compound of  claim 2  which is the trans or E-isomer.  
   
   
       5 . The compound of  claim 2 , wherein the alkyl group R 4  and/or R 5  is a methyl or ethyl group.  
   
   
       6 . The compound of  claim 2 , wherein the compound is selected from one of compounds 208 to 220 or 80 to 82 having the formula defined in Table 22.  
   
   
       7 . A compound according to  claim 1  represented by the structural formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 X is selected from hydroxyl, nitro, amino, aryl, heteroaryl, alkyl, alkoxy, CHO, COR, haloalkyl, NH 2 , NHR, NRR′, SR, CONH 2 , CONHR, CONHRR′, O-aryl, O-heteroaryl or O-ester;  
 R 1  is selected from alkyl, CHO, alkoxy, NH 2 , NHR, NRR′, SR, CF 3  or halogen;  
 R 2  and R 3  are independently selected from hydrogen, alkyl, alkoxy, hydroxyl, NH 2 , NHR, NRR′, SR, haloalkyl or halogen;  
 R 4  and R 5  are independently selected from hydrogen, alkyl, CH 2 NHCOR″ or CH 2 CONHR″; and,  
 wherein R 6 , R 7  and R 8  are independently selected from alkyl or alkoxy such that at least one of these substituents is an alkyl group; and  
 wherein R and R′ are independently selected from C 1-10  alkyl groups and R″ is a C 1-10  alkyl group, aryl group or heteroaryl group;  
 or a salt, an ester, a free acid or base or a hydrate thereof.  
 
   
   
       8 . The compound of  claim 7 , wherein two of the R 6 , R 7  and R 8  groups are alkyl groups.  
   
   
       9 . The compound of  claim 7 , wherein all three of the R 6 , R 7  and R 8  groups are alkyl groups.  
   
   
       10 . The compound of  claim 7 , wherein the groups of the R 6 , R 7  and R 8  groups which are alkyl groups are methyl, ethyl or propyl groups.  
   
   
       11 . The compound of  claim 7 , wherein the compound is selected from one of compounds 117, 120, 133 or 137 to 142 having the formula defined in Tables 14 or 17.  
   
   
       12 . A compound represented by the structural formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is selected from alkyl, alkoxy, NH 2 , NHR, NRR′, SR, CF 3 , CHO or halogen;  
 R 2  and R 3  are independently selected from hydrogen, alkyl, alkoxy, hydroxyl, NH 2 , NHR, NRR′, SR, haloalkyl or halogen;  
 R 4  and R 5  are independently selected from the hydrogen, alkyl, CH 2 NHCOR″ or CH 2 CONHR″; and,  
 R 6 , R 7  and R8 are independently selected from hydrogen, alkyl or alkoxy; and,  
 wherein R and R are independently selected from substituted or unsubstituted C 1-10  alkyl groups and R″ is a substituted or unsubstituted C 1-10  alkyl group, aryl group or heteroaryl group;  
 or a salt thereof;  
 wherein X is a group represented by:  
                     
 wherein BOC represents a t-butoxycarbonyl group and the A group is a naturally occurring amino acid side chain.  
 
   
   
       13 . The compound of  claim 12 , wherein the BOC amino acid ester comprises Phe, Ile, Gly, Trp, Met, Leu, Ala, His, Pro, D-Met, D-Trp, or Tyr.  
   
   
       14 . The compound of  claim 12 , wherein the amino acid is Phe, the A group is —CH 2 Ph.  
   
   
       15 . A compound according to  claim 1  represented by the structural formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 the zigzag line indicates that the compound can be cis or trans;  
 R 1 , R 2  and R 3  are independently selected from hydrogen, alkyl, CHO, COR, alkoxy, hydroxyl, NH 2 , NHR, NRR′, SR, haloalkyl or halogen;  
 R 4  and R 5  are independently selected from hydrogen, alkyl, CH 2 NHCOR″ or CH 2 CONHR″; and,  
 R 6 , R 7  and R 8  are independently selected from alkyl or alkoxy; and  
 wherein R and R′ are independently selected from substituted or unsubstituted C 1-10  alkyl groups and R″ is a substituted or unsubstituted C 1-10  alkyl group, aryl group or heteroaryl group; or  
 a salt, an ester, a free acid or base or a hydrate thereof.  
 
   
   
       16 . The compound of  claim 15 , wherein the compound is compound 97-96 or 98-40, 98-23, 98-33 or 98-24 having the formula set out in Table 2.  
   
   
       17 . A composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       18 . A composition comprising the compound of  claim 2  and a pharmaceutically acceptable carrier.  
   
   
       19 . A composition comprising the compound of  claim 7  and a pharmaceutically acceptable carrier.  
   
   
       20 . A composition comprising the compound of  claim 12  and a pharmaceutically acceptable carrier.  
   
   
       21 . A composition comprising the compound of  claim 15  and a pharmaceutically acceptable carrier.  
   
   
       22 . A method for the treatment of cancer or a condition characterized by abnormal proliferation of the vasculature in a patient in need of said treatment by administering a therapeutically effective amount of a compound of  claim 1 .  
   
   
       23 . The method of  claim 22 , wherein said compound is administered for treatment of a condition characterized by abnormal proliferation of the vasculature that is selected from the group of diabetic retinopathy, psoriasis and endometriosis.  
   
   
       24 . A method for the treatment of cancer or a condition characterized by abnormal proliferation of the vasculature in a patient in need of said treatment by administering a therapeutically effective amount of a compound of  claim 2 .  
   
   
       25 . The method of  claim 24 , wherein said compound is administered for treatment of a condition characterized by abnormal proliferation of the vasculature that is selected from the group of diabetic retinopathy, psoriasis and endometriosis.  
   
   
       26 . A method for treatment of cancer or a condition characterized by abnormal proliferation of the vasculature in a patient in need of said treatment by administering a therapeutically effective amount of a compound of  claim 7 .  
   
   
       27 . The method of  claim 26 , wherein said compound is administered for treatment of a condition characterized by abnormal proliferation of the vasculature that is selected from the group of diabetic retinopathy, psoriasis and endometriosis.  
   
   
       28 . A method for the treatment of cancer or a condition characterized by abnormal proliferation of the vasculature in a patient in need of said treatment by administering a therapeutically effective amount of a compound of  claim 12 .  
   
   
       29 . The method of  claim 28 , wherein said compound is administered for treatment of a condition characterized by abnormal proliferation of the vasculature that is selected from the group of diabetic retinopathy, psoriasis and endometriosis.  
   
   
       30 . A method for the treatment of cancer or a condition characterized by abnormal proliferation of the vasculature in a patient in need of said treatment by administering a therapeutically effective amount of a compound of  claim 15 .  
   
   
       31 . The method of  claim 30 , wherein said compound is administered for treatment of a condition characterized by abnormal proliferation of the vasculature that is selected from the group of diabetic retinopathy, psoriasis and endometriosis.  
   
   
       32 . The compound of  claim 1 , having the formula:  
     
       
         
         
             
             
         
       
     
   
   
       33 . The compound of  claim 1 , having the formula:

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