Treatment of cancer and inhibition of metastasis

Abstract

Compounds and methods are disclosed for reducing or preventing metastatic behaviour in VGSC expressing cancer by the effect of at least reducing the persistent part of the voltage gated sodium channel current without eliminating the transient part.

1 . A compound of the formula I 
       
         
           
           
               
               
           
         
         wherein R1 is trifluoromethyl or trifluoromethoxy, or a pharmaceutically acceptable salt thereof, 
         for use in a method of reducing or preventing metastatic behaviour and/or pain sensation in a patient suffering from cancer. 
       
     
     
         2 . The compound for the use according to  claim 1 , wherein R1 is trifluoromethoxy, i.e. a compound of the formula 4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one, of the formula 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound for the use according to  claim 1 , wherein R1 is trifluoromethyl, i.e. a compound of the formula 4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one, of the formula 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound for the use according to any one of the preceding claims, wherein the cancer is a haematological cancer. 
     
     
         5 . The compound for the use of  claim 4 , wherein the cancer is leukaemia or lymphoma. 
     
     
         6 . The compound for the use according to any one of  claims 1 - 3 , wherein the cancer is a solid tumour cancer. 
     
     
         7 . The compound for the use according to  claim 6 , wherein the cancer is a carcinoma, mesothelioma, sarcoma, a melanoma, or a neuroblastoma. 
     
     
         8 . The compound for the use according to any one of  claims 6  and  7 , wherein the cancer is breast cancer. 
     
     
         9 . The compound for the use according to any one of  claims 6  and  7 , wherein the cancer is colon cancer. 
     
     
         10 . The compound for the use according to any one of  claims 6  and  7 , wherein the cancer is prostate cancer. 
     
     
         11 . The compound for the use according to any one of  claims 6  and  7 , wherein the cancer is non-small cell lung carcinoma (NSCLC). 
     
     
         12 . The compound for the use according to any one of  claims 6  and  7 , wherein the cancer is pleural cancer (e.g., mesothelioma), cervical cancer, ovarian cancer, gastric cancer, or neuroblastoma. 
     
     
         13 . The compound for the use according to any one of the preceding claims, wherein the cancer is a voltage gated sodium channel (VGSC) expressing cancer. 
     
     
         14 . The compound for the use according to any one of the preceding claims, wherein the cancer is in phase 3, 4 or 5. 
     
     
         15 . The compound for the use according to any one of  claims 1  to  12 , wherein the cancer is not a VGSC expressing cancer. 
     
     
         16 . The compound for the use according to  claim 15 , wherein the cancer is in phase 1 or 2. 
     
     
         17 . The compound for the use according to any one of  claims 1  to  14 , wherein the use is in a method of reducing metastatic behaviour of cancer in a patient. 
     
     
         18 . The compound for the use according to any one of  claims 1  to  16 , wherein the use is in a method of preventing metastatic behaviour of cancer in a patient. 
     
     
         19 . The compound for the use according to any one of the preceding claims for use in a method of reducing or preventing metastatic behaviour in VGSC expressing cancer without killing the cancer cells. 
     
     
         20 . The compound for the use according to any one of the preceding claims for use in a method of reducing or preventing metastatic behaviour in VGSC expressing cancer without substantially affecting proliferation of the cancer cells. 
     
     
         21 . The compound for the use according to any one of the preceding claims for use in a method of reducing or preventing metastatic behaviour in VGSC expressing cancer by the effect of at least reducing the persistent part of the VGSC current without eliminating the transient part. 
     
     
         22 . The compound for the use according to any one of the preceding claims, wherein the metastatic behaviour is reduced or prevented by:
 (a) reducing the invasiveness of cancer cells;   (b) reducing the motility of cancer cells, optionally under hypoxic but not normoxic conditions;   (c) decreasing cancer cell expression of at least one VGSC, optionally under both normoxic and hypoxic conditions;   (d) increasing the adhesiveness of cancer cells;   (e) reducing the ability of cancer cells to migrate; or   (f) a combination of (a) and (b), (b) and (c), (a) and (c), (a) to (c), or (a) to (e).   
     
     
         23 . The compound for the use according to any one of the preceding claims, wherein the compound is administered at a therapeutically effective dose, optionally at a dosage level corresponding to the range 1 μmol to 10 μmol. 
     
     
         24 . The compound for the use according to any one of the preceding claims, wherein the compound is administered at a dosage from about 1 mg to about 30 mg, optionally at a dosage from about 1 mg to about 20 mg and wherein the patient is an adult human patient, such as an adult human patient having a weight in the range of about 50 to about 150 kg. 
     
     
         25 . The compound for the use according to  claim 24 , wherein the compound is administered at a dosage of about 3 mg, about 5 mg, about 6 mg, about 9 mg, about 10 mg, about 12 mg, about 15 mg, or about 19 mg. 
     
     
         26 . The compound for the use according to any one of the preceding claims, wherein the compound is administered once daily, once every two days, once every 3 days, once every 5 days, once every week, once every two weeks, or once monthly, such as once daily. 
     
     
         27 . The compound for the use according to  claim 26 , wherein the compound is administered over a period of at least 4 weeks, such as at least 8 weeks, such as at least 12 weeks, such as at least 24 weeks, such as at least 48 weeks, or more. 
     
     
         28 . The compound for the use according to any one of  claims 26  and  27 , comprising administering a one-time initial boost dose of the compound of from about 10 mg to about 100 mg. 
     
     
         29 . The compound for the use according to any one of the preceding claims, comprising administering the compound at a one-time initial boost dose of from about 10 mg to about 100 mg followed by administering a dosage from about 1 mg to about 20 mg once daily for a period of at least 4 weeks, such as a daily dosage of 3 mg or 6 mg. 
     
     
         30 . The compound for the use according to any one of the preceding claims, wherein the compound is administered orally. 
     
     
         31 . A method of reducing or preventing metastatic behaviour and/or pain sensation in a patient suffering from cancer, comprising administering to the patient a therapeutically effective amount of a compound of the formula I, wherein R1 is trifluoromethyl or trifluoromethoxy, or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The method of  claim 31 , further comprising the features of any one of  claims 1  to  30 .