US2017114019A1PendingUtilityA1

18-20 member bi-polycyclic compounds

Assignee: HARO PHARMACEUTICAL INCPriority: Jun 4, 2014Filed: Jun 4, 2015Published: Apr 27, 2017
Est. expiryJun 4, 2034(~7.9 yrs left)· nominal 20-yr term from priority
A61P 35/00C07D 209/42C07D 409/04C07D 215/48C07D 215/54C07C 2602/10C07C 259/10C07D 209/08C07C 2102/10
43
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Claims

Abstract

The invention relates to 18-20 member bi-polycyclic compounds, methods of making these compounds, and methods of using them in treating hyperproliferative disorders (e.g., cancer) and non-malignant tumors; promoting muscle formation; inhibiting muscle degeneration or the loss of muscle mass or muscle function; and myofibers ex vivo.

Claims

exact text as granted — not AI-modified
1 . A compound of Formula I:
   A-W—Z  (I)
   
       or a pharmaceutically acceptable salt thereof, wherein
 A is 
 
       
         
           
           
               
               
           
         
         W is a heterocyclylene, arylene, heteroarylene, alkenylenearylene, arylenealkenylene alkenyleneheteroarylene, or heteroarylenealkenylene; and 
         Z is a hydrogen bond donor, with the proviso that the compound is not 
       
       
         
           
           
               
               
           
         
       
       where R is —OH, —OCH 3  and —NHOH; and R′ is —OH or —OCH 3 . 
     
     
         2 . The compound of  claim 1 , wherein W is an indolinylene linked to A at any one of positions 2, 3, 4, 5, 6 or 7 of the indolinylene; a quinolinene linked to A at any one of positions 2, 3, 4, 5, 6, 7, or 8; or an isoquinolinene linked to A at any one of positions 1, 3, 4, 5, 6, 7, or 8. 
     
     
         3 . The compound of  claim 1 , wherein W is -propylene-phenylene-. 
     
     
         4 . The compound of  claim 1 , wherein Z is —C(O)NR 1 R 2  or —C(O)OR 3 , wherein R 1  and R 2  are each independently hydrogen (H), hydroxyl (OH), C 1-6  alkyl, hydroxyC 1-6  alkyl, aminoC 1-6  alkyl, or aminoaryl; and R 3  is H or C 1-6  alkyl. 
     
     
         5 . The compound of  claim 2 , wherein Z is linked to the indolinylene, quinolinene, or isoquinolinene at any one of the positions that is not linked to A. 
     
     
         6 . The compound of  claim 4 , wherein W is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , wherein W is an indolinylene linked to A at any one of positions 2, 3, 4, 5, 6 or 7 of the indolinylene; Z is —C(O)NR 1 R 2  or —C(O)OR 3 , wherein R 1  and R 2  are each independently hydrogen, hydroxyl, C 1-6  alkyl, hydroxyC 1-6  alkyl, aminoC 1-6  alkyl, or aminoaryl; and R 3  is H or C 1-6  alkyl, and wherein Z is linked to the indolinylene at any one of positions 2, 3, 4, 5, 6 or 7 of the indolinylene not linked to A. 
     
     
         8 . The compound of  claim 1 , wherein W is a quinolinene linked to A at any one of positions 2, 3, 4, 5, 6, 7 or 8 of the quinolinene; Z is —C(O)NR 1 R 2  or —C(O)OR 3 , wherein R 1  and R 2  are each independently hydrogen, hydroxyl, C 1-6  alkyl, hydroxyC 1-6  alkyl, aminoC 1-6  alkyl, or aminoaryl; and R 3  is H or C 1-6  alkyl, and wherein Z is linked to the quinolinene at any one of positions 2, 3, 4, 5, 6, 7 or 8 of the quinolinene. 
     
     
         9 . The compound of  claim 1 , W is a isoquinolinene linked to A at one of positions 1, 3, 4, 5, 6, 7 or 8 of the isoquinolinene moiety; Z is —C(O)NR 1 R 2  or —C(O)OR 3 , wherein R 1  and R 2  are each independently hydrogen, hydroxyl, C 1-6  alkyl, hydroxyC 1-6  alkyl, aminoC 1-6  alkyl, or aminoaryl; and R 3  is H or C 1-6  alkyl, and wherein Z is linked to the quinoline ring at any one of positions 2, 3, 4, 5, 6, 7 or 8 of the isoquinolinene. 
     
     
         10 . The compound of  claim 7 , wherein Z is —C(O)NR 1 R 2 ; R 1  is H; and R 2  is OH. 
     
     
         11 . The compound of  claim 7 , wherein Z is —C(O)NR 1 R 2 ; R 1  is H; and R 2  is aminoaryl. 
     
     
         12 . The compound of  claim 7 , wherein Z is —C(O)OR 3 ; and R 3  is H. 
     
     
         13 . The compound of  claim 7 , wherein Z is —C(O)OR 3 ; and R 3  is C 1-6  alkyl. 
     
     
         14 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         16 . A method of treating a subject who has cancer or a non-malignant tumor, the method comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the cancer is non-small cell lung cancer, colon cancer, melanoma, breast cancer, renal cancer, ovarian cancer, prostate cancer, cancer of the central nervous system, a blood cancer, or a neuroblastoma. 
     
     
         18 . (canceled) 
     
     
         19 . A method of inhibiting loss of muscle mass or muscle function in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I:
   A-W—Z  (I)
   
       or a pharmaceutically acceptable salt thereof, wherein
 A is 
 
       
         
           
           
               
               
           
         
         W is a heterocyclylene, arylene, heteroarylene, alkenylenearylene, arylenealkenylene or alkenyleneheteroarylene, heteroarylenealkenylene; and 
         Z is a hydrogen bond donor. 
       
     
     
         20 .- 21 . (canceled) 
     
     
         22 . The method of  claim 19 , wherein the loss of muscle mass is associated with intensive care unit-acquired weakness (ICUAW), chronic obstructive pulmonary disease (COPD), heart failure, traumatic injury or malignancy. 
     
     
         23 . A method for treating myofibers ex vivo, the method comprising:
 providing an ex vivo preparation of myofibers, optionally comprising a natural or synthetic biological matrix; and   contacting the preparation with an amount of a compound of Formula I:
   A-W—Z  (I)
 
   
       or a pharmaceutically acceptable salt thereof, wherein the amount of the compound is sufficient to promote muscle mass or muscle function and
 A is 
 
       
         
           
           
               
               
           
         
         W is a heterocyclylene, arylene, heteroarylene, alkenylenearylene, arylenealkenylene alkenyleneheteroarylene, or heteroarylenealkenylene; and 
         Z is a hydrogen bond donor.

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