US2006079531A1PendingUtilityA1

Pharmaceutically active ornithine derivatives, ammonium salts thereof and methods of making same

Assignee: ASH STEVENSPriority: Apr 30, 2002Filed: Nov 22, 2005Published: Apr 13, 2006
Est. expiryApr 30, 2022(expired)· nominal 20-yr term from priority
C07D 471/04A61P 35/00C07D 475/08A61P 35/02A61P 43/00
52
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Claims

Abstract

The present invention relates to pharmaceutically active ornithine compounds, particularly to pharmaceutically acceptable ammonium salts of N δ -acyl derivatives of N α (4-amino-4-deoxypteroyl)-L-ornithine compounds; and methods of treatment and pharmaceutical compositions that utilize or comprise one or more of such ammonium salts. The ammonium salts provided by the invention exhibit superior chemical stability than corresponding acidic N δ -acyl derivatives of N δ -acyl derivatives of N α (4-amino-4-deoxypteroyl)-L-ornithine compounds.

Claims

exact text as granted — not AI-modified
1 .- 52 . (canceled)  
   
   
       53 . A method of inhibiting growth of a cancer cell comprising contacting the cell with an effective amount of an ammonium salt of the compound of formula II:  
     
       
         
         
             
             
         
       
       wherein:  
       R represents up to four groups independently selected at each occurrence of R 2  from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 1-6  alkoxy, chloro, fluoro, hydroxy, and —COOH;  
       R 3 , R 4 , and R 5  are each independently selected from hydrogen and C 1-6  alkyl; or NR 3 R 4  taken in combination can form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and  
       x is a real number greater than 0 and less than about 4.  
     
   
   
       54 . The method of  claim 53 , wherein the growth of the cancer cell is methotrexate-resistant.  
   
   
       55 . The method of  claim 54 , wherein the cancer cell is a carcinoma cell.  
   
   
       56 . The method of  claim 54 , wherein the cancer cell is a leukemia cell.  
   
   
       57 . The method of  claim 54 , wherein the cancer cell is a lymphoblast cell.  
   
   
       58 . The method of  claim 54 , wherein the cancer cell is a sarcoma cell.  
   
   
       59 . A method of inhibiting growth of a cancer cell comprising contacting the cell with an effective amount of an ammonium salt of the compound of formula III:  
     
       
         
         
             
             
         
       
       wherein:  
       R 2  represents up to four groups each independently selected at each occurrence of R 2  from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 1-6  alkoxy, chloro, fluoro, hydroxy, and —COOH;  
       R 3 , R 4 , and R 5  are each independently selected from hydrogen and C 1-6  alkyl; or NR 3 R 4  taken in combination form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and  
       x is a real number greater than 0 and less than about 4.  
     
   
   
       60 . The method of  claim 59 , wherein the growth of the cancer cell is methotrexate-resistant.  
   
   
       61 . The method of  claim 60 , wherein the cancer cell is a carcinoma cell.  
   
   
       62 . The method of  claim 60 , wherein the cancer cell is a leukemia cell.  
   
   
       63 . The method of  claim 60 , wherein the cancer cell is a lymphoblast cell.  
   
   
       64 . The method of  claim 60 , wherein the cancer cell is a sarcoma cell.  
   
   
       65 . A method of inhibiting growth of a cancer cell comprising contacting the cell with an effective amount of an ammonium salt of the compound of formula IV:  
     
       
         
         
             
             
         
       
       wherein:  
       R 3 , R 4 , and R 5  are each independently selected from hydrogen and C 1-6 alkyl or NR 3 R 4  taken in combination form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and  
       x is a real number greater than 0 and less than about 4.  
     
   
   
       66 . The method of  claim 65 , wherein the growth of the cancer cell is methotrexate-resistant.  
   
   
       67 . The method of  claim 66 , wherein the cancer cell is a carcinoma cell.  
   
   
       68 . The method of  claim 66 , wherein the cancer cell is a leukemia cell.  
   
   
       69 . The method of  claim 66 , wherein the cancer cell is a lymphoblast cell.  
   
   
       70 . The method of  claim 66 , wherein the cancer cell is a sarcoma cell.  
   
   
       71 . A method of inhibiting growth of a cancer cell comprising contacting the cell with an effective amount of an ammonium salt of the compound of formula V:  
     
       
         
         
             
             
         
       
       wherein x is a real number greater than 0 and less than about 4.  
     
   
   
       72 . The method of  claim 71 , wherein the growth of the cancer cell is methotrexate-resistant.  
   
   
       73 . The method of  claim 72 , wherein the cancer cell is a carcinoma cell.  
   
   
       74 . The method of  claim 72 , wherein the cancer cell is a leukemia cell.  
   
   
       75 . The method of  claim 72 , wherein the cancer cell is a lymphoblast cell.  
   
   
       76 . The method of  claim 72 , wherein the cancer cell is a sarcoma cell.  
   
   
       77 . A method of treating a methotrexate-resistant tumor in a mammal in need thereof, comprising administering to a mammal an effective amount of an ammonium salt of the compound of formula II:  
     
       
         
         
             
             
         
       
       wherein:  
       R represents up to four groups independently selected at each occurrence of R 2  from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 1-6  alkoxy, chloro, fluoro, hydroxy, and —COOH;  
       R 3 , R 4 , and R 5  are each independently selected from hydrogen and C 1-6  alkyl; or NR 3 R 4  taken in combination can form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and  
       x is a real number greater than 0 and less than about 4.  
     
   
   
       78 . The method of  claim 77 , wherein the tumor is a carcinoma tumor.  
   
   
       79 . The method of  claim 77 , wherein the tumor is a sarcoma tumor.  
   
   
       80 . The method of  claim 77 , wherein the mammal is a human.  
   
   
       81 . A method of treating a methotrexate-resistant tumor in a mammal in need thereof, comprising administering to a mammal an effective amount of an ammonium salt of the compound of formula III:  
     
       
         
         
             
             
         
       
       wherein:  
       R 2  represents up to four groups each independently selected at each occurrence of R 2  from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 1-6  alkoxy, chloro, fluoro, hydroxy, and —COOH;  
       R 3 , R 4 , and R 5  are each independently selected from hydrogen and C 1-6  alkyl; or NR 3 R 4  taken in combination form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and  
       x is a real number greater than 0 and less than about 4.  
     
   
   
       82 . The method of  claim 81 , wherein the tumor is a carcinoma tumor.  
   
   
       83 . The method of  claim 81 , wherein the tumor is a sarcoma tumor.  
   
   
       84 . The method of  claim 81 , wherein the mammal is a human.  
   
   
       85 . A method of treating a methotrexate-resistant tumor in a mammal in need thereof, comprising administering to a mammal an effective amount of an ammonium salt of the compound of formula IV:  
     
       
         
         
             
             
         
       
       wherein:  
       R 3 , R 4 , and R 5  are each independently selected from hydrogen and C 1-6 alkyl or NR 3 R 4  taken in combination form a 5 to 7 member heterocycle having at least one nitrogen ring atom; and  
       x is a real number greater than 0 and less than about 4.  
     
   
   
       86 . The method of  claim 85 , wherein the tumor is a carcinoma tumor.  
   
   
       87 . The method of  claim 85 , wherein the tumor is a sarcoma tumor.  
   
   
       88 . The method of  claim 85 , wherein the mammal is a human.  
   
   
       89 . A method of treating a methotrexate-resistant tumor in a mammal in need thereof, comprising administering to a mammal an effective amount of an ammonium salt of the compound of formula V:  
     
       
         
         
             
             
         
       
       wherein x is a real number greater than 0 and less than about 4.  
     
   
   
       90 . The method of  claim 89 , wherein the tumor is a carcinoma tumor.  
   
   
       91 . The method of  claim 89 , wherein the tumor is a sarcoma tumor.  
   
   
       92 . The method of  claim 89 , wherein the mammal is a human.

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