Anhydro-and isomer-a-21978c cyclic peptides

Abstract

Two new groups of A-21978C cyclic peptides, anhydro- and isomer-A21978C peptide derivatives, have antibacterial activity and are useful as intermediates. The two groups are prepared via transpeptidation of the parent cyclic peptides. Pharmaceutical formulations containing the new peptides as active ingredients and methods of treating infections caused by susceptible Gram-positive bacteria with the formulations are also provided. The invention also provides an antibacterial composition containing the new drug substance LY 146032 in substantially pure form.

1. A An isolated compound of the formula  1  
                 
 
       in which R is C 5 -C 14 -alkanoyl; R 1 , R 2 , R 3 , R 4  and R 5  are hydrogen; or a pharmaceutically acceptable salt thereof; and wherein the alanine is D- alanine and the serine is D - serine.    
     
     
       2. A An isolated compound of the formula  2  
                 
 
       in which R is C 5 -C 14 -alkanoyl; R 1 , R 2 , R 3 , R 4  and R 5  are hydrogen; or a pharmaceutically acceptable salt thereof; and wherein the alanine is D- alanine and the serine is D - serine.    
     
     
       3. A The compound of  claim 1  wherein R is alkanoyl of the formula 
                 
 
       and n is an integer from 3 to 12. 
     
     
       4. The compound of  claim 3  wherein R is octanoyl. 
     
     
       5. The compound of  claim 3  wherein R is nonanoyl. 
     
     
       6. A The compound of  claim 1  wherein R is decanoyl. 
     
     
       7. A The compound of  claim 2  wherein R is alkanoyl of the formula 
                 
 
       and n is an integer from 3 to 12. 
     
     
       8. The compound of  claim 7  wherein R is octanoyl. 
     
     
       9. The compound of  claim 7  wherein R is nonanoyl. 
     
     
       10. A The compound of  claim 2  wherein R is decanoyl. 
     
     
       11. A The compound of  claim 2  wherein R is undecanoyl. 
     
     
       12. A composition useful for the treatment of bacterial infections comprising an effective antibacterial amount of a the compound of  claim 1  together with a vehicle. 
     
     
       13. A composition useful for the treatment of bacterial infections comprising an effective antibacterial amount of a the compound of  claim 2  together with a vehicle. 
     
     
       14. A method for treating bacterial infections which comprises administering an effective amount of a the composition of  claim 12  to an animal. 
     
     
       15. A method for treating bacterial infections which comprises administering an effective amount of a the composition of  claim 13  to an animal. 
     
     
       16. The compound of  claim 6  or  10  wherein R is n- decanoyl.   
     
     
       17. A method for treating bacterial infections which comprises administering an effective amount of the composition of  claim 12  or  13  to a human. 
     
     
       18. An antibiotic composition comprised of a combination of a compound of formula  1 , a compound of formula  2  and a compound of formula  3 , or pharmaceutically acceptable salts thereof, wherein the formula  1  compound is 
                   
         in which R is a C   10    alkanoyl; R   1   , R   2   , R   3   , R   4    and R   5    are hydrogen, and wherein the alanine is D - alanine and the serine is D - serine; the formula  2  compound is                      
         in which R is a C   10    alkanoyl; R   1   , R   2   , R   3   , R   4    and R   5    are hydrogen, and wherein the alanine is D - alanine and the serine is D - serine; and the formula  3  compound is an A 21978 C cyclic peptide of                      
         wherein R   N    is n - decanoyl; and wherein the total amount of the compound of formula  1  and the compound of formula  2 , or salts thereof, in the combination is less than  6  weight percent.   
     
     
       19. The antibiotic composition of  claim 18  wherein the combined total amount of the compound or salt of formulas  1  and  2  is less than or equal to  2 . 5  weight percent. 
     
     
       20. An antibiotic composition useful for the treatment of bacterial infections comprising a combination of a compound of formula  1 , a compound of formula  2  and a compound of formula  3 , or pharmaceutically acceptable salts thereof, wherein the formula  1  compound is 
                   
         in which R is a C   10    alkanoyl; R   1   , R   2   , R   3   , R   4    and R   5    are hydrogen, and wherein the alanine is D - alanine and the serine is D - serine; the formula  2  compound is                      
         in which R is C   10    alkanoyl; R   1   , R   2   , R   3   , R   4    and R   5    are hydrogen, and wherein the alanine is D - alanine and the serine is D - serine; and the formula  3  compound is an effective antibacterial amount of an A 21978 C cyclic peptide compound of                      
         wherein R   N    is n - decanoyl, in substantially pure form.   
     
     
       21. A method for treating bacterial infections which comprises administering an effective amount of the composition of  claim 18  or  20  to an animal. 
     
     
       22. A method for treating bacterial infections which comprises administering an effective amount of the composition of  claim 18  or  20  to a human. 
     
     
       23. The method of  claim 21 , wherein the cyclic peptide compound or its pharmaceutically acceptable salt is administered at an effective amount between about  0 . 1  and about  100  mg of the compound or its pharmaceutically acceptable salt per kg of the animal. 
     
     
       24. The method of  claim 23 , wherein the amount is between about  1  and about  30  mg of the compound or its pharmaceutically acceptable salt per kg of the animal. 
     
     
       25. The method of  claim 21 , wherein the animal is a human and the effective amount is between about  100  mg and about  1  g per day. 
     
     
       26. A pharmaceutical formulation comprising a combination of a compound of formula  1 , a compound of formula  2  and a compound of formula  3 , or pharmaceutically acceptable salts thereof, wherein the formula  1  compound is 
                   
         in which R is a C   10    alkanoyl; R   1   , R   2   , R   3   , R   4    and R   5    are hydrogen, and wherein the alanine is D - alanine and the serine is D - serine; the formula  2  compound is                      
         in which R is a C   10    alkanoyl; R   1   , R   2   , R   3   , R   4    and R   5    are hydrogen, and wherein the alanine is D - alanine and the serine is D - serine; and the formula  3  compound is an A 21978 C cyclic peptide of                      
         wherein R   N    is n - decanoyl; and wherein the total amount of the compound of formula  1  and the compound of formula  2 , or salts thereof, in the combination is less than  6  weight percent, and the pharmaceutical formulation further comprises from about  0 . 1  to about  90  weight percent of the A 21978 C cyclic peptide of formula  3 .   
     
     
       27. The pharmaceutical formulation of  claim 26  comprising from about  10  to about  30  weight percent of the cyclic peptide compound or salt of formula  3 . 
     
     
       28. The pharmaceutical formulation of  claim 26  wherein the combined total amount of the compound or salt of formulas  1  and  2  is less than or equal to  2 . 5  weight percent. 
     
     
       29. The antibiotic composition of  claim 18  or  20 , produced by a process comprising separating a combination of a i)  a compound of formula  1 ; or a pharmaceutically acceptable salt thereof, ii )  a compound of formula  2 ; or a pharmaceutically acceptable salt thereof; and iii )  a compound of formula  3 ; or a pharmaceutically acceptable salt thereof from a solution comprising the compound of formula  1 , the compound of formula  2  and the compound of formula  3  or salts thereof; wherein the pH level of the solution is less than  4  or above  6 .   
     
     
       30. A pharmaceutical composition comprised of a combination of a compound of formula  1 , a compound of formula  2  and a compound of formula  3 , or pharmaceutically acceptable salts thereof, wherein the formula  1  compound is 
                   
         in which R is a C   10    alkanoyl; R   1   , R   2   , R   3   , R   4    and R   5    are hydrogen, and wherein the alanine is D - alanine and the serine is D - serine; the formula  2  compound is                      
         in which R is a C   10    alkanoyl; R   1   , R   2   , R   3   , R   4    and R   5    are hydrogen, and wherein the alanine is D - alanine and the serine is D - serine; and the formula  3  compound is an A 21978 C cyclic peptide of                      
         wherein R   N    is n - decanoyl; and the total amount of the compound of formula  1  and the compound of formula  2 , or salts thereof, in the combination is less than  6  weight percent; and wherein an effective dose of the compound or salt of formula  3  is between about  0 . 1  and about  100  mg/kg of the compound; or its pharmaceutically acceptable salt.   
     
     
       31. The pharmaceutical composition of  claim 30  wherein the combined total amount of the compound or salt of formulas  1  and  2  is less than or equal to  2 . 5  weight percent.