Intermediates for lhrh antagonist synthesis, process for their production, and process for lhrh antagonist production

Abstract

The novel tripeptides Ac-D-2Nal-D-4ClPhe-D-3Pal-OH and Boc-D-2Nal-D-4ClPhe-D-3Pal-OH are intermediates useful in the synthesis of LHRH analogs by coupling with suitable heptapeptides, in particular with the heptapeptides P 1 -Ser(P 2 )-NMeTyr(P 3 )-D-Lys(Nic)-Leu-Lys(iPr, P 4 )-Pro-D-AlaNH 2 and P 1 -Ser(P 2 )-NMeTyr(P 3 )-D-Asn-Leu-Lys(iPr, P 4 )-Pro-D-AlaNH 2 .

1 - 13 . (canceled)  
     
     
         14 . A process for preparing a tripeptide, including a salt thereof, of the formula (I)  
         Ac-D-2Nal-D-4ClPhe-D-3Pal-OH   (I)  
       or (IX)  
         Boc-D-2Nal-D-4ClPhe-D-3Pal-OH   (IX),  
       comprising the following consecutive steps for the preparation of (I): 
 (a) Reacting Boc-D-4ClPhe-OH with HONSu to form Boc-D-4ClPhe-OSu (VII);  
 (b) Reacting Boc-D-4ClPhe-OSu (VII) with H-D-3Pal-OH to form Boc-D-4ClPhe-D-3Pal-OH (VIII);  
 (c) Reacting Boc-D-4ClPhe-D-3Pal-OH (VIII) with Boc-D-2Nal-OSu prepared by reacting Boc-D-2Nal-OH with HONSu to form Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX);  
 (d) Reacting Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) with acetic acid to form Ac-D-2Nal-4ClPhe-D-3Pal-OH (I);  
 or the consecutive steps (a) through (c) for the preparation of (IX).  
 
     
     
         15 . A process for preparing an LHRH antagonist or a pharmaceutically acceptable salt thereof, comprising coupling a tripeptide Ac-D-2Nal-D-4ClPhe-D-3Pal-OH (I) prepared according to the process of  claim 14  with a heptapeptide (IV) of the general formula  
         P 1 -Ser(P 2 )-AA1-AA2-Leu-Lys(iPr,P 4 )-Pro-D-AlaNH 2    (IV),  wherein P 1  is selected from H or amino protecting group, P 2  is H or OH-protecting group, P 4  is H or an amino protecting group such as Boc, AA1 is natural or synthetic amino acid and AA2 is natural or synthetic amino acid or zero.    
     
     
         16 . The process of  claim 15 , wherein the heptapeptide of the general formula (IV) is a heptapeptide of the general formula  
         P 1 -Ser(P 2 )-NMeTyr(P 3 )-D-Lys(Nic)-Leu-Lys(iPr,P 4 )-Pro-D-AlaNH 2    (V)  wherein P 3  is H or —OH protecting group.    
     
     
         17 . The process of  claim 15 , wherein the heptapeptide of the general formula (IV) is a heptapeptide of the general formula  
         P 1 -Ser(P 2 )-NMeTyr(P 3 )-D-Asn-Leu-Lys(iPr,P 4 )-Pro-D-AlaNH 2    (Va).  wherein P 3  is H or —OH protecting group.    
     
     
         18 . The process of  claim 16 , wherein the heptapeptide of the general formula (V) is a heptapeptide of the formula  
         H-Ser(tBu)-NMeTyr-D-Lys(Nic)-Leu-Lys(iPr,Boc)-Pro-D-AlaNH 2    (VI).  
     
     
         19 . The process of  claim 17 , wherein the heptapeptide of the formula (VI) is a heptapeptide of the formula  
         H-Ser(tBu)-NMeTyr-D-Asn-Leu-Lys(iPr,Boc)-Pro-D-AlaNH 2    (VIa).  
     
     
         20 . (New) A process for preparing an LHRH antagonist or a pharmaceutically acceptable salt thereof, comprising coupling the tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) prepared by the process of  claim 14 . 
 with a heptapeptide (IV) of the general formula      Ser(P 2 )-AA1-AA2-Leu-Lys(iPr,P 4 )-Pro-D-AlaNH 2    (IV),    wherein P 1  is selected from H or amino protecting group, P 2  is H or OH-protecting group, P 4  is H or amino protecting group such as Boc, AA1 is a natural or synthetic amino acid and AA2 is a natural or synthetic amino acid or zero.    
     
     
         21 . The process of  claim 20 , wherein the heptapeptide of the general formula (IV) is a heptapeptide (V) of the general formula  
         P 1 -Ser(P 2 )-NMeTyr(P 3 )-D-Lys(Nic)-Leu-Lys(iPr,P 4 )-Pro-D-AlaNH 2    (V)  wherein P 3  is H or OH-protecting group.    
     
     
         22 . The process of  claim 21 , wherein the heptapeptide of the general formula (V) is the heptapeptide  
         H-Ser(tBu)-NMeTyr-D-Lys(Nic)-Leu-Lys(iPr,Boc)-Pro-D-AlaNH 2    (VI).  
     
     
         23 . The process of  claim 20 , wherein the heptapeptide of the general formula (IV) is a heptapeptide of the general formula  
         P 1 -Ser(P 2 )-NMeTyr(P 3 )-D-Asn-Leu-Lys(iPr,P 4 )-Pro-D-AlaNH 2    (Va),  followed by substituting the Boc group by an acyl group, in particular an acetyl group.    
     
     
         24 . The process of  claim 23 , wherein the heptapeptide of the general formula (IV) is the heptapeptide  
         H-Ser(tBu)-NMeTyr-D-Asn-Leu-Lys(iPr,Boc)-Pro-D-AlaNH 2    (VIa),  followed by substituting the N-terminal Boc group by an acyl group, in particular an acetyl group.    
     
     
         25 . The tripeptide Ac-D-2Nal-D-4ClPhe-D-3Pal-OH (I) or a salt thereof prepared by the process of  claim 14 .  
     
     
         26 . The tripeptide Boc-D-2Nal-D-4ClPhe-D-3Pal-OH (IX) or a salt thereof prepared by the process of  claim 14.