Novel GnRH analogues with antitumour effects and pharmaceutical compositions thereof

Abstract

The present invention provides peptides and pharmacologically active compounds including gonadotropin-releasing hormone (GnRH) analogues according to formulas of the invention, wherein the compounds show an antitumour effect. The invention additionally provides compositions including these peptides and compounds.

1 - 17 . (canceled)  
     
     
         18 . A pharmacologically active compound of formula (I)  
         Y(W u ,V z ,X r ,A k )  (I)  
       wherein 
 Y represents the molecular moiety of formula (Ia),  
                     
  wherein n is an integer from 10 to 400; one of R 1  and R 2  represents hydrogen atom whereas the other one represents a group of formula (B);  
                     
 R 3  represents a polymerization-initiating group;  
 W represents a hydroxyl group, optionally as a salt formed with an alkali metal ion;  
 V represents a C1-8 alkylamino group bonded through its amino group or a valence bond;  
 X is a “spacer” group being an amino acid group or an oligopeptide group of at most six members wherein the amino acid or oligopeptide group is coupled through its N-terminal to the Y group and is optionally bearing a hydroxyl group or a valence bond on its C-terminal, wherein the amino acids are Gly, Ala, Leu, Ile, Val, Phe, Tyr, Ahx, Pro, Arg, or His;  
 A is present and represents a pharmacologically active polypeptide hormone group containing an amino group and directly coupled therethrough to the Y group when r is 0; or coupled to the C-terminal of the X group, respectively, when r is larger than 0;  
 r is an integer from 0 to 0.2 n;  
 k is an integer being at most equal to r; z is an integer from 0 to (n-r); and  
 u is an integer from n to 2n-r-z, as well as the salts and complexes of these compounds.  
 
     
     
         19 . The pharmacologically active compound of formula (1) of  claim 18 , wherein R 3  is a (CH 3 ) 2 CCN group.  
     
     
         20 . The pharmacologically active compound of formula (I) of  claim 19 , wherein: 
 A represents a native gonadotropin-releasing hormone (GnRH) coupled through its amino group or a pharmacologically active analogue thereof; and k, r, u, z, X, Y, V and W are as defined in  claim 18 , as well as the salts and complexes of these compounds.    
     
     
         21 . The pharmacologically active compound of formula (I) of  claim 20 , wherein 
 A represents 
 pGlu-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH 2  (SEQ ID NO:2),  
 Ac-D-Trp 1,3 , p-chlorophenyl-D-alanine 2 (D-Cpa 2 ),D-LyS 6 ,D-Ala 10 -gonadotropin-releasing hormone (GnRH)  
 Ac-D-Trp 1,3 ,D-Cpa 2 ,Lys 5 ,[Asp(a-DEA)] 6 ,D-Ala 10 -Gln 8 -GnRH,  
 D-Phe 2 ,D-Trp 3 ,D-Lys 6 -GnRH,  
 Lys 5 ,cyclo(Asp 6 -Lys 8 )-GnRH-III,  
 Lys 4 ,[Lys(ε-Fmoc)] 8 -GnRH-III,  
 Lys 4 -GnRH-III,  
 D-Lys 6 -GnRH,  
 Lys 5 ,D-Trp 6 -GnRH  
   coupled to X or Y through the ε-amino group of their Lys side chains; and k, r, u, z, X, Y, V and W are as defined in  claim 18 , as well as the salts and complexes of these compounds.    
     
     
         22 . The pharmacologically active compound of formula (I) of  claim 18 , wherein X represents an oligopeptide group consisting of four members; and k, r, u, z, A, Y, V and W are as defined in  claim 18 , as well as the salts and complexes of these compounds.  
     
     
         23 . The pharmacologically active compound of formula (I) of  claim 18 , wherein X represents an oligopeptide group consisting of three members; and k, r, u, z, A, Y, V and W are as defined in  claim 18 , as well as the salts and complexes of these compounds.  
     
     
         24 . The pharmacologically active compound of formula (I) of  claim 18 , wherein V is a C4-6 alkylamino group.  
     
     
         25 . The pharmacologically active compound of formula (I) of  claim 18 , wherein r. is 0; and k, u, z, A, Y, V and W are as defined in  claim 18 , as well as the salts and complexes of these compounds.  
     
     
         26 . A compound containing an activated ester group of formula (Ic),  
         Y[W u ,V′ z ,(XOQ) r ]  (Ic)  
       wherein Y represents the molecular moiety of formula (Ia), wherein n is an integer from 10 to 400; one of R 1  and R 2  represents hydrogen atom whereas the other one represents a group of formula (B); R 3  represents a polymerization-initiating group; W represents a hydroxyl group, optionally as a salt formed with an alkali metal ion; V′ represents a C1-8, alkylamino group bonded through its amino group; X represents an amino acid group or an oligopeptide group of at most six members coupled through its N-terminal to the Y group; OQ represents an activated ester group on C-terminal of the X group; r is an integer from 0 to 0.2 n; z is an integer from 0 to (n-r); and u is an integer from n to (2n-r-z), as well as the salts of these compounds.  
     
     
         27 . Compounds of formula (Ic) as claimed in  claim 26 , wherein X 
 represents an oligopeptide group consisting of at most four members, preferably -Gly-Phe-Leu-Gly-, -Gly-Phe-Gly-, -Phe-Leu- Gly- or -Ahx-; OQ represents ONp group; and k, r, u, z, A, Y, V′ as well as W are as defined in  claim 26 , as well as the salts of these compounds.    
     
     
         28 . A pharmaceutical composition comprising a compound of formula (I) of  claim 18 , wherein k. r, u, z, X, Y, V and W are as defined in  claim 18 , or a pharmaceutically acceptable salt or complex thereof in admixture with carriers and/or additives commonly used in the pharmaceutical industry.  
     
     
         29 . A tumour-inhibiting pharmaceutical composition comprising a compound of formula (I) of  claim 20  or a pharmaceutically acceptable salt or complex thereof in admixture with carriers and/or additives commonly used in the pharmaceutical industry.  
     
     
         30 . A tumour-inhibiting and immunostimulatory pharmaceutical composition comprising a compound of formula (I), wherein A represents Ac-D-Trp 1,3 ,p-chlorophenyl-D-alanine 2 (D-Cpa 2 ),Lys 5 ,[Asp(a-DEA)] 6 ,D-Ala 10 -Gln 8 -GnRH, and k, r, z, u, X, Y, V and W are as defined in  claim 18 , or a pharmaceutically acceptable salt or complex thereof in admixture with carriers and/or additives commonly used in the pharmaceutical industry.  
     
     
         31 . A composition comprising a compound of  claim 18  in combination with a pharmaceutically acceptable carrier.  
     
     
         32 . The pharmacologically active compound of  claim 18 , wherein n is an integer from 20 to 200.  
     
     
         33 . The pharmacologically active compound of  claim 22 , wherein X represents -Gly-Phe-Leu-Gly- (SEQ ID NO:5).  
     
     
         34 . The pharmacologically active compound of  claim 23 , wherein X represents -Phe-Leu-Gly-.  
     
     
         35 . The pharmacologically active compound of  claim 23 , wherein X represents -Gly-Leu-Gly-.  
     
     
         36 . The compound of  claim 26 , wherein n is an integer from 20 to 200.  
     
     
         37 . The compound of  claim 26 , wherein R 3  represents (CH 3 ) 2 CCN.  
     
     
         38 . The compound of  claim 26 , wherein W represents a hydroxyl grop as a salt formed with a sodium ion.  
     
     
         39 . The compound of  claim 26 , wherein V′ represents a C4-6 alkylamino group.  
     
     
         40 . The compound of  claim 26 , wherein the activated ester group is selected from the group consisting of ONp, OPcp, Opfp, and ONsu.  
     
     
         41 . A tumour-inhibiting pharmaceutical composition comprising a compound of formula (I) of  claim 21  or a pharmaceutically acceptable salt or complex thereof in admixture with carriers and/or additives commonly used in the pharmaceutical industry.