Didepsipeptide-based endoparasiticides, new didepsipeptides and process for preparing the same

Abstract

The present invention relates to the use of didepsipepides of the general formula (I) and their salts in which the radicals have the meaning given in the description, and to new didepsidpeptides and processes for their preparation.

1 . Use of didepsipeptides of the general formula (I) and their salts  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  represent hydrogen, straight-chain or branched alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, heteroarylalkyl, each of which is optionally substituted,  
 R 1  and R 2  together with the atoms to which they are bonded represent a 5- or 6-membered ring which can optionally be interrupted by oxygen, sulphur, sulphoxyl or sulphonyl and is optionally substituted,  
 R 2  and R 3  independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which is optionally substituted, or  
 R 2  and R 3  together represent a spirocyclic ring, which is optionally substituted,  
 R 4  and R 5  independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which is optionally substituted, or  
 R 4  and R 5  together represent a spirocyclic ring, which is optionally substituted,  
 A represents hydrogen, alkyl, aralkyl, formyl, alkoxydicarbonyl or a radical of the group G 1    
                     
 in which  
                     
 can denote carboxyl, thiocarboxyl, —CH═CH—NO 2 , —CH═CH—CN, —C═N—R 6 , sulphoxyl, sulphonyl, —P(O)—OR 7  or P(S)—OR 7 ,  
 R 6  represents hydrogen, hydroxyl, alkoxy, alkylcarbonyl, halogenoalkylcarbonyl, alkylsulphonyl, nitro or cyano, and  
 R 7  represents hydrogen or alkyl, and  
 Q represents straight-chain or branched alkyl, alkenyl, alkinyl, cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl, each of which is optionally substituted, or optionally represents a radical from the group G 2  and G 3    
                     
 R 8 —Y—(G 2 )  
 in which  
                     
 can denote carboxyl, thiocarboxyl or sulphonyl,  
 Y represents oxygen, sulphur or —NR 9 ,  
 R 8  in the case where Y represents nitrogen can denote a cyclic amino group linked via a nitrogen atom,  
 R 8  and R 9  independently of one another represent hydrogen, straight-chain or branched alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl, hetarylalkyl, each of which is optionally substituted, or  
 R 8  and R 9  together with the adjacent N atom, [lacuna] a carbocyclic 5-, 6- or 7-membered ring system or a 7 to 10-membered bicyclic ring system which can optionally also be interrupted by oxygen, sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O—, —N═, —NR 11 — or by quatemized nitrogen and is optionally substituted,  
 R 10  represents hydrogen or alkyl,  
 R 11  represent represents hydrogen, straight-chain or branched alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cyano, aryl, arylalkyl, hetaryl, hetarylalkyl, each of which is optionally substituted, and  
 B represent represents hydroxyl, alkoxy, alkenyloxy, alkinyloxy, cycloalkyloxy, cycloalkylalkyloxy, aryloxy-, arylalkyloxy, hetaryloxy, hetarylalkyloxy, each of which is optionally substituted, or represents the radicals —NR 12 R 13 , —NR 14 —NR 12 R 13  and —NR 15 —OR 16 ,  
 in which  
 R 12  and R 13  independently of one another represent hydrogen, straight-chain or branched alkyl, alkylcarbonyl, alkyl sulphonyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, aryl, arylcarbonyl, arylsulphonyl, arylalkyl, hetaryl, hetarylcarbonyl, hetarylsulphonyl or hetarylalkyl, each of which is optionally substituted, or  
 R 12  and R 13  together with the adjacent N atom [lacuna] a carbocyclic 5-, 6-, 7- or 8-membered ring system or a 7 to 10-membered bicyclic ring system which can optionally also be interrupted by oxygen, sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O, —N═, NR 11 — or by quaternized nitrogen and is optionally substituted,  
 R 14  represents hydrogen, straight-chain or branched alkyl, cycloalkyl, arylalkyl or hetarylalkyl, each of which is optionally substituted,  
 R 15  and R 16  independently of one another denote hydrogen, straight-chain or branched alkyl, alkylcarbonyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, arylalkyl or hetarylalkyl, each of which is optionally substituted,  
 R 15  and R 16  together with the adjacent N—O-group represent a carbocyclic 5-, 6- or 7-membered ring,  
 and their optical isomers and racemates,  
 for the control of endoparasites in medicine and veterinary medicine.  
 
     
     
         2 . New didepsipeptides of the general formula (Ia) and their salts  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  represents hydrogen, straight-chain or branched C 1-4 -alkyl, C 3-6 -cycloalkyl, aryl-C 1-2 -alkyl or hetaryl-C 1-2 -alkyl, each of which is optionally substituted, and  
 R 1  and R 2  together with the atoms to which they are bonded represent a 5- or 6-membered ring which can optionally be interrupted by oxygen, sulphur, sulphoxyl or sulphonyl and is optionally substituted,  
 R 2  represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, alkenyl having up to 4 carbon atoms, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-2 -alkyl, aryl, aryl-C 1-2 -alkyl, hetaryl, hetaryl-C 1-2 -alkyl each of which is optionally substituted,  
 R 3  and R 4  represent hydrogen,  
 R 5  represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, alkenyl having up to 4 carbon atoms, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-2 -alkyl, aryl, aryl-C 1-2 -alkyl, hetaryl, hetaryl-C 1-2 -alkyl each of which is optionally substituted,  
                     
 represents carboxyl, thiocarboxyl, —C═CH—NO 2 , —C═CH—CN, —C═N—R 6 , sulphoxyl, sulphonyl, —P(O)—OR 7  or P(S)—OR 7 ,  
 R 6  represents hydrogen, hydroxyl, C 1-4 -alkoxy, C 1-4 -alkylcarbonyl, C 1-4 -halogenoalkylcarbonyl, C 1-4 -alkylsulphonyl, nitro or cyano, and  
 R 7  represents hydrogen or C 1-4 -alkyl, and  
 Q represents straight-chain or branched C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkinyl, C 3-6 -cycloalkyl or hetaryl-C 1-2 -alkyl, each of which is optionally substituted, or optionally represents a radical from the group G 2  and G 3    
                     
 R 8 —Y—(G 2 )  
 in which  
                     
 can denote carboxyl, thiocarboxyl or sulphonyl,  
 Y represents oxygen, sulphur or —NR 9 ,  
 R 8  in the case where Y represents nitrogen can denote a cyclic amino group linked via a nitrogen atom,  
 R 8  and R 9  independently of one another represents hydrogen, straight-chain or branched C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkinyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-2 -alkyl, hetaryl or hetaryl-C 1-2 -alkyl, each of which is optionally substituted, or  
 R 8  and R 9  together with the adjacent N atom represent a carbocyclic 5-, 6- or 7-membered ring system or a 7 to 10-membered bicyclic ring system which can optionally also be interrupted by oxygen, sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O—, —N═, —NR 11 — or by quaternized nitrogen and is optionally substituted,  
 R 10  represents hydrogen or C 1-4 -alkyl, and  
 R 11  represents hydrogen, straight-chain or branched C 1-6 -alkyl, C 3-6 -cycloalkyl, C 2-6 -alkenyl, C 2-6 -alkinyl, C 3-6 -cycloalkyl, C 3-6 -Cycloalkyl-C 1-2 -alkyl, C 1-4 -alkoxycarbonyl, C 1-4 -alkylcarbonyl, C 3-6 -cycloalkylcarbonyl, cyano, aryl, aryl-C 1-2 -alkyl, hetaryl or hetaryl-C 1-2 -alkyl, each of which is optionally substituted, and  
 B represents C 1-6 -alkoxy, C 2-6 -alkenyloxy, C 2-6 -alkinyloxy, C 3-7 -cycloalkyloxy, C 3-7 -cycloalkyl-C 1-2 -alkyloxy, aryloxy-, aryl-C 1-2 -alkyloxy, hetaryloxy, hetaryl-C 1-2 -alkyloxy, each of which is optionally substituted, or  
 represents the amino radicals —NR 12 R 13 , —NR 14 —NR 12 R 13  and —NR 15 —OR 16 , in which  
 R 12  and R 13  independently of one another represent hydrogen, straight-chain or branched C 1-6 -alkyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulphonyl, C 2-6 -alkenyl, C 2-6 -alkinyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-2 -alkyl, aryl, arylcarbonyl, arylsulphonyl, aryl-C 1-2 -alkyl, hetaryl, hetarylcarbonyl, hetarylsulphonyl or hetaryl-C 1-2  alkyl, each of which is optionally substituted, or  
 R 12  and R 13  together with the adjacent N atom represent a carbocyclic 5-, 6-, 7- or 8-membered ring system or a 7 to 10-membered bicyclic ring system, which can optionally also be interrupted by oxygen, sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O, —N═, —NR 11 — or by quaternized nitrogen and is optionally substituted,  
 R 14  represents hydrogen, straight-chain or branched C 1-6 -alkyl, C 3-6 -cycloalkyl, each of which is optionally substituted,  
 R 15  and R 16  independently of one another denote hydrogen, straight-chain or branched C 1-6 -alkyl, C 1-6 -alkylcarbonyl, C 2-6 -alkenyl, C 2-6 -alkinyl or C 3-6 -cycloalkyl, each of which is optionally substituted, and  
 R 15  and R 16  together with the adjacent N—O-group represent a carbocyclic 5-, 6- or 7-membered ring,  
 with the proviso in the case where in formula (Ia) R 1 , R 5  and ═G═X together represent the following radicals:  
 R 1  represents hydrogen and methyl,  
 R 5  represents hydrogen,  
                     
 represents carboxyl,  
 the radicals Q and B must fulfil the following condition:  
 Q represents radicals other than methyl,  
 B represents radicals other than —NH 2 ,  
 and with the proviso in the case where in formula (Ia) G 2  and ═G═X together represent the following radicals:  
                     
 represents carboxyl,  
 G 2  represents tert-butyloxy, benzyloxy and 4-nitro-benzyloxy,  
 the radical B represents radicals other than tert-butyloxy, benzyloxy and 4-nitro-benzyloxy,  
 and their optical isomers and racemates.  
 
     
     
         3 . Process for the preparation of the new didepsipeptides of the general formula (Ia) and their salts according to  claim 2   
       
         
           
           
               
               
           
         
       
       in which  
       the radicals R 1 , R 2 , R 3 , R 4 , R 5 , G, Q, X and B have the meaning indicated in  claim 2 ,  
       characterized in that 
 a) N-terminal-substituted amino acids of the general formula (II)  
                     
 in which  
 the radicals R 1 , R 2 , R 3 , G, Q, and X have the meaning indicated in  claim 2 , or their carboxyl-activated derivatives or their alkali metal salts, are reacted, if appropriate in the presence of a catalyst, if appropriate in the presence of an acid-binding agent and if appropriate in the presence of a diluent, with carboxylic acid derivatives of the general formula (III)  
                     
 in which  
 the radicals R 4 , R 5  and B have the meaning indicated in  claim 2  and Z represents a suitable leaving group for example halogen such as bromine, chlorine fluorine, or hydroxyl, or  
 b) N-terminal-deblocked didepsipeptides of the general formula (Ib)  
                     
 in which  
 the radicals R 1 , R 2 , R 3 , R 4 , R 5  and B have the meaning indicated in  claim 2 , are reacted, if appropriate in the presence of a catalyst, if appropriate in the presence of an acid-binding agent and if appropriate in the presence of a diluent, with compounds of the general formula (IV)  
                     
 in which  
 the radicals G, Q, W and X have the meaning indicated in  claim 2  and W represents a suitable leaving group, for example halogen, alkoxy, alkylthio or aryloxy, or  
 c) N-terminal-deblocked didepsipeptides of the general formula (Ib)  
                     
 in which  
 the radicals R 1 , R 2 , R 3 , R 4 , R 5  and B have the meaning indicated in  claim 2 , are reacted, if appropriate in the presence of a catalyst, if appropriate in the presence of an acid-binding agent and if appropriate in the presence of a diluent, with compounds of the general formulae (V) or (VI) 
 R 8 —N═C═X  (V) 
                     
 in which  
 the radicals R 8 , G 1 , X, X 1  and Y have the meaning indicated in  claim 2 , or  
 for the preparation of the depsipeptides of the general formula (Ia) and their salts in which the group  
                     
 represents carboxyl and Y represents oxygen,  
 d) N-terminal-deblocked didepsipeptides of the general formula (Ib)  
                     
 in which  
 the radicals R 1 , R 2 , R 3 , R 4 , R 5  and B have the meaning indicated in  claim 2 ,  
 are reacted in a first reaction step with carbon dioxide and an alkali metal carbonate of the formula (VII) 
 M 2 CO 3   (VII) 
 in which  
 M represents a monovalent alkali metal cation, preferably lithium, sodium, potassium or caesium, in particular potassium or caesium,  
 then in a second reaction step the resulting alkali metal salt of the formula (VIII)  
                     
 in which  
 the radicals R 1 , R 2 , R 3 , R 4 , R 5  and B have the meaning indicated in  claim 2 ,  
 M represents a metal cation equivalent bound like a salt,  
 is reacted with alkylating agents of the formula (IX) 
 R 8 —Hal  (IX) 
 in which  
 R 8  has the meaning indicated in  claim 2  and  
 Hal represents a halogen such as fluorine, chlorine, bromine or iodine,  
 if appropriate in the presence of a diluent and if appropriate in the presence of a basic reaction auxiliary, or  
 e) didepsipeptides of the general formula (Ic)  
                     
 in which  
 the radicals R 1 , R 2 , R 3 , R 4 , R 5 , G, W, X and B and have the meaning indicated in  claim 2  and 3b, are reacted, if appropriate in the presence of a catalyst, if appropriate in the presence of an acid-binding agent and if appropriate in the presence of a diluent, with compounds of the general formula (X) 
 R 8 —Y—H  (X) 
 in which  
 the radicals R 8  and Y have the meaning indicated above in  claim 2 , or  
 f) didepsipeptides of the general formula (Id)  
                     
 in which  
 the radicals R 1 , R 2 , R 3 , R 4 , R 5 , G, Q, X and B have the meaning indicated in  claim 2  or their carboxyl-activated derivatives or their alkali metal salts are reacted, if appropriate in the presence of a catalyst, if appropriate in the presence of an acid-binding agent and if appropriate in the presence of a diluent, with compounds of the general formula (XI) 
 H—B  (XI) 
 in which  
 the radical B has the meaning indicated above in  claim 2 .  
 
     
     
         4 . Endoparasiticidal compositions, characterized in that they contain at least one didepsipeptide of the formula (I) according to  claim 1 .  
     
     
         5 . Process for the production of endoparasiticidal compositions, characterized in that didepsipeptides of the formula (I) according to  claim 1  are mixed with extenders and/or surface-active agents.  
     
     
         6 . Use of didepsipeptides of the formula (I) according to  claim 1  for the production of endoparasiticidal compositions.