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

1. A method of treating an endoparasitic infection comprising administering to a human or animal in need thereof an effective amount of a didepsipeptide of the formula (I)

wherein

R 1 represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, C 3-6 -cycloalkyl, aryl-C 1-2 -alkyl or het-C 1-2 -alkyl,

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 sulphur, and is optionally substituted,

R 2 and R 3 independently of one another represent hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, halogenoalkyl, hydroxyalkyl, C 1-4 -alkanoyloxyalkyl, C 1-2 -alkoxyalkyl, mercaptoalkyl, C 1-2 -alkylthioalkyl, C 1-2 -alkylsulphinylalkyl, C 1-2 -alkylsulphonylalkyl, carboxyalkyl, carbamoylalkyl, aminoalkyl, C 1-6 -alkylaminoalkyl, C 1-6 -dialkylaminoalkyl, guanidinoalkyl, which can optionally be substituted by one or two benzyloxycarbonyl radicals or by one, two, three or four C 1-2 -alkyl radicals, C 1-4 -alkoxycarbonylaminoalkyl, C 2-6 -alkenyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-2 -alkyl, and optionally substituted aryl, aryl-C 1-2 -alkyl, heteroaryl, heteroaryl-C 1-2 -alkyl, or

R 2 and R 3 together represent a spirocyclic ring,

R 4 and R 5 independently of one another represent hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, halogenoalkyl, hydroxyalkyl, C 1-4 -alkanoyloxyalkyl, C 1-2 -alkoxyalkyl, mercaptoalkyl, C 1-2 -alkylthioalkyl, C 1-2 -alkylsulphinylalkyl, C 1-2 -alkylsulphonylalkyl, carboxyalkyl, carbamoylalkyl, aminoalkyl, C 1-6 -alkylaminoalkyl, C 1-6 -dialkylaminoalkyl, guanidinoalkyl, which can optionally be substituted by one or two benzyloxycarbonyl radicals or by one, two, three or four C 1-2 -alkyl radicals, C 1-4 -alkoxycarbonylaminoalkyl, C 2-6 -alkenyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-2 -alkyl, and optionally substituted aryl, aryl-C 1-2 -alkyl, heteroaryl, heteroaryl-C 1-2 alkyl, or

R 4 and R 5 together represent a spirocyclic ring,

A represents hydrogen, C 1-6 -alkyl, formyl, C 1-4 -alkoxydicarbonyl or a radical of the group G 1

in which

can denote carbonyl, 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 1-6 -halogenoalkyl, hydroxy-C 1-6 -alkyl, C 1-4 -alkanoyloxy-C 1-6 -alkyl, C 1-2 -alkoxy-C 1-6 -alkyl, mercapto-C 1-6 -alkyl-, C 1-2 -alkylthio-C 1-6 -alkyl, C 1-2 -alkylsulphinyl-C 1-6 -alkyl, C 1-2 -alkylsulphonyl-C 1-6 -alkyl, carboxy-C 1-6 -alkyl, carbamoyl-C 1-6 -alkyl, amino-C 1-6 -alkyl, C 1-6 -alkylamino-C 1-6 -alkyl, C 1-6 -dialkylaminoalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 2-6 -halogenoalkenyl, C 3-6 -cycloalkyl, and optionally substituted aryl, aryl-C 1-2 -aryl, hetaryl or hetaryl-C 1-2 -alkyl, or optionally represents a radical from the group G 2 and G 3

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 C 1-6 -alkyl, C 1-6 -alkenyl, C 1-6 -alkynyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-2 -alkyl, aryl, arylalkyl, hetaryl, hetarylalkyl, each of which is optionally substituted, or

R 8 and R 9 together with the adjacent N atom 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,

R 11 represents hydrogen, straight-chain or branched C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-2 -alkyl, C 1-4 -alkoxycarbonyl, C 1-4 -alkylcarbonyl, C 3-6 -cycloalkylcarbonyl, cyan, aryl, aryl-C 1-2 -alkyl, hetaryl, hetaryl-C 1-2 -alkyl, each of which is optionally substituted, and

B represents hydroxyl, C 1-6 -alkoxy, C 2-6 -alkenyloxy, C 2-6 -alkynyloxy, C 3-7 -cycloalkyloxy, C 3-7 -cycloalkylalkyloxy, aryloxy-, aryl-C 1-2 -alkyloxy, hetaryloxy, hetaryl-C 1-2 -alkyloxy, 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 C 1-6 -alkyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylsulphonyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -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, or

R 12 and R 13 together with the adjacent N atom represents 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, aryl-C 1-2 -alkyl or hetaryl-C 1-2 -alkyl, 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 -alkynyl, C 3-6 -cycloalkyl, aryl-C 1-2 -alkyl or hetaryl-C 1-2 -alkyl, 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,

or an optical isomer or salt thereof.

2. A method of treating an endoparasitic infection comprising administering to a human or animal in need thereof an effective amount of a didepsipeptide of the formula (Ia) and its salt

in which

R 1 represents hydrogen, straight-chain or branched C 1-4 -alkyl,

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,

alternatively, 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 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)—O—R 7 or P(S)—O—R 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 -alkynyl, C 3-6 -cycloalkyl or hetaryl-C 1-2 -alkyl, or optionally represents a radical from the group G 2 and G 3

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 -alkynyl, 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 -alkynyl, C 3-6 -cycloalkyl, 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 -alkynyloxy, 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 alkynyl, 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, 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 -alkynyl 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 fulfill 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 with the proviso that, if in formula (Ia) R 4 and R 5 are hydrogen, B must not represent NH 2 ,

and with the proviso that, if in formula (Ia) R 1 and R 5 represent hydrogen and

B does not represent methylamino,

and with the proviso that, if in formula (Ia)

 represents benzyloxycarbonyl or

B does not represent benzylamino,

and with the proviso that, if in formula (Ia)

 represents tert-butyloxycarbonyl and R 1 and R 3 represent H and either R 4 and R 5 represents methyl and the other radical represents H,

B does not represent ethoxy,

and with the proviso that the compound of formula

is excluded,

furthermore with the proviso that the compounds

methyl O-(N-carbobenzoxy-l-leucyl)-hydroxyethanoate,

methyl O-(N-carbobenzoxy-l-leucyl)-(S)-2-hydroxy-3-phenylpropanoate,

methyl O-(N-carbobenzoxy-l-leucyl)-(S)-2-hydroxypropanoate,

methyl O-(N-carbobenzoxy-l-leucyl)-(S)-2-hydroxy-4-methylpentanoate,

ethyl N-(benzyloxycarbonyl)amino-2-(O-glycyl)-glycolate,

ethyl N-(benzyloxycarbonyl)-amino-2-(O-glycyl)-lactate,

ethyl N-(benzyloxycarbonyl)-amino-2-(O-alanyl)-glycolate,

ethyl N-(benzyloxycarbonyl)-amino-2-(O-alanyl)-lactate

are excluded,

and their optical isomers and racemates.