Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Patent
1997-04-10
1999-02-23
Tsang, Cecilia J.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
514 9, 514 11, 530345, C07K 512, A61K 3702, A61K 3800
Patent
active
058745300
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/03926 filed Oct. 5, 1995.
The present invention relates to a process for the sulfonylation, sulfenylation, thiocyanation and phosphorylation of cyclic depsipeptides, to novel compounds and their use as endoparasiticides.
Cyclic depsipeptides and their action as endoparasiticides are already known from EP 381 173, PCT WO 93/19 053. However, the activity of these compounds is not always satisfactory.
The present invention relates to
1. The process for the aromatic sulfonylation, sulfenylation, thiocyanation and phosphorylation of cyclic depsipeptides having 6 to 24 ring atoms which are synthesized from .alpha.-hydroxycarboxylic acids and .alpha.-amino acids and contain at least one phenyl radical, characterized in that these cyclic depsipeptides are reacted with sulfonylating, sulfenylating, thiocyanating or phosphorylating agents, optionally in the presence of catalysts, auxiliaries and/or diluents.
2. Aromatically sulfonylated, sulfenylated, thiocyanated and/or phosphorylated cyclic depsipeptides having 6 to 24 ring atoms which are synthesized from .alpha.-hydroxycarboxylic acids and .alpha.-amino acids and contain at least one phenyl radical.
Cyclic depsipeptides, which are employed as starting materials in the process according to the invention, are natural compounds usually prepared by fermentation. Structurally, they are similar to proteins. Therefore, they would be expected to be sensitive toward aggressive chemicals and to be destroyed entirely or at least partially. Surprisingly, it was found that the process according to the invention can be carried out without destroying the basic structure of the depsipeptides. Compounds are thus obtained which are sulfonylated, sulfenylated, thiocyanated or phosphorylated on the phenyl ring and which have outstanding endoparasiticidal activity.
The process according to the invention is preferably employed for preparing the novel and preferred compounds of the formula (I) ##STR1## as the core structure and in which at least one of the radicals R.sup.3,R.sup.4,R.sup.5,R.sup.6,R.sup.7,R.sup.8,R.sup.9 or R.sup.10 represents phenyl or benzyl, each of which is substituted by a sulfonyl, sulfenyl, thiocyanato or phosphoryl radical substituted C.sub.1-8 -alkyl, C.sub.3-6 -cycloalkyl, aralkyl or aryl radicals, or branched C.sub.1-8 -alkyl which is optionally substituted by hydroxyl, C.sub.1-4 -alkoxy, aryloxy, hetaryloxy, carboxyl, ##STR2## carboxamide, ##STR3## imidazolyl, indolyl, guanidino, --SH or C.sub.1-4 alkylthio, and further represent optionally substituted aryl, hetaryl or aralkyl, straight-chain or branched C.sub.1-8 -alkyl, C.sub.2-6 -alkenyl or C.sub.3-7 -cycloalkyl, each of which is optionally substituted by hydroxyl, C.sub.1-4 -alkoxy, carbonyl, carboxamide, imidazolyl, indolyl, guanidino, SH or C.sub.1-4 -alkylthio, or represent optionally substituted aryl, hetaryl or aralkyl.
Particularly preferred are compounds of the formula (I) in which at least one of the radicals R.sup.3 to R.sup.10 represents benzyl which is substituted by a sulfonyl, sulfenyl, thiocyanato or phosphoryl radical and in which otherwise the radicals have the meanings stated above.
Particularly preferred are compounds of the formula (I) in which one or both of the radicals R.sup.3 and R.sup.7 represent benzyl which is substituted by a sulfonyl, sulfenyl, thiocyanato or phosphoryl radical and in which otherwise the radicals have the meanings stated above.
Suitable sulfonyl, sulfenyl, thiocyanato or phosphoryl radicals are: ##STR4## --SO.sub.2 --A; --SO--A, --S--A SCN, wherein
______________________________________ Hal represents halogen,
A represents halogen, hydroxyl, --OR, --NH.sub.2, --NHR', --NR'R",
R represents optionally substituted alkyl, alkenyl, alkinyl, aryl or
aralkyl,
R' represents optionally substituted alkyl, aryl or aralkyl,
R" represents optionally substituted alkyl, aryl, or aralkyl,
______________________________________
attached an optionally substituted heterocyclic radical which may contain
further heteroatoms such as
REFERENCES:
patent: 5116815 (1992-05-01), Takagi et al.
Proceedings of Nobel Symposium, vol. 34, 1976, Stockholm, pp. 345-372, XP002005330, Yu. A. Ovchinnikov, "Recent Findings in the Structural and Functional Aspects of the Peptide Ionophores".
Shimohigashi et al, Cyclic Peptide, Int. J. Peptide Protein Res. 12, pp. 7-16, 1978.
Harder Achim
Jeschke Peter
Mencke Norbert
Plant Andrew
Scherkenbeck Jurgen
Bayer Aktiengesellschaft
Marshall S. G.
Tsang Cecilia J.
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