Thiodepsipeptides for combating endoparasites and a method...

Details Thiodepsipeptides for combating endoparasites and a method... Thiodepsipeptides for combating endoparasites and a method...

1999-09-27

2001-07-24

Swartz, Rodney P (Department: 1643)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

C530S300000, C530S330000, C514S016700, C514S018700

Reexamination Certificate

active

06265537

ABSTRACT:

The present invention relates to cyclic thiodepsipeptides, in particular 18- to 24-membered cyclothiodepsipeptides, to a simple process for their preparation and to their use for controlling endoparasites.
The preferred structural variations of biologically active peptides include the ex-change of amide-oxygen for sulfur, since the thioamide group (&PSgr;[CSNH]) shows a pronounced isosterism to the amide group (CONH) (cf. for example B. D. B. Sherman et al., J. Amer. Soc. 112, 1990, p. 433; M. Kajtar et al., Tetrahedron 42, 1986, p. 3931; D. J. S. Guthrie et al., Int. J. Peptide Protein Res. 28, 1986, p. 208). However, it is difficult to predict the expected biological potency of the thiopeptide, in spite of the great physical similarity to the parent peptide. (cf. L. Lankiewics et al., Biochem. Biophys. Res. Comnnun. 184, (1), 1992, p. 359).
Methods for preparing various endothiopeptides are known from the literature. By way of example, the thionation strategies for various hormones, such as the neurohypophysio hormone oxytocin, the thyrotropin releasing-hormone (THR), the growth hormone-releasing peptide, and the neuropeptides leucine-enkephalin and demorphine, may be mentioned. (cf. [1-deamino,9-thio-glycine] oxytocin: W. C. Jones et al., J. Amer. Chem. Soc. 95, 1973, p. 5677; thio-TRH: Zs. Majer et al., Biochem. Biophys. Res. Conmmun. 150, 1988, p. 1017; thionated leucine-enkephalines: K. Clausen et al., J. Chem. Soc., Perkin Trans. I 1984, p.785 and Biochem. Biophys. Res. Commun. 120, 1984, p. 305; Thio-demorphin: S. Salvadori et al., Farmaco Ed. Sc., 39, 1984, p. 216; Thio-TRH: M. Kruszynski et al., Experentia 41, 1985, p. 1576).
The authors Ried et al., Mock et al., Campbell et al. or Bartlett et al. worked out further possible syntheses of N-protected endothiodipeptide esters and salts thereof, Brown et al. gained access to N-protected endothiotripeptide esters (cf. W. Ried et al., Angew. Chem. 72, 1960, p. 268; W. L. Mock et al., Biochem. Biophys. Res. Commun. 102, 1981, p. 389; 1973, p. 5677; Campbell et al., J. Amer. Chem. Soc. 104, 1982, p. 5221; P. A. Bartlett et al., 21, 1982, p. 1608; D. W. Brown et al., Tetrahedron 39, 1983, 1075).
Compared to the abovementioned methods for preparing various endothiopeptides, only little is known about the preparation of thiodepsipeptides comprising amino acids, hydroxythiocarboxylic acids and, if appropriate, hydroxycarboxylic acids.
The preparation of some thiol esters of amino acids and their use as insecticides and acaricides are known (cf. DE-A 2812169, C. A. Henrick et al., Pestic. Sci. 11, (2), 1980, p. 224; U.S. Pat. No. 4,243,819, U.S. Pat. No. 4,231,953).
Furthermore, a thiodepsipeptide PM-93135, which was isolated as a fermentation product from a rmicromonospora strain (actinomycetes) and has antibacterial activity, is known (cf. WO 95/277730).
Cyclothiodepsipeptides comprising amino acids, hydroxythiocarboxylic acids and, if appropriate, hydroxycarboxylic acids as ring building blocks have not been disclosed before.
Cyclodepsipeptides having 18 to 24 ring atoms for use as agents for controlling endoparasites are known (cf. for example B. Y. Kodama et al., Sci. Reports of Meiji Seika Kaisha 31, 1992, p. 1-8; EP-A 382 173; EP-A 503 538; WO 93/19 053; WO 94/19334; WO 95/07272; EP 626 375; EP 626 376; EP 664 297; EP 634 408; 718 298).
The present invention, accordingly, provides novel cyclic thiodepsipeptides and a process for preparing the cyclic thiodepsipeptides comprising amino acids, hydroxythiocarboxylic acids and, if appropriate, hydroxycarboxylic acids as ring building blocks and 18 to 24 ring atoms.
The use of cyclic thiodepsipeptides comprising amino acids, hydroxythiocarboxylic acids and, if appropriate, hydroxycarboxylic acids as ring building blocks and 18-24 ring atoms for use as agents for controlling endoparasites also form part of the subject matter of the invention.
The present invention provides in particular:
1. Cyclic thiodepsipeptides of the general formula (I) and salts thereof
in which
R
1
, R
4
, R
7
and R
10
each represent independently of one another hydrogen, straight-chain or branched C
1-4
-alkyl,
R
2
, R
5
, R
8
and R
11
each represent independently of one another hydrogen, straight-chain or branched C
1-8
-alkyl, C
1-8
-alkenyl, C
3-6
-cycloalkyl, C
3-6
-cycloalkyl-C
1-2
-alkyl, aryl-C
1-2
-alkyl, hetaryl-C
1-2
-alkyl, aryl or hetaryl, each of which is optionally substituted,
R
9
and R
10
together with the atoms that they are attached to represent a 5- or 6-membered ring which may optionally be substituted,
R
10
and R
11
together with the atoms that they are attached to represent a 5-, 6- or 7-membered ring which may optionally be interrupted by oxygen, sulfur, sulfoxy or sulfonyl and may optionally be substituted,
R
3
and R
9
each represent independently of one another hydrogen, C
1-8
-alkyl or aryl-C
1-2
-alkyl, C
3-6
-cycloalkyl-C
1-2
-alkyl,
R
6
and R
12
each represent independently of one another hydrogen, straight-chain or branched C
1-8
-alkyl, C
1-8
-alkenyl, C
3-6
-cycloalkyl, C
3-6
cycloalkyl-C
1-2
-alkyl, aryl-C
1-2
-alkyl, hetaryl-C
1-2
-alkyl, aryl or hetaryl, each of which is optionally substituted, and
X
1
, X
2
, X
3
and X
4
each represent independently of one another oxygen or sulfur, it being necessary for at least one of the radicals X
1
, X
2
, X
3
and X
4
to represent sulfur, and their optical isomers and racemates.
2. The novel cyclic thiodepsipeptides of the general formula (I) and salts thereof
in which
R
1
to R
12
and X
1
to X
4
are as defined under 1 are prepared by thionating the depsipeptides of the general formula (II) and salts thereof
in which
R
1
to R
12
and X
1
to X
4
are as defined under 1
in the presence of a suitable sulfurizing agent and in the presence of the suitable diluent.
Depending on the kind of the substituents, the compounds of the general formula (I) can be present as mixtures of geometrical and/or optical isomers of various compositions. The invention relates to the pure isomers and also the mixtures of isomers.
Preference is given to cyclic thiodepsipeptides comprising amino acids, hydroxythiocarboxylic acids and optionally hydroxycarboxylic acids as ring building blocks and having 24 ring atoms, of the general formula (I) and salts thereof
in which
R
1
, R
4
, R
7
and R
10
each represent straight-chain or branched C
1-4
-alkyl, in particular methyl,
R
2
, R
5
, R
8
and R
11
each represent C
1-4
-alkyl, in particular isobutyl,
R
3
and R
9
each represent independently of one another C
1-4
-alkyl or aryl-C
1-2
-alkyl, in particular benzyl,
R
6
and R
12
each represent independently of one another C
1-4
-alkyl, hetaryl-C
1-2
-alkyl, C
1-4
-alkoxycarbonylmethyl, aryl-C
1-2
-alkyl, in particular benzyl, suitable substituents including hydrogen, halogen, cyano, carbamoyl, C
1-4
-alkyl, hydroxyl or hydroxyl carrying a protecting group, C
1-8
-alkoxy, C
1-4
-alkoxy-C
1-4
-alkoxy, C
2-4
-alkenyloxy, hetaryl-C
1-4
-alkoxy where the heterocycles may in turn be substituted, nitro, amino or amino carrying a protecting group, amino-C
1-6
-alkoxy or amino-C
1-6
-alkoxy carrying a protecting group, n-mono-C
1-6
-alkyl-amino-C
1-6
-alkoxy, N-methylamino-N,N-di-C
1-6
-alkylamino-C
1-6
-alkoxy, N,N-di-[(C
1-6
-alkoxy-C
1-6
-alkyl)]amino-C
1-6
-alkoxy, C
1-4
-alkylamino, C
1-4
-dialkylamino, N,N-di[(C
1-6
-alkoxy-C
1-6
-alkyl)]amino-sulfonyl, C
1-4
-dialkyl-amino-sulfonyl, sulfamidyl, C
3-7
-cycloalkylamino-C
1-6
-alkylamino-sulfonyl, C
3-7
-cycloalkyl-amino-C
1-6
-alkoxy, C
3-7
-cycloalkylamino-sulfonyl, C
3-7
-cyclo-alkylamino- (where each cycloalkyl may contain one or more nitrogen atoms as ring-forming atoms and additionally oxygen or sulfuir atoms), and
(i)
X
1
represents sulfur,
X
2
, X
3
and X
4
each represent independently of one another oxygen or sulfur, or
(ii)
X
2
represents sulfur,
X
1
, X
3
and X
4
each represent independently of one another oxygen or sulfur, or
(iii)
X
3
represents sulfur,
X
1
, X
2
and X
4
each represent independently of one another oxygen or su

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