Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Novel cvcloiminodepsiuentides, processes for their preparation and their use
for
controlling endoparasites
The present invention relates to cycloiminodepsipeptides, in particular 24-
membered
cycloiminodepsipeptides, to processes for their preparation and to their use
for
controlling endoparasites.
The interesting backbone modifications of peptides, which are carried out in
particular to reduce their lability to enzymatic hydrolysis, include, in
addition to the
exchange of the amide oxygen for sulfur, without any doubt also the exchange
of
amide oxygen for an optionally substituted imino grouping.
Naturally occurring peptides having an iminopeptide bond or an amidine
grouping in
the molecule are extremely rare. Examples which may be mentioned are
bottromycin,
a peptide antibiotic from Str~tomyces bottropensis, amidinomycin and netropsin
(J.
M. Waiswisz et al., J. Am. Chem. Soc. 79, 1957, p. 4520; S. Nakamura Chem.
Pharm. Bull. 9, 1961, p. 641; S. Nakamura et al., J. Antibiot. 17A, 1964, p.
220).
Methods for introducing optionally substituted imino functions into synthetic
peptides are known from the literature. Examples which may be mentioned here
are
,.....
the syntheses of amidoxime, cyanamidine and amidrazone analogs of chemotactic
peptides (G. Sauve et al., Can. J. Chem. 61, 1985, p. 3089). Chemotactic
peptides of
the N-formyl-methionyl-leucyl-phenylalanine (f Met-Leu-Phe-OR) type are of
interest as bioregulator prototypes of immune cells - they induce, for
example, the
release of lysozyme from human neutrophiles (S. V. Rao et al., Spectroscopy
(Ottawa) 4 (3), 1985, p. 153; B. Belleau et al., Int. J. Immunopharmacol. 11
(S),
1989, p. 467; E. Schiffmann et al., Proc. Natl. Acad. Sci. U.S.A. 72, 1975, p.
1059;
R. J. Freer et al., Biochemistry 21, 1982, p. 257). H. A. Moynihan et al. have
described a preparation variant of Nw-hydroxy-N'~-methyl-L-arginine, a novel
NO
synthase inhibiter (J. Chem. Soc. Perkin Traps. I 1994, p. 769). Suitable
starting
materials for preparing the iminopeptides mentioned further above are,
according to
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G. Sauve et al. or H. A. Moynihan et al., preferably the corresponding
endothiopeptides.
Also known is the synthesis of iminodipeptides from corresponding a-amino-
nitrites
(cf. N-benzyloxycarbonyl-irninodipeptides: W. Ried et al. Chem. Ber. 95, 1962,
p. 728; Ann. Chem. 661, 1963, p. 76; T. Yamada et al., Bull. Chem. Soc. Jpn.
50 (5),
1977, p. 1088; analogs of N-phthalyl(iminoglycyl)-(S)-valine: E. Vargha et al.
Studia
Univ. Babes-Bolyai, Ser. Chem. 11, 1966, p. 85, ref. Chem. Abstr. 66, 1967,
2757).
Poly(dipeptamidines) in which the carbonyl oxygen of every second peptidic
amide
group is replaced by an imine nitrogen have been prepared as comparison
products
for the oligomerization of a-amino-nitrites (cf. A. Eschenmoser et al., Helv.
Chim.
Acta 69, 1986, p. 1224).
In contrast to the processes already mentioned for preparing various N-
substituted
iminopeptides, nothing has been disclosed concerning the preparation of
cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic
acids
and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids.
~...,.
In particular, nothing has hitherto been disclosed concerning the preparation
of
cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic
acids
and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring
building
blocks and 24 ring atoms from corresponding cyclothiodepsipeptides.
Cyclic depsipeptides and their preparation and use as endoparasiticides have
already
been the subject of numerous publications.
A cyclodepsipeptide with the name PF 1022A, for example, and its action
against
endoparasites is already known (EP-A 382 173 and EP-A 503 538)
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Further cyclic depsipeptides (cyclooctadepsipeptides: WO 98/55 469;
WO 98/43 965; WO 98/15 523; WO 98/37 088; WO 97/02 256; WO 97/09 331;
WO 96/11 945; WO 95/07 272; WO 94/19 334; WO 93119 053; EP-A 634 408;
EP-A 626 375; EP-A 626 376; EP-A 664 297; EP-A 6:34 408; EP-A 718 298;
WO 97/09 331; cyclohexadepsipeptides: WO 93/25 543; WO 95/27 498;
EP-A 658 551; cyclotetradepsipeptides: EP-A 664 297; dioxomorpholines:
WO 96/38 165; JP 08 225 552) and open-chain depsipeptides (EP-A 657 171;
EP-A 657 172; EP-A 657 173; WO 97/07 093) and their endoparasiticidal action
have been described.
Cyclothiodepsipeptides consisting of amino acids, hydroxythiocarboxylic acids
and
optionally hydroxycarboxylic acids as ring building blocks and 24 ring atoms,
their
preparation and their use for controlling endoparasites are subject of an
earlier patent
application (WO 98/43 965) of the applicant.
In addition to the novel cycloiminodepsipeptides, the present invention also
provides
a process for preparing cycloiminodepsipeptides, in particular
cycloiminodepsipeptides consisting of amino acids, hydroxyiminocarboxylic
acids
and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring
building
blocks and 24 ring atoms.
The invention also provides the use of cycloiminodepsipeptides, in particular
of
cycloiminodepsipeptides consisting of amino acids, hydroxyaminocarbvxylic
acids
and optionally hydroxycarboxylic acids, hydroxythiocarboxylic acids as ring
building
blocks and 24 ring atoms for preparing compositions for controlling
endoparasites.
The present invention relates in particular to:
1. Cycloiminodepsipeptides of the general formula (I)
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R'Z O
X ~ ~ R"
~C O
RZ N R~ R~o~N'C~X3
O ~' R9
O O
R3.,_ / O
''~ R4 R~
Ra n)
Rs~O~C:Xz
[O' R6
in which
Rl, R4, R' and R1° independently of one another represent hydrogen,
straight-chain or
branched alkyl,
R2, R5, R8 and R" independently of one another represent hydrogen, optionally
substituted straight-chain or branched alkyl, alkenyl, cycloalkyl,
cycloalkylalkyl, arylalkyl, hetarylalkyl and also aryl or hetaryl,
R1° and R" together with the atoms to which they are attached
represent an
optionally substituted 5- or 6-membered ring which may optionally be
interrupted by oxygen, sulfur, sulfoxy or sulfonyl,
R6 and R~Z independently of one another represent hydrogen, optionally
substituted alkyl or arylalkyl, and also optionally substituted
cycloalkylalkyl,
R3 and R9 independently of one another represent hydrogen, optionally
substituted straight-chain or branched alkyl, alkenyl, cycloalkyl,
alkoxycarbonylalkyl, cycloalkylalkyl, arylalkyl, hetarylalkyl, aryl or
hetaryl,
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and
C=X', C=X2, C=X3 and C=X4 independently of one another each represent
one of the groups C=O, C=S or CHZ or a group C=N-A, where at least one of
the groups C=X~, C=X2, C=X3 and C=X4 must represent C=N-A,
in which
A represents hydrogen, optionally substituted alkyl, alkenyl, alkinyl,
.-..
alkylcarbonyl, alkylsulfonyl, and also cyano, nitro, carbamoyl,
alkoxycarbonyl, formyl, -(C=NH)-NH2, -P(O)-O-alkyl, -P(S)-O-alkyl
or optionally represents a radical A'
-Y-R~3 (A')
in which
Y represents oxygen, sulfur or -N-R~4,
R'3 and R14 independently of one another represent hydrogen, optionally
substituted
- straight-chain or branched, alkyl, alkenyl, alkinyl, cycloalkyl, cyclo-
~""..
alkylalkyl, arylalkyl, hetarylalkyl, aryl or hetaryl and also represent
formyl,
alkoxydicarbonyl, alkylsulfonyl, haloalkoxyalkylsulfonyl, alkoxycarbonyl,
alkylaminocarbonyl, alkenyloxycarbonyl, alkinyloxycarbonyl, aryloxyalkyl,
hetarylcarbonyl,alkylcarbonyl or optionally represent a radical from the group
consisting of BI, BZ, B3 and B4,
Z O
I I
Y
Q ~ G ~ (CNR~s~n- 1 Rya i
(B ) (B )
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Rz, O
O I
,a~Y,,~'~ O~G~N:
R i~ II R R
,s R2o
R (B3) Z (8a)
in which
Q represents optionally substituted straight-chain or branched alkyl, alkenyl,
alkinyl, cycloalkyl, alkoxy, alkenyloxy, alkinyloxy, cycloalkoxy, aryloxy,
arylalkoxy, hetaryloxy, hetarylalkoxy, alkylthio, alkenylthio, alkinylthio,
cycloalkylthio, arylthio, arylalkylthio, hetarylthio, hetarylalkylthio, alkyl-
amino, alkenylamino, alkinylamino, cycloalkylamino, arylamino, arylalkyl-
amino, hetarylamino, hetarylalkylamino, dialkylamino, dialkenylamino, aryl,
arylalkyl, hetaryl or hetarylalkyl, cyano, amino or an optionally substituted
cyclic amino group which is attached via nitrogen,
Z
I I
G
~'' represents carboxyl, thiocarboxyl, sulfoxy, sulfonyl, -P(O)-O-alkyl,
, -P(S)-O-alkyl or -C=N-Rls,
R's represents hydrogen, hydroxyl, alkoxy, alkylcarbonyl, alkoxycarbonyl,
haloalkylcarbonyl, alkylsulfonyl, nitro or cyano,
R'6 represents hydrogen or alkyl,
n represents 0, 1 or 2,
Y' represents oxygen or sulfur or -N-R'7,
R~8 represents, if YI represents nitrogen, a cyclic amino group which is
attached via this nitrogen atom,
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R" and R~g independently of one another represent hydrogen, optionally
substituted
straight-chain or branched alkyl, alkenyl, alkinyl, cycloalkyl,
cycloalkylalkyl,
alkoxycarbonyl, aryl, arylalkyl, hetaryl or hetarylalkyl, or
S R1' and R'8 together with the adjacent N atom represent an optionally
substituted
heterocyclic 4-, 5-, 6- or 7-membered ring system or represent an optionally
substituted 7- to 10-membered bicyclic ring system which may optionally also
be interrupted by oxygen, sulfur, sulfoxyl, sulfonyl, carbonyl, -N-O, -N=,
-NR22 or by quaternary nitrogen,
R19 and RZ° independently of one another represent hydrogen, straight-
chain or
branched alkyl, alkenyl, cycloalkyl and also optionally substituted aryl,
arylalkyl, hetaryl, hetarylalkyl, or
R19 and RZ° together represent an optionally substituted
spirocyclic ring,
R2° and RZ~ together with the atoms to which they are attached
represent an
optionally substituted 5-, 6- or 7-membered ring which may optionally be
interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,
R2' represents hydrogen, optionally substituted straight-chain or branched
alkyl, cycloalkyl, arylalkyl, hetarylalkyl, and also aryl or hetaryl,
R22 represents hydrogen, optionally substituted straight-chain or branched
alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl,
alkylcarbonyl, cycloalkylcarbonyl, cyano, arylalkyl, hetaryialkyl, and
also aryl or hetaryl,
R13 may also represent a protective group which can be removed
selectively, or a polymeric support which is attached to Y via an
anchor group which can be removed selectively,
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_g_
and to the pure optical isomers, racemates and physiologically acceptable
salts
thereof,
for controlling endoparasites in medicine and veterinary medicine.
Depending on the nature of the substituents, the compounds of the general
formula
(I) can exist as geometrical and/or optical isomer mixtures and also as
mixtures of
regioisomers of varying compositions. The invention relates both to the pure
isomers
and to the isomer mixtures.
Preference is given to the cycloiminodepsipeptides consisting of amino acids,
hydroxyiminocarboxylic acids and optionally hydroxycarboxylic acids,
hydroxythiocarboxylic acids as ring building blocks and 24 ring atoms of the
general
formula (I)
1~
R' Z O
X'~ ,~ R"
~C O
R2 N R~ R,o N~C=Xa
Ra
O O
Rs l O
R4 R'
RB (I)
Rs~O~C:Xz
IOI ~R6
in which
R', R4, R' and R~° represent straight-chain or branched C»-alkyl, in
particular
2U methyl,
RZ, R5, R8 and RBI independently of one another represent Ci.~-alkyl, in
particular
isobutyl,
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R6 and R12 independently of one another represent optionally substituted C,~-
alkyl or aryl-C,_2-alkyl, in particular optionally substituted benzyl,
R3 and R9 independently of one another represent optionally C,.~-alkyl,
S hetaryl-C,_2-alkyl, C,-C4-alkoxycarbonylmethyl, aryl-C,_2-alkyl, in
particular optionally substituted benzyl,
substituents that may be mentioned being hydrogen, halogen, cyano,
carbamoyl, Cite-alkyl, hydroxyl which carries a protective group or
unprotected hydroxyl, C i _g-alkoxy, C 1 ~,-alkoxy-C, ~,-alkoxy, Cz.~-
alkenyloxy, hetaryl-CL~-alkoxy, where the heterocycles for their part
may be substituted, nitro,
or
IS
a radical from the group consisting of R23R24N_CI-C6_alkoxy,
R23R24N-C1_Cg-alkyl, NR23R24 and -SOZ-NR23R24, in which
R23 and R24 independently of one another each represent hydrogen,
C~-C6-alkyl, CI-C6-alkoxy-C~-C6-alkyl, C3-C~-cycloalkyl,
C3-C~-cycloalkylamino-C~-C6-alkyl, wherein the cycloalkyl
ring one or more carbon atoms may also be replaced by
nitrogen, oxygen or sulfur atoms, hetaryl-C1-C4-alkyl or a
protective group, or
2S
R23 and R24 together with the nitrogen atom to which they are
attached represent hetaryl or heterocycloalkyl, in particular N
pyrrolidino, N-piperazino, N-morpholino, N-thiomorpholino,
N-piperidino, N-imidazolo, 2-oxo-pyrrolidinyl, phthalimino or
tetrahydrophthalimino,
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and
( i ) C=X' represents a group C=N-A,
C=Xz, C=X3 and C=X4 represent C=O, C=S or CHZ,
or
( iii ) C=X3 represents a group C=N-A,
C=X1, C=X2 and C=X4 represents C=O, C=S or CHZ,
or
( iv ) C=X' and C=X3 represent a group C=N-A,
C=X2 and C=X4 represent C=O, C=S or CHZ,
in which
A represents hydrogen, optionally substituted C,~-alkyl, C2.~-alkenyl, C2_
4-alkinyl, C1-C4-alkylcarbonyl, C,_6-alkylsulfonyl and also cyano,
2U nitro, carbamoyl, CZ_6-alkoxycarbonyl, formyl, -(C=NH)-NH2, -P(O)-
O-C,_3-alkyl, -P(S)-O-CI_3-alkyl or optionally represents a radical A1
I'-R~3 (A~)
where
Y represents oxygen or -N-R~4,
R'3 and R~4 independently of one another represent hydrogen, optionally
substituted straight-chain or branched C1_8-alkyl, C2_g-alkenyl, C2_$
alkinyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C,_2-alkyl, aryl-C1_2-alkyl,
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hetaryl-C,_z-alkyl, aryl or hetaryl and also formyl, C~-Cg-alkylsulfonyl,
C~-C2-haloalkoxy-Ct-2-alkylsulfonyl, C~-Cg-alkylcarbonyl, C1-Cg-
alkoxycarbonyl, C1-Cg-alkylaminocarbonyl, C2-Cg-alkenyloxy-
carbonyl, C2-C$-alkinyloxycarbonyl, aryloxy-Ct-CZ-alkyl, hetaryl-
carbonyl, Cite-alkoxydicarbonyl or optionally represent a radical from
the group consisting of B1, B2, B3 and B4
Z O
II tt
Y
Q~G~(CHR'6)n- ~ R,si ~,"is~
(B ) O (Bz)
R2~ O
O I 'I
,siY~ Q
R i~ I ( ' 9 Ri''''o
R~9 Rio (B3) Z R (B4)
in which
Q represents optionally substituted straight-chain or branched C1_g-alkyl,
C2_g-alkenyl, C2_g-alkinyl, C3_~-cycloalkyl, C,_6-alkoxy, C2_6-
- alkenyloxy, C2~-alkinyloxy, C3_~-cycloalkoxy, aryloxy, aryl-C,_2-
_.,
alkoxy, hetaryloxy, hetaryl-Ci_2-alkoxy, C~_6-alkylthio, C2~-alkenyl-
thio, C2_6-alkinylthio, C3_~-cycloalkyl-thio, arylthio, aryl-C1_2-alkylthio,
hetarylthio, hetaryl-Ci_2-alkylthio, C~_6-alkylamino, C2~-alkenylamino,
CZ_6-alkinylamino, C3~-cyclo-alkylamino, arylamino, aryl-C,_2-alkyl-
amino, hetarylamino, hetaryl-CI_Z-alkylamino, di-C,~-alkylamino, di-
C2.~-alkenylamino, aryl, aryl- C1_2-alkyl, hetaryl, hetaryl-C~-C2-alkyl
and also cyano, amino or an optionally substituted cyclic amino group
which is attached via nitrogen,
Z
I I
G
~ ~ represents thiocarboxyl or carboxyl,
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R15 represents hydrogen, hydroxyl, C1.~-alkoxy, C»-alkylcarbonyl, Ci.~-
alkoxycarbonyl, halogeno-C,.~-alkylcarbonyl, CIA-alkylsulfonyl, nitro
or cyano,
R~6 represents hydrogen or C~.~-alkyl,
n represents 0, 1 or 2,
Y' represents oxygen, sulfur or -N-R~~,
RIg represents, if Y1 represents nitrogen, a cyclic amino group which is
attached via this nitrogen atom,
R~~ and R~g independently of one another represent hydrogen, optionally
substituted
straight-chain or branched Cite-alkyl, CZ~-alkenyl, C2~-alkinyl, C3_~-
cycloalkyl, C3_~-cycloalkyl-C1~-alkyl, C~_6-alkoxycarbonyl, aryl, aryl-CI_Z-
alkyl, hetaryl, hetaryl-C,_2-alkyl, or
R" and R1g together with the adjacent N atom represent an optionally
substituted
~ heterocyclic 4-, 5-, 6- or 7-membered ring system or represent an optionally
7- to 10-membered bicyclic ring system which may optionally also be
interrupted by oxygen, sulfur, sulfoxyl, sulfonyl, carbonyl, -N-O, -N=, -NR22
or by quaternary nitrogen,
R~9 and R2° independently of one another represent hydrogen, optionally
substituted
straight-chain or branched CL~-alkyl, CZ_6-alkenyl, (:3_~-cycloalkyl and also
optionally substituted aryl, aryl-C1_2-alkyl, hetaryl, hetaryl-C,_2-alkyl, or
R~9 and R2° together represent an optionally substituted spirocyclic
ring,
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RZ° and R2~ together with the atoms to which they are attached
represent an
optionally substituted S-6- or 7-membered ring which may optionally be
interrupted by oxygen, sulfur, sulfoxyl, sulfonyl,
S R2' represents hydrogen, optionally substituted straight-chain or branched
C,~-alkyl, C3.~-cycloalkyl, aryl-C1_2-alkyl, hetaryl-C,_2-alkyl, and also
aryl or hetaryl,
R22 represents hydrogen, optionally substituted straight-chain or branched
C,_6-alkyl, C2~-alkenyl, C2_6-alkinyl, C3_~-cycloalkyl, C3_~-cycloalkyl-
C~.~-alkyl, C»-alkoxycarbonyl, C~_6-alkylcarbonyl, C3_~-
cycloalkylcarbonyl, cyano, aryl-C,_z-alkyl, hetaryl-Ct_Z-alkyl, and also
aryl or hetaryl,
1S R~3 also represents a protective group which can be removed selectively,
for example allyl, allyloxycarbonyl (Alloc), benzyl (Bn),
benzyloxycarbonyl (Z), tert-butyloxycarbonyl (Boc), tetrahydropyran
2-yl (THP) or fluorenylmethoxycarbonyl (Fmoc) and also represents a
polymeric support which is attached to Y via an anchor group which
= can be removed selectively,
and optical isomers, racemates and physiologically acceptable salts thereof.
The general formula (I) provides a general definition of the
cycloiminodepsipeptides
2S according to the invention and their salts.
The cycloiminodepsipeptides according to the invention and their acid addition
salts
and metal salt complexes have good endoparasiticidal, in particular
anthelmintic,
action and can preferably be used in the field of veterinary medicine.
2. Process 1 for preparing the novel compounds of the general formula (I)
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R~2 O
X~~~ ~R~~
O
R2 N N , . X3
~R~ Rio C.
~R9
O
O O
R3 / O
'( R4 R~
X'~~C'N~ \N R8 (
R II O I C: X2
O R6 and salts thereof,
"""~' in which
RI to R'2 and the groups C=X1 to C=X4 have the meanings given in point 1,
characterized in that
cyclothiodepsipeptides of the general formula ( I )
R~2 O
X\C~O~R~1
R2 N~R~ io ~C Xs
,"~., R ~
O / _R9
O O
R3_ / O
'( R4 R~
X'~'C'N~ \N R8 (I)
R II OYC:X2
O R6 and salts thereof,
in which
RI to RI2 have the meanings given in point 1, and
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C=X', C=X2, C=X3 and C=X4 independently of one another represent C=O, C=S or
CH2, where at least one of the groups C=X', C=X2, C=X3 and C=X4 has to
represent
a C=S group,
are reacted with amino compounds of the general formula (II}
H2N-A (II)
in which
A has the meanings given in point 1
in the presence of suitable metal salts or metal oxides, in particular mercury
(II)
acetate, mercury(II) chloride or mercury(II) oxide, in the presence of a basic
reaction
auxiliary and in the presence of a suitable diluent.
The process according to the invention relates in particular and preferably to
the
preparation of the novel cycloiminodepsipeptides of the general formula (Ia)
A R~2 O
"~°. N '\C~ O ~ R 11
R2 N N O
~R~ Rio
O R9
O O
R3 O
R4 R~
O N~ \N R8 (Ia)
R~O~O
O Rs and salts thereof,
in which
A and R~ to R~z have the meanings given in point 1.
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The process 2 according to the invention for preparing the novel and preferred
cycloiminodepsipeptides of the general formula (Ia) and salts thereof is
characterized
in that
a) the cyclothiodepsipeptides of the general formula (Ib) or salts thereof,
R~2 O
S'C~O~Ro
R2 N ' ~N' O
~T. ~R~ Rio
O R9
O O
R3 O
~ ~Ra R~
O' -N N R8 (
R~'O~O
O R6
in which
R' to R'2 have the meanings given in point 1
are reacted with amino compounds of the general formula (II)
H2N-A (II)
1 S in which
A has the meanings given in point 1
in the presence of suitable metal salts or metal oxides, in particular mercury
(II)
2U acetate, mercury (II) chloride or mercury(II) oxide, and in the presence of
a basic
reaction auxiliary and in the presence of a suitable diluent, or
b) for preparing the novel cycloiminodepsipeptides of the general formula (Ia)
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A R~2 O
N1~C~O~R~~
R2 N N O
~R~ Rio
O~ R9
O O
R3 O
,R4 R\
O N N R$ (Ia)
R~p~O
O R6 and salts thereof,
in which
S R1 to R12 have the meanings mentioned in point 1,
A represents a radical -Y-R'3 (A'),
in which
Y has the meaning given in point l,
°'~ R'3 represents radicals from the group consisting of B' to B3
O O
I I
/G~(CHR'6)n- R~siYvS\ R~s~Y
Q (B~) O (B2) R,s Rio (B3)
in which
Z
G
~ , Q, Y', n, R~6, and Rl8-R2° have the meanings given in point 1,
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the novel cycloiminodepsipeptides of the general formula (Ic) obtained by
processes
2a) and 3 according to the invention
H~Y R~2 O
N',C~O~R~~
RZ N N O
~R~ Rio
O~ R9
O O
R3 O
R4 R~
O N~ 'N R8 (Ic) and salts thereof,
R~O~O
O R6
in which
Y and R~ to R~2 have the meanings given in point 1,
are reacted with compounds of the general formula ( IIIa-c )
Z O O
~~.~ G Rya ~- Y ~ S R, a ~. Y'
i w ~s II'W ~W
(CHR )n-W
O (~) R,s Rio (IIIc)
in which
Z
G
~ , Q, Y', n, R~6, and RI8-RZ° have the meanings given in point 1,
W represents a suitable leaving group, such as, for example, halogen,
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if appropriate in the presence of a catalyst, if appropriate in the presence
of a basic
reaction auxiliary and if appropriate in the presence of diluents, or
c) to prepare the novel cycloiminodepsipeptides of the general formula (Ia)
and
salts thereof,
in which A represents a radical -Y-R'3 (A')
in which
Y has the meanings given in point 1,
R13 represents radicals from the group consisting of B~ and B3
Z O
Y /~
18 /
(~ ~ G ~ (CHR'6)n- B~ R R1s R2o
( ) (83)
in which
Q, Y1, n, R1g-R2° have the meanings given in point 1,
n represents 0,
Z
G
and the group ~ ~ represents carboxyl,
the compounds of the general formula (Ic) and salts thereof
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H~Y R~2 O
N'C~O~R~~
R2 N N O
~R~ Rio
O~ R9
O O
R3 O
R4 R~
O N~ \N R$ (IC)
R~O~O
O R6
in which
Y and R~ to RIZ have the meanings given in point 1
are reacted with a carboxylic anhydride of the general formula (IV)
(Q-CO)ZO (IV)
in which
Q has the meaning given in point 1 or
f
R,e~Y
R~9 ~R2o
represents the radical
1 S in which
Yl, R'$-R2° have the meaning given in point 1,
if appropriate in the presence of a catalyst, if appropriate in the presence
of a
basic reaction auxiliary and if appropriate in the presence of diluents, or
d) by reacting compounds of the general formula (Ic)
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a) with amino acid derivatives of the general formula (V)
R2~ O
Q~G~N
i~ OH
II R~s Rzo (V)
Z
in which
S
Z
I I
G
~ , Q, and R'9 to RZ~ have the meaning given in point 1
if appropriate in the presence of coupling agents and if appropriate in the
presence of
a basic reaction auxiliary and also, if appropriate, in the presence of
diluents, or
1U
~3) with compounds of the general formulae (VI) and (VII)
Z
R15
i G ~. N=C=Y
Ris-N=C=Y (VI) Y (VII)
15 in which
Z
I I
G
~ , Y and R15 have the meaning given in point 1,
if appropriate in the presence of a basic reaction auxiliary or a catalyst, if
appropriate
20 in the presence of diluents.
The invention furthermore relates to:
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3. Process 3 for preparing cycloiminodepsipeptides of the general formula (Ic)
and salts thereof,
HAY R~2 O
~Rii
O
R2 N N O
~R~ Rio
O~ R9
O O
R3 O
R4 R~
O~N~ \N R8 (IC)
R~O~O
O R6
in which
Y and R~ to R12 have the meanings given in pointl,
characterized in that
1U
a) from the cycloiminodepsipeptides of the general formula (Ia) obtainable
according to process 2a and salts thereof,
A R~2 O
N'~C~O~R»
R2 N N O
R~ Rio
O R9
O O
R3 O
/ R4 R;
O N N R8 (Ia)
R~O~O
O R6
in which
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Rl to R12 have the meanings given in point 1,
A represents a radical -Y-R~3 (A~),
in which
Y represents oxygen or -N-H,
R13 represents a protective group which can be removed selectively, for
example, allyl, allyloxy-carbonyl (Alloc), benzyl (Bn),
benzyloxycarbonyl (Z), tert-butyloxycarbonyl (Boc), tetrahydropyran-
2-yl (THP) or in fluorenylmethoxycarbonyl (Fmoc),
the radical R13 is selectively removed, depending on the removable protective
group
either in the presence of a hydrogenation catalyst, in the presence of a
protic acid or a
basic reaction auxiliary and in the presence of a diluent,
or
b) - from the cycloiminodepsipeptides of the general formula (Ia), attached to
a
polymeric support, which are obtainable by process 2a, and salts thereof,
A R~2 O
~Ro
O
R2 N N O
~R~ Rio
O R9
O O
3 O
R Ra R7
O N ~ \N R a (Ia)
R~O'~O
O 'R6
in which
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R' to R'2 have the meanings given in point 1,
A represents a radical -Y-R'3 (A')
in which
Y represents oxygen or -N-H,
R'3 represents a selectively removable anchor group on a polymeric support,
the compounds of the formula (Ic) are released by selective removal of the
anchor
group from the polymeric support R13 in the presence of a suitable catalyst or
in the
presence of a protic acid and in the presence of a diluent.
The general formula (I) provides a general definition of the
cycloiminodepsipeptides
according to the invention and their salts.
The cycloiminodepsipeptides according to the invention and their acid addition
salts
and metal salt complexes have good endoparasiticidal, in particular
anthelmintic,
action and can preferably be used in the field of veterinary medicine.
The definitions of terms below apply to all of the general formulae and
descriptions
mentioned above or below.
Optionally substituted alkyl, alone or as component of a radical in the
general
formulae, represents straight-chain or branched alkyl having preferably 1 to
6, in
particular 1 to 4, carbon atoms. Examples which may be mentioned are
optionally
substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tent-butyl,
pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-
dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-
methyl-
pentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
2,3-
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dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-
trimethylpropyl, 1,2,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl
and
ethylbutyl.
Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-
butyl may be
mentioned as being preferred.
Optionally substituted alkenyl, alone or as component of a radical in the
general
formulae, represents straight-chain or branched alkenyl having preferably 1 to
6, in
particular 1 to 4, carbon atoms. Examples which may be mentioned are
optionally
substituted vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-
methyl-2-
propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-
butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-
3-
butenyl, 1,1-dimethyl- 2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl,
2-
hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-
pentenyl,
3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-
pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-
methyl-
4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-
butenyl,
1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-
dirilethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-
butenyl, 2-
ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-
methyl-2-
propenyl and 1-ethyl-2-methyl-2-propenyl.
Optionally substituted ethenyl, 2-propenyl, 2-butenyl or 1-methyl-2-propenyl
may be
mentioned as being preferred.
Optionally substituted alkinyl, alone or as component of a radical in the
general
formulae, represents straight-chain or branched alkinyl having preferably 1 to
6, in
particular 1 to 4, carbon atoms. Examples which may be mentioned are
optionally
substituted ethinyl, 2-propinyl, 2-butinyl, 3-butinyl, 1-methyl-2-propinyl, 2-
pentinyl,
3-pentinyl, 4-pentinyl, 1-methyl-3-butinyl, 2-methyl-3-butinyl, 1-methyl-2-
butinyl,
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1,1-dimethyl-2-propinyl, 1-ethyl-2-propinyl, 2-hexinyl, 3-hexinyl, 4-hexinyl,
5
hexinyl, 1-methyl-2-pentinyl, 1-methyl-3-pentinyl, 1-methyl-4-pentinyl, 2-
methyl-3
pentinyl, 2-methyl-4-pentinyl, 3-methyl-4-pentinyl, 4-methyl-2-pentinyl, l,l
dimethyl-3-butinyl, 1,2-dimethyl-3-butinyl, 2,2-dimethyl-3-butinyl, 1-ethyl-3-
butinyl,
2-ethyl-3-butinyl and 1-ethyl-1-methyl-2-propinyl.
Optionally substituted ethinyl, 2-propinyl or 2-butinyl may be mentioned as
being
preferred.
Optionally substituted cycloalkyl, alone or as component of a radical in the
general
formulae, represents mono-, bi- and tricyclic cycloalkyl, preferably having 3
to 10, in
particular 3, 5 or 7, carbon atoms. Examples which may be mentioned are
optionally
substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclo-hexyl, cycloheptyl,
cyclooctyl,
bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and adamantyl.
Halogenoalkyl, alone or as component of a radical in the general formulae,
contains 1
to 4, in particular 1 or 2, carbon atoms having preferably 1 to 9, in
particular 1 to S,
identical or different halogen atoms, preferably fluorine, chlorine or
bromine, in
particular fluorine or chlorine. Examples which may be mentioned are
trifl~oromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl,
chloromethyl, bromomethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-
trifluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl,
pentafluoroethyl and
pentafluoro-tert-butyl.
Optionally substituted alkoxy, alone or as component of a radical in the
general
formulae, represents straight-chain or branched alkoxy having preferably 1 to
6, in
particular 1 to 4, carbon atoms. Examples which may be mentioned are
optionally
substituted methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-
butoxy and tert-butoxy.
Optionally substituted alkoxyalkoxy, alone or as component of a radical in the
general formulae, represents 2 alkoxy radicals as mentioned above which are C-
O-
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attached to each other. Examples which may be mentioned are optionally
substituted
methoxymethoxy, methoxyethoxy, methoxy-n-propoxy and ethoxyisopropoxy.
Optionally substituted alkoxyalkoxyalkoxy, alone or as component of a radical
in the
general formulae, represents 3 alkoxy radicals as mentioned above which are in
each
case C-O-attached to each other. Examples which may be mentioned are
optionally
substituted methoxymethoxyethoxy, methoxyethoxyethoxy and methoxyethoxy-n-
propoxy.
Optionally substituted halogenoalkoxy, alone or as component of a radical in
the
general formulae, represents straight-chain or branched halogenoalkoxy having
preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be
mentioned are optionally substituted difluoromethoxy, trifluoromethoxy,
trichloromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-
difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy and 2-chloro-
1,1,2-
trifluoroethoxy.
Optionally substituted alkylthio, alone or as component of a radical in the
general
formulae, represents straight-chain or branched alkylthio having preferably 1
to 6, in
particular 1 to 4, carbon atoms. Examples which may be mentioned are
optionally
substituted methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,
isobutylthio, sec-butylthio and tert-butylthio.
Optionally substituted halogenoalkylthio, alone or as component of a radical
in the
general formulae, represents straight-chain or branched halogenoalkylthio
having
preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be
mentioned are optionally substituted difluoromethylthio, trifluoromethylthio,
trichloromethylthio, chlorodifluoromethylthio, 1-fluoroethylthio, 2-
fluoroethylthio,
2,2-difluoroethylthio, 1,1,2,2-tetrafluoroethylthio, 2,2,2-trifluoroethylthio
and 2
chloro-1,1,2-trifluoroethylthio.
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Optionally substituted alkylcarbonyl, alone or as component of a radical in
the
general formulae, represents straight-chain or branched alkylcarbonyl having
preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be
mentioned are optionally substituted methylcarbonyl, ethylcarbonyl, n
propylcarbonyl, isopropylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl.
Optionally substituted cycloalkylcarbonyl, alone or as component of a radical
in the
general formulae, represents mono-, bi- and tricyclic cycloalkylcarbonyl,
having
preferably 3 to 10, in particular 3, 5 or 7, carbon atoms. Examples which may
be
mentioned are optionally substituted cyclopropylcarbonyl, cyclobutylcarbonyl,
cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl,
cyclooctylcarbonyl,
bicyclo[2.2.1]heptylcarbonyl, bicyclo[2.2.2]octylcarbonyl and
adamantylcarbonyl.
Optionally substituted alkoxycarbonyl, alone or as component of a radical in
the
general formulae, represents straight-chain or branched alkoxycarbonyl having
preferably 2 to 7, in particular 2 to 5, carbon atoms. Examples which may be
mentioned are optionally substituted methoxycarbonyl, ethoxycarbonyl, n-
propoxy-
carbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxy-
carbonyl and tert-butoxycarbonyl.
Aryl is, for example, a mono-, bi- or polycyclic aromatic radical, such as
phenyl,
naphthyl, tetrahydronaphthyl, indanyl, fluorenyl and the like, but preferably
phenyl or
naphthyl.
Optionally substituted aryl in the general formula represents preferably
optionally
substituted phenyl or naphthyl, in particular phenyl.
Optionally substituted arylalkyl in the general formulae represents preferably
arylalkyl which is optionally substituted in the aryl moiety and/or alkyl and
has
3U preferably 6 or 10, in particular 6, carbon atoms in the aryl moiety
(preferably phenyl
or naphthyl, in particular phenyl) arid preferably 1 to 4, in particular 1 or
2, carbon
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atoms in the alkyl moiety, where the alkyl moiety may be straight-chain or
branched.
By way of example and by way of preference, optionally substituted benzyl and
1-
phenylethyl may be mentioned.
The optionally substituted radicals of the general formulae may carry one or
more,
preferably 1 to 3, in particular 1 to 2, identical or different substituents.
Substituents
which may be mentioned by way of example and by way of preference are:
Alkyl having preferably 1 to 4, in particular 1 to 2, carbon atoms, such as
methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl;
alkoxy having
preferably 1 to 4, in particular 1 to 2, carbon atoms, such as methoxy,
ethoxy, n-
propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy;
alkylthio,
such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,
isobutylthio,
sec-butylthio; halogenoalkyl having preferably 1 to 5, in particular 1 to 3,
halogen
atoms, where the halogen atoms are identical or different and halogen atoms
preferably represent fluorine, chlorine or bromine, in particular fluorine or
chlorine,
such as difluoromethyl, trifluoromethyl, trichloromethyl; hydroxyl, halogen,
preferably fluorine, chlorine, bromine and iodine, in particular fluorine and
chlorine,
cyano; nitro; amino; mono- and dialkylamino having preferably 1 to 4, in
particular 1
or 2; carbon atoms per alkyl group, such as methylamino, methylethylamino,
dimethylamino, n-propylamino, isopropylamino, methyl-n-butylamino;
alkylcarbonyl
radicals, such as methylcarbonyl; alkoxycarbonyl having preferably 2 to 4, in
particular 2 to 3, carbon atoms, such as methoxycarbonyl and ethoxycarbonyl;
alkylsulfinyl having 1 to 4, in particular 1 to 2, carbon atoms;
halogenoalkylsulfinyl
having 1 to 4, in particular 1 to 2, carbon atoms and 1 to 5 halogen atoms,
such as
trifluoromethylsulfinyl; halogenoalkylsulfonyl having 1 to 4, in particular 1
to 2,
carbon atoms and 1 to S halogen atoms, such as trifluoromethylsulfonyl,
perfluoro-n-
butylsulfonyl, perfluoroisobutylsulfonyl; arylsulfonyl having preferably 6 or
10 aryl
carbon atoms, such as phenylsulfonyl; acyl, aryl, aryloxy, which for their
part may
cant' one of the abovementioned
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substituents and the formimino radical (-HC=N-O-alkyl).
The number of these substituents is not limited, it is preferably from 1 to 4
identical
or different substituents. It is also possible for two identical or different
substituents
to be present at the same atom or at atoms of cyclic amino groups.
Optionally substituted mono- or dialkylamino groups, alone or as component of
a
radical in the general formulae, represents straight-chain or branched alkyl
having
preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples of substituted
mono-
or dialkylamino groups which may be mentioned are methylamino, ethylamino,
dimethylamino, diethylamino, di-n-propylamino, diisopropylamino or
dibutylamino.
Optionally substituted mono- or dialkoxyalkylamino groups, alone or as
component
of a radical in the general formulae, represents straight-chain or branched
alkoxyalkyl
having preferably I to 6, in particular 1 to 4, carbon atoms. Examples of
substituted
mono- or dialkoxyalkyl-amino groups which may be mentioned are methoxy-
methylamino, methoxyethylamino, di-(methoxymethyl)-amino or di-(methoxyethyl)-
amino.
Suitable cyclic amino groups are heteroaromatic or aliphatic ring systems
having one
or more nitrogen atoms as heteroatom, where the heterocycles may be saturated
or
unsaturated, be one ring system or a plurality of fused ring systems and may
optionally contain further heteroatoms, such as, for example, one or two
nitrogens,
oxygen and sulfur, etc. Moreover, cyclic amino groups may also represent a
spiro
ring or a bridged ring system. The number of atoms which form the cyclic amino
groups is not limited, in the case of a one ring system, for example, the
groups
consist of 3 to 8 atoms and in the case of a three-ring system, of 7 to 11
atoms.
Examples of cyclic amino groups having saturated and unsaturated monocyclic
groups having a nitrogen atom as heteroatom which may be mentioned are 1
azetidinyl, pyrrolidino, 2-pyrrolin-I-yl, 1-pyrrolyl, piperidino, 1,4-
dihydropyrazin-I
yl, 1,2,5,6-tetrahydropyrazin-1-yl, 1,4-dihydropyridin-I-yl, 1,2,5,6-
tetrahydropyridin-
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1-yl, homopiperidinyl; examples of cyclic amino groups having saturated and
unsaturated monocyclic groups having two or more nitrogen atoms as heteroatoms
which may be mentioned are 1-imidazolidinyl, 1-imidazolyl, 1-pyrazolyl, 1-
triazolyl,
1-tetrazolyl, 1-piperazinyl, 1-homopiperazinyl, 1,2-dihydro-pyridazin-1-yl,
1,2-di-
hydro-pyrimidin-1-yl, perhydropyrimidin-1-yl, 1,4-diazacyclo-heptan-1-yl;
examples
of cyclic amino groups having saturated and unsaturated monocyclic groups
having
one or two oxygen atoms and one to 3 nitrogen atoms as heteroatoms, such as,
for
example, oxazolidin-3-yl, 2,3-dihydroisoxazol-2-yl, isoxazol-2-yl, 1,2,3-
oxadiazin-2-
yl, morpholino, examples of cyclic amino groups having saturated and
unsaturated
monocyclic groups having one to three nitrogen atoms and one to two sulfur
atoms as
heteroatoms which may be mentioned are thiazolidin-3-yl, isothiazolin-2-yl,
thiomorpholino, or dioxothiomorpholino; examples of cyclic amino groups having
saturated and unsaturated fused cyclic groups which may be mentioned are indol-
1-
y1, 1,2-dihydrobenzimidazol-1-yl, perhydropyrrolo[1,2-a]pyrazin-2-yl; examples
of
cyclic amino groups having spirocyclic groups which may be mentioned are 2-
azaspiro[4,5]decan-2-yl; examples of cyclic amino groups having bridged
heterocyclic groups which may be mentioned are 2-azabicyclo[2,2,1 ]heptan-7-
yl.
Suitable monovalent amino protective groups are acyl groups having preferably
1 to
6, in 'particular 1 to 4, carbon atoms, such as, for example, formyl, acetyl,
propionyl,
pivaloyl, hexanoyl or mono- (or di- or tri-) halogen-containing acyl groups,
such as,
for example, 2-chloro-, 2-bromo-, 2-iodo-, 2,2-dichloroacetyl, 2,2,2-
trifluoroacetyl or
2,2,2-trichloroacetyl, alkoxycarbonyl groups having preferably 1 to 14, in
particular 1
to 4, carbon atoms, such as, for example, rnethoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, tert-butoxycarbonyl (Boc), tert-amyloxycarbonyl {Aoc),
hexyloxy-
carbonyl, methylsulfonylethoxycarbonyl, adamantyloxycarbonyl (Adoc) and 1-[1-
adamantyl]-1-methylethoxycarbonyl (Adpoc), carbamoyl groups, amyl groups, such
as, for example phenylacetyl and phenylpropionyl, aryloxycarbonyl groups, such
as,
for example, phenoxycarbonyl and naphthyloxycarbonyl, aryloxyalkanoyl groups,
such as, for example, phenoxyacetyl, and phenoxypropionyl, arylglyoxyloyl
groups,
such as, for example, phenylglyoxyloyl and naphthylglyoxyloyl, alkoxycarbonyl
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groups having customary substituents, such as, for example, benzyloxycarbonyl
(Cbo- or Cbz, Z), 4-methoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,
4-phenylazobenzyl-oxycarbonyl, phenethyloxycarbonyl, nitro-benzyloxycarbonyl,
chloro-benzyloxycar-bonyl, a,a-dimethyl-3,5-dimethoxy-benzyloxycarbonyl, 2-
nitro-
4,5-dimethoxy-benzyl-oxycarbonyl (Nvoc), fluorenyl-9-methoxycarbonyl (Fmoc),
substituted or unsubstituted alkylidene groups, such as, for example,
benzylidene,
hydroxybenzylidene, mono- (or di- or tri-) phenylalkyl-containing alkyl
groups, such
as, for example, benzyl, phenethyl, benzhydryl or triphenylmethyl (trityl) and
the
like. Suitable bivalent amino protective groups which may be are mono- or
disubstituted methylidene groups, such as 1-lower-alkoxy (for example methoxy
or
ethoxy)-lower alky-lidene (for example ethylidene or 1-n-butylidene), for
example
=C(CH3)(O-CZHS), furthermore, for example, =C(CH3)2 or =CH-phenyl, and in
particular bisacyl radicals, for example the phthalyl radical, which together
with the
nitrogen atom to be protected forms a 1H-isoindole-1,3(2H)-dione (phthalimide
group).
Amino protective group and their introduction and removal are known per se and
described, for example, in J. F. W. McOmie, "Protective Groups in Organic
Chemistry", Plenum Press, London, New York, 1973, and T. W. Greene,
"Protective
Groups in Organic Synthesis", Wiley, New York, 1984.
Suitable hydroxyl protective groups are optionally substituted alkyl groups
having
preferably 1 to 6, in particular 1 to 4, carbon atoms, such as, for example,
tent-butyl,
methylthiomethyl and trimethylsilyl, phenylalkyl-containing alkyl groups, such
as,
for example, benzyl or diphenylmethyl, heterocyclic groups, such as
tetrahydropyranyl and the like.
Suitable thiol protective groups are optionally substituted alkyl groups
having
preferably 1 to 6, in particular 1 to 4, carbon atoms, such as, for example,
acetamidomethyl and chloroacetamidomethyl, arylalkyl-containing alkyl groups,
such
as, for example, benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl and
pyridyldiphenylmethyl and the like.
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The protective groups mentioned further above have the function, known in
peptide
chemistry, to protect amino hydroxyl or thiol groups of compounds temporarily.
Suitable synthetic resin for use as polymeric carriers for the solid-phase
synthesis of
the cyclodepsipeptides according to the invention are appropriately
functionalized
basic polymers (in the most common form on a chloromethylated polystyrene),
such
as, for example, amino-oxy- or hydrazino-functionalized resins of the
Merrifield
type. Particularly suitable here is the commercially available DHP HM resin
from
Novabiochem which allows simple anchoring using a hydraxylamino- or hydrazino
function and thus permits the cyclodepsipeptides according to the invention to
be
provided.
Particular preference is given to compounds of the general formula (Ia)
A R~2 O
N'~C~O~R~~
R2 N ' ~N' O
~R~ Rio
O R9
O O
R3 O
R4 R~
O N~ \N R8 (Ia)
.... R ~ O ~O
O TR6
in which
R~, R4, R' and R~° represent methyl,
RZ, R5, Rg and R1l represent isobutyl,
R6 and R~Z represent methyl,
R3 and R9 independently of one another represent optionally substituted
benzyl,
substituents that may be mentioned being hydrogen, halogen, in particular
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bromine, fluorine, chlorine or iodine, cyano, carbamoyl, hydroxyl which
carries a protective group or unprotected hydroxyl, Ci.B-alkoxy, in particular
methoxy, tert-butyloxy, C~.~-alkoxy-C1~-alkoxy, in particular methoxy-
methoxy, 2-methoxyethoxy, Cz~-alkenyloxy, in particular allyloxy, hetaryl-
C,.~-alkoxy, in particular fur-2-yl-methoxy, tetrahydrofur-2-yl-methoxy, N
Boc-pyrrolidin-2-yl-methoxy, pyrrolidin-2-yl-methoxy, 5-sec-butyl-1,2,4
oxadiazol-3-yl-methoxy, S-cyclopropyl-1,2,4-oxadiazol-3-yl-methoxy, imi
dazol-5-yl-methoxy, thiazolylmethoxy, tetrazol-5-yl-methoxy, thienyl
methoxy, nitro, or a radical from the group consisting of -O-CHz-CHz
I O NRz3R24, -CHz-NRz3Rza~ -NRz3Rza and -SOz-NRz3Rza~
Rz3 and Rz4 independently of one another each represent hydrogen, C,~-alkyl,
in
particular methyl, ethyl, hetaryl-C1.~-alkyl, in particular fur-2-yl-methyl,
tetrahydrofur-2-yl-methyl, pyrrolidin-2-yl-,
Rz3 and Rz4 together with the nitrogen atom to which they are attached
represent
hetaryl, in particular N-pyrrolidino, N-piperazino, N-morpholino, N-
thiomorpholino, N-piperidino, N-imidazolo, 2-oxo-pyrrolidino, phthalimino
or tetrahydrophthalimino,
A represents hydrogen, cyano or optionally represents a radical Al
-Y-Ri3 Ai)
in which
Y represents oxygen or -N-R14, where
R13 and R'4 independently of one another represent hydrogen, straight-chain
or branched C »-alkyl, in particular methyl, ethyl, propyl, isopropyl,
isobutyl, sec-butyl, tert-butyl, C~-C4-alkylcarbonyl, in particular
methylcarbonyl, ethylcarbonyl, cyano-C ~ -C4-alkyl, amino-C 1-C4-
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alkyl, hydroxy-C~-C4-alkyl, C,~-alkylsulfonyl, in particular
methylsulfonyl, C~_2-halogenoalkoxy-C~_2-alkylsulfonyl, in particular
1,1,1-trifluoroethoxyethylsulfonyl, straight-chain or branched C,~-
alkyloxy-carbonyl, in particular methoxycarbonyl, ethyloxycarbonyl,
propyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, sec-
butyloxycarbonyl, tert-butyl-oxycarbonyl, straight-chain or branched
C1~-alkylaminocarbonyl, in particular methylaminocarbonyl, ethyl-
aminocarbonyl, C2.~-alkenyl, in particular vinyl, 2-propenyl, 2-butenyl,
C2.~-alkenyloxycarbonyl, in particular vinyloxycarbonvl, 2-
propenyloxycarbonyl, 2-butenyloxycarbonyl, C2~-halogenoalkenyl-
oxycarbonyl, in particular 1,1,2-trifluorobut-1-en-4-yl-oxycarbonyl,
C2.~-alkenylaminocarbonyl, in particular 2-propenylaminocarbonyl,
C2~-alkinyl, in particular 2-propinyl, C2.~-alkinyloxycarbonyl, in
particular 2-propinyloxycarbonyl, cyanomethyl, hydroxyethyl, amino-
ethyl, aryl-C ,_2-alkyl, in particular optionally substituted benzyl,
hetaryl-C ,_2-alkyl, in particular optionally substituted hetarylmethyl,
in particular optionally substituted tetrahydrofurylmethyl, furylmethyl,
thienylmethyl, thiadiazolylmethyl, tetrazolylmethyl, pyridylmethyl,
aryloxy-C,_2-alkyl, in particular optionally substituted phenoxyethyl,
= optionally substituted hetarylcarbonyl, substituents that may be
mentioned being hydrogen, nitro, amino, halogen, in particular
bromine, chlorine or fluorine, C~~,-alkyl, in particular methyl, C»-
halogenalkyl, in particular trifluoromethyl, phenyl, C1~-alkoxy, in
particular methoxy, C ~.~-alkoxycarbonyl, in particular
methoxycarbonyl, N-morpholinyl, or hetarylcarbonylmethyl, in
particular N-morpholinocarbonylmethyl, N-pyrrolidinocarbonyl-
methyl, or optionally represent a radical of group B4,
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R2, O
I
QwG~Ni
I ) R,s Rio (B4)
Z
in which
Z
ii
,G~
G represents a selectively removable protective group, for
example acetyl (Ac), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Z)
or tert-butyloxycarbonyl (Boc),
R19 represents hydrogen,
RZ° represents hydrogen, propyl, isopropyl, isobutyl, benzyl, 4-
hydroxybenzyl, imidazol-4-yl-methyl, indol-3-ylmethyl,
phenyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-methylthioethyl, 2-
carbamoylethyl,
. R21 represents hydrogen or C1-C4-alkyl,
and their optical isomers, racemates and their physiologically acceptable
salts.
Ver~particular preference is given to compounds of the general formula (Ia)
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A R~2 O
Brit
O
R2 N N O
~R~ Rio
O R9
O O
R3 O
R4 R~
O N~ \N R8 (Ia)
R~O~O
O R6
in which
R~, R4, R~ and R'° represent methyl,
S
R2, R5, R8 and R1' represent isobutyl,
R6 and R12 represent methyl,
R3 and R9 represent benzyl,
A . represents -NHMe or a radical A'
,M..
-1'-R~3 (A
1S
in which
Y represents oxygen,
R'3 represents hydrogen, straight-chain or branched C1.~-alkyl, in
particular methyl, ethyl, propyl, tert-butyl, C,~-alkylsulfonyl,
in particular methylsulfonyl, C~-C4-alkylcarbonyl, in particular
methylcarbonyl, cyano-C~-Cg-alkyl, hydroxy-C1-C4-alkyl,
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amino-C~-C4-alkyl, C1_Z-halogenoalkoxy-C,_2-alkylsulfonyl, in
particular 1,1,1-trifluoroethoxyethylsulfonyl, straight-chain or
branched C,.~-alkyloxycarbonyl, in particular methoxy-
carbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxy-
carbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, tert-
butyloxycarbonyl, C2~-alkenyl, 2-propenyl, CZ.~-alkenyl-
oxycarbonyl, in particular vinyloxycarbonyl, 2-propenyl-
oxycarbonyl, C2~-halogenoalkenyloxycarbonyl, in particular
1,1,2-trifluorobut-1-en-4-yl-oxycarbonyl, C2.~-alkenylamino-
carbonyl, in particular 2-propenylaminocarbonyl, C2.~-alkinyl-
oxycarbonyl, in particular 2-propinyloxycarbonyl, aryl-C,_2-
alkyl, in particular optionally substituted benzyl, N-morph-
olinocarbonylmethyl, N-pyrrolidinocarbonylmethyl, hetaryl-
C,_2-alkyl, in particular optionally substituted tetrahydio-
furylmethyl, furylmethyl, 5-chloro-thiadiazol-4-yl-methyl, N-
methyl-tetrazol-5-yl-methyl, pyridyl-methyl, 2-chloro-pyrid-5-
yl-methyl, aryloxy-Ci_2-alkyl, in particular optionally
substituted phenoxyethyl, trifluoromethylphenoxyethyl,
optionally substituted hetarylcarbonyl, in particular optionally
~ substituted furylcarbonyl, pyridylcarbonyl, substituents that
may be mentioned being hydrogen, nitro, amino, halogen, in
particular bromine, chlorine or fluorine, methyl, trifluoro-
methyl, phenyl, methoxy, methoxycarbonyl, N-morpholinyl, or
optionally represents a radical from the group B4,
Rz~ O
I
Q.~G~.N
II R~s Rzo
in which
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Z
n
,G~
Q represents a selectively removable protective group, for
example acetyl (Ac), allyloxycarbonyl Alloc), benzyloxy-
carbonyl (Z) or tert-butyloxycarbonyl (Boc),
S R19 represents hydrogen,
RZ° represents hydrogen, methyl, propyl, isopropyl, isobutyl,
R21 represents hydrogen or methyl,
and their optical isomers, racemates and their physiologically acceptable
salts.
The general or preferred radical definitions or illustrations listed above can
be
combined with one another as desired, i.e. including combinations between the
respective ranges and preferred ranges. They apply to the end product and,
correspondingly, to precursors and intermediates.
The cycloiminodepsipeptides of the general formula (I) to be used according to
the
""'' invention and their salts furthermore contain one or more centers of
chirality, and
they can therefore be present as pure stereoisomers or in the form of various
enantiomer and diastereomer mixtures which, if required, can be separated in a
manner known per se or else be prepared by stereoselective reactions in
combination
with the use of stereochemically pure starting materials.
However, preference is given to using, according to the invention, the
optically active
stereoisomeric forms of the compounds of the general formula (I) and their
salts.
Particular preference is given to using the cyclic depsipeptides which are
constructed
of (S)-configured amino acids (L form) and D-configured hydroxycarboxylic
acids
(D form) as ring building blocks.
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Accordingly, the invention relates both to the pure enantiomers and
diastereomers
and to their mixtures for controlling endoparasites, in particular in the
field of
medicine and veterinary medicine.
Suitable salts of the cycloiminodepsipeptides of the general formula (I) which
may be
mentioned are customary nontoxic salts, i.e. salts with differing bases and
salts with
added acids. Salts with inorganic bases, such as alkali metal salts, for
example
sodium, potassium or cesium salts, alkaline earth metal salts, for example
calcium or
magnesium salts, ammonium salts, salts with organic bases and also with
inorganic
amines, for example triethylammonium, dicyclohexylammonium, N,N'-dibenzyl-
ethylenediammonium, pyridinium, picolinium or ethanolammonium salts, salts
with
inorganic acids, for example hydrochlorides, hydrobromides, dihydrosulfates,
trihydrosulfates, or phosphates, salts with organic carboxylic acids or
sulfonic acids,
for example formates, acetates, trifluoroacetates, maleates, tartrates,
methane-
sulfonates, benzenesulfonates or para-toluenesulfonates, salts with basic
amino acids,
for example arginates, aspartates or glutamates and the like may be mentioned
as
being preferred.
Methods for introducing optionally substituted imino functions into synthetic
peptides or pharmacologically interesting heterocycles are known from the
literature.
Suitable for use as starting components are here preferably the corresponding
endothiopeptides or heterocyclic thiolactames. By way of example, the
syntheses of
amidoxime, cyanamidine and amidrazone alalogs of chemotactic peptides from
endothiopeptides may be mentioned (G. Sauve et al., Can. J. Chem. 61, 1985,
p. 3089). One variant for preparing the N~'-hydroxy-N~'-methyl-(R)-arginine
from
tert-butyl Na-tert-butoxycarbonyl-8-(N-methyl-thioureido)-(R)-norvalinate has
been
described by H. A. Moynihan et al. (J. Chem. Soc. Perkin Trans. I 1994, p.
769).
Likewise, it is possible to convert heterocyclic thiolactames into amidines
(pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione: M. Robba et al., Tetrahedron
Lett. 33
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(20), 1992, p. 2803) or, without any problems, azetidine-2-thiones into
azetidin-2-
imines (13-lactams: L. Ghosez et al., J. Chem. Soc., Chem. Commun. 1983, p.
818).
Surprisingly, it has now been found that the novel cyclic iminodepsipeptides
of the
S general formula (I) according to the invention can also be prepared from the
corresponding cyclic thiodepsipeptides using amino compounds of the general
formula (II), by reacting one or more thioamide groups. Particular preference
according to the invention is given to reacting one thioamide group.
The compounds of the general formula ()7 are novel, they can be prepared, for
example, by processes mentioned above under points 2 and 3.
Below, the processes according to the invention are illustrated using selected
examples (cf. also Preparation Examples).
If, in the process 2a according to the invention for preparing the novel
cycloiminodepsipeptides of the general formula (Ia), the compounds of the
general
formula (Ib) used is the cyclic thiodepsipeptide cyclo(-N-methyl-L-leucinyl-D-
thiolactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-
methyl-L-leucinyl-D-phenyllactyl-) as amino compound of the general formula
(II)
the O-methyl-hydroxylamine (A: -O-Me; cf.. route A) or N-methylhydrazine (A: -
NH-Me; cf. route B), the process can be represented by the reaction scheme
Scheme I
below:
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Scheme I
Me~~ Me Me
Me Me
N
Me O O
O Me N ' N ..~
Me N ' N O ~ A~ Me ~ Me Me/
Me Me/ ~~~ O
Me0 /
O O
O
Me Me\ Me B~ Me~NrH Me p Me Me
O N N Me N
O O
O
Me Me N ' N ~",
Me Me ~ Me Me/
MeO
syn-/anti- isomer mixtures
A): HZN-O-Me ' HCI, Hg(O-Ac)Z, base
B): HZN-NH-Me, Hg(O-Ac)2, base
If the amino compounds of the general formula (II) are used, the compounds of
the
1 U general formula (I) may be formed as a mixture of syn- and anti- isomers
in the
process 2a according to the invention.
The formula (Ib) provides a general definition of the cyclothiodepsipeptides
required
as starting materials for carrying out process 2a according to the invention.
In this formula (Ib), R' to R'2 preferably represent those radicals which have
already
been mentioned in connection with the description of the substances of the
general
formula (I) according to the invention as being preferred for these
substituents.
The cyclic thiodepsipeptides used as starting materials are known from an
earlier
patent application and can be obtained correspondingly via thionation of
cyclic
depsipeptides using suitable sulfurizing agents (cf. WO 98/43965, see also
Preparation Examples).
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The general formula (II) provides a definition of the amino compounds further
to be
used as starting materials for carrying out the process 2a according to the
invention.
In this formula (II), A has the meaning which has already been mentioned in
connection with the description of the substances of the general formula (I)
according
to the invention as being preferred for this substituent.
The amino compounds of the formula (II) are commercially available, some are
known and can be obtained by known methods (cf., for example, hetaryl-
methoxamine: US-Pat. 5 489 680; DE-OS (German Published Specification)
2119012, alkoxyamines: EP-OS 495 750; DE-OS (German Published Specification)
2206890; D. Favara et al. Farmaco, Ed. Sci. 42 ( 10), 1987, p. 697).
A general route for preparing aminoxy compounds (A = A': -Y-R'3, Y: -O-) of
the
1 S formula (II) comprises, for example, reacting a hydroxylamine derivative
which has a
protective group on nitrogen (for example R' and R" together: phthaloyl,
isopropylidene, a-hydroxy-benzylidene group) with a compound R'3-E (O-
alkylation) in a diluent, followed by removal of the corresponding protective
group.
In compound R'3-E, R'3 has the same meaning as above and E represents a
nucleofugic leaving group, for example aliphatically or aromatically
substituted
sulfonyloxy, for example methanesulfonyloxy, salts of sulfonic acid, p
toluenesulfonyloxy (tosyloxy), and furthermore also, for example, halogen, in
particular bromine, chlorine or iodine. (cf. O-alkylation). In reaction scheme
II
below, the preparation of amino compounds of the formula (II;) is shown (A =
A' : -Y
R'3, Y: -O-):
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Scheme 1l
R13
R'
R' ~
HO-NCR" + R'3 E -.. O-N\ --.-,, R'3 p-NH2
R"
Alternatively, if a hydroxyl compound (R13-OH) is used, it is also possible to
carry
out, for example, an intermolecular dehydration reaction. Particularly
suitable for this
purpose is a variant of the Mitsunobu reaction [Synthesis 1976, p. 682] where
the
hydroxy compounds with N-protected hydroxylamine derivatives, such as, for
example, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dicarboximide or
ethyl acetylhydroxamate, and, for example, triphenylphosphine and diethyl N,N'-
azodicarboxylate.
The compounds of the formula (II) can expediently be released in the following
manner: the hydrazinolysis can preferably be carried out in a diluent, for
example
alcohol, at boiling point. The hydrolysis can preferably be carried out in an
aqueous,
aqueous-alcoholic or alcoholic solution, by heating for a number of hours. If
R' and
"~ R" together represent an isopropylidene group, it is possible to use acid
hydrolysis
and, if R' and R" together represent an a-hydroxy-benzylidene group or R"
represents a carbethoxy group, it is possible to use both alkaline and acidic
hydrolysis
(cf. DE-OS (German Published Specification) 2119012; D. Favara et al. Farmaco,
Ed. Sci. 42 ( 10), ( 1987) p. 697).
For preparing the salts, it is preferred to use inorganic acids, such as
hydrochloric
acid or sulfuric acid, in ethanolic or isopropanolic solution.
The reaction of the thiodepsipeptide of the general formula (Ib) with the
amino
compounds of the general formula (II) is preferably carried out in the
presence of a
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metal salt or metal oxide and; if appropriate, in the presence of a basic
reaction
auxiliary, using diluents.
Suitable metal salts or metal oxides for carrying out the process according to
the
invention are all metal salts with elements of the I. and II. transition group
of the
Periodic Table of the Elements. Examples which may be mentioned are the
acetates,
chlorides, bromides, iodides, fluorides, nitrates, sulfates, carbonates,
trifluoroborates,
trifluoromethanesulfonates of copper, silver, gold, zinc, cadmium or mercury.
However, preference is given to using the carbonates, trifluoroborates and
trifluoromethansulfonates of the metals of the I. transition group, in
particular silver,
and the acetates, oxides and the halides of the metals of the II. transition
group, in
particular mercury.
Suitable for use as basic reaction auxiliaries for carrying out the process 2a
according
to the invention are all suitable acid binders, such as amines, in particular
tertiary
amines, and alkali metal and alkaline earth metal compounds.
Examples which may be mentioned are the hydroxides, oxides and carbonates of
lithium, sodium, potassium, magnesium, calcium and barium, furthermore further
basic compounds such as amidine bases or guanidine bases, such as 7-methyl-
1,5,7-
triazabi-cyclo(4.4.0)dec-S-ene (MTBD); diazabicyclo(4.3.0)nonene (DBN),
diazabicyclo(2.2.2)-octane (DABCO), 1,8-diaza-bicyclo(5.4.0)undecene (DBU),
cyclohexyl-tetrabutylgua-nidine (CyTBG), cyclohexyltetramethylguanidine
(CyTMG), N,N,N,N-tetramethyl-1,8-naphthalenediamine, pentamethylpiperidine,
tertiary amines, such as triethylamine, trimethylamine, tribenzylainine,
triisopropylamine, tributylamine, tribenzylamine, tricyclohexylamine,
triamylamine,
trihexylamine, N,N-dimethyl-aniline, N,N-dimethyl-toluidine, N,N-dimethyl-p-
aminopyridine, N-methyl-pyrrolidine, N-methyl-piperidine, N-methyl-imidazole,
N-
methyl-pyrrole, N-methyl-morpholine, N-methyl-hexamethylenimine, pyridine, 4-
pyrrolidinopyridine, 4-dimethylamino-pyridine, quinoline, a-picoline, (3-
picoline,
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isoquinoline, pyrimidine, acridine, N,N,N',N'-tetramethylenediamine, N,N',N'-
tetraethylenediamine, quinoxaline, N-propyl-diisopropylamine, N-ethyl-
diisopropylamine, N,N'-dimethylcyclohexylamine, 2,6-lutidine, 2,4-lutidine or
triethylendiamine.
Preference is given to using tertiary amines, in particular trialkylamines
such as
triethylamine, N,N-diisopropylethylamine, N-propyl-diisopropylamine, N,N'-
dimethyl-cyclohexylarnine or N-methylmorpholine.
In general, it is advantageous to carry out the process 2a according to the
invention in
the presence of diluents. Diluents are preferably employed in such an amount
that the
reaction mixture remains readily stirrable during the entire process. Suitable
diluents
for carrying out the process 2a according to the invention are all inert
organic
solvents.
Examples which may be mentioned are: halogenated hydrocarbons, in particular
chlorinated hydrocarbons, such as tetrachloroethylene, tetrachloroethane,
dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon
tetrachloride, trichloroethane, trichloro-ethylene, pentachloroethane,
difluorobenzene,
1,2=dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene,
chlorotoluene,
"~"" trichlorobenzene; alcohols such as methanol, ethanol, isopropanol,
butanol; ethers
such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole,
phenetole,
cyclohexyl methyl ether, dimethyl ether, diethyl ether, dipropyl ether,
diisopropyl
ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol
dimethyl
ether, tetrahydrofuran, dioxane, dichlorodiethyl ether and polyethers of
ethylene
oxide and/or propylene oxide: amines such as trimethyl-, triethyl-, tripropyl-
,
tributylamine, N-methylmorpholine, pyridine and tetramethylenediamine,
nitrohydrocarbons such as niromethane, nitroethane, nitropropane,
nitrobenzene,
chloronitrobenzene, o-nitrotoluenes; nitrites such as acetonitrile,
propionitrile,
butyronitrile, isobutyronitrile, benzonitrile, rn-chlorobenzonitrile and also
compounds
such as tetrahydrothiophene dioxide and dimethyl sulfoxide, tetramethylene
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sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide,
dibutyl
sulfoxide, diisoamyl sulfoxide; sulfones, such as dimethyl, diethyl, dipropyl,
dibutyl,
diphenyl, dihexyl, methyl ethyl, ethyl propyl, ethyl isobutyl and
pentamethylene
sulfone; aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane,
hexane,
heptane, octane, nonane and industrial hydrocarbons, for example white spirits
with
components having boiling points in the range of, for example, from
40°C to 250°C,
cymene, benzine fractions within a boiling point range of from 70°C to
190°C,
cyclohexane, methylcyclohexane, petroleum ether, ligroine, octane, benzene,
toluene,
chlorobenzene, bromobenzene, nitrobenzene, xylene; esters such as methyl,
ethyl,
''°°'' 10 butyl, isobutyl acetate, and also dimethyl, dibutyl,
ethylene carbonate; amides such as
hexamethylenephosphoric triamide, formamide, N-methyl-formamide, N,N-
dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methyl-
pyrrolidine, N-methyl-caprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidine, octylpyrrolidone, octylcaprolactam, 1,3-dimethyl-2-
imidazolinedione, N-
formyl-piperidine, N,N'-1,4-diformylpiperazine; ketones such as acetone,
acetophenone, methyl ethyl ketone, methyl butyl ketone.
It is, of course, also possible to use mixtures of the solvents and diluents
mentioned
for the process according to the invention.
"~ However, preferred diluents for carrying out the process according to the
invention
are nitriles such as acetonitrile, propionitrile, butyronitrile,
isobutyronitrile,
benzonitrile or m-chlorobenzonitrile, in particular acetonitrile,
propionitrile or
butyronitrile, ethers such as ethyl propyl ether, methyl tert-butyl ether, n-
butyl ether,
cyclohexyl methyl ether, dimethyl ether, diethyl ether, dipropyl ether,
diisopropyl
ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol
dimethyl
ether, tetrahydrofuran or dioxane, in particular tetrahydrofuran or dioxane,
halogenated hydrocarbons, in particular chlorinated hydrocarbons, such as
tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride,
dichlorobutane, chloroform, carbon tetrachloride, trichloroethane,
trichloroethylene
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or pentachloroethane, in particular methylene chloride, chloroform or carbon
tetrachloride.
The reaction of amino compounds of the general formula (II) according to
process 2a
S is carried out by reacting the cyclothiodepsipeptides of the general formula
(Ib) in the
presence of an amino compound of the general formula (II), in the presence of
one of
metal salts or metal oxides mentioned with elements of the I. and II.
transition group
of the Periodic Table of the Elements and, if appropriate, in the presence of
one of
the basic reaction auxiliaries mentioned in one of the mentioned diluents.
The reaction time is from 10 minutes from 48 hours. The reaction is carned out
at
temperatures between -10°C and +200°C, preferably between
+10°C and +180°C,
particularly preferably at room temperature. In principle, the reaction can be
carried
out under atmospheric pressure. It is preferably carned out under atmospheric
1 S pressure or at pressures of up to 1 S bar and, if appropriate, under an
atmosphere of
protective gas (nitrogen or helium).
For carrying out the process 2a according to the invention, in general from
O.S to
7.0 mol, preferably from 1.0 to S.0 mol, particularly preferably from 2.0 to
3.0 mol,
of amino compound of the general formula (II) are employed per thioamide group
present in the cyclothiodepsipeptides of the general formulae (Ib).
Furthermore, for carrying out the process 2a according to the invention, in
general
from O.S to 6.0 mol, preferably from 1.0 to 4.0 mol, particularly preferably
from 1.S
2S to 2.S mol, of metal salt or metal oxide are employed per thioamide group
present in
the compounds of the general formulae (Ib).
After the reaction has ended, the entire reaction mixture is separated from
the metal
sulfide which precipitates out and, if appropriate, washed. The resulting
products can
be purified in a customary manner by recrystallization, distillation under
reduced
pressure or column chromatography (cf. also the preparation examples).
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If, in the processes 2b and 2c according to the invention for preparing the
novel
cycloiminodepsipeptides of the general formula (Ia), the compounds of the
formula
(Ic) used is, for example, the cyclic iminodepsipeptide cyclo[-N-methyl-L-
leuci-nyl-
D-(hydroxy-imino)-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-
leucinyl-
D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) and the compounds of the general
formula (III) used is vinyl chloroformate (cf. route C) and the compounds of
the
general formula (IV) used is acetic anhydride (cf. route D), the processes can
be
represented by reaction scheme III below.
"~' 10 Scheme III
~ Me Me
~O~$ Me O
H Me O
M M N O
N O Me N' N
Me
Me N ~ Me N 0 ~ 0~ MeO Me
MeO Me
O O
O
Me Me ~ Me
~ ~ M D~ Me" Me p Me
O N N Me
O O O
Me Me N ' N .,~
Me Me Me Met
MeQ
..
syn-/anti- isomer mixtures
C): Cl-CO-O-CH=CH2, base
D): (CH3-CO)20
The formula (Ic) provides a general definition of the cycloiminodepsipeptides
required as starting materials in particular for carrying out the processes 2b
and 2c
according to the invention and their salts.
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In this formula (Ic), Y and R~ to R12 preferably represent those radicals
which have
already been mentioned in connection with the description of the substances of
the
general formula (I) according to the invention as being preferred for these
substituents.
The cycloiminodepsipeptides of the general formula {Ic) (Y: -O-) used as
starting
materials are novel and can be obtained either by the process 2a described
further
above or by the process 3 described further below.
°"""~ 10 According to process 2a, the cycloiminodepsipeptides of the
general formula (Ic) (Y:
-OH) can be prepared from the cyclothiodepsipeptides of the general formula
(Ib) and
hydroxylamine as compound of the general formula (II) (cf. Scheme IV).
Scheme IV
Me
Me O Me ~H Me p Me Me
O N~ O
Me N \ Me N O ~ Me N N O
Me
MeO I / HONHZ Me , Me Me /
--
O O O O
Me Me O Me ~ ~ Me Me\ O Me
O N \N Me
O O O~ Me
Y'O
,,~~'' 0
Me
Me Me MeMeO Me
The formulae (III) and (N) provide general definitions of the compounds
furthermore to be used as starting materials for carrying out the processes 2b
and 2c
according to the invention.
Z
G
In the formulae (III) and (IV), ~ ~ , W, Q and Y have the meaning which have
already been mentioned for these substituents in connection with the
description of
the substances of the general formula (I) according to the invention.
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The compounds of the formula (III) are generally known compounds of organic
chemistry, and/or some of them can be obtained commercially or by methods
known
from the literature (for example Houben Weyl, Methoden der organischen Chemie
[Methods of Organic Chemistry], Volume E 4).
The reaction of the cycloiminodepsipeptides (Ic) with compounds of the general
formula (III) is preferably carried out in the presence of basic reaction
auxiliaries
using diluents.
Suitable for use as basic reaction auxiliaries for carrying out the process 2b
according
to the invention are all acid binders mentioned under process 2a, such as
amines, in
particular tertiary amines.
In process 2b, preference is given to using the tertiary amines, in particular
trialkylamines such as triethylamine, N,N-diisopropylethylamine, n-
propyldiisopropylamine, N,N'-dimethylcyclohexylamine or N-methylmorpholine,
and also pyridine derivatives, in particular pyridine.
In the process 2b according to the invention it is, of course, also possible
to use
mixtures of the acid binders mentioned.
.
Suitable diluents for carrying out the process 2b according to the invention
are the
inert aprotic solvents mentioned under process 2a, such as, for example,
dioxane,
acetonitrile or tetrahydrofuran, but also halogenated hydrocarbons, in
particular
chlorinated hydrocarbons, such as methylene chloride or chloroform.
The process 2b is carned out by reacting compounds of the general formula (Ic)
in
the presence of basic reaction auxiliaries with compounds of the general
formula
(III), if appropriate in one of the diluents mentioned.
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Alternatively and preferably, process 2b can also be carried out directly in a
suitable
basic reaction auxiliary without a diluent.
The formula (IV) provides a general definition of the carboxylic anhydrides to
be
used as starting materials for carrying out the process 2c according to the
invention.
The reaction time is from 4 to 72 hours. The reaction is carried out at
temperatures
between -10°C and +150°C, preferably between -5°C and
+80°C, particularly
preferably at from 0°C to room temperature. The reaction is carned out
under
atmospheric pressure.
For carrying out the process 2b according to the invention, in general from
2.0 to
8.0 mol, preferably from 2.0 to 4.0 mol, of acetylating agent are employed per
mole
of compound of the formula (Ic).
For carrying out the process 2c according to the invention, in general from
1.0 to
3.0 mol, preferably from 1.0 to 1.5 mol, of carboxylic anhydride are employed
per
mole of compound of the formula (Ic).
Alternatively, process 2c can also be carned out using excess carboxylic
anhydride of
the formula (IV) without a diluent, as long as the reaction mixture remains
readily
stirrable.
After the reaction has ended, the reaction solution is washed and the organic
phase is
separated off, dried and concentrated under reduced pressure. The resulting
products
can be purified in a customary manner by recrystallization, distillation under
reduced
pressure or column chromatography (cf. also the Preparation Examples).
If in the process 2d a) and (3) according to the invention for preparing the
novel
cycloiminodepsipeptides of the general formula (Ia) the compounds of the
formula
(Ic) used is, for example, the cyclic iminodepsipeptide cyclo[-N-methyl-L-
leuci-nyl-
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D-(hydroxy-imino)-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-
leucinyl-
D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) the compounds of the general
formula
(V) used is (S)-N-tert-butyloxycarbonyl-N-methylalanine ((S)-Boc-MeAla-OH; cf.
route E) and the compounds of the general formula (VI) used is allyl
isocyanate (cf.
route F), the processes can be represented by reaction scheme V below.
Scheme V
Me
Me~O N~ Me Me
'~' ~h Me O
Me Me Me ~ Me N w
~H Me O O
N O Me N ' N
Me
Me N ' N O ~ E~ Me ~ Me
Me~
Me Me/ ~~~ O
O O
Me Me O Me F7 \ Me Me
/ / ~ ~ ~'~"N Me O
O N N Me t
O H N~
O O
Me Me N ' N .,.,
Me Me ~ Me Me/
MeO
syn-/anti- isomer mixtures
E): (~)-Boc-MeAla-OH, BOP, base
F): O=C=N-CHZ-CH=CH2, base
The formula (Ic) provides a general definition of the cycloiminodepsipeptides
1 S required as starting materials for carrying out the process 2d a) and (3)
according to
the invention.
In these formulae (Ic), Y and R' to R'2 preferably represent those radicals
which have
already been mentioned in connection with the description of the substances of
the
general formula (I) according to the invention as being preferred for these
substituents.
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The formula (V) provides a general definition of the compounds to be used as
starting materials in particular for carrying out the process 2d a) according
to the
invention.
Z
G
In the formula (V), ~ ~ , Q', R16, R" and R~g have the meaning which has
already been mentioned in connection with the description of the substances of
the
general formula (I) according to the invention for substituents.
The natural or synthetic amino acids used as starting materials can, if
chiral, be
present in the (S)- or (R)-form (or L- or D-form).
Examples which may be mentioned are:
Aad, Abu, yAbu, Abz, 2Abz, sAca, Acp, Adpd, Ahb, Aib, (3Aib, Ala, (3Ala, ~Ala,
Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph,
Can,
Cit, Cys, {Cys)Z, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel,
Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hIle, hLeu, hLys, hMet,
hPhe, Pro, hSer, hThr, hTrp, hTyr, HyI, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant,
Lcn, Leu,
Lsg, Lys, (3Lys, OLys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen,
Phe,
Phg, Pic, Pro, OPro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi,
(3Thi, Thr,
Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, Nal, Tbg, Npg, Chg, Thia (cf.,
for
example, Houben- Weyl, Methoden der Organischen Chemie, Volume XV/1 and 2,
Stuttgart, 1974).
Some of the compounds of the general formula (V) can be obtained commercially
or
by methods known from the literature (cf., for example, N-Methylamino acids:
R. Bowmann et al., J. Chem. Soc. 1950, p. 1346; J. R. McDermott et al., Can J.
Chem. 51 (1973), p. 1915; H. Wurziger et al., Kontakte (Merck, Darmstadt) 3
(1987),
p. 8).
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The reaction of the cycloiminodepsipeptides of the general formula (Ic) with
amino
acid derivatives of the formula (V) is preferably carried out in the presence
of
coupling agents and in the presence of a basic reaction auxiliary using
diluents.
Suitable coupling agents for carrying out process 2d a are all coupling agents
which
are suitable for forming an amide bond [cf., for example: Houben-Weyl,
Methoden
der organischen Chemie, Volume 15/2; Bodanszky et al., Peptide Synthesis 2nd
ed.
(Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides, Analysis
Synthesis, Biology (Academic Press, New York 1979)]. Preference is given to
using
the following methods: activated ester method using pentachloro- (Pcp) and
penta-
fluorophenol (Pfp), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-
dicarboxamide (HONB), 1-hydroxy-benzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-
dihydro-1,2,3-benzotriazine as alcohol component, coupling with carbodiimides
such
as dicyclohexylcarbodiimide (DCCI) according to the DCC additive process, or
using
n-propanephos-phonic anhydride (PPA) and the mixed anhydride method using
pivaloyl chloride, ethyl- (EEDQ) and isobutyl chloroformate (IIDQ) or coupling
with
phosphonium reagents, such as benzotriazol-1-yl-oxy-tris(dimethylamino-phos-
phonium) hexafluorophosphate (BOP), bis(2-oxo-3-oxazolidinyl)phosphonium acid
chloride (BOP-Cl), benzotriazol-1-yl-tris-pyrrolidino-phosphonium hexafluoro-
phosphate (PyBOB~), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate
(PyBroP~) or using phosphonic acid ester reagents, such as diethyl
cyanophosphonate
(DEPC) and diphenylphosphoryl azide (DPPA) or uronium reagents, such as 2-( 1
H-
benzotriazol-1-yl)-1,1,3,3-tetra-methyluronium tetrafluoro-borate (TBTU), 2-(5-
nor-
bornene-2,3-dicarbox-amido)-1,1,3,3-tetramethyluronium tetrafluoroborate
(TNTU),
2-(2-oxo-1(2H)-pyridyl-1,1,3,3-bis-pentamethylene-tetramethyluronium
tetrafluoro-
borate (TSTU) or such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU).
Coupling with phosphonium reagents such as bis(2-oxo-3-oxazoli-dinyl)-
phosphonium acid chloride (BOP-Cl), benzotriazol-1-yl-oxy-tris(dimethylamino-
phosphonium) hexafluorophosphate (BOP), benzotriazol-1-yl-tris-pyrrolidino-
phos-
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phonium hexafluorophosphate (Py BOB~), bromo-tris-pyrrolidino-phosphonium
hexa-fluorophosphate (PyBroP~ and phosphonic acid ester reagents, such as
diethyl
cyanophosphonate (DEPC) or diphenylphosphoryl azide (DPPA) is preferred.
Suitable for use as basic reaction auxiliaries for carrying out the process 2d
a)
according to the invention are likewise all acid binders suitable for process
2a.
Preferably suitable are tertiary amines, in particular trialkylamines such as
triethylamine, N,N-diisopropylamine, N-propyldiisopropylamine, N,N'-dimethyl
cyclohexylamine or N-methylmorpholine.
Suitable for use as diluents for carrying out the process 2d a) are the
solvents
mentioned under process 2a such as, for example, halogenated hydrocarbons, in
particular chlorinated hydrocarbons, such as methylene chloride, chloroform or
1,2
dichloroethane and mixtures of these with other solvents mentioned.
The process is generally carried out by reacting compounds of the general
formula
(Ic) in the presence of one of the basic reaction auxiliaries mentioned with
compounds of the general formula (V) in one of the solvents mentioned.
The reaction time is from 4 to 72 hours. The reaction is carried out at
temperatures
between -10°C and +120°C, preferably between -5°C and
+50°C, particularly
preferably at from 0°C to room temperature. The reaction is carried out
under
atmospheric pressure.
For carrying out the process 2d according to the invention, in general from
1.0 to
3.0 mol, preferably from 1.0 to 1.5 mol, of coupling agent are employed per
mole of
compound of the formula (Ic).
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The formula (VI) or (VII) provides a general definition of the compounds to be
used
as starting materials in particular for carrying out the process 2d l3)
according to the
invention.
Z
G
In these formulae (VI) or (VII), ~ ~ , Y and R~5 have the meaning which has
already been mentioned in connection with the description of the substances of
the
general formula (I) according to the invention as being preferred for
substituents.
Some of the compounds of the general formulae (VI) or (VII) can be obtained
commercially or by methods known from the literature (cf., for example, Houben-
Weyl, Methoden der Organischen Chemie, Volume E 4).
The reaction of the cycloiminodepsipeptides of the general formula (Ic) with
compounds of the general formulae (VI) or (VII) is preferably carried out in
the
presence of diluents, if appropriate in the presence of a basic reaction
auxiliary.
Suitable diluents for carrying out the process 2d 13) according to the
invention are the
solvents mentioned under process 2a such as, for example, halogenated
hydrocarbons, in particular chlorinated hydrocarbons, such as methylene
chloride,
r"
chloroform or 1,2-dichloroethane, nitriles such as acetonitrile,
propionitrile,
butyronitrile, in particular acetonitrile, ethers such as ethyl propyl ether,
n-butyl ether,
diethyl ether, dipropyl ether, diisopropyl ether, tetrahydrofuran or dioxane,
in
particular tetrahydrofuran or dioxane, aliphatic or aromatic hydrocarbons such
as n
hexane, n-heptane, benzene, toluene or xylenes and mixtures of these with
other
diluents mentioned.
The process 2d !3) can also be carried out in the presence of basic reaction
auxiliaries.
Suitable as such basic reaction auxiliaries for carrying out the process 2e
according to
the invention are all acid binders mentioned further above, but preferably
tertiary
amines, in particular trialkylamines such as triethylamine, N,N-
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diisopropylethylamine or N-methylmorpholine, and amidine bases or guanidine
bases
such as diazabicyclo(4.3.0)nonene (DBN), diazabicyclo(2.2.2)octane (DABCO),
1,8-
diazabicyclo(5.4.0)undecene (DBU), in particular 1,8-
diazabicyclo(5.4.0)undecene
(DBU).
S
The process 2d 13) is generally carried out by reacting compounds of the
general
formula (Ic) with compounds of the general formulae (Vn or (VII), if
appropriate in
the presence of one of the basic reaction auxiliaries mentioned in one of the
diluents
mentioned.
The reaction time is from 4 to 72 hours. The reaction is earned out at
temperatures
between -10°C and +180°C, preferably between -5°C and
+120°C, particularly
preferably at from 0°C to the boiling point of the diluent used. In
principle, the
reaction is carried out under atmospheric pressure; however, it can also be
carried out
1 S under elevated or reduced pressure. It is preferably earned out at
atmospheric
pressure or at pressures of up to 1 S bar.
For carrying out the process 2d f3) according to the invention, in general
from 1.0 to
3.O,mol, preferably from 1.0 to 1.5 mol, of compound of the general formulae
(VI) or
(VII) is used per mole of compound of the formula (Ic).
The invention furthermore relates to novel processes for preparing
cycloiminodepsipeptides of the general formula (Ic).
The cycloiminodepsipeptides of the general formula (Ic) (Y: -O-) can either be
prepared directly according to process 2a from the thiodepsipeptides of the
general
formula (Ib) and hydroxylamine as compound of the general formula (II) or can
be
obtained according to process 3 from suitable cycloiminodepsipeptides of the
general
formula (Ia).
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If, for example, in process 3a the novel cycloiminodepsipeptide cyclo[-N-
methyl-L-
leucinyl-D-(benzyloxy-imino)-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-
methyl-
L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-) is used as compound
of
the general formula (Ia) (A = A1= -Y-R~3: -O-CH2-phenyl) is used for
hydrogenation,
the corresponding cycloiminodepsipeptide cyclo[-N-methyl-L-leucinyl-D-(hydroxy-
imino)-lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-
N-
methyl-L-leucinyl-D-phenyl-lactyl-) is formed (cf. Scheme VI, route G).
The formula (Ia) provides a general definition of the cycloiminodepsipeptides
required as starting materials for carrying out the process 3a according to
the
invention. In these formulae (Ia), A, R~ to R'2 preferably represent those
radicals
which have already been mentioned in connection with the description of the
substances of the general formula (I) according to the invention as being
preferred for
these substituents.
The cycloiminodepsipeptides of the general formula (Ia) can be prepared
according to
process 2a mentioned further above from the thiodepsipeptides of the general
formula (Ib) and compounds of the general formula (II) in which A represents a
radical -Y-R13 (Ai) having a selectively removable O protective group R13, for
example benzyl-, benzyloxycarbonyl-. Allyl-, tert-butyloxycarbonyl-,
tetrahydro-
pyranylhydroxylamine.
Depending on the protective group R13, in the compounds of the general formula
(Ia)
this group can either be selectively removed by hydrogenolysis in the presence
of a
suitable hydrogenation catalyst or by acidolysis in the presence of a protic
acid.
According to the invention and particularly preferred is the hydrogenolysis of
cycloiminodepsipeptides of the general formula (Ia) in the presence of a
hydrogenation catalyst, in the presence of a diluent and, if appropriate, in
the
presence of an acid reaction auxiliary (Scheme VI, route G, H, I).
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Scheme VI
13
R~~ Me Me
Me O
N
O
Me N N O
G) H~~ Me p Me Me
Me ~ Me Me
N~ 0
O O O Me N' N.,
Me Me\ Me I) MeO Me Me /~
O N N Me
O
'O
Me
Me Me
Sylt-~aYlh-lSOmer mlXtLireS
G: H2, 10% Pd(OH)-carbon, H+/Me-OH (RI3: -benzyl)
H: H+ (R13: -THP) THP = tetrahydropyranyl
I: Pyridine para-toluenesulfonic acid (R'3 = -THP-CH2-O-CHZ-C6H4-polymer)
Suitable catalysts for carrying out the catalytic hydrogenation are all
customary
hydrogenation catalysts, such as, for example, platinum catalysts (platinum
foil,
platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum
wire
etc.), palladium catalysts (for example palladium sponge, palladium black,
palladium
oxide, palladium/carbon, colloidal palladium, palladium/barium sulfate,
palladium/-
barium carbonate, palladium hydroxide, etc.), nickel catalysts, for example
reduced
nickel, nickel oxide, Raney nickel etc.), ruthenium catalysts, cobalt
catalysts (for
example reduced cobalt, Raney cobalt etc.), iron catalysts (for example
reduced iron,
Raney iron etc.), copper catalysts, (for example reduced copper, Raney copper,
Ullman copper etc.). However, preference is given to using noble metal
catalysts,
such as, for example, platinum and palladium or ruthenium catalysts, if
appropriate
on a suitable support, such as, for example, carbon or silicon.
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For hydrogenating cycloiminodepsipeptides of the general formula (Ia), the
inert
organic solvents mentioned under process 2a, such as, for example, alcohols,
in
particular methanol or ethanol, are used.
Acid reaction auxiliaries which may be mentioned are, for example, mineral
acids.
The mineral acids preferably include hydrohalic acids such as hydrofluoric
acid,
hydrobromic acid, hydrochloric acid or hydroiodic acid, and also sulfuric
acid,
phosphoric acid, phosphorous acid and nitric acid.
According to the invention, for carrying out the hydrogenation, an alcoholic
solution
of the cyclic benzyloxyiminodepsipeptides of the formula (Ia) is reacted in
the
presence of a suitable hydrogenation catalyst and, if appropriate, in the
presence of an
acid reaction auxiliary.
Preferred for use as hydrogenation catalysts are palladium catalysts, in
particular
palladium/ or palladium hydroxide/carbon.
Preferred for use as acid reaction auxiliary are mineral acids, in particular
hydrohalic
acids such as hydrochloric acid.
,~ 20
The reaction time is from 5 minutes to 20 hours. The hydrogenation is carried
out at
temperatures between -5°C and +100°C, preferably between
0°C and +30°C.
Alternatively, the cyclic hydroxy-iminodepsipeptides of the general formula
(lc)
(Y: -O-) can also be obtained from cyclic allyloxyiminodepsipeptides of the
general
formula (Ia) (A: -O-CHZ-CH=CHZ)by palladium(II) acetate-catalyzed cleavage in
the
presence of triethylammonium formate and triphenylphosphine (T. Yamada et al.,
Tetrahedron Lett. 28, 1987, p. 4557).
Of course, and according to the invention, the cycloiminodepsipeptides of the
general
formula (Ic) (Y: -O-) can also be formed by acid-catalyzed removal of a
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tetrahydropyranyloxy radical (A: -O-THP, cf. route H) or by removal of the
anchor
group R13 from polymer-O-bonded cycloiminodepsipeptides of the general formula
(Ia) (for example A = A' = Y-R~3 = -O- with selectively removable anchor
group) (cf.
Scheme VI, route I).
S
If, for example, in process 3b for the selective removal, the polymer-bound
cycloiminodepsipeptide cyclo[-N-methyl-L-leucinyl-D-(polymer-THP-oxy-imino)-
lactyl-N-methyl-L-leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-me-
thyl-L-leucinyl-D-phenyllactyl-) is used as compound of the general formula
(Ia) (A
= A~ _ -Y-R13 = -O- with selectively removable anchor group), the
corresponding
cycloiminodepsipeptide cyclo[-N-methyl-L-leucinyl-D-(hydroxy-imino)-lactyl-N-
methyl-L-leu-cinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-
leucinyl-D-phenyl-lactyl-) is formed (cf. Scheme VI, route I).
The formula (Ia) provides a general definition of the cycloiminodepsipeptides
required as starting materials for carrying out the process 3b according to
the
invention.
In these formulae (Ia), A and R' to R'2 preferably represent those radicals
which have
already been mentioned in connection with the description of the substances of
the
general formula (I) according to the invention for these substituents.
The polymer-bound cycloiminodepsipeptides of the general formula (Ia) can be
prepared according to process 2a mentioned further above from the
2~ cyclothiodepsipeptides of the general formula (1b) and polymeric supports
with
selectively removable anchor group for A = -Y-R'3 (A') of the general formula
(II)
(cf. Schema VII).
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Scheme VII
Me Me
P Me
f S~O
\ O O O~NHz Me N' N."~ ---
MeO Me Me
P
\ Ow,,/CO~,~ Me O Me
NN O
Me N ' N .."~
MeO Me Me
Some of the polymeric Garners used as starting materials and having
selectively
removable anchor group for A = -Y-R'3 (A1) of the general formula (I>7 are
known
from the literature (cf., for example, Syntheses of Hydroxamic acids:
Mitsunobu
reaction on Wang resin using N-hydroxyphthalimide: D. Floyd et al. Tetrahedron
Lett. 37 (44), 1996, p.8045; Reaction of trityl chloride resin with N-
hydroxyphthalimide: U. Bauer et al. Tetrahedron Lett. 38 (41), 1997, p. 7233),
or
they can be obtained by methods known from the literature (cf. Synthesis of
ketones:
Reactions with DHP HM resin: O. B. Wallace Tetrahedron Lett. 38 (28), 1997,
s.
p. 4939; Alcohol coupling: J. A. Ellmann et al. J. Org. Chem. 60, 1995, p.
7712; J. A.
Ellmann et al. Tetrahedron Lett. 35 (50), p. 9333) (cf. Scheme Vl~.
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Scheme VIII
P
O~ DHP HM resin
~~..//1~~ J (Novabiochem)
O
P O
\ I O.,~O,N
O
"~.», P
,~ I O 1~ O . NHZ
For carrying out the process 3b according to the invention, preference is
given to
using the 6-(aminoxy)-3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-
polystyrene
resin obtained according to Scheme VIII (cf. Preparation Examples).
The cyclic hydroxy-iminodepsipeptides formed in this manner are worked up in a
customary manner, for example by chromatographic purification (cf. also
Preparation
Examples). However, they can also be reacted directly (without further
purification)
according to process 2b.
The iminodepsipeptides of the general formula (I) obtainable by process 2
according
to the invention can be present as syn- and anti- isomers; however, under the
given
reaction conditions for process 2, a mixture of the two isomeric forms is
preferably
formed.
The "inert solvents" referred to in process variants 2 above in each case
refer to
solvents which are inert under the respective reaction conditions but which do
not
have to be inert under any reaction conditions.
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The active compounds are suitable for controlling pathogenic endoparasites
encountered in humans and in animal husbandry and livestock breeding, in
productive livestock, breeding stock, zoo animals, laboratory animals, animals
used
in experiments, and pets, and have low toxicity toward warm-blooded animals.
They
are active against resistant and normally sensitive species and against all or
some
stages of development of the pests. By controlling the pathogenic
endoparasites, it is
intended to reduce disease, mortality and decreasing performance (for example
in the
production of meat, milk, wool, hides, eggs, honey, etc.), so that more
economical
and simpler animal husbandry is possible by using the active compounds. The
pathogenic endoparasites include cestodes, trematodes and nematodes, in
particular:
From the order of the Pseudophyllidea, for example Diphyllobothrium spp.,
Spirometra
spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoorus spp.
From the order of the Cyclophyllidea, for example Mesocestoides spp.,
Anoplocephala
spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia
spp.,
Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp.,
Taenia spp.,
Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp.,
Hymenolepis
spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp.,
Joyeuxiella
spp.,-Diplopylidium spp.
From the subclass of the Monogenea, for example Gyrodactylus spp.,
Dactylogyrus
spp., Polystoma spp.
From the subclass of the Digenea, for example Diplostomum spp.,
Posthodiplostomum
spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp.,
Austrobilharzia
spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp.,
Echinostoma
spp., Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciola
spp.,
Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp.,
Paramphistomum spp., Calicophoron spp, Cotylophoron spp., Gigantocotyle spp.,
Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp.,
Plagiorchis
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spp., Prosthogonismus spp., Dicrocoelium spp., Collyriclum spp., Nanophyetus
spp.,
Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp.,
Metagonimus
spp.
From the order of the Enoplida, for example Trichuris spp., Capillaria spp.,
Trichlomosoides spp., Trichinella spp.
From the order of the Rhabditida, for example Micronema spp., Strongyloides
spp.
From the order of the Strongylida, for example Stronylus spp., Triodontophorus
spp.,
Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx
spp.,
Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum
spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp.,
Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp.,
Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp.,
Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp.,
Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma
spp.,
Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides
spp.,
Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp.,
Cooperia
spp., ~Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum
spp.,
Ollulanus spp., Cyclicocyclus spp., Cylicodontophorus spp.
From the order of the Oxyurida, for example Oxyuris spp., Enterobius spp.,
Passalurus
spp., Syphacia spp., Aspiculuris spp., Heterakis spp.
From the order of the Ascaridia, for example Ascaris spp., Toxascaris spp.,
Toxocara
spp., Parascaris spp., Anisakis spp., Ascaridia spp.
From the order of the Spirurida, for example Gnathostoma spp., Physaloptera
spp.,
3U Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia
spp.,
Dracunculus spp.
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From the order of the Filariida, for example Stephanofilaria spp., Parafilaria
spp.,
Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp.,
Wuchereria
spp., Onchocerca spp.
From the group of the Gigantorhynchida, for example Filicollis spp.,
Moniliformis
spp., Macracanthorhynchus spp., Prosthenorchis spp.
- The productive livestock and breeding stock include mammals, such as, for
example,
cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits,
fallow deer,
reindeer, fur-bearing animals, such as, for example, minks, chinchilla or
raccoon, birds,
such as, for example chickens, geese, turkeys or ducks, fresh and saltwater
fish, such
as, for example, trouts, carps, eels, reptiles, insects, such as, for example,
honeybee and
silkworm.
1S
The laboratory and animals used in experiments include mice, rats, guinea
pigs, golden
hamsters, dogs and cats.
The pets include dogs and cats.
Administration can be effected prophylactically as well as therapeutically.
The active compounds are administered, either directly or in the form of
suitable
preparations, enterally, parenterally, dermally, nasally, by treating the
habitat or with
2S the aid of shaped articles containing the active compound, such as, for
example, strips,
plates, tapes, collars, ear tags, limb bands and marking devices.
Enteral administration of the active compounds is effected for example orally
in the
form of powders, suppositories, tablets, capsules, pastes, drinks, granules,
drenches,
boluses, medicated feed or drinking water. Dermal application is effected, for
example,
in the form of dipping, spraying, bathing, washing, pouring-on and spotting-on
and
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powdering. Parenteral administration is effected, for example, in the form of
injection
(intramuscular, subcutaneous, intravenous or intraperitoneal) or by implants.
Suitable preparations include:
solutions, such as solutions for injection, oral solutions, concentrates for
oral
administration after dilution, solutions for use on the skin or in body
cavities, pour-on
formulations, gels;
emulsions and suspensions for oral or dermal administration and for injection;
semi-
solid preparations;
formulations in which the active compound is incorporated in an ointment base
or in an
oil-in-water or water-in-oil emulsion base;
solid preparations, such as powders, premixes or concentrates, granules,
pellets, tablets,
boluses, capsules; aerosols and inhalants, shaped articles containing the
active
compound.
Solutions for injection are administered intravenously, intramuscularly and
subcutaneously.
Solutions for injection are prepared by dissolving the active compound in a
suitable
solvent and, if desired, adding additives, such as solubilizers, acids, bases,
buffer salts,
antioxidants, or preservatives. The solutions are sterile-filtered and
decanted into
containers.
Suitable solvents include: physiologically acceptable solvents, such as water,
alcohols,
such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene
glycol,
polyethylene glycols and N-methylpyrrolidone, and their mixtures.
If appropriate, the active compounds can also be dissolved in physiologically
acceptable vegetable or synthetic oils which are suitable for injection.
Suitable solubilizers include: solvents which facilitate the dissolution of
the active
compound in the main solvent or which prevent precipitation of the active
compound.
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Examples of solubilizers are polyvinylpyrrolidone, polyethoxylated castor oil
and
polyethoxylated sorbitan esters.
The following are preservatives: benzyl alcohol, trichlorobutanol, p-
hydroxybenzoic
S esters or n-butanol.
Oral solutions are administered directly. Concentrates are first diluted to
the
administration concentration and then administered orally. Oral solutions and
concentrates are prepared as described above in the case of the solutions for
injection,
sterile procedures not being necessary.
Solutions for use on the skin are applied drop by drop, smoothed on, rubbed
in,
splashed on or sprayed on, or applied by dipping, bathing or washing. These
solutions
are prepared as described above in the case of the solutions for injection.
It may be advantageous to add thickeners in the preparation process.
The following are thickeners: inorganic thickeners, such as bentonites,
colloidal silica,
aluminium monostearate, or organic thickeners, such as cellulose derivatives,
polyvinyl
alcohols and their copolymers, acrylates and methacrylates.
Gels are applied to the skin or smoothed on or introduced into body cavities.
Gels are
prepared by adding such an amount of thickener to solutions which have been
prepared
as described for the solutions for injection that a clear composition is
formed which has
an ointment-like consistency. The thickeners used are the thickeners indicated
further
above.
Pour-on and spot-on formulations are poured or splashed onto limited areas of
the skin,
the active compound either penetrating the skin and acting systemically or
being
distributed on the surface of the body.
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Pour-on and spot-on formulations are prepared by dissolving, suspending or
emulsifying the active compound in suitable solvents or solvent mixtures which
are
tolerated by the skin. If appropriate, other auxiliaries, such as colorants,
bioabsorption
promoters, antioxidants, photostabilizers or tackifiers are added.
Suitable solvents include: water, alkanols, glycols, polyethylene glycols,
polypropylene
glycols, glycerol, aromatic alcohols, such as benzyl alcohol, phenylethanol or
phenoxyethanol, esters, such as ethyl acetate, butyl acetate or benzyl
benzoate, ethers,
such as alkylene glycol alkyl ethers, such as dipropylene glycol monomethyl
ether or
..
diethylene glycol monobutyl ether, ketones, such as acetone or methyl ethyl
ketone,
aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF,
dimethylacetamide, N-methylpyrrolidone, or 2,2-dimethyl-4-oxy-methylene-1,3-
dioxolane.
Colorants are all colorants which can be dissolved or suspended and which are
approved for use in animals.
Examples of bioabsorption promoters are DMSO, spreading oils, such as
isopropyl
myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters,
triglycerides or
fatty alcohols.
The following are antioxidants: sulfites or metabisulfites, such as potassium
metabisulfite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or
tocopherol.
Example of photostabilizers are substances from the class of the benzophenones
or
novantisolic acid.
Tackifiers are, for example, cellulose derivatives, starch derivatives,
polyacrylates or
natural polymers such as alginates or gelatin.
Emulsions can be administered orally, dermally or as injections.
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Emulsions are either the water-in-oil type or the oil-in-water type.
They are prepared by dissolving the active compound either in the hydrophobic
or in
the hydrophilic phase arid by homogenizing this phase with the solvent of the
other
phase, with the aid of suitable emulsifiers and, if appropriate, other
auxiliaries, such as
colorants, bioabsorption promoters, preservatives, antioxidants,
photostabilizers, and
viscosity-increasing substances.
Suitable hydrophobic phases (oils) include: paraffin oils, silicone oils,
natural vegetable
oils such as sesame oil, almond oil or castor oil, synthetic triglycerides,
such as
caprylic/capric acid biglyceride, a triglyceride mixture with vegetable fatty
acid of chain
length C8_,2 or other specifically selected natural fatty acids, mixtures of
partial
glycerides of saturated or unsaturated fatty acids which may also contain
hydroxyl
groups, and mono- and diglycerides of the C8/C~o-fatty acids.
Fatty acid esters, such as ethyl stearate, di-n-butyryl adipate, hexyl
laurate, dipropylene
glycol pelargonate, esters of a branched fatty acid having a medium chain
length with
saturated fatty alcohols of chain length Ci6-C18, isopropyl myristate,
isopropyl
palmitate, caprylic/capric esters of saturated fatty alcohols of chain length
C~2-C,B,
isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate,
waxy fatty acid
esters such as artificial duck uropygial fat, dibutyl phthalate, diisopropyl
adipate, ester
mixtures related to the latter, etc.
Fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl
alcohol or
oleyl alcohol.
Fatty acids, such as, for example, oleic acid and its mixtures.
Suitable hydrophilic phases include:
water, alcohols, such as, for example, propylene glycol, glycerol, sorbitol
and their
mixtures.
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Suitable emulsifiers include: nonionic surfactants, for example
polyethoxylated castor
oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol
monostearate, polyoxyethyl stearate or alkylphenol polyglycol ethers;
ampholytic surfactants, such as disodium N-lauryl-(3-iminodipropionate or
lecithin;
anionic surfactants, such as sodium lauryl sulfate, fatty alcohol ether
sulfates, and the
monoethanolamine salt of mono/dialkylpolyglycol ether orthophosphoric ester;
cationic surfactants such as cetyltrimethylammonium chloride.
Other suitable auxiliaries include: substances which increase the viscosity
and stabilize
the emulsion, such as carboxymethylcellulose, methylcellulose and other
cellulose and
starch derivatives, polyacrylates, alginates, gelatin, gum arabic,
polyvinylpyrrolidone,
polyvinyl alcohol, methylvinyl ether/maleic anhydride copolymers, polyethylene
glycols, waxes, colloidal silica, or mixtures of the listed substances.
Suspensions can be administered orally, dermally or as an injection. They are
prepared
by suspending the active compound in a liquid excipient, if appropriate with
the
addition of other auxiliaries, such as wetting agents, colorants,
bioabsorption
promoters, preservatives, antioxidants, photostabilizers.
Suitable liquid excipients include all homogeneous solvents and solvent
mixtures.
Suitable wetting agents (dispersants) include the surfactants indicated
further above.
Other suitable auxiliaries include those indicated further above.
Semi-solid preparations can be administered orally or dermally. They are only
distinguished from the above-described suspensions and emulsions by their
higher
viscosity.
To prepare solid preparations, the active compound is mixed with suitable
excipients, if
appropriate with the addition of auxiliaries, and the mixture is formulated as
desired.
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Suitable excipients include all physiologically acceptable solid inert
substances. All
those are inorganic and organic substances. Inorganic substances are, for
example,
common salt, carbonates such as calcium carbonate, hydrogen carbonates,
aluminium
oxides, silicas, clays, precipitated or colloidal silica, and phosphates.
Organic substances are, for example, sugars, cellulose, foodstuffs and animal
feeds,
such as powdered milk, animal meals, cereal meals, coarse cereal meals and
starches.
Auxiliaries are preservatives, antioxidants and colorants which have akeady
been
mentioned further above.
Other suitable auxiliaries are lubricants and glidants, such as, for example,
magnesium
stearate, stearic acid, talc, bentonites, disintegrants, such as starch or
crosslinked
polyvinylpyrrolidone, binders, such as, for example, starch, gelatin or linear
polyvinylpyrrolidone, and dry binders, such as microcrystalline cellulose.
The active compound according to the invention can be present in its
commercially
available formulations and in the use forms, prepared from these formulations,
as a
mixture with other active compounds, such as insecticides, sterilizing agents,
bactericides, acaricides, nematicides or fungicides. The insecticides include,
for
example, phosphoric acid esters, carbamates, carboxylates, chlorinated
hydrocarbons,
phenylureas, nicotinyles, neonicotinyles and substances produced by
microorganisms,
inter alia.
Particularly favourable examples of co-components in mixtures are the
following
compounds:
Fungicides:
aldimorph, ampropylfos, ampropylfos-potassium, andoprim, anilazine,
azaconazole,
azoxystrobin,
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benalaxyl, benodanil, benomyl, benzamacril, benzamacril-isobutyl, bialaphos,
binapacryl, biphenyl, bitertanol, blasticidin-S, bromuconazole, bupirimate,
buthiobate,
calcium polysulfide, capsimycin, captafol, captan, carbendazim, carboxin,
carvon,
S quinomethionate, chlobenthiazone, chlorfenazole, chloroneb, chloropicrin,
chlorothalonil, chlozolinate, clozylacon, cufraneb, cymoxanil, cyproconazole,
cyprodinil, cyprofuram,
debacarb, dichlorophen, diclobutrazole, diclofluanid, diclomezine, dicloran,
diethofencarb, difenoconazole, dimethirimol, dimethomorph, diniconazole,
diniconazole-M, dinocap, diphenylamine, dipyrithione, ditalimfos, dithianon,
dodemorph, dodine, drazoxolon,
edifenphos, epoxiconazole, etaconazole, ethirimol, etridiazole,
famoxadon, fenapanil, fenarimol, fenbuconazole, fenfuram, fenitropan,
fenpiclonil,
fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam,
ferimzone,
1 S fluazinam, flumetover, fluoromide, fluquinconazole, flurprimidol,
flusilazole,
flusulfamide, flutolanil, flutriafol, folpet, fosetyl-aluminium, fosetyl-
sodium, fthalide,
fuberidazole, furalaxyl, furametpyr, furcarbonil, furconazole, furconazole-
cis,
furmecyclox,
guazatine,
hexachlorobenzene, hexaconazole, hymexazole,
imazalil, imibenconazole, iminoctadine, iminoctadine albesilate, iminoctadine
triacetate, iodocarb, ipconazole, iprobenfos (IBP), iprodione, irumamycin,
isoprothiolane, isovaledione,
kasugamycin, kresoxim-methyl, copper preparations, such as: copper hydroxide,
2S copper naphthenate, copper oxychloride, copper sulfate, copper oxide, oxine-
copper
and Bordeaux mixture,
mancopper, mancozeb, maneb, meferimzone, mepanipyrim, mepronil, metalaxyl,
metconazole, methasulfocarb, methfuroxam, metiram, metomeclam, metsulfovax,
mildiomycin, myclobutanil, myclozolin,
nickel dimethyldithiocarbamate, nitrothal-isopropyl, nuarimol,
ofurace, oxadixyl, oxamocarb, oxolinic acid, oxycarboxim, oxyfenthiin,
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paclobutrazole, pefurazoate, penconazole, pencycuron, phosdiphen, pimaricin,
piperalin, polyoxin, polyoxorim, probenazole, prochloraz, procymidone,
propamocarb, propanosine-sodium, propiconazole, propineb, pyrazophos,
pyrifenox,
pyrimethanil, pyroquilon, pyroxyfur,
quinconazole, quintozene (PCNB),
sulfur and sulfur preparations,
tebuconazole, tecloftalam, tecnazene, tetcyclacis, tetraconazole,
thiabendazole,
thicyofen, thifluzamide, thiophanate-methyl, thiram, tioxymid, tolclofos-
methyl,
tolylfluanid, triadimefon, triadimenol, triazbutil, triazoxide, trichlamide,
tricyclazole,
1U tridemorph, triflumizole, triforine, triticonazole,
uniconazole,
validamycin A, vinclozolin, viniconazole,
zarilamide, zineb, ziram and also
Dagger G,
OK-8705,
OK-8801,
a-( 1,1-dimethylethyl)-J3-(2-phenoxyethyl)-1 H-1,2,4-triazole-1-ethanol,
a-(2,4-dichlorophenyl)-(3-fluoro-b-propyl-1 H-1,2,4-triazole-1-ethanol,
a-(2,4-dichlorophenyl)-(3-methoxy-a-methyl-1 H-1, 2,4-triazo le-1-ethanol,
a-(5-methyl-1,3-dioxan-5-yl)-[3-[[4-(trifluoromethyl)-phenyl]-methylene]-1H-
1,2,4-
triazole-1-ethanol,
(5RS,6RS)-6-hydroxy-2,2,7,7-tetramethyl-5-( 1 H-1,2,4-triazol-1-yl)-3-
octanone,
(E)-a-(methoxyimino)-N-methyl-2-phenoxy-phenylacetamide,
isopropyl {2-methyl-1-[[[1-(4-methylphenyl)-ethyl]-amino]-carbonyl]-propyl}-
carbamate,
1-(2,4-dichlorophenyl)-2-( 1 H-1,2,4-triazol-1-yl)-ethanone-O-(phenylmethyl)-
oxime,
1-(2-methyl-1-naphthalenyl)-1 H-pyrrole-2, 5-dione,
1-(3,5-dichlorophenyl)-3-(2-propenyl)-2,5-pyrrolidinedione,
1-[(diiodomethyl)-sulfonyl]-4-methyl-benzene,
1-[[2-(2,4-dichlorophenyl)-1,3-dioxolan-2-yl]-methyl]-1 H-imidazole,
1-[[2-(4-chlorophenyl)-3-phenyloxiranyl]-methyl]-1 H-1,2,4-triazole,
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1-[ 1-[2-[(2,4-dichlorophenyl)-methoxy]-phenyl]-ethenyl]-1 H-imidazole,
1-methyl-5-nonyl-2-(phenylmethyl)-3-pyrrolidinol,
2',6'-dibromo-2-methyl-4'-trifluoromethoxy-4'-trifluoro-methyl-1,3-thiazole-5-
carboxanilide,
2,2-dichloro-N-[ 1-(4-chlorophenyl)-ethyl]-1-ethyl-3-methyl-
cyclopropanecarboxamide,
2,6-dichloro-5-(methylthio)-4-pyrimidinyl-thiocyanate,
2,6-dichloro-N-(4-trifluorornethylbenzyl)-benzamide,
2,6-dichloro-N-[[4-(trifluoromethyl)-phenyl]-methyl]-benzarnide,
2-(2,3,3-triiodo-2-propenyl)-2H-tetrazole,
2-[( 1-methylethyl)-sulfonyl]-5-(trichloromethyl)-1,3,4-thiadiazole,
2-[[6-deoxy-4-O-(4-O-methyl-(3-D-glycopyranosyl)-a-D-glucopyranosyl]-amino]-4-
methoxy-1 H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile,
2-aminobutane,
2-bromo-2-(bromomethyl)-pentanedinitrile,
2-chloro-N-(2,3-dihydro-1,1, 3-trimethyl-1 H-inden-4-yl )-3-
pyridinecarboxamide,
2-chloro-N-(2,6-dimethylphenyl)-N-(isothiocyanatomethyl)-acetamide,
2-phenylphenol (OPP),
3,4-dichloro-1-[4-(difluoromethoxy)-phenyl]-1 H-pyrrole-2,5-dione,
3,5-dichloro-N-[cyano-[(1-methyl-2-propynyl)-oxy]-methyl]-benzarnide,
3-( 1,1-dimethylpropyl)-1-oxo-1 H-indene-2-carbonitrile,
3-[2-(4-chlorophenyl)-5-ethoxy-3-isoxazolidinyl]-pyridine,
4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1 H-imidazole-1-sulfonamide,
4-methyl-tetrazolo[ 1,5-a]quinazolin-5(4H)-one,
8-(1,1-dimethylethyl)-N-ethyl-N-propyl-1,4-dioxaspiro[4.5]decane-2-
methanamine,
8-hydroxyquinoline sulfate,
9H-xanthene-2-[(phenylamino)-carbonyl]-9-carboxylic hydrazide,
bis-( 1-methylethyl)-3-methyl-4-[(3-methylbenzoyl)-oxy]-2,5-
thiophenedicarboxylate,
cis-1-(4-chlorophenyl)-2-( 1 H-1,2,4-triazol-1-yl)-cyc loheptanol,
cis-4-[3-[4-(l,l-dimethylpropyl)-phenyl-2-methylpropyl]-2,6-dimethyl-
morpholine
hydrochloride,
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ethyl [{4-chlorophenyl)-azo]-cyanoacetate,
potassium hydrogen carbonate,
methanetetrathiol sodium salt,
methyl 1-(2, 3-dihydro-2,2-di methyl-1 H-inden-1-yl)-1 H-imidazole-5-
carboxylate,
methyl N-(2,6-dimethylphenyl)-N-(5-isoxazolylcarbonyl)-DL. alaninate,
methyl N-(chloroacetyl)-N-(2,6-dimethylphenyl)-DL-ataninate,
N-{2,3-dichloro-4-hydroxyphenyl)-1-methyl-cyclohexanecarboxamide,
N-(2,6-dimethylphenyl)-2-methoxy-N-(tetrahydro-2-oxo-3-furanyl)-acetamide,
N-(2,6-dimethylphenyl)-2-methoxy-N-(tetrahydro-2-oxo-3-thienyl)-acetamide,
N-{2-chloro-4-nitrophenyl)-4-methyl-3-nitro-benzenesulfonarnide,
N-(4-cyclohexylphenyl)-1,4,5,6-tetrahydro-2-pyrimidinamine,
N-(4-hexylphenyl)-1,4,5,6-tetrahydro-2-pyrimidinamine,
N-(5-chloro-2-methylphenyl)-2-methoxy-N-(2-oxo-3-oxazolidinyl)-acetamide,
N-(6-methoxy)-3-pyridinyl)-cyclopropanecarboxamide,
N-[2,2,2-trichloro-1-[(chloroacetyl)-amino]-ethyl]-benzamide,
N-[3-chloro-4,5-bis-(2-propinyloxy)-phenyl]-N'-methoxy-methanirnidamide,
N-formyl-N-hydroxy-DL-alanine sodium salt,
O,O-diethyl [2-(dipropylamino)-2-oxoethyl]-ethylphosphorarnidothioate,
O-methyl S-phenyl phenylpropylphosphoramidothioate,
S-methyll,2,3-benzothiadiazole-7-carbothioate,
spiro[2H]-1-benzopyrane-2,1'(3'H)-isobenzofuran]-3'-one.
Bactericides:
bronopol, dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate,
kasugamycin,
octhilinone, furancarboxylic acid, oxytetracyclin, probenazole, streptomycin,
tecloftalam, copper sulfate and other copper preparations, quinoloes, such as
ciprofloxacin, danofloxacin, difloxacin, enrofloxacin, flumequine,
ibafloxacin,
marbofloxacin, norfloxacin, ofloxacin, orbifloxacin, premafloxacin,
sarafloxacin.
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Insecticides / acaricides / nematicides:
abamectin, acephate, acetamiprid, acrinathrin, alanycarb, aldicarb,
aldoxycarb, alpha-
cypermethrin, alphamethrin, amitraz, avermectin, AZ 60541, azadirachtin,
azamethiphos, azinphos A, azinphos M, azocyclotin,
Bacillus popilliae, Bacillus sphaericus, Bacillus subtilis, Bacillus
thuringiensis,
Baculoviruses, Beauveria bassiana, Beauveria tenella, bendiocarb, benfuracarb,
bensultap, benzoximate, betacyfluthrin, bifenazate, bifenthrin,
bioethanomethrin,
biopermethrin, BPMC, bromophos A, bufencarb, buprofezin, butathiofos,
butocarboxim, butylpyridaben,
....
cadusafos, carbaryl, carbofuran, carbophenothion, carbosulfan, cartap,
chloethocarb,
chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos,
chlorpyrifos, chlorpyrifos M, chlovaporthrin, cis-resmethrin, cispermethrin,
clocythrin, cloethocarb, clofentezine, clothianidine, c;oumafos, cyanophos,
cycloprene, cycloprothrin, cyfluthrin, cyhalothrin, cyhexatin, cypermethrin,
cyromazine, cythioate, chlorothianidin,
deltamethrin, demeton M, demeton S, demeton-S-methyl, diafenthiuron, diazinon,
dichlorvos, dicyclanil, diflubenzuron, dimethoate, dimethylvinphos,
diofenolan,
disulfoton, docusat-sodium, dofenapyn, dinotefuran,
eflusilanate, emamectin, empenthrin, endosulfan, eprinomectin, esfenvalerate,
ethiofencarb, ethion, ethiprole, ethoprophos, etofenprox, etoxazole, etrimfos,
fenamiphos, fenazaquin, fenbutatin oxide, fenitrothion, fenothiocarb,
fenoxacrim,
fenoxycarb, fenpropathrin, fenpyrad, fenpyrithrin, fenpyroximate, fenthion,
fenvalerate, fipronil, fluazinam, fluazuron, flubrocythxinate, flucycloxuron,
flucythrinate, flufenoxuron, flumethrin, flutenzine, fluvalinate, fonophos,
fosmethilan, fosthiazate, fubfenprox, furathiocarb, flupyrazofos,
granulosis viruses,
halofenozide, HCH, heptenophos, hexaflumuron, hexythiazox, hydroprene,
imidacloprid, indoxacarb, isazofos, isofenphos, isoxathion, ivermectin,
nuclear polyhedrosis viruses,
lambda-cyhalothrin, lufenuron,
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malathion, mecarbam, metaldehyde, methamidophos, metharhizium anisopliae,
metharhizium flavoviride, methidathion, methiocarb, methomyl, methonrene_
methoxyfenozide, metolcarb, metoxadiazone, metrifonat, mevinphos, milbemectin,
rnonocrotophos, moxidectin,
naled, nitenpyram, nithiazine, novaluron, NEEM,
omethoate, oxamyl, oxydemethon M,
Paecilomyces fumosoroseus, parathion A, parathion M, ;permethrin, phenthoate,
phorate, phosalone, phosmet, phosphamidon, phoxim, pirimicarb, pirimiphos A,
pirimiphos M, profenofos, promecarb, propoxur, prothiofos, prothoate,
pymetrozine,
pyraclofos, pyresmethrin, pyrethrum, pyridaben, pyridathion, pyrimidifen,
pyriproxyfen, protrifenbute,
quinalphos,
ribavirin,
salithion, sebufos, selamectin, silafluofen, spinosad, spiiodiclofen,
sulfotep,
sulprofos, S 1812,
tau-fluvalinate, tebufenozide, tebufenpyrad, tebupirimiphos, teflubenzuron,
tefluthrin, temephos, temivinphos, terbufos, tetrachlorvinphos,
thetacypermethrin,
thiamethoxam, thiapronil, thiatriphos, thiocyclam hydrogen oxalate,
thiodicarb,
thiofanox, thuringiensin, tralocythrin, tralomethrin, triarathene, triazamate,
triazophos, triazurone, trichlophenidine, trichlorfon, triflumuron,
trimethacarb,
.~-..
thiacloprid,
vamidothion, vaniliprole, Verticillium lecanii,
YI 5302,
zeta-cypermethrin, zolaprofos,
( 1 R-cis)-[5-(phenylmethyl)-3-furanyl]-methyl-3-[(dihydro-2-oxo-3(2H)-furanyl-
idene)-methyl]-2,2-dimethylcyclopropanecarboxylate,
(3-phenoxyphenyl)-methyl 2,2,3,3-tetramethylcyclopropanecarboxylate,
1-[(2-chloro-5-thiazolyl)methyl]tetrahydro-3,5-dimethyl-N-nitro-1,3,5-triazine-
2( 1 H)-imine,
2-(2-chloro-6-fluorophenyl)-4-[4-(l,l-dimethylethyl)phenyl]-4,5-dihydro-
oxazole,
2-(acetyloxy)-3-dodecyl-1,4-naphthalenedione,
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2-chloro-N-[[[4-( 1-phenylethoxy)-phenyl]-amino]-carbonyl]-benzamide,
2-chloro-N-[[[4-(2,2-dichloro-l,1-difluoroethoxy)-phenyl]-amino]-carbonyl]-
benzamide,
3-methylphenyl propylcarbamate,
4-[4-(4-ethoxyphenyl)-4-methylpentyl]-1-fluoro-2-phenoxy-benzene,
4-chloro-2-( 1,1-dimethylethyl)-5-[[2-(2,6-dimethyl-4-
phenoxyphenoxy)ethyl]thio]-
3(2H)-pyridazinone,
4-chloro-2-(2-chloro-2-methylpropyl)-5-[(6-iodo-3-pyridinyl;)methoxy]-3(2H)-
pyridazinone,
4-chloro-5-[(6-chloro-3-pyridinyl)methoxy]-2-(3,4-dichlorophenyl)-3(2H)-
pyridazinone,
Bacillus thuringiensis strain EG-2348,
[2-benzoyl-1-(1,1-dimethylethyl)-hydrazinobenzoic acid,
2,2-dimethyl-3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-yl
butanoate,
[3-[(6-chloro-3-pyridinyl)methyl]-2-thiazolidinylidene]-cyanamide,
dihydro-2-(nitromethylene)-2H-1,3-thiazine-3(4H)-carboxaldehyde,
ethyl [2-[[1,6-dihydro-6-oxo-1-(phenylmethyl)-4-pyridazinyl]oxy]ethyl]-
carbamate,
N-(3,4,4-trifluoro-1-oxo-3-butenyl)-glycine,
N-(4-chlorophenyl)-3-[4-(difluoromethoxy)phenyl]-4,5-dihydro-4-phenyl-1H-
pyra~ole-1-carboxamide,
N-[(2-chloro-5-thiazolyl)methyl]-N'-methyl-N"-nitro-guanidine,
N-methyl-N'-( 1-methyl-2-propenyl)-1,2-hydrazinedicarbothioamide,
N-methyl-N'-2-propenyl-1,2-hydrazinedicarbothioamide,
O,O-diethyl [2-(dipropylamino)-2-oxoethyl]-ethylphosphorarnidothioate.
The active compounds according to the invention can furthermore be present in
their
commercially available formulations and in the use forms, prepared from these
formulations, as a mixture with synergistic agents. Synergistic; agents are
compounds
which increase the action of the active compounds, without it being necessary
for the
synergistic agent added to be active itself.
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Ready-to-use preparations comprise the active compound in concentrations of
from
ppm to 20% by weight, preferably from 0.1 to 10% by weight.
Preparations which are diluted prior to use comprise the active compound in
5 concentrations of from 0.5 to 90% by weight, preferably from 5 to 50% by
weight.
In general, it has been found to be advantageous to administer amounts of from
about
1 to 100 mg of active compound per kilogram of body weight per day to obtain
effective results.
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Preparation Examples
Example 1
Cyclo( N methyl-L-1eutipy1-D-(hydroxy-imino)-lactyl-N methyl-L-1eutipy1-D
phenyl-
lactyl-N methyl-L-1eutipy1-D-lactyl-N methyl-L-1eutipy1-D phenyllactyl J
Me
HBO Me p Me
N ~ O ~''~"..
Me N ' N O
Me0 ~ Me Me
O O
O Me
Me Me'
O N N
Me
Me ~ ,M'e1~0~~ Me
a) according to process 2a using mercury(II) acetate
20Q.0 mg (0.20 mmol) of cyclo(-N-methyl-L-1eutipy1-D-thiolactyl-N-methyl-L-
.~-.. 1eutipy1-D-phenyllactyl-N-methyl-L-1eutipy1-D-lactyl-N-methyl-L-1eutipy1-
D-
phenyllactyl-) (cf. WO 98/43 965) in 5 ml of acetonitrile are treated
successively with
43.6 mg (0.62 mmol) of hydroxylamine hydrochloride, 145.0 mg (0.45 mmol) of
mercury(II) acetate and 162.2 mg (1.25 mmol) of ethyldiisopropylamine
("Hiinig's
Base"), and the mixture is stirred at room temperature for l8 hours. To bring
the
reaction to completion, another 21.8 mg (0.31 mmol.) of hydroxylamine
hydrochloride, 72.5 mg (0.45 mmol) of mercury(II) acetate and 107.4 mg
(1.25 mmol) of ethyldiisopropylamine ("Hiinig's Base") are added, and the
mixture is
stirred at room temperature for another 6 hours. The entire reaction mixture
is then
stirred into about 20 ml of aqueous NH4C1 solution and extracted four times
with
15 ml of chloroform. The crude product that remains is chromatographed over a
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silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm)
using the
mobile phase cyclohexane : acetone ( 4 : 1 ).
This gives 70.4 mg (35% of theory) of cyclo[-N-methyl-L-leucinyl-D-(hydroxyimi-
no)-lactyl-N-methyl-L-leuc inyl-D-phenyl lactyl-N-methyl-L-leucinyl-D-lactyl-N-
methyl-L-leucinyl-D-phenyllactyl-] as anti-/syn-isomer mixture.
b) according to process 2a using mercury(II] chloride / mercury(II) acetate
The reaction with hydroxylamine hydrochloride is carried out similarly to the
reaction procedure of Example 1 (Variant a) using:
500.0 mg (0.52 mmol) of cyclo(-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-
L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-
lactyl-N-methyl-L-leucinyl-D-phenyllactyl-)
107.9 mg (1.55 mmol) of hydroxylamine hydrochloride
422.0 mg (1.55 mmol) of rnercury(II) chloride
230.2 mg (1.81 mmol) of ethyldiisopropylamine ("Hunig's Base")
30 ml of tetrahydrofuran
After 20 hours of stirring at 50°C, another 180.0 mg (0.56 mmol) of
mercury(II)
acetate are added, and stirring is continued at 50°C for another 24
hours. The entire
reaction mixture is then filtered and worked up as under Example 1 (Variante
a).
Yield: 250 mg (50% of theory)
b) according to process 3a by hydrogenation of derivative 17
400.0 mg (0.37 mmol) of cyclo[-N-methyl-L-leucinyl-D-(benzyloxyimino)-lactyl-N-
methyl-L-leucinyl-D-phenyl(actyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-
leucinyl-D-phenyllactyl-] 17 (cf. Table 1) are stirred in 40 ml of methanol
and, in the
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presence of 200 mg of Pd/carbon [palladium content 10'%) and 0.7 ml of conc.
hydrochloric acid, hydrogenated at room temperature until hydrogen uptake has
ended (about 20 minutes). The catalyst is filtered off and the entire reaction
solution
is then concentrated under reduced pressure and the crude product that remains
is
chromatographed over an RP-18 column using the mobile phase acetonitrile :
water.
Yield: 110 mg (30% of theory)
c) according to process 3b by deblocking from a polymeric resin support
A mixture of 100 mg cyclodepsipeptide-containing polystyrene resin, 3.0 ml of
n-
butanol and 3.0 ml of 1,2-dichloroethane is treated with 8.5 mg of pyridine
para-
toluenesulfonic acid and stirred at 60°C for one hour. The polystyrene
resin is then
filtered off and washed five times with methylene chloride. Concentration
under
reduced pressure gives 9.4 mg of crude product in which Example 1 could be
demonstrated by APCI-MS.
LC-MS (acidic) m/z (%): 964 (M+, 100). C52H~~N5012 (964.2)
Rt - value (HPLC column: 125 x 2.1 Kromasil ~, C-18): 17.4; 17.66 min; anti-
/syn-
isomer mixture (20:80).
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Example 2
Cyclo~ N methyl-L-leucinyl-D-(O-methyl-imino)-lactyl-N methyl-L-leucinyl-D
phenyl-lactyl-N methyl-L-leucinyl-D-lactyl-N methyl-L-leucinyl-D phenyllactyl
J
Me Me
Me,O Me O
N ~., O
Me N \ N O
Me0 ~ Me Me
'""'"'' O O
O Me
Me Me\
O N N
Me
Me ~ ,M'e' 0~ MY '~e
The reaction with an O-substituted amine component was carried out similarly
to the
reaction procedure of Example 1 using:
200.0 mg (0.20 mmol) of (-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-L-
leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-
N-methyl-L-leucinyl-D-phenyllactyl-)
52.4 mg (0.62 mmol) of O-methyl-hydroxylamine hydrochloride
145.0 mg (0.45 mmol) of mercury(II) acetate
162.2 mg (1.25 mmol) of ethyldiisopropylamine ("Hiinig's Base")
5 ml of acetonitrile
The crude product that remains is chromatographed over a silica gel columne
(silica
gel 60 - Merck, particle size: 0.04 to 0.063 mm), initially using the mobile
phase
cyclohexane : acetone ( 4 : 1 ). This gives 170 mg (83% of theory) of cyclo[-N-
methyl-L-leucinyl-D-(O-methyl-imino)-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-
N-methyl-L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] .
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'H-NMR (600 MHz, CDC13, 8): 2.85; 2.87; 2.90; 3.04 (4 x N-CH ); 3.65 (-O-CH ,
oxime) ppm.
13C-NMR (100 MHz, CDCl3, 8): 29.3; 30.2; 30.9; 31.0 (4 x N-CH ); 61.3 (-O-CH3,
oxime); 66.9; 68.1; 69.7; 71.1; (4 x -CH-O-); 56.9; 53.9; 53.9; 59.5 (4 x -CH-
N-);
170.3; 170.3; 172.5; (3 x -N-C=O); 152.9 (1 x -C=N-O, oxime); 170.2; 170.7;
171.1;
172.5 (4 x -O-C=O) ppm.
LC-MS (acidic) m/z (%): 978 (M+, 100). CS3H~91V50~2 (978.x')
R~ - value (HPLC column: 125 x 2.1 Kromasil ~, C-18): 18.34 min
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Example 3
Cyclo~ N methyl-L-leucinyl-D-(O-acetyl-imino)-lactyl-N methyl-L-1eutipy1-D-
phenyl-lactyl-N methyl-L-1eutipy1-D-lactyl-N methyl-L-1eutipy1-D phenyllactyl
J
S
0
~ Me Me
Me" p Me O
N w ":
~O~
Me~ N' N O
Me0 Me Me
O O
O Me
Me Me
O N \N
O Me
Me M''e11~'O~~// Me
200.0 mg (0.20 mmol) of 1 (see Ex. 1 ) are treated in 1 ml of acetic anhydride
and
stirred at 70°C for about 30 minutes. The entire reaction mixture is
then treated with
saturated NaHC03 solution and extracted three times with 15 ml of ethyl
acetate. The
organic phase is separated off, dried over magnesium sulfate and concentrated
under
reduced pressure. The crude product that remains is chromatographed over a
silica
gel columne (silica gel 60 - Merck, particle size: 0.04 to 0.06:3 mm) using
the mobile
phase cyclohexane : acetone ( 10 : 1 ). This gives 125.8 mg (fi0% of theory)
of crude
product which, after preparative HPLC (RP-18), gives 80 mg (38% of theory) of
pure
cyclo[-N-methyl-L-1eutipy1-D-(O-acetyl-imino)-lactyl-N-methyl-L-1eutipy1-D-
phenyllactyl-N-methyl-L-1eutipy1-D-lactyl-N-methyl-L-1eutipy1-D-phenyl-lactyl-
] as
anti/syn isomer mixture (purity: 98.7%).
LC-MS (acidic) m/z (%): 1006 (M+, 100). C$4H7gNSO~3 (1006.2)
R~- value (HPLC column: 125 x 2.1 Kromasil ~, C-18): 7.35 min
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Examale 4
Cyclo~ N methyl-L-leucinyl-D-(O-vinylo~ycarbonyl-imino)-lactyl-N methyl-L-
leucinyl-D phenyllactyl-N methyl-L-leucinyl-D-lactyl-N methyl-L-leucinyl-D-
phenyllactyl J
0
Me
~O~ O Me O Me
r
N ~ O ~,~,,
Me N ' N O
Me0 ~ Me Me
O O
O Me
Me Me
/ O N \N
O Me
Me ~ Me'0I ~~,~Me
At 0°C, 300.0 mg (0.31 mmol) of 1 (see Ex. 1) are stirred in 10 ml of
dry pyridine
and treated with 99.4 mg (0.93 mmol) of vinyl chloroformate. Stirring at
0°C is then
continued for another 6 hours. The entire reaction mixture is then
concentrated under
reduced pressure and the residue is taken up in chloroform and washed once
with
1N HCI and twice with NaE-IC03 solution. The organic phase is separated off
and
dried over magnesium sulfate and then concentrated under reduced pressure, and
the
crude product that remains is chromatographed over a silica gel column (silica
gel 60
- Merck, particle size: 0.04 to 0.063 mm) using the mobile phase cyclohexane :
ethyl
acetate {2 : 1). This gives 188.7 mg (58.7% of theory) of cyclo[-N-methyl-L-
leucinyl-
D-(O-vinyloxycarbonyl-imino)-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-
methyl-
L-leucinyl-D-lactyl-N-methyl-L-leucinyl-D-phenyllactyl-] as anti/syn isomer
mixture.
LC-MS (acidic) mlz (%): 1037 (MH+, 100) CSSHB~NSC)~Q (103b.2)
RL- value (HPLC column: 125 x 2.1 I~romasil ~, C-18): 17.82 min
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Example 5
Cyclo~ N methyl-L-1eutipy1-D-(D-methylsulfonyl-imino)-lactyl-N methyl-L-
leucinyl-
D phenyllactyl-N methyl-L-1eutipy1-D-lactyl-N methyl-L-1eutipy1-D phenyllactyl
J
0
Me
Me~~ O Me O Me
N ~.. O .".
Me N ' N O
MeO~ Me Me
O O
O Me
Men
O N
N Me
""~~O~O
Me ~ Me0 Me
The reaction with methanesulfonyl chloride is carried out similarly to the
reaction
procedure of Example 4 using:
200.0 mg {0.20 mmol) of cyclo[-N-methyl-L-1eutipy1-D-(hydroxy-imino)-lactyl-N-
methyl-L-1eutipy1-D-phenyl-lactyl-N-methyl-L-1eutipy1-D-lactyl-N-methyl-L-
leucinyl-D-phenyllactyl-] (Ex. 1)
71.3 mg (0.62 mmol) of methanesulfonyl chloride
8 ml of dry pyridine
The crude product that remains is chromatographed over a silica gel column
(silica
gel 60 - Merck, particle size: 0.04 to 0.063 mm) initially using the mobile
phase
cyclohexane : ethyl acetate (3 : 2). This gives 81.8 mg (38% of theory) of
cyclo[-N-
methyl-L-1eutipy1-D-(O-methylsulfonyl-imino)-lactyl-N-methyl-L-1eutipy1-D-
phenyllactyl-N-methyl-L-1eutipy1-D-lactyl-N-methyl-L-1eutipy1-D-phenyllactyl-]
as
antilsyn isomer mixture.
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LC-MS (acidic) m/z (%): 1042 (MH+, 100). C53H~9Ng014S (1042.3)
R~- value (HPLC column: 125 x 2.1 Kromasil ~, C-18): 17.18 min
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Example 6
Cyclo~ N methyl-L-1eutipy1-D-(O-allylaminocarbonyl-imino)-lactyl-N methyl-L-
leucinyl-D phenyllactyl-N methyl-L-1eutipy1-D-lactyl-N methyl-L-1eutipy1-D-
phenyllactyl J
0
~ Me
~N~O Me O Me
H N .., O
Me N\ ~N O
Me Me
Me0
O O
O
Me Me Me
O' _N \N
O Me
Me ~''M''e'' 0~~ 'Me
300.0 mg (0.31 mmol) of cyclo[-N-methyl-L-1eutipy1-D-(hydroxy-imino)-lactyl-N-
methyl-L-1eutipy1-D-phenyl-lactyl-N-methyl-L-1eutipy1-D-lactyl-N-methyl-L-
1eutipy1-D-phenyl-lactyl-] (Ex. 1) in 10 ml of abs. toluene are treated
successively
with 30.4 mg (0.36 mmol) of allyl isocyanate and 2 drops of 1,8-
diazabicyclo[5.4.0]undec-7-ene {"DBU") and stirred at roam temperature for 33
hours. The entire reaction mixture is then concentrated under reduced
pressure. The
crude product which remains is initially chromatographed over a silica gel
column
(silica gel 60 - Merck, particle size: 0.04 to 0.063 mm) using the mobile
phase
cyclohexane : acetone (3 : 1 ) and then over a second silica gel column
(silica gel 60 -
Merck, particle size: 0.04 to 0.063 mm) using the mobile phase cyclohexane :
ethyl
acetate (2 : 1 to 1 : 1). This gives 52.4 mg (16.1% of theory) of cyclo[-N-
methyl-L-
leucinyl-D-(O-allylaminocarbonyl-imino)-lactyl-N-methyl-L-1eutipy1-D-
phenyllactyl-N-methyl-L-1eutipy1-D-lactyl-N-methyl-L-leucin,yl-D-phenyllactyl-
] as
anti/syn isomer mixture.
LC-MS (acidic) m/z (%): 1047 (M+, 100). C56H81N6O1j (104'7.3)
RL- value {HPLC column: 125 x 2.1 Kromasil ~, C-18, pH 2.3): 17.09; 17.39 min
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Example 7
Cyclo( N methyl-L-leucinyl-D-(O-N tert-butyloxycarbonyl-71~ methyl-alanyl-
imino)-
lactyl-N methyl-L-leucinyl-D phenyllactyl-N methyl-L-leucirayl-D-lactyl-N
methyl-L-
leucinyl-D phenyllactyl J
Me O
Me~O~N~ Me Me
O Me O
Ma O Me N
O
Me N' ~ N O
Me Me
Me0
O O
~ a Me\ O Me
O N N
O Me
Me ~ Me O ''''Me
At 0°C, 184.0 mg (4.1 mmol) of benzotriazol-1-yl-oxy-
tris(dimethylamino-
phosphonium) hexafluorophosphate (BOP) and 124.0 mg (0.95 mmol) N,N-
diisopropylethylamine ("Hiinigs Base") are added to a solution of 300.0 mg
(0.3 F mmol) of cyclo[-N-methyl-L-leucinyl-D-(hydroxy-imino)-lactyl-N-methyl-L-
leucinyl-D-phenyl-lactyl-N-methyl-L-leucinyl-D-lactyl-N-me-thyl-L-leucinyl-D-
phenyl-lactyl-] (Ex. 1) and 75.7 mg (0.37 mmol) of N-tent-butyloxy-carbonyl-N-
methyl-alanine in 10 ml of abs. acetonitrile, and the mixture is stirred at
0°C for 30
minutes and then at room temperature for 24 hours. The entire reaction mixture
is
then concentrated under reduced pressure, the residue is taken up in
chloroform and
extracted twice with water and the organic phase is separated off, dried over
sodium
sulfate and then concentrated under reduced pressure. The crude product that
remains
is purified by preparative HPLC. This gives 15.6 mg (4.4% of theory) of cyclo[-
N-
methyl-L-leucinyl-D-(O-N-tert-butyloxycar-bonyl-N-methyl-alanyl-imino)-lactyl-
N-
methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-methyl-L-
leucinyl-D-phenyllactyl-] as anti/syn isomer mixture.
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LC-MS (acidic) m/z (%): 1150 (MH+, 100). C6~H91N6O~s (1149.4)
R,- value (HPLC column: 125 x 2.1 Kromasil ~, C-18): 7.69; 7.76 min
The com ounds of the formula Ia R' R3 R4 R' R9 R'°; -Me' RZ RS Rg
R": -
P ( )( > > > > > > > > >
iso-butyl; XZ: =N-A; X2-X4: =O) listed in Table 1 below can be prepared
analogously.
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Table 1
~~Me
A Me ~J'O
N~O~,~
Me N ' fN O ~ R"
MeO~ Me Me
O O
O Me
Me Me'
R' ~ O N N Me (Ia)
O~O
Me ~ Me0 Me
Ex. -A R' R" Physical data a
No.
993 (MH+, 100); R~: 20.05
8 -O-CH2-Me -H -H
C'sal~s~NsW z (992.2)
1005 (MH+, 100); R~:
20.21;
9 -O-CH2-CH=CHz -H -H 20.31
(anti/syn isomer mixture)
- Css~~a~Ns~m (1048.3)
1006 (MH+, 100); Rt:
13.75
-O-CHZ-CH2-Me -H -H
CssH8.~s4m (1006.3)
1006 (MH~~, 100); Rt:
13.54
11 -O-CHMe2 -H -H
CssF.~83Ns~12 (100b.3)
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Table 1 (Continued)
Ex. -A R' R" Physical T)ata a
No.
1006 (MH+, 100); R~:
22.52;
12 -O-CMe3 -H -H 22.85
,.~. (anti/syn isomer mixture)
Css~~ssNsW 2 (1006.3)
1003 (M+, 100); Rt: 7.49
13 -O-CHZ-CN -H -H
Csa~~~sN641a (1003.2)
1008 (M+, 100); R~: 17.58
14 -O-CH2-CHZ-OH -H -H
Cs~BlNs013 (1 x08.2)
1008 {MH ~, 100)
15 -O-CH2-CH2-NHZ -H -H
Cs4~~81N6~11 (1 ~~7.3)
978 {MH+, 100); R~: 18.33
16 -NHMe -H -H
Cs3~~80N6011 (977.2)
1055 (MH+, 100); R,:
21.23;
17 -O-CH2-phenyl -H -H 21.50
(anti/syn isomer mixture)
Cs9H83Ns~12 (1054.3)
1100 (MH+, 100); Rt:
20.50
18 -O-CH2-(4-N02-phenyl)-H -H
Cs9H82N6~14 (j 099. 3)
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Table 1 (Continued)
Ex. -A R' R" Physical Data a
No.
1099 (M+, 100); Rt:
19.06
19 -O-CHZ-(2-NOZ-phenyl)-H -H
Cs9H~2N60,4 (1099.3)
1123 (MH+, 100);
20 -O-CHZ-(3-CF3-phenyl)-H -H R,: 19.50; 19.68
(anti/syn isomer mixture)
C6oN~~zNsW z (1122.3)
1123 (MH+, 100); Rt:
19.43
21 -O-CH2-(4-CF3-phenyl)-H -H
C6oHdINSOl2 (1122.3)
1088 (MH+, 100)
22 -O-CHZ-(2-Cl-phenyl)-H -H Rt: 19.65; 20.07
(anti/syn :isomer mixture)
C's~s.~CINs0~2 (1088.7)
",~ 1088 (MH+, 100)
23 -O-CHZ-(3-Cl-phenyl)-H -H Rt: 19.61; 19.78
Cs9H8 ~CINSOII (1088.
7)
1088 (MH:+, 100);
24 -O-CH2-(4-Cl-phenyl)-H -H R,: 19.65; 19.82
(anti/syn iisomer mixture)
Cs9H8,eClNsOl1 (1088.7)
1124 (MH:+, 100);
25 -O-CH2-(3,4-Cl2-phenyl)-H -H Rt: 20.14; 20.40
(anti/syn isomer mixture)
Csv~a~ClzNs0~2 (1123.2)
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Table 1 (Continued)
Ex. -A R' R" Physical Data a
No.
1124 (MH*, 100);
26 -O-CH2-(2,6-C12-phenyl)-H -H R~: 19.82; 20.12
(anti/syn isomer mixture)
CspNB~CIzNs4~a (1123.2)
1124 (MH*, 100);
27 -O-CH2-(2,4-Cl2-phenyl)-H -H R~: 20.68; 21.16
(anti/syn isomer mixture)
Cs9H8,C11Ns4m (1123.2)
1124 (MHO, 100);
28 -O-CH2-(2,3-Cl2-phenyl)-H -H R,: 20.32; 20.79
(anti/syn isomer mixture)
Cs9H8~(:IzN50~2 (1123.2)
1106 (M*, 100);
29 -O-CH2-(2-C1,6-F-phenyl)-H -H R,: 19.24; 19.44
(anti/syn isomer mixture)
Cs9H8l(:IFN50~2 (1106.8)
1084 (MH*, 100); R,:
18.97
30 -O-CH2-(4-Me0-phenyl)-H -H
C6oH85N5O~3 (1084.3)
1112 (MH*, 100); R,:
18.89
31 -O-CH2-(4-Me00C-phenyl)-H -H
CsoHssNsW s (1112.3)
1072 (MH*, 100); R~:
19.48
32 -O-CH2-(4-F-phenyl) -H -H
CsvHBZ~'Ns~m (1072.3)
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Table 1 (Continued)
Ex. -A R' R" Physical Data a
No.
1068 (M+" 100); R~: 19.95
33 -O-CHZ-(4-Me-phenyl) -H -H
CaoHsaNs4i2 (1068.3)
964 (MH+, 100); R~: 16.24
34 -NHZ -H -H
C51H78N6~11 (963.2)
1022 (MH+, 100); Rt:
7.32
35 -O-CO-O-Me -H -H
CsaHwNs4~a (1022.2)
1036 (MH+, 100); Rt:
17.69
36 -O-CO-O-CHZ-Me -H -H
CssHsrNs4~a (1036.2)
1048 (MH+, 100); R,:
17.83
37 -O-CO-O-CH2-CH=CHz -H -H
,
CssHBrNsW a (1048.3)
1046 (M+, 38); R,: 7.32
38 -O-CO-O-CH2-C---CH -H -H
C56H79NSOI4 (1046.3)
1064 (MH~~, 100); R~:
18.28
39 -O-CO-O-CHMe-CHz-Me -H -H
Cs~HssNsO,a (1064.3)
1064 (MH*, 100); Rt:
18.33
40 -O-CO-O-CH2-CHMez -H -H
Cs~NsslVs0~4 (1064.3)
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Table 1 (Continued)
Ex. -A R' R" Physical Data a
No.
1116 (MH ~, 100); Rt:
18.01
41 -O-CO-O-CHZ-CHZ-CF=CFZ-H -H
Cs7H80~'.3Ns~14 (1116.3)
42 -O-SOZ-CHz-CHZ-O-CHz--H -H Cs6HszF3IVsSOrs (1154.3)
CF3
0 1076 (MHO-, 100); Rt:
o~ 18.01
43 N _H _H
~
Cs8H86N6~13 (1 X7.5.3)
1091 (M+, 100); R,: 17.64
0
44 ~ -H -H
0
Cs8H86N6~14 (1091.3)
~. O
1049 (MH+, 100); R,:
19.94
45 (s) O -H -H
,
'~," C's~HssNs4~3 (1048.3)
1044 (M+, 100); R,: 18.73
46 O -H -H
CssHs~.NsOla (1044.3)
1045 (MH+, 100); Rt:
O 18.86
47 ~ -H -H
CssHs3NsW a (1044.3)
CI 1096 (MH+, 100);
S
48 ~ O ~ , N -H -H R~: 18.82; 19.02
N ' (anti/syn isomer mixture)
CssH~sC.'IN~0~1S (1096.8)
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Table 1 (Continued)
Ex. -A R' R" Physical Data a
No.
Me, 1060 (MH+, 100);
N-N
49 .~ o ~ 'N -H -H Rt: 17.5 8; 17.70
N
(anti/syn isomer mixture)
"~..
CssHsrN9W z (1059.8)
1055 (M+, 100); R,: 18.08
~ ~
I
50 ' -H -H
N
Cs8H82N6012 (1 ~.s.s.3)
-- ci 1089 (M+, 100); R~: 18.87
~ o
51 \ N -H -H
CssHsW1N64u (1089.7)
1084 (M+, 100); Rt: 19.34
52 ~O \ ~ -H -H
C60H8sNs~73 (1084.3)
. ~ o ~- 1152 (M+, 100); Rt: 19.80
~
,~,... 53 o \ / _H _H
CF3
C61H84F3Ns013 (1152.3)
1059 (M+, 100); R~: 17.69
~
54 ~ -H -H
0
Cs~H~9Ns4,Q (1058.3)
1139 (M+, 100); R,: 11.24
55 -O-CH2-(4-N-morpholino--H -H
phenyl) C63H9PN6~13
iH_NMR (400 MHz, 8, ppm); ~3C-NMR (100 MHz, 8, ppm); LC-MS (acidic)
m/z (%);
Rt-value (min, HPLC column: 125 x 2.1 Kromasil °, C-18)
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Example I-56
Reaction of the polymer-bound hydroxylamine with cyclo[-N-methyl-L-leucinyl-
thiolactyl-N-methyl-L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-lactyl-N-
S methyl-L-leucinyl-D-phenyllactyl-]
The reaction of 6-(amino-oxy)-3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-
polystyrene with the cyclothiodepsipeptide is carned out similarly to the
reaction
procedure of Example 1 (variant a) using:
500.0 mg (0.52 mmol) of cyclo(-N-methyl-L-leucinyl-D-thiolactyl-N-methyl-
L-leucinyl-D-phenyllactyl-N-methyl-L-leucinyl-D-
lactyl-N-methyl-L-leucinyl-D-phenyllactyl-)
200.0 mg of 6-(amino-oxy)-3,4,5,6-tetrahydro-2H-pyran-2-yl-
methoxy-methyl-polystyrene
181.0 mg ( 1.55 mmol) of mercury(II) acetate
15 ml of dichloromethane
The 6-(amino-oxy)-3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene
resin is initially stirred at room temperature in dichloromethane for 30
minutes and
then Heated with the cyclothiodepsipeptide and mercury(II) acetate. The
polystyrene
resin is then separated off and washed successively in each case three times
with
dichloromethane, dimethylformamide/water ( 1:1 ), dimethylformamide and dried
under high vacuum.
Yield: 180 mg of polystyrene resin
IR (KBr): 1730 cm'' (vC~; cyclodepsipeptide)
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Starting materials ofthe formula (1b)
Example ( Ib -1 )
Cyclo~ N methyl-L-leucinyl-D-thiolactyl-N methyl-L-1eutipy1-D phenyllactyl-N
methyl-L-1eutipy1-D-thiolactyl-N methyl-L-1eutipy1-D phenylthiolactyl
Me Me
Me O
S~O
Me N \ N S
MeO~ Me Me
O O
O
Me Me Me
S' _N \N
~O~S Me
Me Me IO' Me
1.0 g (1.05 mmol) of cyclo(-N-methyl-L-1eutipy1-D-lactyl-N-methyl-L-1eutipy1-D-
phenyl-lactyl-N-methyl-L-1eutipy1-D-lactyl-N-methyl-L-1eutipy1-D-phenyllactyl-
)
PF 1022A (cf. EP-A 382173, US-Pat. 511681 S) in 20 ml of toluene were treated
with
1.4 g (3.5 mmol) of 2,4-bis-(4-methoxy-phenyl)-2,4-dithioxo-1,3,2,4-
.
dithiadiphosphetane ("Lawesson's Reagent") and stirred at reflux temperature
for 3.5
hours. The entire reaction mixture is then cooled to 0°C and filtered
and the resulting
filtrate is concentrated under reduced pressure. The crude product that
remains is
chromatographed over a silica gel column (silica gel 60 - Merck, particle
size: 0.04 to
0.063 mm) using intially the mobile phase methylene chloride and then the
mobile
phase cyclohexane : acetone (3 : 1 ). This gives 0.46 g (43.6% of theory) of
cyclo(-N-
methyl-L-1eutipy1-D-thiolactyl-N-methyl-L-1eutipy1-D-phenylthiolactyl-N-methyl-
L-
leu-cinyl-D-thiolactyl-N-methyl-L-1eutipy1-D-phenylthiolactyl-).
'H-NMR (CDCl3, S): 2.99, 3.06, 3.26, 3.42 (4 x -N-Me); 4.86, 6.42, 6.61 (4 x -
N-
CH2-);
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5.31, 5.55, 5.81, 5.89 (4 x -O-CHZ-); 7.26 (phenyl-H) ppm.
LC-MS (acidic) m/z (%): 1013 (M+, 100); 310 (21); 274 (30); 198 (42).
C,slH~61V408S4 (1013.4)
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Example (1b - 2)
Cyclo( N methyl-L-1eutipy1-D-thiolactyl-N methyl-L-1eutipy1-D phenyllactyl-N
methyl-L-1eutipy1-D-lactyl-N methyl-L-1eutipy1-D phenyllactyl
Me ~ Me
Me O
S~O
MeN' N O
Me0 ~ Me Me
O O
O
Me Me Me
O"N \N
Me
O
MeMeO Me
At 0°C, 1.0 g ( 1.05 mmol) of cyclo(-N-methyl-L-ieucinyl-D-lactyl-N-
methyl-L-
1eutipy1-D-phenyl-lactyl-N-methyl-L-1eutipy1-D-lactyl-N-methyl-L-1eutipy1-D-
phenyllactyl-) PF 1022A (cf. EP-A 382173, US-Pat. 5116815) in 15 ml of
tetrahydrofuran was treated with 0.26 g (0.05 mmol) of 2,4-bis-(4-phenoxy-
phenyl)-
2,4-dithioxo-1,3,2,4-dithiadiphosphetane ("Belleau's Reagent") and stirred at
room
temperature for 18 hours. The entire reaction mixture is then concentrated
under
reduced pressure. The crude product that remains is chromatographed twice over
a
silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm)
using the
mobile phase cyclohexane : acetone (3 : 1). This gives 0.12 g (11.8% of
theory) of
cyclo(-N-methyl-L-1eutipy1-D-thiolactyl-N-methyl-L-1eutipy1-D-phenyllactyl-N-
methyl-L-1eutipy1-D-lac-tyl-N-methyl-L-1eutipy1-D-phenyllactyl-).
LC-MS (acidic) m/z (%): 965 (M+, 100); 200 (45).
C52H~6N40"S (965.2)
The compounds of the formula (Ib) (R', R3, R4, R', R9, R1°: -Me; R2,
R5, Rg, Rrl:
iso-butyl) listed in Table 2 below can be prepared analogously.
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Table 2
Me ~ Me
Me O
X~~O~,,
Me N ' ~N X2 ,,~ R"
MeO~ Me Me /
O O
~Me Met O Me
R' X, N N ~ Me
.~O~X3
Me ~Me~O Me
Ex. X' Xz X3 X4 R' R" Physical Data $~
No.
3.04, 3.09, 3.25,
3.50 (4 x -N-Me);
4.87, 6.38, 6.56,
6.63 (4 x -N-CHZ-);
Ib S S S S -NOz -NO~ 5.31, 5.52, 5.81,
- 5.91 (4 x -O-CH2-);
3
8.17; 7.46 (aryl-H).
1103 (MH+, 100); 392
(38);
177(40); 136 (30).
CSZHlV6O,z,S,
(l 103.4)
1056 (M+H, 39).
Ib S O O O -NO~ -NOZ CSZH7alV6O, jS (1055.26)
-
4
Ib 1184 (MH', 100); 986
- ( 13); 593
S S S S j ~ j ~ (32); 392 (73); 177
(78).
C6~90N6~1~J (1183.6)
Ib ~ 1135 (M+, 56); 361
- S O O O N~ N~ ( 100).
6 5 (1135
4
C
~
~
0
/ / .
)
6
9
6
13
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Table 2 (Continued)
Ex. X~ XZ X'X4 R' R" Physical Data's
No.
F.: 120-125 C
3.15, 3.21, 3.42,
3.57 (4 x -N-Me);
o ~ ~ 5.03, 6.55, 6.78 (4
x -N-CHZ-); 5.45,
Ib S S S S o -H 5.69, 5.89-6.08 (4
- x -O-CHZ-); 7.05-
7
'""""" 7.60 (aryl-H, furyl-H).
1109 (M+, 2); 1108
(3); 370 (15);
274 (32). C;,HBOIVfO,pS.,
(1109.54)
Ib ro ~ ~ 1061 (MT, 100); 198
- (58).
8
S O O O o -H C;,H8aN~0, jS (1061.
3)
F.: 107-110 C
3.01, 3.07, 3.26,
3.41 (4 x -N-Me);
Ib ~o ~ \ ~o ~ \ 4.96 (2 x -O-CHz-);
- 4.86, 6.42, 6.62
9
S S S S o o (4 x -N-CHZ-); 5.32,
5.56, 5.78, 5.85
(4 x -O-CHZ-); 6.91-7.44
(aryl-H,
furyl-H).
1205 (M+, 3); 1204
(5); 370 (41);
198 ( 100). C6lHa,N.,O,iS,
(1205.63)
Ib !o ~ ~ o ~ ~ 1158 (MH+, 60); 391
- (28).
S O O O o o C6zH8,JVa~I;S (1157.4)
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Table 2 (Continued)
Ex. X~ Xz X' X"R' R" Physical Data's
No.
34.8, 35.2, 37.1, 39.2
(N-Me); 71.8,
73.3, 75.4 (-C_H-O-);
40.1, 40.6
(-CH2-); 62.3, 62.5,
62.6 (-C_H-N-);
121.4, 122.8, 136.9,
149.4 (=C_H-,
Py); 70.7 (-C_Hz-O-);
115.0, 130.9
(=CH-, phenyl); 203.2,
203.4,
204.8, 205.7 (N-C_=S);
Ib S S S S o I ~ 168.8, 169.5,
- 170
11 0
O
C
=O
~ ~o .
N ~ (-
N -
_
).
3.01, 3.19, 3.26, 3.41
(4 x -N-Me);
5.17 (2 x -O-CH -);
4.86, 6.41, 6.64,
6.66 (4 x -N-CH -);
5.31, 5.75, 5.57,
5.85 (4 x -O-CH -);
6.91, 7.16
(phenyl-H), 7.24, 7.51,
7.72, 8.59
(pyridyl-H).
1228 (MH+, 18); 383
(58); 224
( 100).
C6~H8~6~1~~ (1227.68)
1181 (MH', 23); 383
Ib ~o ~ N ~o ~ ~ (100).
- N C6~H86N6~13 S
12
S O O O (1179. 5J
al 1H-NMR (400 MHz, 8, ppm); 13C-NMR (100 MHz, 8, ppm); LC-MS (acidic) m/z
(%)
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Starting materials of the formula (II)
Example (II-1)
a) (S)-N-[(Tetrahydrofur-2-yl)-methoxy]-phthalimide
(cf. S. Bailey et al., J. Med. Chem. 34, 1991, pp. 57-65)
0
N-O
O (s~
1.5 g ( 14.7 mmol) of (S)-tetrahydrofur-2-yl-methanol (A. Mravik et al.,
Tetrahedron:
Asymmetry 7 (5), 1996, pp. 1477-1484), 2.4 g (14.7 mmol) of N-hydroxy-
phthalimide and 3.85 (14.7 mmol) of triphenylphosphine are stirred in 50 ml of
THF
and, at 0°C (atmosphere of protective gas) treated with 3.4 g (19.5
mmol) of diethyl
azodicarboxylate and stirred at room temperature for 18 hours. The entire
reaction
mixture is then concentrated under reduced pressure and the residue is taken
up in
ether and extracted twice with water. The crude product that remains is
chromatographed over a silica gel column (silica gel 60 - Merck, particle
size: 0.04 to
0.063 mm) using the mobile phase cyclohexane : acetone (6 : 1). This gives 1.7
g
M
(46.8% of theory) of (S)-N-[(tetrahydrofur-2-yl)-methoxy]-phthalimide.
LC-MS-LOOP m/z (%): 248 (MH+, 100) C13Hi3NO4 (247.2)
RI- value (HPLC column: 125 x 2.1 Kromasil ~, C-18): 7.56 min
b) (S)-Tetrahydrofur-2-yl-methoxy-amine
H2N-O
(s~
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1.6 g (6.47 mmol) of (S)-N-[(tetrahydrofur-2-yl)-methoxyJ-phthalimide are
stirred in
30 ml of methylene chloride, 0.6 g ( 12.9 mmol) of N-methyl-hydrazine are
added at
0°C and the mixture is stirred at room temperature for 18 hours. The
entire reaction
mixture is then filtered and the filtrate is concentrated under reduced
pressure. The
crude product that remains is chromatographed over a silica gel column (silica
gel 60
- Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl
acetate. This
gives 130 mg (17.2% of theory) of (S)-tetrahydrofur-2-yl-methoxy-amine.
LC-MS (acidic) m/z (%): 118 (MH+, 100). CSZH76N4~1IS (117.1)
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Example (II-2
a) N-tert-Butyloxycarbonyl-amino-oxyacetomorpholide
CH >
~N-O N
Me
Me Me
2.0 g (10.5 mmol) of N-tert-butyloxycarbonyl-amino-oxyacetic acid
(Novabiochem:
O1-63-0060) are stirred in 75 ml of methylene chloride and, at 0°C,
treated with 3.1 g
(24.0 mmol) of N,N-diisipropylethylamine (Hunig's Base), 3.1 g (12.0 mmol) of
bis(2-oxo-3-oxazolidinyl)-phosphonium acid chloride (BOP-Cl) and stirred for
30
minutes. 1.05 g (12.0 mmol) of morpholine are then added, and stirring at
0°C is
continued for 6 hours. The reaction solution is extracted twice with water and
the
organic phase is separated off and, after drying over sodium sulfate,
concentrated
under reduced pressure. The crude product that remains is chromatographed over
a
silica gel column (silica gel 60 - Merck, particle size: 0.04 to 0.063 mm)
using the
mobile phase cyclohexane : acetone (3 : 1). This gives 1.0 g (37% of theory)
of N-
tert-butyloxycarbonyl-amino-oxyacetomorpholide.
1H-NMR (CDCl3, b): 1.47 (s, 9H, C(CH )3); 3.37-3.72 (3m, 8H, 2 x -N-CH -; 2 x -
O-
CH -;); 4.54 (s, 2H, -O-CH -); 8.06 (s, 1H, N-H) ppm.
LC-MS (acidic) m/z (%): 205 (M+- HZC=CMe2, 12), 161 (100). Cl~H2oN20s
(260.3)
R~- value (HPLC column: 125 x 2.1 Kromasil ~, C-18): 5.22 min
b) Hydrochloride of the amino-oxyacetomorpholide
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\ c+~
H-N-O N
H C~ ~_~
For 30 minutes, dry hydrogen chloride gas is introduced into a solution,
cooled to
0°C, of 0.65 g (2.5 mmol) of N-tert-butyloxycarbonyl-amino-
oxyacetomorpholide are
into 220 ml of absolute methylene chloride. The mixture is then stirred at
room
temperature for about 16 hours and the entire reaction mixture is concentrated
under
reduced pressure. This gives 380 mg (77% of theory) of the hydrochloride of
the
amino-oxyacetomorpholide.
LC-MS (acidic) m/z (%): 161 (MH+-HCI, 100), 146 (12), 129 (45).
C6H,3C1N203 (196.6)
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Examine (II-3)
a) 6-(N-Succinimidyl-oxy)-3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-
polystyrene resin
P O
,N
O O
O
1.0 g (0.51 mmol) of DHP HM resin (Novabiochem: O1-64-0192) are allowed to
swell in 8.0 ml of 1,2-dichloroethane for about 30 minutes. 293.5 mg (2.5
mmol) of
N-hydroxy-succinimide and 261.4 g (1.0 mmol) of pyridinium para-
toluenesulfonate
(PPTS) are then added, and the mixture is stirred at 80°C for 16 hours.
The resin is
then separated off and washed once with methylene chloride, four times with
dimethylformamide/water ( 1:1 ), three times with dimethylformamide and three
times
with methylene chloride. The purified 6-(N-succinimidyl-oxy)-3,4,5,6-
tetrahydro-2H-
pyran-2-yl-methoxymethyl-polystyrene resin is dried under high vacuum and can
be
used for the subsequent reaction step.
IR (I~Br): 1730 cm 1 (vc~; succinimidyl radical)
b) 6-(Amino-oxy)-3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene
P
NHZ
O O
Under an atmosphere of protective gas (argon), 1,0 g of 6-(N-succinimidyl-oxy)-
3,4,5,6-tetrahydro-2H-pyran-2-yl-methoxymethyl-polystyrene resin is treated in
20 ml of benzene with 127.7 mg (2.55 mmol) of hydrazine hydrate and stirred
under
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reflux for 20 hours. The resin is then separated off, washed five times with
methylene
chloride and dried under high vacuum.
IR (KBr): 1630 cm-~ (V~_H deform. -~-NHz); 3300 cm"' (VN-H valences -C-NH2)
The compounds of the formula (In (A= -Y-R~3) listed in Table 3 below can be
prepared analogously to Examples II-1 and II-2 above.
Table 3
r 10
H
R13
N-Y~
H (II)
Ex. No. Y R'~ Physical Data's
II - -O- ~ ' 149 (M+, 12);
4
p 5.02 (s, 2H, -CH -O-)
:...
II - -O-
5
149 (M+-HCI, 100)
II - -O- N' 0 163 (MH+-HCI, 100);
6 Me
(hydrochloride)
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Ex. No. Y R" Physical Data's
II - 7 -O- Me.,, 163 (MH'-HCI, 100);
N N (hydrochloride)
N
"".......
II - 8 -O- / ~ 124 (MH+-2HCI, 100);
N
(dihydrochloride)
II - 9 -0-
5.26 (br.
s
2H
-O-NH
)
O
,
,
,
~
II - 10 -O- 145 (MH+-HCI, 100);
N
O (hydrochloride)
~., II - 11 -O- / ~ N O 207 (MH+-HCI, S);
4.91 (s, 2H, -CH -O-);
7.02;
7.28 (2d, 2x -CH -,
morpholine)
(hydrochloride)
e~'H-NMR (400 MHz, 8, ppm); '3C-NMR ( 100 MHz, 8, ppm); LC-MS (acidic) m/z (%)
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Biological Examples
Example A
In vivo Nematode test
Heterakis spumosa / Mouse
Mice were experimentally infected with nematodes of the species Heterakis
spumosa. To infect the mice, Heterakis spumosa was administered orally as 90
embryonate eggs.
After the prepatency period had expired, the suspended active compounds were
administered intraperitoneally on day 46 after the infection.
Determination of the activity:
The mice are selected on day 54 after the infection. The adult parasites are
counted in
the colon and caecum using a microscope. The success of treatment in the dose
group
as compared to the untreated control group.
Active compounds tested and effective dosages (Dosis effectiva) are shown in
the
table below.
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Active compound Dosis effectivaReduction rate
Example No. in [mg/kg] in [%]
Cyclo(-MeLeu-D-Lac-MeLeu-D-PhLac-25 p
MeLeu-D-Lac-MeLeu-D-PhLac)
PF 1022A,known a)
Cyclo(-MeLeu-D-Lact-MeLeu-D-PhLac-
""~.
MeLeu-D-Lac-MeLeu-D-PhLac) 25 p
1C1'IOWIl b)
Ex. 1 according to the invention25 5-90
7
a) cf. EP-A 382 173, EP-A 503 538; b) cf. WO 98/43 965
MeLeu = N-methyl-L-leucine, D-Lac = D-lactic acid, D-PhLac =
D-phenyllactic acid, D-Lact = D-thiolactyl
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Example B
In vivo Nematode test
Nematospiroides dubius / Mouse
Mice were experimentally infected with nematodes of the species Nemato~iroides
dubius. To infect the mice, Nematospiroides dubius was administered orally as
90
embryonate eggs.
After the prepatency period had expired, the suspended active compounds were
administered intraperitoneally on day 46 after the infection.
Determination of the activity:
The mice are selected on day 54 after the infection. The adult parasites are
counted in
the colon and caecum using a microscope. The success of treatment in the dose
group
as compared to the untreated control group.
Active compounds tested and effective dosages (Dosis effectiva) are shown in
the
...,.
table below.
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Active compound Dosis effectivaReduction
Example No. in [mg/kg] rate
in [%]
Cyclo(-MeLeu-D-Lac-MeLeu-D-PhLac-25 0
MeLeu-D-Lac-MeLeu-D-PhLac)
PF 1022A knowna)
"..,..,
Cyclo(-MeLeu-D-Lact-MeLeu-D-PhLac-
MeLeu-D-Lac-MeLeu-D-PhLac) 25 0
known b)
Ex. 1 according to the invention25 100
e) cf. EP-A 382 173, EP-A 503 538; b) cf. WO 98/43 965
MeLeu = N-methyl-L-leucine, D-Lac = D-lactic acid, D-PhLac =
D-phenyllactic acid, D-Lact = D-thiolactyl
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Example C
In vivo Nematode test
S Haemonchus contortus / Sheep
Sheep experimentally infected with Haemonchus contortus were treated after the
end
of the prepatency period of the parasite. The active compounds were
administered
orally and/or intravenously as pure active compound.
The efficacy is determined by quantitatively counting the worm eggs excreted
with
the faeces, before and after treatment.
Complete cessation of the excretion of eggs after treatment means that the
worms
have been expelled or are so severely damaged that they no longer produce any
eggs
(Dosis effectiva).
Active compounds tested and effective dosages (Dosis effectiva) are shown in
the
table below.
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Active compound Dosis effectivaReduction
Example No. in [mg/kg) rate
in [%)
Cyclo(-MeLeu-D-Lac-MeLeu-D-PhLac-0.25 100
MeLeu-D-Lac-MeLeu-D-PhLac) 0.01 0
PF 1022A knowne~
Ex. 8 according to the invention0.01 100
Ex. 36 according to the invention0.01 100
Ex. 46 according to the invention0.10 100
cf. EP-A 382 173, EP-A 503 538;
MeLeu = N-methyl-L-leucine, D-Lac = D-lactic acid, D-PhLac =
D-phenyllactic acid
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