Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-11-29
2002-03-12
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S323000, C530S345000
Reexamination Certificate
active
06355615
ABSTRACT:
The invention relates to novel deoxycyclodepsipeptides, to processes for their preparation and to their use for controlling parasites, in particular helminths, in veterinary and human medicine.
Various cyclodepsipeptides having antiparasitic activity are described in the literature. EP-A 382 173 discloses a cyclooctadepsipeptide designated PF 1022. EP-A 626 376, EP-A 634 408 and EP-A 718 293 disclose further 24-membered cyclodepsipeptides. Their anthelmintic activity is not in all cases satisfactory.
The invention relates to novel deoxycyclodepsipeptides which are prepared from cyclodepsipeptides having 24 ring members which are constructed from alternating &agr;-aminocarboxylic acids and (&agr;-hydroxycarboxylic acids, by complete or partial chemoselective reduction of the carbonyl groups of the amide function to give methylene groups using suitable reduction processes, and to mixtures and derivatives thereof.
The cyclodepsipeptides employed as starting materials are constructed from alternating 4 &agr;-aminocarboxylic acids and 4 &agr;-hydroxycarboxylic acid-units.
&agr;-Aminocarboxylic acids are natural or synthetic amino acids which may be identical or different. They may be N-alkylated, i.e. substituted by a straight-chain or branched C
1
-
4
-alkyl group, preferably a methyl group, which for its part may also be substituted.
&agr;-Hydroxycarboxylic acids are natural and synthetic 2-hydroxycarboxylic acids which may be identical or different.
Complete or partial chemoselective reduction means that one or more amidic carbonyl groups (C═O adjacent to N) are reduced without the ester carbonyl groups (C═O adjacent to O) in the cyclodepsipeptide skeleton being attacked.
The reduction is carried out either directly or in a multi-stage process, depending on the reducing agent chosen.
Complete or partial reduction means that, for example, in an octadepsipeptide having 4 amidic carbonyl groups, all 4 of the carbonyl groups in question or 1 to 3 of these carbonyl groups are reduced.
The reduction generally yields mixtures of the deoxydepsipeptides in varying degrees of reduction. The individual components are present in varying proportions, depending on the stoichiometry and the kind of reduction process. Homogeneous deoxydepsipeptides are obtained from the mixtures by employing the customary physical or chemical separation processes.
The products obtained in the reduction can be converted chemically into further derivatives.
The deoxycyclodepsipeptides according to the invention can be characterized by the formula (I):
in which
C═X
1
, C═X
2
, C═X
3
and C═X
4
independently of one another each represent one of the groups CO, CS or CH
2
, where at least one of these groups represents CH
2
,
R
1
and R
2
independently of one another each represent hydrogen, alkyl, hydroxymethyl or alkoxymethyl,
R
3
and R
4
independently of one another each represent alkyl or represent phenyl or benzyl, each of which is optionally mono- or polysubstituted by radicals W,
where
W represents halogen, nitro, cyano, carbonyl, alkoxycarbonyl, alkyl, —CH(R
13
)NR
14
R
15
, alkenyl, alkoxycarbonylalkenyl, alkynyl, alkoxy-carbonylalkynyl, hydroxyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, dialkylaminoalkoxy, respectively optionally substituted aryl, arylalkyl, aryloxy or arylmethoxy, represents heterocyclylmethoxy, —NR
16
R
17
, —SO
2
—NR R
16
R
17
, —SR
18
, —S(O)R
18
or —S(O)
2
R
18
,
R
13
represents hydrogen or carboxyl,
R
14
represents hydrogen, alkyl, optionally halogen-substituted alkylcarbonyl or benzoyl or
R
13
and R
14
together represent a radical —(CH
2
)
n
—CO—, where n=2, 3 or 4,
R
15
represents hydrogen, alkyl, optionally halogen-substituted alkylcarbonyl or benzoyl or
R
14
and R
15
together represent a radical —(CH
2
)
o
—CO—, where o=3, 4 or 5, represent a diacyl radical of a C
4
-C
6
-dicarboxylic acid or represent optionally halogen-substituted phthaloyl,
R
16
represents hydrogen, optionally halogen-, hydroxyl- or alkoxy-substituted alkyl, represents heterocyclylmethyl, formyl, alkylcarbonyl or optionally substituted arylmethyl or benzoyl or represents the radical —CO—CR
19
R
20
—NR
21
R
22
and
R
17
represents hydrogen, optionally halogen-, hydroxyl- or alkoxy-substituted alkyl, represents heterocyclylmethyl, alkylcarbonyl or optionally substituted arylmethyl or benzoyl,
R
16
and R
17
together represent optionally substituted phthaloyl or, together with the linking nitrogen atom, represent an optionally substituted mono- or polycyclic, optionally bridged and/or spirocyclic, saturated or unsaturated heterocycle which may contain one to 3 further hetero atoms from the group consisting of nitrogen, oxygen and sulfur,
R
18
represents alkyl or optionally substituted phenyl or benzyl,
R
19
represents one of the radicals of a natural or synthetic &agr;-amino acid, where functional groups may optionally be protected,
R
20
represents hydrogen, alkyl or phenyl,
R
19
and R
20
together represent —(CH
2
)
p
—, where p=2, 3, 4 or 5, or represent —(CH
2
)
2
—NR
23
—(CH
2
)
2
—, where R
23
represents alkyl, phenyl or benzyl,
R
21
represents hydrogen or alkyl,
R
19
and R
21
together represent —(CH
2
)
3
— and —(CH
2
)
4
— and
R
22
represents hydrogen or a protective group known from peptide chemistry, such as acetyl, tert-butoxy carbonyl (Boc), benzyl-oxycarbonyl (Cbz) or benzyl (Bzl),
R
5
, R
6
, R
7
and R
8
independently of one another each represent hydrogen, optionally amino- or hydroxyl-substituted alkyl, represent mercaptomethyl, methylthioethyl, carboxymethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl, represent optionally amino-, nitro-, halogen-, hydroxyl- or methoxy-substituted phenyl or benzyl, represent naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, where functional groups may optionally be protected, and
R
9
, R
10
, R
11
and R
12
independently of one another each represent hydrogen or optionally substituted C
1
-
4
-alkyl.
The protective groups known from peptide chemistry are listed, for example, in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2
nd
Ed., John Wiley & Sons, New York 1991.
The configuration at the chiral carbons is immaterial, i.e. the compounds of the formula (I) according to the invention are constructed from D- and/or L-configured amino acids and hydroxycarboxylic acids. The invention provides the pure stereoisomers and mixtures thereof. The compounds are preferably constructed from alternating D-hydroxycarboxylic acids and L-amino acids.
The invention furthermore provides a process for preparing the compounds according to the invention, characterized in that cyclodepsipeptides which have been prepared by fermentation or synthetically and which have 24 ring members
a) are reduced with borane (boron hydride) or complex hydrides in the presence of metal salts, or
b) are reacted with a sulfurizing agent and subsequently reduced with complex hydrides in the presence of metal salts and
the compounds according to the invention obtained by one of the processes a) or b) are optionally derivatized further.
Furthermore, it has been found that the compounds according to the invention are outstandingly suitable for controlling helminths in human and veterinary medicine.
The formula (I) given above defines preferred compounds according to the invention.
C═X
1
, C═X
2
, C═X
3
and C═X
4
independently of one another each preferably represent one of the groups CO, CS or CH
2
, where at least one of these groups represents CH
2
.
R
1
and R
2
independently of one another each preferably represent hydrogen, C
1
-C
6
-alkyl, hydroxymethyl or C
1
-C
6
-alkoxymethyl.
R
3
and R
4
independently of one another each preferably represent C
1
-C
6
-alkyl or phenyl or benzyl, each of which is optionally mono- or disubstituted by a radical W.
R
5
, R
6
, R
7
and R
8
independently of one another each preferably represent hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl,
Dyker Hubert
Harder Achim
Mencke Norbert
Samson-Himmelstjerna Georg von
Scherkenbeck Jürgen
Akorli Godfried R.
Bayer Aktiengesellschaft
Gil Joseph C.
Russel Jeffrey E.
LandOfFree
Desoxycyclodepsipeptides and their use for combatting... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Desoxycyclodepsipeptides and their use for combatting..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Desoxycyclodepsipeptides and their use for combatting... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2818161