Derivatives of cyclodepsipeptide PF1022 substance

Details Derivatives of cyclodepsipeptide PF1022 substance Derivatives of cyclodepsipeptide PF1022 substance

1998-05-20

2001-12-11

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S011400, C514S183000, C530S317000, C540S454000

Reexamination Certificate

active

06329338

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel derivatives of PF1022 substance which have a skeletal structure of cyclodepsipeptide same as that of PF1022 substance, that is, a cyclodepsipeptide known as a fermentation product of a microorganism and having an antelmintic activity, and which exhibit a higher anthelmintic activity. This invention also relates to a vermicidal or anthelmintic composition containing said novel PF1022 derivative. The novel PF1022 derivatives according to this invention exhibit an excellent anthelmintic activity capable of expelling a variety of helminths or parasites living in animals and thus are very useful as an anthelmintic agent.
BACKGROUND ART
PF1022 substance is a known cyclodepsipeptide which was discovered as a result of studies on anthelmintic substances against fowl roundworms [refer to Japanese patent application Kokai No. Hei 3-35796, European patent application publication No. 0382173A2 and J. Antibiotics, 45, 692, (1992)]. The PF1022substance is a fermentation product which is produced by the cultivation of a filamentous fungus, PF1022 strain (deposited under FERM BP-2671 with National Institute of Bioscience and Human-Technology Agency in Tsukuba-City in terms of the Budapest Treaty) belonging to Agonomycetales. PF1022 substance is a compound classified into a class of cyclodepsipeptide compounds represented by the following formula (A)
wherein Me stands for methyl group.
The cyclodepsipeptide represented by the above formula (A) includes the following eight particular substances.
PF1022 substance: R
1
═R
3
═Me, R
2
═R
4
═CH
2
C
6
H
5
PF1022 B substance: R
1
═R
2
═R
3
═R
4
═CH
2
C
6
H
5
PF1022 C substance: R
1
═Me, R
2
═R
3
═R
4
═CH
2
C
6
H
5
PF1022 D substance: R
1
═R
3
═R
4
═Me, R
2
═CH
2
C
6
H
5
PF1022 E substance: R
1
═R
3
═Me, R
2
═CH
2
C
6
H
4
OH-p, R
4
═CH
2
C
6
H
5
PF1022 F substance: R
1
═R
2
═R
3
═R
4
═Me
PF1022 G substance: R
1
═R
2
═R
3
═Me, R
4
═CH
2
C
6
H
4
OH-p
PF1022 H substance: R
1
═R
3
═Me, R
2
═R
4
═CH
2
C
6
H
4
OH-p
The PF1022 substance is a cyclodepsipeptide which is formed of L—N-methylleucine [(CH
3
)
2
CHCH
2
CH(NHCH
3
)COOH] (abbreviated as H—L-MeLeu-OH), D-lactic acid [CH
3
CH(OH)—COOH] (abbreviated as H—D-Lac-OH) and D-phenyl-lactic acid [C
6
H
5
CH
2
CH(OH)COOH] (abbreviated H—D-PhLac-OH) via ester-bonds and amido-bonds and which may also be represented by the following formula (B):
Formula B: Cyclo(L-MeLeu-D-Lac-L-MeLeu-D-PhLac-L-MeLeu-D-Lac-L-MeLeu-D-PhLac)
The cultivation of the filamentous fungus PF1022 strain results not only in the production of PF1022 substance as the main product, but also in the production of PF1022 B substance, PF1022 C substance, PF1022 D substance, PF1022 E substance, PF1022 F substance, PF1022 G substance and PF1022 H substance which have the structures represented in the above formula (A), respectively [see Japanese patent application first publications Kokai Nos. Hei 3-35796, 5-170749 and 6-184126 and Japanese patent application No. Hei 8-208201 (filed on Aug. 7, 1996, not yet laid open)].
The PF1022 substance and PF1022 B to H substances all possess anthelmintic activities and have specific structural characteristics such that they have a common cyclodepsipeptide structure as a basic skeleton, that they have, as side chains, four N-methyl groups, four isobutyl groups, 0-4 methyl groups, 0-4 benzyl groups and 0-2 p-hydroxybenzyl groups and also that they have eight asymmetric carbon atoms in their molecules. Further, it can be presumed that the presence of a 24-membered ring formed of the four ester-linkages and four amido-linkages as shown in the formula (A) above plays an important role in the expression of biological activities.
So-called helminthic infections can cause serious damages to human and animal health and also to agricultural and stock-breeding industries, so that there always exists in the art, as an important theme, a demand for finding and providing such novel and useful substances which exhibit anthelmintic activities.
As explained above, PF1022 substance was found originally as a fermentation product, and later was prepared by chemical syntheses [see Japanese patent application first publication Kokai No. Hei 5-320148, and Biosci. Biotech. Biochem., 58, 1193 (1994)].
It is already known that PF1022 substance and PF1022 B to H substances themselves possess very high anthelmintic activities, but some researcher groups are still working in an attempt to produce and find out novel related substance(s) having a higher anthelmintic activity, with utilizing those PF1022 substances as the starting materials.
We, the present inventors, also have proceeded investigations from the initial stage when PF1022 substance was found, in order to produce and find out novel derivatives with starting from PF1022 substance and PF1022 B to H substances, and we have already found several novel derivatives (see internationally published specification No. WO94/19334 of PCT application No. PCT/JP/00252 and European patent application publication No. 0685469 A1 and Japanese patent application No. Hei 7-244051). One of the other researcher groups also has disclosed some novel derivatives as produced by total synthetic processes (see PCT international publications WO093/19033 and No. WO95/07272).
DISCLOSURE OF INVENTION
As described above, we have carried out our researches and development in an attempt to provide novel derivative(s) having a higher anthelmintic activity than that of PF1022 substance, by means of a method of chemical syntheses using the PF1022 substance as the starting compound. As a result, we have now been able to produce and find out several novel PF1022 derivatives which posesess an anthelmintic activity equal to or higher than that of any known PF1022 related compounds shown in the above-mentioned literatures and specifications.
Further, we have proceeded our investigations with taking notice of the D-phenyllactic acid moiety as one of the constituents of forming PF1022 substance, and now we have successfully synthesized novel cyclodepsipeptides which may be represented collectively by the undermentioned general formula (I), general formula (II) and general formula (III), through total synthetic processes or through chemical synthetic processes with starting from PF1022 substance, PF1022 E substance and PF1022 H substance. We have found that these novel PF1022 derivatives exhibit strong anthelmintic activities on the basis of animal tests.
According to a first aspect of this invention, therefore, there is provided a novel cyclodepsipeptide derivative of PF1022 substance, which is represented by the following general formula (I)
wherein (i) R
1
stands for a hydrogen atom and R
2
stand for a cyano-(C
1
-C
6
)alkoxy group, a thiocarbamoyl-(C
1
-C
6
)alkoxy group, an amino-(C
1
-C
6
)alkoxy group, an amino-(C
1
-C
6
)alkoxy group having a protecting group, an N-mono-(C
1
-C
6
)alkylamino-(C
1
-C
6
)alkoxy group, an N,N-di-(C
1
-C
6
)alkylamino-(C
1
-C
6
) alkoxy group, an N,N-di-((C
1
-C
6
)alkoxy-(C
1
-C
6
)alkyl)amino-(C
1
-C
6
)alkoxy group, or a cyclic amino-(C
1
-C
6
)alkoxy group of which the cyclic amino group is a 5- or 6-membered ring containing one or more nitrogen atoms and further optionally containing oxygen or sulfur atom(s) as the cyclic amino group-constituting atoms, or a (C
1
-C
6
)alkoxy group having as a substituent, a saturated or unsaturated 5- or 6-membered heterocyclic ring containing three or less hetero atoms (which is or are nitrogen atom, oxygen atom or sulfur atom) as the heterocyclic ring-constituting atoms and further optionally having as a substituent a phenyl group which may optionally be substituted by a (C
1
-C
6
)alkyl group, a (C
3
-C
6
)cycloalkyl group or a halogen atom (chlorine, bromine or fluorine), or a (C
2
-C
6
)alkanoyl group optionally having a substituent (which is a halogen atom or hydroxyl g

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