Depsipeptide derivatives, production thereof and use thereof

wherein A is benzyl group which has suitable substituent(s) or phenyl group which may have suitable substituent(s), PA1 A.sup.a is benzyl group which may have suitable substituent(s) or phenyl group which may have suitable substituent(s), PA1 B and D are each lower alkyl, PA1 C is hydrogen or lower alkyl, and a pharmaceutically acceptable salt thereof. The compound or a salt thereof of the present invention has excellent parasiticidal activities as an anthelmintic agent for animals and human bodies.

TECHNICAL FIELD 
The present invention relates to new depsipeptide derivatives having 
antiparasitic activity. 
BACKGROUND ART 
Japanese Kokai Tokkyo Koho 3-35796 discloses depsipeptide derivative 
prepared by culturing microorganisms. 
DISCLOSURE OF INVENTION 
The object compound of the present invention, depsipeptide derivatives can 
be represented by the following general formula (I). 
##STR2## 
wherein A is benzyl group which has suitable substituent(s) or phenyl 
group which may have suitable substituent(s), 
A.sup.a is benzyl group which may have suitable substituent(s) or phenyl 
group which may have suitable substituent(s), 
B and D are each lower alkyl, 
C is hydrogen or lower alkyl. 
According to the present invention, the object compound of depsipeptide 
derivatives (I) can be prepared by processes which are illustrated in the 
following schemes. 
It should be indicated that any of D-configured compound, L-configured 
compound and/or DL-configured compound are in the extent of the present 
invention; however, for the convenience, only D-configured compounds and 
L-configured compounds are explained in the process for preparation as 
follows. 
##STR3## 
wherein A, A.sup.a, B, C and D are each as defined above, 
R is hydrogen or amino protective group, 
A.sup.1 is benzyl group which may have lower alkoxy, 
A.sup.2 is benzyl group which has nitro, or benzyl group which has nitro 
and lower alkoxy, 
A.sup.3 is benzyl group which has amino, or benzyl group which has amino 
and lower alkoxy, 
A.sup.4 is benzyl group which has mono- or di-lower alkylamino, or benzyl 
group which has mono- or di-lower alkylamino and lower alkoxy, 
A.sup.5 is benzyl group which has cyclic amino, or benzyl group which has 
cyclic amino and lower alkoxy, 
A.sup.6 is benzyl group which has hydroxy, or benzyl group which has 
hydroxy and lower alkoxy, 
A.sup.7 is benzyl group which has lower alkoxy. 
Throughout the present specification, the amino acid, peptides, protective 
groups, condensing agents, etc. are indicated by the abbreviations 
according to the IU-IUB (Commission on Biological Nomenclature) which 
are in common use in the field of art. 
Moreover, unless otherwise indicated, the amino acids and their residues 
when shown by such abbreviations are meant to be L-configured compounds 
and residues, and when shown by D- abbreviations, they are meant to be 
D-configured compounds and residues. 
In the present invention, there are employed the following abbreviations. 
p-MeOPhLac: 2-hydroxy-3-(4-methoxyphenyl) propionic acid 
.beta.-(p-methoxyphenyl)lactic acid! 
Man: 2-hydroxyphenylacetic acid mandelic acid! 
p-Me.sub.2 NPhLac: 3-(4-dimethylaminophenyl)-2-hydroxypropionic acid 
.beta.-(p-dimethylaminophenyl)lactic acid! 
p-PipPhLac: 2-hydroxy-3-(4-piperazinophenyl)propionic acid 
.beta.-(p-piperazinophenyl)lactic acid! 
p-PyrPhLac: 2-hydroxy-3-(4-pyrrolidinophenyl)propionic acid 
.beta.-(p-pyrrolidinophenyl)lactic acid 
p-NO.sub.2 PhLac: 3-(4-nitrophenyl)-2-hydroxypropionic acid 
.beta.-(p-nitrophenyl)lactic acid! 
p-NH.sub.2 PhLac: 3-(4-aminophenyl)-2-hydroxypropionic acid 
.beta.-(p-aminophenyl)lactic acid! 
p-Et.sub.2 NPhLac: 3-(4-diethylaminophenyl)-2-hydroxypropionic acid 
.beta.-(p-diethylaminophenyl)lactic acid! 
p-Hex.sub.2 NPhLac: 3-(4-di-n-hexylaminophenyl)-2-hydroxypropionic acid 
.beta.-(p-di-n-hexylaminophenyl)lactic acid! 
p-PylPhLac: 2-hydroxy-3-(1H-pyrrol-1-yl-phenyl)propionic acid 
.beta.-(p-1H-pyrrol-1-yl)phenyl)lactic acid! 
p-OHPhLac: 2-hydroxy-3-(4-hydroxyphenyl)propionic acid 
.beta.-(p-hydroxyphenyl)lactic acid! 
p-EtOPhLac: 3-(4-ethoxyphenyl)2-hydroxypropionic acid 
.beta.-(p-ethoxyphenyl)lactic acid! 
p-HexOPhLac: 3-(4-n-hexyloxyphenyl)-2-hydroxypropionic acid 
.beta.-(p-n-hexyloxyphenyl)lactic acid! 
p-MEPhLac: 2-hydroxy-3- 4-(2-methoxyethoxy)phenyl!propionic acid 
.beta.- p-(2-methoxyethoxy)phenyl!lactic acid! 
p-MEEPhLac: 2-hydroxy-3-{4- 2-(2-methoxyethoxy)ethoxy!phenyl}propionic acid 
.beta.-{p- 2-(2-methoxyethoxy)ethoxy!phenyl}lactic acid! 
o-MeOPhLac: 2-hydroxy-3-(2-methoxyphenyl)propionic acid 
.beta.-(o-methoxyphenyl)lactic acid! 
m-MeOPhLac: 2-hydroxy-3-(3-methoxyphenyl)propionic acid 
.beta.-(m-methoxyphenyl)lactic acid! 
3,4-DMOPhLac: 3-(3,4-dimethoxyphenyl)-2-hydroxypropionic acid 
.beta.-(3,4-dimethoxyphenyl)lactic acid! 
2,4-DMOPhLac: 3-(2,4-dimethoxyphenyl)-2-hydroxypropionic acid 
.beta.-(2,4-dimethoxyphenyl)lactic acid! 
3,4-MODPhLac: 2-hydroxy-3-(3,4-methylenedioxyphenyl)propionic acid 
.beta.-(3,4-methylenedioxyphenyl)lactic acid! 
3-MA-4-MOPhLac: 3-(3-dimethylamino-4-methoxyphenyl)-2-hydroxypropionic acid 
.beta.-(3-dimethylamino-4-methoxyphenyl)lactic acid! 
3,4-DMAPhLac: 3- (3,4-bis(dimethylamino)phenyl!-2-hydroxyphenyl!propionic 
acid .beta.- 3,4-bis(dimethylamino)phenyl!lactic acid! 
o-FPhLac: 3-(2-fluorophenyl)-2-hydroxypropionic acid 
.beta.-(o-fluorophenyl)lactic acid! 
m-FPhLac: 3-(3-fluorophenyl)-2-hydroxypropionic acid 
.beta.-(m-fluorophenyl)lactic acid! 
p-FPhLac: 3-(4-fluorophenyl)-2-hydroxypropionic acid 
.beta.-(p-fluorophenyl)lactic acid! 
Glycol: Glycolic acid 
PhLac: 2-hydroxy-3-phenylpropionic acid .beta.-phenyllactic acid! 
Lac: 2-hydroxypropionic acid lactic acid! 
p-MorPhLac: 2-hydroxy-3-(4-morpholinophenyl)propionic acid 
.beta.-(p-morpholinophenyl)lactic acid! 
Suitable salts of the compound (I) are conventional non-toxic, 
pharmaceutically acceptable salt and may include a salt with a base or an 
acid addition salt such as a salt with an inorganic base, for example, an 
alkali metal salt (e.g. sodium salt, potassium salt, cesium salt, etc.), 
an alkali earth metal salt (e.g. calcium salt, magnesium salt, etc.), an 
ammonium salt; a salt with an organic base, for example, an organic amine 
salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine 
salt, triethanolamine salt, dicyclohexylamine salt, 
N,N'-dibenzylethylenediamine salt, etc.), etc.; an inorganic acid addition 
salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); an 
organic carboxylic or sulfonic acid addition salt (e.g. formate, acetate, 
trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, 
p-toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g. 
arginine, aspartic acid, glutamic acid,etc.); and the like. 
In the above and subsequent descriptions of the present specification, 
suitable examples and illustrations of the various definitions which the 
present invention include within the scope thereof are explained in detail 
as follows. 
The term "lower" is intended to mean 1 to 6 carbon atom (s), preferably 1 
to 4 carbon atom(s), unless otherwise indicated. 
Suitable substituent(s) in the term "benzyl group which has 
substituent(s)", "phenyl group which may have substituent(s)" and "benzyl 
group which may have substituent(s)" may include hydroxy, lower alkoxy, 
lower alkoxy lower alkoxy, lower alkoxy lower alkoxy lower alkoxy, 
halogen, lower alkyl, amino, cyclic amino, nitro, halogen (e.g. fluoro, 
chloro, bromo, iodo, etc.) and the like. These may have 1 or more than 2 
substituents. 
Suitable "lower alkyl" may include straight or branched one having 1 to 6 
carbon atom(s) such as methyl, ethyl, n-propyl, isopropyl, butyl, 
isobutyl, tert-butyl, pentyl, hexyl, and the like. 
Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, 
butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy, and the like. 
Suitable "lower alkoxy lower alkoxy" may include methoxymethoxy, 
methoxyethoxy, methoxypropoxy, ethoxyisopropoxy, and the like. 
Suitable "lower alkoxy lower alkoxy lower alkoxy" may include 
methoxymethoxyethoxy, methoxyethoxyethoxy, methoxyethoxypropoxy, 
ethoxymethoxyisopropoxy, and the like. 
Suitable "cyclic amino group" may be aromatic ring or alicyclic compound 
which have more than 1 nitrogen atom(s) as hetero atom(s), and it 
containing monocyclic group or condensed polycyclic group which may be 
saturated or unsaturated. Also, cyclic amino group may further contain 
hetero atom(s) such as more than 1 or 2 nitrogen atom(s), oxygen atom(s), 
sulfur atom(s), and the like and still further the cyclic amino group may 
be spiro ring or bridged cyclic compound. The number of the constructive 
atom(s) of cyclic amino group are not limited, but for example, monocyclic 
group have 3 to 8-membered rings and bicyclic have 7 to 11-membered rings. 
Example of such cyclic amino group may include saturated or unsaturated 
monocyclic group which contain one nitrogen atom as hetero atom(s) such as 
1-azetidinyl, pyrrolidino, 2-pyrroline-1-yl, 1-pyrrolyl, piperidino, 
1,4-dihydropyrizine-1-yl, 1,2,5,6-tetrahydropyrizine-1-yl, homopiperidino 
and the like, saturated or unsaturated monocyclic group which contain more 
than two nitrogen atom(s) as hetero atom(s) such as 1-imidazolidinyl, 
1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 1-tetrazolyl, 1-piperazinyl, 
1-homopiperazinyl, 1,2-dihydropyridazine-1-yl, 1,2-dihydropyrimidine-1-yl, 
perhydropyrimidine-1-yl, 1,4-diazacyclo heptane-1-yl, saturated or 
unsaturated monocyclic group which contain 1 to 2 oxygen atom(s) and 1 to 
3 nitrogen atom(s) as hetero atom(s) such as oxazolidine-3-yl, 
2,3-dihydroisooxazole-2-yl, morpholino, saturated or unsaturated 
monocyclic group which contain 1 to 2 sulfur atom(s) and 1 to 3 nitrogen 
atom(s) as hetero atom(s) such as thiazolidine-3-yl, isothiazoline-2-yl, 
thiomorpholino, condensed polycyclic group such as indole-1-yl, 
1,2-dihydrobenzimidazole-1-yl, perhydropyrrolo 1,2-a!pyrazine-2-yl, 
spirocyclic group such as 2-azaspiro 4,5!decane-2-yl, bridged cyclic 
heterocyclic group such as 7-azabicyclo 2,2,1!heptane-7-yl, and the like. 
Said lower alkoxy, lower alkyl, amino, cyclic amino group and the like may 
have suitable substutuent(s), such as lower alkylamino which is mono- or 
di-substituted, lower alkenyl, aralkyl, aryl, hydroxy, hydroxy lower 
alkyl, nitro, cyano, above mentioned cyclic amino, above mentioned lower 
alkoxy, lower alkoxy lower alkyl, halogen, halo lower alkyl, amino, 
protected amino, amino lower alkyl, protected amino lower alky, cyclo 
lower alkylamino, and the like. 
The numbers of these substituent(s) are not limited, preferably 1 to 4, and 
the substituent(s) may be the same or not the same. Also two of the same 
or not the same substituent(s) may substitute the same atom(s) on cyclic 
amino group. 
"Mono- or di-lower alkylamino group" may include amino group which has the 
group of one or two lower alkyl (e.g. methyl, ethyl, isopropyl, 
tert-butyl, tert-pentyl, etc. ), preferably methylamino, ethylamino, 
dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, 
dibutylamino, etc. 
"Lower alkenyl group" may include vinyl, allyl, isopropenyl, and the like. 
"Aralkyl group" may include benzyl, 1-phenylethyl, and the like. 
"Aryl group" may include phenyl, naphthyl, and the like. 
"Hydroxy lower alkyl group, alkoxy lower alkyl group, halo lower alkyl 
group, amino lower alkyl group, protected amino lower alkyl group" means 
that optional carbon atom(s) of above mentioned lower alkyl has each 
hydroxy, alkoxy, halogen, amino, protected amino. 
"Amino protecting group", may include acyl such as lower alkanoyl (e.g. 
formyl, acetyl, propionyl, pivaloyl, hexanoyl, etc.), mono- (or di- or 
tri-) halo (lower) alkanoyl group (e.g. chloroacetyl, bromoacetyl, 
dichloroacetyl, trifluoroacetyl, etc.), lower alkoxycarbonyl group, (e.g. 
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, 
tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.), carbamoyl group, aroyl 
group (e.g. benzoyl, toluoyl, naphthoyl, etc.), ar (lower) alkanoyl group 
(e.g. phenylacetyl, phenylpropionyl, etc.), aryloxycarbonyl group (e.g. 
phenoxycarbonyl, naphthyloxycarbonyl, etc.), aryloxy (lower) alkanoyl 
group (e.g. phenoxyacetyl, phenoxypropionyl, etc.), arylglyoxyloyl group, 
(e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc.), ar (lower) 
alkoxycarbonyl group which may have suitable substituent(s), (e.g. 
benzyloxycarbonyl, phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.), 
ar (lower) alkylidene group which are substituted or not substituted (e.g. 
benzylidene, hydroxybenzylidene etc.), ar (lower)alkyl group such as mono- 
(or di- or tri-) phenyl (lower) alkyl (e.g. benzyl, phenethyl, benzhydryl, 
trityl, etc.) and the like. 
Above mentioned amino protective group contain the protective group which 
have the function to temporarily protect amino group which is often used 
in the field of amino acid and peptide chemistry. 
Suitable "benzyl group which has lower alkoxy" may include lower alkoxy 
substituted benzyl such as 4-methoxybenzyl, 2,4-dimethoxybenzyl, 
3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2,3,4-trimethoxybenzyl, 
2-ethoxybenzyl, 4-hexyloxybenzyl, etc. 
Suitable "benzyl group which has halogen" may include halogen substituted 
benzyl such as 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 
2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 
2,6-dichlorobenzyl, 2-bromobenzyl, 2-bromo-4-chlorobenzyl, etc. 
Suitable "benzyl group which has lower alkyl" may include lower alkyl 
substituted benzyl such as 4-methylbenzyl, 4-ethylbenzyl, 4-propylbenzyl, 
4-isopropylbenzyl, 4-butylbenzyl, 4-isobutylbenzyl, 4-tert-butylbenzyl, 
4-pentylbenzyl, 4-hexylbenzyl, 2,3-dimethylbenzyl, 2,6-dimethylbenzyl, 
3,4-dimethylbenzyl, 2,4,6-trimethylbenzyl, etc. 
Suitable example of phenyl group which have such substituent(s) may include 
lower alkoxy substituted phenyl group (e.g. 4-methoxyphenyl, 
3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 
2-ethoxyphenyl, 4-hexyloxyphenyl, etc.), halogen substituted phenyl (e.g. 
2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 
2,6-dichlorophenyl, 2-bromophenyl, 2-bromo-4-chlorophenyl, 4-fluorophenyl, 
2,4-difluorophenyl etc.), hydroxy substituted phenyl (e.g. 
2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, etc.), lower alkoxy- 
and hydroxy-substituted phenyl (e.g. 2-(hydroxymethoxy) phenyl, etc.). 
Suitable example of benzyl group which have such substituent(s) may include 
lower alkoxy substituted benzyl (e.g. 4-methoxybenzyl, 
3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 2,3,4-trimethoxybenzyl, 
2-ethoxybenzyl, 4-hexyloxybenzyl, etc.), halogen substituted benzyl (e.g. 
2-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 
2,6-dichlorobenzyl, 2bromobenzyl, 2-bromo-4-chlorobenzyl, etc.), hydroxy 
substituted benzyl (e.g. 2-hydroxybenzyl, 3-hydroxybenzyl, 
4-hydroxybenzyl, etc.), lower alkoxy and hydroxy substituted benzyl (e.g. 
2-(hydroxymethoxy) benzyl, etc.) 
More preferable example of "cyclic amino group which may have 
substituent(s)" may include pyrrolidino, morpholino, 1-piperazino, 
4-methylpiperazino, piperidino and the like. 
The processes for preparing the object compound (I) are explained in detail 
in the following. 
Process 1 
The object compound (I) or a salt thereof can be prepared by subjecting the 
compound (II) or its reactive derivative at the amino group or carboxy 
group or a salt thereof to cyclization reaction. 
The starting compound (II), its reactive derivative or a salt thereof is 
new and such compounds can be prepared by the methods described in 
Preparation mentioned below or in substantially the same manner. 
Suitable reactive derivative at the amino group of the compound (II) may 
include Schiff's base type imino or its tautomeric enamine type isomer 
formed by the reaction of the compound (II) with a carbonyl compound such 
as aldehyde, ketone or the like; a silyl derivative formed by the reaction 
of the compound (II) with a silyl compound such as 
bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, 
bis(trimethylsilyl)urea or the like; a derivative formed by reaction of 
the compound (II) with phosphorus trichloride or phosgene, and the like. 
Suitable reactive derivative at the carboxy group of the compound (II) may 
include an acid halide, an acid anhydride, an activated amide, an 
activated ester, and the like. Suitable examples of the reactive 
derivatives may be an acid chloride; an acid azide; a mixed acid anhydride 
within acid such as a aliphatic carboxylic acid e.g. acetic acid, 
propionic acid, burytic acid, trichloroacetic acid, etc.! or aromatic 
carboxylic acid e.g. benzoic acid, etc.!; a symmetrical acid anhydride, 
and the like. These reactive derivatives can optionally be selected from 
them according to the kind of the compound (II) to be used. The reaction 
is usually carried out in the usual method which is used in cyclization 
reaction, under heating or in the presence of a conventional condensing 
agent. When R in the compound (II) is amino protective group, the 
elimination of the amino protective group is carried out previous to ring 
cyclization reaction. 
Suitable condensing agent may include carbodiimide or a salt thereof e.g. 
N,N'-dicyclohexylcarbodiimide, 
N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylami 
nocyclohexyl)carbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide 
or hydrochloride thereof, diphenyl phosphoryl azide, diethyl 
phosphorocyanidate, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, etc.!; 
N,N'-carbonyldiimidazole, N,N'-carbonylbis-(2-methylimidazole); 
keteneimine compound(e.g. pentamethyleneketene-N-cyclohexylimine; 
diphenylketene-N-cyclohexylimine; ethoxyacetylene; 
1-alkoxy-1-chloroethylen; ethyl polyphosphate; isopropyl polyphosphate; 
phosphorus oxychloride; phosphorus trichloride; thionyl chloride; oxalyl 
chloride; combining triphenylphosphine, and carbon tetrachloride or siazen 
carboxylate; 2-ethyl-7-hydroxybenzisoxazolium salt; 
2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 
1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; 
1-hydroxybenzotriazol; so-called Vilsmeier reagent prepared by the 
reaction of N,N-dimethylformamide with thionyl chloride, phosgene, 
trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like. 
The reaction in the presence of conventional condensing agent may be 
carried out in an organic solvent such as dichloromethane, methanol, 
ethanol, propanol, acetonitrile, pyridine, N,N-diethylformamide, 
4-methyl-2-pentanone, tetrahydrofuran, benzene, toluene, xylene, etc. or 
any other solvent mixture which does not adversely influence the reaction. 
The reaction temperature is not critical and the reaction is usually 
carried out under cooling to heating. Further, ring cyclization reaction 
under heating can be carried out to heat under boiling point in the 
solvent which is used in an organic solvent as above. 
Process 2 
The compound (Ia) or a salt thereof can be prepared by subjecting the 
compound (III) or a salt thereof to nitration reaction. 
The starting compounds (III) contain known compounds (Japanese Kokai Tokkyo 
Koho No. 3-35796) and novel compounds. The novel compounds can be prepared 
by the procedures described in Preparations and Examples mentioned later 
or in substantially the same manner. 
This reaction is carried out by reacting the compound (III) or a salt 
thereof with nitration agent (e.g. nitric acid, etc.). 
The reaction can usually be carried out in a conventional solvent such as 
dichloromethane which does not adversely influence the reaction. 
The reaction temperature is not critical and the reaction is usually 
carried out under cooling to heating. 
This reaction can be carried out in substantially the same manner as 
Example 7 mentioned later. 
Process 3 
The object compound (Ib) or a salt thereof can be prepared by subjecting 
the compound (Ia) or a salt thereof to the reduction reaction. 
This reaction can be carried out in a conventional manner for reducing: 
nitro to amino, and it may include chemical reduction and catalytic 
reduction. 
Suitable reducing agents to be used in chemical reduction are a combination 
of metal e.g. tin, zinc, iron, etc.! or metallic compound e.g. chromium 
chloride, chromium acetate, etc.! and an organic or inorganic acid e.g. 
formic acid, acetic acid, propionic acid, trifluoroacetic acid, 
p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.!. 
Suitable catalysts to be used in catalytic reduction are conventional ones 
such as platinum catalysts e.g. platinum plate, spongy platinum, platinum 
black, colloidal platinum, platinum oxide, platinum wire, etc.!. palladium 
catalysts e.g. spongy palladium, palladium black, palladium oxide, 
palladium on carbon, colloidal palladium, palladium on barium sulfate, 
palladium on barium carbonate, etc.!, nickel catalysts e.g. reduced 
nickel, nickel oxide, Raney nickel, etc.!, cobalt catalysts e.g. reduced 
cobalt, Raney cobalt, etc.!, iron catalysts e.g. reduced iron, Raney iron 
etc.!, copper catalysts e.g. reduced copper, Raney copper, Ullman copper, 
etc.! and the like. 
The reduction is usually carried out in a conventional solvent which does 
not adversely influence the reaction such as water, methanol, ethanol, 
propanol, N,N-dimethylformamide, or a mixture thereof. Additionally, in 
case that the above-mentioned acid to be used in chemical reduction are in 
liquid, they can also be used as a solvent. Further, a suitable solvent to 
be used in catalytic reduction may be the above-mentioned solvent, and 
other conventional solvent such as diethyl ether, dioxane, 
tetrahydrofuran, etc., or a mixture thereof. 
The reaction temperature of this reduction is not critical and the reaction 
is usually carried out under cooling to warming. 
Process 4 
The object compound (Ic) or a salt thereof can be prepared by subjecting 
the isolated or not isolated the compound (Ib) or a salt thereof, which is 
obtained by the Process 3, to alkylation reaction. This reaction can be 
carried out by combining aldehyde and reduction agent or alkylhalide and 
base. Suitable reduction agents are metallic hydride complex compound, 
e.g. sodium borohydride, sodium cyanoborohydride, potassium borohydride, 
bis(2-methoxyethoxy) aluminium hydride, etc.!, a combination of hydrogen, 
formic acid, or ammonium formate, and palladium catalysts e.g. palladium 
on carbon, palladium hydroxide on carbon, palladium black, etc.!. 
Suitable base may include an inorganic base such as sodium bicarbonate, 
potassium carbonate, etc., or an organic base such as pyridine, 
triethylamine, etc. The reaction is usually carried out in a conventional 
solvent which does not adversely influence the reaction. The reaction 
which is combined by aldehyde and reduction agents can be carried out in 
substantially the same manner as Preparation 23 or Example 8 mentioned 
later, and the reaction which is combined by an alkyl halide and a base 
can be carried out in substantially the same manner as Preparation 41 
mentioned later. 
The reaction which is combined by the compound containing two aldehydes and 
reduction agents can be carried out in substantially the same manner as 
Example 31 mentioned later. 
Process 5 
The object compound (Id) or a salt thereof can be prepared by subjecting 
the isolated or not isolated compound (Ib) or a salt thereof, which is 
obtained by the Process 3, to mono alkylation reaction followed by 
intramolecular alkylation reaction. The reaction can be carried out by 
combining a compound, which has two aldehydes in the molecule, and 
reduction agents or by combining a compound, which has two halogens and a 
base. 
Process 6 
The object compound (Ie) or a salt thereof can be prepared by subjecting 
the isolated or not isolated object compound (Ib) or a salt thereof, which 
is obtained by the Process 3, to hydroxylation reaction by diazotization 
reaction followed by decomposition of diazonium salt. This reaction can be 
carried out by reacting the compound (Ib) or a salt thereof with sodium 
nitrite in the presence of an inorganic or an organic acid and decomposing 
a growing diazonium salt in water or an organic acid under the room 
temperature to heating, carrying out hydrolysis if necessary. It is 
possible to prepare the compound (Ie) or a salt thereof by transforming 
the amino group of the compound (Ib) or a salt thereof into a hydroxyl 
group. Suitable acid may include an inorganic acid e.g. sulfuric acid, 
hydrochloric acid, borofluoric acid, etc.!, and an organic acid e.g. 
acetic acid, trifluoroacetic acid, etc.!. 
Process 7 
The object compound (If) or a salt thereof can be prepared by subjecting 
the compound (Ie) or a salt, which is obtained by the Process 6, thereof 
to alkylation reaction. This reaction can be prepared by combining a 
alkylhalide and a base. 
The reaction can be carried out substantially in the same manner as the 
later mentioned Example 15 and Example 16. Suitable base may include an 
inorganic base e.g. sodium bicarbonate, potassium carbonate, etc. and an 
organic base e.g. pyridine, triethylamine, etc.!. 
The compound or its salt of the present invention has excellent 
parasiticidal activities as an anthelmintic agent for animals and human 
bodies. It is effective to nematodes which are infected particularly to 
the domestic animals, domestic fowls or pets such as pigs, sheep, goats, 
cattle, horses, dogs, cats, and chickens. 
Haemonchus genus, Trichostrongylus genus, Ostertagia genus, Nematodirus 
genus, Cooperia genus, Ascaris genus, Bunostomum genus, Oesophagostomum 
genus, Chabertia genus, Trichuris genus, Strongylus genus, Trichonema 
genus, Dictyocaulus genus, Capillaria genus, Heterakis genus, Toxocara 
genus, Ascaridia genus, Oxyuris genus, Ancylostoma genus, Uncinaria genus, 
Toxascaris genus, Parascaris genus, Nippostrongylus genus, Metastrongylus 
genus, Hyostrongylus genus, Strongyloides genus, Cyathostomum genus. 
The parasiticidal activities are pointed out in some kind of Nematodirus 
genus, Cooperia genus, and Oesophagostomum genus which attack the 
intestinal tract, however, just Haemonchus genus and Ostertagia genus are 
parasitic on the stomach, and parasites of Dictyocaulus genus are found in 
lungs. 
The parasites of Filariidae or Setariidae activities are found in heart and 
blood vessels, hypodermis, or lymphatic vessel or any other organisms or 
organs. 
It is also effective to parasites which infect human beings. The most 
common parasites in the alimentary canal of human beings are as follows: 
Ancylostoma genus, Necator genus, Ascaris genus, Strongyloides genus, 
Tichinell genus, Capillaria genus, Trichuris genus, and Enterobius genus. 
It is also active for other medically important parasites, which is found 
in the blood or other organisms or organs out side of the alimentary 
canal, such as Wuchereria genus, Brugia genus, Onchocerca genus and Loa 
genus in Filariidae, as well as parasites such as Dracunlus genus in 
Dracunculidae. It is also active for parasites such as Strongyloides genus 
and Trichinella genus in the intestinal tract in a particular conditioned 
parasitism out side of intestinal tract. 
Test 
Test 1 
(1) Test Compounds 
The compounds which are illustrated in Example 1, Example 3, Example 4, 
Example 5, Example 10, Example 17, Example 23, Example 24, Example 25, and 
Example 29. 
(2) Test 
The effect of parasiticides was examined with the rats which was infected 
by nematodes which are parasitic on rats, Nippostrongylus brasilienses. 
Wistar strain rats (female 6 weeks old, 120-130 g weight) were sacrificed 
by infecting them and giving them subcutaneous injections of 3000 
infective larvae per rat. 
Test compound of 50 mg was dissolved in 0.25 ml dimethylsulfoxide, 0.5% 
methylcellulose solution was added, and liquid volume was adjusted to be 
prescribed volume of 100, 10, 5, 2.5, 1.25, 1.0, 0.63, 0.32 mg/kg to 
utilize. After they were infected, on each 7th, 8th, and 9th day, the test 
compound was administered orally with above concentration. On the 11th 
day, the rat was dissected and the numbers of parasites in the small 
intestines were measured. 
The given measurement was based to calculate the reduction rate from the 
percentage of the numbers of the parasites of unadministered rats 
(control). The result of it is shown in the 
Test 2 
The reduction rate was calculated in a similar manner as Test 1 except when 
the test compound was subcutaneously administered to the rats instead of 
oral administration as in Test 1. The result of that is shown in the Table 
2. 
Test 3 
For 1 rat, the 5000 infective larvae of Strongyloides venezuelensis were 
infected percutaneously to one group (2 rats) of 8 weeks old Mongolian 
gerbils. On the 10th day after they were infected, the suspended test 
compound was orally administered once with the amount of established 
administration. The effect was judged according to the amount of the eggs 
in the feces or the numbers of worms in the intestinal tract. The 
measurement of the numbers of the eggs were taken from O ring method, and 
the numbers of the eggs (EPG) in 1 g of feces were counted on the day 
before, on the day, and on the 1st, 2nd, 3rd, and 4th day after the 
administration. The numbers of the parasites were measured by dissecting 
Mongolian gerbils the 4th day after the administration (on the 14th day 
after infection). The method of measurement was followed by releasing the 
parasites, which live in the small intestines, into saline solution over 
night, and the released parasites were set to be as numbers of worms 
recovered. 
The result (the mean number of each group) is shown in the Table 3. 
Test Results 
TABLE 1 
______________________________________ 
Minimum Amount of Administration 
indicated by more than 95% of 
Test Compounds Reduction Rate 
______________________________________ 
PF1022 (Japanese Patent 
10 mg/kg 
Application 3 - 35796) 
Example - 1 2.5 mg/kg 
Example - 3 1.25 mg/kg 
Example - 4 2.5 mg/kg 
Example - 5 0.63 mg/kg 
Example - 10 2.5 mg/kg 
Example - 17 2.5 mg/kg 
Example - 23 5 mg/kg 
Example - 24 5 mg/kg 
Example - 25 5 mg/kg 
Example - 29 5 mg/kg 
______________________________________ 
TABLE 2 
______________________________________ 
Minimum Amount of Administration 
indicated by more than 95% of 
Test Compounds Reduction Rate 
______________________________________ 
PF1022 (Japanese Patent 
&gt;100 mg/kg 
Application 3 - 35796) 
Example - 1 10 mg/kg 
Example - 3 5 mg/kg 
Example - 5 1.25 mg/kg 
Example - 12 50 mg/kg 
______________________________________ 
TABLE 3 
__________________________________________________________________________ 
Change in Numbers of Numbers 
Parasites' Number of the 
Test of Eggs in Feces (EPG/100) 
Worms 
Compounds 
Dose -2 0* 1 2 3 4 recovered 
__________________________________________________________________________ 
Unadminist 
-- 574 
1240 
1725 
2343 1533 1505 
3005 
ered 
control 
PF1022 
20 mg/ 
332 
1615 
581 1563 935 1005 
3088 
kg 
Example - 
5 mg/ 
455 
1890 
701 0 0 0 
0 
5 kg 
Example - 
2.5 mg/ 
838 
1665 
452 0 0 0 
0 
5 kg 
Example - 
1.25 551 
2800 
536 0 0 30 
8 
5 mg/ 
kg 
__________________________________________________________________________ 
*stands for the starting day of administration. 
When the compound of the present invention are used for animals and human 
being as an anthelmintic agent, it can be administered orally as a liquid 
drink. The liquid drink is usually suspended agent such as bentonite, and 
wetting agent, or other excipients with non-toxic solution, or solution 
made of water, suspension, or dispersed solution, and generally it 
comprises liquid drinks or antifoaming agent. The prescription of a liquid 
drink contains generally activated compound for 0.01-0.5 weight %, 
preferably 0.0-0.1 weight %. When it is preferably administered orally as 
a dried solid single dose, capsules, pills, or tablets, which comprise the 
desired amount of activated compounds are usually used. These forms of 
dosage are prepared by homogeneous admixtures of diluent, filler, 
disintegrator and/or excipient agents such as dextrine, lactose, talc, 
magnesium stearate, vegetable rubber, etc. 
The usage of such single dose prescription can be varied broadly by kind of 
hosts, or kind of parasites, or weight of hosts which are to be treated 
and referring to the weight and containing quantity of anthelmintics. 
When it is administered in animal feed, it is used as to disperse 
homogeneously, or as top dressing, or in the form of pellet. To achieve 
preferable effect of antiparasites, the activated compound of 0.0001-2% is 
usually contained in feed. 
The dosage which was dissolved or dispersed in liquid carrier excipients 
can be administered to animals parenterally by giving them injections in 
the anterior stomach, muscle, tachea, or under the skin. The activated 
compound is mixed with suitable vegetable oil such as peanut oil or 
cottonseed oil for parenteral administration. These prescriptions 
generally contain the activated compound of 0.05-50 weight %. It can also 
be administered locally by mixing in a suitable carrier such as 
dimethylsulfoxide or hydrocarbon solvent. The prepared solvents can be 
used directly on the exterior of animals by sprays or direct injections. 
The most suitable usage amount of the activated compound to achieve the 
most effective result depends on the kind of animals, which are to be 
treated, and type of parasital infection and its stage. It can be achieved 
by oral administration of the activated compound 0.01-100 mg, preferably 
0.5-50.0 mg, per kg of the treated animal. Such dosage amount is given in 
a relatively short term of 1-5 days at once or separately.