Novel 5,6-dihydro-2-(substituted phenyl)-1,2,4-triazine-3,5(2H,4H)-diones which are effective in destroying or preventing the growth of Protozoa in subjects suffering from such Protozoa.

BACKGROUND OF THE INVENTION 
2-Phenyl-as-triazine-3,5(2H,4H)-diones and their use for controlling 
coccidiosis have been described in U.S. Pat. No. 3,912,723. The phenyl 
moiety in the said triazines may, inter alia, be substituted with a 
benzoyl-, an .alpha.-hydroxy-phenylmethyl- and a phenylsulfonyl radical. 
Substituted 2-phenyl-hexahydro-1,2,4-triazine-3,5-diones and their use for 
combatting Protozoa have been disclosed in Published Eur. Pat. Application 
No. 0,154,885. 
The 5,6-dihydro-2-phenyl-1,2,4-triazine-3,5(2H,4H)-diones, described in the 
present application, differ from the hereinabove-mentioned triazinones, by 
the specific substitution of the 2-phenyl moiety, resulting in 
5,6-dihydro-1,2,4-triazine-3,5(2H,4H)-diones which are very effective in 
destroying or preventing the growth of Protozoa in subjects suffering from 
such Protozoa. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The present invention is related with 
5,6-dihydro-2-(substituted-phenyl)-1,2,4-triazine-3,5(2H,4H)-diones having 
the formula 
##STR1## 
the pharmaceutically acceptable acid addition, metal or amine substitution 
salts, and stereochemically isomeric forms thereof, wherein: 
Ar is thienyl, halo substituted thienyl, naphthalenyl or a radical of 
formula 
##STR2## 
R is hydrogen, C.sub.1-6 alkyl, cyclo C.sub.3-6 alkyl, aryl or 
(aryl)C.sub.1-6 alkyl; 
R.sup.1 is cyano or a radical of formula --C(.dbd.X)--Y--R.sup.9 ; 
said 
X being O or S, 
Y being O, S, NR.sup.10 or a direct bond; 
R.sup.9 being hydrogen, aryl, C.sub.3-6 cycloalkyl or C.sub.1-6 alkyl 
optionally substituted with aryl, hydroxy, amino, mono- and di(C.sub.1-6 
alkyl)amino, piperidinyl, pyrrolidinyl, 4-morpholinyl, piperazinyl, 
4-(C.sub.1-6 alkyl)-piperazinyl, 4-(C.sub.1-6 alkyl-carbonyl)-piperazinyl, 
4-(C.sub.1-6 alkyloxycarbonyl)-piperazinyl or 4-((aryl)C.sub.1-6 
alkyl)-piperazinyl; and where Y is a direct bond, R.sup.9 may also be 
halo; 
R.sup.10 is hydrogen, C.sub.1-6 alkyl or (aryl)C.sub.1-6 alkyl; or R.sup.9 
and R.sup.10 taken together with the nitrogen atom bearing said R.sup.9 
and R.sup.10 may form a piperidinyl, pyrrolidinyl, 4-morpholinyl, 
piperazinyl, 4-(C.sub.1-6 alkyl)piperazinyl, 4-(C.sub.1-6 
alkylcarbonyl)-piperazinyl, 4-(C.sub.1-6 alkyloxycarbonyl)-piperazinyl or 
a 4-((aryl)C.sub.1-6 alkyl)-piperazinyl radical; 
R.sup.2, R.sup.3, R.sup.6, R.sup.7 and R.sup.8 are each independently 
hydrogen, halo, trifluoromethyl, C.sub.1-6 alkyl, hydroxy, C.sub.1-6 
alkyloxy, C.sub.1-6 alkylcarbonyloxy, mercapto, C.sub.1-6 alkylthio, 
C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylsulfinyl, 
(trifluoromethyl)-sulfonyl, cyano, nitro, amino, mono- and di(C.sub.1-6 
alkyl)amino, or (C.sub.1-6 alkylcarbonyl)amino; 
R.sup.4 and R.sup.5 are each independently hydrogen, aryl, cyclo C.sub.3-6 
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (aryl)C.sub.2-6 alkenyl or 
C.sub.1-6 alkyl optionally substituted with aryl, hydroxy, amino, mono- 
and di(C.sub.1-6 alkyl)amino, piperidinyl, pyrrolidinyl, 4-morpholinyl, 
piperazinyl, 4-(C.sub.1-6 alkyl)-piperazinyl, 4-(C.sub.1-6 
alkylcarbonyl)piperazinyl, 4-(C.sub.1-6 alkyloxy-carbonyl)-piperazinyl or 
4-((aryl)C.sub.1-6 alkyl)-piperazinyl; 
and R.sup.5 may also be C.sub.1-6 alkylcarbonyl, C.sub.1-6 
alkyloxycarbonyl, (aryl)C.sub.1-6 alkyloxycarbonyl or (aryl)carbonyl; 
wherein aryl is phenyl, optionally substituted with up two 3 substituents 
each independently selected from the group consisting of halo, C.sub.1-6 
alkyl, C.sub.1-6 alkyloxy, trifluoromethyl, hydroxy, mercapto, C.sub.1-6 
alkylthio, C.sub.1-6 alkylsulfonyl, C.sub.1-6 alkylsulfinyl, 
trifluoromethylsulfonyl, cyano, nitro, amino, mono- and di(C.sub.1-6 
alkyl)amino and (C.sub.1-6 alkylcarbonyl)amino. 
In the foregoing definitions the term "halo" is generic to fluoro, chloro, 
bromo and iodo; "C.sub.1-6 alkyl" is meant to include straight and 
branched saturated hydrocarbon radicals, having from 1 to 6 carbon atoms, 
such as, for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, 
propyl, butyl, pentyl, hexyl and the like; "cyclo C.sub.3-6 alkyl" 
embraces cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; "C.sub.2-6 
alkenyl" is meant to include straight and branch chained hydrocarbon 
radicals containing one double bond and having from 2 to 6 carbon atoms 
such as, for example, ethenyl, 3-propenyl, 2-butenyl and the like; 
"C.sub.2-6 alkynyl" is meant to include straight and branch chained 
hydrocarbon radicals containing one triple bond and having from 2 to 6 
carbon atoms such as, for example, ethynyl, 3-propynyl, 2-butynyl and the 
like. 
Preferred compounds within the invention are those wherein Ar is 
halothienyl or a radical of formula (a) wherein R.sup.6 and R.sup.7 are, 
each independently, hydrogen, halo, trifluoromethyl, C.sub.1-6 alkyloxy, 
hydroxy or C.sub.1-6 alkyl; R.sup.8 is hydrogen; R is hydrogen, C.sub.1-6 
alkyl, phenyl or halophenyl; R.sup.2 and R.sup.3 are, each independently, 
hydrogen, halo, trifluoromethyl or C.sub.1-6 alkyl; and R.sup.4 is 
hydrogen or C.sub.1-6 alkyl. 
Particularly preferred compounds within the invention are those preferred 
compounds wherein Ar is a radical of formula (a) wherein R.sup.6 is halo, 
R.sup.7 and R.sup.8 are hydrogen, R is hydrogen or C.sub.1-6 alkyl, 
R.sup.2 and R.sup.3 independently are halo or hydrogen. 
More particularly preferred compounds within the invention are those 
particularly preferred compounds wherein R.sup.6 is 4-chloro, R is 
hydrogen, R.sup.2 is 2-chloro, R.sup.3 is 6-chloro or hydrogen and R.sup.4 
is hydrogen. 
The most preferred compounds within the invention are 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2, 
4-triazin-2(1H)-yl)benzeneacetonitrile and 
2-chloro-.alpha.-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2,4-tr 
iazin-2(1H)-yl)benzeneacetonitrile and the pharmaceutically acceptable acid 
addition, metal or amine substitution salts thereof. 
The compounds of formula (I) may conveniently be prepared by a reduction 
reaction of the corresponding 1,2,4-triazine-3,5-(2H,4H)-dione of formula 
(II), or an acid-addition salt, metal or amine substitution salt form 
thereof, thus preparing a compound of formula (I) wherein R.sup.5 is 
hydrogen, said compounds being represented by the formula (I-a), and if 
desired, subsequently reacting the compounds of formula (I-a) with a 
reagent R.sup.5-a -W (III), thus preparing compounds of formula (I), 
wherein R.sup.5 is other than hydrogen, said compounds being represented 
by the formula (I-b). In (III) W represents an appropriate reactive 
leaving group such as, for example, halo, e.g., chloro, bromo or iodo, or 
a sulfonyloxy group, e.g. methylsulfonyloxy or 4-methylphenyl-sulfonyloxy 
and R.sup.5-a has the previously defined meaning of R.sup.5, provided that 
it is not hydrogen. 
##STR3## 
The said reduction reaction is conveniently conducted following art-known 
procedures for converting a 1,2,4-triazine-3,5-(2H,4H)-dione into a 
5,6-dihydro-1,2,4-triazine-3,5-(2H,4H)-dione moiety. A number of such 
procedures are described in for example the Published Eur. Pat. 
Application No. 0,154,885 and the references cited therein. 
Said reduction reaction may for example be conducted by contacting the 
starting material of formula (II) with hydrogen in the presence of an 
appropriate catalyst such as, for example, Raney-nickel, platinum, 
palladium, platinum(IV) oxide, and the like. Preferably, said reduction 
reaction is conducted by reacting the starting material (II) with zinc in 
acetic acid or tin(II) chloride in hydrochloric acid, optionally in the 
presence of a reaction-inert organic solvent or mixture of such solvents 
such as, for example, a lower alkanol, e.g. methanol or ethanol; a 
hydrocarbon, e.g. methylbenzene or dimethylbenzene; a ketone, e.g. 
2-propanone, 1-butanone; an ether, e.g. tetrahydrofuran, 
1,2-dimethoxyethane, 1,4-dioxane, an ester, e.g. ethyl acetate; 
N,N-dimethylformamide, N,N-dimethylacetamide; pyridine; acetic acid. 
Higher temperatures may be used to enhance the reaction rate. 
The alkylation reaction of (I-a) with the reagent R.sup.5-a -W may be 
conducted following art-known N-alkylation procedures. The alkylation 
reaction is conveniently conducted in an inert organic solvent such as, 
for example, an aromatic hydrocarbon, e.g., benzene, methylbenzene, 
dimethylbenzene, and the like; a lower alkanol, e.g., methanol, ethanol, 
1-butanol and the like; a ketone, e.g., 2-propanone, 4-methyl-2-pentanone 
and the like; and ether, e.g., 1,4-dioxane, 1,1'-oxybisethane, 
tetrahydrofuran and the like; N,N-dimethylformamide (DMF); 
N,N-dimethylacetamide (DMA); nitrobenzene; dimethyl sulfoxide (DMSO); 
1-methyl-2-pyrrolidinone; and the like. The addition of an appropriate 
base such as, for example, an alkali metal carbonate or hydrogen 
carbonate, sodium hydride or an organic base such as, for example, 
N,N-diethylethanamine or N-(1-methylethyl)-2-propanamine may be utilized 
to pick up the acid which is liberated during the course of the reaction. 
In some circumstances the addition of an iodide salt, preferably an alkali 
metal iodide, is appropriate. Somewhat elevated temperatures may enhance 
the rate of the reaction. 
The compounds of formula (I) wherein R.sup.1 is cyano, said compounds being 
represented by the formula 
##STR4## 
may alternatively be prepared by converting the hydroxy function of a 
triazinedione of formula 
##STR5## 
into a nitrile function. 
The conversion of (IV) into (I-c) may be effected by art-known procedures. 
For example, by first converting the hydroxy function into a suitable 
leaving group and subsequently converting the said leaving group in the 
thus obtained intermediate having the formula 
##STR6## 
into a nitrile function. 
In (V) W has the meaning of an appropriate reactive leaving group such as, 
for example, halo, e.g., chloro, bromo or iodo, or a sulfonyloxy group, 
e.g., methylsulfonyloxy or 4-methylphenylsulfonyloxy. 
For example, where W represents chloro, the intermediates (V) may be 
prepared by reacting (IV) with thionyl chloride in a suitable 
reaction-inert solvent. 
The conversion of (V) into (I-c) may be effected, e.g., by reacting (V) 
with a cyanide, such as, for example, an alkalimetal cyanide, e.g. 
potassium cyanide, sodium cyanide; copper cyanide; silver cyanide and the 
like, if desired, in the presence of an appropriate solvent. 
The compounds of formula (I) can also be prepared by reacting a 
5,6-dihydro-1,2,4-triazine-3,5(2H,4H)-dione having the formula (VII) with 
a reagent of formula (VI) following art-known procedures for arylating an 
amine functionality. 
##STR7## 
In (VI) W represents an appropriate reactive leaving group as defined 
hereinabove and preferably is halo. The reaction of (VI) with (VII) is 
most conveniently conducted in an appropriate reaction-inert solvent, 
preferably at higher temperature and in the presence of a suitable base. 
Suitable reaction inert solvents may, for example, be aromatic 
hydrocarbons, e.g., benzene, methylbenzene and dimethylbenzene; 
halogenated hydrocarbons, e.g. trichloromethane and trichloroethane; 
dipolar aprotic solvents such as N,N-dimethylformamide, 
N,N-dimethylacetamide, dimethylsulfoxide and the like. 
The compounds of formula (I) can also be converted into each other 
following art-known procedures of functional grouptransformation. Some 
examples will be cited hereinafter. 
In order to simplify the structural representations of the compounds of 
formula (I) in the schemes illustrating these grouptransformation 
procedures, the 
##STR8## 
group will hereafter be represented by the symbol D. 
For example, the compounds of formula (I) wherein R.sup.1 is cyano, said 
compounds being represented by the formula (I-c) may partially or 
completely by hydrolysed, thus yielding compounds of formula (I) wherein 
the radical R.sup.1 is a carboxyl or an aminocarbonyl group, the former 
compound being represented by the formula (I-e), the latter by (I-d). The 
said partial hydrolysis reaction is preferably conducted in an aqueous 
acidic medium, e.g. an aqueous sulfuric, hydrochloric or phosphoric acid 
solution, at room temperature or at slightly increased temperature. 
Complete hydrolysis is accomplished when increasing either the reaction 
temperature or the reaction time or both. In the said complete hydrolysis 
reaction it may be advantageous to add a second acid to the reaction 
mixture, e.g. acetic acid. In turn, the compounds of formula (I-d) can 
further by hydrolysed to obtain compounds of formula (I-e) by treating the 
starting compounds of formula (I-d) with an aqueous acidic solution in the 
same way as for obtaining (I-e) from (I-c). 
##STR9## 
Furthermore, the compounds of formula (I-c) can be converted to the 
corresponding compounds of formula (I) wherein R.sup.1 is an 
aminothioxomethyl group, said compounds being represented by the formula 
(I-f), by reacting (I-c) with hydrogen sulfide, preferably in a suitable 
solvent such as pyridinine, optionally in the presence of an organic base 
such as a trialkylamine, e.g. triethylamine. 
##STR10## 
The acids of formula (I-e) can be converted to the corresponding 
acylhalides of formula (I-g) by treatment with a suitable halogenating 
agent such as, for example, thionyl chloride, pentachlorophosphorane, 
sulfuryl chloride. The thus obtained acylhalides of formula (I-g) can 
further be derivatized to the corresponding amides of formula (I-h) by 
reacting the starting acylhalide compounds of formula (I-g) with a 
suitable amine optionally in the presence of an appropriate solvent such 
as an ether, e.g. tetrahydrofuran, acetonitrile, trichloromethane or 
dichloromethane. 
Or, the said acylhalides of formula (I-g) can conveniently be converted to 
the corresponding aryl or alkyl ketones of formula (I-i), respectively 
(I-j), by reacting (I-g) with benzene or substituted benzene in the 
presence of a Lewis acid catalyst such as aluminum chloride, respectively 
with an metal alkyl, e.g. methyl lithium, butyl lithium, optionally in the 
presence of a suitable catalyst, e.g. copper(I) iodide, or with a complex 
metal alkyl, in a suitable solvent, e.g. tetrahydrofuran. 
The acylhalides of formula (I-g) can further be converted to the 
corresponding esters of formula (I-k) by a suitable alcoholysis reaction. 
Or, the acids of formula (I-f) can be esterified following art-known 
procedures, e.g. by treating the starting acids with a alkylhalide in a 
suitable solvent in the presence of a base, e.g. in N,N-dimethylformamide 
or N,N-dimethylacetamide in the presence of an alkalimetal carbonate, or 
by reacting (I-g) with the appropriate alcohol in the presence of a 
reagent capable of forming an ester functionality e.g. 
N,N'-methanetetraylbis[cyclohexanamine]. 
##STR11## 
The compounds of formula (I), wherein either R.sup.4 or R.sup.5 is hydrogen 
may be converted to the compounds of formula (I) having an R.sup.4 and/or 
R.sup.5 other than hydrogen by N-alkylating or N-acylating the starting 
compounds following art-known procedures, e.g. following the same 
procedures as described hereinabove for the preparation of (I-b) starting 
from (I-a). 
The compounds of formula (I) which contain an Ar moiety which is a phenyl 
radical substituted with one or more alkyloxy radicals may be converted to 
the corresponding alkylcarbonyloxy compounds by treating the starting 
compounds with an alkanoic acid in the presence of anhydrous hydrohalic 
acid, e.g. hydrobromic acid in acetic acid. The said alkylcarbonyloxy 
compounds can in turn be converted to the corresponding hydroxyphenyl 
compounds by a suitable hydrolysis reaction, e.g. by treatment with an 
aqueous hydrohalic solution. 
A number of intermediates and starting materials in the foregoing 
preparations are known compounds which may be prepared according to 
art-known methodologies of preparing said or similar compounds and others 
are new. A number of such preparation methods will be described 
hereinafter in more detail. 
Several of the intermediates of formula (II) are known compounds and their 
synthesis is described in the Published Eur. Pat. Application No. 
0,170,316. 
They may generally be prepared by cyclizing an intermediate of formula 
##STR12## 
and eliminating the group E of the thus obtained dione 
##STR13## 
In the intermediates (VIII) L has the meaning of an appropriate leaving 
group such as C.sub.1-6 alkyloxy, halo and the like. The group E, as 
described in the intermediate (VIII) and the triazinedione (IX), 
represents an appropriate electron attracting group which may conveniently 
be eliminated from the dione (IX) such as, for example, a carboxyl, a 
sulfonyloxy, a sulfinyloxy group or a precursor and/or derivative thereof, 
e.g. an ester, an amide, a cyanide, a C.sub.1-6 alkylsulfonyloxy, 
phenylsulfonyloxy, C.sub.1-6 alkylphenylsulfonyloxy and 
halophenylsulfonyloxy and the like like groups. 
A particularly suitable process for preparing intermediates of formula (II) 
consists of cyclizing an intermediate of formula (VIII-a) and eliminating 
the E.sup.1 functionality in the thus obtained intermediate of formula 
(IX-a). In (VIII-a) and (IX-a) E.sup.1 represents a cyano, C.sub.1-6 
alkyloxycarbonyl or amido group. 
##STR14## 
The cyclization reaction may be effected following art-known cyclization 
procedures as described, for example, in Monatshefte der Chemie, 94, 
258-262 (1963), e.g. by heating the starting compound of formula (VIII-a) 
over its melting point, or by refluxing a mixture of (VIII-a) with a 
suitable solvent such as, for example, an aromatic hydrocarbon, e.g. 
benzene, methylbenzene, or dimethylbenzene, an acid, e.g. acetic acid, 
optionally in the presence of base, e.g. potassium acetate, sodium acetate 
and the like. 
The elimination of the E.sup.1 functionality may be effected following 
art-known procedures as described, for example, in Monatshefte der Chemie, 
96, 134-137 (1965), e.g. by converting (IX-a) into a carboxylic acid (X) 
in a suitable acidic reaction medium such as acetic acid, aqueous 
hydrochloric acid solutions or mixtures thereof. Elevated temperatures may 
enhance the rate of the reaction. 
The thus obtained carboxylic acids of formula 
##STR15## 
may be converted into an intermediate of formula (II) by art-known 
decarboxylation reaction procedures, e.g. by heating the carboxylic acid 
(X) or by heating a solution of (X) in 2-mercaptoacetic acid as described, 
for example, in U.S. Pat. No. 3,896,124. 
The intermediates of formula (VIII) may generally be prepared by reacting a 
diazonium salt of formula (XI) with a reagent of formula (XII). 
##STR16## 
X.sup.-, described in (XI) has the meaning of an appropriate anion and E 
and L, as described in (XII), have the previously defined meanings. 
The reaction of (XI) with (XII) may conveniently be conducted in a suitable 
reaction medium as described, for example, in Monatshefte der Chemie, 94, 
694-697 (1963). Suitable reaction mediums are, for example, aqueous sodium 
acetate solutions, pyridine and the like. 
The starting diazonium salts (XI) may be derived from a corresponding amine 
of formula (XIII) following art-known procedures, e.g. by reacting the 
latter with an alkalimetal or earth alkaline metal nitrite, e.g. sodium 
nitrite, in a suitable reaction medium. 
##STR17## 
In the hereinabove-described reaction scheme M.sup.n+ is a alkalimetal or 
earth alkaline metal kation and n is the integer 1 or 2. 
The amines of formula (XIII) may be prepared following procedures analogous 
to those described in U.S. Pat. No. 4,005,218. 
The triazinediones of formula (IV) may conveniently be prepared by reducing 
the corresponding 1,2,4-triazine-3,5(2H,4H)-diones of formula (XIV) 
following the same procedures as described hereinabove for the preparation 
of (I) starting from (II) and, if desired, by further N-alkylating the 
thus obtained triazinedione of formula (IV-a) with a reagent R.sup.5-a -W 
(III) following the same procedures described hereinabove for the 
preparation of (I-b) starting from (I-a). 
##STR18## 
The triazinediones of formula (XIV) may be prepared following the 
procedures described in U.S. Pat. No. 3,912,723. 
The intermediates of formula (II) wherein R.sup.1 is cyano, said 
intermediates being respresented by the formula 
##STR19## 
may alternatively be prepared by converting the hydroxy function of a 
triazinedione of formula 
##STR20## 
into a nitrile function. 
The conversion of (XV) into (II-a) may be effected by art-known procedures. 
For example, by first converting the hydroxy function into a suitable 
leaving group and subsequently converting the said leaving group in the 
thus obtained intermediate having the formula 
##STR21## 
into a nitrile function. 
In (XVI) W has the previously defined meaning of an appropriate reactive 
leaving group. 
For example, where W represents chloro, the intermediates (XVI) may be 
prepared by reacting (XV) with thionyl chloride in a suitable 
reaction-inert solvent. 
The conversion of (XVI) into (II-a) may be effected, e.g., by reacting 
(XVI) with a cyanide, such as, for example, an alkalimetal cyanide, e.g. 
potassium cyanide, sodium cyanide; copper cyanide; silver cyanide and the 
like, if desired, in the presence of an appropriate solvent. 
The intermediates of formula (II) may alternatively be prepared by reacting 
a 1,2,4-triazine-3,5-(2H,4H)-dione of formula (XVII) with an aromatic 
compound of formula (VI) following the same procedures as described 
hereinabove for the preparation of (I) starting from (VI) with (VII). 
##STR22## 
The intermediates of formula (II) can also be converted into each other 
following art-known procedures of functional groupstransformation. A 
number of such groupstransformations are represented by the following 
scheme. In order to simplify the structural representations of the 
intermediates of formula (II) in these schemes, the 
##STR23## 
group will hereafter be represented by the symbol D'. 
##STR24## 
The convertion of (II-a) to (II-b), of (II-a) to (II-c) and of (II-b) to 
(II-c) can conveniently be done following the same procedures as described 
hereinabove for the conversion of (I-c) to (I-d), (I-c) to (I-e) and of 
(I-d) to (I-e). 
A further series of such groupstransformations can be represented by the 
following scheme. 
##STR25## 
The convertion of (II-a) to (II-d), of (II-d) to (II-e), of (II-e) to 
(II-f), of (II-d) to (II-i), of (II-e) to (II-i), of (II-e) to (II-h) and 
of (II-e) to (II-g) can conveniently be done following the same procedures 
as described hereinabove for the conversion of (I-c) to (I-f), of (I-f) to 
(I-g), of (I-g) to (I-h), of (I-f) to (I-k), of (I-g) to (I-k), of (I-g) 
to (I-j) and of (I-g) to I-i). 
The intermediates of formula (II), wherein R.sup.4 is hydrogen may be 
converted to the compounds of formula (II) having an R.sup.4 other than 
hydrogen by N-alkylating the starting compounds following art-known 
procedures, e.g. the procedures described hereinabove for the preparation 
of (I-b) starting from (I-a). 
The intermediates of formula (II) which contain a phenyl radical 
substituted with one or more alkyloxy radicals may be converted to the 
corresponding alkylcarbonyloxy compounds which in turn may be converted to 
the corresponding hydroxyphenyl compounds following the same procedures as 
described hereinabove for the analogous conversions of the compounds of 
formula (I). 
An additional feature of the present invention comprises the fact that a 
number of intermediates mentioned in the foregoing preparation schemes are 
novel compounds. 
More particularly, the intermediates of formula (II) wherein R.sup.1 is 
other than cyano, and the intermediates of formula (II) wherein R.sup.1 is 
cyano and in the latter case one of the following conditions is met: 
(a) R is other than hydrogen, C.sub.1-6 alkyl, cyclo C.sub.3-6 alkyl or 
aryl; or 
(b0) Ar is other than a radical of formula (a) wherein in said radical of 
formula (a) R.sup.6 is other than hydrogen, halo, trifluoromethyl, 
C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6 alkylthio or C.sub.1-6 
alkylsulfonyl; or 
(c) R.sup.2 is other than hydrogen, halo, trifluoromethyl or C.sub.1-6 
alkyl; or 
(d) R.sup.4 is other than hydrogen, 
said intermediates being represented by the formula 
##STR26## 
and the pharmaceutically acceptable acid-addition, metal or amine 
substitution salts, and stereochemically isomeric forms thereof are novel 
compounds. 
Preferred, particularly preferred and more particularly preferred 
intermediates of formula (II-j) are those of which the preferred, 
particularly preferred and more particularly preferred compounds of 
formula (I) can be derived, i.e. those intermediates wherein Ar', r, 
r.sup.1, r.sup.2, r.sup.3 and r.sup.4 are as defined hereinabove for the 
corresponding radicals Ar, R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 of the 
preferred, particularly preferred and more particularly preferred 
compounds of formula (I). 
Furthermore, the pharmaceutically acceptable metal or amine substitution 
salts of those intermediates of formula (II), wherein Ar is a radical of 
formula (a), and wherein R.sup.6, R.sup.7 and R.sup.8 are each 
independently hydrogen, halo, trifluoromethyl, C.sub.1-6 alkyl, C.sub.1-6 
alkyloxy, C.sub.1-6 alkylthio, or C.sub.1-6 alkylsulfonyl; R.sup.2 and 
R.sup.3 are each independently hydrogen, halo, trifluoromethyl or 
C.sub.1-6 alkyl; and wherein R.sup.1 is cyano, R.sup.4 is hydrogen and 
wherein R is hydrogen. C.sub.1-6 alkyl, cyclo C.sub.3-6 alkyl or phenyl 
optionally substituted with up to 3 substituents each independently 
selected from the group consisting of halo, trifluoromethyl, C.sub.1-6 
alkyl, C.sub.1-6 alkyloxy, C.sub.1-6 alkylthio and C.sub.1-6 
alkylsulfonyloxy, said compounds being represented by the formula 
##STR27## 
and the stereochemically isomeric forms thereof are also novel compounds. 
Preferred are those metal or amine salts of those intermediates of formula 
(II-k) wherein R.sup.6-a is halo and more preferably is chloro, R.sup.7-a 
and R.sup.8-a are hydrogen, R.sup.a is hydrogen or C.sub.1-6 alkyl and 
more preferably is hydrogen and R.sup.2-a and R.sup.3-a independently are 
hydrogen, halo, C.sub.1-6 alkyl or C.sub.1-6 alkyloxy and more preferably 
R.sup.2-a is chloro and R.sup.3-a is hydrogen or chloro. 
Both the intermediates of formula (II-j) and (II-k) are not only novel 
compounds useful in the preparation of the compounds of formula (I), but 
they also possess anti-protozoal and more particularly anti-coccidial 
activity. 
The compounds of formula (I) and the intermediates of formula (II) may be 
converted to their therapeutically active non-toxic acid addition salt 
forms by treatment with appropriate acids, such as, for example, inorganic 
acids, such as hydrohalic acid, e.g. hydrochloric, hydrobromic and the 
like, and sulfuric acid, nitric acid, phosphoric acid and the like; or 
organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 
2-hydroxy-propanoic, 2-oxopropanoic, ethanedioic, propanedioic, 
butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 
2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, 
methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, 
cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the 
like acids. Conversely the salt form can be converted by treatment with 
alkali into the free base form. 
The compounds of formula (I) and the intermediates of formula (II), 
containing one or more acidic protons, may also be converted to their 
therapeutically active non-toxic metal or amine substitution salt forms by 
treatment with appropriate organic or inorganic bases. Appropriate 
inorganic bases may, for example, be ammonia or bases derived from alkali 
or earth alkaline metals, e.g. alkali metal or earth alkaline metal oxides 
or hydroxides such as lithium hydroxide, sodium hydroxide, potassium 
hydroxide, magnesium hydroxide, calcium hydroxide, calciumoxide and the 
like; alkalimetal or earth alkaline metal hydrides, e.g. sodium hydride, 
potassium hydride and the like; alkalimetal hydrogen carbonates or 
carbonates, e.g. sodium carbonate, potassium carbonate, sodium hydrogen 
carbonate, calcium carbonate and the like. Appropriate organic bases may, 
for example be primary, secondary and tertiary aliphatic and aromatic 
amines such as, for example, methylamine, ethylamine, propylamine, 
isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, 
diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, 
pyrrolidine, piperidine, morpholine, N-methylmorpholine, trimethylamine, 
tripropylamine, quinuclidine, pyridine, quinoline, isoquinoline, 
diethanolamine and 1,4-diazabicyclo[2,2,2]octane; or quaternary ammonium 
bases e.g. tetramethylammonium hydroxide, trimethylbenzylammonium 
hydroxide, triethylbenzylammonium hydroxide, tetraethylammonium hydroxide, 
and trimethylethylammonium hydroxide. 
It is obvious from formulae (I) and (II) that the compounds of the present 
invention have an asymmetric carbon atom. Consequently, these compounds 
may exist under two different enantiomeric forms. Pure enantiometic forms 
of the compounds of formula (I) and the intermediates of formula (II) may 
be obtained by the application of art-known procedures. 
The compounds of formula (I) and the intermediates of formula (II), the 
pharmaceutically acceptable acid addition salts, metal or amine 
substitution salts and the possible stereochemically isomeric forms 
thereof are useful agents in combatting Protozoa. For example, said 
compounds are found to be active against a wide variety of said Protozoa 
such as, for example, Sarcodina, Mastigophora, Ciliophora and Sporozoa. 
The compounds of formula (I) and the intermediates of formula (II), the 
pharmaceutically acceptable acid addition salts, metal or amine 
substitution salts and the possible stereochemically isomeric forms 
thereof are especially useful agents in combatting Rhizopoda such as, for 
example, Entamoeba; and Mastigophora such as, for example, Trichomonas, 
e.g. Trichomonas vaginalis, Histomonas, e.g. Histomonas maleagridis, and 
Trypanosoma spp. 
In view of their potent activity in combatting Protozoa the compounds of 
this invention constitute useful tools for the destroying or prevention of 
the growth of Protozoa and more particularly they can effectively be used 
in the treatment of subjects suffering from such Protozoa. 
In view of the potent activity in combatting Protozoa this invention 
provides valuable compositions comprising the compounds of formula (I) and 
the intermediates of formula (II), the acid addition salts, metal or amine 
substitution salts or possible stereochemically isomeric forms thereof, as 
the active ingredient in a solvent or a solid, semi-solid or liquid 
diluent or carrier, and, in addition, it provides an effective method of 
combatting Protozoa by use of an effective anti-protozoal amount of such 
compounds of formula (I) and the intermediates of formula (II), or acid 
addition salts or metal or amine substitution salts thereof. 
Anti-protozoal compositions comprising an effective amount of an active 
compound of formula (I) or an active intermediate of formula (II), either 
alone or in combination with other active therapeutic ingredients, in 
admixture with suitable carriers may be readily prepared according to 
conventional pharmaceutical techniques for the usual routes of 
administration. 
Preferred compositions are in dosage unit form, comprising per dosage unit 
an effective quantity of the active ingredient in admixture with suitable 
carriers. Although the amount of the active ingredient per unit dosage may 
vary within rather wide limits, dosage units comprising from about 10 to 
about 2000 mg of the active ingredient are preferred. 
In view of the anti-protozoal properties of the compounds of formula (I) 
and the intermediates of formula (II) it is evident that the present 
invention provides a method of inhibiting and/or eliminating the 
development of Protozoa in warm-blooded animals suffering from diseases 
caused by one or more of those Protozoa by the administration of an 
antiprotozoal effective amount of a compound of formula (I) and 
intermediates of formula (II), a pharmaceutically acceptable acid addition 
salt, metal or amine substitution salts or a possible stereochemically 
isomeric form thereof. 
More particularly, in view of their extremely potent activity in combatting 
Coccidia the compounds of this invention are very useful in the destroying 
or prevention of the growth of Coccidia in warm-blooded animals. 
Consequently, the compounds of formula (I) and the intermediates of 
formula (II), the acid addition salts, metal or amine substitution salts 
and possible stereochemically isomeric forms thereof are particularly 
useful anti-coccidial agents as well as coccidiostatics. 
Due to their useful anti-coccidial and coccidiostatic activity the subject 
compounds may be administered in combination with any solid, semi-solid or 
liquid diluent or carrier as described hereinabove. Additionally, due to 
their useful coccidiostatic activity the subject compounds may be mixed 
with any kind of feed supplied to warm-blooded animals although it may 
also be administered while dissolved or suspended in the drinking water. 
The following examples are intended to illustrate and not to limit the 
scope of the present invention. Unless otherwise stated all parts therein 
are by weight.

EXAMPLES 
(A) Preparation of Intermediates 
Example 1 
Procedure A 
To a stirred mixture of 16 parts of 
2-[3-chloro-4-[(2,4-dichlorophenyl)hydroxymethyl]phenyl]-1,2,4-triazine-3, 
5(2H,4H)-dione and 150 parts of trichloromethane are added dropwise, during 
a period of 5 minutes, 16 parts of thionyl chloride. Upon completion, 
stirring is continued for 3 hours at reflux temperature. The reaction 
mixture is evaporated in vacuo. Methylbenzene is added and the whole is 
evaporated again, yielding 
2-[3-chloro-4-[chloro(2,4-dichlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5 
(2H,4H)-dione. 
A mixture of 12 parts of 
2-[3-chloro-4-[chloro(2,4-dichlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5 
(2H,4H)-dione and 5.4 parts of copper cyanide is stirred and heated first 
for 3 hours at 130.degree. C. and for 3 hours at 180.degree. C. After 
cooling, the precipitated product is dissolved in a mixture of 
trichloromethane and methanol (90:10 by volume). The inorganic precipitate 
is filtered off and the filtrate is evaporated in vacuo. The residue is 
purified by column chromatography over silica gel using first a mixture of 
trichloromethane and acetonitrile (93:7 by volume) as eluent. The pure 
fractions are collected and the eluent is evaporated. The residue is 
dissolved in 20 parts of N,N-dimethylformamide and 25 parts of 
1,1'-oxybisethane. The product is allowed to crystallize, filtered off and 
dried, yielding 
2-chloro-.alpha.-(2,4-dichlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benezeneacetonitrile (intermediate 1). 
Procedure B 
To a stirred mixture of 68 parts of 1-chloro-2-methoxy-4-nitrobenzene, 230 
parts of a sodium hydroxide solution 50%, 5 parts of 
N,N,N-triethylbenzenemethanaminium chloride and 360 parts of 
tetrahydrofuran is added dropwise, during a 5 minutes period, a solution 
of 43.2 parts of 4-chlorobenzeneacetonitrile in 90 parts of 
tetrahydrofuran. Upon completion, stirring is continued for 4 hours at 
60.degree. C. The reaction mixture is poured into 2000 parts of crushed 
ice. The whole is acidified with concentrated hydrochloric acid. The 
layers are separated. The aqueous phase is extracted with dichloromethane. 
The combined extracts are dried, filtered and evaporated. The residue is 
crystallized from 2,2'-oxybispropane. The product is filtered off and 
dried, yielding 
.alpha.-(4-chlorophenyl)-2-methoxy-4-nitrobenzeneacetonitrile. 
A mixture of 8.1 parts of 
.alpha.-(4-chlorophenyl)-2-methoxy-4-nitrobenzeneacetonitrile, 2 parts of 
a solution of thiophene in methanol 4% and 200 parts of methanol is 
hydrogenated at normal pressure and at 50.degree. C. with 2 parts of 
platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen 
is taken up, the catalyst is filtered off and the filtrate is evaporated 
in vacuo. The residue is stirred in a small amount of 2-propanol. The 
product is filtered off and dried, yielding 
4-amino-.alpha.-(4-chlorophenyl)-2-methoxybenzeneacetonitrile. 
To a stirred and cooled (5.degree.-10.degree. C.) mixture of 5.6 parts of 
4-amino-.alpha.-(4-chlorophenyl)-2-methoxybenzeneacetonitrile, 6.2 parts 
of concentrated hydrochloric acid and 50 parts of acetic acid is added 
dropwise, during a 15 minutes period, a solution of 1.25 parts of sodium 
nitrite in 10 parts of water at about 10.degree. C. Upon completion, the 
whole is stirred for 60 minutes and then 3.6 parts of anhydrous sodium 
acetate and 2.8 parts of ethyl (2-cyanoacetyl)carbamate are added and 
stirring is continued for 2 hours at room temperature. The reaction 
mixture is poured into 250 parts of water. The product is filtered off, 
washed with water and dissolved in a mixture of trichloromethane and 
methanol (90:10 by volume). The organic layer is dried, filtered and 
evaporated. The residue is purified by column chromatography over silica 
gel using a mixture of trichloromethane and methanol (95:5 by volume) as 
eluent. The pure fractions are collected and the eluent is evaporated in 
vacuo, yielding ethyl 
[2-[[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]hydrazono]-2-cyanoace 
tyl]carbamate. 
A mixture of 8.3 parts of ethyl 
[2-[[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]hydrazono]-2-cyanoace 
tyl]carbamate, 1.77 parts of anhydrous potassium acetate and 100 parts of 
acetic acid is stirred for 2 hours at reflux temperature. The reaction 
mixture is evaporated in vacuo. The residue is stirred in water. The 
product is filtered off and dissolved in trichloromethane. The organic 
layer is dried, filtered and evaporated. The residue is purified by column 
chromatography over silica gel using a mixture of trichloromethane and 
methanol (90:10 by volume) as eluent. The pure fractions are collected and 
the eluent is evaporated in vacuo, yielding 
2-[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5 
-dioxo-1,2,4-triazine-6-carbonitrile. 
A mixture of 4 parts of 
2-[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5 
-dioxo-1,2,4-triazine-6-carbonitrile, 24 parts of concentrated hydrochloric 
acid and 40 parts of acetic acid is stirred and refluxed for 3 hours. The 
reaction mixture is evaporated in vacuo and the residue is stirred in 
water. The product is extracted with a mixture of trichloromethane and 
methanol (90:10 by volume). The extract is dried, filtered and evaporated, 
yielding 
2-[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5 
-dioxo-1,2,4-triazine-6-carboxylic acid. 
A mixture of 4.2 parts of 
2-[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5 
-dioxo-1,2,4-triazine-6-carboxylic acid and 13 parts of 2-mercaptoacetic 
acid is stirred and heated for 2 hours at 175.degree. C. After cooling, 
150 parts of water are added. The aqueous phase is decanted and the 
remaining oil is stirred in water. The whole is treated with sodium 
hydrogen carbonate. The product is extracted with a mixture of 
trichloromethane and methanol (90:10 by volume). The extract is dried, 
filtered and evaporated. The residue is purified by column chromatography 
over silica gel using a mixture of trichloromethane and methanol (97:3 by 
volume) as eluent. The pure fractions are collected and the eluent is 
evaporated in vacuo. The residue is crystallized from 8 parts of 
acetonitrile. The product is filtered off, washed with 2,2'-oxybispropane 
and dried, yielding 
.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)- 
3-methoxybenzeneacetonitrile (intermediate 2). 
Following the same procedures there are further prepared: 
______________________________________ 
##STR28## 
int. 
no. R.sup.6 R.sup.7 R.sup.8 
R.sup.2 
R.sup.3 
______________________________________ 
3 2-Cl 4-Cl 6-Cl 2-Cl H 
4 4-Br H H 2-Cl H 
5 4-Br H H 2-Cl 6-Cl 
6 4-CH.sub.3 COO 
H H 2-Cl 6-Cl 
7 4-OH H H 2-Cl 6-Cl 
8 4-Cl H H 2-OH H 
9 4-CH.sub.3 S 
H H 2-Cl H 
10 4-CH.sub.3 S 
H H 2-Cl 6-Cl 
11 4-CH.sub.3 S 
H H 2-CH.sub.3 
6-CH.sub.3 
12 4-CH.sub.3 S 
3-CH.sub.3 
H 2-Cl H 
13 4-CH.sub.3 S 
3-CH.sub.3 
H 2-Cl 6-Cl 
14 4-CH.sub.3 SO 
H H 2-Cl H 
15 4-CH.sub.3 SO 
H H 2-Cl 6-Cl 
16 4-CH.sub.3 SO.sub.2 
H H 2-Cl H 
17 4-CH.sub.3 SO.sub.2 
H H 2-Cl 6-Cl 
18 4-HS H H 2-Cl H 
19 4-HS H H 2-Cl 6-Cl 
______________________________________ 
______________________________________ 
##STR29## 
Comp. Ar R R.sup.2 
R.sup.3 
______________________________________ 
20 2-Cl5-thienyl H Cl Cl 
21 2-Cl5-thienyl H Cl H 
22 2-Cl5-thienyl CH.sub.3 Cl Cl 
23 2-Cl5-thienyl CH.sub.3 Cl H 
24 1-naphthalenyl 
H Cl Cl 
25 1-naphthalenyl 
H Cl H 
______________________________________ 
Example 2 
To 30 parts of a sulfuric acid solution in water (90:10 by volume) were 
added portionwise during a period of 5 minutes 2 parts of 
2-chloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2 
(3H)-yl)benzeneacetonitrile at room temperature. Upon completion, stirring 
was continued for 2 hours at 80.degree. C. The reaction mixture was poured 
into ice water. The product was filtered off, washed with water and 
purified by column chromatography over silica gel using a mixture of 
trichloromethane and methanol (95:5 by volume) as eluent. The pure 
fractions were collected and the eluent was evaporated in vacuo. The 
residue was stirred in 2,2'-oxybispropane. The product was filtered off 
and dried, yielding 1.1 parts (54%) of 
2-chloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2 
(3H)-yl)-benzeneacetamide; mp. 160.7.degree. C. (intermediate 26). 
Following the same procedure and using equivalent amounts of the 
appropriate starting materials, there was also prepared: 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetamide; mp. 276.4.degree. C. (intermediate 27). 
Example 3 
To a stirred mixture of 9.2 parts of concentrated sulfuric aid, 5 parts of 
acetic acid and 5 parts of water were added 1.5 parts of 
2-chloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2 
(3H)-yl)benzeneacetonitrile at room temperature. The whole was stirred and 
refluxed for 18 hours. The reaction mixture was poured into 100 parts of 
ice water. The product was filtered off, washed with water and purified by 
column chromatography over silica gel using a mixture of trichloromethane, 
methanol and acetic acid (95:4:1 by volume) as eluent. The pure fractions 
were collected and the eluent was evaporated in vacuo. The residue was 
stirred in 2,2'-oxybispropane. The product was filtered off and dried, 
yielding 0.9 parts (59%) of 2-chloro 
-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl) 
benzeneacetic acid; mp. 196.3.degree. C. (intermediate 28). 
Example 4 
A mixture of 13.2 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetamide, 648 parts of concentrated hydrochloric acid 
and 200 parts of acetic acid was stirred and refluxed for 224 hours. The 
resulting product was filtered off, washed with water and taken up in 100 
parts of water. After treatment with a sodium hydroxide solution, the 
resulting solution was acidified with concentrated hydrochloric acid. The 
product was filtered off and purified by column chromatography over silica 
gel using a mixture of methylbenzene, tetrahydrofuran and acetic acid 
(70:30:1 by volume) as eluent. The pure fractions were collected and the 
eluent was evaporated, yielding 3.8 parts (27.8%) of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetic acid; mp. 219.5.degree. C. (intermediate 29). 
Example 5 
A mixture of 6 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetonitrile, 1.5 parts of N,N-diethylethanamine and 40 
parts of pyridine was stirred at room temperature. Gaseous hydrogen 
sulfide was bubbled through the mixture during 24 hours. The solvent was 
evaporated in vacuo and the residue was stirred in water. The precipitated 
product was filtered off, stirred in 2-propanol and filtered off again. 
The product was purified by column chromatography over silica gel using a 
mixture of trichloromethane and methanol (97:3 by volume) as eluent. The 
pure fractions were collected and the eluent was evaporated in vacuo. The 
residue was crystallized from 16 parts of acetonitrile. The product was 
filtered off, washed with 2,2'-oxybispropane and dried, yielding 1.4 parts 
(21.1%) of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneethanethioamide; mp. 262.7.degree. C. (intermediate 30). 
Following the same procedure there is prepared: 
2-chloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-1,2,4-triazin-2(3H)-y 
l)benzeneethanethioamide (intermediate 31). 
Example 6 
A mixture of 2 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetic acid and 48 parts of thionyl chloride was stirred 
for 1 hour at reflux temperature. The reaction mixture was evaporated, 
yielding 2.28 parts (100%) of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetyl chloride as a residue (intermediate 32). 
Following the same procedure there is prepared: 
2-chloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2 
(3H)-yl)benzeneacetyl chloride (intermediate 33). 
Example 7 
A mixture of 2.28 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetylchloride and 18 parts of piperidine was stirred 
for 17 hours at room temperature (exothermic reaction). After the addition 
of water, the solution was acidified with hydrochloric acid. The product 
was extracted with a mixture of trichloromethane and methanol (95:5 by 
volume). The extract was dried, filtered and evaporated. The residue was 
purified by column chromatography over silica gel using a mixture of 
trichloromethane, methanol and acetic acid (95:4:1 by volume) as eluent. 
The pure fractions were collected and the eluent was evaporated. The 
residue was washed with 2,2'-oxybispropane and dried, yielding 1 part 
(44.0%) of 
1-[2-(4-chlorophenyl)-2-[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)phenyl]acetyl]piperidine; mp. 216.9.degree. C. (intermediate 
34). 
Example 8 
A mixture of 2.28 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetylchloride, 4.5 parts of pyrrolidine and 40 parts of 
acetonitrile was stirred for 17 hours at room temperature. After 
evaporation in vacuo, the residue was taken up in water and the mixture 
was acidified with hydrochloric acid. The product was extracted with 
trichloromethane. The extract was dried, filtered and evaporated. The 
residue was purified by column chromatography over silica gel using a 
mixture of trichloromethane and methanol (95:5 by volume) as eluent. The 
pure fractions were collected and the eluent was evaporated. The residue 
was dried in vacuo for 48 hours at 110.degree. C., yielding 0.8 parts 
(36.2%) of 
1-[2-(4-chlorophenyl)-2-[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)phenyl]acetyl]pyrrolidine; mp. 153.9.degree. C. (intermediate 
35). 
Example 9 
To a stirred mixture of 10 parts of 1-methylpiperazine in 45 parts of 
tetrahydrofuran was added dropwise a solution of 6.7 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetyl chloride in 45 parts of tetrahydrofuran during a 
period of 5 minutes. Upon complete addition, stirring was continued for 2 
hours at room temperature. After evaporation in vacuo, the residue was 
purified by column chromatography over silica gel using a mixture of 
trichloromethane and methanol (90:10 by volume) as eluent. The pure 
fractions were collected and the eluent was evaporated in vacuo. The 
residue was boiled in acetonitrile. After cooling, the precipitated 
product was filtered off, washed with 2,2'-oxybispropane and dried, 
yielding 4.8 parts (62.8%) of 
1-[2-(4-chlorophenyl)-2-[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)phenyl]acetyl]-4-methylpiperazine; mp. 261.5.degree. C. 
(intermediate 36). 
Following the same procedure there was also prepared: 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)-N-methylbenzeneacetamide; mp. 278.7.degree. C. (intermediate 
37). 
Following the same procedure there are further prepared: 
2-chloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2 
(3H)-yl)-N-methylbenzeneacetamide (intermediate 38). 
4-acetyl-1-[2-(4-chlorophenyl)-2-[2-chloro-4-(4,5-dihydro-3,5-dioxo-1,2,4- 
triazin-2(3H)-yl)phenyl]acetyl]piperazine (intermediate 39). 
1-[2-(4-chlorophenyl)-2-[2-chloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2 
(3H)-yl)phenyl]acetyl]-4-(phenylmethyl)piperazine (intermediate 40). 
Example 10 
A mixture of 4.7 parts of aluminum trichloride and 67.5 parts of benzene 
was stirred in an ice bath till a temperature of .+-.10.degree. C. A 
solution of 4.9 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetylchloride in 22.5 parts of benzene was added 
dropwise during a period of 15 minutes at this low temperature (exothermic 
reaction). Upon complete addition, stirring was continued for 20 hours at 
room temperature. The reaction mixture was poured into 500 parts of ice 
water and the whole was acidified with concentrated hydrochloric acid. The 
product was extracted with trichloromethane. The extract was dried, 
filtered and evaporated. The residue was purified by filtration over 
silica gel using a mixture of trichloromethane and methanol (95:5 by 
volume) as eluent. The pure fractions were collected and the eluent was 
evaporated. The residue was further purified three times by column 
chromatography over silica gel using first a mixture of trichloromethane 
and methanol (97:3 by volume) and then a mixture of trichloromethane and 
methanol (99:1 by volume) and finally a mixture of trichloromethane and 
ethyl acetate (92.5:7.5 by volume) as eluent. The pure fractions were 
collected and the eluent was evaporated in vacuo. The residue was 
crystallized from 8 parts of ethanol. The product was filtered off, washed 
with 2,2'-oxybispropane and dried, yielding 0.7 parts (13.0%) of 
2-[3,5-dichloro-4-[1-(4-chlorophenyl)-2-oxo-2-phenylethyl]phenyl]-1,2,4-tr 
iazine-3,5(2H,4H)-dione; mp. 143.0.degree. C. (intermediate 41). 
Example 11 
To a stirred and cooled (-70.degree. C., 2-propanone/CO.sub.2 bath) 
solution of 5.7 parts of copper(I) iodide in 67.5 parts of tetrahydrofuran 
were added dropwise 37.5 parts of a methyllithium solution 1.6M in 
1,1'-oxybisethane during a period of 15 minutes under nitrogen atmosphere. 
Upon complete addition, stirring was continued for 30 minutes at this low 
temperature. A mixture of 4.45 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetyl chloride and 22.5 parts of tetrahydrofuran was 
added dropwise during a period of 30 minutes at -65.degree. C. Upon 
completion, stirring was continued first for 2 hours at -60.degree. C. and 
then for 1 hours at -20.degree. C. A saturated ammonium chloride solution 
in water was added dropwise (exothermic reaction). The precipitate was 
filtered off and from the filtrate, the organic layer was dried, filtered 
and evaporated. The residue was purified three times by column 
chromatography over silica gel: twice using a mixture of trichloromethane 
and methanol (95:5 and 98:2 by volume) and then a mixture of 
trichloromethane and ethyl acetate (92.5:7.5 volume) as eluents. The pure 
fractions were collected and the eluent was evaporated in vacuo. The 
residue was stirred in acetonitrile. The product was filtered off, washed 
with 2,2'-oxybispropane and dried, yielding 0.8 parts (18.8%) of 
2-[3,5-dichloro-4-[1-(4-chlorophenyl)-2-oxopropyl]phenyl]-1,2,4-triazine-3 
,5(2H,4H)-dione; mp. 208.4.degree. C. (intermediate 42). 
Example 12 
A mixture of 5.53 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetyl chloride and 160 parts of methanol was stirred 
for 1 hour at reflux temperature. After evaporation, water was added to 
the residue and the product was extracted with dichloromethane. The 
extract was dried, filtered and evaporated. The residue was purified by 
column chromatography over silica gel using a mixture of trichloromethane, 
methanol and acetic acid (95:4:1 by volume) as eluent. The pure fractions 
were collected and the eluent was evaporated. The residue was further 
purified by column chromatography over silica gel using a mixture of 
trichloromethane, hexane and methanol (45:45:10 by volume) as eluent. The 
pure fractions were collected and the eluent was evaporated, yielding 0.9 
parts (17.6%) of methyl 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetate; mp. 121.1.degree. C. (intermediate 43). 
Following the same procedure there is also prepared: methyl 
2-chloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2 
(3H)-yl)benzeneacetate (intermediate 44). 
Example 13 
To a stirred mixture of 8.5 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetic acid, 5.5 parts of potassium carbonate and 45 
parts of N,N-dimethylformamide were added 8.52 parts of iodomethane at 
room temperature. After stirring for 2 hours at 40.degree. C., the 
reaction mixture was evaporated in vacuo. The residue was stirred in 
water. The precipitated product was filtered off and dissolved in 
trichloromethane (the remaining water was separated). The organic layer 
was dried, filtered and evaporated. The residue was purified by column 
chromatography over silica gel using a mixture of trichloromethane and 
methanol (99:1 by volume) as eluent. The pure fractions were collected and 
the eluent was evaporated in vacuo. The residue was crystallized from 
acetonitrile. The product was filtered off (the filtrate was set aside) 
and dried, yielding a first fraction of 1.9 parts (20.9%) of methyl 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-4-methyl-3,5-dioxo-1, 
2,4-triazin-2(3H)-yl)benzeneacetate. The filtrate, which was set aside (see 
above), was evaporated in vacuo, yielding a second fraction of 4 parts 
(44%) of methyl 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-4-methyl-3,5-dioxo-1, 
2,4-triazin-2(3H)-yl)benzeneacetate as a residue. Total yield: 5.9 parts 
(64.9%) of methyl 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-4-methyl-B 
3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetate; mp. 173.4.degree. C. 
(intermediate 45). 
Example 14 
To a stirred mixture of 4 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetonitrile, 1.4 parts of potassium carbonate and 22.5 
parts of N,N-dimethylformamide were added 2.84 parts of iodomethane at 
room temperature. The reaction mixture was stirred for 1.5 hours at 
40.degree. C. After evaporation in vacuo, the residue was taken up in 
water. The precipitated product was filtered off and washed with water. 
After crystallization from acetonitrile, the product was filtered off, 
washed with 2,2'-oxybispropane and dried, yielding 2.5 parts (59.2%) of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-4-methyl-3,5-dioxo-1, 
2,4-triazin-2(3H)-yl)benzeneacetonitrile; mp. 159.7.degree. C. 
(intermediate 46). 
Following the same procedure there were also prepared: 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-[4,5-dihydro-3,5-dioxo-4-(phenylmet 
hyl)-1,2,4-triazin-2(3H)-yl]benzeneacetonitrile; mp. 128.0.degree. C. 
(intermediate 47); 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-4-methyl-3,5-dioxo-1,2 
,4-triazin-2(3H)-yl)benzeneacetamide (intermediate 48); and 
(E)-2,6-dichloro-.alpha.-(4-chlorophenyl)-4-[4,5-dihydro-3,5-dioxo-4-(3-phe 
nyl-2-propenyl)-2H-1,2,4-triazin-2-yl]benzeneacetonitrile; mp. 
159.2.degree. C. (intermediate 49). 
Following the same procedures there are further prepared: 
______________________________________ 
##STR30## 
Int. no. R.sup.4 
______________________________________ 
50 C.sub.2 H.sub.5 
51 C.sub.3 H.sub.7i 
52 C.sub.4 H.sub.9n 
53 CH.sub.2CHCH 
54 CH.sub.2CCH 
55 CH.sub.2 CH.sub.2C.sub.6 H.sub.5 
______________________________________ 
Example 15 
A mixture of 13 parts of 
2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-.alpha.-(4-m 
ethoxyphenyl)benzeneacetonitrile and 300 parts of acetic acid, saturated 
with hydrogen bromide was stirred for 24 hours at 90.degree. C. The 
reaction mixture was poured into 500 parts of ice water. The precipitated 
product was filtered off, washed with water and disolved in 
trichloromethane. The remaining aqueous layer was removed. The organic 
layer was dried, filtered and evaporated. The residue was purified by 
column chromatography over silica gel using a mixture of trichloromethane 
and ethyl acetate (80:20 by volume) as eluent. The pure fractions were 
collected and the eluent was evaporated in vacuo. The residue was purified 
twice by column chromatography over silica gel using a mixture of 
trichloromethane and ethyl acetate (85:15 by volume) as eluent. The first 
fraction was collected and the eluent was evaporated. The residue was 
crystallized from acetonitrile. The product was filtered off, washed with 
2,2'-oxybispropane and dried, yielding 2 parts (14.4%) of 4-[cyano[ 
2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl]methyl 
]phenol acetate(ester); mp. 221.5.degree. C. (intermediate 56). 
A mixture of 2.3 parts of 
4-[cyano[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phen 
yl]methyl]phenol acetate(ester) and 50 parts of a hydrochloric acid 
solution 4N was stirred for 4 hours at reflux temperature. The precipitate 
was filtered off (the filtrate was set aside), washed successively with 
water, 2-propanol and 2,2'-oxybispropane and dried. The precipitate was 
combined with the filtrate, which was set aside (see above) and the 
solvent was evaporated. The residue was stirred and refluxed for 4 hours. 
After evaporation in vacuo, the residue was dissolved in a mixture of 
trichloromethane and methanol (90:10 by volume). The solution was dried, 
filtered and evaporated. The residue was purified by column chromatography 
over silica gel using a mixture of trichloromethane and methanol (95:5 by 
volume) as as eluent. The pure fractions were collected and the eluent was 
evaporated in vacuo. The residue was dissolved in a mixture of 
acetonitrile and 2,2'-oxybispropane (5:20 by volume). The crystallized 
product was filtered off and dried, yielding 1 part (48.4%) of 
2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-.alpha.-(4-h 
ydroxyphenyl)benzeneacetonitrile; mp. 209.9.degree. C. (intermediate 57). 
Example 16 
To a stirred mixture of 5 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetonitrile in 40 parts of water were added 5 parts of 
a solution of 9.6 parts of sodium hydroxide in 100 parts of water under 
nitrogen atmosphere. The whole was stirred for 10 minutes. The precipitate 
was filtered off. The product in the filtrate was allowed to crystallize. 
The product was filtered off, washed with water and dried over weekend at 
50.degree. C., yielding 2.4 parts (44.6%) of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)-yl)benzeneacetonitrile, sodium salt monohydrate; mp. 213.1.degree. 
C. (intermediate 58). 
Following the same procedure and using equivalent amounts of the 
appropriate starting materials, there was also prepared: 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in-2(3H)benzeneacetonitrile, potassium salt sesquihydrate; mp. 
150.7.degree. C. (intermediate 59). 
(B) Preparation of Final Compounds 
Example 17 
To a stirred and refluxed solution of 1.5 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triaz 
in2(3H)-yl)benzeneacetic acid in 100 parts of acetic acid were added 3 
parts of zinc. Stirring was continued for 30 minutes at reflux 
temperature. The zinc salts were filtered off and the filtrate was 
evaporated. The residue was washed with water whereupon the solid product 
was filtered off and dissolved in a mixture of trichlorometmhane and 
methanol (90:10 by volume). The solution was dried, filtered and 
evaporated. The residue was washed with ethyl acetate and 
2,2'-oxybispropane and dried, yielding 0.98 parts (67.2%) of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2, 
4-triazin-2(1H)-yl)benzeneacetic acid; mp. 194.2.degree. C. (compound 1). 
Example 18 
To a stirred and refluxed mixture of 1.5 parts of 
2-chloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-.alpha.-(4-fluor 
ophenyl)-.alpha.-methylbenzeneacetonitrile and 75 parts of acetic acid were 
added portionwise 3 parts of zinc during a period of 30 minutes. Upon 
complete addition, stirring was continued for 3 hours at reflux. The 
reaction mixture was filtered while hot and the filtrate was concentrated 
in vacuo to 10 parts of its volume. Water was added to the concentrate. 
The precipitated product was filtered off and purified by column 
chromatography over silica gel using a mixture of trichloromethane and 
methanol (95:5 by volume) as eluent. The pure fractions were collected and 
the eluent was evaporated in vacuo. The residue was crystallized from 
acetonitrile. The product was filtered off, washed with 2,2'-oxybispropane 
and dried, yielding 0.8 parts (53.6%) of 
2-chloro-.alpha.-(4-fluorophenyl)-.alpha.-methyl-4-(3,4,5,6-tetrahydro-3,5 
-dioxo-1,2,4-triazin-2(1H)-yl)benzeneacetonitrile; mp. 122.5.degree. C. 
(compound 2). 
Example 19 
Following the procedures of examples 17 and 18 and using the appropriate 
starting materials the following compounds are prepared: 
__________________________________________________________________________ 
##STR31## 
comp. no. 
R.sup.1 R.sup.7 
R.sup.8 
R R.sup.2 
R.sup.3 
m. p. .degree.C. 
__________________________________________________________________________ 
3 H H H CH.sub.3 
H H -- 
4 4-Cl H H CH.sub.3 
2-Cl H -- 
5 4-Cl H H CH.sub.3 
2-CF.sub.3 
H -- 
6 4-Cl H H 4-ClC.sub.6 H.sub.4 
2-Cl H -- 
7 4-Cl H H C.sub.3 H.sub.7n 
2-Cl H -- 
8 4-Cl H H C.sub.4 H.sub.9n 
2-Cl H -- 
9 3-CF.sub.3 
4-Cl 
H CH.sub.3 
2-Cl H -- 
10 4-Cl H H CH.sub.3 
2-Cl 6-Cl 
-- 
11 4-Cl H H H 2-Cl H 168.0 
12 4-Cl H H CH.sub.3 
2-Cl 6-CH.sub.3 
211.1 
13 4-Cl H H CH.sub.3 
2-Cl 5-CH.sub.3 
-- 
14 4-Cl H H H 2-Cl 6-Cl 
231.2 
15 4-Cl H H H 2-Cl 6-CH.sub.3 
-- 
16 4-F H H H 2-Cl H -- 
17 4-CH.sub.3 
H H H 2-Cl H -- 
18 4-F H H CH.sub.3 
2-F H 165.6 
19 4-F H H H 2-Cl 6-Cl 
-- 
20 4-F H H H 2-Cl 6-CH.sub.3 
-- 
21 4-F H H H 2-CH.sub.3 
6-CH.sub.3 
-- 
22 4-Cl H H H 2-CH.sub.3 
6-CH.sub.3 
-- 
23 H H H H 2-Cl 6-Cl 
-- 
24 4-CH.sub.3 O 
H H H 2-Cl 6-Cl 
201.9 
25 2-Cl 4-Cl 
H H 2-Cl H -- 
26 2-Cl 4-Cl 
6-Cl 
H 2-Cl H -- 
27 4-Cl H H H 2-CH.sub.3 O 
H -- 
28 4-Br H H H 2-Cl H -- 
29 4-Br H H H 2-Cl 6-Cl 
-- 
30 4-CH.sub.3 COO 
H H H 2-Cl 6-Cl 
-- 
31 4-OH H H H 2-Cl 6-Cl 
-- 
32 4-Cl H H H 2-OH H -- 
33 4-CH.sub.3 S 
H H H 2-Cl H -- 
34 4-CH.sub.3 S 
H H H 2-Cl 6-Cl 
-- 
35 4-CH.sub.3 S 
H H H 2-CH.sub.3 
6-CH.sub.3 
-- 
36 4-CH.sub.3 S 
3-CH.sub.3 
H H 2-Cl H -- 
37 4-CH.sub.3 S 
3-CH.sub.3 
H H 2-Cl 6-Cl 
-- 
38 4-CH.sub.3 SO.sub.2 
H H H 2-Cl 6-Cl 
-- 
39 4-CH.sub.3 SO.sub.2 
H H H 2-Cl H -- 
40 
##STR32## 
H H H 2-Cl H -- 
41 
##STR33## 
H H H 2-Cl 6-Cl 
-- 
42 4-HS H H H 2-Cl 6-Cl 
-- 
43 4-HS H H H 2-Cl H -- 
__________________________________________________________________________ 
__________________________________________________________________________ 
##STR34## 
Comp. 
R.sup.1 R.sup.3 
R.sup.4 m.p. .degree.C. 
__________________________________________________________________________ 
44 CONHCH.sub.3 6-Cl 
H 227.8 
45 CONH.sub.2 6-Cl 
H 247.7 
46 
##STR35## 6-Cl 
H 192.1 
47 COOH H H -- 
48 CONH.sub.2 H H -- 
49 CONHCH.sub.3 H H -- 
50 COOCH.sub.3 H H -- 
51 COOCH.sub.3 6-Cl 
H -- 
52 CSNH.sub.2 6-Cl 
H -- 
53 CSNH.sub.2 H H -- 
54 
##STR36## 6-Cl 
H -- 
55 
##STR37## 6-Cl 
H -- 
56 
##STR38## 6-Cl 
H -- 
57 
##STR39## 6-Cl 
H -- 
58 
##STR40## 6-Cl 
H -- 
59 COC.sub.6 H.sub.5 
6-Cl 
H 202.5 
60 COCH.sub.3 6-Cl 
H -- 
61 CN 6-Cl 
CH.sub.3 oil 
62 CN 6-Cl 
C.sub.2 H.sub.5 
-- 
63 CN 6-Cl 
C.sub.3 H.sub.7i 
-- 
64 CN 6-Cl 
C.sub.4 H.sub.9n 
-- 
65 COOCH.sub.3 6-Cl 
CH.sub.3 123.0 
66 CONH.sub.2 6-Cl 
CH.sub.3 220.9 
67 CN 6-Cl 
CH.sub.2CHCH -- 
68 CN 6-Cl 
CH.sub.2CCH -- 
69 CN 6-Cl 
CH.sub.2CHCHC.sub.6 H.sub. 5 
175.4 
(E-form) 
70 CN 6-Cl 
CH.sub.2C.sub.6 H.sub.5 
186.4 
71 CN 6-Cl 
CH.sub.2 CH.sub.2C.sub.6 H.sub.5 
__________________________________________________________________________ 
______________________________________ 
##STR41## 
Comp. Ar R R.sup.2 
R.sup.3 
______________________________________ 
72 2-Cl5-thienyl H Cl Cl 
73 2-Cl5-thienyl H Cl H 
74 2-Cl5-thienyl CH.sub.3 Cl Cl 
75 2-Cl5-thienyl CH.sub.3 Cl H 
76 1-naphthalenyl 
H Cl Cl 
77 1-naphthalenyl 
H Cl H 
______________________________________ 
Example 20 
A mixture of 4 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-4-methyl-3,5-d 
ioxo-1,2,4-triazin-2(1H)-yl)benzeneacetonitrile, 12 parts of acetic acid 
anhydride and 36 parts of methylbenzene was stirred for 90 hours at reflux 
temperature. After cooling, 16 parts of methanol were added. The solvent 
was evaporated in vacuo. The residue was stirred in water and the product 
was extracted with trichloromethane. The extract was dried, filtered and 
evaporated. The residue was purified by column chromatography over silica 
gel using trichloromethane as eluent. The pure fractions were collected 
and the eluent was evaporated. The residue was crystallized for ethanol. 
The precipitated product was filtered off, washed with 2,2'-oxybispropane 
and dried, yielding 2.0 parts (42.9%) of 
1-acetyl-2-[3,5-dichloro-4-[(4-chlorophenyl)cyanomethyl]phenyl]-1,6-dihydr 
o-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione; mp. 178.1.degree. C. (compound 
78). 
Example 21 
To a stirred mixture of 3 parts of 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-4-methyl-3,5-d 
ioxo-1,2,4-triazin-2(1H)-yl)benzeneacetonitrile and 20 parts of pyridine 
were added dropwise 1.7 parts of benzoyl chloride during a period of 5 
minutes at room temperature and under nitrogen atmosphere. Upon complete 
addition, stirring was continued overnight at room temperature. The 
reaction mixture was evaporated in vacuo and the residue was stirred in 
water. The product was extracted with trichloromethane. The extract was 
dried, filtered and evaporated. The residue was purified twice by column 
chromatography over silica gel using trichloromethane as eluent. The pure 
fractions were collected and the eluent was evaporated in vacuo. The 
residue was crystallized from 8 parts of acetonitrile. The product was 
filtered off, washed with 2,2'-oxybispropane and dried, yielding 0.8 parts 
(20.2%) of 
1-benzoyl-2-[3,5-dichloro-4-[(4-chlorophenyl)cyanomethyl]phenyl]-1,6-dihyd 
ro-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione; mp. 148.4.degree. C. (compound 
79). 
Example 22 
Following the same procedures of examples 20 and 21 there are further 
prepared: 
______________________________________ 
##STR42## 
Comp. R.sup.3 R.sup.4 R.sup.5 
______________________________________ 
80 Cl CH.sub.3 CH.sub.3 
81 Cl CH.sub.2 C.sub.6 H.sub.5 
CH.sub.2 C.sub.6 H.sub.5 
82 H CH.sub.3 COC.sub.6 H.sub.5 
83 H CH.sub.3 COCH.sub.3 
84 Cl CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 
85 Cl CH.sub.3 C.sub.2 H.sub.5 
______________________________________ 
Example 23 
To a stirred mixture of 5 parts of 
2-chloro-.alpha.-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2 
(3H)-yl)benzeneacetonitrile in 40 parts of water are added 5 parts of a 
solution of 9.6 parts of sodium hydroxide in 100 parts of water under 
nitrogen atmosphere. The whole is stirred for 10 minutes. The precipitate 
is filtered off. The product in the filtrate is allowed to crystallize. 
The product is filtered off, washed with water and dried for 48 hours at 
50.degree. C., yielding 
2-chloro-.alpha.-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2,4-tr 
iazin-2(1H)-yl)benzeneacetonitrile, sodium salt; (compound 86). 
Following the same procedure and using equivalent amounts of the 
appropriate starting materials, there was also prepared: 
2-chloro-.alpha.-(4-chlorophenyl()-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2,4-tr 
iazin-2(1H)-yl)benzeneacetonitrile, potassium salt (compound 87); 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2,4 
-triazin-2(1H)-yl)benzeneacetonitrile, sodium salt (compound 88); 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2,4 
-triazin-2(1H)-yl)benzeneacetonitrile, potassium salt (compound 89); 
2,6-dichloro-.alpha.-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2,4 
-triazin-2(1H)-yl(benzeneacetonitrile, ammonium salt (compound 90); 
(c) Pharmacological Examples 
The strong anti-protozoal activity of the compounds of formula (I) and the 
intermediates of formula (II), the pharmaceutically acceptable acid 
addition salts, metal or amine substitution salts and the possible 
stereochemically isomeric forms thereof is clearly evidenced by the data 
obtained in the following experiments, which data are only given to 
illustrate the useful anti-protozoal properties of all the compounds 
embraced within the invention and not to limit the invention either with 
respect to the scope of susceptible Protozoa nor with respect to the scope 
of formula (I) or of formula (II). 
Example 13 
Outline of anticoccidial efficacy test against Eimeria tenella 
Hisex chickens were fed with a commercial basal ration not containing a 
coccidiostatic agent. 
Eighteen-day-old chickens were sorted in groups of two birds. Water was 
supplied automatically and medicated feed was supplied ad libitum from the 
day of infection (day 0) until the seventh day (not included) after 
infection. Unmedicated feed was supplied ad libitum to two groups of four 
birds for uninfected and infected controls. 
Unmedicated feed was a commercial basal ration not containing a 
coccidiostatic agent. Medicated feed was prepared from unmedicated feed by 
thoroughly mixing the latter with an amount of the tested compound. 
On day 0 the birds were inoculated orally with 10.sup.5 sporulated oocysts 
of Eimeria tenella. On day 5 the faecal score was determined and graded: 
0=no blood spots 
1=one or two blood spots 
2=three to five blood spots 
3=more than five blood spots 
On the seventh day oocyst production is determined by collecting the faces 
and the oocyst count per gram feces (OPG) and the birds are weighed. 
In table 1 the first column shows the average relative weight gain in 
percent compared with the non-infected controls. The second column shows 
the average faecal score and the third column illustrates the average 
oocyst count. 
TABLE I 
______________________________________ 
dose of 
tested average relative average 
compound faecal average oocyst 
int./comp. 
in ppm count 
No. in feed weight gain 
score (OPG) .times. 1000 
______________________________________ 
int. 27 100 107 0 0 
int. 29 100 98 0 0 
10 93 0.5 0 
int. 30 10 104 0 0 
int. 42 10 102 0 0 
int. 43 100 96 0 0 
10 98 0 0 
int. 46 10 96 0 0 
1 98 0.5 0 
int. 58 0.5 101 0 0 
0.1 100 0 1 
int. 59 100 98 0 0 
1 96 0 0 
0.5 97 0 0 
comp. 1 10 101 1 0 
comp. 2 10 100 0 0 
comp. 12 
10 95 0 0 
comp. 14 
10 100 0 0 
1 100 0 0 
0.1 101 0 0 
comp. 18 
10 95 0.5 0 
comp. 24 
10 92 0 0 
______________________________________