Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-30
2003-05-27
Tsang, Cecilia (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S304700
Reexamination Certificate
active
06569881
ABSTRACT:
The present invention relates to new substituted benzimidazoles, their preparation and their use as agents against parasitic protozoa.
The present invention further relates to mixtures of these compounds with polyether antibiotics or synthetically prepared coccidiosis agents in compositions for controlling parasitic protozoa, in particular coccidia.
Substituted benzimidazoles and their use as insecticides, fungicides and herbicides have already been disclosed (EP-OS(European Published Specification) 87 375, 152 360, 181 826, 239 508, 260 744, 266 984, U.S. Pat. Nos. 3,418,318, 3,472,865, 3,576,818, 3,728,994.
Halogenated benzimidazoles and their action as anthelmintics, coccidiostatics and pesticides have been disclosed (DE-OS(German Published Specification) 2 047 369, DE-OS (German Published Specification) 4 237 617). Mixtures of nitro-substituted benzimidazoles and polyether antibiotics have been disclosed as coccidiosis agents (U.S. Pat. No. 5,331,003). In all cases, their action is still not satisfactory.
Coccidiosis is a disease which is caused by single-celled parasites (protozoa). In particular in poultry breeding, it can cause great losses. In order to avoid these, the populations are treated prophylactically with coccidiosis agents. Owing to the development of resistance to the agents employed, serious problems occur even shortly after introduction of the agents. By means of the use of coccidiosis agents which are chemically completely new, in particular combinations, it is also possible, on the other hand, to control polyresistant parasite strains.
New benzimidazoles of the formula (I)
in which
R
1
represents fluoroalkyl,
R
2
represents hydrogen or alkyl,
R
3
represents alkyl,
X
1
, X
2
, X
3
and X
4
independently of one another represent hydrogen, halogen, halogenoalkyl, halogenoalkoxy, halogenoalkylthio or halogenoalkylsulfonyl,
or alternatively
X
2
and X
3
or X
3
and X
4
together represent a dioxyhaloalkylene, have been found, which exhibit outstanding activity against coccidiosis.
The benzimidazoles of the formula (I)
in which
R
1
, R
2
, R
3
, X
1
to X
4
have the abovementioned meanings,are prepared by
reacting 1 H-benzimidazoles of the formula (II)
in which
R
1
and X
1
to X
4
have the meaning indicated above,
with an alkylating agent of the formula (III)
in which
A represents a suitable leaving group,
R
2
and R
3
have the meaning indicated above, if appropriate in the presence of diluents and/or reaction auxiliaries.
Depending on the type and number of the substituents, the compounds of the formula (I) can optionally be present as geometrical and/or optical isomers or regioisomers or isomer mixtures thereof in varying composition. Both the pure isomers and the isomer mixtures are claimed according to the invention.
Formula (I) provides a general definition of the substituted benzimidazoles according to the invention. Preferred compounds of the formula (I) are those in which
R
1
represents C
1
-C
4
-fluoroalkyl,
R
2
represents hydrogen or C
1
-C
4
-alkyl,
R
3
represents C
1
-C
4
-alkyl,
X
1
, X
2
, X
3
and X
4
independently of one another represent hydrogen, F, Cl, Br, C
1
-C
4
-halogenoalkyl, C
1
-C
4
-halogenoalkoxy, C
1
-C
4
-halogenoalkylthio, C
1
-C
4
-halogenoalkylsulfonyl,
X
2
and X
3
or X
3
and X
4
can also together represent a dioxyhalo-C
1
-C
4
-alkylene radical.
Particularly preferred compounds of the formula (I) are those in which
R
1
represents CF
3
, CHF
2
, CHF,
R
2
represents hydrogen, methyl, ethyl, n-propyl or isopropyl,
R
3
represents methyl, ethyl, n-propyl or isopropyl,
X
1
, X
2
, X
3
and X
4
independently of one another represent hydrogen, F, Cl, Br, CF
3
, CHF
2
, CH
2
F, OCF
3
, OCH
2
F, OCHF
2
, SCF
3
, SCHF
2
, SCH
2
F, SO
2
CF
3
, SO
2
CHF
2
, SO
2
CH
2
F, where
X
2
and X
3
or X
3
and X
4
can also together represent a radical —O—CF
2
—O—, —O—CF
2
—CF
2
—O—, —O—CF
2
—CF
2
—CF
2
—O—, —O—CF
2
—CHF—O—, —O—CCIF—CCIF—O—, —O—CHF—O—, —O—CHF—CHF—O— or —O—CCIF—O—.
Very particularly preferred compounds of the formula (I) are those in which
R
1
represents —CF
3
or —CHF
2
,
R
2
represents hydrogen,
R
3
represents methyl,
X
1
represents hydrogen, —CF
3
, Cl, Br, F or —SCF
3
,
X
2
represents hydrogen, —OCF
3
, F, Br, Cl or CF
3
,
X
3
represents F, Br, Cl, —OCF
3
, —CF
3
or —SO
2
CF
3
,
X
4
represents hydrogen, where
X
2
and X
3
or X
3
and X
4
can also represent —OCF
2
—CFHO—, —O—CCIF—CCIF—O—, —OCF
2
—CF
2
—O— or —O—CF
2
—O—.
If, for carrying out the process according to the invention for the preparation of compounds of the formula (I), 4-bromo-2,6-bis-trifluoromethylbenzimidazole, for example, is used, the course of the reaction of the preparation process can be represented by the following equation:
Formula (II) provides a general definition of the 1H-benzimidazoles needed as starting substances for carrying out the preparation process. In this formula (II), R
1
to R
3
and X
1
to X
4
preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the compounds of the formula (I) according to the invention.
The 1H-benzimidazoles of the formula (II) are known or obtainable in analogy to known processes (cf., for example, J. Amer. Chem. Soc. 75, 1292 [1953] U.S. Pat. No. 3.576.818).
Formula (III) provides a general definition of the alkylating agents furthermore necessary as starting materials for carrying out the preparation process. In this formula (III), R
2
and R
3
preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the formula (I) according to the invention.
A represents a leaving radical which is customary in alkylating agents, preferably halogen, in particular chlorine, bromine or iodine, or in each case optionally substituted alkylsulfonyloxy, alkoxysulfonyloxy or arylsulfonyloxy, such as, in particular, methanesulfonyloxy, trifluoromethanesulfonyloxy, methoxysulfonyloxy, ethoxysulfonyloxy or p-toluenesulfonyloxy.
The compounds of the formula (III) are generally known or obtainable in analogy to known processes (cf., for example, JP 58152879 [CA 100: 121042]; U.S. Pat. Nos. 4,434,173; 4,448,732).
Suitable diluents for carrying out the preparation process are inert organic solvents. These in particular include aliphatic, alicyclic or aromatic, optionally halogenated hydrocarbons, such as, for example, benzine, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform or carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl or diethyl ether; ketones, such as acetone, butanone or methyl isobultyl ketone; nitriles, such as acetonitrile, propionitrile or benzonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethyl phosphoramide; esters, such as methyl acetate or ethyl acetate or bases such as pyridine or organic acids, such as formic acid or acetic acid.
The preparation process is preferably carried out in the presence of a suitable reaction auxiliary. Those suitable are all customary inorganic or organic bases. These include, for example, alkaline earth metal or alkali metal hydrides, hydroxides, amides, alkoxides, acetates, carbonates or hydrogencarbonates, such as, for example, sodium hydride, sodium amide, lithium diethylamide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium acetate, calcium acetate, ammonium acetate, sodium carbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate or ammonium carbonate, organolithium compounds, such as n-butyllithium, and tertiary amines, such as trimethylamine, triethylamine, tributylamine, di-isopropyl-ethylamine, tetramethylguanidine, N,N-dimethylaniline, pyridine, piperidine, N-methylpiperidine, N,N-dimethylaminopyri
Baasner Bernd
Greif Giesela
Haberkorn Axel
Lieb Folker
Marhold Albrecht
Bayer Aktiengesellschaft
Pellegrino Susan M.
Small Andrea D.
Tsang Cecilia
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