Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-09
2003-09-16
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S302100
Reexamination Certificate
active
06620833
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 the control of 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 already 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 coccidosis agents (U.S. Pat. No. 5,331,003). In all cases their action is still not satisfactory.
Coccidiosis is a disorder which is caused by single-cell parasites (protozoa). It can cause great losses, in particular when raising poultry. In order to avoid these, the stocks are treated prophylactically with coccidiosis agents. Owing to the development of resistance to the agents employed, serious problems already occur shortly after introduction of the agents. By means of the use of chemically completely new coccidiosis agents, in particular combinations, it is possible, on the other hand, to control even polyresistant parasite strains.
The benzimidazoles of the formula (I)
in which
X
1
represents chlorine or bromine,
R
1
represents hydrogen or C
1-4
-alkyl,
R
3
represents fluoroalkyl,
R
2
represents the radical
R
4
represents alkyl or substituted phenyl,
R
5
represents alkyl,
are new and especially suitable for combating a parasitic protozoa.
The benzimidazoles of the formula (I)
in which
X
1
represents chlorine or bromine
R
1
represents hydrogen or C
1-4
-alkyl,
R
3
represents fluoroalkyl,
R
2
represents the radical
R
4
represents alkyl or substituted phenyl,
R
5
represents alkyl,
are prepared by a process in which
1H-benzimidazoles of the formula (II)
in which
X
1
and R
3
have the meaning indicated above.
are reacted with an alkylating agent of the formula (III)
A—CHR
1
R
2
(III),
in which
A represents a suitable leaving group,
R
1
and R
2
have the meaning indicated above,
if appropriate in the presence of diluents and/or reaction auxiliaries.
The compounds of the formula (I) can optionally be present in differing compositions as geometrical and/or optical isomers or regioisomers or isomer mixtures thereof, depending on the type and number of substituents. 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
X
1
represents chlorine or bromine,
R
1
represents hydrogen or C
1-4
-alkyl such as methyl, ethyl, i-propyl,
R
2
represents the radical
R
4
represents C
1-6
-alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, cyclohexyl, as well as substituted phenyl. Possible substituents of the phenyl ring in this case are: C
1-4
-alkyl, in particular methyl, C
1-4
-halogenoalkyl, in particular trifluoromethyl, halogen, nitro, C
1-4
-alkoxy, in particular methoxy, C
1-4
-halogenoalkoxy, in particular trifluoromethoxy, methylenedioxy, ethylenedioxy, which for their part can be halogen-substituted,
R
5
represents C
1-4
-alkyl, in particular methyl or ethyl,
R
3
represents perfluoro-C
1-4
-alkyl, in particular trifluoromethyl.
Particularly preferred compounds of the formula (I) are those in which
X
1
represents chlorine or bromine,
R
1
represents hydrogen,
R
2
represents the radical
R
4
represents C
1-6
-alkyl,
R
5
represents methyl or ethyl,
R
3
represents trifluoromethyl.
If, for example, benzimidazole is used for the preparation of the compounds of the formula (I) according to the invention, the course of 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), X
1
and R
3
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
1
and R
2
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 customary in alkylating agents, preferably halogen, in particular chlorine, bromine or iodine or alkylsulphonyloxy, alkoxysulphonyloxy or arylsulphonyloxy, each of which is optionally substituted, such as, in particular, methanesulphonyloxy, trifluoromethanesulphonyloxy, methoxysulphonyloxy, ethoxysulphonyloxy or p-toluenesulphonyloxy.
A moreover also represents a hydroxyl, alkanoyloxy or alkoxy group, such as, for example, an acetoxy or methoxy group, in particular if compounds of the formula (I) in which R
1
is other than hydrogen are to be prepared with the aid of the process according to the invention.
The compounds of the formula (III) are generally known or obtainable in analogy to known processes (cf., for example, DE-A 20 40 175; DE-A 21 19 518; Synthesis 1973, 703).
Suitable diluents for carrying out the preparation process are inert organic solvents. These in particular include aliphatic, alicyclic or aromatic, optinally 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 isobutyl ketone; nitriles, such as acetonitrile, propionitrile or benzonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide; 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, alcoholates, 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 hydrogencarbonates or ammonium carbonate, organolithium compounds, such as n-butyllithium, and also tertiary amines, such as trimethylamine, triethylamine, tributylamine, diisopropylethylamine, tetramethylguanidine, N,N-dimethylaniline, pyridine, piperidine, N-methylpiperidine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).
Alternatively, suitable reaction auxiliaries are also organic or inorganic acids, such as, for example, sulphuric acid, hydrochlor
Baasner Bernd
Greif Gisela
Haberkorn Axel
Lieb Folker
Marhold Albrecht
Bayer Aktiengesellschaft
Morris Patricia L.
Pellegrino Susan M.
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