U.S. patent application number 11/601036 was filed with the patent office on 2007-03-22 for substituted benzimidazoles, production and use thereof as agents for combating parasitic protozoas.
This patent application is currently assigned to Bayer Aktiengesellschaft. Invention is credited to Bernd Baasner, Gisela Greif, Axel Haberkorn, Folker Lieb, Albrecht Marhold.
Application Number | 20070066671 11/601036 |
Document ID | / |
Family ID | 7874277 |
Filed Date | 2007-03-22 |
United States Patent
Application |
20070066671 |
Kind Code |
A1 |
Greif; Gisela ; et
al. |
March 22, 2007 |
Substituted benzimidazoles, production and use thereof as agents
for combating parasitic protozoas
Abstract
The present invention relates to new substituted benzimidazoles,
their preparation and their use as agents against parasitic
protozoa. The active compounds are characterized by the following
formula (I): ##STR1## in which X.sup.1 represents chlorine or
bromine, R.sup.1 represents hydrogen or C.sub.1-4-alkyl, R.sup.3
represents fluoroalkyl, R.sup.2 represents the radical ##STR2##
R.sup.4 represents alkyl or substituted phenyl, R.sup.5 represents
alkyl.
Inventors: |
Greif; Gisela; (Remagen,
DE) ; Haberkorn; Axel; (Wuppertal, DE) ;
Baasner; Bernd; (Bergisch-Gladbach, DE) ; Lieb;
Folker; (Leverkusen, DE) ; Marhold; Albrecht;
(Leverkusen, DE) |
Correspondence
Address: |
JEFFREY M. GREENMAN
BAYER PHARMACEUTICALS CORPORATION
400 MORGAN LANE
WEST HAVEN
CT
06516
US
|
Assignee: |
Bayer Aktiengesellschaft
Leverkusen
DE
|
Family ID: |
7874277 |
Appl. No.: |
11/601036 |
Filed: |
November 17, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
10613818 |
Jul 3, 2003 |
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11601036 |
Nov 17, 2006 |
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09743440 |
Jan 9, 2001 |
6620833 |
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PCT/EP99/04650 |
Jul 5, 1999 |
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10613818 |
Jul 3, 2003 |
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Current U.S.
Class: |
514/393 ;
548/302.1 |
Current CPC
Class: |
C07D 491/04 20130101;
A61P 33/02 20180101 |
Class at
Publication: |
514/393 ;
548/302.1 |
International
Class: |
A61K 31/4188 20060101
A61K031/4188; C07D 491/02 20060101 C07D491/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 16, 1998 |
DE |
198 31 985.1 |
Claims
1. The benzimidazoles of the formula (I) ##STR19## in which X.sup.1
represents chlorine or bromine, R.sup.1 represents hydrogen or
C.sub.1-4-alkyl, R.sup.3 represents fluoroalkyl, R.sup.2 represents
the radical ##STR20## R.sup.4 represents alkyl or substituted
phenyl, R.sup.5 represents alkyl.
2. Process for the preparation of the benzimidazoles of the formula
(I) ##STR21## in which X.sup.1 represents chlorine or bromine
R.sup.1 represents hydrogen or C.sub.1-4-alkyl, R.sup.3 represents
fluoroalkyl, R.sup.2 represents the radical ##STR22## R.sup.4
represents alkyl or substituted phenyl R.sup.5 represents alkyl,
characterized in that 1 H-benzimidazoles of the formula (II)
##STR23## in which X.sup.1 and R.sup.3 have the meaning indicated
above, are reacted with an alkylating agent of the formula (III)
A-CHR.sup.1R.sup.2 (III), in which A represents a suitable leaving
group, R.sup.1 and R.sup.2 have the meaning indicated above, if
appropriate in the presence of diluents and/or reaction
auxiliaries.
3. Composition against parasitic protozoa, characterized in that it
contains at least one substituted benzimidazole of the formula (I)
according to claim 1.
4. Process for controlling parasitic protozoa, characterized in
that substituted benzimidazoles of the formula (I) according to
claim 1 are allowed to act on these and/or their environment.
5. Use of substituted benzimidazoles of the formula (I) according
to claim 1 for controlling parasitic protozoa.
6. Use of substituted benzimidazoles of the formula (I) according
to claim 1 for the preparation of compositions against parasitic
protozoa.
7. Mixtures of substituted benzimidazoles of the formula (I)
according to claim 1 with polyether antibiotics or synthetic
coccidiosis agents for controlling parasitic protozoa.
Description
[0001] The present invention relates to new substituted
benzimidazoles, their preparation and their use as agents against
parasitic protozoa.
[0002] 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.
[0003] 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).
[0004] 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.
[0005] 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.
[0006] The benzimidazoles of the formula (I) ##STR3## in which
[0007] X.sup.1 represents chlorine or bromine, [0008] R.sup.1
represents hydrogen or C.sub.1-4-alkyl, [0009] R.sup.3 represents
fluoroalkyl, [0010] R.sup.2 represents the radical ##STR4## [0011]
R.sup.4 represents alkyl or substituted phenyl, [0012] R.sup.5
represents alkyl, are suitable as agents against parasitic
protozoa.
[0013] The benzimidazoles of the formula (I) ##STR5## in which
[0014] X.sup.1 represents chlorine or bromine [0015] R.sup.1
represents hydrogen or C.sub.1-4-alkyl, [0016] R.sup.3 represents
fluoroalkyl, [0017] R.sup.2 represents the radical ##STR6## [0018]
R.sup.4 represents alkyl or substituted phenyl [0019] R.sup.5
represents alkyl are prepared by a process in which
[0020] 1 H-benzimidazoles of the formula (II) ##STR7## in which
[0021] X.sup.1 and R.sup.3 have the meaning indicated above, are
reacted with an alkylating agent of the formula (III)
A-CHR.sup.1R.sup.2 (III), in which [0022] A represents a suitable
leaving group, [0023] R.sup.1 and R.sup.2 have the meaning
indicated above, if appropriate in the presence of diluents and/or
reaction auxiliaries.
[0024] 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.
[0025] Formula (I) provides a general definition of the substituted
benzimidazoles according to the invention. Preferred compounds of
the formula (I) are those in which [0026] X.sup.1 represents
chlorine or bromine, [0027] R.sup.1 represents hydrogen or
C.sub.1-4-alkyl such as methyl, ethyl, i-propyl, [0028] R.sup.2
represents the radical ##STR8## [0029] R.sup.4 represents
C.sub.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.sub.1-4-alkyl, in particular methyl,
C.sub.1-4-halogenoalkyl, in particular trifluoromethyl, halogen,
nitro, C.sub.1-4-alkoxy, in particular methoxy, methylenedioxy,
C.sub.1-4-halogenoalkoxy, in particular trifluoromethoxy and
ethylenedioxy, which for their part can be halogen-substituted,
[0030] R.sup.5 represents C.sub.1-4-alkyl, in particular methyl or
ethyl, [0031] R.sup.3 represents perfluoro-C.sub.1-4-alkyl, in
particular trifluoromethyl.
[0032] Particularly preferred compounds of the formula (I) are
those in which [0033] X.sup.1 represents chlorine or bromine,
[0034] R.sup.1 represents hydrogen, [0035] R.sup.2 represents the
radical ##STR9## [0036] R.sup.4 represents C.sub.1-6-alkyl, [0037]
R.sup.5 represents methyl or ethyl, [0038] R.sup.3 represents
trifluoromethyl.
[0039] 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: ##STR10##
[0040] 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.sup.1 and R.sup.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.
[0041] 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).
[0042] 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.sup.1 and R.sup.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.
[0043] 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.
[0044] 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.sup.1 is
other than hydrogen are to be prepared with the aid of the process
according to the invention.
[0045] 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).
[0046] 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.
[0047] 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 acetation, 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).
[0048] Alternatively, suitable reaction auxiliaries are also
organic or inorganic acids, such as, for example, sulphuric acid,
hydrochloric acid, p-toluenesulphonic acid,
perfluorobutanesulphonic acid or strongly acidific ion exchangers,
particularly if A represents a hydroxyl, acyloxy or alkoxy radical
in the alkylating agents of the formual (III) used.
[0049] The preparation process can optionally also be carried out
in a two-phase system, such as, for example, water/toluene or
water/dichloromethane, if appropriate in the presence of a suitable
phase-transfer catalyst. Examples of such catalysts which may be
mentioned are: tetrabutylammonium iodide, tetrabutylammonium
bromide, tetrabutylammonium chloride, tributyl-methylphosphonium
bromide, trimethyl-C.sub.13/C.sub.15-alkylammonium chloride,
trimethyl-C.sub.13/C.sub.15-alkylammonium bromide,
dibenzyl-dimethyl-ammonium methylsulphate,
dimethyl-C.sub.12/C.sub.14-alkyl-benzylammonium chloride,
dimethyl-C.sub.12/C.sub.14-alkyl-benzylammonium bromide,
tetrabutylammonium hydroxide, triethylbenzylammonium chloride,
methyltrioctylammonium chloride, trimethylbenzylammonium chloride,
15-crown-5, 18-crown-6 or
tris-[2-(2-methoxyethoxy)-ethyl]-amine.
[0050] When carrying out the preparation process, the reaction
temperatures can be varied within a relatively wide range. In
general, the reaction is carried out at temperatures between
-70.degree. C. and +200.degree. C., preferably at temperatures
between 0.degree. C. and 130.degree. C.
[0051] The preparation process is customarily carried out under
normal pressure. However, it is also possible to work at increased
or reduced pressure.
[0052] To carry out the preparation process, in general 1.0 to 5.0
mol, preferably 1.0 to 2.5 mol, of alkylating agent of the formula
(III) and, if appropriate, 0.01 to 5.0 mol, preferably 1.0 to 3.0
mol, of reaction auxiliary are employed per mol of 1H-benzimidazole
of the formula (II).
[0053] In a particular embodiment, it is also possible to silylate
the 1H-benzimidazole of the formula (II) first in an earlier
reaction step with the aid of customary silylation processes, for
example using hexamethyldisilazane or trimethylsilyl chloride, if
appropriate in the presence of a suitable catalyst, such as, for
example, sulphuric acid, trifluoroacetic acid, ammonium sulphate,
imidazole or saccharin at temperatures between -20.degree. C. and
+150.degree. C. and to react the 1-trimethylsilyl-benzimidazoles
thus obtained in a subsequent second stage with alkylating agents
of the formula (II) according to the preparation process. In this
case, it is advantageous to add tin tetrachloride to the alkylation
reaction as a catalyst (cf., for example, Chem. Heterocycl. Comp.
USSR 24, 514 [1988]).
[0054] The reaction is carried out and worked up and the reaction
products are isolated according to known processes (cf. Preparation
Examples).
[0055] The final products of the formula (I) are purified with the
aid of customary processes, for example by column chromatography or
by recrystallization.
[0056] Characterization is carried out with the aid of the melting
point or in the case of non-crystallizing compounds--in particular
in the case of regioisomer mixtures--with the aid of proton nuclear
magnetic resonance spectroscopy (.sup.1H-NMR).
[0057] The active compounds have favourable toxicity to
warm-blooded animals and are suitable for the control of parasitic
protozoa which occur in animal husbandry and animal breeding in the
case of useful, breeding, zoo, laboratory and experimental animals
and pets. At the same time, they are active against all or
individual stages of development of the pests and also against
resistant and normally sensitive strains. By means of the control
of the parasitic protozoa, illness, cases of death and yield
reductions (e.g. in the production of meat, milk, wool, hides,
eggs, honey etc.) should be decreased, so that more economical and
simpler animal husbandry is possible due to the use of the active
compounds.
[0058] The parasitic protozoa include:
[0059] Mastigophora (Flagellata) such as, for example,
Trypanosomatidae, for example, Trypanosoma b. brucei, T.b.
gambiense, T.b. rhodesiense, T. congolense, T. cruzi, T. evansi, T.
equinum, T. lewisi, T. percae, T. simiae, T. vivax, Leishmania
brasiliensis, L. donovani, L. tropica, such as, for example,
Trichomonadidae, for example, Giardia lamblia, G. canis.
[0060] Sarcomastigophora (Rhizopoda) such as Entamoebidae, for
example, Entamoeba histolytica, Hartmanellidae, for example,
Acanthamoeba sp., Hartmanella sp.
[0061] Apicomplexa (Sporozoa) such as Eimeridae, for example,
Eimeria acervulina, E. adenoides, E. alabahmensis, E. anatis, E.
anseris, E. arloingi, E. ashata, E. auburnensis, E. bovis, E.
brunetti, E. canis, E. chinchillae, E. clupearum, E. columbae, E.
contorta, E. crandalis, E. debliecki, E. dispersa, E.
ellipsoidales, E. falciformis, E. faurei, E. flavescens, E.
gallopavonis, E. hagani, E. intestinalis, E. iroquoina, E.
irresidua, E. labbeana, E. leucarti, E. magna, E. maxima, E. media,
E. meleagridis, E. meleagrimitis, E. mitis, E. necatrix, E.
ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E. perforans, E.
phasani, E. piriformis, E. praecox, E. residua, E. scabra, E.
spec., E. stiedai, E. suis, E. tenella, E. truncata, E. truttae, E.
zuernii, Globidium spec., Isospora belli, I. canis, I. felis, I.
ohioensis, I. rivolta, I. spec., I. suis, Neospara caninum,
Cystisospora spec., Cryptosporidium spec. such as Toxoplasmadidae,
for example, Toxoplasma gondii, such as Sarcocystidae, for example,
Sarcocystis bovicanis, S. bovihominis, S. ovicanis, S. ovifelis, S.
spec., S. suihominis such as Leucozoidae, for example,
Leucozytozoon simondi, such as Plasmodiidae, for example,
Plasmodium berghei, P. falciparum, P. malariae, P. ovale, P. vivax,
P. spec., such as Piroplasmea, for example, Babesia argentina, B.
bovis, B. canis, B. spec., Theileria parva, Theileria spec., such
as Adeleina, for example, Hepatozoon canis, H. spec.
[0062] Furthermore Myxospora and Microspora, for example, Glugea
spec. Nosema spec.
[0063] Furthermore Pneumocystis carinii, and also Ciliophora
(Ciliata) such as, for example, Balantidium coli, Ichthiophthirius
spec., Trichodina spec., Epistylis spec.
[0064] The compounds according to the invention are also active
against protozoa which occur as parasites in insects. Those which
may be mentioned are parasites of the strain Microsporida, in
particular of the genus Nosema. Particular mention may be made of
Nosema apis in the case of the honey bee.
[0065] The useful and breeding animals include mammals, such as,
for example, cattle, horses, sheep, pigs, goats, camels, water
buffalo, donkeys, rabbits, fallow deer, reindeer, fur-bearing
animals such as, for example, mink, chinchilla, racoons, birds,
such as, for example, hens, geese, turkeys, ducks, doves, bird
species for keeping at home and in zoos. Useful and ornamental fish
are furthermore included.
[0066] The laboratory and experimental animals include mice, rats,
guinea pigs, golden hamsters, dogs and cats.
[0067] The pets include dogs and cats.
[0068] The fish include useful, breeding, aquarium and ornamental
fish of all age levels, which live in fresh and salt water. The
useful and ornamental fish include, for example, carps, eels,
trout, whitefish, salmon, bream, roach, rudd, chub, sole, plaice,
halibut, Japanese yellowtail (Seriola quinqueradiata), Japanese eel
(Anguilla japonica), red seabream (Pagurus major), seabass
(Dicentrarchus labrax), grey mullet (Mugilus cephalus), pompano,
gilthead seabream (Sparus auratus), Tilapia ssp., Chichlidae
species such as, for example, Plagioscion, Channel catfish. The
compositions according to the invention are particularly suitable
for the treatment of fry, e.g. carp of 2 to 4 cm body length. The
compositions are also very highly suitable in eel feeding.
[0069] Administration can be carried out both prophylactically and
therapeutically.
[0070] The administration of the active compounds is carried out
directly or enterally, parenterally, dermally or nasally in the
form of suitable preparations.
[0071] Enteral administration of the active compounds takes place,
for example, orally in the form of powders, suppositories, tablets,
capsules, pastes, drinks, granules, drenches, boli, medicated feed
or drinking water. Dermal administration takes place, for example,
in the form of dipping, spraying, bathing, washing, pouring on and
spotting on, and dusting. Parenteral administration takes place,
for example, in the form of injection (intramuscular, subcutaneous,
intravenous, intraperitoneal) or by means of implants.
[0072] Suitable preparations are:
[0073] Solutions such as injection solutions, oral solutions,
concentrates for oral administration after dilution, solutions for
use on the skin or in body cavities, pour-on formulations,
gels;
[0074] Emulsions and suspensions for oral or dermal administration
and for injection; semi-solid preparations;
[0075] Formulations in which the active compound is incorporated in
an ointment base or in an oil-in-water or water-in-oil emulsion
base.
[0076] Solid preparations such as powders, premixes or
concentrates, granules, pellets, tablets, boli, capsules; aerosols
and inhalations, active compound-containing shaped articles.
[0077] Injection solutions are administered intravenously,
intramuscularly and subcutaneously.
[0078] Injection solutions are prepared by dissolving the active
compound in a suitable solvent and possibly adding additives such
as solubilizers, acids, bases, buffer salts, antioxidants,
preservatives. The solutions are sterile-filtered and buffered.
[0079] Solvents which may be mentioned are: physiologically
tolerable solvents such as water, alcohols such as ethanol,
butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol,
polyethylene glycols, N-methylpyrrolidone, and mixtures
thereof.
[0080] If appropriate, the active compounds can also be dissolved
in physiologically tolerable vegetable or synthetic oils which are
suitable for injection.
[0081] Solubilizers which may be mentioned are: solvents which
promote the dissolution of the active compound in the main solvent
or prevent its precipitation. Examples are polyvinylpyrrolidone,
polyethoxylated castor oil, polyethoxylated sorbitan ester.
[0082] Preservatives are: benzyl alcohol, trichlorobutanol, esters
of p-hydroxybenzoic acid, n-butanol.
[0083] Oral solutions are administered directly. Concentrates are
used orally after prior dilution to the use concentration. Oral
solutions and concentrates are prepared as described above in
connection with injection solutions, it being possible to dispense
with sterile operation.
[0084] Solutions for use on the skin are spotted on, painted on,
rubbed in, squirted or sprayed on or applied by dipping, bathing or
washing. These solutions are prepared as described above in
connection with the injection solutions.
[0085] It may be advantageous to add thickeners during preparation.
Thickeners are: inorganic thickeners such as bentonites, colloidal
silica, aluminium monostearate, organic thickeners such as
cellulose derivatives, polyvinyl alcohols and their copolymers,
acrylates and methacrylates.
[0086] Gels are applied to or painted onto the skin or introduced
into body cavities. Gels are prepared by mixing solutions, which
have been prepared as described in connection with the injection
solutions, with sufficient thickener to form a clear composition
with an ointment-like consistency. Thickeners employed are the
thickeners indicated further above.
[0087] Pour-on formulations are poured or squirted onto limited
areas of the skin, the active compound either penetrating the skin
and acting systemically or being dispersed on the surface of the
body.
[0088] Pour-on formulations are prepared by dissolving, suspending
or emulsifying the active compound in suitable skin-tolerable
solvents or solvent mixtures. If appropriate, further auxiliaries
such as colorants, absorption-promoting substances, antioxidants,
sunscreen agents, adherents are added.
[0089] Solvents which may be mentioned are: water, alkanols,
glycols, polyethylene glycols, polypropylene glycols, glycerol,
aromatic alcohols such as benzyl alcohol, phenylethanol,
phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl
benzoate, ethers such as alkylene glycol alkyl ethers such as
dipropylene glycol monomethyl ether, diethylene glycol mono-butyl
ether, ketones such as acetone, methyl ethyl ketone, aromatic
and/or aliphatic hydrocarbons, vegetal or synthetic oils, DMF,
dimethylacetamide, N-methylpyrrolidone,
2-dimethyl-4-oxy-methylene-1,3-dioxolane.
[0090] Colorants are all colorants approved for use on animals and
which can be dissolved or suspended.
[0091] Absorption-promoting substances are, for example, DMSO,
spreading oils such as isopropyl myristate, dipropylene glycol
pelargonate, silicone oils, esters of fatty acids, triglycerides,
fatty alcohols.
[0092] Antioxidants are sulphites or metabisulphites such as
potassium metabisulphite, ascorbic acid, butylhydroxytoluene,
butylhydroxyanisole, tocopherol.
[0093] Sunscreen agents are, for example, substances from the
benzophenones or novantisolic acid class.
[0094] Adherents are, for example, cellulose derivatives, starch
derivatives, polyacrylates, natural polymers such as alginates,
gelatine.
[0095] Emulsions can be used orally, dermally or as injections.
[0096] Emulsions are either of the type water-in-oil or of the type
oil-in-water.
[0097] They are prepared by dissolving the active compound either
in the hydrophobic or in the hydrophilic phase and homogenizing
this with the solvent of the other phase with the aid of suitable
emulsifiers and, if appropriate, further auxiliaries such as
colorants, absorption-promoting substances, preservatives,
antioxidants, sunscreen agents, viscosity-increasing
substances.
[0098] Hydrophobic phases (oils) which may be mentioned are:
paraffin oils, silicone oils, natural vegetable oils such as sesame
oil, almond oil, castor oil, synthetic triglycerides such as
caprylic/capric acid biglyceride, triglyceride mixtures with
vegetable fatty acids of chain length C.sub.8-12 or other specially
selected natural fatty acids, partial glyceride mixtures of
saturated or unsaturated fatty acids possibly also containing
hydroxyl groups, mono- and diglycerides of the C.sub.8/C.sub.10
fatty acids.
[0099] Esters of fatty acids such as ethyl stearate, di-n-butyryl
adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a
branched fatty acid of medium chain length with saturated fatty
alcohols of chain length C.sub.16-C.sub.18, isopropyl myristate,
isopropyl palmitate, caprylic/capric acid esters of saturated fatty
alcohols of chain length C.sub.12-C.sub.18, isopropyl stearate,
oleyl oleates, decyl oleates, ethyl oleate, ethyl lactates, waxy
fatty acid esters such as dibutyl phthalate, diisopropyl adipate,
ester mixtures related to the latter, inter alia fatty alcohols
such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl
alcohol, oleyl alcohol.
[0100] Fatty acids such as, for example, oleic acid and its
mixtures.
[0101] Hydrophilic phases which may be mentioned are:
[0102] water, alcohols such as, for example, propylene glycol,
glycerol, sorbitol and their mixtures.
[0103] Emulsifiers which may be mentioned are:
[0104] nonionic surfactants, e.g. polyethoxylated castor oil,
polyethoxylated sorbitan monooleate, sorbitan monostearate,
glycerol monostearate, polyoxyethyl stearate, alkylphenyl
polyglycol ethers;
[0105] ampholytic surfactants such as di-Na
N-lauryl-.beta.-iminodipropionate or lecithin;
[0106] anionic surfactants, such as Na laurylsulphates, fatty
alcohol ether sulphates, mono/dialkyl polyglycol ether
orthophosphate monoethanolamine salt;
[0107] cationic surfactants such as cetyltrimethylammonium
chloride.
[0108] Further auxiliaries which may be mentioned are:
[0109] viscosity-increasing and emulsion-stabilizing substances
such as carboxymethylcellulose, methylcellulose and other cellulose
and starch derivatives, polyacrylates, alginates, gelatine, gum
arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of
methyl vinyl ether and maleic anhydride, polyethylene glycols,
waxes, colloidal silica or mixtures of the substances
mentioned.
[0110] Suspensions can be used orally, dermally or as an injection.
They are prepared by suspending the active compound in a suspending
agent, if appropriate with addition of further auxiliaries such as
wetting agents, colorants, absorption-promoting substances,
preservatives, antioxidants, sunscreen agents.
[0111] Suspending agents which may be mentioned are all homogeneous
solvents and solvent mixtures.
[0112] Wetting agents (dispersing agents) which may be mentioned
are the surfactants indicated further above.
[0113] Further auxiliaries which may be mentioned are those
indicated further above.
[0114] Semi-solid preparations can be administered orally or
dermally. They differ from the suspensions and emulsions described
above only by their higher viscosity.
[0115] To prepare solid preparations, the active compound is
brought into the desired form with suitable excipients, if
appropriate with addition of auxiliaries.
[0116] Excipients which may be mentioned are all physiologically
tolerable solid inert substances. Those which are used are
inorganic and organic substances. Inorganic substances are, for
example, sodium chloride, carbonates such as calcium carbonate,
hydrogencarbonates, aluminium oxides, silicicas, argillaceous
earths, precipitated or colloidal silica, phosphates.
[0117] Organic substances are, for example, sugar, cellulose,
foodstuffs and feedstuffs such as powdered milk, animal meals,
cereal meals and shreds, starches.
[0118] Auxiliaries are preservatives, antioxidants, colorants which
have already been mentioned further above.
[0119] Further suitable auxiliaries are lubricants and glidants
such as, for example, magnesium stearate, stearic acid, talc,
bentonites, disintegration-promoting substances such as starch or
crosslinked polyvinyl pyrrolidone, binding agents such as, for
example, starch, gelatine or linear polyvinylpyrrolidone and also
dry binding agents such as microcrystalline cellulose.
[0120] The active compounds can be present in the preparations even
as a mixture with synergists or with other active compounds.
[0121] Particular emphasis may be given to mixtures of the
compounds according to the invention with a polyether antibiotic or
a synthetically prepared coccidiosis agent.
[0122] Synthetic coccidiosis agents or polyether antibiotics which
may preferably be mentioned for use in the mixtures according to
the invention are:
[0123] Amprolium, in some cases in combination with folic acid
antagonists
[0124] Robenidine
[0125] Toltrazuril
[0126] Monensin
[0127] Salinomycin
[0128] Maduramicin.
[0129] Particular emphasis may be given to the mixture with
maduramicin.
[0130] Ready-to-use preparations contain the active compounds in
concentrations of 10 ppm to 20 percent by weight, preferably from
0.1 to 10 percent by weight. Preparations which are diluted before
use contain the active compound in concentrations from 0.5 to 90
percent by weight, preferably from 1 to 50 percent by weight.
[0131] In general, it has proved advantageous to administer amounts
from approximately 0.5 to approximately 50 mg, preferably 1 to 20
mg, of active compound per kg of body weight per day to achieve
effective results.
[0132] In the mixture with other coccidiosis agents or polyether
antibiotics, the active compounds according to the invention are in
the ratio 1 to 0.1-10 to 1 to 1-10. The ratio 1 to 5 is
preferred.
[0133] The active compounds can also be administered to the animals
together with the feed or drinking water.
[0134] Feedstuffs and foodstuffs contain 0.01 to 250 ppm,
preferably 0.5 to 100 ppm, of the active compound in combination
with a suitable edible material.
[0135] Such a feedstuff and foodstuff can be used both for curative
purposes and for prophylactic purposes.
[0136] Such a feedstuff or foodstuff is prepared by mixing a
concentrate or a premix which contains 0.5 to 30%, preferably 1 to
20%, by weight of an active compound as a mixture with an edible
organic or inorganic carrier with customary feedstuffs. Edible
carriers are, for example, maize flour or maize and soya bean flour
or mineral salts, which preferably contain a small amount of an
edible dust prevention oil, e.g. maize oil or soya oil. The premix
obtained in this way can then be added to the complete feedstuff
before feeding it to the animals.
[0137] By way of example, use in coccidiosis may be mentioned:
[0138] For the healing and prophylaxis, for example, of coccidiosis
in poultry, in particular in hens, ducks, geese and turkeys, 0.1 to
100 ppm, preferably 0.5 to 100 ppm, of an active compound are mixed
with a suitable edible material, e.g. a nutritious feedstuff. If
desired, these amounts can be increased, particularly if the active
compound is well tolerated by the recipient. Correspondingly,
administration can be carried out via the drinking water.
[0139] For the treatment of individual animals, e.g. in the case of
the treatment of coccidiosis in mammals or of toxoplasmosis,
amounts of active compound of 0.5 to 100 mg/kg of body weight are
preferably administered daily in order to achieve the desired
results. In spite of this, it may occasionally be necessary to
depart from the amounts mentioned, in particular depending on the
body weight of the experimental animal or on the type of
administration method, but also because of the animal genus and its
individual reaction to the active compound or the nature of the
formulation and the time or the interval at which it is
administered. Thus in certain cases it may be sufficient to manage
with less than the abovementioned minimum amount, while in other
cases the upper limit mentioned must be exceeded. When
administering relatively large amounts, it may be advisable to
divide these into several individual administrations during the
course of the day.
[0140] The efficacy of the compounds according to the invention can
be confirmed, for example, in cage experiments with the following
experimental arrangement, in which the animals are treated with the
respective individual components and with the mixtures of the
individual components.
[0141] An active compound-containing feed is prepared such that the
required amount of active compound is basically mixed with a
nutritionally balanced animal feed, e.g. with the chick feed
indicated below.
[0142] If a concentrate or a premix is to be prepared, which is
finally to be diluted in the feed to the values mentioned in the
experiment, in general approximately 1 to 30%, preferably
approximately 10 to 20% by weight, of active compound are mixed
with an edible organic or inorganic carrier, e.g. maize and soya
meal or mineral salts which contain a small amount of an edible
dedusting oil, e.g. maize oil or soya bean oil. The premix thus
obtained can then be added to the complete poultry feed before
administration.
[0143] A suitable example of the use of the substances according to
the invention in the poultry feed is the following composition.
TABLE-US-00001 52.00% of feed cereal shreds, mainly: 40% maize, 12%
wheat 17.00% of soya shreds extr. 5.00% of maize gluten feed 5.00%
of wheat feed meal 3.00% of fish meal 3.00% of mineral mixture
3.00% of alfalfa meal 2.50% of vitamin premix 2.00% of wheat germs,
comminuted 2.00% of soya oil 2.00% of meat and bone meal 1.50% of
whey powder 1.00% of molasses 1.00% of brewer's yeast, bound to
brewer's gains 100.00%
[0144] Such a feed contains 18% raw protein, 5% raw fibre, 1% Ca,
0.7% P and, per kg, 1200 I.U. of vitamin A, 1200 I.U. of vitamin
D3, 10 mg of vitamin E, 20 mg of zinc bacitracin.
Cage Experiment on Coccidiosis/Chicks
[0145] 8 to 12 day-old male chicks (e.g. LSL Brinkschulte/Senden)
which have been reared coccidia-free receive the compounds
according to the invention (test substances) in the concentration
indicated in ppm with the feed from 3 days before (day-3) infection
(=a.i.) until 8 (9) days after infection (=p.i.). 3 animals are
kept in each cage. One or more groups of this type are employed per
dose. Infection is carried out by means of a stomach tube directly
into the crop with approximately 100,000 sporulated oocysts of
Eimeria acervulina and with approximately 30,000 oocysts each of E.
maxima and 40,000 sporulated oocysts of E. tenella. These are
highly virulent strains. The exact infection dose is adjusted so
that, if possible, one of three experimentally infected untreated
chicks dies due to the infection. For assessment of the efficacy,
the following criteria are taken into account: weight increase from
the start of the experiment to the end of the experiment, death
rate due to infection, macroscopic assessment of the faeces with
respect to diarrhoea and excretion of blood on days 5 and 7 p.i.
(assessment 0 to 6), macroscopic assessment of the intestinal
mucosa, in particular of the appendices (assessment 0 to 6) and the
oocyst excretion as well as the proportion (in %) of the oocysts
sporulating in the course of 24 hours. The number of oocysts in the
faeces was determined with the aid of a McMaster counting chamber
(see Engelbrecht and coworkers "Parasitologische Arbeitsmethoden in
Medizin and Veterinarmedizin" [Parasitological Working Methods in
Medicine and Veterinary Medicine], Akademie-Verlag, Berlin (1965)).
The individual findings are related to the untreated non-infected
control groups and a total score is calculated (cf. A. Haberkorn
(1986), pp. 263 to 270 in Research in Avian Coccidiosis ed L. R.
McDougald, L. P. Joyner, P. L. Long, Proceedings of the Georgia
Coccidiosis Conference, Nov. 18-20, 1985, Athens/Georgia USA).
[0146] Experimental results with combinations according to the
invention are shown by way of example in the following tables. The
synergistic activity of the combinations in comparison with the
individual components is particularly evident in the reduction of
oocysts excretion but also with respect to the section findings,
weight gain and better tolerability.
[0147] In the following tables, in the column "Treatment" the
information means
[0148] n.inf.contr.=non-infected control group
[0149] inf.contr.=infected control group
[0150] 1=benzimidazole example No.
[0151] In the column "ppm", the concentration of the active
compound employed in the feed is indicated in ppm.
[0152] In the column "mortality" the percentage of the dead animals
is indicated under % and the number of dead animals/animals
employed in the experiment is indicated under n.
[0153] In the column "weight % of not inf. control" the ratio of
the weight of the treated animals to the weight of the non-infected
control group is indicated.
[0154] In the columns "dropping scores", "lesion score" and "oocyst
control", individual details of the action are given.
[0155] In the column "% efficacy", the total score is assessed; 0%
means no action, 100% means full action. TABLE-US-00002 TABLE 1
Experimental infection with Eimeria acervulina, Eimeria maxima and
Eimeria tenella in chicks. Ex. 1 in combination with monensin.
weight % of % mortality not inf. dropping lesion oocyst in % of
inf. control efficacy Treatment ppm % n control scores score ac.
max. ten. tot. tot. n.inf.contr. 0 0 0/6 100 0 0 0 0 0 0 100
inf.contr. 0 100 6/6 0 6 6 100 100 100 100 0 Ex. 1 7.5 0 0/3 76 6
5.3 3 0 1 1.3 65 Ex. 1 10 0 0/3 84 6 3.3 0 0 1 0 75 Mon. 25 33 1/3
36 6 6 98 0 100 66 45 Mon. 50 33 1/3 81 6 6 44 0 13 19 36 Mon. 100
33 1/3 30 6 6 8 0 100 36 24 Ex. 1 + Mon. 7.5 + 25 0 0/3 93 6 0 0 0
2 0.6 88 Ex. 1 + Mon. 10 + 25 33 1/3 95 3 0.5 0 0 0 0 100 Ex. 1 +
Mon. 7.5 + 50 0 0/3 100 0 1.7 0 0 0 0 100 Ex. 1 + Mon. 10 + 50 0
0/3 95 0 0.7 0 0 0 0 100 Ex. 1 + Mon. 7.5 + 100 33 1/3 114 0 0 0 0
0 0 100 Ex. 1 + Mon. 10 + 100 0 0/3 99 0 0 0 0 0 0 100
[0156] TABLE-US-00003 TABLE 2 Experimental infection with Eimeria
acervulina, Eimeria maxima and Eimeria tenella in chicks. Ex. 1 in
combination with maduramicin. weight % of % mortality not inf.
dropping lesion oocyst in % of inf. control efficacy Treatment ppm
% n control scores score ac. max. ten. tot. tot. n.inf.contr. 0 0
0/6 100 0 0 0 0 0 0 100 inf.contr. 0 50 3/6 58 6 6 100 100 100 100
0 Ex. 1 1 33 1/3 31 6 6 49 100 97 82 36 Ex. 1 2.5 33 1/3 42 4-6 6
19 100 55 58 36 Ex. 1 5 0 0/3 110 1 0 1 100 11 37 90 MAD 1 0 0/3 93
1 2 8 100 30 46 73 MAD 2 0 0/3 114 0 2 8 100 45 51 84 MAD 3 0 0/3
112 0 0 1 0 3 1.3 100 Ex. 1 + MAD 2.5 + 1 0 0/3 122 0 0 0 0 0 0 100
Ex. 1 + MAD 5 + 1 0 0/3 119 0 0 0 0 0 0 100 Ex. 1 + MAD 2.5 + 2 0
0/3 122 0 0 0 0 0 0 100 Ex. 1 + MAD 5 + 2 0 0/3 105 0 0 0 0 0 0 100
Ex. 1 + MAD 2.5 + 3 0 0/3 117 0 0 0 0 0 0 100 Ex. 1 + MAD 1 + 3 0
0/3 121 0 0 0 0 0 0 100
[0157] TABLE-US-00004 TABLE 3 Experimental infection with Eimeria
acervulina, Eimeria maxima and Eimeria tenella in chicks. Ex. 1 in
combination with salinomycin. weight % of % mortality not inf.
dropping lesion oocyst in % of inf. control efficacy Treatment ppm
% n control scores score ac. max. ten. tot. tot. n.inf.contr. 0 0
0/6 100 0 0 0 0 0 0 100 inf.contr. 0 100 6/6 0 6 6 100 100 100 100
0 Ex. 1 5 0 0/3 72 6 6 6 0 30 12 45 Ex. 1 7.5 0 0/3 76 6 5.3 3 0 1
1.3 65 Ex. 1 10 0 0/3 84 6 3.3 0 0 1 0 75 Sal. 15 100 3/3 T T T T T
T T T Sal. 30 100 3/3 T T T T T T T T Sal. 60 0 0/3 106 6 1.3 6 0
31 12 67 Ex. 1 + Sal 7.5 + 15 0 0/3 107 0 0 0 0 0 0 100 Ex. 1 + Sal
10 + 15 33 1/3 103 0 0 0 0 0 0 100 Ex. 1 + Sal 5 + 30 0 0/3 121 0 0
0 0 0 0 100 Ex. 1 + Sal 10 + 30 33 1/3 103 0 0 0 0 0 0 100 Ex. 1 +
Sal 5 + 60 0 0/3 91 2 0 0 0 0 0 100 Ex. 1 + Sal 10 + 60 33 1/3 97 0
0 0 0 0 0 100
[0158] The results of the efficacy experiments with the compounds
according to the invention are summarized in the following table:
TABLE-US-00005 TABLE 4 Efficacy against Eimeria acervulina, Eimeria
maxima and Eimeria tenella Dose in ppm Compound 10 5 2.5 Ex. 1 2 2
2 2 2 2 1 1 1 Ex. 2 D D D 2 2 2 1 2 1 Ex. 3 2 2 2 2 2 2 0 2 1 Ex. 4
1 1 1 1 1 1 1 2 1 Ex. 5 1 1 2 1 1 1 1 2 1 Ex. 6 2 2 2 2 2 2 1 1 1
Ex. 7 2 2 1 2 2 2 2 1 2 Ex. 8 2 2 2 0 1 1 0 0 0 Ex. 9 2 2 2 2 2 1 0
1 1 Assessment scheme: 2 = full action 1 = slight action 0 =
inactive D = death
[0159] The following preparation examples are intended to
illustrate but not to restrict the present invention:
EXAMPLE 1
[0160] ##STR11##
[0161] 39.0 g (0.1 mol) of
4-bromo-6,7-tetrafluoro-6,7-dihydro-2-trifluoromethyl-1H-[1,4]dioxino[2,3-
-e]benzimidazole is introduced into 1000 ml of CH.sub.2Cl.sub.2,
17.5 ml (0.125 mol) of triethylamine are added and 18.9 g (0.125
mol) of methyl N-chloromethyl-N-ethyl-carbamate are added dropwise
at 20.degree. C. and the mixture is refluxed for 24 h. It is washed
twice with 250 ml each of water and with 250 ml of saturated,
aqueous sodium chloride solution and dried over sodium sulphate.
The residue obtained after evaporation (54.4 g) is chromatographed
on 1 kg of silica gel (35-70 .mu.m) using cyclohexane/ethyl acetate
(10:1).
[0162] Yield: 30.6 g (60% of theory), m.p.: 92-93.degree. C.
EXAMPLES 2-12 BELOW OF THE FORMULA
[0163] ##STR12##
[0164] were obtained analogously to Example 1 and according to the
general instructions for preparation. TABLE-US-00006 Example M.p.
.sup.1H-NMR(CDCl.sub.3): No. X.sup.1 R.sup.1 R.sup.2 R.sup.3
[.degree. C.] .delta. [ppm] 2 Br H CH.sub.2N(Me)CO.sub.2Me CF.sub.3
2.8(s, 3H), 6.07(s, 2H) 3 Cl H CH.sub.2N(Me)CO.sub.2Me CF.sub.3
72-74 4 Cl H CH.sub.2N(Et)CO.sub.2Me CF.sub.3 0.97(t, 3H), 3.80(s,
3H), 7.26(s, 1H), 5 Br H CH.sub.2N(Bu)CO.sub.2Et CF.sub.3 0.76(t,
3H), 3.06(q, 2H), 6.08(s, 2H), 6 Br H CH.sub.2N(iPr)CO.sub.2Et
CF.sub.3 1.13(d, 6H), 3.32(sept., 1H), 6.06(s, 2H), 7 Cl H
CH.sub.2N(iPr)CO.sub.2Et CF.sub.3 1.15(d, 6H), 3.38(sept., 1H)
6.12(s, 2H) 8 Cl H CH.sub.2N(2-Me--C.sub.6H.sub.4)CO.sub.2Me
CF.sub.3 134-136 9 Cl H CH.sub.2N(C.sub.6H.sub.11)CO.sub.2Et
CF.sub.3 85-88 10 Br H CH.sub.2N(2-Me--C.sub.6H.sub.4)CO.sub.2Me
CF.sub.3 135-136 11 Cl H CH.sub.2N(Pr)CO.sub.2Et CF.sub.3 0.77(t,
3H) 4.23(q, 2H) 6.14(s, 2H) Me = Methyl Bu = n-Butyl Et = Ethyl iPr
= iso-Propyl Pr = n-Propyl
[0165] The preparation of the starting compound for Examples 1, 2,
6 and 8 can be carried out as indicated below: ##STR13##
[0166] 1400 g (6.7 mol) of 2,3-tetrafluoro-1,4-benzodioxane and 7 g
(0.08 mol) of FeS (powder) are introduced, 1190 g (7.4 mol) of
bromine are added dropwise at 20 to 30.degree. C. in the course of
about 4 h and the mixture is stirred for about 20 h until evolution
of gas is complete. It is washed with aqueous sodium sulphite
solution and dried over sodium sulphate. The residue is distilled
in vacuo.
[0167] Yield: 1540 g (80% of theory), b.p..sub.10: 70-74.degree. C.
(GC: 99%). Example b) ##STR14##
[0168] 350 g (1.2 mol) of 6-bromo-2,3-tetrafluoro-1,4-benzodioxane
are added dropwise at 20.degree. C. in the course of 75 min to 273
ml (98% strength) of nitric acid and 293 ml of conc. sulphuric
acid, and the reaction mixture is stirred at 20.degree. C. for 1 h
and at 40.degree. C. for 3 h. The mixture is poured onto ice,
extracted with methylene chloride, and the organic phase is washed
with water and with aqueous sodium hydrogencarbonate solution and
dried over sodium sulphate. The organic phase is evaporated and
reacted further as a crude product.
[0169] Yield: 396 g (98% of theory), (crude, GC: 99.1%),
b.p..sub.16: 121-124.degree. C., n.sub.D: 1.5065 at 20.degree. C.
Example c) ##STR15##
[0170] 396 g (1.2 mol) of
6-bromo-7-nitro-2,3-tetrafluoro-1,4-benzodioxane are introduced
into 1400 ml of ethanol, 253 g (4.5 mol) of Fe powder are added and
the mixture is heated to reflux. 29 g of conc. hydrochloric acid
are then added dropwise under reflux and the mixture is stirred for
1 h, 43 ml of water are added dropwise at boiling heat and the
reaction mixture is stirred for 2 h. The mixture is cooled, and the
precipitate is filtered off with suction and washed with ethanol.
The mother liquor is rendered alkaline and evaporated. The residue
is taken up in methylene chloride and washed twice with water and
dried over sodium sulphate. The organic phase is evaporated.
[0171] Yield: 313 g (87% of theory), (GC: 95.3%). Example d)
##STR16##
[0172] 313 g (1.04 mol) of
7-amino-6-bromo-2,3-tetrafluoro-1,4-benzodioxane are introduced
into 1250 ml of toluene and 500 g (4.4 mol) of trifluoroacetic
acid, and 188 g (1.3 mol) of phosphorus pentoxide are added in
portions at 20 to 25.degree. C. The mixture becomes lumpy. It is
heated at 80.degree. C. for 1 h (not stirrable). The mixture is
treated with 500 ml of water and stirred for a further 1 h at
80.degree. C. After cooling, the organic phase is separated off and
dried over sodium sulphate. The evaporated residue (340 g) still
contains 50% starting material (GC).
[0173] The residue (340 g, 50% pure) is therefore again treated
with 1250 ml of toluene and 500 g (4.4 mol) of trifluoroacetic
acid, then 188 g (1.3 mol) of phosphorus pentoxide are added in
portions and the mixture is heated at 80.degree. C. for 5 h. The
organic phase is decanted off, washed twice with water, dried over
sodium sulphate and evaporated.
[0174] Yield: 273 g (66% of theory), m.p.: 79-81.degree. C. (GC:
98%)
[0175] The lumpy reaction residue is treated with water, and the
organic portion is separated off, dried over sodium sulphate and
evaporated.
[0176] Yield: 56 g (14%), (GC: 87%). Example e) ##STR17##
[0177] 273 g (0.7 mol) of
6-bromo-7-trifluoromethylcarbonylamino-2,3-tetrafluoro-1,4-benzodioxane
are introduced into 2047 ml of conc. sulphuric acid and 300 g of
mixed acid are added dropwise at 0.degree. C. in the course of 15
min and the thick paste is treated at 0 to 20.degree. C. with 1000
ml of methylene chloride. The solution is then stirred at
40.degree. C. for 2 h. The cooled contents of the flask are poured
onto ice water and the precipitate is isolated. The organic phase
is separated off from the mother liquor and dried over sodium
sulphate. The evaporated residue and the isolated precipitate are
combined.
[0178] Yield: 269 g (88% of theory), m.p.: 158-159.degree. C. (GC:
100%). Example f) ##STR18##
[0179] 347 g (0.8 mol) of
6-bromo-8-nitro-7-trifluoromethylcarbonylamino-2,3-tetrafluoro-1,4-benzod-
ioxane are introduced into 1735 ml of ethanol and 183 g (3.3 mol)
of Fe filings and 183 g (3.3 mol) of Fe powder are added. 38.5 ml
of hydrochloric acid are added dropwise under reflux, the mixture
is stirred for 1 h, then 58 ml of water are added dropwise and it
is refluxed for 15 h. The cooled mixture is filtered off with
suction, and the mother liquor is rendered alkaline and evaporated.
The residue is taken up in methylene chloride, washed twice with
water, dried over sodium sulphate and evaporated. The residue (170
g) is chromatographed on 1 kg of silica gel (35-70 .mu.m) using
cyclohexane/ethyl acetate (5:1).
[0180] Yield: 125 g (40% of theory), m.p. 162-164.degree. C.
[0181] The compound of Example f) obtainable in this way can
optionally be reacted further without further purification by
alkylation to the compounds according to the invention.
* * * * *