DE1695414C3 - 4-Hydroxy-quinoline-3-carboxylic acid ester derivatives, process for their preparation and feed additives - Google Patents

Description

2. Process for the preparation of the quinoline derivatives according to claim 1, characterized in that a compound of the general formula is used in a manner known per se

RO

R ₁ O

NH-CH = C

COOR ₁

COOR ₂

in which R, Ri and R2 have the abovementioned meanings, cyclized by heating in an acidic medium or by heating to 180 to 350 ^° C. or the group A of a compound of the general formula tung hau or a compound of the general formula

OH

COOR,

HO

in which R and R2 have the abovementioned meaning, treated with a reactive ester of the general formula R ₁ Xi, in which Xi represents a halogen atom or a reactive ester radical, and Ri has the abovementioned meaning, or one or more unsaturated radicals of a compound of the general formula

OH
R ₅ O [COOR ₇

R.O

in which R ₅ , R * and R _{7 are} either one of the symbols R, Ri or R2 or represent a radical which is able to provide the corresponding radical R, R or R2 by reduction, where at least one of the symbols R5, Rb and R7 represents one of these unsaturated radicals, reduced

3. Beifuttertnittel, consisting of one of the compounds according to claim 1 and usual Auxiliary and carrier materials.

COOR ₂

40

R ₁ O

in which R, Ri and R _{2 have} the abovementioned meanings, and A denotes a halogen atom, an amino or mercapto radical or an alkoxy, alkylthio or alkanesulfonyl radical having 1 to 6 carbon atoms, converted into a hydroxyl group or a compound of the general formula

COOR ₈

N <

55

60

in which R and Ri have the abovementioned meaning and Rg is a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms, or an aralkyl or 6s aryl radical and which is different from the radical R2, with an alcohol of the general formula R ₂ OH, in the R _{2 has} the above meaning. The invention relates to 4-hydroxy-quinoline-3-carboxylic acid ester derivatives of the general formula

COOR ₂

in which R is a straight-chain alkyl radical with 8 to 10 carbon atoms, Ri is an alkyl radical with a straight or branched chain with 1 to 4 carbon atoms and R _{2 is} a straight-chain alkyl radical with 1 to 2 carbon atoms, their salts, processes for their production and supplementary feed.

Coccidiosis, a disease caused by infections caused by protozoal parasites of the genus Eimeria one of the major potential causes of economic loss in chicken farming, in particular when the animals are bred under intensive conditions. This disorder comes from the all over the world and can occur anywhere, wherever Poultry is raised. If left untreated, this condition often causes one extremely high loss of poultry. The economic loss is not just due to the Mortality of the infected birds, but also on the morbidity, which in e'ner reduction of the body

growth rate. Decrease in feed evaluation and general deterioration seen in the slaughtered animals The elimination or control of cocridiosis occurs is therefore of the utmost importance in successful chicken breeding. Others come too Species in chickens, but the following five Eimeria species, namely E. tenella, E. acervulina, E necatrix, E. bruneiti and E. maxima, generally as considered responsible for the economic loss due to coccidiosis in chicken farming. Previously, disease control was done through the use of anticoccidial drugs, which were generally administered in the feed to prevent breakout by inhibition or retardation to prevent Eimeria from multiplying in birds, or in drinking water for the treatment of diagnosed diseases were administered. Coccidiostatic Means that are used commercially. belong to different chemical types, for example

\\ 4 amino-2-n-propyl-5-pyrimidinylmethyl) -

2-picounium chloride hydrochloride,

3,5-dinitro-o-toluamide,

2-sulfanilamidoquinoxaline and

5-nitro-2-furaldehyde semicarbazone,
and it has been found that small changes in chemical structure significantly alter their usefulness and, in some cases, reduce the anticoccidial activity to such an extent that the compounds are no longer useful. However, the effectiveness of the coccidiostats that are currently widely used is usually limited in that they have a narrow spectrum of activity with respect to the Eimeria species which are controllable at practical rates of administration, and these coccidiostats do not individually provide complete protection against all five of the economically important species. The protection achieved therefore depends on the species and the severity of the infestation. neither of which can be predicted. Infections with E tenella, which is responsible for severe infection of the appendix of chickens, and with E. necatrix often lead to mortality, while infections from the other three species lead to less mortality, but nevertheless an economic loss due to a decrease in the growth rate and feed evaluation and deterioration of the slaughtered animals. E. tenella and E. necatrix have heretofore generally been considered to be the most important species, and efforts in the selection of coccidiostats have mainly been directed towards the control of these species. In recent years, however, it has been found that, although the control of E. tenella and E. necatrix remains an important problem, the incidence of diseases caused by E acervulina, E. maxima and E. brunetti increased, thereby increasing the importance of their control. The restrictions on the usefulness of coccidiostats with only a narrow spectrum of activity are therefore important. The use of mixtures containing two or more coccidiostats lead to an increase in the spectrum of activity, but they also lead to an increase in the costs of medication. Another problem which is encountered in the control of coccidiosis and which is of increasing importance is the occurrence of strains of Eimeria which are active against coccidiostats. which normally control the species in question are resistant.

In addition to controlling the disease, it is of course important that a CGCciostatic agent is good is tolerable at the dosage levels used and has no adverse effect on health of the birds it is administered to

Despite the success achieved so far in the control of coccidiosis in chickens through medication attempts have therefore been made to find useful others at an acceptably low concentration to find effective coccidiostats in the feed continued. Among the different types of organic Compounds that have been investigated in this regard are certain of the alkoxy-substituted ones 4-Hydroxyquinine-3-carboxylic acid ester (cf. American Patent 32 67 101). Extensive research and experiments have confirmed that, as in the case of other types of chemical compounds, the have been tested for their anticoccidial effectiveness, both the nature and degree of beneficial effect (if any) even with apparent small changes in chemical structure can be changed radically.

In particular, an activity against E. tenella, E. acervulina and E. necatrix for certain chinincline derivatives of the formula

Q ₁ O

shown in which Q and Qi are each a straight-chain or branched alkyl radical with 2 to 4 carbon atoms and Q _{2 is} a lower alkyl group, the best of these compounds being ethyl 6,7-diisobutoxy-4-hydroxyquinoline-3-carboxylate, which is also known as "Buchinolat". In a marked contrast to this, if there is an alkoxy group in the 6-position with 5 or 6 carbon atoms in a straight or branched chain, the anticoccidial effectiveness falls sharply. For example, the compounds for which Q is an n-pentyl, n-hexyl or 2-ethyl-n-butyl radical, Qi is a methyl radical and Q _{2 is} an ethyl radical. very poor efficacy compared to Buchinolate and of no practical value. Similarly, compounds for which Q and Q _{1 are} both methyl groups or higher alkyl groups, e.g. B. n-octyl or n-decyl, or benzyl groups, so for example the compound ethyl ^ -hydroxy-e-methoxy ^ -n-octylquinoline O-carboxylate, in which Q is a lower alkyl radical and Qi is a higher alkyl radical.

It has now been found that a narrow class of new quinoline derivatives of the above general Formula unexpectedly has a very high level of anticoccidial effectiveness and at in the prophylactic control of coccidiosis in poultry.

The new Coccidiostatica of the general formula I are at the same time with the prophylactic control a number of Eimeria, which cause both intestinal and appendix coccidiosis in chickens, are effective

I am. When administered in concentrations of 0.0001 ) is 0.05% by weight (preferably 0.001 to 0.004% by weight) η a balanced chicken feed or in the drinking water of chickens exposed to coccidiosis, They inhibit the development of fimeria and, more closely, switch mortality and morbidity to the intestinal junction Cecum coccidiosis usually cause, and therefore have a beneficial effect on the Weight gain in birds. They are non-toxic and do not have an adverse effect on the health of the ι ο Chickens at administration rates useful in preventing coccidiosis

Preferred compounds of general formula 1 are those in which R is an n-octyl, n-nonyl or n-Deeyl radical, Ri is a methyl, ethyl, n-propyl, Represents isopropyl or sec-butyl group and R2 represents Is methyl or ethyl. In particular methyl-hydroxy-T-ethoxy-ö-n-nonyloxychino! In-3-carboxyla t,

Ethyl 4 hydroxy-y-athoxy-o-n-nonyloxyquinoline-J-carboxylate,

Methyl ^ -hydroxy-y-isopropoxy-o-n-nonyloxyquinoline-3-carboxylate,

Ethyl ^ -hydroxy-y-isopropoxy-ö-n-nonyloxyquinoline-3-carboxylate, MethyM-hydroxy-Z-isopropoxy-ö-n-decyloxyquinine-3-earboxylate,

Ethyl ^ -hydroxy-J-isopropoxy-e-n-dccyloxyquinoline-3-earboxylate,

Ethyl ^ -hydroxy-y-sec.-butoxy-o-n-decyloxyquinoline-3-carboxylate,

Ethyl ^ -hydroxy-Z-methoxy-fc-n-nonyloxyquinoline-3-carboxylate,

Ethyl ^ -hydroxy-Z-methoxy-ii-n-decyloxyquinoline-3-carboxylate, Methyl 4-hydroxy-7-methoxy-6-n-octyloxyquinoline-3-carburoxylate.

Ethyl ^ -hydroxy-Z-athoxy-b-n-octyloxyquinoline-3-carboxylate,

Ethyl 1-hydroxy-b-n-octyloxy-Z-n-propoxyquinoline-3-carboxylate.

Methyl 4-hydroxy-7 methoxy-6-n-nonyloxyquinoline-3-carboxylate,

MethyM-hydroxy ^ -methoxy-ö-n-decyloxyquinoline-3-carboxylate,

Ethyl ^ -hydroxy-Z-isopropoxy-ö-n-octyloxyquinoline-3-carboxylate,

Methyl ^ -hydroxy ^ -isopropoxy-o-n-octyloxyquinoline-3-carboxylate,

Methyl ^ -hydroxy-y-ethoxy-ö-n-octyloxy- so

quinoline-3-carboxylate.

MethyM-hydroxy-y-ethoxy-e-n-decyloxyquinoline-3-carboxylate and

Ethyl ^ -hydroxy-Z-ethoxy-ö-n-decyloxyquinoline-3-carboxylate.

The compounds of the general formula I according to the invention are carried out in a manner known per se Cyclization of an anilinomethylene malonate derivative of the general formula

have obtained by heating in an acidic medium or by heating to 180 to 350 ⁰ C.

The cyclization can, for example, by treatment with an acidic reagent, e.g. B. a mixture of acetic anhydride and sulfuric acid, or by heating the compound of formula II at elevated temperature, for example at 180 to 350 ° C and especially at 200 to 280 ⁰ C, yorteilhaftweise in a suitable solvent with a high boiling point, such as a mineral oil , be performed.

The compounds of general formula II can be prepared in the following way:
(i) by reacting an aniline of the general formula

RO

R ₁ O

(IH)

NH,

in which R and Ri have the meanings given above have, with a dialkylalkoxymethylene malonate of the general formula

R ₃ O-CH =

COOR ₅

COOR ₂

(IV)

in which R _{2 has} the meaning given above and R _{3 is} an alkyl group having 1 to 6 carbon atoms, preferably a methyl or ethyl group. Suitable compounds of the general formula IV include diethyl ethoxymethyl malonate and dimethyl methoxymethylene malonate. The reaction can be carried out in the presence or absence of a suitable solvent, such as, for example, a lower alkanol, ζ. Β. Ethanol, at room temperature or with gentle heating. The reaction product of the general formula III can, if desired, be separated off by filtering or concentrating the reaction medium and, if desired, by crystallization from a suitable solvent, e.g. B. ethanol or benzene cleaned.

(ii) by treating a formamidine of general formula

RO

R ₁ O

OR

NH-CH- N

OR ₁

RO

R ₁ O

(H)

NH

COOR,

/ CH = C (II)

COOR, in which R, R ₁ and R, the meanings given above in which R and Ri have the meanings given above, with an alkyl orthoformate and an alkyl malonate, for example according to the method of L. L e ν ai and colleagues, J . org. Chem., 1966,31,4003.

The formamidines of the general formula V can iius an aniline of the general formula III by Treatment with an alkyl chloroformate, for example according to the method of CC. Price and Milarb ..). Aiiicr. Chem. Soc, 1946,68,1251.

The compounds according to the invention of the general Formula I can also be prepared in a manner known per se by adding the group A to a Quinoline compound of the general formula

A.
RO I COOR ₂

(VIi

R ₁ O

in which R, R and R _{2 have} the meanings given above and A is a halogen atom, an amino or mercapto radical or an alkoxy, alkylthio or an alkanesulfonyl radical having 1 to 6 carbon atoms is converted into a hydroxyl group. A preferably denotes a chlorine atom, and the compound of the general formula VI is preferably prepared, for example, by treating a compound of the general formula II with phosphorus oxychloride. The 4-chloro compound obtained is then hydrolyzed, for example by contacting with an acidic medium to obtain the required compound of general formula 1, for example by contacting with an acidic medium to obtain the required compound of general formula I, for example by boiling in acetic acid solution buffered with sodium acetate. The 4-chloro compound of the general formula VI, which occurs as an intermediate, can, if desired, be separated off from the reaction mixture in which it was prepared before the hydrolysis by methods known per se , or it can also be hydrolyzed without isolation after removal of the excess phosphorus oxychloride . If the symbol A in the formula VI represents a mercapto or alkylthio group, the replacement of A by a hydroxyl group is preferably carried out by treating the compound of the general formula VI with an acidic medium, for example aqueous acetic acid, in the presence of an oxidizing agent, e.g. B. hydrogen peroxide, is brought into contact.

The compounds of the general formula VI, for which A represents a halogen atom, can also by Implementation of compounds of the general formula

RO I COX

R ₁ O

(VIU

in which R and Ri have the meanings given above and X represents a halogen atom (preferably a chlorine atom), with alcohols of the formula R2OH, in which R _{2 has} the meaning given above. getting produced.

The compounds of the general formula VH can be prepared from quinoline-3-carbomic acid compounds of general formula **

RO

R ₁ O

COOH

(VIII)

m of R and Ri have the meanings given above

have, according to methods known per se, by converting hydroxycarboxylic acids into the corresponding Halogic acid halides, for example by treatment with a phosphorus halide. z. B. phosphorus oxychloride, getting produced.

The compounds of general formula VIII can be obtained in the following way:
(i) by hydrolysis of a corresponding amide or ester, of the general formula I, by heating with a base such as sodium hydroxide in aqueous-alcoholic solution, e.g. B. in aqueous ethanol, and obtaining the acid of the general formula VlH by acidifying the solution formed;

(ii) by hydrolysis of a corresponding Niirils der general formula

OH
RO I CN

R ₁ O

(IX)

in which R and Ri have the meanings given above, for example with alkali or acid according to the method of C. C. P ric e and colleagues, J. Amer. Chem. Soc, 1946, 68, 1251. The nitrile of general formula IX can be obtained by cyclizing an ix-cyano-ß-anilinoacrylate of the general formula

RO

R ₁ O

COOR ₂

NH-CH = C (X)

\
CN

in the R. Ri and R? have the meanings given above, are obtained. The cyclization is preferably carried out by heating the compound of the general formula X at elevated temperature, for example at 180 to 350 ° C. and in particular at 200 to 280 ° C., in a suitable high-boiling solvent, such as, for example, a mineral oil.
The derivatives of general formula X may be prepared by reaction of an aniline of general formula 111 with an alkyl orthoformate and an alkyl cyanoacetate. 7. B. according to the method of RH Baker and colleagues, J. Amer. Chem. Soc, 1949, 71. 3060, or by reacting an aniline of the general formula IH with an alkylaikoxymethylene cyanoacetate, e.g. B. according to the method of CCP rice and colleagues, J. Amer. Chem. Soc, 1946.68,1251.

In addition, the compounds of the general formula I according to the invention can be known per se Way by reacting compounds of the general formula Viii with alcohols of the general Formula RjOH. in the R2 the above Meaning has to be established.

The reaction is preferably carried out in the presence of a catalyst such as sulfuric acid. Hydrochloric acid or boron trifluoride carried out, wherein the last-mentioned catalyst expediently in the form of a complex with an ether, such as, for example, with that with dimethyl or diethyl ether will be used.

709 622/47

The compounds of general formula I according to the invention can also be prepared by transesterification of 3-position esters of compounds of general formula VIII, for example by transesterification of esters in which the hydrocarbon radical of the ester group is an alkyl group, preferably with 1 to 6 carbon atoms, an aralkyl group, e.g. B. a benzyl group or an aryl group, e.g. B. a phenyl group, means can be obtained by methods known per se. The 3-position ester of a compound of the general formula VIII used as the starting material is preferably another compound of the general formula I. The transesterification can be carried out by treating the 3-position ester of a compound of the general formula VIII with a suitable alcohol of the general formula R2OH, in which R2 is the above Has given meaning and has a meaning other than that of the hydrocarbon radical of the Esierhälfie of the ester starting material, in the presence of a catalyst such as sulfuric acid, hydrogen chloride or boron trifluoride. the latter compound being expediently used in the form of a complex, for example that formed with dimethyl or diethyl ether.

Furthermore, the compounds of the general formula I according to the invention can be used in a manner known per se Way by alkylation of the hydroxyl group in the 7-position of the quinoline compounds of the general formula

(XI)

in which R and R2 have the meanings given above have, with a reactive ester of the general formula R1X1, in which Xi is a halogen atom or the Acid residue of a reactive ester such as p-toluene sulfonate, and Ri denotes the above Has meaning to be produced.

The compounds of general formula XI can be obtained by hydrolysis of an acyl derivative general formula

OH

RO

COOR,

NR ₄ COO

in which R and R2 have the meanings given above and R _{4 represents} an alkyl group with 1 to 6 carbon atoms, an aralkyl group with 7 to 10 carbon atoms or an aryl group with 6 to 10 carbon atoms, for example by treatment with an alkali bicarbonate in a lower aliphatic alcohol will.

The quinolines of the general formula XII are in turn by cyclization of an aniline derivative general formula RO

have, preferably by heating at elevated temperature, for example at 180 to 350 ° C and especially at 200 to 280 ° C, in a suitable high-boiling solvent, such as a Mineral oil.

The aniline derivatives of the general formula XIII are prepared according to methods known per se by reacting an aniline of the general formula

R ₄ COO

COOR,

RO

R ₄ COO

(XlV)

NH ₂

in which R and R _{4 have} the meanings given above, obtained with a dialkyl alkoxymethylene malonate of the general formula IV.

Finally, the compounds of the general formula I according to the invention can be known per se Way by reducing compounds of the general formula

COOR ₇

(XV)

in which R ₅ , R _h and R _{7 are} either one of the symbols R, Ri or R ₂ or represent a radical which, by reduction, gives rise to the corresponding radical R, Ri and R2

capable of delivering, where at least one of the symbols Rs,

Rb and R _{7 represent} one of these unsaturated radicals,

getting produced.

The reduction can be carried out by methods known per se, for example by treatment with hydrogen in an inert solvent, e.g. B. acetic acid or ethanol, in the presence of a suitable hydrogenation catalyst, such as palladium carbon can be carried out.

The compounds of the general formula XV, for which one of the radicals R ₅ and R ₆ or both represent unsaturated hydrocarbon radicals, can be prepared using methods already described for the compounds of the general formula I, for example from an aniline methylene malonate of the general formula

COOR,

NH-CH = C

(XHlI

COOR ₂ in R. R2 and R « the meanings given above (KVl)

in the R ₂ . R ₅ and R _{6 have} the meanings given above, where one of the radicals R ₅ and R ₆ or both represent an unsaturated hydrocarbon group, are produced. Compounds of the general formula XV are for their part described by applying the already ffl analogous compounds of the general formula I using a method

Aniline of the general formula
R ₅ O

R.O

(XVII)

NH,

in the Rs and Re the definitions given above own, obtained as a starting material. "O

Compounds of the general formula XV, for which R7 represents an unsaturated hydrocarbon oil can by applying the above for the compounds of the general formula I described methods, in particular by esterification of acids of i.s general formula

OH
R ₅ O [ COOH

YY) (XVIlI)

in which R5 and Rb have the meanings given above have to be produced.

The compounds of the general formula XVMI are made by applying the information already provided for the compounds of the general formula VIII described methods obtained.

The salts of the compounds of the general formula I with bases, for example the alkali metal salts, can by methods known per se, for example by treating a compound of the general formula I in solution or suspension in a suitable solvent, e.g. dimethylformamide, with a equivalent or excess amount of a base, e.g. B. an alkali hydroxide or hydride, e.g. B. sodium or Potassium hydroxide or sodium hydride, and obtaining the salt by filtering or evaporating it Solvent are produced.

The following examples illustrate the preparation of the compounds according to the invention.

example 1

45

13.0 g of 1- (2-methoxy-4-nitrophenoxy) -n-octane in 65 ml of ethyl acetate were catalytically reduced with hydrogen in the presence of 13 g of 5% palladium carbon at atmospheric pressure and room temperature l- {4-Amino-2-methoxyphenoxy) -n-octane was filtered and treated with 10.5 g of diethyl ethoxymethylene malonate and the mixture was evaporated to dryness on a steam bath in vacuo. n-octyloxyanilinomethylenmalonat crystallized (mp = 48-50 ⁰ C) and was dissolved in 130 ml of mineral oil Kp. 250 ⁰ C, the solution was heated in a Woods metal bath at 260-270 ⁰ C for 1 hour The cooled 1-dissolution was with light petroleum (rich Siedebe: 60-80 ⁰ C) the crude product was diluted abfihriert and dried recrystallization by dissolving in 50 ml of boiling acetic acid. Filtering in the warm and precipitating the product by adding 100 ml of boiling methanol for 6s, 4.95 g of ethyl 4-hydroxy ^ -methoxy-ö-n-octyloxvquinoline ^ -carboxylate (d) with a melting point of 25 ° -258 ° C. were obtained.

The 1 - (2-methoxy-4-nitrophenoxy) -n-octane used as the starting material in the above preparation was following the method of R. F. Collins and M.Davis,). Chem. Soc, 1961, 1863, as follows manufactured:

103.6 g of potassium p-nitroguayakolate were added in 515 ml Dimethylformamide treated with 95 ml of n-octyl bromide, heated with stirring on a steam bath for 1 hour and poured into water and the product was filtered off. Crystallization from 500 ml of methanol gave 116 g l- (2-Methoxy-4-nitrophenoxv) -n-oclane vom

F. = 3b, obtained 5-38 "C.

According to a procedure similar to the one above, the production of ethyl ^ -hydroxy-Z-methoxy-6-n-octyloxyquinoline-3-carboxylate described, but with replacement of 1- (4-amino-2-meihoxyphenoxy) -n-octane through the appropriate

Aminophenoxyalkane derivative, which was obtained by reducing the corresponding nitrophenoxyalkane, which in turn according to the method of RF C o 11 i η s and M. Davis. ). Chem. Soc. 1961. In 1863 from the corresponding potassium 2alkoxy-4-nitrophenolate and the appropriate alkyl halide, the following compounds were prepared: (e) Ethyl ^ -ethoxy ^ -hydroxy-ö-n-octyloxyquinoline-3-carboxylate from F. = 250-251 ⁰ C [from 1- (2-ethoxy-4-nitrophenoxy) -n-octane, mp = 49-50 ⁰ C]; (j) Ethyl ^ -hydroxy ^ -methoxy-6-n-nonyloxyquinoline-3-carboxylate of m.p. = 258-260 ° C [from 1- (2-methoxy-4-nitrophenoxy) -n-nonane from F. = 47.5-49 "C];

(p) Ethyl ^ -hydroxy ^ -methoxy-δ-n-decyloxyquinoline-3-carboxylate of m. = 250-252 ° C [from 1- {2-methoxy-4-nitrophenoxy) -n-decane of m. = 49- 50 ⁰ C];

Ethyl 4-hydroxy - / - isobutoxy-6-n-octyloxyquinoline-3-carboxylate of m. = 257-259 "C [from i- (2-isobutoxy-4-nitrophenoxy) -n-octane of m. = 52 - 53 ° C, which in turn was made from 2-! Sobutoxy-4-nitrophenol, an oil that was prepared from 3,4-diisobutoxynitrobenzene by the method of RF Collins and M.Davis, J. Chem. Soc, 1961, 1863, was prepared, was obtained]; (r) EthyM-hydroxy ^ -ethoxy-ö-n-decyloxyquinoline-3-carboxylate of m.p. = 244-246 ° C [from 1- (2-ethoxy-4-nitrophenoxy) -n -decane from the temperature = 57.5-59 ° C] and
(u) Ethyl ^ -hydroxy ^ -isopropoxy-6-n-decyloxyquinoline-3-carboxylate of m.p. 45.5 to 47.5 ⁰ C].

Example 2

According to the procedure described in Example 1 10.2 g of l- (2-ethoxy-4-nitrophenoxy) -n-decane were re reduced and the 1- (4 ~ amino-2-ethoxypher oxy) -n-decane was obtained by treatment with 6.8 diethylethoxymethylene malonate in diethyl-4-n-decy oxy-3-ethoxyaniiinomethylemnalonat voi

Mp = 38-40 ⁰ C and transferred boiling mineral m "Kp. 250 ⁰ C to give crude ethyl-4-hydrc xy ^ -ätnoxy-ö-n-decyloxychinolin-S-carboxylate (71 \ cyclized One of acetic acid and Methanol as described in Example 1 recrystallized P ^ be schmo at 244 to 246 ^o C

That as the starting point in the above production 1- (2-ethoxy-4-nitrophenoxy) -n-decane was used obtained as follows:

17.2 g of the monosodium salt of 4-nitrobrincatechol were dissolved in 180 ml of dimethylformamide, and 22.1 g of n-dccyl bromide were added. The mixture was heated with stirring on a steam bath for 1 hour and poured into 1 liter of water. The precipitated solid matter was filtered off and dissolved in a minimal amount of boiling methanol. The solution was treated with 7.0 ml of 50% sodium hydroxide solution and diluted with 500 ml of water. The mixture was clarified with activated charcoal and filtered. The filtrate was acidified with 15 ml concentrated hydrochloric acid and the separated oil was extracted with diethyl ether, κ The extracts were washed with water, dried over anhydrous sodium sulfate and evaporated, and the residue was crystallized from petroleum ether: recrystallized (boiling range 40 -60 ⁰ C) . 13.11 g of 1- (2-hydroxy-4-nitrophenoxy) -n-decane with a melting point of 46-49'C were obtained in this way.

10.8 g of 1- (2-hydroxy-4-nitrophenoxy) -n-decane were dissolved in 50 ml of dimethylformamide, and the solution was treated with sodium hydride (1.95 g, 50% suspension in oil). The mixture was on a steam bath 5 minutes crhit / t and then with 8.0 g of ethyl p-toluenesulfonate, dissolved in 50 ml of dimethylformamide. After heating for one hour, the mixture became in 500 ml of ice-cold water poured and made alkaline with sodium hydroxide solution, and the solid product was filtered off. Crystallization from methanol gave 10.7 g of 1- (2-ethoxy-4nitrophenoxy) -n-decane of m.p. = 50-55 ° C. F.ine recrystallized from methanol Sample melted at 53 to 55 ° C.

In a corresponding manner, the following is Connections made:

(f) Ethyl-4-hydroxy-ö-n-oetyloxy ^ -n-propoxyquinoline-3-carboxyiate with a temperature of 252-254 ° C! (2 propoxy-4-nitrophenoxy) -n-octane, mp = 52 - 53 ⁰ C, which in turn was prepared from 1- (2-hydroxy-4-nitrophenoxy) -n-octane, mp = 46-49 ° C and n-propyl bromide was produced. 1- (2-Hydroxy-4-nitrophenoxy) -n-octane was prepared from 4-nitrocatechol, monosodium salt and n-propyl bromide by the method described above,
(h) ethyl ^ -hydroxy ^ -isopropoxy-ö-n-octyloxy-

Quinoline-3-carboxyIate with a temperature of 215-217 ° C from 1- (2-isopropoxy-4-nitrophenoxy) -n-octane with a temperature of 43-44 ° C, which in turn consists of 1- (2-hydroxy- 4- _S o nitrophenoxy) -n-octane and isopropyl bromide was produced,
(n) ethyl-4-hydroxy-7-isopropoxy-6-n-πonyIoxy-

quinoline-3-carboxylate with a melting point of 203-2O5 ° C l- (2-Isopropoxy-4-nitrophenoxy) -n-nonane from ss F. = 43-45 ° C, which in turn consists of 1- (2-hydroxy-4-nitrophenoxy) -n- "onane with a temperature of 42-45 ° C and isopropyl bromide. 1- (2-Hydroxy-4-nitrophenoxy) -n-nonane was made from 4-nitrocatechol according to the procedure described above. Monosodium salt and n-nonyl bromide manufactured.

(1) EthyM-hydroxy ^ -ethoxy-ö-n-nonyloxyquinoline-S-carboxylate from F. = 243-245 ⁰ C from 1- (2-ethoxy-4-nitrophynoxy) -n-nonane from F. = 40 -42 "C, fis which in turn was obtained from 1- (2-hydroxy-4-trophenoxy) -n-nonane from Γ. = 42-45 C and ethyl-p-tohioKulfon.it. O; is l- (2 -Hydroxy-4-nilrophcnoxy) -n-nonane was prepared according to the procedure described under (n) above.
Ethyl-4-hydroxy-7-n-buU) xy-6-n-dceyloxyquinoline-3-earboxyla · 'of mp = 239-242 ° C from 1- (2-n-biitoxy-4-niirophenoxy) -n -dccan vom F. = 35 - 37 'C. That in turn from 1- (2-Hydroxy-4-niiropheno \ y) -n-dccan vom I'. = 46 - 48 ° C and n-butyl iodide was obtained. The

1 - (2-Hydroxy-4-nitrophynoxy) -n-dccan was prepared according to the procedure described above.

(v) ethyl-4-hydro \ y-7-sec.-butoxy-6-n-decyloxy-

Quinoline-3-carboxylate of F. = 177-179 'C from 1 (2-sec-lkitoxy-4-nitrophcno \ y) -n-decane of F. = 33-36 ¹ C, which in turn consists of 1- (2- Hydroxy-4-iiilrophcnoxy) -n-dccan and sec-butylbroniid was prepared. The 1- (2-hydroxy-4-nitrophenoxy) -n-decane was prepared as described above.

(s) Ethyl ^ -hydroxy ^ -n-propoxy-ö -n-decyloxyquinoline-3-carboxylate vom F. = 244-245 "Caus 1- (4-nitro-2-n-propoxyphynoxy) -n-dccan vom F. = 59 - 61 C. which in turn consists of l- (2-hydroxy-4-nitrophenoxy) -n-decane and n-propyl bromide was produced. 1- (2-Hydroxy-4-nitrophenoxy) n-decane was obtained as described above.

Example 3

154 g of 1- (2-methox \ 4 nitrophenoxy) -n dccan (prepared as described in Example 1) were converted into 1- (4-amino) with hydrogen in 1 l of ethyl acetate in the presence of 5% palladium-carbon as a catalyst at atmospheric pressure and room temperature -2-methoxyphenoxy) -n-decane reduced. The solution was filtered, washed with 108 g of diethyl-äthoxymcthylcnmalonat treated and evaporated under reduced pressure to give diethyl-4-n-decyloxy-3-methoxyanilinomethylenmalonat mp = 68 ⁰ C were obtained. This solid was dissolved in 200 ml of phosphorus oxychloride and heated on a steam bath for 3 hours. The excess phosphorus oxychloride was evaporated in vacuo and the residue was dissolved in 2 l of glacial acetic acid. The solution was treated with 200 g of anhydrous sodium acetate, heated under reflux for 6 hours with stirring and poured into 12 liters of ice-cold water. The precipitated solid was filtered, washed with water and ethanol and dried at about 90 ⁰ C. 160 g of EthyM-hyttroxy ^ -methoxy-δ-n-decyloxyquinoline-3-carboxylate with a temperature of 240-250 ° C., which was identical to the product described in Example 1, were obtained. A sample recrystallized from acetic acid and methanol as described in Example 1 melted at 252-256 ° C.

The following connection was established in the appropriate!] Way:
(u) EthyM-hydroxy ^ -isopropoxy-ö-n-decyloxy-

cbinolin-3-carboxylate, mp = 194- 196 ° C au · 1 (2-isopropoxy-4-nitrophenoxy) -n-decane of F. = ⁰ 45,5-47.5 C which in turn according to the Example 1 ii (u ) described method from 1 - {2-Hy droxy-4-nitrophenoxy) -n-decane and isopropyl bromide was prepared.

Example 4

50 g of ethyl ^ -hydroxy ^ -ethoxy-en-decyloxyquinoline 3-carboxylate [prepared as described in Example 1 (r)] were contained in 500 ml of ethanol and 500 ml of water, d: 50 g of sodium hydroxide. Heated under reflux for 1 hour. The solution obtained was ^{diluted with water to just about x} riibunsr and heated through

filtered through a filter aid. By acidifying the filtrate with concentrated hydrochloric acid gave 48 g of 6-n-decyloxy ^ -ethoxy - ^ - hydroxyquinoline-S-carboxylic acid of m.p. = 260-262 ° C. The melting point rose by recrystallization from dimethylformamide 263-264 ° C. 65 g of this acid were dissolved in 1.4 l of methanol suspended and with 65 ml of boron trifluoride diethyl ether complex and the mixture was refluxed with stirring for 1.5 hours. The solution was added to ice-cold water and the obtained solid was filtered off, with water washed and recrystallized by being dissolved in boiling acetic acid, filtered while hot and the product was precipitated by adding boiling methanol. This gave 51 g of methyl 4-hydroxy-7-ethoxy-6-n-decyloxyquinoline-3-carboxylate from the

M.p. = 247-249 ° C.

The following compounds were prepared in a corresponding manner, starting from the corresponding ethyl esters (prepared as described in Examples 1 and 2):
(d) methyl ^ -hydroxy ^ -athoxy-on-octyloxy-

quinoline-3-carboxylate with a temperature of 251-253 ° C:
(g) MethyM-hydroxy ^ -isopropoxy-ö-n-octyloxy-

quin «lin-3-carboxylate of m.p. = 239-241 ° C;

(i) Methyl-4-hydroxy-7-methoxy-6-n-nonyloxychinoiin-3-carboxylate, mp = 245-246 ⁰ C;
(k) MethyM-hydroxy ^ -ethoxy-ö-n-nonyloxy-

quinoline-3-carboxylate of m.p. = 247-249 ° C;
(m) methyl ^ -hydroxy ^ -isopropoxy-δ-n-nonyloxyquinoline-3-carboxylate, mp = 222-225 ° C;
(o) methyl ^ -hydroxy ^ -methoxy-en-decyloxyquinoline-2-carboxylate of m.p. = 237-239 ° C;
Methyl 4-hydroxy-7-methoxy-6-n-octyloxyquinoline-3-carboxylate, mp = 247-249 ° C;

(t) methyl 4-hydroxy-7-isopropoxy-6-n-decyloxyquinoline-3-carboxylate from the F. = 225-227 ° C.

Example 5

5.0 g of diethyl ^ -n-decyloxy-S-methoxyanilinomethylene malonate (prepared as described in Example 2) and 4.4 ml of phosphorus oxychloride were together 3 Heated on a steam bath for hours.

The excess phosphorus oxychloride was evaporated under reduced pressure, the residue in 20 ml Dissolved methanol and poured the solution into 100 ml of ice-cold water. The mixture was made with sodium hydroxide solution neutralized, and the precipitate was filtered off, washed with water, dried and off Recrystallized mineral spirits (boiling range: 60-80 ° C). This gives AthyM-chloro-o-n-decyloxy ^ -athoxyquinoline-3-carboxylate from the F. = 82.5 -83.5 ° C.

3.0 g of this ester were heated for 1 hour under reflux in 30 ml glacial acetic acid with a content of 6.0 g Wasserf ^r eiem sodium acetate, and the mixture was poured into 100 ml of water. The product was filtered off and recrystallized from acetic acid and methanol as described in Example 1. This gave ethyl 4-hydroxy-7-ethoxy-6-n-decyloxyquinoline-3-carboxylate with a temperature of 241-244 ° C., which was identical to the product described in Example 1.

In a similar manner, ethyl 4-hydroxy-7-methoxy-b-n-octyloxyquinoline-3-carboxylate was obtained from the

F. = 258-260 ° C.

Bc i s ρ i c 1 6

A solution of 8.3 mg of ethyl 4-hydroxy-7-ethoxyh-n-decvloxvquinoline-3-earboxylate (prepared as described in Example 1) in 300 ml of methanol and 10 ml concentrated sulfuric acid was refluxed for 12 hours, then concentrated in vacuo and in Poured ice water. The precipitate was filtered off, washed with water, dried and extracted from dimethylformamide recrystallized, methyl 4-hydroxy-7-ethoxy-6-n-decyloxyquinoline-3-carboxylate from the

M.p. = 245-248 ° C. The melting point was not reduced by a sample prepared according to Example 4.

Example 7

1.0 g AthyM-mercapto ^ -athoxy-o-n-decyloxyquinoline-3-carboxylate, dissolved in 10 ml of acetic acid, were mixed with a solution of 1.2 ml of 3O% hydrogen peroxide treated in 10 ml acetic acid. The solution was heated on a steam bath for 2 hours, with an additional 1.2 ml Treated hydrogen peroxide and heated for a further 2 hours. The solution was then diluted with water and the product extracted with chloroform. By evaporating the washed and dried extracts a solid was obtained which was triturated with ethanol and recrystallized twice from acetic acid would. EthyM-hydroxy ^ -ethoxy-ö-ndecyloxyquinoline-3-carboxylate was obtained in this way from the F. = 235-238 ° C. The melting point was determined by a method according to Example 1 produced authentic sample not degraded. The product exhibited on thin layer chromatography identical properties.

The mercapto compound used as a starting material was obtained as follows:

A solution of 1.01 g of sodium in 180 ml of dry ethanol was saturated with hydrogen sulfide. 17.5 g of EthyM-chloro-e-decyloxy ^ -ethoxyquinoline-S-carboxylate (F. = 82.5-83.5 ⁰ C), prepared as described in Example 5, were added to the solution, which was refluxed for 1 hour, poured into water and acidified with hydrochloric acid. The product was extracted with chloroform. The washed and dried extract was evaporated and the

Ethyl-4-mercapto-7-ethoxy-6-n-decyloxyquinoline-3
carboxylate crystallized from ethanol as an orange solid (10.0 g) with a temperature of 203-206 ° C. A sample recrystallized from methanol had a melting point of 200 ° C., and resolidification had a melting point of 24 ° C.

Example 8

A solution of 2 g of ethyl ^ -methylmercapto ^ -ethoxy-ö-n-decyloxyquinoline-S-carboxylate in 20 ml of acetic acid was treated with 1.04 ml of 30% hydrogen peroxide and heated on a steam bath for 16 hours. The solution was cooled and the solid substance was filtered off and recrystallized from acetic acid. The Product had a melting point of 235-238 ° C, the authentic one produced according to Example 1 Sample of ethyl ^ -hydroxy ^ -ethoxy-b-n-decyloxyquinoline-3-carboxylate was not reduced. The product was found to be this substance according to thin layer chromatography identical.

The starting substance used the 4-methylcapto compound was made as follows:

2.0 g of ethyl-4-mercapto-7-ethoxy-6-n-dccyloxyquinoline-3-carboxylal prepared according to Example 8 were dissolved in 10 ml of dimethylformamide with 0.12 g of a 50% strength Suspension of nairium hydride in mineral oil and, after stopping the exposure to water, with 0.37 ml Mclhyliodide treated. The l.ösunsi winds on one

AO

Steam bath heated for 1 hour and poured into water. The solid product was recrystallized from methanol. Was obtained as 1.4 g ÄthyM-methylmercapto-Z-ethoxy-6-n-decyloxychinolin-3-carboxylate in the form of a cream-colored solid, mp = 82-83 ⁰ C.

Example 9

14 g of bis-p-ethoxy ^ -n-decyloxyphenylJ-formamidine, 10 g of diethyl malonate, 2 g Äthylorthoformiat and 0.25 g of ammonium chloride were HEATER together under nitrogen at 125- 130 ⁰ C (bath temperature) for 2 hours! Another portion of ethyl orthoformate (2 g) was added and the mixture was heated for 1 hour. The ethanol present was then allowed to distill off from the mixture while the mixture was heated for an additional 6 hours. The mixture was cooled and diluted with 100 ml of benzene. 10 ml of 30% hydrochloric acid were added, and the benzene layer was washed three times with 10 ml of water each time, dried and evaporated. The remaining oil was refluxed in 50 ml of mineral oil for 30 minutes, and the solution was poured into 500 ml of light gasoline (boiling range: 100-120 ° C.). The gelatinous solid was centrifuged off and mixed with about 30 ml of glacial acetic acid. Centrifugation of this mixture gave an oily solid which was crystallized from glacial acetic acid. This gave ethyl ^ -hydroxy-y-ethoxy-on-decyloxyquinoline-3-carboxylate with a temperature of 244 - 245.5 ° C, which with an according to Example! 1 produced sample was identical.

The bis (3-ethoxy-4-p-decyloxyphenyl) formamidine was obtained as follows:

1- (4-Amino-2-ethoxyphenoxy) -n-decane, prepared as described in Example 2 from 1- (2-ethoxy-4-nitrophenoxy) -n-decane (64.6 g). was _{heated under reflux for 2} hours with 15 ml of ethyl orthoformate (bath temperature: 145 ° C.). The ethanol formed during the reaction was distilled off and the product was extracted with an equal volume of mineral spirits diluted and cooled (boiling range 80-100 ⁰ C). 48 g of a solid substance with a temperature of 61.5-63.5 ° C. were obtained. Recrystallization gave 42.5 g of bis (3-ethoxy-4-n-decyloxyphenyl) foi-mamidine with a melting point of 62.5-64.5 ° C.

Example 10

45

0.5 g of S-cyano-ö-n-decyloxy ^ -ethoxy ^ -hydroxychinoün were dissolved in 15 ml of hot ethylene glycol ether mixture, and 0.75 g of potassium hydroxide and 5 ml of water were added. The mixture was refluxed for 4 hours. After cooling, the mixture was diluted with water and acidified with 2N hydrochloric acid. The solid was collected and recrystallized from ethanol, unchanged starting material having a melting point of 315-318 ° C. After standing overnight, a pale cream-colored solid, mp give 6-n-decyloxy-7-ethoxy-4-hydroxyquinoline-3- different from the Äthanolmutterlaugen = 240-255 ⁰ C (dec.), Which was recrystallized from ethanol, Carbic acid with a melting point of 259-264 ° C. (decomp.), which was converted into its ethyl ester by the method of Example 4.

The S-cyano-ö-n-decyloxy ^ -ethoxy ^ -hydroxyquinoline is manufactured as follows:

25 g of 4-n-dccyloxy-3-ethoxynitrobenzene were catalytically reduced in 175 ml of methanol and the solution was evaporated at atmospheric pressure under nitrogen. 11.5 g of ethyl orthoformate and 17.5 g of ethyl cyanoacctate were added to the residue, and the mixture was heated with stirring at Ife5 C until almost the theoretical amount of ethanol had distilled off (2 hours). The residue was cooled and recrystallized once from methanol and twice from cyclohexane. wherein ethyl-a-cyano -? (4-n-deeyloxy-3-äthoxyanilino) acrylate was obtained, mp = 105-107 ⁰ C - /. Fifteen grams of this ester was added to 75 ml of mildly refluxed mineral oil and refluxed with stirring for 4 hours using a short air condenser to allow the ethanol formed in the reaction to escape. The mixture was allowed to cool and diluted with petroleum ether (boiling range: 40-60 "C). The brown solid substance was collected and recrystallized from dimethylformamide. This gave 3-cyano-6-n-decyloxy-7-ethoxy-4- hydroxyquinoline of m.p. = 325-327 ° C.

Example 11

377 mg of ethyl-one-decyloxy-y-dihydroxyquinoline-3-carboxylate and sodium hydride (58 mg, 50% w / w in oil) were heated together in 5 ml of dimethylformamide. 200 mg of ethyl p-toluenesulfonate were added and the mixture was refluxed for 1 hour and poured into water. The precipitate was filtered off, washed with water, dried and crystallized from ethanol, a colorless solid substance with a temperature of 232-239 ° C. being obtained. Recrystallization from methanol gave ethyl 4 hydroxy ^ -ethoxy-ö-n-decyloxyquinoline-S-carboxylate from. F. = 236-24O ⁰ C. The melting point was not reduced by a sample produced according to Example 1.

The 4,7-dihydroxyquinoline derivative used as a starting material was made as follows:

1- (2-Hydroxy-4-nitn> phenoxy) -n-decane prepared according to Example 2 was acetylated with acetic anhydride and pyridine. The product, 6.87 g of 3-acetoxy-4-ndecyloxynitrobenzol was hydrogenated in 50 ml of ethyl acetate over 0.85 g of 5 ° / cent palladium on carbon at 40 ⁰ C and normal pressure. When the reduction was complete, the catalyst was removed and the filtrate was taken to dryness in vacuo to give 6.25 g of the amine. This was treated with 4.9 g of diethyl ethoxymethylene malonate, and the mixture was heated on a steam bath for 10 minutes before it was slowly poured into 120 ml of boiling mineral oil, boiling point 250 ° C. After the addition had ended, the mixture was allowed to boil for 20 minutes. The product was then filtered off, washed with light gasoline and crystallized from dimethylformamide, ethyl 7-acetoxy-6-n-decyloxy-4-hydroxyquinoline-3-carboxylate having a melting point of 240-242 ° C 0.45 g of this product and 0.11 g of potassium bicarbonate were refluxed in 100 ml of methanol and 10 ml of water for 30 minutes, the solvent was removed in vacuo, water was added and the precipitated product was filtered off, washed with water and crystallized from methanol, giving ethyl 6-n-decyloxy-4,7-dihydroxyquinoline-3-carboxy! at melting point = 214-216 ° C.

Example 12

0.86 g of ethyl ^ -hydroxW-allyloxy-en-decyloxychinolin-3-carboxylate were hydrogenated in 100 ml of glacial acetic acid over 0.3 g of 5% palladium-carbon IGCR at 60 to 65 ⁰ C and normal pressure. After one mole of hydrogen had been taken up, the catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. the

Residue was triturated with ethanol, whereby ethyl ^ -hydroxy ^ -n-propoxy-en-decyloxychinolin-S- _car boxylat was obtained, mp = 240-242 ° C. The melting point was not lowered by a sample prepared according to Example 2.

The 7-allyioxyquinoline derivative used as the starting material was by the method of Example 3 from i- (2-AHyloxy-4-nitrophenoxy) -n-decane with a melting point of 36-38 ° C obtained, which in turn by the method of Example 2 from 1- (2-hydroxy-4-nitrophenoxy) -n-decane and allyl bromide was produced.

Example 13

10.0 g prepared according to Example 1 Ethyl-4-hydroxy ^ -ätnoxy-ö-n-decyloxychinolin-S-carboxylate wur- _{l $} to, suspended in 100 ml of dimethylformamide, treated with sodium hydride (50% suspension in mineral oil, 1, 26 g) and stirred while gently warming on a steam bath for 10 minutes, a solution of the sodium salt of ethyl 4-hydroxy-7-ethoxy-6-n-decyloxyquinoline ^ -carboxylate was obtained.

Example 14

A mixture of 4.17 g of ethyl ^ -hydroxy ^ -gihoxyö-n-decyloxyehinoline-S-carboxylate (prepared as in Example 1). 0.56 g of potassium hydroxide and 200 ml of ethanol was heated on a steam bath until a clear solution was obtained. The solution was then on Cooled to room temperature and clarified with filter aid to give a clear solution that contained the Potassium salt of ethyl 4-hydroxy-7-ethoxy-6-n-decyloxyehinoline-3-carboxylate contained

According to a further feature of the invention, supplementary feed is made available that for administration to chickens for the prevention of coccidiosis, including concentrates for Addition to chicken feed or drinking water which, as a cocciostatic agent, consists of at least one quinoline derivative of the general formula 1 or a non-toxic salt thereof together with a physiological harmless carrier exist. Under the expression "physiologically harmless carrier", as he is here is used is to be understood as meaning a carrier which is not harmful to the chickens. The carrier can be solid or be semi-solid or a liquid. Such compositions are expediently through intimate Distributing the active ingredient in the carrier, if necessary, when the carrier is a liquid in the the active ingredient is only sparingly soluble, for example water, using an emulsifying, dispersing agent. Suspending or wetting agent produced

Preferred means are solid or semi-solid means in which the carrier is at least partially through a Chicken feed is supplied, for example an organic or inorganic substance that is used for Feeding to the chickens is intended. That is, the active ingredient in a solid or semi-solid Lining can be incorporated. The introduction of the active substance into the lining, which is a commercially available Starter, breeding, laying or brood means can be, by any conventional method, such as by stirring, tumbling or grinding. It can mean different concentrations by changing the ratio of carrier to active substance produced fts will. The active substance can also be incorporated into the feed in the form of a powder concentrate, Hn <; Hip active ingredient and a solid, physiological

harmless carriers, such as shredded wheat, Talc, kaolin or chalk or a diatomaceous earth such as kieselguhr or a mixture thereof, contains, such agents also belonging to the scope of the invention. These compositions can also means to promote the adhesion of the active substance to the carrier, such as soybean oil, contain. To the active substance or the powders containing it, before mixing with one or more physiologically harmless wetting and / or dispersing agents are added to the feed such as the condensation product of / f-naphthalenesulfonic acid and formaldehyde, sodium lauryl sulfate or polyoxyethylene (20) sorbitan monooleate. If a network, suspending, emulsifying or Dispersant is added to the active substance or the powder, the composition thus obtained can can also be mixed with water to form stable dispersions that can be added to feed materials suitable to receive.

Liquid compositions can be dispersions of the active substance in drinking water, and these Compositions can be made from concentrates that can be added to water or be self-emulsifying with water. Such concentrates contain the active ingredient together with a wetting, suspending, dispersing or emulsifying agent in the presence or absence of a physiological harmless carrier or together with a water-soluble physiologically harmless carrier. she also belong to the scope of the invention. Examples of such concentrates are:

(1) Mixtures of the active substance? with a wetting or dispersing agent;

(2) Powder containing the active ingredient, a physiologically harmless carrier and a wetting, suspending or Contain dispersants;

(3) stable dispersions obtained by mixing concentrates of the type (1) or (2) with water are preserved, and

(4) Mixtures of the active substance with a water-soluble, physiologically harmless carrier, such as for example sucrose or glucose.

It is also possible to give the compounds according to the invention orally to chickens in the form of granules, To administer grains, suspensions, solutions and emulsions that contain the active quinoline ingredient together with suitable physiologically harmless carriers and adjuvants. Such However, administration is less convenient and such means are therefore not preferred.

The agents according to the invention can contain from about 0.0001 to about 90% by weight of one or more of the compounds of the formula I. Concentrates for addition to chicken feed generally contain from about 1 to about 90 weight ⁰ / »at one or more of the compounds of general formula 1, and preferably about 4 to 50 wt .-%, absorbed, or mixed with a carrier. As already mentioned, the feed generally contains 0.0001 to 0.05% active substance.

The amount of active needed for effective prophylactic control of coccidiosis in chickens Quinoline compound is very low. Good results have been obtained in the prevention of E. tenella and E. acervulina caused disease by administration of an amount of quinoline equivalent to the general Formula I in the feed from about 0.0002 to 0.05% by weight

of the consumed feed achieves optimal results are prepared by administering an amount of the active ingredient. about 0.001 to about 0.025 weight percent and In particular 0.001 to 0.004% by weight of the feed consumed, in particular with the special ones mentioned above Connections of particular value. Besides that have found methyl 4-hydroxy-7-isopro |> oxy-i> -n-ociyloxyquinoline-3-carboxylate and ethyl 4-hydroxy-7-isopropoxy-6-n-octyloxyquinoline-3-carboxylate as prophylactically effective against E. tenella and E acervulina when administered in an amount of 0.001% by weight of the food consumed while, as was found,

MethyM-hydroxy ^ -ethoxy-ö-n-oetyloxyquinoline-3-carboxylate, ' ⁵

MethyM-hydroxy-y-ethoxy-en-decyloxyquinoline-3-carboxylate and
Ethyl ^ -hydroxy ^ -ethoxy-ö-n-decyloxyquinoline-3-carboxylate

provide an effective prophylactic control of these organisms when administered in an amount of 0.0002 to 0.0005% (w / w) in the feed. In addition, the quinoline derivatives of the general formula I and in particular the preferred compounds in the prevention of by other Eimeria species ² S infections caused, including the important species E. necatrix, E. maxima and E. brunetii, when administered in similar concentrations in the feed extremely effective. For example, it has been found that ethyl 4-hydroxy-7-ethoxy-6-π-decyl-3-oxyquinoline-S-carboxylate can be used prophylactically in the prevention of diseases caused by E. necatrix when administered in an amount of 0.002 to 0.004% (Weight / weight) in the feed and is effective in preventing diseases caused by E. maxima and L. brunetti when administered in an amount of 0.001% (weight / weight) in the feed

It should be noted that when using concentrates in the form of grains or granules as a means for Administration of the quinoline derivatives to the proportion present in the grains and granules themselves Quinoline compound considerably higher than the above-mentioned proportions suitable in feed materials for the effective prophylactic control of coccidiosis and that the concentrates are so> in a chicken feed can be distributed that on average in the whole feed an amount of 0.0001 to 0.05 wt .-% of quinoline compound is present.

Advantageously, the average particle size is that introduced into the chicken feed Quinoline compound of the general formula I about 1 to about 50 μ and preferably less than 30 μ.

The following examples explain the agents according to the invention. The percentages are based on that Based on weight.

Example 15

EthyM hydroxy? Ethoxyl 6-n-decyloxyquinoline-3-carboxylate (18 parts by weight) were added to Wcizcnsch-ot f «(82 parts by weight) and mixed thoroughly. The mixture was introduced into a feed suitable for chickens in such an amount that a final concentration of 0.002 to 0.004 (each% quinoline derivative was present. The treated fuller was for weathering on chickens to prevent V .. tenella , EI. Acervulina, Ii. Necatrix, F .. brunetti and Eg. Maxima caused C oeeidinsen suitable.

* 11
Example 16

Ethyl ^ -hydroxy-y-ethoxy-ö-n-octyloxyquinoline-3-carboxylate (5 parts by weight) were added to Kalksteii, powder (20 parts by weight). The mixture became ground and introduced into a feed suitable for chickens in such an amount that the final concentration of quinoline derivative was 0.002 to 0.004% by weight. The treated feed was on for feeding Chickens suitable to prevent coccidiosis caused by infections with E. tenella and E. acervulina.

Example 17

Soybean oil (3 parts by weight) was sprayed onto crushed wheat (88 parts by weight), which was being stirred, to obtain a

to achieve uniform distribution. Ethyl 4-hydroxyf-ethoxy-en-decyloxyquinoline-S-carboxylate ( _{9 wt}

Parts) were added and mixed intimately. The concentrate thus obtained was for incorporation into a Höhnerfuiter in such an amount that the The final concentration was 0.002 to 0.004% by weight of the quinoline derivative, suitable. The treated feed was for filling on chickens to prevent E. tenella, E. acervulina, E. necatrix, E. brunetti and E. maxima caused coccidiosis suitable.

Example 18

A 5 g of ethyl ^ -hydroxy ^ -ethoxy-b-n-decyloxyquinoline-3-carboxylate, 92 A composition containing g sucrose and 3 g sodium lauryl sulfate was prepared by Grinding of the constituents produced. The resulting mixture then became drinking water in a quantity of 0.8 g / l was added, whereby a concentration of 0.004% active substance in water was obtained.

Example 19

1 g of ethyl ^ -hydroxy ^ -ethoxy-o-n-decyloxyquinoline-3-carboxylate was triturated with 5 ml of distilled water. 1.25% (3 ml) tragacanth mucus was added was added and the mixture was made up to 10 ml with distilled water. The final suspension was for oral administration to chickens.

Example 20

50 mg EthyM-hydroxy ^ -ethoxy-ö-n-decyloxyquinoline-3-carboxylate were with 0.1 ml of a reaction product of ethylene oxide with castor oil as an emulsifier and a little water mixed and the mixture was ground to a fine suspension and then diluted with water to a total volume of 5 ml. The final suspension was for oral administration Suitable for chickens.

Similar compositions to those in US Pat Examples 15-20 described can be prepared in which that given in these examples Quinoline derivative by another of the compounds of general formula I or their non-toxic Salts, in particular by one of the preferred compounds, such as, for example

Ethyl ^ -hydroxy ^ -isopropoxy-b-n-octyloxyquinoline-3-carboxylate,

Methyl ^ -hydroxy ^ -isopropoxy-b-n-octyloxyehinoline-3-carboxylate,

Methyl ^ -hydroxy ^ -ethoxy-b-n-octyloxyquinoline-3-carboxylal or

Mclhyl-4 hydroxy ^ -ethoxy-b-n-dccyloxy-

quinoline-3-carboxylal,
is replaced

The following values show that the invention Compounds in comparison with the known agent against coccidiosis, namely the 6,7-diisobutoxy-4-hydroquinoline-3-carboxylic acid ethyl ester (in in the following tables as "a") have a superior effectiveness and at the same time compared to

is not the case.

The compounds according to the invention are practically non-toxic and indicated when administered orally Chicken in doses up to 1 lg / kg body weight no negative effects.

The following effective dosages (ED50) were

different Eimeria species, which was determined on 6 to 7 day old infected chicks used so far.

OH

COOR ₂

E. acervuiina

Epso values by weight%) in E. acervuiina

a Isobutyl Isobutyl ethyl 0.0024 d Octyl ethyl methyl 0.00052 e Octyl ethyl ethyl 0.00061 f Octyl Propyl ethyl 0.00081 G Octyl Isopropyl methyl 0.000059 H Octyl isopropyl ethyl 0.00044 i Nonyl methyl methyl 0.00038 j Nonyl methyl ethyl 0.00071 k Nonyl ethyl methyl 0.000088 1 Nonyl ethyl ethyl 0.00017 m Nonyl Isopropyl methyl 0.00005 η Nonyl Isopropyl ethyl 0.0001 O Decyl methyl methyl 0.00062 P. Decyl methyl ethyl 0.0011 q Decyl ethyl methyl 0.00012 r Decyl ethyl ethyl 0.00024 S. Decyl Propyl Äihyl 0.00028 t Decyl Isopropyl methyl 0.000022 U Decyl Isopropyl ethyl 0.000079 V Decyl sec-butyl ethyl 0.00018

In the following table the reference numbers refer to a. H. d. q. r and g on the table above. ED50 values in E. brunetti, E. maxima, E. necatrix, E. tenella

Verb. No. ED »(weight%) E. maxima E. necatrix IL tenella E. brunetti 0.00089 <0.005 0.002 a 0.00052 0.00022 <0.0005 0.00023 H 0.00022 0.00022 <0.002 0.00041 d 0.00032 0.000064 <0.001 0.000069 q 0.000061 0.000092 <0.000125 0.00013 r 0.00018 0.000046 <0.0001 0.000035 0.000031

Claims (1)

Patent claims: 1. ^ Hydroxy-quinoline-S-carboxylic acid ester derivatives the general formula COOR, in which R is a straight-chain alkyl radical with 8 to IO Carbon atoms, Ri is an alkyl radical with a straight line or branched chain with 1 to 4 carbon atoms and R2 is a straight-chain alkyl radical with 1 to 2 Mean carbon atoms, as well as their salts.