DE2033969A1 - Quinoline carboxylates - Google Patents

Description

PATENT ADVOCATE DR. HANS-GUNTHER EGGERT, DIPLOMA CHEMIST

5 KDLN-LINDENTHAL PETER-KINTGEN-STRASSE 2

Cologne, July 5, 1970 Eg / Ax / Hz

Janssen Pharmaceutloa N.V., Turnhoutsebaan 3> Oj Beerse (Belgium)

Quinoline carboxylates

The invention relates to quinoline carboxylates and preparations which contain these quinoline carboxylates and are valuable Means for combating coccidiosis are. Lower alkyl esters of 6,7-di (lower alkoxy) -4-hydroxy - ^ - quinoline carboxylic acid are known, effective against coccidiosis and described in U.S. Patent 3,267,106 will. In contrast, the compounds according to the invention are ethyl esters of 6-alkoxy-4-hydro: xy 5-quinolinecarboxylic acid with an alkyloxymethyl radical, benzyloxymethyl radical or Phenyläthyloxymethylreet in the 7-position. These new connections are very strong Coccidiostats

The invention accordingly relates to a new class of ghinoline carboxylates, in particular of ethyl esters of e-alkoxy - ^ - hydroxy ^ -ohinolinecarboxylic acid »it de» above mentioned B ^ -Oxyttethylrest in the 7-position. tuck Quinolincarboxylainl can be used alone or in combination with other therapeutically effective means of combating the coccidiae are used and are therefore valuable Aids for di · poultry mowing.

009886/2231 _BAD

The invention is hereinafter described in connection with Illustrations described.

Fig. 1 is a graph of the mean weight ratio, that in a group of uninfected 14 day old chicks for a period of 11 days was observed.

Fig. 2 is a similar illustration for chicks with Coccidia have been vaccinated.

The new ethyl 6-alkoxy-7- (H ^ j-oxymethyl) -4-hydroaqr-3-quinoline carboxylates according to the invention can be represented by the following formula:

(I)

H is an alkyl radical with 1 to 10 carbon atoms and an alkyl radical with 2 to 11 carbon atoms, a benzyl radical or phenylethylreat. Compounds are particularly preferred of formula (I), in which B is an ethyl radical and B ^ a Heptyl radical or Oc ty Ire st, namely xthyl-6-ethoxy-7- (heptyloxymethyl) -4-hydroxy-3-quinoline carboxylate baw

carboxylate.

The compounds (I) according to the invention are obtained from nitrobene derivatives the formula

HO- / ^ -HO ₂ (II)

JO-CH ₂

hähem as defined above in which R and B ^ · made ₉ This Zwischenprodukt® (II) as I llkoxy ° ~ 2- (E "| oxymethyl) -4-nitroben8sole beaeiclmet""Zaif ©© stel = -

BATH ORIGINAL

Development of the desired compounds (I), the nitro function of the intermediate (II) is selectively reduced to an amino function by customary processes, for example by catalytic hydrogenation using molecular hydrogen and a suitable catalyst such as platinum oxide or by treatment with polyammonium sulfides or with a suitable fine-grained or powdered metal and an acid or a salt, for example with zinc and acetic acid, tin and hydrochloric acid or with iron and ammonium chloride solution. The 1-alkoxy-2- (R, - oxymethyl) -4-aminobenzene (III ) is then treated with diethyl ethoxymethylene malonate (IV), preferably under reflux conditions, in a lower alkanol as solvent, for example ethanol and propanol, the corresponding diethyl- ^ 5- (ICj -oxymethyl) -4-alkoxy-aniline methylene7-malonate (V) being obtained is then heated to elevated temperatures of about 240 to 280 ⁰ C, preferably about 15 to 30 minutes in a high-boiling L. Solvent such as diphenyl ether or diphenyl methane to 240 to 250 ° C, whereby a cyclization takes place and the desired quinolinearboxylate of the formula (I) is formed. It is assumed that these Llalonates (V) are new intermediates and accordingly represent a further characteristic of the invention. The reaction scheme described above can be represented as follows:

(II) (III)

009886/2231

EtOCH-C (COOEt) ₂

-> R-O

R ₁ -O-CH ₂

NK-CH = C

COOEt

/ COOEt "

The intermediates of formula (II), ie. the 1 * -Alkoxy-2- (H ^ -oxymethyl) -4-nitrobenzenes can be prepared from nitrobenzyl chlorides with a formula using various methods

(VI)

Ql-GB ₂ '

* a hydrogen atom in the R or a Alley! radical having 1 10 carbon atoms bie

for example

material atom is an a
the ob on alkyl

obem. gen door eiaige

₉ & _o h® weaa R ehaadluag with

ΙΟ-

2033919

If 2-alkoxy-5-nitrobenzyl chloride (VIII) as the starting point? material is used, i.e. when R '* R * alkyl with 1 to 10 carbon atoms, the conversion into the corresponding 1-alkoxy-2- (R ^ -oxymethyl) - ^ - nitrobenzenes takes place Formula (II) easily by treating the former with sodium and a corresponding alcohol of the formula R ^ OH optionally in the presence of a small amount of potassium iodide, which, however, is not essential for the reaction to proceed is · It is also possible to use the 2-alkoxy-5-nitrobenzyl chloride (VIII) into the corresponding benzyl iodide (IX) to convert by conventional treatment with sodium iodide and then the 2-alkoxy-5-nitrobenzyl ^ odide thus obtained to be treated with sodium and a corresponding alcohol of the formula R> jOH, with the desired nitro-like intermediates of formula (II) are obtained;

Na /% OH

(AI)

■ ^R l- • (VIII) "... (II)

That is, represented by the formula (VII), i. 2-Bydroxy-5-nitrobenzyl chloride, is as well as some of the 2-alkoxy-5-nitrobenzyl chlorides of the formula (VIII) known. The latter can, however, in general

9 888/2231 BAD

common easy to prepare) by a mixture of a corresponding p-alkoxynitrobenzene of the formula O ₀ H- / 7 »OR,

me £ \ ~ n /

wherein B is as defined above, with p-formaldehyde and waiserfreiem zinc chloride some ßtuMen at moderately elevated temperatures, preferably about 2 to 3 hours at 75 to 85 ⁰ O with the HOL ÖAS held in intimate contact, will · Sas mixture is then cooled and poured into water and the 2-alkox7 ^> -5-flitroben8yJ.chloride (VIII) obtained in this way is isolated by conventional extraction.

Some of the 1-Alk03qf »2- (l ^ ™ 03 ^ iietIiyI) - iil« nitro "fe © ii.zole of the formula (II) are new “In view of their great values, all intermediate products at the YorstefaeiKL feesonritteneii ^ nthes These compounds represent an iron- further »aspect of the invention dar · These new 1-alkoxy- £> · (H ^ «Qs ^ metäyl)« = 4 * »_ nitrobenzenes, in which E ^ eia Beaaylrest or Fitaylättyl rest, you can use the Fon & el. -. ■

1-0

«Äejrf.a hais · S" die @ te © & geasiaat. © Be interpretation, wätoead aralkyl a Bemsylsdst @ <& 1 © 2? rest, vorugöweise e ± a B-HiesylatfeyJ ^ gst ist.ο

The connections of the

kologiaelie Eigeaecliafteiag

Effectiveness Psas-caitong

chen, s «B · dir Staaee

the Gefliigeüaditsteic at the iaoio-bG3

namely Eineria ac oil M ^1- IiCa ₅ A Iq üsQa © llQ wsu SioGi? ia brunettie Weiia they oimern anoQOüQQQ & ^ m. Fisfetss ¹ Xw. 9ia®s>"Amount from about O ₅ OOOI to 0 ₉ 1 G- © Wo = # smg @ s © ts ^ iaat ®a -

Chicks are fed ^, di @ sit K @ Isaidi © a g

switch the mortality mat! © s ^ feiditätj dl © g © u © toli © 3b.

Associated with coccidiosis, sisäg miss naä feiibea © -a, a @ m ■ favorable. Influence on the Waefestnn uad Aiissglbiea d © s Si © r © _Q Through admixture, to the shatter of the fiere - ia deg ¹ kias?

009886/2231

2033963

These new connections can lend in a benign way a form that is easy to administer * They can optionally be incorporated into tablets, gelatine capsules, suspensions or similar preparations made from suitable carriers and There are auxiliary substances that are used in the manufacture of pharmaceutical clay Preparations are common

In the following examples, the parts are understood as Weight parts, unless otherwise stated

example 1

A mixture of 75 parts of 2- (chloromethyl) -4-nitrophenetol, 57 parts of sodium iodide and 520 parts of acetone is heated under reflux for 30 minutes with stirring. The reaction mixture is poured into water and the precipitated product is filtered off propanol is obtained 2- (iodomethyl) -4-nitrophenetol melting at 88 ⁰ C ·

Example 2

A mixture of 37 parts of a-ghlor-2- (deoylo ^ y) -5-nitrotoluene, 18 parts of sodium iodide and 96 parts of acetone are heated for 30 hours with stirring on a Rüokflufi. Bas reaction mixture is cooled and is. Poured water »The precipitated -Product is filtered off and recrystallized from acetone, where '2- (3} ec7lbxj) -a «> 4od" 5 Haitrotolttol vom Schaela point 63? 5 ° 0 is obtained

A mixture of 30.7 parts of ^ -Butoa ^ nitrobenxol »28« 2 parts p-? ormaldehyde and 61.3 parts of Zinkohlorld nird 2 hours heated to 80 ° G, with gaseous hydrogen chloride is initiated. That reaction mixture is between Waeeer and chloroform. Until organic phase becomes separated, dried, filtered and evaporated ^ The oily residue is distilled, with 2-Bmtozj-a-chloro-5-nitrotoluene from the boiling point 1Bö ° C / 2 mm is obtained «

_BAD ™, ^ 009886/2231

The experiment described in Example 3 is carried out using an equivalent amount of p-decyloxynitrobenzene Place τοη 4-butoxynitrobenzene repeated · Here is a-Ohlor-2- (decyloxy) -5-nitrotoluene obtained

Example 4

75 parts of 2-hydroxy- ^ nitrobenzyl chloride are added to a solution of 23% sodium in 640 parts of n-propanol. The mixture is refluxed with stirring for 2 hours. Then, 83 parts of butyl bromide at a temperature about 50 ⁰ C τοη added · After the addition of a further 2 days is heated to reflux with stirring. The reaction mixture is cooled and poured onto water. The product is extracted with chloroform. The extract is dried, filtered and evaporated to give 2-butoxy-5-nitro-a-propoxytoluene as a residue.

example 5

A warm solution of 4.2 parts of sodium in 100 parts of 1-heptanol is added dropwise to a stirred solution of 29.3 parts of 2-butoxy-a-chloro-5-nitrotoluene and 1 part of potassium iodide in 40 parts of 1-heptanol at one temperature τοη 35 to 40 ° C given. After the addition, the mixture is stirred for a further 72 hours at room temperature ». The reaction mixture is diluted with 160 parts of ether and washed neutral with water. The organic phase is dried - and evaporated. The residue is fractionated under Termiadertem Bxnek, with 2 ^ utoxy ^ ~ (lieptyloxy) -5-nitrotolttol-Tom boiling point 184 Me 188 ° G / 0 _y 2-iu.e; cliaiten. lixd.

Dtaroh repetition of the experiment described in the example ^ * however, using the entepreehead alcohols.

formula H ^ OH aa place worn 1-leftamol «earth the following. Connections received: · - '.-..- 2-butoxy-5-aitro "" - (oetyleacy> toliio.l _s .etedeponkt '192 * -1f * ° 6 / · 0.2 mm,

2-Buto3qr «-5-mitrci -« - »(maiiyleacy) toluene, boiling point - 20 * -208 ° 0 / 0.25 mm.

BATH

Example 6

67 parts of phenylethyl alcohol are added dropwise to a boiling suspension of 5.5 parts of sodium in 200 parts of anhydrous toluene. The mixture is refluxed with drilling until all solids have gone into solution. Pas obtained sodium salt is added to a solution of 61,4- parts of 2- (iodomethyl) -4-nitrophenetole in 120 parts of anhydrous toluene at a temperature of 50 ⁰ C * is followed by stirring overnight at room temperature. After adding water, the organic layer is separated off. The aqueous phase is extracted twice with ether. The combined organic layers are washed with water, dried, filtered and evaporated.The oily residue is distilled.The distillate is triturated in a mixture of petroleum ether and ethanol and the undissolved material is filtered off and dried, whereby 4-nitro-2- (phenyläthyloxyaethyl) phenetol is obtained.

Example 7

To a solution of 117 »2 parts of 2- (iodomethyl) -4-nitroanisole in 80 parts of isobutanol, a solution of 11.5 parts of sodium in 240 parts is added dropwise with stirring Isobutanol given at 50 ° C. After the addition is made the mixture was stirred overnight at room temperature. Bas The reaction mixture is poured into water and the product is extracted with biisopropyl ether. The extract is dried, filtered and evaporated. The solid residue is crystallized from petroleum ether, 2- (isobutyloxymethyl) -4-nitroanisole of melting point 35 ° C is obtained.

By repeating the search described in Example 7, but using an equivalent amount corresponding 2-alkoxy-5-nitrobenzyl halides of the formula VIII or IX instead of 2- (iodomethyl) -2-nitroanisole and using an equivalent amount of a corresponding alcohol of the formula B ^ OH in place of Isobutanol are those mentioned in the following table Get connections

009886/2231

-ιο-

0-R

< • 3H ₂ -OR ₁ - 50 ι C) /
Hg) Melting point (° 50 R. AC ₇ H ^ " (Boiling point / mm • (173-176 / 0.4). CH ₃ nC ₈ H ₁₇ 50 (243-244 / 0. 7y ti CH ₂ -C ₀ H ₅ 54 (196-200 / 0. 3) Il IC ₄ H ₉ 83 C ₂ H ₅ ^nC 6 ^H I3 84th S. M. C ₇ H ₁₅ em Il I) CoH ₁ "τ nt? M. ^nC 9 ^H 19 Il nC H ' M. C ₂ H ₅ BC ₇ H ₁₅ CH ₂ -C ₆ H ₅ • - Il ^C Z ^U 5 ^dC 10 ^H 21

Il

A mixture of 11 »9 parts

anisol, 160 Seiles Äthanol maä, O ₀ I ff @ il © s Platia @ ssyel- is

at Noraaldruck and Heumtea calculated laaserstorfmeng © the hydrogenation stopped triert and the filtrate methyl) -p- »anisidine as

i @ -fe ₀ ? iird

By repeating the search in Example 8 and using equivalent amounts of the 1 "-alkoxy-2" - (R ^ -oxymethyl) - ⁱ } -EitrobeÄZol ©

(II) instead of 2- (isobttt0sgrmethyl) -4-aitroaaiBO: 1, "we" get the following compounds :

003886/2231

2033? $!

base

R B. or melting point (C) / (boiling point /

Sal «mm Hk) -

(155-158 / 0.2)

g · HGl 69 (GH ₂ ^ -C ₆ H ₅ Baae

₉ HG ₇ H ₁₅ G ₂ H ₅

CH ₂ -O ₆ H ₅

° 2 ^H 5

Example 9

To a Büekflmfi heated under drilling (reaieeh ton 50 parts of Sisen in 500 ropes of a 0.78n ~ ammonium chloride solution «ground in portions 68 parts of 2- (IthoiyEethyl) -4-nitroanieoi (described by Quelet and coworkers in Bull.Soo.Gnia.Xrv , P.2445 »1963, Schaelspwdtt? 2 ° G). The mixture is heated under reflux for a further 6 hours with stirring. The reaction mixture is cooled and the product is extracted with toluene. The extract is dried, filtered and the filtrate under reduced pressure The oily residue is distilled, giving 3- (ithoxymethyl) -p-anisidine with a boiling point of 109 ⁰ G / 0 _f 4 mm Hg.

009886/2231

2033 ^ 69

By repeating the experiment described in Example 9 using an equivalent amount of the corresponding 1-AUcoxy-2- (E _/ j-oxymethyl) -4-nitrobenzenes of the formula (II) instead of 2 »(a'thoxymethyl) -4-- nitroanisol the following products are obtained:

Boiling point, ⁰ O

3- (heptyloxymethyl) -p-anisidine 163-164 / 0.5 mm

3- (Octyloxymethyl) -p-anisidine 17V0.5 mm

3- (hexyloxymethyl) -p-phenetidine 163-168 / 1.2 mm

3- (heptyloxymethyl) -p-phenetidine 155-158 / 0.4 mm

Example 10

A mixture of 13.5 parts of 3- (ethoxymethyl) -p-anisidine, 16.8 parts of diethyl ethoxymethylene malonate in 160 parts of 2-propanol is refluxed with stirring for 5 hours. Sas reaction mixture is evaporated under reduced pressure and the residue is crystallized from petroleum ether to give diethyl / 5- (ethoxymethyl) -p-anisidinmethylen7-malonate is obtained with a melting point of 47 ⁰ C.

By repeating the experiment described in Example 10 and using an equivalent amount of the corresponding 1-alkoxy-2 - (R _< . -Oxymethyl) -4-aminobenzenes of the formula (III) instead of 3- (ethoxymethyl) -p-anisidine the following connections are obtained:

009886/223 1

Il Il Il

- 13 -

y -ν GOOEt

R-O - // \ V_ NH-OH = G

^ 000Et

R R ₁ melting point, ⁰ C

OH ₂ -G ₆ H ₅

46.5 HG ₈ H ₁₇ 62.5

(GH ₂ J ₂ -C ₆ H ₅

HC ₇ H ₁₅ HC ₈ H ₁₇ HC ₉ H ₁₉ G ₂ H ₅ CH ₂ -C ₆ H ₅ C ₂ H ₅ HG ₃ H ₇

Example 11

A mixture of 20 parts of di-ethyl £ 5- (ethoxymethyl) -pani sidinmethylen / iaalonat and 200 parts of diphenyl ether was stirred for 30 minutes while erhitat at 245-250 ⁰ C. The reaction mixture is ^{cooled to 60 °} C. After adding acetone, the product is crystallized. It is filtered off and uakristallisiert from dirnethylsulfoxyd, whereby ethyl-7- (äthO3cymethyl) -4-hydroxy-6-methoxy-3-quino-

009886/2231

lincarboxylate with a melting point of 293.5 ° C is obtained.

By repeating the experiment described in Example 11 using an equivalent amount of corresponding diethyl ^ -iE ^ -oxyme thyl) - ^ - alkoxyaniline methylene / malonate of formula (V) instead of diethyl ^ 5- (ethoxymethyl) -p-anisidinmethylene / aialonate the following products will be obtained:

R ₁ -O-CH ₂

RO ' ^^ "V ^ COOEt

R. 1 example Melting point, ° C 12th CH ₃
C ₂ H ₅ HC ₇ H ₁₅ +300
222 C ₂ H ₅ HC ₈ H ₁₇ 226.5 It (CHg) ₂ -C ₆ H ₅ 228.5 nC ^ Ho ηΟ, Ηγ, 226.5 η HC ₇ H ₁₅ 217 η HC ₈ H ₁₇ 215.5 η HCqH ₁₉ 213 HC ₇ H ₁₅
η C ₂ H ₅
CH ₂ -C ₆ H ₅ 220.5
218.5

A mixture of 23 parts of diethyl / 5- (isobutoxymethyl) -panisidinmethylen7malonat and 200 parts of diphenylmethane is heated for 15 minutes 25O ⁰ C. The reaction mixture is ^{cooled to 150 °} C. and poured into 320 parts of acetone. The precipitated product is filtered off and recrystallized from a mixture of methanol and dimethylformamide, ethyl 4-hydroxy-7- (isobutoxymethyl) -6-methO3Ey-3-quinolinecarboxylate having a melting point of 248 ° C. being obtained.

By repeating the procedure described in Example 12. Method, but using one @ r equiiral

009886/2231

th amount entsprechende.r diethyl ^ 5- (R ₁ -oxyaetnyl) - ^J l-alkoxyanilinnethylen / malonateder Fornel (V) in place of diethyl / 5- (isobutoxyisethyl) -p-anisidinnethylen / nalonat be obtained the following products:

RR ^ cutting point, ⁰ C

° 2 ^H 5

²³ °

^M CH ₂ -C ₆ H ₅ 231

246

UC ₇ H ₁₅ 225

^ H 225

222

213 205

009 886/22 3 1

Example 13

This example illustrates the effectiveness of the compounds of formula (I) against coccidiosis.

In the in Pig. The graph shown in I shows the mean weight ratio of a group of normal, uninfected, 14 day old chicks (day 0) over the next 11 days. In Fig. 2 the mean weight ratio is plotted during the same time for an equal number of chicks which were inoculated at the age of 14 days with about two million speculated oocysts of Eimeria aoervulina. "Each chick is kept in a" single cage ", both Groups of uninfected and infected chicks received the same nutritionally balanced diet during the 11 day observation period. "The term" weight ratio "represents the weight of a chick on each day % of its weight on day 0", - As Fig. 1 shows oils growth ". speed of the non-tofial chicks increased steadily during the 11 days, while Fig. ₀ 2 illustrates the clear decrease in the number of infected cults after days 0 to 3 (felmbafcionsgelt) _o On day 5, seigern oil® inflsiestea Külc © n © in middle 6 © tjlofots ~ of l _ö o2 ₀

The WIiteairJLGit eixaes ³ given connection as being sz, iiirGv v3 & ®h & tW3i (B £ U $ ru.Qx®a®n effect & ut intiz ± ®rt chick fi ^f rlitieltJs w <mm m & Q öa® glelote WuttQV wi © the ob

ter the “ic

is. Eliio lorhiMumhg is considered irlHmm® MUtteX ^ UCDiI that mitfclQWQ ßQWlQhtsvQThElinlB asn T & .Q value VQLZ I ₅ I? or does feafe ₀ usxm © ia food offer that? ο _ΰ '

2 2

Qew.-Ji containing the compound is given to the infected chick will*

The values in the following table compare the effectiveness of the compounds of the formula (I) with three of the leading commercial coccidiostats used today, namely (A) ethyl 6-n ~ decyloxy ~ 7-ethoxy-4-hydroxy-3-ohtaoline carboxylate, (B) Methyl 7-benzyloxy-6-n-butyl-4-hydroxy-3-quinolinecarboxylate and (C) methyl 7-diethylamino-4-hydroxy-6-n-propyl-3-quinoline carboxylate. A group of 4 chicks is tested for each compound. Apart from the values given below for day 5, the rate of growth of the treated increased Chicks subsequently continued steadily without any adverse effects on the growth and appearance of the animals being observed.

With the list below the new connection is of course, it is not intended to limit the invention thereto, rather only the valuable properties are intended all compounds falling under the formula (I) are illustrated.

R ₁ -OC

R-O - ^^^ X ^ N COOEt (I)

009086/2231

Weight ratio (day 5 / day concentration o, ol %

Ethyl hexyl y-4-.hydi 1.2o ι - oh iiOxy-3- "3tt" Methyl ethyl 1.18 ■ ... -1-.24 Methyl heptyl yl-4-byc 1.25 Ethyl heptyl 1.24 Ethyl octyl dro5öf-6 1.26 Heptyl ethyl 1.18 Methyl octyl 1.25 Ethyl isobutyl 1.24 Decyl propyl 1.19 Heptyl benzyl 1.18 Butyl propyl 1.19 Ethyl phenylethyl 1.25- Decyl ethyl Io3o Methyl isobutyl 1.17 ■ Methyl benzyl 1.17 Decyl pentyl 1.2o '- Ethyl Uhdeeyl 1.21 Ethyl nonyl 1.22 Butyl heptyl I ₀ 2 © Butyl octyl 1.2 © Butyl nonyl 1.17 A. Xthyl-6 * 4i-deoyloxy-7i »atbox quinoline carboxylate B. Methyl «7-benzyloxy-6-n-but eminolinearboxylate C. Metbyl «7-cUätfaylainlno-4-liar

1.22

009886/2231

Belsplel 14

In an experiment according to the described in Example 15 Method was carried out on day 5 ©! N average weight ratio of 1.25 when using a Futters found that the preferred compounds of formula (i), namely ethyl-6-ethoxy-7 "(heptyloxyinethyl) -4-hydrocyc - ^ - quinoline carboxylate and ethyl-δ-ethoxy - ^ - hydroxy-7- (oetyloxymethyl) -3-ch4nolinoarboxylate contained in the low concentration of ο, οοΐ Qew.- £.

Example 15

This example illustrates the weight gain of uninfected chicks (NIK), infected chicks (IjC.) And infected chicks treated with ethyl 6-ethoxy-7 ^ heptyloxymethyl) -4-hydroxy-3-quinoline carboxylate as the active ingredient (A. .!.) * that were mixed with the feed in concentrations of o, oil $> and ο, οοΐ %. The experimental method described in Example 13 is used using various mutes from Elmeria. Treatment with the active ingredient (AI) begins on the day of infection (simultaneously) or two days before infection (propilactic). The weight ratios given in the following table were for Bimerla acervulina on the 5th day * for Binerla brunette! on the 6 * day and for Eimeria tenella on the 7th day. Zwh -comparison are the values "for the. In example. 13 mentioned. Commercial coccidiostatic agent (B) mentioned (concentration ο, οοΐ $),

0 098 86/22 3 1 ■

- 2ο -

Medium weight ratios

Trunk of
Einierla ra « 5 O same
in time N.I.K. I. K. A.Ι
ο.oil % A.I.
o.ooI ^ ^(B) "
o.ool ^ rag rag-2
CaK 6 6th prophylactic 1.33 I.o4 1.24 1.23 acervulina TaK Dag -2
7th table
same 1.19 Pag O in time 1.6o 1.16 MM 1.50 brunetti Day
Ta « Pag 7
Pag -2 prophylactic
table
same
in time 1.42 1.14 1.4o 1.42 1.5o Day prophylactic
table 1.65
1.34 1.14
1.19 1.53 1.66
1.51 1.41 tenella 1.78 1.33 1.79 1.74
-C? 1.62
1.49 1.72

009886/2231

Claims (1)

Claims y ithyl-e-alkoxy - ^ - hydroaqjr ^ -CH ^ -oxymethyl) -3-ohinoline carboxylate the formula in which R is an alkyl radical with 1 to 10 carbon atoms and B * Benzyl radical, Ehenyläthylrest or alkyl radical with 2 to 0 atoms is carboxylate carboxylate lincarboxylate Ätlayl-6-ätlioxy-7- (heptyloxymethyl) - ^ - hydroxycarboxylate Ethyl-e-ätlxoxy - ^ - bydroxy-V-C octyloxymethyl) -3-quinoline carboxylate 7 xthyl-7- (ethoxymethyl) -6- (heptyloxy) -4-hydroxy-3-quinolinecarboxylate · Ethyl-4-hydroxy-6-methoxy-7- (oc tyloxymethyl) -3-ohinoliii carboxylate. -.--. Ethyl-7- C isobutoxymethyl) -ö-ethoxy - ^ - hydroxy-3-quino lin carboxylate. 10. Ethyl 6- (decyloxy) -4-hydroxy-7- (propoxymethyl) -3-quinolinecarboxylate. 00 9886/22 3 Ethyl 7- (benzyloxymethyl) - »6- (heptyloxy) - ^ - hydroxy-3-quinoline carboxylate, 12 · Ethyl ^ -butoxy-4-hydroxy-7- (propoxymethyl) -3-ohinoline-carboxylate. 13. Ethyl-e-ätlioxy - ^ - hydroxy -? - (phenät by loxymethyl) -3-quinolinearboxyIate 14 ÄtliyX-6- (decyloxy) -7-ethoxymethyl) -4-liydroxy - 3 » quinoline carboxylate 15 · ethyl-4 «hydroxy-7- (isobutoxymethyl) -6-methoxy-" 3 ~ ohinoline carboxylate 16 · quinoline carboxylate 17 · chlnolinc arboxylate 18 · Ethyl-6-ätlioxy-4-bj ^ droxy-7 - («Beoyloxymethyl) -3-cbino line arboxylate 19 · Ethyl 6-ethoxy-4-hydroxy-7 " ^p (aonyloxyiietbjl) -3-ciaino liB" carboxylate. 20 · Xthyl "" 6 "" biitoxy · ™? ""(B> eptyloJtyBi®tliy3. / "^> ^ ^Mi liydi? O3Ey" = ⁱ 3 "* cbizioXiii" · carboxylate · · carboxylate 22 · carboxylate 009886/2231 2033069 HK-Clfc COOC ₂ H ₅ wherein R is an alkyl resir having 1 to 10 carbon atoms and R ^ is Benzyl radical, Phenyljrehylrest or alkyl radical with 2 to 11 carbon atoms is. ^ 24. 1-alkoxy-4-r The same applies to the formula Aralkyl-O-CH ₂ inXler R is an alkyl radical with 1 to 10 carbon atoms and the _— ■■> Itj-l ^ - »--Χ. J st. 25. Use of compounds according to claim 1 to 24 as Means for combating eoccidiosis and as active ingredients in pharmaceutical preparations. 26 · Process for the preparation of Ätbyl-e-alkoxy - ^ - hydroxy-7- (R - oxymethyl) -3-quinoline carboxylates according to claim 1, characterized in that compounds of the form ael WH-CH-C COOEt COOEt cyclieiert by heating to a temperature from 240 to 280 ⁰ C. 009886/2231 27. Process for the preparation of ethyl 6-ethoxy-7- (hexyloxymethyl) -4-hydroxy-3-quinolinecarboxylate, characterized in that a compound of the formula (V) according to Claim 26, in which H is an ethyl radical and R, j is a hexyl radical, cyclized by heating to a temperature between 240 and 280 ⁰ C · - - ' 28. Process for the preparation of ethyl 7- (ethoxymethyl) -4-hydroxy-ö-methoxy ^ -quinoline carboxylate, characterized in that a compound of the formula (V) according to Claim 26, in which R is methyl and R ^ is ethyl is cyclieiert by heating to a temperature between 240 and 280 ° C. 29 · Process for the preparation of ethyl 7-chptyloxymethyl) -4-hydroxy-6-methoxy-3-quinolinecarboxylate, characterized in that a compound of the formula (V) according to claim 26, in which R is a methyl radical and R ^ is a Heptyl radical is cyclized by heating to a temperature between 240 and 280 ^{0 C.} 30 · Process for the preparation of ethyl 6-ethoxy-7- (heptyloxy methyl) -4-hydroxy-3-quinolinecarboxylate, characterized in that a compound of the formula (V) according to claim 26, in which R is an ethyl radical and R ^ is an ileptyl radical, cyclized by heating to a temperature between 240 and 280 ⁰ C. · J1. Process for the preparation of ethyl-e-ethoxy ^ -hydroxy-7- (octyloxymethyl) -3-quinolinecarboxyiate, characterized in that a compound of the formula (V) according to claim 26, in which K is an ethyl radical and R ^ is an octyl radical , cyclized by heating to a temperature between 240 and 280 ^{0 C.} 32 · Process for the preparation of ethyl 7 - * (ethoxymethyl) -6- (heptyloxy) -4-hydroxy-3-quinolinecarboxylate, characterized in that a compound of the formula (V) according to claim 26, in which R is a heptyl radical and R ₁ a 009886/2231 Ethyl radical is cyclized by heating to a temperature between 240 and 280 ^{0 O.} 33 · Process for the preparation of 7- (octyloxymethyl) -3-quinolinecarboxylate, characterized in that a compound of the formula (V) according to Claim 26, in which E is a methyl radical and B ^ is an octyl radical, is cyclized ^{by heating to a temperature between 240 and 280 0 O.} . 34. A process for the preparation of ethyl 7- (isobutoxymethyl) 6-ethoxy-4-hydroxy-3-quinoline carboxylate, characterized in that a compound of the formula (V) according to claim 26, in which R is an ethyl radical and R _{1 is} a Isobutyl radical is cyclized by heating to a temperature between 240 and 280 ^{0 O.} 35 · Process for the preparation of ethyl 6- (decyloxy) -4-hydroxy-7- (propoxymethyl) -3-quinolinecarboxylate, characterized in that a compound of the formula (V) according to claim 26, in which R is a decyl radical and R * is a propyl radical, cyclized by heating to a temperature between 240 and 280 ^{0 O.} 36. Process for the preparation of ethyl 7- (benzyloxymethyl) -6- (heptyloxy) -4-hydroxy-3-quinolinecarboxylate, characterized in that a compound of the formula (V) in which R is a heptyl radical and R "j is a benzyl radical, I cyclized by heating to a temperature between 240 and 280 ^{0 O.} 37 · Process for the preparation of ethyl-ö-butoxy - ^ - hydroxy-7 ~ (pi ^> opoxymethyl) -3-quinolinecarboxylate, characterized in that a compound of the formula (V) in which R is a butyl radical and R ^ is a Propyl radical is through Heating to a temperature between 240 and 280 ⁰ O cyclized 38. Process for the preparation of ethyl-6-ethoxy-4-hydroxy- 009886/2231 7- (phenäthyloxymethyl) - ^ - quinolinecarboxylate, characterized in that one cyclizes a compound of formula (V) in which R is an ethyl radical and R ^ is a PhenyläthyIrest by heating to a temperature of 240-280 ⁰ C · 39 · Process for the preparation of ethyl 6- (decyloxy) -7- (ethoxy methyl) -4-hydroxy-3-quinoline arboxylate, characterized in that a compound of the formula (V) in which R is a decyl radical and R ^ is an ethyl radical, cyclized by heating to a temperature between 240 and 280 ⁰ C. 40 · Process for the preparation of ethyl 4-hydroxy-7- (isobutoxymethyl) -6-methoxy-3-quinoline carboxylate, characterized in that a compound of the formula (V) in which R is He thy Ire st and R ,. is an isobutyl radical, cyclized by heating to a temperature between 240 and 280 ° C 41, a process for the preparation of ethyl 7- (benzyloxymethyl) -4-hydroxy-6-methoxy-3-quinolinecarboxylate, characterized in that a compound of the formula (V) according to claim 26, in which R is a methyl radical and R ^ is a benzyl radical, cyclized by heating to a temperature between 240 and 280 ⁰ C · 42. A process for the preparation of ethyl 6- (decyloxy) -4-hydroxy-7- (pentyloxymethyl) -3-quinoline carboxylate, characterized in that a compound of the formula (V) in which R is a decyl radical and H _-1 is a fentyl radical, cyclized by heating to a temperature between 240 and 280 C - 43 · Process for the preparation of ethyl-ö-ethoxy - ^ - hydroxy-7- (undecyloxymethyl) -3-quinolinecarboxylate, characterized in that a compound of the formula (V) in which R is an ethyl radical and R _{1 is} an undecyl radical , cyclized by heating to a temperature between 240 and 280 ⁰ C · 009886/2231 44, method of making (nonyloxyaethylO ^ -quinoline carboxylate, characterized in that a compound of the formula (V), in which R is an ethyl radical and R _{1 is} a nonyl radical, is eyeIized by heating to a temperature between 240 and 280 ° 0. '.:. "'.:.;■"'■.; 45 · Process for the preparation of ethyl-6-butoxy-7- (heptyloxynethyl) -4-.hydroxy-3-quinolinecarboxylate, characterized in that a compound of the formula (V) in which R is a butyl radical and R ^ is a heptyl radical is cyclized by heating to a temperature of 240-260 ⁰ C. 46 · Process for the preparation of ethyl-ö-butoxy - ^ - hydroxy-7- (octyloxymethyl) -5-quinolinecarboxylate, characterized in that a compound of the formula (V) in which R is a butyl radical and B * is an octyl radical , cyclized by heating to a temperature between 240 and 280 ⁰ C · 47 · Process for the preparation of ethyl-e-butoxy - ^ - hydroxy-7- (nonyloxymethyl) -3-quinolinecarboxylate, characterized in that a compound of the formula (V) in which R is a butyl radical and R _{1 is} a nonyl radical , cyclized by heating to a temperature between 240 and 280 ⁰ C ·. -. "- .. ■■■■. ■ '■ ■ ·.>; / · - ^, ·". ·'. "^: 4-alkoxy-aenilinomethylene 7-malon 009886/2231 in which R is an alkyl radical with 1 to 10 carbon atoms and R ^ a Benzylreet, phenylethyl radical or alkyl radical with 2 to 11 C atoms, characterized in that there are compounds the formula R-O H ₁ -O-CH ₂ Hit a compound of the formula ^ COOethyl (Xthyl) -OCH - C ^ COOXthyl uaeetst. ^ α; Ά ^ the formula JLralkyl-O-CI in the R © in alkyl regions with 1 to 10 Arallqrlreet a Ben $ ylrest or thereby mteowazaimsket · that one a) a verb g of the formula with MMtTlms, and eiaea
lorJk HBr / implemented or