DE2854558A1 - METHOD FOR PRODUCING SUBSTITUTED QUINOLINES - Google Patents

Description

The invention relates to a method for producing substi-

tuated quinolines, which are effective against coccidiosis. Characteristics of the known technical solutions

Eb are quinoline-3-carboxylic acid esters already substituted in the 4-position known to be effective against coccidiosis, which carry alkoxy groups in the 6- and 7-positions. Also the arrangement an alkoxy group in the 6-position and an alkyl radical in the 7-position was called. The reverse placement has also been protected. There are also 6-alkoxy-7-alkoxymethyl derivatives described. Also corresponding thio compounds are known.

All of the 4-substituted quinoline-3-carboxylic acid esters listed are characterized in that those in the 6- and 7-position or in one of these positions are bonded between the benzoid part of the ohinoline molecule and oxygen or sulfur.

The quinoline cardonic acid derivatives of the structures mentioned are based on expensive raw materials, which are usually not available in the required quantity. Manufacture and use of such Connections are therefore limited for economic reasons.

909836/0490

2654558

Object of the invention

The aim of the invention is to use cheap raw materials to produce ghinoline-3-carboxylic acid ester with high action against coccidiosis by simple processes.

Explain the essence of the invention

The invention is based on the object of generating highly effective coccidiostats by forming derivatives of quinolines which have a carboxyl group esterified with a lower alcohol in the 3-position, halogen or a free, etherified or esterified hydroxyl group in the 4-position, - ^ s has been found that compounds which have in ^u egensatz to known, effective on coccidiosis quinolines on the benzenoid portion of the molecule does not carry oxygen or sulfur, excellent properties. The compounds according to the invention are characterized by the general formula I, in which R _{1 is} an alkyl or alsnyl radical with 1-4 C atoms, Rp is halogen, in particular chlorine and bromine, hydroxy, alkoxy with 1 to 6 C atoms or an optionally halogen-substituted acyloxy radical with 1-5 C atoms, R ^ hydrogen or alkyl with 1 to 1 ° C atoms, R, a phenyl optionally substituted by halogen, alkoxy, -aryloxy, alkylthio, alkyl, aryl, acyl and carbalkoxy - Or iTaphthylrest and X is oxygen or sulfur.

For the synthesis of the compounds according to the invention, as Large-scale chemical industry products cheap nitrobenzenes started out, which are chloromethylated by known processes, preferably with chloromethyl alkyl ethers.

The Nitrobenzylchloride above by reaction with phenols, thiophenols or naphthols in the ^u egenwart basic agents and expedient preferably above in inert solvents using potassium carbonate and acetone, in substituted phenyl or naphthyl-3-nitrobenzyläther or thioether.

909836/0490

2954558

From these Mtrobenzyläthern or -thioethern are after the conventional methods of reducing aromatic nitro compounds, for example, 3-aminobenzyl ethers substituted catalytically with hydrogen, hydrazine, metals or sulfides or thiaether received.

The conversion of the 3-aminobenzyl ethers or thioethers in the invention ^ erbindungen according to formula I or their precursors are carried out by reaction with ortho-formic acid ester and Malonic acid esters or cyanoacetic acid esters by several processes.

For this purpose, the 3-aminobenzyl ethers or thioethers are converted with orthoformic acid esters into substituted ¥ -alkoxymethylene anilines and substituted N.U'-bisphenylforinamides, which form substituted ß-phenylamino-cf-carbalkoxyacrylic acid esters when exposed to malonic acid esters. However, the preferred embodiment of the representation of substituted β-phenylamino- aC -carbalkoxyacrylic acid esters is the condensation of the substituted 3-aminobenzyl ethers or thioethers with alkoxymethylene malonic esters. Substituted ß-phenylamino-fP-cyanoacrylic acid esters are correspondingly synthesized from alkoxymethylene cyanoacetic esters.

When heating substituted ß-phenylamino-c ^ -carbalkoxyacrylic acid esters in phosphorus oxyhalides, preferably phosphorus oxychloride, an excess of this or an organic solvent serving as diluent, to temperatures expediently between 80 and 100 ⁰ C, compounds of the general formula I, in which R ₂ Halogen means won. These compounds are also obtained from the 4-hydroxy derivatives by reaction with phosphorus oxyhalides, additives * · of tert. Amines are possible.

Compounds of the general formula I in which Rp denotes hydroxyl are obtained from those in which Rp denotes halogen, preferably by heating ^with hydrochloric acid in an alcoholic solution

909836/0490

or dimethyl sulf oxide obtained. By heating of the substituted .beta.-phenylamino-EC carbalkoxyacrylsäurester in inert diluents such as paraffin, diphenyl or diphenyl oxide, to temperatures above 200 ⁰ C, if necessary in the presence of catalytic amounts of metal halides, for example Zinkch ^ ORID, zinc acetate, Mckelsulfat, cobalt chloride, compounds according to formula I, in which R _{2 is} hydroxyl, obtained directly. Substituted ß-phenylamino-ef-carbaiicaxyacrylic acid esters can also be cyclized to the quinoline derivative on exposure to mixtures of phosphorus pentoxide and alcohols in inert solvents, for example xylene.

The same compounds are also accessible when mixtures of 3-aminobenayl ether or thioether, ortho-formic acid esters and malonic esters heated in inert diluents or with mixtures of phosphorus pentoxide and alcohols be treated, substituted ß-phenylamino-of-carbalkoxyacrylic acid ester arises in situ.

These ring closure processes for compounds according to formula I, in which R “denotes hydroxyl, are particularly suitable for one continuous working method suitable.

Compounds of the general formula I in which Rp denotes hydroxyl are also obtained by esterification of compounds of the general formula I when R ₁ denotes hydrogen. The esterification is under acid catalysis, preferably in ^u egenwart of ITineralsäuren such as hydrochloric acid or sulfuric acid, and cation exchangers in protonated form or by reaction of an active derivative of the substituted quinoline-carboxylic acid 3-, for example the acid chloride, preferably obtained from the acid and thionyl chloride, executed with alcohol.

Such quinoline-3-carboxylic acids of the general formula I, in which R .. denotes hydrogen, are obtained by acidic or alkaline-catalyzed saponification of compounds of the general formula I in which R ₁ denotes alkyl or alkenyl. They are also produced by cyclization of substituted β-phenylamino-cyanoacrylic acid esters according to the processes mentioned to give substituted 4-hydroxy-3-cyanoquinolines and saponification of the gyan residue. 909836/0490

-JO-

2 * 14558

Compounds of the general formula I, in which R _{2 is} alkoxy, are expediently prepared from compounds of the general formula I in which R _{2 is} halogen, by the action of alcoholates, preferably in excess alcohol, according to processes known in the art.

Compounds of general formula I in which B ₂ quines denote acyloxy radical are selected from compounds of general formula I in which R ₂ denotes halogen, when reacting with IJ et all salts of the acid corresponding to the acyl, expediently by heating in inert To obtain solvents. On the other hand, they are obtained from compounds of the general formula I in which E _{2 is} hydroxyl by the customary aoylation process, preferably by heating with the anhydride of the acid on which the acyl is based in the presence of catalytic amounts of tert. Amine or the anhydrous alkali salt of the acid to be introduced.

The present invention results in highly effective pharmaceuticals against coccidiosis through simple procedural steps from cheap Products of large-scale chemical synthesis.

Embodiments

Representation of the starting products

43.2 g of p-cresol, 79.9 g of 4-nitro-2-chloromethylethylbenzene, 67.4 g of potassium iodide, 56.2 g of potassium carbonate and 200 ml of acetone were refluxed for 12 hours. 1 l of water was added and the organic layer was separated off. 86.6 g of crude 4-nitro-2- (4 ^l -methylphenoxymethyl) ethylbenzene were obtained.

86.6 g of crude 4-nitro (4 * -methylphenoxymethyl) ethylbenzene were dissolved in 600 ml of ethanol. 160 g 25% Hydrazine hydrate was added. At a temperature of 30 to 40 ⁰ C the Gasentwioklung was added with stirring Haney-Niokel catalyst in small portions until completion. It was heated for one hour under a flow of gas, the catalyst was filtered off, the solvent was distilled off in vacuo, the organic phase

909836/0490

-44-

separated and distilled. 72.5 g of 4-amino-2- (4'-methylphenoxymethyl) ethylbenzene were obtained. Boiling point .165 ° C / 0.1 torr; n ^ ⁰ 1.5956. Calc .: Έ 5.81 %, found : N 6.10 %.

69.1 g of ethoxymethylene malonic ester, 72.0 g of 4-amino-2- (4'-methylphenoxymethyl) ethylbenzene and 100 ml of ethanol were refluxed for 1 hour. The solvent was chased away. 118.4 g of β- / 5- (4 ^l -methylphenoxymethyl) -4-ethylphanylamino _i 7- * C-carbethoxyacrylic acid ethyl ester were obtained.

example 1

118.4 g SS / 3 "- (4i-methylphenoxymethyl) -4-äthylphenylamino7 e6 carbethoxy-ethyl acrylate were added at ⁰ G I60 to 200 ml of paraffin oil was rapidly heated to 245 ⁰ G, and 15 min at this temperature. stirred. wax on cooling was filtered off with suction, washed with petrol and boiled in ethyl acetate. There were 28.5 g of 4-hydroxy-7- ^(4! methylphenoxymethyl) -6-äthylchinolin-3-carboxylate obtained. melting point 264-269 ⁰ C Ber .: N 3.84%. Found: W 4.12%.

Example 2

105.0 g of β- (3-phenoxymethyl-4-ethylphenylamino) - ^ C-carbethoxyacrylic acid ethyl ester were added dropwise at 160 ° C. to 200 ml of paraffin oil. It was heated quickly to 245 ° 0 and stirred at this temperature for 15 min. It was worked up as described in Example 1. Yield ΖΛ , 8 g of 4-hydroxy-7-phenoxymethyl-6-ethyl-quinoline-3-carboxylic acid ethyl ester. Melting point 271-274 ⁰ C. Calc .: 3.99 Έ ·%. Found: N 4.07%

Example 3

88.0 g of 4-chloro-7- (4'-methylthiophenoxymethyl) -quinoline-3-carboxylic acid allyl ester in 3u0 ml of n-hexyl alcohol were with a Solution of 5 g of sodium in 2UO ml of n-hexyl alcohol for 30 min Heated water bath. Uas solvent was driven off in vacuo and the residue was recrystallized from dilute dimethylformamide

909836/0490

siea-t. 67.3 g of 4-n-hexyloxy-7- (4'-methylthiophenoxymethyl) -quinoline-3-carboxylic acid allyl ester were obtained. Melting point 82 to 85 ⁰ C.

Example 4

83.7 g of β- / 3- (2 ^f -naphthoxymethyl) ^ - ethylphenylaminoZ-C ^ -carbathoxyacrylic acid ethyl ester were added to 200 ml of ^{paraffin oil heated to 160 0 g.} It was heated quickly to 250 ^° C. and kept at this temperature for 15 min. In the usual work-up, 10.7 g of 4-hydroxy-7- (2 ^f -naphthoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ethyl ester were obtained. Melting point 263-267 ° C.

Example 5

109 »9 g of 4-methoxy-7- (2 ^l -äthylphenoxymethyl) -6-n-decyl-quinoline-3-carboxylic acid were concentrated with 500 ml of methanol and 5 ml. Sulfuric acid heated under reflux for 20 h. It was diluted with water, filtered off with suction and recrystallized from dilute dimethylformamide. 32.0 g of methyl 4-methoxy-7- (2'-ethylphenoxymethyl-δ-decylquinoline-3-carboxylate, melting point 70 to 75 ° C., were obtained.

Example 6

85.0 g of 4-hydroxy-7- (4'-chlorophenoxymethyl) -6-ethylquinoline-3-carboxylic acid chloride were with 250 ml of abs. Ethanol and 20 g of pyridine were heated under reflux for 3 h with the exclusion of moisture, and after cooling, 750 ml of water were added, filtered off with suction, dried and recrystallized from dimethylformamide. 65.5 g of ethyl 4-hydroxy-7- (4 ^l -chlorophenoxymethyl) -6-ethyl-quinoline-3-carboxylate were obtained. Melting point 274 to 279 ⁰ O.

909836/0490

2014558

Example 7

57.8 g of ethyl 4-chloro-7- (4'-chlorophenoxymethyl) -6-ethyl-quinoline-3-carboxylate and 23.6 g of the sodium salt of trimethyl acetic acid were ^{heated to 120 °} C. for 5 hours with stirring in 380 ml of dimethylformamide. The precipitated sodium chloride was filtered off with suction, the filtrate was diluted with 850 ml of water, filtered and dried. Yield 39.7 g of 4-trimethylacetoxy-7- (4'-chlorophenyloxymethyl) -ö-ethyl-quinoline ^ -carboxylic acid ethyl ester. Melting point 132 to 138 ⁰ G.

Example 8

To 65 ml techn. Xylene was added to 37 g of phosphorus pentoxide with stirring at room temperature and then 22 ml of abs. Ethanol was added dropwise so that the temperature of the reaction mixture remained below 100 ⁰ G. 43.2 g of ß- / 5- (2'-chlorophenoxymethyl) -4-ethylphenylamino7-öf-carbethoxy-acrylic acid ethyl ester were entered. It was heated for 30 min at 150 ⁰ G, after cooling, poured onto ice, neutralized by passing ammonia gas, suctioned off, dried, boiled with ethyl acetate and suction filtered. Yield 28.4 g of 4-hydroxy-7- (2'-chlorophenoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ether. Melting point 269 to 274 ⁰ G. B _e r .: N 3.63 %, Calc .: N 4.05 %.

Example 9

81.4 g of .beta. / 3- (2 x -Methoxyphenoxymethyl) -4-äthylphenoxymethyl7-ÄF - carbäthoxyacrylsäureäthylester were added at I60 ⁰ C to 200 ml of paraffin oil. It was heated quickly to 245 ° C. and stirred at this temperature for 15 minutes. After cooling, it was filtered off with suction, washed with gasoline and boiled in ethyl acetate. 10.6 g of 4-hydroxy-7- (2'-methoxyphenoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ethyl ester were obtained. Melting point 256 to? 61 ⁰ C. Calc .: ΪΤ 3.68%. Found: 3.68 %.

909836/0450

2314558

Example 10

4-Hydroxy-7- (4'-methylphenylmercaptomethyl) -6-ethyl-quinoline Ethyl 3-carboxylate was described as in Example 9 synthesized. Melting point 278-283 ° C.

Example 11

4-Hydrojy-7- (1 ^f -naphthoxymethyl) -Ö-ethyl-quinoline ^ -carboxylic acid ethyl ester was synthesized as described in Example 9. Melting point 235 to 240 ⁰ C.

Example 12 to 27

the table below shows further quinoline derivatives according to the invention of the general formula II, which were synthesized as described in Example 9.

No. ^R 1 R ₂ ^R 3 Melting point ( ⁰ C) until 280 Ber. Found 12th H H Cl 275 Il 286 3.63 3.62 13th H H Br 281 Il 261 14th H H CH ₃ O 257 Il 270 15th H E. C ₂ H ₅ O 265 η 175 • 16 H H C ₂ H ₅ 171 π 285 17th H H COCH ₃ 280 Il 289 18th H CH ₃ H 286 It 29Ο 3.84 3.72 19th H CH- Cl 285 ti 275 20th Cl H H 270 Il 285 3.63 4.07 21st Cl E. Cl 275 It 259 22nd CH ₃ H ff 256 It 266 3.84 4.16 23 C ₂ H H H 263 It 285 3.70 3.54 24 H H J 280 > 300 2.94 3.42 25th H H N (CH ₃ ) ₂ It 270 26th H H COOC ₂ H ₅ 265 It 276 27 H H CgH ₅ O 272

909836/0490

Example 28

20.0 g of ß-3- / i'-bromophenoxyinethyl) -4-äthylphenylainino7- ^ C-carbethoxyacrylic acid ethyl ester and 120 ml of phosphorus oxychloride were refluxed for 4 h. Most of the excess phosphorus oxychloride was driven off in vacuo, and the residue was poured onto ice, filtered off with suction and washed with water. 17.0 g of 4-chloro-7- (4'-bromophenoxymethyl) -G-ethylquinoline - ^ - carboxylic acid ethyl ester were obtained. Melting point 143 to 146 ⁰ G.

Example 29

15.0 g of ethyl 4-hydroxy-7- (4 ^f -broniphenoxymethyl) -6-ethylquinoline-3-carboxylate and 150 ml of phosphorus oxychloride were refluxed for 32 h. Most of the excess phosphorus oxychloride was distilled off in vacuo and the residue was stirred with ice. It was filtered off with suction and dried. 9.6 g of 4-chloro-7- (4'-bromophenoxymethyl) -G-ethyl-quinoline ^ -carboxylic acid ethyl ester were obtained. Melting point 142 to 147 ⁰ O.

Example 30

26.9 g of ethyl 4-chloro-7- (4'-bromophenoxymethyl) -6-ethylquinoline-3-carboxylate were heated on a water bath with 216 ml of dimethyl sulfoxide for 2 hours. After cooling, it was filtered off with suction, washed with dimethyl sulfoxide and dried in a drying cabinet. 18.3 g of ethyl 4-hydroxy-7- (4'-bromophenoxymethyl) -6-ethylquinoline-3-carboxylate were obtained. Melting point 287 ⁰ C.

Example 31

40.0 g of 4-chloro-7- (4'-bromophenoxymethyl) -6-ethylquinoline-3-carboxylic acid ethyl ester were with 500 ml of abs. Ethanol and 4 ml conc. Hydrochloric acid heated under reflux for 10 h. It was filtered off with suction and washed with ethanol. There were 33.4 g of 4-hydroxy-7- (4'-bromophenoxymethyl) -o-äthylchinolin-S-carboxylic acid ethyl ester obtained · Melting point 281-286 ⁰ G.

909836/0490

23S4558

Example 32 .

38.5 g of ethyl 4-hydroxy-7- (4'-chlorophenoxymethyl) -6-ethylquinoline-3-carboxylate, 88.0 g of acetic anhydride and 25 g of anhydrous potassium acetate were refluxed for 4 hours. After the reaction mixture had cooled to 100 ^° C., it was filtered off with suction and dried in a drying cabinet. 27.0 g of 4-acetoxy-7- (4'-chlorophenozymethyl) -G-ethylquinoline ^ -carboxylic acid ethyl ester were obtained. Melting point 145 to 147 ° C.

The ^ erbungen according to the invention were used in primary screening of coccidiostats selected with Eimeria tenella and were particularly characterized by a positive influence on the weight development of the test animals.

Leghorn chicks 5-7 days old received 25,000 transported oocysts from Eimeria tenella. The medication of the active ingredient took place via the putter and extended from the 1st to the 5th day after the infection. On the 8th ^x ag post infection, the surviving animals were killed and dissected. Lethality, morbidity and weight gain serve as test parameters. Table 1 compares the results from the primary screening. Even here, the particularly good weight gains stand out, which are above the standard control group (METIGHLOR-PIIiDOL) and in some cases better than that of the control group.

In the event of a massive infection with a highly virulent strain of Eimeriatenella, which causes a mortality of 37.5% in the infection control group, prevent the substances described in the doses of 100 and 50 ppm no longer an acute outbreak of coccidiosis, but influence the course of the disease positive and show a better weight gain than the animals treated with HETICHLOR-PIUDOL (standard control group), as well as a very good general condition.

The results of the in-depth pharmacological-parasitological Investigations (secondary screening) showed that the substances according to the invention provide reliable protection against economic ones

909836/0490

2654558

-si? -

Losses from various types of pathogen in goccidiosis (Appendix, small and large intestine) Table 2-4

It can be seen that the excitation cycle in the commercially available Dosages are not completely interrupted as there will be low oocyst excretion with the medication of the substances described comes · This allows the development of an immunity during the feeding of the active substance, what happens through reinfection was tested after discontinuation of the substances according to the invention (Table 5)

The very low toxicity of the invention should be emphasized Connection both with a single oral administration and with permanent application via the butter · After a single Oral application of 9,000 mg / kg KEI in Tylose suspension of the substances described do not fry any deviating from normal clinical and pathological-anatomical findings on

The compounds of the invention were tested in a 56 day trial (Broiler fattening period) tested for tolerance · The broilers were kept on deep litter and the application of the Substances passed through the putter

Test parameters were:

- weight development

- Assessment of the general condition during the entire experiment

- Section findings of 5 animals per test group on the 21st day of the test and of 20 animals each on the 56th day of the experiment, as well as pathological-histological evaluation

- various clinical-chemical (e.g. blood sugar content, GOT, LHP, AP, LDH determination) and hematological-morphological (erythrocyte count, leukocyte count, hematocrit, differential blood count) parameter

- the putter effort calculated at the end of the experiment per kg gain in live weight «

909836/0490

2614558

Long-term application of up to 800 ppm of the compounds according to the invention was tolerated by the broilers without adversely affecting the test providers. The weight gain in the V _er. Search groups during these long-term experiments were higher than those of the empty control and standard control groups.

The compounds according to the invention act as broad-spectrum coccidiostats which allow the formation of immunity (Table 5). They can therefore be used in broiler fattening as well as in the rearing of laying hens.

The optimal concentration of the agents depends on the species and the purpose of treatment, i. H. Prophylaxis or therapy and will range between 80 and 120 ppm in the putter.

909836/0490

Table 1:

2914558

Comparison of the coccidiostatic effectiveness of two substances

(Tt)

of the general formula I and METICHLOR-: Pindol ^v 'after infection of 25,000 oocysts each of Eimeria tenella that were deported to 5-7 days old male Leghorn chicks.

dosage Lethality morbidity Weight to substance in ppm % % taking in g Empty control 0 0 20.4 Infection control 14.5 100 11.3 METIGHLOR-PIHDOL 1,000 0 0 10.1 Substance A 1,000 0 0 16.3 Substance B 1,000 0 0 13.8 Empty control 0 0 27.8 Infection control 14.7 100 19.9 METIGfILOR-PINDOL 200 0 95.0 20.2 Substance A 200 5 10.5 30.9 Substance B 200 0 65 33.0 L e erko ntro11e 0 0 31.1 Infection control 37.5 100 12.9 METICHLORINE-PHnX) L 100 5 100 14.7 Substance A 100 5 100 15.4 Substance A 50 30th 100 13.1 Substance B 100 10 100 21.3 Substance B 50 25th 100 19.5

Substand A:

= OH;

4-methylphenyl X = O

Substance B:

= OH;

X = O

- = 4-chlorophenyl,

909836/0490

Table 2: Results of the secondary screening with Eitneria tenella
- 25,000 oooysts / chicks (4 weeks old) transported

substance dosage Lethality 0 Morbidity 0 0 weight gain Oocysts from r 1 ppm % 15th Ji 100 in g divorce in % Empty control 0 80 140.8 0 Infection control 10 77.7 93.2 100 Amprol plus 50 0 20th 127.3 53.8 100 20th 100 139.7 19.3 (O
ο 200 0 80 115.4 20.4 co
α » Substance A 50 0 75 146.5 34.8 (O
ο * 100 0 80 138.6 74.8 200 0 40 150.3 59.4 4M Substance B 50 0 0 116.1 76.7 tv
O 100 138.6 40.4 200 152.5 22.0

Table 3 »Results of the secondary screening with Eimeria acervulina - 120,000 transported oocysts / chicks (3 weeks old)

substance

dosage

Lethality

Morbidity weight gain
in g

Oocyst excretion %

Empty control

9098 Infection ControlJ
Amprol plus Le
50 co. 100 O;-
<0 Substance A 200
50
100 200 Substance 6 50 100 200

0 0

0 0 0

0 0 0

10 0

0 100

80 100 100

100 100 100

100 100 100

116.4 0 92.7 100 100.5 113.3 115.7 152.7 139.1 26.1 84.4 35.6 113.1 20.7 121.5 10.6 105.7 60.6 96.8 21.8 123.7 6.7

Table 4: Results of the secondary screening with Eimeria brunetti - 90 000 transported oocysts / chicks (9 days old)

substance

Dosage ppm

L et al it ät

Morbidity 5 "

Weight gain
in g

0οcyst excretion in %

CO
O
(O CO

Empty control Infection control METICLOS-FINDOL Substance A

Substance B

100

200 100

50

200 100

50

0 0 0 100 0 90 0 50 0 70 0 100 10 ^x ) 88.8 0 100 0 90

102.4 0 56.8 100 90.0 0.24 96.9 0.45 91.6 0.17 98.7 0.35 88.2 0.167 95.4 0.048 96.0 0.189

) Unexplained death, not due to goccidiosis ro «N cn

Table 5? Examination of a trained immunity by reinfection attempts

Test animals: 28-day-old Leghorn chicks, 1st infection with 15,000 and after 7 days

Reinfection with 30,000 sports Eimeria tenella oocysts, 1st to 6th day of the experiment, application of 100 ppm substance via the feed

substance

Ti narrate

CD O CO

LK

VK

IK

METICLOR-PINDOL

Substance A

Substance B

substance

LK

VK

IK

METICLOB PINDOL

Substance A

Substance B

20 10 10 20 20 20

Animal number

20 10 10 20 20 20

7 days after infection

Lethality % 0 Weight szun all me in

166 126

174

160.5

176.5

7th day post reinfection morbidity) %

Lethality % ft Weight gain in g chronologically

acute

232

142.5

184

236

215

232

87.5 22 80 80

LK = empty control, VK = experimental control group - no medication, infected on day 7, IK = infection control group - not medicated, infected on the 1st and 7th day,

^x ) Morbidity of the survivors was determined by dissection and differentiated according to chronic (1st infection) and acute (2nd infection).

eerse

it

Number: 2854558 Int. CI.2: C 07 D 215/54 Registration date: 18th December 1978 2854558 Disclosure date: September 6, 1979

COOR

COOCH 2 5

Il

909836/0490

Claims (40)

1. Process for the preparation of substituted quinolines general formula I, COOR ₁ in which E ^ an alkyl or alkenyl radical with 1 to 4 carbon atoms, H £ halogen, in particular chlorine or bromine, B * hydrogen or alkyl with 1 to 10 carbon atoms, B * an optionally duroh halogen, alkoxy, aryloxy, alkylthio , Alkyl, aryl, acyl and carbalkoxy substituted phenyl or naphthyl radical and X is oxygen or sulfur, characterized in that substituted β-phenylamino - oCoarbalkoxy-acrylic acid esters are heated in phosphorus oxyhalides. 2. The method according to item 1, characterized in that connections of the general formula I, in which B £ is hydroxyl, are heated with phosphorus oxyhalides. 3. Process for the preparation of substituted quinolines of the general formula I in which E _{1 is} an alkyl or alkenyl radical with 1 to 4 carbon atoms, B £ hydroxy, B ^ hydrogen or alkyl with Λ to 10 carbon atoms, E ^ a optionally by halogen, alkoxy, aryloxy, alkylthio, alkyl, aryl, acyl and carbalkoxy-substituted phenyl or haphthyl radical and X is oxygen or sulfur, characterized in that compounds of the general formula 1 in which B is halogen, with hydrochloric acid in alcoholic Solution to be heated. 4 · Method according to point 3, characterized in that compounds of the general formula 1 in which H ^ is halogen are heated with dimethyl sulfoxide. 909836/0490 ORIGINAL INSPECTED 2354558 -λ- 5. The method according to point 3> characterized in that substituted P-phenylamino-Ofecarbalkoxyacrylic acid esters obtained from substituted 5-amino-2-R., - Benzyl ethers or thioethers by the action of ortho-formic esters and malonic esters or alkoxymethylene malonic esters by heating in inert diluents Temperatures above 200 ⁰ C cyclized v / ground. 6. Procedure according to points 3 and 5> characterized in that the ring closure is effected by the action of mixtures of phosphorus pentoxide and alcohols, expediently in inert solvents, is consumed. 7. The method according to item 3 »characterized in that connections of the general formula I, in which R .. hydrogen means by heating with alcohols in the presence of mineral acids or cation exchangers in protonated Esterified form. 3. The method according to item 3> characterized in that connections of the general formula I, in which R .. denotes hydrogen, into a reactive acid derivative, preferably acid chloride, transferred and heated with alcohols. 9. ^ experience the production of substituted quinolines General formula I in which R _{1 is} an alkyl or alkenyl radical with 1 to 4 carbon atoms, Rp is alkoxy with 1 to 6 carbon atoms, R is hydrogen or alkyl with 1 to 10 carbon atoms, R, one optionally by halogen , Alkoxy, aryloxy, alkylthio, alkyl, aryl, acyl and carbalko & y substituted phenyl or uaphthyl radical and X denotes oxygen or sulfur, characterized in that compounds of the general formula I in which Rp denotes halogen are reacted with alcoholates. 909836/0490 1 ^night Process for the preparation of substituted quinolines of the general formula I ₅ in which R _{1 is} an alkyl or alkenyl radical having 1 to 4 carbon atoms, Rp is an optionally substituted by halogen acyloxy radical having 1 to 5 carbon atoms, R ^ is hydrogen or alkyl having 1 to 10 carbon atoms, R. a phenyl or ITaphthyl radical optionally substituted by halogen, alkoxy, aryloxy, alkylthio, alkyl, aryl, acyl and carbalkoxy and X denotes oxygen or sulfur, characterized in that compounds of the general formula I in which R. ₂ halogen means to be reacted with metal salts of the acid corresponding to the acyl radical. 11. The method according to item 10, characterized in that compounds of the general formula I in which R _? Hydroxyl means reacted with reactive acid derivatives, preferably acid anhydrides. 12. Compounds of general formula I, characterized in that that R ^ is an alkyl or alkenyl radical with 1 to 4 carbon atoms, Rp is alkoxy with 1 to 6 carbon atoms, optionally one halogen-substituted acyloxy radical with 1 to 5 carbon atoms, halogen, in particular chlorine and bromine, hydroxy, R, hydrogen or alkyl with 1 to 10 carbon atoms, R * one optionally by halogen, alkoxy, aryloxy, alkylthio, Alkyl, aryl, acyl and carbalkoxy-substituted phenyl or maphthyl radical and X is oxygen or sulfur. 13. 4-Hydroxy-7- (4 '-methylphenoxymethyl) -S-ethyl-quinoline ^ - carbonic acid ethers 14. ^. ^T Iy '"lro: -cy-7-phenoxymethyl-6-ethyl-quinoline-3-carboxylic acid ethyl ester 15. 4-n-Kexyloxy-7- (4 ¹ -methylthiophenoxymethyl) -quinoline-3-carboxylic acid ester 1 6. 4-Hydroxy-7- (? - '-najtthoyymethyl) -Ö-ethyl-quinoline ^ -carboxylic acid ethyl ester 909836/0490 23 * 4558 17. 4-Methoxy-7- (2x-ethylphenoxymethyl) -S-carboxylic acid methyl ester 18. 4 ~ Hydroxy-7- (4 ^l -chlorophenoxymethyl) -Ö-ethyl-quinoline ^ -carboxylic acid ethyl ester 19. 4-Trimethylacetoxy-7- (4 ^f -chlorophenoxymethyl) -6-ethylquinoline-5-carboxylic acid ethyl ester 20. 4-Hydroxy-7- (2'-chlorophenoxymethyl) -6-eth3 ^ 1-quinoline-3-carboxylic acid eäthyl ea t er 21. 4-hydroxy-7- (2 ^t -methoxyphenoxymethyl) -6-ethyl-quinoline-3 carboxylic acid ethyl ester 22. 4-Hydroxy-7- (4'-methylphenylmercaptomethyl) -6-ethylquinoline-3-carboxylic acid ethyl ester 23t 4-Hydroxy-7- (1 '-naphthoxymethylJ-G-ethyl-quinoline ^ - carboxylic acid ethers 24. 4-hydroxy-7- (4'-methoxyphenoxymethyl) ^{-6-ethyl-quinoline-3-r} carbonsäureäth3 lester 25. 4-Hydroxy-7- (4 ¹ -ethoxyphenoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ethyl ester 26. 4-Hydroxy-7- (4 ^f -ethylphenoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ethyl ester 27. 4-Hydroxy-7- (4 ¹ -actylphenoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ethyl ester 28. 4-Hydroxy-7- (3 '-tdyloxymethyl) -G-ethyl-quinoline ^ - ethyl carboxylate 29. 4-Hydroxy-7- (4'-chloro-3'-methylphenoxymethyl) -6-ethylquinoline-3-carboxylic acid ethyl ester 909836/0490 2914558 30. 4-Hydroxy-7- (2 ^l -chlorophenoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ethyl ester 31. 4-Hydroxy-7- (2 ', 4 ¹ -dichlorophenoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ethyl ester 32. 4-Hydroxy-7- (2'-tolyloxymethyl) -6-ethyl-quinoline-3-carbon acid ethyl ester 33. 4-Hydroxy-7- (2'-ethylphenoxymethyl) -ö-ethyl-quinoline ^ - ethyl carboxylate 34. 4-Hydroxy-7- (4'-iodophenoxymethyl) -6-ethyl-quinoline-3-carbomic acid ethyl ester 35. 4-Hydroxy-7- (4 ^l IT, IT-dimethylanilinoxymethyl) -6-ethylquinoline-3-carboxylic acid ethyl ester 36. 4-Hydroxy-7- (4'-carbethoxyphenoxymethyl) -6-ethyl-quinoline-3-ca3? -Bo acid ethyl ester 37. 4-Hydroxy-7- (4'-phenoxyphenoxymethyl) -6-ethyl-chiholin-3-carboxylic acid ethyl ester 38. 4-chloro-7- (4 ^f bromophenoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ethyl ester 39. 4-Hydroxy-7- (4 ^l -bromophenoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ethyl ester 40. 4-Acetoxy-7- (4'-chlorophenoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ethyl ester 909836 / 0A90