HU182510B - Process for producing substituted quinoline derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of substituted quinolines which have in the 3-position a carboxyl group esterified with a lower alcohol and in the 4-position halogen or a free, etherified or esterified hydroxyl group having activity against coccidiosis. It has been found that compounds which, unlike known coccidioic quinolines, do not bear oxygen or sulfur on the benzoic part of the molecule, have excellent properties. The compounds according to the invention are characterized by the general formula I in which R ind 1 is an alkyl or having 1 to 4 C atoms, R 2 is halogen, in particular chlorine and bromine, hydroxy having 1 to 6 C atoms or an optionally halogen-substituted one Acyloxyrest having 1 to 5 carbon atoms, R ind 3 is hydrogen or alkyl having 1 to 10 carbon atoms, R ind 4 is an optionally substituted by halogen, alkoxy, aryloxy, alkylthio, alkyl, aryl, acyl and carbalkoxy substituted phenyl or naphthyl radical and X is oxygen or sulfur. For the synthesis of the compounds of the invention is based on cheap nitrobenzenes, which are products of the chemical industry.

Description

The present invention relates to novel quinoline derivatives of general formula (I). In formula I, 5

R 1 is C 1-5 alkyl,

R2 is hydroxy,

R _{3 is C} 1-5 alkyl,

R4 is phenyl or naphthyl optionally substituted by halogen, alkoxy, aryloxy, alkyl, aryl, acyl or carbalkoxy; and

X is oxygen.

The compounds of formula (I) are prepared by methods known per se. The compounds are useful as active ingredients in anti-coccidiosis drugs.

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The present invention relates to novel quinoline derivatives. The new compounds are useful as active ingredients in anti-coccidiosis drugs.

Quinoline-3-carboxylic acid 4-substituted 4-position-containing alkoxy groups are known to be effective against coccidiosis. It is also known to have a configuration where an alkoxy group at the 6-position, an alkyl group at the 7-position, and the reverse arrangement is also known. Finally, 6-alkoxy-7-alkoxymethyl derivatives as well as the corresponding thio compounds are also known.

A common feature of said 4-substituted quinoline-3-carboxylic acid ester is that at the 6- and / or 7-positions, there is a chemical bond between the benzoid ₁₅ of the quinoline molecule and the oxygen or sulfur atom.

Quinolinecarboxylic acid derivatives of the structure described in claim expensive, usually in an amount corresponding to ₂₀ can not be obtained from raw materials in that their application limited by economic reasons.

SUMMARY OF THE INVENTION It is an object of the present invention to provide quinoline-3-carboxylic acid esters which are effective against coccidiosis by a simple process.

Containing a hydroxy quinoline derivatives to give highly effective coccidiostats and _two short chain alcohol esterified carboxyl group and the 4-position 3-position according to the invention. In fact, it has been found that, unlike known lanolin derivatives which are effective against coccidiosis, compounds which do not contain oxygen or sulfur in the benzoid portion of the molecule have excellent properties.

The compounds of the present invention have the general formula (I). In the general formula (I)

R 1 is C 1-5 alkyl,

R _{2 is} hydroxy,

R _{3 is C} 1-5 alkyl, 40

R4 is phenyl or naphthyl optionally substituted by halogen, alkoxy, aryloxy, alkyl, aryl, acyl or carbalkoxy; and

X is oxygen.

The 3-aminobenzyl ethers are converted into the compounds of formula (I) or their intermediates by reaction with ortho-formic acid ester and malonic acid ester in various ways.

For this purpose, N-alkoxymethylene aniline and substituted N, N'-bisphenylformamidine derivatives, which are substituted with malonic acid esters / N-phenylamino-α-carbalkoxyacrylic acid, are prepared from 3-aminobenzyl ethers by ortho-acetic acid ester. However, a process for preparing the substituted 3-aminobenzyl ether with alkoxymethylene malonate is preferred for the preparation of the substituted 3-phenylamino-α-carboxyalkoxyacrylic acid esters.

When the substituted 0-phenylamino-α-carbalkoxy acrylic acid esters in inert organic solvents such as paraffin, diphenyl or diphenyloxide are optionally added in the presence of a catalytic amount of a metal halide such as zinc chloride, zinc acetate, nickel sulfate or cobalt chloride, 65 Compounds of general formula (I) are obtained directly. Substituted 3-phenylamino-α-carbalkoxy acrylic acid esters can be cyclized to a quinoline derivative with a mixture of phosphorus pentoxide, alcohols and an inert solvent such as xylene.

The same compounds may also be prepared by heating a mixture of 3-aminobenzyl ethers and / or thioethers, ortho formic acid and malonic esters in inert diluents or treating them with a mixture of phosphorus pentoxide and an alcohol; in this case, the substituted / 3-phenylarnino-α-carbalkoxyacrylic acid esters are formed in situ.

(1) resulting in compound of formula cyclization methods already mentioned hydroxyl, R ₂ is particularly suitable for continuous operation.

Compounds of formula (I) wherein R ₂ is halogen are prepared by heating the substituted β-phenylamino-α-carbalkoxyacrylic acid esters in phosphorus oxyhalides, preferably in phosphorus oxychloride, at a temperature of 80-100 ° C, using an organic solvent or solvent. excess phosphorus oxychloride is used. The obtained, R; The compounds of formula (I) wherein R ₂ is halogen are converted to the compounds of formula (I) wherein R ₂ is hydroxy when heated with alcoholic hydrochloric acid or dimethylsulfoxide.

Compounds of formula (I) wherein R ₂ is hydroxy may also be prepared by esterification of compounds wherein R 1 is hydrogen. The esterification is acidally catalyzed, for example, by addition of mineral acids such as hydrochloric acid or sulfuric acid or by using an H-form cation exchanger or by reacting a reactive derivative of the substituted quinoline-3-carboxylic acid, such as acid chloride (preferably from acid and thionyl chloride).

The process according to the invention is based on the cheap nitrobenzenes which are dichloromethylated by known methods, preferably chloromethylalkyl ethers.

Said nitrobenzyl chlorides can be converted to substituted phenyl or naphthyl 3-nitrobenzyl ethers by reaction with phenols and naphthols in the presence of basic agents and preferably in the presence of inert solvents (particularly preferably potassium carbonate and acetone).

The resulting nitrobenzyl ethers are converted to 3-aminobenzylethers substituted by reduction such as catalytic hydrogenation, hydrazine, metals or sulfides.

In accordance with the present invention, inexpensive starting materials are prepared in simple process steps from high-potency coccidial inhibitors.

Execution examples

Preparation of starting materials

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 3

A mixture of -2182510 and 200 ml of acetone was refluxed for 12 hours. After addition of one liter of water, the organic phase is separated. 86.6 g of crude 4-nitro-2- (4'-methyl-phenoxymethyl) -ethylbenzene are obtained.

86.6 g of crude 4-nitro-2- (4'-methylphenoxymethyl) ethylbenzene are dissolved in 600 ml of ethanol and 160 g of 25% hydrazine hydrate are added. Raney nickel was added in small portions at 30-40 ° C with stirring until gas evolution ceased. The mixture is refluxed for 1 hour, the catalyst is filtered off, the solvent is distilled off in vacuo, the organic phase is separated off and then distilled. 72.5 g of 4-amino-2- (4'-methylphenoxymethyl) ethylbenzene are obtained. Boiling point 165 ° C / 0.1 mm Hg; n ²⁰ : 1.5956; N. = 5.81%;

_ _ _. _14 s z3 m.

N, _t = 6.10%.

A mixture of 69.1 g of ethoxymethylene malonate, 72.0 g of 4-amino-2- (4'-methylphenoxymethyl) ethylbenzene and 100 ml of ethanol is refluxed for 1 hour and the solvent is removed. 118.4 g of ethyl [3- (4'-methylphenoxymethyl) -4-ethylphenylamino] -? - carboxyoxyacrylic acid are obtained.

Example 1

118.4 g of ethyl 3- (3- [4- (4'-methylphenoxymethyl) -4-ethylphenylamino] -? - carbethoxyacrylic acid) are added to 200 ml of paraffin oil at 160 [deg.] C. The mixture is rapidly mixed at 245 [deg.] C. After warming to C, stirring at this temperature for 15 minutes, the solid was filtered off with suction, washed with gasoline and then boiled in ethyl acetate to give 28.5 g of 4-hydroxy-7- (4'-methylphenoxymethyl) -6. ethyl-quinoline-3-carboxylic acid ethyl ester, mp 264-269 ° C. N _numbers. = 3.84%, N, _b1. = 4.12%.

Example 2

105.0 g of ethyl ethyl o- (3-phenoxymethyl-4-ethylphenylamino) -α-carbethoxy acrylic acid are added dropwise at 160 ° C to 200 ml of paraffin oil. The mixture was quickly heated to 245 ° C and stirred at this temperature for 15 minutes. The processing is as described in Example 1. Yield: 21.8 g of ethyl 4-hydroxy-7-phenoxymethyl-6-ethylquinoline-3-carboxylic acid, m.p. 271-274 ° C; ^N % - ³ >%> ^N , al = ⁴ > ⁰⁷ % ·

Example 3

83.7 g of ethyl ethyl g- [3- (2'-naphthoxymethyl) -4-ethylphenylamino] -acarbethoxy acrylic acid are added to 200 ml of 160 ° C paraffin oil. The mixture was heated rapidly to 250 ° C and maintained at this temperature for 15 minutes. After conventional work-up, 10.7 g of ethyl 4-hydroxy-7- (2'-naphthoxymethyl) -6-ethylquinoline-3-carboxylic acid are obtained, m.p. 263-267 ° C.

EXAMPLE 4 To 37 ml of technical grade xylene with stirring was added 37 g of phosphorus pentoxide at room temperature, and 22 ml of anhydrous ethanol was added dropwise at a temperature such that the temperature of the reaction mixture did not exceed 100 ° C. To the mixture was added 43.2 g of ethyl N- [3- (2'-chlorophenoxymethyl) -4-ethylphenylamino] -acarbethoxy acrylic acid, kept at 150 ° C for 30 minutes, and the mixture was cooled. The reaction mixture was poured onto ice, neutralized with ammonia gas, filtered off with suction, dried, boiled in ethyl acetate and filtered again. 28.4 g of 4-hydroxy-7- (2'-chloro-phenoxymethyl) -6-ethyl-quinoline-3-carboxylic acid ethyl ester, mp 269-274 ^o C. N _number . = 3.63%, N _tal . = 4.05%.

Example 5

81.4 g of 0- [3- (2'-methoxyphenoxymethyl) -4-ethylphenoxymethyl] -? - carbethoxyacrylic acid ethyl ester are added at 200C to 200 ml of paraffin oil. The mixture was rapidly heated to 245 ° C and stirred at this temperature for 15 minutes. After cooling, the solid was separated, washed with gas and boiled in ethyl acetate. 10.6 g of ethyl 4-hydroxy-7- (2'-methoxyphenoxymethyl) -6-ethylquinoline-3-carboxylic acid are obtained, m.p. 256-261 ° C. _No. N a _m. = 3.68%, N _ta i. = 3.68%.

Example 6

The ethyl ester of 4-hydroxy-7- (4'-methylphenylmercaptomethyl) -6-ethylquinoline-3-carboxylic acid was prepared as in Example 5. M.p. 278-283 ° C.

Example 7

As in Example 5, 4-hydroxy-7- (1'-naphthoxymethyl) -6-ethylquinoline-3-carboxylic acid ethyl ester was prepared. Mp 235-240 ° C.

8-9 Examples

The following table summarizes further compounds of Formula I. The compounds correspond to Formula II, which is a narrower group of Formula I, wherein R 4 is mono- or polysubstituted phenyl. The substituents on the phenyl group are given in the table.

See table on page 5!

Example 24

26.9 g of ethyl 4-chloro-7- (4'-bromophenoxymethyl) -6-ethylquinoline-3-carboxylic acid and 216 ml of dimethylsulfoxide are heated in a water bath for 2 hours. After cooling, the solid is filtered off with suction, washed with dimethyl sulfoxide and dried in an oven. 18.3 g of ethyl 4-hydroxy-7- (4'-bromophenoxymethyl) -6-ethylquinoline-3-carboxylic acid are obtained, m.p. 287 ° C.

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Example R7 Rs M.p. Nszám. N _ta i. 8 H H cl 275-280 3.63 3.62 9 H H Br 281-286 10 H H CH ₃ O 257-261 11 H H C ₂ H _f O 265-270 12 H H c ₂ h _s 171-175 13 H H COCH ₃ 280-285 14 H ch ₃ H 286-289 3.84 3.72 15 H ch ₃ cl 285-290 16 the H H 270-275 3.63 4.07 17 the H cl 275-285 18 ch ₃ H H 256-259 3.84 4.16 19 c ₂ h ₅ H H 263-266 3.70 3.54 20 H H J 280-285 2.94 3.42 21 H H N (CH ₃ ) ₂ Over 300 22 H H COOC ₂ Hs 265-270 23 H H c ₆ h ₅ o 272-276

Example 25

A mixture of 40.0 g of ethyl 4-chloro-7- (4'-bromophenoxymethyl) -6-ethylquinoline-3-carboxylic acid, 500 ml of anhydrous ethanol and 4 ml of concentrated hydrochloric acid is refluxed for 10 hours. . The solid was filtered off with suction and washed with ethanol. 33.4 g of ethyl 4-hydroxy-7- (4'-bromophenoxymethyl) -6-ethylquinoline-3-carboxylic acid are obtained, m.p. 281-286 ° C.

The compounds of the present invention are primarily selected for the coccidiostatic activity by the microorganism Eimeria tenella. In particular, the compounds had a beneficial effect on the weight of experimental animals.

5-7 day old chickens (Leghom breed) were infected with 25,000 oocysts encapsulated in Eimeria tenella spore. The compounds to be tested are shown in Figures 1-5 after infection. on the day. 8 days after infection, the remaining animals were killed and necropsied. Examination parameters: mortality rate, disease symptoms, weight gain. The results are shown in Table 1 below, where the effects of two compounds of the invention are compared with those of the known METICHLOR-Pindol.

Compound A): R 1 = C ₂ H _S , R ₂ = OH, R ₃ = C ₂ H _S , R * = 4-methylphenyl? .

X = O;

B. The active compound): R, = C ₂ H _s; R ₂ = OH, R ₃ = C ₂ H _5, R 4 is 4-chloro-phenyl,

X = O.

The experimental chickens were male.

Table 1

Active substance or treatment Dose in ppm Mortality rate (%) Weight gain g blank control 0 0 20.4 infected control 14.5 100 11.3 METICHLOR-PINDOL 1000 0 0 10.1 Active ingredient A) 1000 0 0 16.3 Active ingredient (B) 1000 0 0 13.8 blank control 0 0 27.8 infected control 14.7 100 19.9 METICHLOR-PINDOL 200 0 95.0 20.2 Active ingredient A) 200 5 10.5 30.9 Active ingredient (B) 200 0 65 33.0 blank control 0 0 31.1 infected control 37.5 100 12.9

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Claims (5)

1. Continue Table Active substance or treatment Dose in ppm Mortality rate (%) Weight gain g METICHLOR-PINDOL 100 5 100 14.7 Active ingredient A) 100 5 100 15.4 50 30 100 13.1 Active ingredient (B) 100 10 100 21.3 50 25 100 19.5 especially the compounds of the invention 20 The favorable results of the above experiments al is characterized by good weight gain, which outweighs not only the weight gain of the known drug-treated group but also, in some cases, the control of the uninfected. The strain used for infection, Eimeria tenella, is highly virulent and causes 37.5% mortality in the infected control group. The test compounds, at doses below 200 ppm, are no longer able to prevent the onset of coccidiosis, but even at doses of 100 and 50 ppm, they have a beneficial effect on the course of the disease and on weight gain. The treated chickens also felt better. compounds have also been tested using other coccidiosis microorganisms, and have been found to provide reliable protection against the economic losses of various coccidiosis cultivated in the small intestine and the small intestine. 2-4. Table 1 shows that the compounds do not completely interrupt the disease cycle at the usual doses, since the animals produce a small amount of oocysts during treatment. As a result, immunity may develop during the treatment period, as shown by the experimental data in Table 5 (drug discontinuation followed by re-infection). Table 2 Experiment with 4 week old chickens (25,000 oocysts / chicken). Pathogen: Eimeria tenella Treatment mortality disease The proportion φ weight gain. g Oocystic Choice % blank control 0 0 140.8 0 infected control 15 100 93.2 100 Amprol plus (50 ppm) 0 80 127.3 53.8 100 ppm 10 77.7 139.7 19.3 200 ppm 0 20 115.4 20.4 Substance A) 50 ppm 20 100 146.5 34.8 100 ppm 0 80 138.6 74.8 200 ppm 0 75 150.3 59.4 Active ingredient (B) 50 ppm 0 80 116.1 76.7 100 ppm 0 40 138.6 40.4 200 ppm 0 0 152.5 22.0 -5182510 Table 3 Experiment with 3-week-old chickens: Eimeria acervulína; (120,000 oocysts / chicken encased in spores) Treatment mortality disease The proportion Φ weight gain. g Oocystic Choice % blank control 0 0 116.4 0 .. infected control 0 100 92.7 100 Amprol plus 50 ppm 0 80 100.5 113.3 100 ppm 0 100 115.7 152.7 200 ppm 0 100 139.1 26.1 The active ingredient is 50 ppm 0 100 84.4 35.6 100 ppm 0 100 113.1 20.7 200 ppm 0 100 121.5 10.6 Substance B) 50 ppm 0 100 105.7 60.6 100 ppm 10 100 96.8 21.8 200 ppm 0 100 123.7 6.7 Table 4 Experiment with 9-day-old chickens, pathogen: Eimeria brunetti (90,000 oocysts / chicken) Treatment mortality disease The proportion 0súly- gyarap. g Oocystic Choice % blank control 0 10 102.4 0 infected control 0 100 56.8 100 METIKLOR-PINDOL 100 ppm 0 90 90.0 0.24 Substance A) 200 ppm 0 50 96.9 0.45 100 ppm 0 70 91.6 0.17 50 ppm 0 100 98.7 0.35 Substance B) 200 ppm 10+ ⁾ 88.8 88.2 0.167 100 ppm 0 100 95.4 0,048 50 ppm 0 90 96.0 0.189 ⁺ ) The cause of death was unclear, but there was no coccidiosis. -6182510 Table 5 Experiment on 28 day old chickens (Leghorn breed) to test for immunity. 15,000 oocysts were used for infection 1, and 30,000 oocysts (Eimeria tenella) were used for infection 7 days later; 100 ppm test compound in food daily. Treatment (the experimental 7 days after infection number of animals) death% Φ weight gain, g blank control (20) 0 166 infected control (infected on day 7) (10) 0 126 infected control (infected on days 1 and 7) (10) 10 141 METICLOR-PINDOL (20) 5 174 Substance A) (20) 0 1604 Substance B) (2) 0 176.5 7 days after the second infection death, % φ weight gain, cause of death 1.2. infection ♦)% blank control (20) 0 232 0 0 infected control (10) 20 142.5 100 (Infected on day 7) infected control (10) 10 184 87.5 12.5 (Infected on days 1 and 7) METICLOR-PINDOL (20) 0 236 22 68 Substance A) (20) 5 215 80 Substance B) (20) 0 232 80 An autopsy of the animals was used to determine the percentage of deaths that caused the first and the percentage of the second infection. Of note is the low toxicity of the compounds both in single oral administration and in long term (dietary) administration. For single oral administration, a dose of 9000 mg / kg in tilose suspension was used. No clinical or pathological autopsy findings were observed. The tolerability of the compounds was also tested in a 56-day experiment (the time required for fattening the barbecue chicken). The chickens were kept on fodder and the test compounds were applied to the diet. The following parameters were examined: - changes in weight, - well-being, - 5 animals per experimental group on day 21, the On day 56, 20 animals were necropsied, the allele was evaluated pathologically and histologically, - chemical tests (blood glucose, G0T, LHP, AP, LDH determination) and blood tests (red and white blood cell count, hemotocrit, etc.), - at the end of the experiment, the amount of feed used per 1 kg of weight gain was calculated. Sustained consumption of the compounds at 800 ppm did not produce any negative symptoms. Weight gain outweighed that of the blank control and comparator treated groups. The compounds of the present invention have a broad spectrum coccidiostatic activity and are therefore useful in both chicken fattening and rearing. The optimal concentration will depend on the species of animal being treated and the purpose of the treatment (treatment or prevention). The concentration of the compounds in the feed is generally between 80 and 120 ppm. Claim: Process Quinoline Derivatives of Formula I - Formula I R 1 is C 1 -C 5 alkyl, R _{2 is} hydroxy, -716 812 510 R _{3 is C} 1-5 alkyl, R 4 is phenyl or naphthyl optionally substituted by halogen, alkoxy, aryloxy, alkyl, arl, acyl or carbalkoxy; X represents an oxygen atom for the production of - ⁵ , characterized in that a) Substituted 0-phenylamino-α-carbalkoxy acrylic acid esters obtained from d-substituted 5-amino-2-R _3- benzyl ethers by reaction with ortho-formic and malonic acid esters or alkoxymethyl malonic acid esters in an inert solvent at 200 ° C. or by heating with a mixture of phosphorus pentoxide and an alcohol to give the compound of formula (I), or b) cyclizing the appropriately substituted 0-phenylamino-α-carbalkoxyacrylic acid esters to a substituted 4-haloquinoline derivative with phosphorus oxyhalides and reacting them with alcoholic hydrochloric acid or dimethylformamide to form the compound of formula I, or c) converting a compound of formula I wherein R ₁ is hydrogen, wherein R ₂ , R ₃ , R 4 and X are as defined above, into a reactive acid derivative, preferably an acid chloride, and reacting the acid derivative with the corresponding alcohol. 1 drawing, 2 formulas Responsible for publishing: Director of Economic and Legal Publishing House 85.4008 - Zrínyi Nyomda, Budapest -8182510 International Classification: C 07 D 215/56