IL28656A - 4-hydroxy-3-quinoline-carboxylic acid compounds,their manufacture and animal feedstuffs containing them - Google Patents

Description

4*%drozy*3^lnoline^ar¾oxylie acid compounds^their manufacture and animal feedstuffe containing them .

CIBA-GEIGI A .

C? 27213 butyl, sec — butyl or tert. -butyl group, a . free ;hydroxy group, ! a lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, n-butyloxy or isobutyioxy group, a phenyl-lower alkoxy group, e.g. benzyl -oxy or.l ■ or 2-phenyleth.ny.y the group having the formula -X-A-R in which X, A and R have the previously given meaning, which ;wi hin. he definitions may differ from one another, halogen, e.g fluorine, chlorine or bromine atoms, trifluoromethyl, nitro, or . di —lower alkyl-amino, e.g. dimethylamino or diethylamino, .

; In. an ester of a compound of the formula I the esterifying portion is preferably a lower alkyl group, as well as a . phenyl-lower alkyl, e.g. a benzyl or 1- sor 2-phenylethyl group, whereas in a carbamyl or hydroazinocarbonyl group , the nitrogen atoms may optionally be substituted by lower, alkyl groups, as .· well a phenyl-lower alkyl group..

The group ^, apart from being hydrogen, ma also stand for lower alkyl as defined above. ; ^, which also stands. or hydrogen, is a lower. alkyl group as defined above5, as well as a lower alkyl radical (as represented, for example, by the above lower alkylene group A) substituted by phenyl. ' .'. ·· ■ i As indicated above, the .present invention also comprises the. tautom'ers of the compounds of the above formula I, in which is hydrogen, as well as O-esters of such tauto ers, in which the esterifying portion is preferably the acyl radical of a lower alkanoic, e.g. acetic, propionic or pivalic acid.

The compounds of this invention possess, valuable properties. Thus, they exhibit growth promoting effects, which can be demonstrated, for example, by feeding a feed containing from about 0.0001$ to about 0.1$ of the above compounds to 28656/2 chickens during part or during the whole span of their lives . These growth promoting effects can even be shown in diseased :: animals, for example, in poultr infected by bacteria and protozoa/ particularly by parasites causing cocc.idiosis, such as ' Eimeria teneJLla, Eiroeria acervuline, Eimeria adenoides, Eimeria aftridiS* Siberia brunetti, Eimeria hagani, Eimeria maxima or Eimeria nscatrix. The coccidiostatic effects can be demonstrated, for example, by feeding the above ifeedstuffs to chickens 1 to 2 days prior or then after their inoculation with sporulated oocysts of Eimeria strains.

The compounds of this invention are, therefore, useful as growth promoting agents, particularl in poultry, even in animals, especially in poultry, which are diseased with bacteria or protozoa infections, especially with coccidiosis - producing parasite infections. They are also useful as inter mediates in the manufacture of other valuable products .

•Particularly useful properties of the above type are shown by the compounds of the formula I, in which R, A, have the previously given meaning, and X -stands for an oxygen atom, and particularl the lower alk 1 esters of such compounds, as well as salts, such as ammonium, alkali metal, alkaline earth metal or acid addition salts thereof.

Useful properties of the above type are primarily exhibited by the compounds of the formula II OH in which compounds of formula II each of R' and R" stands for the identical cycloalkyl group having 3 to 6 ring carbon atoms and each of the letters n and m stands for the identical integer from 1 to 4» or in -which compounds of the formula II each of RT and Rn has the above meaning, and each of the letters n and m stands for 0, and in which compounds of formula II, one of the groups R* and R" is hydrogen and the other represents one of the above cycloalkyl groups having 3 to 6 ring carbon atoms and each of the letters n and m represents an integer from 1 to 4, or in which compounds of formula II one of the groups R' and RH is a phenyl group and the other represents a cycloalkyl group having ?—6 ring-carbon atoms, and each of n and m stands for an integer from 1 to 4, and particularly the lower alkyl esters of compounds of formula II, as well as ammonium, alkali metal, alkaline earth metal and acid addition salts, of such compounds, particularly their non-toxic salts of the above typee Of special value is the 6,7-bis-cyclopropylmethoxy-4-hydroxy-3-quinolinecarboxylic acid ethyl ester which, when given with a balanced feed at a level of about 0.001 to about 0.01% to healthy or infected (for example, with one of the above Bimeria strains) chickens, causes pronounced weight gains and The compounds of the present invention are prepared according to known methods, for example,/by ring-closing a di-lower alkyl ester or a s&ll¾¾e-lower alkyl-halfester of acom-pound of the formula in which RQ stands for a carbo-lower alkoxy group, and R^° represents a carbo-lower alkoxy group or a cyano group* or a tautomer of such compound, in which R_ represents hydroge by intramolcecular condensation, or'convert ng in a compound of the formula or an ester, an amide, a hydrazide or a nitrile thereof, in which Y is a functionally converted oxo group capable of being liberated by hydroljels, or in a tautomer of such compound, in which R¾ is hydrogen and Y is a halogen atom, the group Y into the oxo or hydroxyl group by hydrolysis, or ring-closing a compound of the formula in which one of the groups and Z≥ is a group of the formula -CO-R^ and the other is hydrogen, by intramolecular condensation, and, if desired, converting any resulting compound into another compound within the scope, of the invention.

A lower alkyl ester is e.g. the methyl or ethyl ester. Ring-closure is preferably carried out at an elevated temperature. A functional oxo derivative is, for example, an optionally substituted oxime, hydrazone or semicarbazone, as well as the imine, or a ketal, the latter preferably with a lower alkylene glycol.

The above-mentioned reactions are carried out according to standard methods, e.g. according to the Gould-Jacobs or Camps syntheses, in the presence or absence of solvents or diluents, preferably those inert towards the reaction components or of catalysts and/or condensing agents, if necessary, while cooling or heating, at increased pressure, and/or in the atmosphere of an inert gas-. Usually, condensing agents need not be present during reaction modification a), but may be useful in reaction c) in order to eliminate generated water; the usual acidic or basic dehydrating agents, e.g. zinc halides, phosphorus, oxyhalides or alkali- metal amides or alkoxides may serve in the elimination of water. Hydrolyzing agents used in reaction modification b), capable of generating a hydroxy and a keto group, respectively, are, for example, acidic agents, such as aqueous mineral, or carbo-xylic acids, such as hydrochloric or acetic acid, or basic reagents, e.g. alkali metal hydroxides, these reagents being used, if desired, in the presence of solvents, such as lower Resulting compounds of the invention may be converted into each other according · o known methods. Thus, compound containing free hydroxy o^-fi*e#fcai>&9- groups in the carbocyclic ring, may be etherified; by treatment with - a halogeno-lower alkene, a halogeno- lower alkoxy group may be introduced. Resulting esters, such as lower alkyl —, -—- ■. ;—'■— esters, may be hydrolyzed, for example, by treatment with alkali metal hydroxides or lower alkoxides, or transesterified in the presence of acidic or basic catalysts, or converted into amides or hydrazides by reaction with ammonia, amines or hydrazines, preferably lower alkyl-amines or lower alkyl-hydra zines. Resulting free acids may be esterified . or amidated, for example by way of the corresponding acid halides or anhydrides, which may be obtained for example, by reaction with thionyl halides or ketenes. Resulting compounds, unsub-stituted in 1-position, may be substituted in that position, for example, by treatment with reactive esters of corresponding alcohols, e.g. esters with hydrohalic, sulfuric or organic sulfonic acids, advantageously in an alkaline medium.

The compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which they are prepared; the salts are also included in the present invention. Resulting salts can be converted in a known manner, into the free acids and bases, respectively, for example, by treatment with acids, alkaline reagents or ion exchangers. Resulting free bases can be converted into acid addition salts e.g. by reaction with inorganic or organic acids, especially those suitable for the formation of non-toxic salts. Such acids are, for example, mineral acids, e.g. hydrochloric,hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or aliphatic or aromatic carboxylic or sulfonic acids, e^g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, maleic, hydroxy-maleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, an-thranilic, 4-hydroxybenzoic, salicylic, -amino-salicylic, embonic, nicotinic, methanesulfonic, ethanesul onic, hydroxy-ethanesulfonic, ethylenesulfonic, halogero-benzenesulfonic, toluenesulfonic, naphthalenesulfonic, N-cyclohexylsulfamic, and sulfanilic acid, as well as ascorbic acid. Resulting free acids may be converted into ammonium or metal salts, preferably those with ammonia or aliphatic amines, e.g. lower alkyl-amines, or with alkali metals or alkaline earth metals, e.g. sodium, potassium, magnesium or calcium.

These or other salts, for example, the picrates, can also be used for identification, as well as purification of resulting free compounds; thus, the latter may be converted, for example, in the reaction mixture into salts, resulting salts are separated and the free compounds may be liberated from the isolated salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a free compound or a salt is referred to in this context, a corresponding salt or free compound is also intended, provided such is possible or appropriate under the circumstances.

The invention further includes any modification of terial and any remaining steps are carried out, or the process is discontinued at any stage, or in which the starting materials are formed under the reaction conditions or are used in the form of their derivatives, such -as their salts. Preferably those starting materials are used in the process of the invention which lead to the formation of preferred compounds mentioned before.

The starting materials used are known or, if new, may be prepared according to known methods. For example, those used in reaction a) may be prepared by condensing a cycloali- thio phatyloxy- or cycloaliphatylme_?eap½e-aniline with a lower alkoxy- lower alkylidene-malonic acid ester or an equivalent derivative of the acid, or by reacting an N- (cycloaliphatyl- thio oxy- or cycloaliphatylme-3i1e-&^^e~phenyl )-N ' -aryl-lower alkanoic acid amidine with a malonic acid ester or a corresponding amide. Starting materials used in reaction b) are prepared, for example, analogous to reaction a), however, the malonic acid derivative is condensed in the presence, for example, of a halogenating or ketalizing agent, such as a phosphorus oxyhalide, e.g. phosphorus oxychloride, or a lower alkylene glycol, e.g. ethylene glycol in the presence of an acid, e.g. p-toluenesulfonic acid.

The starting materials used in reaction c) may, for example, either be prepared by acylation of the corresponding primary or secondary anilines or by reaction of corresponding anthranilic acid esters or halides with alkali metal salts of alkanoyl-acetic acid derivatives, e.g. sodium ethyl acetoacetate .

The compounds of the invention can be used, for example, in the form of veterinary compositions, animal feed-stuffs or additives suitable for feedstuffs or drinking water, which are a further object of' the present invention. Veteri-nary compositions contain said compounds in conjunction or admixture with inorganic or organic, solid or liquid exci-pients, particularly those suitable for enteral administration . These are substances which do not react with the compounds of the invention, for example, water, gelatine, gums, sugars, e.g. lactose, glucose or sucrose, starches, e.g. corn starch, wheat starch, rice starch or arrowroot, stearic acid or salts thereof, e.g. magnesium stearate or calcium stearate, talc, alcohols, e.g. stearyl or benzyl alcohol, propylene glycol or polyalkylene glycols, alginic acid or any other known pharmaceutical excipients. The compositions may be, for example, in the form of tablets or pills, e.g. micropills, or in liquid form as solutions, suspensions or emulsions. They solubilizers, salts for regulating the osmotic pressure or buffers. They are prepared by conventional methods, and contain from about 0. 1 $ to about 75 $, more particularly, from about 1 $ to about 50$, of the active ingredient: they may, in addition and if desired, contain other physiologically active substances.

Feedstuffs, which are particularly useful in raising poultry, particularly animals with parasitic infections, such as coccidiosis, and additives to feedstuffs or to the drinking water contain compounds of the invention together with conventional extenders, diluents and/or nutrients, such as sucrose, glucose, molasses, fermentation residues, cdrhmeal, ground and rolled oats, wheat shorts and middlings, meat scraps, oil cake, soybean and fish meal, alfalfa, clover or grass clippings, mineral supplements, such as bone meal, calcium carbonate or iodized salt, vitamins, such as vitamins A , Bj. .C or P, and other suitable substances, such as preser-vants, e.g. benzoic acid.

Feedstuffs, as well as drinking water contain the active ingredients in an amount ranging from about 0.0001$ to about 0. 1$, preferably from about 0.001$ to about 0.02$; additives may consist of pure substances, when used, for exam le > for the drinking water, but usually contain from about 1$ to about- 75$/ preferably about 1$ to about 50$, thereof..;. The total amount of the compounds of the invention administered by way of veterinary compositions or drinking water corresponds to that given with the feedstuffs shown above . s i ns edstuffs and additives amide or N^- (2-quinoxalinyl )-sulfanilamide, but also Ν^-(2,6-dimethoxy- -pyrimidinyl )-sulfanilamide, N^- (5-ethyl-l, 3* -thiadiazol-"2-yl )- sulfanilamide, ^- (5-methyl-3-isoxazolyl )-sulfanilamide, N^- (6-methoxy-3-pyridazinyl )-sulfanilamide and the N-^-acetyl derivative thereof, ^- ( -methyl-2-pyrimi-dinyl)-sulfanilamide, N^- (2, 6-dimethyl- -pyrimidinyl)-sulfaniL-amide, N^- (5-methyl-l, 3, -thiadiazol-2-yl )- ulfanilamide, 1~ (6-chloro-3-pyridazinyl)-sulfanilamide and the sodium salt thereof, N.^- (2-phenyl-3-pyrazolyl ^sulfanilamide , or N.,-(2-phenyl-5^methyl-3-pyrazolyl)-su.lfanilamide . Sulfonamides of the above type can be used in approximately 1/5 to 1/2 of the amount effective as an antibacterial. In addition, veterinary compositions, feedstuffs and additives of the invention may contain antibiotic substances, e.g. penicillin, streptomycin, aureomycin, terramycin, or tetracycline, antiparasitic agents, e.g. methyl 4-acetamino-2-ethoxy-benzoate , 2-amin -5-nitro~thiazole, 1- (5-nitro-2-thiazolyl )-2-oxo-tetra-hydroimidazole, 6, 7-dialkoxy- -hydroxy-3-quinolinecarboxyl.ie acids or their lower alkyl esters, and/or quaternary 5-am~ moniummethyl- -aminb-pyrimidine salts, such as the 2-cyclo-propyl- or 2-cyclopropyimethyl- -amino-5- (2, -dimethyl-pyri-dinium)-methyl-pyrimidine chloride hydrochloride, as well as the 2-methyl- or 2-n-propyl- -amino-5- (2-methyl- or 2, -di-methyl~pyridinium)*methyl-pyrimidine chloride hydrochloride, and/or tr nquilizing agents, such as reserpine, methyl 18-epi-O-methyl-reserpate, or meprobamate .

In the following examples temperatures are given in degrees Centigrade.

Example 1 A mixture of 19 g of (3, 4-bis-cyclopropyl-methoxy-phenylamino )-methylene-malonate and 95 ml of diphenyl ether is refluxed for 3 hours, then cooled, diluted with n-hexane and filtered. The residue is washed with n-hexane and recrystallized from dimethylformamide to yield the 6,7-bis-cyclopr0pylmethoxy-4-hydroxy-3-quin01inecarboxylic acid ethyl ester of the formula m.p. 288-288.5 (with decomposition) .

Upon heating a mixture of the above compound in ethanolic ammonia at 8O-IOO0, one obtaines the 6, 7-bis-cycl.o-propylmethoxy-4-hydroxy-3-quinolinec'arboxylic acid amide.

A mixture of 6, 7-bis-cyclopropylmethoxy-4-hydroxy-3-quinolinecarboxylic acid ethyl ester and methyl iodide in dimethylformamide is heated in the presence of anhydrous potassium carbonate; one thus obtain the 6, 7-bis-cyclopropyl-methoxy-l-methyl-4-oxo-l, 4-dihydro-3-quinolinecarboxylic acid ethyl ester.

The above starting material may be prepared as follows: A solution of 12 g of sodium hydroxide in 20 ml of water is added to the stirred and chilled mixture of 20.5 g of 4-nitro-pyrocatechol and 40 ml of $ ethanol; the mixture is kept under an atmosphere of nitrogen and after 15 minutes, it is poured into acetone (about 10 times of its volume). The resulting precipitate is filtered off quickly, washed with acetone, and dried under reduced pressure for a short period the residue is dissolved in 900 ml of dimethyl sulfoxidej and the solution is treated- at 50-55° with .46.5 g of cyclopropylmethyl bromide (8 .5$ pure) while maintaining an atmosphere of nitrogen. The reaction mixture is allowed to stand for 6 hours at 60°, then cooled and poured into ice-water. The resulting precipitate is filtered off, washed with water and recrystallized from isopropanol to yield the 3>4- nitrobenzene in 210 ml of anhydrous ethanol is hydrogenated in the presence of 2 g of 10$ palladium-on-carbon. After the hydrogen uptake has ceased, the mixture is filtered; the filtrate is treated with- 16 g of diethyl ethoxymethylene-malo-nate, the mixture s refluxed for, 6 hours under an atmosphere of nitrogen, hen · iltered and the filtrate is evaporated under reduoed; pressure i The residue is recrystallized from petroleum ether to yield the diethyl (>,4-bis-cyclopropylmeth-oxy-phenylamino )^methylene-malonate, m-.p. 62-64°.

..Example 2 A mixture of 10 g of diethyl (3, 4-bis-cyclobutyl-methoxy-phenylamino )-methylene-malonate and 100 ml of diphen-yl ether is refluxed for 18 minutes. It is cooled, then diluted with petroleum ether; the resulting precipitate is filtered off, dried under reduced pressure and recrystallized from dimeth'ylformamide to yield the 6, 7-bis-cyclobutylmethoxy 4-hydroxy--3-quinolift$c¾rboxylic acid ethyl ester of the formula m.p. 299-300° .

The above starting material may be prepared as follows i A solutio of 15 - 5 g of 4-nitro-pyrocatechol in l80 ml of dimethylformamlde is added over a period of 30 minutes to the stirred mixture of 11 - 5 g of sodium methoxide in 200 bromide are then added dropwise during one hour, the mixture is heated at 75_80° for hours while stirring, cooled and poured onto The solid material is filtered off and recry-stallized from isopropanol to yield the 3* -bis-cyclobutyl-methoxy-nitrobenzene, m.p. 60-6l°.

A mixture of 9 g of 3* -bis-cyclobutylmethoxy-nitro-benzene in.60 ml of anhydrous ethanol is hydrogenated in the presence of 0.37 S of platinum oxide. After the absorption of the theoretical amount of hydrogen, the reaction mixture is filtered, the filtrate is combined with 6.7 g of diethyl eth-oxymethylene-malonate and refluxed for hours under an atmosphere of nitrogen. After filtration, the filtrate is evaporated under reduced pressure to yield the diethyl (3,> -bis-cyclobutylmethoxy-phenylamino )-methylene-malonate, which is used without further purification..

Example 3 A mixture of 50 g of diethyl (3, -bis-cyclopropyl- ethoxy-phenylamino )-methylene-malonate and 600 ml of diphen-yl ether is heated for 15 minutes at 250-260°. After cooling to room temperature, it is diluted with petroleum ether; the resulting precipitate is filtered off, dried at 80° Under reduced pressure and recrystallized from dimethylformamide . The resulting 6, 7-bis-cyclopropylmethoxy-4-hydroxy-3-quinoline~ carboxylic acid ethyl ester melts at 290 to 293° (with decomposition) and is identical with the compound obtained according to the procedure of Example 1. Using the corresponding cyanoacetate in place of the malonate compound and following the procedure, the corresponding 3-cyano-6, 7-bis-cyclopropyl-methoxy-4-hydroxy-quinoline is obtained. and 00 ml of dimethylformamide while stirring under an atmosphere of nitrogen and cooling with ice. The mixture is stirred for an additional 1-1/2 hour, then treated with 60.4 g of cyclopropylmethyl bromide, added during 5 minutes while cooling. The mixture is stirred for 42 hours at room temperature, then diluted with 100 ml of water and poured into water (twice its volume). The mixture is extracted with methylene chloride, the extract is washed with a 5 aqueous sodium hydro xide solution, dried, filtered and evaporated. The residue is distilled and the fraction' boiling at l68-172°/l5 mm Hg is collected; it represents the 1, 2-bis-cyclopropylmethoxy-ben-zene .

A total of 151 g of 1, 2-bis-cyclopropylmethoxy-benzene is finely ground in a mortar and added portionwise while stirring to a solution of 400 ml of concentrated nitric acid in 400 ml of water, kept at 20° while cooling in an ice bath. After stirring for 3 hours at 10-15°, the mixture is 'diluted with 3000 ml of water and filtered; the residue is washed with water, dried and necrystallized from cyclohexane to yield the 3, 4-bis-cyclopropylmethoxy-nitrobenzene, m.p. 80.5. to 8l.5°.

A total of 26.4 g of 3 4-bis-cyclopropyl-methoxy-nitrobenzene in 200 ml of anhydrous ethanol is hydrogenated in the presence of 1.2 g of platinum oxide at an initial pressure about 3 1/2 atmospheres. After the hydrogen uptake has ceased, the mixture is combined with 22 g of diethyl ethoxymethylene-malonate and refluxed for 3 hours. After cooling, the catalyst is filtered off, the filtrate evaporated under reduced pressure and the residue is dried and recrystallized from pe By using the ethyl ethoxymethylene-cyanoaeetate and proceeding as outlined, one obtains the ethyl (3, 4-bis-cyclo-propylmethoxy-phenylaminp )-methylene-cyanoacetate .

Example 4 The mixture of 22 g of diethyl (4-cyclopropylmeth-oxy-2-trifluoromethyl-phenylamino )-methylene-malonate and 220 ml of diphenyl ether is heated for 20 minutes at 250-260° while stirring. It is cooled to rpom temperature and diluted with petroleum ether; the resulting precipitate is filtered off and recrystallized from isopropanol to yield the 6-cyclopro-pylmethoxy-4-hydroxy-8-trifluoromethyl-3-quinolinecarbox lic acid ethyl ester of the formula melting p The starting material may be prepared as follows; To a mixture of 20.7 g of 4-hydroxy-2-trifluoromethyl-nitro-benzene in 100 ml of dimethylformamide are added . g of a 56 suspension of sodium hydride in mineral oil and 100 ml of dimethylformamide while cooling, followed by 15· 3 g of cyclo-propylmethyl bromide. The mixture is stirred for 15 minutes under an atmosphere of nitrogen and poured into an excess of acetone. The resulting precipitate is filtered off and dried under reduced pressure to yield the 4-cyclopropylmethoxy-2-trifluoromethyl-nitrobenzene, m.p. 46-48°.

A total of 1 .7 g of 4-cyclopropylmethoxy-2-trifluo-romethyl-nitrobenzene in 100 ml of ethanol is hydrogenated in the presence of 0.8 g of platinum oxide at an initial pressure of about 1 4 atmos heres. After the u take of the theoreti diethyl ethoxymethylene-rnalonate and refluxed for 3 hours, then filtered; the filtrate is evaporated under reduced pres^ sure to yield the diethyl ( -cyclopropylmethoxy-2-trifluoro-methyl-phenylamino )-methylene-malonate, m.p. 55-58° Example 5 A mixture of 37.6 g of diethyl ( -cyclopropyl-meth-oxy-2-methyl-phenylamino)-methylene-malonate and 300 ml of diphenyl ether is refluxed for 20 minutes. After cooling, it is diluted with ether, the resulting precipitate is filtered off, dried and recrystallized from dimethylformamide to yield the 6-eyelopropylmethoxy-^--hydroxy- 8-methyl-3-quinolinecar-boxylic acid ethyl ester of the formula Using in the above procedure the diethyl ( -cyclo- thio propylmeth li«»4¾>€irp^-2-meth l-phenylamino )-methylen-malonic thio acid, one obtains the 6-eyclopropylmethyln3 i¾>ap4 ©- 4-hydroxy- 8-methyl-3-quinolinecarboxylic acid ethyl ester.

The starting material may be prepared as follows: A mixture of 150 ml of dimethylformamide and 10. 8 g of a 6$ suspension of sodium hydride in mineral oil is added to a solution of 38.3 g of -hydroxy-2-methyl-nitrobenzene in 200. ml of dimethylformamide; the mixture is stirred for 4 hours under an atmosphere of nitrogen and then treated with 36 g of cyclopropylmethyl bromide. The mixture is heated for hours at 75- 80°, then cooled, diluted with water and extracted with methylene chloride; the organic extract is washed with a 2% a ueous solution of sodium h droxide and with water,, dried A total of 23 . 7 g of 4-cyclopropyl-methoxy-2-methyl-nitrobenzene in 100 ml of anhydrous ethanol is hydrogenated in the presence of 1 . 2 g of platinum oxide at an initial pressure of about 2 3/4 atmospheres. After the hydrogen uptake has ceased, the mixture is combined with 20 . 4· g of diethyl ethoxymethylene-malonate and refluxed for 3 hours; it is filtered and the filtrate is evaporated to yield the diethyl ( 4-cyclopropyl-methoxy- 2-phenylamino )-meth lene-malonate, m.p, 9 0. thio The diethyl ( 4-cyclopropylmethylme*v©af>4 ©- 2-methyl-phenylamino )-methylen-malonate starting material is obtained thio by reducing 4-cyclopropylmethylme.?eap½«-2-methyi-nitrobenzene with hydrogen sulfide in an ammonia solution at 50- 60° and reacting the intermediate with diethyl ethoxymethylene-malo-nate .

Exam le 6 A mixture of 12 g of diethyl ( 2-cyclopropyl-methoxy-phenylamino )-methylene-malonate and 100 ml of diphenyl ether' is refluxed for minutes, then allowed to stand at room tem-perature for two days and poured into 2000 ml of n-hexane.

The resulting precipitate is filtered off and recrystallized from ethanol to yield the 8-cyclopropylmethoxy- 4-hydroxy-3-quinolinecarboxylic acid ethyl ester of the formula The starting material may be prepared as follows: A solution of 4 . 9 g of sodium hydroxide in 20 ml of water is added to the solution of 13 · 9 g of 2-nitro-phenol in 50 ml ice-water and extracted with ether; the extract is dried, filtered and evaporated. The residue is distilled and the frac tion boiling at 120-125°/0.2 mm Hg is collected, representing the 2-cyclopfopylmethoxy-nitrobenzene .

A total of g of 2-cyclopropylmethoxy-nitrobenzene in 150 ml of anhydrous ethanol is hydrogenated for two hours in the presence of 1-5 g of palladium-on-carbon at a pressure of about 3-1/4 atmospheres. The mixture is filtered, the filtrate is combined with 12 g of diethyl ethoxymeth lene-malo-nate, refluxed for six hours and allowed to stand at room temperature for 16 hours, then filtered. The filtrate is evaporated to yield the diethyl (2-cyclopropylmethoxy-phenylamino )-methylene-malonate, which is used without further purification.

Example 7 A mixture of 3 g of 6, 7-bis-cyclopropylmethoxy-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, 3-5 ml of hydrazine hydrate (99$) and 50 ml of ethanol is heated' in a sealed tube at 150° for 12 hours. After cooling, the content is filtered, the residue is washed with cold ethanol and re-crystallized from a mixture of ethanol and isopropanol to yield the 6, ?-bis-cyclopropylmethoxy-4-hydroxy-3-quinoline-carbox lic acid hydrazide of the formula OH C0-NH-NH2 "V Example 8 A mixture of 4 g of diethyl (3, 4-bis-cyclopropyl-methoxy-phenylamino)-methylene-malonate and 2 g of phosphorus oxychloride is heated on the steam bath or 4 hours . After cooling, it is treated with ice and chloroform, then made slightly alkaline with a 2N aqueous sodium hydroxide solution. The resulting solid material is filtered off, washed.with benzene and with aqueous ethanol and recrystallized from dimethyl-formamide to yield the 6, 7-bis-cyclopropylmethoxy-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, m.p. 287 to 288° (with decomposition), which is identical with the product obtained according to the process described in Example 1.

The 4-chloro-6, 7-bis-cyclopropylmethoxy-3-quinoline-carboxylic acid ethyl ester, formed as an intermediate in the above procedure, may also be hydrolyzed with dilute acetic acid after the phosphorus oxychloride has been evaporated under reduced pressure to yield the desired product.

Example 9 A mixture of 3.2 g of ethyl (2-acetylamino-5-cyclo-propylmethoxy-benzoyl)-acetate, 50 ml of anhydrous ethanol and 0.6 g of sodium methoxide is stirred for 2 hours at room temperature, refluxed for an additional 2 hours and then evaporated under reduced pressure. The residue is taken up in water, the mixture is quickly neutralized with 2N hydrochloric acid and the resulting precipitate is filtered off, washed with water, dried and recrystallized from dimethylformamide . The 6-cyclopropylmethoxy-4-hydroxy-2-methyl- -quinolinecar-boxylic acid ethyl ester of the formula melts at 275-278°.

The starting material may be prepared as follows: A mixture of 2.1 g of ethyl (2-amino-5-hydroxy-benzoyl ^acetate, 0.8 g of acetyl chloride, 10; ml of benzene and 1 ml of pyridine is heated on the steam bath for 2 hours, then evaporated under reduced pressure. The residue is taken up in water and extracted with ether; the organic extract is dried filtered and evaporated, and the residue is taken up in 20 ml of dimethyl sulfoxide and treated with 0.25 g of sodium hydride (in the form of a 5 $ suspension in mineral oil), followed by 1.4 g of cyclopropyl methyl bromide. The mixture is kept on the steam bath for 16 hours while stirring; after cooling, it is poured into ice-water. The mixture is extracted with ether, the organic extract is dried, filtered and evaporated to yield the ethyl (2-acetylamino-5-cyclopropyl-methoxy-benzoyl)-acetate, which is used without further purification.

Example 10 A mixture of 1 g of diethyl ( 4-cyclopropylme hoxy- 3-isobutyioxy-phenylamino )-methylene-malonate and 200 ml of diphenyl ether is heated at 250° for 45 minutes, then cooled and diluted with n-hexane. After being filtered off, the precipitate is recrystallized from 250 ml of dimethylformamide to yield the 6-cyclopropylmethoxy-4-hydroxy- 7-isobutylox - 3-quinolinecarboxylic acid ethyl ester of the formula m.p. 28 (with decomposition) The starting material may be prepared as follows s A total of 500 g of the crude mixture, containing 6 of the pyrocatechc. mono-C clopropylmethyl ether and 3 $ of the py~ rocatechol bis-cyclopropylmethyl ether, is dissolved in 2000 ml of toluene and treated with 196 g of a 0$ aqueous sodium, hydroxide solution. The resulting precipitate is filtered off and washed with a mixture of ethanol and toluene to yield the sodium salt of the pyrocatechol mono-eyelopropylme h l o ether, mj? . at 165 · A suspension of 1 g of the sodium salt of pyrocatechol monocy'c lopropylmethyl ether in 1000 ml of toluene is treated portionwise with 352 g of benzoyl chloride while stirring and keeping the temperature at 20° . After stirring is distilled; the fraction boiling at .143°/0.25 mm Hg represents the 2-cy.clopropylmethoxy-phenyl benzoate.

The Solution of 100 g of 2-cyclopropylmethoxy-phenyl benzoate in 450 ml of glacial acetic acid is treated with 100 ml of fuming nitric acid; the mixture is heated for 1 minutes on the steam bath and is then evaporated under. reduced pressure. The residue is recrystallized from 500 ml of isopropanol to yield the 2-cyclopropylmethoxy-5-nitro-phenyl benzoate, m.p. 99-101°.

A mixture of 69.8 g of 2-cyclopropylmethoxy-5-nitro-phenyl.benzoate, 500 ml of 95 aqueous ethanol and 23 g of a 50$ aqueous sodium hydroxide solution is refluxed for 2 hours and then evaporated under reduced pressure. The residue is dissolved in 300 ml of water, the mixture is acidified with 42 ml of concentrated hydrochloric acid and extracted with 300 ml of methylene chloride . The organic extract is washed with water and with aqueous sodium hydrogen carbonate, dried, filtered and evaporated. The residue is recrystallized from 200 ml of isopropanol to yield the 4-cyclopropylmethoxy-3-hydroxy-nitrobenzene, m.p. 105-108°.

. To a suspension of 35 g of 4-cyclopropylmethoxy-3-hydroxy-nitrobenzene in 500 ml benzene is added 6.4 g of sodium hydroxide pellets; the mixture is refluxed for 2-1/2 hours, during which time the generated water is collected. The mix-ture is then filtered, the residue is added to 200 ml of dimethyIformamide, followed by 1 g of sodium iodide and 30 g of isobutyl bromide, and the mixture is heated at 60° for 48 hours. After dilution with 500 ml of water, the resulting precipitate m.p. 55-59° .

A total of 21.3 g of 4-cyclopropylmethoxy-3-isobut-yloxy-nitrobenzene in 120 ml of ethanol Is hydrogenated In the presence of 0.44 g of wet 5^ palladium-on-carbon. After the hydrogen uptake has ceased, the mixture is filtered and the filtrate combined with 19· g of diethyl ethoxymethylene-malonate . The mixture is refluxed for 3 hours and then evaporated under reduced pressure to yield the diethyl (4-cyclo-propylmethoxy-3-isobutyloxy-phenylamiho )*methylene-malonate, which is used without further purification.

Example 11 A mixture of 29 g of diethyl( 3-cyclopropylmethoxy-4-isobUtyloxy-phenylamino)-methylene-malonate and 200 ml of diphenyl ether is heated at 252° for 10 minutes. After cooling, it is filtered and the residue is recrystallized from 400 ml of dimethylformamide to yield the 7-cyclopropylmethoxy 4-hydroxy-6-isobutyloxy-3-quinolinecarboxylie acid ethyl ester of the formula m.p. 283° .

The starting material may be prepared as follows: To a solution of 55 g of pyrocatechol in 250 ml of anhydrous ethanol, there is added a concentrated solution of 20 g of sodium hydroxide in ethanol; the mixture is stirred. for 1 hour, then treated with 1 g of sodium iodide, followed by 75 g of After being diluted with 500 ml of water, the mixture is ex- traoted with 200 ml of methylene chloride; the organic extract is dried, filtered and evaporated and the residue is distilled. The fraotion. boiling at 85°/1 ·5> mm Hg represents the pyroca- teohol mon - sobutyl ether.

To the solution of 80 g of pyrocatechol mono-isobu-tyl ether' In JOOml of benzene, there are added 20 g of sodium hydroxide; the mixture is stirred and refluxed for 30 minutes. The resulting precipitate is filtered off, dried, and again suspended in 3 0 ml of benzene . The suspension is treated dropwise and at 25° with 70 g of benzoyl chloride while stirring) the addition' akes 4 hours . The.mixture is washed with §00 ml of a aqueous sodium hydroxide solution and with gOO ml of water, !the organio solution is dried and evaporated, and the residue is distilled; the fraction boiling at 165°/ 0 * mm Hg represents the 2-isobutyloxy-phenyl benzoate-.

A solution of t>5 g of 2-isobutyloxy-phenyl benzoate in 650 ml of g aoia.1 aoetic acid is treated with 65 ml of fuming nitric aoid; the mixture is heated on the steam bath er go minutes, the diluted with 650 ml of water. The resulting preeipitate is filtered off and reerystallized from 400 ml ©f isopropanol to yield the 2-isobutyloxy-5-nitro-phenyl benzoate, m.p. 7β-780.

A mixture of 55 g of 2-isobutyloxy-5-nitro-phenyl benzoate, 200 ml of 9 $ aqueous ethanol and 15 g of 0$ aqueous sodium hydroxide is refluxed for 2 hours and evaporated under reduced pressure. The residue is dissolved in 300 ml of water, the solution is acidified with 40 ml of concentrated hydro- aqueous sodium hydrogen carbonate, the organic layer is separated, washed With 100 ml of water, dried, filtered and evaporated to yield the 3-hydroxy-4-isobutyloxy-nitrobenzene, m.p. 60°. · .· To a suspension of 29 g of 3-hydroxy-4-isobutyloxy-nitroben2ene in 200 ml of toluene are added 5· 5 g of sodium hydroxide, the mixture is refluxed for 1 hour and evaporated under reduced pressure. The residue is taken up in 100 ml of dimethylformamide and treated with 0.5 g of sodium iodide, followed by 20 g Of cyclopropylmethyl chloride. The mixture is stirred on the steam bath for 24 hours and diluted with 200 ml of water'. The resulting precipitate is filtered off and recrystallized from 200ml of isopropanol to yield the 3-cyclopropylmethoxy-4-isobutyloxy-nitrobenzene, m.p. 71-73°· A mixture.1 of 22 g of 3-cyclopropylmethoxy-4-iso-butyloxy-hitrobenaiene in 120 ml of ethanol is hydrogenated in the presence of 0Λ6 g of wet palladium-on-carbon.

After the hydrogen Uptake has ceased, the mixture is filtered and the filtrate ¾ « ined With l8.1 g of diethyl ethoxymethyl-ene-malonate . The mixture is refluxed for 3 hours and then evaporated unde r&duced pressure to yield the diethyl (3-cyclopropylmethoxy~4»isobutyloxy-phenylamino )-methylene-malo-nate which is used Without further purification.

Example 1 A mixtu.ttfc of 8 g of diethyl (3, 4-bis-cyclopentyloxy-phenylamino)-methylene-malonate and 75 ml of diphenyl ether is refluxed for 5 minutes. After chilling and* diluting the mixture with petroleum ether, the resulting precipitate is J- acid ethyl ester of the formula m.p. 24-7° (with decomposition).

The starting material may be prepared as follows: To a solution of 11.2 g of potassium hydroxide in 60 ml of anhydrous ethanol, there are added over a period of 1 hour and at 70°* 11 g of pyrocatechol while stirring under a . nitrogen atmosphere, followed by 44.6 g of cyclopentyl chloride, added within 10 minutes. he mixture is refluxed for 3 hours, then cooled and filtered; the filtrate is evaporated under reduced pressure and the residue is taken up in water. The mixture is extracted with ether; the organic extract is washed with a 5$ aqueous potassium hydroxide solution, then with water, dried, filtered and evaporated. The residue is distilled; the fraction boiling at 199-202°/l6 mm Hg represents thedpyfcocatechol bis-cyclopentyl ether.

A total of 12.5 g of pyrocatechol bis-cyclopentyl ether is added at 4° portionwise to a mixture of JO ml of concentrated nitric acid and 30 ml of water; the mixture is stirred for 4 hours at 0°, then poured into 120 ml of water and extracted with methylene chloride. The. organic extract is washed with water, dried, filtered and evaporated. The residue is triturated with ether and recrystallized from aqueous etha-nol to yield the 3* 4-bis-Qclopentyloxy-nitrobenzene, m.p. 45- A mixture of 7 g of 3* -bis-cyclopentyloxy-nitro-benzene in 50 ml ethanol is hydrogenated in the presence of 0.2 g of platinum oxide, until the theoretical amount of hydrogen is absorbed. The mixture is: filtered, the filtrate is combined with 5 g of diethyl ethoxymethylene-malonate and re-fluxed for 3 hours. The mixture is evaporated under reduced pressure and the residue, consisting of the diethyl (3* -bis-cyclopentyloxy-phenylamino )-methylene-malonate, is used without further purification.

Example 13 The mixture of 5 g of ether 6, 7-bis-cyclopropyl-methoxy- -hydroxy-3"QUiholinecarboxylic acid ethyl ester and 29 ml of a 10$ aqueous sodium hydroxide solution is refluxed for 1 hour. After cooling, it is acidified with βΝ hydrochloric acid> the precipitate formed is filtered off and washed with water, to yield the 6, 7-bis-cyclopropylmethoxy- -hydroxy-3-quinolinecarboxyllcj acid of the formula melting at 260-263°.

A mixture of 1 g of 6, 7-bis-cyclopropylmethoxy- -hydroxy-3-iqulnolineearboxylic acid, 0.507 ml of 6N aqueous sodium hydroxide and 20 ml of water is heated to 100° for 30 minutes. After cooling, toluene is added to in order to coagulate the corresponding sodium salt, which is filtered off, washed with hot toluene and dried under reduced pressure; it 6, 7-bis-cyclopropylmethoxy-4-hydroxy- 3-quinolinecarboxylic acid ethyl ester- 50 S Standard Feed Formula (for 912585 g) Corn meal 5085OO g Soybean meal (44 % protein) 2973ΟΟ g.

Alfalfa meal I35QO g Dicalcium phosphate l8000 g Limestone meal 4500 g: .

Sodium chloride, 2250 g Fish meal (60 % protein) l8000 g Stabilized fat 27000 g Dried whey l8000 g Manganese sulfate 225 g Zinc oxide 135 g d, 1-methionine 675 g Vitamin premix 4500 g (4536 g of the vitamin composition contain: 16,000,000 I.U. of Vit. A; 1,000,000 I.U. of Vit. D^ 5,000 I.U. of Vit. E acetate; 6 g of Vit. K , 0.006 g of Vit. Β12ί'3 g of riboflavin; 30 g of niacin; 5 g of calcium pantothenate and 100 g of ethoxyquin, made p to 4 36 g with corn meal).

The 6, 7-t>is-cyclopropylmethoxy-4-hydroXy-3-quino-linecarboxylic acid ethyl ester is first premixed with about 1000 g of the finely ground feed mixture; the premix is increased to about 25ΟΟΟ g with the feed and then thoroughly mixed with the main batch in a horizontal mixer.

Example 17 A poultry feed containing 0.004 % and 0.006 %, respectively, of the two active ingredients is prepared as j Premlx: I . 6, 7-bis-cyclopropylmethoxy-4-hydroxy-3- quinolinecarboxylic acid ethyl ester 40 g II. 4-amino-2-cyclopropylmethyl-5- (2, 4- dimethyl-pyridinium)-methyl-pyrimidine chloride hydrochloride 60 g III. Confectioners Sugar- 50 g IV. Soybean Peed, solvent extracted 275 g · The premix is prepared by triturating I and II with III and the mixture is then screened through a JO mesh screen, U.S. standard sieve size. The screened material is then blended with IV in a mixer, the thoroughly mixed ingredients are added to 999500 g of the feed formula as described in Example l6 and the whole is homogenized in a horizontal mixer.

Example 18_ A poultry feed containing .0.004 and 0.001 , respectively, of the active ingredients is prepared as follows. Premix: I . 6, 7-bis-cyclopropylmethoxy-4-hydroxy- 3-quinolinecarboxylic acid ethyl ester 40 g II. 4-amiho-2-cyclopropyl-5- (2, 4-dimethyl- pyridinium)-methyl-pyrimidine chloride hydrochloride 10 g III. Soybean Oil l8 g IV. Corn Gluten Peed 282 g About one third of the amount of IV is combined with I and II, mixed and then screened through a j50 mesh screen, U.S. standard sieve. The remainder of IV is then placed into a mixer, III is added and the material mixed to form a uniform dispersion, to which the screened material is added. After mixing until uniformity is obtained, the mixture is then added to Example 19 A poultry feed is prepared as follows: Premix: I . 6, 7-bis-cyclopfopylmethoxy- -hydroxy- 3^quinolinecarboxylic acid ethyl ester 100 g II. ^" (2-quinoXalinyl )- sulfanilamide 125 g III. Confectioners Sugar 150 g IV. Soybean Peed, solvent extracted 570 g The premix is prepared by triturating I and II with III and the mixture is then screened through screen (sieve opening: 0.59 mm)j the screened material is then blended with IV in a mixer and the thoroughly mixed ingredients are added to 9999000 g of the feed formula shown in Example 16 ; the whole is homogenized in a horizontal mixer.

The above examples may otherwise be modified so as to obtain a poultry feed containing from about 0.001 % to about 0.02 % of the active component shown in Examples 1 to 1½ alone or in admixture with another therapeutic agent, for example a sulfonamide, which may be present in an amount of between about 0.001 % and about 0.01 %. In preparing the premix (or feedstuff additives, respectively) in the above-identified examples one may, of course, substitute an equivalent amount of other carriers or nutrients respectively, such as cottonseed meal linseed meal or oatmeal.

Example £0 A feed, prepared in analogy to the process described in Example 16 and containing 6, 7-bis-cyclopropylmethoxy- -hydroxy-3-quinolinecarboxylic acid ethyl ester at doses between 0.004 % and 0.008 %, is fed to broilers (breed: Peterson time they are exposed to Eimeria acervulina . Their weight gain is- compared with that of untreated, non-infected or with Eimeria acervulina, infected birds; each group contains 40 birds. The results are shown in the following table: Birds Level in feed % Weight gain untreated non-infected 0 100 untreated infected 0 9 treated non-infected 0,008 io6 treated infected 0.006 105 treated infected 0.004 105 Example 21 The following compounds are prepared according to the procedure described and illustrated in the previous examples by selecting the appropriate starting materials: 7-cyclopropylmethoxy-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, m.p. above 290° after recrystallization from dimethylformamide ; the compound may be obtained by ring-closure of diethyl ( 3-cyclopropylmethoxy-phenylamino ) -methylene -malonate , which may be prepared from 3-nitro-phenpl by way of 3-cyclopropylmethoxy-nitrobenzene ; b.p. 124°/0. 3 ■ mm Hg ;and 3-cyclopropylmethoxy-aniline , which is reacted with diethyl ethoxymethylene-malonate ; 7-chlor0-6-eyelopropylmethoxy - -hydroxy -5-quinoline-carboxylic acid ethyl ester, m.p. above 2βθ° ' after recrystallization from dimethylformamide; the compound may be obtained by ring-closure of diethyl ( 3-chloro-4-cyclopropylmethoxy-phenylamino ) -methylene-malonate , which may be prepared from. 2-chloro-4-nitro-phenol by way of 3-chloro-4-cyclopropylme-thoxy-nitrobenzene;- m.p. 3- 7°; and 3-chloro-4-cyclopropyl-methoxy-aniline , which is reacted with diethyl ethoxymethylene-malonate ; 7-benzyloxy-6-cyclopropylmethoxy-4-hydroxy-3-quino-linecarboxylic acid ethyl ester, m.p. 294 -295° after recrystallization from dimethylformamide ; the compound may be obtained by ring-closure of diethyl ( 3-benzyloxy-4-cyclopropyl-methoxy-phenylamino ) -methylene-malonate , which may be prepared from pyrocatechol by way of pyrocatechol monocyclopro-pylmethyl ether; b.p. 90-94°/0. 3 mm Hg; 2-cyclopropylmethoxy- zation from isopropanol; 4-cyclopropylmethoxy -3-hydroxy-nitrobenzene ; m.p. 104-105° after triturating with benzene; 3-benzyloxy-4-cyclopropylmethoxy-nitrobenzene ; m.p. 91-92° after recrystallization from a mixture of isopropanol and hexane; and 3-benzyloxy-4-cyclopropylmethoxy-aniline , which is reacted with diethyl ethoxymethylene-malonate ; 7-cyclopropylmethoxy-6-n-propyl-4-hydroxy- -quinoline carboxylic acid ethyl ester, m.p. 292-295° (decomposition) after recrystallization from dimethyl ormamide ; the compound may be obtained by ring-closure of diethyl (^-cyclopropyl-methoxy-4-n-propyl-phenylamino ) -methylene-malonate , which may be prepared from 3-acetylamino-phenol by way of 2-acetylamino-phenyl allyl ether; m.p. 85-88° after recrystallization from a mixture of benzene and petroleum ether; 3-acetylamino-6-all l-phenol ; m.p. l65-l66° after recrystallization from water; which is obtained together with the 2-acetylamino-2-allyl- henol;, m.p. 147.-152° after recrystallization from water 3-acetylamino-6-n-propyl-phenol; m.p. 178-179° after recrystallization from isopropanol; 3-cyclopropylmethoxy-4-n-propyl-acetylanilide ; m.p. 70-74°; and 3-cyclopropylmethoxy-4-n-pro yl-aniline ; b.p. 100-120 /0.075 mm Hg; which is reacted with diethyl ethoxymethylene-malonate; 7-cyclopropylmethoxy-4-hydroxy-8-n-propyl-3-quinoline carboxylic acid ethyl ester, m.p. 192-193° after recrystallization from dimethylformamide ; the compound may be prepared by ring-closure of diethyl ( 2-cyclopropylmethoxy-2-n-propyl-phenylamino) -methylene-malonate, which is obtained, for exampl from 3-acetylamino-2-allyl-phenol by way of ^-acetylamino-2- 28656/2 6-cyclopropylmethox -7-dieth 1amino-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, m.p. 194-195° after recrystallization from a mixture of ethanol and ethyl acetate; the compound may be prepared by. ring-closure of diethyl (4- '. cyclopropylmethoxy-5-diethylamino-phenylamino ) -methylene-malonate, which is obtained, for example, from 2-amino-4-nitro-phenol by way of 2-diethylamino-4-nitro-phenol; m.p. 91-94° after recrystallization from aqueous ethanol; 2-cyclo-propylmethoxy-N,N-diethyl-5-nitro-aniline b.p..1ΐβ-124°/0.05 mm Hg; and 4-cyclopropylmethoxy-5-diethylamino-aniline which is reacted with diethyl ethoxymethylene-malonate ; 6-n-butyl-7-cyclopropylme hoxy-4-hydroxy- -q inoline-carboxylic acid methyl ester, m.p. 285-287° after recrystallization from dimethylformamide the compound may be obtained by ring-closure of dimethyl (3-cyclopropylmethoxy-4-n-butyl-phenylamino)-methylene-malonate , which is obtained, for exampl from 5-acetylamino-phenol by way of 3-butyryloxy-acetyl- anilide; m.p. 88-98.5° after recrystallization from a mixture of benzene and hexane; 5-acetylamino-2-butyrylphenol ; m.p. 115-117° after washing with water; 5-acetylamino-2-n-butyl-phenol; m.p. 1 5-1 °; 4-n-butyl-3-cyclopropylmethoxy-acetylanilide ; m.p. 77-79° after crystallization from petroleum ether; and 4-n-butyl-3-cyclopropylmethoxy-aniline , which is reacted with dimethyl ethoxymethylene-malonate ; 6-n-butyl-7-cyclopropylmethoxy-4-hydroxy-3-quinoline-carboxylic acid ethyl ester, m.p. 291-292° (decomposition); the compound may be obtained by ring-closure of diethyl (}-cyclopropylmethoxy-4-n-butyl-phenylamino ) -methylene -malonate , which is obtained, for example, from 4-n-butyl-3-cyclopropyl-methoxy-aniline by treatment with diethyl ethoxymethylene-malonate; 6,7-bis-cyclopropylmethoxy-4-hydroxy-3-quinolinecarboxy-lic acid methyl ester, m.p. 269-272° after recrystallization from dimethylformamide ; the compound may be prepared by ring-closure of dimethyl (3,4-bis-cyclopropylmethoxy-phenylamino)-methylene-malonate ; m.p. 68-69° after recrystallization from petroleum ether; which is- obtained, for example, by treatment of 3>^-bis-cyclopropylmethoxy-aniline with dimethyl ethoxymethylene-malonate; . 7-n-but 1-6-cyclopropylmethox - -hydrox -5-quinoline-carboxylic acid ethyl ester, m.p. 259-261° (decomposition) after washing with petroleum ether; the compound may be prepared by ring-closure of diethyl ( 5-n-butyl-4-cyclopropyl-methoxy-phenylamino ) -methylene -malonate , which is obtained, for example, from 4-acetylamino-phen;ol by way of 4-butyryloxy ° m.p. 85-85° after trituration with n-hexane; 5-n-butyl- -cyclopropylmethoxy-acetylanilide , m.p. 65-67° after trituration with petroleum ether; and 3-n-butyl-4-cyclopropyl-methoxy-aniline ^ which is reacted with diethyl ethoxymethyl-ene-malonate ; 7-n-butyl-6-cyclopropylmethoxy- -hydroxy-5-quinoline carboxylic acid methyl ester, m.p. 257-259° (decomposition); the compound may be prepared by ring-closure of dimethyl ( 5-n-butyl-4-cyclopropylmethoxy-phenylamino ) -methylene-malonate, which is obtained by treatment of 3-n-butyl-4-cyclopropylmethoxy-aniline with dimethyl ethoxymeth lene-malonate ; 7-benzoyloxy-6-cyclopropylmethoxy-4-hydroxy-2-q i-nolinecarboxylic acid ethyl ester, m.p. 282° after trituration with hot acetone; the compound may be prepared by ring-closure of diethyl (3-benzoyloxy-4-cyclopropylmethoxy-phenylamino) -methylene-malonate , which is obtained, for. example, from 4-cyclopropylmethoxy-3-hydroxy-nitrobenzene by way of 3-t>enzoyloxy-4-cyclopropylmethoxy-nitrobenzene and ' 5-benzoyloxy-4-cyclopropylmethoxy-aniline , which is reacted with diethyl ethoxymethylene-malonate ; and 6-cycloprop methoxy -4 ,7-dihydroxy-^-quinolinecarboxylic acid ethyl ester, m.p. 2760 after recrystallization from dimethylformamide the compound may be prepared by ring-closure of diethyl (4-cyclopropylmethoxy-3-hydroxy-phenyl-amino ) -methylene-malonate which is obtained, for example, from 4-cyclopropylmethoxy-3-hydroxy-nitrobenzene by way of 4-cyclopropylmethoxy-3-hydroxy-aniline , which is reacted with Example 22 A mixture of 22 g of 6,7-bis-cyclopropylmethoxy-4-hydroxy-^-quinolinecarboxylic acid ethyl ester, 5-2 g of a 56 suspension of sodium hydride in mineral oil and 250 ml of dimethylformamide is heated at 85° for 1 hour while stirring under a nitrogen atmosphere, then cooled to 75°· A total of 15-6 g of ethyl iodide is added within minutes while stirring; stirring is continued for 2 1/2 hours at 75°. Another .8 g of ethyl iodide are then added, and the mixture is stirred for 2 additional hours at 75° , then allowed to stand for 16 hours at room temperature. It is filtered; the filtrate evaporated under reduced pressure and the residue is triturated with water and recrystallized from a mixture of ethyl acetate and hexane to yield the 6,7-bis-cyclo-propylmethoxy-l-ethyl-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid ethyl ester of the formula m.p. 108-111°.

A mixture of 5.8 g of 6,7-bis-cyclopropylmethoxy-l-ethyl-4-oxo-l ,4-dihydro-3-quinolinecarboxylic acid ethyl ester in 100 ml of a aqueous sodium hydroxide solution is re-fluxed for 2 1/2 hours, then cooled, and filtered. The filtrate is acidified with hydrochloric acid; the resulting precipitate is filtered off and recrystallized from dime Example 2·Ί> A mixture of 15 g of 6-cyclopropylmethoxy-7-isobutyl oxy-4-hydroxy-3-quinolinecarboxylic acid ethyl ester and 1 0 ml of n-decanol is refluxed for 30 minutes; the generated ethanol is collected. The mixture is cooled, stirred for l6 hours at room temperature, and the resulting precipitate i filtered off and dissolved in 500 ml of boiling isopropanol. The solution is filtered, the filtrate is cooled to -10°, and the resulting precipitate is filtered off to yield the 6-cyclopropylmethoxy-7-isobut.yloxy-4-hydroxy-3-quinoline- ■ ,- ■ carboxylic acid n-decyl ester of the formula m.p. 152 .. · In an analogous manner the 6,7-bis-cyclopropylme-thoxy-4-hydroxy-3-quinolinecarboxylic acid n-decyl ester is obtained, which melts at 150-151° after recrystallization from isopropanol.

Example 24 A mixture of 1 g of 6,7-bis-eyclopropylmethoxy-4-hydroxy-5-quinolinecarboxylic acid ethyl ester, 10 g of terphenyl and 20 g of isopropanol is heated in an autoclave at I O0 for 2 hours. The mixture is cooled and diluted to twice _ its volume with a l:l-mixture of toluene and heptane. The resulting precipitate is filtered off and recry- 4 of the formula m.p. 269°.

In an analogous manner the following compounds may be prepared; 6J7-bis-cyclopropylmethoxy- -hydroxy-3-quinoline-carboxylic acid n-butyl ester, m.p. 204°; and 6,7-bis-cyclopropylmethoxy- -hydroxy-3-quinoline-carboxylic acid isopentyl ester, m.p. 155°· Example 2 ¾ A mixture of 8 g of 6,7-bis-cyclopropylmethoxy- -hydroxy-3-quinoline carboxylic acid and .20 ml of thionyl chloride is refluxed for 2 hours and evaporated under reduced pressure. The residue is taken up in 100 ml of anhydrous ethanol and the mixture is allowed to stand for 1 day at room temperature. It is concentrated under reduced pressure; the concentrate is filtered and the filter residue is washed with ethanol to yield the 6,7-bis-cyclopropylmethoxy- -hydroxy-3-q inoline carboxylic acid ethyl ester, m.p. 288° (decomposition) .

Example 26 To a mixture of 33 · 5 g of l-benzyl-6 , 7-dihydroxy-4-oxo-1 ,4-dihydro-quinolinecarboxylic acid ethyl ester and 200 ml of dimethylformamide is added while stirring a mixture of 8 .6 g of a 5 $ suspension of sodium hydride in mineral oil and 75 ml of dimethylformamide ; stirring is continued for 4 hours at room temperature. A total of 32 g of cyclo-propylmethyl bromide {91%) is added; the mixture is stirred for 56 hours at 80° under a nitrogen atmosphere, then cooled and poured into water. The resulting precipitate is filtered off, washed with water and dried at 50° under reduced pressure to yield the amorphous l-benzyl-6 , 7-bis-cyclopropyl-methoxy-4-oxo-l,4-dihydro-3-q inolinecarboxylic acid ethyl ester of the formula The starting material is prepared as follows: A solution of 33 - 3 S °f 6 ,7-diacetyloxy-4-hydroxy-3-quinoline-carboxylic acid ethyl ester in 100 ml of dimethylformamide is added to a mixture of 4.3 g of a 56$ suspension of sodium hydride in mineral oil and 25 ml of dimethylformamide . The mixture is stirred for 24 hours at room temperature; 17 .1 g of benzyl bromide are added dropwise while stirring, and stirring is continued for 8 hours at 80° . The mixture is oxy-4-oxo-l ,4-dihydro-3-q inolinecarboxylic acid ethyl ester A mixture of 55 g of l-benzyl-6,7-diacetyloxy-4-oxo l1 -dihydro-3-quinolinecarboxylic acid ethyl ester and 250 ml of ethanolic hydrogen chloride is allowed to stand for 1 day at room temperature and concentrated under reduced pressure. The concentrate is filtered off and the residue is washed with ethanol to yield the 1-benzyl-6,7-dihydroxy- -oxo-l ,4-dihydro-3-quinolinecarboxylic acid ethyl ester, which is used as such without further purification.

Example 27 Chlorine gas is bubbled through a mixture of 10 g of 5-acetyl-6,7-bis-cyclopropylmethoxy- -hydroxy-quino-line , 10 g of sodium hydroxide and 100 ml of water while cooling in an ice bath. After saturation, the mixture is brought to room temperature and is heated for 10 minutes on the steam bath, then cooled and acidified with 6N hydrochloric acid. The resulting precipitate is filtered off, washed with water and recrystallized from aqueous methanol to yield the 6,7-bis-eyelopropylmethoxy- -hydroxy-5-quinolinecarbox -lie acid, m.p. 260-262°.

The starting material may be prepared as follows: A mixture of 11.6 g of 3, -bis-cyclopropylmethoxy-aniline , 9 g of ethyl a-ethoxymethylene-acetoacetate and 100 ml of anhydrous ethanol is refluxed for 5 hours and evaporated. The residue is added to 75 ml of refluxing diphenyl ether; the mixture is refluxed for 10 minutes, then cooled and diluted with hexane . The resulting precipitate is filtered off and recrystallized from ethanol to yield the 5-acetyl-6,7-bis-cyclopropylmethoxy- -hydroxy-quinoline .

. Example 28 A mixture of 10 g of 6 ,7-t>is-cyclopropylmethoxy- -oxo-1,2 ,3, -tetrahydro-3-quinolinecarboxylic acid ethyl ester 150 ml of -isopropyl-toluene and 5 g of a 10$ palladium-on-charcoal catalyst is refluxed for l6 hours and filtered hot. The filtrate is concentrated; the resulting precipitate is filtered off and recrystallized from dimethylformamide to yield the 6,7-Dis-cycl°ProPylmethoxy- -hydroxy-3-quinolinecar boxylic acid ethyl ester, m.p. 288° (decomposition).

The starting material is prepared as follows: A mixture of 20.2 g of diethyl (3, -bis-cyclopropylmethoxy-phenylamino) -methylene -malonate , 150 ml of anhydrous ethanol and 2 g of a 10$ palladium-on-charcoal catalyst is hydrogen-ated at 5 atm. and room temperature until the theoretical amount of hydrogen has been absorbed. It is filtered hot and the filtrate is evaporated to yield the diethyl (j>^-bis-cyclopropylmethoxy-phenylamino ) -methyl-malonate .

A mixture of 20 g of diethyl ( 5,4-bis-cyclopropyl-methoxy-phenylamino ) -methyl-malonate and 180 ml of the boiling eutectic mixture of diphenyl ether and diphenyl is re fluxed for 50 minutes, then cooled and diluted with pentane. The resulting precipitate is filtered off and the residue is washed with pentane to yield the 6,7-bis-cyclopropylmethoxy- -oxo-l ,2,3, -tetrahydro-5-quinolinecarboxylic acid ethyl ester. 28656/2

Claims (1)

1.CLAIMS stands for an oxygen atom, and the lower alkyl esters of such compounds. 3. Compounds of the- formula - in which each group R» and R" represents the same ' cycloalkyl group with 3 to 6 sing carbon atoms, and each of the letters n 28656/2 49 group R* and R" has the above given meaning and each of the letters n and m stands for 0, or in which one of the group R' and Rn stands fir a hydrogen atom and the other is a cyeloalkyl residue with 3 to 6 ring carbon atoms, and each of the letters n and m is an integer from 1 to 4, or in which one of the groups R* and RM stand for a phenyl group, and the other is a cyeloalkyl residue with 3-6 ring carbon atoms, and each of the letters n and m is an integer from 1 to 4# 4. Lower alkyl esters of the compounds according to Claim 3* 5. Compounds of the formula II according to Claim 3» in which each group R' and R represents the same cyeloalkyl group with 3 to 6 ring carbon atoms, being optionally substituted by lower alkyl groups and each of the letters n and m represents the same integer from 1 to 4. 6· Lower alkyl esters of the compounds according to Claim 5. 7. , -bis-cyclopropylmethoxy-4-hydroxy-3-¾uinolinecarboxylic acid ethyl ester, 8· 6 , -bis-cyclobutylmethoxy-4-hydroxy-3-quinolinecarboxylic acid ethyl ester. 9· 6-cyclopropylmethoxy-4-hydroxy-8-trifiuoromethyl-3-quinolinecarboxylic acid ethyl ester. 10. 6-cyclopropylmethoxy-4-hydroxy-8-methyl-3-quinolinecarboxylic acid ethyl ester. 11. 8-cyelopropylmethoxy-4-hydroxy-3-q.uinolinecarboxylic 28656/2 ^ - 50 - 12. 6,7~bis-cyclopropylmetho£y-4-hydroxy-3-quinolinecarboxylic acid hydraside. 13· 6-cyelopropylmethoxy-4-hydrox -2-methyl-3-quino-llnecarboxylie acid ethyl ester. 14. 6-cyclopropylraethoxy-4-hydroxy-7-isobutyloxy-3-quinolineearboxylic acid ethyl ester. 15· 7-cyclopropylmethoxy-4-hydroxy-6-isobutyloxy-3-quinolinecarboxylic acid ethyl ester. 16· 6,7-bis-cyclopentyloxy-4- ydroxy-3-quinolinecar-boxylic acid ethyl ester. 17. 6,7-bis-cyclopropylmethoxy-4-hydroxy-3-qu±noline-c¾rboxylic acid. 18· 6-cyclopropylmethoxy-4-hydroxy-3-quinolinecarboxy-lic acid ethyl ester. 19. The compounds of Claims 1 to 18 in free form. 20· The compounds of Claims 1 to 18 in form of their salts. 21. The compounds of Claims 1 to 18 in form of their non-toxic salts. 22. The compounds of Claims 1 to 3, 5 and 17 in form of their non-toxic ammonium, alkali metal or earth alkaline metal salts. 23. The compounds of Claims 1 to 18 in form of their nontoxic acid addition salts. 24. Animal ferdstuffs or drinking water useful in raising poultry or animal feed or drinking water additives comprising 28656/2 - 51 - or an ester, amide, hydrazide or nitrile. of such compound, in which. R.is a cycloalkyl . residue, A represents- a direct bond or a lower alkylene residue, X represents "an oxygen or sulfur atom, ' i . ■ ■· ' , ' : R2 is a' hydrogen atom or a lower alkyl radical, is a hydrogen !atom, a lqwer alkyl group, or a lower alkyl group substituted by ■'an aryl group, R represents a hydrogen atom, a lower alkyl group, a hydroxy group; a lower alkqxy group, a phenyl-lower alkoxy' group, a group of the formula R7A-X-, in which R, A and :X have the above given meaning, a halogen atom, a trifluoro-imethyl group or a di-lower alkylamino group, or a tautomer of •a compound, in which R_, is a hydrogen atom thereof, or an 0- ester of such tautomer:., or a non-toxic" salt of such cDmpounds. ;25. Animal feedstuffs or drinking water useful in raising. ; poultry or animal feed or drinking water additives comprising i . * . i la compound of the formula laaccording to claim 24, in which R, A, : ' . ·· ' ■ X R^, R^ and R^ have the meaning given' in claim 24 and & stands- I for an oxygen atom or a lower alkyl ester of such compound, or la non-toxic, salt thereof. : g , , . _ ' drinki g water lisef l in raising poultry or animal feed or drinking water additives comprising a. compound of formula (II) 28656/2 ^ - 52 - in which each group R' and R" represents the same cycloalkyl group with 3 to 6 ring carbon atoms, and each of the letters n and m represents the same integer from 1 to 4» or in which each group Rf and R" has the above given meaning and each of the letters n and m stands for 0, or in which one of the groups R' and R" stands for a hydrogen atom and the other is a cycloalkyl residue with 3 to 6 ring carbon atoms, and each of the letters n and o Is an integer from 1 to 4, or in which one of the groups R' and Rw stand for a phenyl group, and the other is a cycloalkyl residue with 3-6 ring carbon atoms, and each of the letters n and m is an integer from 1 to 4, or a nontoxic salt thereof. 27. Animal fee&stuffs or drinking water useful in raising poultry or animal feed or drinking water additives comprising a lower alkyl ester of a compound according to Claim 26 or a non-toxic salt thereof. 28656/2 - 53 - 28, Artimai feedetuffs or drinking water useful in raising poultry or animal feed or drinking water additives comprising a compound of the formula II according to claim 26, in which eadh group R* a d R" represents the same cycloalkyl group wifh 3 p 6 ring carbon atoms, being optionally substi' tuted by lower aIky1 groups and each of the letters n and m represents the same integer from 1 to 4, or a non-toxic salt thereof. 29. . Animal feedstuf s or drinking water useful in rais ing poultry Or animal feed or drinking water additives comprising a low©** alky1 ester of a compound according to claim 28- or a non-toxio salt thereof. 3 Animal feedstuffs or drinking water useful in rais ing poultry Or animal feed or drinking water additives comprising 6, 7- e-oyeloprOpylmethoxy-4-hydroxy-3-quinolinecar-boxylic ac d ethyl eater or a non-toxic salt thereof. 31,. Animal feedstuffs or drinking water useful in rais ing poultry, or animal feed or drinking water additives comprising 6,7*'biB-oyclobUtylmethoxy-4-hydroxy-3-quinolinecar-boxylic acid ethyl ester or a non-toxic salt thereof. 32, Animal feedstuffs or drinking water useful in rais ing poultry or animal feed or drinking water additives comprising 6-cyolopr6pylmethoxy-4-hydroxy-8-trifluoromethyl-3-quinolineoarboxylic acid ethyl ester or a non-toxic salt thereof. . ■' ; ' ·'. .. ' . 33. Animal feedstuffs or drinking water useful in rais ,.28656/2, ; ■ , . - 5 - '■ ' . :'· lng poultry or animal feed or drinking water., additives comprising 6-cyclopropylmethoxy-4-hydroxy-8-methyl-3-quinoline-carboxylic acid ethyl ester or a non-toxic salt thereof. 34'. Animal feedstuffs or drinking water useful in rais' ing poultry of animal feed or drinking water additives comprising 8-cyclopropylmethoxy-4-hydroxy-3-quinolinecarboxylic acid ethyl ester or a non-toxic salt thereof. .35:.. Animal feedstuffs or drinking water useful in rais ing poultry or animal feed or drinking water additives com-, prising 6,7-bis-cyolopropylmethoxy-4-hydroxy- -quinoline.car-boxylic acid hydrazide or a non-toxic salt thereof. 6,' Animal feedstuffs or drinking water useful in rais ing poultry or animal feed or drinking-water additives comprising 6-cyclopropylmethoxy-4-hydroxy-2-methyl-5-quinoline-carboxylic acid ethyl ester or a non-toxic salt thereof. 37... Animal feedstuffs or drinking water useful in rais ing poultry or animal feed or drinking water additives comprising 6-cyclopropylmethoxy-4-hydroxy-7-isobutyloxy-3-quino linecarboxylic acid ethyl ester or a non-toxic salt thereof. 38.. Animal feedstuffs or drinking water useful in rais ing poultry or animal feed or drinking water additives comprising 7-cyclopropylmethoxy-4-hydroxy-6-isobutyloxyi-3-quino linecarboxylic acid ethyl ester or a non-toxic salt thereof. 39? Animal feedstuffs or drinking water useful in rais ing poultry or animal feed or drinking water additives comprising 6, 7-bis-cyclopentyloxy-4-hydroxy-j5^quinolinecarboxy-lic acid ethyl ester or a non-toxic salt thereof. 4Q.. Animal feedstuffs or drinking water useful in rais ing poultry or animal feed or drinking water additives com carboxylic acid or a non-toxic salt. 41. Animal feedsutffs or drinking water useful in raising poultry or animal feed or drinking water additives comprising 6-cyclopropylmethoxy-4-hydroxy-3-quinolinecarboxylic acii ethyl ester or a non-toxic salt thereof. 42. Animal feedstuffs or drinking water according to any one of Claims 24-41 composing from about 0.0001 to about 0.1% of the compound. 43· Animal feedstuffs or dinking water according to any one of Claims 24-41 comprising from about 0.001% to about 0.02% of the compound. 44. Animal feedstuffs according to any one of Claims 24-43 comprising in addition a sul onamide. 45· Animal feedstuffs according to Claim 44» comprising the sulfonamide in approximately 1/5 to 1/2 of the amount effective as an antibacterial. 46» Animal feedstuffs according to any one of Claims 24-45 comprising in addition an antibiotic. 47· Animal feedstuffs according to any one of Claims 24-46 comprising in addition an antiparasitic compound. 48· Animal feedstuffs according to any one of Claims 24-47 comprising in addition a tranquillizing agent. 49· Process for the manufacture of the compounds of formula I i Claim 1, or esters, amides, hydrazides or nitriles of such compounds, or salts thereof, which comprises a) ring-closing a di-lower alkyl ester or a nitrile- . . f ■ 28656/2 - 56 - .in which is a carbo - lower alkoxy or a cyano group, by intramolecular condensation, . or or thereof,· n wh up capable of thereof, in which Y is a halogen atom, or in an ester, amide, hydrazide or nitrile of such compound, the group Y into the oxo gnd hydro xy group, respectively, by hydrolysis, or ) ng-.closin a compound of the formula 0 r' II or an ester, an amide, a hydrazide or a nitrile thereof, in which one of the groups and Z^, is the group -C0-R2 and the · other is hydrogen, by intramolecular condensation and, if desired, converting a resulting compound into another compound of the formula I, and/or, if desired, converting a resulting free com - 57 - 50. Process according to Claim 4% wherein ring-closure ( a) is carried out at an elevated temperature. 51. Process according to Claim 49, wherein hydrolysis b) is carried out with an acidic agent. 52. Process according to Claim 51» wherein an aqueous mineral or carhoxylic acid is used. 53. Process according to Claim 491 wherein ring-closure (c) is carried out ia the presence of a dehydration agent. 54· Process for raising poultry which comprises using as feedstuffs or drinking water compositions any one of the feedstuffs or drinking water compositions claimed in Claims 24-48. For the AnBlicants DR. REI HOLD COfflf AND