US3830817A - 1-aziridinylcarbonyl-quinoline-carboxylic acid derivatives - Google Patents

1-aziridinylcarbonyl-quinoline-carboxylic acid derivatives Download PDF

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Publication number
US3830817A
US3830817A US00306262A US30626272A US3830817A US 3830817 A US3830817 A US 3830817A US 00306262 A US00306262 A US 00306262A US 30626272 A US30626272 A US 30626272A US 3830817 A US3830817 A US 3830817A
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United States
Prior art keywords
aziridinylcarbonyl
compound
quinoline
acid
compounds
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Expired - Lifetime
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US00306262A
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English (en)
Inventor
V Narayanan
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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Publication date
Priority to CA122,444A priority Critical patent/CA942748A/en
Priority to GB4328071A priority patent/GB1374463A/en
Priority to CH1364671A priority patent/CH550796A/fr
Priority to CH36473A priority patent/CH554881A/fr
Priority to DE19712146675 priority patent/DE2146675A1/de
Priority to FR7133597A priority patent/FR2106612B1/fr
Application filed by ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
Priority to US00306262A priority patent/US3830817A/en
Application granted granted Critical
Publication of US3830817A publication Critical patent/US3830817A/en
Anticipated expiration legal-status Critical
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Definitions

  • the present invention relates to quinoline derivatives having the structure wherein Z is hydroxy or halogen; R is hydrogen or lower alkyl; R R R and R can be the same or different and represent hydrogen, lower alkyl and monocyclic aryl; however, not more than two of R R -R and R can be aryl and neither of the carbon atoms in the aziridinyl ring may contain two branched chain lower alkyl groups; and to pharmaceutically acceptable salts thereof.
  • the aziridinylcarbonyl group can be in the 6 or 7 position.
  • lower alkyl as employed herein includes both straight and branched chain radicals of up to and including eight carbon atoms, for instance, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl and the like.
  • the lower alkyl group can include substituents such as aryl.
  • the halogen can be Br, Cl, I or F, with Br and Cl being preferred.
  • monocyclic aryl as employed herein includes monocyclic carbocyclic aryl radicals, for instance, phenyl and substituted phenyl radicals, including lower alkyl phenyl, such as tolyl, ethylphenyl, butylphenyl and the like, di(lower a1kyl)phenyl (e.g., dimethylphenyl, 3,5-diethylphenyl and the like), halophenyl (e.g., chlorophenyl, bromophenyl, and 2,4,6-trichlorophenyl) and nitrophenyl. Phenyl is the preferred monocyclic aryl group.
  • the compounds of the invention wherein Z is OH may exist as the keto tautomer United States Patent 0 "Ice Preferred are compounds wherein R to R are hydrogen or lower alkyl of 1 to 4 carbon atoms and R is lower alkyl. Particularly preferred are compounds wherein R to R is hydrogen.
  • Examples of compounds falling within the present invention include, but are not limited to, the following:
  • a nitrobenzoic acid II is reduced to the corresponding aminobenzoic acid III by reaction with hydrogen in the presence of a catalyst for reduction, such as palladium or platinum on charcoal.
  • the aminobenzoic acid III is reacted with an alkoxymethylene malonic acid or ester IV (in a molar ratio of IIIzIV of within the range of from about 0.8:1 to about 1.2:1) at a temperature within the range of from about to about 140 C. to form compounds of structure V.
  • Compound V is cyclized by heating it above about 200 C.
  • hydroxy quinoline VI in an inert solvent such as Dowtherm, triethylene glycol, or nitrobenzene, for a period ranging from about 0.5 to about 3 hours, to yield a hydroxy quinoline of formula VI.
  • the hydroxy quinoline VI can then be reacted with a halogenating agent such as oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorus pentabromide, thionyl bromide, oxalyl bromide or the like under appropriate conditions as described below, to yield either compound VII or compound VIII.
  • a halogenating agent such as oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorus pentabromide, thionyl bromide, oxalyl bromide or the like under appropriate conditions as described below, to yield either compound VII or compound VIII.
  • the alkali metal salt of compound VI is reacted with a halogenating agent such as oxalyl chloride or thionyl bromide, in a molar ratio of VI: halide of within the range from about 2:1 to about 50:1 at a temperature within the range of from about 20 to about C.
  • a halogenating agent such as oxalyl chloride or thionyl bromide
  • compound VI is reacted with halogenating agent, such as oxalyl chloride or thionyl bromide, in a molar ratio of VIzhalide of within the range of from about 1:1 to about 20:1, at a temperature Within the range of from about 30 to about 80 C.
  • halogenating agent such as oxalyl chloride or thionyl bromide
  • Compound VII and compound VIII can then be reacted with an ethyleneimine of the structure R v-(l) in a molar ratio of VII or VIIIzimine of within the range of from about 1:1 to about 5:1 in the presence of an organic or inorganic base such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide or ethyleneimine, at a temperature within the range of from about 0 to about 30 C.
  • an organic or inorganic base such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide or ethyleneimine
  • the starting material of formula II may be either m or p-nitrobenzoic acid.
  • Illustrative starting materials of formula XI include aziridine; Z-ethylaziridine; 2,2-dimethylaziridine; 2,2,3,3- tetramethylaziridine; 2,3 dimethylaziridine; 2 phenylaziridine, 2,3-diphenylaziridine; 2-phenyl-2-ethylaziridine and the like.
  • the bases of formula I form pharmaceutically acceptable acid-addition salts by reaction with the common inorganic and organic acids.
  • inorganic salts as the hydrohalides, e.g., hydrobromide, hydrochloride, hydroiodide, sulfates, nitrates, phosphates, borates, etc.
  • organic salts as acetate, tartrate, malate, citrate, succinate, benzoate, ascorbate, salicylate, theophyllinate, camphorsulfonate, alkanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g., benzenesulfonate, toluenesulfonate and the like are also within the scope of the invention.
  • the base may be obtained therefrom by neutralization with an alkali hydroxide such as sodium hydroxide and the base in turn can be transformed into a different salt by reaction with the appropriate acid.
  • an alkali hydroxide such as sodium hydroxide
  • the new compounds of this invention are useful in combatting coccidiosis, a disease afiecting primarily poultry, caused by protozoa of the genus Eimeria, especially E. tenella, E. necatrix and E. acenvulina. This disease causes severe and frequently fatal infection in poultry flocks. It constitutes a serious economic hazard.
  • a current practice in poultry raising is the feeding of coccidiostatic preparations in the general diet as a prophylactic measure and the compounds of this invention may be used in this manner.
  • Compounds of this invention are administered at levels about 0.05% by weight of the feed for this purpose. However, they are used in a therapeutic manner to combat the disease when it occurs.
  • compositions containing one or more compounds of this invention may be formulated by intimately dispersing the active coccidiostatic ingredient or mixture of active ingredients throughout a carrier or diluent which is either solid or liquid.
  • a carrier or diluent which is either solid or liquid.
  • the compound is thoroughly admixed with a major proportion of poultry feed supplied to the fowl, e.g., chick starter feed, broiler and grower feeds, laying mashes, breeder and turkey breeder mashes, turkey starter and grower feeds and the like.
  • the active material may also be incorporated in premixes wherein higher proportions of the active ingredients are present.
  • the concentrated premix is then diluted with additional feed by the feed supplier or poultry grower, for example, one pound of premix per ton of feed, to obtain a feed containing the requisite amount of coccidiostat.
  • the active ingredients may be supplied in combination with an inert carrier or diluent such as Attapulgus clay, bentonite or edible vegetable materials, distillers dried grains, corn meal, fermentation residue and the like.
  • Liquid dispersions in Water can be prepared by using emulsifiers and/or surface active agents.
  • the amount of compound of formula I incorporated in the food or water is in the range of about 0.005 to 0.5% (by weight), preferably about 0.02 to 0.04%.
  • the incorporation of a tetraalkylthiuram disulfide, e.g., tetramethylthiuram disulfide and the like frequently enhance the action of a compound of formula I and thus conserve the amount of the latter required.
  • a total of about 0.005 to 0.1% (by weight) preferably about 0.01 to 0.03% of the combined substances in the feed is usually adequate.
  • the preferred composition contains quinoline derivative as the single active substance or in combination with tetraethylthiuram disulfide.
  • the compounds are also of value as nematocides. Nematodes like ascarides or pinworms are effectively controlled by feeding infected animal diets containing about 0.05% by weight of a compound of the class described.
  • EXAMPLE 1 6-( l-Aziridinylcarbonyl)-4-chloro-3-quinolinecarboxylic acid, ethyl ester A.
  • [(p-Carboxyanilino)methylene1malonic acid, diethyl ester.A mixture of 13.7 g. (0.1 mole) of p-aminobenzoic acid and 21.6 g. (0.1 mole) of diethyl ethoxymethylene malonate is heated slowly to C. The liquid begins to reflux and the mixture gradually solidifies. The mixture is kept at this temperature for approximately 30 min. After cooling, the solid is thoroughly mixed with ether and the insoluble material filtered to give 28 g. of product. Recrystallization from MeOH gives white needles, mp 220-223 C.,
  • the product is recrystallized from dimethylformamide to give white crystals melting above 270.
  • EXAMPLE 2 6-( l-Aziridinylcarbonyl) -4-hydroxy-3-quinolinecarboxylic acid, ethyl ester
  • a suspension of 6 g. of 4-hydroxy-3,6-quinolinedicarboxylic acid, ethyl ester (Example 1, A and B) in 200 ml. of dry benzene and 100 ml. of dry chloroform, 18 ml. of oxalyl chloride is added and the mixture is refluxed for 2 hr.
  • the oil obtained after evaporation of the s0lvent and excess oxalyl chloride in vacuo, is triturated with ether to give 2.5 g. of the 4-hydroxyquinolinecarboxylic acid chloride, mp 180-190".
  • a suspension of 2.5 g. of the above compound is 200 ml. of benzene is added dropwise with stirring to a mixture of 0.49 g. of sodium hydroxide, 75 g. of ice, 50 ml. of benzene and 0.43 g. of ethyleneimine (addition time 1 hr., temp. 0-5"). The mixture is allowed to warm up to room temperature and stirred at room temperature for 0.5 hr. The benzene layer is separated, washed with water, dried (MgSO and evaporated to give 1.79 g. of solid. Two recrystallizations from acetonitrile gives yellow crystals, mp 184-187;
  • EXAMPLE 10 6-( l-Aziridinylcarbonyl)-4-chloro-3-quinolinecarboxylic acid
  • a solution of 3.05 g. (0.01 mole) of 6-(l-aziridinyl carbonyl)-4-chloro-3-quinolinecarboxylic acid ethyl ester in ml. of ethyl alcohol 10 ml. of 0.1N alcoholic sodium hydroxide is added and the mixture refluxed for an hour. The solvent is removed in vacuo, the residue neutralized with 0.1N HCl to give 6-(l-aziridinylcarbonyl)- 4-chloro-3-quinolinecarboxylic acid. It may be crystallized from dilute methyl alcohol.
  • the ethyleneimine employed in preparing the compounds of the invention can include substituents such as alkyl or aryl as defined hereinbefore so that the aziridinyl group in any of the Examples can include as R R R and R such alkyl and/ or aryl groups.
  • R R R and R are selected from the group consisting of hydrogen and lower alkyl of 1 to 4 carbons.
  • R is lower alkyl of 1 to 8 carbons.
  • a compound in accordance with claim 1 having the name 6-(l-aziridinylcarbonyl)-4-chl0ro 3 quinolinecarboxylic acid, ethyl ester.
  • a compound in accordance with claim 1 having the name 6-(l-aziridinylcarbonyl)-4-hydroxy 3 quinolinecanboxylic acid, ethyl ester.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US00306262A 1970-09-18 1972-11-13 1-aziridinylcarbonyl-quinoline-carboxylic acid derivatives Expired - Lifetime US3830817A (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA122,444A CA942748A (en) 1970-09-18 1971-09-09 1-aziridinylcarbonyl substituted-3-quinolinecarboxylic acid compounds
GB4328071A GB1374463A (en) 1970-09-18 1971-09-16 Quinoline derivatives
CH1364671A CH550796A (fr) 1970-09-18 1971-09-17 Procede de preparation de derives de quinoleine.
CH36473A CH554881A (fr) 1970-09-18 1971-09-17 Procede de preparation de derives de quinoleine.
DE19712146675 DE2146675A1 (de) 1970-09-18 1971-09-17 Aziridinocarbonyl-chinolin-S-carbonsäurederivate und ihre Säureadditionssalze, Verfahren zu ihrer Herstellung und Arzneipräparate
FR7133597A FR2106612B1 (enrdf_load_stackoverflow) 1970-09-18 1971-09-17
US00306262A US3830817A (en) 1970-09-18 1972-11-13 1-aziridinylcarbonyl-quinoline-carboxylic acid derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7366970A 1970-09-18 1970-09-18
US00306262A US3830817A (en) 1970-09-18 1972-11-13 1-aziridinylcarbonyl-quinoline-carboxylic acid derivatives

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US3830817A true US3830817A (en) 1974-08-20

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US (1) US3830817A (enrdf_load_stackoverflow)
CA (1) CA942748A (enrdf_load_stackoverflow)
CH (2) CH554881A (enrdf_load_stackoverflow)
DE (1) DE2146675A1 (enrdf_load_stackoverflow)
FR (1) FR2106612B1 (enrdf_load_stackoverflow)
GB (1) GB1374463A (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4129737A (en) * 1972-08-02 1978-12-12 Laboratoire Roger Bellon Process for the preparation of an 8-alkyl-5-oxo-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acid
US4476132A (en) * 1981-03-24 1984-10-09 Ciba-Geigy Corporation Acylquinolinone derivatives, and antiallergic preparations and methods of inhibiting allergic reactions using them

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8804448D0 (en) * 1988-02-25 1988-03-23 Smithkline Beckman Intercredit Compounds
GB8804443D0 (en) * 1988-02-25 1988-03-23 Smithkline Beckman Intercredit Compounds
GB8804446D0 (en) * 1988-02-25 1988-03-23 Smithkline Beckman Intercredit Compounds
GB8804447D0 (en) * 1988-02-25 1988-03-23 Smithkline Beckman Intercredit Compounds
GB8804445D0 (en) * 1988-02-25 1988-03-23 Smithkline Beckman Intercredit Compounds
GB8804444D0 (en) * 1988-02-25 1988-03-23 Smithkline Beckman Intercredit Compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3478084A (en) * 1965-12-22 1969-11-11 Merck & Co Inc Lower alkyl alpha-carboalkoxy-beta-(3,4-disubstituted anilino) acrylates

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4129737A (en) * 1972-08-02 1978-12-12 Laboratoire Roger Bellon Process for the preparation of an 8-alkyl-5-oxo-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acid
US4476132A (en) * 1981-03-24 1984-10-09 Ciba-Geigy Corporation Acylquinolinone derivatives, and antiallergic preparations and methods of inhibiting allergic reactions using them

Also Published As

Publication number Publication date
CA942748A (en) 1974-02-26
CH550796A (fr) 1974-06-28
CH554881A (fr) 1974-10-15
FR2106612B1 (enrdf_load_stackoverflow) 1974-11-15
DE2146675A1 (de) 1972-03-23
GB1374463A (en) 1974-11-20
FR2106612A1 (enrdf_load_stackoverflow) 1972-05-05

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