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WO1993012795A1 - Derives de quinazolin-4(3h)-one utilises comme agents anticoccidiose - Google Patents

Derives de quinazolin-4(3h)-one utilises comme agents anticoccidiose Download PDF

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Publication number
WO1993012795A1
WO1993012795A1 PCT/US1985/001685 US8501685W WO9312795A1 WO 1993012795 A1 WO1993012795 A1 WO 1993012795A1 US 8501685 W US8501685 W US 8501685W WO 9312795 A1 WO9312795 A1 WO 9312795A1
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compound
chloro
bromo
hydrogen
poultry
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Edward A. Glazer
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Priority to PCT/US1985/001685 priority Critical patent/WO1993012795A1/fr
Priority to US07/067,766 priority patent/US4762838A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention is concerned with certain trans-3-[3-(3-hydroxy-2-piperidyl)-2-oxopropyl]quinazo- lin-4 (3H)-one derivatives, a method of using same as anticoccidial agents, intermediates therefor, and a process for certain intermediates therefor.
  • Coccidiosis a poultry disease, is caused by several species of protozoan parasites of the genus Eimeria, such as E. acervulina and E. tenella.
  • E. tenella is the causative agent of a severe and often fatal infection of the ceca of chickens which is manifested by extensive hemorrhage, accumulation of blood in the cecum (a pouch between the large and small intestines) and the passage of blood in the droppings.
  • coccidiosis is an intestinal disease which is disseminated by birds picking up the infectious organism in droppings on contaminated litter or ground. By damaging the intestinal wall, the host animal is unable to utilize its food, goes off its feed, and in untreated cases the disease terminates in either the death of the animal or the survival of unthrifty birds known commonly as "culls.”
  • European Patent Application 98589 broadly discloses structurally related hydrazine derivatives of trans-3-[3-(3-hydroxy-2-piperidyl)-2-oxopropyl]quinazo- lin-4(3H)-ones as anticoccidial agents.
  • Structurally related compounds are also reported to be useful in combatting theileriosis in cattle
  • Structurally related compounds including broad generic disclosure of 3-[3-(3-hydroxy-2-piperidyl)-2- oxopropyl]quinazolin-4(3H)-ones substituted on the aromatic ring with halogen, trifluoromethyl, lower alkylthio, methoxy, phenoxy and benzyloxy groups, have also been disclosed as antimalarial agents by Baker et al., U.S. Patent 2,694,711; see also Baker et al., U.S. Patents 2,651,632 and 2,796,417 for compounds related to present intermediates. Although not in any manner specifically disclosed, a number of the instantly claimed compounds can be defined by said genera, once having knowledge of the present invention. While Baker et al. ('711) specifically disclose the 5-trifluoromethyl analog
  • X is fluoro, chloro, bromo or. iodo substituted at the 6- or 7-position;
  • R is (C 1 -C 4 )alkylthio
  • X 1 is hydrogen or fluoro, chloro, bromo, iodo or methoxy substituted either at the 7- or at the 8-position;
  • R 1 is cyano, trifluoromethyl, (C 1 -C 4 ) alkylthio,
  • Y 1 is hydrogen, fluoro, chloro, bromo or phenoxy; and Y 2 is chloro or bromo; with the proviso that Y 1 is other than hydrogen when X 1 is other than hydrogen,
  • the compounds of the present invention are racemic (not optically active).
  • the heavy and dotted bonds in the various formulae therefore indicate relative, not absolute, stereochemistry.
  • Pharmaceutically-acceptable acid addition salts include, but are not restricted to, those with HCl, HBr, H- 2 SO 4 , CH 3 SO 3 H, p-CH 3 C 6 H 4 SO 3 H, lactic acid, fumaric acid, citric acid and the like.
  • the present invention also encompasses a method of controlling or preventing coccidiosis in poultry which comprises administering to said poultry an anticoccidially effective amount of a compound of the formula (I) in drinking water or in nutritionally-balanced feed.
  • X, R, X 1 and R 1 are as defined above;
  • R 2 is hydrogen, acetyl or (C 1 -C 4 ) alkyl
  • R 3 is hydrogen or COOR 4 ; where R 4 is allyl or
  • X, R, X 1 and R 1 are as defined above.
  • R is (C 1 -C 4 )alkylthio
  • R 5 and R 6 are each independently (C 1 -C 4 ) alkyl
  • X is fluoro, chloro, bromo or iodo
  • R 7 is (C 1 -C 4 ) alkyl, 4-picolyl or Y 2 is chloro or bromo;
  • X 3 is fluoro, chloro, bromo or iodo substituted at the 3- or 4-position
  • a nucleophile in a reaction inert solvent comprising water or a (C 1 -C 4 )- alkanol
  • X 4 is a nucleophilically displaceable group, in the same or another reaction inert solvent to form a compound of the formula (VII) or (VIII).
  • the preferred nucleophile is an alkali metal alkoxide, particularly methoxide.
  • the preferred solvent comprises methanol.
  • the compounds of the present invention are readily prepared by nucleophilic displacement:
  • R 2 and R 4 are both defined as above but R 2 is other than hydrogen, and Y 3 is a nucleophilically displaceable group such as chloro, bromo, iodo or mesylate; followed by solvolytic or hydrolytic removal of the groups R 2 and COOR 4 . Because of their ready availability, preferred compounds of the formula (IX) have Y 3 as bromo, R 2 as methyl and R 4 as methyl or allyl.
  • nucleophilic displacement reaction between compounds of the formulae (V) or (VI) and (IX) in all cases involves replacement of the leaving group, Y 3 , with a relatively non-nucleophilic nitrogen. For this reason it is essential to employ a base of sufficient strength to form the anion of the compound (V) or (VI) in an amount at least sufficient to neutralize all of the acid (HY 3 ) coproduced in the reaction.
  • reaction inert solvent such as a lower alkanol, acetonitrile or
  • the solvent should be less acidic than the compound (V) or (VI), so as to facilitate formation of the required anion.
  • Sodium methoxide as base in methanol as solvent represent conditions particularly well suited for the present reaction.
  • the temperature employed for this reaction is best kept below 40° C.
  • rate will vary with the nature of the leaving group (e.g. rate:
  • reaction time should be such that the reaction is nearly complete [e.g. >95% conversion when equivalent amounts of the compounds (V) or (VI) and
  • the present nucleophilic displacement reactions produce compounds of the above formula (III) or (IV) wherein R 2 is (C 1 -C 4 ) alkyl and R is COOR 4 (where R 4 is defined above).
  • R 2 is (C 1 -C 4 ) alkyl and R is COOR 4 (where R 4 is defined above).
  • the groups R 2 and COOR 4 are readily removed, stepwise or in a single step, to produce the desired compounds of the formula (I) or (II).
  • the (C 1 -C 4 ) alkyl ether group is conveniently and selectively removed by the action of BBr 3 in a reaction inert solvent at a temperature ranging from -70° to 0° C.
  • R 3 is hydrogen and R 2 is generally acetyl. The latter is removed by mild hydrolysis, e.g., 6N HCl at 10-30° C.
  • the groups R 2 and R 3 are removed in reverse order, using 33% HBr in acetic acid at 10-30° C. to remove the group R 3 , followed by heating at or near reflux in 48% aqueous HBr to remove the group R 2 ; or both groups R 2 and R 3 are concurrently removed by use of the latter 48% HBr conditions.
  • the free base form is conveniently formed from an acid addition salt by neutralization of the latter in water with recovery of the free base by filtration or extraction into a water immiscible organic solvent.
  • the required starting compounds of the formula (V) or (VI) are generally prepared by methods known in the chemical art. Some of the required starting 2-amino- benzoic acids or esters required in the synthesis of the compounds (V) and (VI) are known, or accesible by known methods. Others, in particular those of the above formula (VII) or (VIII) are now more practically accessible via the presently discovered, improved process for their preparation, as summarized above and as detailed in specific preparations below.
  • the cocciodiostatic activity of the compounds of the present invention is demonstrated as follows.
  • Groups of chicks are fed a nutritionally complete basal ration into which the test compound is incorporated at various concentrations.
  • the basal ration is generally a commercial chick starter (e.g. Agway Commercial Chick Starter, available from the Agway Feed Co., Franklin, Connecticut), and is presented ad libitum to the chicks 24 hours before infection and continuously thereafter throughout the course of the tests.
  • the chicks are inoculated orally with 100,000 sporulated oocysts (Eimeria tenella) and the average weight per bird per group determined.
  • a group of six chicks is fed the basal ration which contains none of the test compound (infected, untreated controls).
  • a further group of six chicks serves as uninfected, untreated controls.
  • the chicks are examined on the fifth and sixth day post-infection for signs of hemorrhage. On the sixth day post-infection, the average body weight per bird per group is determined, the birds necropsied, the cecum examined macroscopi- cally, and a pathology index (average degree of infection [A.D.I.]) determined.
  • the compounds of the present invention generally show a value of said ratio no higher than 0.6 at a feed concentration no higher than 25 p.p.m.
  • a ratio of 0.0 indicates 100% control of pathology due to the infection at the indicated feed concentration.
  • the compounds of this invention are orally administered to poultry in a suitable carrier. Conveniently, the medication is simply carried in the drinking water or in the poultry feed, so that a therapeutic dosage of the agent is ingested with the daily water or poultry ration.
  • the agent can be directly metered into drinking water, preferably in the form of a liquid, water- soluble concentrate Csuch as aqueous solution of a water soluble salt) or added directly to the feed, as such, or in the form of a premix or concentrate.
  • a premix or concentrate of therapeutic agent in a carrier is commonly employed for the inclusion of the agent in the feed.
  • Suitable carriers are liquid or solid, as desired, such as water, various meals (for example, soybean oil meal, linseed oil meal, corncob meal), and mineral mixes such as are commonly employed in poultry feeds.
  • a particularly effective carrier is the poultry feed itself; that is, a small portion of poultry feed.
  • the carrier facilitates uniform distribution of the active materials in the finished feed with which the premix is blended. This is important because only small proportions of the present potent agents are required. It is important that the compound be thoroughly blended into the premix and, subsequently, the feed.
  • the agent may be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then blended with the carrier.
  • the proportions of active material in the concentrate are capable of wide variation since the amount of agent in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of therapeutic agent.
  • High potency concentrates may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated supplements which are suitable for direct feeding to poultry. In such instances, the poultry are permitted to consume the usual diet.
  • concentrated supplements may be added directly to the poultry feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of one or more of the compounds of this invention.
  • the mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity.
  • Continuous low-level medication during the growing period; that is, during the first 6 to 12 weeks for chickens, is an effective prophylatic measure. In the treatment of established infections, higher levels may be necessary to overcome the infection.
  • the use level in feed will generally be in the range of 3 to 100 ppm.
  • Mien administered in drinking water the level which will be that which will provide the same daily dose of medication, i.e. 3 to 100 ppm, factored by the weight ratio of the average daily consumption of feed to the average daily consumption of water.
  • 6-phenoxyquinazolin-4(3H)-ones were converted to allyl trans-2-[3-(7-X 1 substituted)-6-(Y 1 substituted phenoxy)- quinazolin-4(3H-)-on-3-yl]-2-oxopropyl]-3-methoxypiperidine-1-carboxylates as follows:
  • tiplet 2H, NCH 2
  • 3.1-3.6 multiplet,4H, CH 2 N, CHOH, CH 2 CHN
  • 5.1 singlet, 2H, NCH 2 CO
  • 5.6 doublet, 1H
  • Example 6 0.31 g (0.00058 mol) of title product of the preceding Example was converted to present title compound: yield 0.263 g (87%); mass spectrum m/e 439 (molecular ion with expected isotope pattern), 421 (-18, -H O), 137, 96, 82 (parent peak) among others.
  • 1 H-NMR(DMSO-d 6 ) 1.35 ppm (triplet, 3H, SCH 2 CH 3 ), 1.4-2.0 (multiplet, 4H, OCHCH 2 CH 2 CH 2 N), 2.8- 3.0 ( multiplet, 2H, NCH 2 ), 3.1-3.6 (mu ltiplet, 6H,
  • Example 4 In the manner of Example 4, 0.462 g (0.0018 mol) of 7-fluoro-6-methylthioquinazolin-4(3H)-one formic acid salt and 0.750 g (0.00224 mol) of allyl trans-2-(3- bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound: yield 0.50 g (60%).
  • 1H-NMR(CDCl 3 ) 1.4-2.1 ppm (multiplet, 4H, OCHCH 2 CH 2 CH 2 N) , 2.6 (singlet, 3H, SCH 3 ), 2.8-3.4 (multiplet, 4 H, NCH COCH 2 CH), 3.4 (singl
  • Example 5 In the manner of Example 5, 0.48 g (0.001 mol) of the title product of the preceding Example was transformed into the instant title compound: yield 0.324 g (58%); m.p. 214-216° C.
  • Example 6 In the manner of Example 6, 0.32 g (0.00059 mol) of the title product of the preceding Example was converted to present title compound: yield 0.188 g (60%); mass spectrum m/e 366 (molecular ion + H), 347 (-18,
  • Example 5 In the manner of Example 5, 0.53 g (0.00093 mol) of title product of the preceding Example was trans- formed into instant title compound: yield 0.264 g (44%); m.p. 210-230° C.; mass spectrum m/e 488 (molecular ion + H+), 469 (-18, -H 2 O?), 455 (-32, -CH 3 OH), 137 (parent peak among others.
  • 1 H-NMR(DMSO-d 6 ) 1.2-2.0 ppm (multiplet, 4H, OCHCH 2 CH 2 CH 2 N), 2.6 (singlet, 3H, SCH 3 ), 2.8- 3.0 (multiplet
  • Example 22 was converted to the instant title product, m.p. 260-263° C., in 47% yield.
  • N-(4-Fluoro-2-methylphenyl)acetamide In the manner of Preparation 5, 20 g (0.160 mol) of 5-fluoro-2-methylaniline was converted into the title compound: yield 25.0 g (94%); m.p. 131-132° C., [lit. m.p. 133.5-134° C.: E. A. Steck, L. T. Fletcher, J. Am. Chem. Soc. 70, 439-440 (1948)].
  • chloroform 6:4) was 10.3 g (57%): m.p. 164-165.5° C.; ir (KBr) cm -1 3449, 3345, 2966, 2920, 2142, 1693, 1613, 1566, 1534 among others; mass spectrum m/e 348
  • 6-Aminoquinazolin-4(3H)-one was slurried in 300 ml of 5% hydrochloric acid and the reaction mixture was cooled to 5° C. A solution of 6.72 g (0.097 mol) of sodium nitrite in 30 ml of water was added dropwise over 2.5 hours while maintaining the reaction temperature below 10° C. The resulting diazonium salt was then added portionwise to a hot (86° C.) solution of 7.84 g (0.0876 mol) of copper cyanide and 11.0 g (0.224 mol) sodium cyanide in 60 ml of water. Evolution of nitrogen was evident throughout the addition. After stirring for 30 minutes, the reaction mixture was filtered, washed with water, and air-dired. The crude product

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Abstract

T^_r^_a^_n^_s^_-3-[3-(3-hydroxypipérid-2-yl)-2-oxopropyl]quinazolin-4(3H)-ones présentant différentes substitutions, procédé de prévention ou de lutte contre la coccidiose chez les volailles à l'aide de ces dérivés et procédé de préparation de certains intermédiaires de ces derniers.
PCT/US1985/001685 1985-08-30 1985-08-30 Derives de quinazolin-4(3h)-one utilises comme agents anticoccidiose Ceased WO1993012795A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/US1985/001685 WO1993012795A1 (fr) 1985-08-30 1985-08-30 Derives de quinazolin-4(3h)-one utilises comme agents anticoccidiose
US07/067,766 US4762838A (en) 1985-08-30 1985-08-30 Quinazolin-4(3H)-one derivatives as anticoccidial agents

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2565186A1 (fr) * 2011-09-02 2013-03-06 Hybrigenics S.A. Inhibiteurs sélectifs et réversibles de la protéase 7 spécifique de l'ubiquitine

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2625549A (en) * 1951-03-17 1953-01-13 American Cyanamid Co Synthesis of 3-[beta-keto-gamma-(2-piperidyl) propyl]-4-quinazolone compounds
US2694711A (en) * 1952-12-02 1954-11-16 American Cyanamid Co Quinazolone antimalarial compounds
US3047462A (en) * 1959-03-06 1962-07-31 Lab Jacques Logeais Soc D Expl Quinazolone anti-inflammatory composition
US3282979A (en) * 1963-06-17 1966-11-01 Dow Chemical Co Phenolic thioethers
US3674857A (en) * 1970-03-02 1972-07-04 Dow Chemical Co (((alkylthio) alkyl)thio)phenols
US4338257A (en) * 1980-03-04 1982-07-06 Gulf Oil Corporation Benzoyl arylthioureas and use as plant growth regulators
EP0098589A1 (fr) * 1982-07-06 1984-01-18 VETEM S.p.A. Dérivés de quinazolinone actifs contre la coccidiose
US4440596A (en) * 1982-05-21 1984-04-03 Northern Telecom Limited Control of diameter of fiber insulation on conductors

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2625549A (en) * 1951-03-17 1953-01-13 American Cyanamid Co Synthesis of 3-[beta-keto-gamma-(2-piperidyl) propyl]-4-quinazolone compounds
US2694711A (en) * 1952-12-02 1954-11-16 American Cyanamid Co Quinazolone antimalarial compounds
US3047462A (en) * 1959-03-06 1962-07-31 Lab Jacques Logeais Soc D Expl Quinazolone anti-inflammatory composition
US3282979A (en) * 1963-06-17 1966-11-01 Dow Chemical Co Phenolic thioethers
US3674857A (en) * 1970-03-02 1972-07-04 Dow Chemical Co (((alkylthio) alkyl)thio)phenols
US4338257A (en) * 1980-03-04 1982-07-06 Gulf Oil Corporation Benzoyl arylthioureas and use as plant growth regulators
US4440596A (en) * 1982-05-21 1984-04-03 Northern Telecom Limited Control of diameter of fiber insulation on conductors
EP0098589A1 (fr) * 1982-07-06 1984-01-18 VETEM S.p.A. Dérivés de quinazolinone actifs contre la coccidiose

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2565186A1 (fr) * 2011-09-02 2013-03-06 Hybrigenics S.A. Inhibiteurs sélectifs et réversibles de la protéase 7 spécifique de l'ubiquitine
US9546150B2 (en) 2011-09-02 2017-01-17 Hybrigenics Sa Substituted quinazolin-4-ones for inhibiting ubiquitin specific protease 7

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