EP0214158A1 - Acylhydrazones de pyridinyle anthelmintiques, procede d'utilisation et compositions - Google Patents

Acylhydrazones de pyridinyle anthelmintiques, procede d'utilisation et compositions

Info

Publication number
EP0214158A1
EP0214158A1 EP19860900935 EP86900935A EP0214158A1 EP 0214158 A1 EP0214158 A1 EP 0214158A1 EP 19860900935 EP19860900935 EP 19860900935 EP 86900935 A EP86900935 A EP 86900935A EP 0214158 A1 EP0214158 A1 EP 0214158A1
Authority
EP
European Patent Office
Prior art keywords
cpd
hydrazide
acid
pyridinyl
ethylidene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP19860900935
Other languages
German (de)
English (en)
Inventor
Douglas L. Rector
George A. Conder
Sylvester D. Folz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of EP0214158A1 publication Critical patent/EP0214158A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C07D213/87—Hydrazides; Thio or imino analogues thereof in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/88—Nicotinoylhydrazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention pertains to a new method for killing and controlling worms (Helminths), and new formulations for killing and controlling worms in animals, and new chemical compounds.
  • the invention is more particularly directed to a new method for killing and controlling parasitic worms in animals with certain pyridinyl acylhydrazones, to new anthelmintic formulations comprising the same, and to new pyridinyl acylhydrazones.
  • the anthelmintic pyridinyl acylhydrazones have the general structural formula I.
  • helminthiasis The diseases or groups of diseases descr i bed generally as helminthiasis are due to infection of the animal with parasitic worms known as helminths .
  • Helminthiasis and helminthosis are prevalent and may lead to serious economic problems in sheep , swine , cattle , goats , dogs , cats , horses , poultry and man .
  • the groups of worms known as nematodes , trematodes and cestodes cause widespread and often-times serious infections in various species of animals including man.
  • the most common genera of nematodes and cestodes infecting the animals referred to above are Dictyocaulus , Haemonchus , Trichostrongylus , Oatertagia, Nematodirus , Cooperia, Bunostornurn , Oesophagostomum, Chabertia, Strongyloides , Trichuris , Fasciola , Dicrocoelium, Enterobius , Ascaris , Toxascaris , Toxocara , Ascaridia, Capillaria, Heterakis , Ancylostoma, Uncinaria, Onchocerca , Taenia, Moniezia, Dipylidium, Metastrongylus , Macracanthorhynchus , Hyostrongylus , and Strongyl ⁇ s .
  • pyridinyl acylhydrazones of this invention including hydrates or pharmaceutically acceptable salts thereof, are represented by Formula I wherein X is (a) hydrogen; (b) C 1 -C 10 alkyl; (c) C 2 -C 6 alkenyl, preferably C 2 -C 4 alkenyl; (d) C 2 -C 6 alkynyl; (e) cyclo(C 3 -C 10 )alkyl optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, trifluoromethyl, or halo; (f) pyrrolidinyl; (g) piperidinyl; (h) 1-methylpyrrolidinyl; (i) 1-methylpiperidinyl; (j) C 2 -C 6 alkoxyalkyl; (k) cyclo(C 3 -C 10
  • (C 1 -C 3 ) alkyl refers to alkyl of one to 3 carbon atoms, inclusive or methyl, ethyl, propyl, and isopropyl.
  • Halogen atom (halo) refers to a bromo, chloro, iodo or fluoro atom.
  • Heteroaromatic refers to an aromatic heterocycle of 5 to 10 members, containing one or two heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur and includes quinoline, pyrrole, indole, benzofuran, benzothiophene, quinazoline, quinoxaline, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyridazine, pyrimidine, pyrazine, benzimidazole, benzothiazole, benzoxazole, pyridine, thiophene or furan, as well as the N-oxides, hydrates and pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacologicallytoxicological point of view and to the manufacturing pharmaceutical chemist from a physical-chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • Examples of C 1 -C 4 alkyl are methyl, ethyl, propyl, butyl and isomeric forms thereof.
  • Examples of C 1 -C 3 alkoxy are methoxy, ethoxy, propoxy and isomeric forms thereof.
  • phenoxy substituted with one, 2 or 3 C 1 -C 4 alkyl are (o-, m-, or p-)tolyl, (o-, m-, or p-)ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,4-dimethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 2,4,5-)trimethylphenyl.
  • C 2 -C 6 dialkylamino are dimethyl amino, diethylamino, methylethylamino, dipropylamino and ethylpropylamino.
  • Examples of phenyl (C 1 -C 3 ) alkyl are benzyl, phenylethyl and phenylpropyl.
  • Examples of phenyl(C 1 -C 3 )alkyl substituted with one, 2 or 3 C 1 -C 4 alkoxy, halo or trifluoromethyl include 4-chlorobenzyl, 2-chlorophenylethyl, p-tolylethyl, 2-methylbenzyl, 4-methoxybenzyl.
  • Examples of C 1 -C 3 alkylthio include methylthio, ethylthio, and n-propylthio.
  • Examples of substituted cyclo(C 3 -C 10 )alkyl are chrysanthemyl, 1-methylcyclopropyl and 2-methylcyclopropyl.
  • Examples of cyclo(C 3 -C 10 )-alkyl(C 1 -C 4 )alkyl are 2-cyclohexylethyl and cyclohexylmethyl.
  • An example of substituted cyclo(C 3 -C 6 )alkyloxy is menthyl.
  • naphthyl(C 1 -C 3 )alkyl examples include 2-naphthylmethyl and 1-naphthylethyl.
  • substituted naphthyl(C 1 -C 3 )alkyl is ( 3,8-dichloro-1-naphthyl) methyl; (4-chloro-1-naphthyl)methyl; and (4-methoxy-1-naphthyl)methyl.
  • substituted naphthyl examples include 3,6-dichloro-1-naphthyl; 3,5-dichloro-2-naphthyl; 6-methyl-2-naphthyl; and 4,6-dichloro-1-naphthyl.
  • bridged polycyclic hydrocarbon substituents of six to 10 nuclear carbons, optionally .substituted with one, 2 or 3 (C 1 -C 3 ) alkyl groups include exo or endo-2-norbonyl, bicyclo[2,2,2]oct-1-yl, and 1-adamantyl.
  • perhalo (C 1 -C 7 ) alkyl examples include trifluoromethyl, n-heptafluoropropyl and n-undecafluoropentyl.
  • Preferred pyridinyl acylhydrazones of Formula I are 3-pyridinyl acylhydrazones or 4-pyridinyl acylhydrazones, most preferably are 4-pyridinyl acylhydrazones.
  • R 1 and R 2 include hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or a chloro atom.
  • R 3 includes hydrogen and methyl or ethyl.
  • R 4 is preferably hydrogen.
  • Preferred X include hydrogen; C 1 -C 4 alkyl; cyclohexylethyl; phenyl optionally substituted with one, 2 or 3 C 1 -C 2 alkyl, C 1 -C 2 alkoxy, trifluoromethyl and chloro; C 1 -C 4 alkoxy; phenoxy optionally substituted with one, 2 or 3 C 1 -C 2 alkyl, C 1 -C 2 alkoxy, trifluoromethyl and chloro.
  • Most preferably X includes hydrogen, C 1 -C 4 alkyl; cyclohexylethyl; phenyl; phenyl substituted with C 1 -C 2 alkoxy and ethoxy.
  • One embodiment of this invention includes, of course, the anthelmintic use and anthelmintic compositions of compounds of Formula I, IA, IB, IC, ID or IE, hydrates thereof or pharmaceutically acceptable salts thereof.
  • Still another embodiment of this invention are the novel compounds, hydrates thereof or pharmaceutically acceptable salts thereof according to Formula I.
  • Another embodiment of this invention are the compounds of Formula I, the hydrates thereof or pharmaceutically acceptable salts thereof where X is selected from (a) hydrogen; (b) C 1 - C 10 alkyl; with the proviso that when X is methyl and the compound is a 2-pyridinyl acylhydrazone, and R 1 , R 2 and R 4 are hydrogen, R 3 is other than hydrogen or methyl; with the further proviso that when X is methyl and the compound is a 4-pyridinyl acylhydrazone, and R 1 , R 2 and R 4 are hydrogen, R 3 is other than hydrogen; (c) C 2 -C 6 alkenyl; (d) C 2 -C 6 alkynyl; (e) cyclo(C 3 -C 6 )alkyl optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, trifluoromethyl, or halo; (
  • Another embodiment of this invention are the compounds of IB and the novel compounds of Formula IA, IC, ID or IE; the hydrates thereof or pharmaceutically acceptable salts thereof.
  • R 5 , R 5 and R 7 are the same or different and are selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, a halogen atom, C 1 -C 4 alkylthio, phenoxy optionally substituted with a halogen atom, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 3 alkoxy; with the provisio that at least either R 5 , R 6 or R 7 is other than hydrogen.
  • R 5 , R 6 and R 7 include hydrogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and chloro.
  • R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, a halogen atom, C 1 -C 4 alkylthio, C 2 -C 6 dialkylamino and nitro.
  • Preferred R 3 and R 9 include hydrogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and chloro.
  • Another embodiment of this invention are the novel compounds of Formula IC , the hydrates thereof or pharmaceutically acceptable salts thereof where -OR' 5 is selected from the group consisting of (o) C 1 -C 6 alkoxy, preferably C 1 -C 4 alkoxy; (p) diphenylmethoxy; (q) cyclo(C 3 - C 6 )alkyloxy optionally substituted with one or two C 1 -C 3 alkyl; (r) phenoxy optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, or trifluoromethyl; or (s) benzyloxy optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, or trifluoromethyl.
  • Another embodiment of this invention are the compounds of Formula IC, the hydrates thereof or pharmaceutically acceptable salts thereof where -OR' 5 is selected from the group consisting of (o) C 1 -C 6 alkoxy, preferably C 1 -C 4 alkoxy; (p) diphenylmethoxy; (q) cyclo(C 3 -C 6 ) alkyloxy optionally substituted with one or two C 1 -C 3 alkyl; (r) phenoxy optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, or trifluoromethyl; or (s) benzyloxy optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, or trifluoromethyl; with the.
  • -R" 5 is selected from the group consisting of (a) hydrogen; (b) C 1 -C 10 alkyl; (c) C 2 -C 6 alkenyl, preferably C 2 -C 4 alkoxy; (d) C 2 -C 5 alkynyl; (e) cyclo(C 3 -C 6 )alkyl optionally substituted with one, 2 or 3 C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, trifluoromethyl, or halo; (f) pyrrolidinyl; (g) piperidinyl; (h) 1-methylpyrrolidinyl; (i) 1-methylpiperidinyl; (j) C 2 -C 6 alkoxyalkyl; (k) cyclo(C 4 -C 10 )alkyl(C 1 -C 4 )al
  • R 1 , R 2 , R 3 , R 4 and n are defined in Formulas IA, IB, IC, ID, and IE as in Formula I.
  • pyridinyl acylhydrazones of Formula IA benzoic acid (3-pyridinylmethylene)hydrazide (Cpd #6), benzoic acid (4-pyridinylmethylene)hydrazide (Cpd #7), benzoic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #1), benzoic acid (2-pyridinylmethylene)hydrazide (Cpd #9, hydrate),
  • 2-nitrobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #69), 2-nitrobenzoic acid (2-pyridinylmethylene)hydrazide, 2-nitrobenzoic acid (3-pyridinylmethylene)hydrazide, 4-nitrobenzoic acid [(2-ethyl-4-pyridinyl)methylene]hydrazide, benzoic acid [(2-ethyl-4-pyridinyl)methylene]hydrazide,
  • Cpd #71 methyl (2-pyridinylmethylene)carbazate
  • Patent 3,654, 294, 04/04/72 Chem. Abstr. 77, 5448b; J. Amat Badrinas, Spain Patent, ES 490,004 A1 , 04/01/81; Chem. Abstr. 96, 34898w; N.R. El-Rayyer and F.M. Al-Kharafi, Egypt. J. Chem. 23, 151-6 (1981); Chem. Abstr. 96, 14575X; N.R. El ⁇
  • pyridinyl acylhydrazones of Formula ID acetic acid (4-pyridinylmethylene)hydrazide, acetic acid (2-pyridinylmethylene)hydrazide, acetic acid [1-(2-pyridinyl)ethylidene]hydrazide,
  • the pyridinyl acylhydrazones of this invention are readily prepared by reacting the appropriate pyridyl ketone (II) with the acylhydrazide/carbazate (III) (Chart A, Scheme A) or by heating the pyridyl ketone (II) with the appropriate hydrazine (IV) to form the hydrazone intermediate (V) which is then acylated with the halide or anhydride (VI) to form the pyridinyl acylhydrazone (I) (Chart A, Scheme B).
  • the ketone VII is then reacted with the appropriate acylhydrazide or carbazate (III) to give the pyridinyl acylhydrazone N-oxide (I) or alternatively the pyridinylacylhydrazone (I) is formed by first reacting the ketone VII with a hydrazine IV to form hydrazone intermediate N-oxide VIII which is in the final step is acylated with the halide VI to furnish the pyridinyl acylhydrazone N-oxide I.
  • the reaction of Scheme A is carried out in the presence of a suitable solvent, for example, water, alcohols, ethers, halogenated hydrocarbons, hydrocarbons and include methanol, ethanol, isopropanol, propanol, hexane, tetrahydrofuran, dioxane, methylene chloride, preferably ethanol.
  • a catalyst such as glacial acetic acid, hydrochloric acid, sulfuric acid or p-toluenesulfonic acid can be utilized to. enhance the yield/rate of the reaction, particularly when R 3 is alkyl of 3 or more atoms, arylalkyl or aryl.
  • the acylation reaction of Scheme B is carried out in the presence of a suitable base such as a tertiary amine, for example, triethylamine or preferably, pyridine.
  • a suitable base such as a tertiary amine, for example, triethylamine or preferably, pyridine.
  • the base may also be the solvent.
  • the desired N-oxide is prepared by oxidizing the appropriate ketone using a peracid such as perbenzoic, m-chlorobenzoic, performic, peracetic or generating the peracid in situ preferably with hydrogen peroxide/acetic acid to furnish the pyridinyl ketone N-oxide which is reacted with the appropriate hydrazide or carbazate (Chart A, Scheme C).
  • a peracid such as perbenzoic, m-chlorobenzoic, performic, peracetic or generating the peracid in situ preferably with hydrogen peroxide/acetic acid to furnish the pyridinyl ketone N-oxide which is reacted with the appropriate hydrazide or carbazate (Chart A, Scheme C).
  • the starting compounds are known or can be readily prepared by known methods.
  • R. L. Frank and C. Weatherbee J. Am. Chem. Soc, 70, 3482-3 (1948); N. B. Mahishi, et al., J. Indian Chem. Soc, 42, 67-74 (1965) andM. Ogata and H. Kano, Chem. Pharm. Bull (Tokyo), 11, 32 (1963).
  • the title compound is resynthesized employing the above procedure, at about 6X scale-up to yield 58.4 gm (60%) having a melting point of 158.7°C.
  • the title compound is remade, with a scale-up of 3X, using the above procedure to yield 34.4 gm (66$) having a melting point of 177.5-178.5°C.
  • reaction mixture was diluted with water to the cloud point and cooled to room temperature then chilled in the refrigerator.
  • the solids that separated were collected, washed with Skellysolve B and dried to give 11.88 gm (74%) of product having a melting point of 119.4°C.
  • Procedure 57 Preparation of propanoic acid [(1,3-dioxan-5-yl)-4- pyridinyl-methylene]hydrazide, Compound 433 Following the general method of procedure 56 and making non-critical variations, except 12 drops of glacial acetic acid is used and extraction with methylene chloride in the work-up is not required, 8.36 gm (0.0433 mole) of 1,3-dioxan-5-yl 4-pyridyl ketone and 3.81 gm (0.0433 mole) of propanoic acid hydrazide yields 3.04 gm (27%) of the title compound having a melting point of 125.7°C. Analysis Calcd: C, 59.30; H, 6.51; N, 15.60.
  • Compounds 404, 406-407, 418 and 427-429 can be prepared by following the general procedure indicated in Table A and making non-critical variations, except starting with the appropriate pyridyl ketone (II) and acyl hydrazide/carbazate (III).
  • the pyridinyl acylhydrazones of this invention are effective against worms, particularly parasitic worms of warm-blooded animals and more particularly helminth parasites in ovines (sheep) and bovines (cattle).
  • Oral compounds are suspended in 20-30 ml of sterile vehicle #98 (each ml contains: carboxymethylcellulose - 10 mg, polysorbate80 -4 mg, propylparaben - 0.42 mg) using a sonicator and administered along with a tap water wash via a stomach tube.
  • the parenteral compounds are similarly suspended in 20-30 ml of the sterile vehicle and given by intraperitoneal injection using a 13 gauge, 2 inch needle and a 50 ml syringe. All test compounds are given to a single sheep/route of administration. Two or more sheep are treated with levamisole hydrochloride and five are used as nontreated controls. All animals are monitored for signs of toxicity following treatment.
  • the sheep are sacrificed 7-12 days after treatment (days 35-49 PI), and the abomasum is ligated and removed from each sheep. Each abomasum is longitudinally sectioned and rinsed into an 80 mesh sieve. Sieve contents are collected in individual containers and fixed in formol-alcohol. Later each sample is transferred to a 1000 or 2000 ml beaker and the volume brought to 400-1000 ml with tap water. The total number of worms in a 40-100 ml aliquot (10%) is determined. When no worms are found in the 10% aliquot, the entire sample is examined. Total worm number/sheep and percentage clearance for each treatment are calculated.
  • Parasitized sheep are randomly assigned to groups of five animals based on parasitic burden, weight, sex, and farm origin. Sheep are double ear-tagged, weighed, housed in a barn in community pens, fed hay supplemented with calf starter pellets or 1/2 lb corn/head/ day. Water was given ad lib. Animals were allowed to acclimate for one-two weeks prior to treatment.
  • Each group of sheep receives a test compound either orally or parenterally at a dosage rate of 100 mg/kg.
  • a group of sheep is treated with 8 mg/kg of levamisole hydrochloride and another group serves as an untreated control group.
  • Orally administered compounds are suspended in 20-30 ml of sterile vehicle #98 (each ml contains: carboxymethylcellulose - 10 mg, polysorbate80 -4 mg, propylparaben - 0.12 mg), using a sonicator and administered along with a tap water wash via a stomach tube.
  • compounds are similarly suspended in 20-30 ml of the sterile vehicle and given by intraperitoneal injection using a 13 gauge, 2 inch needle and a 50 ml syringe. Following treatment, all animals are observed for signs of toxicity.
  • the number and classification of helminth eggs per gram of feces are determined for each sheep during the acclimation period and in some cases at necropsy. Egg counts are made using the McMaster counting chamber technique and rectal fecal samples. Animals dying during the 24 hours immediately following dosing are not subjected to necropsy. Sheep that die 1-6 days posttreatment are posted and complete worm counts performed. All remaining animals are sacrificed on days 7-8 posttreatment; equal numbers of sheep are sacrificed from each group on each day when necropsy requires more than one day. Each sheep is euthanised and bled out prior to opening the abdominal cavity.
  • Ligatures are placed at the reticulo-omasal junction, the pyloric valve, and the ileo-cecal junction.
  • the abomasum and small intestine are freed of fat and mesenteric attachments, longitudinally opened, and their contents placed in individual containers.
  • the mucosal surface of each is washed with tap water, rubbed clean, and rinsed several times. Washings and ingesta for each organ are made up to 1 or 5 liters and a 10 or 20% aliquot in formalin is stored for later examination.
  • the cecum, large intestine, and colon are freed of mesenteric attachments, each is longitudinally opened, and their contents washed, collected, and made up to 1 or 5 liters in 10% formalin. A 20% aliquot or the entire sample is stored. All carcasses are incinerated.
  • the number and species of helminth eggs per gram of feces were determined for each lamb on days 0-2 of the acclimation period, on the day of treatment, and at necropsy. Egg counts were made using the double centrifugal flotation technique and rectal fecal samples.
  • the pyridinyl acylhydrazones of Formula I can be used as the pure compounds or as mixtures of pure compounds but for practical reasons the compounds are preferably formulated as anthelmintic compositions and administered as a single or multiple dose, alone or in combination with other anthelmintics (e.g. avermectins, benzimidazoles, levamisole, praziquantel, etc.).
  • anthelmintics e.g. avermectins, benzimidazoles, levamisole, praziquantel, etc.
  • aqueous or oil suspensions can be administered orally, or the compounds can be formulated with a solid carrier for feeding.
  • an oil suspension can be converted into an aqueous emulsion by mixing with water and injecting the emulsion intramuscularly, subcutaneously or into the peritoneal cavity.
  • the active compound(s) can be administered topically to the animal in a conventional pour-on formula. Pure compounds, mixtures of the active compounds, or combinations thereof with a solid carrier can be administered in the animal's food, or administered in the form of tablets, pills, boluses, wafers, pastes, and other conventional unit dosage forms, as well as sustained/controlled release dosage forms which deliver the active compound over an extended period of days, weeks or months. All of these various forms of the active compounds of this invention can be prepared using physiologically acceptable carriers and known methods of formulation and manufacture.
  • Solid carriers conveniently available and satisfactory for physiologically acceptable, unit dosage formulations include corn starch, powdered lactose, powdered sucrose, talc, stearic acid, magnesium stearate, finely divided bentonite, and the like.
  • the active agent can be mixed with a carrier in varying proportions from, for example, about 0.001 percent by weight in animal feed to about 90 or 95 percent or more in a pill or capsule. In the latter form, one might use no more carrier than sufficient to bind the particles of active compound.
  • the compounds can be formulated in stable powders or granules for mixing in an amount of feed for a single feeding or enough feed for one day and thus obtain therapeutic efficacy without complication. It is the prepared and stored feeds or feed premixes that require care. A recommended practice Is to coat a granular formulation to protect and preserve the active ingredient. A prepared hog-feed containing about 0.2 percent of the active compound will provide a dosage of about 100 mg per kg body weight for each 100 lb pig in its daily ration.
  • a solid diluent carrier need not be a homogeneous entity, but mixtures of different diluent carriers can include small proportions of adjuvants such as water; alcohols; protein solutions and suspensions like skimmed milk; edible oils; solutions, e.g., syrups; and organic adjuvants such as propylene glycols, sorbitol, glycerol, diethyl carbonate, and the like.
  • the solid carrier formulations of the inventions are conveniently prepared in unit dosage forms, to facilitate administration to animals. Accordingly, several large boluses (about 20 g weight) amounting to about 54 g of active compound would be required for a single dosage to a 900 lb horse at a dosage rate of 50 mg/kg of body weight.
  • a 60 lb lamb at a dosage rate of 100 mg/kg of body weight would require a pill, capsule, or bolus containing about 2.7 g of active compound.
  • a small dog, on the other hand, weighing about 20 lbs. wouid require a total dosage of about 225 mg at a dosage rate of 25 mg/kg of body weight.
  • the solid, unit dosage forms can be conveniently prepared in various sizes and concentrations of active ingredient, to accomodate treatment of the various sizes of animals that are parasitized by worms.
  • Liquid formulations can also be used.
  • Representative liquid formulations include aqueous (including isotonic saline) suspensions, oil solutions and suspensions, and oil in water emulsions.
  • Aqueous suspensions are obtained by dispersing the active compound in water, preferably including a suitable surface-active dispersing agent such as cationic, anionic, or non-ionic surface-active agents.
  • suitable ones are polyoxyalkylene derivatives of fatty alcohols and of sorbitan esters, and glycerol and sorbitan esters of fatty acids.
  • dispersing or suspending agents can be included and representative ones are synthetic and natural gums, tragacanth, acacia, alginate, dextran, gelatin, sodium carboxymethylcellulose, methylcellulose, sodium polyvinylpyrrolidone, and the like.
  • the proportion of the active compound in the aqueous suspensions of the invention can vary from about 1 percent to about 20 percent or more.
  • Oil solutions are prepared by mixing the active compound and an oil, e.g. an edible oil such as cottonseed oil, peanut oil, coconut oil, modified soybean oil, and sesame oil. Usually, solubility in oil will be limited and oil suspensions can be prepared by mixing additional finely divided compound in the oil.
  • an oil e.g. an edible oil such as cottonseed oil, peanut oil, coconut oil, modified soybean oil, and sesame oil.
  • solubility in oil will be limited and oil suspensions can be prepared by mixing additional finely divided compound in the oil.
  • Oil in water emulsions are prepared by mixing and dispersing an oil solution or suspension of the active compound in water preferably aided by surface-active agents and dispersing or suspending agents as indicated above.
  • the formulations of this invention are administered to animals so as to achieve therapeutic or prophylactic levels of the active compound.
  • a dose of 1 00 mg/kg of body weight in sheep of various pyridinyl acylhydrazones of thi s invention will effectively combat a wide variety of parasites .
  • Much lower effective dosages are contemplated , e .g . , in the range of 1 to 75 mg/kg of body weight .
  • def ini tive dosages can be proposed .
  • Contemplated are dosage rates of about 1 mg to about 800 mg/kg of body weight .
  • a preferred, contemplated range of dosage rates is from about 5 mg to about 400 mg/kg of body weight.
  • concentration of active compound in the formulation selected for administration is in many situations not cri tical .
  • Unit dosage forms in accordance with this invention can have anywhere from less than 1 mg to 500 g of act ive compound per uni t .
  • the anthelminti c agents of this invention will find their primary use in the treatment and/or prevention of helminth parasitisms in domesticated animals such as sheep , cattle , horses , dogs , swine , goats and poultry , they are also effective in treatment that occurs in other warm blooded animals including man.
  • the optimum amount to be employed for best results will , of course , depend upon the particular pyridinyl compound employed , species of animal to be treated , the regimen treatment and the type and severi ty of helminth infect ion.
  • the pyridinyl acylhydrazones of Formula I can be used to treat various helminth diseases in humans, including those caused by Ascaris, Enterobius, Ancylostoma, Trichuris, Strongyloides, Fasciola, Taenia, and/or Onchocerca or other filaria at a dose of from 1 mg/kg to 200 mg/kg of body weight upon oral and/or parenteral administration.
  • TLC refers to thin-layer chromatography
  • Brine refers to an aqueous saturated sodium chloride solution.
  • the ratio of solvents used are volume/volume (v/v).
  • Alkyl of _ to _ carbon atoms, inclusive is used, it means and includes isomers thereof where such exist.
  • Halogen atom refers to a bromo, chloro, iodo or fluoro atom.
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacologicaltoxicological point of view and to the manufacturing pharmaceutical chemist from a physical-chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • N.T. 424 100 N.T. 425 95.5 N.T. 426 10.3 N.T. 427 N.T. N.T. 428 N.T. N.T. 429 N.T. N.T. 430 100 N.T. 431 100 N.T. 432 98.5 N.T. 433 100 N.T. 434 98.5 N.T. 435 100 N.T. 436 100 N.T.
  • Z is a halogen atom or other active group, for example, an anhydride.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

Procédé permettant d'éliminer des parasites internes, en particulier des nématodes et des cestodes affectant les animaux à sang chaud tels que les moutons, le bétail à corne, les porcs, les chèvres, les chiens, les chats, les chevaux et les êtres humains ainsi que la volaille en administrant une quantité efficace d'un composé de formule (I). Certains des composés de formule (I) sont nouveaux et, dans d'autres modes de réalisation de l'invention, ils constituent de nouveaux composés et compositions utilisés dans le procédé de l'invention. Les composés sont préparés aisément par des réactions chimiques conventionnelles. Diverses acylhydrazones de pyridinyle de formule (I) présentent une activité anthelmintique à large spectre chez les moutons, ces composés pouvant être administrés par voie orale et/ou parentérale.
EP19860900935 1985-02-11 1986-01-23 Acylhydrazones de pyridinyle anthelmintiques, procede d'utilisation et compositions Ceased EP0214158A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US70037585A 1985-02-11 1985-02-11
US71542585A 1985-03-25 1985-03-25
US700375 1985-03-25
US715425 2003-11-19

Publications (1)

Publication Number Publication Date
EP0214158A1 true EP0214158A1 (fr) 1987-03-18

Family

ID=27106595

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19860900935 Ceased EP0214158A1 (fr) 1985-02-11 1986-01-23 Acylhydrazones de pyridinyle anthelmintiques, procede d'utilisation et compositions

Country Status (6)

Country Link
EP (1) EP0214158A1 (fr)
AU (1) AU582214B2 (fr)
DK (1) DK484986D0 (fr)
ES (1) ES8801544A1 (fr)
NZ (1) NZ215046A (fr)
WO (1) WO1986004582A1 (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3678240D1 (de) * 1985-08-20 1991-04-25 Sandoz Ag Semicarbazone und thiosemicarbazone.
WO1987003872A1 (fr) * 1985-12-26 1987-07-02 Nippon Soda Co., Ltd. Derives d'hydrazone
WO1987006132A1 (fr) * 1986-04-07 1987-10-22 The Upjohn Company Acylhydrazones d'alkyle quaternaire anthelmintiques, procede d'utilisation et compositions
ES2037709T3 (es) * 1986-07-14 1996-07-16 Rohm & Haas Derivados heterociclicos de seis miembros de n,n'-diacilhidrazinas n'-sustituidas.
US5049561A (en) * 1987-07-31 1991-09-17 The Upjohn Company Anthelmintic acylhydrazones, method of use and compositions
EP0370065A1 (fr) * 1987-07-31 1990-05-30 The Upjohn Company Acylhydrazones anthelmintiques, procede d'utilisation et compositions
JPH10338673A (ja) * 1997-06-04 1998-12-22 Nippon Bayeragrochem Kk イソニコチン酸ヒドラジド誘導体および有害生物防除剤
AUPQ262499A0 (en) * 1999-09-02 1999-09-23 University Of Queensland, The Novel iron chelators
AU780717C (en) * 1999-09-02 2005-12-01 Heart Research Institute Ltd., The Iron chelators and uses thereof
AU2004210010B2 (en) * 2003-02-05 2011-02-03 Lovejoy, David Metal ion chelators and therapeutic use thereof
BRPI0617204A2 (pt) 2005-10-11 2011-07-19 Hoffmann La Roche derivados de imidazo benzodiazepina
BRPI0601885A (pt) * 2006-05-15 2008-03-25 Univ Rio De Janeiro composição farmacêutica antiinflamatória e analgésica contendo derivados n-acilidrazÈnicos do safrol, uso, e processo para sua preparação
US8138191B2 (en) 2007-01-11 2012-03-20 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods
WO2009079797A1 (fr) 2007-12-26 2009-07-02 Critical Outcome Technologies, Inc. Composés et procédé pour le traitement du cancer
CA2999435A1 (fr) 2010-04-01 2011-10-06 Critical Outcome Technologies Inc. Composes et methodes pour le traitement du vih
JP2023539859A (ja) 2020-08-27 2023-09-20 オールテリティ セラピューティクス リミテッド 疾患を治療するための化合物および疾患を治療する方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4317776A (en) * 1979-01-04 1982-03-02 The United States Of America As Represented By The Secretary Of The Army 2-Acetyl-and 2-propionylpyridine thiosemicarbazones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8604582A1 *

Also Published As

Publication number Publication date
AU5358586A (en) 1986-08-26
AU582214B2 (en) 1989-03-16
WO1986004582A1 (fr) 1986-08-14
ES8801544A1 (es) 1988-02-16
NZ215046A (en) 1990-05-28
DK484986A (da) 1986-10-10
DK484986D0 (da) 1986-10-10
ES551807A0 (es) 1988-02-16

Similar Documents

Publication Publication Date Title
AU582214B2 (en) Anthelmintic pyridinyl acylhydrazones, method of use and compositions
US4022901A (en) 3-Pyridinyl-5-isothiocyanophenyl oxadiazoles
DE60204718T2 (de) 3-substituierte oxindol beta 3 agonisten
EP0299972B1 (fr) Acylhydrazones d'alkyle quaternaire anthelmintiques, procede d'utilisation et compositions
US4460588A (en) 5-Substituted pyrimidine derivatives active against internal animal parasites
EA009323B1 (ru) Ингибиторы вирусной полимеразы
JPH04503212A (ja) ５―リポキシゲナーゼ阻止剤としての４―ヒドロキシチアゾール
US3701780A (en) Imidazo(1,2-a)pyridines
EP0299973B1 (fr) Acylhydrazones anthelmintiques, procede d'utilisation et compositions
US5023334A (en) Anthelmintic pyridinyl acylhydrazones
EP0299974B1 (fr) Acylhydrazones anthelmintiques, procede d'utilisation et compositions
EP0550493B1 (fr) 3-carbamoyl-4-hydroxycoumarines anthelmintiques et anticoccidiennes, mode d'emploi et compositions
US4870082A (en) Anthelmintic quinolinyl acylhydrazones, method of use and compositions
US5011932A (en) Anthelmintic pyridinyl acylhydrazones derivatives
US4632926A (en) Quinazolinone derivatives which are active against coccidiosis
WO1986005982A3 (fr) Quinolinylacylhydrazones vermifuges, procede d'utilisation et compositions
US5049561A (en) Anthelmintic acylhydrazones, method of use and compositions
US4221796A (en) Substituted imidazolo-pyridines and method
EP0263209A2 (fr) Quinolinyl acylhydrazones anthelmintiques
KR900003373B1 (ko) 알릴계 아민및 그의 제조방법
EP0370065A1 (fr) Acylhydrazones anthelmintiques, procede d'utilisation et compositions
JPS62501709A (ja) 駆虫薬ピリジニル・アシルヒドラゾン、その使用方法および組成物
JPS61161275A (ja) 新規なアリルアミン類
JPH0544456B2 (fr)
US3398157A (en) Process for preparing benzimidazole nu-oxides

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19860819

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17Q First examination report despatched

Effective date: 19881020

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 19930212

RIN1 Information on inventor provided before grant (corrected)

Inventor name: CONDER, GEORGE, A.

Inventor name: FOLZ, SYLVESTER, D.

Inventor name: RECTOR, DOUGLAS, L.