AU582214B2 - Anthelmintic pyridinyl acylhydrazones, method of use and compositions - Google Patents

Anthelmintic pyridinyl acylhydrazones, method of use and compositions

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AU582214B2
AU582214B2 AU53585/86A AU5358586A AU582214B2 AU 582214 B2 AU582214 B2 AU 582214B2 AU 53585/86 A AU53585/86 A AU 53585/86A AU 5358586 A AU5358586 A AU 5358586A AU 582214 B2 AU582214 B2 AU 582214B2
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cpd
hydrazide
acid
pyridinyl
ethylidene
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George A. Conder
Sylvester D. Folz
Douglas L. Rector
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Pharmacia and Upjohn Co
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Upjohn Co
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    • 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
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    • 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
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    • 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

Description

ANTHELMINTIC PYRIDINYL ACYLHYDRAZONES, METHOD OF USE AND COMPOSITIONS
SUMMARY OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
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 . Among the helminths , 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 Strongylαs . Some of these genera attack primarily the intestinal tract while others , inhabit the stomach , lungs , liver and subcutaneous tissues . The parasitic infections causing helminthiasis and helminthosis lead to anemia , malnutrition , weakness , weight loss , unthriftiness , severe damage to the gastrointestinal tract wall and , if left to run their course , may result in death of the infected animals.
The anthelmintic activity of pyridinyl acylhydrazones has not been previously reported.
DETAILED DESCRIPTION OF THE INVENTION The pyridinyl acylhydrazones of this invention, including hydrates or pharmaceutically acceptable salts thereof, are represented by Formula I wherein X is (a) hydrogen; (b) C1-C10 alkyl; (c) C2-C6 alkenyl, preferably C2-C4 alkenyl; (d) C2-C6 alkynyl; (e) cyclo(C3-C10)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, trifluoromethyl, or halo; (f) pyrrolidinyl; (g) piperidinyl; (h) 1-methylpyrrolidinyl; (i) 1-methylpiperidinyl; (j) C2-C6 alkoxyalkyl; (k) cyclo(C3-C10)alkyl(C1-C4)alkyl; (1) phenyl (C1-C4)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (m) phenoxy (C1-C4) alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (n) naphthyl(C1-C3)alkyl optionally substituted with one or two C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (o) C1-C6 alkoxy, preferably C1-C4 alkoxy; (p) diphenylmethoxy; (q) cyclo(C3-C6)alkyloxy optionally substituted with one or two C1-C3 alkyl; (r) phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (s) benzyloxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; with the proviso that when a 2-pyridinyl acylhydrazone and R1 , R2, R4 are hydrogen, R3 is not benzyl; (t) heteroaromatic optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, C1-C3 alkylthio, or trifluoromethyl; (u) phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitro, or phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, or trifluoromethyl; (v) phenyl optionally substituted with the divalent C1-C2 alkylenedioxy; (w) naphthyl optionally substituted with one or 2 C1-C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitro; (x) bridged polycyclic hydrocarbon substituents of six to 10 nuclear carbons, optionally substituted with one, 2 or 3 (C1-C3) alkyl groups; (y) perhalo(C1-C7)alkyl; wherein R1 and R2, being the same or different, are hydrogen; hydroxy; C1-C4 alkyl, preferably C1-C3 alkyl; C1-C3 alkoxy; C1-C3 alkylthio; halo or trifluoromethyl; wherein R3 is hydrogen; C1-C4 alkyl; cyclo(C3-C6)alkyl optionally substituted with one, 2 or 3 C1-C3 alkyl, preferably cyclo(C3-C5)alkyl optionally substituted; phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; phenyl (C1-C3) alkyl optionally substituted with one, 2 or 3C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; or 1,3-dioxacyclohexan-5-yl; wherein R4 is hydrogen; C1-C2 alkyl; cyclo(C3-C6)alkyl optionally substituted with one, 2 or 3 C1-C3 alkyl, preferably cyclo(C3-C5)alkyl optionally substituted; phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; phenyl (C1-C3) alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; wherein n is zero or one. means the carbon content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of. carbon atoms in the moiety. Thus (C1-C3) 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 C1-C4 alkyl are methyl, ethyl, propyl, butyl and isomeric forms thereof. Examples of C1-C3 alkoxy are methoxy, ethoxy, propoxy and isomeric forms thereof. Examples of phenoxy substituted with one, 2 or 3 C1-C4 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.
Examples of C2-C6 dialkylamino are dimethyl amino, diethylamino, methylethylamino, dipropylamino and ethylpropylamino.
Examples of phenyl (C1-C3) alkyl are benzyl, phenylethyl and phenylpropyl. Examples of phenyl(C1-C3)alkyl substituted with one, 2 or 3 C1-C4 alkoxy, halo or trifluoromethyl include 4-chlorobenzyl, 2-chlorophenylethyl, p-tolylethyl, 2-methylbenzyl, 4-methoxybenzyl. Examples of C1-C3 alkylthio include methylthio, ethylthio, and n-propylthio.
Examples of substituted cyclo(C3-C10)alkyl are chrysanthemyl, 1-methylcyclopropyl and 2-methylcyclopropyl. Examples of cyclo(C3-C10)-alkyl(C1-C4)alkyl are 2-cyclohexylethyl and cyclohexylmethyl. An example of substituted cyclo(C3-C6)alkyloxy is menthyl.
Examples of naphthyl(C1-C3)alkyl include 2-naphthylmethyl and 1-naphthylethyl. Examples of substituted naphthyl(C1-C3)alkyl is ( 3,8-dichloro-1-naphthyl) methyl; (4-chloro-1-naphthyl)methyl; and (4-methoxy-1-naphthyl)methyl. Examples of substituted naphthyl include 3,6-dichloro-1-naphthyl; 3,5-dichloro-2-naphthyl; 6-methyl-2-naphthyl; and 4,6-dichloro-1-naphthyl.
Examples of bridged polycyclic hydrocarbon substituents of six to 10 nuclear carbons, optionally .substituted with one, 2 or 3 (C1-C3) alkyl groups include exo or endo-2-norbonyl, bicyclo[2,2,2]oct-1-yl, and 1-adamantyl.
Examples of perhalo (C1-C7) alkyl 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.
Preferred R1 and R2 include hydrogen, C1-C3 alkyl, C1-C3 alkoxy or a chloro atom.
Preferred R3 includes hydrogen and methyl or ethyl. R4 is preferably hydrogen.
Preferred X include hydrogen; C1-C4 alkyl; cyclohexylethyl; phenyl optionally substituted with one, 2 or 3 C1-C2 alkyl, C1-C2 alkoxy, trifluoromethyl and chloro; C1-C4 alkoxy; phenoxy optionally substituted with one, 2 or 3 C1-C2 alkyl, C1-C2 alkoxy, trifluoromethyl and chloro. Most preferably X includes hydrogen, C1-C4 alkyl; cyclohexylethyl; phenyl; phenyl substituted with C1-C2 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) C1- C10 alkyl; with the proviso that when X is methyl and the compound is a 2-pyridinyl acylhydrazone, and R1, R2 and R4 are hydrogen, R3 is other than hydrogen or methyl; with the further proviso that when X is methyl and the compound is a 4-pyridinyl acylhydrazone, and R1 , R2 and R4 are hydrogen, R3 is other than hydrogen; (c) C2-C6 alkenyl; (d) C2-C6 alkynyl; (e) cyclo(C3-C6)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, trifluoromethyl, or halo; (j) C2-C6 alkoxyalkyl; (k) cyclo(C4-C10)alkyl(C1-C4)alkyl; (1) phenyl(C1-C3)alkyl optionally substituted with, one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; with the proviso that when X is phenylmethyl and R1, R2 and R4 are hydrogen, R3 is other than hydrogen or methyl; (m) phenoxy(C1-C4)alkyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; with the proviso that when X is phenoxymethyl substituted with 4-chloro, 2, 4-di chloro or 2,4,5-trichloro and R1 , R2 and R4 are hydrogen, R3 is other than hydrogen (n) naphthyl(C1-C3)alkyl optionally substituted with one or 2 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; with the proviso that when X is 1-naphthylmethyl and R1 , R2 and R4 are hydrogen, R3 is other than hydrogen or methyl; (o) C1- C6 alkoxy, with the proviso that when the compound is a 4-pyridinyl acylhydrazone and R1, R2, R3 and R4 are hydrogen, X is other than methoxy; with the further proviso that when the compound is a 3-pyridinyl acylhydrazone and R1 , R2 and R4 are hydrogen and R3 is methyl, X is other than ethoxy; with the further proviso that when the compound is a 2-pyridinyl acylhydrazone and R1, R2 and R4 are hydrogen, X is other than methoxy when R3 is methyl, or ethoxy when R3 is hydrogen or methyl; (p) diphenylmethoxy; (q) cyclo(C3- C6)alkyloxy optionally substituted with one or two C1-C3 alkyl; (r) phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (s) benzyloxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; with the proviso that when a 2-pyridinyl acylhydrazone and R1, R2, R4 are hydrogen, R3 is not benzyl; (u) phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitro, or phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, or trifluoromethyl; with the proviso that when X is phenyl and R1 and R2 are hydrogen, either R3 or R4 is other than hydrogen; with the further proviso that when X is phenyl and the compound is a 2- or 4-pyridinyl acylhydrazone and R1 , R2 and R4 are hydrogen, R3 is other than hydrogen; with the further proviso that when X is phenyl, R1 is 2-ethyl, R2, R3 and R4 are hydrogen, the compound is other than a 4-pyridinyl acylhydrazone; with the further proviso that when X is phenyl substituted with 4-dimethylamino and R1, R2, R3 and R4 are hydrogen, the compound is other than a 4-pyridinyl acylhydrazone; with the .further proviso that when X is phenyl substituted with 4-methyl, the compound is a 2- or 4-pyridinyl acylhydrazone, either R1, R2, R3 or R4 is other than hydrogen; with the further proviso that when X is phenyl substituted with 4-methoxy, R3 is methyl, and R1, R2 and R4 are hydrogen, the compound is other than a 4-pyridinyl achlhydrazone; with the further proviso that when X is phenyl substituted with 3,4-dimethoxy, R1 is 2-ethyl and R2, R3 and R4 are hydrogen, the compound is other than a 4-pyridinyl acylhydrazone; with the further proviso that when X is phenyl substituted with 4-t-butyl and R1 , R2, R3 and R4 are hydrogen, the compound is other than a 3-pyridinyl acylhydrazone; with the further proviso that when X is phenyl, R1, R2 and R4 are hydrogen, and R3 is benzyl, the compound is other than a 2-pyridinyl acylhydrazone; with the further proviso that when X is phenyl substituted with 2-nitro, either R2, R3 or R4 is other than hydrogen; with the further provison that when X is phenyl substituted with 4-nitro, R1 is 2-ethyl, and R2, R3 and R4 are hydrogen, the compound is other than a 4-pyridinyl acylhydrazone; with the further proviso that when X is phenyl substituted with 4-nitro, R3 is methyl, and R1, R2 and R4 are hydrogen, the compound is other than a 4-pyridinyl acylhydrazone; (v) phenyl optionally substituted with the divalent C1-C2 alkylenedioxy; and (w) naphthyl optionally substituted with one or 2 C1-C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitro;
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.
Another embodiment of this invention are the novel compounds of Formula IA, the hydrates thereof or pharmaceutically acceptable salts thereof where R5, R5 and R7 are the same or different and are selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl, a halogen atom, C1-C4 alkylthio, phenoxy optionally substituted with a halogen atom, trifluoromethyl, C1-C4 alkyl, C1-C3 alkoxy; with the provisio that at least either R5, R6 or R7 is other than hydrogen.
Preferred R5, R6 and R7 include hydrogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and chloro.
Another embodiment of this invention are the novel compounds of Formula IB, the hydrates thereof or pharmaceutically acceptable salts thereof where R8 and R9 are the same or different and are selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl, a halogen atom, C1-C4 alkylthio, C2-C6 dialkylamino and nitro.
Preferred R3 and R9 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) C1-C6 alkoxy, preferably C1-C4 alkoxy; (p) diphenylmethoxy; (q) cyclo(C3- C6)alkyloxy optionally substituted with one or two C1-C3 alkyl; (r) phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; or (s) benzyloxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 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) C1-C6 alkoxy, preferably C1-C4 alkoxy; (p) diphenylmethoxy; (q) cyclo(C3-C6) alkyloxy optionally substituted with one or two C1-C3 alkyl; (r) phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; or (s) benzyloxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; with the. proviso that when a 4-pyridinyl acylhydrazone and R1, R2, R3 and R4 are hydrogen, -OR'5 is other than methoxy; with the further proviso that when a 3-pyridinyl acylhydrazone and R1, R2 and R4 are hydrogen and R3 is methyl, -OR '5 is other than ethoxy; with the further proviso that when a 2-pyridinyl acylhydrazone and R1, R2 and R4 are hydrogen, -OR'5 is other than (a) methoxy when R3 is methyl, or (b) ethoxy when R3 is hydrogen or methyl.
Another embodiment of this invention are the novel compounds of Formula ID, the hydrates thereof or pharmaceutically acceptable salts thereof where -R"5 is selected from the group consisting of (a) hydrogen; (b) C1-C10 alkyl; (c) C2-C6 alkenyl, preferably C2-C4 alkoxy; (d) C2-C5 alkynyl; (e) cyclo(C3-C6)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, trifluoromethyl, or halo; (f) pyrrolidinyl; (g) piperidinyl; (h) 1-methylpyrrolidinyl; (i) 1-methylpiperidinyl; (j) C2-C6 alkoxyalkyl; (k) cyclo(C4-C10)alkyl(C1-C4)alkyl; (1) phenyl(C1-C3) alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (m) phenoxy (C1-C4) alkyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; or (n) naphthyl(C1-C3)alkyl optionally substituted with one or 2 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl.
R1, R2, R3, R4 and n are defined in Formulas IA, IB, IC, ID, and IE as in Formula I.
Among the 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),
4-dimethylaminobenzoic acid (4-pyridinylmethylene)hydrazide, 4-methylbenzoic acid ( 2-pyridinylmethylene)hydrazide (Cpd #4, hydrate),
4-methylbenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #33), 4-methylbenzoic acid (2-pyridinylmethylene)hydrazide 1-oxide, 4-t-butylbenzoic acid (3-pyridinylmethylene)hydrazine,
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,
3,4-dimethoxybenzoic acid [2-(ethyl-4-pyridinyl)methylene]hydrazide, benzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #3), 4 -methoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide, 4-nitrobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide, and benzoic acid (α-2-pyridinylbenzylidene)hydrazide are known. See Y. Nishimoto and S. Toyashimo, Yakuguku Zasshi 87, 27-32 (1967); Chem. Abstr, 66, 98544r; S.E. Livingstone and J.E. Oluka, Transition Met. Chem 3, 261-7 (1978); H. Schlesinger, U.S. Patent 3,066,023, 11/27/62 - cf. H. Schlesinger, Ger. Patent 1,101,145, Appl. 12/19/58 - Chem. Abstr. 56, P2104b; S. Tanaka, T. Kato, S. Yamamoto andH. Yoshiaka, Agric. Biol. Chem. 41, 1953-1959 (1977); A. C. Sartorelli, K.C. Agrawal, B.A. Booth, J. Pittman, D.G. Bartholomew and A.D. Bloom, J. Med. Chem. 19, 830-833 (1976); A. Pedrazzoli et al., Bull. Soc. Chim. Fr., 407-14 (1968), Chem. Abstr. 69, 27401T; I. Babic et al., Chim. Ther. 7, 220-2(1972); Y. Arataetal, Am. Rept. Fac. Pharm. Kanazawa Univ., No. 5, 46-9 (1955), Chem. Abst. 50, 14974e; Chem. Abst. 101, 1624ot.
Among the pyridinyl acylhydrazones of Formula IC: ethyl[1-(3-pyridinyl)ethylidene]carbazate (Cpd #71), methyl (2-pyridinylmethylene)carbazate, ethyl(2-pyridinylmethylene)carbazate (Cpd #73), ethyl(4-pyridinylmethylene)carbazate (Cpd #75), and ethyl[1-(2-pyridinyl)ethylidene]carbazate (Cpd #70). are known. SeeR.U. Lemieux and R. Raap, U.S. 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¬
Rayyes and A.H. Katric, J. Chem. Eng. Data 28, 132-4 (1983); and A.B. deMilo, R.E. Redfern and A.B. Borkovec, J. Agri. Food Chem. 31, 713-18
(1983). Among the pyridinyl acylhydrazones of Formula ID: acetic acid (4-pyridinylmethylene)hydrazide, acetic acid (2-pyridinylmethylene)hydrazide, acetic acid [1-(2-pyridinyl)ethylidene]hydrazide,
2,4,5-trichlorophenoxyacetic acid (4-pyridinylmethylene)hydrazide, 2,4,5-trichlorophenoxyacetic acid (3-pyridinylmethylene)hydrazide,
2,4,5-trichlorophenoxyacetic acid (2-pyridinylmethylene)hydrazide,
2,4,-dichlorophenoxyacetic acid (4-pyridinylmethylene)hydrazide,
2,4,-dichlorophenoxyacetic acid (3-pyridinylmethylene)hydrazide,
2,4,-dichlorophenoxyacetic acid (2-pyridinylmethylene)hydrazide,
4-chlorophenoxyacetic acid (4-pyridinylmethylene)hydrazide,
4-chlorophenoxyacetic acid (3-pyridinylmethylene)hydrazide,
4-chlorophenoxyacetic acid (2-pyridinylmethylene)hydrazide,
1-napthylacetic acid [1-(3-pyridinyl)ethylidene]hydrazide,
1-napthylacetic acid [1-(4-pyridinyl)ethylidene]hydrazide,
1-napthylacetic acid [1-(2-pyridinyl)ethylidene]hydrazide,
1-napthylacetic acid (2-pyridinylmethylene)hydrazide,
1-napthylacetic acid (3-pyridinylmethylene)hydrazide,
1-napthylacetic acid (4-pyridinylmethylene)hydrazide, phenylacetic acid [1-(2-pyridinyl)ethylidene]hydrazide, phenylacetic acid [1-(3-pyridinyl)ethylidene]hydrazide, phenylacetic acid [l-(4-pyridinyl)ethylidene]hydrazide (Cpd #157), phenylacetic acid (2-pyridinylmethylene)hydrazide, phenylacetic acid (3-pyridinylmethylene)hydrazide, and phenylacetic acid (4-pyridinylmethylene)hydrazide are known. See G. Palla, C. Pelizzi, G. Predieri ,and C. Vignalo,
Grazz. Chim. Ital. 112 (7-8), 339-41 (1982) - Cnem. Abstr. 98, (13),
106703v; C. Mochon and G. Azira, Microchem. Journal, 1981, 26 (4),
463-71 - Chem. Abstr. 96 (8), 62225t; S.E. Livingstone and J.E. Oluka,
Trans. Met. Chem. 3, 261-7 (1978); J. Klosa, J. Prakt. Chem., 31 (1-2),
20-33 (1966) - Chem. Abstr. 64, 11124a; N.B. Mahishi, B.H. Iyer and
M. Sirisi, J. Indian Chem. Soc, 42 (2), 67-74 (1965) - Chem. Abstr. 62, l6654g; H. Bojarska-Dahlig, Acta Polon. Pharm., 20 (4), 293-302 (1963) - Chem. Abstr. 62, 2975i; N.R. El-Rayyes and F.M. Al-Kharafi, Egypt. J. Chem., 23, 151-6 (1981) - Chem. Abstr., 96, 142575X; H. Bojarska-Dahlig, Acta Polon. Pharm., 21 (4), 337-41 (1967) - Chem. Abstr. 62, 104016; Y. Takeda, Y. Maejima and H. Namekata, Japan. J. Tuberc. 2, 184-5 (1954), Chem. Abstr. 49, 13243i.
Among the pyridinyl acylhydrazones of Formula IE: isonicotinic acid (2-pyridinylmethylene)hydrazide (Cpd #221), isonicotinic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #217), picolinic acid (2-pyridinylmethylene)hydrazide, picolinic acid [1-(4-pyridinyl)ethylidene]hydrazide, picolinic acid [(6-methyl-2-pyridinyl)methylene]hydrazide, quinaldic acid [(6-methyl-2-pyridinyl)methylene]hydrazide, 4,5-dimethyl-2-furancarboxylic acid (4-pyridinylmethylene)hydrazide, 4,5-dimethyl-2-furancarboxylic acid (3-pyridinylmethylene)hydrazide, 4,5-dimethyl-2-furancarboxylic acid (2-pyridinylmethylene)hydrazide, 5-ethyl-2-furancarboxylic acid (4-pyridinylmethylene)hydrazide, 5-ethyl-2-furancarboxylic acid (3~pyridinylmethylene)hydrazide, 5-ethyl-2-furancarboxylic acid (2-pyridinylmethylene)hydrazide, 5-methyl-2-furancarboxylic acid (4-pyridinylmethylene)hydrazide, 5-methyl-2-furancarboxylic acid (3-pyridinylmethylene)hydrazide, 5-methyl-2-furancarboxylic acid (2-pyridinylmethylene)hydrazide, nicotinic acid (3-pyridinylmethylene)hydrazide, indole-3-carboxylic acid (4-pyridinylmethylene)hydrazide, indole-2-carboxylic acid (4-pyridinylmethylene)hydrazide, indole-2-carboxylic acid (3-pyridinylmethylene)hydrazide, indole-2-carboxylic acid (2-pyridinylmethylene)hydrazide, isonicotinic acid (3-pyridinylmethylene)hydrazide, nicotinic acid (2-pyridinylmethylene)hydrazide, nicotinic acid (4-pyridinylmethylene)hydrazide, picolinic acid (2-pyridinylmethylene)hydrazide, picolinic acid (3-pyridinylmethylene)hydrazide, picolinic acid (4-pyridinylmethylene)hydrazide, isonicotinic acid (4-pyridinylmethylene)hydrazide (Cpd #220), pyrazine-2-carboxylic acid [(2-ethyl-4-pyridinyl)methylene]hydrazide, nicotinic acid [(2-ethyl-4-pyridinyl)methylene]hydrazide, isonicotinic acid [(2-ethyl-4-pyridinyl)methylene]hydrazide,
2-ethylpyridine-4-carboxylic acid [(2-ethyl-4-pyridinyl)methylene]-hydrazide,
4,5-dichloroquinolinic-2-carboxylic acid (4-pyridinylmethylene)-hydrazide,
4,5-dichloroquinoline-2-carboxylic acid (3-pyridinylmethylene)-hydrazide,
6-methyl-3-pyridinecarboxylic acid [1-(6-methyl-3-pyridinyl)ethyl-idene]hydrazide,
3-n-propyl-1,4-dioxoquinoxaline-2-carboxylic acid (2-pyridinylmethylene)hydrazide,
3-methyl-1,4-dioxoquinoxaline-2-carboxylic acid (2-pyridinylmethylene)hydrazide,
3-ethyl-1,4-dioxoquinoxaline-2-carboxylic acid (2-pyridinylmethylene)hydrazide,
4-methyl-2-pyridinecarboxylic acid (α-2-pyridinylbenzylidene)-hydrazide, picolinic acid (α-2-pyridinylbenzylidene)hydrazide, 5-n-butyl-2-pyridinecarboxylic acid (4-pyridinylmethylene)hydrazide, 5-n-butyl-2-pyridinecarboxylic acid (3-pyridinylmethylene)hydrazide, 5-n-butyl-2-pyridinecarboxylic acid (2-pyridinylmethylene)hydrazide, isonicotinic acid N-oxide [1-(4-pyridinyl)ethylidene]hydrazide, isonicotinic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide, isonicotinic acid N-oxide [1-(4-pyridinyl)ethylidene]hydrazide
1-oxide, isonicotinic acid [1-(6-methyl-2-pyridinyl)ethylidene]hydrazide, isonicotinic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #219), nicotinic acid [1-( 2-pyridinyl )ethylidene]hydrazide (Cpd #200), nicotinic acid [1-(6-methyl-2-pyridinyl)ethylidene]hydrazide, isonicotinic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #218), nicotinic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #199), isonicotinic acid (α-2-pyridinylbenzylidene)hydrazide, thiophene-2-carboxylic acid [1-(2-pyridinyl)ethylidene]hydrazide, furan-2-carboxylic acid (2-pyridinylmethylene)hydrazide (Cpd #216, hydrate), quinaldic acid (2-pyridinylmethylene)hydrazide, 5-n-butyl-2-pyridinecarboxylic acid [1-methyl-3-pyridinium]hydrazide methanesulfonate, indazole-3-carboxylic acid (4-pyridinylmethylene)hydrazide; isonicotinic acid [(3-hydroxy-4-pyridinyl)methylene]hydrazide; and pyridazine carboxylic acid (4-pyridinylmethelene)hydrazide are known. See M. Nonoyama, Inorg. Chim. Acta. 10, 133-137 (1974); A. L. Mndzhoyan, V. G. Afrikyan, R. S. Organesyan, A. O. Shakhmuradova, L. D. Zhuruli, S. G. Karagezan and V. G. Sarafyar, Arm. Khim. Zh. 21, 340-7 ( 1968); D. Koruncev, S. Cvetnicandl. Babic, Acta. Pharm. Jugoslav, 23, 1-8 (1973); D. Koruncev, I. Babic, D. Cvek and A. Deljac, Acta. Pharm. Jugoslav, 24, 9-11 (1974); M. Kawai, U.S. Patent 3,503,987, January 17, 1970. Chem. Abstr., 72, 121378z; W. Durckheimer, H. Hartung and E. Schrinner, Ger. Offen. DE 2002712, July 29, 1971; Chem. Abstr. 75, 98595u; F. Capitan, F. Salinas and J. Gimenez Plaza, Afinidad, 35, 263-5 (1978); F. H. Case, J. Heterocycl. Chem., 10, 353-5 (1973); H. Vogt and H. Mayer, Arzneim. Forsch., 20, 1532-6 (1970); A. Risaliti and L. Lolli, Farmaco (Pavic) Ed. Sci., 12, 705-11 (1957), Chem. Abstr., 52, 11038f; N. P. Buu-Hoi and N. Dut Xuong., Bull. Soc. Chim. France, 1377-9 (1961); M. L. Vitalo, J. Webb and P. Saltman, J. Inorg. Biochem., 20, 255-62 (1984); A. Alemany, M. Bernabe, C. Elorriagu, E. F. Alvarez, M. Lora-Tamajo and J. Ofelia Nieto, Bull. Soc. Chim. France, 2486-2497 (1966); F. Capitan, F. Salinar and J. Gimenez Plaza, Ars. Pharm., 16, 293-304 (1975); Chem. Abstr., 84, 11787X; S. E. Livingstone and J. E. Oluka, Trans. Met. Chem. , 3, 261-7 (1978); E. Requena, J. J. Laserna, A. Novar, and F. G. Sanchez, Analyst, 108, 933-38 (1983); E. Baker et al, Biochemical Pharmacology, 37, 3011-3017 (1985); H. Bojarska-Dahlig, Rec. Trav. Chim. 83, pp. 177-85 (1964), Chem. Abstr., 60, I4467d.
The preparation of piperonylic acid (4-pyridinylmethylene)hydrazide (Cpd #19) and 3, 4, 5-trimethoxy benzoic acid (4-pyridinylmethylene)hydrazide (Cpd #224) is described in G. Mazzone et al, J. Heterocyclic Chem., 21, 181 (Jan. -Feb. 1984).
The pyridinyl acylhydrazones of this invention (Formula I) 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 pyridinyl acylhydrazone N-oxides (formula I where n = 1 ) are generally prepared by first oxidizing the pyridylketone (II) to furnish the pyridylketone N-oxide (VII) (Scheme C). 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 R3 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. 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).
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 following detailed examples/procedures describe how to prepare various pyridinyl acylhydrazones of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants as well as to reaction conditions and techniques.
Procedure 1 Preparation of benzoic acid [1-(2-pyridinyl)ethylidene]hydrazide, Compound 1 A mixture of 6.81 gm (0.05 mole) of benzhydrazide, 6.06 gm (0.05 mole) of 2-acetylpyridine and 100 ml of ethanol is stirred at reflux 2 hr. Then sufficient dioxane is added to the boiling mixture to furnish a solution. The hot solution is filtered. The filtrate is diluted to the cloud point with water, cooled to room temperature, and then chilled in the refrigerator. The product is collected and dried to yield 7.61 gm (64%) of the title compound having a melting point of 151.6°C. Analysis Calcd: C, 70.29; H, 5.44.
Found: - C, 70.28; H, 5.43- Procedure 2 Preparation of 2-methylbenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide, Compound 10 A mixture of 3.63 gm (0.03 mole) of 4-acetylpyridine, 4.51 gm (0.03 mole) of o-toluic acid hydrazide and 100 ml of 95. ethanol is refluxed 8 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point and cooled to room temperature. The mixture is chilled in the refrigerator and the product collected, washed with water, and dried to yield 4.78 gm (63%) of the title compound having a melting point of 187.4°C.
Analysis Calcd: C, 71.15; H, 5.93; N, 16.60.
Found: C, 70.82; H, 5.86; N, 16.61
Procedure 3 Preparation of benzoic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide, Compound 48 A mixture of 5.48 gm (0.04 mole) of 4-acetylpyridine 1-oxide, 5.45 gm (0.04 mole) of benzhydrazide and 100 ml of absolute ethanol is refluxed for a total of 4 hr and cooled. The reaction mixture is evaporated in vacuo to yield a solid which is crystallized from ethanol to yield 7.82 gm (77%) of the title compound having a melting point of 248.9°C (decomp).
Analysis Calcd: C, 65.88; H, 5.10; N, 16.47.
Found: C, 65.44; H, 5.23; N, 16.39.
Procedure 4 Preparation of benzoic acid [1-(4-pyridinyl)propylidene]hydrazide, Compound 51 A mixture of 4.05 gm (0.03 mole) αf 4-propionylpyridine, 4.08 gm
(0.03 mole) of benzhydrazide and 100 ml of Ethanol is refluxed 6 hr. The hot solution is filtered. The filtrate is cooled to room temperature and then chilled in the refrigerator. The product is collected, washed with Skellysolve B and dried to yield 5.36 gm (71%) of the title compound having a melting point of 177.6°C. Analysis Calcd: C, 71.15; H, 5.93; N, 16.60.
Found: C, 71.13; H, 5.98; N, 16.77.
Procedure 5 Preparation of 2-phenoxybenzoic acid [3-methyl-1-(4- pyridinyl)butylidene]hydrazide, Compound 54 Following the general method of procedure 4 and making noncritical variations, except 12 drops of glacial acetic acid is added as a catalyst, 9.00 gm (0.055 mole) of isobutyl 4-pyridyl ketone and 12.59 gm (0.055 mole) of 2-phenoxybenzhydrazide yield 13.89 gm (67%) of the title compound having a melting point of 137.6°C.
Analysis Calcd: C, 73-97; H, 6.21; N, 11.25. Found: C, 74.16; H, 6.24; N, 11.19.
Procedure 6 Preparation of benzoic acid 1 -methyl-2-[1-(4-pyridinyl)- ethylidene]hydrazide, Compound 55
To 100 ml of pyridine is added successively, under dry nitrogen,
8.83 gm (0.0592 mole) of 1-methyl-2-[1-(4-pyridinyl)ethylidene]hydrazine and 6.87 gm (0.0592 mole) of benzoyl chloride. Upon addition of the acid chloride the color changes from clear orange to a clear, deep rose color which changes to an orange solid within about 5 minutes. The reaction mixture is stirred at room temperature overnight, the pyridine removed via a Buchi evaporator at 70 °C and the cooled residue slurried with water to yield 6.32 gm (42%) of the title compound having a melting point of 128.3°C.
Analysis Calcd: C, 71.13; H, 5.97; N, 16.59.
Found: C, 71.02; H, 6.02; N, 16.27.
Procedure 7 Preparation of benzoic acid [1-(3-py-'idinyl)propylidene]hydrazide, Compound 58
A mixture of 6.76 gm (0.05 mole) of 3-propionylpyridine, 6.81 gm (0.05 mole) of benzhydrazide and 100 ml of absolute ethanol is refluxed 8.5 hr. The hot solution is filtered. The filtrate is cooled to room temper ature and then chilled. The crystals that separate are collected and dried to yield 10.18 gm (80%) of the title compound having a melting point of 169.4°C. Analysis Calcd: C, 71.15; H, 5.93; N, 16.60.
Found: C, 71.46; H, 5.97; N, 16.52.
Procedure 8 Preparation of benzoic acid [1-(4-pyridinyl)pentylidene]hydrazide, Compound 60 A mixture of 5.97 gm (0.0366 mole) of n-butyl 4-pyridinyl ketone,
5.45 gm (0.04 mole) of benzoic acid hydrazide and 100 ml of absolute ethanol is refluxed 4.5 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point, cooled to room temperature and chilled. The solids which deposit are collected, washed with water and dried to yield 7.89 gm (77%) of the title compound having a melting point of 142.1°C.
Analysis Calcd: C, 72.60; H, 6.76; N, 14.95.
Found: C, 72.83; H, 6.86; N, 14.90. Procedure 9 Preparation of 2-methoxybenzoic acid [3-methyl-1-(4pyridinyl)butylidene]hydrazide, Compound 65
To 9.00 gm (0.0551 mole) of isobutyl 4-pyridyl ketone in 100 ml of absolute ethanol is added 9.20 gm (0.0551 mole) of 2-methoxybenzhydrazide and 12 drops of glacial acetic acid. The reaction mixture is refluxed on the steam bath overnight, filtered hot, the volume reduced to 1/3, titrated with cold water to the cloud point and set aside. Crystals do not form at room temperature nor in the freezer. The product is extracted in chloroform, the extracts washed 2x with water, dried with saturated sodium chloride solution and anhydrous sodium sulfate and the solvent removed via a rotoevaporator at 70 °C until a solid forms (2 hours); mp. 130.4°C.
Analysis Calcd: C, 69.43; H, 6.80; N, 13.49.
Found: C, 69.03; H, 6.72; N, 13.30. Procedure 10 Preparation of benzoic acid [2-phenyl-1-(4-pyridinyl)ethylidene]hydrazide, Compound 61 Following the general method of procedure 9 and making non-critical variations, except 12 drops of glacial acetic acid was used, 6.00 gm (0.0304 mole) of benzyl 4-pyridyl ketone and 4.14 gm (0.0304 mole) of benzhydrazide yield 8.90 gm (93%) of the title compound in two crops melting at 84.4° and 90.9°. Analysis Calcd: C, 76.17; H, 5.43; N, 13.32.
Found: C, 75.15; H, 5.45; N, 13.19. C, 74.88; H, 5.42; N, 13.03. Procedure 11 Preparation of ethyl [1-(2-pyridinyl)ethylidene]carbazate, Compound 70 A mixture of 6.06 gm (0.05 mole) of 2-acetylpyridine, 5.21 gm (0.05 mole) of ethylcarbazate and 100 ml of absolute ethanol is refluxed 2 hr. The hot solution is filtered. The filtrate is cooled to room temperature and then chilled in the refrigerator. The product is collected, washed with Skellysolve B and dried to yield 3.8 gm (37%) of the title compound having a melting point of 113.2°C. Analysis Calcd: C, 57.97; H, 6.28; N, 20.29.
Found: C, 58.05; H, 6.33; M, 20.64.
Procedure 12 Preparation of benzyl (α-2-pyridinylphenethylidene)carbazate, Compound 77 A mixture of 8.31 gm (0.05 mole) of carbobenzoxyhydrazide, 9.86 gm (0.05 mole) of benzyl 2-pyridyl ketone and 100 ml of 95% ethanol is refluxed 6 hr. The reaction mixture is treated with decolorizing carbon and filtered. The heated filtrate is diluted with water to the cloud point. The mixture is cooled to room temperature and then chilled in the refrigerator. The product is collected, washed with water and dried to yield 11.06 gm (64%) of the title compound having a melting point of 155.1°C.
Analysis Calcd: C, 73.04; H, 5.51; N, 12.17.
Found: C, 73.06; H, 5.71; N, 12.30.
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.
Found: C, 72.73; H, 5.43; M, 11.96.
Procedure 13 Preparation of 1,1-dimethylethyl (α-4-pyridinylbenzylidene)carbazate, Compound 81 To 6.61 gm (0.05 mole) of t-butylcarbazate dissolved in 100 ml of warm water is added 9.16 gm (0.05 mole) of 4-benzoylpyridine in 30 ml of ethanol. The mixture Is refluxed 7 hr. Cooling several weeks yields 1.77 gm (12%) of the title compound having a melting point of 134.5°C. Analysis Calcd: C, 68.69; H, 6.40; N, 14.14.
Found: C, 69.06; H, 6.44; N, 14.22. Procedure 14 Preparation of methyl (4-pyridinylmethylene)carbazate hydrate, Compound 83 A solution of 2.70 gm (0.03 mole) of methyl carbazate, 3.21 gm (0.03 mole) of 4-pyridinecarboxaldehyde and 50 ml of anhydrous methanol is refluxed 8 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point and cooled to room temperature. The mixture is chilled in the refrigerator. The crystals are collected, washed with water and dried to yield 5.87 gm (99%) of the title compound having a melting point of 159.6°C. (decomp.). Analysis Calcd: C, 52.32; H, 5.18; N, 22.89.
Found: C, 52.70; H, 5.03; N, 22.81.
Procedure 15 Preparation of benzyl (4-pyridinylmethylene)carbazate, Compound 84 A mixture of 8.31 gm (0.05 mole) of carbobenzoxyhydrazide, 5.36 gm (0.05 mole) of 4-pyridinecarboxaldehyde and 100 ml of 95% ethanol is refluxed 4 hr. The hot solution is filtered. The filtrate is cooled to room temperature and then chilled in the refrigerator. The cream crystals are collected and dried to give 9.47 gm (74%) of the title compound having a melting point of 133.8°C. Analysis Calcd: C, 65.88; H, 5.10; N, 16.47.
Found: C, 65.49; H, 5.07; N, 16.54.
Procedure 16 Preparation of diphenylmethyl (4-pyridinylmethylene)carbazate, Compound 86 To 24.11 gm (0.1 mole) of benzhydryl carbazate in 200 ml of warm absolute ethanol is added 10.66 gm (0.1 mole) of 4-pyridinecarboxaldehyde in 75 ml of absolute ethanol. The mixture is refluxed 7 hr and cooled. The solvent is removed in vacuo. Recrystallization from ethanol/Skellysolve B yields 26.03 gm (78.5%) of the title compound having a melting point of 159-160°C. Analysis Calcd: C, 72.49; H, 5.17; N, 12.68.
Found: C, 72.39; H, 5.36; N, 12.77.
The title compound is resynthesized using the above procedure at a 5X scale-up to yield 137.5 gm (41%) of the title compound having a melting point of 158-159°C. Found: C, 72.44; H, 5.10; N, 12.46. Procedure 17 Preparation of diphenylmethyl (4-pyridinylmethylene)carbazate monohydrate, Compound 87
To 10.89 gm (0.045 mole) of benzhydryl carbazate in 100 ml of warm ethanol is added 4.82 gm (0.045 mole) of 4-pyridinecarboxaldehyde in 50 ml of ethanol. The mixture is refluxed 4.5 hr and cooled. The solvent is removed in vacuo to give the crude product. Recrystallization of the crude material from ethanol yields 14.6 gm (93%) of the title compound having a melting point of 96.9°C.
Analysis Calcd: C, 68.77; H, 5.44; N, 12.03. Found: C, 69.07; H, 5.42; N, 11.50.
Procedure 18 Preparation of ethyl [1-(4-pyridinyl)propylidene]carbazate, Compound 90 A solution of 4.05 gm (0.03 mole) of 4-propionylpyridine, 3.12 gm (0.03 mole) of ethyl carbazate and 100 ml of absolute ethanol is refluxed 6 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point. The mixture is cooled to room temperature and then chilled in the refrigerator to give crystals which are collected, washed with Skellysolve B and dried to yield 3.25 gm (49%) of the title compound having a melting point of 147.1°C. Analysis Calcd: C, 59.73; H, 6.79; N, 19.00.
Found: C, 59.83; H, 6.96; N, 18.99. Procedure 19 Preparation of 1,1-dimethylethyl [1-(4-pyridinyl)propylidene]carbazate, Compound 91 A solution of 4.05 gm (0.03 mole) of 4-propionylpyridine, 3.96 gm (0.03 mole) of t-butylcarbazate and 100 ml of absolute ethanol is refluxed 6 hr. The reaction mixture is treated with decolorizing carbon and filtered. The filtrate yields crystals on cooling. The product is collected, washed with Skellysolve B and dried to yield 3.16 gm (40%) of the title compound having a melting point of 170.1°C. Analysis Calcd: C, 62.65; H, 7.63; N, 16.87.
Found: C, 62.67; H, 7.79; N, 17.05.
The title compound is resynthesized two times, employing the above proced'ure at a scale-up of 2.3X and 11.56X to yield 11.9 gm (68%) and 57.5 gm (67%), respectively. Analysis Found: C, 62.60; H, 7.67; N, 16.89; mp 183.0°C.
Found: C, 62.69; H, 7.59; N, 16.85; mp 181.5-l82°C. Procedure 20 Preparation of methyl [1-(4-pyridinyl)propylidene]carbazate, Compound 93
A solution of 4.05 gm (0.03 mole) of 4-propionylpyridine, 2.70 gm
(0.03 mole) of methyl carbazate and 100 ml of absolute ethanol is refluxed 6 hr. The solution is evaporated in vacuo to give a solid.
The crude product is crystallized from ethyl acetate/Skellysolve B to yield 3.90 gm (63%) of the title compound having a melting point of
216.2°C. (decomp.).
Analysis Calcd: C, 57.97; H, 6.28; N, 20.29. Found: C, 57.67; H, 6.35; N, 20.58.
Procedure 21 Preparation of phenyl [1-(4-pyridinyl)ethylidene]carbazate, Compound 94 A solution of 5.66 gm (0.03 mole) of phenyl carbazate hydrochloride, 3.63 gm (0.03 mole) of 4-acetylpyridine and 50 ml of ethanol is refluxed 2 hr. The solution is cooled and evaporated to dryness in vacuo to give an oil. The oil is triturated with ethyl acetate-methanol to afford a solid. The solid is dissolved in 50 ml of water and treated with 50 ml water containing 5 gm sodium carbonate. A gummy solid separates which solidifies on standing. The crude product is collected and crystallized from ethyl acetate-Skellysolve B to yield 4.13 gm (54%) of the title compound having a melting point of 120.4°C (decomp.). Analysis Calcd: C, 65.88; H, 5.10; N, 16.47.
Found: C, 66.01; H, 5.12; N, 16.33.
Procedure 22 Preparation of phenyl [1-(4-pyridinyl)ethylidene]carbazate monohydrochloride, Compound 95
A mixture of 12.11 gm (0.1 mole) of 4-acetylpyridine, 18.85 gm (0.1 mole) of phenyl carbazate hydrochloride and 250 ml of absolute ethanol is refluxed 6 hr and cooled. The reaction mixture is evaporated to dryness in vacuo to give a rose-colored solid. The crude product is crystallized from absolute ethanol to yield 28.13 gm (97%) of the title compound having a melting point of 159.1°C.
Analysis Calcd: C, 57.63; H, 4.80; Cl, 12.18; N, 14.41.
Found: C, 57.84; H, 4.86; Cl, 11.87; N, 14.25.
Procedure 23 Preparation of ethyl (α-4-pyridinylbenzylidene)carbazate, Compound 96 A mixture of 9.16 gm (0.05 mole) of phenyl 4-pyridyl ketone, 5.21 gm (0.05 mole) of ethylcarbazate and 75 ml of glacial acetic acid is heated at 100°C for 8 hr. The acetic acid is removed in vacuo. The residue is slurried with ethyl ether and collected to yield 5.76 gm (39%) of the title compound having a melting point of 138.7°C. Analysis Calcd: C, 67.91; H, 5.58; N, 15.61.
Found: C, 67.39; H, 5.61; N, 15.36.
Procedure 24 Preparation .of 5-methyl-2-(1-methylethyl)cyclohexyl [1-(4-pyridinyl)ethylidene]carbazate, Compound .97 A solution of 6.43 gm (0.03 mole) of 1-menthylcarbazate, 3.63 gm
(0.03 mole) of 4-acetylpyridine and 100 ml of absolute ethanol is refluxed 3 hr. The solvent is evaporated in vacuo to give a solid. The product is crystallized from ethyl acetate/Skellysolve 3 to yield 4.07 gm (43%) of the title compound having a melting point of 188.2°C. Analysis Calcd: C, 68.14; H, 8.52; N, 13.25.
Found: C, 67.76; H, 8.59; N, 13-24.
Procedure 25 Preparation of 1,1-dimethylethyl [1-(4-pyridinyl)pentylidene]carbazate, Compound 98 A solution of 11.2 gm (0.0751 mole) of n-butyl 4-pyridyl ketone, 9.80 gm (0.0741 mole) of butyl carbazate, 100 ml of tetrahydrofuran and 0.1 gm of p-toluenesulfonic acid is refluxed 17 hr. The reaction mixture is poured into 300 ml of ice and water with stirring to give a white solid. The crude product is collected, washed with water and dried. The crude product is crystallized from acetone/hexane to yield 9.27 gm (44%) of the title compound having a melting point of 156.2°C. Analysis Calcd: C, 64.98; H, 8.30; N, 15.16.
Found: C, 64.89; H, 8.50; N, 14.87. Procedure 26 Preparation of ethyl [1-(4-pyridinyl)pentylidene]carbazate, Compound 99 A mixture of 8.3 gm (0.055 mole) of n-butyl 4-pyridyl ketone, 6.1 gm (0.059 mole) of ethyl carbazate and 150 ml of absolute ethanol is refluxed 17 hr. A Tlc (3% MeOH/CH2Cl2 on Silica gel) shows 50% starting material remaining. p-Toluenesulfonic acid (0.3 gm) is added and the reaction mixture refluxed 17 hr more. Tic shows no remaining starting materials. The reaction is concentrated in vacuo. The residue is slurried with water and the solid collected, washed with water and dried. Crystallization yields 7.41 gm of the title compound having a melting point of 102.1°C.
Analysis Calcd: C, 62.63; H, 7.68; N, 16.85.
Found: C, 62.51; H, 7.73; N, 17.39. Procedure 27 Preparation of phenyl (4-pyridinylmethylene) carbazate monohydrochloride, Compound 101 A solution of 6.43 gm (0.06 mole) of 4-pyridinecarboxaldehyde, 11.31 gm (0.06 mole) of phenyl carbazate hydrochloride and 300 ml of 95% ethanol is refluxed 4 hr. The reaction mixture is evaporated to dryness. The crude product is suspended in 200 ml of boiling absolute ethanol and sufficient methanol added to give a solution. The hot solution is filtered, the filtrate cooled to room temperature and then chilled in the freezer. The crystals are collected, washed with Skellysolve B and dried to yield 11.0 gm (66%) of the title compound having a melting point of 224.4°C (decomp).
Analysis Calcd: C, 56.22; H, 4.32; Cl, 12.79; N, 15.14.
Found: C, 56.13; H, 4.46; Cl, 12.62; N, 15.35.
Procedure 28 Preparation of ethyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide, Compound 109 A solution of 5.48 gm (0.04 mole) of 4-acetylpyridine 1-oxide,
4.16 gm (0.04 mole) of ethylcarbazate and 100 ml of absolute ethanol is refluxed 6 hr. The solution is evaporated in vacuo to give a solid. The crude product is crystallized from ethyl acetate/ ethanol to yield 6.47 gm (73%) of the title compound having a melting point of 220.1°C. Analysis Calcd: C, 53.81; H, 5.83; N, 18.83.
Found: C, 53.63; H, 5.78; N, 13.63. Procedure 29 Preparation of phenyl [1-(4-pyridinyl)butylidene]carbazate 1-oxide, Compound 112 To 6.61 gm (0.04 mole) of 4-butyrylpyridine 1-oxide in ca. 100 ml of ethanol is added 7.54 gm (0.04 mole) of phenyl carbazate hydrochloride and the mixture heated on the steam bath for a total of 6 hr. After 4 hr the solution is allowed to evaporate to less than 100 ml and cooled. The mixture is chilled in the freezer to yield 5.17 gm (43%) of the title compound having a melting point of 206.5°C (decomp). Analysis Calcd: C, 63.99; H, 6.25; N, 13.92.
Found: C, 64.20; H, 5.72; N, 14.04. Procedure 30 Preparation of phenyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide monohydrochloride, Compound 113
A mixture of 5.48 gm (0.04 mole) of 4-acetylpyridine 1-oxide, 7-54 gm (0.04 mole) of phenyl carbazate hydrochloride and 100 ml of absolute ethanol is refluxed 4 hr. The solvent is stripped in vacuo to give a solid. The crude product is crystallized from ethanol/ethyl acetate to yield 8.45 gm (78%) of the title compound having a melting point of
196.8°C.
Analysis Calcd: C, 54.63; H, 4.55; Cl, 11.54; N, 13.66. Found: C, 54.27; H, 4.66; Cl, 11.58; N, 13.44.
Procedure 31 Preparation of benzyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide hydrate, Compound 119. A mixture of 5.48 gm (0.04 mole) of 4-acetylpyridine-1-oxide, 6.64 gm (0.04 mole) of benzyl carbazate and 200 ml of absolute ethanol is refluxed 7 hr. The solvent is removed in vacuo to give a solid. The crude product is recrystallized from isopropyl alcohol to yield 10.14 gm (87%) of the title compound having a melting point of 219.4°C (decomp). Analysis Calcd: C, 61.98; H; 5.37; N, 14.46; H2O, 1.86.
Found: C, 61.86; H, 5.76; N, 13.93; H2O, 1.73. Procedure 32 Preparation of 1,1-dimethylethyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide, Compound 120 A mixture of 5.48 gm (0.04 mole) of 4-acetylpyridine 1-oxide, 5.29 gm (0.04 mole) of butyl carbazate and 100 ml of absolute ethanol is refluxed 7 hr. The reaction mixture is evaporated to dryness in vacuo to furnish a solid. The crude product is crystallized from ethanol to yield 4.5 gm (45%) of the title compound having a melting point of 214.3°C. Analysis Calcd: C, 57.37; H, 6.77; N, 16.73. Found: C, 57.29; H, 6.76; N, 16.77. Procedure 33 Preparation of 4-trifluorcmethylbenzoic acid [1-(4pyridinyl)ethylidene]hydrazide, Compound 121
A mixture of 2.97 gm (0.0245 mole) of 4-acetylpyridine, 5.0 gm
(0.0245 mole) of 4-trifluoromethylbenzhydrazide and 100 ml of absolute ethanol is refluxed for 6 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point, cooled to room temperature and chilled. The crystals which separate are collected, washed with water and dried to yield 6.29 gm (84%) of the title compound having a melting point of 198.4°C.
Analysis Calcd: C, 58.63; H, 3.91; N, 13.68.
Found: C, 58.48; H, 4.05; N, 13.76. Procedure 31 Preparation of acetic acid [1-(4-pyridinyl)ethylidene]hydrazide, Compound 136 A mixture of 2.22 gm (0.03 mole) of acetic acid hydrazide, 3.63 gm (0.03 mole) of 4-acetylpyridine and 100 ml of absolute ethanol is refluxed 2 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point. The mixture is cooled to room temperature and then chilled in the refrigerator. The product is collected, washed with water and dried to yield 3.63 gm (69%) of the title compound having a melting point of 178.1°C.
Analysis Calcd: C, 61.02; H, 6.21. Found: C, 61.22; H, 6.24.
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.
Analysis Calcd: C, 61.02; H, 6.21; N, 23.73. Found: C, 60.99; H, 6.52; N, 23.88.
Procedure 35 Preparation of (2,4,5-trichlorophenoxy)acetic acid [1-(4-pyridinyl)ethylidene]hydrazide, Compound 137 A solution of 5.39 gm (0.02 mole) of 2,4,5-trichlorophenoxyacetic acid hydrazide, 2.42 gm (0,02 mole) of 4-acetylpyridine, 125 ml of dioxane and 2 ml of acetic acid is refluxed 4 hr. The hot solution is filtered. The filtrate is diluted with water until cloud point. The mixture is cooled to room temperature and then chilled in the refrigerator. The product is collected to yield 6.24 gm (83%) of the title compound having a melting point of 227.4°C (decomp). Analysis Calcd: C, 48.32; H, 3.22; N, 11.28.
Found: C, 48.47; H, 3.28; N, 11.33.
Procedure 36 Preparation of benzoic acid [1,3-dioxan-5-yl)-3-pyridinylmethylene]hydrazide, Compound 421
Following the general method of procedure 56 and making non-critical variations, except overnight refluxing is required, 12 drops of concentrated hydrochloric acid is used and no methylene chloride extraction in the work-up is employed, 9.66 gm (0.05 mole) of 1,3-dioxan-5-yl 3-pyridyl ketone and 6.81 gm (0.05 mole) of benzhydrazide yield 6.58 gm (42%) of the title compound having a melting point of 131.8°C. Analysis Calcd: C, 65.58; H, 5.50; N, 13.50. Found: C, 65.02; H, 5.57; N, 13.14.
Procedure 37 Preparation of formic acid [1-(4-pyridinyl)pentylidene]hydrazide, Compound 141 A solution of 14.26 gm (0.0956 mole) of n-butyl 4-pyridyl ketone, 5.70 gm (0.0956 mole) of formylhydrazine, 50 ml of THF, 30 ml of absolute ethanol and 0.1 gm of p-toluenesulfonic acid is refluxed 24 hr. The reaction is chilled to give a white solid which is collected and discarded. The filtrate is concentrated in vacuo to furnish a solid. This material is dissolved in methylene chloride. The methylene chloride solution is washed with saturated sodium bicarbonate solution; then brine. The organic layer is dried over magnesium sulfate and concentrated in vacuo in the presence of excess hexane to yield 5.14 gm (26%) of the title compound having a melting point of 143.4°C.
Analysis Calcd: C, 64.47; H, 7.33; N, 20.73. Found: C, 64.47; H, 7.33; N, 20.73. Procedure 38 Preparation of butyric acid [1-(4-pyridinyl)ethylidene]hydrazide oxalic acid salt, Compound 145 A mixture of 6.15 gm (0.03 mole) of butyric acid [1-(4-pyridinyl)ethylidene]hydrazide (Compound 144), 2.70 gm (0.03 mole) of oxalic acid and 100 ml of absolute ethanol is refluxed 3 hr. The mixture is cooled and then chilled in the refrigerator. Two crops of the product are collected and dried to yield 6.9 gm (78%) of the title compound having a melting point of 207.2°C.
Analysis Calcd: C, 52.88; H, 5.76; N, 14.24.
Found: C, 52.60; H, 6.13; N, 13.15. Found: C, 52.47; H, 6.31; N, 13.13.
Procedure 39 Preparation of butyric acid [1-(4-pyridinyl)ethylidene]hydrazide 1-hydroxy-2-naphthoic acid salt, Compound 147
A mixture of 8.2 gm (0.04 mole) of butyric acid [1-(4-pyridinyl)ethylidene]hydrazide (Compound 144), 7.53 gm (0.04 mole) of 1-hydroxy-2-naphthoic acid and 100 ml of absolute ethanol is refluxed 7 hr. Cooling the reaction mixture to room temperature and then chilling yields a solid which is collected and dried to provide 13.67 gm (87%) of the title compound having a melting point of 158.7°C.
Analysis Calcd: C, 67.18; H, 5.85; N, 10.69.
Found: C, 67.06; H, 5.86; N, 10.71. Procedure 40 Preparation of butyric acid [1-(4-pyridinyl)ethylidene]hydrazide phenoxyacetic acid salt, Compound 151 A mixture of 8.2 gm (0.04 mole) of butyric acid [1-(4-pyridinyl)ethylidene]hydrazide (Compound 144), 6.09 gm (0.04 mole) of phenoxyacetic acid and 100 ml of absolute ethanol is refluxed 7.5 hr. The reaction mixture is evaporated to dryness in vacuo. The solid is crystallized from ethanol to yield 9.48 gm (66%) of the title compound having a melting point of 105.8°C.
Analy3is Calcd: C, 63.37; H, 6.44; N, 11.76.
Found: C, 63.41; H, 6.54; N, 11.87. Found: C, 63.80; H, 6.59; N, 11.88.
Procedure 41 Preparation of cyclohexanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide, Compound 159 A solution of 4.26 gm (0.03 mole) of cyclohexanecarboxylic acid hydrazide, 3.63 gm (0.03 mole) of 4-acetylpyridine and 100 ml of ethanol is refluxed 7 hr. The solvent is evaporated in vacuo to give a white solid. The product is crystallized from ethyl acetate to yield 5.38 gm (73%) of the title compound having a melting point of 195.3°C. Analysis Calcd: C, 68.57; H, 7.76; N, 17.14.
Found: C, 68.54; H, 8.00; N, 17.27. Procedure 42 Preparation of 2-methoxybenzoic acid ( 4-pyridinylbenzylidene)hydrazide monohydrochloride, Compound 285 To 9.16 gm (0.05 mole) of 4-benzoylpyridine in 100 ml of absolute ethanol and 4.4 ml (0.05 mol) concentrated hydrochloric acid (yellow solution) was added 8.31 gm (0.05 mole) of 2-methoxybenzylhydrazide. The reaction mixture was refluxed 12 hrs and filtered. The filtrate was concentrated to about 1/2 volume and cooled. The yellow crystals which formed were collected, worked with cold absolute ethanol and dried to give 17.4 gm (95%) of the title compound having a melting point of 242.1°. Analysis Calcd: C, 65.31; H, 4.93; N, 11.42; Cl, 9.64.
Found: C, 65.08; H, 5.03; N, 11.53; Cl, 9.33. Procedure 43 Preparation of cyclohexanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide, Compound 287 A mixture of 5.48 gm (0.04 mole) of 4-acetylpyridine 1-oxide, 5.68 gm (0.04 mole) of cyclohexanecarboxylic acid hydrazide and 100 ml of absolute ethanol is refluxed 4 hours. The reaction mixture is concentrated in vacuo to dryness to give a solid. The solid is crystallized from isopropanol to furnish 8.20 gm (79%) of the title compound; mp 245-3°. Analysis Calcd: C, 64.37; H, 7.28; N, 16.09.
Found: C, 63.77; H, 7-55; N, 15.84. Procedure 44 Preparation of butyric acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide hydrate, Compound 289 A mixture of 5.48 gm (0.04 mole) of 4-acetylpyridine 1-oxide, 4.09 gm (0.04 mole) of butyric acid hydrazide and 100 ml of absolute ethanol is refluxed 6 hours. The reactions mixture is evaporated in vacuo to give a solid. The crude product is crystallized from ethyl acetate/ethanol to yield 7.41 gm (84%) of the title compound; mp 209.7°. Analysis Calcd: C, 59.25; H, 6.32; H, 18.85.
Found: C, 59.18; H, 6.94; N, 18.53. Procedure 45 Preparation of cyclobutanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide, Compound 290
A mixture of 6.06 gm (0.05 mole) of 4-acetylpyridine, 5.7 gm (0.05 mole) of cyclobutanecarboxylic acid hydrazide, and 100 ml of absolute ethanol is refluxed 5 hours. The reaction mixture is evaporated in vacuo to give a solid. The product is crystallized from ethanol/ethylacetate/diethylether to give 2.92 gm (27%) of the title compound; mp 138.6°.
Analysis Calcd: C, 66.36; H, 6.91; N, 19.35.
Found: C, 65-97, H, 6.81; N, 19.11.
Procedure 16 Preparation of 4-nitrobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide, Compound 291
A mixture of 3.62 gm (0.02 mole) of p-nitrobenzhydrazide, 2.42 gm
(0.02 mole) of 4-acetylpyridine and 100 ml of absolute ethanol is refluxed 3 hours. Sufficient dimethylformamide is added to the mixture at boiling to give a solution. The hot solution is filtered. The filtrate is diluted with water to the cloud point. The mixture is chilled in the refrigerator. The product is collected, washed with ether and dried to yield 4.46 gm (79%) of the title compound; mp 251.2°. Analysis Calcd: C, 59.15; H, 4.23;N, 19.72.
Found: C, 59.24; H, 4.80; N, 19.79. Procedure 47 Preparation of 2-methylcyclopropanecarboxylic acid [1- (3-pyridinyl)propylidene]hydrazide, Compound 313 A mixture of 8.0 gm (0.07 mole) of 2-methylcyclopropanecarboxylic acid hydrazide, 9-46 gm (0.07 mole) of ethyl-3-pyridyl ketone, 10 drops of glacial acetic acid and 100 ml of EtOH was refluxed 20 hr. Tlc (9:1 Skellysolve B/Ethyl acetate on silica gel) shows no remaining starting material. The reaction mixture was cooled to room temperature and evaporated in vacuo to give a liquid. The liquid solidified on standing. The solid was slurried in ether, collected and dried to give 4.77 gm (29%) of the title compound having a melting point of 137.3°C. Analysis Calcd: C, 67.51; H, 7.41; N, 18.86.
Found: C, 66.99; H, 7.48; N, 18.08.
Procedure 48 Preparation of 3-trif luoromethylbenzoic acid [1-(3- pyridinyl)propylidene]hydrazide, Compound 316
A mixture of 10.21 gm (0.05 mole) of 3-trifluoromethylbenzoic acid hydrazide, 6.76 gm (0.05 mole) of ethyl-3-pyridyl ketone, 10 drops of glacial acetic acid and 100 ml of absolute ethanol was refluxed 15 hr.
The 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.
Analysis Calcd: C, 59.81; H, 4.39; 13.07; F, 17.74.
Found: C, 59.65, H, 4.49; 13.14; F, 18.25.
Procedure 49 Preparation of acetic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide, Compound 327 A mixture of 6.76 gm (0.05 mole) of 2-methyl-5-acetylpyridine, 3.7 gm (0.05 mole) of acetic acid hydrazide and 100 ml of ethanol was refluxed 5 hr. The solution was diluted with Skellysolve B until cloudy. The mixture was cooled to room temperature and then chilled in the freezer. The product was collected, washed with Skellysolve B and dried to afford 7.93 gm (83%) of the title compound having a melting point of 178.5°C. Analysis Calcd: C, 62.81; H, 6.35; N, 21.97.
Found: C, 62.33; H, 6.83; N, 22.03.
Procedure 50 Preparation of 3-trifluoromethylbenzoic acid [1-(3- pyridinyl)ethylidene]hydrazide, Compound 301 A mixture of 10.21 gm (0.05 mole) of 3-trifluoromethylbenzoic acid hydrazide, 100 ml of ethanol and 10 drops of glacial acetic acid was refluxed for 14 hr. The solution was cooled to room temperature and then chilled in the freezer. The product was collected, washed with water and dried to give 11.77 gm (77%) of white solid which had a melting point of 183.3°C.
Analysis Calcd: C, 58.64; H, 3.94; N, 13.67. Found: C, 58.36; H, 4.08; N, 13.68. Procedure 51 Preparation of 3-nitro-1-naphthalenecarboxylic acid [1- (4-pyridinyl)ethylidene]hydrazide, Compound 342 A mixture of 5.0 gm of (0.0216 mole) of 3-nitro-1-naphthalenecarboxylic acid hydrazide, 2.62 gm (0.0216 mole) of 1-acetylpyridine, 400 ml of ethanol, 100 ml of tetrahydrofuran, and 20 drops of glacial acetic acid was refluxed 10 hr. The hot solution was filtered. The filtrate was cooled to room temperature and then chilled. The product was collected, washed with Skellysolve B and dried to furnish 6.31 gm (87%) of the title compound having a melting point of 228.5°C. Analysis Calcd: C, 64.67; H, 4.22; N, 16,75.
Found: C, 64.56; H, 1.55; N, 16.29.
Procedure 52 Preparation of nicotinic acid (phenyl-4-pyridinylmethylene)hydrazide, Compound 353
A mixture of 9.16 gm (0.05 mole) of 4-benzoyl pyridine, 6.86 gm (0.05 mole) of nicotinic acid hydrazide, 100 ml of ethanol and 4.4 ml of concentrated hydrochloric acid was refluxed 16 hr. The reaction mixture was cooled to room temperature. An equal volume of water was added containing 5.4 gm (0.05 mole) of sodium carbonate. The mixture was placed in the refrigerator. The product which separated was collected, washed with water and dried to give 8.21 gm (54%) of the title compound having a melting point of 74.0°C.
Analysis Calcd: C, 71.51; H, 4.67; N, 18.13. Found: C, 71.66; H, 4.98; N, 18.20. Procedure 53 Preparation of formic acid [1-(3-chloro-4-pyridinyl)ethylidene]hydrazide, Compound 391
A mixture of 6.30 gm (0.0405 mole) of 4-acetyl-3-chloropyridine,
2.46 gm (0.041 mole) of formic acid hydrazide and 100 ml of ethanol was refluxed 13 hr. The mixture was chilled in the freezer to give a solid which was collected in two crops. The product was purified by chromatography [keiselgel 60 (230-400 mesh)] and eluting with 5% methanol/methylene chloride to give 2.56 gm (32%) of white flakes which have a melting point of 175.2°C. Analysis Calcd: C, 48.62; H, 4.08; N, 21.26; Cl, 17.94.
Found: C, 48.29; H, 4.14; N, 20.92; Cl, 17.93.
Procedure 54 Preparation of butyric acid [1-(3-chloro-4-pyridinyl)ethylidene]hydrazide, Compound 395
A mixture of 5.20 gm (0.0335 mole) of 4-acetyl-3-chloropyridine, 3.43 gm (0.0336 mole) of butyric acid hydrazide and 100 ml of ethanol was refluxed 18 hr. The mixture was chilled in the freezer. The solid which separated was collected to give 2.01 gm (25%) of white solid having a melting point of 103.8°C.
Analysis Calcd: C, 55.12; H, 5.89; N, 17.53; Cl, 14.79. Found: C, 54.97; H, 5.92; N, 17.12; Cl, 14.83.
Procedure 55 Preparation of cyclopropanecarboxylic acid [1-(6-chloro- 3-pyridinyl)ethylidene]hydrazide, Compound 414 Following the general method of procedure 53 and making non-critical variations, except the product was purified by recrystallization from absolute ethanol rather than by chromatography, 5.25 gm (0.0337 mole) of 3-acetyl-6-chloropyridine and 3.40 gm (0.034 mole) of cyclopropanecarboxylic acid hydrazide yield 6.52 gm (81%) of the title compound having a melting point of 218.1°C.
Analysis Calcd: C, 55.59; H, 5.09; N, 17.68; Cl, 14.92. Found: C, 55.40; H, 5-18; N, 17.56; Cl, 15.02.
Procedure 56 Preparation of ethyl [(1,3-dioxan-5-yl)-3-pyridinylmethylene]carbazate, Compound 422
To 8.30 gm (0.043 mole) of 1,3-dioxan-5-yl-3-pyridyl ketone in 100 ml of absolute ethanol is added 4.47 gm (0.043 mole) of ethyl carbazate and one equivalent of concentrated hydrochloric acid. The reaction mixture is refluxed for 8 hr, then treated with activated charcoal and filtered hot. The filtrate is concentrated to about 100 ml volume and one equivalent of sodium carbonate in warm water added to give a final Ph of 8. The solution is concentrated to approximately 100 ml total volume (nearly all ethanol stripped) on the rotoevaporator. The aqueous solution is extracted with 3 × 75 ml methylene chloride. The combined chloride extracts are washed with brine, dried over sodium sulfate, then evaporated to give a solid. The product is crystallized from absolute ethanol to give 4.97 gm (40%) of the title compound having a melting point of 131.8°C. Analysis Calcd: C, 55.91; H, 6.14; N, 15.04.
Found: C, 55.62; H, 6.36; N, 14.70.
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.
Found: C, 58.92; H, 6.63; N, 15.45.
Procedure 58 Preparation of ethyl [(1,3-dioxan-5-yl)-4-pyridinylmethylene]carbazate, Compound 431 Following the general method of procedure 56 and making non-critical variations, except extraction with methylene chloride in the work-up is not required and the product is crystallized from aqueous ethanol, 8.30 gm (0.043 mole) of 1,3-dioxan-5-yl 5-pyridyl ketone and 4.47 gm (0.0430 mole) of ethyl carbazate yield 6.13 gm (55%) of the title compound in two crops having melting points of 64.9°C and 65.0°C. Analysis Calcd: C, 55.91; H, 6.14; N, 15.04.
Found: C, 55.23; H, 5-95; N, 14.99.
Procedure 59 Preparation of benzoic acid [(1,3-dioxan-5-yl)-4-pyridinylmethylene]hydrazide, monohydrochloride, Compound 423
Following the general method of procedure 56 and making non-critical variations, except no neutralization with sodium carbonate is used and extraction with methylene chloride in the work-up is not required, 4.23 gm (0.0219 mole) of 1,3-dioxan-5-yl 4-pyridyl ketone and 2.98 gm (0.0219 mole) of benzhydrazide yield 5.29 gm (77%) of the title compound having a melting point of 157.7°C.
Analysis Calcd: C, 58.71; H, 5.22; N, 12.08; Cl, 10.19. Found: C, 58.37; H, 5.15; N, 11.97; Cl, 10.58.
The compounds prepared according to Procedures 1-59 are tabulated in Table A along with other illustrative compounds of the invention prepared following the general procedure indicated (Procedures 1-59) and making non-critical variations, except starting with the appropriate pyridyl ketone (II) and acyl hydrazide/carbazate (III).
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).
Although a significant number of the pyridinyl acylhydrazones of this invention have failed to demonstrate significant activity against Nematospiroides dubius in mice or Caenorhabditis elegans in vitro, observations in sheep experimentally infected with Haemonchus contortus in accordance with Procedure I, generally confirm anthelmintic activity at 100 mg/kg of body weight upon oral and/or parenteral administration as set forth in Table I. Pyridinyl acylhydrazones which are toxic at 100 mg/kg of body weight are expected to exhibit anthelmintic activity at a lower non-toxic dose, see for example compound No. 139. Further observations in sheep naturally infected with various helminths also confirmed broad-spectrum anthelmintic activity of various pyridinyl acylhydrazones of this invention. See Procedure II and the results as set forth in Table II.
Procedure No. I In individual experiments all sheep are treated identically, however non-critrcal variations occur between experiments. All of the sheep used in this procedure are treated twice with levamisole hydrochloride orally at 3 mg/kg or once each. with ivermectin parenterally at 200 μg/kg and levamisole hydrochloride orally at 3 mg/kg. The second treatment in each case is administered 4-7 days after the first treatment. Two weeks after the second treatment all sheep are inoculated per os with -3,500 to -7,500 infective larvae of H. contortus. Rectal fecal samples are taken from each sheep 26-41 days post-inoculation (PI), and these samples are examined for eggs of H. contortus using the McMaster counting chamber technique. All sheep harboring good infections of H. contortus are randomly allocated to a treatment group; those which do not exhibit suitable infections are dropped from the study. One-three days later on days 27-42 PI each sheep remaining in the study (excluding the nontreated controls) is treated with a test compound (orally or parenterally at 100 mg/kg unless indicated otherwise) or a standard (levamisole hydrochloride orally at 8 mg/kg) or is used as untreated control. All sheep received food and water ad lib. throughout the experiment. Prior to administration, all solid compounds are finely ground using a mortar and pestle. 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. Percentage clearance for a particular test compound in a given trial is determined according to the following formula: Percentage Clearance = [(Mean number of worms recovered from nontreated (Test Compound) control sheep - Number of worms recovered from treated sheep)/Mean number of worms recovered from nontreated control sheep] × 100. Sheep which die within 21 hr following treatment are not examined for worm3, while any that die between 24 hr post-treatment and necropsy are examined in an identical manner as that described above. The results of various trials are combined and reported in Table I as percentage clearance. Procedure No. II
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. For parenteral administration, 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 (e.p.g.) 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.
Ten percent of the total contents collected from the abomasum and small intestine and 10% or the entire contents of the large intestine, cecum, and colon are examined under stereoscopic magnification (40X). All worms are identified to genus and in some instances species. Separate adult and larval counts are determined. The mean percentage clearance against specific helminths in the test sheep is calculated by subtracting the mean number of helminths observed in the treated sheep at necropsy from the mean number observed in the nontreated controls at necropsy, dividing the remainder by the latter mean number and multiplying by 100. The mean percentage clearances against the various helminths identified in the test sheep are calculated.
The results from various trials for particular pyridinyl acylhydrazones of Formula I are combined and set forth in Table II. From an evaluation of the test results set forth in Tables I and II, it is clear that the pyridinyl acylhydrazones of this invention are efficacious, broad-spectrum anthelmintic agents.
Eight pyridinyl acylhydrazones; benzoic acid [1-(3-pyridinyl)ethylidene]hydrazide, butyric acid [1-(4-pyridinyl)ethylidene]hydrazide, butyric acid (4-pyridinylmethylene)hydrazide, 4-ethoxybenzoic acid [1- (4-pyridinyl)ethylidene]hydrazide, 2-methylpropionic acid [1-(4-pyridinyl)ethylidene]hydrazide, 3-cyclohexanepropionic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide, formic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide and ethyl (2-pyridinylmethylene)carbazate (Compounds 2, 144, 153, 16, 275, 160, 203 and 73); have been selected as representative of the class and the test results from various trials of the foregoing compounds are combined and set forth in Table IIA.
4-Ethoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Compound
#16) has been tentatively identified for further evaluation in sheep while 2-methoxypropionic acid [1-(4-pyridinyl)ethylidene]hydrazide
(Compound #275) has been tentatively identified for further evaluation in cattle.
The results of a multidose study of butyric acid [1-(4-pyridinyl)ethylidene]hydrazide, compound 144, are set forth in Table III. Five sheep were used for each dosage level, medicated and unmedicated controls in accordance with Procedure III.
Procedure III Forty (40) sheep were selected from a flock of forty-six (46) pastured animals which had been placed in concrete-floored pens and allowed to acclimate for 12 days. The animals were selected and allocated (5/group) on the basis of weight, sex, fecal egg count, and number of parasite species observed in the fecal egg counts. The animals were treated two days after grouping. Throughout the study, lambs were fed alfalfa hay and given water ad lib. One group of lambs each (Groups 1-6, respectively) received 100,
50, or 25 mg of compound 144 per kg of body weight by either an oral or parenteral route. Lambs in the remaining two groups (7 and 8, respectively) received a standard (levamisole hydrochloride, 8 mg/kg orally) treatment or served as nontreated controls. Groups 1, 2 and 4 each had one sheep die after allocation to groups and prior to treatment. In addition, one lamb in Group 4 was not included in the data for that group because the animal was moribund shortly after treatment and it was felt that his response was altered significantly by his condition at the time of treatment. One lamb in Group 5 and two lambs in Group 8 died following treatment, but egg and worm counts taken at the time of death were considered with data taken at necropsy for the remaining animals in each of these groups. Helminth Egg Counts
The number and species of helminth eggs per gram of feces (e.p.g.) 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. Necropsy
All lambs were necropsied on day 7 posttreatment. Each animal was euthanized prior to opening the abdominal cavity. Ligatures were placed at the reticulo-omasal junction, the pyloric valve, and the ileo-cecal junction. Contents of the abomasum and small. intestine were placed in individual jars and preserved with 10% formalin, while both organs were incubated separately in a physiological saline solution for 6-8 hours at 37°C. Following the incubation period, both organs were washed, and then the wash plus the digest for each were added together and fixed with 10% formalin. The combined cecum, large intestine, and colon contents were washed numerous times using a 100 mesh screen with openings of 0.53 mm and then fixed in 10$ formalin. All carcasses were incinerated. Helminth Counts
Aliquots from each abomasum and small intestine totaling 10% for contents and 20% for digests plus each total cecum, large intestine, colon sample were examined under stereoscopic magnification (15x), and all worms which were found were collected and stored. Worms were later identified to species and stage of development (L4, L5, or adult). L5's were those worms which possessed adult reproductive organs without eggs in the uterus or darkened spicules. Few immature worms were recovered and, therefore, only adult worms were considered. Signs of toxicosis were observed following treatment in animals given the high dosage of Compound No. 144 by either route or the medium dosage administered parenterally. Discomfort persisted in affected lambs for several hours. DETAILED DESCRIPTION (cont'd) The pyridinyl acylhydrazones of Formula I (IA, IB, IC, ID or IE) 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.). For example, aqueous or oil suspensions can be administered orally, or the compounds can be formulated with a solid carrier for feeding. Furthermore, 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. In addition, 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.
Representative 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.
In general, 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. Similarly, 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. Representative suitable ones are polyoxyalkylene derivatives of fatty alcohols and of sorbitan esters, and glycerol and sorbitan esters of fatty acids. Various 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.
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. In general , the formulations of this invention are administered to animals so as to achieve therapeutic or prophylactic levels of the active compound. At present , it is known that 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 .
In other animals , and for other kinds of parasi tic worms , 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. In this regard, it should be noted that the concentration of active compound in the formulation selected for administration is in many situations not cri tical . One can administer a larger quantity of a formulation having a relatively low concentration and achieve the same therapeutic or prophylact ic dosage as a relatively small quanti ty of a relatively more concentrated formulation . More frequent small dosages will likewise give results comparable to one large dose. One can also administer a sustained release dosage system ( protracted delivery formulation) so as to provi de therape ut i c and/or prophylactic dosage amounts over an extended period . 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 .
Although 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. Generally good results are obtained with compounds of Formula I by the oral or parenteral route of administration of about 1 to 200 mg/kg of animal bodyweight (such total dose being given at one time , in a protracted manner or in divided doses over a short period of time such as 1 -4 days) . The technique for administering these materials to animals are known to those skilled in the veterinary and medical fields . It is contemplated that 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. DEFINITIONS
The definitions and explanations below are for the terms as used throughout the entire patent application including both the specification and claims.
All temperatures are in degrees Celsius.
TLC refers to thin-layer chromatography.
Brine refers to an aqueous saturated sodium chloride solution.
When solvent pairs are used, 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.
TABLE A
C a n R1 R2 R3 R4 X m.p, P H
1 2 0 H H CH3 H Ph 151.6 1 -
2 3 0 H H CH3 H Ph 163.9 1 -
3 4 0 H H CH3 H Ph 174.5 1 -
4 2 0 H H H H 4-CH3Ph 155.3 1 +
5 3 0 H H CH3 H 4-CH3Ph 164.8 1 -
6 3 0 H H H H Ph 188.4 1 -
7 4 0 H H H H Ph 205.3 1 -
8 4 0 H H Ph H Ph 114.4 1 +
9 2 0 H H H H Ph 36.4 1 +
10 4 0 H H CH3 H 2-CH3Ph 187.4 2 -
11 4 0 H H CH3 H 3-CH3Ph 146.3 2 -
12 4 0 H H CH3 H 2-CH3OPh 152.0 2 -
13 4 0 H H CH3 H 4-CH3OPh 171.4 2 -
14 4 0 H H CH3 H 2-CH3CH2OPh 163.5 2 -
15 4 0 H H CH3 H 3-CH3CH2OPh 137.4 2 -
16 4 0. H H CH3 H 4- CH3CH2OPh 185.6 2 -
17 4 0 H H CH3 H 3,4,5-(CH3O)3Ph 198.4 2 -
18 4 0 H H CH3 H 3,4-(CH3O)2Ph 181.7 2 -
19 4 0 H H H H 3,4-(0CH20)Ph 214.6 2 -
20 4 0 H H CH3 H 2-PhO-Ph 134.8 2 -
21 4 0 H H H H 2-CH3Ph 186.2 2 -
22 4 0 H H CH3 H 3-CH3OPh 155.3 2 -
23 4 0 H H CH3 H 3,5-(CH3O)2Ph 190.7 2 -
24 4 0 H H CH3 H 2-ClPh 158.3 2 -
25 4 0 H H CH3 H 4-CH3Ph (2 crops) 189.1 2 - 190.6
26 4 0 H H CH3 H 2,4-(Cl)2Ph 189.1 2 -
27 4 0 H H CH3 H 3,4-(Cl)2Ph 223.2 2 -
28 4 0 H H H H 2,4-(Cl)2Ph 193-7 2 -
29 4 0 H H H H 3,4-(Cl)2Ph 164.3 2 +
30 4 0 H H H H 2-CH3OPh 110.5 2 +
31 4 0 H H H H 3-CH3OPh 164.0 2 -
31 A 4 0 H H H H 3-CH3Ph 175.7 2 - TABLE A (cont'd) c a n R1 R2 R3 R4 X m.p. P H
32 4 0 H H H H 1-CH3OPh 180.2 2 -
33 4 0 H H H H 1-CH3Ph 186.5 2 - 31 4 0 H H H H 4-CH3CH2OPh 207.6 2 -
35 4 0 H H H H 3,5-(CH3O)2Ph 185.2 2 -
36 4 0 H H H H 2-ClPh 119.9 2 -
37 4 0 H H H H 4-t-C4H9Ph 195.0 2 -
38 2 0 H H CH3 H 4-t-C4H9Ph 118.3 2 - 39 4 0 H H CH3 H 4-t-C4H9Ph 194.7 2 -
10 2 0 H H H H 4-t-C4H9Ph 200.1 2 +
11 3 0 H H H H 4-t-C4H9Ph 138.1 2 +
12 3 0 H H CH3 H 4-t-C4H9Ph 169.6 2 -
13 2 0 H H H H 2-PhOPh 169.4 2 - 11 4 0 H H H H 2-CH3CH2OPh 100.4 2 -
15 2 0 H H CH3CH2 H 2-CH3CH2OPh 137-3 2 -
16 3 0 H H CH3CH2 H 2-CH3CH2OPh 115.6 2 -
47 4 0 H H CH3CH2CH2 H 2-CH3CH2OPh 120.5 2 -
47A 4 1 H H CH3CH2CH2 H 2-CH3CH2OPh 156.3 2 - 18 4 1 H H CH3 H Ph 248.9 3 -
18A 4 1 H H H H 4-CF3Ph 270.7 3 -
19 4 1 H H CH3 H 2-PhOPh 227.2 3 _
50 4 0 H H CH3CH2CH2 H 2-PhOPh 116.1 2 -
51 4 0 H H CH3CH2 H Ph 177.6 4 - 52 4 0 H H CH3CH2 H 4-ClPh 170.5 4 -
53 4 0 H H CH3CH2 H 3,4-(CH3O)2Ph 182.0 4 -
51 4 0 H H i-C4H9 H 2-PhOPh 137-6 5 -
55 4 0 H H CH3 CH3 Ph 128.3 6 -
56 4 1 H H CH3 H 2-CH3OPh 248.3 3 - 57 2 0 6-CH3 H H H 2-CH3OPh glass 2 -
58 3 0 H H CH3CH2 H Ph 169.4 7 -
59 3 0 H H CH3CH2 H 4-ClPh 176.1 7 -
60 4 0 H H n-C4H9 H Ph 142.1 8 -
61 4 0 H H PhCH2 H Ph (2 crops) 84.4 10 -
90.9
62 4 1 H H CH3 H 2,4-(Cl)2Ph 269.4 3 - TABLE A (cont'd) c a n R1 R2 R3 X m.p. P H
63 3 0 H H H H 2,4-(Cl)2Ph 196.0 3 -
64 3 0 H H CH3 H 2,4-(Cl)2Ph 175.1 3 -
65 4 0 H H i-C4H9 H 2-CH3OPh 130.1 9 -
66 4 0 H H n-C4H9 H 2,4(Cl)2Ph 135.7 3 -
67 2 0 6-CH3 H H H Ph 150.2 1 -
68 4 0 H H CH3 H 2-NO2Ph 150.5 2 -
69 4 0 H H H H 2-NO2Ph 201.1 2 -
70 2 0 H H CH3 H CH3CH2O 113.2 11 -
71 3 0 H H CH3 H CH3CH2O 116.9 11 -
72 4 0 H H CH3 H CH3CH2O 176.5 11 -
73 2 0 H H H H CH3CH2O 128.9 11 -
74 3 0 H H H H CH3CH2O 158.1 11 -
75 4 0 H H H H CH3CH2O 176.1 11 -
76 4 0 H H CH3 H t-C4H9O 118.3 11 -
77 2 0 H H PhCH2 H PhCH2O (2 exp.) 155.1 12 - 158.7
73 2 0 H H CH3 H PhCH2O 155.1 12 -
79 4 0 H H CH3 H PhCH2O 151.7 12 -
80 4 0 H H CH3 H PhCH2O (2 exp.) 172.9 12 - 179.5
80 A 2 0 H H CH3 H PhCH2O 210.1 12 -
81 4 0 H H Ph H t-C4H9O 131.5 13 ~
82 4 0 H H Ph H PhCH2O 124.3 13 -
83 4 0 H H H H CH3O 159.6 14 +
84 4 0 H H H H PhCH2O 133.8 15 -
85 4 0 H H CH3 H CH3O 178.4 15 -
86 4 0 H H H H PhCH2O (2 exp.) 159-160 16 -
158-159
86A 4 1 H H H H 4-ClPh 244.2 16 -
87 4 0 H H H H PhCH2O 96.9 17 +
88 2 0 H H CH3 H CH3O 137.3 15 -
89 3 0 H H CH3 H CH3O 141.4 15 -
90 4 0 H H CH3CH2 H CH3CH2O 147.1 15 -
91 4 0 H H CH3CH2 H t-C4H9O 170.1 19 - · TABLE A (cont'd) c a n R1 R2 R3 R4 X m.p. P H
92 4 0 H H CH3CH2 H PhCH2O 134.8 3 -
93 4 0 H H CH3CH2 H CH3O 216.2 20 -
91 4 0 H H CH3 H PhO 120.1 21 -
95 4 0 H H CH3 H PhO · HCl 159.1 22 -
96 4 0 H H Ph H CH3CH2O 188.7 23 -
97 4 0 H H CH3 H 1-menthyl-O 138.2 24 -
98 4 0 H H n-C4H9 H t-C4H9O 156.2 25 -
99 4 0 H H n-C4H9 H CH3CH2O 102.1 26 -
100 4 0 H H CH3CH2CH2 H PhO · HC1 203-3 22 -
101 4 0 H H H H PhO · HCl 221.4 27 -
102 4 0 H H H H 1-menthyl-O 131-1 18 -
103 3 0 H H CH3CH2 H t-C4H9O 176.6 18 -
101 2 0 H H CH3CH2 H CH3O 115.1 18 -
105 2 0 H H CH3CH2 H CH3CH2O 131.0 18 r
106 2 0 H H CH3CH2 H t-C4H9O 184.4 18 -
107 3 '0 H H CH3CH2 H CH3CH2O 115.8 18 -
108 4 0 H H CH3CH2CH2 H t-C4H9O 169-4 18 -
109 4 1 H H CH3 H CH3CH2O 220.1 28 -
110 4 0 H H CH3CH2CH2 H CH3CH2O 127-9 20 -
111 4 1 H H CH3 H CH3O 228.4 22 -
112 4 1 H H CH3CH2CH2 H PhO 206.5 29 -
113 4 1 H H CH3CH2CH2 H t-C4H9O 186.2 29 -
114 4 1 H H CH3CH2CH2 H CH3CH2O 196.6 29 -
115 4 0 H H i-C4H9 H PhO • HC1 200.5 29 -
116 4 0 H H i-C4H9 H t-C4H9O 163-4 29 -
117 4 0 H H i-C4H9 H 1-menthyl-O 143.4 29 -
118 4 1 H H CH3 H PhO · HCl 196.8 30 -
119 4 1 H H CH3 H PhCH2O 219.4 31 +
120 4 1 H H CH3 H t-C4H9O 214.3 32 -
121 4 0 H H CH3 H 4-CF3Ph 198.4 33 -
122 2 0 H H H H 4-(CH3)2NPh 223.. 33 -
123 3 0 H H H H 4-(CH3)2NPh 250.8 33 -
124 4 0 H H H H 4-(CH3)2NPh 239.8 33 -
125 3 0 H H CH3 H 4-(CH3)2NPh 168.4 33 - TABLE A (cont'd) c a n R1 R2 R3 R4 X m.p. P H
126 4 0 H H CH3 H 4-(CH3)2NPh 233-0 33 -
127 3 0 H H CH3 H 4-CF3Ph 203-5 33 -
128 3 0 H H H H 4-CH3OPhCH2O 156.9 33 -
129 4 0 H H H H 4-CH3OPhCH2O 164.3 33 -
130 3 0 H H CH3 H 4-CH3OPhCH2O 138.7 33 +
131 4 0 H H CH3 H 4-CH3OPhCH2O 157.6 33 -
132 2 0 6-CH3 H H H CH3CH2O 102.8 2 +
133 2 0 H H H H 4-CH3OPhCH2O 121.3 2 -
134 3 0 H H CH3CH2 H PhCH2θ 99.7 2 -
135 4 0 H H i-C4H9 H CH3CH2O 99-0 2 -
136 4 0 H H CH3 H CH3 177-5 -178.5 34 -
137 4 0 H H CH3 H 2,4,5-(Cl)3Ph0CH2 227.4 35 -
138 2 0 6- CH3 H H H H 158.5 34 -
139 2 0 H H CH3 H H 169.9 34 -
140 3 0 H H CH3 H H 165-6 31 -
141 4 0 H H n-C4H9 H H 143.4 37 -
142 2 0 6- CH3 H H H PhCH2 96.6 31 -
143 2 0 H H CH3 H CH3CH2CH2 123.5 31 -
144 4 0 H H CH3 H CH3CH2CH2 131.8 31 -
145 4 0 H H CH3 H CH3CH2CH2 · (CO2H)2 207.2 38 -
146 4 0 H H CH3 H CH3CH2CH2 · panoic 291.5 38 - acid salt
147 4 0 H H CH3 H CH3CH2CH2 · 1-OH-2- 158.7 39 - naphthoic acid salt
148 4 0 H H CH3 H CH3CH2CH2 · 3-OH-2- 149-1 39 - naphthoic acid salt
149 4 0 H H CH3 H CH3CH2CH2 · CH2(CO2H)2 140.0 39 -
150 4 0 H H CH3 H CH3CH2CH2 · PhCH2CO2H 102.3 39 -
151 4 0 H H CH3 H CH3CH2CH2 · PhOCH2CO2H 105.8 40 -
152 4 0 H H CH3 H CH3CH2CH2 · PhSCH2CO2H 97.2 40 -
153 4 0 H H H H CH3CH2CH2 156.6 34 -
154 4 0 H H H H CH3CH2CH2 · (CO2H)2 175.4 38 -
155 4 0 H H CH3 H H 195.7 31 -
156 3 0 H H CH3 H CH3CH2CH2 106.7 34 - TABLE A (cont'd)
C a n R1 R2 R3 R4 X m.p. P H
157 4 0 H H CH3 H PhCH2 148.5 34 -
158 4 0 H H CH3 H 2-Cl-4-NO2Ph 232.2 2 -
159 4 0 H H CH3 H C-C6H11 195.3 41 -
160 4 1 H H CH3 H C-C6H11-CH2CH2 183-1 3 -
161 4 0 H H CH3 H 1 -naphthyl 183-7 2 -
162 4 0 H H CH3 H 2-naphthyl 206.5 2 -
163 4 0 H H 4-ClPh H CH3CH2O · HCl 216.9 42 -
161 4 0 H H H H 1-naphthylCH2 185.2 2 -
165 3 0 H H CH3 H 1-naphthylCH2 159.3 2 -
166 4 0 H H CH3 H 1-naphthylCH2 168.6 2 -
167 2 0 6-CH3 H H H C-C6H11 102.4 2 +
168 2 0 6- CH3 H H H CH 2 - 3CH2CH2 115.1
169 2 0 6-CH3 H H H (CH3)2CH 99.2 2 -
170 4 0 H H PhCH2 H CH3CH2CH2 108.9 2 -
171 4 1 H H CH3 H 1 -naphthyl 251.7 2 -
172 3 0 H H H H 1 -naphthyl (2 crops) 197.1 2 - 199.5
173 4 0 H H PhCH2 H 1 -naphthyl 187.9 2 -
174 3 0 H H CH3CH2 H 3 -pyridyl 163.5 2 -
175 4 0 H H n-C4H9 H 3-pyridyl 125.6 2 -
176 4 0 H H n-C4H9 H 2-thienyl 176.6 2 -
177 4 0 H H CH3 H 2-thienyl 198.4 2 -
178 3 0 H H CH3 H 2-thienyl 159.8 2 -
179 3 0 H H H H 2-thienyl 223-9 2 -
180 4 0 H H H H 1 -naphthyl 199.2 2 -
181 4 0 H H H H 2-thienyl 200.9 2 -
182 4 0 H H H H 3,4,5-(CH3O)3Ph 187.8 2 +
183 2 0 6-CH3 H H H c-C4H7 120.0 2 -
184 2 0 6-CH3 H H H CH3 156.9 2 -
185 3 0 H H CH3CH2 H C-C4H7 153.6 2 -
186 3 0 H H CH3CH2 H 1 -naphthyl 166.7 2 -
187 3 0 H H CH3 H 1 -naphthyl 166.9 2 +
188 4 0 H H CH3 H 4-ClPh 182.0 2 -
189 4 1 H H CH3 H 4-ClPh 224.0 2 - TABLE A (cont'd)
C a n R1 R2 R3 R4 X m.p . P H
190 3 0 H H CH3 H 4-ClPh 180.9 2 -
191 2 0 6-CH3 H H H 4-ClPh 169.3 2 -
192 4 0 H H PhCH2 H CH3CH2O 131-133 2 -
193 4 0 H H H H 4-ClPh 170.5 2 -
194 3 0 H H H H 4-ClPh 233-5 2 -
195 2 0 H H CH3 H 1 -naphthylCH2 201.2 3 -
196 4 0 H H CH3CH2 H CH3CH2CH2 151-3 3 -
197 4 0 H H CH3CH2 H PhCH2 147-2 3 -
198 4 0 H H CH3 H 3-pyridyl 143.7 3 -
199 3 0 H H CH3 H 3-pyridyl 166.7 3 -
200 2 0 H H CH3 H 3-pyridyl 178.0 3 -
201 4 0 H H CH3 H chrysanthemyl 161.9 3 -
202 4 1 H H CH3 H (CH3)3CH 251.3 3 -
203 4 1 H H CH3 H H 236.1 3 -
204 2 0 H H CH3CH2 H CH3 173.1. 3 -
205 4 1 H H CH3 H CH3 240.7 3 -
206 4 1 H H CH3 H c-C3H5 292.4 3 -
207 4 1 H H CH3CH2CH2 H H (3 crops) 221.3 3 -
221.2
215.9
208 4 1 H H CH3CH2CH2 H c-C3H5 238.5 3 -
209 4 1 H H CH3CH2CH2 H i-C3H7 241.6 3 -
210 2 0 H H CH3CH2 H H 141.2 3 -
211 4 1 H H CH3CH2CH2 H CH3CH2CH2 199.2 3 -
212 4 1 H H CH3CH2CH2 H CH3 218.9 3 -
213 4 1 H H CH H C-C6H11 3CH2CH2 265.9d 3 -
214 3 0 H H CH3 H 2-furyl 130.6 3 +
215 2 0 H H CH3 H 2-furyl 123.9 3 -
216 2 0 H H H H 2-furyl 154.7 3 -
217 4 0 H H CH3 H 4-pyridyl 174.5 3 -
218 3 0 H H CH3 H 4-pyridyl 174.0 3 -
219 2 0 H H CH3 H 4-pyridyl 166.9 3 -
220 4 0 H H H H 4-pyridyl 234.4 3 -
221 2 0 H H H H 4-pyridyl 163.4 3- - TABLE A (cont'd)
C a n R1 R2 R3 R4 X m.p. P H
222 4 0 H H CH3CH2 H 1 -naphthyl 204.3 3 -
223 3 0 H H H H 1-naphthylCH2 209.4 3 -
224 4 0 H H H H 3,1,5-(CH3O)3Ph 188.7 3 - 225 3 0 H H CH3 H 2-furyl 133.1 3 -
226 3 0 H H CH3CH2 H PhO · HCl 155.3 3 -
227 4 1 H H CH3 H c-C4H7 232.3 3 +
228 4 1 H H CH3 H CH3CH2OCH2CH2 202.1 3 -
229 4 1 H H H H 2-CH3OPh 216.1 3 -
230 4 1 H H H H PhO · HCl 187.0 3 -
231 4 1 H H H H H 290.4d 3 -
232 4 1 H H H H 3-pyridyl 255.6d 3 -
233 4 1 H H H H CH3CH2O 252.9d 3 -
234 4 1 H H H H Ph 234-1 3 -
235 4 1 H H H H CH3CH2CH2 250.8d 3 -
236 4 1 H H H H 2-PhOPh 186.7 3 -
237 4 1 H H H H i-C3H7 238.5 3 -
238 4 1 H H H H c-C6H11 266.6 3 -
239 4 1 H H H H 2-thienyl 262.4d 3 -
240 4 1 H H H H 1 -pyridyl 273.1d 3 -
241 4 1 H H H H c-C6H11-CH2CH2 193.4 3 -
242 4 0 H H CH3CH2CH2 H CH3CH2CH2 112.8 9 -
243 4 0 H H i-C4H9 H c-C6H11-CH2CH2 166.2 9 -
244 4 0 H H i-C4H9 H c-C3H5 210.8 9 -
245 4 0 H H i-C4H9 H c-C6H11-CH2 141.3 9 -
246 4 0 H H c-C5H9 H c-C6H11 163.0 9 -
247 4 0 H H c-C5H9 H CH3CH2CH2 98.1 9 -
248 4 0 H H CH c-C3H5 181.7 9 3CH2CH2 H -
249 4 0 H H CH3CH2CH2 H (CH3)2CH 165.4 9 -
250 4 0 H H CH H 3CH2CH2 c-C6H11-CH2CH2 154.6 9
251 2 0 H H Ph H 2-furyl 139.6 9 -
252 4 0 H H CH3CH2CH2 H c-C6H11-CH2 151.4 9 -
253 4 0 H H CH3CH2CH2 H c-C6H11 184.1 9 -
254 4 0 H H i-C4H9 H (CH3)2CH 146.3 9 -
255 4 0 H H i-C4H9 H c-C6H11 178.2 9- - TABLE A (cont'd)
C a n R1 R2 R3 R4 X m.p . P H
256 4 0 H H i-C4H9 H CH3CH2CH2 106.0 9 -
257 4 0 H H i-C4H9 H 2-CH3CH2OPh 108.4 9 -
258 3 0 H H CH3 H c-C6H11-CH2 117.2 24 -
259 2 0 H H CH3 H c-C6H11-CH2 116.3 24 -
260 2 0 H H CH3 H CH3CH2OCH2CH2 98.3 24 -
261 3 0 H H H H CH3CH2OCH2CH2 99.0 24 -
262 4 0 H H CH3 H CH3CH2OCH2CH2 116.7 24 -
263 4 0 H H CH3CH2CH2 H H 117.4 41 -
264 4 0 H H H H c-C4H7 178.1 41 -
265 4 0 H H CH3 H 3-[(1-CH3)-c-C5H9N] 112.8 41 -
266 4 0 H H CH3 H 2-[(1-CH3)-c-C5H9N] 140.1 41 -
267 3 0 H H CH3 H 2-[(1-CH3)-c-C5H9N] 102.5 41 +
268 3 0 H H CH3 H 3-[(1-CH3)-c-C5H9N] 121.5 41 +
269 2 0 H H CH3 H c-C6H11 147.3 41 -
270 4 0 H H H H c-C6H11 159.3 41 -
271 3 0 H H CH3CH2 H H 128.7 41 -
272 4 0 H H H H (CH3)2CH 154.9 41 -
273 4 0 H H CH3 H c-C3H5 197.7 41 -
274 4 0 H H H H c-C3H5 191.6 41 -
275 4 0 H H CH3 H (CH3)2CH 149.2 41 -
276 4 0 H H CH3 H c-C6H11-CH2CH2 139.2 41 -
277 4 0 H H H H c-C6H11-CH2CH2 131.2 41 -
278 4 0 H H H H c-C6H11-CH2 114.4 41 -
279 3 0 H H CH3 H c-C6H11 172.3 41 -
280 4 0 H H CH3 H c-C6H11-CH2 159.3 41 -
281 4 0 H H CH3CH2 H CH3CH2OCH2CH2 123.1 41 -
282 4 0 H H CH3CH2 H c-C4H7 177.5 41 -
283 4 0 H H H H CH3CH2OCH2CH2 92.3 41 -
284 4 0 H H Ph H 2-CH3OPh · HCl 242.1 42 -
285 4 0 H H Ph H 2-PhOPh · HCl 249.8 42 -
286 4 0 H H Ph H PhO · HCl 217.0d 42 -
287 4 1 H H CH3 H c-C6H11 245.3 43 -
288 4 1 H H CH3 H c-C6H11-CH2 214.7 43 - TABLE I
H. Contortus % Clearance
Compound No. P.O. I.P. 1 99.6 100
2 100 100 3 100 93.7-100
4 N.T. N.T.
5 N.T. N.T. 6 98.9 87.7
7 100 100 8 99.9 N.T. 9 N.T. N.T. 10 61.9 N.T. 11 99.2 99.6
12 N.T. N.T.
13 N.T. N.T. 14 76.1 11.1
15 100 N.T. 16 100 100
17 85.9 100
18 100 94.3
19 99.6 86.5
20 96.6 100 21 N.T. N.T.
22 98.2 N.T.
23 91.1 100 24 N.T. N.T.
25 N.T. N.T. 26 99.8 75.0
27 100 N.T.
28 100 64.7
29 N.T. N.T.
30 100 97.1-98.8 31 99.6 N.T.
31 A 100 N.T. TABLE I (conf d)
H. Contortus % Clearance
Compound No. P.O. I. P. 32 N.T. N.T.
33 N.T. N.T.
31 97.0 93.5
35 99.2 N.T.
36 100 N.T. 37 N.T. N.T.
38 22.3 N.T.
39 N.T. N.T.
40 98.8 N.T.
41 91.4 N.T. 42 96.9 0
43 75.1 91.1
44 96.4 100
45 82.5 12.7
46 96.6 86.7 47 20.3 N.T.
47A 0 2.3
48 100 99.7
48A N.T. N.T.
49 98.9 100 50 29.8 12.7
51 97.9 100
52 99.6 N.T.
53 7.0 0
54 13.3 N.T. 55 75.8 N.T,
56 100 Toxic
57 100 19.6
58 N.T. N.T.
59 N.T. N.T. 60 100 N.T.
61 84.3 N.T. TABLE I (cont' d)
H. Contortus
% Clearance
Compound No. P.O. I. P. 62 N.T. N.T.
63 N.T. N.T. 64 N.T. N.T.
65 N.T. N.T.
66 33.9 65.3 67 100 100
68 5.7 0
69 79.0 N.T.
70 100 99.6
71 N.T. N.T. 72 98.6 99.3
73 100 98.9
74 Toxic 98.9
75 99.6 100
76 99.3 100 77 0 N.T.
78 N.T. 0-69.0
79 99.9 0
80 99.9 N.T.
80 A 75.4 68.3 81 N.T. N.T.
82 N.T. N.T.
83 99.3 N.T.
84 100 0-99.6
85 97.9 100 86 73.7-99 .3 0-100
86A 100 99.8
87 N.T. N.T.
88 N.T. N.T.
89 98.9 Toxic 90 N.T. N.T.
91 21.1-99 .6 94-5-99-8 TABLE I (cont' d)
H. Contortus
% Clearance
Compound No. P.O. I. P. 92 89.0 98.9
93 100 Toxic 94 99.6-100 100
95 100 N.T.
96 N.T. N.T. 97 73.8-84.6 97.6-98.6
98 55.5 53.7
99 89.3 91.1
100 43.1-70,2 46.1-75.1 101 99.9 98.9 102 67.4 36.6
103 100 100 104 85.6 N.T.
105 N.T. 100 106 100 98.9 107 100 N.T.
108 96.2 82.5 109 80.3 N.T. 110 99.6 100 111 98.9 100 112 35.5 67.0
113 98.8 95.7 114 99.9 94.5
115 38.4 0 116 8.2 91.0 117 3.5 0
118 100 99.7 119 100 82.8 120 69.4 100 121 100 100 122 99.9 100
123 96.7 0 TABLE I (cont' d)
H. Contortus % Clearance
Compound No. P.O. I. P. 24 100 19.6
125 99.6 99.3 126 100 63.7 127 100 24.7 128 100 78.7 129 100 100
130 98.7 Toxic 131 100 99.6 132 94.0 97.9 133 100 N.T. 134 N.T. N.T.
135 N.T. N.T. 136 90.7- 100 N..T. 137 75.3 N.T. 138 84.0 98.5 139 Toxic Toxic
98.3++ Toxic++
140 Toxic Toxic 141 76.9 100 142 98.6 100 143 Toxic N.T.
144 100 95.4
145 98.9-99.9 91.1-98.7 146 85.0 99.9 147 100 Toxic 148 100 93.2
149 99.6 100 150 100 100 151 99.6 99.6 152 99.9 100 153 100 100
151 98.1 99.1 TABLE I (cont' d)
H. Contortus
% Clearance
Compound No. P.O. I. P. 155 78.1- 100 87.8
156 100 99.6 157 99.6 99.6 158 0-49.3 0 159 N.T. N.T. 160 99.6 99.6
161 99.6 98.3 162 99.3 N.T. 163 N.T. N.T. 164 99.1 100 165 97.1 100
166 99.6 44.5 167 100 100 168 100 96.7 169 N.T. N.T. 170 N.T. N.T.
171 99.6 N.T. 172 100 N.T. 173 N.T. N.T. 174 100 N.T. 175 N.T. N.T.
176 N.T. N.T. 177 100 99.1 178 100 N.T. 179 99.6 82.6 180 99.1 15.7
181 100 100 182 83.3 N.T. 183 100 99.6 184 100 100 185 N.T. N.T.
186 N.T. N.T. TABLE I (cont' d)
H. Contortus % Clearance
Compound No. P.O. I. P. 187 N.T. N.T.
188 N.T. N.T. 189 100 N.T. 190 99.8 99.6 191 N.T. N.T. 192 N.T. N.T.
193 100 N.T. 194 100 N.T. 195 26.8 19.6 196 N.T. N.T. 197 92.4 100
198 100 Toxic 199 N.T. N.T. 200 Toxic N.T. 201 100 N.T. 202 100 100
203 99.1- 100 100 204 Toxic N.T. 205 100 94.3 206 98.9 87.8 207 N.T. 100
208 76.1 N.T. 209 92.2 99.2 210 Toxic N.T. 211 85.5 99.6 212 96.9 64.7
213 76.1 50.5 214 99.9 99.6
215 98.8 84.7-99.8
216 N.T. N.T. 217 100 100
218 N.T. N.T. T ABLE I (cont' d)
H. Contortus % Cle arance
Compound No. P.O. I. P. 219 49.1 68.7
220 N.T. N.T.
221 91.8 97.7
222 98.8 N.T.
223 46.8 0 224 N.T. 0-54.0
225 N.T. 99.6 226 100 100 227 100 0 228 100 99.5 229 100 N.T.
230 N.T. N.T.
231 N.T. N.T. 232 N.T. N.T.
233 N.T. N.T. 234 N.T. N.T. 235 N.T. N.T. 236 100 N.T. 237 N.T. N.T. 238 N.T. N.T. 239 99.8 99.9 240 N.T. N.T. 241 100 N.T. 242 99.2 N.T. 243 54.9 36.4 244 76.5 0 245 62.7 39.6 246 96.9 100 247 100 100 248 79.1 68.1 249 98.1 92.0 250 99.8 99.6 T ABLE I (cont' d)
H. Contortus % Clearance
Compound No. P.O. I. P. 251 N.T. N.T. 252 69.8 41.3 253 90.5 Toxic 254 86.7 0 255 87.4 0 256 0 52.5 257 N.T. N.T. 258 N.T. N.T. 259 N.T. N.T. 260 N.T. N.T. 261 N.T. N.T.
262 99.6 100 263 99.2 100
264 100 Toxic 265 N.T. N.T. 266 N.T. N.T. 267 N.T. N.T. 268 N.T. N.T. 269 N.T. N.T. 270 99.9 100 271 100 N.T. 272 98.9 97.3 273 100 100 274 70.2 100 275 99.8 100 276 100 100 277 99.9 100 278 100 100 279 99.6 N.T. 280 96.1-97 .2 85.8-96.6 281 100 0 282 99.6 99.6 TABLE I (cont' d)
H. Contortus % Clearance
Compound No. P.O. I. P. 283 99.6 N.T.
284 N.T. N.T. 285 N.T. N.T. 286 27.7 65.3
287 100 99.8 288 99.8 Toxic
289 100 100 290 99.7 N.T. 291 98.6 N.T. 292 51.7 N.T. 293 N.T. N.T.
294 N.T. N.T. 295 N.T. N.T. 296 N.T. N.T. 297 N.T. N.T. 298 N.T. N.T.
299 N.T. N.T. 300 39.6 49.9 301 100 N.T. 302 32.8 N.T. 303 100 N.T.
304 100 N.T.
305 100 N.T. 306 100 N.T. 307 99.3 N.T. 308 100 N.T.
309 N.T. N.T. 310 100 N.T.
311 100 99.9 312 Toxic N.T. 313 100 N.T.
314 Toxic N.T. TABLE I (cont' d)
H. Contortus
% Clearance
Compound No. P.O. I. P. 315 100 N.T. 316 100 N.T. 317 100 N.T. 318 100 N.T. 319 99.3 N.T. 320 92.5 N.T. 321 100 N.T. 322 97.0 N.T.
323 99.3 N.T. 324 100 N.T. 325 100 N.T.
326 Toxic N.T. 327 77.6 N.T.
328 100 N.T.
329 100 N.T. 330 100 N.T. 331 10.1 N.T. 332 70.1 N.T.
333 92.5 N.T. 334 100 N.T. 335 0 N.T. 336 92.5 N.T. 337 100 N.T. 338 77.6 N.T. 339 100 N.T. 340 N.T. N.T. 341 100 N.T. 342 32.8 N.T. 343 N.T. N.T. 344 N.T. N.T. 345 N.T. N.T. 346 97.8 N.T. TABLE I (cont' d)
H. Contortus % Clearance
Compound No. P.O. I. P. 347 100 N.T. 348 77.6 N.T. 349 89.6 99.8 350 N.T. N.T. 351 100 100 352 99.9 N.T. 353 N.T. N.T. 354 100 N.T. 355 3.0* N.T. 356 Toxic N.T. 357 Toxic N.T. 358 100 N.T. 359 N.T. N.T. 360 99-3-100 N.T. 361 N.T. N.T. 362 100 N.T. 363 99.3 N.T. 364 100 N.T. 365 100 N.T. 366 100 N.T. 367 100 N.T. 368 100 N.T. 369 85.1 N.T. 370 100 N.T. 371 85.1 N.T. 372 62.7** N.T. 373 92.5 N.T. 374 92.5 N.T. 375 55.2 N.T. 376 N.T. N.T. 377 77.6 N.T. 378 100 N.T. TABLE I (cont' d)
H. Contortus
% Clearance
Compound No. P.O. I. P. 379 92.5 N.T. 380 100 N.T. 381 92.5 N.T. 382 92.5 N.T. 383 92.5 N.T. 384 55.2 N.T. 385 100 N.T. 386 85.1 N.T. 387 N.T. N.T. 388 77.6 N.T. 389 85.1 N.T. 390 N.T. N.T. 391 100X N.T. 392 47.8 N.T. 393 85.1 N.T. 394 97.8 N.T. 395 92.5 N.T. 396 100+ N.T. 397 62.7 N.T. 398 0 N.T. 399 100 N.T. 400 85.1 N.T. 401 93.3 N.T. 402 70.1 N.T. 403 3.0 N.T. 404 N.T. N.T. 405 62.7 N.T. 406 N.T. N.T. 407 N.T. N.T. 408 55.2 N.T. 409 Toxic N.T. 410 85.1 N.T. TABLE I(cont'd) H. Contortus % Clearance
Compound No. P.O. I. P.
411 92.5 N.T.
412 100 N.T.
413 92.5 N.T.
414 99.3 N.T.
415 85.1 N.T.
416 85.1 N.T.
417 0 N.T.
418 N.T. N.T.
419 N.T. N.T.
420 N.T. N.T.
421 100 N.T.
422 100 N.T.
423 100 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.
++ 50 mg/kg I. P. = Parenteral administration
* 95 mg/kg P.O. = Oral administration
**60 mg/kg Toxic = Death within 21 hours post-treatment x88 mg/kg
+84 mg/kg
N.T. = not tested means the compound was tested two or more times and the extreme values reported (for example, 0-97.6) I
•
Z is a halogen atom or other active group, for example, an anhydride.

Claims (20)

  1. CLAIMS 1. A method of killing parasitic worms in animals which comprises administering to an animal a therapeutic or prophylactic dosage of a pyridinyl acylhydrazone, hydrate thereof or pharmaceutically acceptable salt thereof of the formula:
    wherein X is selected from (a) hydrogen; (b) C1-C10 alkyl; (c) C2-C6 alkenyl; (d) C2-C6 alkynyl; (e) cyclo(C3-C10)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, trifluoromethyl, or halo; (f) pyrrolidinyl; (g) piperidinyl; (h) 1-methylpyrrolidinyl; (i) 1-methyl piperidinyl; (j) C2-C6 alkoxyalkyl; (k) cyclo(C3-C10)alkyl- (C1-C4) alkyl; (1) phenyl (C1-C4) alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (m) phenoxy- (C1-C4)alkyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (n) naphthyl(C1-C3)alkyl optionally substituted with one or 2 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (o) C1-C6 alkoxy; (p) diphenylmethoxy; (q) cyclo(C3-C6)alkyloxy optionally substituted with one or two C1-C3 alkyl; (r) phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (s) benzyloxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; with the proviso that when a 2-pyridinyl acylhydrazone and R1 , R2, R4 are hydrogen, R3 is not benzyl; (t) heteroaromatic optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, C1-C3 alkylthio, or trifluoromethyl; (u) phenyl optionally substituted with one, 2 or 3 C1- C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitro, or phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, or trifluoromethyl; (v) phenyl optionally substituted with the divalent C1-C2 alkylenedioxy; (w) naphthyl optionally substituted with one or 2 C1-C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitro; (x) bridged polycyclic hydrocarbon substituents of six to 10 nuclear carbons, optionally substituted with one, 2 or 3 (C1-C3) alkyl groups; (y) perhalo(C1-C7)alkyl; wherein R1 and R2, being the same or different, are hydrogen; hydroxy; C1-C4 alkyl; C1-C3 alkoxy; C1-C3 alkylthio; halo or trifluoromethyl; wherein R3 is hydrogen; C1-C4 alkyl; cyclo(C3-C6) alkyl optionally substituted with one, 2 or 3 C1- C3 alkyl; phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; phenyl (C1-C3) alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; or 1,3-dioxacyclohexan-5-yl; wherein R4 is hydrogen; C1-C2 alkyl; cyclo(C3-C6)alkyl optionally substituted with one, 2 or 3 C1-C3 alkyl; phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; phenyl (C1-C3)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; and wherein n is zero or one.
  2. 2. The method according to Claim 1 wherein the compound, hydrate or pharmaceutically acceptable salt thereof is a 4-pyridinyl acylhydrazone.
  3. 3. The method according to Claim 1 wherein X is phenyl or phenyl substituted with one, 2 or 3 methyl, ethyl, methoxy, ethoxy, trifluoromethyl or chloro.
  4. 4. The method according to Claim 1 wherein R1 and R2 are selected from the group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy or a chloro atom.
  5. 5. The method according to Claim 1 wherein R3 is selected from the group consisting of hydrogen, methyl or ethyl and R4 is hydrogen.
  6. 6. The method according to Claim 1 wherein the compound, hydrate or pharmaceutically acceptable salt thereof is selected from the group consisting of: benzoic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #1 ) ; benzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #2); benzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #3); benzoic acid (3-pyridinylmethylene)hydrazide (Cpd #6); benzoic acid (4-pyridinylmethylene)hydrazide (Cpd #7); benzoic acid (α-4-pyridinylbenzylidene)hydrazide hydrate (Cpd #8); 3-methyl benzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #11); 2-ethoxybenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #14); 3-ethoxy benzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #15); 4-ethoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #16);
    3,1,5-trimethoxybenzoic acid [1-(1-pyridinyl)ethylidene]hydrazide (Cpd #17);
    3,1-dimethoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #18); piperonylic acid (4-pyridinylmethylene)hydrazide (Cpd #19);
    2-phenoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #20);
    3-methoxybenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #22);
    3,5-dimethoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #23); 2,4-dichlorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #26);
    3,4-dichlorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #27);
    2,4-dichlorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #28); 2-methoxybenzoic acid (4-pyridinylmethylene)hydrazide monohydrate
    (Cpd #30);
    3-methoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #31); 3-methylbenzoic acid ( 4-pyridinylmethylene)hydrazide (Cpd #31 A); 4 -ethoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #34); 3,5-dimethoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #35);
    2-chlorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #36); 4-(1,1-dimethylethyl)benzoic acid (2-pyridinylmethylene)hydrazide hydrate (Cpd #40);
    4-(1,1-dimethylethyl)benzoic acid (3-pyridinylmethylene)hydrazide hemihydrate (Cpd #41); 4-(1,1-dimethylethyl)benzoic acid [1-(3-pyridinyl)ethylidene]-hydrazide (Cpd #42);
    2-phenoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #43);
    2-ethoxy benzoic acid (4-pyridinylmethylene)hydrazide (Cpd #44); 2-ethoxybenzoicacid [1-(2-pyridinyl)propylidene]hydrazide (Cpd #45);
    2-ethoxybenzoicacid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #46); benzoic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #48);
    2-phenoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #49); benzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #51);
    4- chlorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #52); benzoic acid 1-methyl-2-[1-(4-pyridinyl)ethylidene]hydrazide (Cpd #55);
    2-methoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #56);
    2-methoxybenzoic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #57); benzoic acid [1-(4-pyridinyl)pentylidene]hydrazide (Cpd #60); benzoic acid [2-phenyl-1-(4-pyridinyl)ethylidene]hydrazide (Cpd #61); benzoic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #67);
    2-nitrobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #69); ethyl [1-(2-pyridinyl)ethylidene)carbazate (Cpd #70); ethyl [1-(4-pyridinyl)ethylidene)carbazate (Cpd #72); ethyl (2-pyridinylmethylene)carbazate (Cpd #73) ethyl (3-pyridinylmethylene)carbazate (Cpd #74) ethyl ( 4-pyridinylmethylene)carbazate (Cpd #75)
    1 ,1-dimethylethyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #76); benzyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #79); diphenylmethyl [1-14-pyridinyl)ethylidene]carbazate (Cpd #80); diphenylmethyl [1-(2-pyridinyl)ethylidene]carbazate (Cpd #80A); methyl (4-pyridinylmethylene)carbazate hydrate (Cpd #83); benzyl ( 4-pyridinylmethylene)carbazate (Cpd #84); methyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #85); diphenylmethyl (4-pyridinylmethylene)carbazate (Cpd #86); 4-chloro benzoic acid (4-pyridinylmethylene)hydrazide 1-oxide (Cpd
    #86 A); methyl [1-(3-pyridinyl)ethylidene]car bazate (Cpd #89); 1 ,1-dimethylethyl [1-(4-pyridinyl)propylidene]carbazate (Cpd #91); benzyl [1-(4-pyridinyl)propylidene]carbazate (Cpd #92); methyl [1-(4-pyridinyl)propylidene]carbazate (Cpd #93); phenyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #94); phenyl [1-(4-pyridinyl)ethylidene]carbazate monohydrochloride (Cpd #95);
    5-met hyl-2-(1-methylethyl)cyclohexyl [1-(4-pyridinyl)ethylidene]-carbazate (Cpd #97); ethyl [1-(4-pyridinyl)pentylidene]carbazate (Cpd #99); phenyl [1-(4-pyridinyl)butylidene]carbazate monohydrochloride (Cpd #100); phenyl (4-pyridinylmethylene)carbazate monohydrochloride (Cpd #101); 1 ,1-dimethylethyl[1-(3-pyridinyl)propylidene]carbazate (Cpd #103); methyl [1-(2-pyridinyl)propylidene]carbazate (Cpd #104); ethyl [1-(2-pyridinyl)propylidene]carbazate (Cpd #105); 1 ,1-ditnethylethyl[1-(2-pyridinyl)propylidene]carbazate (Cpd #106); ethyl [1-(3-pyridinyl)propylidene]carbazate (Cpd #107); 1 ,1-dimethylethyl [1-(4-pyridinyl)butylidene]carbazate (Cpd #108); ethyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide (Cpd #109); ethyl [1-(4-pyridinyl)butylidene]carbazate (Cpd #110); methyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide (Cpd #111); phenyl [1-(4-pyridinyl)butylidene]carbazate 1-oxide (Cpd #112); 1,1-dimethylethyl [1-(4-pyridinyl)butylidene]carbazate 1-oxide (Cpd #113); ethyl [1-(4-pyridinyl)butylidene]carbazate 1-oxide (Cpd #114); 1 ,1-dimethylethyl [3-methyl-1-(4-pyridinyl)butylidene]carbazate (Cpd #116); phenyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide monohydrochloride (Cpd #118); benzyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide hydrate (Cpd #119);
    1 ,1-dimethylethyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide (Cpd #120); 4-trifluoromethylbenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #121); 4-dimethylaminobenzoic acid (2-pyridinylmethylene)hydrazide (Cpd #122);
    4-dimethylaminobenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #123); 4-dimethylaminobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd
    #124);
    4-dimethylaminobenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #125);
    4-dimethylaminobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #126);
    4-trifluoromethylbenzoic acid [1-(3-pynidinyl)ethylidene]hydrazide (Cpd #127);
    4-methoxybenzyl (3-pyridinylmethylene)carbazate (Cpd #128);
    4-methoxybenzyl (4-pyridinylmethylene) carbazate (Cpd #129); 4-methoxybenzyl [1-(3-pyridinyl)ethylidene]carbazate monohydrate
    (Cpd #130);
    4-methoxybenzyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #131); ethyl [(6-methyl-2-pyridinyl)methylene]carbazate hydrate (Cpd #132) ;
    4-methoxybenzyl (2-pyridinylmethylene)carbazate (Cpd #133); acetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #136);
    (2,4,5-trichlorophenoxy)acetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #137); formic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #138); formic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #139); formic acid [1-(4-pyridinyl)pentylidene]hydrazide (Cpd #141); phenylacetic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #142); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #144); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide oxalic acid salt (Cpd #145); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide pamoic acid salt (Cpd #146); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide 1-hydroxy-2-naphthoic acid salt (Cpd #147); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide 3-hydroxy-2-naphthoic acid salt (Cpd #148); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide malonic acid salt (Cpd #149); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide phenylacetic acid salt (Cpd #150); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide phenoxyacetic acid salt (Cpd #151); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide phenylthioacetic acid salt (Cpd #152); butyric acid (4-pyridinylmethylene)hydrazide (Cpd #153); butyric acid (4-pyridinylmethylene)hydrazide oxalic acid salt
    (Cpd #154); formic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #155); butyric acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #156); phenylacetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #157); 3-cyclohexanepropionic acid [1-( 4-pyridinyl )ethylidene]hydrazide
    1-oxide (Cpd #160);
    1-naphthalenecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #161);
    2-naphthalenecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (cpd #162);
    1-naphthaleneacetic acid (4-pyridinylmethylene)hydrazide (Cpd #164); 1-naphthaleneacetic acid [1-(3-pyridinyl)ethylidine]hydrazide (Cpd #165); 1-naphthaleneacetic acid [1-(4-pyridinyl)ethylidine]hydrazide (cpd #166); cyclohexanecarboxylic acid [(6-methyl-2-pyridinyl)methylene]hydrazide monohydrate (Cpd #167); butyric acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #168); 1 -naphthalene car bo xylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #171);
    1-naphthylenecarboxylic acid (3-pyridinylmethylene)hydrazide (Cpd #172); nicotinic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #174); 2-thiophenecarboxyllic acid [1-(4-pyridinyl)ethylidene]hydrazide (cpd #177); 2-thiophenecarboxylic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #178);
    2-thiophenecarboxylic acid (3-pyridinylmethylene)hydrazide (Cpd #179); 1-naphthalenecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd
    #180);
    2-thiophenecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #181);
    3,1,5-trimethoxybenzoiα acid (4-pyridinylmethylene)hydrazide monohydrate (Cpd #182); cyclobutanecarboxylic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #183); acetic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #181);
    1-chlorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (cpd #189);
    4-chlorobenzoicacid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #190);
    4-chlorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #193);
    4-chlorobenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #194); phenylacetic acid [1-(4-pyridinyl)propylidine]hydrazide (Cpd #197); nicotinic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #198);
    2,2-dimethyl-3-(2-methylpropenyl)cyclopropane carboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #201);
    2-methylpropionic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #202); formic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #203) ; acetic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #205); cyclopropanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #206); formic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #207) ; cyclopropanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide
    1-oxide (Cpd #208);
    2-methylpropionic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #209); butyric acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #211); acetic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #212); cyclohexanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #213);
    2-furoic acid [1-(3-pyridinyl)ethylidine]hydrazide monohydrate (Cpd #214); 2-furoic acid [1-(2-pyridinyl)ethylidine]hydrazide (Cpd #215); isonicotinic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #217); isonicotinic acid (2-pyridinylmethylene)hydrazide (Cpd #221);
    1-naphthalenecarbo xylic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #222); 2-furoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #225); phenyl [1-(3-pyridinyl)propylidene]carbazate monohydrochloride (Cpd #226); cyclobutanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #227); 3-ethoxypropionic acid [1-(4-pyridinyl)ethylidene]hydrazide
    1-oxide (Cpd #228);
    2-methoxybenzoic acid (4-pyridinylmethylene)hydrazide 1-oxide (Cpd #229);
    2-phenoxybenzoic acid (4-pyridinylmethyIene)hydrazide 1-oxide (cpd #236):
    2-thiophenecarboxylic acid (4-pyridinylmethylene)hydrazide 1-oxide (Cpd #239);
    3-cyclohexanepropionic acid (4-pyridinylmethylene)hydrazide 1-oxide (Cpd 241); butyric acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #242); cyclopropanecarbo xylic acid [3-methyl-1-(4-pyridinyl)butylidene]-hydrazide (Cpd #244); cyclohexanecarboxylic acid (cyσlopentyl-4-pyridinylmethylene)hydrazide (Cpd #246); butyric acid (cyclopentyl-4-pyridinylmethylene)hydrazide (Cpd #247); cyclopropanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #248);
    2-methylpropionic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #249); 3-cyclohexanepropionic acid [1-(4-pyridinyl)butylidene]hydrazide
    (Cpd #250); cyclohexaneacetic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #252); cyclohexanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #253); 2-methyl propionic acid [3-methyl-1-(4-pyridinyl)butylidene]hydrazide
    (Cpd #254); cyclohexanecarboxylic acid [3-methyl-1-(4-pyridinyl)butylidene)hydrazide (Cpd #255);
    3-ethoxypropionic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #262); formic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #263); cyclobutanecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #264); cyclohexanecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #270); formic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #271);
    2-methylpropionic acid (4-pyridinylmethylene)hydrazide (Cpd #272); cyclopropanecarboxylic acid [1 -(4-pyridinyl)ethylidene]hydrazide (Cpd #273); cyclopropanecar bo xylic acid ( 4-pyridinylmethylene )hydrazide (Cpd
    #274);
    2-methylpropionic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #275);
    3-cyclohexanepropionic acid [4-(pyridinyl)ethylidene]hydrazide (cpd #276);
    3-cyclohexanepropionic acid (4-pyridinylmethylene)hydrazide (Cpd #277); cyclohexaneacetic acid (4-pyridinylmethylene)hydrazide (Cpd #278); cyclohexanecarboxylic acid [1-(3-pyridinyl)ethylidene]hydrazide (cpd #279); cyclohexaneacetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #280); 3-ethoxypropionic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #281); cyclobutanecarboxylic acid [1-(4-pyridinyl)propylidene]hydrazide (cpd #282);
    3-ethoxypropionic acid (4-pyridinylmethylene)hydrazide (Cpd #283); cyclohexanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #287); cyclohexaneacetic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #288); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide hydrate
    (Cpd #289); cyclobutanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #290);
    4-nitrobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #291); 3-trifluoromethylbenzoic acid [1-(2-pyridinyl)ethylidene]hydrazide
    (Cpd #301);
    2-fluorobenzoic acid (2-pyridinylmethylene)hydrazide (Cpd #303); 2-fluorobenzoic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #304); 3-fluorobenzoicacid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #305); 3-fluorobenzoic acid (2-pyridinylmethylene)hydrazide (Cpd #306);
    2-methylcyclopropane carboxylic acid (2-pyridinylmethylene)hydrazide (Cpd #307); piperonylic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #308); propanoic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #310); propanoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #311);
    2-methylcyclopropane carboxylic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #313);
    3-trifluoromethylbenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #315); 3-trifluoromethylbenzoic acid [1-(3-pyridinyl)propylidene]hydrazide
    (Cpd #316);
    3-trifluoromethylbenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #317);
    2-fluorobenzoic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #318);
    3-fluorobenzoic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #319);
    2-fluorobenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #320); 2-fluorobenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #321); 3-fluorobenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #322);
    3-fluorobenzoicacid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #323); 4-phenylbutyric acid [1-(3-pypidinyl)propylidene]hydrazide (Cpd #324);
    4 -phenylbutyric acid (3-pyridinylmethylene)hydrazide (Cpd #325); acetic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #327); 2-methylpropionic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide
    (Cpd #328); butyric acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #329); propanoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #330); ethyl [1-(6-methyl-3-pyridinyl)ethylidene]carbazate (Cpd #332); 1 ,1-dimethylethyl[1-(6-methyl-3-pyridinyl)ethylidene]carbazate
    (Cpd #333); phenyl[1-(6-methyl-3-pyridinyl)ethylidene]carbazate monohydrochloride (Cpd #334); benzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #336);
    4-chlorobenzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #337); 2-ethoxybenzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide
    (Cpd #338);
    4-ethoxybenzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #339);
    2-methyl-1-naphthaleneacetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #341); piperonylic acid [1-(1-pyridinyl)ethylidene]hydrazide 1-oxide hydrate (Cpd #316); piperonylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #347); 3,4-dimethoxyphenylacetic acid [1 -(4-pyridinyl)ethylidene]hydrazide 1-oxide hydrate (Cpd #348);
    3,4-dimethoxyphenylacetic acid (4-pyridinylmethylene)hydrazide (Cpd #349); propanoic acid (4-pyridinylmethylene)hydrazide (Cpd #351); propanoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #352); 1-methyleyclopropanecarboxylic acid [1-(4-pyridinyl)ethylidene]-hydrazide (Cpd #354); 3-trifluoromethylbenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #358);
    2-methylcyclopropanecarboxylic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #360); 2-fluorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd
    #362);
    3-fluorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #363);
    2-fluorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #364); 2-fluorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #365);
    3-fluorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #366); 4-phenylbutyric acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #367); 4-phenylbutyric acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #368); 4-phenylbutyric acid (4-pyridinylmethylene)hydrazide (Cpd #369);
    3-fluorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #370); 2-methylbenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #371);
    4-methylbenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #373);
    2-chlorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #374); acetic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #377); 2-furoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #378); isonicotinic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #379); propanoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #380); 2-methylpropanoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #381);
    2-thiophenecarboxylic acid [1-(4-pyridinyl)propylidene]hydrazide (cpd #382); phenyl [1-(4-pyridinyl)propylidene]carbazate monohydrochloride (Cpd #383);
    2-ethoxybenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #385); formic acid [11(4-pyridinyl)propylidene]hydrazide (Cpd #386); 4-ethoxybenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #388);
    3-chlorobenzoie acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #389); butyric acid (2-chloro-3-pyridinylmethylene)hydrazide (cpd #391) propanoic acid (3-hydroxy-2-pyridinylmethylene)hydpazide (Cpd #393) formic acid [1-(3-chloro-4-pyrrdinyl)ethylidene]hydrazide (Cpd #394) butyric acid [1-(3-chloro-4-pyridinyl)ethylidene]hydrazide (Cpd #395); methyl [1-(3-chloro-4-pyridinyl)ethylidene]carbazate (Cpd #396); propanoic acid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #399); butyric acid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #400); 2-methylpropanoicacid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide
    (Cpd #401); cyclopropanecarboxylic acid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #402); acetic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #410); propanoic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (#411); butyric acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #412);
    2-methylpropanoicacid [1-(6-chioro-3-pyridinyl)ethylidene]hydrazide (cpd #413); cyclopropanecarboxylic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #414); eyolohexaneaceticacid [1-(6-chloro-3-pyrldinyl)ethylidene]hydrazide
    (Cpd #415); benzoic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd
    #416); benzole acid [(1,3-dioxan-5-yl)-3-pyridinylmethylene]hydrazide (Cpd #421); ethyl [(1,3-dioxan-5-yl)-3-pyridinylmethylene]carbazate (Cpd #422); benzoic acid [( 1,3-dioxan-S-yl)-4-pyridinylmethylenelhydrazide
    (Cpd #423); formic acid (4-pyridinylmethylene)hydrazide (Cpd #424); formic acid (3-pyridinylmethylene)hydrazide (Cpd #425); butyric acid [(1,3-dloxan-5-yl)-3-pyridinylmethylene)hydrazide (Cpd #430); ethyl [(1,3-dioxan-5-yl)-4-pyridinylmethylene]carbazate (Cpd #431); methyl [(1,3-dioxan-5-yl)-3-pyridinylmethylene]carbazate (Cpd #432); propanoic acid [(1,3-dioxan-5-yl)-4-pyridinylmethylene]hydrazide (Cpd #433); propanoic acid [(1,3-dioxan-5-yl)-3-pyridinylmethylene]hydrazide (Cpd #434); butyric acid [(1,3-dioxan-5-yl)-4-pyridinylmethylene]hydrazide (Cpd #435); methyl [(1,3-dioxan-5-yl)-4-pyridinylmethylene]carbazate (Cpd #436).
  7. 7. A compound, hydrate thereof or pharmaceutically acceptable salt thereof of the formula
    wherein X is selacted from (a) hydrogen; (b) C1-C10 alkyl; (c) C2-C6 alkenyl; (d) C2-C6 alkynyl; (e) cyclo(C3-C10)alkyl optionally substituted with one, 2 or 3C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, trifluoromethyl, or halo; (f) pyrrolidinyl; (g) piperidinyl; (h) 1-methylpyrrolidinyl;
    (i) 1-methylpiperidinyl; (j) C2-C6 alkoxyalkyl; (k) cyclo(C3-C10)alkyl- (C1-C4)alkyl; (l) phenyl (C1-C4)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (a) phenoxy- (C1-C4)alkyl optionally substituted with C1-C4 alkyl C1-C4 alkoxy, halo, or trifluoromethyl; (n) naphthyl (C1-C3) alkyl optionally substituted with one or 2 C1-C4 alkyl, C1-C4 alxoxy, halo, or trifluoromethyl; (o)
    C1-C6 alkoxy; (p) diphenylmethoxy; (q) cyclo(C3-C6)alkyloxy optionally substituted with one or two C1-C3 alkyl; (r) phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (3) benzyloxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1- C4 alkoxy, halo, or trifluoromethyl; with the proviso that when a 2- pyridinyl acylhydrazone and R1 , R2, R4 are hydrogen, R3 is not benzyl; (t) heteroaromatic optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, C1-C3 alkylthio, or trifluoromethyl; (u) phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitro, or phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl. C1-C3 alkoxy, halo, or trifluoromethyl; (v) phenyl optionally substituted with the divalent C1-C2 alkylenedioxy; (w) naphthyl optionally substituted with one or 2 C1-C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitre, (x) bridged polycyclic hydrocarbon substltuents of six to 10 nuclear carbons, optionally substituted with one, 2 or 3 (C1-C3) alkyl groups; (y) perhalo(C1-C7)alkyl; wherein R1 and R2, being the saae or different, are hydrogen; hydroxy;
    C1-C4 alkyl; C1-C3 alkoxy; C1-C3 alkylthio; halo or trifluoromethyl; wherein R3 is hydrogen; C1-C4 alkyl; cyclo(C3-C6)alkyl optionally substituted with one, 2 or 3 C1-C3 alkyl; phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; phenyl(C1-C3)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; or 1,3-dioxacyclohexan-5-yl; wherein R4 is hydrogen; C1-C2 alkyl; cyclo(C3-C6)alkyl optionally substituted with one, 2 or 3 C1-C3 alkyl; phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; phenyl (C1-C3) alkyl optionally substituted with one, 2 or 3 Cι-Cu alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; and wherein n is zero or one; other than: benzoic acid (2-pyridinylmethylene)hydrazide; benzoic acid (3-pyridinylmethylene)hydrazide; benzole acid (4-pyrldinylmethylene)hydrazide; benzoic acid [1-(4-pyridinyl)ethylidene]hydrazida; benzoic acid [1-(2-pyridinyl)ethylidene]hydrazlde; benzoic acid [(2-ethyl-4-pyrldlnyl)methylene]hydrazide; 4-dimethylamino benzole acid (4-pyridinylmethylene)hydrazide;
    4-methylbenzoic acid (2-pyridlnylmethylene)hydrazide; 4-methylbenzoic acid ( 2-pyridinylmethylene )hydrazide 1-oxlde; 4-methylbenzoic acid (4-pyridinylmethylane)hydrazide; 4-methoxybenzolc acid [1-(4-pyridinyl)ethylidene]hydrazide; 3, 4-dimethoxybenzoic acid [( 2-ethyl-4-pyridinyl)methylene]hydrazide; 4-t-butylbenzoic acid(3-pyridinylmethylene)hydrazide; benzoic acid ( α-2-pyridinylbenzylidene)hydrazide; 2-nitrobenzoic acid (4-pyridinyltnethylene )hydrazide;
    2-nitrobenzoic acid (2-pyridinylmethylene )hydrazide;
    2-nitrobenzoic acid (3-pyridinylmethylene)hydrazide; 4-nitrobenzoi c acid [(2-ethyl-4-pyridinyl)methylene]hydrazide; 4-nitrobenzoic acid [ 1-(4-pyridinyl)ethylidene]hydrazide; ethyl[1-(3-pyridinyl)ethylidene]carbazate; methyl(2-pyridinylmethylene )carbazate; ethyl (2-pyridinylmethylene)carbazate; ethyl(4-pyridinylmethylene )carbazate; ethyl[1-(2-pyridinyl)ethylidene]carbazate; acetic acid ( 4-pyridinylmethylene )hydrazide; acetic acid (2-pyridinylmethylene)hydrazide; acetic acid [1-(2-pyridinyl )ethylidene]hydrazide;
    2, 4, 5-trichlorophenoxyacetic acid ( 4-pyridinylaethylene)hydrazide;
    2, 4, 5-trichlorophenoxyacetic acid (3-pyridinylmethylene)hydrazide;
    2, 4,5-trichlorophenoxyacetic acid (2-pyridinylmethylene )hydrazide;
    2, 4-dichlorophenoxyacetI ic acid (4-pyridinylmethylene)hydrazide ;
    2,4-dichlorophenoxyacetic acid (3-pyridinylmethylene)hydrazide; 2, 4-dichlorophenoxyacetic acid (2-pyridinylmethylene)hydrazide;
    4-chl orophenoxyaceti c acid ( 4-pyridinylmethylene )hydr a zide;
    4-chlorophenoxyacetic acid (3-pyridinylmethylene)hydrazide; 4-chlorophenoxyacetic acid (2-pyridinylmethylene)hydrazide; 1 -napthylacetic acid [1-(3-pyridinyl )ethylidene]hydrazide; 1-napthylacetic acid [1-(4-pyrtdinyl)ethylidene]hydrazide; 1-napthylacetic acid [ 1-( 2-pyridinyl )ethyl idene]hydrazide, 1-napthylacetic acid (2-pyridinylmethylene )hydrazide; 1-napthylacetic acid (3-pyridinylmethylene)hydrazide; 1-napthylacetic acid (4-pyridinylmethylene )hydrazide; phenylacetic acid [ 1-(2-pyridinyl )ethylidene]hydrazide; phenylacetic acid [ 1-(3-pyridinyl)ethylidene]hydrazide; phenylacetic acid [1-(4-pyridinyl)ethylidene]hydrazide; phenylacetic acid (2-pyridinylmethylene)hydrazide; phenylacetic acid (3-pyridinylmethylene)hydrazide; phenylacetic acid ( 4-pyridinylmethylene)hydrazide; isonicotinic acid (2-pyridinylmethylene)hydrazide; isonicotinic acid [1-(4-pyridinyl)ethylidene]hydrazida; picolinic acid (2-pyridinylmethylene)hydrazide; picolinic acid [1-(4-pyridinyl)ethylidene]hydrazide; picolinic acid [(6-methyl-2-pyridinyl)methylene]hydrazide; quinaldic acid [(6-methyl-2-pyridinyl)methylene]hydrazide;
    4, 5-dimethyl-2-furancarboxylic acid (4-pyridinylmethylene)hydrazide;
    4,5-dimethyl-2-furancarboxylic acid (3-pyridinylmethylene)hydrazide;
    4,5-dimethyl-2-furancarboxylic acid (2-pyridinylmethylene)hydrazide;
    5-ethyl-2-furancarboxylic acid (4-pyridinylmethylene)hydrazide; 5-ethyl-2-furancarboxylic acid (3-pyridinylmethylene)hydrazide;
    5-ethyl-2-furancarboxylic acid (2-pyridinylmethylene)hydrazide;
    5-methyl-2-furancarboxylic acid (4-pyridinylmethylene)hydrazide;
    5-methyl-2-furancarboxylic acid (3-pyridinylmethylene)hydrazide;
    5-methyl-2-furancarboxylic acid (2-pyridinylmethylene)hydrazide; nicotinic acid (3-pyridinylmethylene)hydrazide; indole-3-carboxylic acid (4-pyridinylmethylene)hydrazide; indole-2-carboxylic acid (4-pyridinylmethylene)hydrazide; indole-2-carboxylic acid (3-pyridinylmethylene)hydrazide; indole-2-carboxylic acid (2-pyridinylmethylene)hydrazide; isonicotinic acid (3-pyridinylmethylene)hydrazide; nicotinic acid (2-pyridinylmethylene)hydrazide; nicotinic acid (4-pyridinylmethylene)hydrazide; picolinic acid (2-pyridinylmethylene)hydrazide; picolinic acid (3-pyridinylmethylene)hydrazide; picolinic acid (4-pyridinylmethylene)hydrazide; isonicotinic acid (4-pyridinylmethylene)hydrazide; pyrazine-2-carboxylic acid [(2-ethyl-4-pyridinyl)methylene]hydrazide; nicotinic acid [(2-ethyl-4-pyridinyl)methylene]hydrazide; isonicotinic acid [(2-ethyl-4-pyridinyl)methylene]hydrazide; 2-ethylpyridine-4-carboxylic acid [(2-ethyl-4-pyridinyl)methylene]hydrazide; 4,5-dichloroquinolinic-2-carboxylic acid (4-pyridinylmethylene)hydrazide;
    4,5-dichloroquinoline-2-carboxylic acid (3-pyridinylmethylene)hydrazide;
    6-methyl-3-pyridinecarboxylic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide;
    3-n-propyl-1,4-dioxoquinoxaline-2-carboxylic acid (2-pyridinylmethylene)hydrazide;
    3-methyl-1,4-dioxoquinoxaline-2-carboxylic acid (2-pyridinylmethylene)hydrazide;
    3-ethyl-1,4-dioxoquinoxaline-2-carboxylic acid (2-pyridinylmethylene)hydrazida;
    4-methyl-2-pyridinecarboxylic acid (α-2-pyridinylbenzylidene)hydrazide; picolinic acid (α-2-pyridinylbenzylidene)hydrazide;
    5-n-butyl-2-pyridinecarboxylic acid (4-pyridinylmethylene)hydrazide;
    5-n-butyl-2-pyridinecarboxylic acid (3-pyridinylmethylene)hydrazide;
    5-n-butyl-2-pyridinecarboxylic acid (2-pyridinylmethylene)hydrazide; isonicotinic acid N-oxide [1-(4-pyridinyl)ethylidene]hydrazide; isonicotinic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide; isonicotinic acid N-oxide [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide; isonicotinic acid [1-(6-methyl-2-pyridinyl)ethylidene]hydrazide; isonicotinic acid [1-(2-pyridinyl)ethylidene]hydrazide; nicotinic acid [1-(2-pyridinyl)ethylidene]hydrazide; nicotinic acid [1-(6-methyl-2-pyridinyl)ethylidene]hydrazide; isonicotinic acid [1-(3-pyridinyl)ethylidene]hydrazide; nicotinic acid [1-(3-pyridinyl)ethylidene]hydrazide; isonicotinic acid (α-2-pyridinylbenzylidene)hydrazide; thiophene-2-carboxylic acid [1-(2-pyridinyl)ethylidene]hydrazide; furan-2-carboxylic acid (2-pyridinylmethylane)hydrazide; quinaldic acid (2-pyridinylmethylene)hydrazide;
    5-n-butyl-2-pyridinecarboxylic acid [1-methyl-3-pyridinium]hydrazide methanesulfonate; indazole-3-carboxylic acid (4-pyridinylmethylene)hydrazide; isonicotinic acid [(3-hydroxy-4-pyridinyl)methylene]hydrazide; and pyridazinecarboxylic acid (4-pyridinylmethylene)hydrazide.
  8. 8. A compound, hydrate or pharmaceutically acceptable salt thereof according to Claim 7 wherein X is selected from (a) hydrogen; (b) C1-C10 alkyl; (c) C2-C6 alkenyl; (d) C2-C6 alkynyl; (e) cyclo (C3-C10) alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, trifluoromethyl, or halo; (f) pyrrolidinyl; (g) piperidinyl; (h) 1 -methylpyrrolidinyl; (i) 1-methylpiperidinyl; (j) C2-C6 alkoxyalkyl; (k) cyclo(C3-C10)alkyl(C1-C4)alkyl; (1) phenyl (C1-C4) alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (m) phenoxy (C1-C4) alkyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; or (n) naphthyl- (C1-C3)alkyl optionally substituted with one or 2 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (o) C1-C6 alkoxy; (p) diphenylmethoxy; (q) cyclo(C3-C6)alkyloxy optionally substituted with one or two C1-C3 alkyl; (r) phenoxy optionally substituted with one, 2 or 3 C1- C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; or (s) benzyloxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl. with the proviso that when a 2-pyridinyl acylhydrazone and R1 , R2 and R4 are hydrogen, R3 is not benzyl; (u) phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitro, or phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, or trifluoromethyl; (v) phenyl optionally substituted with the divalent C1-C2 alkylenedioxy; and (w) naphthyl optionally substituted with one or 2 C1-C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitro; (x) bridged polycyclic hydrocarbon substituents of six to 10 nuclear carbons, optionally substituted with one, 2 or 3
    (C1-C3) alkyl groups; (y) perhalo(C1-C7) alkyl.
  9. 9. A compound, hydrate or pharmaceutically acceptable salt thereof according to Claim 7 wherein X is phenyl substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl, a halogen atom, C1-C3 alkylthio, phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, or trifluoromethyl.
  10. 10. A compound, hydrate or pharmaceutically acceptable salt thereof, according to Claim 9 wherein the compound is a 3- or 4-pyridinyl acylhydrazone.
  11. 11. A compound, hydrate or pharmaceutically acceptable salt thereof, according to Claim 9 wherein phenyl is subsituted with one, 2 or 3 C1-C3 alkyl, C1-C3 alkoxy, or a chloro atom.
  12. 12. A compound, hydrate or a pharmaceutically acceptable salt thereof, according to Claim 9 wherein R3 is selected from the group consisting of hydrogen, methyl or ethyl and R4 is hydrogen.
  13. 13. A compound, hydrate or a pharmaceutically acceptable salt thereof, according to Claim 9 wherein phenyl is substituted with one, 2 or 3 methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or chloro.
  14. 14. A compound, hydrate or pharmaceutically acceptable salt thereof, according to Claim 7 wherein X is (o) C1-C6 alkoxy; (p) diphenylmethoxy; (q) cyclo(C3-C6)alkyloxy optionally substituted with one or two C1-C3 alkyl; (r) phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1 -C4 alkoxy, halo, or trifluoromethyl; or (3) benzyloxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; with the proviso that when a 2-pyridinyl acylhydrazone and R1 , R2 and R4 are hydrogen, R3 is not benzyl.
  15. 15. A compound, hydrate or pharmaceutically acceptable salt thereof, according to Claim 7 wherein X is (a) hydrogen; (b) C1-C10 alkyl; (c) C2-C6 alkenyl; (d) C2-C6 alkynyl; (a) cyclo(C3-C10)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, trifluoromethyl, or halo; (f) pyrrolidinyl; (g) piperidinyl; (h) 1-methylpyrrolidinyl; (i) 1-methylpiperidinyl; (j) C2-C6 alkoxyalkyl; (k) cyclo(C3-C10)alkyl(C1-C4)alkyl; (1) phenyl (C1-C4)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (m) phenoxy (C1-C4) alkyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; or (n) naphthyl (C1-C3) alkyl optionally substituted with one or 2 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl.
  16. 16. A compound, hydrate or pharmaceutically acceptable salt thereof, according to Claim 7 wherein X is naphthyl or naphthyl substituted with one or 2 methyl, ethyl, methoxy, ethoxy, chloro atom or trifluoromethyl.
  17. 17. A compound, hydrate or pharmaceutically acceptable salt thereof, according to Claim 7 selected from the group consisting of benzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #2); benzoic acid (α-4-pyridinylbenzylidene)hydrazide hydrate (Cpd #8) 3-methylbenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #11) 2-ethoxybenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #14) 3-ethoxybenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #15) 4-ethoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #16)
    3,4,5-trimethoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #17);
    3,4-dimethoxybenzoic acid [1-(4-pyridinyl)ethyiidene]hydrazide (Cpd #18); piperonylic acid (4-pyridinylmethylene)hydrazide (Cpd #19);
    2-phenoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #20);
    3-methoxybenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #22);
    3,5-dimethoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #23); 2,4-dichlorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #26);
    3,4-dichlorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #27);
    2,4 dichlorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #28); 2-methoxybenzoic acid ( 4-pyridinylmethylene )hydrazide monohydrate
    (Cpd #30);
    3-methoxybenzoic acid (4-pyridinylmethylane)hydrazide (Cpd #31); 3-methylbenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #31A); 4-ethoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #34); 3,5-dimethoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #35);
    2-chlorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #36); 4-(1,1-dimethylethyl)benzoic acid (2-pyridinylmethylene)hydrazide hydrate (Cpd #40);
    4-(1,1-dimethylethyl)benzoic acid (3-pyridinylmethylene)hydrazide hemihydrate (Cpd #41); 4-(1,1-dimethylethyl)benzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #42);
    2-phenoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #43); 2-ethoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #44); 2-ethoxybenzoicacid [1-(2-pyridinyl)propylidene]hydrazide (Cpd #45) 2-ethoxybenzoicacid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #46) benzoicacid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #48) 2-phenoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #49); benzoic acid [1-(4-pyridinyl)propylidene]hydrazida (Cpd #51); 4-chlcrobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #52); benzoic acid 1-methyl-2-[1-(4-pyridinyl)ethylidene]hydrazide (Cpd #55);
    2-methoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #56); 2-methoxybenzoic acid [(6-methyl-2-pyridinyl)methylene]hydrazide
    (Cpd #57); benzoic acid [1-(4-pyridinyl)pentylidene]hydrazide (Cpd #60); benzoicacid [2-phenyl-1-(4-pyridinyl)ethylidene]hydrazide (Cpd #61); benzoic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #67); ethyl [1-(4-pyridinyl)ethylidene)carbazata (Cpd #72); ethyl (3-pyridinylmethylene)carbazate (Cpd #74); 1,1-dimethylethyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #76); benzyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #79); diphenylmethyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #80); diphenylmethyl [1-(2-pyridinyl)ethylidene]carbazate (Cpd #80 A); methyl (4-pyridinylmethylene) carbazate hydrate (Cpd #83); benzyl (4-pyridinylmethylene)carbazate (Cpd #84); methyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #85); diphenylmethyl (4-pyridinylmethylene)carbazate (Cpd #86); 4-chlorobenzoic acid (4-pyridinylmethylene)hydrazide 1-oxide (Cpd
    #86 A) ; methyl [1-(3-pyridinyl)ethylidene]carbazate (Cpd #89); 1 ,1-dimethylethyl [1-(4-pyridinyl)propylidene]carbazate (Cpd #91); benzyl [1-(4-pyridinyl)propylidene]carbazate (Cpd #92); methyl [1-(4-pyridinyl)propylidene]carbazate (Cpd #93); phenyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #94); phenyl [1-(4-pyridinyl)ethylidene]carbazate monohydrochloride (Cpd #95);
    5-methyl-2-(1-methylethyl)cyclohexyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #97); ethyl [1-(4-pyridinyl)pentylidene]carbazate (Cpd #99); phenyl [1-(4-pyridinyl)butylidene]carbazate monohydrochloride (Cpd #100); phenyl (4-pyridinylmethyiene)carbazate monohydrochloride (Cpd #101); 1,1-dimethylethyl[1-(3-pyridinyl)propylidene]carbazate (Cpd #103); methyl [1-(2-pyridinyl)propylidene]carbazate (Cpd #104); ethyl [1-(2-pyridinyl)propylidene]carbazate (Cpd #105); 1 ,1-dimethylethyl [1-(2-pyridinyl)propylidene]carbazata (Cpd #106); ethyl [1-(3-pyridinyl)propylidene]carbazate (Cpd #107); 1 ,1-dimethylethyl [1-(4-pyridinyl)butylidene]carbazate (Cpd #108); ethyl [1-(4-pyridinyl)ethylidene]carbazata 1-oxide (Cpd #109); ethyl [1-(4-pyridinyl)butylidene]carbazate (Cpd #110); methyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide (Cpd #111); phenyl [1-(4-pyridinyl)butylidene]carbazate 1-oxide (Cpd #112); 1,1-dimethylethyl [1-(4-pyridinyl)butylidene]carbazate 1-oxide (cpd #113); ethyl [1-(4-pyridinyl)butylidene]carbazate 1-oxide (Cpd #114); 1 ,1-dimethylethyl [3-methyl-1-(4-pyridinyl)butylidene]carbazate (Cpd #116); phenyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide monohydrochloride (cpd #118); benzyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide hydrate (Cpd #119);
    1,1-dimethylethyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide (Cpd #120); 4-trifluoromethylbenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #121); 4-dimethylaminobenzoic acid (2-pyridinylmethylene)hydrazide (Cpd #122);
    4-dimethylaminobenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #123); 4-dimethylaminobenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide
    (Cpd #125);
    4-dimethylaminobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #126);
    4-trifluoromethylbenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #127);
    4-m thoxybenzyl (3-pyridinylmethylene)carbazate (Cpd #128);
    4-methoxybenzyl (4-pyridinylmethylene)carbazate (Cpd #129);
    4-methoxybenzyl [1-(3-pyridinyl)ethylidene]carbazate monohydrate (Cpd #130); 4-methoxybenzyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #131); ethyl [(6-methyl-2-pyridinyl)methylene]carbazate hydrate (Cpd #132);
    4-methoxybenzyl (2-pyridinylmethylene)carbazate (Cpd #133); acetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #136);
    (2,4,5-trichlorophenoxy)acetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #137); formic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #138); formic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #139); formic acid [1-(4-pyridinyl)pentylidene]hydrazide (Cpd #141); phenylacetic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #142); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #144); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide oxalic acid salt (Cpd #145); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide pamoic acid salt (Cpd #146); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide 1-hydroxy-2-naphthoic acid salt (Cpd #147); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide 3-hydroxy-2-naphthoic acid salt (Cpd #148); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide malonic acid salt (Cpd #149); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide phenylacetic acid salt (Cpd #150); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide phenoxyacetic acid salt (Cpd #151); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide phenylthioacetic acid salt (Cpd #152); butyric acid (4-pyridinylmethylene)hydrazide (Cpd #153); butyric acid (4-pyridinylmethylene)hydrazide oxalic acid salt (Cpd #154); formic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #155); butyric acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #156);
    3-cyclohexanepropionic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #160);
    1-naphthalenecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #161);
    2-naphthalenecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #162);
    1-naphthaleneacetic acid (4-pyridinylmethylene)hydrazide (Cpd #164);
    1-naphthaleneacetic acid [1-(3-pyridinyl)ethylidine]hydrazide (Cpd #165);
    1-naphthaleneacetic acid [1-(4-pyridinyl)ethylidine]hydrazide (Cpd #166); cyclohexanecarboxylic acid [(6-methyl-2-pyridinyl)methylene]hydrazide monohydrate (Cpd #167); butyric acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #168);
    1-naphthalenecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #171);
    1-naphthylenecarboxylic acid (3-pyridinylmethylene)hydrazide (Cpd #172); nicotinic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #174);
    2-thiophenecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #177);
    2-thiophenecarboxylic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #178); 2-thiophenecarboxylic acid (3-pyridinylmethylane)hydrazide
    (Cpd #179);; 1-naphthalenecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #180);
    2-thiophenecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #181); 3,4,5-trimethoxybenzoic acid (4-pyridinylmethylene)hydrazide monohydrate (Cpd #182); cyclobutanecarboxylic acid [(6-methyl-2-pyridinyl)methylane]hydrazide (Cpd #183); acetic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #184); 4-chlorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide
    (Cpd #189);
    4-chlorobenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #190);
    4-chlorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #193);
    4-chlorobenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #194); phenylacetic acid [1-(4-pyridinyl)propylidine]hydrazide (Cpd #197); nicotinic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #198);
    2,2-dimethyl-3-(2-methylpropenyl)cyclopropane carboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #201);
    2-methylpropionic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #202); formic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #203); acetic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #205); cyclopropanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #206); formic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #207); cyclopropanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #208);
    2-methylpropionic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #209); butyric acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #211); acetic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #212); cyclohexanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #213);
    2-furoic acid [1-(3-pyridinyl)ethylidine]hydrazide monohydrate (Cpd #214);
    2-furoic acid [1-(2-pyridinyl)ethylidine]hydrazide (Cpd #215); 1 -naphthalenecarboxylic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #222);
    2-furoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #225); phenyl [1-(3-pyridinyl)propylidene]carbazate monohydrochloride (Cpd #226); cyclobutanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #227);
    3-ethoxypropionic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #228); 2-methoxybenzoic acid (4-pyridinylmethylene)hydrazide 1-oxide
    (Cpd #229);
    2-phenoxybenzoic acid (4-pyridinylmethylene)hydrazide 1-oxide (Cpd #236):
    2-thiophenecarboxylic acid (4-pyridinylmethylene)hydrazide 1-oxide (Cpd #239);
    3-cyclohexanepropionic acid (4-pyridinylmethylene)hydrazide 1-oxide (Cpd 241); butyric acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #242); cyclopropanecarboxylic acid [3-methyl-1-(4-pyridinyl)butylidene]hydrazide (Cpd #244); cyclohexanecarboxylic acid (cyclopentyl-4-pyridinylmethylane)hydrazide (Cpd #246); butyric acid (cyclopentyl-4-pyridinylmethylene)hydrazide (Cpd #247); cyclopropanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #248);
    2-methylpropionic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #249);
    3-cyclohexanepropionic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #250); cyclohexaneacetic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd
    #252); cyclohexanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #253); 2-methylpropionic acid [3-methyl-1-(4-pyridinyl)butylidene]hydrazide (Cpd #254); cyclohexanecarboxylic acid [3-methyl-1-(4-pyridinyl)butylidene)hydrazide (Cpd #255);
    3-ethoxypropionic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #262); formic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #263); cyclobutanecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #264); cyclohexanecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #270); formic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #271);
    2-methylpropionic acid (4-pyridinylmethylene)hydrazide (Cpd #272); cyclopropanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #273); cyclopropanecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #274);
    2-methylpropionic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd#275);
    3-cyclohexanepropionic acid [4-(pyridinyl)ethylidene]hydrazide (Cpd #276); 3-cyclohexanepropionic acid (4-pyridinylmethylene)hydrazide
    (Cpd #277); cyclohexaneacetic acid (4-pyridinylmethylene)hydrazide (Cpd #278); cyclohexanecarboxylic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #279); cyclohexaneacetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd
    #280);
    3-ethoxypropionic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #281); cyclobutanecarboxylic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #282);
    3-ethoxypropionic acid (4-pyridinylmethylene)hydrazide (Cpd #283); cyclohexanecarboxylic acid [1-(4-pyridinyl)athylidene]hydrazide 1-oxide (Cpd #287); cyclohexaneacetic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #288); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide hydrate (Cpd #289); cyclobutanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #290); 3-trifluoromethylbenzoic acid [1-(2-pyridinyl)ethylidene]hydrazide
    (Cpd #301);
    2-fluorobenzoic acid (2-pyridinylmethylene)hydrazide (Cpd #303); 2-fluorobenzoic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #304); 3-fluorobenzoic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #305); 3-fluorobenzoic acid (2-pyridinylmethylene)hydrazide (Cpd #306);
    2-methylcyclopropane carboxylic acid (2-pyridinylmethylene)hydrazide (Cpd #307); piperonylic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #308); propanoic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #310); propanoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #311);
    2-methylcyclopropane carboxylic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #313);
    3-trifluoromethylbenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #315); 3-trifluoromethylbenzoic acid [1-(3-pyridinyl)propylidene]hydrazide
    (Cpd #316);
    3-trifluoromethylbenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #317);
    2-fluorobenzoic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #318);
    3-fluorobenzoic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #319);
    2-fluorobenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #320); 2-fluorobenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #321); 3-fluorobenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #322);
    3-fluorobenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #323); 4-phenylbutyric acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #324); 4-phenylbutyric acid (3-pyridinylmethylene)hydrazide (Cpd #325); aceticacid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #327); 2-methylpropionic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #328); butyric acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #329); propanoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd
    #330); ethyl [1-(6-methyl-3-pyridinyl)ethylidene]carbazate (Cpd #332); 1 ,1-dimethylethyl[1-(6-methy1-3-pyridinyl)ethylidene]carbazate (Cpd #333); phenyl[1-(6-methyl-3-pyridinyl)ethylidene]carbazatemonohydroohloride
    (Cpd #334); benzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #336);
    4-chlorobenzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #337);
    2- ethoxybenzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #338);
    4-ethoxybenzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #339); 2-methyl-1-naphthaleneacetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #341); piperonylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide hydrate (Cpd #346); piperonylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #347); 3 ,4-dimethoxyphenylacetic acid [1-14-pyridinyl)ethylidene]hydrazide
    1-oxide hydrate (Cpd #348);
    3, 4-dimethoxyphenylacetic acid (4-pyridinylmethylane)hydrazide (Cpd #349); propanoic acid ( 4-pyridinylmethylene)hydr azide (Cpd #351); propanoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #352);
    1 -methyl cyclopropanecar bo xylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #354);
    3-trifluoromethylbenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #358); 2-methylcyclopropanecarboxylic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #360); 2-fluorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazids (Opd #362);
    3-fluorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #363); 2-fluorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #364);
    2-fluorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #365); 3-fluorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #366); 4-phenylbutyric acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #367); 4-phenylbutyric acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #368);
    4-phenylbutyric acid ( 4-pyridinylmethylene)hydrazide (Cpd #369); 3-fluorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #370); 2- methylbenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #371); 4 -methylbenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd
    #373);
    2-chlorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #374); acetic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #377); 2-furoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #378); isonicotinic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #379); propanoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #380); 2- methylpropanoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #381); 2-thiophenecarboxylic acid [1-(4-pyridinyl)propylidene]hydrazide
    (Cpd #382); phenyl [1-(4-pyridinyl)propylidene]carbazate monohydrochloride (Cpd #383);
    2-ethoxybenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #385); formic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #386); 4-ethoxybenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #388); 3-chlorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #389); butyric acid (2-chloro-3-pyridinylmethylene)hydrazide (Cpd #391); propanoic acid (3-hydroxy-2-pyridinylmethylene)hydrazide (Cpd #393); formic acid [1-(3-chloro-4-pyridinyl)ethylidene]hydrazide (Cpd #394); butyric acid [1-(3-chloro-4-pyridinyl)ethylidene]hydrazide (Cpd #395); methyl [1-(3-chloro-4-pyridinyl)ethylidene]carbazate (Cpd #396); propanoic acid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #399); butyric acid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #400); 2-methylpropanoicacid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide
    (Cpd #401); cyclopropanecarboxylic acid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #402); acetic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #410); propanoic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (#411); butyric acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #412);
    2-methylpropanoicacid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #413); cyclopropanecarboxylic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #414); cyclohexaneacetic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #415); benzoic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd
    #416); benzoic acid [(1,3~dioxan-5-yl)-3-pyridinylmethylene]hydrazide (Cpd #421); ethyl [(1,3-dioxan-5-yl)-3-pyridinylmethylane]carbazate (Cpd #422) ; benzoic acid [(1,3-dioxan-5-yl)-4-pyridinylmethylene]hydrazide
    (Cpd #423); formic acid ( 4-pyridinylmethylene)hydrazide (Cpd #424); formic acid (3-pyridinylmethylene)hydrazide (Cpd #425); butyric acid [(1,3-dioxan-5-yl)-3~pyridinylmethylane)hydrazide (Cpd #430); ethyl [(1,3-dioxan-5-yl)-4-pyridinylmethylene]carbazate (Cpd #431); methyl [(1,3-dioxan-5-yl)-3-pyridinylmethylene]carbazate (Cpd #432); propanoic acid [(1,3-dioxan-5-yl)-4-pyridinylmethylene]hydrazide (Cpd #433); propanoic acid [(1,3-dioxan-5-yl)-3-pyridinylmethylene]hydrazide (Cpd #434); butyric acid [(1,3-dioxan-5-yl)-4-pyridinylmethylene]hydrazide (Cpd #435); methyl [(1,3-dioxan-5-yl)-4-pyridinylmethylane]carbazate (Cpd #436).
  18. 18. A compound, hydrate or pharmaceutically acceptable salt thereof, according to Claim 7 selected from the group consisting of benzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #2); 4-ethoxybenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #16); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #144); butyric acid (4-pyridinylmethylene)hydrazide (Cpd #153);
    3-cyclohexanepropionic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #160); formic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #203); or 2-methylpropionic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #275).
  19. 19. An anthelmintic composition for administration to animals comprising a physiologically acceptable carrier and adjuvants, and at least an effective anthelmintic amount of a pyridinyl acylhydrazone, hydrate or pharmaceutically acceptable salt thereof of the formula:
    wherein X is selected from (a) hydrogen; (b) C1-C10 alkyl; (c) C2-C6 alkenyl; (d) C2-C6 alkynyl; (e) cyclo(C3-C10)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, trifluoromethyl, or halo; (f) pyrrolidinyl; (g) piperidinyl; (h) 1-methylpyrrolidinyl; (i) 1-methylpiperidinyl; (j) C2-C6 alkoxyalkyl; (k) cyclo(C3-C10)alkyl- (C1-C4) alkyl; (1) phenyl(C1-C4)alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (m) phenoxy-(C1-C4)alkyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (n) naphthyl(C1-C3)alkyl optionally substituted with one or 2 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (o) C1-C6 alkoxy; (p) diphenylmethoxy; (q) cyclo(C3-C6)alkyloxy optionally substituted with one or two C1- C3 alkyl; (r) phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; (s) benzyloxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C4 alkoxy, halo, or trifluoromethyl; with the proviso that when a 2-pyridinyl acylhydrazone and R1 , R2 and R4 are hydrogen, R3 is not benzyl; (t) heteroaromatic optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, C1-C3 alkylthio, or trifluoromethyl; (u) phenyl optionally substituted with one, 2 or 3 C1 -C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitro, or phenoxy optionally substituted with one, 2 or 3 C1-C4 alkyl, C1-C3 alkoxy, halo, or trifluoromethyl; (v) phenyl optionally substituted with the divalent C1-C2 alkylenedioxy; (w) naphthyl optionally substituted with one or 2 C1-C4 alkyl, C1-C3 alkoxy, halo, trifluoromethyl, C2-C6 dialkylamino, C1-C3 alkylthio, nitro; (x) bridged polycyclic hydrocarbon substituents of six to 10 nuclear carbons, optionally substituted with one, 2 or 3 (C1-C3) alkyl groups; (y) perhalo(C1-C7) alkyl; wherein R1 and R2, being the same or different, are hydrogen; hydroxy; C1-C4 alkyl; C1-C3 alkoxy; C1-C3 alkylthio; halo or trifluoromethyl; wherein R3 is hydrogen; C1-C4 alkyl; cyclo(C3-C6)alkyl optionally substituted with one, 2 or 3 C1-C3 alkyl; phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; phenyl (C1-C3) alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; or 1,3-dioxacyclohexan-5-yl; wherein R4 is hydrogen; C1-C2 alkyl; cyclo(C3-C6)alkyl optionally substituted with one, 2 or 3 C1-C3 alkyl; phenyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; phenyl (C1-C3) alkyl optionally substituted with one, 2 or 3 C1-C4 alkyl, halo, trifluoromethyl, or C1-C3 alkoxy; and wherein n is zero or one.
  20. 20. The composition of Claim 19 in which the compound, hydrate or pharmaceutically acceptable salt thereof is selected from the group consisting of benzoic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #1) benzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #2) benzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #3) benzoic acid (3-pyridinylmethylene)hydrazide (Cpd #6); benzoic acid (4-pyridinylmethylene)hydrazide (Cpd #7); benzoic acid (α-4-pyridinylbenzylidene)hydrazide hydrate (Cpd #8)
    3-methylbenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #11) 2-ethoxybenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #14) 3-ethoxybenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #15) 4-ethoxybenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #16) 3,4,5-trimethoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #17);
    3,4-dimethoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #18); piperonylic acid (4-pyridinylmethylene)hydrazide (Cpd #19); 2-phenoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #20);
    3-methoxybenzoicacid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #22); 3,5-dimethoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #23);
    2,4-dichlorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #26);
    3,4-dichlorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #27);
    2,4-dichlorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #28);
    2-methoxybenzoic acid (4-pyridinylmethylene)hydrazide monohydrate (Cpd #30);
    3-methoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #31);
    3-methylbenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #31 A);
    4-ethoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #34); 3,5-dimethoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #35); 2-chlorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #36); 4-(1,1-dimethylethyl)benzoic acid (2-pyridinylmethylene)hydrazide hydrate (Cpd #40);
    4-(1,1-dimethylethyl)benzoic acid (3-pyridinylmethylene)hydrazide hemihydrate (Cpd #41); 4-(1,1-dimethylethyl)benzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #42);
    2-phenoxybenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #43); 2-ethoxybenzoic acid ( 4-pyridinylmethylene)hydrazide (Cpd #44); 2-ethoxybenzoicacid [1-(2-pyridinyl)propylidene]hydrazide (Cpd #45) 2-ethoxybenzoicacid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #46) benzoicacid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #48) 2-phenoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #49); benzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #51); 4-chlorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #52); benzoic acid 1-methyl-2-[1-(4-pyridinyl)ethylidene]hydrazide (Cpd #55);
    2-methoxybenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #56); 2-methoxybenzoic acid [(6-methyl-2-pyridinyl)methylene]hydrazide
    (Cpd #57); benzoic acid [1-(4-pyridinyl)pentylidene]hydrazide (Cpd #60); benzoicacid [2-phenyl-1-(4-pyridinyl)ethylidene]hydrazide (Cpd #61 ); benzoicacid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #67); 2-nitrobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #69); ethyl [1-(2-pyridinyl)ethylidene)carbazate (Cpd #70); ethyl [1-(4-pyridinyl)ethylidene)carbazate (Cpd #72); ethyl (2-pyridinylmethylene)carbazate (Cpd #73); ethyl (3-pyridinylmethylene)carbazate (Cpd #74); ethyl (4-pyridinylmethylene)carbazate (Cpd #75);
    1,1-dimethylethyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #76); benzyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #79); diphenylmethyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #80); diphenylmethyl [1-(2-pyridinyl)ethylidene]carbazate (Cpd #80A); methyl (4-pyridinylmethylene)carbazate hydrate (Cpd #83); benzyl (4-pyridinylmethylene)carbazate (Cpd #84); methyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #85); diphenylmethyl (4-pyridinylmethylene)carbazate (Cpd #86); 4-chlorobenzoic acid (4-pyridinylmethylene)hydrazide 1-oxide (Cpd #86 A) ; methyl [1-(3-pyridinyl)ethylidene]carbazate (Cpd #89);
    1,1-dimethylethyl [1-(4-pyridinyl)propylidene]carbazate (Cpd #91); benzyl [1-(4-pyridinyl)propylidene]carbazate (Cpd #92); methyl [1-(4-pyridinyl)propylidene]carbazate (Cpd #93); phenyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #94); phenyl [1-(4-pyridinyl)ethylidene]carbazate monohydrochloride
    (Cpd #95);
    5-methyl-2-(1-methylethyl)cyclohexyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #97); ethyl [1-(4-pyridinyl)pentylidene]carbazate (Cpd #99); phenyl [1-(4-pyridinyl)butylidene]carbazate monohydrochloride (Cpd
    #100); phenyl (4-pyridinylmethylene)carbazate monohydrochloride (Cpd #101); 1 ,1-dimethylethyl [1-(3-pyridinyl)propylidene]carbazate (Cpd #103); methyl [1-(2-pyridinyl)propylidene]carbazate (Cpd #104); ethyl [1-(2-pyridinyl)propylidene]carbazate (Cpd #105);
    1,1-dimethylethyl [1-(2-pyridinyl)propylidene]carbazate (Cpd #106); ethyl [1-(3-pyridinyl)propylidene]carbazate (Cpd #107); 1,1-dimethylethyl [1-(4-pyridinyl)butylidene]carbazate (Cpd #108); ethyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide (Cpd #109); ethyl [1-(4-pyridinyl)butylidene]carbazate (Cpd #110); methyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide (Cpd #111); phenyl [1-(4-pyridinyl)butylidene]carbazate 1-oxide (Cpd #112); 1,1-dimethylethyl [1-(4-pyridinyl)butylidene]carbazate 1-oxide (Cpd #113); athyl [1-(4-pyridinyl)butylidene]carbazate 1-oxide (Cpd #114);
    1,1-dimethylethyl [3-methyl-1-(4-pyridinyl)butylidene]carbazate (Cpd #116); phenyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide monohydrochloride (Cpd #118); benzyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide hydrate (Cpd
    #119); 1,1-dimethylethyl [1-(4-pyridinyl)ethylidene]carbazate 1-oxide (Opd #120);
    4-trifluoromethylbenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #121); 4-dimethylaminobenzoic acid (2-pyridinylmethylene)hydrazide (Cpd
    #122);
    4-dimethylaminobenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #123);
    4-dimethylaminobenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #125);
    4-dimethylaminobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #126);
    4-trifluoromethylbenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #127); 4-methoxybenzyl (3-pyridinylmethylene)carbazate (Cpd #128);
    4-methoxybenzyl (4-pyridinylmethylene) carbazate (Cpd #129);
    4-methoxybenzyl [1-(3-pyridinyl)ethylidene]carbazate monohydrate (Cpd #130);
    4-methoxybenzyl [1-(4-pyridinyl)ethylidene]carbazate (Cpd #131); ethyl [(6-methyl-2-pyridinyl)methylene]carbazate hydrate (Cpd #132);
    4-methoxybenzyl (2-pyridinylmethylene)carbazate (Cpd #133); acetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #136);
    (2,4,5-trichlorophenoxy) acetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #137); formic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #138); formic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #139); formic acid [1-(4-pyridinyl)pentylidene]hydrazide (Cpd #141); phenylacetic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #142); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide (Opd #144); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide oxalic acid salt (Cpd #145); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide pamoic acid salt (Cpd #146); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide 1-hydroxy-2-naphthoic acid salt (Cpd #147); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide 3-hydroxy-2-naphthoic acid salt (Cpd #148); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide malonic acid salt (Cpd #149); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide phenylacetic acid salt (Cpd #150); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide phenoxyacetic acid salt (Cpd #151); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide phenylthioacetic acid salt (Cpd #152); butyric acid (4-pyridinylmethylene)hydrazide (Cpd #153); butyric acid (4-pyridinylmethylene)hydrazide oxalic acid salt (Cpd #154); formic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #155); butyric acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #156); phenylacetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #157); 3-cyclohexanepropionic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #160);
    1 -naphthalene carboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #161);
    2-naphthalenecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #162);
    1-naphthalεneacetic acid (4-pyridinylmethylene)hydrazide (Cpd #164); 1-naphthaleneacetic acid [1-(3-pyridinyl)ethylidine]hydrazide (Cpd #165);
    1-naphthaleneacetic acid [1-(4-pyridinyl)ethylidine]hydrazide (Cpd #166); cyclohexanecarboxylic acid [(6-methyl-2-pyridinyl)methylene]hydrazide monohydrate (Cpd #167); butyric acid [(6-methyl-2-pyridinyl)methylsne]hydrazide (Cpd #168);
    1-naphthalenecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #171);
    1 -naphthylenecarboxylic acid (3-pyridinylmethylene)hydrazide (Cpd #172); nicotinic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #174) ; 2-thiophenecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #177);
    2-thiophenecarboxylic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #178); 2-thiophenecarboxylic acid (3-pyridinylmethylene)hydrazide
    (Cpd #179);
    1-naphthalenecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #180);
    2-thiophenecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #181);
    3,4,5-trimethoxybenzoic acid (4-pyridinylmethylene)hydrazide monohydrate (Cpd #182); cyclobutanecarboxylic acid [(6-methyl-2-pyridinyl)methylene]hydrazide (Cpd #183); acetic acid [(6-methyl-2-pyridinyl)methylane]hydrazide (Cpd #184);
    4-chlorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #189);
    4-chlorobenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #190);
    4-chlorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #193); 4-chlorobenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #194); phenylacetic acid [1-(4-pyridinyl)propylidine]hydrazide (Cpd #197); nicotinic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #198);
    2,2-dimethyl-3-(2-methylpropenyl)cyclopropane carboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #201); 2-methylpropionic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide
    (Cpd #202); formic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #203); acetic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #205); cyclopropanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #206); formic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #207); cyclopropanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #208);
    2-methylpropionic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #209); butyric acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #211); aceticacid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #212); cyclohexanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide 1-oxide (Cpd #213);
    2-furoic acid [1-(3-pyridinyl)ethylidine]hydrazide monohydrate (Cpd #214);
    2-furoic acid [1-(2-pyridinyl)ethylidine]hydrazide (Cpd #215); isonicotinic acid [1 -(4-pyridinyl)ethylidene]hydrazide (Cpd #217); isonicotinic acid (2-pyridinylmethylene)hydrazide (Cpd #221); 1-naphthalenecarboxylic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #222);
    2-furoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #225); phenyl [1-(3-pyridinyl)propylidene]carbazate monohydrochloride (Cpd #226); cyclobutanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #227);
    3-ethoxypropionic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #228);
    2-methoxybenzoic acid (4-pyridinylmethylane)hydrazide 1-oxide (Cpd #229); 2-phenoxybenzoic acid (4-pyridinylmethylane)hydrazide 1-oxide
    (Cpd #236):
    2-thiophenecarboxylic acid (4-pyridinylmethylene)hydrazide 1-oxide (Cpd #239);
    3-cyclohexanepropionic acid ( 4-pyridinylmethylene )hydrazide 1-oxide (Cpd 241); butyric acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #242); cyclopropanecarboxylic acid [3-methyl-1-(4-pyridinyl)butylidene]hydrazide (Cpd #244); cyclohexanecarboxylic acid (cyclopentyl-4-pyridinylmethylane)hydrazide (Cpd #246); butyric acid (cyclopentyl-4-pyridinylmethylene)hydrazide (Cpd #247); cyclopropanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #248); 2-methylpropionic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #249); 3-cyclohexanepropionic acid [1-(4-pyridinyl)butylidene]hydrazide (Opd #250); cyclohexaneacetic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #252); cyclohexanecarboxylic acid [1-(4-pyridinyl)butylidene]hydrazide
    (Cpd #253);
    2-methylpropionic acid [3-methyl-1-(4-pyridinyl)butylidene]hydrazide (Cpd #254); cyclohexanecarboxylic acid [3-methyl-1-(4-pyridinyl)butylidene)hydrazide (Cpd #255);
    3-ethoxypropionic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #262); formic acid [1-(4-pyridinyl)butylidene]hydrazide (Cpd #263); cyclobutanecarboxylic acid ( 4-pyridinylmethylene)hydrazide (Cpd #264); cyclohexanecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #270); formic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #271); 2-methylpropionic acid (4-pyridinylmethylene)hydrazide (Cpd #272); cyclopropanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #273); cyclopropanecarboxylic acid (4-pyridinylmethylene)hydrazide (Cpd #274);
    2-methylpropionic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #275);
    3-cyclohexanepropionic acid [4-(pyridinyl)ethylidene]hydrazide (Cpd #276);
    3-cyclohexanepropionic acid (4-pyridinylmethylene)hydrazide (Cpd #277); cyclohexaneacetic acid (4-pyridinylmethylene)hydrazide (Cpd #278); cyclohexanecarboxylic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #279); cyclohexaneacetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #280); 3-ethoxypropionic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #281); cyclobutanecarboxylic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #282);
    3-ethoxypropionic acid (4-pyridinylmethylene)hydrazide (Cpd #283); cyclohexanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #287); cyclohexaneacetic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide (Cpd #288); butyric acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide hydrate (Cpd #289); cyclobutanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide
    (Cpd #290);
    4-nitrobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #291); 3-trifluoromethylbenzoic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #301); 2-fluorobenzoic acid (2-pyridinylmethylene)hydrazide (Cpd #303);
    2-fluorobenzoic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #304); 3-fluorobenzoic acid [1-(2-pyridinyl)ethylidene]hydrazide (Cpd #305); 3-fluorobenzoic acid (2-pyridinylmethylene)hydrazide (Cpd #306); 2-methylcyclopropane carboxylic acid (2-pyridinylmethylene)hydrazide (Cpd #307); piperonylic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #308); propanoic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #310); propanoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #311); 2-methylcyclopropane carboxylic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #313);
    3-trifluoromethylbenzoic acid (3-pyridinylmethylene)hydrazide (Cpd #315);
    3-trifluoromethylbenzoic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #316); 3-trifluoromethylbenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide
    (Cpd #317);
    2-fluorobenzoic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #318); 3-fluorobenzoic acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #319);
    2-fluorobenzoic acid (3-pyridinylmethylane)hydrazide (Cpd #320); 2-fluorobenzoicacid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #321) 3-fluorobenzoic acid (3-pyridinyl)methylene)hydrazide (Cpd #322) 3-fluorobenzoic acid [1-(3-pyridinyl)ethylidene]hydrazide (Cpd #323) 4-phenylbutyric acid [1-(3-pyridinyl)propylidene]hydrazide (Cpd #324);
    4-phenylbutyric acid (3-pyridinylmethylane)hydrazide (Cpd #325); acetic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #327); 2-methylpropionic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #328); butyric acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd
    #329); propanoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #330); ethyl [1-(6-methyl-3-pyridinyl)ethylidene]carbazate (Cpd #332); 1,1-dimethylethyl[1-(6-methyl-3-pyridinyl)ethylidene]carbazate
    (Cpd #333); phenyl[1-(6-methyl-3-pyridinyl)ethylidene]carbazate monohydrochloride (Cpd #334); benzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #336);
    4-chlorobenzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #337);
    2-ethoxybenzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide (Cpd #338); 4-ethoxybenzoic acid [1-(6-methyl-3-pyridinyl)ethylidene]hydrazide
    (Cpd #339);
    2-methyl-1-naphthaleneacetic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #341); piperonylic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide hydrate (Cpd #346); piperonylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #347); 3,4-dimethoxyphenylacetic acid [1-(4-pyridinyl)ethylidene]hydrazide 1-oxide hydrate (Cpd #348);
    3,4-dimethoxyphenylacetic acid (4-pyridinylmethylene)hydrazide (Cpd #349); propanoic acid (4-pyridinylmethylene)hydrazide (Cpd #351); propanoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #352);
    1 -methylcyclopropanecarboxylic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #354);
    3-trifluoromethylbenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #358);
    2-methylcyclopropanecarboxylic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #360);
    2-fluorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #362); 3-fluorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd
    #363);
    2-fluorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #364);
    2-fluorobenzoicacid[1-(4-pyridinyl)ethylidene]hydrazide (Cpd #365);
    3-fluorobenzoic acid (4-pyridinylmethylene)hydrazide (Cpd #366); 4-phenylbutyric acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #367);
    4-phenylbutyric acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #368);
    4-phenylbutyric acid (4-pyridinylmethylene)hydrazide (Cpd #369);
    3-fluorobenzoic acid [1-(4-pyridinyl)ethylidene]hydrazide (Cpd #370); 2-methylbenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd
    #371);
    4-methylbenzoic acid [1-(4-pyridinyl)propylidene]hydrazida (Cpd #373);
    2-chlorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #374); acetic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #377);
    2-furoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #378); isonicotinic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #379); propanoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #380); 2-methylpropanoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd
    #381);
    2-thiophenecarboxylic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #382); phenyl [1-(4-pyridinyl)propylidene]carbazate monohydrochloride (Cpd #383); 2-ethoxybenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #385); formic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #386); 4-ethoxybenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #388);
    3-chlorobenzoic acid [1-(4-pyridinyl)propylidene]hydrazide (Cpd #389); butyric acid (2-chloro-3-pyridinylmethylene)hydrazide (Cpd #391); propanoic acid (3-hydroxy-2-pyridinylmethylene)hydrazide (Cpd #393); formic acid [1-(3-chloro-4-pyridinyl)ethylidene]hydrazide (Cpd #394); butyric acid [1-(3-chloro-4-pyridinyl)ethylidene]hydrazide (Cpd
    #395); methyl [1-(3-chloro-4-pyridinyl)ethylidene]carbazate (Cpd #396); propanoic acid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #399); butyric acid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #400);
    2-methylpropanoicacid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #401); cyclopropanecarboxylic acid [1-(2-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #402); acetic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #410); propanoic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (#411); butyric acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd
    #412);
    2-methylpropanoicacid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #413); cyclopropanecarboxylic acid [1-(6-chlor0-3-pyridinyl)ethylidene]hydrazide (Cpd #414); cyclohexaneaceticacid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #415); benzoic acid [1-(6-chloro-3-pyridinyl)ethylidene]hydrazide (Cpd #416); benzoic acid [(1,3-dioxan-5-yl)-3-pyridinylmethylene]hydrazide
    (Cpd #421); ethyl [(1,3-dioxan-5-yl)-3-pyridinylmethylene]carbazate (Cpd #422); benzoic acid [(1,3-dioxan-5-yl)-4-pyridinylmethylene]hydrazide (Cpd #423); formic acid (4-pyridinylmethylene)hydrazide (Cpd #424); formic acid (3-pyridinylmethylene)hydrazide (Cpd #425); butyric acid [(1,3-dioxan-5-yl)-3-pyridinylmethylene)hydrazide (Cpd #430); ethyl [(1,3-dioxan-5-yl)-4-pyridinylmethylene]carbazate (Cpd #431); methyl [(1,3-dioxan-5-yl)-3-pyridinylmethylene]carbazate (Cpd #432); propanoic acid [(1,3-dioxan-5-yl)-4-pyridinylmethylene]hydrazide
    (Cpd #433); propanoic acid [(1,3-dioxan-5-yl)-3-pyridinylmethylene]hydrazide (Cpd #434); butyric acid [(1,3-dioxan-5-yl)-4-pyridinylmethylene]hydrazide (Cpd #435); methyl [(1,3-dioxan-5-yl)-4-pyridinylmethylene]carbazate (Cpd #436).
AU53585/86A 1985-02-11 1986-01-23 Anthelmintic pyridinyl acylhydrazones, method of use and compositions Ceased AU582214B2 (en)

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WO1987003872A1 (en) * 1985-12-26 1987-07-02 Nippon Soda Co., Ltd. Hydrazone derivatives
ATE72980T1 (en) * 1986-04-07 1992-03-15 Upjohn Co ANTHELMINTIC QUATERNARY ALKYL-ACYL HYDRAZONE, METHODS OF USE AND COMPOSITIONS.
US5049561A (en) * 1987-07-31 1991-09-17 The Upjohn Company Anthelmintic acylhydrazones, method of use and compositions
EP0370065A1 (en) * 1987-07-31 1990-05-30 The Upjohn Company Anthelmintic acylhydrazones, method of use and compositions
JPH10338673A (en) * 1997-06-04 1998-12-22 Nippon Bayeragrochem Kk Isonicotinic acid hydrazide derivative and pest controlling agent
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AUPQ262499A0 (en) 1999-09-02 1999-09-23 University Of Queensland, The Novel iron chelators
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KR101009860B1 (en) 2005-10-11 2011-01-19 에프. 호프만-라 로슈 아게 Imidazo benzodiazepine derivatives
BRPI0601885A (en) * 2006-05-15 2008-03-25 Univ Rio De Janeiro antiinflammatory and analgesic pharmaceutical composition containing n-acylhydrazenic derivatives of safrol, use, and process for their preparation
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