CA1270828A - Semicarbazide derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same - Google Patents

Abstract

ABSTRACT

Semicarbazide derivatives of the formula:

wherein R1 is hydrogen, R2 is hydrogen, lower alkyl, ar(lower)alkyl, lower alkenyl or aryl, R3 is lower alkyl, ar(lower)alkyl, lower alkenyl or aryl, or R2 and R3 are taken together to form (C2-C6)-alkylidene group optionally substituted with aryl or taken together with the adjacent nitrogen atom to form a saturated or unsaturated, 5- or 6-membered heterocyclic group optionally substituted with aryl; or R1 and R2 are taken together with the adjacent nitrogen atoms to form a saturated or unsaturated, 5- or 6-membered heterocyclic group or 1,2-diazaspiroalkane-1,2-diyl group, R3 is hydrogen, lower alkyl, ar(lower)alkyl, lower alkenyl or aryl;
R4 is aryl which may have substituent(s) selected from lower alkyl, halogen lower alkoxy, lower alkylamino, halo(lower)alkyl, hydroxy, lower alkanoyl, esterified carboxy and carboxy, R5 is hydrogen or lower alkyl, and X is O or S, provided that the lower alkyl group for R3 is (C3 -C6) alkyl, when R2 is hydrogen or (C1-C2) alkyl and R4 is aryl option-ally having substituent(s) selected from groups consisting of halogen, lower alkyl, lower alkoxy and halo(lower)alkhyl, and their pharmaceutically acceptable salts may be used as anti-inflammatory and analgesic agents.

Description

SEMICARBAZIDE DERIVATIVES, PROCESSES FOR
PREPARATION THEREOF AND PHARMACEUTICAL
COMPOSITION COMPRISING THE SAME
-The present invention relates to novel semicarbazide derivatives. ~ore particularly, it relates to novel semicarbazide derivatives which have antiinflammatory and analgesic activities, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to methods of using the same therapeutically in the treatment of inflammation and various pains in human being and animals.
Accordingly, one object of this invention is to provide novel semicarbazide derivatives which are useful as antiinflammatory and analgesic agents.
Another object of this invention is to provide processes for preparation of said semicarbazide derivativesO
A further object of this invention is to provide pharmaceutical composition comprising, as an active ingredient, said semicarbazide derivative.

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Still further object of this invention is to provide a method of usi.ng said semi.carbazide derivatives in the treatment of inflammation and various pains in human being and animals.
Some N-substituted-1,2,3,6-tetrahydropyridine derivatives having antiinflamatory and analgesic activities have been known as described, for example, in U.S. Patent 4,088,653 and Journal of Medicinal Chemistry Vol. 25, 720-723, 1982.
And some semicarbazide derivatives having similar chemical structure to the object compounds of this invention have been known as described, for example, in Journal of Medicinal Chemistry Vol. 11, 171-172, 1968, Journal of Chemical Society 1956, 2160-2165 and France Patent 1,521,959. sut it has not been known that these compounds possess antiinflammatory and analgesic activities.
The object semicarbazide derivatives are novel and can be represented by the following general formula [I] :
Rl R5 3- N-N-C-N-R4 [I]
R ~ 1l wherein Rl is hydrogen, R2 is hydrogen, lower alkyl, ar(lower)alkyl, lower alkenyl or aryl, R is lower alkyl, ar(lower)alkyl, lower alkenyl or aryl, or R2 and R3 are taken together to form (C2-C6)-alkylidene group optionally substituted with aryl or taken together with the adjacent nitrogen atom to form a saturated or unsaturated, 5- or 6-membered hetero~
cyclic group optionally substituted with aryl; or r~

Rl and R2 are taken toge-ther with the adjacent nitrogen atoms to form a saturated or unsa-turated, 5- or 6-membered heterocyclic group or 1,2-diazaspiroalkane-1,2-diyl group, R3 is hydrogen, lower alkyl, ar(lower)alkyl, lower alkenyl or aryl;
R4 iS aryl which may have substituent (5) selected from lower alkyl, halogen, lower alkoxy, lower alkylamlno, halo(lower)alkyl~
hydroxy, lower alkanoyl, esterified carboxy and carboxy, R5 is hydrogen or lower alkyl, and X is O or S, provided that the lower alkyl group for R3 is (C3-C6)-alkyl, when R2 is hydrogen or (Cl-C2)alkyl and R4 is aryl optionally having substituent(s) selected from groups consisting of halogen, lower alkyl, lower alkoxy and halo(lower)alkyl.
The object compound [I] and its pharmaceutically acceptable salt can be prepared by the following processes.

-25 Process 1 Rl R4-NCX [III] R2 R - M-M-H or its salt ~ N-N-C-NH-R
R3 ~ R3~ 11 X
[II~ [Ia~
or its salt or its salt ~t7~3~2~

Process 2 5 - R X

Rl R -N-C-XH [rv] Rl R5 R2 or its react:ive R2 1 1 4 N-N-H derivative o:r a ~ N-N-C-N-R
R3~ sal.t thereof ~ R3/
[II] [I]
or itS salt or its salt lO Process 3 Rlx R4-N-H [VI] Rl R5 3~ N-N-C-XH or itS salt 3~ N-N-C-N-R4 X
[V] [I]
or its reactive or ~ts salt derivative or a salt thereof ~0 Process 4 25~ ~-Ne-C-N-R4 reductlon a~ N-N-C-N-R4 Y X a X
[VII] [Ib]
or its salt or its salt 3 0Process 5 Rl R5 Rl R5 b~ N-N-C_N_R4 reduction 3~ N-N-C-~-R4 ~ X
[Ic] [Id]
or its salt or its salt 21~

_roce.ss 6 Rl R5 Rl R5 R2 1 1 4 de-esterification R~ 4 N-N-C-N-R ~ - ?N-N-C-N-R
R3~ 11 ~ R3~ li D
X X
[Ie] [If]
or its salt or its salt wherein Rl R2 R3 R4 ~5 d X h d fi d above, Y is hydrogen or aryl, Ra and R3 are taken together with the adjacent nitrogen atom to form a partially or fully saturated 6-membered heterocyclic group optionally substituted with aryl, Rb and Rb are taken together with the adjacent nitrogen atoms to form unsaturated 5- or 6-membered heterocycllc group, Rc and Rc are taken together with the adjacent nitrogen atoms to form a partially or fully saturated 5- or 6-membered heterocyclic group, Ra is aryl substituted with esterified carboxy, and ~ is aryl substituted with carboxy, provided that the lower alkyl group for R3 is (C3-C6)-alkyl, when R is hydrogen or (Cl-C2)alkyl and R4 is aryl optionally having substituent(s) selected from groups consisting of halogen, lower alkyl, lower alkoxy and halo(lower)alkyl.

In the above and subsequent descriptlon of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in det:ail in the following.
The term "lower" is interlded to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
Suitable examples of lower alkyl for R2, R and R
ma~ be a straight or branched one such a~ methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl or the like.
Suitable examples of lower alkenyl for R2 and R3 may be vinyl, allyl, l-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl or the like.
Suitable examples of aryl for R ~ R3 ~ R I Y and the subs~ituent on the heterocyclic group formed by R
and R3 or ~2 and Ra may be phenyl, naphthyl or the like.
Sultable examples of ar( lower) alkyl for R2 and R
may be benzyl, phenethyl, phenylpropyl, benzhydryl, trityl or the like.
Suitable examples of the (C2-C6)alkylidene group formed by R and R may be ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene or the like. These (C2-C6)alkylidene groups may be substituted with aryl group(s), wherein said aryl group(s) may have suitable substituent(s). Suitable examples of the aryl group optionally having substituent(s) may be phenyl, 2-methylphenyl, 4-chlorophenyl, naphthyl, or ~5 the like. Accordingly, suitable examples of the (C2-C6)alkylidene group having such substituent(s) may be l-phenylethylidene, 2-phenylethylidene, 1,2-diphenyl-ethylidene, l-phenylpropylidene, 1-(4-chlorophenyl)-ethylidene or the like.
Suitable examples of the saturated or unsaturated, 5- or 6-membered heterocyclic group formed by R2, R3 and the adjacent nitrogen atom may ~e pyrrolidin-l-yl, pyrrolin-l-yl, imidaæolidin-l~yl, imidazolin-l-yl, imidazol-l-yl, pyrazolidin-1-yl, morpholino, piperidino, piperazin-l-yl, 1,4-dihydropyridin-1-yl, :~2~

1,2-dihydropyridin~l-yl, 1.,2,3,6-tetrahydropyridin-1-yl or the like. These heterocyclic groups may be suhstituted with -the aryl grou.p as exemplified before.
Suitable examples of these het.erocycl.ic groups having the aryl group may be 4-phenyl-1,2,3,6~tetrahydro-pyridl~-l-yl, 4-phenylpiperazin-1-yl or the like.
Suitable examples of the partially or fully saturated 6-membered heterocyclic group formed by Ra, Ra and the adjacent nitrogen atom may be piperidino, 1,4-dihydropyridin-1-yl, 1,2 dihydropyridin-l-yl or 1,2,3,6-tetrahydropyridin l-yl. Said heterocyclic groups may be substituted with the aryl group as exemplified for Y. Suitable examples of said heterocyclic groups having the aryl group may be 4-phenyl-1,2,3,6-tetrahydropyridine, 4-phenylpiperidino or the like.
Suitable examples of the saturated or unsaturated, 5- or 6-membered heterocyclic group formed by Rl, R2 and the adjacent nitrogen atoms may be pyrazolidinediyl, perhydropyridazinediyl, pyrazolinediyl, 1,2,3,4-tetrahydropyridazinediyl, 1,2,3,6-tetrahydropyridazinediyl or the like.
Suitable examples of the unsaturated 5- or 6-membered heterocyclic group formed by Rb, Rb and the adjacent nitrogen atoms may be 1,2,3,6-tetrahydro-pyridazinediyl, 1,2,3,4-tetrahydropyridazinediyl, 1,2-dihydropyridazinediyl, pyrazolinediyl or the like.
Suitable examples of the partially or fully saturated 5- or 6-membered heterocyclic group formed by Rl, R2 and the adjacent nitrogen atoms may be 1,2,3,6-tetrahydropyridazinediyl, perhydropyridazinediyl, pyrazolidinediyl~ or the like.
Suitable examples of the 1,2-diazaspiralkane-1,2-diyl group formed by Rl, R2 and the adjacent nitrogen atoms may be l,~-diazaspiro[2,5]octane-1,2-diyl, 1,2-diazaspiro[2,6]nonane-1,2-diyl, 1,2-diazaspiro[4,5]-decane-1,2-diyl or the like.

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~he aryl group for R may be substituted with substituent(s) sel~cted from the aforementioned lower alkyl; halogen [e.g. fluorine" chlorine, bromine and iodine]; lower alkoxy [e.g. metho~y, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, etc.]; lower al~ylamino [e.g. methylamino, ethylamino, propylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dihexylamino, etc.]; halo(lower)alkyl [e.g.
chloromethyl, fluoromethyl, bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl,

2-fluoroe~hyl, etc.]; hydroxyi lower alkanoyl [e.g.
formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, hexanoyl, etc.]; esterified carbo~y such as substituted or unsubstituted lower alkoxy-carbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, 2-iodoeth ~ carbonyl, 2,2,2-trichloroethoxycarbonyl, etc.], substituted or unsubstituted aryloxycarhonyl [e.g.
phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphtyloxy-carbonyl, etc.], substituted or unsubstituted ar(lower)-alkoxycarbonyl [e.g. benzyloxycarbonyl, phenethyloxy-carbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxy-carbonyl, etc.]; and carboxy.
Suitable examples of the aryl group for R4 having such substituent(s) may be lower alkyl substituted aryl [e.g. o~tolyl, m-tolyl, p-tolyl, etc.], halogenated aryl [e.g. 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 4-fluoronaphthalen-l-yl, etc.], lower alkoxy substituted aryl [e.g.
2-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-hexyloxyphenyl, 5-methoxynaphthalen-1-yl, etc.], lower alkylamino substituted aryl [e.g. 4-methylamino-phenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 5-dimethylaminonaphthalen-1-yl, etc.], halo(lower)alkyl subs~ituted aryl [e.g. 4-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-trichloromethylphenyl, 4-trifluoromethylnaphthalen-1-yl, etc.], hydroxy substituted aryl [e.g. 4-hydroxyphenyl, 3-h~droxy-phenyl, 2-hydroxyphenyl, 2-hydroxynaphthalen-1-yl, etc.], lower alkanoyl substituted aryl [e.~. 4-formyl-phenyl, 4-acet~lphen~l, 2-propionylphenyl, etc.], esterified carboxy substituted aryl [e.g. 4-methoxy-10 carbonylphe~yl, Z-ethoxycarbonylphenyl, 4-phenoxycarbonyl-phenyl, 4-benzyloxycarbonylphenyl, etc.], carboxy substituted aryl [e.g. 4-carboxyphenyl, 3-carboxyphenyl, 2-carboxyphenyl, etc.], lower alkyl and halogen substituted aryl [e.g. 4-fluoro-2-methylphenyl, 15 2-fluoro-4-methylphenyl, 4-fluoro-2-ethylphenyl, 2,4-difluoro-6-methylphenyl, etc.], halogen and lower alkoxy substituted aryl [e.g. 3-chloro-2-metho~yphenyl, 4-fluoro-2-methoxyphenyl, 2-fluoro-4-ethoxyphenyl, 2,4-difluoro-6-methoxyphenyl, etc.] or the like.
Suitable examples of the esterified carboxy substituted aryl for Ra and the carboxy substituted aryl for ~ can be referred ~o those exemplified for R as mentioned above.
Suitable pharmaceutically acceptable salts of the 25 object compounds [I] are conventional non-toxic salts and include a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g.
30 trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzyl-ethylenediamine salt, etc.], an organic acid salt [e.g. formate, acetate, maleate, tartrate, methane-sulfonate, benzenesulfonate, toluenesulfonate, etc.], 35 an inorganic acid salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. arglnine salt, aspartic acid salt, glutamic acid salt, etc.], and the like.
In th:is respect, it is to be noted the compounds [Ia], [Ib], [Ic] [Id], [le] and [If] are included within the scope of the compound [I], and accordingly the suitable salts of these compounds [Ia], [Ib], [Ic], [Id], [Ie] and [If] are to be referred to those as exemplified for the object compound [I~ mentioned above.
The processes for preparing the object compounds [I]
and their salts are explained in detail in the following.

Process 1 The object compound [Ia] and its salt can be prepared by reacting a compound [II] or its salt with a compound [III] or its salt.
Suitable salts of the compounds [II] and ~III] may be the same as those exemplified for the compound [I].
This reaction is usually carried out in a solvent such as water, methanol, ethanol, dioxane, tetrahydrofuran, benzene, chloroform, methylene chloride or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

Process 2 The object compound [I] and its salt ca~ be prepared by reacting a compound [II] or its salt with a compound [IV] or its reactive derivative at the carboxy, dithiocarboxy, mercaptocarbonyl or hydroxy thiocarbonyl group or a salt thereof.
Suitable salts of the compound [II] may be an acid addition salt exemplified for the compound [I].

7~8~

Suitable reactive derivative at the carboxy~
dithiocarboxy, mercaptocarbon~l or hydroxy thiocarbonyl group of the compound ~IV] may include an ester, an acid halide, an acid anhydride and the like. The suitable examples of -ti~e reactive derivatives may be an acid halide [e.g O acid chloride, acid bromide, etc.]; a symmetrical acid anhydride; a mixed acid anhydride with an acid such as aliphatic carboxylic acid [e.g. acetic acid, pivalic acid, etc.], substituted phosphoric acid ~e~g. dialkylphosphoric acid, diphenylphosphoric acid, etc.];
an ester such as lower alkyl ester ~e.g. methyl ester, ethyl ester, propyl ester, hexyl ester, etc.], substituted or unsubstituted ar~lower)alkyl ester [e.g.
benzyl ester, benzhydryl ester, p-chlorobenzyl ester, etc.], substituted or unsubstltuted aryl ester ~e g.
phenyl ester, tolyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, naphthyl ester, etc.], or an ester with N,N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxyphthalimide or l-hydroxy-6-chloro-lH-benzotriazole, or the like. These reactive derivatives can be optionally selected according to the kind of the compound [IV] to be used.
Suitable salts of the compound [I'J] and its reactive derivative may be the same as those exemplified for the compound [I].
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate~ N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. Among these solvents, hydrophilic solvents may be used in a mixture with water.
When the compound ~IV] is used in a free acid form or its salt form in the reaction, the reaction is ~7~

preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, thionyl chloride, oxalyl chloride, lower alkoxycarbonyl halide [e.g. ethyl chloroformate, isobutyl chloroformate, etc.], l-(p-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole, or the like. The reaction is also preferably carried out in the presence of a conventional base such as triethylamine, pyridine, sodium hydroxide or the like.
The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.

Proces_ 3 The object compound [I] and its salt can be prepared by reacting a compound [V] or its reactive deriva~ive at the carboxy,dithiocarboxy, mercaptocarbonyl or hydroxy thiocarbonyl group or a salt thereof with a compound [VI]
or its salt.
Suitable reactive derivatives at the carboxy~
dithiocarboxy, mercaptocarbonyl or hydroxy thiocarbonyl group of the compound [V] and suitable salts of the compound [V] and its reactive derivative may be the same as those exemplified for the compound [IV] in the above Process 2.
Suitable salts of the compound [VI] may be the same as those exemplified for the compound [I].
This reaction can be carried out substantially in the same manner as Process 2, and therefore the reaction made and reaction conditions [e.g. solvent, condensing agent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 2.

8~'~

Process 4 __.
The objec~ compound [Ib] and its salt can be prepared by reducing a compound [VII] or its salt.
The reaction can be carried out in a conventional manner, namely, c~emical reduction or catalytic reduction.
Suitable reducing agents to be used in chemical reduction are a metal hydride compound such as aluminum hydride compound [e.g. lithium aluminum hydride, sodium aluminum hydride, aluminum hydride, lithium trimethoxy-aluminum hydride, lithium tri-t-butoxyaluminum hydride, etc.], borohydride compound ~e.g. sodium borohydride, lithium borohydride, sodium cyanoborohydride, tetramethylammonium borohydride, borane, diborane, etc.]
and the like~
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst [e.g.
platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalyst [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.J, nickel catalyst [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalyst ~e.g. reduced cobalt, Raney cobalt, etc.], iron catalyst [e.g. reduced iron, Raney iron, etc.], copper catalyst [e.g. reduced copper, Raney copper, Ullman copper, etc ] or the like.
The reaction of this process is usually carried out in a solvent such as water, alcohol [e.y. methanol, ethanol, propanoyl, etc.], acetic acid, diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.
~he reaction i preferably carried out under some-what milder conditions such as under cooling to warming.
In this process, the pyridinio moiety of the compound [VII] is reduced to-piperidino, 1,4-dihydropyridin-1-yl, 1,2-dihydropyridin-1-yl or 1,2,3,6-tetrahydropyridin-1-yl ~'7~8;~

gxoup accordiny to the reducing method and ~he reagent to be used in this process.

Process 5 The object compound [Id] and its salt can be prepared by reducing a compound [Ic] or its salt.
This reaction can be carried out substantially in the sa~e manner as Process 4, and therefore the reaction mode and reaction conditions [e.g. reduction method, reducing agent, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 4.

Process 6 The object compound [If] and its salt can be prepared by subjecting a compound [Ie] or its salt to de-esterification reaction.
The reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g.
magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4,3,0]-non-5-ene, 1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]undec-7-ene, or the like. Suitable acid may include an organic acid ~e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
hydrochloric acid, hydrobromic acid, sulfuric acid, etc.].
The elimination using Lewis acid such as trihaloacetic ~L~ 7~8~

acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trappin~ agents [e.g. anisole, phenol, etc.].
The reaction is ~sually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], Methylene chloride, tetrahydrofuran, a mixture thereof or any o her solvent which does not adversely influence the reactio~. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The reduction can be applied preferably for elimination of the ester moiety such as 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl~ or the like. The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].
Suitable catalysts to be used in catalytic reduction may be the same catalysts as exemplified in Process 4.
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.
Additionally, in case that the abovementioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the abovementioned solvent, and other conventional solvent such as diethyl ether, dio~ane, tetrahydrofuran, etc., or a mixture thereof.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.

The ob~ect compounds [I] obtained by the above processes are isolated and purified by a conventional manner such as recrystallization, reprecipitation, column chromatography or the like.
Among the starting compounds [IV], [V] and [VII~, new compounds can be prepared by the methods oE
Preparations mentioned later and any process known in the art for preparing structurally analogous compounds thereto.
It is to be noted that each of the object compound [I] and the starting compounds [II] to [VII] may include one or more stereoisomers due to asymmetric carbon atoms in the molecule, and all of such isomers of the compounds [I] to [VII] are included within the scope of this invention.
The new semicarbazide derivatives [I] and pharma-ceutically acceptable salt thereof possess anti-inflammatory and analgesic activities, and are useful for a therapeutic treatment of inflam~.. ation and various pains [e.g. headache, toothache, menorrhalgia, etc~].
For therapeutic purpose, the compounds according to the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically accepta~le carried such as an organic or inorganic solid or liquid excipient suitable for oral or parenteral administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, solution, suspension, emulsion, or the like. If desired, ~7~

there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
While the dosage of the c:ompounds [I] will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, l mg, 10 mg, 50 mg, lO0 mg, 250 mg, 500 mg and lO00 mg of the compounds [I] may be effective for treating inflammation and various pains. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.

In order to illustrate the usefulness of the object compounds [I], the pharmacological test data of the representative compound [I] are shown in the following.

[A] ANTIINFLAMMATORY ACTIVITY:
(l) Carrageenin foot edema :
(1) Test Method :
Five male Sprague-Dawley rats weighing about 200 g were used per group.
Paw edama was induced by subplantar injection of 1%
carrageenin (0.1 ml/rat) into the right hind paw.
The test drug was suspended in 0.5~ methylcellulose and administered orally 60 minutes before phlogogen.
Paw volume was measured with plethysmometer (Ugo Bazil Co., Ltd.) by water displacement immersing the paw to the lateral malleolus. The difference of paw volume before and 3 hours after the phlogogen was designated as edema volume.
The data were analyzed statistically by student's t-test.

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(ii) Test Results :

Test compound Inhibition (Q ) (E~ample No.) (Dose : 32 mg/kg) _~
Example l 54.7 Example 7 78.8 Ex~nple 26 45.0 Example 27 39.0 Example 36 35.5 (2) Arthus foot edema :
(i) Test Method :
Five male Sprague-Dawley rate weighing about 200 g were used per group.
Paw edema was induced by intravenous injection of egg albumin (0.5 mg/rat) and subplantar injection of anti egg albumin antiserum (0.1 ml/rat) in Arthus type foot edema. The test drug was suspended in methylcellulose and administered orally 60 min. before phlogogen.
Paw volume was measured with plethysmometer (Ugo Bazil Co., Ltd.) by water displacement immersing the paw to the lateral malleolus. The difference of paw volume before and 3 hours after the phlogogen was designated as edema volume. The data were analyzed statistically by student's t-test.

(ii) Test Result :
_ .
Test Compound ~nhibition (%) (Example No.) (Dose : lO0 mg/kg) _ _ _ Example l 33.3 7~

~ 19 --[B] ANALGESIC ACTIVITY:
(1) Acetic acid induced writhing :
(i) Test Method Ten male ddY strain mice were used per group.
To estimate the frequency of writhing syndrome, the animals were observed from 3 to 13 minutes after an intraperitoneal injection of 0.2 ml/10 g of 0.6% acetic acid. The drugs were given orally 60 minutes before ace~ic acid. The frequency of writhing syndrome in the treated animals was compared with that in the non-treated control animals~

~ii) Test Results :
. _ Test compound Inhibition (~) (Example No. ) (Dose : 32 mg/kg) , _ Example 1 72.3 Example 7 78.8 Example 36 66.7 As being apparent from the above test results, the object compound [I] of the present invention are useful as antiinflammatory and analgesic agents.

~7~

The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.

Preparatlon 1 To a soll~tion of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (2.024 g) in methylene chloride (60 ml) was added a solution of phenyl chloroformate ~1.566 g) in methy~ene chloride t40 ml) and the mixture wa~ stirred for 4 hours at 5c.
~vaporation of the solvent gave a residue, which was extracted with ethyl acetate t150 ml). The extract was washed with water and dried ov~r magnesium sulfate.
The solvenc was evaporated in vacuo to give N (phenoxy-carbonylami~lo)-1,2,3,6-tetrahydropyridine (2.01 g), which was recrystalli~ed from diisopropyl ether to give the desired compound (0.732 g) as colorless needles.
mp: 124-125.5*C.
! IR (Nujol) : 3230, 1720, 1600, 1540 cm 1 NMR tCDC13, /S): 2.30 (2H~ m)~ 3.06 (Z~, t, .J=6HZ),

3.47 (2~ m), 5.69 (2H~ m)~ 6,33 (lE~ s), 7.10-7,47 ~5H~ m) Analysis: Calcd, ~or C12H14N22 Calcd. : C 66.04, H 6.47, N 12.84 ~ound : C 66.28, H 6.44, N 13.08 Preparation 2 N-(Phenoxycarbonyl)-2~fluoroaniline (3.76 g) was obtained according to a similar manner to that of Preparation 1 from 2-fluoroaniline (2~22 g) and phenyl chloroformate (3.13 g).
IR (Nujo~ ~ 3310~ 1720, 1530 cm 1 NMR (~DC13, ~) : 6.9-7.60 (9H, m), 8.20 (lH, br.s) *T~adernark 35~

. .
.

&~

Preparation 3

4-(Phenoxycarbonylamino)-N,N-dimethylaniline (9.06 g) was obtained according to a similar manner to that of Preparation 1 ~rom 4-amino-N,N-dimethylaniline (5.45 g) and phenyl chloroformate (7.52 g).
mp : 163.5-~64.5C
IR (Nujol) : 3340, 2940, 2855, 1720 cm Preparation 4 A mixture of N-aminopyridinium iodide (0.67 g), phenylisocyanate (0.39 g) and triethylamine (0.34 g) in dioxane (12 ml) was stirred for 3 hours under ice-bath cooling. The reaction mixture was diluted with water (12 ml), concentrated to a volume of ca. 5 ml, and then diluted with water. The precipitates were filtered off and the filtrate Was evaporated to dryness to give N-(phenylcarbamoylimino)pyridinium ylide, which was used without further purification for the next reaction, Preparation 5 To a stirred solution of N-aminopyridinium iodide (4.44 g) and triethylamine (2.02 g) in dry dioxane (60 ml) was added a solution of 4-fluorophenyl isocyanate (3.02 g) in dry dioxane (20 ml) under ice-bath cooling.
After stirring for one hour, the reaction mixture was evaporated to dryness. The residue was washed with water and dried to give N-[~(4-fluorophenyl)carbamoyl]-imino]pyridinium ylide (4.24 g). mp : 207-209C
IR (Nujol): 3250, 3200, 3100, 1630, 1620 cm 1 NMR (DMSO-d6, ~): 6.78-7.93 (7H, m), 8.28 (lH, s), 8.88-9.05 (2H, m) Preparation 6 A mixture of N-aminopyridinium iodide (1.11 g), triethylamine (0.50 g) and 4-fluoro-N-phenoxycarbonylaniline (l.i5 g) in tetrachloroethylene (40 ml) was stirred under reflux for 5 hours.
After evaporation of the solvent, the residue was washed with diisopropyl ether, triturated with diethyl ether, washed with water and dried to give N~[[(4-fluoro-phenyl)carbamoyl]imino]pyridinium ylide (0.54 g).
IR (Nujol~ : 3250, 3200, 3100, 1630, 1620, 159G cm 1 _~
N-[[(4-Fluorophenyl)carbamoyl]imino]pyridinium ylide (0.93 g) was obtained according to a similar manner to that of Preparation 6 from phenoxycarbonyl-iminopyridinium ylide (2.14 g) and 4-fluoroaniline (1.11 g~.
IR (Nujol) : 3250, 3200, 3100, 1630 1620 cm NMR (DM50-d6, ~ : 6.78-7.93 (7H, m), 8.28 (lH, s), 8.88-9.05 (2H, m) Example 1 N-Amino-1,2,3,6-tetrahydropyridine hydrochloride (3.42 g) was dissolved in a mixture of dioxane (30 ml) and water (20 ml). The solution was adjusted tc pH 7 5 with lN-aqueous sodium hydroxide and to the resultant mixture was added a solution of 4-fluorophenylisocyanate (0.548 g) in dioxane (5 ml). Then, the mixture was kept to pH 7.5 and stirred for Z hours at 5C. After evaporation of organic solvent, the crystalline product was collected by filtration and recrystallized from diisopropyl ether to give white needles ~f N-[[(4-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (0.73 g). mp : 156-157C
Mass : m/e = 235 (M ) IR (Nujol) : 3380, 3190, 3100, 1680, 1660 cm 1 NMR (CDC13, ~) : 2.31 (2H, m), 2.92 (2~, t, J=7Hz), 5.78 (2H, m), 6.87-7.48 (4H, m) Analysis : Calcd. for C12H14FN30 Calcd. : C 61.26, H 6.00, N 17.84 Found : C 61.37, H 6.06, N 18.04 Example 2 N-[[(4-Fluorophenyl)carbamoyl]amino~-4-phenyl-1,2,3,6-tetrahydropyridine (l.Oi g) was obtained according to a similar manner to that of Example 1 from N-amino-4-phenyl-1,2,3,6-tetrahydro-pyridine hydrochloride (1.16 g) and 4~fluorophenyl-isocyanate (0.91 g). mp : 200.5-212C
Mass : m/e = 311 (M+) IR (Nujol) : 3340~ 3160, 3070, 1670, 1540 cm 1 NMR (DMSO-d6, ~) : 2.S-3.2 (4H, m), 3.3-3.7 (2H, m), 6.0-603 (lH, m), 6.9-7.8 (lOH, m), 8~63 (lH, s) Analysis : Calcd. for C18H18FN30 Calcd~ : C 69.44, H 5.83, N 13.50 Found : C 69.43, H 5.90, N 13.49 ~ 11. ?r j~

Example 3 1,1-Diisopropyl-4-~4-fluorophenyl)semicarbazide (0.38 g) was obtained according to a similar manner to tna~ of Example 1 from l,l-diisopropyl-hydrazine hydrochlo~ide (l.So g) and 4-fluorophenyl-isocyanate (1.65 g). mp : 126.5-128C
Mass : m/e = 253 (~+) IR (Nujol) : 3320, 3080, 1680, 1500 1540 cm 1 NMR (CDC13 , 0 ): 1 . 03 ( 6E~ , d , J=6HZ ), 1 . 13 ( 6H , d , 0 J=6Hz), 2.9-3.4 (2H, m), 5.65 (lH, br.s), 608-7.6 (4H, m), 8.00 (lH, br.s) Analysis o Calcd. for C13H20FN3O
Calcd. : C 61.64, H 7.96, N 16.~9 Found : C 61.44, H 7.86, N 16.43 ~ .
l-Benzyl-4-(4-fluorophenyl)semicarbazide (1.55 g) was obtained according to a similar manner to that of Example 1 from benzylhydrazine dihydrochloride (1.95 g) and 4-fluorophenylisocyanate (1.33 g). mp : 102~C
IR (Nujol) : 3260, 1640 cm 1 NMR (CDC13, ~) : 3.57 (2H, s), 4.75 (2H, s), 7.00 (2H, dd, J=6, 6Hz), 7.35 (5H, s), 7.49 (2H, m), 8.66 (lH, s) Analysis : Calcd. for C14II14FN3O
Calcd. : C 64.85, H 5.44, N 16.21 ~ound : C 64.53, H 5.70, N 15.91 Example 5 ~0 1,1-Dially-4-(4 fluorophenyl)semicarbazide (1.16 g) was obtained according to a sLmilar manner to ~hat of Example 1 from l,l-diallylhydrazine hydrochloride (1.85 g) and 4-fluorophenylisocyanate (1.37 g).
Mass : m/e = 250 (M ~ 1) ~5 IR (Film) : 3350, 3225, 3080, 1685 cm N~R (CDC13, ~) : 3038 (4H, d, J=6Hz),

5.10-5.40 ~4H, m), 5.80-6.30 (3H, m),

6.85 7.40 (4H, m), 8.00 (lH, 5) Example_6 1,1-Diphenyl-4-(4-fluorophenyl)semicarbazide (1.88 g) was obtained according to a similar manner to that of Example 1 ~r~m 1,l-diphenyl-hydrazine (1.84 g) and 4-fluorophenylisocyanate ~1.65 g).
mp : 214-214.5C
Mass: m/e = 3Zl ~
IR (Nuj~ 3280, 1640, 1600, 158~ cm 1 N~ ~DMSO~d6~ 6.9~-7.68 (14H, m), 8.93 (lH, s), 9.01 (1~, s~
Analysis ~ Calcd. for C~gH16FN30 Calcd. . C 71.02, X 5.02, N 13.08 Found : C 70.8S, H S.35, N 12.89 Ex~m ~e 7 To a olution of N-amlno-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (1.012 g) in dry methylene chloride (40 ml) was added a solution of 3-fluorophenyl isocyanate (1.37 g) in dry methylene chloride under ice-bath cooling. After stirring for one hour, the reaction mixture w s e~aporated to dryness.
The residue w s extracted with ethyl acetate (100 ml)~
~he extract was washea with water, evaposated to ~ es~
a~d re:ystallized frcm ethyl acetAte to give N-t [ (3-fluorophenyl) carbamoyl] ami~o] -1, 2, 3, 6-tetrahydropyridine (1~ 43 g) ~ ~Itp 136 n~i~l38 ~5 C
IR (Nujol~ : 3280, 3200, 3100, 1685 ~ 1 NMæ (CDC13, ~) : 2~33 (2~, m), 2.98 (2~, m), 3.37 (2E, m), 5.71 ~2~, m), 6.37 (lH, s), 6.57-7.60 (4~, m)~ 8.28 (1~, s) Analysis: Calcd. for C12H14FN3O
~5 Calcd.~ C 61.26, ~ 6.00, N 17.86 Found: C 61.44, H 5.83, N 17.91 - 2 6 - 1~76~i3;~

N- [ r ( 4-Chlorophenyl ) ca~l~amoyl ] amino ] -l, 2, 3, 6-tetrahydropyridine (l. 32 g) was obtained according to a slmilar manner to that o~ Exa~lple 7 from N-amino--1, 2, 3, 6 -tetrahydropyridine hydrochloride ( l . i 46 g ) a~d 4-chlorophenyl isocyaslate (l. 536 g) .
mp: 165 ~ 5-167 . 5C
IR (Nujol) : 3330 ~ 3170 ~ 3100 ~ 1685 cm ~MR (CDC13, ~) . 2.35 (2~, m), 2.98 (2~, m), 3.37 (2~, m)l 5.73 (2~, m), 6.25 (l~t 8),

7.22 t2H. d, J-8~z), 7.48 (2~, d, J=8 ~.23 (1~, s~
A~alysiso calcd. for C12~14C1~30 Cal~d.: C 57.26, ~ 5.61, ~ 16.69 Found : C ~7~15, ~ 5.87, ~ 16.78 Example 9 N-[t~3-Chlorophenyl)carb~moyl]aminol-1,2,3,6-te~rahydropyridine (1.52 g) was o~ained accordi~g to a similar manner to that of Example 7 from N-amino-1,2,3,6-tetrahydropyridine hydrochloride (l.346 g) arld 3-chlorophenyl isocyanate (1.536 g).
mp: 145.5-147C
IR (Nujol) : 3340, 3190, 309n, 1680 cm 1 ~IR (CDC13 , ~) : 2. 38 ~2~I, m), 3 . 02 (2~1, m), 3.40 (2~ m) ~ 5.73 (2~I~ m), 6.48 6.93-7.30 ~4EI, m), 8.45 (l}I~ 3) Analysis: calca. for Cl2~l4Cl~3~
Calcd.~ C 57.26, H 5.61, N 16~,69 3~ Fo~d: C 57.39, ~I 5.75, N 16~,67 Examl~le 1 0 N- ~ [ (2-Methoxy-5 chlorophenyl) ~æbamoyl] aIs~no] -1, 2, 3, 6 -tetrahydropyridine ( 1. 3 3 g ) was obtained according 3~ to a s:L~ Ll?r manner to that of ExamplP 7 from ~i2'7~

N-amino-l~Z~3,6~tetrahydropyridine hydr~ch~oride (1~346 g) and 2-methoxy-5~chlorophenyl isocy~late (1.842 g).
m 153 5-154 5C
P~ . .
IR (Nujol) : ~875, 3300, 3:200, 3100, 1680 cm 1 NMR (CDC13, ~) : Z.35 ~2H, m), 2.98 (2~, m), 3.37 ~2~, m), 3.83 (3H, s), 5~73 (2H, m), 5~9B (1~, s), 6.6~7.27 (2H, m), 8.3 (1~, d, - J=3~z), 8.78 (lH, s) Analysis- calcdO for C13~1~ClN3O
Calcd.: C 55.42, ~ 5.72, N 14.91 Found : C 55.21, H S.74, N 14.81 Ex2m~1e 11 N-[~(4~Methoxyphenyl)car~moyll2mlno~-1,2,3,6-tetrahydropyridine (1.25 g) was obtained acoording to a si~il~r ma~ner to that of Example 7 from N-amino-1,2,3,6-tetrahydropyrldine hydrochloride (1O346 g) and 4-methoxyphenyl isoc~anate (1.49 g).
mp: 146-147C
IR (Nujol) : 3300, 3200, 3180, 3100, 1680 cm 1 NMR (CDC13, ~) : 2.33 (2~, m), 2.98 (2~, m), 3.37 (2H, m), 3.95 (3~, s), 5.73 (2~, m) 9 ~.93 (lH, s)~ 6.83 (2H, d, J=8Hz), 7.83 (2H, d, Jc8~z), 8.06 (lH, s) A~alysis: calcd. for C13H17~3O~
Calcd~: C 63.14, ~ 6.93, N 16.99 Fou~d : C 63.06, ~ 6.72, N 17.10 Example 12 ~ (2-Methoxyphe~yl)carhamovl]~ino]-1,2,3,6-tetrahvdropyridine (1.25 g) was obtained according to a similar manner to that of Example 7 from N-Y~ino-1,2,3~6Dtetrahydrop ridine hydrochloride ~1.346 g) and 2 methoxyphenyl isocyanate (1.491 g).

- 28 - -~ ~7l~8 mp: 137-139C
IR (Nujol) : 3330, 3200, 3:L00, 1580 cm 1 NMR (CDC13, ~) ~ 2.33 (2~, m), 2.97 (2~ m), 3.37 (2H, m), 3.83 (3H,, s), ~.7C (2~r m) r 6~02 (lH, s), 6.87 (3~, m), 8.22 (1~, m),

8.75 (1~
Analysis: Calcd. for C13H17N3O2 Calcd.: C 63.14~ ~ 6.93, N 16.99 Fou~d : C 63.25, ~ 6.91, N 16.99 1~

N [(p-Tolylcarb2moyl)aminol-1,2,3,6-tetrahydro~
pyridine (1.73 g) was obtained according to a similar mann~r to that of Example 7 ~rom N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and 4-methylphenyl isocyanate (1.323 g).
mp: 179~180C
IR t~ujol) : 3350, 3170, 3050, 16~ cm 1 MMR (CDC13, ~) : 2.28 (3~, s), 2.28 (2~, m~, 2.63 (2~, t, J-7~z), 3.35 (2~, m), ~.70 (2~, m), 5.95 (lH, s), 7.07 (2~, d, JS8HZ, 7.37 (2~, d, J=8~z), 8.08 (1~ s) Analysis : Calcd. for C13~17N3O
Calcdr: C 67.51~ ~ 7.41, N 1~.17 Found : C 67.8~, ~ 7.58, N 18.12 Example 14 N~ 4~ifluoro~ethylphenyl)carb~moyl]ami~o~-1,2,3,6-tatrahydropyridine (1.9 g) w~s obtained according to a similar manner to that of Exa~ple 7 from N-asnino-l, 2, 3, 6-tetrahydropyridine hydrocAloride (1.346 g) and 4-trifluoromethylph~nyl isocyanate (1. 871 5) .
mp: 159~,5 - 161C
IR (Nujol) : 3340 9 3200, 3100, 1690 t~

NMR (CDC13, ~) : 2q33 (2~, m), 2.97 (2E, t, J=7~z), 3.37 (2~, m), $.70 (2~, m), ~.25 (l~f s), 7.40~7.72 (4~, m), 8.20 (lH, s) Analysis: Calcd. for C13~14~3N3O
Calcd.: C 54.74, ~ 4.95, N 14.73 Found : C SS~18, H 5.05, N 14.79 N~ Naphthylcarbamoyl)amino~-1,2,3,6-tetrahydropyridine t~.S3 g) W~5 obtai~ed ac~ording to a similar ma~ner to tha~ of Example 7 from N-amino-1,2,3,6-tetrahydropyridine hydrochl~rid~ (1.346 g~ and l-naphthyl isocya~ate (1.692 g)O
mp: 181.5 - 183~5C
lS IR (Nujol) : 3350~ 3175, 3075, 1675 ~m 1 ~MR (CDC13, ~) : 2.40,(2~, m), 3.08 (2~, m), 3.4~ (2~, ~), 5.93 (2H, m), ~.28 (1~, 5), 7.33-8.20 (7~, m) t 8.87 (1~, s) Analysis: Calcd. for ~ 6~17~3 Calcd.: C 71.89, ~ 6.41, N 15.72 Found : C 71.98, ~ 6.47, N 15.65 Exam~le 16 . ~ ~ .
N-[~(4-Fluorophenyl)c rbamoyl]amino~morpholine 2~ 04 g) was obtained according to a simil~r manner t~ that of Example 7 from N-aminomorp~oline (1.021 g) and 4-fluorophenyl isocyanate (1.645 g).
mp: 184 - 185C
Mass: 239 ~M+) IR (Nujol) : 3340, 3200, 3100, 1685 cm 1 NMR (CD3OD, ~) : 2.98 ~4~, t, J26~z), 3.80 (4~, t, J~6~z), 6.8~-7.40 (4~, m), ~nalysis: Calcd. for C~ 4FN~O
Calcd.: C 5~.22, ~ 5.90, N 17.56 Found : C ~5.28, ~ 5.92, N 17.56 i2~3 Ex~m le 17 1-[(4-Fluorophenyl)carbamoyl]-1,2,3,6-tetrahydro-pyridazine (2.43 g) was obtai~ed ac~ordi~g to a 6im~1~r ma~ner to that o Example 7 $rom 1 f 2,3,6-tetrahydro~
pyridazine (1.177 g) and 4-~luorophenyl isocy~nate tl.918 g).
mp: 100-- 101C
IR tNujol) : 3330, 3250, 1670, 1650 cm NMR (CDC13, ~) . 3.40 (3H, m~, 4.07 ~2~, m), i0 5.87 (2H, m), 6~78-7.53 (4~, m), 8.45 (1~, s), Analysis : calcd. Xor C~ 2FN3O
ealcd. C 59.72, ~ 5.47, N 18.99 Found : C 59.95, ~ 5.76, N 19.05 ~
1-[(4-Fluorophenyl)carbamoyl]-1,2-diazaspiro~2,5]-octane (1.03 g) was obtained a~cording to a similar manner to that of Example 7 fr~m 1,2-diazaspiro~2,~]-octane (.1.122 g) ~nd 4-fluorophenyl isocyanate (1.37 g).
mp: 140 - 141C
~ass.: 249 (M~) IR (Nujol) : 3270, 3200, 1675 cm 1 NMR (CDC13, ~) : 1.72 (10~, m), 2.42 (lH, s), 6.88-7.62 (4E, m), 8.05 (lH, s), Ex2mple 19 ~o a sti~red solution of N-ami~o-4-~henyl-1,2,3,6-tetrahydropyridine ~ydrochloride (1.05 g) in a mixture of dioxane (10 ml) and water (5 ml) was added lN ~odi~m hydroxide solution (5 ml) under ice-oath cooling; and then a solution of 4-fluorophenyl isothiocya~ate ~1.15 g) Ln diox~ne (S ml) was added thereto. The mixture was - 31 - ~ ~7~

stirred for 5 hours under ice-b,ath cooling.
The reaction mixture was evapor,ated in ~acuo a~d ~he residue wa~ extracted several t.Lmes with ethyl acet ~e.
The com~ine~ ~xtract was washed with water, dried o~er magnesium sulfate and evaporatel~ in vacuo to give a crude product, which was recrystallized from ethyl acetate ~o sive N-~[(4-fluoroph~nyl)thiocar~amoyl]amino]-4-phenyl-1~2,3,6-tetrahydropyridine ~1.05 g~.
mp: 192.5 - 194.5C
IR ~Nujol) : 3300 ~ 31Z5, 1540 ~ 1~10 cm 1 ~I:R (CDC13~ 2072 (2~, m) ~ 3.17 t2H~ m~ ~
3.~8 (2~, m), 5~97 (2~, m), 6.B3-7.63 (4~, m), 7.27 (5~, s), 7.83 (1~, s), 9.12 (1~, s) Analysis: Calcd. for cl8~18FN3S
Calcd.: C 66.03, ~ 5.54, N 12.83 Found : C 66.79, E 5.63, N 12.65 Example 20 1,1-D~isopropyl-4-(4-fluorophenyl)thio~emicar~azide ~o (0.42 g) was obtained according to a si~ilar manner to that of Example 19 ~rom 1,l-diisopropylhydrazine hydrochloride (4.575 g) and 4-fluorophenyl isothiocyanate (2.757 g).
mp: 127.5 - 128.5C
Mass.: 259 (M+) IR (Nujol) : 3290, 3150, lS25, lS10 cm 1 NNR (CDC13, ~) : 1.08 ~6H,d, J=6Hz), 1.13 (6H, d, J=
6Hz), 3.03-3.47 (2H, m), 6.87-7063 (5H, m), 9.03 (lH, s) Analysis: Calcd. for C13~20FN35 Calcd.: C 57.96, ~ 7.48, N 15~60 Found : C 58.23, ~ 7~55, N 15.3Q

3~

Exam~le 21 N-Amino-1,2,3,6-tetrahydropyridine hydrochloride (3.768 g) was dissolved in a mixture of dioxane (60 ml) and water (30 ml). The solution was adjusted to pH 7 with lN-aqueous sodium hydroxide, and to the resultant S mixture was added a solution of 4-fluorophenyl iso~hlocyandte (3.984 g) in dioxane (20 ml). The mixture was kept to pH 7.5 and stirred for 6 hours at ambient temperature.
After evaporation of organic solvent, the residue was extracted with ethyl acetate (300 ml). The extract was washed with water and dried over magnesium sulfate.
The solvent was distilled off to give a residue (l.S g), which was subjected to column chromatography on silica gel (37 g) eluting with chloroform. The fractions containing the desired compound were combined and concentrated under reduced pressure. ~he residue was recrystallized from ethyl acetate to give white needles of N-[[(4-fluorophenyl)thiocar~amoyl]amino]-1,2,3,6-tetrahydropyridine ~0.779 g). mp : 163-164~5C
Mass : m/e = 251 (M ) IR (Nujol) : 3260, 2930, 1540, 1505, 1460 cm NMR (DMSO-d~, ~) : 2.88 (2H, m), 5.72 (2H, m), 7.00-7.73 (4~, m), 9.26 (lH, s), 9.60 (lH, s) Analysis : Calcd. for C12H14N3FS
Calcd. : C 57.35, H 5.61,`N 16.72 Found : C ~7.17, H 5.92, N 16.53 Exzmple 22 1,1-Diallyl-4-(4-fluorophenyl)thiosemicarbazide (0.57 g) was obtained according to a similar manner to that of Example21 from l,l-diallyl-hydrazine hydrochloride (1.48 g) and 4-fluorophenyl lso_ thiocyanate (1.225 g). mp : 73-74 ~C
Mass : m/e = 265 (M ) 3~ IR (Nujol) : 3240, 3150, 1546, 1500, 1460 cm NMR (CDC13, ~) : 3~42 (4H, d, J=6Hz), 5.1-6.3 (6H, m), 6.9~7.3 (5H, m), 9.03 (lH, br. s) Analysis : Calcd. for C13H16FN3S
Calcd. : C 58.84, H 6.08, N 15.84 Found ; C 59cn2, H 6.30, N 15.74 Exa~nple 2 3 1,1-Diphenyl-4-(4-~luorophenyl)thiosemicarbazide (0.88 g) was obtained according to a similar manner to that of Example 21 from 1,l-diphenylhydrazine (1~84 g) and 4~fluorophenyl isothiocyanate (1.84 g).
mp : 199.5-200.5C
Mass : m/e =337 (M ) IR (Nujol) : 3340, 3000, 1586, 1524 cm 1 NMR (DMSO-d6, ~) : 7.0-7.6 (14H, m), 10.22 (lH, s), 10.67 (lH, s) Analysis : Calcd. for ClgH16FN3S
Calcd. : C 67.64, H 4.?8, N 12.45 Eound : C 67.88, H 5.09, N 12.13 E ample 24 The following compounds are obtained according to a similar manner to that of Example 1.
(1) N-[[(2-Fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 119-121C
IR (Nujol) : 3360, 3200, 3100, 1690, 1620, 1600 cm 1 (2) N-(Phenylcarbamoylamino)-1,2,3,6-tet-ahydro-pyridine.
mp : 157~159C
IR (Nujol) : 3340, 3190, 3100, 1680 cm (3) 1-[(4-Fluorophenyl)carbamoyl]hexahadro-pyridazin~

- 3~ -mp : 78.5-79.5C
IR (Nujol) : 3375, 3250, 1685, 1600 cm (4) N~-[[(4-Dimethylaminophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 179.5-180C
IR (Nujol) : 1680 cm ( 5 ) N--[ [ ( 4--Acetylphenyl ~ carbamoyl ] z~rnirlo ]--1, 2, 3, 6--tetrahydropyridine.
mp : 142.5-143C
IR (Nujol) : 1685, 1670 cm ( 6 ) N- ~ [ ( 2, 4 - Di f 1 uo rophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 136.5-137C
IR (Nujol): 1695 cm (7) N-[~(4-Methoxycarbonylphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 182.5-184C
IR (Nujol) : 1715, 1680 cm Example 25 A solution of 4-fluoro-N-phenoxycarbonylaniline (2.29 g), N-amino-1,2,3,6-tetrahydropyridine hydro-chloride (1.346 g) and triethylamine (1.02 g) in chloroform (25 ml) was refluxed for 20 hours. After evaporation of chloroform, the residue was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) using chloroform as an eluent to give N-~[(4-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetra-hydropyridine (1.05 g). mp : 156-157C.

Mass : m/e = 235 (~1 ) IR (Nujol~ : 3380, 3190, 3100, 1680, lG60 cm N~ (CDC13, ~ : 2~31 (2H, m), 2.92 (2H, t, J=7E~z), 5.78 (2H, m),. 6.87-7.48 (4H, m) S Analysis : Calccl. for Cl,~Hl~FN3O
Calcd. : C 61.26, H 6.00, N 17.84 Found : C 61.37, H 6.06, N 18.04 Example 26 .
N-~(2-Fluorophenyl)carbamoyl]amino]-1,2,3,6~
~etrahydropyridine (0.56 g) was obtained according to a sLmilar man~er to that of Example 25 from N-amino-1,2,3,6-tetrahydropyridine hydrochloride (2.34 g~ and 2-fluoro-N-phenoxycaxbonylaniline (2. 77 g) .
mp ^ 119 - 121C
IR (Nujol): 3360, 3200, 3100, 1690, 1620, 1600 cm 1 NMR (CDC13, ~) : 2.32 (2H, m), 2.98 (2H, m), 3.38 (2H, m), 5.71 (2H, m), 6.10 (lH, s), 6.94-7~20 (3H, m), 8.20-8.37 (lH, m), 8.53 (lH, s) Analysis : Calcd. for C12H14FN3O
Calcd. : C 61.26, H 6.00, N 17.86 Found : C 61.87, H 6.09, N 17.95 Example 2 7 N-[[(4-Dlmethylaminophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (1.98 g~ was obtained according to a similar manner to that of Example 25 from N-amino-l, 2,3, 6-tetrahydropyridine hydrochloride (2.02 g) and 4 (phenoxycarbonylamino)-N,N-dimethyl-aniline (2.56 g) .
mp : 179.5 - 180C
IR (Nujol): 1680 cm NMR (CDC13, ~): 2.26 (2H, m), 2~84 (6H, s), ~271~8~'~

2.70-3.13 (2H, m), 3.30 (2H, m), 5.66 (2H, m), 6.06 (1l~, s) Example 28 N-[[(4-Acetylphenyl)carbamoyllamino]-1,2,3,6-tetrahydropyridine (1.72 g) was obtained according to a similar manner to that of Example 25 from N-amino-1,2,3,6-tetr~hydropyridine hydrochloride (1.94 g) and 4'-tphenoxycarbonyl~lino)acetophenone (3.06 g).
mp: 142.5-143C
IR (Nu jol) : 1685, 1670 cm Example 29 N-[[(2,4-Difluorophenyl)carbamoyl]aminol-~,2,3,6-tetrahydropyridine (1.14 g~ was obtained according to a similar manner to that of Example 25 from N-amino-1,2,3,6-tetrahydropyridine hydrochloride (2.22 g) and 2,4-difluoro-N-phenoxycarbonylaniline (2.74 g).
mp : 136.5-137C
IR (Nujol) : 1695 cm 1 NMR (CDC13, ~) : 2.06-2.50 (2H, m), 2.73-3.09 (2H, m), 3.15-3.64 (2H, m), 5.56-5.87 (2H, m), 5.90-6.23 (lH, m), 6.59-7.13 (2H, m), 7.88-8.48 (2H, m) Example 30 The following compounds are obtained according to a similar manner to that of Example 25.
(1) N-~[(4-Fluorophenyl)carbamoyl]amino]-4-phenyl-1,2,3,6-tetrahydropyridine.
mp : 200.5-212C
IR (Nujol) : 3340, 3160, 3070, 1670, 1540 cm (2) 1,1-Diisopropyl-4-(4-fluorophenyl)semicarbazide.
mp : 126.5-128C
IR (Nujol) : 3320, 3080, 1680, 1500-1540 cm ~7~

(3) 1-Benzyl-4-(4-fluorophenyl)semicarbazide.
mp : 102C
IR (Nujol) : 3260, 1640 cm (4) l,l-Diallyl-4-(4-fluorop~enyl)semicarba2ide.
IR (Film) : 3350, 3225, 3080, 1685 cm (5) 1,1-Diphenyl~4-(4-fluorophenyl)semicarbazide.
mp : 214-214.5C
IR (Nujol) : 3280, 1640, 1600, 1585 cm (6) N-[[(3-Fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 136.5-138.5~C
IR (Nujol) : 3280, 3200, 3100, 1685 cm (7) N-[[(4-Chlorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 165.5-167.5C
IR (Nujol) : 3330, 3170, 3100, 1685 cm (8) N-~[(3-Chlorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp 145.5-147C
IR (Nujol) : 3~40, 3190, 3090, 1680 cm

(9) N-[[(2-~lethoxy-5-chlorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 153.5-154.5C
IR (Nujol) : 3375, 3300, 3200, 3100, 1680 cm

(10) N-[[(4-Methoxyphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 146-147C
IR (Nujol) : 3300t 3200l 3180, 3100, 1680 cm

(11) N-[[(2-Methoxyphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 137-139C
IR (Nujol) : 3330, 3200, 3100, 1680 cm 1

(12) N-[(p-Tolylcarbamoyl)amino]-1,2,3,6-tetrahydro-pyridine.
mp : 179-180C
IR (Nujol) : 3350, 3170, 3050, 1675 cm ~ 13) N-[[(4-Trifluoromethylphenyl)carbamoyl]amino]-1,2,3,6~tetrahydropyridine~
mp . 159~5-161C
IR (Nujol) : 3340, 3200, 3100, 1690 cm (].4) N-[(l-Naphthylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine.
mp : 181.5-183.5C
IR (Nujol) : 3350, 3175, 3075, 1675 cm (15) N-[[(4-Fluorophenyl)carbamoyl]amino]morpholine.
mp : 184-185C
IR (Nujol) : 3340, 3200, 3100, 1685 cm (16) 1-[(4-Fluorophenyl)carbamoyl]-1,2,3,6-tetrahydropyridazine.
mp : 100 101C
IR (Nujol) : 3330, 3250, 1670, 1650 cm (17) 1-[(4-Fluorophenyl)carbamoyl]-1,2-diazaspiro-[2,5]octaneO
mp : 140-141C
~R (Nujol) : 3270, 3200, 1675 cm (18) N-(Phenylcarbamoylamino)-1,2,3,6-tetrahydro-pyridine~

~7~

mp : 157-159C
IR (Nujol) : 3340~ 3190, 3100, 1680 cm (19) 1-[(4-Fluorophenyl)carbamoyl]hexahydro-pyridazine.
mp : 78.5-79.5C
I~ (Nujol) : 3375, 3250, 1685, 1600 cm (20) N-[(N-Methyl-N-phenylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine.
mp 99-99.5C
IR (Nujol) : 3250, 2950, 2870, 1645 cm 1 (21) N-[[(4-Hydroxyphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 185.5-187C
IR (Nujol) : 3190, 1660 cm (22) N-[[(4-Methoxycarbonylphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 182.5-183C
IR (Nujol) : 1715, 1680 cm (23) N [[(4-Carboxyphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : >240C
IR (Nujol) : 1700 cm (24) N-[[(4-Fluorophenyl~thiocarbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 163-164.5C
IR (Nujol) : 3260, 2930, 1540, 1505, 1460 cm (25) 1,1-Diallyl-4-(4-fluorophenyl)thiosemicarbazide.
mp : 73-74C
IR (Nujol) : 3240, 3150, 1546, 1500, 1460 cm -- ~10 --(26~ Diphenyl-4- (4-fluorophenyl) thiosemicarb~Lzide .
mp : 199 . 5-200 ~ 5 C
IR (Nu~ol) : 3340 ~ 3000 ~ 1586 ~ 1524 cm (27) N-[[(4-Fluorop11enyl)thiocarbamoyl]amino]-4-phenyl-l.,2,3,6-tetrahydropyridine~
mp : 192.5-194.5C
IR (Nu~ol) 3300, 3125, 1540, 1510 cm (28) 1,1-Diisopropyl-4-(4~-fluorophenyl)-thiosemi-carbazide~
mp : 127.5-128.5C
IR (Nujol) . 3290, 3150, 1525, 1510 cm 1 Example 31 N-~[(4-Fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (0.70 g) was obtained according to a similar manner to that of Example 25 from N-(phenoxycarbonylamino)-1,2,3,6-tetrahydropyridine (1.09 g) and 4-fluoroaniline (0.555 g).
mp : 156-157C
Mass : m/e = 235 (~I ) IR (Nujol) : 3380, 3190, 3100, 1680, 1660 cm NMR (CDC13, ~) : 2.31 (2H, m), 2.92 (2H, t, J=7Hz), 5.78 (2H, m), 6.87-7.48 (4H~ m) Analysis : Calc~. for C12H14FN3O
Calcd. : C 61.26, H 6.00, N 17.84 Found : C 61.37, H 6.06, N 18~04 Example 32 N-[(N-Methyl-N-phenylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine (1.24 g) was obtained according to a similar manner to that of Example 25 from N-phenoxy-carbonylamino-1,2,3,6-tetrahydropyridine (2.18 g) and N~methylaniline (2.19 g). mp : 99-99.5C

IR (Nu jol) : 3250, 2950, 2870, 1645 cm 1 N~ (CDC13, ~) : 2.13 (2H, m), 2.86 (2H, t, J=6Hz), 3.16 (3H, s), 3.13-3.46 (2~, m), 5.23-5.76 (2H, m), 7.02-7.53 (5H, m) Example 33 ... . _ , N-[[(4~Hydroxyphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (1.04 g) was obtained according to a similar manner to that of Example 25 from N-phenoxy-carbonylamino-1,2,3,6-tetrahydropyridine (1.53 g) and 4-hydroxyaniline (1.09 g). mp : 185.5-187C
IR (Nujol) : 3190, 1660 cm 1 NMR (CD3OD, ~) : 2.10-2.58 (2H, m), 2.93 (2H, t, J=5.5Hz), 3.20-3.52 (2H, m), 5.59-5.86 (2H, m), 6.70 (2H, d, J=8Hz), 7.20 (2H, d, J=8Hz) Example 34 N-[~(4-Methoxycarbonylphenyl)carbamoyl]amino]-1,2,3,Ç-tetrahydropyridine (1.25 g) was obtained according to a similar manner to that of Example 25 from N-phenoxycarbonylamino-1,2,3,6-tetrahydropyridine (1.53 g) and methyl 4-aminobenzoate tl.51 g).
mp : 182.5-183C
IR (Nujol) : 1715, 1680 cm 1 NMR ~CDC13, ~) : 2.16 2.63 (2H, m), 2.76-3.23 (2H, m), 3.26-3.74 (2H, m), 3.87 (3H, s), 5.53-5.98 (2H, m), 6.04 (lH, s), 7.58 (2H, d, J=6Hz), 8.02 (2H~ d, J=6Hz), 8.44 (lH, s) Example 35 The following compounds are obtained according to a similar manner to that of Example 25.
(1) N-[[(4-Fluorophenyl)carbamoyl]amino]-4-phenyl-1,2,3,6-tetrahydropyridine.
mp : 200.5-212C
IR (Nujol) : 3340, 3160, 3070, 1670, 1540 cm ~L~7~

(2) 1,1-Diisopropyl-4-(4-fluorophenyl)semicarbazide.
mp : 12 6 . 5-12 8 C
IR (Nu jol) : 3320, 3080, 1680, 1500--1540 cm (3) 1-Benzyl--4-(4-fluorophenyl)semicarbazide.
mp : 102C
IR (Nu jol) : 3260, 1640 cm (4) 1,1-Dially-4-(4-~luorophenyl)semicarbazide.
IR (Film) : 3350, 3~25, 3080, 1685 cm (5~ Diphenyl-4-(4-fluorophenyl)semicarba~ide.
mp : 214-214.5C
IR (Nujol) : 3280, 1640, 1600, 1585 cm 1 (6) N-[~(3-Fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 136.5-138.5C
IR (Nujol) : 3280, 3200, 3100, 1685 cm (7) N-[[(4-Chlorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 165.5-167.5C
IR (Nujol) : 3330, 3170, 3100, 1685 cm (8) N-[[(3-Chlorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridire.
mp : 145.5-147C
IR (Nujol) : 3340, 3190, 3090, 1680 cm (9) N [[(2-Methoxy-5-chlorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp ~ 153.5-154.5C
IR (Nujol) : 3375, 3300, 3200, 3100~ 1680 cm ~7~

(10) N-[[(4-Methoxyphenyl)carbamoyl]amino]-1,2,3,6-tetxahydropyridine.
mp : 146-147C
IR (Nu~ol) : 3300~ 3200~ 3180, 3100, 1680 cm (11) N-[[(2-Methoxyphenyl~carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 137-139C
IR (Nujol) : 3330, 3200, 3100, 1680 cm (12) N-[(p-Tolylcarbamoyl)amino]-1,2,3,6-tetrahydro-pyridine.
mp : 179-180C
IR (Nujol) : 3350, 3170, 3050, 1675 cm

(13) N-[[(4-Trifluoromethylphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyrldine.
mp : 159.5-161C
IR (Nujol) : 3340, 3200, 3100, 1690 cm

(14) N-[(l-Naphthylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine.
mp : 181.5-183.5C
IR (Nujol) : 3350, 3175, 3075, 1675 cm

(15) N~[[(4-Fluorophenyl)carbamoyl]amino]morpholine.
mp : 184-185C
IR (Nujol~ : 3340, 3200, 3100, 1685 cm

(16) 1-[(4-Fluorophenyl)carbamoyl]-1,2,3,6-tetrahydropyridazine.
mp : 100-101C
IR (Nujol) : 3330, 3250, 1670, 1650 cm

(17) 1-[(4-Flllorophenyl)carbamoyl]-1,2-diazaspiro-[2,5]octane.
mp : 140-141C
IR (Nujol) : 3270, 3200, 1675 cm ~7~

(18) N-(Phenylcarbamoylam.ino)-1,2,3,5-tetrahydro-pyridine.
mp : 157-159C
IR (Nujol) : 3340, 3190, 3100, 1680 cm 1 s

(19) 1-[(4-Fluorophenyl)carbamoyl]hexahydro-pyridazine.
mp : 78.5-79.5C
IR (Nujol) : 3375, 3250, 1685, 1.600 cm

(20) N-[~(2-Fluorophenyl)carbamoyl]amino3-1,2,3~6-tetrahydropyridine.
mp : 119-121C
IR (Nujol) : 336Q, 3200, 3100, 1690, 1620, 1600 cm~l

(21) N-[[(4-DLmethylaminophenyl)carbamoyl]amino]-1,2~3,6-tetrahydropyridine.
mp : 179.5-180C
IR (Nujol~ : 1680 cm

(22) ~~[[(4-Acetylphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 142.5-143C
I~ (Nujol) : 1685, 1670 cm

(23) N-[[(2,4-Difluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 136.5-137C
IR (Nujol) : 1695 cm

(24) N-[[(4-Carboxyphenyl)carbamoyl~amino]-1,2,3,6-tetrahydropyridine.
mp : >240C
IR (Nujol) : 1700 cm _ ~5 _ ~25) N-[[(4-Fluorophenyl)thiocarbamoyl]amino]-11 2 r 3,6-tetrahydropyridine.
mp : 163-164.5C
IR (~ujol) : 3260, 2930, 1540, 1505, 1460 cm (26) 1,1-Diallyl-4-(4-fluorophenyl)thiosemicarbazide.
mp ~ 73-74C
IR (Nujol) : 3240, 3150, 154~, 1500, 1460 cm (27) 1,1-Diphenyl-4-(4-fluorophenyl)thiosemi-carbazide.
mp : 199.5-200.5C
IR (Nujol) : 3340, 3000, 1586, 1524 cm (28) N [[(4-Fluorophenyl)thiocarbamoyl]amino]-4-phenyl-1,2~3,6-tetrahydropyridine.
mp : 192.5-194.5C
IR (Nujol) : 3300, 3125, 1540, 1510 cm (29) 1,1-Diisopropyl-4-(4-fluorophenyl)-thiosemicarbazide.
mp : 127.5-128.5~C
IR (Nujol) : 3290, 3150, 1525, 1510 cm Example 36 To a solution of N-(phenylc~rbamoylimino)pyridinium ylide (0.64 g) in a mixture of ethanol (30 ml) and water (10 ml) was added sodium borohydride (0.20 g) at ambient temperature. After being stirred for 4 hours, the reaction mixture was acidified with lN hydrochloric acid, concentrated to a volume of ca. 15 ml. The crystalline precipitate was collected, washed with water and dried in vacuo. The crude product was dissolved in ethyl acetate and extracted with 10~
hydrochloric acid (20 ml)~ The extract was adjusted to 1~7~B~

pH 3 with aqueous sodium bicarbonate and extracted with ethyl acetate (30 ml). The organic layer was washed with aqueous sodium ~icarbonate (10 ml), dried over magnesium sulfate and evaporated to give N-(phenyl-S carbamoylamino)-1,2,3,6-tetrahydropyridine (0.28 g), whlch was recrystallized from ethyl acetate to afford colorless needles (0.15 g). mp : 157-159C
IR (Nujol) : 3340t 3190, 3100, 1680 cm NMR (CD3OD, ~) : 2.36 (2H, m), 2.96 (2H, t, J=5.5Hz), 5.73 (2H, m), 7.0-7.6 (5H, m~

Example 37 A suspension of N-[[(4-fluorophenyl)carbamoyl]-imino]pyridinium ylide (1.04 g) and sodium borohydride (2.55 g) in ethanol (100 ml) was stirred at ambient temperature for 16 hours. Excess of sodium borohydride was decomposed with water, and the resulting mixture was evaporated. The residue was extracted with chloroform (20 ml x 3). The combined organic extract was washed with water, dried over magnesium sulfate and evaporated to give crystalls. Recrystallization from diisopropyl ether gave N-[[(4-fluorophenyl)-carbamoyl]amino]-1,2,3,6-tetrahydrcpyridine (0.60 g).
mp : 156-157C
IR (Nujol) : 3340, 3GOO, 3100, 1680, 1605 cm NMR ~CDC13, ~) : 2.31 (2H, m), 2.92 (2H, t, J-7Hz), 5.78 (2H, m), 6.87-7.48 (4H, m) Example 3 8 The following compounds are obtained according to a similar manner to that of Example 36.
(1) N-[[(4-Fluorophenyl)carbamoyl]amino]-4-phenyl-1,2,3,6-tetrahydropyridine.
mp : 200.5-212C
IR (Nujol) : 3340, 3160, 3070, 1670, 1540 cm 1 (2) N-[[(3-Fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 136.5-138.5C
IR ~Nujol) : 3280, 32~0, 3100, 1685 cm (3) N-[[~4-Chlorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 165.5-167~5C
IR (Nujol) : 3330, 3170, 3100, 1685 cm 1 1~
(4) N-[[(3-Chlorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 145.5-147QC
IR (Nujol) : 3340, 3190, 3090, 1680 cm 1 (5) N-[[(2-Methoxy-5-chlorophenyl)carbamoyl]-amino~-1,2,3,6-tetrahydrop~rridine.
mp : 153.5-154.5C
IR (Nujol) : 3375, 3300, 3200, 3100, 1680 cm (6) N-[[(4-Methoxyphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 146-147C
IR (Nujol) : 3300, 3200, 3180, 3100, 1630 cm (7) N-[[(2-Methoxyphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 137-139C
IR (Nujol) : 3330, 3200, 3100, 1680 cm (8) N-[(p-Tolylcarbamoyl)amino3-1,2~3,6-tetrahydropyridine.
mp : 179-180C
IR (Nujol) : 3350, 3170, 3050, 1675 cm >~

_ a8 -(9) N-~[(4-Trilluoromethylphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 159.5-161C
IR (Nujol) : 3340, 3200, 3100, 1690 cm 1 (10) N-[(l-Naphthylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine.
mp : 181.5-183.5c IR (Nujol) : 3350, 3175, 3075, 1675 cm (11) N-[ L ( 2-Fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 119-121C
IR (Nujol) : 3360, 3200, 3100, 1690, 1620, 1600 cm 1 (12) N-[[(4-Dimethylaminophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 179.5-180C
IR (Nujol) : 1680 cm 1 (13) N-[[(2,4-Difluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : 136.5-137C
IR (Nujol) : 1695 cm (14) N-[(N-Methyl-N-phenylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine.
mp 99-99.5C
IR (Nu~ol) : 3250, 2950, 2870, 1645 cm (15) N-~[(4-Hydroxyphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp 185~5-187C
IR (N~ljol) : 3190, 1660 cm ~7~

(16) N-[[(4-M~thoxycarborlylphenyl)car~amoyl]-amino]-1,2~3,6-tetrahydropyricline.
mp : 182.5-183C
IR (Nujol) : 1715, 1680 cm (17) N-[~(4-Carboxyphenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine.
mp : ~240C
IR (Nujol) : 1700 cm (18) N~[[(4-Fluorophenyl)thiocarbamoyl]amino]~
1,2,3,6-tetrahydropyridine.
mp : 163-164.5C
IR (Nujol) : 3260, 2930, 1540, 1505, 1460 cm 1 (19) N-[[(4-Fluorophenyl)thiocarbamoyl]amlno]-4-phenyl-1,2,3,6-tetrahydropyridine~
mp : 192.5-194.5C
IR (Nujol) : 3300, 3125, 1540, 1510 cm Example 39 A solution of 1-[(4-fluorophenyl)carbamoyl]-1,2,3,6-tetrahydropyridazine (1.327 g) in acetic acid (40 ml) was hydrogenated under an atmospheric pressure of hydrogen over 10% palladium charcoal (400 mg).
After removal of the catalyst, the solvent was evaporated under reduced pressure to give an oil (0.8 g), which was subjected to column chromatography on silica gel (16 g) eluting with chloroform. The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give white needles of 1-[(4-fluorophenyl)carbamoyl]hexahydropyridazine (0.3 g).
mp : 78.5-79.5C
IR (Nujol) : 3375, 3250, 1685, 1600 cm ~ ~7~

~MR (CD30D, ~) : 1.80-20()0 (4H, m), 2.30 (2H, m), 3.73 ~2H, t, J=6Hz), 6.89-7.50 (4H, m) E~ample 40 -1~(4-Fluoropheny])carbamoyl]-:L,2,3,6-tetra-hydropyridaæine is obtained according to a similar manner to that of Example 39.
mp : 100-101C
IR (Nujol) : 3330, 3250, 1670, 1650 cm 1 Example 41 To a solution of N- C[~4-methoxycarbo~ylphenyl)-ca~bamoyl]amino]-1,2,3,6-tetrahydropyridine (1.21 g) in a mixture of methanol (30 ml) and chloroform (30 ml~
was added. lN sodium hydroxide (10 ml~ and the mixture was stirred at ambient temperature for 18 hours.
After evaporation of the solvent, the residue was extracted with chloroform (20 ml x 3). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gèl (40 g) ~luting with chloro~orm, to give N-[[(4-carboxyphenyl)-carbamoyl]amino]-1~2,3,6-tetrahydropyridine (0.65 g).
mp : >240C
IR (Nujol) : 1700 cm 1 NMR (D20 +NaOD, ~) : 2.12-2.49 ~2H, m), 2.94 (2H, t, J=5Hz), 3.16-3.44 (2H, m), 5.68-6.01 (2H, m), 7.41 (2H, d, J=8Hz), 7.87 (2H, d, J=8Hz)

Claims (12)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A compound of the formula:

wherein R1 is hydrogen, R2 is lower alkenyl or phenyl, R3 is lower alkenyl or phenyl, or R2 and R3 are taken together with the adjacent nitrogen atom to form tetra-hydropyridyl optionally substituted with phenyl; or R1 and R2 are taken together with the adjacent nitrogen atoms to form perhydro-pyridazinediyl, tetrahydropyridazinediyl or 1,2-diazaspiroalkane-1,2-diyl group, R3 is hydrogen;
R4 is phenyl or naphthyl, each of which may have substituent(s) selected from lower alkyl, halogen, lower alkylamino, halo (lower)alkyl, hydroxy, lower alkanoyl, esterified carboxy and carboxy, R5 is hydrogen or lower alkyl, and X is O or S, and pharmaceutically acceptable salts thereof.

2. A compound of claim 1, wherein R1 is hydrogen, and R2 and R3 are taken together with the adjacent nitrogen atom to form tetra-hydropyridyl optionally substituted with phenyl.

3. A compound of claim 2, wherein X is O.

4. A compound of claim 3, wherein R4 is phenyl optionally having substituent(s) selected from halogen and lower alkylamino.

5. A compound of claim 4, which is N-(phenylcarbamoylamino)-1,2,3,6-tetrahydropyridine.

6. A compound of claim 4, which is N-[[(2-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetra-hydropyridine.

7. A compound of claim 4, which is N-[[(3-f1uorophenyl)carbamoyl]amino]-1,2,3,6-tetra-hydropyridine.

8. A compound of claim 4, which is N-[[(4-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetra-hydropyridine.

9. A compound of claim 1, wherein R1 and R2 are taken together with the adjacent nitrogen atoms to form perhydropyridazinediyl, tetrahydropyrictazinediyl or 1,2-diazaspiroalkane-1,2-diyl group, and R3 is hydrogen.

10. A compound of claim 9, which is 1-[(4-fluorophenyl)carbamoyl]-1,2,3,6-tetrahydro-pyridazine.

11. A process for preparing a compound of the formula:

wherein R1 is hydrogen, R2 is lower alkenyl or phenyl, R3 is lower alkenyl or phenyl, or R2 and R3 are taken together with the adjacent nitrogen atom to form tetra-hydropyridyl optionally substituted with phenyl; or R1 and R2 are taken together with the adjacent nitrogen atoms to form perhydropyridazinediyl, tetrahydro-pyridazinediyl or 1,2-diazaspiroalkane-1,2-diyl group, R3 is hydrogen, R4 is phenyl or naphthyl, each of which may have substituent(s) selected from lower alkyl, halogen, lower alkylamino, halo(lower)alkyl, hydroxy, lower alkanoyl, esterified carboxy and carboxy, R5 is hydrogen or lower alkyl, and X is O or S, and pharmaceutically acceptable salts thereof, which comprises, a) reacting a compound of the formula:

or its salt with a compound of the formula:

or its salt to provide a compound of the formula:

or its pharmaceutically acceptable salt, R1, R2, R3, R4 and X in the above formulas; are each as defined above, b) reacting a compound of the formula:

or its salt with a compound of the formula:

or its reactive derivative or a salt thereof to provide a compound of the formula:

or its pharmaceutically acceptable salt, R1, R2, R3, R4, R5 and X in the above formulas are each as defined above, c) reacting a compound of the formula:

or its reactive derivative or a salt thereof with a compound of the formula:

or its salt to provide a compound of the formula:

or its pharmaceutically acceptable salt, R1, R2, R3, R4, R5 and X in the above formulas are each as defined above, d) reducing a compound of the formula:

or its salt to provide a compound of the formula:

or its pharmaceutically acceptable salt, in the above formulas, R4, R5 and X are each as defined above, Y is hydrogen or phenyl, and R? and R? are taken together with the adjacent nitrogen atom to form tetrahydropyridyl optionally substituted with phenyl, e) reducing a compound of the formula:

or its salt to provide a compound of the formula:

or its pharmaceutically acceptable salt, R3, R4, R5 and X in the above formulas are each as defined above, R? and R? are taken together with the adjacent nitrogen atoms to form tetrahydropyridazinediyl or dihydropyridazinediyl, and R? and R? are taken together with the adjacent nitrogen atoms to form tetrahydropyridazinediyl or perhydropyridazinediyl, or f) subjecting a compound of the formula:

or its salt to de-esterification reaction to provide a compound of the formula:

or its pharmaceutically acceptable salt, R1, R2, R3, R5 and X in the above formulas are each as defined above, R? is phenyl or naphthyl, each of which is substituted with esterified carboxy, and R? is phenyl or naphthyl, each of which is substituted with carboxy.

12. A pharmaceutical composition comprising a compound of claim 1, as the active ingredient, in association with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.