JPS6144864A - Semicarbazide derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial Application Field" The present invention relates to a novel semicarbazide derivative useful as an anti-inflammatory and analgesic drug, and is used in the medical field.

[Prior art]

Certain N-position J negative 1. with anti-inflammatory and analgesic properties.
2.3.6-Titrahydropyridine derivatives are, for example,
U.S. Patent No. 4.088.653 and “Journal
Oshimethicinal Chemistry (JO-urnal)
of Medicinal Chemistry)
J 25 @, pages 720-723, 1982, etc.

Indeed, certain semicarbazide derivatives having a chemical structure similar to that of the target compound of the present invention are also available, for example, in
nal of Medicinal Chemi
stry) J11, pp. 171-172, 1968,
“Journal Osh Chemical Society”
nalof Chemical 5ociety)
J 2160-2165, 1956, and French Patent No. 1.521°959.

However, it is not known that these compounds have anti-inflammatory and analgesic effects.

[Object of the Invention] The object of the present invention is to provide a novel semicarbazide derivative having anti-inflammatory and analgesic effects.

[Structure of the Invention] The semicarnocyto derivative, which is the target compound of the present invention, is represented by the following general formula [I].

[In the formula, R1 is a hydrogen atom, R2 is a hydrogen atom, a lower alkyl group, an al(lower) alkyl group, a lower alkenyl group, or an aryl group; R3 is a lower alkyl group, an al(lower) alkyl group
Alkyl, lower alkenyl or aryl groups, or R2 and R3, are bonded to each other to form a (C2C6) alkyritene group which may be substituted with an aryl group, or together with adjacent nitrogen atoms. a saturated or unsaturated 5- or 6-membered heterocyclic group, which may be substituted with an aryl group or a lower alkyl group; or, R1 and R2 are bonded to each other and the adjacent two a saturated or unsaturated 5- or 6-membered heterocyclic group or a 1,2-diazaspiroalkane-1,2-diyl group formed with two nitrogen atoms; R3 is a hydrogen atom, a lower alkyl group, an alkyl group; (lower) alkyl group, lower alknyl primary or aryl group; R4 is a lower alkyl group optionally substituted with a di(lower) alkylamino group or a heterocyclic group, or optionally substituted with a suitable substituent [heterocyclic group, R5 is a hydrogen atom or a lower alkyl group, and can.

Production method 1 5
[Idco or its salt
or a salt thereof [in the formula, Y is a hydrogen atom, an aryl group or a lower alkyl group, R: and town are bonded to each other,
Partially unsaturated or fully saturated pyridin-1-yl, optionally substituted with an aryl group type or lower alkyl group, formed together with the adjacent nitrogen atom, LR4 and R% are bonded to each other, and the adjacent nitrogen atom unsaturated 5 formed with
A 6-membered heterocyclic group, J and Machi are bonded to each other, and refer to a fully saturated 5- or 6-membered heterocyclic group formed with an adjacent nitrogen atom, respectively, R1, R2, R3
, R4, R5 and X each have the same meaning as before1
In this specification, preferred examples of various definitions included within the scope of the present invention will be explained in detail below.

"Lower" means groups having 1 to 6 carbon atoms, unless otherwise specified.

Preferred examples of the "lower alkyl group" include those with a rectangular shape such as methyl, ethyl, propyl, isopropyl, butyl, etc. Among them, C, -C4 alkyl group is more preferred. It is the basis.

Preferred examples of the "lower alkenyl group" include vinyl, allyl, 1-7'ropenyl, 3-ytenyl, 4-pentenyl, 5-hexenyl, etc. Among them, C2- It is a C4 alkenyl group.

Suitable examples of "lower alkoxy group" include methoxy,
Examples include ethoxy, propoxy, impropoxy, butoxy, imbutoxy, tertiary butoxy, pentyloxy, hexyloxy, etc., among which C,
-C4 alkoxy group.

Suitable examples of the "aryl group" include phenyl, naphthyl, and the like.

Preferred examples of the "al(lower) alkyl group" include benzyl, phenethyl, phenylpropyl, benzhydryl, trityl and the like, among which the phenyl (CIC4) alkyl group is preferred.

Suitable examples of "(C2C6) alkyritene group" include:
Examples include ethylidene, propyritine, impropylidene, butylidene, pentylidene, hexylidene, and the like. These (C2C6) alkyritene groups may be substituted with an aryl group, and the aryl group may further have a suitable substituent.

Suitable examples of the aryl group which may have a substituent include phenyl, 2-tolyl, 4-talolophenyl,
Examples include naphthyl.

Therefore, suitable examples of the (C2C6) alkyritene group having such a substituent include 1-phenylethylidene,
Examples include 2-phenylethylidene, 1,2-diphenylethylidene, 1-phenylprobilitene, and 1-(4-talolophenyl)ethylethene.

formed by R2, R3 and adjacent nitrogen atoms.
Preferred examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, pyrrolin-1-yl, 1,4-dihydropyridin-1-yl, yl, 1,2-dihydropyridin-1-yl, 1,2.3.6-tetrahydrobiridin-l-yl, and the like. These heterocyclic groups may be substituted with a lower alkyl group in the case of an aryl group, and suitable examples of the aryl group and lower alkyl group include those mentioned above.

"Partially cleaved or fully saturated pyridin-1-yl group"
Suitable examples include piperidino, 1,4-dihydropyridin-1-yl, 1,2-dihydropyridin-1-yl or 1.2.3.6-tetrahydropyridin-1-yl.
Il is mentioned. These pyridin-1-yl groups may be substituted with an aryl group or a lower alkyl group, and preferable examples of the aryl group and lower alkyl group include those mentioned above. .

formed by R1, R2 and adjacent nitrogen atoms.
Preferred examples of "saturated or unsaturated 5- or 6-membered heterocyclic groups" include pyrazolidinyl, perhydropyridazinyl, pyrazolinyl, 1,2,3.4-tetrahydropyridazinyl, 1.2.3 .6-tetrahydropyridazinyl and the like.

Preferred examples of the "unsaturated 5- or 6-membered heterocyclic group" include 1.2.3.6-tetrahydropyridazinyl, 1, 2.
Examples include 3,4-tetrahydropyridazinyl, 1,2-dihydropyridinyl, and the like.

Preferred examples of the "partially truncated or fully saturated 5 to 6-membered heterocyclic group" include 1.2.3.6-tetra, hydropyridazinyl, perhydropyridazinyl, and the like.

"112-diazaspiroalkane-1,2-diyl group"
Suitable examples include 1,2-diazaspiro[25]octane-1,2-diyl, 1,2-diazaspiro[26
]nonane-1,2-diyl,1,2-diazaspiro[4
, 5]tecan-1,2-diyl and the like.

A preferred "heterocyclic group" is a saturated or unsaturated monocyclic or polycyclic group containing at least one heteroatom selected from oxygen, sulfur and nitrogen atoms.

Suitable examples of such heterocyclic groups include cyclic groups containing 1 to 4 nitrogen atoms, 3 to 8 members, more preferably 51 to 6 membered unsaturated heterocyclic groups, such as pyrrolyl, eg 2 −
pyrrolyl, etc.], pyrrolinyl [e.g., 2-viroline-3
-yl], imidazolyl [e.g. 2-imidazolyl,
1, imidazolinyl such as 4-imidazolyl, 2-
imidapurin-4-yl, etc.], pyrazolyl [e.g. 3-
birazolinope 4-pyrazolyl etc.], pyridyl [e.g.
2-pyridyl, 3-pyridyl and 4-pyridyl 1, pyridyl N-oxide, pyridinio, dihydropyridyl, tetrahydropyridyl [e.g. 1,2,3,6-tetrahydropyridyl etc.], pyrimidinyl, e.g. 2-
pyrimidinyl, 4-pyrimidinyl, etc.], pyrazinyl, pyridazinyl [e.g., 3-pyridazinyl, 4-pyridazinyl, etc.], triazolyl [e.g., IH-1,2,4-
triazol-3-yl, LH-1,2,3-triazol-4-inoto2H-1,2,3-)riazol-4-yl, etc.], tetrazolyl [e.g., lH-tetrazol-5-yl, 2H-tetrazol-5-yl etc. 1
3- to 8-membered, more preferably 5-1 or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl [sidelight, 1-pyrrolidinyl, 2-pyrrolidinyl] etc.], imidazolidinyl [e.g. imidazolidine-2
-yl, etc.], piperidyl [e.g., 2-piperidyl, etc.]
, piperidino, piperazinyl [e.g. 1-piperazinyl, 2-piperazinyl, etc.], pyrazolidinyl [e.g.
unsaturated fused heterocycles containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, intridinyl, benzimidazolyl, quinolinoisoquinolyl, imidazolyl benzotriazolyl, 6°7-sihydro 5H-
1-(1-piperazinyl), etc.; 3- to 8-membered unsaturated heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxasilyl, inoxasilyl, oxadiazolyl [e.g. .2.
4-oxadiazolyl, 1.3.4-oxadiazolyl, 1,2.5-oxadiazolyl, etc.; 3- to 8-membered, more preferably containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; is a 5- or 6-membered saturated heteromonocyclic group, such as morpholinyl [e.g. morpholino, 2-morpholinyl and 3-morpholinyl], cytononyl, etc.; containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms Unsaturated fused heterocyclic groups, such as benzoxacylyl,
benzoxadiazolyl, etc.; 3 to 8 ring groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, more preferably 5 to 6 membered unsaturated heteromonocyclic groups, such as thiazolyl [e.g. Zolyl [for example, 1,3.4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, etc.], thiazolinyl [for example, 2-thiazolinyl, etc.].

Unsaturated fused heterocyclic groups containing 1 to 2 seedling atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl, benzothiadiazolyl, etc.; 3 to 8 atoms containing oxygen atoms, more preferably 5 Examples include straight or 6-membered unsaturated heteromonocyclic groups, such as furyl; 3- to 8-, more preferably 5- or 6s-saturated heteromonocyclic groups containing an oxygen atom, such as tetrahydrofuryl;

The above heterocyclic group may be substituted with a suitable substituent. Examples of the substituent include halogen atoms, such as fluorine, chlorine, bromine, iodine, lower alkyl groups, lower alkoxy groups, and oxo groups. Examples of the lower alkyl group and lower alkoxy group include those mentioned above.

Suitable di(lower) alkylamino groups include dimethylamino, diethylamino, dipropylamino, diisopropylamino, and the like.

In this invention, a more preferable specific example of compound [I] can be represented by the following formula.

[In the formula, 2+ and R3' are bonded to each other and are formed together with adjacent nitrogen atoms, an unsaturated 6-membered heterocyclic group optionally substituted with a lower alkyl group, more preferably C, 1.2 optionally substituted with -C4 alkyl group
．． 3.6-tetrahydropyridin-1-yl [e.g.
1,2,3.6-tetrahydropyridin-1-yl, 4
-Methyl-1,2,3,6-tetrahydropyridine-1
-yl, 5-methyl-1,'2.3.6-tetrahydropyridin-1-yl, etc.], or R2' and R3' are each a lower alkenyl group, more preferably c2-c
, an alkenyl group [e.g., vinyl, alinope 1-propenyl, etc.], and R4' is a lower alkyl group optionally substituted with a di(lower)alkylamide group or a heterocyclic group, more preferably a di(CIC4) C, =C, which may be substituted with alkylamino or pyridyl,
Alkyl groups [e.g. methyl, ethyl, propyl, butyl, tertiary butyl, dimethylaminomethyl, 1- or 2-dimethylaminoethyl, 1-dimethylaminoethyl, 2- or 3-
dimethylaminopropyl, 2- or 3-dimethyl or 4-pyridylmethyl, etc.], or a heterocyclic group which may be substituted with a halogen atom, a lower alkyl group or a lower alkoxy group, more preferably a halogen atom, C,-
Pyridyl optionally substituted with a C, alkyl group or a C, -C4 alkoxy group [e.g. 2- or 3- or 4-pyridyl, 2-chloropyridin-5-yl, 6
-methylpyridin-2-yl, 3-methylpyridin-2
-yl, 4-methylpyridin-2-yl, 2-methoxypyridin-5-yl, etc.], pyrimidinyl [e.g.
4-pyrimidinyl, pyrazinyl, thiazolyl [for example, 2- or 4-pyrimidinyl or 5-thiazolyl],
Thiazolinyl [e.g., 2-thiazolinyl, etc.], benzothiazolyl [e.g., 2-benzothiazolyl, etc.], 1.
2.3.6-tetrahydropyridin-1-yl, pyrazolyl [e.g., rhopyrazolyl, etc.], pyrrolidinyl [e.g., 1-pyrrolidinyl, etc.], 1, morpholinyl [e.g.,
morpholino, etc.] or tetrahydrofuryl substituted with an oxo group [e.g., 2-oxotetrahydrofuran-3
Suitable examples of pharmaceutically acceptable salts of monochemical compounds include the common non-toxic salts,
Organic acid salts (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, tolulene sulfonate, etc.), inorganic acid salts [e.g., hydrochloric acid Salts, hydrobromides, sulfates, phosphates, etc. 1. Salts with amino acids [e.g. aspartate,
Examples include glutamate and the like.

In this regard, the compounds [Idl,
Since [Ib], [Icl and [Idl] are included in the range of compounds, suitable salts of these compounds include those exemplified above for the target compound [I].

The method for producing the target compound [11 and its salts] will be described in detail below.

Production method 1 The target compound [Idl and its salt] can be produced by reacting the compound [m1 or its salt with the compound [ ] 1 or its salt.

A preferred salt of the compound [Kawa and Koi is Compound I11]
Examples are similar to those exemplified in .

This reaction typically involves water, methanol, ethanol, dioxane, tetrahydrofuran, benzene, chloroform,
It is carried out in a solvent such as methylene chloride or any other organic solvent that does not adversely affect the reaction.

Furthermore, this reaction can be carried out in the presence of an inorganic or organic base. Such bases include alkali metal bicarbonates [e.g., cum, potassium bicarbonate, etc.], alkali metal carbonates [e.g., sodium carbonate, potassium carbonate, etc.], and alkaline earth metal carbonates [e.g., sodium carbonate, potassium carbonate, etc.]. For example, magnesium carbonate, lucium carbonate, etc.], tri(
lower) alkylamines [e.g., trimethylamine, triethylamine, N,N-diisopropyl-N-ethylamine, etc.], pyridine compounds [e.g., pyridine, picoline, ludidine, etc.] , N-di(lower) alkylaminopyridine etc. 1, quinoline, N-lower alkylmorpholine [e.g.
) Alkyl esters (eg, N,N-dimethylbenzylamine, etc.).

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Production method 2 Target compound [I] or its salt is obtained by reacting compound [11] or its salt with compound [IV] or a reactive derivative at its carboxyl group or hydroxythiocarbonyl group or a salt thereof. It can be manufactured by

Suitable salts between the compounds include the same salts as those exemplified as the salts of the compounds.

Suitable reactive derivatives of the carboxy group or hydroxythiocarbonyl group of compound [IV] include esters, acid halides, acid anhydrides, and the like. Suitable examples of reactive derivatives include acid halides [e.g. acid chlorides, acid bromides, etc.]; symmetrical acid anhydrides; aliphatic carboxylic acids [e.g. acetic acid, piparic acid, etc.], substituted phosphoric acids [e.g. dialkyl phosphoric acid, diphenylphosphoric acid, etc.]; mixed acid anhydrides with phosphoric acid; esters or lower alkyl esters [e.g. methyl ester, ethyl ester, propyl ester, hexyl ester, etc.], optionally substituted alkyl (lower) alkyl; Esters [e.g. evabenzyl ester,
becishydryl ester, p-chlorobenzyl ester, etc.], optionally substituted aryl esters [e.g., phenyl ester, tolyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, naphthyl ester] etc.Jmaf
Mention may be made of nystyl such as thN, N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxyfuculimide or esters with 1-hydroxy-6-chloro-LH-benzotriazole.

These reactive derivatives can be appropriately selected depending on the type of compound [IV] used.

Preferred salts of the reactive derivatives of compound [I] include acid addition salts such as those exemplified for compound [I];
Salts with common bases, e.g. salts with organic bases [e.g.
Trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'-
Dibenzylethylenediamine salt etc. 1, ammonium salt,
Examples include alkali metal salts (eg, sodium salts, potassium salts, etc.), alkali group V salts (eg, calcium salts, magnesium salts A), and the like.

This reaction is typically carried out using conventional solvents such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylbormamide, pyridine, or any other organic solvent that does not adversely affect the reaction. carried out in a solvent. Among these solvents, hydrophilic solvents may be used in combination with water.

When compound [IV] is used in this reaction in the form of a free acid or its salt, 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 ricoloformate, etc.], 1
-(p-talolobenzene sulfonyloxy) -6-
It is desirable to carry out in the presence of conventional condensing agents such as chloro-IH-benzotriazole and the like.

The reaction temperature is not particularly limited, and the reaction can be carried out under cooling or under heating.

Production method 3 The target compound [I] and its salts can be prepared by compound [V[
] Or you can make it by reacting the salt.

Suitable reactive derivatives of the carboxy group or hydroxythiocarbonyl group of compound [V] include those similar to those exemplified for compound FIVI in production method 2 above.

Suitable salts for compound [VI] include those exemplified for compound [I].

This reaction can be carried out in substantially the same manner as Production Method 2, and therefore the reaction mode and reaction conditions (e.g. solvent, condensing agent, reaction temperature, etc.) of this reaction are the same as those explained in Production Method 2. I can list them.

Production method 4 Target compound [1b] and its salt are compound IVIl1
It can be produced by reducing the salt by a certain amount.

This reaction can be carried out in a conventional manner, ie by chemical reduction, catalytic reduction.

Suitable reducing agents used in the chemical reduction include aluminum hydride compounds [e.g. lithium aluminum hydride, sodium aluminum hydride, aluminum hydride, lithium trimethoxyaluminum hydride, tri-t-butoxyaluminum hydride, ], hydrogenated boronate compounds [e.g., sodium borohydride, lithium borohydride, sodium cyanoborohydride, tetramethylammonium borohydride, borane, diborane, etc.] Examples include metal hydride compounds.

Suitable catalysts used in the catalytic reduction include platinum catalysts [e.g. platinum plates, platinum sponges, platinum black, platinum colloids, platinum oxide,
platinum wire, etc.], palladium catalyst [palladium sponge from fallen trees,
Palladium black, palladium oxide, baladium carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, etc.], nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc. 1, cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.] ],
These are conventional catalysts such as iron catalysts (eg, reduced iron, Raney iron, etc.), copper catalysts (eg, reduced copper, Raney copper, Kulmann copper, etc.).

The reaction of this manufacturing method is usually carried out in a mixture of water, alcohol (eg, methanol, ethanol, propatool, etc.), acetic acid, diethyl ether, dioxane, tetrahydrofuran, etc. in a solvent.

The reaction is preferably carried out under mild conditions such as cooling or heating.

In this method, the pyridinio moiety of one compound [VIIl is reduced depending on the reduction method and reagent used, including a piperidino group, a 1,4-dihydropyridin-1-yl group,
1.2-dihydropyridin-1-yl or 1.2.
3.6-thitrahy-10pyridin-1-yl group.

Production method 5 Target compound [Idl and its salt are compound [Ic]t
or its salt can be reduced [7].

This reaction can be carried out in substantially the same manner as Production Method 4, and therefore the reaction mode and reaction conditions [
For example, for reduction method, reducing agent, solvent, reaction temperature, etc. 1, those explained in production method 4 can be applied.

Compounds [I] and [I] obtained by the production method described in -1-
dl, [1bl and [Idl can be purified by a conventional method such as recrystallization, column chromatography, reprecipitation, etc.
F. Can be purified.

Target compound [I] and starting compound [11], ■1, [
IV], [Vl, [W] and [VI] are asymmetric carbon atoms and/or double bonds between carbon atoms (i.e. Z-
isomer and E-isomer), and may contain as many as two or more stereoisomers, all of which are included within the scope of this invention.

Among the raw material compounds [IV], Kan and Sono, the new compounds can be produced by the production examples described below, or by methods known to those skilled in the art as methods for producing compounds structurally similar thereto.

The semicarbazide derivative which is the target compound of this invention 1 [
I] and its pharmaceutically acceptable salts have anti-inflammatory and analgesic effects and are useful in the treatment of inflammation and various pains [eg, headaches, toothaches, menstrual pains, etc.].

For therapeutic purposes, the compounds of this invention may be contained as active ingredients together with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral or parenteral administration. It can be used in the form of a pharmaceutical preparation. Forms of the pharmaceutical preparation include capsules, tablets, dragees, granules, solutions, suspensions, emulsions, and the like. In these preparations,
If desired, cutting, stabilizing, wetting, emulsifying agents, buffers and other commonly used additives may be included.

The monthly dosage of the compound [I] varies depending on the patient's age and symptoms, but usually the compound [I] is administered at a dose of about O1 to lfng.
, 10fng, 50rn9.100~. 250mQ15
Administered in the range of 00m, q, 1,000mg. In general, 0.1 to 1. Amounts between 00 and 000 may be administered.

The pharmacological test results for representative examples of compound [I] are shown below.

Test compound - N"[(4-pyridylcarbamoyl)amino] = 1.2
．． 3.6-Titrahydropyridine (hereinafter referred to as compound A) N-((3-pyridylcarbamoyl)amino]-1,2
,3,6-titrahydropyridine (hereinafter referred to as compound B) N-((2-pyridylcarbamoyl)amino]-1,2
,3,6-titrahydrobiridine (hereinafter referred to as compound C) N-((4-pyrimidinylcarbamoyl)amino] -
1,2,3,6-titrahydropyridine (hereinafter referred to as compound) N-(bilarinylcarbamoyl tri)) -1,2゜3
．． 6-titrahydropyridine (hereinafter referred to as compound E) N-[[(2-chloropyridin-5-yl)carbamoylopyridine (hereinafter referred to as compound F) N-((1-hyroricinylcarpamoyl)amino] - 1. 2,
3. 6-Titrahydropyridine (hereinafter referred to as Compound G) N,N'-[bis-(1,2,3.6-titrahyF-ropyridin-1-yl)]Cuffrere (hereinafter referred to as Compound H) Test A (anti-inflammatory effect) fllll carrageenin pulmonary edema 1) Test method: Sprague-Dawley male rats weighing approximately 200 y were used in groups of 5 rats.

Carrageenin paw edema was induced by subcutaneously injecting 1% carrageenin (0.1 me/rat) into the right hind paw print. The test drug was suspended in methylcellulose and orally administered 60 minutes before administration of carrageenan.

The foot volume was measured using a plethysmometer (manufactured by Nygo-Basil) by a water displacement method in which the foot was immersed in a tube directly above the fibular outpatient clinic. The difference in paw volume between before and 3 hours after administration of carrageenan was considered to be a measure of edema volume. The test results were statistically analyzed using the Stutent test.

(11) Test results: Test B (analgesic effect) 1+) Acetic acid rising: (I) Test method: Ten male ddY mice were used per group.

0, 6 to assess the frequency of writhing symptoms (rising).
Animals were observed between 3 and 13 minutes after intraperitoneal injection of 0.2% acetic acid/dose. Drugs were orally administered 60 minutes before acetic acid administration. The frequency of writhing symptoms in drug-treated animals was compared with the frequency of writhing symptoms in untreated control animals.

(11) Test results: [Efficacy] From the results of the test 11 described in -1-, it is clear that the target compound [11] of this invention exhibits significant anti-inflammatory and analgesic effects, and has anti-inflammatory effects. Useful as an inflammatory and analgesic.

[Example 1] Hereinafter, the present invention will be explained in detail with reference to production examples and examples.

Production Example 1 N-amino-1,2,3,6-titrahyF ropyridine hydrochloride (1,346y) and triethylamine (2,024y)
Phenyl chloroformate (1,566y) in methylene chloride (40me) in a solution of phenyl chloroformate (1,566y) with
Add the solution and stir at 5°C for 4 hours. Distill the solvent,
The resulting residue is extracted with ethyl acetate (150me). Wash the extract with water and dry with magnesium sulfate. The solvent was distilled off under pressure to obtain N-(phenoxycarbonylamino)
1.2.3.6-titrahydropyridine (2,01y
). This is recrystallized from diisopropyl ether to obtain the above-mentioned target compound (0,732j/) as colorless needle-like crystals.

Melting point: 124-125.5°C IR (Nujol): 3230. 1720. 1
600. 1540ci-1HMRCCDCI3, δ
): 2.30 (2H, m), 3.06 (2H, t
.

J=6Hz), 3.47 (2H, m), 5.6
9 (2H, m), 6.33 (IH+s), 7.10
-7.47 (5H, m) Elemental analysis: C12H14N2
Calculated value as 02: C66, 04, H6, 47, N12
．． 84 actual measurements: C66, 28, H6, 44, N13.
From 08 onwards, the compounds of Production Examples 2 to 9 are obtained in the same manner as in Production Example 1.

Production Example 2 4-(phenoxycarbonylamino)pyridine IR (Nujol): 1760. 1630. 1600.
1550cm-1HMR (CDCρ4.δ)+7.
10-7.60 (7H, m), 8.50-8.57
(2H, m), 9.17 (IH, s) production example 3 2-(phenoxycarbonylamide melting point: 149-150°C IR (nujol): 3200, 1745,
1610, 1590C〃+-1HMR(CDC/
! 3, δ) + 6.9-8.6 (9H, m), 1
0.66 (IH, s) Production Example 4 2-(phenoxycarbonylamino)pyrimidine Melting point: 131-132°C 1R (Nujol): 1770. 1445cm
NMR (CDCe31δ): 7.06 (LH, m),
7.18-7.66 (5H.

m), 8.76 (2H, d, J=3Hz), 1
1.04(LH,s) Production Example 5 2-(phenoxycarbonylamino)thiaso Melting point: 1
85-185.5°C IR (Nujol): 1735. 1460cm
-1 Production Example 6 2-chloro-5-(phenoxycarbonylamino melting point:
142.5-144℃ IR (Nujol): 1745, 1460 K-
1HMR(CDCl,, δ)+7.00-7.56(
6H, m), 7.96(H(, dd, J=9H
z, 3Hz), 8. 34 (LH, d, J
=3Hz) Production Example 7 2-Methoxy-5-(phenoxycarbonylamino)pyridine Melting point: 117-118°C IR (Nujol): 3230, 1735.
1460cm-1HMR (CDC 11' 3
, δ): 3.88 (3H, s), 6.64 (IH
,d.

J=9Hz), 7.01-7.48 (6H.m),
7.71 (IH, dd.

J--9Hz, 2.5Hz), 8.08(IH,
d, J=2.5Hz) Production Example 8 N-(phenoxycarbonylamino Melting point: 133.5-134°C IR (Nujol): 3200. 1720.1
460K-1HMR (CDCl3, δ): 1.
86' (4H, m), 2.98 (4H+m).

6.01 (LH, s), 6.98-7.58 (5H, m
) Production Example 9 N-(phenoxycarbonylamino)morpholine Melting point: 143-144°C IR (Nujol): 3210. 1710cm
'NMR (CDCl 3.δ): 2.88 (4H,
i + J = 5Hz), 3.77 (4H, t + J = 5H
z), 6.07 (IH, s), 7.02-7.48 (5
H, m) Example 1 N-amino-1,2,3゜6 in a solution of tertiary butyl isocyanate (0,991p) in methylene chloride (8mf7)
A solution of -titrahydropyridine hydrochloride (1,346y) and triethylamine (1,01251') in methylene chloride (40me) is added dropwise under water cooling, and the mixture is stirred at 5°C for 1 hour. The reaction mixture was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (5
0me). The solution was washed with water (40me), dried over magnesium sulfate, and then evaporated under reduced pressure.

The residue was washed with diethyl ether, dried and purified with N-[
(tertiary butylcarbamoyl)amino] -1,2,3
,6-titrahydropyridine (0,50p) is obtained.

Melting point = 155.5-156.5°C IR (Nujol): 3350. 3200. 3
100. 1675σ-1HMR (CDCls, δ)
: 1.35 (9H, s), 2.27 (2H, m)
.

2.85 (2H, t, J=7Hz), 3.23 (2
H, m), 5.27 (LH, s), 5.67 (
2H, m), 6.03 (IH, br s) Compounds of Examples 2 to 25 were obtained in the same manner as in Example 1.

Example 2 N-((4-pyridylcarbamoyl)amino 1-1.2
．． 3.6-Titrahydropyridine Melting point: 185-187
°C IR (nujol): 3200. 3100. 1
680. 1ssoσ−1HMR(CDCls, δ)
: 2.10-2.60 (2H, m), 2.70-
3.30 (2H, m), 3.10-3.60 (2H
, m), 5.74 (2H.

br s), 6.54 (IH, s), 7.30-7
．． 60 (2H2m).

8,30-8.60 (2H,m) Example 3 N-((3-pyridylcarbamoyl)amino]-1,2
,3,6-titrahydropyridine Melting point: 163-16
6°C IR (Nujol): 3180. 3070. 1
667, 1578°1520-153061n-1 NMR (CD30D, δ): 2.20-2.60 (2
H, m), 2.98 (2H.

t+J-6Hz), 5.72 (2H2s), 7.30-
7.50 (IH, m).

7.90-8.30 (2H, m), 8.69 (LH
, d, J=2.5Hz) Example 4 N-[(2-pyridylcarnocumoyl)aminoco-1,
2,3,6-titrahydropyridine Melting point: 163-16
4.5°C IR (Sujoor): 3300. 3200. 3
100. 1,685°1650c〃+-1 NMR (CDC/'3, δ): 2.33 (2H,
m), 2.97 (2H, m).

3.38 (2H, m), 5.70 (2H, m),
6.35 (IH, s).

6, 8:3--8.28 (4H, +η), 8.80
(IH,s) Example 5 N-[[(2-chloropyridin-5-yl)carbamoylcoamino]-1,2,3,6-titrahydropyridine Melting point: 173-174°C IR (Nujol): 3210. 1670. 1
460cm-1HMR (CDC13, δ): 2.35
(2H, m), 2.98 (2H, m).

3.36 (2H, m), 5.70 (2H, m),
6.45 (IH,s).

7.20 (IH, d, J=8Hz), 7.97-8
．． 46(3H,m) Example 6 N-[[(2-methoxypyridin-5-yl)carbamoylcoamino]-1,2,3,6-titrahydropyridine Melting point: 164-164.5°C IR( Nujol): 3350. 1680. 1
460cm' NMR (CDCl1.δ): 2.33
(2H, m), 2.98 (2H + m) + 3.37 (
2H, m), 3.9'0 (3H, s), 5.7
3 (2H, m).

6.30 (IH, s), 6.73 (IH, d, J
=6Hz).

7, 87 (LH, dd, J=6Hz, 2Hz),
8.05 (IH, s) + 8, 18 (LH, d, J
= 2Hz) Example 7 N-[(2-HiJmylinyllupamoyl)amino]
-1,2,3,6-titrahydropyridine Melting point: 20
2-203°C IR (Nujol): 1690cIn-1HMR (
CDC13, δ): 2.37 (2H, m), 3.
18 (2H, m).

3.57 (2H, m), 5.77 (2H+m)+
6.96 (LH, t+J=5Hz), 8.65 (
2H, d, J=5Hz), 9.50 (IH, s)
.

10.16(LH,s) Example 8 N-((4-pyrimidinylcarbamoyl)amine] -
1,2,3,6-titrahydropyridine Melting point: 187.
5-188°C IR (Nujol): 1707. 1500. 1
460□″'1HMR (CDC13, δ): 2.10
-2.66 (2H, m), 2.60-3.74 (4
H, m), 5.60-5°86 (2H, m), 6.
14-6.60 (IH, m), 8.08 (IH, d
, J=6Hz), 8.55 (IH, d.

J=6Hz), 8.80(IH,s), 8.68
-9.10 (LH, m) Example 9 N-(pyrazinylcarbamoylamino) -1,2゜3
．． 6-Titrahydropyridine Melting point: 154-155°C IR (Nujol): 1690. 1515. 1
415cm-1HMR (CDC13, δ): 2.04
-2.68 (2H, m), 2.68-3.19 (2
H, m), 3.19-3.68 (2H, m),
5.56-5.86 (2H, m), 6.36-6.
74 (IH, m), 8.05-8.36 (2H+m
), 8.66-9.00 (IH, m), 9.46 (L
H,s) Example 1O N-[(2-thiazolylcarbamoyl)amino]-1,
2,3,6-titrahydropyridine Melting point: 171-1
72℃ IR (Nujol): 3320. 3180. 3
100. 1700°1520cm-1 NMR (CDCI!3, IV): 2.42 (2H
, m), 3.06 (2H, m).

3.43 (2H, m), 5.78 (2H, m),
6.97 (IH, m).

7.26-7.66 (2H, m), 9.74 (IH
,s) Example 11 N-[(2-thiasolinylcarbamoyl)amine] =
12.3.6-Titrahydropyridine Melting point: 137.
5-1388C IR (Nujol): 1710. 1610>NM
RCCDCIl, δ): 2.00-2.47 (2H
, m), 2.78-3.14 (2H, m), 3
．． 16-3.48 (4H, m).

3.65-4.16 (2H, m), 5.50"-5,8
2 (2H, m).

6.11-6.58 (IH, m), 8.62-9.04
(IH,m) Example 12 N-((2-benzothiazolylcarbamoyl)amine]
-1,2,3,6-titrahyF ropyridine melting point: >
2508C IR (Nujol): 3340. 1710. 1
535cTn-1HMR(DMSO-d6.δ)=2.
00-2.66 (2H, m), 2.66-3, 10
(2H, m), 3.10-3.53 (2H, m),
5.55-5.83 (2H, m), 7.04-
8.03 (4H, m), 8.52 (IH, s) + l
0014(LH,s) Example 13 N,N'-[bis-(1,2,3,6-tetrahydropyridin-1-yl)]urea Melting point: 172-173.5°C IR (Nujol): 3240 ．． 1670c++
+-1HMR (CDCl3, δ): 2.12-2
．． 53 (4H, m), , 2.84 (4H, t, J=6
Hz), 3.21-3.50 (2H, m).

5.51-5.70 (2H, m), 6.34 (2H, s
) Example 14 N[(3-pyrazolylcarbamoyl)amino 1-1.2
．． 3.6-Titrahydropyridine Melting point: 154-156
°C IR (nujol): 3250. 2950. 1
660. 1565cm'NMR (DMSO-d61δ
): 2.01-2.40 (2H, m), 2.86
(2H, t, J=6Hz), 3.12-3.50(
2H, m), 5.53-5.80 (2H, m),
6.28 (IH, d, J=2Hz), 7.44
(IH.

d, J=2Hz), 7.60 (IH, s), 8
．． 43 (LH, s).

12.11[LH,s) Example 15 N-[(1-pyrrolidinylcarbamoyl)amine] -
1,2,3,6-titrahydropyridine Melting point: 182.
5-183°C IR (Nujol): 1665. 1460cm
'NMR (CDCI!3.δ): 1.81 (4H, m
), 2.30 (2H, m).

2.62-3.10 (6H, m), 3.30 (2H
, m),' 5.67 (2H, m), 6.04-6
,56(2H,m)Example 16 N-[(morpholinocarbamoyl)amino]-1,2,
3,6-titrahydropyridine melting point = 204.5-20
5℃ IR (Nujol): 3230. 1660. 1
495. 1460cm 'NMR (CDC/3.δ)
: 2. oo-2,4a(2H,m), 2.53-
3.10 (6H, m), 3.16-3.47 (2H
, m), 3.62-3.94 (4H+m), 5.5
3-5.78 (2H, m), 5.98-6; 33 (IH
, m).

6,35-6.64(IH,m) Example 17 N-[[(2-oxotetrahydrofuran-3-yl)
Carbamoylcoamino]-1,2,3,6-titrahydropyridine Melting point: 202-20358C IR (Nujol); 3350. 1770. 1
670. 1530cm-1HMR (DMSOd6.δ
): 1.96-2.39 (3H, m).

2.62-2.88 (2H, m), 3.03-3.
31 (3H, m).

4.02-4.60 (3H, m), 5.54-5.
72 (2H, m).

6.96 (LH, d, J=7Hz), 7.30 (
IH,s) Example 18 N [(4-H')Cylmethylcarbamoyl)amine]-1,,2,3,6-titrahydropyridine Melting point:
183-183.5°C IR (Nujol): 1660. 1535σ-1
HMR (CDCf8.δ): 2.00-2.53 (2
H, m), 2.68-3.11 (2H, m),
3.11-3.48 (2H, m), 4.46 (2H
.

d, J=6Hz), 5.53-5.83(2H, m
), 5.83-6.08 (IH, m), 6.3
4-6.76 (IH, m), 7.09-7.32 (
2H, m), 8.38-8.64 (2H, m) Example 19 N-[(4-pyridylcarbamoyl)amino]・-4-
Methyl-1,2,3,6-titrahydropyridine melting point:
164.5-1668C IR (Nujol): 3190. 3090. 1
685cm 'NMR (CDC7?3.δ): 1.7
8 (3H, s), 2.01-2.49 (2H, m),
2.67-3.20 (2H, m), 3.20-
3.67 (2H.

m), 5.23-5.55 (2H, m), 6.
54 (IH, s), 7.45 (2H, d, J=5
．． 5Hz), 8.22-8.68 (3H, m) Example 2O N-[[(6-methylpyridin-2-yl)carbamoyl]amine]-1,2,3,6-titrahydropyridine Melting point: 145.5-147°C IR (Nujol): 3340. 1720σ-1
HMR (CDC13, 5 units 2.03-2.61 (2H,
m), 2.41 (3H.

s), 2.72-3.12 (2H, m), 3.
12-3.68 (2H, m).

5.55-5.81 (2H, m), 6.10-6.
60 (IH, m).

6.75 (LH, d, J=7Hz), 7.21-7
．． 96 (2H, m).

8, 37-8.88 (IH,s) Example 21 N-[[3-(cyf-ylamino)propylcarbamoyl lysine Melting point: 86-88°C IR (nudicol): 3400, 1640cT
n-1 Example 22 N-((4-pyridylcarbamoyl)aminoco-5-medyru) 1.2,3.6-tetrahydropyridine Melting point: 169.0-171., 0°C IR. (Nujol): 3170. 308
0. 1675cm'NMR (CDCl2, δ):
1.65 (3H, s), 2, 10-2. 4 8 (2
H, m), 2.51-3.63 (4H, m),
5.38-5.57(IN(,m), 6.44(I
H, s), 7.43 (2'H, dd, J=7
Hz.

2Hz), s. 26-8.55 (3H, m) Example 23 1,1-diallyl-4-(4-pyridyl)semicarbazide Melting point: 85. , 5-86. 5°CIR (Nujol): 3240. 1680cm'NMR (
CDC13, δ): 3.37 (4H, d, J=5H
z), 5.11-5, 44 (4H+m), 5.63
-6.14 (2H, m), 6.43 (IH.

s), 7.40 (2H, dd, J=7Hz,
2Hz), 8.26 (IH, S).

8, 42 (2H, dd, J=7Hz, 2Hz
) Example 24 N-[[(4-methylpyridin-2-yl)carbamoylcoamino] - 1. 2, 3. 6-Titrahydropyridine Melting point: 163.5-165°C IR (Nujol 3320, 3190, 1
680cInNMR (CDC73, δ): 2.14-
2.48 (5H, m), 2.70-3.11 (2H
, m), 3.16-3.62 (2H, m), 5
．． 56-5.79 (2H.

m), 6.30 (IH, s), , 6.76 (I
H, d, J=6Hz).

7.93 (IH, s), 8.08 (LH, d, J
=6Hz), 8.75(LH,s) Example 25 N-[[(3-methylpyridin-2-yl)carbamoylcoamino]-1,2,3,6-titrahydropyridine Melting point: 135.0 -137.0°C IR (Nujol): 3220. 1675cm-
1HMR(CDCl3, δ)+2.00-2.5
4 (5H, m), 2.78-3.66 (4H+m)
+ 5.55-5.86 (2H, m), 6.65
-7.08 (2H, m), 7.22-7.61 (2
H,m), 7.96-8.30 (IH,m) Example 26 4-(phenoxycarbonylamino)pyridine (4,2
84P), N-amino-1,2,3,6-titrahydropyridine hydrochloride (4,038y) and tri,1.4-
/l/ 7 E (3, o36p) in chloroform (
7°me) and reflux for 20 hours. The solvent was distilled off, and the residue was dissolved in ethyl acetate (200ml).The solution was washed with water, dried over magnesium sulfate, and then evaporated under reduced pressure.The residue was subjected to column chromatography using silica gel (52, P). , developed with chloroform and purified to give N-[(4-pyridylcarbamoyl)amino]-1,
2,3,6-titrahydropyridine (2,00'5fi
l) is obtained.

Melting point: 185-187°C IR (Nujol): 3200. 3100. 1
680. 1580cm 'NMR (CDCI!3.δ
): 2.10-2.60 (2H, m), 2.70
-3.30(2HIm)+3.10-3.60(2
H, m), 5.74 (2H.

br s), 6.54 (LH, s), 7.30
-7.60 (2H, m).

8.30-8.60 (2H, m) Compounds of Examples 27 to 49 were obtained in the same manner as in Example 26.

Example 27 N-[(2-pyridylcarbamoyl)amino]-1,2
,3,6-titrahydropyridine Melting point: 163-164
．． 5°C IR (Nujol): 3300. 3200. 3
100. 1685°1650cm-1 NMR (CDCf3, δ) + 2.33 (2H, m)
, 2.97 (2H*m).

3.38 (2H, m), 5.70 (2H, m),
6.35 (LH, s).

6, 83-8.28 (4H, m), 8.80 (IH
,s) Example 28 N-((2-pyrimidinylcarbamoyl)amino]-1
．． 2,3.6-titrahydropyridine Melting point: 202-
203°C IR (nujol) = 1690cm''1NMR (C
DCI! , , δ:): 2.37 (2H, m), 3
．． 18 (2H, m).

3.57 (2H+m), 5.77 (2H, m),' 6
．． 96 (IH, t+J-5Hz), 8.65 (2H
, d, J=5Hz), 9.50 (IH, s).

10.16(LH,s) Example 29 N-[(2-4 asorylcarpamoyl)7mz]-1,
2,3,6-titrahydropyridine Melting point: l7l-17
2°C IR (Nujol): 3320. 3180. 3
100. 1700°] 520 (J-1 NMR (CDCe 3 , δ): 2.42 (2H, m
), 3.06 (2H, m).

3.43 (2H+m), 5.78 (2H, m), 6
．． 97 (IH, m).

7.26-7.66 (2H, m), 9.74 (LH
,s) Example 3O N-[[(2-chloropyridin-5-yl)carbamoylcoamino]-1,2,3,6-titrahydropyridine Melting point: 173-174°C IR (Nujol) + 3210. 1670. 1
460cm-1HMR (CDCI!1.δ): 2.
35 (2H+m), 2.98 (2H, m).

3.36 (2H, m), 5.70 (2H, m),
6.45 (IH, s).

7.20 (IH, d, J=8Hz), 7.97-8
．． 46 (3H, m) Example 31 N-[[(2-methoxypyridin-5-yl)carbamoyllopyridine Melting point: 164-164.5°C IR (Nujol): 3350, 1680.
1460cm-1HMR (CDCl3,δ)
: 2.33 (2H, m), 2.98 (2H, m)
.

3, 37 (2H, m), 3.90 (3H, S),
5.73 (2H.m).

6,30(LH, s), 6.73(IH, d,
J=6Hz).

7, 87 (IH, dd. J=6Hz, 2Hz),
8.05 ('IH.s).

8, 18 (I H, d, J=2Hz) Example 32 N-((1-pyrrolidinylcarbamoyl)amino] -
1,2,3,6-titrahydropyridine Melting point: 182.
5-183°C IR (Nujol): 1665. 1460 side-1
HMR (CDC13, δ): 1.81 (4H, m),
2.30 (2H+m).

2.62-3.10 (6H, m), 3.30 (2H
, m).

5.67 (2H, m), 6.04-6.56 (2H
, m) Example 33 N-[(morpholinocarbamoyl 1, 2, 3. 6-titrahydropyridine Melting point:
204.5-205°C IR (Sujo 7tz): 3230, 1660
, 1495, 1460C7'l'NMR (C
DCl3, δ): 2.00-2.43 (2H, m)
, 2.53 -3, 10 (6H, m), 3.1
6-3.47 (2H, m), 3.62-3.94 (
4H+m), 5.53-5.78(2H,m), 5
．． 98-6.33 (LH+m), 6.35-6.64 (
IH, m) Example 34 N-EC tertiary butylcarbamoyl)amino]-1.
2, 3. 6-Titrahydropyridine Melting point: 155.
5-156. 5°CIR (Nujol):
3350, 3200, 3100, 1675
cya-'NMR (CDCe3, δru1,3
5 (9H, s), 2.27 (2H, m).

2, 85 (2H, t, J = 7Hz), 3.23 (2
H, m), 5.27 (IH, s), 5.67 (
2H, m), 6.03 (IH, br s) Example 35 N-((4-pyrimidinylcarbamoyl)amino] -
1. 2, 3. 6-titrahydropyridine melting point:
187.5-188°C IR (Nujol): 1707, 1500.
1460cm-1HMR (CDC13.δ): 2.
10-2.66 (2H, m), 2.60-3, 7
4 (4H, m), 5.60-5.86 (2H, m)
, 6. '14-6.60 (LH, m) + 8.0
8(LH+d, J=6Hz)+8.55(LH,d
.

J=6Hz), 8.80(IH,s), 8.6
8-9.10 (LH, m) Example 36 N-(bilarinylcarpamoyl anino 1. 2, 3
.

6-Titrahydropyridine Melting point: 154-155°C IR (Nujol): 1690, 1515.
141'5cm NMR (CDC13, δ):
2.04-2.68 (2H, m), 2.68 -
3, 19 (2H, m), 3.19-3.68 (2H
, m), 5.56-5.86 (2H, m), 6
．． 36-6, 74 (LH, m), 8.05-8.3
6 (2H.

m), 8.66-9.00 (IH, m), 9.
46(IH,s) Example 37 N-[(2-thiazolinylcarbamoyl)amine] -
1. 2, 3. 6-titrahydropyridine melting point:
137.5-138°C IR (Nujol): 1710. 1610cm
"NMR (CDCl, d): 2.00-2.47 (
2H, m), 2.78-3, 14 (2H, m),
3.16-3.48 (4H, m), 3.65-4
．． 16 (2H, m), 5.50-5.82 (2H,
m), 6.11-6.58 (IH, m) + s
．． 62-9. 04 (IH, m) Example 38 N-[(2-Benzithiasolylcarpamoylamino]-1.2,3.6-titrahydropyridine Melting point: >250°C IR (Nujol): 3340.1710 ．．
1535cm'NMR (DMSO d6, δ): 2
．． 00-2.66 (2H, m).

2, 66-3.10 (21-(, m), 3.10-
3.53 (2H, m).

5, 55-5.83 (21-11m) + 7.04-
8.03 (4H+m).

8, 52 (IH, s), 10.14 (IH, s) Example 39 N,N'-(bis-(1,2,3.6-tetrahydropyridin-1-yl)1 urea Melting point: 172-173 .5℃ IR (Nujol): 3240, 1670c+
++-1HMR (CDCl3, δ): 2.
12-2.53 (4H, m), 2.84 (4H, t
, J=6Hz), 3.21-3.50 (2H, m)
, 5.51-5, 70 (2H, m), 6.34
(2H, s) Example 4O N-((3-pyrazolylcarbamoyl)amino]-1
．． 2, 3. 6-TitrahyF ropyridine Melting point: 1
54 - 156°C IR (Nujol): 3250, 2950,
1660, 1565. >-”NMR (DMSO
d6, δ): 2.01-2.40 (2H, m),
2.86 (2H.t, J=6Hz), 3.12
-3.50 (2H, m), 5.53 -5, 80 (
2H, m), 6.28 (LH, d, J=2Hz),
7.44 (lH. d, J=2Hz), 7.
60 (LH, s), 8.43 (IH, s).

12, 11 (LH, s) Example 41 N-([(2-oxotetrahydrofuran-3-yl)
Carbamoylcoamino] -1,2,3,6-titrahydropyridine Melting point: 202-203.5°C IR (Nujol): 3350. 1770. 1
670. 1530cIn' NMR (DMSO-d6
．． δ): 1.96-2.39 (3H, m).

2.62-2.88(2)(,m), 3.03-3
．． 31 (3H, m).

4.02-4.60 (3H, m), 5.54-5.
72 (2H, m).

6.96 (LH, d, J=7H2), 7.30 (
IH,S) Example 42 N-((4-pyridylmethylcarbamoyl)amino 1-
1.2.3.6-Titrahydropyridine Melting point: 183-
183.5°C IR (Nushor): 1660. 1535cm'
NMR (CI) Ce 7. δ): 2.00-2.53
(2H, m), 2.68-3.11 (2H, m),
3.11-3.48 (2H, m), 4.46 (
2H.

d, J=6Hz), 5.53-5.83(2H, m
), 5.83-6.08 (IH, m), 6.3
4-6.76 (IH,, m), 7.09-7.32
(2H, m), 8.38-8.64 (2H, m) Example 43 N-[(4-pyridylcarbamoyl-4-methyl-1.2,3,'6-titrahydropyridine Melting point: 164. 5-166℃ IR (Nujol): 3190, 3090.
1685cm-1HMR (CDCe3, δ
): 1.78 (3H, S), 2.01-2.49
(2H, m), 2.67-3.20 (2H, m),
3.20-3.67 (2H.

m), 5.23-5.55 (2H, m), 6.
54 (IH+s), 7.45 (2H+d, J””5.5
Hz), 8.22-8.68 (3H, m) Example 44 N-[[(6-methylpyridin-2-yl)carbamoylcoamino] - 1. 2, 3. 6-Titrahydropyridine Melting point: 145.5-147°C IR (Nujol) + 3340. 1720cr
n-1HMR (CDCe3, δ): 2.03-2.6
1 (2H, m), 2.41 (3H, s), 2.
72-3.12 (2H, m), 3.12-3.68
(2H, m), 5.55-5.81 (2H, m),
6.10-6.60 (LH, m), 6.75 (
IH, d, J=71(z), 7.21-7.96
(2H, m), 8.37-8.88 (IH, s) Example 45 N-4[3-(dimethylamino)propylcarbamoylcoamino] - 1. 2, 3. 6-Tetrahydropyridine Melting point: 86-88°C IR (Nujol): 3400, 1640
z' Example 46 N-((4-pyridylcarbamoyl-5-methyl-1. 2, 3. 6-titrahydropyridine Melting point: 169.0 - 171.0°C IR (Nujol): 3170, 3080. 167
5cm NMR (CDCZ3, δ): 1.65 (3H+
s) + 2.10-2.48 (2H, m), 2.
51-3.63 (4H.m+), 5.38-5.5
7 (IH, m), 6.44 (IH, s), 7.
43 (2B', dd, J=7Hz.

2Hz), 8.26-8.55 (3H, m) Example 47 1,1-diallyl-4-(4-pyridyl) semicarbazide Melting point: 85.5-86.5°C IR (Nujol): 3240, 1680cr
n' NMR (CDCe., δ): 3.37 (4H
, d, J=5Hz), 5.11-5, 44 (4
H, m), 5.63-6.14 (2H, m), 6.
43 (LH, s).

7, 40 (2H, dd, J-7Hz.2Hz), 8
．． 26 (IH, s).

8, 42 (2H, dd, J=7Hz, 2Hz) Example 4
8 N-[[(4-methylpyridin-2-yl)carbamoylcoamino]-1. 2, 3. 6-Titrahydropyridine Melting point: 163.5-165°C IR (Nujol) + 3320. 3190.
1680cm' NMR (CDC13, δ):
2.14-2.48 (5H, m), 2.70 -3
, 11 (2H, m), 3.16-3.62 (2H,
m), 5.56 -5, 79 (2H, m), 6
．． 30 (IH, s), 6.76 (IH, d.

J=6Hz), 7.93(lH, s), 8.
08 (IH., d, J=6Hz).

8, 75 (IH, s) Example 49 N-[[(3-methylpyridin-2-yl)carbamoylcoamino] -1. 2, 3. 6-tetrahydropyridine melting point: 135. 0-137. 0°CIR (Nujol): 3220, 1675m 1NMR (
CDCl2. δ): 2.00-2. ．． 54 (5H,
m), 2.78-3.66 (4H, m), 5.55
-5.86 (2H, m), 6.65-7.08 (2H,
m), 7.22-7.61 (2H, m), 7.
96-8.30 (IH, m) Example 50 3-Aminopyridine (2
, 1655') (7) Stir the methylene chloride (50ffIe) solution at -1-50°C for 2 hours. This mixture was combined with N-amino-1,2,3,6-titrahydropyridine hydrochloride (3,096y) and triethylamine (2
, 3277) in methylene chloride, stirred for 1 hour at -50°C, and further stirred at room temperature for 17 hours. The solvent was distilled off, and the residue was dissolved in water (50 meK). The aqueous solution was diluted with carbonic acid. Hydrogen) l) Rum pH 8,0-8
,5. The resulting precipitate is removed and the lachrymal fluid is extracted with ethyl acetate (300me).

The extract was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is subjected to chromatography using a silica gel column (40y). Develop with chloroform, combine the two fractions containing the target product, and evaporate under reduced pressure. The residue was recrystallized from ethyl acetate to give N-[(3-pyridylcarbamoyl)
Amino]-1,2,3゜6-titrahydropyridine (1
, 62gI).

Melting point: 163-166℃ IR (Nujol) 3180. 3070. 16
67, 1578°1520-1530cm' NMR (CD30D, δ): 2.20-2.60(
2H, m), 2.98 (2H, t+ J=6Hz)
, 5.72 (2H, s), 7.30-7.50
(IH, m), 7.90-8.30 (2H, m),
8.69 (IH, d.

J=2.5H2) Example 51 N-(phenoxycarbonylamino)-1,2,3°6-titrahydropyridine (2,61p), 4-aminopyridine (0,95y) and 4-dimethylami/pyridine ( 1,83y) total 1,2-dichloroethane (80
mt and reflux for 25 hours. The reaction mixture is evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50me) and dissolved in water (50me).
After washing with 0ml, extract with 5% hydrochloric acid (30meX2). The extract is neutralized with sodium hydrogen carbonate, and further extracted with chloroform (30 me x 2). Wash with chloroform and water (50 ml), dry with magnesium sulfate, and remove the solvent. The residue was recrystallized from ethyl acetate to give N-[(4-hi')"; nylcarbamoyl)amino]-1,2,3,6-titrahydropyridine (1,
41, P ) is obtained.

Melting point:]]87.5-1888 IR (Nujol): 1707. 1500. 1
460cm'NMR (CDC13, δ): 2.10-2
．． 66 (2H, m), 2.60-3.74 (4H,
m), 5.60-5.86 (2H, m), 6.14
-6.60 (IH, m), 8.08 (LH, d, J
=6Hz), 8.55(IH, d.

T=6Hz), 8.80 (1B, s), 8.
68-9.10 (lH, m) Compounds of Examples 52 to 75 were obtained in the same manner as in Example 51.

Example 52 N-(pyrazinylcarbamoylamine) -1,2°3
．． 6-Titrahydropyridine Melting point: 154-155°C IR (Sujoor): 1690. 1515. 1
415σ-1HMR(CI)C//3, δ): 2.
04-2.68 (2H, m), 2.68-3.19
(2H, m), 3.19-3.68 (2H, m),
5.56-5.86 (2H, m), 6.36-
6.74 (LH, m), 8.05-8.36 (2H
.

m), 8.66-9.00 (IH, m), 9.
46(IH,'s) Example 53 N-[(2-thiasolinylcarbamoyl)amino] -
1,2,3,6-titrahydropyridine Melting point: 137.
5-138°C IR (Nujol): 1710. 1610cm-
'NMR (CDC13, δ): 2.00-2.47 (
2H, m), 2.78-3.14 (2H, m),
3.16-3.48 (4H, m).

3.65-4.16 (2H,, m), 5.50-5
．． 82 (2H', m).

6.11-6.58 (IH, m), 8.62-9.
04 (IH, m) Example 54 N E (4-H')ylmethylcarbamoyl)amine]-1,2,3,6-titrahydropyridine Melting point: 18
3-18.3.5°C IR (Nujol): 1660. 1535cm-
'NMR (CDCI!3.δ): 2.00-2.53
(2H, m), 2.68-3.11 (2H, m),
3.11-3.48(2H+m)+'4.46(2
H+d, J=6H2), 5.53-5.83(2H
, m), 5.83-6.08 (LH, m), 6
．． 34-6.76 (IH, m), 7.09-7.3
2 (2H, m), 8.38-8.64 (2H, m)
Example 55 N-[(2-penzothiazolyllupamoyl)amine]
-L 2.3.6-tetrahydropyridine melting point: )
250”C IR (Nujol): 3340.1710.1
535cm ”NMR (DMSO-d, , δ): 2
．． 00-2.66 (2H, m), 2.66-3.1
0 (2H, m), 3.10-3.53 (2H, m)
, 5.55 = 5.83 (2H, m), 7.0
4-8.03 (4H, m), 8.52 (lH, s)
, 10.1.4(LH,s) Example 56 N-[[(2-oxotetrahydrofuran-3-yl)
Carbamoylcoamino] -1,2,3,6-titrahydropyridine Melting point: 2 (12-203,5°C IR (nu>yol): 3350.1770.1
670. 1530c〃+'MMR(DMSO-d6
．． δ): 1.96-2.39 (3H, m).

2.62-2.88 (2H, m), 3.03-3
．． 31 (3H, m).

4.92-4.60 (3H, m), 5.54-5.
72 (2H, m).

6.96 (LH, d, J = 7Hz), 7.30 (I
H,s) Example 57 N,N'-[bis-(1,2,3,6-tetrahydropyridin-1-yl)]Coufleur point: 172-173.5°C IR (Nujol): 3240. 1670cm-
1HMR(CDCI!3.δ): 2.12=2.53
(4H, m), 2.84 (4H, t, J=6Il
'z),, 3.21-3.50 (2H, m),
5.51-5.70 (2H, m), 6.34 (2H
,s) Example 58 N-[(3-pyrazolylcarbamoyl)amino 1-1.
2.3.6-Titrahydropyridine Melting point: 154-1
56°C IR (Nujol) + 3250. 2950. 1
660. 1565cm”NMR (DMSO-d6.δ
): 2.01-2.40 (2H, m), 2.86
(2H, t+ J=6Hz), 3.12-3.50
(2H, m), 5.53-5.80 (2H, m),
6.28 (IH, d, J=2)Tz), 7.
44 (IH, d, J=2Hz), 7.60 (IH
,s), 8. -43 (IH, s).

12.11 [IH, s) Example 59 N ((th-R) thylcarbamoyl-], 2,
, 3. 6-titrahydrobiridine Melting point: 155.5
-156.5°C IR (Nujol): 3350, 3200,
3100. 1675cm='NMR (CD
C e 3, δ): 1.35 (91-I,s
), 2.27 (2H, m).

2,85(2H+t,J”71(z)+3.23(
2H,m), 5.27(11(,s)+5
．． 6”/(2H,m)+603(IH
+ b r S ) Example 6O N-[(4-pyridylcarbamoyl)ami,/]-1
．． :2. 3. 6-titrahydrobiridine melting point:
185-187°C IR: 3';'. 00. 31
0(1, 1680, 1580c〃+-1Nhi
R (CDCl3, δ): 2.10-2.60
(2H, m), 2.70 -3, 30 (2H, m)
, 3.10-3.60 (2H, m), 5.74
(2H.

br s), 6.54 (IH, s), 7.30
-7.60 (2H, m).

8, 30-8. 6 (] (2H, m)
Example 61 N-((3-pyridylcarbamoyl)amino]-1.
2. 3. 6-titrahydropyridine Melting point: 163
-166°C IR (Nujoru door 3180, 3070, 1
667, 1578.

1, 520-1530 cm' NMR (CD30D, δ): 2.20-2.60 (
2H, m), 2.98 (2H.t+, I=6Hz
), 5.72 (2H, s), 7.30-7, 5
0 (LH, m), 7.90-8.30 (2H, m)
.

8, 69 (11-(, d, J=2.5Hz
) Example 62 N-[(2-pyridylcarbamoyl)amino]-1.
2, 3. 6-Tetrahydropyridine Melting point: 163-
164.5°C IR (Nujol) + 3300. 3200,
3100, 1685.

1650 cm-1 NMR (CDCj?3, δ:): 2.33 (2H, m
), 2.97 (2H, m) + 3, 38 (2H, m)
, 5.70 (2H, m), 6.35 (IH, s
).

6, 83-8.28 (4H, m), 8.80 (IH
,s) Example 63 N-[[(2-chloropyridin-5-yl)carnocumoylcoamino] - 1. 2, 3. 6-Titrahydropyridine Melting point: 173-174°C IR (Nujol): 3210. 1670. 1
460σF1HMR (CDC7?1.δ): 2.3
5 (2H, m), 2.98 (2H, m).

3.36 (2H, m), 5.70 (2H, m),
6.45 (LH, s).

7.20 (IH, d, J-8Hz), 7.97-8
．． 46(3H,m) Example 64 N-[[(2-methoxypyridin-5-yl)carbamoylcoamino]-1,2,3,6-titrahydropyridine Melting point: 164-164.5°C IR( Nujol): 3350. 1680. 1
460cm 'NMR (CDCf3.δ): 2.33
(2H, m), 2.98 (2H, m).

3.37 (2H, m), 3.90 (3H, s),
5.73 (2H, m).

6.30 (IH, S), 6.73 (IH, d, J=
6H2).

7.87 (IH, dd, J=6Hz, 2Hz),
8.05 (LH, s).

8, 18 (IH, d, J=2Hz) Example 65 N-[(2-pyrimidinylcarbamoyln]-1.2,
3.6-titrahydropyridine sub (points: 202-203
℃ TR (nujol): 1690cm 'NMR (C
DCe3, δ): 2.37 (2H, m), 3.18
(2H, m).

3, 57 (2H.m), 5.77 (2H,m), 6
, 96 (IH, t.

J=5Hz), 8.65 (2H, d, J=5Hz)
, 9.50 (IH, s).

10, 16 (IH, s) Example 66 N-[(2-thiazolylcarbamoyl-1, 2, 3.6-thitrahyF ropyridine melting point:
171-172°C IR (Nujol): 3320. 3rso,
3100, 1700.

1520cm-1 NMR (CDCJ3, δ): 2.42 (2H, m),
3.06 (2H, m).

3, 43 (2H, m), 5.78 (2H, m),
6.97 (LH, m).

7, 26-7, 66 (2H, m), 9.74 (IH
, s) Example 67 N-[(1-pyrrolidinylcarbamoyl)amine] -
1. 2, 3. 6-titrahydropyridine melting point:
182.5-183℃ IR (Nujol): 1665, 1460cm
'NMR (CDC13, δ): 1.81 (4H, m
), 2.30 (2H, m).

2, 62-3.10 (6H, m), 3.30 (2H
, m), 5.67 (2H.

m), 6.04-6.56 (2H, m) Example 68 N-[(morpholinocarbamoyl)amino 1-1, 2
, 3. 6-titrahydropyridine Melting point: 204.5
-205°C IR (Nujol)・3230, 1660,
1495. 1460cm 1HMR (CDCe3,
δ): 2.00-2.43 (2H, m), 2.5
3-3, 10 (6H.m), 3.16-3.47 (
2H, m), 3.62-3.94 (4H, m),
5.53-5.78 (2H, m), 5.98-6
．． 33 (IH, m), 6.35-6.64 (IH,
m) Example 69 N-((4-Hyridylcarbamoyl-4-methyl-1.2,3.6-titrahydropyridine Melting point: 164.5-1668C IR (Nujol): 3190, 3090,
1685cTn-1HMR(CDCe, , δ)+
1.78 (3H, s), 2.01-2.49 (2
H, m), 2.67-3.20 (2H.m),
3.20-3.67 (2H, m), 5.23-5.
55 (2H, m), 6.54 (IH, s).

7, 45 (2H, d, J = 5.5Hz), 8.22
-8.68 (3H, m)' Month Example 7O N-4[(6-methylpyridin-2-yl)carbamoylpyridine Melting point: 145.5-147°C IR (Nujol) + 3340+ 1720c++
+ 1HMR (CDCf 3, δ): 2, 03-2.6
1 (2H, m), 2.41 (3H, s), 2.
72-3.12 (2H, m), 3.12-3.68
(2H, m), 5.55-5.81 (2H, m),
6.10-6.60 (IH, m), 6.75 (
IH, d, J=7Hz), 7.21-7.96 (2
H, m), 8.37-8.88 (IH, s) Example 71 N-[[3-(dimethylamino)propylcarbamoylcoamino] - 1. 2, 3. 6-Titrahydropyridine Melting point: 86-88°C IR (Nujol): 3400. 1640cm
"Example 72 N-1 (4-pyridylcarbamoyl-5-methyl-1.2,3.6-titrahydropyridine Melting point: 169.0 - 171.0° CI
R (Nujol): 3170. 3080. 16
75ci 1HMR (CDC131δ): 1.65
(3H2s) + 2.10-2.48 (2H, m),
2.51-3.63 (4H, m), 5.38-
5.57 (IH, m), 6.44 (LH+s), 7.4
3 (2H+dd, J=7Hz.

2Hz), 8.26-8.55 (3H, m) Example 73 1.1-Diallyl-4-(4-pyridyl)semicarbazide Melting point: 85.5-86.5°C IR (Nujol): 3240. 1680 翿-1
HMR (CDCI!1.δ): 3.37 (4H, d,
J=5H2), 5.11-5.44 (4H, m),
5.63-6.14 (2H, m), 6.43 (
IH.

s), 7.40(2)1. , dd, J=7Hz, 2
T(,z), 8.26(IH.

s), 8.42 (2H, dd, J=7Hz, 2
Hz) Example 74 N-[[(4-methylpyridin-2-yl)carbamoylcoamino]-1,2,3,6-titrahydropyridine Melting point: 163.5-165°C IR (Nujol:): 3320. 3190.
1680σ-1HMR (CDC131δ): 2.14
-2.48 (5H, m), 2.70-3.11 (2
H, m), 3.16-3.62 (2H, m),
5.56-5.79 (2H, m), 6.30 (IH
, s), 6.76 (IH, d.

J=6Hz), 7.93(IH,s)+8.08(
IH, d, J=6Hz).

8.75(IH,s) Example 75 N-[[(3-methylpyridin-2-yl)carbamoylcoamino]-1,2,3,6-titrahydropyridine

Claims (13)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a hydrogen atom, R^2 is a hydrogen atom, a lower alkyl group, an alkyl group, a lower alkenyl group, or an aryl group. , R^3 is a lower alkyl group, Al(
(lower) alkyl group, lower alkenyl group or aryl group, or R^2 and R^3 are bonded to each other to form a (C_2-C_6) alkylidene group which may be substituted with an aryl group, or the adjacent nitrogen saturated or unsaturated 5 or 6 formed together with atoms
a membered heterocyclic group, the heterocyclic group may be substituted with an aryl group or a lower alkyl group; or R^1 and R^2 are bonded to each other and formed together with two adjacent nitrogen atoms; saturated or unsaturated
or a 6-membered heterocyclic group or a 1,2-diazaspiroalkane-1,2-diyl group, R^3 is a hydrogen atom, a lower alkyl group, an alkyl group, a lower alkenyl group, or an aryl group; 4 is a di(lower) alkylamino group or a lower alkyl group which may be substituted with a heterocyclic group, or a heterocyclic group which may be substituted with an appropriate substituent, R^5 is a hydrogen atom or a lower alkyl group, and X is an oxygen atom or a sulfur atom] and pharmaceutically acceptable salts thereof. (2) R^1 is a hydrogen atom, R^2 is a lower alkenyl group,
R^3 is a lower alkenyl group, or R^2 and R^3 are bonded to each other and formed with adjacent nitrogen atoms, a saturated or unsaturated 5 optionally substituted with a lower alkyl group or a 6-membered heterocyclic group, R^5 is a hydrogen atom, and X is an oxygen atom, the compound according to claim 1. (3) An unsaturated 6-membered heterocyclic group optionally substituted with a lower alkyl group, formed when R^2 and R^3 are bonded to each other and joined with adjacent nitrogen atoms; (
(lower) alkylamino group or a lower alkyl group optionally substituted with an unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms; a halogen atom, a lower alkyl group, or a lower alkoxy group An unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, which may be substituted; a saturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms; a saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; an unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; 5- or 6-membered heteromonocyclic group; 1
an unsaturated fused heterocyclic group containing ~2 sulfur atoms and 1 to 3 nitrogen atoms; or a saturated 5- or 6-containing 1 oxygen atom, optionally substituted with an oxo group
3. The compound according to claim 2, which is a membered heteromonocyclic group. (4) A tetrahydropyridyl group optionally substituted with a lower alkyl group, which is formed when R^2 and R^3 are bonded to each other and together with the adjacent nitrogen atom, and R^4 is di(lower) alkylamino lower alkyl group which may be substituted with a group or pyridyl; pyrazolyl; pyridyl which may be substituted with a halogen atom, lower alkyl group or lower alkoxy group; tetrahydropyridyl; pyrimidinyl; pyrazinyl; pyrrolidinyl; morpholinyl;
The compound according to claim 3, which is thiazolyl; thiazolinyl; benzothiazolyl; or tetrahydrofuryl optionally substituted with an oxo group. (5) The compound according to claim 4, wherein R^4 is pyridyl optionally substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group. (6) N-[(4-pyridylcarbamoyl)amino]-
The compound according to claim 5, which is 1,2,3,6-tetrahydropyridine. (7) N-[(3-pyridylcarbamoyl)amino]-
The compound according to claim 5, which is 1,2,3,6-tetrahydropyridine. (8) The compound according to claim 5, which is N-[[(2-chloropyridin-5-yl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine. (9) Claim 4 in which R^4 is pyrimidinyl
Compounds described in Section. (10) The compound according to claim 9, which is N-[(4-pyrimidinylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine. (11) Claim 2 in which R^2 and R^3 are each a lower alkenyl group, and R^4 is pyridyl.
Compounds described in Section. (12) (A) Formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a hydrogen atom, R^2 is a hydrogen atom, a lower alkyl group, an alkyl group, a lower alkenyl group, or Aryl group, R^3 is lower alkyl group, Al(
(lower) alkyl group, lower alkenyl group or aryl group, or R^2 and R^3 are bonded to each other to form a (C_2-C_6) alkylidene group which may be substituted with an aryl group, or the adjacent nitrogen saturated or unsaturated 5 or 6 formed together with atoms
a membered heterocyclic group, the heterocyclic group may be substituted with an aryl group or a lower alkyl group; or R^1 and R^2 are bonded to each other and formed together with two adjacent nitrogen atoms; saturated or unsaturated 5 or 6
membered heterocyclic group or 1,2-diazaspiroalkane-1,
2-diyl group, R^3 means a hydrogen atom, a lower alkyl group, an ar(lower) alkyl group, a lower alkenyl group or an aryl group, respectively] or a salt thereof with the formula R^4-NCX [Formula where R^4 is a di(lower) alkylamino group or a lower alkyl group optionally substituted with a heterocyclic group, or a heterocyclic group optionally substituted with an appropriate substituent, and
means an oxygen atom or a sulfur atom respectively] A compound represented by or a salt thereof is reacted, and the formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ [In the formula, R^1, R^2, R^3, R ^4 and X have the same meanings as before] or (b)
Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2 and R^3 each have the same meaning as before] A compound or its salt represented by the formula ▲ Numerical formula, chemical formula, table, etc. etc. ▼ Reacting the compound represented by the formula [wherein R^5 is a hydrogen atom or a lower alkyl group, and R^4 and It is shown by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^3, R^4, R^5 and obtain the compound or its salt, or (c)
Compounds represented by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^2, R^3 and X each have the same meanings as before] or their reactive derivatives or salts thereof There are formula ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^4 and R^5 each have the same meaning as before] React the compound or its salt, and form the formula ▲ mathematical formula, chemical formula, table, etc. etc. ▼ [In the formula, R^1, R^2, R^3, R^4, R^5 and X each have the same meaning as before] to obtain a compound or a salt thereof, or (d)
Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, Y is a hydrogen atom, an aryl group, or a lower alkyl group, and R^4, R^5 and X each have the same meaning as before] A compound or its salt is subjected to a reduction reaction, and the formula ▲ has a mathematical formula, chemical formula, table, etc. ▼ [In the formula, R^2_a and R^3_a are bonded to each other,
A moiety optionally substituted with an aryl group or a lower alkyl group, or a fully saturated pyridin-1-yl group formed together with adjacent nitrogen atoms, R^4, R
＾5 and are combined with each other,
It is an unsaturated 5- or 6-membered heterocyclic group formed together with adjacent nitrogen atoms, and R^3, R^4, R^5 and X have the same meanings as above] or its When salt is subjected to a reduction reaction, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1_c and R^2_c are bonded to each other,
A moiety formed together with adjacent nitrogen atoms or a fully saturated 5- or 6-membered heterocyclic group, R^3, R^4,
R^5 and , R^3, R^4, R^5 and X have the same meanings as above.] A method for producing a semicarbazide derivative or a salt thereof. (13) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 is a hydrogen atom, R^2 is a hydrogen atom, a lower alkyl group, an alkyl group, a lower alkenyl group, or an aryl group. , R^3 is a lower alkyl group, Al(
(lower) alkyl group, lower alkenyl group or aryl group, or R^2 and R^3 are bonded to each other to form a (C_2-C_6) alkylidene group which may be substituted with an aryl group, or the adjacent nitrogen saturated or unsaturated 5 or 6 formed together with atoms
a membered heterocyclic group, the heterocyclic group may be substituted with an aryl group or a lower alkyl group; or R^1 and R^2 are bonded to each other and formed together with two adjacent nitrogen atoms; saturated or unsaturated
or a 6-membered heterocyclic group or a 1,2-diazaspiroalkane-1,2-diyl group, R^3 is a hydrogen atom, a lower alkyl group, an alkyl group, a lower alkenyl group, or an aryl group; 4 is a di(lower) alkylamino group or a lower alkyl group which may be substituted with a heterocyclic group, or a heterocyclic group which may be substituted with an appropriate substituent, R^5 is a hydrogen atom or a lower alkyl group, and X is an oxygen atom or a sulfur atom] An anti-inflammatory agent or analgesic agent containing a semicarbazide derivative or a pharmaceutically acceptable salt thereof.