JPH013172A - Cycloheptoimidazole derivatives - 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 cyclohebutoimidazole derivative and its salt, and this compound is useful as an anti-inflammatory agent or analgesic agent.

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

[Structure of the Invention] The cyclohebutoimidazole derivative of the present invention is represented by the following formula (I).

[In the formula, R1 is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group, and R2 is a lower alkyl group, a cycloalkyl group, a substituted aryl group or optionally substituted heterocyclic group] Examples of the salt in the cyclohebutoimidazole conductor of the present invention include hydrochloride, hydrobromide, sulfate, phosphate, etc. salts with inorganic acids, salts with acidic amino acids such as aspartate, glutamate, formate, acetate, fumarate,
Examples include salts with organic carboxylic acids or sulfonic acids such as benzenesulfonate and toluenesulfonate, and these are generally pharmaceutically acceptable salts.

- Lower alkyl groups represented by R1 and R2 in formula (1) include methyl, ethyl, propyl, butyl,
In addition to saturated linear hydrocarbon residues having 1 to 6 carbon atoms such as pentyl and hexyl, 1 to 6 carbon atoms such as isopropyl, isobutyl, tertiary butyl, isopentyl, neopentyl, tertiary pentyl, isohexyl, etc. Non-limiting examples include saturated branched hydrocarbon residues. Also R1 and R2
The cycloalkyl group represented by is cyclopropyl,
Non-limiting examples include saturated cyclic hydrocarbon residues such as cyclobutyl, cyclopentyl, cyclohexyl, cyclohebutyl, cyclooctyl, and the like. Similarly, R1 and R
Aryl groups in the optionally substituted aryl group shown in 2 include phenyl, naphthyl, anthryl,
Examples of substituents that can be substituted with these include lower alkyl groups, halogens, hydroxy groups, nitro groups, aryl groups, amino groups, alkylamino groups, carboxy groups, lower alkoxy groups, lower alkoxycarbonyl groups, Non-limiting examples include a carbamoyl group and a cyano group. The lower alkyl groups exemplified here as substituents are those exemplified above as the lower alkyl groups for R1 and R2, the halogens include fluorine, chlorine, bromine, and iodine, and the aryl groups include the lower alkyl groups listed above. Those exemplified as aryl groups are listed again; alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, propylamino, etc., and lower alkoxy groups include methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, etc., and lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
imbutoxycarbonyl, tertiary butoxycarbonyl,
Non-limiting examples include pentyloxycarbonyl and hexyloxycarbonyl. Finally, a heterocyclic group in an optionally substituted heterocyclic group is a saturated or unsaturated monocyclic or polycyclic group containing one or more heteroatoms such as a nitrogen atom, a sulfur atom, or an oxygen atom. more specifically, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, pyridyl, or their N-oxides, pyrimidinyl, pyrazinyl, pyridazinyl, 4H-1,2,4-
Triazolyl, IH-1,2,3-1-riazolyl, 2
Triazolyl such as H-1,2,3-triazolyl, I
Nitrogen-containing unsaturated monocyclic heterocyclic groups such as tetrazolyl such as H-tetrazolyl and 2H-tetrazolyl, nitrogen-containing saturated monocyclic heterocyclic groups such as pyrodinyl, imidazolidinyl, piperidino, pyrazolidinyl, piperadiel, indolyl,
Nitrogen-containing unsaturated fused heterocyclic groups such as isoindolyl, intridinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazolyl, hensitriazolyl, oxygen-containing unsaturated monocyclic heterocyclic groups such as furyl, oxasilyl,
Isoxazolyl, 1,2,4-oxadiazolyl, IJ
, 4-oxadiazolyl, 1,2.5-oxadiazolyl, etc., oxygen- and nitrogen-containing unsaturated monocyclic heterocyclic groups such as oxadiazolyl, oxygen- and nitrogen-containing saturated monocyclic heterocyclic groups such as morpholinyl, benzoxazolyl , oxygen- and nitrogen-containing unsaturated fused heterocyclic groups such as benzoxadiazolyl, thiazolyl, 1,2.4-thiadiazolyl,
Sulfur- and nitrogen-containing unsaturated monocyclic heterocyclic groups such as thiadiazolyl such as 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, sulfur- and nitrogen-containing saturated monocyclic heterocyclic groups such as thiazolidinyl, thienyl Sulfur-containing unsaturated monocyclic heterocyclic groups such as benzothienyl, sulfur-containing unsaturated fused heterocyclic groups such as benzothienyl, oxygen-containing unsaturated monocyclic heterocyclic groups such as furyl, benzopyranyl, benzofuranyl, etc. Examples include oxygen-containing unsaturated condensed heterocyclic groups, sulfur- and nitrogen-containing unsaturated condensed heterocyclic groups such as hendithiazolyl and benzothiadiazolyl. Furthermore, as the substituents that can be substituted on these heterocyclic groups, those exemplified above as substituents that can be substituted on the aryl group are again exemplified.

It goes without saying that formula (I) includes both the case where the above-mentioned examples are the same (Rl = R2) and the case where they are different from each other (RI≠R2).

Since the cyclohebutoimidazole derivative represented by the general formula (1) can be produced according to various production processes, each of these production methods will be explained below. It should be noted that among the raw materials used in the following manufacturing methods A-D, the formula [■! Since the compounds represented by ] and [rV] include new substances, they will be further described below with reference to production methods E-H.

In the reaction formula below, R1 and R2 have the same meanings as before, and other symbols will be explained each time.

Production Method A This method is carried out by subjecting the carbodiimide conductor (11) to a dehydration condensation reaction with 2-aminotrobone (II+) under anhydrous conditions. The reaction is generally carried out without a solvent or in benzene, toluene, xylene or N,N-
The reaction is carried out at room temperature or under heating in an anhydrous solvent such as dimethylformamide which does not adversely affect the progress of the reaction.

Production method B (IV) (V) (I) [In the formula, X1 means a halogen or lower alkoxy group. This method involves adding 2-halo (or lower alkoxy) trobone (V) to the guanidine derivative (IV) in anhydrous form. It is carried out by dehydration and dehydrohalogenation (or dealcoholization) condensation under conditions. - Examples of the halogen represented by xl in formula (V) include fluorine, chlorine, and bromine, and examples of the lower alkoxy group include methoxy, ethoxy, propoxy, butoxy, and tertiary butoxy. The reaction is carried out without a solvent or in a solvent that does not adversely affect the progress of the reaction, such as benzene, toluene, xylene or N,N-dimethylformamide, at room temperature or under heating.

Production method C [■] [■:] (Ia) [In the formula, x2 means halogen] This reaction produces 2-aminocyclohebutoimidazole [V+
] is carried out by reacting the compound [■],
Compound [1a] is obtained. x in the above formula [■]
Examples of the halogen represented by 2 include fluorine, chlorine, and bromine. The reaction is carried out in the presence of a dehydrohalogenating agent, and examples of the dehydrohalogenating agent include basic substances such as sodium hydride and triethylamine. The reaction is carried out at room temperature or under heating in a solvent such as dimethyl sulfoxide which does not adversely affect the progress of the reaction.

Production method D (■) (K) (I) [In the formula, x3 means halogen] This reaction is carried out by reacting 2-substituted aminotrobonimine [■] with substituted carbonimidoyl dihalide [IX]. It will be done. X3 in the above formula [IX]
Examples of the halogen represented by include fluorine, chlorine, and bromine. The reaction is carried out in the presence of a dehydrohalogenating agent, and examples of the dehydrohalogenating agent include sodium hydride,
Basic substances such as triethylamine are exemplified. The reaction is carried out at room temperature or under heating in a solvent such as 1,2-dichloroethane which does not adversely affect the progress of the reaction.

Next, the carbodiimide derivative used in the above production method A [
[II]] and the method for producing the new compound contained in the guanidine derivative [IV] will be explained.

Production method E R'NCQ' [Xal R2NHCN
[Xbl■ R'-NHCNH-R2[X[I] ↓ R'-N=C=N-R2[+1] [In the formula, Q1 means an oxygen atom or a sulfur atom] This method is applicable to the general formula [Xal or A urea compound or thiourea compound represented by the general formula [Kari] is produced by reacting an isocyanate compound or isothiocyanate compound represented by [Xb] with an amino compound represented by the general formula [XIal or [XIb], and then dehydrated. This is carried out by producing a carbodiimide derivative [11] by subjecting it to reaction or desulfurization reaction.

The reaction to obtain the urea compound or thiourea compound [X[I] is carried out in a non-oxidizing atmosphere under cooling or heating in a solvent that does not adversely affect the progress of the reaction, such as N,N-dimethylformamide or toluene. .

Next, in the reaction to obtain carbodiimide [II], compound [X[I] is treated with a dehydrating agent or a desulfurizing agent (for example, triphenylphosphine, etc.) in a solvent such as carbon tetrachloride that does not adversely affect the progress of the reaction. It is done by doing. The reaction temperature is not particularly limited, but the reaction is carried out at room temperature or under heating.

Production method F R' NHCN [Xal R2NHCN [X
1lIb] ■ R'-NH-'C-NH-R2 [XIV]
]k Niamino compound [XIal or [XIb1] to produce a guanidine compound [+Wl. The reaction can be carried out without solvent or in toluene, N, N-
The reaction is carried out at room temperature or under heating in the presence of a solvent such as dimethylformamide that does not adversely affect the progress of the reaction.

Production method G [In the formula, R5 is a lower alkyl group and X4 means a halogen] This method is used to prepare a thiourea conductor [XVal or
is reacted with (lower) alkyl halide [XV+] to produce an amidine compound [X[Xal or [■b]], and further reacted with an amino compound [XIal or [XIb1] to produce a guanidine compound [X111]. It will be carried out. The lower alkyl group represented by R5 is methyl, ethyl, propyl, isopropyl.

Examples include butyl, isobutyl, tertiary butyl, etc.
Examples of the halogen represented by are chlorine, bromine, and iodine. The first step of the reaction is carried out at room temperature or under heating in a solvent such as methanol that does not adversely affect the progress of the reaction, and the second step of the reaction is carried out in a solvent such as methanol or ethanol that does not adversely affect the progress of the reaction. , carried out under the heating rate of the solvent.

Production method H ↓NH3 [In the formula, Q2 means an oxygen atom or a sulfur atom. The first step of this method is carried out in the same manner as the first step of production method E, and the resulting urea compound or thiourea compound [XII] - This is carried out by reacting ammonia in the presence of lead oxide or the like to produce a guanidine compound. The reaction in the second step is carried out under heat and pressure in a solvent such as methanol or ethanol that does not adversely affect the reaction.

[Example] Example 1 (8) 4.50 g of N,N'-bis(4-methoxyphenyl)carbodiimide and 2.14 g of 2-aminotropone
The reaction mixture was stirred for 6 hours while heating at 110° C., and the reaction mixture was developed on a column chromatography packed with 133 g of basic alumina, and eluted with a mixed solvent of toluene and ethyl acetate. The concentrated residue of the eluate was washed with diisopropyl ether to give dark red crystals of 1,2-dihydro-1-(4
2.81 g of -methoxyphenyl)-2-(4-methoxyphenylimino)cyclohebutoimidazole was obtained.

m p: 180-182°C IR (nujiol): 1630.1245 cm-
'NMR (CD[d23.δ): 3.74(3)1
, S), 3.84 (3H, S), 6.4-7.
55 (13H, Il+) M A S S (m/e): 358 (M″″+
1), 343, 224,143 Elemental analysis: C22) 1198302 Calculated value: C73,93, H5,3B, 811.7
6 Experimental values: C73, 73, 115, 96, N 11
．． 53(B) 1,2-dihydro-1-(4-methoxyphenyl)-2-(4-methoxyphenylimino)cyclohebutoimidazole obtained as above 2.65
1.2-dihydro-1-(4-methoxyphenyl) -
2.15 g of 2-(4-methoxyphenylimino)cyclohebutoimidazole hydrochloride was obtained.

mp+88-91℃ IR (Nushiyoru): 1620.1245cm-
'NMR(DMSO-d6.δ): 3.75(
311, S), 3.88(3)1. S), 6.95(
2)1. d, J-9Hz).

7.25 (2H, d, J-9Hz), 7.2-8.65
(9Lm), 10.4 (IH, bs) Elemental analysis: C22H19N302・H (:, Q・2%
]120 calculated value ・C60, 20, H5, 74, H9,
57 Experimental values: CH, 32, H5, 75, N 9.6
2 Example 2 (8) 40 g of N-(2-benzothiazolyl)-No-cyclohexylcarbodiimide, 2-aminotrobone 1
82g and 100ml toluene1. The mixture of
The mixture was heated and stirred for 13 hours, and the resulting reaction mixture was suspended in diethyl ether and filtered. The filtrate was concentrated under reduced pressure, and the concentrated residue was developed on a column chromatography packed with silica gel and eluted with a mixed solvent of toluene and ethyl acetate (9:1). 4.6 g of 2-dihydro-1-(2-benzothiazolyl)-2-cyclohexyliminocyclohebutoimidazole was obtained.

mp: 197-198°C (recrystallized from a mixed solvent of chloroform, isopropyl alcohol and methanol) IR (Nujiol): 1680.1590 cm-
'NMR(CDCu3, δ): 1
, 3-2.1OH, m).

4.15 (IH, br), 6.7-7.0 (1M,
m).

7.2-7.6 (5N, m), 7.8-8.0 (2H,
m).

9.35 (ltl, d, J-10Hz) MA
S S (m/e): 360CM”),
317ax Elemental analysis: C21H2ON4S Calculated value: C69,97, H5,59, N 15.5
4 Experimental values: C70, 17, 115, 52, N 15
．． 68(B) 1,2-dihydro-1- obtained in (8) above
4.6 g of (2-benzothiazolyl)-2-cyclohexyliminocyclohebutoimidazole was converted into a hydrochloride by adding ethanolic hydrochloric acid, washed with diethyl ether, and recrystallized from a mixed solvent of ethyl acetate and isopropanol.
3.65 g of 1,2-dihydro-1-(2-benzothiazolyl)-2-cyclohexyliminocyclohebutoimidazole hydrochloride as a dark yellow powder was obtained.

mp・125-130℃ (decomposition) IR (Nujiol): 3500-3150, 1
650cm-'NMR(DMSO-d,,δ)
: 0.9-2.2 (IOH, m).

4.15(l)I, m), 7.55-8.8(
8) 1, m).

9.55 (II-1, m) M A S S (m/e): 360 (M”)
, 317 elemental analysis: C2+H2oNaS・HGl,
4%H20 calculation value: C59.08, H5.74,
N 13.12 experimental value: C59.09, H5.54
, N 13.01 (C) In addition, the powder collected by filtration from the diethyl ether suspension after the reaction described in section (8) was developed on a column chromatography packed with alumina, and the (9 :1) When eluted with the mixture, reddish-purple crystals of 1,2-dihydro-1-cyclohexyl-2
2.45 g of -(2-benzothiazolylimino)cyclohebutimidazonyl was obtained.

mp: 250℃ (decomposition) IR (Nujiol): 1605cm-'N M
R(DMSO-da, δ) + 1.15-2.8
(IOH, m).

4.85 (IH, m), 7.05-8.3 (9N, m)
M A S S (m/e): 380 (M”),
278 elemental analysis: C2+1hoNaS calculated value・C59,97, H5,59, N 15.54
, S 8.89 Experimental value: C70.09, H5.56
, N 15.52, S 8.86 (chemical structure confirmed by X-ray structural analysis) Example 3 N'-(2-benzothiazolyl)-N3-cyclohexylguanidine 150 mg, 2-chlorotrobone 77 m
After stirring a mixture of g and 2.3 mA of toluene under heating and reflux for 15 hours, 55 mg of sodium hydrogen carbonate was added.
was added, and the mixture was further stirred under heating and reflux for 9 hours. After the reaction was completed, the mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, concentrated under reduced pressure, and the concentrated residue was washed with basic alumina 4.
Developed on column chromatography packed with 5 g,
Elution was carried out with a mixed solvent of toluene and ethyl acetate (39:1), and the eluate was concentrated to dryness to give red needle-like crystals of 1,2-dihydro-1-(2-benzothiazolyl)-2-cyclohexyliminocyclohebutoimidazole. 33 mg was obtained.

mp: 197-200.5℃ IR and NMR were as described in Example 2 (8).

Example 4 (A) N'-(tH-benzimidazole-2-
yl)-N3-cyclohexylguanidine 3.0 g.

2-chlorotrobone 1.64g, potassium carbonate 1.8
2g.

A mixture of 3 ml of toluene and 1 mJZ of N,N-dimethylformamide was stirred at 100°C for 10 hours,
The reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was developed on a column chromatography packed with silica gel and eluted with a mixed solvent of chloroform and methanol (50:1) as the first eluate, and then eluted with a mixed solvent of chloroform and methanol (1:1). This was used as the second eluate.

The first eluate was concentrated under reduced pressure, the residue was developed on column chromatography packed with aluminum nanoparticles, eluted with a mixed solvent of toluene and ethyl acetate (7:3), and the concentrated residue of the eluate was mixed with chloroform. Recrystallization from a mixed solvent of isopropanol gives red crystals of 1,2-dihydro-1-(I
0.66 g of H-benzimidazol-2-yl)-2-cyclohexyliminocyclohebutoimidazole was obtained.

mp: 207-208°C IR (nujiol): 3300 (broa+i)
, 1650cm-'NMR(DIASO-da,
δ): 1.1-2.2(11))I, m).

4.1B (IH, m), 7.0 (211, dd, J-
4and6Hz), 7.52 (2H, dd, J-4
and 6) 1z).

7.95 (1)1. m), 8.2 (3H, m)
, 10.28 (IH, d.

J-10,5)1z) M A S S ([[/e) : 343(M”,
base), 300 elemental analysis: C21) 121N
S calculated value: C73.44, H6.16, N 20.3
9 Experimental values: C73,92, H6,18, N 20.
59CB) The second eluate described in section (A) above was concentrated under reduced pressure, the residue was developed on a column chromatography packed with alumina, and a mixture of toluene and ethyl acetate (8:
2) Elution was performed with a mixed solvent. The concentrated residue of the eluate was treated with diisopropyl ether to crystallize it, and then recrystallized from a mixed solvent of ethanol and water to give a dark purple powder of 1,2-dihydro-1-cyclohexyl-2-(IH-benzimidazole- 0.13 g of 2-ylimino)cyclohebutoimidazole was obtained.

mP: 215°C (decomposition) IR (Nujiol): 3300. 1620cm
“NMR(DMSO-d6.δ): 1.
2-2.7 (IOH, m).

4.95 (IH, In1.7.0-7.9 (911, m
) M A S S (m/e): 3.43 (M”
), 261 (base) Example 5 A mixture of 2.58 g of N'-(2-benzoxasilyl)-N3-cyclohexylguanidine, 1.41 g of 2-chlorotrobone, 1.38 g of potassium carbonate, and 15++ l of toluene was heated under reflux. After stirring for 14 hours, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroborum. The chloroform solution was washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was developed on a chromatography column packed with alumina. The eluate was concentrated under reduced pressure. When the residue is washed with toluene, a purple powder of 1,2-dihydro-1-
0.26 g of cyclohexyl-2-(2-benzoxacyly, lumino)cyclohebutoimidazole was obtained.

m p: 2BB-270℃ IR (nujiol): 1620cm-'N M
R(CDCu3.δ): 1.1-2.5(
IOH, m).

4.93 (1)1, m), 7.1-8.0
(8H, m).

8.21 (E, d, J-11Hz) M A S
S (m/e): 3.44 (M”), 28
2 (base) elemental analysis: C2+H2oN40 Calculated value: C73,23, H5,85, N 16.2
7 Experimental values ・C73.48, H6.19, N 15.8
8 Example 6 (A) 4.84 g of 4-methoxyphenylguanidine.

2-chlorotrobone 4.12g, potassium carbonate 8.1g
and N,N-dimethylformamitro 4.51nfl
The mixture was stirred at room temperature for 2 days. Filter off insoluble matter,
The filtrate was concentrated under reduced pressure, and the residue was applied to a column chromatography packed with 250 g of silica gel, and eluted with chloroform. The eluate was concentrated under reduced pressure to obtain 1,2-dihydro-2-(4-methoxyphenylimino)cyclohebutoimidazole.

m p: 213-218°C IR (nujiol): 1B30.1570.12
40cm-'NMR(CDCl23.δ)
: 3.79 (3H, S), 6.87 (2) 1. d,
J-9H2), 7.35-7.85 (5119m).

8.10 (2H, dd, J-10andll(z)9
．． 0 (18, bs) M A S S (m/e), 251 (M”),
236 (base) (B) 1 obtained in the above (A),
2-dihydro-2-(4-methoxyphenylimino)cyclohebutoimidazole is treated with ethanolic hydrochloric acid to form a hydrochloride salt, and recrystallized from a mixed solvent of acetonitrile and methanol to give purple crystals of 1,2-dihydro-2. −(
0.83 g of 4-methoxyphenylimino)cyclohebutoimidazole hydrochloride was obtained.

mp: 258℃ IR (Nujo Jlz) +3250~3000.2800
~2000°1650, 1625.1580 cm-'
N'M R (CFsCOOH, δ): 4.43 (
3H, S).

7.15-7.85 (4L m), 8', 7-9.8
(5L m) MASS (m/e): 251
(M”), 236 elemental analysis: C+58+3N30
・HCJ2 calculation value: C62, 21, H4, 90, N
14.60 Experimental value: C62,72, H4,85,
N 14.86 Example 7 2-benzothiazolylguanisine 192 mg.

2-chlorotrobone 141mg and toluene 3.3m
The mixture of IL was stirred under heating under reflux for 30 hours. After the reaction was completed, it was cooled to room temperature, and the precipitated powder was collected by filtration and washed with methanol to give 120 m of 1,2-dihydro-2-(2-benzothiazolylimino)cyclohebutoimidazole as a dark yellow powder.
I got g.

m p: 346-350.5℃ IR (K Br home appliance) + 2750
(broad), 1620cm-Summer N M
R(CF3COOH, δ): 7.6-8.25
(4H, m) 8.75-9.5 (5H, m) M A S S : 278 (M”, base) Example 8 706 mg of 2-benzothiazolylguanicine and 500 mg of 2-methoxytrobone The reaction mixture was heated and stirred at 120-140°C for 13 hours and triturated in 6 mu of methanol to give a dark yellow powder of 1,2-dihydro-2-(2-
Benzothiazolylimino) cyclohebutoimidazole 0
．． 52g was obtained.

mp・347-349℃ IR, NMR, MASS: Same as Example 7 0.48 g of 1,2-dihydro-2-(2-benzothiazolylimino)cyclohep-imidazole obtained above was mixed with methylene chloride, It was dissolved in a mixed solvent of methanol and ethanolic hydrochloric acid and treated with activated carbon. The resulting solution was concentrated to dryness under reduced pressure, and the residue was recrystallized from a mixed solvent of methylene chloride and methanol to give a red powder of 1,2-dihydro-2-(
0.28 g of 2-benzothiazolyl imino)cyclohebutoimidazole hydrochloride was obtained.

m p: 351-353℃ IR (nujiol) + 2750.1600cm-
'NMR(CF3COOH,δ): 7.65
-8.2 (4H, m) 8.75-9.55 (5)1.
m) M A S S (m/e): 278 (M
”, base) Elemental analysis: C+sH+oN4S-H
CJ2 calculated value, C57, 23, H3, 52, N 1
7.80 Experimental value: C57,00, H3,42,N
17.88 Example 9 218 mg of 2-aminocyclohebutoimidazole was suspended in dimethyl sulfoxide 3++1, 66 mg of sodium hydride (60% oil suspension) was added at room temperature,
Stir for a minute. Then 2-chlorohendithiazole 25
After adding 4 mg and stirring at room temperature for 23 hours, water was added and the precipitated powder was collected by filtration, and the filtered powder was developed on a column chromatography packed with silica gel. ) It was eluted with a mixed solvent.

The eluate was concentrated and the concentrated residue was washed with ethanol and diethyl ether to give 1,2-dihydro-
60 mg of 2-(2-benzothiazolylimino)cyclohebutoimidazole was obtained. mp.

IR and NMR were as described in Example 7.8.

Example 10 939 mg of 4-methoxyphenylcarbonimidoyl dichloride, 649 mg of 2-(isopro-ruamino)trobonimine, 1.208 mg of l-ethylamine and 1
．． A mixture of 10 ml of 2-dichloroethane was stirred at room temperature for 3 hours, left at the same temperature overnight, and further heated under reflux for 1 hour.
Stirred for 0 hours. The reaction mixture was cooled to room temperature and 2.5
% aqueous sodium hydroxide solution was added and extracted with methylene chloride. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was developed on a column chromatography packed with 23.5 g of silica gel, eluted with a mixed solvent of methylene chloride and methanol (49:1), and the eluate was concentrated under reduced pressure. The concentrated residue was recrystallized from a mixed solvent of diisopropyl ether and isopropanol to obtain 0.23 g of 1,2-dihydro-1-isopropyl-2-(4-methoxyphenylimino)cyclohebutoimidazole as a dark red powder. Ta.

m p: 123-128°C IR (nujiol): 1835.1590.12
40cm-'NMR(CDf:j2s, δ)+
1.60 (6H, d, J-71(z).

3.78 (3H, S), 5.15 (IH, 5epte
t.

J=7)1z), B, [i-7,45(9B, m
) MA S S (m/e): 293 (M”)
, 251, 238 (base) elemental analysis/C1aH
+9N30・1/101120 Calculated value: C73,2
5, H8, 54, N 14.24 Experimental value: C73,
11, H6,48,N 13.95 Example 11 N-(2-methyl-4-quinolyl)-No-cyclohexylcarbodiimide and 2-aminotrobone were treated in the same manner as in Example 1, and the following compound was simultaneously added. Obtained.

(8) Orange crystal 1,2-dihydro-1-(2-methyl-4-quinolyl)-2-cyclohexyliminocyclohebutoimidazole mp; 200-206°C (recrystallized from isopropanol) IR (Nuxiol) ): 1640.1595cm-
'NMR(CDCJZ3, δ): 0.9~
2.110H, ml.

2.80 (311, S) 3.95 (IH, br).

5.94(11(,dd,J-!1andll+z)
.

8.67(1)1. m), 6.90 (IH, m).

7.27 (IH, S), 7.50 (41 (, m).

7.75 (IH, m), 8.15 (IH, d, , I'-
9Hz) M A S S (m/e): 365 (
M""), 325 (base) elemental analysis: C2
4H24N4 Calculated value: C78,23, H6,56,N 15.2
0 Experimental value: C78,38, H6,61,N 14.
9B゛ (Chemical structure was confirmed by X-ray structural analysis performed with fumaric acid.) (B) 1,2-dihydro-1-cyclohexyl-2-
(2-Methyl-4-quinolyl imino) cyclohebutoimidazole mp: 155-167°C (recrystallized from diisopropyl ether) IR (nudyl): 1610 cm-'NMR (
CDC, ff13. δ): 1.2-2.9(IOH
, m).

2.73 (3H, S), 4.78 (1! (, m).

7.0-7.9 (8H, m).

8.02 (IH, dd, J-1 and 9H2) 8.2
8 (IH, dd, J-1 and !lHy,) M A
S S (m/e): 368 (M”), 28
5 (base) (C) The 1,2-dihydro-1-cyclohexyl-2-(2-methyl-4-quinolyl imino)cyclohebutoimidazole obtained in (B) above is treated with ethanolic hydrochloride to give an orange color. A powdered monohydrochloride was obtained.

m p: 300°C (decomposition, recrystallization from a mixed solution of ethanol and methanol) IR (Nujiol): 3450.2650.16
30cm-'NMR(CDCu3, δ):
1.2-2.9 (101-1, m).

3.0 (3H, S), 4.85 (1) 1. m).

7.3-8.2 (811, m), 8.48 (1) 1. d
d, J-1 and 9Hz), 8.70 (IH, dd
, J-1and9Hz) Elemental analysis: C24H24N4・HCl・H20 Calculated value ・C68,15, H6,43, N 13.24 Experimental value: C67,79, H6J5. N 13.28 Example 12 (8) N-(4-methoxyphenyl)-No-cyclohexylcarbodiimide and 2-aminotrobone Example 1
1,2-dihydro-1-(4-methoxyphenyl)-2-cyclohexyliminocyclohebutoimidazole was obtained in the same manner as above.

m p: 135-141'C IR (Nushiol): 1640.1590.12
50cm-'NMR (CDCJZ 3.δ):
0.85-2.1 (IOH, m).

3.83 (3H, S), 4.0 (Ill, m).

fi, 33 (broad d, J-9tlz, IH) [
i, 45-7.55 (8)1. m) MA S S (
m/e): 333 (M”), 290 (bas
e) Elemental analysis: 021823N30 Calculated value: C75,65, H6,95, N 12.8
0 Experimental value: C76.05, H7.04, N 12.
16(B) 1,2-dihydro-1-( obtained in (A) above)
4-methoxyphenyl)-2-cyclohexylimino-
Cyclohebutoimidazole was treated with fumaric acid to give the fumarate salt.

mp: 104.5-107°C (decomposition, recrystallization from a mixed solvent of acetone and isopropanol) IR (Nujiol): 3400 (broad)
, 2800-2300(m), 1700.1640
．． 1590cm-'NMR(oMso-da, δ
): 0.95-2.1 (1011, m).

3.86 (3H, S), 4.0 (IH, m).

6.45(2)1. S), 6.9-8.35 (IIH
, m) MA S S (m/e): 333 (M”
), 290, 43 (base) elemental analysis: C2
1H23N30・C4H404・% acetone calculation value:
C6L51, H8,32,N 8.78 experimental value
: C66,05, H6,54, N 8.26 Example 1
3 (8) N-phenyl-N'-cyclohexylcarbodiimide and 2-aminotrobone were treated in the same manner as in Example 1 to obtain 1,2-dihydro-1-phenyl-2-cyclohexyliminocyclohebutoimidazole.

m p: 126-130.5°C (recrystallized from a mixed solvent of n-hexane and diisopropyl ether) IR (Nudyol): 1635.1595 cm-'NMR
(CDCJZ3.δ): 1.0-2.0 (1011
,m), 3.9(11(,+n), 6.32(IH
, d, J-9) 1z) 6.45-7.65 (9H, addition) (DMSO-d,, δ): 0,95-1.8
5 (1011, m).

3.85 (ILm), 6.39 (1B, d, J-
9Hz), 6.85-7.7 (9H, m) ax 255 (14200), 227 (20300)
Elemental analysis: C2a) I2+N3 Calculated value: C79,17, I+ 6.98. N 1
3.85 Experimental value: c 79.44, i+ 7.
23. N 14.06 (Chemical structure confirmed by X-ray structural analysis) (B) Treatment of 1,2-dihydro-1-phenyl-2-cyclohexyliminocyclohebutoimidazole obtained in (A) above with fumaric acid 1,2-dihydro-1-phenyl-2-cyclohexyliminocyclohebutoimidazole fumarate was obtained.

mp: 123-126.5°C (recrystallized from isopropanol) IR (nudyl): 2750-2350, 1
715°1850, 1595cm-' NMR(oMso-d6.δ): 1.0-2.
05 (IOH, m).

4.0 (IH, m), 6.50 (2H, S).

7.1-8.2 (IOH, m), 8.8 (2H, bs
) M A S S (m/e): 303 (M”)
, 260 (base) elemental analysis: C2oH21N3
・C4H404・y2H20 calculated value IC67, 27, H
8,12,N 9.81. )1202.10 Experimental value:
C87,53, H6,36, N 9.45. H20
2,09 Example 14 N-(2-benzothiazolyl)-N'-cyclooctylcarbodiimide and 2-aminotrobone were treated in the same manner as in Example 1 to obtain the following two compounds at the same time.

(A) 1.2-dihydro-1-(2-benzothiazolyl)-2-cyclooctyliminocyclohebutoimidazole mp: 141-142°C (red crystals, recrystallized from diisopropyl ether) IR (Nudiyol): 1670.1595 cm ”
NMR (CDCJ28.δ): 1.3-2
．． N141+, m).

4.28 (IH, m), 6.85 (LH, m).

7.1-7.55 (5H, m).

7.7-8.0 (211, m), 9.25 (IH,
d, J-10Hz) M A S S (m/e): 388 (M”)
, 317 (base) elemental analysis: C23H24N4
S Calculated value: C71.10, H6.23, N 14.4
2 Experimental values: C71,67, H6,36, N 14.
34(B) 1,2-dihydro-1-cyclooctyl-
2-(2-Benzothiazolylimino)-cyclohebutoimidazole. The amount of rice was further converted into hydrochloride by a conventional method, and 1,2-dihydro-1-cycloocdyl-2-(2
-Benzothiazolylimino)cyclohebutoimidazole hydrochloride.

mp・296℃ (decomposition, yellowish brown powder, ether washing) IR (Nujiol): 2500.160ON M
R(CDSO-d6.δ) + 1.3 to 2.2 (14
H, m).

5.22 (IH, m), 7.2-8.0 (4) 1. m
).

8.1-8.8 (5H, m) M A S S (m/e): 388 (M”)
, 317 elemental analysis: C2J24N4S-1 (Cu.
H20 calculated value ・C62, 36, H6, 14, N 12
J5 experimental value: C62, 45, H5, 84, N 12
．． 69 Example 15 N,N'-dicyclohexylcarbodiimide and 2-aminotrobone were treated in the same manner as in Example 1 to obtain 1,2-dihydro-1-cyclohexyl-2-cyclohexyliminocyclohebutoimidazole. .

mp: 104-106°C (recrystallized from n-hexane) IR (Nujiol): 1635.1590c
m-'NMR (CDI[3, δ): 0.95-2
．． 7 (20H, m).

3.87 (IH, m), 4.37 (18, m).

6.35-7.3 (5H, m) MA S S (m/e): 309 (M”)
, 227, 184.

145 (base) Elemental analysis: G2oH2tN3 Calculated value: C77,63, H8,79, N 13.5
8 Experimental values: C77.82, H8.43, N 13.
64 Example 16 N-(2-thiazolyl)-N'-cyclohexylcarbodiimide and 2-aminotrobone were treated in the same manner as in Example 2 to obtain 1,2-dihydro=1-(2-thiazolyl)- as an orange powder. 2-Cyclohexyliminocyclohebutoimidazole was obtained.

mp: 135-137°C (recrystallized from isopropanol) IR (Nujiol): 1660.1595 cm-
'NMR(CDCu3.δ): 1.3
~2.1 (IOH, m).

4.15 (IH, m), 7.15 (IH, d, J-4)
1z).

67-7.6 (4H, m), 7.65 (ill, d, J
-41-1z).

9.15 (LH, d, J-10Hz) M A S S (m/e): 310 (M”)
, 267(base)308 (18800)
, 255 (14200), 227 (20300)
Elemental analysis + Cl7H18N4S Calculated values: C65.78, H5°84. N18.
05 experimental value: C6B, 11, H5,55,N
18.30 (Chemical structure confirmed by X-ray structure analysis) Example 17 N-(2-pyridyl)-No-cyclohexylcarbodiimide and 2-aminotrobone were treated in the same manner as in Example 2 to form a red powder. 1,2-dihydro-1-(2-pyridyl)
-2-Cyclohexyliminocyclohebutoimidazole was obtained.

mp: 112-115°C (recrystallized from a mixed solvent of diisopropyl ether and n-hexane) IR (Nujiol): 1645.1595 cm-
'NMR(CDCl2s, δ): 1.0
-2.0 (10)1. m).

3.9 (IH, m), 6.2-7.5 (611, m
).

7.9 (2H, m), 8.5 (ill, m) MA
S S (m/e): 304 (M”), 26
1 (base) elemental analysis: C19H2ON4 Calculated value: C74,94, H6,82, N 18.4
1 Experimental value ・C74.88, H6.66, N 17.9
4 Example 18 N-(4-pyridyl)-No-cyclohexylcarbodiimide and 2-aminotrobone were treated in the same manner as in Example 2 to obtain 1,2-dihydro-1-(4-pyridyl)-2-cyclohexylimino. Cyclohebutoimidazole was obtained.

m p > 114-116.5°C (dark red crystals, recrystallized from a mixed solvent of diisopropyl ether and n-hexane) IR (Nudyol): 1B50.1600.15
85cm-'NMR(CDCus, δ):
1.0-1.9 (lOH, m).

3.9 (IH, m), 6.50 (IH, d, J
-10tlz).

6.7 (IH, m), 8.95 (III, d,
J-10Hz).

7.1 ~7.4 (2H, m), 7.43
(2)1. dd, J-1,5and 7)1z)
, 8.78 (211, dd, J-1, 5 and
IHz) M A S S (m/e): 304 (M”)
, 2 [11 (base) elemental analysis: C1982
ON4 calculated value: C74.98, H6.62, N 18.4
1 Experimental value: C75,67,'H7,01,N 18
．． 39 Example 19 N-(2-benzothiazolyl)-N'-isopropylcarbodiimide and 2-aminotrobone were treated in the same manner as in Example 2 to give 1,2-dihydro-1-(2-
Benzothiazolyl)-2-isopropyliminocyclohebutoimidazole was obtained.

mp: 201-201'C (recrystallized from a mixed solvent of isopropanol and chloroform) IR (Nushiol): 1675.1595 cm-
'NMR(CD(:J23.δ): 1.36
(6H, d, J-6Hz), 4.42 (IH, 5ep
tet, J-61-1z), 6.7-7.1(1
)1. m), 7.2-7.7 (5Hm), 7.8-8
．． 2 (21 (, m), 9.38 (IH, d, J-9H
z) M A S S (m/e): 320 (M”
), 305 (base) elemental analysis: C+aH
+aN, +S Calculated value: C67.48, H5.03, N 17.4
9 Experimental values: C67.85, H4.93, N 17.
41 Example 2O N-(2-benzothiazolyl)-No-tertiary-butylcarbodiimide and 2-aminotrobone were treated in the same manner as in Example 2 to give 1,2-dihydro-1-(2-benzothiazolyl)-2- (Tertiary-butylimino)cyclohebutymidazole was obtained.

m p: 182-185°C (recrystallized from a mixed solvent of ethyl acetate and acetone) IR (Nujiol): 1675 cm-'N M
R(CDCl13.δ): 1.55(9H,S)
, 6.90 (ill, m) 7.15-7.6 (5H,
m), 7.8-8.0 (2H, m).

9.38 (LH, d, J-1011z) MA S S
(m/e): 334 (M”), 319, 2
77.

237 (base) Elemental analysis: Cl9)1111N4S Calculated value: C68,24, H5,42,N 1B,7
5 Experimental values: C68, 39, H5, 40, N 16.
76 Example 21 N'-(2-benzothiazolyl)-N3-methylguanidine and 2-chlorotrobone were treated in the same manner as in Example 4 to obtain the following compound.

(A) 1,2-dihydro-1-methyl-2-(2-benzothiazolylimino)cyclohebutoimidazole IR (Nudiyol): 1610.1580 cm-
'NMR(CDCl23, δ): 3.70
(3H,S), 6.7-8.1(+n+,m) (B) 1,2-dihydro-1-methyl-2-(2-benzothiazolylimino)cyclohebutoimidazole hydrochloride m p : 299-301℃ (recrystallized from ethanol) IR (nujiol) 2700-2000.1600
゜1560cm-' NMR (CDCI 3.δ): 3.9 (3H
, S), 7.0-7.35 (3H, m), 7.55
-7.65 (IH, m), 7.9-8.5 (5H, m) M A S S (m/e): 292 (M”, b
ase) Elemental analysis: Cla) 1+2N4S-HCu・
1.7H20 calculated value: C53,72, H4,62,
N 15.6B experimental value: C53,69, H4,57
, N 15.81 Example 22 (1) N'-(2-benzothiazolyl) N5-(
The following compounds were obtained by treating 1-n-pentyl)guanidine and 2-chlorotrobone in the same manner as in Example 5 or in the same manner as in Example 7.

(8) 1,2-dihydro-1-(1-n-pentyl)-
2-(2-benzothiazolylimino)cyclohebutoimidazole mp: 182.5-187°C (decomposition) IR (Nudyol): 1B10.1575cRho 1N M
R(CDCILs, δ): 0.65-2.1(
98, m).

4.25 (2H, m), 7.0-8.05 (91 (,
m) MASS (m/e) +348 (M”), 3
33, 319, 305゜29'l, 278 (
base) (B) 1.2-dihydro-1-(1-n-pentyl)
-2-(2-benzothiazolylimino)cyclohebutoimidazole hydrochloride mp: 255-257°C (recrystallized from a mixed solvent of acetone and isopropanol) IR (Nudiyol): 2800-2300.1[
105cn+-'NMR(DMSO-d6.δ):
0.89 (3H, m), 1.35 (4H, m) 1.8
5(2)1. m), 4.49(2)1. t, J-7H
z) 7.2-7.65 (3H, m), 7.97 (IH
, dd, J-7 and 1flz), 8.2-8.
85 (5H, m) elemental analysis: C2oH2oN4S'1
lCj2 calculated value: C62,41, H5,50,N
14.56 Experimental value: C62,09, H5,51,N
14.65 Example 23 N'-(2-benzothiazolyl)-N3-(4-fluorophenyl)guanidine and 2-chlorotrobone were treated in the same manner as in Example 7 to obtain the following compound.

(A) 1.2-dihydro-1-(4-fluorophenyl)-2-(2-benzothiazolylimino)cyclohebutoimidazole IR (Nudiyol): 1B15.1580cm-
'NMR (MSO-d, δ):
7.05-84 (13H, m) M A S S (II
l/e): 372 (M+, base) (B) 1
．． 2-dihydro-1-(4-fluorophenyl)-2-
(2-Benzothiazolylimino)cyclohebutoimidazole hydrochloride mp: 298.5-299.5°C (recrystallized from ethanol) IR (Nudiyol): 1600. 1565cm
-'NMR(CD30D, δ): 7.25-
8.0 (8H, m).

8.0-8.65 (4H, m).

8.3 (18,d, J-10,5Hz) Elemental analysis'
C21H13F N4S・1Ic4 calculation value: C55
,97,I+ 3.95. N 12.43 Experimental value:
C56,25, H4,26,N 12.00 Example 2
4 N-(2-benzothiazolyl)-No-cyclohexylthiourea 41.0 g, triphenylphosphine 4
4.3g of triethylamine, 17.1g of triethylamine, and 26.0g of carbon tetrachloride were dissolved in 450ml of methylene chloride, and the mixture was stirred at room temperature in a nitrogen stream for 3.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in diethyl ether and filtered. The filtrate was concentrated under reduced pressure to give a syrupy N-(2-
49.54 g of benzothiazolyl-N'-cyclohexylcarbodiimide was obtained. This carbodiimide derivative was used as a raw material for the next reaction (for example, Example 2) without being purified.

IR (film): 2'IO0, 2800, 21
00c+n-' Example 25 N-(2-benzothiazolyl)-No-tertiary-butyl urea 2.0 g, triphenylphosphine 2.13 g
A mixture of 1.36 g of carbon tetrachloride, 0.974 g of 1-ethylamine and 20 mj2 of methylene chloride was stirred at room temperature for 22 hours, and then stirred under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was extracted with n-hexane. Concentrating the extract under reduced pressure yields a yellow oily N
1.18 g of -(2-benzothiazolyl)-N'-tertiary-butylcarbodiimide was obtained. This carbodiimide derivative can be purified by the following reaction (for example, Example 20).
It was used as a raw material.

IR (film): 2140 cm-'Example 26 N-cyclohexyl-N'-(4-methoxyphenyl)thiourea was treated in the same manner as in Example 24 to form a yellow oily N.
-cyclohexyl-N' -(4-methoxyphenyl)
Carbodiimide was obtained. This carbodiimide derivative was used as a raw material for the next reaction (for example, Example 12) without being purified.

IR (film) + 2120.1245cl'N
MR(C[1Cj2s, δ):
1.1-2.2 (101(, m).

3.45 (11 (, m), 3.75 (31 (, S).

6.7-7.15 (4H, m) Example 27 N-(2-benzothiazolyl)-N'-cyclooctylthiourea was treated in the same manner as in Example 24 to give syrupy N-(2-benzothiazolyl). -No-cyclooctylcarbodiimide was obtained. This carbodiimide derivative was used as a raw material for the next reaction (for example, Example 14) without being purified.

IR (film): 2900.2100cm-'
Example 28 N-cyclohexyl-N'-(2-pyridyl)thiourea was treated in the same manner as in Example 24 to obtain syrupy N-cyclohexyl-N'-(2-pyridyl)carbodiimide. . This carbodiimide derivative was subjected to the following reaction (
For example, it was used as a raw material in Example 17).

IR (Film): 2995.2985.213
0cm-'Example 29 N-cyclohexyl-N'-(4-pyridyl)thiourea was treated in the same manner as in Example 24 to obtain syrupy N-cyclohexyl-N'-(4-pyridyl)carbodiimide. I got it. This carbodiimide derivative was used as a raw material for the next reaction (for example, Example 18) without being purified.

IR (Film): 2995.2985.215
0 cm-' Example 3O N-(2-benzothiazolyl)-No-isopropylthiourea was treated in the same manner as in Example 24 to give syrupy N-
(2-Benzothiazolyl)-N'-isobrovir luposiimide was obtained. This carbodiimide derivative was used as a raw material for the next reaction (for example, Example 19) without purification.

IR (Film): 2995.2'IQ0.21
00 cm-' Example 31 Sodium hydride was soaked in 300 m of a mixture of N,N-dimethylformamide and toluene and cooled with water. On the other hand, a mixed solution was prepared by adding 100 g of 2-aminobenzothiazole to 200 ml of a mixed solvent of N,N-dimethylformamide and toluene, and added dropwise to the sodium hydride solution while stirring under a nitrogen stream. 103.4 g of thiocyanate was added dropwise and stirred at room temperature for 2 hours.

The resulting reaction mixture was poured into ice water and adjusted to pH 7 using concentrated hydrochloric acid, and the precipitate was collected by filtration and recrystallized from a mixed solvent of methanol and chloroform to form a white powder of N.
139.8 g of -(2-benzothiazolyl)-N'-cyclohexylthiourea was obtained.

m p: 218-219°C IR (nujiol): 3200.3050.15
70°1520cl' NMR (DMSO-da, δ): 1.0-2.2
(10)1. m).

4.2 (IH, m), 7.0-8.0 (41 (, m
).

9.9 (IH, m), 11.8 (IH, m) MA
S S (m/e): 29HM”),
150 (base) Example 32 2-Aminobenzothiazole and cyclooctyl isothiocyanate were treated in the same manner as in Example 31 to form a white powder of N.
-(2-benzothiazolyl)-No-cyclooctylthiourea was obtained.

mp・196.0-198°5°C (Washed with water and diisopropyl ether) IR (Nujiol): 3250.3050. x
s75゜1525cm-'NMR(DMSO-d,,δ): 1.4~2
．． 2 (14H, m).

4.25 (IH, m), 7.2-8.0 (4) 1. m
).

10.15(1)1. m) , 11.8 (IH, +n
) M A S S (m/e): 319 (M”)
, 150 (base) Example 33 4-Aminopyridine and cyclohexyl isothiocyanate were treated in the same manner as in Example 31 to give N-cyclohexyl-
N'-(4-pyridyl)thiourea was obtained.

mp: 159-160°C (white powder, powdered with a mixed solvent of ethanol and n-hexane) IR (Nujiol): 3200.1600.15
80°1535, 1515 cm-' NMR (DMSO-da, δ): 1.0-2.2
(1ON, m).

41 (11 (, m).

7.60 (2H, dd, J-1 and 7 Hz).

8.0 (11 (, broad d, J-8Hz).

8.31 (2B, dd, J-1 and 7 Hz).

9.55 (IH, m) M A S S (m/e): 235 (M”, b
ase), 206, 202 Example 34 2-Aminobenzothiazole and isopropyl isothiocyanate were treated in the same manner as in Example 31 to obtain a white powder of N-
(2-benzothiazolyl)-N'-isopropylthiourea was obtained.

mp: 202-204°C (recrystallized from a mixed solvent of methanol and chloroform) IR (Nujiol): 3150.1560.15
10cm-'NMR(DMS(lda, δ):
1.37 (6H, d, J-6Hz) 4.17-4.8
(ill, m).

7.15-8.1(4)1. m).

! 1.5-10.1 (18, m).

11.9 (1Lbroad S) Example 35 While heating 2.55 g of 2-cyanamidobenzoxazole and 7.93 g of cyclohexylamine to 80°C,
Stir for hours. The reaction mixture was concentrated under reduced pressure, and the residue was developed on a column chromatography packed with silica gel and eluted with chloroform. 2.0 g of N'-(2-benzoxasilyl) N3-cyclohexylguanidine as a light brown powder was obtained from the eluate.

mp: 181-183℃ (recrystallized from toluene)
IR (Nujiyor): 3400.3070.166
5゜1605cl' NMR (CDCJZ 3.δ): 1.0~2
．． 2 (IOH, m).

3.4 (DI, m), 6.4 (2H, m).

6.9-7.4 (5H, m) Example 36 2.7 g of 2-benzothiazolylthiourea, 2 methyl iodide
．． 2.5 g of a mixture of 19 g and 32 mfl of methanol
The mixture was stirred and refluxed while heating for an hour. The reaction mixture was concentrated under reduced pressure, the residue was treated with diethyl ether to powder, and this powder was collected by filtration to give 3.3 ml of N-(2-benzothiazolyl)-8-methylisothiourea hydroiodide as a pale yellow powder.
1 g was obtained.

m p: 137-160°C IR (nujiol): 3160.2800-200
0.

1630, 1575 cm-' NMR (DMSO-da, δ): 2.67 (
38, S).

7.25-8.1' (4H, m), 9.3 (:E, b
load) Example 37 A mixture of 2.41 g of N-(2-benzothiazolyl)-8-methylisothiourea hydroiodide, 2.39 g of n-pentylamine and 18 ml of ethanol was stirred and refluxed while heating for 7 hours. The reaction mixture was concentrated under reduced pressure, a 5% aqueous sodium hydroxide solution and chloroform were added to the residue, and the chloroform layer was separated, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was developed on a column chromatography packed with 38 g of basic alumina and eluted with chloroform. The eluate was concentrated under reduced pressure and the residue was washed with n-hexane to give a colorless powder of N'-(2-benzothiazolyl)N3-[1-
(n-pentyl)]guanidine (1.35 g) was obtained.

m p: 106-108.5°C IR (nujiol): 3450.3340.32
10゜3110, 1655.1590cm-'N M
R(DMSO-d6.δ): 0.7-1.7(
9H, m).

3.15 (2H, m), 6.9-7.8 (7H, m)
MASS (m/e): 262(M”ba
se), 247, 233.

279, 205, 150 Elemental analysis = Cl3H18N4S Calculated values: C59,51, H6,91, N 21.3
5 Experimental values: C59.24, H6.99, N 21.
31 Example 38 2-Aminobenzothiazole and 4-fluorophenyl isothiocyanate were treated in the same manner as in Example 31 to obtain N-(
2-benzothiazolyl)-N'-(4-fluorophenyl)thiourea was obtained.

mp: 202-203°C (recrystallized from a mixed solvent of ethanol and chloroform) IR: 315 (1,1[115,1
580°1550, 1525.1510cm""N M
R(DMSO-d6.δ) + 7.0-7.9(
8H, m).

10.8 (IH, broad), 12.7 (11-1
,broad) M A S S (m/e): 3
02(M”-1), 219.

192 (base), 151 Example 39 60 g of N-(2-benzothiazolyl)-N'-(4-fluorophenyl)thiourea, 12.0 g of lead oxide and 268++ l of ethanolic ammonia (approximately 13%)
The mixture was heated and stirred at 100° C. for 4 hours in an autoclave.

The reaction mixture was cooled and filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to yield N'-(2-benzothiazolyl) N5-(4-fluorophenyl)guanidine4. Obtained Og.

m p: 170-180°C IR (nujiol): 3450.3200.16
20°1570c(n-'NMR(DMSO-d6.δ): 7.0
-7.85 (8N, m).

8.0 (21 (, broad S), 9.2 (IH
,broad) M A S S (m/e): 2
86 (M", base) Next, the results of testing the anti-inflammatory effect and analgesic effect of the cyclohebutoimidazole conductor of the present invention are shown.

Test A (Anti-inflammatory effect) Carrageenin paw edema: (1) Test method: Sprague-Dawley male rats weighing approximately 200 g were used in groups of 5 rats.

Carrageenin paw edema was induced by subcutaneously injecting 1% carrageenin (0,1+nQ/rat) into the right hind heel. Test drug suspended in methylcellulose and carrageenin administration 6
Administered orally 0 minutes before administration.

The foot volume was measured using a plethysmometer (manufactured by Nigor Hasil) by the water displacement method in which the foot was immersed up to just above the lateral malleolus of the fibula. The difference in paw volume between before and 3 hours after administration of carrageenan was regarded as the edema volume. The test results were statistically analyzed using the Student's test.

(2) Test results: Trial 1 (analgesic effect) Acetic acid rising: (1) Test method: Ten male ddY mice were used per group.

0.6 to assess the frequency of writhing symptoms (rising).
3 after intraperitoneal injection of 0.2 mu 710 g dose of % acetic acid.
Animals were observed from 1 minute to 13 minutes. 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.

(2) Test results: [Effects of the invention] As is clear from the above test results, the object compound [11] of the present invention exhibits remarkable anti-inflammatory and analgesic effects, and is useful as an anti-inflammatory agent and analgesic. be.

Claims (1)

[Claims] General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, R^2 means a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group, respectively] The indicated cycloheptoimidazole derivatives and salts thereof.