WO1997009306A1

WO1997009306A1 - Novel isothiourea derivatives

Info

Publication number: WO1997009306A1
Application number: PCT/JP1996/002491
Authority: WO
Inventors: Manabu Hori; Takeshi Yamamoto; Hiroshi Ohtaka; Fumio Nakajima; Kengo Harada; Tominori Morita
Original assignee: Kanebo, Limited
Priority date: 1995-09-04
Filing date: 1996-09-03
Publication date: 1997-03-13
Also published as: JPH0967336A

Abstract

Isothiourea derivatives represented by general formula (I) or pharmacologically acceptable salts thereof, wherein R?1, R2 and R3¿ independently represent each hydrogen, halogeno, nitro, lower alkyl or lower alkoxy; R?4 and R5¿ independently represent each hydrogen, lower alkyl or substituted alkyl, or R?4 and R5¿ together form -(CH¿2?)n-; Z represents -(CH2)m- or CH2O(CH2)2-; n is 2 or 3; and m is 1, 2 or 3. The compounds (I) of pharmacologically acceptable salts thereof have an excellent function of inhibiting the Na?+/Ca2+¿ exchange mechanism.

Description

Specification

New isothiourea derivatives

Technical field

The present invention relates to novel isothiourea derivatives. More specifically, the following formula (I) having an inhibitory effect on Na + / Ca ²⁺ exchange

(In the formula, R ¹ , R ² and R ³ each independently represent a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group or a lower alkoxy group, and R ⁴ and R ⁵ each independently represent , A hydrogen atom, a lower alkyl group or a substituted alkyl group, or R ⁴ and R "together represent a group represented by 1 (CH ₂ ) -1;

(CH ₂ ) _m One or one CH. 0 (CH ₂ ) ₉ represents a group represented by 1. n represents 2 or 3, and m represents 1, 2 or 3. )

Or a pharmacologically acceptable salt thereof.

The Na ⁺ / Ca ²⁺ exchange mechanism is one of the ion transport mechanisms responsible for regulating intracellular sodium and calcium ion concentrations. For example, once the myocardium enters ischemia, intracellular acidosis is induced, and excessive Na ions flow into the cells by activating the Na ⁺ ZH + exchange mechanism or activating the Na + channel. Then, the Na ⁺ Ca ²⁺ exchange mechanism is activated by reperfusion, and excess sodium ions are pumped out of the cells, and calcium ions flow into the cells instead. Excessive accumulation of calcium ions is known to cause cardiac dysfunction, myocardial necrosis and arrhythmias [Circulation Research 65, 1045-1056 (1989), Journal of Cardiovascular Pharmacology ^ 23, 72-78 (1994) ] Te ₀従Tsu, compounds which inhibit the Na + ZCa ²⁺ exchange mechanism is caused to ischemia-reperfusion such as myocardial Can be used as a medicament against various disorders induced by excessive accumulation of calcium ions.

Compounds having an inhibitory effect on the Na ⁺ ZCa ²⁺ exchange mechanism include amide mouth derivatives such as diclomouth benzamil represented by the following formula (II) [Proceedings of the National Academy of sciences of the United States of America, 181, 3238 -3242 (1984)].

Isothiourea derivatives having an inhibitory effect on the Na + ZCa ²⁺ exchange mechanism are not known.

Disclosure of the invention

The present inventors have made various studies for the purpose of providing a novel compound having a Na + ZCa2 ⁺ exchange mechanism inhibitory action.

As a result of repeated studies by the present inventors, the novel isothiourea derivative represented by the formula (I) and a pharmacologically acceptable salt thereof have an excellent Na + / ^{Ca2 +} exchanger inhibitory action. And completed the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

In the formula (I), the halogen atom of R ¹ , R ² and R ³ is, for example, a chlorine atom or a bromine atom, and the lower alkyl group is, for example, a methyl group, an ethyl group, etc. Examples of the group include a methoxy group and an ethoxy group. Examples of the lower alkyl group or substituted alkyl group of R ⁴ and R ⁵ include a methyl group, an ethyl group, and a hydroxyethyl group.

Specific examples of the compound (I) of the present invention include N, Ν'-diethyl-S— [4- (4-cyclobenzyloxy) benzyl] isothiourea and S— [2-—4- (4-cyclobenzyloxy) phenyl ] Ethyl] isothioperia, 2- [2- [4- (4-chlorobenzyloxy) phenyl] ethyl] thio-4,5-dihydroimi Dazol, S— [2 -— [4- (4-cyclobenzyloxy) phenyl] ethyl] -1-N— (2-hydroxyxetyl) isothiourea, Ν, Ν'—Jetyl-S—

[2- [4- (4-chlorobenzyloxy) phenyl] ethyl] isothiourea, S— [2- [4- (4-methylbenzyloxy) phenyl] ethyl] isothiourea, S— [2— [4 -(3,4-Dichroic benzyloxy) phenyl] ethyl] isothioperia, S— [2— [4- (4-Nitrobenzyloxy) phenyl] ethyl] isothioperia, S— [2— [4— ( 3- (2-nitrobenzyloxy) phenyl] ethyl] isothioprea, S— [2- (4- (2-chloro-412-opentylbenzyloxy) phenyl] ethyl] isothioprea, N-ethyl-S— [2-1- [4-1] (4-chlorobenzyloxy) phenyl] ethyl] isothioprea, 2- [2- [4- (2,4-dichlorobenzyloxy) phenyl] ethyl] thio 4,5-dihydroimidazole, 2- [2- [4-- (4 Benzoxy) Benzoxy] Ethyl] Thio 4,5-dihydroimidazole, 2- [2-1- (4- (3,4-dichloromethylbenzyloxy) phenyl] ethyl] thio-1,4,5-dihydroimidazole, N, N'-Jetyl-S— [2 -[4-(3,4-Dichroic benzyloxy) phenyl] ethyl] isothioprea, S— [2- (4-benzyloxyphenyl) ethyl] isothiopurea, S— [2— [4-1,2,3 , 6-trichloro mouth benzyloxy) phenyl] ethyl] isothiourea, S—

[2 -— [4 -— (4-Methoxybenzyloxy) phenyl] ethyl] isothiourea, 2- [2- [2-((4-chlorobenzyloxy) phenyl] ethyl] thiol 4,5-dihydroimidazole, 2 — [2 -— [3-((4-chlorobenzoyloxy) phenyl] ethyl] thio4,5-dihydroimidazole; and the pharmacologically acceptable salts of compound (I) of the present invention include: Examples thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid and nitric acid, and salts with organic acids such as methanesulfonic acid and p-toluenesulfonic acid.

In the compound of the present invention, in the above formula (I), the substituted benzyloquine group is at the 4-position, and R ¹ , R ² and R ³ are each independently a hydrogen atom, a halogen atom, a methyl group or a nitro group. , R ⁴ and R "are both hydrogen atoms, or Is a group R ⁴ and R ⁵ are shown together in a connexion one (CH ₂₎ ₂ in one, Z gar ₂ (CH.) - or a _{_{CH 2 0 2 (CH.)}} - a group represented by Certain isothiourea derivatives or pharmacologically acceptable salts thereof are mentioned as preferred compounds.

The preferred compounds of the present invention include S- [2- [4- (4-chlorobenzyloxy) phenyl] ethyl] isothioprea, 2- [2- [4- (4-cyclobenzylbenzyloxy) phenyl] ethyl] Thio 4,5-dihydroimidazole, S—

[2 -— [4- (4-methylbenzyloxy) phenyl] ethyl] isothiourea, S— [2-—4- (1- (3,4-dichlorobenzyloxy) phenyl] ethyl] isothiourea, S— [2-—4 — (4-12throbenzyloxy) phenyl] ethyl] isothiourea, S— [2— [4— (3-Nitrobenzyloxy) phenyl] ethyl] isothioperia, S— [2— [4— (2-Chloro-4,12-trobenziloxy) phenyl] ethyl] isothioprea, 2- [2- [4-1 (2,4-1dichlorobenzyloxy) phenyl] ethyl] thio 4,5-dihydroimidazole, 2- [2 — [4- (4-chlorobenzyloxy) benzyloxy] ethyl] thio 4,5-dihydroimidazole, 2- [2- [4- (3,4-dichloromethylbenzyloxy) phenyl] ethyl] thio— 4, 5-dihydroimidazole, S- [2- (4 Roxyphenyl) ethyl] isothioprea, S— [2— [4- (2,3,6-trichloromethylbenzyloxy) phenyl] ethyl] isothioprea.

In addition, among the compounds of the present invention, 2- [2- [4-((4-chlorobenzyloxy) phenyl] ethyl] thio 4,5-dihydroimidazole, S— [2- [4-1-

(4-12throbenzyloxy) phenyl] ethyl] isothioprea and their pharmacologically acceptable salts, such as hydrochloride, methanesulfonate, and P-toluenesulfonate, are particularly preferred compounds.

The compound (I) of the present invention and a pharmacologically acceptable salt thereof can be produced, for example, by the following method.

, R ¹ , R, 2, R, 3

(In the formula, ^u , R, 4, R, 5 "and Z are the same as described above. Y represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group.)

That is, a pharmacologically acceptable salt of compound (I) can be produced by reacting compound (III) with compound (IV). This reaction can be carried out by reacting the compound (III) with an equivalent amount of the compound (IV) in an inert organic solvent at room temperature to the boiling point of the solvent for 1 to 24 hours. Examples of the inert organic solvent include methanol, ethanol, dioxane, acetate nitrile, and the like, or a mixed solvent obtained by appropriately mixing them.

The compound (I) of the present invention is prepared by reacting a pharmacologically acceptable salt of the compound (I) obtained by the above-mentioned production method with an aqueous solution of an inorganic base such as sodium hydrogencarbonate in a conventional manner. Can be manufactured.

The compound (I) of the present invention can also be produced by performing the above reaction in the presence of a base.

Further, a pharmacologically acceptable salt of the compound (I) of the present invention can also be produced according to a conventional method using the compound (I) of the present invention and an organic or inorganic acid.

Compound (III) used as a raw material in the above production method can be produced by the following method.

(Wherein, R ¹ , R ² , R ³ , Y, and Ζ are the same as described above.)

That is, the compound (III) is a compound produced by reacting a substituted benzyl halide 'with a hydroxyalkylphenol, etc., according to the method described in JP-A-50-148357. (V) can be produced by halogenation, alkylsulfonyl esterification or arylsulfonyl esterification, or by performing a dehydration reaction with ethylene chlorohydrin.

The compound (I) of the present invention and a pharmacologically acceptable salt thereof show an excellent Na + / C a ⁺ exchange mechanism inhibitory action and are induced by excessive accumulation of calcium ions during myocardial ischemia. Can be used as a drug for disorders such as cardiac dysfunction, myocardial necrosis and arrhythmia.

Compound (I) and its pharmacologically acceptable salts of the present invention exhibits excellent N a ⁺ ZC a ²⁺ exchange mechanism inhibitory effect as shown in the following Test Examples, it is considered to be based on for the acting Fig. 4 shows a reperfusion arrhythmia suppressing effect and a reducing effect on myocardial infarction lesions. Therefore, the compound (I) of the present invention and a pharmacologically acceptable salt thereof are useful for treating disorders induced by excessive accumulation of calcium ions during myocardial ischemia, for example, for treating cardiac dysfunction, cardiomyocardial infarction and arrhythmia. Effective for prevention.

Hereinafter, the effects of the compound of the present invention will be described with reference to Test Examples.

Test example 1

Na ⁺ noCa2 ⁺ exchange mechanism inhibitory action:

The inhibitory effect of the Na + ZCa2 ⁺ exchange mechanism was determined by the method of Reeves et al. [Journal of Biological Chemistry, 258, 3178-3182, using canine myocardial vesicle membranes prepared from fresh canine myocardium. 1983)].

1) Test compound Compounds of Examples 2, 3, 6, 7, 8, 9, 10, 12, 13, and 14 (Compounds of the Present Invention)

Dichlorobenzamil (control compound)

2) Test method

In order to load sodium ion into myocardial vesicle membrane preparations, the cells were incubated in a buffer solution [160 mM sodium chloride, 20 mM 3-N-morpholinopropanesulfonic acid (pH 7.4)] at 37 ° C for 30 minutes. Next, the membrane sample was prepared using the reaction solution [16 OmM potassium chloride, 20 M ⁴⁵ CaCl. , 0.4 mM vinomycin, 20 mM 3-N-morpholinopropanesulfonic acid (pH 7.4)] at 37 ° C for 2 seconds, followed by filtration using a glass filter. The radioactivity of ⁴⁵ Ca in the vesicle membrane captured by the glass filter was measured [internal sodium ion concentration-dependent calcium ion inflow (A)]. Radioactivity was measured in the same manner by replacing potassium chloride in the reaction solution with sodium chloride [internal sodium ion concentration-independent calcium ion inflow (B)].

In the same manner, the drug-untreated group was measured in the same manner, and the internal sodium ion concentration-dependent calcium ion inflow was C, the internal sodium ion-independent calcium ion inflow was D, and Na ⁺ at each concentration of the test compound was determined. The ZC a ²⁺ exchange mechanism inhibition rate {%) was calculated by the following equation.

Inhibition rate (%) = [1— (A-B) / (C-D)] X 100 Then, the concentration at which the test compound inhibits the Na + / ^{Ca2 +} exchange mechanism by 50% (ic _{5 ( )} ) Was determined from the regression equation.

3) Test results

The results are shown in Table 1. W

8

Test example 2

Inhibitory effects on reperfusion arrhythmias:

The inhibitory effect on reperfusion arrhythmia was examined using a rat acute myocardial infarction model according to the method of Tagliavini et al. [European Journal of Pharmacology, 194, 7-10 (1991)].

1) Test compound

Compound of Example 3 (Compound of the present invention)

2) Test method

Male Sprague-Dawley rats (body weight: 360-420 g) were anesthetized by intraperitoneal administration of sodium pentobarbital (50 mg / kg). Under anesthesia, a force neuron was inserted into the trachea of the rat and connected to a ventilator. The electrocardiogram (Lead II) was guided from an electrode inserted into the limb and measured via a bioelectric amplifier. ° C was maintained. The rat was opened at the left intercostal space and the pericardium was incised to expose the heart. Next, the test compound was dissolved in a mixed solvent of 15% (v / v) polyethylene glycol 400, 15% (v / v) ethanol and 70% (v / v) physiological saline, and the solution was injected into the femoral vein. Was administered. Ten minutes after drug administration, the origin of the left coronary artery was occluded. After occlusion for 5 minutes, reperfusion was performed for 10 minutes, and duration of ventricular fibrillation after reperfusion (s) (mean SST, n = 6) was measured from the electrocardiogram. Ventricular fibrillation was determined according to the guidelines of The Lambeth Convention [Cardiovascular Research, 22, 447-455 (1988)].

As a control, the ventricle when only a mixed solvent of 15% (v / v) polyethylene glycol 400, 15% (v / v) ethanol, and 70% (v / v) saline was administered. The duration of fibrillation (s) was measured as above.

3) Test results

The results are shown in Table 2.

Test example 3

Reduction effect on myocardial infarction lesion:

The reduction effect on myocardial infarction lesions was examined using a rat acute myocardial infarction model according to the method of Petty et al. [European Journal of Pharmacology, 192, 383-388 (1991)].

1) Test compound

Compound of Example 3 (Compound of the present invention)

2) Test method Male Sprague-Dawley rats (body weight: 360-430 g) were anesthetized by intraperitoneal administration of sodium pentobarbital (50 rag / kg). Under anesthesia, the body temperature was maintained at 37 ° C. after inserting a force neuron into the trachea of the rat and connecting it to a ventilator. The rat was opened at the left intercostal space and the pericardium was incised to expose the heart. Dissolve the test compound in a mixture of 15% (v / v) polyethylene glycol 400, 15% (v / v) ethanol, 70% (v / v) Was administered within. Ten minutes after drug administration, the origin of the left coronary artery was occluded. After occlusion for 30 minutes, reperfusion was performed. Two hours after reperfusion, the heart was removed and the origin of the left coronary artery was ligated. After inserting a force neuron into the aorta and perfusing a 0.025% Evans blue solution using a syringe pump, the ischemic area (Evans blue unstained area) and the non-ischemic area (Evansble-stained area) divided. After incubating the ischemic area (ischemic area) in 0.1% triphenyltetrazolium chloride (TTC) solution at 37 ° C for 30 minutes, the TTC stained area and unstained area (infarct area) The infarct area (TTC unstained area wet weight) and the ischemic area (Evansable-unstained area wet weight) were determined, and the percentage (mean SEM, n = 3) was calculated. displayed. As a control, the infarct area / imaginary area when only a mixed solvent of 15% (v / v) polyethylene glycol 400, 15% (v / v) ethanol, and 70% (v / v) saline was administered. Blood areas were determined and expressed as percentages as above.

3) Test results

Table 3 shows the results.

Next, the present invention will be described more specifically with reference to examples and reference examples. Example 1

N, Ν'-Jetyl-S— “4- (4-chlorobenzyloxy) benzyl] isothiodiale hydrochloride“ In the formula (I), R ¹ , R ² , and R ³ -substituted benzyloxy are substituted with 4-1-1 (4 Hydrochloride of a compound in which R ⁴ and R ⁵ are ethyl groups, and Z is —CH ₂ 1—.

A mixture of 4- (4-chlorobenzyloxy) benzyl chloride (see Reference Example 1) (0.75 g), N, N'-getylthiodialea (0.37 g), and ethanol (10 ml) Was refluxed for 1 hour. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue for crystallization. The generated crystals were collected by filtration and recrystallized from acetonitrile to give the title compound (0.44 g).

Melting point: 143-144 ° C

½-NMR (DMS0-d ₆ ) 5: 1.02-1.12 (6H, m), 3.23-3.37 (4H, m), 4.52 (2H, s), 5.09 (2H, s), 6.98 (2H, d, J = 9Hz), 7.33 (2H, d, J = 9Hz), 7.44 (4H, s), 9.41 (2H, br).

Elemental analysis value (as C ₁₉ H ₂₃ C 1 N ₂ OS · HC 1):

Calculated value (%) C, 57.14; H, 6.06; N, 7.01

Actual value (%) C, 57.04; H, 5.99; N, 7.06

Example 2

S- “2 -—” 4- (4-chlorobenzyloxy) phenyl 1-ethyl 1-isothioperia methanesulfonate In the formula (I), R ¹ , R ² , and R ³ substituted Methanesulfonate of a compound in which R ⁴ and R ⁵ are hydrogen atoms and Z is — (CH ₂ ) ₂ 1).

Methanesulfonic acid 2- [4- (4-chlorobenzyloxy) phenyl] ethyl ester (see Reference Example 2) (0.90 g), thioprea (0.22 g), and ethanol (10 ml) were mixed with 1 晚Refluxed. The solvent was evaporated under reduced pressure, and the obtained crystals were washed with acetonitrile and recrystallized from methanol to give the title compound (0.50 g).

Melting point: 188 ~ 190 ° C

½-NMR (DMS0-d ₆ ) 5: 2.32 (3H, s), 2.85 (2H, t, J = 7 Hz), 3.37 (2H, t, J = 7 Hz), 5.07 (2H, s), 6.94 (2H , D, J = 9Hz), 7.19 (2H, d, J = 9Hz), 7.44 (4H, s), 8.99 (4H, br) Elemental analysis (as _{_{_{C 16 H 17 C 1 N 2}}} OS · CH 3 S0 3 H):

Calculated value (%) C, 48.97; H, 5.08; N, 6.72

Actual value (%) 49.14; H, 5.02; N, 6.64

Example 3

2— “2—“ 4- (4-chlorobenzyloxy) phenyl 1-ethyl] thio—4,5-dihydroimidazole methanesulfonate “In the formula (I), R ¹ , R, and RO-substituted benzyloxy groups are 4 one (4 one black port Benjiruokishi) group, R ⁴ and R ⁵ together _{_{- (CH 2) 2 -,}} Z Gar (CH ₂₎ ₂ - methanesulfonate of compounds wherein:

Methanesulfonic acid 2- [4-((4-chlorobenzyloxy) phenyl] ethyl ester (see Reference Example 2) (2.20 g), a mixture of ethylenethiourea (0.60 g) and ethanol (20 ml) Was refluxed for 1 晚. The solvent was distilled off under reduced pressure, and dimethyl ether was added to the residue for crystallization. The resulting crystals were collected by filtration and recrystallized from ethyl acetate-nitrile acetate to give the title compound (0.70 g).

Melting point: 114-116 ° C

½- thigh _{(DMS0-d 6) 5:} 2.31 (3H, s), 2.88 (2Η, t, J = 7Hz), 3.41 (2Η, t, J = 7Hz), 3.82 (4H, s), 5.08 (2H , s), 6.94 (2H, d, J = 9Hz), 7.20 (2H, d, J = 9Hz), 7.44 (4H, s), 10.07 (2H, br). elemental analysis (C ₁₈ H ₁₉ C 1 as _{_{CH 3 S0 3 H) - N}} 2 OS:

Calculated value (%) C, 51.52; H, 5.23; N, 6.32

Actual value (%) C, 51.49; H, 5.14; N, 6.39

Example 4

S— “2-—4- (4-cyclobenzyloxy) phenyl 1-ethyl 1-N- (2-hydroxyethyl) isothiourea, methanesulfonate“ In the formula (I), R ¹ , R ² , methane R ^J substituents base Njiruokishi group 4 one (4 black port base Njiruoki sheet) group, R ⁴ is 2-hydroxy E methyl group, R ⁵ is a hydrogen atom, Z gar (CH ₂₎ ₂ one, compound Sulfonate]:

Methanesulfonic acid 2- [4- (4-cyclobenzyloxy) phenyl] ethyl ester (see Reference Example 2) (1.19 g), N- (2-hydroxyethyl) thioperia (0.42 g), A mixture of ethanol (3.5 ml) was refluxed for 3 hours. The solvent was distilled off under reduced pressure, and the residue was crystallized by adding ethyl ether monoethyl acetate-ethanol. The resulting crystals were collected by filtration and recrystallized from acetonitrile to give the title compound (0.27 g).

Melting point: 100-101. C

½-NMR (DMS0-d ₆ ) 5: 2.31 (3H, s), 2.85 (2H, t, J = 7 Hz), 3.31-3.39 (4H, m), 3.49-3.60 (2H, m), 5.05 (1H , Br), 5.07 (2H, s), 6.94 (2H, d, J = 9Hz), 7.18 (2H, d, J = 9Hz) '7.44 (4H, s), 9.01 (IH, br), 9.17 (1H , Br), 9.52 (1H, br).

Elemental analysis (as _{_{_{C 18 H 21 C 1 N 2}}} 0 2 S · CH 3 S0 3 H · 1 / 2H 2 0): Calculated (%) C, 48. 55; H, 5. 58: N, 5 . 96

Actual value (%) C, 48.83; H, 5.40; N, 5.93

Example 5

N, Ν'-I-ethyl-S- [2- [4- (4-chlorobenzyloxy) phenyl 1-ethyl 1-isothiourea-p-toluenesulfonate [In the formula (I),

P-toluenesulfonic acid of a compound in which R ¹ , R, and R ³ substituted benzyloxy groups are 4- (4-cyclobenzyloxy) groups, R ⁴ and R ⁵ are ethyl groups, and Z is — (CH ₂ ) 2 — salt] :

p-Toluenesulfonic acid 2- [4- (4-cyclohexylbenzyloxy) phenyl] ethyl ester (see Reference Example 3) (1.00 g), N, N'-getylthiourea (0.30 g), ethanol (10 ml ) Was refluxed for 1 晚. The solvent was distilled off under reduced pressure, and the residue was crystallized by adding getyl ether. The resulting crystals were collected by filtration and recrystallized from ethyl acetate-nitrile to give the title compound (0.60 g).

Melting point: 1 18-120 ° C

^! H-NMR (DMS0-d ₆ ) <5: 1.13 (6H, t, J = 7Hz), 2.28 (3H, s), 2.85 (2H, t, J = 7Hz), 3.22-3.39 (4H, m), 3.44 (2H, t, J = 7Hz), 5.08 (2H, s), 6.94 (2H, d, J = 9Hz), 7.10 (2H, d, J = 8Hz), 7.17 (2H, d, J = 9Hz), 7.44 (4H, s), 7.47 (2H, d, J = 8Hz), 8.93 (IH, br), 9.07 (IH, br). Elemental analysis [C ₂₀ H ₂₅ C 1 N ₂ OS · _{_{p-CH 3 (C 6 H}} 4) as the S 0 ₃ H]:

Calculated value (%) C, 59.05; H, 6.06; N, 5.10 Actual value (%) C, 58.87; H, 5.98; N, 5.1.1 Example 6

S— [2— [4— (4-Methylbenzyloxy) phenyl] ethyl 1 isothioperia methanesulfonate In the formula (I), R ¹ , R 2 and R ³ substituted benzyloxy Methanesulfonic acid salt of a compound in which (4 monomethylbenzyloxy) group, R ⁴ and R ⁵ are hydrogen atoms and Z is — (CH ₂ ) ₂ —

Methanesulfonic acid 2- [4- (4-methylbenzyloxy) phenyl] ethyl ester (See Reference Example 4) (1.43 g), a mixture of thiopurea (0.34 g), and ethanol (4.4 ml) Was refluxed for 1 晚. The resulting crystals are collected by filtration, washed with ethyl ether, and recrystallized from ethyl acetate-methanol to give the title compound.

(0.70 g) was obtained.

Melting point: 196-198 ° C

^ -NMR (MSO-d _fi ) (5: 2.29 (3H, s), 2.32 (3H, s), 2.84 (2H, t, J = 7Hz), 3.36 (2H, t, J = 7Hz), 5.02 ( 2H, s), 6.93 (2H, d, J = 9Hz), 7.18 (4H, d, J = 9Hz), 7.31 (2H, d, J = 9Hz), 8.98 (4H, br).

Elemental analysis (as _{_{_{C 17 H 20 N 2 OS ·}}} CH 3 S0 3 H):

Calculated value (%) C, 54.52; H, 6.10; N, 7.06

Actual value (%) C, 54.75; H, 6.13; N, 7.11

Example 7

S-“2—“ 4- (3,4-dichlorobenzyloxy) phenyl 1-ethyldiisothiourea methanesulfonate “In the formula (I), R ¹ , R ² , and R ³ substituted benzyloxy groups have 4—1 (3 , 4-dichlorobenzyloxy) group, R ⁴ and R ⁵ are hydrogen atoms, and Z is −1 (CH _? ) 9,1. Methanesulfonic acid salt]: Methanesulfonic acid 2— [4— (3 , 4-Dichloro mouth benzyloxy) phenyl] ethyl ester (see Reference Example 5) (1.67 g), thioperea (0.34 g), and ethanol (4.4 ml) were refluxed for 1 hour. The residue was washed with dimethyl ether and recrystallized from ethyl acetate-methanol to obtain the title compound (1.10 g).

Melting point: 177-178 ° C ½-wake (DMS0-d ₆ ) 5: 2.33 (3H, s), 2.85 (2H, t, J = 7Hz), 3.37 (2H, t, J = 7Hz), 5.10 (2H, s), 6.95 (2H , D, J = 9Hz), 7.20 (2H, d, J = 9Hz), 7.42 (1H, dd, J = 8, 2Hz), 7.64 (1H, d, J = 8Hz), 7.69 (IH, d, J = 2Hz), 8.99 (4H, br).

Elemental analysis (as _{_{_{C 16 H 16 C 1 2 N}}} 2 OS · CH 3 S0 3 H):

Calculated value (%) C, 45.23; H, 4.46; N, 6.21

Actual value (%) C, 45.2 1; H, 4.43; N, 6.27

Example 8

S-"2-" 4- (4-nitrobenzyloxy) phenyl, ethyl] isothiourea methanesulfonate "In the formula (I), R ¹ , R ² , and R ³ substituted benzyloxy groups have 41 (4-nitrobenzyloxy) group, R ⁴ and R ⁵ are hydrogen atoms, and Z is-(CH ₂ ) ₂ methanesulfonate]:

Methanesulfonic acid 2- [4- (4-nitrobenzyloxy) phenyl] ethyl ester (see Reference Example 6) (10.00 g), a mixture of thioperia (2.20 g), and ethanol (100 ml) Was refluxed for 2 hours. The solvent was evaporated under reduced pressure, and the residue solid was recrystallized from ethanol to give the title compound (8.30 g).

Melting point: 175-177V

-NMR (DMS0-d ₆ ) δ: 2.35 (3Η, s), 2.85 (2H, t, J = 7Hz), 3.37 (2H, t, J = 7Hz), 5.26 (2H, s), 6.97 (2H, d, J = 9Hz), 7.21 (2H, d, J = 9Hz), 7.70 (2H, d, J = 8Hz), 8.25 (2H, d, J = 8Hz), 8.99 (4H, br).

Elemental analysis (as _{_{_{_{C 16 H 17 N 3 0 3}}}} S · CH 3 S0 3 H):

Calculated value (%) C, 47.76; H, 4.95; N, 9.83

Obtained value (%) C, 47.54; H, 4.84; N, 9.93

Example 9

S- "2-"-(4- (3-nitrobenzyloxy) phenyl dimethyl] isothiourea methanesulfonate "In the formula (I), R ¹ , R ² , R ³ substituted benzyloxy group is 4 one (3 two Toro benzyl O alkoxy) group, methanesulfonate of R ^4, R ⁵ is a hydrogen atom, Z gar (CH ₂₎ ₂ one, compound:

Methanesulfonic acid 2- [4- (3- (2-nitrobenzyloxy) phenyl] ethyl ester (see Reference Example 7) (3.50 g), thioperia (0.76 g), ethanol A mixture of knol (10 ml) was refluxed for 7 hours. Ethyl acetate was added and the precipitated crystals were collected by filtration and recrystallized from isopropyl alcohol to give the title compound (2.69 g).

Melting point '. 1 63-1 64 ° C

½-soul (DMS0-d _fi ) 5: 2.34 (3H, s), 2.86 (2Η, t, J = 7Hz) '3.37 (2H, t, J = 7Hz), 5.24 (2H, s), 6.99 (2H , D, J = 9Hz), 7.21 (2H, d, J = 9Hz), 7.69 (IH, t, J = 8Hz), 7.90 (IH, dt, J = 8, 1Hz), 8.18 (IH, ddd, J = 8, 2, 1Hz), 8.29 (IH, t, J = 2Hz), 9.01 (4H, br).

Elemental analysis (as _{_{_{_{C 16 H 17 N 3 0 3}}}} S · CH 3 S0 3 H):

Calculated value (%) C, 47.76; H, 4.95; N, 9.83

Obtained value (%) C, 47.71; H, 4.95; N, 9.81

Example 10

S— “2—“ 4-1- (2-chloro-1-4-benzyloxy) phenyl] ethyl 1 isothiourea methanesulfonate “In the formula (I), R ¹ , R ² , and R ^{J are} substituted. base Njiruokishi group 4 one (2- chloro-4 twelve Toro benzyl O alkoxy) group, _R ^4, R ⁵ is a hydrogen atom, one Z gar _ _(? CH) of ₂ one, compound methanesulfonic emissions salt 1:

Methanesulfonic acid 2- [4- (2-chloro-4-212-trobenzyloxy) phenyl] ethyl ester (see Reference Example 8) (1.50 g), thioperia (0.30 g), ethanol (10 The mixture of m 1) was refluxed for 1 晚. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol-isopropyl alcohol to give the title compound.

(1.07 g) was obtained.

Melting point: 180-182 ° C

½-NMR (DMS0-d ₆ ) <5: 2.34 (3H, s), 2.87 (2H, t, J = 7 Hz), 3.38 (2H, t, J = 7 Hz), 5.26 (2H, s), 7.00 ( 2H, d, J = 9Hz), 7.23 (2H, d, J = 9Hz), 7.85 (IH, d, J = 9Hz), 8.25 (IH, dd, J = 9, 2Hz), 8.35 (IH, d, J = 2Hz), 9.01 (4H, br).

Elemental analysis (as _{_{_{C 16 H 16 C 1 N 3}}} 0 3 S · CH 3 S0 3 H):

Calculated value (%) C, 44.20; H, 4.36; N, 9.10

Actual value (%) 44.37; H, 4.43; N, 9.07

Example 1 1 N-ethyl-S— “2-—4- (4-chlorobenzyloxy) phenyl: 1-ethyl-1-isothiourea methanesulfonate” In the formula (I), R ¹ , R ² , and R ³ -substituted benzyloxy groups Is a methanesulfonic acid salt of a compound in which is a 4- (4-cyclobenzyloxy) group, R ⁴ is an ethyl group, R ⁵ is a hydrogen atom, and Z is — _ (CH ₂ ) ₂ —.

Methanesulfonic acid 2- [4- (4-chlorobenzyloxy) phenyl] ethyl ester (see Reference Example 2) (1.00 g), a mixture of ethylthioperia (0.30 g), and ethanol (10 ml) was refluxed for 1 hour. did. The solvent was distilled off under reduced pressure, and the residue solid was recrystallized from acetonitrile to obtain the title compound (0.70 g).

Melting point: 1 14-1 16 ° C

½— NMR (DMS0-d ₆ ) 5: 1.12 (3H, t, J = 7Hz), 2.30 (3H, s), 2.84 (2H, t, J = 7Hz), 3.28 (2H, q, J = 7Hz) , 3.40 (2H, t, J = 7Hz), 5.07 (2H, s) '6.94 (2H, d, J = 9Hz), 7.18 (2H, d, J = 9Hz), 7.44 (4H, s), 9.10 ( 2H, br), 9.48 (1H, br).

Elemental analysis (as C _lg H ₂₁ C 1 N ₂ OS · CH ₃ SO ₃ H):

Calculated value (%) C, 5 1.28; H, 5.66; N, 6.30

Actual value (%) C, 51.36; H, 5.60; N, 6.26

Example 12

2— “2—“ 4- (2,4-diclo-benzyloxy) phenyl dimethyl] thio 4,5—dihydroimidazole * methanesulfonate “In the formula (I), R ¹ , R ² , R ³ A compound in which the substituted benzyloxy group is a 4- (2,4-dichlorobenzene) group, and R ⁴ and R ⁵ are joined together to form one (CH ₂ ) ₂ — and Z is — (CH ₂ ) ₂ — Methanesulfonate]:

Methanesulfonic acid 2- [4- (2,4-dichlorobenzyloxy) phenyl] ethyl ester (see Reference Example 9) (2.00 g), ethylene thiourea (0.65 g), ethanol (20 ml) The mixture was refluxed for 2 hours. The solvent was distilled off under reduced pressure, and acetonitrile was added to the residue for crystallization. The resulting crystals were collected by filtration and recrystallized from acetonitrile-ethanol to give the title compound (0.80 g).

Melting point: 1 77-1 80 ° C

^ -NMR (DMS0-d ₆ ) (5: 2.30 (3H, s), 2.90 (2H, t, J = 7Hz), 3.41 (2H, t, J = 7Hz), 3.83 (4H, s), 5.1K2H, s), 6.97 (2H, d, J = 8Hz), 7.22 (2H, d, J = 8Hz), 7.47 (IH, dd, J = 8, 2Hz), 7.60

(1H, d, J = 8Hz), 7.67 (1H, d, J = 2Hz), 10.06 (2H, br).

Elemental analysis value (as C _lg H ₁₈ C 1 ₂ N ₂ OS · CH ₃ S0 ₃ H):

Calculated value (%) 47.80; H, 4.64; N, 5.87

Obtained value (%) 47. 70; H, 4.62; N, 5.85

Example 13 o 4,5-Dihydroimidazole "In the formula (I), R ¹ , R ² , R ³ -substituted benzyloxy group is a 4- (4-monobenzyloxy) group, and R ⁴ is Compound in which 1 (CH ₂ ) ₉ 1 and Z are —CH ₂ 0 (CH ^) 2 1]: 2— [4- (4-chlorobenzyloxy) benzyloxy] ethyl chloride

(Refer to Reference Example 10) A mixture of (1.00 g), ethylene thiourea (0.33 g), and ethanol (10 ml) was refluxed for 24 hours. Further, potassium iodide (0.53 g) was added, and the mixture was refluxed for 3 days. An aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer is washed with an aqueous solution of sodium hydrogen carbonate, dried, and the solvent is distilled off under reduced pressure. The residue is subjected to medium pressure liquid chromatography (MS: methanol = methanol = 10: 1 (V / V)). After purification, recrystallize from ethanol to give the title compound

(0.28 g) was obtained.

Melting point: 96-98 ° C

½-title K (DMS0-d ₆ ) <5: 3.16 (2H, t, J = 6Hz), 3.37-3.52 (4Η, m), 3.58 (2Η, t, J = 6Hz), 4.39 (2H, s), 5.09 (2H, s), 6.58 (1H, br), 6.96 (2H, d, J = 9Hz), 7.23 (2H, d, J = 9Hz), 7.44 (4H, s).

Elemental analysis (as _{_{_{C 19 H 21 C 1 N 2}}} 0 2 S):

Calculated value (%) C. 60.55; H, 5.62; N, 7.43

Actual value (%) C, 60.50; H, 5.66; N, 7.24

Example 14

2— [2— “4- (3,4-dichlorobenzyloxy) phenyl, ethyl チル thio 4,5-dihydroimidazole.methanesulfonate” In the formula (I), R ¹ , _R, R ^4- substituted benzyloxy group B) the methanesulfonate of a compound in which the radicals R ⁴ and R ⁵ together form one (CH ₂ ) 2 — and Z is — (CH ₂ ) 21

Methanesulfonic acid 2- [4- (3,4-dichroic benzyloxy) phenyl] ethyl ester (see Reference Example 5) (4.33 g), a mixture of ethylenethioperia (1.12 g) and ethanol (40 ml) Was refluxed for 21 hours. The solvent was distilled off under reduced pressure, and the crystals of the residue were recrystallized from acetonitrile to obtain the title compound (3.37 g).

Melting point: 1 1 1 ~ 1 12 ° C

½- thigh _{(DMSO- d 6) (5:} 2.30 (3H, s), 2.89 (2H, t, J = 7Hz), 3.41 (2H, t, J = 7Hz), 3.82 (4H, s), 5.10 ( 2H, s), 6.95 (2H, d, J = 8Hz), 7.21 (2H, d, J = 8Hz), 7.42 (IH, dd, J = 8, 2Hz), 7.65

(IH, d, J = 8Hz), 7.70 (1H, d, J = 2Hz), 10.06 (2H, br).

Elemental analysis (as _{_{_{C 18 H 18 C 1 2 N}}} 2 OS · CH 3 S0 3 H):

Calculated value (%) C, 47.80; H, 4.64; N, 5.87

Obtained value (%) C, 47.54; H, 4.63; N, 5.74

Example 15

N._ N '—Jetil one S— 丄 2— 丄 4— (3 ^ 4—dichlorobenzene:

[Phenyl] ethyl 1 isothiourea methanesulfonate [In the formula (I), R ¹ , R ² , and R ³ substituted benzyloxy groups are 4- (3,4-dichlorobenzene) groups, and R ⁴ and R ⁵ are Methanesulfonate of a compound that is an ethyl group, H (CH ₂ ) ₂ —

Methanesulfonic acid 2- [4- (3,4-dichlorobenzyloxy) phenyl] ethyl ester (see Reference Example 5) (6.38 g), N, N'-Jetylthiourea (1.92 g), ethanol ( (40 ml) was refluxed for 1 晚. The solvent was distilled off under reduced pressure, dimethyl ether was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give the title compound (5.00 g).

Melting point: 74-75 ° C

½- MR (MS0-d _fi ) 5: 1.13 (6H, t, J = 7Hz), 2.31 (3H, s), 2.86 (2H, t, J = 7Hz), 3.20-3.40 (4H, m) , 3.45 (2H, t, J = 7Hz), 5.10 (2H, s), 6.95 (2H, d, J = 9Hz), 7.18 (2H, d, J = 9Hz), 7.41 (IH, dd, J = 8 , 2Hz), 7.64 (IH, d, J = 8Hz), 7.68 (IH, d, J = 2Hz), 8.93 (1H, br), 9.11 (1H, br).

Elemental analysis (as _{_{_{C 20 H 24 CI 2 N 2}}} OS · CH 3 S 0 3 H):

Calculated value (%) C, 49.70; H, 5.56; N, 5.52

Actual value (%) C, 49.44; H, 5.51; N, 5.41

Example 16

S— “2- (4-benzyloxyphenyl) ethyl, isothiourea. Methanesulfonate” In the formula (I), R ¹ ,, R ³ -substituted benzyloxy groups are replaced by 4 benzyloxy groups, R ⁴ , Methanesulfonate of a compound in which R ⁰ is a hydrogen atom and — Z is — (CH ₂ ) 2 —

A mixture of methanesulfonic acid 2- (4-benzyloxyphenyl) ethyl ester (see Reference Example 11) (1.00 g), thioperia (0.25 g), and ethanol (10 ml) was refluxed for 1 hour. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with acetonitrile and recrystallized from ethanol to give the title compound (0.50 g).

Melting point: 186-188 ° C

½ -丽_{(DMS0- d 6) 5: 2.31} (3H, s), 2.85 (2H, t, J = 7Hz), 3.37 (2H, t, J = 7Hz), 5.08 (2H, s), 6.95 (2H , d, J = 9Hz), 7.19 (2H, d, J = 9Hz), 7.31-7.45 (5H, m), 8.98 (4H, br).

Elemental analysis _{_{_{(C 16 H lg N 2 OS}}} - as CH _₃ S0 ₃ H):

Calculated value (%) C, 53.38; H, 5.80; N, 7.32

Actual value (%) C, 53.28; H, 5.62; N, 7.33

Example 17

S— “2—“ 4— (2,3,6-trichloromethylbenzyloxy) phenyl 1-ethylisothiourea methanesulfonate “In the formula (I), R ¹ , R ² , and R ^a substituted benzyloxy groups Is a methanesulfonate of a compound in which R is a 4- (2,3,6-trichloromethylbenzyloxy) group, R ⁴ and R ⁵ are hydrogen atoms, and Z is — (CH ₂ ) 2 —.

Methanesulfonic acid 2- [4- (2,3,6-trichloromethylbenzyloxy) phenyl] ethyl ester (see Reference Example 12) (2.00 g), thioperia (0.37 g), and ethanol (10 ml) Was refluxed for 1 晚. The solvent is distilled off under reduced pressure Then, ethyl acetate was added to the residue for crystallization. The generated crystals were collected by filtration and recrystallized from ethanol to give the title compound (1.50 g).

Melting point: 164 ~ 166 ° C

½- Hokusatsu _{(DMSO- d 6) 5: 2.21} (3H, s), 2.88 (2H, t, J = 7Hz), 3.40 (2H, t, J = 7Hz), 5.24 (2H, s), 7.01 (2H , d, J = 9Hz), 7.23 (2H, d, J = 9Hz), 7.61 (1H, d, J = 9Hz), 7.76 (1H, d, J = 9Hz), 8.94 (2H, br), 9.03 ( 2H, br).

Elemental analysis (as _{_{_{C 16 H 15 C 1 3 N}}} 2 OS · CH 3 S0 3 H):

Calculated value (%) C, 42.03; H, 3.94; N, 5.77

Actual value (%) C, 41.92; H, 3.91; N, 5.78

Example 18

S- “2 -—” 4- (4-methoxybenzyloxy) phenyl 1-ethyl] isothiourea.methanesulfonate [In the formula (I), R ¹ , R ² , and R ³ -substituted benzyloxy groups have 41- (4-Methoxybenzyloxy) group, R ⁴ and R ⁵ are hydrogen atoms, and Z is — (CH ₂ ) 21 methanesulfonate]:

Methanesulfonic acid 2- [4- (4-methoxybenzyloxy) phenyl] ethyl ester (see Reference Example 13) (1.50 g), a mixture of thioperia (0.34 g), and ethanol (5 ml) Was refluxed for 1 晚. The resulting crystals were collected by filtration, washed with getyl ether, and recrystallized from isopropyl alcohol to give the title compound (0.81 g).

Melting point: 175 ~ 176 ° C

NMR (DMS0-d ₆ ) 5: 2.32 (3H, s), 2.84 (2H, t, J = 7 Hz), 3.37 (2H, t, J = 7 Hz), 3.74 (3H, s) '4.98 (2H, s) ), 6.92 (4H, d, J = 9Hz), 7.15 (2H, d, J = 9Hz), 7.45 (2H, d, J = 9Hz), 9.00 (4H, br).

Elemental analysis (as _{_{_{_{C 17 H 20 N 2 0 2}}}} S · CH 3 S0 3 H):

Calculated value (%) C, 52.41; H, 5.86; N, 6.79

Actual value (%) C, 52.58; H, 5.91; N, 6.60

Example 19

2-"2-" 2-(4-cyclobenzyloxy) phenyl] ethyl] thiol is also 5-dihydroimidazole methanesulfonate [-R ^{1 in} formula (I). , R ² , R ³ substituted benzyloxy group is a 2- (4-monobenzyloxy) group, R ⁴ and R ⁵ are joined together, — (CH ₂ ) 2 —, Z is — (CH ₂ ) 2 The methanesulfonate of a compound 1:

Methanesulfonic acid 2- [2- (4-chlorobenzyloxy) phenyl] ethyl ester (See Reference Example 14) (2.00 g), a mixture of ethylenethioperia (0.49 g) and ethanol (15 ml) Was refluxed for 1 晚. The solvent was distilled off under reduced pressure, and diisopropyl ether was added to the residue for crystallization. The generated crystals were collected by filtration and recrystallized from acetonitrile to obtain the title compound (1.34 g).

Melting point: 1 11-1-13. C

_{½ - NMR (CDC1 3) 5} : 2.70 (3H, s), 3.05 (2Η, t, J = 7Hz), 3.50 (2H, t, J = 7Hz), 3.68 (4H, s), 5.06 (2H, s ), 6.87-6.95 (2H, m), 7.17-7.24 (2H, m), 7.39 (4H, s), 9.71 (2H, br). Elemental analysis (C _lg H ₁₉ C 1 N ₂ OS · CH ₃ S0 ₃ H):

Calculated value (%) C, 51.52; H, 5.23; N, 6.32

Actual value (%) 51.30; H, 5.20; N, 6.30

Example 20

2-"2-" 3-(4-monobenzyloxy) phenyl] ethyl 1 thio 4,5-dihydroimidazole * methanesulfonate "In formula (I), R ¹ , R,: substituted benzyloxy group is 3 — (4-cyclobenzyloxy) group, where R ⁴ and R ⁵ are joined together— (CH ₂ ) 2 —, and methanesulfonate of a compound in which Z is — (CH ₂ ) 2 1]:

Methanesulfonic acid 2- [3- (4-chlorobenzyloxy) phenyl] ethyl ester (see Reference Example 15) (1.75 g), ethylene thiourea (0.43 g), ethanol (2 Oml) The mixture was refluxed for 1 晚. The solvent was distilled off under reduced pressure, and diisopropyl ether was added to the residue for crystallization. The generated crystals were collected by filtration and recrystallized from acetonitrile to give the title compound (0.75 g).

Melting point: 96-98 ° C

_{½- NMR (CDC1 3) 5:} 2.74 (3H, s), 2.96 (2H, t, J = 7Hz), 3.54 (2H, t, J = 7Hz), 3.79 (4H, s), 5.03 (2H, s ), 6.80-6.85 (2H, m), 6.90 (1H, t, J = 2Hz), 7.20 (1H, t, J = 8Hz), 7.32-7. 40 (4H, m), 9.92 (2H, br) . Elemental analysis values (as C ₁₈ H ₁₉ C 1 N ₂ OS · CH ₃ SO ₃ H):

Calculated value (%) C, 51.52; H, 5.23; N, 6.32

Actual value (%) C, 51.42; H, 5.21; N, 6.13

Reference example 1

4 one (4 one black port Benjiruokishi) benzyl chloride "te formula (III) ^{^{smell, R 1, R 2, R}} 3 substituents base Njiruokishi group 4 one (4 one black port base Njiruoki sheet) group, Z gar _CH? -, Compounds in which Y is a chlorine atom:!:

4- (4-cyclobenzyloxy) benzyl alcohol [European Journal of Medicinal Chemistry-Chimie Therapeutique, 19, 205-214 (1984)] (3.00 g) and thionyl chloride (3 ml) are mixed at 0 ° C with 1 After stirring for an hour, excess thionyl chloride was distilled off under reduced pressure. Diisopropyl ether-hexane was added to the residue for crystallization. The generated crystals were collected by filtration and washed with diisopropyl ether to give the title compound (1.50 g).

Melting point: 72-74 ° C

½-NMR (CDClo) 5: 4.57 (2H, s), 5.04 (2Η, s), 6.94 (2Η, d, J = 9Hz), 7.32 (2H, d, J = 9Hz), 7.37 (4H, s) .

Elemental analysis (as _{_{_{C 14 H 12 C 1 2 O}}} ):

Calculated value (%) C, 62.94; H, 4.53; N, 0.00

Actual value (%) C, 63.15; H, 4.59; N, 0.09

Reference example 2

Methanesulfonic acid 2 -— (4- (4-cyclobenzyloxy) phenyl) ethyl ester [In the formula (III), R ¹ , R ² , R ³ -substituted benzyloxy groups are 4- (4-cyclobenzyloxy) groups, Z gar (CH ₂₎ ₂ one, compound Y is a methanesulfo Niruokishi group:

2- [4- (4-Broctobenzyloxy) phenyl] ethyl produced from 4-chlorobutenyl chloride and 2- (4-hydroxyphenyl) ethyl alcohol by a method according to Japanese Patent Application Laid-Open No. 50-148357. A mixture of alcohol (1.00 g), methanesulfonyl chloride (0.48 g), triethylamine (0.4 ml) and methylene chloride (10 ml) was stirred at 110 ° C for 30 minutes. Add water and click Extracted with loroform. The organic layer was washed with water, diluted hydrochloric acid, aqueous sodium hydrogen carbonate solution and brine, dried, and the solvent was distilled off under reduced pressure. The residue solid was recrystallized from diisopropyl ether to give the title compound (0.87 g).

Melting point: 97-99 ° C

½- Kasumi _{(CDC1 3) δ 2.86 (3Η} , s), 3.01 (2H, t, J = 7Hz), 4.39 (2H, t, J = 7Hz), 5.03 (2H, s), 6.92 (2H, d, J = 9Hz), 7.16 (2H, d, J = 9Hz), 7.36 (4H, s).

Elemental analysis (as _{_{_{C 16 H 17 C 1 0 4}}} S):

Calculated value (%) C, 56.39; H, 5.03; N, 0.00

Actual value (%) 56.60; H, 5.00; N, 0.03

Reference example 3

p-Toluenesulfonic acid 2- [4- (4-chlorobenzyloxy) phenyl 1-ethyl ester In formula (III), R ¹ , R ² , and R ³ -substituted benzyloxy groups are 4- (4-cyclobenzyloxy) groups A compound wherein Z is — (CH ₂ ) 1 and Y is a p-toluenesulfonyloxy group]:

4- [4- (4-chlorobenzyloxy) phenyl] ethyl produced from 4-chlorobenzylbenzene and 2- (4-hydroxyphenyl) ethyl alcohol by a method according to Japanese Patent Application Laid-Open No. 50-148357. A mixture of alcohol (1.00 g), p-toluenesulfonyl chloride (0.73 g), triethylamine (0.46 g) and methylene chloride (10 ml) was stirred at 0 ° C for 1 °. . Water was added, and the mixture was extracted with black-mouthed form. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid column chromatography [hexane: ethyl acetate = 4: 1 (VA)], and recrystallized from diisopropyl ether to give the title compound (1.17 g).

Melting point: 96-97 ° C

_{½ - NMR (CDC1 0) δ} : 2.44 (3Η, s), 2.90 (2H, t, J = 7Hz), 4.17 (2H, t, J = 7Hz), 5.01 (2H, s), 6.85 (2H, d , J = 9Hz), 7.04 (2H, d, J = 9Hz), 7.29 (2H, d, J = 9Hz), 7.36 (4H, s), 7.71 (2H, d, J = 9Hz).

Elemental analysis (as _{_{_{C 22 H 21 C 1 0 4}}} S):

Calculated value (%) C, 63.38; H, 5.08; N, 0.00 Actual value (%) C, 63.42; H, 5.08; N, 0.01 Example 4

Methanesulfonic acid 2- [4- (4-methylbenzyloxy) phenyl] ethyl ester [In the formula (III), R ¹ , R ² , R ° substituted benzyloxy groups are substituted by 4- (4-methylbenzyloxy) A compound wherein Z is — (CH ₂ ) 2 Y and Y is a methanesulfonyloxy group]:

4-Methylbenzyl chloride [manufactured by Tokyo Chemical Industry Co., Ltd.] and 2- (4-hydroxyfurnil) ethyl alcohol [manufactured by Tokyo Chemical Industry Co., Ltd.] prepared by a method according to Japanese Patent Application Laid-Open No. 50-148357. [4- (4-methylbenzyloxy) phenyl] ethyl alcohol (1.38 g), methanesulfonyl chloride (0.72 g), triethylamine (1.2 ml) and methylene chloride (20 ml) Was stirred at 0 for 30 minutes. Water was added and extracted with black-mouthed form. The organic layer was washed with water, diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and brine, dried, and the solvent was distilled off under reduced pressure. The residue crystals were washed with hexane to give the title compound (1.80 g).

Melting point: 79-80 ° C

½-MR (CDClo) δ: 2.37 (3H, s), 2.84 (3Η, s), 3.00 (2Η, t, J = 7Hz), 4.38 (2Η, t, J = 7Hz), 5.02 (2Η, s) , 6.93 (2H, d, J = 9Hz), 7.15 (2H, d, J = 9Hz), 7.20 (2H, d, J = 8Hz), 7.32 (2H, d, J = 8Hz).

Elemental analysis (as _{_{_{C 17 H 20 O 4 S)}}} :

Calculated value (Q / o) C, 63.73; H, 6.29;, 0.00

Actual value (%) C, 63.84; H, 6.41; N, 0.08

Reference example 5

Methanesulfonic acid 2-[[4- (3,4-dichlorobenzyloxy) phenyl] ethyl ester "In the formula (III), R ¹ , R ² , and R ³ -substituted benzyloxy groups are 4- (3,4-dichlorobenzyloxy) groups. , Z is — (CH ₂ ) 2, Y is a methyl sulfonyloxy group]:

3,4-Dichloro mouth benzyl chloride [manufactured by Tokyo Chemical Industry Co., Ltd.] and 2- (4-hydroxyphenyl) ethyl alcohol [manufactured by Tokyo Chemical Industry Co., Ltd.] 2- [4- (3- (4-dichloroporous benzyloxy) phenyl] ethyl alcohol (1.69 g), methanesulfonyl chloride (0.72 g), triethylamine (1 2 ml) and methylene chloride (20 ml) were stirred at 0 ° C for 30 minutes. Water was added and extracted with black-mouthed form. The organic layer was washed with water, diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and brine, dried, and then the solvent was distilled off under reduced pressure. The crystals of the residue were washed with hexane to obtain the title compound (2.06 g).

Melting point: 83-84 ° C

_{½- NMR (CDC1 3) 5:} 2.87 (3H, s), 3.01 (2H, t, J = 7Hz) '4.39 (2H, t, J = 7Hz), 5.01 (2H, s), 6.91 (2H, d , J = 9Hz), 7.17 (2H, d, J = 9Hz), 7.26 (IH, dd, J = 8, 2Hz), 7.46 (IH, d, J =

8Hz), 7.54 (IH, d, J = 2Hz).

Elemental analysis (as _{_{_{C 16 H 16 C 1 2 0}}} 4 S):

Calculated value (%) 51. 21; H, 4.30; N, 0.00

Actual value (%) 51.10; H, 4.40; N, 0.00

Reference example 6

Methanesulfonic acid 2 -— (4- (4-nitrobenzyloxy) phenyl] ethyl ester In formula (III), R ¹ , R ² , and R ° -substituted benzyloxy groups are substituted with 4 -— (4-nitrobenzyloxy). A compound wherein Z is — (CH ₂ ) 2 — and Y is a methanesulfonyloxy group.

From 4-nitrobenzyl chloride [manufactured by Tokyo Chemical Industry Co., Ltd.] and 2- (4-hydroxyphenyl) ethyl alcohol [manufactured by Tokyo Chemical Industry Co., Ltd.]

2- [4- (4-nitrobenzyloxy) phenyl] ethyl alcohol (0.75 g), methanesulfonyl chloride (0.38 g), and triethylamine (0.41) produced by a method according to 148357 g) and acetonitrile

(10 ml) was stirred at 0 ° C. for 30 minutes. Water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried, and the solvent was distilled off under reduced pressure. The residue solid was recrystallized from disopropyl ether monoethyl acetate to give the title compound (0.

72 g) were obtained.

Melting point: 99-100 ° C 丄 H-NMR (CDCI3) 5: 2.89 (3H, s), 3.02 (2H, t, J = 7Hz), 4.39 (2H, t, J = 7Hz), 5.17 (2H, s), 6.93 (2H, d , J = 9Hz), 7.18 ( 2H, d, J = 9Hz), 7.61 (2H, d, J = 9Hz), 8.26 (2H, d, J = 9Hz). elemental analysis (C ₁₆ H ₁₇ N0 ₆ S As):

Calculated value (%) C, 54.69; H, 4.88; N, 3.99

Actual value (%) C, 54.70; H, 4.92; N, 3.66

Reference Example 7

Methanesulfonic acid 2— “4- (3-Nitrobenzyloxy) phenyl 1-ethyl ester” In the formula (III), R ¹ , R ² , and R ³ -substituted benzyloquine groups are substituted by 4-(3-Nitrobenzyloxy) ) group, Z gar (CH ₂₎ ₂ one, compound Y is a methanesulfo Niruokin group:

It is manufactured from 3-nitrobenzoyl chloride [manufactured by Tokyo Chemical Industry Co., Ltd.] and 2- (4-hydroxyphenyl) ethyl alcohol [manufactured by Tokyo Chemical Industry Co., Ltd.] by a method according to Japanese Patent Application Laid-Open No. 50-148357. 2- [4- (3-nitrobenzylquine) phenyl] ethyl alcohol (0.75 g), methanesulfonyl chloride (0.38 g), triethylamine (0.41 g) and acetonitrile (20 ml) ) Was stirred at 0 ° C for 30 minutes. Water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid column chromatography (black-mouthed form) to obtain the title compound (0.85 g).

Melting point: 65-67 ° C

½- Spirit _{(CDC1 3) (5: 2.88} (3H, s), 3.02 (2H, t, J = 7Hz), 4.39 (2H, t, J = 7Hz), 5.16 (2H, s), 6.94 (2H, d, J = 9Hz), 7.19 (2H, d, J = 9Hz), 7.58 (IH, t, J = 8Hz), 7.78 (IH, d, J = 8Hz),

8.20 (IH, d, J = 7Hz), 8.32 (IH, s).

Elemental analysis (as _{_{_{C 16 H 17 N0 6 S)}}} :

Calculated value (%) C, 54.69; H, 4.88; N, 3.99

Actual value (%) C, 54.83; H, 4.92; N, 3.67

Reference Example 8

Methanesulfonic acid 2 -— “4- (2-chloro-412-trobenzyloxy) phenyl 1-ethyl ester [In formula _ (III), ^ R ¹ , _R ⁰ , _R ³ _ ^ Okishi group 4 one (2- chloro-4-nitrobenzyl O alkoxy) group, Z gar (CH ₂ I) 2 one, compound Y is a methanesulfonyl O carboxymethyl group:

From 2-chloro-412 trobenzyl chloride [manufactured by Tokyo Chemical Industry Co., Ltd.] and 2- (4-hydroxyphenyl) ethyl alcohol [manufactured by Tokyo Chemical Industry Co., Ltd.], according to Japanese Patent Application Laid-Open No. 50-148357. 2- [4- (2-chloro-412-trobenzyloxy) phenyl] ethyl alcohol (3.89 g), methansulfonyl chloride (1.73 g), and triethylamine (1.53 g) produced by the method ) And methylene chloride (40 ml) were stirred at 0 ° C for 1 hour. Water was added and extracted with chloroform. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue solid was recrystallized from benzene to give the title compound (3.26 g).

Melting point: 125-127 ° C

^ -NMR (CDCIQ) (5: 2.90 (3H, s), 3.03 (2H, t, J = 7 Hz), 4.40 (2H, t, J = 7 Hz), 5.22 (2H, s), 6.95 (2H, d , J = 9Hz), 7.20 (2H, d, J = 9Hz), 7.82 (IH, d, J = 9Hz), 8.18 (1H, dd, J = 9,

2Hz), 8.30 (IH, d, J = 2Hz).

Elemental analysis (as _{_{_{C 16 H 16 C 1 N0 6}}} S):

Calculated value (%) C, 49.81; H, 4.18; N, 3.63

Actual value (%) C, 50.00; H, 4.20; N, 3.58

Reference Example 9

Methanesulfonic acid 2- [4- (2,4-dichroic benzyloxy) phenyl 1-ethyl ester In formula (III), R ¹ , R ² , and R ³ -substituted benzyloxy groups have 41- (2,4-dichloro-opening benzyloxy). ) group, Z gar (CH ₂₎ ₂ one, compound Y is a methanesulfonyl O carboxymethyl group:

2,4-Dichloro mouth benzyl chloride [manufactured by Tokyo Chemical Industry Co., Ltd.] and 2- (4-hydroxyphenyl) ethyl alcohol [manufactured by Tokyo Chemical Industry Co., Ltd.] by a method according to Japanese Patent Application Laid-Open No. 50-148357. Manufactured 2- [4- (2,4-dichroic benzoyloxy) phenyl] ethyl alcohol (0.15 g), methanesulfonylc mouth ride (0.07 g), triethylamine (0.08 g) ) And acetonitrile

(20 ml) was stirred at 0 ° C. for 30 minutes. Water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried, and the solvent was distilled off under reduced pressure. Acetic acid residue Crystallization from ethyl hexane gave the title compound (0.12 g).

Melting point: 58-59 ° C

½-NMR (CDClo) 5: 2.87 (3H, s), 3.01 (2H, t, J = 7Hz), 4.39 (2H, t, J = 7Hz), 5.11 (2H, s), 6.93 (2H, d, J = 9Hz), 7.18 (2H, d, J = 9Hz), 7.28 (IH, dd, J = 8, 2Hz), 7.43 (IH, d, J =

2Hz), 7.50 (IH, d, J = 8Hz).

Elemental analysis (as _{_{_{_{C 16 H 16 CI 2 0 4}}}} S):

Calculated value (%) C, 51.21; H, 4.30; N, 0.00

Actual value (%) C, 51.15; H, 4.39; N, 0.02

Reference example 10

2— “4- (4-chlorobenzyloxy) benzyloxy] ethyl chloride“ In the formula (III), R ¹ , R ³ -substituted benzyloxy groups are 4- (4-cyclobenzyloxy) groups, and Z is —CH ₂₀ 0 (CH ₂ ) ₂ —, compound 1 in which Y is a chlorine atom 1:

4- (4-chlorobenzyloxy) benzyl alcohol [European Journal of Medicinal Chemistry-Chimie Therapeutique _N 19 _x 205-214 (1984)], 5.32 g), ethylene chlorohydrin (8.61 g), toluene ( 55 ml) and sulfuric acid (0.57 ml) were stirred at 0 ° C for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid column chromatography [cloth form: hexane = 1: 1 (V / V)] to give the title compound (2.53 g).

Melting point: 54-56 ° C

½-NMK (CDC1 ₃ ) δ: 3.61-3.73 (4Η, in), 4.52 (2H, s), 5.03 (2H, s), 6.93 (2H, d, J = 9Hz),

7.27 (2H, d, J = 9Hz), 7.36 (4H, s).

Elemental analysis (as _{_{_{C 16 H 16 C 1 2 0}}} 2):

Calculated value (%) C, 61.70; H, 5.19; N, 0.00

Actual value (%) C, 61.79; H, 5.16; N, 0.04

Reference example 1 1

Methanesulfonic acid 2- (4-benzyloxyphenyl) ethyl ester [In the formula (III), _R ² , R ³ MJ Alkoxy group, Z gar (CH ₂₎ ₂ one, Y is methanesulfonyl O carboxymethyl compound L- benzylchloride line de is a group [Tokyo Kasei Co., Ltd.] and 2- (4-hydroxy phenylene) ethyl alcohol [ 2- (4-benzyloxyphenyl) ethyl alcohol (1.30 g), methanesulfonyl chloride (0.70) manufactured by Tokyo Chemical Industry Co., Ltd.] by a method according to Japanese Patent Application Laid-Open No. 50-148357. A mixture of triethylamine (0.90 g) and dimethyl chloride (15 ml) was stirred for 30 minutes at 110 ° C. Water was added, and the mixture was extracted with chloroform.The organic layer was diluted with hydrochloric acid, water, and aqueous sodium hydrogen carbonate. After washing with water, brine and drying, the solvent was evaporated under reduced pressure, and the solid residue was recrystallized from diisopropyl ether to give the title compound (1.52 g).

Melting point: 66-67 ° C

(2H, s), 6.94 (2H, d, J = 9Hz), 7.16 (2H, d, J = 9Hz), 7.33-7.46 (5H, m)

Elemental analysis (as _{_{_{C 16 H lg 0 4 S)}}} :

Calculated value (%) C, 62.73; H, 5.72; N, 0.00

Actual value (%) C, 62.84; H, 5.86; N, 0.02

Reference Example 12

Methanesulfonic acid 2 -— “4- (2,3,6-trichloromethylbenzyloxy) phenyl 1-ethyl ester” In the formula (III), R ¹ , R ² , and R ³ -substituted benzyloxy groups have 4—1 (2,3 , 6-trichloro port Benjiruokishi) group, Z gar (CH ₂₎ ₂ one, Y is methanesulfonyl O alkoxy group compounds:

Methanesulfonic acid 2,3,6-trichlorobenzyl ester [2,3,6-trichlorobenzaldehyde [Tokyo Kasei Co., Ltd.]] reduced with sodium borohydride and then reacted with methanesulfonyl chloride And 2- (4-hydroxyphenyl) ethyl alcohol [manufactured by Tokyo Chemical Industry Co., Ltd.] by a method according to Japanese Patent Application Laid-Open No. 50-148357. 2- [4- (2,3,6-trichloromethylbenzyloxy)] Phenyl] ethyl alcohol (2.95 g), methanesulfonyl chloride (1.12 g), triethylamine (1.08 g) and methyl chloride (20 ml) was stirred at 0 ° C. for 30 minutes. Water was added and extracted with a black-mouthed holm. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid column chromatography (black-mouthed form) to give the title compound (3.

03 g) was obtained.

½-NMR (CDC1 ₃ ) 5: 2.89 (3H, s), 3.03 (2H, t, J = 7 Hz), 4.41 (2H, t, J = 7 Hz), 5.29 (2H, s), 6.99 (2H, d , J = 9Hz), 7.20 ( 2H, d, J = 9Hz), 7.33 (IH, d, J = 9Hz), 7.45 (1H, d, J = 9Hz) · elemental analysis (C ₁₆ H ₁₅ C 1 ₃ 0 ₄ S):

Calculated value (%) C, 46.91; H, 3.69; N, 0.00

Actual value (%) C, 46.68; H, 3.62; N, 0.06

Reference Example 13

Methanesulfonic acid 2 -— “4- (4-methoxybenzyloxy) phenyl] ethyl ester In the formula (III), R ¹ , R ² , and R ³ -substituted benzyloxy groups are substituted by 4- (4-methoxybenzyl). Okishi) group, Z gar (CH ₂₎ ₂ one, two compounds Y is a methanesulfonic Ruhoniruokishi group:

A 2-methoxybenzyl chloride [manufactured by Tokyo Chemical Industry Co., Ltd.] and 2- (4-hydroxyphenyl) ethyl alcohol [manufactured by Tokyo Chemical Industry Co., Ltd.] manufactured by a method according to Japanese Patent Application Laid-Open No. 50-148357. — [4 -— (4-Methoxybenzyloxy) phenyl] ethyl alcohol (0.74 g), methanesulfonyl chloride (0.36 g), triethylamine (0.6 ml) and methylene chloride (10 ml) ) Was stirred at 0 ° C for 30 minutes. Water was added and extracted with black-mouthed form. The organic layer was washed with water and diluted hydrochloric acid, dried, and then the solvent was distilled off under reduced pressure. The solid residue was washed with getyl ether and recrystallized from ethyl acetate to give the title compound (0.40 g).

Melting point: 96-97 ° C

_{½ - NMR (CDC1 3) 5} : 2.84 (3H, s), 3.00 (2H, t, J = 7Hz), 3.82 (3H, s), 4.39 (2H, t, J = 7Hz), 4.98 (2H, s ), 6.92 (2H, d, J = 9Hz), 6.93 (2H, d, J = 9Hz), 7.16 (2H, d, J = 9Hz), 7.35 (2H, d, J = 9Hz).

Elemental analysis (as _{_{_{C 17 H 20 O 5 S)}}} :

Calculated value (%) C, 60.70; H, 5.99: N, 0.00 Measured value (%) C, 60.83; H, 6.05; N, 0.00 Reference example 14

Methanesulfonic acid 2 -— “2- (4-cyclobenzyloxy) phenyl 1-ethyl ester [In the formula (III), R ¹ , R ² , R ° -substituted benzyloxy group is a 2- (4-cyclobenzyloxy) group, Z gar (CH ₂₎ ₂ one, compound Y is a methanesulfo Niruokishi group:]:

4-Nitrochloride Benzyl chloride [manufactured by Tokyo Chemical Industry Co., Ltd.] and 2- (2-hydroxyphenyl) ethyl alcohol (manufactured by Aldrich Co., Ltd.) produced by a method according to Japanese Patent Application Laid-Open No. 50-148357. [2- (4-chlorobenzyloxy) phenyl] ethyl alcohol (3.00 g), methanesulfonyl chloride (1.43 g), triethylamine (1.27 g) and methylene chloride (33 ml) ) Was stirred at 0 ° C for 1 hour. Water was added and extracted with black-mouthed form. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography (black-mouthed form) to give the title compound (3.70 g) as an oil.

½— NMR (CDC1) <5: 2.79 (3H, s), 3.11 (2H, t, J = 7Hz), 4.44 (2H, t, J = 7Hz), 5.07 (2H, s), 6.90-6.98 ( 2H, m), 7.19-7.27 (2H, m), 7.38 (4H, s).

Elemental analysis (as _{_{_{C 16 H 17 C 10 4 S}}} ):

Calculated value (%) C, 56.39; H, 5.03; N, 0.00

Actual value (%) C, 56.59; H, 5.02; N, 0.05

Reference Example 15

Methanesulfonic acid 2- [3- (4-cyclobenzyloxy) phenyl] ethyl ester [In the formula (III), R ¹ , R ² , and R ³ -substituted benzyloxy groups are 31- (4-cyclobenzyloxy) groups, A compound wherein Z is — (CH ₂ ) ₂ — and Y is a methanesulfonyloxy group:

(4) A benzoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) and 2- (3-hydroxyphenyl) ethyl alcohol (manufactured by Aldrich) manufactured by a method according to Japanese Patent Application Laid-Open No. 50-148357. [3- (4-chlorobenzyloxy) phenyl] ethyl alcohol (2.88 g), methanesulfonylchlori (1.51 g), triethylamine (1.33 g) and methylene chloride (22 ml) were stirred at 0 ° C. for 2 hours. Water was added and extracted with black-mouthed form. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography [chloroform: methanol = 20: 1 (V / V)] to give the title compound (2.97 g) as an oil.

_{½- NMR (CDC1 3) 5:} 2.87 (3H, s), 3.04 (2H, t, J = 7Hz), 4.42 (2H, t, J = 7Hz), 5.04 (2H, s), 6.84-6.88 (3H , m), 7.21-7.29 (1H, m), 7.37 (4H, s).

Elemental analysis (as _{_{_{C 16 H 17 C 10 4 S}}} ):

Calculated value (%) C, 56.39; H, 5.03; N, 0.00

Actual value (%) C, 56.60; H, 5.01; N, 0.05

Claims

The scope of the claims

1. The following formula (I)

(In the formula, R ¹ R ² and R ^Q each independently represent a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group or a lower alkoxy group, and R ⁴ and R ⁵ each independently represent Represents a hydrogen atom, a lower alkyl group or a substituted alkyl group, or R ⁴ and R ⁵ together represent a group represented by — (CH ₂ ) _n —;

(CH ₂ ) _m — or — represents a group represented by —CH ゥ 0 (CHo) ₂ —. n represents 2 or 3, and m represents 1, 2 or 3. )

Or a pharmacologically acceptable salt thereof.

2. The substituted benzyloxy group is at the 4-position, R ¹ R ² and R ³ are each independently a hydrogen atom, a halogen atom, a methyl group or a nitro group, and both R ⁴ and Ra are hydrogen atoms. Or R ⁴ and R ⁵ are joined together to form a group represented by — (CH ₂ ) o—, and Z is — (CH ₂ ). _2. The isothioperia derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is a group represented by one or —CH ₂ 0 (CH ₂ ) 1.

3. S— [2 -— [4- (4-nitrobenzyloxy) phenyl] ethyl] isothiourea or a pharmaceutically acceptable salt thereof.

4. 2- [2- [4- (4-cyclobenzyloxy) phenyl] ethyl] thio-1,4,5-dihydroimidazole or a pharmaceutically acceptable salt thereof.