CA2008815C - Tetrahydrobenzimidazole derivatives - Google Patents

Abstract

A tetrahydrobenzimidazole derivative represented by formula (I):

<see fig. I>

wherein Het represents a heterocyclic group which may be substituted with 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl-lower alkyl group, an aralkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a lower alkoxycarbonyl group, and a halogen atom; and X
represents a single bond or -NH- which is bonded to the carbon atom or nitrogen atom of the heterocyclic ring, or a pharmaceutically acceptable salt thereof. The compound of formula (I) and a salt thereof exhibits antagonism against 5-HT3 receptor.

Description

2~08~1~

TETRAHYDROBENZIMIDAZOLE DERIVATIVES

FIELD OF THE INVE~TION
This invention relates to a tetrahydrobenzimidazole derivative represented by formula (I) shown below or a pharmaceutically acceptable salt thereof which are useful as a 5-HT3-receptor antagonist.

o Het - X - C ~ ~

wherein Het represents a heterocyclic group which may be substituted with 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl-lower alkyl group, an aralkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a lower alkoxycarbonyl group, and a halogen atom; and X
represents a single bond or -NH- which is bonded to the carbon atom or nitrogen atom of the heterocyclic group.
BACKGROUND OF THE INVENTION
Conventionally known antagonists to 5-HT3-receptors include azabicyclo compounds as disclosed in British Patents 2,125,398, 2,166,726, 2,166,727, and 2,126,728 (corresponding to JP-A-59-36675 and JP-A-59-67284, the term "JP-A" as used herein means an "unexamined published Japanese patent application"), 200~8~

tetrahydrocarbazole compounds as disclosed in sritish Patent 2,153,821 (corresponding to JP-A-60-214784), and azabicyclo compounds as disclosed in EP 200,4~4 (corresponding to JP-A-61-275276).
SUMMARY OF THE INVENTION
The inventors have conducted extensive in~estigations on compounds showing antagonism against 5-HT3-receptors. As a result, they have found that the compound represented by formula (I) is a novel compound exhibiting high 5-HT3-receptor antagonistic activity and thus reached the present invention.
The compounds according to the present invention are entirely different in structure from any of the above-described known 5-HT3-receptor antagonists.
DETAILED DESCRIPTION OF THE INVENTION
In formula (I), the heterocyclic group as represented by Het includes residues of monocyclic or condensed heterocyclic ~ings. Specific examples of the heterocyclic ring are morpholine, pyrrolidine, piperidine,~plperazlne,~pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, triazole, thladiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 4H-cyclopentathiazole, indole, isoindole, ~,3-dihydroindole (indoline), isoindoline, hydroxyindole, indazole, indolizine, benzothiophene, benzofuran, benzothiazole, benzimidazole, benzoxazole, ~,5,6,7-tetrahydrobenzothiophene, 2,3-dihydrobenzimidazol-2-one, 2 ~ 0 ~ 8 ~ ~
quinolina, iso~uinoline, 1,2,3,4~tetrahydroquinoline, 1,2,3,4-t~trahydroisoquinoline, 1,4-benzoxazine, phenothiazine, carbazole, ~-carboline, etc.
(at optional position(s)) The heterocyclic group may have a substituent(s)~, such as a low~r alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl-lower alkyl group, an aralkyl g~oup, a lower alkoxy group, a nitro group, a h~droxyl group, a lower alkoxycarbonyl group, a halogen atom, etc.
Unless otherwise specified, the term "lower alkyl group" as used herein means a straight chain or branched alkyl group having ~rom 1 to 6 carbon atoms. Specific examples of the lower alkyl group are methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, t-butyl, isopentyl, t-pentyl, isohexyl groups, etc.

Examples of the "lower alkenyl group" include vinyl, allyl, l-propenyl, 2-butenyl, isopropenyl groups, etc.
Examples of the "lower aIkynyl group" include ethynyl, 2-propynyl groups, etc. Examples of the "cycloalkyl-lower alkyl group" include cyclopropylmethYl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl groups, etc. ~xamples of the "aralkyl group" include benzyl, phenethyl groups, etc. Examples of the "lower alkoxy group"
include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, isopropoxy, isobutoxy, t-butoxy, isopentyloxy, t-pentyloxy, isohexyloxy, 2-ethylbutoxy groups, etc.
Examples of the "lower alkoxycarbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2~8815 isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl groups, etc.
The halogen atom includes chlorine, bromine, iodine, and fluorine atoms.
Of the compounds represented by formula (I), preferred are those wherein Het is represented by formula:

~R~
~ ' wherein R~ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl-lower alkyl group, or an aralkyl group; R2 represents a hydrogen atom, a lower alkyl group, or an aralkyl group; and R3 represents a hydrogen atom, a lower alkoxy group, a nitro group, a hydro~yl group, a lower alkoxycarbonyl group, or a halogen atom;
and X represents a single bond, and those wherein Het represents a nitrogen-containing heterocyclic group; and X is a single bond connected to the nitrogen atom of the nitrogen-containing heterocyclic ring.
Also included under the present invention are salts of some of the compounds of formula (I). Examples of such salts include salts with inorganic bases, e.g., sodium and potassium;
salts with oryanic bases, e.g., ethylamine, propylamine, diethylamine, triethylamine, morpholine, piperidine, N-2~0~
ethylpiperidine, diethsnol~mine, and cyclohexylamine; s~lts with basic ~mino ~cids, e.g., lysine and ornithineS ammonium salt; salts with mineral acids, e.g., hydrochloric ~cid, sulfuric acid, phosphoric ~cid, ~nd hydrobromic acid; salts with org~nic scids, e.g., ~cetic acid, oxalic ~cid7 succinic acid, citric acid, aleic acid, malic acid, f~maric acid, dibenzolytartaric acid, tartaric acid, and methanesulfonic acid; snd salts with acidic amino acids, e.g., glutamic s~id and ~spartic acid.
~ hile the compounds ~ccording to the present invention are represented by formula (I'), the present invention further includes ~automers of these compounds, i.e., compounds represented by formula:

Het - X - C ~ ~

Furthermore, the compounds of ~he present invention ca~ry asymme~ric carbon atoms in the molecule, and all the isomers assigned to these asymmetric carbon atoms, such zs optically active compounds, racemates, diastereomers, etc., are included in the compounds according to the present invention.
Processes for preparing the compounds according to the present invention are described below.

PROCESS 1 (Amidation):

HOOC _N\ ~
Het - X - H t ~H ~Het - X C~C¢N~

(II) (Ia) H

wherein ~et is as defined above; and X~ represents a single bond connected to the nitrogen atom of the heterocyclic group, or Xl represents -NH- connected to the czrbon atom of the heterocyclic group.
The compound (Ia) of the present invention can be obtzined by reacting an amine, an amide, or urea represented by formulz (III) with 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid represented by formula (II) or a reactive derivative thereof.
The reaction is carried out by any of various known processes for amide linkage formztion. Solvents to be used are not particularly limited and include dioxane, diethyl ether, tetrahydrofuran, chloroform, ethyl acetate, and dimethylformamide.
The compound (II) is subjected to the reaction 25 being eithe~ in the form of a free acid or in the form OI a reac~ive deriv2tive thereof, e.g., an acid halide, an acid anhydride, an acid 2zide, and various active esters ~enerally used in peptide syntheses. In the former case, the amide linkage formztion 2~3~1~

can be effected by using any of commonly employed condensing agents, for example, N,N-dicyclohexylcarbodiimide.
In some cases depending on the kind of the reactive derivative of the compound (II), the reaction is preferably carried out in the presence of a base, such as inorganic bases, e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, and potassium carbonate; and organic bases, e.g., triethylamine, diisopropylethylamine, dimethylaniline, and pyridine.
The compound (III) is usually used as it is or, if desired, after being conYerted to an alkali metal salt thereof.
The co..,~ound (III) is desirably used in an equimolar or excessi~e amount with respect to the compound (Il) or a reactive derivative thereof.
The reaction is possibly carried out at room temperature, under cooling, or under heating as selected depending on the kind of the amide linkage xeaction mode but usually at room temperature or under cooling.
PROCESS 2:

Het-X -H I ~ ~ > Het_x2_ (II) (Ib) .

200g8~

wherein He~ is as defined above; and XZ represents a single bond connected to the carbon atom of the heterocyclic ring as represented by Het.
The compound ~Ib) can be obtained by reacting a heterocyclic compound represented by formula (IIIa) with a carboxylic acid represented by formula (II) or a reactive derivative thereof.
The reaction can be carried out by any of various known pxocesses for synthesizing carbonyl compounds using a carboxylic acid or a derivative thereof.
Where a carboxylic acid of formula (II) is employed, the reaction with the compound of formula (IIIa) is a dehydrating condensation reaction using polyphosphoric acid, for instance, as a condensing agent. The reaction is carried out with or without a solvent. Solvents which can be used are not limited as long as inert to the reaction, but, usually, solvents having an appropriate boiling point are selected taking the reaction temperature into consideration. Examples of suitable solvents are decalin, tetralin, diglyme, etc. The reaction is effected at room temperature or preferably under heating.
Where an acid halide of the carboxylic acid of formula (II) is employed, the reaction is a Friedel-Crafts reaction which can be carried out by known processes or various modifications thereof using a Lewis acid, e.g., aluminum chloride, ferric chloride, stannic chloride, boron trifluoride e~hyl etherate, 2~08~1~

and titanium tetrachloride. Solvents inert to the reaction may be employed preferably being selected depending on the kind of the Lewis acid used. Examples of usable solvents are acetonitrile and carbon disulfide. The reaction is performed at room temperature or, usually, under heating.
Where an acid amide of the carboxylic acid of formula (II) is employed, the reaction is a Vilsmeyer reaction, which is a known reaction mode frequently employed for synthesis of heterocyclic ca.rbonyl compounds. Reagents for converting the acid amide to a Vilsmeyer complex include general halogenating agents, e.g., phosphorus pentachloride and phosphorus oxychloride. This reaction may be effected with or without a solvent. In using a solvent, various kinds of solvents can be employed as long as inert to the reaction. A suitable example of solvents is 1,2-dichloroethane. The reaction is performed at room temperature or under heating, and preferably under heating.
PROCESS 3 ~N-Alkylation):
O O
Hetl - X.- C ~ ,9 ,~ Het2 _ X ~ 11 ~
(Id) ~ (Ic) ~/
tt ~

wherein X is as defined above; Hetl represents a heterocyclic group having -NH- in the ring thereof; and Het2 represents a heterocyclic group in which the -NH- moiety in Het~ is 2~0~

converted to -N-, wherein R4 represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl-lower alkyl group, or an aralkyl group.
This reaction is an N-alkylation reaction. The terminology ~alkylation~ as used herein means introduction of a lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl-lower alkyl or aralkyl group. Any of various known alkylation techniques is applicable. For example, in case where the alkylation is carried out by direct N-alkylation using an alkylating agent, the reaction is conducted under cooling, at room temperature, or under heating, and preferably under cooling or at room temperature. Any solven~ inert to the reaction, e.g., dioxane and dimethylformamide, may be employed. The reaction is effected in the presence of a base or by using an alkali metal salt of the compound (Id) at the amino group thereof. Examples of suitable alkylating agents include alkyl halides and alkyl sulfates. Examples o~ suitable bases include inorganic bases, sodium hydride, e.g.,~sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, and potassium carbonate; and organic bases, e.g., triethylamine, diisopropylamine, dimethylaniline, and pyridine.
The thus prepared compound of the present invention is isolated and purified either in the free form or in the form of a salt through usual chemical means, such as extraction, 2~8~5 crystallization, recrystallization, and various chromatographic techniques.
The compound as obtained in the form of a racemate can be led to stereochemically pure isomers by using an appropriate starting compound or by general resolution techniques (for example, a method comprising once obtaining a diastereomer salt ~ibenzoylJ
with an ordinary optically active acid, e.g.,~tartaric acid, followed by optical resolution).
The compounds according to the present invention and the salts thereof specifically inhibit transient bradycardia induced by serotonin in anesthetized rats as demonstrated by Test Example 1 hereinafter described and are thus believed to have antagonism against 5-HT3-receptor. Therefore, the compounds of the present invention and the salts thereof are considered to suppress vomiting induced by anticancer agents, e.g., Cisplatin, or radiation and to be useful in the prevention and treatment of migraine, cluster headache, trigeminal neuralgia, anxiety, gastrointestinal disorders, peptic ulcer, irritable bowel syndrome, etc.
A pharmaceutical composition containing at least one of the compounds of the present invention or salts thereof as an active ingredient is prepared in various dose forms, such as tablets, powders, granules, capsules, pills, liquids, injections, suppositories, ointments, pastes, and the like using carriers, excipients and other additives conventionally 2~0~

used in pharmaceuticals. The preparation may be a~ninistered or~lly, inclusive of sublingual administration, or parenterally.
Carriers or excipients for pharmaceutical compositions include solid or liquid non-toxic pharmaceutically acceptable materials, e.g., lactose, magnesium stearate, staxch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and the like.
A clinical dose of the compound of the present invention is appropriately determined, taking into account conditions, body weight, age, sex, etc. of the patient. It usually ranges from 0.1 to 10 mg/day for intravenous administration and from 0.5 to 50 mg/day for oral administration for adult in a single or several divided doses.
The pharmacological effects of the compounds of the present invention were confirmed by Test Examples.

Antaqonism Aqainst 5-HT3-Receptor Nine-week-old Wistar male rats were anesthetized by intravenous in~ection of 1 g/kg of urethane, and blood pressure and heart rate were measured under artificial respiration.
Transient reduction in heart rate and blood pressure induced by intravenous administration of serotonin or 2-methylserotonin which is a selective agonist of 5-HT3 was taken as an index of 2 ~

the reaction via 5-HT3 receptor [Bezold-Jarish reflex; Paintal, A.S., Pysiolo. Rev., Vol. 53, p. 159 (1973)]
When the compound of the present invention or a salt thereof was intravenously administered (0.03 to 3 ~g/kg) or orally administered (l to 30 ~g/kg) 10 minutes or 60 minutes before the administration of serotonin (or 2-methylserotonin), respectively, the reduction in heart rate and blood pressure induced by serotonin or 2-methylserotonine was dose-dependently inhibited.
Inhibitory activity of the compound of the present invention on serotonin-induced Bezold-Jarish (BJ) reflex in rats is shown in Table 1 below.

Example No. ofBJ Reflex Inhibitory Activity Test Compound~EDs~; ~q/kq, i.v.) 2 0.29 4 0.044 9 0.80 36 0.063 Inhibition on Anticancer Aqent-Induced Vomitinq When male ferrets weighing from 1 to 1.5 kg subcutaneously or orally received 0.01 to 0.3 mg/kg of the compound of the present invention, vomiting induced by intraperitoneal administration of 10 mg/kg of Cisplatin was inhibited.

2~8~

Inhibition on Stress Defecation Nine-week-old male Wistar rats were encased in a cage for restricted stress, and the number of feces was measured.
Intravenous administration of the compound of the present invention or a salt thereof (1 to 100 ~g/kg) dose-dependently inhibited acceleration of defecation induced by restricted stress.

Toxicity Acute toxicity of the compounds of the present invention in male mice was from 100 to 150 mg/kg i.v. as determined by an up-and-down method, indicating that the compounds are of low toxicity.
The present invention is now illustrated in greater detail with reference to Reference Examples, Examples, and Formulation Examples, but it should be understood that the present invention is not deemed to be limited thereto.

N ~ COOCH, ~l ~ COOCH, ~H2SO~ H2SO~
In 600 m~ of acetic acid was dissolved 40.0 g of methyl 5-benzimidazole carboxylate sulfate in a 1 ~-volume autoclave, 2 ~

and ll g of 10% palladium-on-carbon was added to the solution as a catalyst to conduct hydrogenation at 80~C at a pressure of 60 atm for 5 hours. The catalyst was separated by filtration, and the mother liquor was concentrated under reduced pressure to obtain 41.0 g of methyl 4,5,6,7-tetrahydrobenzimidazole-5-carboxylate sulfate as an oil.

(b) ~r~o~ HCI ~'C OOH

H2 S 0~ , H2 S 0~
In a mixture of 350 m~ of water and 340 mQ of concentrated hydrochloric acid was dissolved 41.0 g of the oily ester sulfate as obtained in (a) above, and the mixture was stirred at 100~C for 3 hours. After concentration, the resulting crystal was washed with acetone to obtain 29.6 g (76.8~ based on the benzimidazole ester) of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate.
Physicochemical Properties:
Melting Point: 145-148~C
NMR (d6-DMS0): ~ 1.60-3.00 (7H, m), 8.84 (lH, s) Mass Spectrum (EI): m/z 166 (M+, as a free compound) (CI): m/z 167 (M++1, as a free compound) o HOOC (H5~ ~ C

To 0.30 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride containing sodium chloride was added 5 mQ of thionyl chloride, followed by stirring at 90~C for 2 hours.
The excess of thionyl chloride was removed by distillation under reduced pressure. ~o the residue was added 10 m~ of dichloromethane, and 2 mQ of diethylamine was added thereto at 5~C, followed by stirring at room temperature for 16 hours. To the mixture was added 40 mQ of dichloromethane, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous magnesium sulfate.
The solvent was removed by distillation under reduced pressure to obtain 0.22 g o-f N,N-diethyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide.
Physicochemical Properties:
NMR (TMS, CDCR3) ~ 1.15 (t, 6H), 2.0-3.5 (m, 7H), 3.10 (q, 4H), 8.15 (s, lH), 9.50 (s, lH) Mass Spectrum (FAB, Pos) m/z 222 (M~
To the above obtained compound was added 1 m~ of a 4N
solution of hydrogen chloride in ethyl acetate, and the solvent was removed by dis-tillation under reduced pressure to obtain 20~1a 0.27 g of N,N-diethyl-4,5,6,7-tetrahydrobenzimida~ole-5-carboxamide hydrochloride.

O
N ~ N
~ TCI , ~ ~> ~CCOO~I
CH, CH~ ~ ~OOCC~

In 0.7 m7 of thionyl chloride, 0.13 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride (containing sodium chloride) was refluxed for 30 minutes, and volatile components were removed by distillation under reduced pressure. The residue was added to a solution of 0.15 g of 3,3-dimethylindoline and 0.15 m~ of triethylamine in 2 m~ of dichloromethane under ice-cooling. After stirring the mixture at room temperature overnight, 5 mQ of a sodium carbonate aqueous solution was added thereto, and the mixture was extracted with chloroform. The organic layer was dried, and the solvent was removed by distillation under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform/methanol as an eluent to obtain 0.11 g of 5-[(2,3-dihydro-3,3-dimethylindol-l-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole as an oily substance. The oily substance was then treated with a solution of fumaric acid in methanol~acetonitrile to obtain 0.09 g of 5-[(2/3-dihydro-3r3 2~0~81~

dimethylindol-1-yl ) carbonyl ] -4, 5, 6, 7-tetrahydrobenzimidazole f umarate .
Physicochemical Properties:
Melting Point: 119-123~C
Elemental Analysis for Cl8H2lN3O ~ C4H404 ~ H2O ~ O ~ 3CH3CN:
Calcd. (96): C 61.44; H 6.36; N 10.46 Found (%): C 61.60; H 6.03; N 10.46 Mass Spectrum (EI): m/z 295 (M~, as a free compound) In the same manner as in Example 1, the following compounds were synthesized.

5- [ ( 2, 3-Dihydroindol-1-yl ) carbonyl ] -4, 5, 6, 7-tetrahydrobenzimidazole fumarate NJ~N~ ~ HC COOH
H HOOC CH

Phys i cochemi ca l Properti es:
Melting Point: 206-208~C (methanol/acetonitrile) Elemental Analysis f or Cl6Hl7N3O ~ C4H404 . 0 ~ 3H2O:
Calcd. (%): C 61.78; H 5.60; N 10.81 Found (%~: C 61.92; H 5.53j N 10.68 Mass Spectrum (EI): m/z 267 (M+, as a free compound) 2~881~

5-[(2-Methyl-2,3-dihydroindol-1-yl)-carbonyll-4,5,6,7-tetrahydrobenzimidazole Physicochemical Properties:
Melting Point: 230-234~C (dec.) (recrystallized from eth~l acetate/hexane) Elemental Analysis for Cl7Hl9N3O:
Calcd. (%): C 72.57; H 6.81; N 14.93 Found (%): C 72.76; H 6.78; N 14.62 Mass Spectrum: m/z 281 (M+) o T C2Hs~ ~ N

CH, H

'~N HOOC
CH, H

A mixture of 0.27 g (1.05 mmol) of N,N-diethyl 4,5,6,7-tetrahydrobenzimidazole-5-carboxamide hydrochloride, 0.16 m~
(1.25 mmol) of 1-methylindole, and 0.15 m~ (1.65 mmol) of phosphorus oxychloride was heated at 80~C for 2 hours while stirring. 30 ml of water were added thereto, and 20~8~1~

the mixture was rendered basic with a lN sodium hydroxide aqueous solution, followed by extracting with eth~1 acetate.
The ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol/aqueous ammonia = 10:1:0.1 by volume) and preparative thin layer c h r o m a t o g r a p h y ( d e v e 1 o p i n g s o 1 v e n t :

dichloromethane/methanol/aqueous ammonia = 10:1: 0.1 by volume) ~to obtain~
~20 mg of a foaming substance. To the product was added 10 mg of fumaric acid to convert it to a fumarate. Recrystallization from eihyl acetate/methanol (10:1 by volume) gave 10 mg of 5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole fumarate.
Physicochemical Properties:
Melting Point: 97-102~C
Mass Spectrum (EI): m/z 279 (M+, as a free compound) NMR (CDC~ (as a free compound):
1.90-3.00 (7H, m, CH2, CH), 3~80 (3H, s, N-Me), 7.20 (2H, m, ArH), 7.50-8.00 (4H, m, ArH), 8.30 (lH, m, NH) 2 ~

o ~ 'X2 S 0~ ~N-C ~ ~
H H HCl In 53 mQ of acetonitrile were added 5.3 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate and 2.9 mQ of thionyl chloride, and the mixture was stirred at 53 to 55~C
for 1.5 hours. The mixture was distilled under reduced pressure to remove 10 to 15 mQ of the solvent. ~f~er 15 mQ of acetonitrile was added thereto, the mixture was further distilled under reduced pressure to remove 10 to 15 m~ of the solvent. The residual solution was added dropwise to a solution of 14.2 g of pyrrolidine in 50 mQ of acetonitrile at 2~C or lower. After the addition, the temperature was returned to room temperature, and the mixture was stirred for 1 hour, followed by concentration under reduced pressure. To the residue was added 30 m~ of a saturated sodium chloride aqueous solution, and the mixture was extracted with chloroform (50 mQ x 3). The chloroform layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, treated with hydrochloric acid in ethanol, and recrystallized from ethanol/ethyl ace~ate to obtain 4.25 g (82.9%) of N-[(~,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine hydrochloride.

230881~

Physicochemical Properties:
Melting Point: 234-236~C
Elemental Analysis for Cl2HI8N3OCQ~0.2H2O:
Calcd. (%): C 55.57; H 7.15; N 16.20; C~ 13.67 ~ound ~%): C 55.64; H 6.99; N 16.18; C~ 13.79 Mass Spectrum (EI): m/z 291 (M+, as a free compound) In the same manner as in Example 5, the following compounds were synthesized.

4-(4,5,6,7-Tetrahydrobenzimidazol-5-ylcarbonyl)-2,3-dihydro-1,4-benzoxazine fumarate COOH
~ ~ H HOOC~

Physicochemical Properties:
Melting Point: 176-178~C (methanol/acetonitrile) Mass Spectrum (EI): m/z 283 (M~, as a free compound) Elemental Analysis for Cl6Hl7N3O2.C4H4O4:
Calcd. (%): C 60.14; H 5.30; N 10.52 Found (%): C 59.95; H 5.28; N 10.55 EXAMPLE 7 ~~
HOOC ~ ~ >

HCI ~ COOH
HOOC
In 5 m~ of thionyl chloride was added 0.58 g (0.98 mmol) of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride , 2~8~1~
~ ntaining sodium chloride),) having a purity of 34.5% ~and the mixture was stirred at 90~C
for 4 hours. After cooling, the solution was distilled under reduced pressure to remove thionyl chloride. To the residue was added 10 m~ of dichloromethane, and 0.20 m~ (1.59 mmol) of 1,2,3,~-tetrahydroquinoline and 0.35 m~ (2.53 mmol) of triethylamine were added thereto, followed by stirring at room temperature for 48 hours. To the reaction mixture was added 40 m~ of dichloromethane, and the mixture was washed with a lN
sodium hydroxide aqueous solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was subjected to silica g e l c o l u m n c h r o m a t o g r a p h y u s i n g dichloromethane/methanol/aqueous ammonia (10:1:0.1 by volume) as an eluent to obtain 100 mg of a foaming substance, which was then treated with 40 mg of fumaric acid in ethanol to be converted to a fumarate. Recrystallization from ethyl acetate/methanol (10:1 by volume) gave 90 mg (33.3%) of 1-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]-1,2,3,4-tetrahydroquinoline fumarate.
Physicochemical Properties:
Melting Point: 98-100~C
Elemental Analysis for C~7HI9N3O.C4H4O4.2H2O:
Calcd. (%): C 58.19; H 6.27; N 9.69 Found (%): C 58.43; H 5.73; N 9.53 2~n8~

NMR (DMSO-d6) ~ ppm: 1~90 (4H, q, 7Hz, quinoline CH2x2), 2.00-3.00 (7H, m, benzimidazole CH2x3, CH), 3.70 (2H, t, J=7Hz, CH2N), 6.60 (2H, s, fumaric acid CHx2), 7.16 (5H, m, ArH, NH), 7.55 (lH, s, imidazole CH) Mass Spectrum (EI): m/z 281 (M~, as a free compound) EXAMPLE 8 o HOOC ~ ~ ~ ~ N~

H H
HCI

To 5 m~ of thionyl chloride was added 0.58 g (0.98 mmol) of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid hydrochloride ~ (containing sodium chloride),~
having a purity of 34.5~followed by~stirring at 90~C for 4 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove thionyl chloride. To the residue were added 10 m~ of dichloromethane, 0.20 m~ (1.57 mmol) of 1,2,3,4-tetrahydroisoquinoline, and 0.35 m~ (2.53 mmol) of triethylamine, and the mixture was stirred at room temperature for 48 hours. To the reaction mixture was added 40 m~ of dichloromethane, and the mixture was washed with a lN sodium hydroxide aqueous solution and dried over anhydrous magnesium sulfate. The solvent was removed from the residue by distillation under reduced pressure. The residue was suhjected to silica gel column chromatography using dichloromethane/methanol/aqueous ammonia (10:1:0.1 by volume) ~ag~s as an eluent to obtain 0.15 g of a white foaming substance, which was then recrystallized from diethyl e-ther/ethyl acetate to obtain 40 mg (14.8%) of 2-[(4l5/6t7-tetrahydrobenzimida 5-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline.
Physicochemical Properties:
Melting Point: 128-130~C
NMR (DMSO-d6) ~ ppm: 2.00-3.00 (7H, m, CH2x3, CH, benzimidazole), 3.00 (2H, t, J=5Hz, CH2), 3.40 (2H, t, J=5Hz, -CH2-), 4.24 (2H, s, CH2N), 7.22 (6H, m, ~rH, NH) Mass Spectrum (EI): m/z 281 (M') HO~C~ ~ NCO N
H~SO~ >
H ~ H H

A mixture of 0.78 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate and 3 m~ of thionyl chloride was heated at 50~C for 20 minutes, and the excess of thionyl chloride was removed by concentration under reduced pressure to obtain a carboxylic acid chloride. A solution of the resulting carboxylic acid chloride in 3 m~ of dimethylformamide was added to a dimethylformamide solution (30 m~) of 1.61 g of 2-hydroxybenzimidazole and 0.50 g of 60% oily sodium hydride under ice-cooling, and the reaction mixture was stirred at room temperature for 1 hour, followed by concentration under reduced 2~8~1~

pressure. The residue was made acidic with 0.SN hydrochloric acid, and any insoluble matter was removed by filtration. The filtrate was made basic with potassium carbonate, and the thus formed crystal was collected by filtration, washed with water, and stirred in acetone overnight. The resulting crystal was collected by filtration to yield 0.20 g (24%) of 1-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]-2/3-dihydrobenzimidazol 2-one.
Physicochemical Properties:
Melting Point: 271-274~C (dec.) Elemental Analysls for Cl5HI4N4O2Ø4H2O:
Calcd. (~): C 62.23; H 5.15; N 19.35 Found (~): C 62.41; H 5.02; N 19.06 Mass Spectrum (EI): m/z 282 ~M+) In the same manner as in Example 9, the following compounds were synthesized.

5-Methoxy-1-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)-carbonv11-2,3-dihvdrobenzimidazol-2-one fumarate ~ ~CO ~ ~ ~COOH

Physicochemical Properties:
Melting Point: 215-218~C (dec.) (recrystallized from methanol) Mass Spectrum (EI): m/z 312 (M+, as a free compound) NMR (DMSO-d6) ~ ppm: 1.57-2.34 (2H, m), 2.34-3.10 (4H, m), 3.76 (3H, s), 3.90-4.28 (lH, m), 6.58 2 ~

(2H, s), 6.3~-6.84 (2H, m), 7.62 (lH, s), 7.89 (lEI, d, J=8Hz) 1-Methyl-3-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)-carbon~ll-2,3-dihydrobenzimidazol-2-one fumarate ~ HOOC~

Physicochemical Properties:
Melting Point: 145-147~C (recrystallized from me-thanol/
acetonitrile) Mass Spectrum (EI): m/z 296 (M~, as a free compound) Elemental Analysis for Cl6Hl6N4o2~c4H4o4-o-5H2o) Calcd. (%): C 57.00; H 5.02; N 13.30 Found (%): C 56.91; H 5.06; N 13.31 ~COOH ~ NH C~
~ H23O, H

In 10 me of 1,2-dichloroethane were heat-refluxed 1.32 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate and 1.78 g of thionyl chloride for 30 minutes. The excess of thionyl chloride and the solvent were removed by distlllation under reduced pressure, and the residue was dissolved in 4.0 m2 of dry dimethylformamide. The solution was added to a solution of 2.7 g of 2-aminobenzothiazole in 10 m~ of dry 2~08~1~

dimethylformamide under ice-cooling, followed by stirring at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using a methylene chloridetme~hanol mixed solvent as a developing solvent followed by recrystallization from ethanol to obtain 0.8 g (53.7%) of N-(2-benzothiazolyl)-4,5,6,7-tetrahydrobenzimidazol-5-ylcarboxamide.
Physicochemical Properties:
Melting Point: 165-167~C
Elemental Analysis for C15H~4N4OSØ25H2O:
Calcd. (%): C 59.49; H 4.82; N 18.50; S 10.59 Found (%): C 59.30; H 4.73; N 18.49; S 10.68 Mass Spectrum (EI): m/z 298 (M~) In the same manner as in Example 12, the following compounds were synthesized.

N-(2-Benzimidazolyl)-4,5,6,7-tetrahydro-benzimidazol-5-ylcarboxamide ~ H~

Physicochemical Properties:
Melting Point: 182-185~C
Elemental Analysis for Cl5Hl5N5O-0-6H2O:
Calcd. (%): C 61.67; H 5.58; N 23.97 - ~8 -2~8~1~

Found (%): C 61.63; H 5.44; N 23.97 Mass Spectrum (EI): m/z 281 (M+) N-(Quinolin-3-yl)-4,5,6,7-tetra-hydrobenzimidazol-5-ylcarboxamide ~'~C~?
Physicochemical Properties:
Melting Point: 296-297~C
Elemental Analysis for CL7Hl6N4O 0 25H2O:
Calcd. (%): C 68.79; H 5.60; N 18.87 Found (%): C 68.69; H 5.66; N 18.75 Mass Spectrum (EI): m/z 292 (M+) N-(5-Methyl-1,3,4-thiadiazol-2-yl)-4,5,6,7-tetrahydrobenzimidazole-5 carboxamide 'N N ~
CX3J~S~ C~
H
Physicochemical Properties:
Melting Point: ~300~C
Elemental ~lalysis for CIlHl3N5os.o-2H2H:
Calcd. (%): C 49.50; H 5.06; N 26.24; S 12.01 Found (~): C 49.86; H 4.97; N 26.40; S 11.68 Mass Spectrum (EI): m/z 263 (M~) 2~0~81~

N-(9-Ethylcarbazol-3-yl)-4,5,6,7-tetrahydrobenzimidazol-5-carboxamide o - ~ NHC

Physicochemical Properties:
Melting Point: 168-170~C
Elemental Analysis for C22H22N4OØ5H2O:
Calcd. (%): C 71.91; H 6.31; N 15.25 Found (%): C 71.77; H 6.13; N 15.13 Mass Spectrum (EI): m/z 358 (Mi) N-[(4j5,6,7-Tetrahydrobenzimidazol-5-yl)carbonyllPhenothiazine hYdrochloride N ~
O-C ~ ~ HCl Physicochemical Properties:
Melting Point: 268-270~C
Elemental Analysis for C2oHI7N3OS.HC~Ø5H2O:
Calcd. (~): C 61.14; H 4.87; N 10.69; C~ 9.02 Found (~): C 61.15; H 4,64; N 10.60; C~ 8.59 Mass Spectrum (EI): m/z 347 (M+, as a free compound) 200~

N-(5,6-Dihydro-4H~cyclopentathiazol-2-yl)-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide ~ ~ N~

Physicochemical Properties:
Melting Point: 164-165~C
NMR (DMSO6) ~ ppm: 1.70-3.00 (13H), 7.426 (lH) Mass Spectrum (EI): m/z 288 (M+), 255 N-(Pyrimidin-2-yl)-4,5,6,7-tetrahydro-benzimidazol-5-carboxamide dihydrochloride N O
~N~ ~r~C

H

Physicochemical Properties:
Melting Point: 287-289~C
Elemental Analysis for C12Hl3N5O.2HC~.1.4H2O:
Calcd. (~): C 42.22; H 5.25; N 20.51; C~ 20.77 Found (%): C 42.35; H 5.00; N 20.69; C~ 20.45 Mass Spectrum (EI): m/z 243 (M~, as a free compound) 2~881~

N-tPyridin-3-yl)-4,5,6,7-tetrahydro-benzimidazole-S-carboxamide dihydrochloride o ~ '0[~9 Physicochemical Properties:
Melting Point: 285-287~C
Elemental Analysis for Cl3Hl4N4O.2HC~:
Calcd. (~): C 49.54; H 5.12; N 17.77 Found (%): C 49,74; H 5.26; N 17.53 Mass Spectrum (EI): m/z 242 (M+, as a free compound) N-(3-Ethoxycarbonyl-4, 5, 6,7-tetrahydrobenzo[b]thiophen-2-yl)-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide Il NHC

Physicochemical Properties:
Mel+~ing Point: 159-161~C
Elemental Analysis for ClgH23N3O3S:
Calcd. (%): C 61.10; H 6.21; N 11.25; S 8.59 Found (%): C 60.87; H 6.16; N 11.05; S 8.62 Mass Spectrum (EI): m/z 373 (M~) 2aos~l~

N-(Indazol-6-yl)-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide Physicochemical Properties:

Melting Point: >300~C

Elemental Analysis for C15HI5N5O:

Calcd. (%): C 64.04; H 5.37; N 24.89 Found (%): C 63.79; H 5.42; N 24.75 Mass Spectrum (EI): m/z 281 (M ) > ~,~ fbc3 ~ou~

4 g of N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine hydrochloride obtained in Exampl~ 5 were added to 40 m~ of dichloroethane, and 2.74 g of indole and 4.4 m~ of phosphorus oxychloride were added thereto. The mixture was stirred at 80 to 85~C for 7 hours and then at room temperature overnight. To the mixture was added 40 m~ of a cold potassium carbonate aqueous solution, followed by extraction with chloroform. The extract was drled over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was subjected 2~088~

to column chromatography using chloroform/methanol as an eluent to obtain 1.82 g oE 5-[(indol-3-y:L)carbonyl~4,5,6,7-tetrahydrobenzimidazole as a foaming substance. In 1 m~ of methanol were dissolved 0.16 g of the resulting product and 0.06 g of fumaric acid, and S m~ of acetonitrile was added to the solution. The formed crystal was collected by filtxation to obtain 0.13 g of 5-[(indol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole fumarate.
Physicochemical Properties:
Melting Point: 153-154~C
Elemental Analysis for Cl6Hl5N3O.C4H4O4Ø15CH3CNØ65H2O:
Calcd. (%): C 61.07; H 5.24; N 11.05 Found (%): C 61.11; H 5.01; N 11.04 Mass Spectrum (FAB): m/z 266 (Mi+l, as a free compound) In the same manner as in Example 23, the following compounds were synthesized.

5-[(1,2-Dimethylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.3/4 fumarate ~[~ 3/4 ~D~CJJ' C~
Physicochemical Properties:
Melting Point: 220-223~C
Elemental Analysis for Cl8HlgN3O.3/4C4H404:
Calcd. (%): C 66.30; H 5.83; N 11.05 2~0881~

Found (~): C 66.50; H 5.83i N 11.13 Mass Spectrum (EI): m/z 293 (M+, as a free compound~
E~AMPLE 25 5-[(2-Methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.~fumarate ~ J~ oo~

Physicochemical Properties:
Melting Point: 221-223~C
Elemental Analysis for C~7HI7N30.~csH4o4.o.25H2o Calcd. (~): C 66.75; H 5.75; N 12.29 Found (%): C 66.73; H 5.75; N 12.29 Mass Spectrum (EI): m/z 279 (M~, as a free compound) 5-[(2-Benzylindol-3-yl)-carbonyl]-4,5,6,7-tetrahydrobenzimidazole-fumarate ~ ~oo5 Physicochemical Properties:
Melting Point: 183-186~C
Elemental Analysis for C23H2lN30.c4H404-O-lH20:
Calcd. (%): C 68.52; H 5.37; N 8.88 Found (%): C 68.38; H 5.50; N 8.87 Mass Spectrum (EI): m/z 355 (M+, as a free compound) ~0~881~

5-[(s-Methoxyindol-3-yl)carbonyl]~
4,5,6,7-tetrahYdrobenzimidazole~3/4 fumarate C~3~ oc~co Physicochemical Properties:
Melting Point: 162-164~C
Elemental Analysis for Cl7H~7N3O2.3/4C4H404Ø2CH3CNØ85H2O:
Calcd. (%): C 60.36; H s.54; N 11.04 Found ~%): C 60.33; ~ 5.25; N 10.93 Mass Spectrum (EI): m/z 295 (M+, as a free compound) 5-[(5-Chloro-2-methylindol-3-yl)-car~onyl]-4,5,6,7-tetrahydrobenzimidazole.fumarate CGO~

Physicochemical Properties:
Melting Point: 212-213~C
Elemental Analysis for Cl7H16N3OC~C4H4O4:
Calcd. (%): C 58.68; H 4.67; N 9.78; C~ 8.25 Found (%): C 58.43; H 4.91; N 9.67; C~ 8.24 Mass Spectrum (FAB, Pos): m/z 314 (M++l, as a free compound) 2o~88l~

5-[(5~Nitroindol-3-yl)carbonyl]
4 5,6,7-tetrahvdrobenzimidazole Physicochemical Properties:
Melting Point: 227-229~C
NMR (DMSO-d6) lOOM, ~: 2.00 (2H, m), 2.70 (4H, m), 3.63 (lH, m), 7.44 (lH, s), 7.64 (lH, d, J6.7=12HZ), 8-10 (lH, dd, J67-12Hz, J46=4Hz), 8.72 (lH, s), 9.07 (lH, d, J4.6=4Hz), 12-56 (lH, br) Mass Spectrum (EI): m/z 310 (M+) 5-[(5-Methoxycarbonylindol-3-yl)-carbonyll-4,5,6,7-tetrahYdrobenzimidazole O o ~JJ~l~
~ H
Physicochemical Properties:
Melting Point: 205-209~C
NMR (DMSO-d6) lOOM ~:1.90-2.15 (2H, m), 2.83 (4H, br), 3.75 (lH, br), 7.56 (lH, d, J67=12Hz), 7.84 (lH~ dd~ J67=12Hz, J46=3Hz), 8.62 (lH, 2~8~1~

d~ J2NH=4Hz), 8-90 (2H, s), 12.60 (lH, d, Jz~NH=4Hz) Mass Spectrum (EI): m/z 323 (M~) 5-[(5-Hydroxyindol-3-yl)carbonyl]-4,5,6,7-tetrah~drobenzimidazole.~fumarate a ~ Y,2, H OGC
Physicochemical Properties:
Melting Point: 282-286~C
NMR (DMSO-d6) lOOM ~:1.90 (2H, br), 2.85 (4H, br), 3.74 (lH, br), 6.76 (lH, s), 6.84 (lH, dd, J67=12Hz, J4~6=4Hz), 7.41 (lH, d, J67=12Hz), 7.74 (lH, d, J46=4Hz), 8-50 (lH, d, J2N~=SHz), 9.07 (lH, s), 11-95 (lH, d, J2.N~) Mass Spectrum (EI): m/z 281 (Mi, as a free compound) O ~ -~OOt ~

In 5 m~ of dry dimethylformamide was added 0.04 g of 60%
~ carbonyl]) oily sodium hydride, and 0.51 g of 5-~(i.ndol-3- ~ -4,5,6,7-tetrahydro-lH-benzimidazole as obtained in Example 23 was slowly added thereto at room temperature. Thirty minutes 2~88 1~

later, 0.07 g of benzyl bromide was slowly added thereto at 0~C, followed by stirring at room temperature overnight. To the reaction mixture were added 20 m~ of water and 20 m~ of chloroform for liquid-liquid separation. The organic layer was washed with water and dried over anhydrous magnesium sulfate.
The solvent was removed by distillation, and the residue was subjected to chxomatography using chloroform/methanol as an eluent. The resulting foaming substance (0.12 g) was recrystallized together with 0.04 g of fumaric acid from ethanol/ethyl acetate to obtain 0.10 g of 5-[1-benzylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole fumarate.
Physicochemical Properties:
Melting Point: 117-118~C
Elemental Analysis for C23H2,N3O.C4H4O4.0-75H2O:
Calcd. (%): C 66.86; H 5.51; N 8.66 Found (%): C 66.83; H 5.48; N 8.88 Mass Spectrum (EI): m/z 321 (M~, as a free compound) In the same manner as in Example 32, the following compounds were synthesized.

20~8~ 5 S-[(1-Cyclohexylmethylindol-3-yl)carbonyl]~
4,5,6,7-tetrahydrobenzimidazole.fumarate ~ O~C~

r~ GG~
~H~ ~
Physicochemical Properties:
Melting Point: 95-100~C (ethanol/ethyl acetate) Elemental Analysis for C23H27N3O-C4H4O4Ø5AcOEt :

Calcd. (%): C 62.46; H 7.05; N 7.54 Found (%): C 62.59; H 6.69; N 7.19 Mass Spectrum (EI): m/z; 361 (M+, as a free compound) 5-[(1-Allylindol~3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole-fumarate O
ho~

11 ~c~
~l1L- CH=C~Il Physicochemical Properties:
Melting Point: 144-145~C (methanol/ethyl acetate) Elemental Analysis for ClgHl9N3O.C4H404Ø35AcOEtØ3H2O:
Cacld. (%): C 64.03; H 5.81; N 9.18 Found (~): C 64.00; H 5.74; N 9.17 20~881~

Mass Spectrum (EI): m/z 305 (M+, as a free compound) 5-[(1-n-Butylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole-fumarate o ~/C~ AC~

Physicochemical Properties:
Melting Point: 104-106~C (ethanol/acetonitrile) Elemental Analysis for C20H23N3O-C4H4O4 ~-8H2~
Calcd. (%): C 63.78; H 6.38; N 9.30 Found (%): C 63.82; H 6.14; N 9.33 Mass~Speetrum (EI): m/z 321 (M~, as a free compound) 5-[[1-(2-Propynyl)indol-3-yl]carbonyl]-4,5,6,7 tetrahydrobenzimidazole-fumarate ~C~
C~ ~_CH

Physicochemical Properties:
Melting Point: 130-131~C (ethanol/acetonitrile) Elemental Analysis for Cl9HI7N3O.C6H4O4.1-3H2O:
Calcd. (%): C 62.38; H 5.37; N 9.49 Found (%): C 62.38; H 5.19; N 9.21 2 ~

Mass Spectrum (EI): m/z 303 (Mt, as a free compound) ' O ' O
~N~ H~S0~ S04 > ~l;~N~ HOOC~
~1 ~ H , ~I coo H

In 5 m~ of acetonitrile was suspended 0.53 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate, and 0.29 m~
of thionyl chloride was added to the suspension. The suspension was stirred at 55 to 60~C for 1 hour, and the solvent was removed by distillation under reduced pressure. To the residue was added 4.6 m~ of benzothiophene, and 0.4 g of aluminum chloride was then added thereto. After stirring at 60~C for 3 hours, the reaction mixture was poured into a cold potassium carbonate aqueous solution. The solution was adjusted to a pH of 8 to 9 and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography using chloroform/methanol as an eluent to obtain 5-[(benzothiophen-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole, The product was treated with an equimolar amount of fumaric acid in a usual 200~

manner and recrystallized from ethanol/acetonitrile to obtain 0.04 g of 5-[(benzothiophen-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole fumarate.
Physicochemical Properties:
Melting Point: 135-137~C
Elemental Analysis for Cl6HI4N2OS.C4H404Ø3EtOHØ2H2O):
Cacld. (%): C 59.50; H 4.90; N 6.74; S 7.71 ~ound (%): C 59.41; H 5.07; N 6.53; S 7.91 Mass Spectrum (EI): m/z 282 (M~, as a free compound) il~~C~~ H~.SOu - > ~

A mixture of 2 g of polyphosphoric acid, 5 mQ of thiophene, and 2.91 gof 4,5,6,7-tetrahydrobenzimidazole 5-carboxylic acid sulfate was stirred at 100~C for 8 hours. After cooling, 20 m~
of cold water was added thereto, and the reaction mixture was washed with toluene (20 m~ x 2). The aqueous layer was adjusted to a pH of 8 to 9 with potassium carbonate and extracted from chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was treated with a 4N solution of hydrogen chloride in ethyl acetate and then recrystallized from 2~881~

methanol/acetonitrile to obtain 0.12 g of 5-[~thiophen-2-yl)carbonyl]-4,5,6,7-tetrahydro~enzimidazole hydrochloride.
Physicochemical Properties:
Melting Point: 218-220~C
Elemental Analysis for C12Hl2N2OS.HCQ:
Calcd. (%): C 53.63; H 4.88; N 10.42; S 11.93 Found (%): C 53.25; H 4.98; N 10.62; S 11.70 Mass Spectrum (EI): m/z; 232 tM+, as a free compound) E~PLE 39 ~ o C ~-C ~ ~ ~~ ~ C~3 ~ ~

To a solution of 0.50 g of N-~(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidinehydrochloride and 0.39 g of 2-methylindolizine in 5 m~ of 1,2-dichloroethane was added dropwise 0.90 g of phosphorus oxychloride. The reaction mixture was refluxed at 85~C for one night. After cooling to room temperature, 5 m~ of water was added thereto.
The organic layer was removed, and lO m~ of chloroform was added to the aqueous layer. The solution was adjusted to a pH
of 9 with a 20% aqueous solution of sodium hydroxide and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica 2~08~1~

gel column chromatography using chloroformtmethanol as an eluent, followed by recrystallization from ethanol to obtain 0.21 g of 5-[(2-methylindolizin-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.
Physicochemical Properties:
Melting Point: 260-264~C
Elemental Analysis for Cl7H~7N3OØ15C2H5OHØ2H2O:
Calcd. (%): C 71.68; H 6.36; N 14.50 Found (%): C 71.71; H 6.16; N 14.46 Mass Spectrum (EI): m/z 279 (M+) In the same manner as in Example 39, except for replacing 2-methylindolizine with pyrrole, 5-[(2-pyrrolyl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole of formula shown below was synthesized.

~ ' Physicochemical Properties:
Melting Point: 225 - 226~C
Elemental Analysis for Cl2HI3N3O

Calcd. (%): C 66.96; H 6.09; N 19.52 Found (%): C 66.74; H 6.23; N 19.41 Mass Spectrum (EI): m/z 215 (Mf ) 2~08~1~

o L,~ ~ > ~ ~~~J
~ CH3 In a suspension of 7.0 g of N~[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidinehydrochloride and 5.4 g of N-methylindole in 70 m~ of ethylene chloride was added 12.6 g of phosphorus oxychloride, and the mixture was stirred at 80 to 85~C for 7 hours. After allowing the mixture to cool, the mixture was cooled to 0 to 5~C, and 70 m~ of cold water was slowly added to the reaction mixture while maintaining the temperature of the mixture below room temperature to thereby decompose the excess of phosphorus oxychloride. The organlc layer was removed, and the aqueous layer was adjusted to a pH of 9 with a 20% sodium hydroxide aqueous solution under cooling, followed by extrac~ing from chloroform. To the chloroform layer was added 70 m2 o~ water, and 6N hydrochloric acid was added thereto under ice-cooling while stirring to adjust to a pH of from 2.4 to 2.8. The chloroform layer was removed. The aqueous layer was washed with chloroform, and 40 m~ of methanol was added thereto. The solution was made alkaline with a 20% sodium hydroxide aqueous solution while cooling. The formed crystal was collected by filtration and washed with a cold 1:1 (by volume) mixture of 20~8~1~

methanol and water to give 6.87 g (89.9%) of 5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrah~drobenzimidazole.
Physicochemical Properties:
Melting Point: 139-141~C
Mass Spectrum (EI): m/z 279 (Mf) H-NMR (CDC~3 DMSO-d6):
1.80-2.32 (m, 2H), 2.56-3.04 (m, 4 H), 3.32-3.60 (m, lH), 3.90 (s, 3H), 7.12-7.20 (m, 3H), 7.40 (s, lH), 7.92 (s, lH), 8~20-8.40 (m, lH) Elemental Analysis for Cl7Hl7N3OØ2EtOHØ35H2O:
Calcd. (%): 70.88; H 6.46; N 14.25 Found (%): 70.83; H 6.50; N 14.23 o 1~ ~¦J~

c~3 5- [ ( l-Methylindol-3-yl ) carbonyl ] -4, 5, 6, 7 -tetrahydrobenzimidazole was treated with a half molecular amount of fumaric acid in ethanol in a known manner to obtain 5- [ ( l-methylindol-3-yl ) carbonyl ] -4, 5, 6, 7-tetrahydrobenzimidazole ~fumarate.
Physicochemical Properties:
Melting Point: 224-225~C
Elemental Analysis for Cl9HI9N3O3:
Calcd. (%): C 67.64; H 5.68; N 12.45 2008~1~

Found (%): C 67.56; H 5.66; N 12.35 Mass Spectrum (FAB): m/z 280 (M++1 , as a free compound) Optical Resolution (1) of 5-[(1-Methylindol-3-yl carbonyll-4,5,6,7-tetrahydrobenzimidazole (a) In 60 m~ of methanol was added 5.87 g of 5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole obtained in Example 41, and a solution of 7.52 g of (+)-dibenzoyltartaric acid in 240 m~ of methanol was added thereto to once form a clear solution. On leaving the solution to stand at room temperature for one night, there were precipitated crystals, which were collected by filtration and recrystallized three times from dimethylformamide/water to obtain 2.30 g of (R)-(-)-5 - [ ( 1 - ~ e t h y li n d o l - 3 - y l ) ca r b o n y l ] -4 , S , 6 , 7 -tetrahydrobenzimidazole (+)-dibenzoyltartarate.
Physicochemical Properties:
[ ~ ~ 20 = + 30.6~ (c=1.10, dimethylformamide) Melting Point: 169.0-170.0~C
Elemental Analysis for Cl7HI7N3O.Cl8Hl4O8.H2O:
Calcd. (%): C 64.12; H 5.07i N 6.41 Found (%): C 64.13; H 5.03; N 6.5~
Mass Spectrum (FAB): m/z ~80 (M+ + 1, as a free compound) (b) In a 2N hydrochloric acid aqueous solution was added 2.2 g of the compound obtained in (a) above, and the solution was washed with ethyl acetate and then adjusted to a pH of about 9 with sodium carbonate. The aqueous layer was extracted wi~h 2~08~5 chloroform/methanol (4:1 by volume). The extract ~as dried over anhydrous magnesium sulfate, and the solvent was removed by distilla-tion to obtain 0.94 g of (R)-(-)-[(5-l~methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole as a foaming substance.
[a]D~ = -16 ~ 5o ( c=l .13, methanol) (c) (R)-(-~(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole (0.56 g) obtained in (b) above was treated with 0.21 g of fumaric acid in methanol/acetonitrile to obtain 0.64 g of (R)-(-)-5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole fumarate.
E~] 2~=-28.1~ (C=1.22, methanol) Melting Point: 150.5-151.5~C
Elemental Analysis for Cl7Hl7N30.C4H404Ø35CH3CNØ25H20:
Calcd. (%): C 62.91; H 5.49; N 11.33 Found (%): C 62.94; H 5.41; N 11.35 Mass Spectrum (EI): m/z 279 ( M~, as a free compound) In ethanol/ethyl acetate was dissolved 100 mg of (R)-(-)-5 - [ ( 1 -methyl - 3 -indolyl ) carbonyl ] -4, 5, 6, 7 -tetrahydrobenzimidazole obtained in Example 43(b), and a solution of hydrogen chloride in ethyl acetate was added thereto. The thus formed crystal was collected and recrystallized from ethanol to obtain 70 mg o~ (R)-(-)-5-[(1-methylindol-3-yl)carbonyl]-4r5r6r7-tetrahydrobenzimidazole hydrochloride.

2 ~ r) [CL]D = -42.9~ (c=1.02, methanol) Melting Point: 215 - 230 ~ C
Elemental Analysis for Cl7HI7N3O.HC~:
Calcd. (%): C 64.66; H 5.75; N 13.31; C~ 11.23 Found (%): C 64.37; H 5.80; N 13.12; C~ 11.17 Mass Spectrum (EI): m/z 279 (M+, as a free compound) Optical Resolution (2) of 5- [ (1-methylindol-3-yl ) carbonyl l -4,5,6,7-tetrahydrobenzimidazole (a) In the same manner as in Example 43(a), except for using ( - ) -dibenzoyltartaric acid, ( S ) - ( + ) -5- [ (1 methylindol-3-yl ) carbonyl ] -4, 5, 6, 7 -tetrahydrobenzimidazole ( - ) -dibenzoyltartarate was obtained.
[ ~ ~ D0 = _ 30.3 ~ ( c = 1.07, dimethyl f ormamide ) Melting Point: 168.5-169.5~C
Elemental Analysis f or C17HL7N3O ~ ClsH14~a ~ H2O
Calcd. (%): C 64.12; H 5.07; N 6.41 Found (gs): C 64.13; H 5.13; N 6.71 Mass Spectrum (FAB): m/z 280 (M+~1, as a free compound) (b) In the san~e manner as in Example 43 (b), except for using the salt as obtained in ( a ) above, ( S ) - ( + ) -5- [ ( l-methylindol-3-yl ) carbonyl ] -4,5,6,7-tetrahydrobenzimidazole was obtained as a foaming substance.
[, ~20 = +16.7~ (c=~.35, methanol) ( c ) In the same manner as in Example 43 ( c ), except f or using ( S ) - ( + ) -5- [ ( l-methylindol - 3 -yl ) carbonyl ] - 4, 5, 6, 7 2 ~

tetrahydrobenzimidazole as obtained in (b) above, a crystal of (S)-(+)-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole fumarate was obtained.
[~]DO = +2g.3~ (c=1.14, methanol) Melting Point: 151.0-152.0~C
Elemental Analysis for Cl7Hl7N30.C4H404.O.35CH3CNØ25H~O:
Calcd. (%): C 62.91; H 5.49; N 11.33 Found (%): C 62.96; H 5.39; N 11.37 Mass Spectrum (EI): m/z 279 (M~, as a free compound) EXAMPL~ 46 ~~ S ~ ~-H So ~ ~ ~ ~

~ ,5,6,7-Tetrahydrobenzimidazole-5-carboxylic acid sulfate (1.32 g) was refluxed in 10 mQ of 1,2-dichloroethane together with 1.78 g of thionyl chloride for 30 minutes, and the excess of thionyl chloride and the solvent were removed by distillation under reduced pressure. To the residue was added 10 m~ of 1,2-dichloroethane, and 1.6 mQ of indoline was added dropwise thereto at 30~C or lower while sitrring, followed by stirring at room temperature for 2 hours. The reaction mixture was successively extracted once with 30 m~ of water and twice with 20 mQ of water. The combined aqueous layer was adjusted to a pH of 9 to 10 with a 10% sodium hydroxide aqueous solution ~Og(~l ~

and then extracted with methylene chloride. The combined methylene chloride layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 1.1 g (82.7%) of 5-[ ( 2, 3 -dihydroindol- 1 -yl ) carbonyl ] -4, 5, 6, 7 -tetrahydrobenzimidazole.
Melting Point: 175-178~C
Mass Spectrum (EI): m/z 267 (Mt) H-NMR (CDCQ3-DMSO-d6):
1.80-2.36 (m, 2H), 2.48-3.12 (m, 5H), 3.24 (t, 2H), 4.20 (t, 2H), 6.84-7.30 (m, 3H), 7.50 (s, lH), 8.20 (dd, lH) Elemental Analysis for Cl6Hl7N30Ø25H20:
Calcd. (%): C 70.70; H 6.49; N 15.46 Found (%): C 70.79; H 6.37; N 15.19 5-[(2,3-Dihydroindol-l-yl)carbonyl]-4,5,6,7-tetrahydrobenz-imidazole as obtained in Example 46 was treated with hydrochloric acid in ethanol in a usual manner to obtain 5-[ ( 2, 3-dihydroindol- 1 -yl ) carbonyl ] -4, 5, 6, 7 -tetrahydrobenzimidazole hydrochloride of formula:

2 0 ~

Physicochemical Properties:
Melting Point: >250~C
Elemental Analysis for Cl6HI8N3Oc~:
Calcd. (%): C 63.26; H 5.97; N 13.83; C~ 11.67 Found (%): C 63.15; H 5.97; N 13.80; C~ 11.78 Mass Spectrum (EI): m/z 267 (M+ , as a free compound) Optical Resolution (1) of 5~[(2,3-Dihydro-indol-1-yl)carbonyll-4,5,6,7-tetrahydrobenzimidazole (a) 4 g of 5-[(2,3-dihydroindol-1-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole as obtained in Example 46 were dissolved in 50 m~ of methanol, and a methanolic solution (250 m~) of 2.70 g of (-)-dibenzoyltartaric acid was added thereto. The thus formed crystal was collected by filtration, and the crystal was recrystallized twice from dimethylformamide/water to obtain 2.88 g of a (-)-dibenzoyltartarate showing optical rotation of -34.0~ (20~C, sodium D-line, c=0.63 g/d~, dimethylformamide).
Physicochemical Properties:
Melting Point: 163.5-165.0~C
Elemental Analysis for Cl6HI7N3~~clsHl4~a o 7DMF 2~2H20 Calcd. (%): C 60.59; H 5.66; N 7.22 Found (~): C 60.53; H 5.28; N 7.26 Mass Spectrum (EI): m/z 267 (Mt , as a free compound) (b) The above prepared salt (2.65 g) was added to 2N
hydrochloric acid, and the solution was washed with ethyl 20~881 ~

acetate. The solution was then adjusted to a pH of 9 with sodium carbonate. The aqueous layer was extxacted with chloroform/methanol (4:1 by volume), and the extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation to obtain 0.95 g of a base showing optical rotation of -6.3~ (20~C, sodium D-line, c=1.05 g/dQ, methanol) as a foaming substance.
Physicochemical Properties:
Melting Point: 100-106~C
Elemental Analysis for Cl6HI7N3OØ2AcoEt.o-5H2o:
Calcd. (%): C 68.64; H 6.72; N 14.29 Found (%): C 68.62; H 6.53; N 14.30 Mass Spectrum (EI): m/z 267 (Mt) (c) The above obtained foaming base was dissolved in ethanol/ethyl acetate, and the solution was treated with a solution of hydrogen chloride in ethyl acetate to obtain 0.94 g of a crystal of a hydrochloride showing optical rotation of +19.1~ (20~C, sodium D-line, c=1.06 g/d~, methanol).
Physicochemical Properties:
Melting Point: 241-244~C (dec.) Elemental Analysis for C~6Hl7N3O.HCQ:
Calcd. (%): C 63.26; H 5.97; N 13.83; CQ 11.67 Found (%): C 63.18; H 6.04; N 13.78; C~ 11.45 Mass Spectrum (EI): m/z 267 (M~ , as a free compound) 2~8~1~

Optical Resolution (2) of 5-[(2,3-Dihydroindol-1-yl)carbonyll-4,5,6,7-tetrahydrobenzimidazole (a) In the same manner as in Example 48(a), except for using (+)-dibenzoyltartaric acid, a crystal of a (+)-dibenzoyltartarate showing optical rotation of +33 4~
(20~C, sodium D-line, c=0.60, dimethylformamide) was obtained.
Physicochemical Properties:
Melting Point: 165.0-166.5~C
Elemental Analysis for Cl6Hl7N3O-C~8Hl4O8-0~7DMF-1-85H2O:
Calcd. (%): C 61.13; H 5.61; N 7.28 Found (%): C 61.12; H 5.28; N 7.28 Mass Spectrum (EI): m/z 267 (M+ , as a free compound) (b) In the same manner as in Example 48(b), except for using the salt as obtained in (a) above, a base showing optical rotation of +7.9~ (20~C, sodium D-line; c=1.06, methanol) was obtained as a foaming substance.
Physicochemical Properties:
Melting Point: 98-103~C
Elemental Analysis for Cl6H~7N3OØ15AcOEtØ5H2O:
Calcd. (~): C 68.86; H 6.68; N 14.51 Found (%): C 68.65; H 6.66; N 14.45 Mass Spectrum (EI): m/z 267 (M+) (c) In the same manner as in Example 48(c), except for using the foaming base as obtained in (b) above, a crystal of a 2~8~ ~

hydrochloride having optical rotation of -19.2~ (20~C, sodium D-line, c=1.07; methanOl) was obtained.
Physicochemical Properties:
Melting Point: 239-242~C (dec.) Elemental Analysis for Cl6H~7N3O.HC~:
Calcd. (%): C 63.26; H 5.97; N 13.83; C~ 11.67 Found (%): C 63.07; H 5.99; N 13.76; C~ 11.58 Mass Spectrum (EI): m/z 267 (~ , as a free compound) 3 ~'Cl ,~ HooC~
In 40 ml of acetonitrile was suspended 5.00 g of 4,5,6,7-tetrahydrobenzimidazole--5-carboxylic acid sulfate, and 2.75 ml of thionyl chloride was added to the suspension. The suspension was stirred at 55~C for 1 hour, and the solvent was distilled off under reduced pressure. To the residue was added 20 ml of nitrobenzene and 1.80 ml of 2-methylbenzofurane, and 2.20 ml of tin tetrachloride was then added thereto. After stirring a-t 85~C for one night, 40 ml of l M aqueous hydrochloric acid solution and 40 ml of ethyl ether were added thereto.
The organic layer was removed, 40 ml of chloroform was added and then the solution was adjusted to a pH of 9 with 10 ~ aqueous solution of sodium hydroxide. The reaction solutlon was filtered through celite and then extracted with chloroform containing 2~8~

lO % methanol. The organic layer was collect~d and the solvent was distilled off. To the free base of objective product obt~ined by treating the residue with silica gel column chromatography using chloroform/methanDl was added calculated amount of fumalic acid to convert it to a fumarate and recrystallized from ethanol to obtain 0.14 g of 5-C(2-methylbenzofuran-3-yl)carbonyl~-4,5,6,7-tetrahydrobenz-imidazole fumarate.
Physicochemical Properties:
Melting Point: 188-189~C
Elemental Analysis for C17H16N202-C4H4O4 Calcd. (%) C 63.63; 'H 5.09; N 7.07 Found ~) C 63.47; H 5.06; N 7.01 Mass Spectrum (EI): m/~ 230 (M , as a free compound) EXAMPLE 51 2 ~ ~ 8 ~15 S-~(indolizin-3-yl~carbony~ ~4,$,6,7-~etr~hydrobenzimidazole ~3~tl~

In the same manner as in Example 39, except for repl~cing 2-methylindolirine with indolizine, above-mentioned compound was obtained.
Physicochemical Properties:
Melting Points 210-212-C
Elemental Analysis for C~ N30-0.1 H20 Calcd. (~): C 71.94; ~ 5.74 N ~5.73 Found ~ts ~ 72.08;~H~.79 N 15.67 Mas- Spectrum (EI)s m/z 265 ~M ) 5-~(1-methylindolizin-3-yl) carbonyl7-4,5,6,7-tetrahydrobenzimidazole c~3 In the same manner as in Example 39, except for replacin~
2-methylindolizine with 1-methylindolizine, above-mentioned compound was obtained.
Physicochemical Propertie~.
Melting ~oint: 122-123CC
Elemental AnalysiS for C17Hl~N30~0.25 C~HloO-0.4 H20 Calcd. (~): C 70.87; H 6.71; N 13.77 ~ound (~)s C 70.88 H 6.68; N 13.66 Mass Spectrum (EI)s mlz 279 (~ ) 2~8~1~

FORMULATION EXAMP~E 1 ( ~ ~ ) Compound of Example 44 (hereinafter 0.2 mg referred to Compound A) Lactose 106.4 mg Corn starch 48.0 mg Hydroxypropyl cellulose 4.8 mg Magnesium stearate 0.6 mg ___________________________________________________ Total: 160.0 mg/tablet Compound A (200 mg), lactose (106.4 mg), and corn starch (48 g) were uniformly mixed, and 48 m~ of a 10~ aqueous solution of hydroxypropyl cellulose was added thereto. The mixture was granulated by means of a granulator. To the granules was added 0.6 g of magnesium stearate, and the mixture was punched to obtain 1000 tablets each weighing 160 mg.

2~0~

FORMULATION EXAMPLE 2 ( ~D~cr~ ) Compound A 0.4 mg Mannitol 770.0 mg Corn starch 199.6 mg Polyvinylpyrrolidone 30.0 mg ___________________________________________________ Total: 1000.0 mg Compound A (0.4 g), mannitol (770 g), and corn starch (199.6 g) were uniformly mixed, and 300 m~ of a 10~ aqueous solution of polyvinylpyrrolidone was added thereto, followed by granulation by means of a granulator to prepare 1 kg of powders.
FORMULATION EXAMPLE 3 f~,ps~ ) Compound A0.2 mg Corn Starch 198.8 mg Calcium stearate 1.0 mg ___________________________________________________ Total: 200 mg Compound A (0.2 g), corn starch (198.8 g), and calcium stearate (1 g~ were uniformly mixed, and the mixture was charged in No. 3 capsules by 200 mg to prepare 1000 capsules.
FORMULATION E~AMPLE 4 (~
Compound A 0.2 mg Sucrose 8.0 mg Pure water to make 5 mQ
Compound A (0.2 g) and sucrose (8 g) were dissolved in distilled water to prepare S Q of a syrup.

3 1 ~

FORMULATION EXAMPLE 5 (o~ CZ~,~'S ) Compound A 0.3 mg Sodium chloride 9 mg Injectable distilled water to make 1.0 mQ
Compound A (300 mg) and sodium chloride (9 g) were dissolved in injectable distilled water to prepare 1000 mQ of a solution. The solution was filtered and charged in 1000 ampules by 1 mQ while displacing the atmosphere of the ampule with nitrogen gas. The ampules were sterilized by autoclaving.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be-apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims (32)

1. A tetrahydrobenzimidazole derivative represented by formula (I) wherein Het represents a member selected from the group consisting of pyrollidine, piperidine, piperazine, morpholine, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 4H-cyclopentathiazole, indole, isoindole, 2,3-dihydroindole (indoline), isoindoline, hydroxyindole, indazole, indolizine, benzothiophene, benzofuran, benzothiazole, benzimidazole, benzoxazole, 4,5,6,7-tetrahydrobenzothiophene, 2,3-dihydrobenzimidazol-2-one, quinoline, isoquinoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,4-benzoxazine, phenothiazine, carbazole and .beta.-carboline, and wherein Het may be substituted with 1 to 3 substituents selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl-lower alkyl, aralkyl, lower alkoxy, nitro, hydroxyl, lower alkoxycarbonyl, and halo; and X
represents a single bond or -NH- whlch is bonded to the carbon atom or nitrogen atom of the heterocyclic ring of said Het, or a pharmaceutically acceptable salt thereof.

2. The derivative as claimed in claim 1 wherein X
represents a single bond.

3. The derivative as claimed in claim 1 wherein X
represents a single bond connected to a nitrogen atom of the Het group.

4. The derivative as claimed in claim 1 wherein X
represents -NH-.

5. The derivative as claimed in claim 1 wherein Het is pyrrolidinyl.

6. The derivative as claimed in claim 1 wherein Het is 1,2,3,4-tetrahydroisoquinolinyl.

7. The derivative as claimed in claim 1 wherein Het is 2,3-dihydrobenzimidazol-2-one-yl.

8. The derivative as claimed in claim 1 wherein Het is N-(2-benzothiazolyl).

9. The derivative as claimed in claim 1 wherein Het represents a member selected from the group consisting of pyrrolidine, pyrrole, furan, thiophene, imidazole, pyrazole, isoindole, 2,3-dihydrobenzimidazole-2-one, isoindoline, hydroxyindole, indazole, benzothiophene, benzofuran, benzimidazole, 4,5,6,7-tetrahydrobenzothiophene, carbazole and beta-carboline.

10. The derivative as claimed in claim 1 wherein Het is indole.

11. The derivative as claimed in claim 1 wherein Het is 2,3-dihydroindol.

12. A compound as claimed in claim 1, wherein Het is represented by the formula:

wherein R1 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl-lower alkyl, or an aralkyl; R2 represents hydrogen, lower alkyl, or aralkyl; and R3 represents hydrogen, lower alkoxy, nitro, hydroxyl, lower alkoxycarbonyl, or halo; and X represents a single bond.

13. A compound as claimed in claim 1, wherein Het represents a nitrogen-containing heterocyclic group; and X
is a single bond connected to the nitrogen atom of the nitrogen-containing heterocyclic ring.

14. A compound as claimed in claim 12, wherein said compound is 5-[(1-methylindol-3-yl)carbonyl]-4,5,6, 7-tetrahydrobenzimidazole.

15. A compound as claimed in claim 1, wherein said compound is (R)-compound.

16. A compound as claimed in claim 1, wherein said compound is an (S)-compound.

17. A compound as claimed in claim 1, wherein said compound is 5-[[1-(2-propynyl)indol-3-yl]carbonyl]-4,5,6, 7-tetrahydrobenzimidazole.

18. A compound as claimed in claim 1, wherein said compound is 5-[(2,3-dihydroindol-1-yl)carbonyl]-4,5,6, 7-tetrahydrobenzimidazole.

19. A compound as claimed in claim 1, wherein said compound is 1-[(4,5,6,7-tetrahydrobenzimidazole-5-Yl)carbonyl]-2,3-dihydrobenzimidazol-2-one.

20. A compound as claimed in claim 1, wherein said compound is 5-[(2-benzylindol-3-yl)-carbonyl]-4,5,6,7-tetrahydrobenzimidazole.

21. A compound as claimed in claim 1, wherein said compound is 5-[(1-n-butylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.

22. A compound as claimed in claim 1, wherein said compound is 5-[(1-cyclohexylmethylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.

23. A compound as claimed in claim 1, wherein said compound is 5-[1-benzylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.

24. A compound as claimed in claim 1, wherein said compound is N-(pyridin-3-yl)-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide.

25. A compound as claimed in claim 1, wherein said compound is N-(5,6-dihydro-4H-cyclopentathiazol-2-yl)-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide.

26. A pharmaceutical composition containing a tetrahydrobenzimidazole derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

wherein Het represents a member selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 4H-cyclopentathiazole, indole, isoindole, 2,3-dihydroindole (indoline), isoindoline, hydroxyindole, indazole, indolizine, benzothiophene, benzofuran, benzothiazole, benzimidazole, benzoxazole, 4,5,6,7-tetrahydrobenzothiophene, 2,3-dihydrobenzimidazol-2-one, quinoline, isoquinoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,4-benzoxazine, phenothiazine, carbazole, and .beta.-carboline, and wherein Het may be substituted with 1 to 3 substituents selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloakyl lower alkyl aralkyl, lower alkoxy, nitro, hydroxyl, lower alkoxycarbonyl, and halo; and X
represents a single bond or -NH- which is bonded to the carbon atom or nitrogen atom of the heterocyclic ring, and a pharmaceutically acceptable carrier.

27. A pharmaceutical composition as claimed in claim 26, wherein said composition is a 5HT3-antagonist.

28. A pharmaceutical composition as claimed in claim 26, wherein said composition is a treating agent for gastrointestinal disorders.

29. A pharmaceutical composition as claimed in claim 26, wherein said gastrointestinal disorders are anaphylactic intestinal syndrome.

30. A pharmaceutical composition as claimed in claim 26, wherein said composition is a treating agent for nausea and/or vomitting induced by chemotherapy or radiation.

31. A pharmaceutical composition as claimed in claim 26, wherein said composition is a treating agent for migraine, cluster headache and trigeminal neuralgia.

32. A pharmaceutical composition as claimed in claim 26, wherein said composition is a treating agent for anxiety and psychotic disorders.