CA1215364A - Benzimidazole derivatives, process for the preparation thereof and pharmaceutical composition containing the same - Google Patents

Abstract

Abstract of the Disclosure:

The invention provides novel benzimidazole derivatives of the formula:

(I) wherein R1 is an alkyl group having 1 to 3 carbon atoms, an allyl group, a propargyl group, or a phenyl group; R
is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; and n is 2 or 3, or pharmaceutically acceptable acid addition salts thereof. These compounds have excellent antihistaminic activities and are useful as antiallergics for various allergic diseases. The invention also pro-vides a process for the preparation of the compounds and antihistaminic compositions containing the compounds as active ingredients.

Description

~S36~

Novel benzimidazole derivatives, process for the preparation thereof and pharmaceutical composition containin~ the same.
The present invention relates to novel benzimidazole derivates, a process for the preparation thereof and a pharmaceutical composition cont~ining the compounds as active ingredients.
Histamine is a physiologically active substance which is present in various animals, plants and microor~anisms.
In humans, it is present in high concentration in skin, mucous membranes of the gastro-intestinal tract, and res-piratory tissue, particularly in the mast cells of these tissues and the blood basophils. Upon antigen-antibody reaction or contact with, or invasion by, certain medica-ments, high polymer materials or toxins, histimine is released from the cells and acts on Hl-receptors to induce various physiological reactions such as broncho-constriction, capillary dilatation, increased capillarypermeability, and the like. Such activity produces various allergic symptoms such as eruption, congestion, inflammation, and the like. In order to prevent or treat such allergic symptoms, various medicaments having antagon-istic activities against histamine on Hl-receptors, i.e.
antihistaminics, have been developed and used in practice.
Conventional antihistaminics are classified by their - chemical structure as ethanolamines (e.g. diphenhydramine), ethylenediamines (e.g. tripelennamine), alkylamines j~, ;364 (e.g chlorpheniramine), piperazines (e.g. cyclizine), and phenothiazines (e.g. promethazine). However, conventional antihistaminics have various drawbacks, e.g. weak activi-ties, or undesirable side-effects such as hypnotic activity s when they have strong activities, or they have compara-tively high toxicity.
These conventional antihistaminics all contain a tertiary amino group in their chemical structures. For example, diphenylmethane derivatives are known which lQ contain a N-substituted piperazinyl group or an N-substituted homopiperazinyl group as the tertiary amino group. These compounds have the formula:

X- ~ C~-N N-Y (A
~ ~CH2)n.

wherein X' is hydrogen atom, a chlorine atom, etc.; Y is an alkyl group or an aralkyl group; n' is 2 or 3. Such compounds differ chemically from the compounds of the present invention as defined below.
The compounds of the present invention show superior antihistaminic activities which may be more than 10 times as strong as those of the known antihistaminics of formula ~A), for example, homochlorcyclizine hydrochloride (formula (A), X' = chlorine atom, Y = methyl group, n' =
3) and also show much lower toxicity. The compounds of the present invention are also far superior to the known representative antihistaminic chlorpheniramine maleate in terms of antihistaminic activity and toxicity.
Benzimidazole derivatives containing a piperazinyl or homopiperazinyl group at the 2-position are also known and these are structurally similar to the compounds of the present invention as defined below. For example, in Japanese Patent Laid Open Application No. 126682/1975, the following compounds having anti-inflammatory and analgesic activities are disclosed:

~i~

ii3~

Rl_~N~ ~J (B) 1 2' wherein Rl is a hydrogen atom, a halogen atom, a satu-rated or unsaturated lower alkyl group, a lower alkoxy group or a nitro group; R is a hydrogen atom, a substi-tuted or unsubstituted alkyl group, an alkenyl group, anacyl group, a sulfonyl group or an aralkyl group; and R is a hydrogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an acyl group, a sulfonyl group, a carbamoyl group, an aryl group, an aralkyl group or a hydroxyalkyl group: specifically, 2~(4-methyl~l-piperazinyl)benzimidazole,l-methyl-2-(4-methyl-1-piperazinyl)benzimidazole and l-benzyl-2-(4-methyl-1-piperazinyl)benzimidazole. Moreover~ in U.S. Patent 4,093,726, the following compounds having hypotensive activities are disclosed:

Rn~ ' (C ) wherein R is a hydrogen atom or a methyl group; R' is a Cl 6 alkyl group, an acyl group, an aryl group7 an aroyl group, an alkoxycarbonyl group, a tetrahydrofuroyl group, a dialkylaminocarbonyl group or a furoyl group; R" is a hydrogen atom or a methoxyl group; and n' is 2 or 3:
specifically, 2-(4-isobutyloxycarbonyl-1-piperazinyl)-5,6-dimethoxy~enzimidazole, 2-[4-2(2-furoyl)-1-homopipera-zinyl]-5,6-dimethoxybenzimidazole and 2-(4-methyl-1-piperazinyl)benzimidazole.
However, these compounds diclosed in the prior art aredifferent from the compounds of the present invention (as defined below~ in view of the fact that no ether bond-containing group is present at the l-position of the benzimidazole nucleus. Besides, this literature discloses merely that the compounds have analgesic, anti-inflammatory or hypotensive activities but does not disclose any anti-~Z~S364 histaminic activity as in the present invention. In fact,according to experiments carried out to determine the protecting activity of the compounds against histamine-induced lethality, the representative compounds disclosed in the above literature, 1-methyl-2-(4-methyl-1-pipe-razinyl3benzimidazole, 1-benzyl-2-(4-methyl-1-piperazinyl)-benzimidazole and 2-(4-methyl-1-piperazinyl)benzimidazole showed merely about one tenth or less of the protecting activity of the compounds of the present invention.
The present inventors carried out an extensive study for new types of antihistaminics having good antihis-taminic activities with low toxicity and high safety. As a result,it has been found that certain novel benzimidazole derivatives and their pharmaceutically acceptable acid addition salts satisfy the desired requirements.
According to the invention there is provided benzimidazole derivatives of the formula:

N ~ N A 2 CH2CH2--R (I) wherein Rl is an alkyl group having 1 to 3 carbon atoms, an allyl group, a propargyl group, or a phenyl group; R2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; and n is 2 or 3, or a pharmaceutically acceptable acid addition salt thereof.
The invention also provides a process for the prepa-ration thereof, and pharmaceutical compositions containing the compound useful as antihistaminics.
The pharmaceutically acceptable acid addition salts forming part of the present invention include salts of organic or inorganic acids, e.g. maleic acid, fumaric acid, hydrochloric acid, or sulfuric acid.
The compounds (I) of the present invention can be pre-pared, for example, by the Method A as shown by the follow-ing reaction scheme:
~'' ~S3~;~

[Method A]

~C 1 + HN~N-R2

2 2 (II) ~III) @~NI ~ \ fCU~

(I~
wherein Rl, R2 and n are as defined above.
The starting compounds (II) of the a~ove Method A are also novel compounds and can be prepared by the following method:
~ ~ Cl f X-cH2cH2-o-R ~ Cl (IV) (V) ~II) wherein R1 is as defined above, and X is a halogen atom lQ e.g. a chlorine or bromine atom.
The above reaction scheme may be carried out by reacting 1 mole of the 2-chlorobenzimidazole (IV) with the halogen compound (V) in an equimolar amount or slightly in excess, usually 1 to 1.5 moles, in an organic solvent in the presence Of a base and optionally a catalyst, e.g. potassium iodide.
The solvent maybe, for example, methanol, ethanol, N,N-dim-ethylformamide, dimethyl sulfoxide, or the like. The base may be, for example, an alkali metal (e.g. sodium metal), an alkali metal hydroxide (e.g. sodium hydroxide, potassium hy-droxide), an alkali metal hydride (e.g. sodium hydride,potassium hydride), or the like. The base is preferably used in an amount of 1 to 1.5 mole per mole of the 2-chloroben~im-idazole (IV~. The reaction temperature is usually in the range of from 0C to the boiling point of the solvent, prefe-rably from room temperature to 80C.

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The reaction of the compound (II) with the compound(III) to form the compound (I) of the present invention (Method A) is carried out by reacting the compound (II) with an excess, usually 2 to 10 molar amounts, of t~e compound (III) without a solvent, or by reacting the compound (II) with an equimolar amount or an excess, usually 1 to 2 molar amounts, of the compound (III) in an organic solvent, preferably in the presence of a base.
When the reaction is carried out in a solvent, a solvent such as N,N-dimethylformamide, dimethyl sulfoxide, or N-methyl-2-~yrrolidone may be used.. The base ~ay be, for example, an aliphatic tertiary amine (e.g. triethylamine) or pyridine, and is preferably used in an amount of 1 to 1.5 moles per mole of the oompound (II). The reaction temperature is preferably in the range of from 100C to 130C when no solvent is present and from 80C to the boiling point of the solvent when a solvent is used.
The compounds (I) of the present invention wherein R2 is hydrogen atom may also be prepared by the following method A':
[Method A']

~ ~ Cl ~ H~ N-R3 >

CH2CH2 -O-Rl (II) (III) N R > ~ ~ N NH
NH o R1 N (CH2)n (VII) (I-a) wherein Rl and n are as defined above, and R3 is a pro-tecting group which can be removed by a catalytic reduction or under acidic or basic conditions.

~ ` ~

ii364 The protecting group (R3) maybe, for example, a benzyl group which can easily be removed by catalytic reduction, or a formyl or ethoxycarbonyl group which can easily be removed under acidic or basic conditions.
Removal of the protecting group may be carried out by a conventional method.
Alternatively, the compounds (I) of the present inven-tion wherein R2 is an alkyl group having l to 3 carbon atoms may be prepared from the compounds (I~ wherein R2 is hydrogen, i.e. the compounds (I-a~, by the following Method A":
[Method A n ]

~ N ~~NH ~ alkyl (Cl_3)-~ > ~ ~ N \ N-alkyl CH2CH2--E~CH2CE~2-0-R
(I-a)(VIII) (I-b) wherein Rl, n and X are as defined above.
The reaction of the above Method A" can be carried out by reacting the compound (I-a) with an equimolar amount or a slight excess, usually 1 to 1.5 moles of the lower alkyl halide (VIII) in an organic solvent in the presence of a base and optionally a catalyst, e.g. potassium iodide Suitable examples of the sovlent are chloroform, methanol and ethanol. The base may be, for example, an alkali metal salt (e.g. sodium hydrogen carbonate, potassium carbonate) or an organic base (e.g. triethylamine, pyridine) and the base is usually used in an amount of 1 to 1.5 moles per mole of the compound (I-a). The reaction temperature is usually in the range of from ODC to the boiling point of the solvent.
Alternatively, the compounds (I) of the present invent-ion can be prepared by the Method B as shown by the follow-ing reaction scheme:

,. I

~s~

lMethod B]

~ -R4 ~ XC~2CH2-O-R
~ ~CH21 ~
H

( IX) (~7) when R = a protecting ~N~ NH
group /~ I (CH2) n ~ CH CH2-0-R
/Removal of 2 (I-a) \

when R = Cl_3 alkyl ~ N
¦ I ~N N-alkyl l~N~ \(CEI2) / (Cl_3) (I-b) wherein Rl, n and X are as defined above, and R4 is an alkyl group having 1 to 3 cabon atoms, or the same protecting group as defined for R .
In the above Method B, when preparing the compounds (I-a) [i.e. R2 = hydrogen atom in the formula (I)], the starting compound (IX), wherein R4 is a protecting group as defined for R3, is reacted with the halide compound (V), followed by removal of the protecting group in the usual manner. When preparing the compounds (I-b) li.e. R2 = an alkyl group having 1 to 3 carbon atoms in the formula (I)], the starting compound (IX), wherein R4 is an alkyl group having 1 to 3 carbon atoms, is reacted with the halide compound (V).
The starting compound (IX) used in the above Method B may be prepared by reacting 2-chlorobenæimidazole of the formula:

~2~S36~

~ ~ Cl (I~) with a compound of the formula:

HN N-R (X) \(CH2) /

wherein R and n are as defined above, under the same reaction conditions as used for the reaction of the compound (II) and th~ compound (III) as disclosed hereinbefore.
The reaction of the compound (IX) with the halide compound (V) in the above Method B may be carried out under the same reaction conditions as those used in the reaction for the preparation of the starting compound (II) in the above Method A, i.e. the reaction of 2-chloro-benzimidazole with the halide compound (V), but in this case an alkali metal (e.g. sodium metal) or an alkali met~l hydride (e.g. sodium hydride, potassium hydride)if preferably used as the base, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are not suitable because they tend to lower the yield of the product when they are used.
The oompounds (I) obtained by the above methods may be converted into their acid addition salts by treating them with an inorganic acid (e.g. hydrochloric acid, sulfuric acid) or an organic acid (e.g. maleic acid, fumaric acid) in the usual manner.
2~ The compounds (I) and their pharmaceutically accep-table acid addition salts of the present invention have excellent antagonistic activity against histamine and low toxicity and are useful for the prophylaxis and treatment of various allergic diseases induced by histamine, such as ~21536~

allergoses in the respiratory tract (e.g. allergic rhinitis, allergic inflammation in the respiratory tracts) hay fever, allergic dermatoses (e.g. urticaria, eczema, dermatitis, puritus, drug eruption, local reactions due to insect bites), and allergic conjunctivitis.
The antihistaminic activities and acute toxicities of the compounds of the present invention were tested as follows.
1. Protecting activity against histamine-induced lethality Test compounds:
(1) Twelve compounds of the present invention as dis-closed in Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 below (2) Chlorpheniramine maleate (reference compound)

(3) Homochlorocyclizine hydrochloride (reference com-pound).
Method:
The test was carried out by a method similar to the Labelle & Tislow method ~cf. ~. Pharmacol Exp. Ther., 113, 2~ 72, 1955). That is, each test compound (in an aqueous solution) or distilled water (as a control) was orally administered to Hartley strain male guinea pigs, weighing 250 to 350 g (one group: 6 to 10 animals) which had been fasted for 20 hours. After one hour, histamine (1.1 mg/kg, in a physiological saline solution) was injected into the animals via the cephalic vein. After two hours, the number of live guinea pigs was counted, and therefrom the ED50 of the compounds was calculated according to the probit method. In the control group (in which distilled water was administered), all of the animals died within 5 minutes after injection of histamine due to dysprlea .
Results:
The results are shown in Table 1 together with the acute toxicity data.
2. Acute toxicity (LD50) 121536~

Test compounds:
The same compounds as used in the above test were also used herein.
Method:
The test compounds (in aqueous solutions) were orally administered to ddY strain male mice, weighing 18 to 22 S
(one group: 5 to 10 animals) which had been fasted overnight. The mice were observed for one week. The LD50 was calculated based on the number of dead mice within one week according to Weil's method.
Results:
The results are shown in Table 1.

..

_ 12 -Table 1 N ~ ~N-R2 . fumarate ~,~N (CH2)n ~ _ _ Test compounds Protecting Acute . _ activity toxicity 1 2 against LD50 Ex n R R histam~ne No ED50(mg/~g) (mg/kg) _ .
1 3 ~C~ C~C~ -CH3 0.0046 990 2 2 -CH2C-CH -CH3 0~0047 818 3 3 CH2CH3 -CH3 0.0047 ~28

4 2 -CH2CH=CH2 -CH3 0.0058 1635 2 -CH2CH3 -CH3 0.0070 1493 6 3 -CH2CH=CH2 -CH3 0.0088 904 7 3 -CH2CH2CH3 -CH3 0.0095 884 8 2 C~2C 3 -H 0.011 2217 9 2 CH2C 3 -CH2CH 0.013 2639 3 ~ -CH3 0~014 1006 11 2 ¦ -CH2CH2CH3 -CH3 0.015 2303 12 2 ¦ ~ -CH3 0.017 1110 _ _ ._ _ Chlorpheniramine maleate 1 0.17 274 Homochlorcyclizine 2 0.26 382 hydrochloride __ . . _ 53~

Cl- ~ / CH3 HCCOOH
fi~ ~ CHcH2cH2-N . il ~ )~ ~ CH3 HCCOOH

Cl ~ CH-N ~ -CH3.2HCl As is clear from the above test results, the compounds of the present invention are far superior to the known anti-histaminic agents such as chlorpheniraminen maleate and homochlorcyclizine hydrochloride in their protecting activity against histamine-induced lethality and are also superior in terms of acute toxicity and hence much safer.
Besides, the conventional antihistaminics have side-effects such as hypnotic activity. For example, accordingto an experiment for the potentiating effect on hexobarbital-induced sleep in mice, homochlorcyclizine hydrochloride showed a remarkable potentiating effect in a dose of 25 mg/kg (p.o.), but, for example, the compounds of Examples 2, 3, 8 and 9 of the present invention did not show such potentiating effect at a dose of 50 mg/kg (p.o.).
The compounds of the present invention, particularly in the form of a pharmaceutically acceptable acid addition salt thereof, can be used for the prophylaxis and treat-~0 ment of various allergic diseases induced by histamine inconventional preparations for oral administration injection or external use.
For oral admininistration, pharmaceutically acceptable acid addition salts of the compounds are prepared in con-ventional dosage forms, for example, solid preparationssuch as tablets, granules, fine granules, powders, capsules, and li~uid preparations such as syrups. The solid preparations are prepared by using conventional pharmaceutically acceptable carriers such as lactose, starches, crystalline cellulose, talc, etc. Capsules are ~21536~

prepared by encapsulating the fine granules or powders containing the active compounds with an appropriate encap-sulating agent. Syrups can be prepared by dissolving or suspending the active compounds of the present invention in an aqueous solutions containing sucrose, carboxymethyl cellulose, etc. The preparation for injection can be pre-pared by dissolving the pharmaceutically acceptable acid addition salts of the present compounds in distilled water or physiological saline solutions. Ointments can be prepared by using conventional ointment bases such as " vaseline, polyethyleneglycol, etc. Intranasal prepara-tions are prepared by dissolving the pharmaceutically acceptable acid addition salts in distilled water or physiological saline solutions.
The dosages of the present compounds may vary depend-ing on the kinds and severity of the diseases, the weight and age of the patients, etc., but are usually in the range of 0.5 to 5 mg (as a free base) per day in adults in the case of oral or injection administration which is divided in two or three times per day. For external use (e.g. in the form of ointments or intranasal preparations), an appropriate amount of the preparations is applied to the area affected by the disease.
The present invention is illustrated by the following Examples and Reference Examples but should not be construed as limited thereto.
Reference Example 1 Preparation of 2-chloro-1-[2-(Rl-oxy)ethyl]benzimi-dazoles (II~
2-Chloro-1-[2-propargyloxy)ethyl]benzimidazole (Table 2, No. 1), was prepared as follows.
2-Chlorobenzimidazole (30.0 g) and 2-bromoethyl pro-pargyl ether (41.0g) were dissolved in N,N-dimethylforma-mide (300 ml), and 25% aqueous sodium hydroxide (40.0 g) was added thereto and the mixture was stirred at 60C for 121S36~

4 hours. Water (700 ml) was added to the reaction mix-ture, and the mixture was extracted with ethyl acetate.
The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting S residue was distilled under reduced pressure to give 2-chloro-1-[2(propargyloxy)ethyl]benzimidazole (24.5 g) as a colorless oily substrance, b.p. 158-160C/1.2 mmHg.
In the same manner as described above except that 2-bromoethyl ethyl ether, 2-bromoethyl allyl ether, 2-bromoethyl n-propyl ether and 2-bromoethyl phenyl ether were used instead of 2-bromoethyl propargyl ether, the other compounds (Table 2, Nos. 2 to 5) were respectively obtained.

Table 2 ~ ~ Cl No. RAppearance Boiling point or melting point _ 1 -CH2C-CHColorless oily 158-160C/1.2 mmHg 2 -CH2CH3 n 132-133.5C/0.65 mmHg 3 -CH2CH=CH2ll 149-150C/0.2 mmHg 4 -CH2CH2CH3,. 128.5-130C/0.27 mmHg ~Colorless crystals 97.5-98.5C

*) Recrystallized from benzene-hexane Reference Example 2 Preparation of 2-(4-methyl-1-piperazinyl)benzimidazole (in the formula (IX~, R = CH3, n = 2) A mixture of 2-chlorobenzimidazole (10.00 9) and :12153~i~

N-methylpiperazine (20.0 g) was stirred at 125C for 5 hours. A 10% aqueous sodium hydroxide solution (100 ml) was added to the reactions mixture, and the precipitated crystals were separated by filtration. ThP filtrate was extracted with chloroform, and the chloroform ex~ract was evaporated to dryness to give the same crystals. The crystals were combined and recrystallized from water-methanol to give 2-(4-methyl-1-piperazinyl)benzimidazole (7.02 g) as colorless needles, m.p. 225-226C.
Example 1 Preparation of 1-[2-(proparqyloxy)ethYl]-2-(4-methyl-l-homopiperazinYl)benzimidazole (Method A) A mixture of 2-chloro-1-[2-(propargyloxy)ethyl]-benzimidazole (3.70 g) and N-methylhomopiperazine (9.00 g) was stirred at 120C for 5 hours. A 5% aqueous sodium hydroxide solution (50 ml) was added to the reaction mixture, and the mixture as extracted with ethyl acetate.
The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The residue was dissolved in a small amount of chloroform and subjected to column chromatography using silica gel (60 g), and then eluted with chloroform-methanol (10 : 1 by volume). The eluate was concentrated to give a pale yellow oily substance (1.90 g). The pale yellow oily substance was dissolved in ethanol (3 ml) and the solution was added to a solution of fumaric acid (1.50 g) in hot ethanol (18 ml). After the mixture was allowed to cool, the preci-pitated crystals were separated by filtration and recrystallized from ethyl acetate-ethanol to give 1-[2-(propargyloxy)ethyl]-2-(4-methyl-1-homopiperazinyl)-benzimidazole difumarate (2.14 g) as colorless needles, m.p. 122-124.5~C.
Elementary analysis for C26H32N409:
Calcd. (%): C,57.34; H,5.92; N,10.29 Found (~): C,57.41; H,5.94; N,9.92 NMR (DMSO-d6, ~ ppm): 1.9-2.3 (m,2H), 2.55-2.75 (4H), 3.0-4.4 (14H), 6.5 (s, 4H), 6.8-7.4 (4H).

36~

Example 2 Preparation of 1-[2-propargyloxy)ethyl]-2-(4-me~hyl l-piperazinyl)benzimidazole (Method Al Crude crystals were obtained in the same manner as described in Example 1 using 2-chloro-1-12-(propargyloxy)-ethyl]benzimidazole (3.00 g), N-methylpiperazine (2.70 g) and fumaric acid (1.52 g). The crystals were recrystal-lized from ethyl acetate-ethanol to give 1-[2-(propar-gyloxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole .3/2 fumarate (2.80 g) as colorless plates, m.p. 145-146.5C.
Elementary analysis fo~ C23H28N407:
Calcd. (%): C,58.47; H,5.97; N,11.86 Found (%): C,57.92; H,6.06; N,11.74 NMR (D~lSO-d6, ~ ppm): 2.4 (s, 3H), 2.45 (lH), 2.6-2.95 (4H), 3.1-3.45 (4H), 3.7-4.0 (2H), 4.0-4.3 (4H), 6.5 (s, 3H), 6.~-7.5 (4H).
The free base (oil) of the above compound has NMR
(CDC13, ~ ppm): 2.3 (s, 3H), 2.35-2.7 (5H), 3.2-3.45 (4H), 3.7-4.3 (6H), 6.95-7.6 (4H).
Example 3 Preparation of 1-12-(ethoxy)ethyl]-2-(4-methyl-1-homo-piperazinyl)benzimidazole (Method A) Crude crystals were obtained in the same manner as described in Example 1 using 2-chloro-1-[2-(ethoxy)ethyl]-ber.zimidazole (3.00 g), N-methylhomopiperazine (3.10 g) and fumaric acid (2.63 g). The crystals were recrystal-lized from ethyl acetate-ethanol to give l-[2-~ethoxy)-ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole.
difumarate (3.78 g) as colorless needles, m.p. 141-143C.
Elementary analysis for C25H34N409:
Calcd. (%): C,56.17; H,6.41; N,10.48 Found (%): C,56.27; H,6.29; N,10.50 NMR (DMSO-d6, ~ ppm): 1.0 (t, 3H), 2.0-2.6 (m, 2H), 2.7 (s, 3H), 3.0-3.9 (12H), 4.0-4.3 (2H), 6.5 (s, 4H), 6.8-7.4 (4~).

~S364 The free base (oil) of the above compound has NMR
(CDC13, ~ ppm): 1.15 (t, 3H), 1.8-2.25 (m, 2H), 2.4 (s, 3H), 2.6-2.9 (4H), 3.25-3.9 (8H), 4.05-4.35 (2H), 7.0-7.7 (4H).
Example 4 Preparation of 1-[2-(allyloxy)ethyl]-2-(4-methyl-1-piper-azinyl)benzimidazole (Method A) Crude crystals were obtained in the same manner as descri~ed in Example 1 using 1-12-(allyloxy)ethyl~-2-chlorobenzimidazole (3.00 g), N-methylpiperazine (3.00 g) and furamic acid (2.16 9). The crystals were recrystal-lized from ethyl acetate-ethanol to give l-[2-(allyloxy)-ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole .3/2 fumarate (3.18 g) as colorless plates, m.p. 161.5-164C.
Elementary analysis for C23H30N407:
Calcd. (%): C,58.22; H,6.37; N,11.81 Found (%) C,58.48; H,6.29; N,ll,99 NMR (DMSO-d6, ~ ppm): 2.5 (s, 3H), 2.75-3.15 (4H), 3.15-3.5 (4H), 3.6-3.9 (4H), 4.0-4.3 (2H), 4.8-5.2 (2H),

5.4-5.9 (lH), 6.5 (s, 3H), 6.9-7.4 (4H).
Example 5 Preparation of 1-[2-(ethoxy)ethYl]-2-(4-methYl-l-pipera-zinyl)benzimidazole (Method A) Crude crystals were obtained in the same manner as described in Example 1 using 2-chloro-1-[2-(ethoxy)ethyl]-benzimidazole (100.0 g), N-methylpiperazine (90.0 9) and fumaric acid (83.0). The crystals were recrystallized from ethanol to give l-[2-(ethoxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole .3/2 fumarate (148.0 g) as colorless plates, m.p. 167.5-168.5C.
Elementary analysis for C22H30N407:
Calcd. (%): C,57.13; H,6.54; N,12.11 Found (%): C,57.04; H,6.44; N,12.02 NMR ~DMSO-d6, ~ ppm): 0.95 (t, 3H) 2.45 (s, 3H), 2.7-3.0 (4H), 3.15-3.45 (4H), 3.3 (q, 2H), 3.65 (t, 2H), 4~1 (t, 2H), 6.45 (s, 3H), 6.85-7.4 ~m, 4H).

:1215364 The free base (oil) of the above compound has NMR
(CDC13, ~ ppm): 1.15 (t, 3H), 2.35 (s, 3H), 2.45-2.75 ~4H), 3.2-3.65 (6H), 3.65-3.9 (2H), 4.0-4.3 (2H), 7.05-7.7 (4H~.
Example 6 Preparation of 1-[2-(allyloxy)ethyl3-2-(4~methYl-l-homo-~iperazinyl)benzimidazole (Method A) Crude crystals were obtained in the same manner as described in Example 1 using 1- [2-(allyloxy)eth~ 2-chlorobenzimidazole (4.00 g), N-methylhomopiperazine (4.00 g) and fumaric acid (2.58 g). The crystals were recrystal-lized from ethyl acetate-ethanol to give l-[2-(allyloxy)-ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difuma-rate (3.85 g) as colorless needles, m.p. 144.5-146.5C.
Elementary analysis for C26H34N409:
Calcd. (%) : C,57.13; H,6.27; N,10.25 Found (%): C,56.g3; H,6.20; N,10.32 NMR (DMSO-d6, ~ ppm): 1.8-2.3 (m, 2H), 2.65 (s, 3H), 3.0-3.9 (12H), 3.9-4.3 (2H), 4.7-5.2 (2H), 5.35-5.9 (lH),

6.45 (s, 4H), 6.8-7.35 (4H3.
The free base (oil) of the above compound has NMR
(CDC13, ~ ppm): 1.8-2.3 (m, 2H), 2.4 (s, 3H), 2.6-2.95 (4H), 3.45-4.3 (lOH), 4.9-5.35 (2H), 5.45-6.1 (lH), 6.9-7.55 (4H).
ExamPle 7 Preparation of 1-12~(n-propoxy)ethyl]-2-(4-methyl-1-homo-piperazinyl)benzimidazole (Method A) Cr~de crystals were obtained in the same manner as described in Example 1 using 2-chloro-1-[2-(n-propoxy)-ethyl]benzimidazole (2.83 g), N-methylhomopiperazine (3.00 g) and fumaric acid (2.04 g). The crystals were recrystal-lized from ethyl acetate-ethanol to give 1-[2-(n-propoxy)-ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (2.86 g) as colorless needles, m.p.
159.5-160.5C.

36~

Elementary analysis for C26H36N409:
Calcd. (%): C,56.93; H,6.61; N,10.21 Found (%): C,57.08; H,6.73; N,10.37 NM~ (DMSO-d6, ~ ppm): 0.75 (t, 3H), 1.1-1.6 (m, 2H), 1.9-2.4 (m, 2H), 2.7 (s, 3H), 3.25 (t, 2H), 3.2-3.9 (lOH), 4.0-4.3 (2H), 6.5 ~s, 4H), 6.95-7.45 (4H).
Example 8 Preparation of 1-[2-(ethoxy)ethyl]-2-(1-piperazinyl)benzi-midazole (Method A) Crude crystals were obtained in the same manner as described in Example 1 using 2-chloro-1-[2-(ethoxy)ethyl]-benzimidazole (5.00 g), piperazine (19.00 g) and fumaric acid (3.19 g). The crystals were recrystallized from ethyl acetate-ethanol to give l-[2-(ethoxy)ethyl]-2-(1-piperazinyl)benzimidazole .3/2 fumarate (2.29 9), as color-less needles, m.p. 167-169C.
Elementary analysis for C21H28N407:
Calcd. (%): C,56.24: H,6.29; ~,12.49 Found ~%): C,55.96; H,6.29: N,12.79 NMR (DMSO-d6, ~ ppm): O.g tt, 3H), 3.0-3.5 (lOH), 3.6 (t, 2H), 4.1 (t, 2H), 6.4 (s, 3H), 6.85-7.4 (m, 4H).
The free base (oil) of the a~ove compound has NMR
(CDC13, ~ pp~): 1.1 (t, 3H), 2.35 (s, lH), 2.85-3.65 (lOH),3.65-3.9 (2H), 4.0-4.3 (2H), 7.0-7.75 (4H).
Example 9 Preparation of 1-12-(ethoxy)ethyl]-2-(4-ethYl-l-pipera-zinyl)benzimidazole (M_thod A) Crude crystals were obtained in the same manner as described in Example 1 using 2-chloro-1-[2-(ethoxy)ethyl]-benzimidazole (5.00 g), N-ethylpiperazine (5.10 g) and fumaric acid (2.91 g). The crystals were recrystallized from ethyl acetate-ethanol to give l-12-(ethoxy)ethyl]-2-(4-ethyl-1-piperazinyl)benzimidazole .3/2 fumarate (5.62 g) as colorless needles, m.p. 134-135.5C.
Elementary analysis for C23H32N O
Calcd. (%): C,57.97; H,6.77; N,11.76 Found (~) : C,58.20; H,6.65; N,ll.90 ~'~1536g NMR (DMSO-d6, ~ ppm): 0.95 (t, 3H), 1.1 (t, 3H), 2.2 (q, 2H), 2.7-3.05 (4H3, 3.3 (q~ 2H), 3.15-3.45 (4H), 3.65 (t, 2H), 4.1 (t, 2H), 6.45 (s, 3H), 6.85-7.35 (m, 4H).
The free base (oil) of the above compound has NMR
(CDC13, ~ ppm) : 0.9-1.25 (6H), 2.25-2.75 (6H), 3.2-3.65 (6H), 3.65-3.9 (2H), 4.0-4.3 (2H), 7.0-7.75 (4H).
Example 10 Preparation of 1-[2-(phenoxy)ethyl]-2-(4-methYl-l-homo~ipe razinyl)benzimidazole (Method A) Crude crystals were obtained in the same manner as desc~ibed in Example 1 using 2-chloro-1-12-(phenoxy)ethyl)-benzimidazole (4.00 g), N-methylhomopiperazine (4.00 g) and fumaric acid (2.65 g). The crystals were recrystallized from ethanol to give l-[2-(phenoxy)ethyl]-2-(4-methyl-l-homopiperazinyl)benzimidazole difumarate (3.50 g) as colorless needles, m.p. 167-168C.
Elementary analysis for C29H34N409:
Calcd. (%): C,59.79; H,5.88; N,9.62 Found (%) : C,59.74; H,5.78; N,9.66 NMR (DMSO-d6, ~ ppm): 1.92-2.4 (2H), 2.75 (s, 3H), 3.05-3.85 (8H), 4.15-4.55 (4H), 6.5 (s, 4H), 6.6-7.5 (9H).
The free base (oil) of the above compound has NMR
(CDC13, ~ ppm): 1.75-2.2 (m, 2H), 2.35 (s, 3H), 2.55-2.85 (4H), 3.45-3.75 (4H), 4.15-4.35 (4H), 6.65-7.6 (9H).
Example 11 Preparation of 1-[2-(n-Propoxy)ethYl]-2-(4-methyl-1-piPer-azinyl)benzimidazole (Method A) Crude crystals were obtained in the same manner as described in Example 1 using 2-chloro-1-[2-(N-propoxy)-ethyl]benzimidazole (3.00 g), N-methylpiperazine (3.00 g) and fumaric acid (2.53 g). The crystals were recrystal-lized from ethyl acetate-ethanol to give l-[2-(n-propoxy)-ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole .3/2 fumarate (3.42 g) as colorless prisms, m.p. 165-166C.
Elementary analysis for C23H32N o .~'1 3~4 Calcd. (%): C,57.97; H,6.77; N,11.76 Found (%) : C,57.79; H,6.87; N,11.80 NMR (DMSO~d6, ~ ppm): 0.75 (t, 3H), 1.05~1.65 (m, 2H), 2.5 (s, 3H), 2.7-3.1 (4H), 3.2 (t, 2H), 3.1-3.5 (4H), 3.5-3.85 (2H), 3.95-4.3 (2H), 6.5 (s, 3H), 6.95-7.45 (4H).
Example 12 Preparation of 1-12-(phenoxy)ethyl]-2-(4-methyl-1-piper-azinyl)benzimidazole (Method A) Crude crystals were obtained in the same manner as described in Example 1 using 2-chloro-1-[2-(phenoxy)-ethyl]benzimidazole (3.00 g), N-methylpiperaæine (3.00 g) and fumaric acid (2.14 g). The crystalslwere recrystal-lized from ethyl acetate-ethanol to give l-[2-(phenoxy)-ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole .3/2 fumarate (2.99 g) as pale yellow plates, m.p. 152-153.5C.
Elementary analysis for C26H30N407:
Calcd. (%): C,61.17; H,5.92; N,10.97 Found (%) : C,61.21; H,5.81; N,10.96 NMR (DMSO-d6, ~jppm): 2.5 (s, 3H), 2.7-3.1 (4H), Zo 3.15-3.5 (4H), 4.35 (4H), 6.5 (s, 3H), 6.6-7.55 (9H).
The free base (oil) of the akove compound has NMR
CDC13, ~ ppm): 2.3 (s, 3H), 2.35-2.65 (4H), 3.15-3.45 ~4H), 4.1-4.4 (4H), 6.55-7.7 (9H).
Example 13 Preparation of 1-[2-(ethoxy)ethyl]-2-(4-methyl-1-piper-azinyl)benæimidazole (Method B) 2-(4-Methyl-l-piperazinyl)benzimidazole (5.00 g) pre-pared in Reference Example 2 was dissolved in N,N-dimethyl-formamide (50 ml) and sodium hydride (concentrations: 50%) (1.50 g) was added thereto at room temperature, and the mixture was stirred for 30 minutes. To the mixture was added 2-bromoethyl ethyl ether (4.00 g), and the mixture was stirred at 70C for 10 hours. Water (150 ml) was added to the reaction mixture and the mixture was extrac-ted with ethyl acetate. The extract was washed in water, dried over anhydrous magnesium sulfate and then ~LZ~36~

concentrated to give a brown oily substance ~5.40 g). The brown oily substance was treated with fumaric acid (3.26 g) in the same manner as described in Example 1~ The crude crystals thus obtained were recrystallized from ethyl acetate-ethanol to give 1-[2-(ethoxy)ethyl]-2-(4-methyl-l-piperazinyl)benzimidazole .3/2 fumarate (6.31 g) as colorless plates. This product had the same physical properties as those of the product in Example 5.
Example 14 Preparation of 1-~2-(ethoxy3ethyl]-2-(1-piperazinyl)-benzimidazole (Method A') (1) a mixture of 2-chloro-1-[2-(ethoxy)ethyl]-benzimi-dazole (9.00 g) and N-benzylpiperazine (15.00 9) was stir-red at 120C for 5 hours. A 5% aqueous sodium hydroxide (150 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was dissolved in a small amount of chloroform and subjected to column chro-matography using silica gel (160 g) and eluted withchloroform-methanol (20 : 1 by volume). The eluate was concentrated to give a pale yellow oily substance (14.24 g).
The pale yellow oily substance (2.69 9) was dissolved in ethanol (3 ml), and the solution was added to a solution of maleic acid (1.71 g) in ethanol (9 ml). The precipi-tated crystals were separated by filtration and recrystal-lized from ethyl acetate-ethanol to give colorless needles (3.52 g) having the following physical properties, m.p.
144-145C.
Elementary analysis for C30H36N409:
Calcd. (%~: C,60.39; H,6.08; N,9.39 Found (%) : C,60.69; H,6.12; N,9.55 NMR (DMSO-d6, ~ ppm): 0.95 (t, 3H), 3.1-3.8 (12H), 3~95-4.35 (4H), 6.0 (4H), 6.9-7.5 (9H).
From the above data, it was identified that the color-less needles having m.p. 144-145C were 1-[2-(ethoxy)-ethyl]-2-(4-benzyl-1-piperazinyl)benzimidazole dimaleate, i~lS36~

and that the pale yellow oily substance was 1-[2-(ethoxy)-ethyl]-2-(4-benzyl-1-piperazinyl~benzimidazole.
(2) The pale yellow oily substance, 1-[2-(ethoxy)ethyl]-2-(4-benzyl-1-piperazinyl)benzimidazole (11.55 g3 obtained above, was dissolved in a 80% aqueous acetic acid (100 ml) and 5% palladium-carbon (4.00 g), was added thereto, and the mixture was subjected to catalytic hydrogenation at 60C under 3 atm. The reaction mixture was filtered, and the filtrate was concentrated. A 10% aqueous soldium hydroxide solution (100 ml) was added to the residue and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and then concen-trated to give a brown oily substance (9.77 g). The brown oily substance was dissolved in a small amount of chloro-form and subjected to column chromatography using silicagel (100 9) and eluted with chloroform-methanol (7.5 : 1 by volume). The eluate was concentrated to give a pale yellow oily substance (7.74 g). The pale yellow oily substance was treated with fumaric acid (4.91 g) in the same manner as described in Example 1. The crude crystals thus obtained were recrystallized from ethyl acetate-ethanol to give l-[2-(ethoxy)ethyl]-2-(1-piperazinyl)benz-imidazole .3/2 fumarate (5.06 g) as colorless needles.
~his product had the same physical properties as those of the product in Example 8.
Example 15 Preparation of 1-[2-(ethoxy)ethyl]-2-(1-piperazinYl)-benzimidazole (Method A') (1) a mixture of 2-chloro-1-[2-(ethoxy)ethyl]-benzimi-dazole (3.00 g) and N-formylpiperazine (3.50 g) was stirred at 120C for 5 hours. A 5% aqueous sodium hydroxide solu-tion (50 ml) was added to the reaction mixture and the mix-ture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated.
The residue was dissolved in a small amount of chloroform and subjected to column chromatography using silica gel (30 9) and eluted with chloroform-methanol (50 : 1 by volume).

-l~lS36~

The eluate was concentrated to give a pale yellow oily sub-stance (1.91 q).
The pale yellow oily substance (0.91 9) was dissolved in ethanol (1 ml) and the solution was added to a solution of maleic acid (0.35 g) in ethanol (5 ml). The precipitated crystals were separated by filtration and recrystallized from ethyl acetate-ethanol to give colorless prisms (0.71 g) having the following physical properties, m.p.
113-114C.
1~ Elementary analysis for C20H26N40~:
Calcd. (~): C,57.40; H,6.26; N,1~.39 Found (%) : C,57.52; H,6.22; N,13.35 NMR (DMSO-d6, ~-ppm): 1.0 (t, 3H), 3.1-3.9 (12H), 4.1-4.35 (2H), 6.1 (s, 2H), 7.0-7.55 (4~), 8.0 (s, lH).
From the above data, it was identified that the colorless prisms having m.p. 113-114~C were 1-[2-(ethoxy)-ethyl]-2-(4-formyl-1-piperazin~l)benzimidazole maleate, and that the pale yellow oily substance was l-[2-(ethoxy)-ethyl]-2-(4-formyl-1-piperazinyl)benzimidazole.
~0 (2) The pale yellow oily substance 1-[2-(ethoxy)-ethyl]-2-(4-formyl-1-piperazinyl)benzimidazole (1.00 g) obtained above was added to a 20~ aqueous sodium hydroxide (3 ml), and the mixture was stirred at 100C for 2 hours.
Water (10 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to give a brown oily substance (0.83 g).The brown oily subs-tance was treated with fumaric acid (0.53 g) in the same manner as described in Example 1. The crude crystals thus obtained were recrystallized from ethyl acetate-ethanol to give l-[2-(ethoxy)ethyl]-2-(1-piperazinyl)benzimidazole .3/2 fumarate (0.54 9) as colorless needles. This product had the same physical properties as those of the product in Example 8.
Example 16 Preparation of 1-[2-(ethoxy)ethyl]-2-(4-ethyl-1-piperazinyl-benzimidazole (Method A") 1-[2-(ethoxy)ethyl]-2-(1-piperazinyl)benzimidazole i ~'~lS36 (5.41 g~ obtained by the same manner as described in Example 8 was dissolved in ethanol ( 30 ml) and thereto were added ethyl iodide (3.24 g) and potassium carbonate (1.60 9), and the mixture was sti~red at 40C for 10 S hours. The reaction mixture was filtered, and the fil-trate was concentrated. The residue was dissolved in a small amount of chloroform and subjected to column chromatography using silica gel (60 g) and eluted b~
chloroform-methanol (30 : 1 by volume). The eluate was concentrated to give a pale yellow oily substance (5.34 g). The pale yellow oily substance was treated with fumaric acid (3.07 g) in the same manner as described in Example 1. The crude crystals thus obtained were recrys-tallized from ethyl acetate- ethanol to give 1-[2-(ethoxy)-ethyl]-2-(4-ethyl-1-piperazinyl)benzimidazole 3/2 fumarate (6.17 g) as colorless needles. This product had the same physical properties-as those of the prodcut in Example 9.
Example 17 Preparation of tablets Compressed tablets containing 1-[2-(propargyloxy)-ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difuma-rate (the compound of Example 1) (0.5 mg in each tablet) were prepared in the following formulation.
~9E~ Amount (g) ~5 The compound of Example 1 10 Crystalline cellulose 1610 Lac~ose 1600 Carboxymethyl cellulose calcium 120 Talc 40 Magnesium stearate 20 The above ingredents were uniformly mixed, and the mix-ture was tableted in the usual manner to give tablets (each 170 mg).
EX~E~
Preparation of powders Powders containing 1-[2-(propargyloxy)ethyl]-2-(4-methyl-l-piperazinyl)benzimidazole.3!2 fumarate (the com-~Z~S36~

pound of Example 2) (0.5 mg in each powder pack) were prepared in the following formulation.
Ingredients Amount (g) The compound of Example 2 5 Lactose 595 Starch 400 The above ingredients were uniformly mixed, and 100 mg portions of the mixture were individually packaged.
Example 19 Preparation of capsules Capsules containing 1-[2-(ethoxy)ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (the compound of Example 3) (0.5 mg in each capsule) were prepared in the following fomulation.
In~redients Amount (g) The compound of Example 3 10 Lactose 2000 Crystalline cellulose 910 Talc 60 Magnesium stearate 20 The above ingredients were uniformly mixed, and lS0 mg portions of the mixture were packed into hard capsules (grade No. 3).
Example 20 Preparation of syrup A syrup containing 1-[2-(allyloxy)ethyl]-2-~4-methyl-1-piperazinyl)benzimidazole.3/2 fumarate (the compound of Example 4) (0.2 mg per 1 g of the syrup) was prepared in the following formulation.
Inqredients Amount (g) The compound of Example 4 0.4 Sucrose 1200 Ethyl p-hydroxybenzoate 0.4 Propyl p-hydroxybenzoate 0.2 Purified water 799 The above ingredients were uniformly dissolved in the purified water with stirring to form the syrup.

~.~
:

~21S36~

Example 21 Preparation of injection An injection containing 1-[2-(ethoxy)ethyl]-2-(4-methyl-l-homopiperazinyl)benzimidazole difumarate (the com-pound of Example 3) (1 mg per each ampoule) was prepared in the following formulation.
~ Amount The compound of Example 3 1 g Physiological saline solution q.s.
Total 1000 ml The compound of Example 3 was completely dissolved inthe physiological saline solution, and 1 ml portions of the solution were filled in ampoules in a usual manner.
Example 22 Preparation of ointment An ointment containing 1-[2-(ethoxy)ethyl]-2-(4-methyl-l-homopiperazinyl)benzimidazole difumarate (the compound of Example 3) (5 mg per 1 g of the ointment) was prepared in the following formulation.
Ingredients Amount (g) The compound of Example 3 0.5 Polyethylene glycol 4000 49.5 Polyethylene glycol 400 50.0 The above ingredients were mixed well and melted with heating and thereafter cooled to form an ointment.
Example 23 Preparation of intranasal preparation An intranasal preparation containing 1-[2-(ethoxy)-ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difumar-ate (the compound of Example 3) (1 mg per g of the prepar-ation) was prepared in the following formulation.
Ingredients Amount (g) The compound of Example 3 Ethyl p-hydroxybenzoate 0.5 Physiological saline solution 998.5 The above ingredients were uniformly mixed to form the intranasal preparation.

Claims (2)

Claims:

1. A process for the preparation of a benzimidazole deriv-ative of the formula:

(I) wherein R1 is an alkyl group having 1 to 3 carbon atoms, an allyl group, a propargyl group, or a phenyl group; R2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; and n is 2 or 3, or a pharmaceutically acceptable acid addition salt thereof, which comprises (i) reacting a compound of the fomula:

(II) wherein R1 is as defined above, with a compound of the formula:

(III) wherein R2 and n are as defined above; or (ii) reacting a compound of the formula:

(IX) wherein n is as defined above, and R4 is an alkyl group having 1 to 3 carbon atoms or a protecting group whch can be removed by catalytic reduction or under acidic or basic conditions, with a compound of the formula:
X-CH2CH2-O-R1 (V) wherein R1 is as defined above, and X is a halogen atom, and optionally removing the protecting group; or (iii) when a benzimidazole derivative of the formula:

(I-a) wherein R1 and n are as defined herein is to be prepared, reacting a compound of the formula:

(II) wherein R1 is as defined herein, with a compound of the formula:

(III) wherein n is as defined herein and R3 is a protecting group which can be removed by catalytic reduction or under acidic or basic conditions, and removing the protecting group R3 from the resulting compound of the formula:

(VII) wherein R1, n and R3 are as defined herein by catalytic reduction or under acidic or basic conditions; or (iv) when a benzimidazole derivative of the formula:

(I-b) wherein R1 and n are as defined herein is to be prepared, reacting a compound of the formula:

(I-a) wherein R1 and n are as defined herein with a compound of the formula:
alkyl C(1-3)-X (VIII) wherein X is a halogen atom in the presence of a base; or (v) when a benzimidazole compound of the formula:

(I-a) wherein R1 and n are as defined herein is to be prepared, reacting a compound of the formula:

(IX-a) wherein n and R3 are as defined above, with a compound of the formula:

X-CH2CH2-O-R1 (V) wherein R1 and X are as defined herein, and removing the protecting group R4 from the resulting compound by catalytic reduction or under acidic or basic conditions, and optionally removing the protecting group; or (vi) when a benzimidazole derivative of the formula:

(I-b) wherein R1 and n are as defined herein is to be prepared, by reacting a compound of the formula:

(IX-b) wherein n is as defined herein with a compound of the formula:

X-CH2CH2-O-R1 (V) wherein R1 and X are as defined herein;
and optionally converting the resulting free compound into a pharmaceutically acceptable acid addition salt thereof.

2. A benzimidazole derivative of the formula:

(I) wherein R1 is an alkyl group having 1 to 3 carbon atoms, an allyl group, a propargyl group or a phenyl group; R2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; and n is 2 or 3, or a pharmaceutically acceptable acid addition salt thereof; whenever prepared by the process of claim 1 or an obvious chemical equivalent.