WO2001058877A1

WO2001058877A1 - Interferon ω production potentiators

Info

Publication number: WO2001058877A1
Application number: PCT/JP2001/000999
Authority: WO
Inventors: Kiyoshi Mizuguchi; Yutaka Kato; Tsutomu Satoh
Original assignee: Mochida Pharmaceutical Co., Ltd.
Priority date: 2000-02-14
Filing date: 2001-02-14
Publication date: 2001-08-16
Also published as: AU2001232272A1

Abstract

Interferon Ω production potentiators and antitumor drugs are provided, which exhibit high safety even when orally administered. Compounds of the general formula (I), particularly 3-(2-(2-phenylethyl)benzimidazol-4-yl)-3-hydroxypropanoic acid and esters thereof; and interferon Ω production potentiators each containing at least one member selected from among the compounds, optical isomers of the same and pharmaceutically acceptable salts thereof wherein R1 is hydrogen or the like; R2 is cyano or the like; A is -CO- or the like; W is -CH¿2?- or the like; Q is phenyl or the like; n is 0 to 2; and R?7¿ is hydrogen or the like.

Description

Description Interferoner production enhancer Technical field

The present invention relates to a benzimidazole derivative, more specifically, 3- (2- (2-phenylethyl) benzimidazole-41-yl) -13-hydroxypropanoic acid and its esters, and the compound or its optical compound. The present invention relates to an interferon alpha production enhancer containing an active form or a pharmaceutically acceptable salt thereof, and more particularly to an antitumor agent which is effective even in oral administration and which is based on the action of enhancing IFN-alpha production. Technology background

Interferon (hereinafter abbreviated as IFN) is a substance found as a protein with antiviral activity that is synthesized and secreted by virus-infected animal cells. It has been shown to have versatile activities such as a cell growth inhibitory effect, an antitumor effect, and an immune response regulating effect. IFN is roughly classified into α-type,] 3 type and α-type, and those produced from Τ cells and the like by stimulating mitogen or the like are called α-type (IFN-α).

The biological activity of IFN-α is known to be antiviral, antitumor, immunomodulatory, and suppresses cell proliferation.Currently, it is used clinically in applications such as renal cancer and myofascial myopathy. Have been. These IFN-αs are composed of native IFN-α produced by immune responder cells and a transformant produced by transforming DNA encoding IFN-α collected from immunocompetent cells into Escherichia coli. They are roughly classified into recombinant IFN-r, and any of them is administered parenterally in the form of injections as "foreign IFN-r".

IFN is originally a biological substance that plays a part in the defense mechanism against foreign substances of biological substances, and has extremely high selective toxicity and is highly safe for living organisms. Therefore, a substance that stimulates living cells to enhance the release of IFN-α has the potential to elicit the biological activity of IFN-α.

The natural IFN-α is usually obtained by culturing the immunocompetent cells in the culture in a culture medium containing mitogen, which induces IFN-α production, and purifying the culture. However, these mitogens show remarkable side effects when administered to a living body, and some substances show toxicity, and it is extremely difficult to administer to a living body to enhance the release of IFN-α.

1_ (carbazolyl 4-yloxy) 13-[[2_ (O-methoxyphenoxy) ethyl] amino] and its optical activity as substances that promote the production of IFN- in vivo Japanese Patent Application Laid-Open No. H10-251148 discloses that the body has an action of eliminating viral infection, and in particular, can reliably eliminate the cause of acute myocarditis involving viral infection and effectively treat acute myocarditis. It is described in the official gazette. Further, the peptide having an IFN-producing promoting action promotes the proliferation of the cell in a normal mouse hepatocyte cell line (NCTCC lone 469) in cell culture, and enhances the IFN-fa production of the cell. Specific promotion is described in JP-A-8-143592. Furthermore, promotion of IFN- Drugs and interleukin_2 (hereinafter abbreviated as IL_2) A compound that has a production-promoting action promotes the production of IFN-α and IL-12 from human peripheral blood mononuclear cells, It is described in JP-A-4-208271 that it is useful as an agent.

However, these compounds have a different structure from the compound of the present invention, and there is a description of the action of stimulating the immunocompetent cells to promote the production of cytokines. There is no disclosure of the effect of acquiring the trait that enhances the basal production in the steady state.

Under these circumstances, there is a need for a drug that is effective by oral administration, has no side effects, is safe, and is easy to use.

Benzimidazole derivatives, especially 3- (2- (2-phenylethyl) benzoimidazole-41-yl) — 3-hydroxypropanoic acid and its esters, suppress eosinophilia and increase eosinophilia. It is disclosed in WO 98Z01429 that it is useful as a prophylactic and / or therapeutic agent. In addition, when the compound is orally treated with the compound and the spleen cells are cultured in the presence of antigen stimulation such as concanapalin A or roundworm extract, production of IL-14 and IL-15 is suppressed and IFN-α It has been reported by Kato et al. (The Journal of Immunology, Vol. 162, pp. 7470-7479, 1999) that the production of E. coli is enhanced. However, there is no suggestion or teaching that the compound has an effect of enhancing IFN-α production on immunocompetent cells itself by oral administration in tumor-bearing mice. Disclosure of the invention

An object of the present invention is to provide an orally effective and safe interferon monoester production enhancer, particularly IFN-7 "containing a compound having an action of enhancing IFN-alpha production by oral administration. It is to provide a production inhibitor, especially an antitumor agent.

The present inventor has proposed a benzimidazole derivative, particularly 3- (2- (2-phenylethyl) benzimidazole-4-1 ^ fur) -13-hydroxypropanoic acid and esters thereof, or optically active forms thereof. As a result of intensive studies, they have found that they have an effect of orally administering splenocytes of mammals including humans to themselves to enhance IFN-α production, and thus completed the present invention.

In a first embodiment of the present invention, the following formula (I)

(In the formula, represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R ² represents a cyano group, a hydroxymethyl group, a 2_ (2-imidazolyl) ethenyl group, a group : _C〇〇R ^: a phenyl group substituted by 1 or 2 with ^I , or a group: —COOR ³ or 1 CONR ′ ¹ R ⁵ , wherein R ³ is a hydrogen atom or a straight chain having 1 to 4 carbon atoms. Or a branched chain alkyl group, wherein R and R ⁵ are each a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, or a group: one CH ₂ COOR ⁶ or one CH (CH ₂ Ph) COOR ⁶ Represent R ⁴ and R ⁵ may be the same or different, and when any one of R ⁴ and R ⁵ is a group: one CH ₂ C〇〇R ⁶ or one CH (CH ₂ Ph) COOR ⁶ the remaining one is a hydrogen atom, a is the following group: -CO-, one CH (OR ⁸⁾ _{one, -CH 2 O-, - CH (} NHR 9) CH 2 one, one CH = CH -, - CH ₂ CH _2- represents any one group selected from the group consisting of: W represents a group: _CH ₂ — or a single bond, and Q represents a phenyl which may be mono-substituted by a hydroxyl group. Represents a group, n represents 0 to 2, R ⁶ represents a linear or branched alkyl group having 1 to 4 carbon atoms, and R ⁷ represents a hydrogen atom, a hydroxyl group, a halogen atom, or a carbon atom number. 1 to a straight-chain or branched-chain alkoxyl groups of 4, R ⁸ represents a hydrogen atom or a Asechiru group, R ⁹ is a hydrogen atom, Asechiru group, Fuenirusuru Honiru group, or Represents a good Benzoiru group which may be monosubstituted by a methoxy group. ) Or an pharmaceutically acceptable salt thereof, which is an interferon alpha production enhancer, particularly for oral administration. Preferred substituents or preferred combinations of the compounds represented by the above formula (I) are shown below, but the present invention is not limited thereto.

R ¹ is preferably a hydrogen atom. R ² is a group: A COOR ³ in 1 or 2-substituted phenyl group or a group: one COOR ³ or - CONR4 It is preferred that R is ^5, group: one COOR ³ 1 or 2 substituted phenyl group or a group: and more preferably an COOR ^3. R ³ is preferably a linear or branched alkyl group having 1 to 4 carbon atoms. A is preferably a group: —C〇, one CH (OR ⁸ ) —, or one CH ₂ O—. W is preferably a group: 1 CH ₂ —. Q is unsubstituted phenyl It is preferably a group. n is preferably 1 or 2, and more preferably 2. R ⁷ is preferably a hydrogen atom, a halogen atom, or a linear or branched alkoxyl group having 1 to 4 carbon atoms, and more preferably a hydrogen atom.

As a combination of substituents, R ¹ is a hydrogen atom, W is a group: —CH ₂ —, and A is a group consisting of —CO—, —CH (OR ⁸ ) —, and one CH ₂ it is any one selected from, and preferably at 1 Moshigu the R ² guard C_〇_〇_R ³ or a C_〇_〇_R ³ is a 2-substituted phenyl group, in particular R ^1, hydrogen An atom, W is a group: —CH ₂ —, and the combination of A and R ^{2 is} a group: —CO— or —CH (OR ⁸ ) — and a group: —COOR ³ , or The combination is preferably a combination of a group: one CH ₂₀ — and a group: a phenyl group substituted by 1 or 2 with one C〇〇R ³ .

More preferably, the following formula (II)

(In the formula, R represents a hydrogen atom or a lower alkyl group.) Or a pharmaceutically acceptable salt thereof.

A second aspect of the present invention is to enhance the amount of IFN-produced by immunocompetent cells containing at least one of the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof. IFN-α production enhancer, particularly for oral administration.

A third aspect of the present invention is an antitumor agent containing at least one compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, particularly an antitumor agent for oral administration.

A fourth embodiment of the present invention provides a compound represented by the following formula (II)

(Wherein, R ′ represents a lower alkyl group, and * represents an asymmetric carbon atom.) Or a pharmaceutically acceptable salt thereof. More preferably, it is (i) an isomer.

According to still another aspect of the present invention, at least one of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for the production of the above-mentioned agent for enhancing the production of insulin-feronone. Use of a compound containing at least one of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for the production of the above antitumor agent; and prevention of tumor 'A method of treatment, comprising administering to a mammal, including a human, a substance selected from the group consisting of a compound represented by the formula (I), or an optically active form thereof, and a pharmacologically acceptable salt thereof. Are provided. BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in detail.

The compound used for the IFN-fer production enhancer of the present invention has the following formula (I)

(Wherein, R ¹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R ² represents a cyano group, a hydroxymethyl group, a 2- (2-imidazolyl) ethenyl group , A group: — a phenyl group substituted by 1 or 2 with COOR ³ or a group: — C〇〇R ³ or one CONR ′ ¹ R ⁵ , wherein R ³ is a hydrogen atom or a C ^{1 to} C 4 Represents a linear or branched alkyl group, and R ′ ¹ and R ⁵ are each a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, or a group: one CH ₂ C〇OR ⁶ or one CH (CH ₂ P h) represents COOR ⁶ , wherein R ′ ¹ and R ⁵ may be the same or different, and ^{one of} R ′ ¹ and R ⁵ is a group: one CH ₂ C〇〇R ^S or one CH ( When CH ₂ P h) COOR ⁶ , the other one is a hydrogen atom, and A is the following group: —CO—, —CH (OR ⁸ ) —, one CH ₂ 〇—, — CH (NHR ⁹ ) CH _2- CH = CH-, — CH ₂ CH ₂ represents any one group selected from the group consisting of: W is a group: —CH ₂ — or a single bond, and Q is monosubstituted by a hydroxyl group N represents 0 to 2; R ^s represents a linear or branched alkyl group having 1 to 4 carbon atoms; R ⁷ represents a hydrogen atom, a hydroxyl group, or a halogen atom; Atom, or Represents a straight-chain or branched-chain alkoxyl group having 1 to 4 carbon atoms, R ⁸ represents a hydrogen atom or an acetyl group, and R ⁹ represents a hydrogen atom, an acetyl group, a phenylsulfonyl group, or a methoxy group; Represents a benzoyl group which may be substituted. R h represents a phenyl group. ) Or a pharmaceutically acceptable salt thereof. The compounds of the present invention can form salts with inorganic or organic acids. Examples of these salts include salts with inorganic acids such as hydrochloride, hydrobromide, phosphate, sulfate, acetate, oxalate, citrate, tartrate, maleate, and alginic acid. Salts, salts with organic acids such as p-toluenesulfonate and salicylate, and salts with acidic amino acids such as glutamate and aspartate. The compound of the present invention can form a salt with an inorganic base or an organic base depending on the type of the substituent. Examples of these salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, salts with inorganic bases such as ammonium salt, triethylamine salt, pyridine salt and the like. Salts with basic amino acids such as salts with organic bases, arginine salts, lysine salts, histidine salts and the like are included. Further, the compound of the present invention or a salt thereof can form a solvate with a solvent such as water, ethanol, and glycerol, and such a solvate is also included in the present invention.

A racemic mixture of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and an optically active substance or a pharmaceutically acceptable salt thereof of the present invention are described in International Publication No. WO 98/0142429. The definition of each substituent, and the definition of a preferable substituent and a combination thereof are also described in the publication. More preferably, the following formula (II) -a

(Wherein, R represents a hydrogen atom or a lower alkyl group.) Or a pharmaceutically acceptable salt thereof.

"Lower" means, unless otherwise stated, a straight or branched carbon chain having any of 1 to 4 carbon atoms. Accordingly, the “lower alkyl group or alkyl group having 1 to 4 carbon atoms” represents, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like. . When R is a lower alkyl group, it is preferably an ethyl group.

Since the compound represented by the formula (I) of the present invention may have an asymmetric carbon atom, an optically active substance is present at that time. The optically active forms include a compound having a negative optical rotation (hereinafter referred to as (1) isomer) and a compound having a positive optical rotation (hereinafter referred to as (+) isomer). Although present, racemic mixtures, and any optically active form are encompassed by the present invention.

It is recognized that an optically active form of the present invention, for example, the (1) isomer is substantially free of the corresponding (+) isomer. The reverse is also true. Preferably, the optically active isomers of the invention contain less than 10% of the corresponding opposite isomer. More preferably, it is less than 5%, and still more preferably, it is less than 1%. "Single optically active substance" Qualitatively free refers to one of the individual enantiomers of a given compound.

Any of a racemic mixture, a (+) isomer or a (1) isomer may be used as the IFN-α release enhancer of the present invention. More preferably, among the optically active substances of the present invention, (1) isomers are more preferable.

As an example of a specific compound of the present invention,

3- (2- (2-phenylethyl) benzimidazole-41-yl) -1-hydroxypropanoic acid; (+) — 3 -— (2- (2-phenylethyl) benzimidazole-41-yl) _ 3-hydroxypropanoic acid; (1-)-1- (2- (2-phenylethyl) benzimidazoyl-41-yl) -1-hydroxypropanoic acid;

3- (2- (2-phenylethyl) benzimidazoyl 4-yl) -1-methyl 3-hydroxypropanoate; (+) — 3- (2- (2-phenylethyl) benzimidazole—4_yl) Methyl 3-hydroxypropanoate; (I) Methyl 3- (2- (2-phenylethyl) benzimidazo-l-41-yl) -3-Methyl 3-hydroxypropanoate;

3- (2- (2-phenylethyl) benzimidazoyl 4- yl) 1-3-hydroxypropanoate; (+) — 3 -— (2- (2-phenylethyl) benzoimidazole-4-yl (1) 3- (2- (2-phenylethyl) benzimidazole-41-yl) _3-hydroxypropanoate;

3- (2- (2-phenylenyl) benzimidazole-41-yl)-propyl 3-hydroxypropanoate; (+)-3- (2- (2-phenyl) (Ethyl) benzimidazole-4-yl) propyl-1-hydroxypropanoate; (1) 1-3- (2- (2-phenylethyl) benzimidazo-1-yl 4-yl) propyl-3-hydroxypropanoate;

3-'(2- (2-phenylethyl) benzimidazole_4-yl) -1-isopropyl-3-hydroxypropanoate; (+) — 3- (2- (2-phenylethyl) benzimidazole-4_ (I) isopropyl 1-3-hydroxypropanoate; (I) 1-3- (2- (2-phenylethyl) benzimidazo-1-yl 41-yl) isopropyl 1-3-hydroxypropanoate;

3- (2- (2-phenylethyl) benzimidazole- 14-yl) 1-3-hydroxybutylpropionate; (+) —3 -— (2-(2-phenylethyl) benzoimidazo-1-yl 4-yl ) _ Butyl 3-hydroxypropanoate; (I) 1-3- (2- (2-phenylethyl) benzimidazol-4-yl) butyl 3-hydroxypropanoate;

3- (2- (2-phenylethyl) benzimidazo-l-41-yl) 1--3-Hydroxypropanoate isoptyl; (+)-3- (2- (2- (2-phenylethyl) -benzimidazole-4-yl) — Isobutyl 3-hydroxypropanoate; (1) 1-3- (2- (2-phenylethyl) benzimidazole-4-yl) isobutyl 1-3-hydroxypropanoate;

3- (2- (2-phenylethyl) benzimidazole-4-yl) 1-butyl sec-butyl 3-hydroxypropanoate; (+) _ 3- (2- (2-phenylethyl) benzimidazoyl 4-yl ) —3-Hydroxypropanoic acid sec-butyl; (1) 1 3_ (2— (2 _phenylethyl) benzimidazolone 41 Yl) sec-butyl-1-hydroxypropanoate;

3- (2- (2-phenylethyl) benzimidazole-41-yl)-tret-butyl 3-hydroxypropanoate; (+)-3- (2- (2-phenylenyl) benzimidazole-4-yl) Tert-butyl 3-hydroxypropanoate; (1) 1-3- (2_ (2-phenylethyl) benzoimidazole-4-yl) tert-butyl propane-13-hydroxypropanoate;

Next, a method for producing the compound of the present invention will be described.

A racemic mixture of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and an optically active substance or a pharmaceutically acceptable salt thereof of the present invention are described in International Publication No. WO 98/0142429. It can be obtained by using the method described or a method analogous thereto. The present specification refers to this publication and constitutes the content of the present invention. As a method for producing an optically active substance, methods such as an asymmetric reduction method and an optical resolution method are disclosed. Examples of more specific methods include chiral pack AD ^™ and chiral cell 〇D ^™ ( Can be separated into optically active compounds by high performance liquid chromatography (HPLC) using an appropriate optically active column such as Daicel Chemical Industries. As a solvent to be used, a mixed solvent of hexane and an alcohol such as ethyl alcohol and isopropyl alcohol, and a solvent to which several% of an amine such as diisopropylamine is added as necessary can be used. In addition, after adding a suitable asymmetric acid or base (such as cisamine) to the racemate to form a diastereomer salt, separation by differences in physical properties such as solubility or separation by chromatography can be performed. Isolated induction The body can obtain a pure optically active compound by dissociation of a salt.

(Experimental example)

Next, the action of the compound of the present invention and the pharmaceutical composition of the present invention will be described in detail. As to specific pharmacological actions and toxicity, the actions of typical compounds are shown as experimental examples, but the present invention is not limited thereto.

(Experimental example 1) Enhancement of IFN-α production in tumor-bearing mice

10 FCS (fetal calf serum) B16F10 cells cultured in DMEM (Dulbecco's medium) are trypsinized, washed with PBS (phosphate-buffered saline, pH 7.4), and then washed 1x in PBS. It was prepared as a ^{1 0 7 ce 1 1 / m} 1. This was injected into the abdominal skin of male C57BL / 6 mice (7 weeks old, weighing about 23 g) in a volume of 0.1 lm 1 Zbody. On the 7th day, the diameter of the tumor was measured with a vernier caliper on the day 0 on which the tumor was carried. The tumor volume was calculated as (minor axis) ² X (major axis), and grouping was performed using this value and body weight as indices. Herd classification was carried out for mice on day 7 of the tumor was fully grown, the average tumor diameter of about 70mm ^3, as the average weight is about 22~ 23 g, were used in the experiment. The test compound was orally administered from the 7th to the 21st. The solvent used was 0.5% HPMC (Hydroxypropylmethylcellulose), and the control group received only the solvent. Tumor diameter measurements were taken on days 7, 11, 14, 18, and 21. On Day 22, blood was collected from the fundus, followed by decapitation and excision of the thymus and spleen. After measuring the organ weight, the spleen was homogenized with a glass homogenizer and adjusted to 5 x 10 ⁶ ce 11 sZml. And cultured in S—C 1 one S F_B medium (Sanko Junyaku). Twenty-four hours later, the culture supernatant was collected and stored frozen at 180 ° C. The IFN- concentration (pg / mL) in the culture supernatant was measured by the EIA method (Enzyme Immu noassay). In addition, the measurement kit of ENDOGEN was used for the measurement. Table 1 shows the dose and IFN-α concentration of the test compound. Table 1 Test compound dose (mg / Kg / day) I FN— concentration (pg / ml)

(Example number) (N = 7)

1 10 125

1 30 194

1 100 263 Control (control) 40 As evident from the above results, the compound of the present invention was orally administered to tumor-bearing mice, and the spleen cells were cultured without immunostimulation (without stimulation). Then, the effect of enhancing the IFN_a production of the spleen cells was observed. Furthermore, the optically active isomer of the present invention was found to have the same level of IFN-α production enhancement activity for both the (+) isomer and the (1) isomer.

(Experimental Example 2) Toxicity test The toxicity of the compound of the present invention was examined. BALB / c male mice (body weight: about 25 g) were orally administered with the compounds of Examples Nos. 1 to 4 of the present invention suspended in 0.5% HPMC aqueous solution for 100 days at 100 mg ZKg daily for 4 days. place, no deaths, also in body weight and general symptoms abnormality was observed _t In addition, SD female rats were orally administered the compounds of Examples Nos. 3 and 4 of the present invention suspended in a 0.5% HPMC aqueous solution at a dose of 30 Omg / kg daily for 14 days. As a result, a significant increase in the specific liver weight was observed in the group to which the compound of Example 3 was administered, but was not observed in the compound of Example 4. Therefore, it was shown that the compound of the present invention (1) the heterologous living body is more excellent in safety.

Since the ester bond of the compounds of Examples 3 and 4 is decomposed into a carbonyl group in rats, the (-) isomer of Example 6 is more preferable in the compounds of Examples 5 and 6.

From the above results, it was shown that the compound of the present invention, when administered orally, has an effect of enhancing IFN-α production on the immunocompetent cells themselves. Further, the toxicity of the compound of the present invention is extremely low, and the compound is excellent in safety. More preferably, among the optically active substances of the present invention, (1) isomers are more preferable as pharmaceuticals.

By using an IFN-fer production enhancer containing the compound of the present invention, it is possible to obtain a trait that enhances the basal production of IFN-fa of the immunocompetent cell itself in a steady state. Therefore, stable IFN-α production can be expected without receiving any drug or irritation. In addition, higher IFN-γ production can be expected with drugs and stimuli. Unlike direct administration of IFN-r or exertion of IFN-r production by stimulation, a safe drug with fewer side effects can be provided.

By using the IFN-α production enhancer of the present invention, it is also possible to enhance the IFN-inducibility of a person whose IFN-inducibility is reduced.

The pharmaceutical composition of the present invention is useful for diseases in which IFN-producing ability enhancing effect is effective, for example, For example, tumors, viral diseases (eg, viral hepatitis (A, B, C or E, etc.), influenza, viral pneumonia, viral bronchitis, herpes infectious diseases (simple virus, EB virus (infectious) Suitable for the treatment or prevention of mononucleosis), shingles, polio, HIV infection, etc., and bacterial infections (eg, liver tumors, hepatic amoebiasis), but is particularly suitable for use as an antitumor agent The types of organs and tissues that can be used are not limited, and include, for example, liver, kidney, spleen, kidney, brain, lung, digestive system (stomach, small intestine, duodenum, large intestine, rectum, etc.) ) Or blood, etc.

The pharmaceutical composition of the present invention can also be used prophylactically. For example, familial tumors and the like can be diagnosed quite accurately by genetic diagnosis in recent years. By administering to patients, it is possible to prevent the onset. In addition, by administering the compound of the present invention to a patient whose tumor has been removed by surgery after surgery, it can be used to prevent recurrence or metastasis of the tumor. In addition, the method of the present invention can be applied to patients with subclinical infection in which the virus infection is positive using a method for directly detecting a virus-specific virus-specific substance (antigen or nucleic acid) or a method for detecting an antibody against the virus. By administering the composition, it can be used to prevent the onset of viral infection. For example, use in AIDS for symptomatic and asymptomatic HIV infections. The compound of the present invention or a salt thereof is usually orally administered to humans and other animals as a drug, but is administered parenterally (for example, intravenous administration, intramuscular administration, subcutaneous administration, rectal administration, transdermal absorption). Or transmucosal absorption, etc.), and oral administration is preferable. The medicament of the present invention is administered in the form of a pharmaceutical composition.

The pharmaceutical composition of the present invention may contain at least one or more of the compounds represented by the formula (I) of the present invention, and is prepared in combination with a pharmaceutically acceptable carrier. More specifically, excipients (eg, lactose, sucrose, mannitol, microcrystalline cellulose, caic acid), binders (eg, microcrystalline cellulose, saccharides (mannitol, sucrose), dextrin, hydroxypropylcellulose (HPC), hydroxy Propylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), macrogol), lubricants (eg, magnesium stearate, calcium stearate, talc), coloring agents, flavoring agents, disintegrants (eg, corn starch, carboxymethyl cellulose) ), Preservatives, isotonic agents, stabilizers (eg, sugars, sugar alcohols), dispersants, antioxidants (eg, ascorbic acid, butylhydroxydisole (BHA), propyl gallate, d1 — Α-tocopherol), buffer, preservative (eg, paraben, benzyl) Alcohol, benzalkonium chloride), fragrance (eg, phosphorus, 1-menthol, mouth oil), solubilizer (eg, cholesterol, trietanolamine), suspending or emulsifying agent, and pharmaceutical Appropriately acceptable carriers or solvents can be combined with the compounds of the present invention to give various dosage forms.

Examples of the dosage form include capsules, pills, tablets, granules, fine granules, powders, suspensions, emulsions, internal liquids such as limonade, elixirs, syrups, and inhalants Solutions, sprays, aerosols, topical solutions such as coatings, ophthalmic solutions, nasal solutions, patches, ointments, lotions, liniments, cataplasms, suppositories, aqueous or non-aqueous injections, emulsions Or suspending injection, or dissolution before use, emulsion or Include solid injections used in suspension.

The dose of the compound of the present invention as a drug is sufficient to treat the disease of interest, but the dosage form of the therapeutic agent, the method of administration, the number of doses per day, the degree of symptoms, Increase or decrease as appropriate according to weight, age, etc. The dose of the compound of the present invention for an adult is 0.01 to 500 Omg per day, preferably 0.1 to 50 Omg, more preferably 0.1 to LO Omg per day. . The daily dose for an adult in the case of oral administration is 0.01 to 5000 mg, preferably 0.1 to 30 Omg, more preferably 0.1 to: L0 Omg. Administration can be divided into one or two to six times daily.

The drug of the present invention can be used in combination with other drugs, for example, drugs for treating diseases such as anticancer drugs, antiviral drugs, antibiotics, and chemotherapeutic drugs, and nutritional supplements such as bismuth agents and sugar solutions. is there.

(Example)

Next, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.

NMR was measured with J EOL J NM-EX 270 or J NM-LA 300 (both manufactured by JEOL Ltd.) and expressed as δ (ppm) using TMS (tetramethylsilane) as an internal standard. The IR was measured using a HOR IBA FT-200 (manufactured by Horiba, Ltd.) tablets of potassium bromide and expressed in cm- ¹ . The melting point was measured using Mett 1er FP 80 or FP 90 (both manufactured by Metra Toledo). Optical purity is determined by high performance liquid chromatography (LC-10, manufactured by Shimadzu Corporation), using Chiral Cell OD ^™ (Daicel Chemical Industries), eluent: Hexane / isopropanol Z Jethylamine (80Z20Z1), wavelength: 254 nm, temperature: 40 ° C And expressed in% ee. The optical rotation was measured using JASCO DIP-1000 (manufactured by JASCO Corporation), and was expressed as specific rotation [Q!] D.

(Example 1)

Synthesis of 3- (2- (2-phenylethyl) benzimidazole-4-yl) -1-ethyl 3-hydroxypropanoate

3- (2- (2-phenylethyl) benzimidazo-l-41-yl) -1-ethyl 3-oxopropanoate (4.0 g) was dissolved in a mixture of ethanol (30 ml) and methylene chloride (30 ml). . Under ice-cooling, sodium borohydride (135 mg) was added little by little, and the mixture was stirred for 30 minutes. At the same temperature, sodium borohydride (90 mg) was added, and the mixture was stirred for 10 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified with a silica gel column (hexane / ethyl acetate = 1 Z 1), and the desired 3- (2- (2-phenylethyl) benzimidazole-4-yl) _3-hydroxyethyl propanoate (3.4 g) was obtained. The obtained crystals were found to have various spectra and melting points identical to those obtained in Example 6 described in WO 98/01429. (Example 2)

Synthesis of 3- (2- (2-phenylethyl) benzimidazole-41-yl) -1-hydroxypropanoic acid

Ethyl 3- (2- (2-phenylethyl) benzimidazoyl 4-yl) _3-hydroxypropanoate (23.5 g) synthesized in Example 1 was suspended in ethanol (70 ml). 1N sodium hydroxide (104 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with ethyl acetate and adjusted to pH 5 with hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain the desired 3- (2- (2-phenylethyl) benzimidazo-1-yl-4-yl) -13-hydroxypropanoic acid (19.0 g). . The obtained crystals were found to have various spectra and melting points consistent with those obtained in Example 7 described in WO 98/0129.

(Examples 3 and 4)

(+) — 3 -— (2- (2-phenylethyl) benzimidazole-41-yl) ethyl 3-hydroxypropanoate (Example 3) and (1-) _ 3- (2- (2-phenylethyl) benzo Separation of imidazoyl 4-propyl) ethyl 3-hydroxypropanoate (Example 4) using an optically active column

3_ (2- (2-phenylethyl) benzimidazole-41-yl) ethyl 3-hydroxypropanoate synthesized in Example 1 was subjected to high performance liquid chromatography (Chiral Cell ラル D ^™ , Daicel Chemical Industries, Eluent: Separation was carried out by using xane / isopropanol / getylamine = 80720 1).

(+) — 3 to (2- (2-phenylethyl) benzimidida as the first fraction (Ethyl 4-yl) -3-ethyl hydroxypropanoate (Example 3) was obtained. ^ -NMR CDCh) δ [ppm]: 9.60 (1H, brs), 7.7-7.5 (1H, m), 7.3-7.1 (6H, m), 7.0-6.9 (1H, m), 5.5-5.4 (lH, ra), 4.22 (2H, q, J-7Hz), 3.3-3.1 (4H, m), 2.9-2.7 (2H, m), 1.30 (3H, t, G7Hz)

IR (KBr) [cm- ¹ ]; 3032, 1734, 1433, 1286, 1024, 748

Melting point; 89.5-90.5 ° C

HPLC optical purity;> 99.5% ee

Specific rotation; [] _D = +16.70 ° (c = 1.023, EtOH)

As a second fraction, (1) 1-3- (2- (2-phenylethyl) benzimidazol-4-yl) _3-ethylethyl propoxylate (Example 4) was obtained.

-麵 R (CDC1 ₃ ) (5 [ppm]: 7.7-7.5 (lH, m), 7.3-7.1 (6H, m), 7.0-6.9 (1H, m), 5.5-5.4 (lH, ra), 4.22 (2H, q, J = 7Hz), 3.3-3.1 (4H, m), 2.9-2.8 (2H, m), 1.30 (3H, i, J-7 Hz)

IR (KBr) [cm- ¹ ]; 3032, 1734, 1435, 1286, 1024, 748

Melting point; 89.8-90.7 ° C

HPLC optical purity; 98.3% ee

Specific rotation; [Hi] D = — 16.75 ° (c = 1.012, EtOH)

(Examples 5 and 6)

(+)-3-(2-(2-phenylethyl) benzimidazole-41-)-3-hydroxypropanoic acid (Example 5) (-) 1-3-(2-(2-phenylethyl) benzimidazo-1- Lou 4-yl) 1-3-Hydroxypropanoic acid Synthesis of (Example 6)

According to the method of Example 8 and Example 9 described in International Publication WO98 / 014929, the target compound (+) — 3-— (2- (2-phenylenyl) benzoimidazoyl 1) -Hydroxypropanoic acid (Example 5), (1) 13- (2- (2-phenylethyl) benzimidazole-41-yl) -3-hydroxypropanoic acid (Example 6) can get. In addition, 3- (2- (2-phenylethyl) benzimidazol-4-yl) _ 3 _hydroxypropanoic acid (3.1 g) synthesized in Example 2 and (+)-cis-N-benzyl-2- (Hydroxymethyl) cyclohexylamine (cisamine, 2.19 g) was dissolved by heating in 5% ethanol-Z acetone (30 ml), and a minus crystal excess seed crystal (73% ee) was added. After standing for an hour, the precipitated crystals were collected by filtration (1.9 g, 74% ee). These crystals were dissolved in 5% ethanol / acetone with heating, and seed crystals (94% ee) were added to the mixture to give (1-) 3- (2- (2-phenylethyl) benzimidazo-l-41-yl) _3 —Hydroxypropanoic acid salt (1.4 g, 91 ee) was obtained. By dissociating the salt of this crystal, the desired (1) -13- (2- (2-phenylethyl) benzimidazo-l-41-yl) -13-hydroxypropanoic acid can be obtained.

(Formulation example)

Examples of preparations containing the compound of the present invention are shown below, but the present invention is not limited thereto. (Formulation Example 1 capsule) Ingredient Amount (g) Compound 50 of Example 4

Lactose 93 5

Magnesium stearate 15 The above components were weighed and mixed uniformly. The mixed fraction was filled into a suitable hard capsule at 20 mg each, and a capsule could be produced. (Formulation example 2 tablets) Ingredient Amount used (g) Compound of Example 1 100

Lactose 350

Potato starch 120

Polyvinyl alcohol 15

Magnesium stearate 15 After weighing the above components, the title compound, lactose, and potato starch were uniformly mixed. An aqueous solution of polyvinyl alcohol is added to this mixture, and the granules are prepared by a wet granulation method. The granules were dried, mixed with magnesium stearate, and compressed and compressed to produce tablets weighing 30 Omg.

(Formulation Example 3 Granules) Ingredient Amount used (g) Compound of Example 5 200

Lactose 450

Corn starch 300

Hydroxypropyl cellulose 50 After weighing each of the above components and mixing them uniformly, granules could be produced by a conventional method.

(Formulation Example 4 Injection) Ingredient Component Amount 2 g of the compound of Example 6

Sodium bicarbonate 10 g

100 OmL of sterile distilled water for injection was dissolved in sodium bicarbonate for injection, and the compound of Example 6 was dissolved in this solution. After filtration sterilization, 5 mL was dispensed into 1 O mL ampules and sealed to obtain injections.

INDUSTRIAL APPLICABILITY The use of the compound having a benzoimidazole skeleton of the present invention exerts an effect on the immunocompetent cell itself to enhance the production of IFN-α. Further, the toxicity of the compound having a benzimidazole skeleton of the present invention is extremely low and excellent in safety. Diseases for which τ production enhancement is effective, such as tumors, viral diseases (eg, viral hepatitis (A, B, C or E, etc.), influenza, viral pneumonia, viral bronchitis, herpes infectious disease ( Adapt to the treatment or prevention of simple viruses, Epstein-Barr virus (Infectious mononucleosis), shingles, polio, HIV infection, etc., bacterial infections (eg liver tumors, hepatic amoebiasis), especially It is expected to be suitably used as an antitumor agent. When an IFN-τ production enhancer containing the compound of the present invention is used, it is possible to obtain a trait that enhances the basal production of the IFN-α of the immunocompetent cell itself in a steady state. Therefore, stable production of IFN-α can be obtained without receiving any drug or irritation. In addition, with drugs and stimuli, it is possible to obtain even higher IFN-a production. Unlike the direct administration of IFN-r or the stimulation of IFN-r to exert its production effect, a safer drug with fewer side effects can be provided.

In addition, the medicament and the pharmaceutical composition of the present invention can achieve the purpose of preventing and / or treating a disease for which IFN a production enhancing effect is effective. Specifically, diseases for which IFN_a production enhancing effect is effective, such as tumors, viral diseases (eg, viral meningitis (A, B, C or E type, etc.), influenza, viral pneumonia, Viral bronchitis, herpes infection (simple virus, Epstein-Barr virus (infectious mononucleosis), shingles, polio, HIV infection, etc.), bacterial infection (eg, liver tumor, hepatic amoebiasis) It is effective for these treatments, including prevention, prevention of onset, prevention of exacerbation of symptoms, improvement of symptoms, and treatment, and is particularly effective for use in the prevention or treatment of various tumors.

Claims

Claims The following formula (I)

(Wherein, R ′ represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R ² represents a cyano group, a hydroxymethyl group, a 2- (2-imidazolyl) ethenyl group) , A group: — a phenyl group substituted by 1 or 2 with COOR ³ , or a group: one COOR ³ or one CONR ′ ¹ R ⁵ , wherein R ³ is a hydrogen atom or a straight chain having 1 to 4 carbon atoms or Represents a branched alkyl group, and R ′ ¹ and R ⁵ are each a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, or a group: one CH ₂ COOR ⁶ or one CH (CH ₂ Ph) COOR ⁶ R ′ and R ⁵ may be the same or different, and when one of R ⁴ and R ⁵ is a group: one CH ₂ COOR ⁶ or one CH (CH ₂ Ph) COOR ⁶ The other one is a hydrogen atom, and A is the following group: —CO—, -CH (OR ⁸ ) one,

CH ₂ 〇_, -CH (NHR ⁹ ) CH _: CH = CH—, -CH ₂ CH: represents one group selected from the group consisting of: W is a group: — CH ₂ — or a single bond And Q represents a phenyl group which may be substituted by 1 with a hydroxyl group, n represents 0 to 2, and R ⁶ represents a linear or branched alkyl group having 1 to 4 carbon atoms. the stands, R ⁷ is a hydrogen atom, a hydroxyl group, a halogen atom or, Represents a straight-chain or branched alkoxyl group having 1 to 4 carbon atoms, R ⁸ represents a hydrogen atom or an acetyl group, and R ³ represents a hydrogen atom, an acetyl group, a phenylsulfonyl group, or a methoxy group; Represents a benzoyl group which may be substituted. Or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, which enhances the amount of IFN-α production of the immunocompetent cells.

3. The interferon-alpha production enhancer according to claim 1 or 2 for oral administration.

4. An antitumor agent comprising at least one compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

5. The antitumor agent according to claim 4, for oral administration.

6. The following formula (I I) b

(Wherein, R ′ represents a lower alkyl group and * represents an asymmetric carbon atom.) Or a pharmaceutically acceptable salt thereof.