WO1997031900A1

WO1997031900A1 - Imidazole derivatives and vascular wall thickening inhibitor

Info

Publication number: WO1997031900A1
Application number: PCT/JP1997/000533
Authority: WO
Inventors: Hiromu Harada; Hiroshi Kusama; Yoshinori Nonaka; Toshikazu Yazaki; Koji Kamata; Yukihiko Hotei; Kiyoshi Kasai
Original assignee: Kissei Pharmaceutical Co., Ltd.
Priority date: 1996-02-29
Filing date: 1997-02-26
Publication date: 1997-09-04
Also published as: AU1811397A

Abstract

Imidazole derivatives represented by general formula (I) and pharmacologically acceptable salts thereof wherein one of A and B represents a group represented by general formula (II) and the other represents a carbamoyl group, having the activity of inhibiting an excessive growth of intimal cells, and being useful as a vascular wall thickening inhibitor.

Description

Description Imidazole derivatives and vascular wall thickening inhibitors

TECHNICAL FIELD The present invention relates to an imidazole derivative which has an inhibitory action on hyperproliferation of intimal cells and is useful as a pharmaceutical. Technology background

Atherosclerosis progresses due to the accumulation of lipids in the blood vessel wall, cell proliferation in the intima of the blood vessel, and the accumulation of collagen, etc., and the blood vessel wall becomes thickened or occluded. If such a state is left unattended, there is a risk of causing serious situations such as angina pectoris, myocardial infarction and cerebral infarction. At present, no drug has been developed to suppress the thickening or occlusion of the blood vessel wall caused by such arteriosclerosis.

For example, angina pectoris and myocardial infarction have been treated with surgical AC bypass surgery. Recently, however, percutaneous transluminal coronary angioplasty (PTCA) However, vascular reconstruction techniques such as DCA (directional coronary atherectomy), which selectively cuts the diseased tissue at the stenotic site, are widely spread and are clinically practiced. However, in PTCA, vascular wall thickening occurs again due to abnormal proliferation of vascular smooth muscle at the site damaged by the insertion of a balloon catheter. %, And the intravascular placement of DCA II stent also causes restenosis similar to that of PTCA. Therefore, a major problem remains in the above-mentioned vascular reconstruction.

Furthermore, in recent years, the number of patients presenting with arterial stenosis is increasing due to factors such as changes in dietary habits, and the frequency of PTCA and DCA is increasing. Therefore, there is a great demand for the development of a drug that suppresses the nervous system and shows an excellent effect on the thickening of the blood vessel wall of arteries and arterioles of various organs such as the heart and brain, particularly the coronary artery. Disclosure of the invention

The compound of the present invention has the general formula

(A or B in the formula is one of the general formulas

(In the formula, R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group, a cycloalkyl alkoxy group, an aralkyloxy group, a lower acetyl group, a mono- or di-lower alkyl-substituted amino group. And R ^s may be the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group or an aralkyloxy group, and R <and R ^s may be the same or different and each is a hydrogen atom or a lower alkyl group), and the other is a group represented by the general formula

— (CH ₂ ) _n — R

(Wherein R is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and n is an integer of 2 to 6) or a rubamoyl group optionally having a tetrazolyl group R ^e is a hydrogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group or a substituent represented by the general formula

— (CH ₂ ) _m — R ⁸

(Wherein R * is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and m is an integer of 2 to 6). R ⁷ is a hydrogen atom or a lower alkyl group which may have a carboxyl group or a lower alkoxycarbyl group as a substituent.)

-Derivatives and their pharmacologically acceptable salts.

The present invention relates to a drug comprising the imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof.

The present invention relates to a vascular wall thickening inhibitor comprising, as an active ingredient, an imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof.

The present invention relates to a method for preventing or treating a disease caused by hyperproliferation of intimal cells by administering an imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof. It is.

The present invention relates to an imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for producing a preparation for preventing or treating a disease caused by hyperproliferation of intimal cells. It is about use.

Further, the present invention relates to the use of the imidazole derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof as a vascular wall thickening inhibitor. BEST MODE FOR CARRYING OUT THE INVENTION

The present inventors have conducted intensive studies to find a compound having an inhibitory effect on abnormal proliferation of endothelial cells, and as a result, a certain imidazole derivative represented by the above general formula (I) The present inventors have found that they have excellent vascular smooth muscle cell proliferation inhibitory activity and the like, and are useful as an agent for suppressing vascular wall thickening, and have accomplished the present invention.

In other words, the present invention provides a compound represented by the general formula:

(I)

[A or B in the formula is one of the general formulas

(In the formula, R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group, a cycloalkyl alkoxy group, an aralkyloxy group, a lower acetyl group, a mono- or di-lower alkyl-substituted amino group Or a lower alkoxycarbonyl group, and R ² and R ^s may be the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group or an aralkyloxy group; And R ⁵ may be the same or different and each is a hydrogen atom or a lower alkyl group), and the other is a group represented by the general formula

— (CH ₂ ) _n -R

(Wherein R is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and n is an integer of 2 to 6) or a rubamoyl group optionally having a tetrazolyl group And R ^e is a hydrogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group or a substituent represented by the general formula — (CH ₂ ) _m -R ^a

(Wherein R * is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and m is an integer of 2 to 6). R ⁷ is a hydrogen atom or a lower alkyl group which may have a carboxyl group or a lower alkoxycarbyl group as a substituent.) And a pharmacologically acceptable derivative thereof. It is useful for preventing or treating diseases caused by intimal cell hyperproliferation.

Here, in the compound represented by the general formula (I) of the present invention, the lower alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group. A straight-chain branched or branched alkyl group having 1 to 6 carbon atoms such as tyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, and hexyl group; Lower alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert —A linear or branched alkoxy group having 1 to 6 carbon atoms such as a pentyloxy group and a hexyloxy group. Aralkyl is a lower alkoxy group substituted with an aromatic hydrocarbon group such as a phenyl group or a naphthyl group, and a cycloalkylalkoxy group is substituted with a 3- to 7-membered cyclic alkyl group. And the lower alkoxy group. A halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and a lower acetyl group refers to a straight or branched alkyl group such as an acetyl group, a propionyl group, and a butyryl group having 2 carbon atoms. ~ 7 alkylcarbonyl groups. In addition, the mono- or di-lower alkyl-substituted amino group refers to an amino group mono-substituted with the lower alkyl group or an amino group di-substituted with the same or different lower alkyl group.

The compound represented by the above general formula (I) of the present invention can be produced, for example, as follows.

That is, the compound represented by the general formula (I) of the present invention is represented by the general formula:

(R ^{1 Q} in the formula is a hydrogen atom, a halogen atom, a hydroxyl group having a protecting group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group having a protecting group, a cycloalkyl alkoxy group, an aralkyloxy group, a lower acryl group, A mono-lower alkyl-substituted amino group, a di-lower alkyl-substituted amino group or a lower alkoxycarbonyl group having a group, wherein R ² , R ³ , R <and R ⁵ have the same meaning as described above. Derivative or its reactive functional derivative such as acid halide, active ester, etc.

(In the formula, one of P and Q is an amino group, and the other is a substituent.

— (CH ₂ ) _n -R °

(Wherein R ° is a hydroxyl group, an amino group having a protecting group, a mono-lower alkyl-substituted amino group or a di-lower alkyl-substituted amino group having a protecting group, and n is an integer of 2 to 6). R ⁸ is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a substituent represented by the general formula:

— (CH ₂ ) _m -R ^a0

(Wherein, is a hydroxyl group, an amino group having a protecting group, a mono-lower alkyl-substituted amino group or a di-lower alkyl-substituted amino group having a protecting group, and m is an integer of 2 to 6). R ^e is a hydrogen atom or a lower alkyl group optionally having a lower alkoxyl group as a substituent. The imidazole derivative is reacted with an imidazole derivative in an inert solvent in the presence of a base, in the presence or absence of a dehydrating agent or a condensing agent, and if necessary, an alkyl group is added to the nitrogen atom in the imidazole ring using an alkyl halide. It can be produced by introducing and, if necessary, removing a protecting group according to a conventional method, followed by hydrolysis and amidation as required.

Further, among the compounds represented by the general formula (I) of the present invention,

(la)

[A ¹ and B ¹ in the formula are either general formulas.

R ¹

^ YC (R ⁴ ) = C (R ^S ) —CONH

(Wherein R ¹ , R ² , R ³ , R <and R ⁵ have the same meanings as described above), and the other is a substituent represented by the general formula

— (CH ₂ ) _N -R

(Wherein R and n have the same meanings as described above) or a carbamoyl group having a tetrazolyl group.] The imidazole derivative represented by the general formula

(Wherein R ² , R ³ , R <, R ⁵ and R ^1D have the same meanings as described above), and a compound represented by the general formula:

H ₂ NR "(V)

(R ¹¹ in the formula is a general formula

— (CH ₂ ) _N -R °

(Wherein R ° and n have the same meanings as described above) or a tetrazolyl group.) With an amine compound represented by the formula: It can be produced by removing a protecting group according to a conventional method.

The compounds represented by the general formulas (II) and (V) used as raw materials in the production method may be purchased as a commercial product, or may be produced by a known method described in a literature or a method similar thereto. it can. The compound represented by the general formula (III) used as a raw material in the production method can be purchased as a commercial product, or can be produced by a known method described in a literature or a method similar thereto (J. Am. Chem. Soc., Vol. 74, pp. 2892-2894 (1952), Tetrahe dron, Vol. 42, No. 10, pp. 2625-2634 (1986)).

The compound represented by the general formula (IV) used as a raw material in the production method may be a reactive functional group such as a gay cinnamate derivative represented by the general formula (II) or an acid halide or an active ester thereof. Derivatives and general formula

(Wherein one of T and U in the formula is an amino group and the other is a lower alkoxycarbonyl group) with an aminoimidazole derivative represented by the following formula: Or reacting in the presence or absence of a condensing agent to convert the ester group to a carboxyl group by hydrolysis,

Z

NH (VII)

[In the formula, either Y or Z is a general formula.

(Wherein R ² , R ^s , R <, R ^5, and R ^lfl have the same meanings as described above), and the other is a carboxyl group. After it is obtained, it can be produced by ring closure in an inert solvent in the presence of a dehydrating agent such as acetic anhydride or a condensing agent, or by dehydration ring closure under heating. The compound represented by the general formula (VI) used in the production method can be produced by a known method described in the literature or a method similar thereto (J. Chem. Soc., 1071). Pp. 1074 (1949), J. Chem. Soc. Perk in Tran s. I, 2310-2315 (1980), etc.).

The imidazole derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt thereof by a conventional method. Such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene Acid addition salts with organic acids such as sulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, and aspartic acid And salts with organic bases such as lysine, lysine and arginine, and salts with inorganic bases such as sodium salt and potassium salt.

The compound represented by the general formula (I) of the present invention also includes hydrates and solvates with pharmaceutically acceptable solvents such as ethanol.

The compound of the present invention represented by the general formula (I) has an unsaturated bond and thus has two geometric isomers. In the present invention, the compound of cis form (Z form) or the trans form (Z form) Any of the compounds of the E-form) may be used.

Among the compounds represented by the general formula (I) of the present invention, a compound having an asymmetric carbon atom has two optical isomers having an R configuration and an S configuration. Optical isomers may be used, and a mixture of those optical isomers may be used.

In the compound of the present invention represented by the general formula (I), R ⁷ is preferably a hydrogen atom.

The compound of the present invention represented by the above general formula (I) is extremely potent in inhibiting vascular smooth muscle proliferation in an in vitro cell proliferation inhibition test using thoracic aortic vascular smooth muscle cells of spontaneously hypertensive rats. It has an action. For example, (E) — 5 (4) 1 (3,4,5-trimethyxincinamoylamino) imidazole 1 4 (5) Carboxamide hydrochloride has a concentration of 46 M, and (E) — 4 (5) — Power Lubamoy Roux 5 (4)-(3, 4, 5—trimethoxycinnamoylamino) imidazole

— 2-ethyl carboxylate hydrochloride is 9 // M concentration, (E) -N- (2-hydroxyethyl) 1 5 (4) ― (3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) One carboxamide at a concentration of 20 M exhibited an activity to inhibit the growth of vascular smooth muscle by 50%.

Thus, the compounds of the present invention represented by the above general formula (I) and their pharmacologically acceptable salts have excellent inhibitory activity against hyperproliferation of intimal cells, It is a very useful compound as an inhibitor.

Therefore, the compound represented by the general formula (I) of the present invention includes, for example, restenosis of a coronary artery after PTCA, restenosis after DCA, restenosis after placement of a stent in a blood vessel, autologous blood vessel and artificial blood vessel. It is effective for diseases caused by hyperproliferation of intimal cells such as restenosis and arteriosclerosis after transplantation.

The compound represented by the general formula (I) of the present invention is a highly safe compound. For example, in an acute toxicity test using mice, (E) -5 (4) — (3,4,5) — Trimetroxycinnamoylamino) Imidazolone 4 (5) — Carboxamide hydrochloride showed no deaths and no abnormalities even after a single administration of 200 OmgZkg.

When the imidazole derivative represented by the above general formula (I) of the present invention and a pharmaceutically acceptable salt thereof are used for actual treatment, a suitable pharmaceutical composition such as a tablet, a powder or a granule is used. It is administered orally or parenterally as capsules, injections and the like. These pharmaceutical compositions can be prepared by the pharmaceutical methods used in general preparations, by using carriers, excipients and other additives commonly used for pharmaceuticals.

The dosage is determined as appropriate depending on the gender, age, weight, degree of symptoms, etc. of the target patient.In the case of oral administration, it is generally 0.1 to 1000 mg per adult per day.

In the case of parenteral administration, it is generally administered in the range of 0.01 to 10 Omg per adult per day, in one or several doses. P / 97/00

1 1 Example

The content of the present invention will be described in more detail in the following Reference Examples, Examples and Formulation Examples, but the present invention is not limited to the content. Reference example 1

(E)-3-ethoxy cinnamate

(E) — 3-Hydroxygaymic acid (500mg) ON, N-Dimethylformamide solution (6ml), add potassium carbonate (1.16g) and thiol iodide (1.31g), 60 ° C for 3 hours After stirring, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crystals. The crystals were dissolved in ethanol (6 ml), 2N aqueous sodium hydroxide solution (3 inl) was added, and the mixture was stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, and the aqueous layer was washed with water. The aqueous layer was acidified using 2N hydrochloric acid, and the precipitate was collected by filtration and washed with water to obtain (III) -3-ethoxygaymic acid (375 mg).

_{1H- NMR (400MHz, CDC1 3)} <5 ppm:

1.44 (t, J = 7.0Hz, 3H), 4.07 (q, J = 7.0Hz, 2H), 6.44 (d, J = 16.0Hz, 1H), 6.9 -7.4 (m, 4H), 7.75 (d, J = 16.0Hz, 1H) Reference Example 2

(E) — 3, 5-dimethoxy 4-— (2-hydroxyethoxy) gay cinnamate

3,5-Dimethoxy-4-hydroxygaymic acid (2.0 g) and potassium carbonate (9.86 g) in N, N-dimethylformamide (50 ml) in an argon atmosphere under stirring at room temperature. Crown-6-ether (50 mg) and 2-bromoethanol (8.92 g) were added. After the mixture was reacted at 60 ° C. for 18 hours, water was added, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The oily substance (1.06 g) obtained by evaporating the solvent under reduced pressure was dissolved in methylene chloride (5 ml), 2N aqueous sodium hydroxide solution (20 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with methylene chloride, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. Organic After the layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain (E) —3,5-dimethoxy-4- (2-hydroxyethoxy) gaymic acid (369 mg) as a white solid. Was.

Ή-NMR (400MHz, CDCls) δ ppm:

3.70-3.80 (m, 2H), 3.91 (s, 6H), 4.15-4.25 (m, 2H), 6.37 (d, J = 15.9Hz,

1H), 6.80 (s, 2H), 7.71 (d, J = 15.9Hz, 1H) Reference example 3

(E) — 4-1- (2-acetoxyethoxy) 1,3,5-dimethoxy cinnamate

(E) — 3,5-Dimethoxy 41- (2-hydroxyethoxy)

Acetic anhydride (369 ml) was added to a solution of 363.8 mg) in pyridine (10 ml) and reacted at room temperature for 24 hours. Water was added to the reaction solution, and the mixture was stirred for 1.5 hours, and then extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white solid (E) -4- (2-acetoxethoxy) -3,5-dimethoxycinnamic acid (360.2 mg).

_{1 H- NMR (400MHz, CDC1 3} ) δ ppm:

2.09 (s, 3H), 3.88 (s, 6H), 4.20-4.40 (m, 4H), 6.36 (d, J = 15.9Hz, 1H), 6.77 (s, 2H), 7.70 (d, J = 15.9Hz) , 1H) Reference example 4

The following compounds were synthesized in the same manner as in Reference Example 3.

(E)-4-Acetoxycholic acid

Ή-NMR (400MHz, CDCls) δ ppm:

2.32 (s, 3H), 6.41 (d, J = 16.0Hz, 1H), 7.15 (d, J = 8.6Hz, 2H), 7.58 (d, J = 8.6Hz, 2H), 7.77 (d, J = 16.0 (Hz, 1H)

(E) 1-Acetoxycholic acid

_{Ή-NMR (400MHz, CDC1 3} ) δ ppm:

2.33 (s.3H), 6.45 (d, J = 16.0Hz, 1H), 7.1-7.5 (m, 4H), 7.75 (d, J = 16.0Hz, 1H)

4-Acetoxy 3, 5-Dimethoxycinnamic acid

'H-NMR (400MHz, CDC1 3) δ ppm:

2.36 (s, 3H), 3.87 (s, 6H), 6.47 (d, J = 15.8Hz, lfl), 6.82 (s, 2H), 7.79 (d, J = 15.8Hz, 1H) Reference example 5

(E) -3,4,5-trimethoxy cinnamate chloride

N, N-Dimethylformamide (0.1 ml) was added to a solution of 3,4,5-trimethoxycinnamic acid (10. Og) and thionyl chloride (6.1 ml) in toluene (100 ml), and the mixture was heated at 80 ° C. Stir for 3 hours. The reaction solution was concentrated under reduced pressure, hexane was added to the residue, and the insoluble material was collected by filtration to obtain (E) -3,4,5-trimethoxysiloxane cinnamate chloride (10.3 g).

'H-NMR (400MHz, CDC1 _S ) δ ppm:

3.911 (s, 3H), 3.917 (s, 3H), 3.918 (s, 3H), 6.55 (d, J = 15.4Hz, 1H), 6.80 (s, 2H), 7.76 (d, J = 15.4Hz, 1H ) Reference example 6

(E)-4-(2-acetoxetoxy) 1,3,5-dimethoxy cinnamate

(E)-4-(2-Acetoxyethoxy) — 3,5-Dimethoxycetic acid (360.2 mg) in toluene (10 ml) suspension in thionyl chloride (414.3 rag) and N, N-dimethylform Add 1 drop of amide, 80. The mixture was stirred at C for 2 hours. The solvent was distilled off under reduced pressure to obtain (E) -41- (2-acetoxetoxy) -13,5-dimethoxy cinnamate chloride (377.7 mg).

_{Ή-NMR (400MHz, CDC1 3} ) δ ppm:

2.09 (s, 3H), 3.89 (s, 6H), 4.25-4.45 (m, 4H), 6.55 (d, J = 15.4Hz, 1H),

6.79 (s, 2H), 7.75 (d, J = 15.4Hz, 1H) Reference Example 7

The following compounds were synthesized in the same manner as in Reference Example 5 or 6.

(E) -3-Chlorokecinnamic chloride

! H-NMR (400MHz, CDC1 ») <5 ppm:

6.65 (d, J = 15.6Hz, 1H), 7.3-7.65 (ra, 4H), 7.77 (d, J = 15.6Hz, 1H)

(E) -3,5-Dimethoxy cinnamate chloride

iH—NMR (400MHz, CDCls) δ ppm:

3.83 (s, 6H), 6.58 (t, J = 2.2Hz, 1H), 6.61 (d, J = 15.5Hz, 1H), 6.70 (d, J = 2.2Hz, 2H), 7.76 (d, J = 15.5 (Hz, 1H)

(E) — 3-ethoxy cinnamate chloride

Ή-NMR (400MHz, CDC) δ ppm:

1.44 (t, J = 7.0Hz, 3H), 4.07 (q, J = 7.0Hz, 2H), 6.62 (d, J = 15.5Hz, 1H),

6.95-7.2 (m, 3H), 7.34 (t, J = 8.0Hz, 1H), 7.80 (d, J = 15.5Hz, 1H)

(E) — 4-methoxy cinnamate mouth lid

_{Ή-NMR (400MHz, CDC1 8} ) 5 ppm:

3.87 (s, 3H), 6.51 (d, J = 15.4Hz, 1H), 6.9-7.6 (m, 4H), 7.80 (d, J = 15.4Hz, 1H)

(E) — 3-Methoxy cinnamate chloride

'H-NMR (400MHz, CDC1 3) 5 ppm:

3.85 (s, 3H), 6.64 (d, J = 15.5Hz, 1H), 7.00-7.25 (m, 3H), 7.36 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 15.5Hz, 1H )

(E) — 2-Methoxy cinnamate chloride

'H-NMR (400MHz, CDCU) δ ppm: 3.93 (s, 3H), 6.78 (d, J = 15.6Hz, 1H), 6.9-7.05 (m, 2H), 7.4-7.5 On, 1H), 7.52 (dd, J = 7.7, 1.7Hz, 1H), 8.13 (d, J = 15.6Hz, 1H) Reference example 8

(E)-4 (5) One strength rubamoyl 5 (4) — [4-(2

) — 3,5-Dimethoxycinnamoylamino] Imidazole-2-ethyl ethyl rubonate

(E) -4- (2-acetoxetoxy) 1,3,5-dimethoxy cinnamate chloride (377.7 mg) and 5 (4) monoamino-4 (5) rubamoyl imidazo mono 2- A solution of ethyl carboxylate (255.2 rag) in pyridine (5 ml) was reacted at 60 in an argon atmosphere for 3 hours. The reaction solution was poured into water (200 ml), and the precipitate was collected by filtration and washed sequentially with water and ethyl acetate. The precipitate was dissolved in methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1). (E) -4 (5) Ichiroku rubamoyl 5 (4) — [4- (2-acetoxetoxy) — 3,5-dimethoxycinnamoylamino] imidazole-l- 2-ethyl carbonate (130 mg) was obtained. Was.

'H-NMR (400MHz, CDCls) δ ppm:

1.44 (t, J = 7.1Hz, 3H), 2.09 (s, 3H), 3.91 (s, 6H), 4.20-4.45 (m, 4H), 4.48 (q, J = 7.1Hz, 2H), 5.47 (brs , 1H), 6.54 (d, J = 15.5Hz, 1H), 6.80 (s, 2H), 6.94 (brs, 1H), 7.70 (d, J = 15.5Hz, 1H), 10.19 (s, 1H), 11 , 97 (brs, 1H) Reference example 9

The following compounds were synthesized in the same manner as in Reference Examples 5 to 6 and 8.

(E) 1 5 (4) — (4-acetoxycinnamoylamino) imidazo 1 4 (5) 1 carboxamide

Ή-NMR (400MHz, DMSO- d e) 5 ppm:

2.29 (s, 3H), 7.1-7.45 On, 6H), 7.63 (d, J = 15.6Hz, 1H), 7.78 (d, J-8.0Hz, 2H), 10.35 (s, 1H), 12.64 (s, 1H)

(E)-5 (4)-(3-Acetoxycinnamoylamino) imidazo 1-ru 4 (5) 1-carboxamide

'H-NMR (270MHz, DMS0 -d e) 5 ppm:

2.29 (s, 3H), 7.1-7.75 (m, 9H), 10.36 (s, 1H), 12.65 (s, 1H)

(E) 1-5 (4) ― (4-acetoxy-1,3,5-dimethoxyxinnamoylamino) imidazo 1 4 (5) 1-carboxamide

'H-NMR (400MHz, DMS0-d _e ) δ ppm:

2.26 (s, 3H), 3.83 (s, 6H), 7.1-7.45 (m, 6H), 7.61 (d, J = 15.6Hz, 1H), 10.31 (brs, 1H), 12.67 (brs, 1H) 1

(E) — 5 (4)-(3,4,5— trimethoxycinnamoylamino) imidazole — 4 (5) —carboxamide (compound 1)

(E) -3,4,5-trimethoxy cinnamate chloride (400mg) and 5 (4) -aminoimidazoyl 4 (5) -carboxamide hydrochloride (510mg) and pyridine

10 ml) and stirred at 125 for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the insoluble material was collected by filtration. The residue was washed with getyl ether, and (E) -5 (4)-(3, 4

, 5-trimethoxycinnamoylamino) imidazo-l-ru 4 (5) -carboxamide (480 mg) was obtained.

^ -NMR (400MHz, DMS0-d _e ) δ ppm:

3.70 (s, 3H), 3.84 (s, 6H), 7.10 (s, 2H), 7.15-7.4 (m, 4H), 7.58 (d, J = 15.6Hz, 1H), 10.28 (s, 1H), 12.65 (s, 1H) Example 2

The following compounds were synthesized in the same manner as in Example 1.

(E)-5 (4)-(3,4 dimethoxy cinnamoylamino) imidazole 4 (5) —Carboxamide (Compound 2)

Ή-NMR (400MHz, DMS0-d _e ) δ ppm:

3.80 (s, 3H), 3.83 (s, 3H), 7.00 (d, J = 8.4Hz, 1H), 7.12 (d, J = 15.5Hz, 1H), 7.15-7.45 (m, 5H), 7.57 (d , J = 15.5Hz, 1H), 10.24 (s, 1H), 12.64 (s, 1H)

(E)-5 (4)-(4-Ethoxy-3-N-methoxycinnamoylamino) imidazole-4 (5) Monocarboxamide (Compound 3)

Ή-NMR (400MHz, DMS0- d e) (5 ppm:

1.34 (t, J = 7.0Hz, 3H), 3.83 (s, 3H), 4.06 (q, J = 7.0Hz, 2H), 6.98 (d, J = 8.4Hz, 1H), 7.05-7.5 (m, 6H ), 7.56 (d, J = 15.5Hz, 1H), 10.24 (s, 1H), 12.63 (s, 1H)

(E) — 5 (4) I- (3-chlorocinnamoylamino) imidazole — 4 (5) — Carboxamide (compound 4)

'H-NMR (400MHz, DMS0-d _e ) δ ppm:

7.0-7.75 (m, 8H), 7.86 (s, 1H), 10.36 (s, 1H), 12.3-12.9 (br, 1H)

(E) -5 (4) I (3,5-dimethoxycinnamoylamino) imidazolu 4 (5) — Carboxamide (Compound 5)

Ή-NMR (400MHz, DMS0-d _e ) δ ppm:

3.79 (s, 6H), 6.55 (t, J = 2.2Hz, 1H), 6.92 (brs, 2H), 7.15-7.45 (m, 4H), 7.55 (d, J = 15.6Hz, 1H), 10.32 (brs , 1H), 12.65 (brs, 1H) (E)-5 (4)-(3-ethoxycinnamoylamino) imidazole-4 (5)-carboxamide (compound 6)

'H-NMR (400MHz, DMS0-d _e ) δ ppm:

1.35 (t, J = 7.0Hz, 3H), 4.08 (q, J = 7.0Hz, 2H), 6.9-7.5 (m, 8H), 7.59 (d, J = 15.6Hz, 1H), 10.31 (s, 1H ), 12.4-13.1 (br, 1H) (E) — 5 (4) — (4-Methoxyxynamamoylamino) imidazole-1 (5) Carboxamide (Compound 7)

Ή-NMR (400MHz, DMSO-d _e ) δ ppm:

3.81 (s, 3H), 6.7-7.9 (m, 9H), 10.26 (brs, 1H), 12.63 (brs, 1H)

(E) -5 (4)-(3-Methoxycinnamoylamino) imidazole-4 (5) carboxamide (compound 8)

¹ H—NMR (400MHz, DMSO-de) δ ppm:

3.81 (s, 3H), 6.9-7.5 (m, 8H), 7.60 (d, J = 15.6Hz, 1H), 10.33 (s, 1H), 12.65 (brs, 1H)

(E) -5 (4) I- (2-Methoxycinnamoylamino) imidazo-Iru 4 (5) -Carboxamide (Compound 9)

Ή-NMR (400MHz, DMSO-d.) Δ ppm:

3.88 (s, 3H), 6.9-7.5 (m, 7H), 7.72 (d, J = 7.4Hz, 1H), 7.89 (d, J = 15.9Hz, 1H), 10.33 (brs, 1H), 12.4-13.0 (br, 1H) Example 3

(E)-4 (5) Immobilized rubamoyl 1 5 (4)-[3,5-Dimethoxy-4- (2-hydroxyethoxy) cinnamoylamino] imidazole-2-carboxylate (Compound 1 0)

(E)-4 (5) —Rubamoyl— 5 (4) — [4-1 (2-acetoxynoxy) 1,3,5-dimethoxycinnamoylamino] Imidazo-Ru 2-ethyl ethyl rubonate A solution of potassium carbonate (296 rag) in water (8 ml) was added dropwise with stirring a solution of (700 mg) in methanol (21 ml) at 0 ° C. After reacting at an external temperature of 5 ° C for 20 hours, the mixture was neutralized with 2N hydrochloric acid and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give (E) -4 (5) one-pot rubamoyl-5 (4) 1-1 [3,5-dimethoxy-41]. (2-hydroxyethoxy) cinnamoylua [Mino] imidazole-2-ethyl ethulbonate (547.4 mg) was obtained.

Ή-NMR (400MHz, DMS0-d _e ) δ ppm:

1.33 (t, J = 7.1Hz, 3H), 3.62 (q, J = 5.7Hz, 2H), 3.84 (s, 6H), 3.92 (t, J = 5.7Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.57 (t, J = 5.7Hz, 1H), 7.08 (s, 2H), 7.25 (d, J = 15.7Hz, 1H), 7.39 (brs, 1H), 7.55-7.75 (m, 2H ), 10.45 (brs, 1H), 12.80 (brs, 1H)

The following compounds were synthesized in the same manner as in Example 3.

(E) One 5 (4) One (4-hydroxycinnamoylamino) imidazo 4 (5) One carboxamide (Compound 11)

lH-NMR (400MHz, DMS0-d _e ) δ ppm:

6.81 (d, J = 8.6Hz, 2H), 6.85-7.7 (m, 7H), 10.22 (brs, 1H), 12.3-13.0 (br, 1H)

(E) 1-5 (4)-(3-hydroxycinnamoylamino) imidazole-4 (5) 1-carboxamide (compound 12)

■ H-NMR (270MHz, DMSO-de) δ ppm:

6.7-7.7 (m, 9H), 9.4-9.8 (br, 1H), 10.34 (s, 1H), 12.63 (s, 1H)

(E) 1-5 (4) ― (3,5-dimethoxy-4-hydroxycinnamoylamino) imidazole-4 (5) 1-carboxamide (compound 13)

^ -NMR (400MHz, DMS0-d _e ) δ ppm:

3.80 (s, 6H), 6.8-7.05 (m, 3H), 7.32 (s, 1H), 7.52 (d, J = 15.4Hz, 1H)

(E)-5 (4)-(3,4,5—trimethoxycinnamylamino) Imidazo —Ru 4 (5) —Carboxamide hydrochloride (Compound 14)

(E)-5 (4) One (3, 4, 5—trimethoxy cincinamoylamino) imida 1N hydrochloric acid (4.2 ml) was added to a mixed solution of ethanol 4 (5) monocarboxamide (470 mg) in methanol (10 ml) and ethanol (5 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ether. (E) -5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide hydrochloride (470 mg).

Ή-NMR (400MHz, DMS0-d _e ) «5 ppm:

3.70 (s, 3H), 3.84 (s, 6H), 7.08 (s, 2H), 7.19 (d, J = 15.6Hz, 1H), 7.62 (d, J-15.6Hz, 1H), 7.65-7.85 (m , 2H), 8.22 (brs, 1H), 10.51 (s, 1H)

(E)-4 (5) — Potassium 5 (4) — [3,5-Dimethoxy-1-cinnamoylamino] imidazole-2-ethyl carboxylate hydrochloride ( Compound 15)

(E) — 4 (5) One-strength rubamoyl 5 (4) — [3,5-Dimethoxyl 4- (2-hydroxyxynoxy) cinnamoylamino] imidazolu-l 2-ethyl carboxylate (300 mg) It was dissolved in a solution of methylene chloride / methanol = 10/1 (10 ml), and a saturated methanol solution of hydrogen chloride was added dropwise until the solution became acidic. 'The solvent is distilled off under reduced pressure, and (E) — 4 (5) rubamoyl 5 (4) — [3,5-dimethoxy-1-41 (2-hydroxyethoxy) cinnamoylamino There was obtained imidazoyl 2-carboxylate hydrochloride (270.9 mg).

Ή-NMR (400MHz, DMS0-d _e ) <5 ppm:

1.33 (t, J = 7.1Hz, 3H), 3.62 (t, J = 5.7Hz, 2H), 3.84 (s, 6H), 3.92 (t, J = 5.7Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 7.08 (s, 2H), 7.23 (d, J = 15.6Hz, 1H), 7.42 (brs, 1H), 7.55-7.8 (m, 2H), 10.41 (s, 1H)

The following compounds were synthesized in the same manner as in Example 5 or 6.

(E) -5 (4) I (3,4 dimethyl cincinamoylamino) imidazole-4 (5) —carboxamide hydrochloride (compound 16) ¹ H—NMR (400 MHz, DMS0-d _e ) <5 ppm:

3.80 (s, 3H), 3.83 (s, 3H), 7.02 (d, J = 8.4Hz, 1H), 7.09 (d, J = 15.6Hz, 1H), 7.25 (dd, J = 8.4, 1.9Hz, 1H ), 7.35 (d, J = 1.9 Hz, 1H), 7.5-7.8 (m, 3H), 8.11 (s, 1H), 10.44 (s, 1H)

(E) — 5 (4) — (4-ethoxin-3-methoxycinnamoylamino) imidazolone 4 (5) monocarboxamide hydrochloride (compound 17)

JH-NMR (400MHz, DMS0-d _e ) δ ppm:

1.34 (t, J = 7.0Hz, 3H), 3.83 (s, 3H), 4.06 (q, J = 7.0Hz, 2H), 7.00 (d, J = 8.4Hz, 1H), 7.10 (d, J = 15.6 Hz, 1H), 7.23 (dd, J = 8.4, 1.9Hz, lH), 7.34 (d,

J = l.9Hz, 1H), 7.62 (d, J = 15.6Hz, 1H), 7.75-8.05 (m, 2H), 8.53 (s, 1H), 10.59 (s, 1H)

(E)-5 (4)-(3,5-Dimethoxycinnamoylamino) imidazolu 4 (5) —Carboxamide hydrochloride (Compound 18)

Ή-NMR (400MHz, DMS0- d e) 5 ppm:

3.79 (s, 6H), 6.57 (t, J = 2.2Hz, 1H), 6.90 (d, J = 2.2Hz, 2H), 7.24 (d, J = 15.7Hz, 1H), 7.61 (d, J = 15.7 Hz, 1H), 7.7-8.0 (m, 2H), 8.44 (brs, 1H), 10.66 (brs, 1H)

(E) -5 (4) 1- (3-ethoxycinnamoylamino) imidazole-4 (5) monocarboxamide hydrochloride (compound 19)

! H—NMR (400MHz, D S0-d _e ) 5 ppm:

1.35 (t, J = 7.0Hz, 3Η), 4.08 (q, J = 7. OHz, 2H), 6.99 (dd, J = 8.2, 1.7Hz, 1H), 7.15-7.45 (m, 4H), 7.64 ( d, J = 15.7Hz, 1H), 7.7-7.9 (br, 2H), 8.38

(brs, 1H), 10.65 (brs, 1H)

(E) 15 (4) 1 (4-Methoxyxinnamoylamino) imidazole-4 (5) —carboxamide hydrochloride (Compound 20) Ή-NMR (270MHz, DMS0-d _e ) δ ppm:

3.81 (s, 3H), 6.85-8.0 (m, 8H), 8.38 (s, 1H), 10.60 (s, 1H)

(E) -5 (4) 1- (3-Methoxycinnamoylamino) imidazole 1 4 (5) Carboxamide hydrochloride (Compound 21)

Ή-NMR (270MHz, DMS0-d _e ) δ ppm:

3.81 (s, 3H), 6.9-8.1 (m, 8H), 8.39 (s, 1H), 10.67 (s, 1H)

(E) — 5 (4) — (2-Methoxycinnamoylamino) imidazole 1 4 (5) monocarboxamide hydrochloride (Compound 22)

'H-NMR (400MHz, DMS0-d _e ) <5 ppm:

3.89 (s, 3H), 6.9-7.15 On, 2H), 7.22 (d, J = 15.9Hz, 1H), 7.35-7.5 (m, 1H), 7.67 (dd, J = 7.7, 1.5Hz, 1H), 7.93 (d, J = 15.9Hz, 1H), 8.03 (brs, 1H), 8.28 (brs, 1H), 8.92 (s, 1H), 10.99 (s, 1H)

(E) — 1-methyl-1 5 (4) — (3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) —carboxamide (compound 23)

(E)-5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) N, N- of carboxamide (100 mg) and methyl iodide (41 mg) Potassium carbonate (40 rag) was added to the dimethylformamide (1 ml) solution, and the mixture was stirred at 40 ° C for 24 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and part of the obtained residue was purified by preparative thin-layer chromatography (developing solvent: methylene chloride // methanol = 10/1) to give (E) -1-methyl- 5 (4)-(3,4,5-trimethoxycinnamoyluamino) imidazole-4 (5) -carboxamide (15. lmg) was obtained.

Ή-NMR (400MHz, D S0-d _e ) δ ppm:

3.45 (s, 3H), 3.71 (s, 3H), 3.84 (s, 6H), 6.9-7.3 (m, 5H), 7.54 (d, J = 15.8Hz, 1H), 7.64 (s, 1H), 9.95 (s, 1H) Example 9

(E)-4 (5)-Potassium 5 (4)-(3, 4, 5-Trimetroxixin Namoylamino) Imidazole-2-ethyl ether of rubonate (Compound 24)

(E) -3,4,5-trimethoxy cinnamate chloride (39mg) and 5 (4)

—Amino — 4 (5) —potassium ethylimidazo-2-ol 2-carboxylate (30 mg) was dissolved in pyridine (1 ml) and stirred at 50 ° C. for 2 hours. Pyridine was distilled off under reduced pressure, water was added, and the precipitate was collected by filtration, washed with water and getyl ether in that order, and then washed with (E) -4 (5) -lebamoyl-5 (4)-( 3, 4, 5-trimethoxycinnamamoylamino) Imidazoyl 2-carboxylate ethyl ester (23 mg) was obtained. • H-NMR (400MHz, D S0-d _e ) δ ppm:

1.34 (t, J = 7.1 Hz, 3H), 3.72 (s, 3H), 3.85 (s, 6H), 4.36 (t, J = 7.1 Hz, 2H), 7.09 (s, 2H), 7.26 (d, J = 16.1Hz, 1H), 7.41 (brs, 1H), 7.5-7.85 On, 2H), 10.5 (brs, 1H), 12.83 (brs, 1H) Reference example 10

Isopropyl iminoisopropyloxyacetate

To a solution of isopropyl cyanoformate (2.98 g) in getyl ether (20 ml) was added isopropyl alcohol (3.6 ml). Under ice cooling and stirring, hydrogen chloride gas was passed for 20 minutes, and the precipitate was collected by filtration. Potassium carbonate (1.43 g) was dissolved in water (1.32 ml), and the precipitate obtained above was added under ice-cooling and stirring, followed by extraction with getyl ether. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain isopropyl iminoisopropyloxylate (1.56 g).

_{Ή-NMR (400MHz, CDC1 3} ) <5 ppm:

1.2-1.5 (m, 12H), 5.0-5.3 (ra, 2H), 8.70 (brs, 1H) Reference example 1 1

5 (4) —Amino 4 (5) —Rubamoylimidazo-2-ru 2-Isopropyl rubonate Isopropyl iminoisopropyloxydoxylate (1.56 g) and 2-aminocyanoacetic acid amide (892 mg) were heated to reflux in ethanol (10 ml) for 1 hour under an argon atmosphere. After the reaction solution became homogeneous, the mixture was stirred at room temperature for 15 hours. The precipitate was collected by filtration, washed successively with getyl ether, water and getyl ether, to give 5 (4) monoamino-4 (5) -rubamoyl imidazole-2-isopropyl rubrate (1.06 g) I got

¹ H—NMR (400MHz, DMSO-d,) 6 ppm:

1.29 (d, J = 6.3Hz, 6H), 5.0-5.2 (m, 1H), 5.80 (s, 2H), 6.7-7.2 (m, 2H), 12.28 (brs, 1H)

(E)-4 (5)-Potassium 5 (4)-(3, 4, 5-Trimethoxycin Namoylamino) Imidazole-2- Isopropyl sorbonate (Compound 25)

5 (4) —Amino-4 (5) —Lubamoyl imidazo-l-2-isopropyl carboxylate (279.6ing) and (E) — 3,4,5-Trimethoxy cinnamate chloride (338.2 mg) Was dissolved in pyridine (8 ml) and 50 under argon atmosphere. The mixture was stirred at C for 2 hours. The pyridine was distilled off under reduced pressure, water was added, and the precipitate was collected by filtration, washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate, water and getyl ether, and (E) -4 (5) One-stroke rubamoyl-5 (4)-(3,4,5-trimethoxy cinnamoylamino) imidazole-2-isopropyl rubonate (40.4 mg) was obtained.

_{Ή-NMR (400MHz, CDC1 3} ) <5 ppm:

1.42 (d, J = 6.3Hz, 6H), 3.90 (s, 3H), 3.92 (s, 6H), 5.25-5.45 (m, 1H), 5.61 (brs, 1H), 6.55, (d, J = 15.5 Hz, 1H), 6.80 (s, 2H), 7.01 (brs, 1H), 7.70 (d, J = 15.5Hz, 1H), 10.20 (s, 1H), 11.75-12.15 (br, 1H) Reference example 1 2

5 (4) Monoamino-2- (2-dimethylaminoethylaminocarbonyl) imidazole-4 (5) Monocarboxamide

N, N-dimethylformamide (268 mg) To the solution (3 ml) was added 5 (4) -amino-4 (5) rubumoylimidazo-l-l-2-ethyl carboxylate (100 mg), and the mixture was stirred for 4 days at TC. Water was added to the reaction mixture. The aqueous layer was washed with methylene chloride, the aqueous layer was concentrated under reduced pressure, and the obtained residue was separated and purified by aminopropylated silica gel chromatography (elution solvent: dichloromethane / methanol = 20/1). 5 (4) -Amino-2- (2-dimethylaminoethylaminocarbonyl) imidazole-4 (5) -carboxamide (37 mg) was obtained.

_{Ή-NMR (400MHz, CDC1 3} ) 5 ppm:

2.25 (s, 6H), 2.50 (t, J = 5.4Hz, 2H), 3.25-3.6 (m, 2H), 5.1-5.95 (m, 2H), 6.2-7.15 (m, 2H), 7.35-7.8 ( (m, 1H) Reference example 1 3

The following compounds were synthesized in the same manner as in Reference Example 12.

5 (4) Monoamino-2- (2-hydroxyethylaminocarbonyl) imidazole 4 (5) —Carboxamide

Ή-NMR (400MHz, DMS0-d _e ) δ ρρια:

3.35-3.7 (m, 2H), 4.75 (t, J = 5.4Hz, 2H), 5.3-5.7 (m, 2H), 6.6-6,9 (br, 2H), 7.7-7.9 (m, 1H), 11.9-12.3 (br, 1H) Example 1 1

The following compounds were synthesized in the same manner as in Example 9 or 10.

(E) — 2-Methyl-1 5 (4) — (3,4,5—trimethoxycinnamoylamino) imidazo 1 4 (5) Monocarboxamide (Compound 26)

'H-NMR (400MHz, DMS0-d _e ) δ ppm:

2.28 (s, 3H), 3.69 (s, 3H), 3.84 (s, 6H), 7.00-7.30 (m, 5H), 7.55 (d, J = 15.5Hz, 1H), 10.25 (s, 1H), 12.40 (s, 1H)

(E)-4 (5)-Potassium 5 (4)-(3, 4-Dimethoxycinnamoyluamino) Imidazoyl 2-Ethyl carboxylate (Compound 27) ¹ H—NMR (400MHz, DMS0-d _e ) δ ppm:

1.33 (t, J = 7.0Hz, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 4.34 (q, J = 7.0Hz, 2H), 7.03 (d, J = 8.3Hz, 1H), 7.05-7.8 On, 6H), 10.2-10.6 (br, 1H), 12.6-13.1 (br, 1H)

(E) 1- (2-Dimethylaminoethylaminocarbonyl) — 5 (4) — (3,4,5-trimethoxycinnamoylamino) imidazole 1 4 (5) —carboxamide (compound 2 8)

Ή-NMR (400MHz, CDC1 _S ) δ ppm:

2.29 (s, 6H), 2.53 (t, J = 5.8Hz, 2H), 3.4-3.6 On, 2H), 3.886 (s, 3H),

3.893 (s, 6H), 5.85-6.1 (br, 1H), 6.54 (d, J = 15.4Hz, 1H), 6.76 (s, 2H), 7.35-7.5 (m, 1H), 7.65 (d, J = 15.4Hz, 1H), 10.14 (brs, 1H)

(E) — 2— (2-Hydroxyshetylaminocarbonyl) — 5 (4)-(3,4,5—trimethoxycinnamoylamino) imidazole-4 (5) —Carboxamide (Compound 2 9)

Ή-NMR (400MHz, CDC) δ ppm:

3.3-3.6 (m, 4H), 3.71 (s, 3H), 3.84 (s, 6H), 4.7-4.9 (m, 1H), 7.08 (s, 2H), 7.23 (d, J = 15.5Hz, 1H) , 7.3-7.45 (m, 2H), 7.61 (d, J = 15.5Hz, 1H), 8.1-8.3 (m, 1H), 10.34 (s, 1H), 12.4-12.6 (br, 1H) Reference example 14

2- (5-amino-4 rubamoylimidazole-1 yl) tert-butyl acetate

2-Aminosianoacetic acid amide (100 mg) and ethyl formate (168 ^ 1) were dissolved in acetonitril (700 1), and the mixture was heated under reflux for 50 minutes. Glycine tert-butyl ester hydrochloride (70.5 mg) and a 5N aqueous solution of sodium hydroxide (881) were added to the reaction solution, and the mixture was stirred at 90 ° C for 40 minutes. Water was added to the reaction solution, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Tert-butyl acetate (50.2 mg) was obtained.

Ή-NMR (400MHz, DMS0- d e) (5 ppm:

1.3 (s, 9H), 4,65 (s, 2H), 5.78 (s, 2H), 6.5-6.85 (m, 2H), 7.06 (s, 1H)

(E) — 2— [4-l-l-bamoyl-5- (3,4,5-trimethoxycinnamoylamino) imidazole-1-yl] tert-butyl acetate (compound 30)

Of 2-tert-butyl 5- (5-amino-4-imidazolidyl-yl) tert-butyl acetate (200mg) and (E) -3,4,5-trimethoxy cinnamate chloride (214mg) The pyridine (5 ml) solution was stirred at 110 ° C. for 2 hours under an argon atmosphere. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 50/1) to obtain (E) — 2— [4-carbamoyl 5-— (3, 4 Tert-Butyl succinate (138. ½g) was obtained.

• H-NMR (400MHz, DMSO-de) <5 ppm:

1.39 (s, 9H), 3.71 (s, 3H), 3.83 (s, 6H), 4.69 (s, 2H), 6.85-7.4 (m, 5H), 7.53 (d, J = 15.7Hz, 1H), 7.64 (s, 1H), 9.98 (s, 1H)

(E) — 2— [4,1 rubamoyl 5 -— (3,4,5-trimethoxycinnamoyluamino) imidazole-11-yl] acetic acid (compound 31)

(E) — 2— [4. One-piece rubamoyl-5— (3,4,5-trimethoxycinnamylamino) imidazole-11-yl] Dissolve tert-butyl acetate (104.4 mg) in 2N hydrochloric acid (10 ml). 5 (The mixture was stirred for 16 hours with TC. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (developing solvent: ethanol) to give (E) —2— (3,4,5-trimethoxycinnamoylamino) imidazo-1-yl] Acetic acid (70.8 mg) was obtained.

'H-NMR (400MHz, D S0-d _e ) <5 ppm: 3.70 (s, 3H), 3.83 (s, 6H), 4.70 (s, 2H), 6.85-7.4 (m, 5H), 7.52 (d, J = 15.7Hz, 1H), 7.65 (brs, 1H), 9.97 (brs, 1H), 11.95-13.8 (br, 1H)

(E) — 4 (5) — Potassium 1-5 (4) — (3,4,5-trimetoxycin namoylamino) imidazole-2 — Potassium rubonic acid (Compound 32)

(E)-4 (5) One-strength rubamoyl 5 (4) — (3,4,5-trimethoxycinnamoylamino) imidazole 2-diethyl rubonate (50 mg) in methanol (27 ml) and 2N aqueous sodium hydroxide (1.2 ml) and stirred at room temperature for 5 days. The precipitate was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in water. 1N hydrochloric acid (2.4 ml) was added to the aqueous solution, and the precipitate was collected by filtration, washed with water, and (E) -4 (5) -levamoyl-5 (4)-(3,4,5-trime) Toxicinnamoylamino) imidazole-2-carboxylic acid (14 mg) was obtained.

'H-NMR (400MHz, DMS0-d _e ) δ ppm:

3.70 (s, 3H), 3.84 (s, 6H), 7.08 (s, 2H), 7.15-7.7 (m, 4H), 10.38 (brs, 1H)

(E)-4 (5)-Potassium 5 (4)-(3,4, 5-Trimethoxycin Namoylamino) Imidazoyl 2- 2-methyl rubonate (Compound 33)

(E)-4 (5) One-strength rubamoyl 5 (4) — (3,4,5-trimethoxycinnamoylamino) imidazole-2—thrurubonic acid (31 mg) in methylene chloride (5 ml) and methanol (0.5 Then, a 10% trimethylsilyldiazomethanehexane solution (1 ml) was added under ice-cooling, and the mixture was stirred as it was for 30 minutes. After treating excess trimethylsilyldiazomethane with acetic acid, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on an aminopropylated silica gel (elution solvent: methylene chloride / methanol = 10/1), and (E) — 4 (5) rubbamoyl 1 (4) — (3, 4) , 5-Trimethylxycinnamoylamino) imidazo-l-u-2-methyl rubnate (llmg) was obtained. Ή-NMR (400MHz, CDCls) δ ppm:

3.90 (s, 3H), 3.92 (s, 6H), 4.01 (s, 3H), 5.60 (brs, 1H), 6.54 (d, J = 15.5Hz, 1H), 6.80 (s, 2H), 6.94 (brs , 1H), 7.69 (d, J = 15.5Hz, 1H), 10.21 (s, 1H) Example 16

(E)-5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazo 1, 2,4 (5) dicarboxamide (compound 34)

(E) I-4 (5) Ichirubamoyl 5 (4) ― (3,4,5-trimethylethoxycinnamoylamino) imidazole 2-ethyl ketorubonate (500iDg) and ammonium chloride (64mg) 28 The mixture was suspended in a 70% aqueous ammonia solution (70 ml) and stirred at 40 ° C for 41 hours. The reaction solution is returned to room temperature, and the precipitated solid is collected by filtration, washed with getyl ether, and (E) —5 (4) — (3,4,5-trimethoxycinnamoylamino) imidazolue 2, 4 (5) Dicarboxamide (182.3nig) was obtained.

'H-NMR (400MHz, DMS0-d _e ) δ ppm:

3.70 (s, 3H), 3.84 (s, 6H), 6.95-8.3 (m, 10H)

(E)-4 (5)-Potassium rubamoyl 5 (4)-(3,4,5-Trimethoxine namoylamino) imidazole-2- isopropyl rubonate hydrochloride (Compound 35)

(E)-4 (5)-Potassium 5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazole-2- Isopropyl rubonate (40 mg) dissolved in methylene chloride (2 ml) and saturated chloride Hydrogen isopropyl alcohol solution was added until the solution became acidic. The solvent was distilled off under reduced pressure, and (E) — 4 (5) rubbamoyl 1 (4) — (3,4,5-trimethoxycinnamoylamino) imidazoru 2 — rubbon Isopropyl propyl hydrochloride (45.2 mg) was obtained.

¹ H—NMR (400 MHz, D S0-d _e ) δ ppm:

1.34 (d, J = 6.3Hz, 6H), 3.71 (s, 3H), 3.85 (s, 6H), 5.1-5.25 (m, 1H), 7.0 -7.7 (m, 6H), 10.41 (s, 1H) Example 18

The following compounds were synthesized in the same manner as in Example 17.

(E)-4 (5) One-stroke rubamoyl 5 (4)-(3,4,5-trimethoxycin namoylamino) imidazole-2-carboxylate methyl hydrochloride (Compound 36)

Ή-NMR (400MHz, DMS0-d _e ) δ ppm:

3.70 (s, 3H), 3.84 (s, 6H), 3.87 (s, 3H), 7.08 (s, 2H), 7.23 (d, J = 16.1 Hz, 1H), 7.43 (brs, 1H), 7.55-7.75 On, 2H), 10.40 (brs, 1H)

(E) I-4 (5) Ichirubamoyl 5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazole-2-ethylethyrubonate hydrochloride (compound 37) 1H-NMR (400MHz, DMSO -d,) δ ppm:

1.33 (t, J = 7.1Hz, 3H), 3.70 (s, 3H), 3.84 (s, 6H), 4.35 (q, J = 7.1Hz, 2H), 7.08 (s, 2H), 7.23 (d, J = 15.4Hz, 1H), 7.43 (brs, 1H), 7.55-7.75 (m, 2H), 10.41 (brs, 1H)

(E) — 4 (5) One-stroke rubamoyl 5 (4)-(3,4-Dimethoxycinnamoyluamino) imidazole 2-diethyl rubonate hydrochloride (Compound 38)

1 H-NMR (400 MHz, DMSO-d _β ) δ ppm:

1.34 (t, J = 7.1Hz, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 4.36 (q, J = 7.lHz, 2H), 7.03 (d, J = 8.3Hz, 1H) , 7.16 (d, J = 15.4Hz, 1H), 7.2-7.75 (m, 5H), 10.39 (s, 1H)

(E) -2- (2-Dimethylaminoethylaminocarbonyl) 1 5 (4) 1 (3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) —Carboxamidoni hydrochloride (Compound 3 9)

Ή-NMR (400MHz, DMSO-d _β ) <5 ppm:

2.7-3.0 (m, 6H), 3.15-3.4 (ra, 2H), 3.5-3.9 (m, 11H), 7.06 (s, 2H), 7.1- 7.7 (m, 3H), 8.65-8.85 (m, 1H), 9.5-9.8 (br, 1H), 10.1-10.4 (br, 1H)

(E) 1-2- (2-hydroxyethylaminocarbonyl) 1-5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide hydrochloride (compound 4 0)

Ή-NMR (400MHz, DMSO- d e) 5 ppm:

3.25-3.6 (in, 4H), 3.71 (s, 3H), 3.84 (s, 6H), 7.07 (s, 2H), 7.15-7.55 (m, 3H), 7.60 (d, J = 15.5Hz, 1H) , 8.15-8.3 (m, 1H), 10.25 (brs, 1H) Reference example 1 5

T-tert-butyl hydroxyiminocyanoate

Under ice-cooling, water (50 ml), sodium nitrite (11.0 g) and acetic acid (8.58 ml) were sequentially added to t-tert-butyl cyanoacetate (15.0 g), and the mixture was stirred at room temperature for 16 hours. Concentrated hydrochloric acid (21.0 ml) was added to the reaction solution, and the precipitate was collected by filtration and washed with water to obtain tert-butyl hydroxyiminocyanoate (12.4 g).

Ή-NMR (400MHz, CDC1 _S ) δ ppm:

1.59 (s, 9H), 11.93 (brs, 1H) Reference example 1 6

2-aminocyanoic acid tert-butyl 12 oxalate

Aluminum foil (190 mg) was added to a solution of mercuric chloride (76 mg) in water (7.6 ml), and the mixture was stirred at room temperature for 1 minute. After removing the solvent, the aluminum amalgam was washed sequentially with water, methanol and getyl ether. Then, under an argon atmosphere, getyl ether (5.5 ml), tert-butyl hydroxyiminocyanoacetate (l.Og) ethyl ether (4 ml) solution and water (0.4 ml) were added sequentially. After stirring at 40 ° C for 30 minutes, the insolubles were filtered through celite, and a solution of oxalic acid (256 mg) in ethanol (1 ml) was added to the filtrate. After allowing to stand at 4 ° C. for 1 hour, the precipitate was collected by filtration to obtain tert-butyl 2-aminocyanoacetate 1Z2 oxalate (596.6 rag).

1H—NMR (400MHz, DMS0-d _e ) δ ppm: 1.46 (s, 9H), 4.75 (s, 1H), 5.0-7.5 (br, 3H) Reference example 17

5 (4) —Aminoimidazole-4 (5) —Carboxylic acid t er t —Butyl

A suspension of 2-aminosinoacetic acid tert-butyl 1Z2 oxalate (500 mg) in methylene chloride (5 ml) was neutralized with a saturated aqueous solution of sodium hydrogen carbonate. After extraction with methylene chloride and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in black-mouthed form (8 ml) and ethanol (6 ml), added with formamidine acetate (374 mg), and heated under reflux for 3 hours under an argon atmosphere. The solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 5 (4) -aminoimidazoyl 4 (5) -tert-butyl carboxylate (324.8 mg). Was.

Ή-NMR (400MHz, CDC1 _S ) <5 ppm:

1.58 (s, 9H), 4.77 (brs, 2H), 7.32 (s, 1H), 10.3-11.6 (br, lfl) Reference example 1 8

(E) — 5 (4) — (3,4,5-trimethoxycinnamoylamino) imidazo 1-ru 4 (5) —Carboxylic acid tert-butyl

(E) — 3,4,5-Trimethoxy cinnamate chloride (454mg) and 5 (4) -aminoimidazoyl chloride 4 (5) — tert-butyl carboxylate (32mg) dissolved in pyridine (10ml) , 1 20. The mixture was stirred at 〇 for 1.5 hours. After the pyridine was distilled off under reduced pressure, water was added and the precipitate was collected by filtration. (E) — 5 (4) — (3,4,5-trimethoxycinnamoylamino) imidazo 4 ( 5) Tert-butyl ester of carboxylic acid (396.5 mg) was obtained.

-NMR (400MHz, CDCls) 5 ppm:

1.65 (s, 9H), 3.90 (s, 3H), 3.93 (s, 6H), 6.53 (d, J = 15.5Hz, 1H), 6.80 (s, 2H), 7.39 (s, 1H), 7.70 (d , J = 15.5Hz, 1H), 9.78 (s, 1H), 11.56 (s, 1H) Reference example 1 9 (E)-5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazo —Lou 4 (5) —Capric acid

(E) -5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) —Tertiary butyl carboxylate (254rag) is suspended in 2N hydrochloric acid (40ml), The mixture was stirred at 50 ° C for 22 hours. The precipitate is collected by filtration and washed sequentially with water and ethyl ether. (E) — 5 (4) — (3,4,5-trimethoxycinnamoylamino) imidazo-l-ru 4 (5) One-pot rubonic acid (209.2 mg). 'H-NMR (400MHz, DMS0-d _e ) δ ppm:

3.70 (s, 3H), 3.84 (s, 6H), 7.04 (s, 2H), 7.12 (d, J-15.6Hz, 1H), 7.45- 7.65 (m, 2H), 9.90 (s, 1H), 12.0 -13.7 (br, 1H) Reference example 20

(E) -5- (3,4,5-trimethystostyryl) imidazo [4,5-d] [1,3] oxazine- 7-one

(E) — 5 (4) — (3,4,5—trimethoxycinnamoylamino) imidazole-4 (5) A solution of rubonic acid (100 mg) in pyridine (5 ml) in acetic acid (81.5 1) Was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1) to give (E) -5- (3,4,5-trimethoxystyryl) imidazo [ [4,5-d] [1,3] oxazine-17-one (75 mg) was obtained.

'H-NMR (400MHz, DMS0-d «) 5 ppm:

3.70 (s, 3H), 3.84 (s, 6H), 7.04 (d, J = 16.1Hz, 1H), 7.16 (s, 2H), 7.70 (d, J = 16.1Hz, 1H), 8.22 (brs, 1H ), 12.7-14.6 (br, 1H)

(E) 1 N— (2-hydroxyethyl) 1 5 (4) — (3,4,5—trimethoxycinnamamoylamino) imidazole-4 (5) —carboxamide (compound 41)

(E) -5- (3,4,5-trimethoxystyryl) imidazo [4,5-d] To a solution of [1,3] oxazin-7-one (50 mg) in pyridine (1 ml) was added 2-aminoethanol (73.31), and the mixture was stirred at room temperature for 20 hours. After the solvent was distilled off under reduced pressure, the residue was washed successively with water and getyl ether, and (E) -N- (2-hydroxyethyl) -1.5 (4) — (3,4,5- Limethoxycinnamoylamino) imidazole-4 (5) One carboxamide (40.3ing) was obtained.

^ -NMR (400MHz, DMSO-d.) <5 ppm:

3.25-3.4 (in, 2H), 3.45-3.6 (m, 2H), 3.70 (s, 3H), 3.85 (s, 6H), 4.77 (t, J = 5.3Hz, 1H), 7.10 (s, 2H) , 7.22 (d, J = 15.5Hz, 1H), 7.37 (s, 1H), 7.57 (d, J = 15.5Hz, 1H), 7.80-7.95 (m, 1H), 10.32 (brs, 1H), 12.5- 12.8 (br, 1H) Example 2 0

(E) — N— (2-dimethylaminoethyl) 1 5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) 1-carboxamide (compound 42)

(E) -5- (3,4,5-Trimethoxystyryl) imidazo [4,5-d] [1,3] oxazine-17-one (23.7 mg) in pyridine (5 ml) — Dimethylethylenediamine (63.2 U) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was washed with dimethyl ether. (E) -N- (2-dimethylaminoethyl) -1.5 (4)-(3,4,5-trimethoxycinnamylamino) ) Imidazolone 4 (5) -carboxamide (18.9 mg) was obtained.

¹ H—NMR (400 MHz, DMSO-d _β ) δ ppm:

2.17 (s, 6H), 2.39 (t, J = 6.7Hz, 2H), 3.2-3.45 (m, 2H), 3.70 (s, 3H), 3.85 (s, 6H), 7.10 (s, 2H), 7.23 (d, J = 15.5Hz, 1H), 7.36 (s, 1H), 7.58 (d, J = 15.5Hz, 1H), 7.75-7.9 (m, 1H), 10.31 (s, 1H), 12.67 (s, 1H) Example 2 1

(E) — N— (1 H—tetrazoyl 5-yl) — 5 (4) — (3, 4, 5-trimethoxycinnamoylamino) imidazo mono-lu 4 (5) — carboxamide ( Compound 4 3) (E) -5- (3,4,5-Trimethoxystyryl) imidazo [4,5-d] [1,3] oxazine-17-one (100 mg) in pyridine (2 ml) solution to 5-amino One H-tetrazole (130 mg) was added, and the mixture was stirred at 100 ° C for 17 hours. The precipitate is collected by filtration, washed successively with water, getyl ether and methanol, and then washed with (E) -N- (1H-tetrazol-15-yl) -15 (4)-(3,4,5) —Trimethoxycinnamoylamino) imidazole— 4 (5) —Carboxamide (60.4 mg)

• H-NMR (400MHz, D S0-d _e ) δ ppm:

3.71 (s, 3H), 3.84 (s, 6H), 7.06 (s, 2H), 7.14 (d, J = 15.3Hz, 1H), 7.5- 7.75 (m, 2H), 10.27 (s, 1H), 11.2 -12.2 (br, 1H), 12.99 (s, 1H), 15.6-16.6 (br, 1H)

(E) -N- (1 H-tetrazoyl 5-yl) — 5 (4) I- (3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) I-carboxamido potassium salt (Compound 44)

(E) — N— (1 H-tetrazoyl 5-yl) 1 5 (4) 1 (3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) 1 carboxamide (36.4 mg )) In methanol (5 ml) was added with potassium carbonate (6.1 mg) and stirred until the reaction mixture became homogeneous. After evaporating the solvent under reduced pressure, the residue was washed with methanol, and (E) -N- (1H-tetrazole-5-yl) 15 (4) — (3,4,5-trimethoxycinnaline) (Moylamino) imidazole-4 (5) Monocarboxamidocalidium salt (39.8 mg) was obtained.

1 H-NMR (400 MHz, DMS0-d _e ) δ ppm:

3.69 (s, 3H), 3.84 (s, 6H), 6.5-7.4 (m, 4H), 7.57 (d, J = 15.7Hz, 1H), 11.7-12.9 (br, 1H)

(E) -N- (2-dimethylaminoethyl) 1 5 (4)-(3, 4, 5—trime Toxicinnamoylamino) imidazole-4 (5) monocarboxamidoni hydrochloride (compound 45)

(E) — N— (2-dimethylaminoethyl) -1.5 (4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxamide (30mg) in methanol (5ml ) A saturated methanol solution of hydrogen chloride was added to the solution until the solution became acidic, and the solvent was distilled off under reduced pressure. The residue was washed with getyl ether, and (E) -N- (2-dimethylaminoethyl) -1.5 (4)-(3,4,5-trimethoxycinnamamoylamino) imidazo-l-ru 4 (5) —Carboxamidoni hydrochloride (28.2 mg) was obtained.

Ή-NMR (400MHz, DMS0-d «) δ ppm:

2.81 (s, 3H), 2.82 (s, 3H), 3.2-3.35 (m, 2H), 3.55-3.7 On, 2H), 3.71 (s, 3H), 3.85 (s, 6H), 7.08 (s, 2H) ), 7.22 (d, J = 15.5Hz, 1H), 7.61 (d, J = 15.5Hz, 1H), 7.75-8.0 (br, 1H), 8.5-8.7 (br, 1H), 9.9-10.2 (br, 1H), 10.4- 10.55 (br, 1H) Reference example 2 1

3- (3,4-dimethoxyphenyl)-2-methyl-1-propenoic acid

To 3,4-dimethoxybenzaldehyde (3.3 g) and methylmalonic acid (4.7 g) were added piperidine (3.9 ml) and pyridine (25 ml), and the mixture was stirred at 100 ° C for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was poured into a hydrochloric acid solution under ice cooling. The precipitated crystals were collected and washed with water to give 3- (3,4-dimethoxyphenyl) -1-methyl-2-monopropenoic acid (3.05 g).

Ή-NMR (400MHz, CDC1, δ ppm:

2.19 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H), 6.92 (d, J-8.4Hz, 1H), 7.00 (d, J = l.9Hz, 1H), 7.09 (dd, J = 8.4, 1.9Hz, 1H), 7.78 (s, 1H) Reference Example 2 2

The following compounds were synthesized in the same manner as in Reference Example 21.

2-Methyl-1- (3,4,5-trimethoxyphenyl) -2-propenoic acid Ή-NMR (400MHz, CDCls) δ ppm:

2.18 (d, J = l.4Hz, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 6.68 (s, 2H), 7.76 (brs, 1H) Reference example 2 3

3- (3,4-Dimethoxyphenyl) 1-2-methyl-2-propenoic acid chloride

To 3- (3,4-dimethoxyphenyl) -2-methyl-2-propenoic acid (2.0 g) was added toluene (15 ml thionyl chloride (1.3 ml) and N, N-dimethylformamide (1 drop). 8 (Stirred with TC for 70 minutes. The reaction mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated again under reduced pressure to give 3- (3,4 dimethyloxyphenyl) -2-methyl-2-propenoic acid chloride (2.21 g) was obtained.

_{Ή-NMR (400MHz, CDC1 3} ) δ ppm:

2.24 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 6.94 (d, J = 8.4Hz, 1H), 7.01 (d, J = 2.0Hz, 1H), 7.14 (dd, J = 8.4, 2.0Hz, 1H), 8.00 (s, 1H)

(E) — 5 (4) — [3- (3,4-dimethoxyphenyl) -l-methyl-l-l-propynylamino] imidazole- 4 (5) —carboxamide (compound 4 6)

3- (3,4-dimethoxyphenyl) 1-2-methyl-2-propenoic acid chloride

(500 mg) and 5 (4) -aminoimidazole-4 (5) -carboxamide hydrochloride (340 mg), pyridine (5 ml) was added, and the mixture was stirred for 2 hours with 125). The reaction mixture was concentrated under reduced pressure, water was added, the precipitate was collected by filtration, washed with water and getyl ether, and washed with (E) -5 (4)-[3- (3,4-dimethoxyphenyl). 1) -Methyl-2-propinoylamino] imidazole-4 (5) -carboxamide (610 mg) was obtained.

^ -NMR (270MHz, DMS0-d e) δ ppm:

2.19 (d, J = 1.0 Hz, 3H), 3.796 (s, 3H), 3.800 (s, 3H), 6.9-7.6 (m, 7H), 10.8 (s, 1H), 12.7 (brs, 1H) Example 2 5

(E) 15 (4)-[3- (3,4-dimethoxyphenyl) 1-2-methyl-12-propynylamino] imidazole-4 (5) —carboxamide hydrochloride (compound 47)

(E) — 5 (4) 1 [3- (3,4-Dimethoxyphenyl) 1-2-methyl-2 1-propynylamino] imidazole-4 (5) Carboxamide (580 mg) in methanol (5 ml) And 2N hydrochloric acid (3.1 ml) were added, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and (E) —5 (4) — [3- (3,4-dimethyloxyfuran) —2-methyl-2-propinoylamino] imidazole-4 (5) -carbo Oxamide hydrochloride (626 mg) was obtained.

Ή-NMR (270MHz, DMSO-de) δ ppm:

2.20 (s, 3H), 3.796 (s, 3H), 3.804 (s, 3H), 6.9-7.2 (m, 3H), 7.53 (s, 1H), 7.7-8.0 (br, 2H), 8.31 (s, 1H), 10.78 (s, 1H) Reference example 2 4

3- (3,4-dimethoxyphenyl) 1-2-butenoic acid

Dry tetrahydrofuran (10 ml) was added to 60% sodium hydride (500 mg) in an argon stream. Under ice-cooling, a solution of ethyl ethylphosphonoacetate (2.6 g) in tetrahydrofuran (5 ml) and a solution of 3,4-dimethoxyacetophenone (2.0 g) in tetrahydrofuran (5 ml) were sequentially added. The reaction mixture was ice-cooled, added with aqueous ammonium chloride solution and concentrated under reduced pressure Water was added to the residue, extracted with methylene chloride, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanol (30 ml) and 2N aqueous sodium hydroxide solution (16.5 ml) were added, and the mixture was stirred at room temperature for 18 hours.The reaction solution was concentrated under reduced pressure, water was added to the residue, and the aqueous layer was washed with diethyl ether. The mixture was acidified with concentrated hydrochloric acid, and extracted with ethyl acetate.The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated to give 3- (3-, 4-dimethoxyphenyl) -1-butenoic acid. (1.1) was obtained.

1H-NMR (400MHz, CDCls) δ ppm: 2.59 (d, J = l.1Hz, 3H), 3.92 (s, 3H), 3.93 (s, 3H), 6.15 (d, J = l.1Hz, 1H), 6.88 (d, J = 8.4Hz, 1H ), 7.03 (d, J = 2.2Hz, 1H), 7.13 (dd, J = 8, 4, 2.2Hz, 1H) Reference Example 2 5

The following compounds were synthesized in the same manner as in Reference Example 24.

3— (3, 4, 5—trimethoxyphenyl) — 2-butenoic acid

Ή-NMR (400MHz, CDCls) δ ppm:

2.59 (d, J = l.2Hz, 3H), 3.88 (s, 3H), 3.90 (s, 6H), 6.14 (d, J = l.2Hz, 1H), 6.70 (s, 2H) Reference example 2 6

3- (3,4-dimethyloxyphenyl) -1-butenoic acid chloride

3- (3,4-Dimethoxyphenyl) To 2-butenoic acid (1.07 g) was added toluene (10 ml), thionyl chloride (0.7 ml) and N, N-dimethylformamide (one drop). The mixture was stirred at 800C for 100 minutes. After the reaction solution was concentrated under reduced pressure, toluene was added, and the mixture was concentrated again under reduced pressure to obtain 3- (3,4-dimethoxyphenyl) -12-butenoic acid chloride (1.27 g).

• H-NMR (400MHz, CDC1 3) δ ppm:

2.5-2.65 (m, 3H), 3.85-4.05 (m, 6H), 6.1-6.5 (m, 1H), 6.8-7.35 (m, 3H) Reference example 2 7

The following compounds were synthesized in the same manner as in Reference Example 26.

3-(3,4,5-trimethoxypropyl) — 2-butenoic acid chloride

Ή-NMR (400MHz, CDCls) <5 ppm:

2.54 (d, J = l.2Hz, 2H), 2.59 (d, J = l.3Hz, 1H), 3.7-4.0 (m, 9H), 6.15 (d, J = l.3Hz, 0.34H), 6.42 (d, J = l.2Hz, 0.66H), 6.70 (s, 0.66H), 6.71 (s, 1.34H)

2-Methyl-3- (3,4,5-trimethoxytriphenyl) -1-2-propenoic acid Re

Ή-NMR (400MHz, CDC1 _S ) 5 ppm:

2.23 (d, J = 1.3 Hz, 3H), 3.90 (s, 6H), 3.91 (s, 3H), 6.70 (s, 2H), 7.98 (brs, 1H)

(E) -5 (4)-[3- (3,4-Dimethoxyphenyl) -1-2-butenoylamino] imidazo-l-ru 4 (5) Carboxamide (compound 48)

3- (3,4-dimethoxyphenyl) -1-butenoic acid chloride (500 mg) and 5 (4) -aminoimidazole-4 (5) -carboxamide hydrochloride (340 mg) in pyridine (5 ml) Was added and the mixture was stirred at 125 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the precipitate was collected by filtration, washed with water and getyl ether, and then washed with (E) -5 (4) -1- [3- (3,4-dimethoxyphenyl). 1) 2-Butenoylamino] midazo 4 (5) One carboxamide (670 mg) was obtained.

1 H— N M R (400 MHz, DMSO-de) δ ppm:

2.58 (s, 3H), 3.79 (s, 3H), 3.83 (s, 3H), 6.66 (s, 1H), 7.00 (d, J = 8.0Hz, 1H), 7.1-7.5 (m, 5H), 10.21 (s, 1H) Example 2 7

The following compounds were synthesized in the same manner as in Example 26.

(E) — 5 (4) 1 [3- (3,4,5-trimethylethoxyphenyl) 1 -2-butenoylamino] imidazo 1-lu 4 (5) —carboxamide (compound 49)

1 H— N M R (400 MHz, DMSO-de) <5 ppm:

2.59 (s, 3H), 3.69 (s, 3H), 3.85 (s, 6H), 6.64 (s, 1H), 6.91 (s, 2H), 7.1 -7.35 (m, 2H), 7.39 (s, 1H) , 10.20 (s, 1H), 12.3-13.0 (br, 1H)

(E) — 5 (4)-[2-Methyl-3- (3,4,5-trimethoxyphenyl) 1-2-propynylamino] imidazole-4 (5) —carboxamide (compound 50) ¹ H-N MR (400MHz, DMSO-de) δ ppm:

2.21 (d, J = l.1Hz, 3H), 3.70 (s, 3H), 3.81 (s, 6H), 6.79 (s, 2H), 7.30 (brs, 1H), 7.36 (s, 1H), 7.44 ( brs, 1H), 7.49 (s, 1H), 10.83 (s, 1H), 12.71 (s, 1H)

(E) -5 (4) ― [3- (3,4 dimethyloxyphenyl) 1-2-butenoylamino] imidazole-4 (5) —Carboxamide hydrochloride (Compound 51)

(E) -5 (4) One [3- (3,4-dimethoxyphenyl) -12-butenoylamino] imidazole-4 (5) One carboxamide (600 mg) in methanol (10 ml) and 2N hydrochloric acid ( 3.1 ml) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and (E) —5 (4)-[3- (3,4-dimethoxyphenyl) —2-butenoylamino] imidazole—4 (5) —carboxamide hydrochloride ( 520 mg).

1H—NMR (400MHz, DMS0-d _e ) δ ppm:

2.59 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 6.74 (s, 1H), 7.01 (d, J = 8, 8Hz, 1H), 7.1-8.0 (m, 4H), 8.53 (s, 1H), 10.62 (s, 1H) Example 2 9

The following compounds were synthesized in the same manner as in Example 28.

(E) — 5 (4) — [3— (3,4,5-trimethoxyphenyl) 1-2-butenoylamino] imidazole-4 (5) monocarboxamide hydrochloride (compound 52) ^ -NMR ( 400MHz, DHS0-d «) δ ppm:

2.59 (s, 3H), 3.70 (s, 3H), 3.85 (s, 6H), 6.71 (s, 1H), 6.92 (s, 2H), 7.6 -7.8 (br, 2H), 8.25 (brs, 1H) , 10.52 (s, 1H)

(E) — 5 (4) — [2-Methyl-3- (3,4,5-trimethoxyphenyl) — 2-propynylamino] imidazole— 4 (5) —Carboxamide hydrochloride (compound 53 ) Ή-NMR (400MHz, DMSO-de) δ ppm:

2.21 (d, J = 1.3 Hz, 3H), 3.70 (s, 3H), 3.81 (s, 6H), 6.79 (s, 2H), 7.51 (s, 1H), 7.66 (brs, 2H), 7.95- 8.15 (br, 1H), 10.77 (s, 1H) Example 30

Vascular smooth muscle cell proliferation inhibition test

Spontaneously hypertensive rat (SHR) Thoracic aortic vascular smooth muscle cells were isolated by the EpXPant method, added to a 96-well plate at 500 cells each, and added at 37 ° C, 95% air, The cells were cultured in a DMEM culture medium containing 10% fetal bovine serum under conditions of 5% carbon dioxide for 3 days. Three days later, the culture solution of each phenyl was replaced with a DMEM culture solution containing a drug, tritiated thymidine was added, and the cells were cultured for 24 hours. After the culture, the radioactivity incorporated in the DNA fraction was measured and used as an index of the cell proliferation activity. The growth inhibitory activity of the compound was represented by a concentration (IC ₅₀ ) showing ₅₀ % inhibition with respect to the untreated group. The results are shown in the table below.

Compound 5 0% inhibition activity concentration (IC _5., ^ M)

4 2 4

1 4 4 6

1 6 7 6

1 8 7 4

1 9 7 0

2 1 9 1

2 6 1 9

3 3 2 8

3 4 3 4

3 5 2 0

3 7 9

3 8 2 4 Compound ₅₀ % inhibitory activity concentration (IC ₅₀ , μΜ)

4 1 2 0

4 5 6 0

5 1 2 6

5 2 1 8

5 3 2 4

Example 3 1

Acute toxicity test

Male 7-week-old ICR mice consisted of 5 mice per group, fasted for 4 hours and suspended in 0.5% sodium carboxymethylcellulose (Ε) -5 (4) 1-2 (3,4,5- Trimethoxycinnamoylamino) imidazole-4 (5) monocarboxamide hydrochloride was administered orally at 100, 300, 100, 200 mg Okg / kg to examine the presence or absence of death. No deaths were observed in the group administered with 200 mg OkgZkg, and no abnormalities occurred. Prescription example 1

Fine grain

Active drug 100 mg

Lactose 600 mg

Corn starch 2 6 5 mg

Hydroxypropyl cellulose 30 mg

Calcium stearate 5 mg

(Total 100 mg)

Prescription example 2

Capsule

Active drug 100 mg

Microcrystalline cellulose 50 mg Carmellose calcium 13 mg Hydroxypropyl cellulose 4 mg Calcium stearate 3 mg

(Total 17 Omg)

Claims

The scope of the claims

1. General formula

(A or B in the formula is one of the general formulas

(In the formula, R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group, a cycloalkyl alkoxy group, an aralkyloxy group, a lower acetyl group, a mono- or di-lower alkyl-substituted amino group. Or R ² and R ³ may be the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkylalkoxy group or an aralkyloxy group; And R ⁵ may be the same or different and each is a hydrogen atom or a lower alkyl group), and the other is a group represented by the general formula

— (CH ₂ ) _n -R

— (CH ₂ ) _m -R ^a

(Wherein R * is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and m is an integer of 2 to 6). R ⁷ is a hydrogen atom or a lower alkyl group which may have a carboxyl group or a lower alkoxycarbyl group as a substituent.) And a pharmacologically acceptable derivative thereof. Salt.

2.

(A 'and Β

(In the formula, R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkoxy group, a cycloalkyl alkoxy group, an aralkyloxy group, a lower acetyl group, a mono- or di-lower alkyl-substituted amino group. Or a lower alkoxycarbonyl group, wherein R ² and R ³ may be the same or different

Each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a consequent opening alkylalkoxy group or Ararukiruokishi group, R <and R ⁵ may be different, even same as, respectively a hydrogen atom or a lower alkyl group R ⁸ is a hydrogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group or a substituent represented by the general formula:

— (CH ₂ ) -R ^a

(Wherein R * is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and m is an integer of 2 to 6). R ⁷ is a hydrogen atom or a carboxyl group or a lower alkoxy group as a substituent. A lower alkyl group which may have a cyclocarbyl group], and a pharmacologically acceptable salt thereof.

3. General formula

[A ^e and B ^e in the formula are either general formulas.

(In the formula, R "is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group or a hydroxy lower alkoxy group; R ² and R ³ may be the same or different; R ⁴ and R ⁵ may be the same or different and each is a hydrogen atom or a lower alkyl group), and the other is a group represented by the general formula

— (CH ₂ ) _n — R

— (CH ₂ ) _m -R *

(Wherein R ′ is a hydroxyl group, an amino group, a mono- or di-lower-alkyl-substituted amino group, and m is an integer of 2 to 6). R ⁷ is a hydrogen atom or a carboxyl group or a lower alkoxy group as a substituent. A lower alkyl group which may have a cyclocarbyl group], and a pharmacologically acceptable salt thereof.

4. General formula

[A ^d and B ^d in the formula, either one of the general formula -

(In the formula, R ¹ * is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group or a hydroxy lower alkoxy group, and R and R ³ * may be the same or different, and are each a hydrogen atom or a lower alkoxy group. And the other is a substituent represented by the general formula

— (CH ₂ ) -OH

(Wherein n is an integer of 2 to 6), and R ^e is a hydrogen atom, a lower alkyl group, a carboxyl group, or a lower alkoxycarbonyl group, which may have a group represented by the formula: As a group or a substituent, a general formula

— (CH ₂ ) _m — R ^a

(Wherein R * is a hydroxyl group, an amino group, a mono- or di-lower alkyl-substituted amino group, and m is an integer of 2 to 6). 4. The imidazole derivative according to claim 3, which is represented by the formula: and a pharmacologically acceptable salt thereof.

5. General formula

(A * and ^Be in the formula are either

Wherein R ¹² is a lower alkyl group and R ¹² is a lower alkyl group, and the pharmacologically acceptable imidazole derivatives thereof according to claim 2 or 4. Salt.

6. —General formula

CH ₂ CH ₃

(Either of Α 'and Β' in the formula

And a pharmacologically acceptable salt thereof. 6. The imidazole derivative according to claim 5, which is a group represented by the formula:

7. A pharmaceutical comprising the imigazole derivative of claim 1 or a pharmacologically acceptable salt thereof.

8. A medicament comprising the imidazole derivative according to claim 2 or a pharmacologically acceptable salt thereof.

9. A medicament comprising the imidazole derivative according to claim 3 or a pharmacologically acceptable salt thereof.

10. A medicament comprising the imidazole derivative according to claim 4 or a physiologically acceptable salt thereof.

11. A pharmaceutical comprising the imidazole derivative according to claim 5 or a pharmacologically acceptable salt thereof.

12. A medicament comprising the imidazole derivative according to claim 6 or a pharmacologically acceptable salt thereof.

13. A vascular wall thickening inhibitor comprising the imidazole derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.

14. A vascular wall thickening inhibitor comprising the imidazole derivative according to claim 2 or a pharmacologically acceptable salt thereof as an active ingredient.

15. A vascular wall thickening inhibitor comprising the imidazole derivative according to claim 3 or a pharmacologically acceptable salt thereof as an active ingredient.

16. A vascular wall thickening inhibitor comprising the imidazole derivative according to claim 4 or a pharmacologically acceptable salt thereof as an active ingredient.

17. The imidazole derivative according to claim 5 or a pharmacologically acceptable thereof. An agent for suppressing vascular wall thickening containing a salt as an active ingredient.

18. A vascular wall thickening inhibitor comprising the imidazole derivative according to claim 6 or a pharmacologically acceptable salt thereof as an active ingredient.

19. A method for preventing or treating a disease caused by hyperproliferation of intimal cells by administering the imidazole derivative according to claim 1 or a pharmacologically acceptable salt thereof.

20. Use of the imidazole derivative or the pharmacologically acceptable salt thereof according to claim 1 for the manufacture of a preparation for preventing or treating a disease caused by intimal cell hyperproliferation.

21. Use of the imidazole derivative according to claim 1 or a pharmacologically acceptable salt thereof as a vascular wall thickening inhibitor.