JP2000095690A - Neovascularization inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a neovascularization inhibitor which inhibits the vascularization by including a specific imidazol carboxilic acid derivative (salt) as an active ingredient. SOLUTION: The objective inhibitor is obtained by including an imidazol carboxylic acid derivative (salt) of formula I [either A or B is formula II (R1 is H, OH or the like; R2 and R3 are each H, a lower alkyl or the like) and the other is a mono- or dihydroxy lower alkoxycarbonyl or the like; R4 is a lower alkyl; R5 is H or a lower alkyl; Both R4 and R5 are mutually combined to form an alicyclic amino group] as an active ingredient. The compound of formula I is obtained by the method or the like, for example, reacting a cinnamic acid derivative (a reactive functional derivative, e.g. an active ester or the like) of formula III (R1a is H, a halogen or the like) with an aminoimidazol derivative of formula IV (either P or Q is an amino group and the other is a mono- or dihydroxy lower alkoxycarbonyl having a protective group or the like) in an inactive solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical composition useful as an angiogenesis inhibitor.

More specifically, the present invention relates to a compound represented by the general formula useful for prevention and treatment of diseases related to angiogenesis:

[0003]

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In the formula, one of A and B is a general formula

[0005]

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(Wherein 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 acyl group, a mono- or di-lower alkyl-substituted amino group or a lower alkoxycarbonyl group, and R ² and R ³ are Which may be the same or different and is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkyl lower alkoxy group or an aralkyloxy group), and the other is a mono or dihydroxy lower alkoxy carbonyl Group,
Mono or di lower alkoxy lower alkoxycarbonyl group, hydroxyaryl lower alkoxycarbonyl group,
A lower alkoxyaryl lower alkoxycarbonyl group or a cycloalkyloxycarbonyl group optionally having an oxygen atom in the ring, R ⁴ is a lower alkyl group, R ⁵ is a hydrogen atom or a lower alkyl group, R
^And R ⁵ may combine with each other to form an alicyclic amino group], or a pharmacologically acceptable salt thereof as an active ingredient. And an angiogenesis inhibitor.

[0007] Examples of the diseases relating to angiogenesis include various diseases caused by angiogenesis as one of the causes thereof, for example, rheumatoid arthritis, psoriasis, edema sclerosis, diabetic retinopathy, premature infants Retinopathy, sickle cell retinopathy, retinal vein occlusion, angiogenesis associated with corneal transplantation or cataract surgery, neovascular glaucoma, iris rubeosis, senile discoid macular degeneration, various tumors, atherosclerosis Abnormal capillaries of the epithelium, neovascularization in the cornea due to long-term wearing of contact lenses, and the like.

[0008]

2. Description of the Related Art In general, angiogenesis refers to digestion and destruction of the basement membrane of blood vessels by proteases, migration and proliferation of vascular endothelial cells, adhesion to extracellular matrix, and formation of a lumen by differentiation of vascular endothelial cells. It is a phenomenon that involves the reconstruction of blood vessels. Angiogenesis occurs physiologically during luteal formation and placental formation, and under pathological conditions, it appears in the above-mentioned diseases. For example, in retinopathy, the retinal tissue intervening between the basement membrane and the vitreous surrounding the existing retinal blood vessels is first destroyed, and then the vascular endothelial cells constituting the existing blood vessels are destroyed from the gaps between the retinal tissue destruction sites. After the vascular endothelial cells proliferate so as to fill the gaps between the migrated and migrated vascular endothelial cells, the vascular endothelial cells migrated into the retinal vitreous reconstitute the blood vessels, thereby promoting angiogenesis.

Angiogenesis is related to various diseases, for example, it is deeply involved in the onset or progression of the above diseases. Therefore, for the prevention or treatment of these diseases,
Intensive research has been actively pursued to search for substances that inhibit angiogenesis. For example, examples of angiogenesis inhibitors include microbial metabolite fumagillin analogs having an inhibitory action on vascular endothelial cells, tetracycline antibiotics having an action of inhibiting collagenase activity, and binding of heparin-binding angiogenic factors to receptors. Microorganism-derived D with inhibitory action
-Drugs such as gluco-galactan sulfate are known. However, it has not been known at all that the imidazole carboxylic acid derivative represented by the general formula (I) has a growth inhibitory effect on vascular endothelial cells and is useful as an angiogenesis inhibitor.

[0010] At present, there is no clinically satisfactory drug as an angiogenesis inhibitor, so that there is no sufficient treatment for the above-mentioned diseases relating to angiogenesis. Especially in diabetic retinopathy, regression of new blood vessels is not observed unless surgical treatment is performed, and visual impairment due to bleeding from the new blood vessels is a problem, so it is excellent for angiogenesis There is a great need for the development of effective drugs.

[0011]

An object of the present invention is to provide a novel angiogenesis inhibitor which suppresses angiogenesis.

[0012]

Means for Solving the Problems The present inventors have conducted intensive studies to find a compound having an inhibitory effect on angiogenesis, and as a result, certain imidazole carboxylic acid derivatives represented by the aforementioned general formula (I) have been obtained. The present inventors have found that the proliferation of human capillary endothelial cells is remarkably suppressed, and have found that they are extremely useful as an angiogenesis inhibitor, leading to the present invention.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION

[0014]

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

[0016]

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(Wherein 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 acyl group, a mono- or di-lower alkyl-substituted amino group or a lower alkoxycarbonyl group, and R ² and R ³ are Which may be the same or different and is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkyl lower alkoxy group or an aralkyloxy group), and the other is a mono or dihydroxy lower alkoxy carbonyl Group,
Mono or di lower alkoxy lower alkoxycarbonyl group, hydroxyaryl lower alkoxycarbonyl group,
A lower alkoxyaryl lower alkoxycarbonyl group or a cycloalkyloxycarbonyl group optionally having an oxygen atom in the ring, R ⁴ is a lower alkyl group, R ⁵ is a hydrogen atom or a lower alkyl group, R
^And R ⁵ may combine with each other to form an alicyclic amino group], or a pharmacologically acceptable salt thereof as an active ingredient. And an angiogenesis inhibitor.

In the compound represented by formula (I), the lower alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
c-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group,
A straight or branched alkyl group having 1 to 6 carbon atoms, such as a hexyl group, refers to a lower alkoxy group. A lower alkoxy group is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, or a sec-butoxy group. Group, te
a linear or branched alkoxy group having 1 to 6 carbon atoms, such as an rt-butoxy group, a pentyloxy group, an isopentyloxy group, a neopentyloxy group, a tert-pentyloxy group, and a hexyloxy group; The group refers to a 3- to 7-membered cyclic alkyl group (however, when the ring has an oxygen atom, refers to a 4- to 7-membered cyclic alkyl group), and the aryl group refers to a phenyl group, a naphthyl group, or the like. An aralkyloxy group refers to an aromatic hydrocarbon group, and an aralkyloxy group refers to the lower alkoxy group substituted with the aryl group.
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and a lower acyl group means a linear or branched alkyl group having 2 to 7 carbon atoms such as an acetyl group, a propionyl group and a butyryl group. Means an alkylcarbonyl group. 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 alicyclic amino group refers to a 5- to 7-membered alicyclic amino group such as a 1-pyrrolidinyl group and a piperidino group. In a mono- or di-hydroxy lower alkoxycarbonyl group, a mono- or di-lower alkoxy lower alkoxycarbonyl group and a cycloalkyloxycarbonyl group having an oxygen atom in the ring, two or more oxygen atoms are bonded to the same carbon atom. Except in cases.

The imidazole carboxylic acid derivative represented by the general formula (I) can be obtained by using i
In the test for confirming the angiogenesis inhibitory effect of n vitro,
It showed a remarkable activity of inhibiting the proliferation of human capillary endothelial cells.

As described above, the imidazolecarboxylic acid derivative represented by the general formula (I) has an excellent endothelial cell growth inhibitory effect in human capillaries.
It is a very useful compound as an agent for preventing and treating diseases relating to angiogenesis. Therefore, it is possible to produce a pharmaceutical composition useful as an angiogenesis inhibitor by using an imidazole carboxylic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. it can.

The compound represented by the general formula (I) can be produced, for example, as follows. That is, the general formula

[0022]

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(Wherein R ^{1a represents a} hydrogen atom, a halogen atom,
Hydroxyl group having a protecting group, lower alkyl group, lower alkoxy group, hydroxy lower alkoxy group having a protecting group, cycloalkyl alkoxy group, aralkyloxy group, lower acyl group, mono-lower alkyl-substituted amino group having a protecting group, di-lower alkyl A substituted amino group or a lower alkoxycarbonyl group, and R ² and R ³ have the same meanings as described above), or a reactive functional derivative such as an acid halide or an active ester thereof;

[0024]

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(In the formula, one of P and Q is an amino group and the other is a mono- or di-hydroxy lower alkoxycarbonyl group having a protecting group, a mono- or di-lower alkoxy lower alkoxycarbonyl group, a hydroxy group having a protecting group. An aryl lower alkoxycarbonyl group, a lower alkoxyaryl lower alkoxycarbonyl group or a cycloalkyloxycarbonyl group optionally having an oxygen atom in the ring, wherein R ⁴ and R ⁵ have the same meaning as described above) With an aminoimidazole derivative in an inert solvent, in the presence or absence of a base, in the presence or absence of a dehydrating agent or a condensing agent, and if necessary, removing a protecting group according to a conventional method. Can be manufactured.

The compound represented by the above general formula (I) of the present invention has the following general formula:

[0027]

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[A ⁰ or B ⁰ in the formula is one of the general formulas

[0029]

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(Wherein R ^1a , R ² and R ³ have the same meanings as described above), and the other is a mono- or di-hydroxy lower alkoxycarbonyl group having a protecting group, or a mono- or di-lower alkoxy group. R ⁶ is a lower alkoxycarbonyl group, a hydroxyaryl lower alkoxycarbonyl group having a protecting group, a lower alkoxyaryl lower alkoxycarbonyl group or a cycloalkyloxycarbonyl group optionally having an oxygen atom in a ring;
Is a methyl group or an ethyl group] and an imidazole dicarboxylic acid derivative represented by the general formula

[0031]

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(Wherein R ⁴ and R ⁵ in the formula have the same meanings as described above), and if necessary, the protective group can be removed by a conventional method.

The compounds represented by the general formulas (II) and (V) used as raw materials in the above-mentioned production method are purchased as commercial products, or are produced by known methods described in literatures or methods similar thereto. be able to.

The compound represented by the general formula (III) used as a starting material in the above-mentioned production method can be produced, for example, by a known method described in a literature or a method similar thereto (for example, Tetrahedr)
on, Vol. 42, No. 10, pages 2625-2634 (1
986)), general formula

[0035]

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(Wherein R ⁶ , P and Q have the same meanings as described above), and can be produced by reacting the compound with the amine compound represented by the above general formula (V). .

The compound represented by the general formula (IV) used as a raw material in the production method may be, for example, a cinnamic acid derivative represented by the general formula (II) or an acid halide or an active ester thereof. The reactive functional derivative and the aminoimidazole derivative represented by the above general formula (VI) are converted into an inert solvent in the presence or absence of a base, in the presence or absence of a dehydrating agent or a condensing agent. It can be produced by appropriately reacting.

The imidazole carboxylic acid derivative represented by the general formula (I) can be converted into a pharmacologically acceptable salt 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-toluenesulfonic acid, propionic acid, citric acid Acid, succinic acid, tartaric acid, fumaric acid,
Examples thereof include acid addition salts with organic acids such as butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, and aspartic acid, and salts with inorganic bases such as sodium salts and potassium salts.

The compounds represented by formula (I) include hydrates and solvates with pharmaceutically acceptable solvents such as ethanol.

The compound represented by the general formula (I) includes 2
There are two geometrical isomers, and in the present invention, any of the cis-form (Z-form) compound and the trans-form (E-form) compound may be used. In the present invention, the trans form (E form) is preferred.

Among the compounds represented by the above general formula (I), compounds having an asymmetric carbon atom have two optical isomers of R configuration and S configuration. May be used, or a mixture of these optical isomers may be used.

When the pharmaceutical composition of the present invention is used for actual treatment, various dosage forms are used depending on the usage. Such dosage forms include, for example, powders, granules, fine granules,
Examples include dry syrups, tablets, capsules, ointments, injections, and eye drops.

[0043] These pharmaceutical compositions can be prepared with appropriate excipients, disintegrants,
Binders, lubricants, diluents, buffers, tonicity agents, preservatives,
It can be produced by appropriately mixing, diluting or dissolving with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents, and dispensing according to a conventional method.

The powder may be prepared, for example, by adding an appropriate excipient, lubricant and the like to the imidazolecarboxylic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, if necessary. Add well to make a powder.

Tablets may be prepared, for example, by adding an appropriate excipient, disintegrant, binder and the like to an imidazole carboxylic acid derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof. , A lubricant and the like, and tableted in a conventional manner to give tablets. Tablets can also be coated if necessary,
Film-coated tablets, sugar-coated tablets and the like can be prepared.

Capsules are prepared, for example, by the above-mentioned formula (I)
In an imidazole carboxylic acid derivative represented by or a pharmacologically acceptable salt thereof, if necessary, a suitable excipient, a lubricant, a solubilizing agent and the like are added and mixed well, and then mixed into an appropriate capsule. Fill into capsules. In addition, it may be filled after granules or fine particles are formed by a conventional method.

When used as an ointment, it may be used as an eye ointment.

When used as an injection, it may be directly injected into a diseased tissue such as the cornea or vitreous body or a tissue adjacent thereto with a thin injection needle, or may be used as an intraocular perfusion solution.

The present preparation may be administered as a sustained release preparation. For example, using a sustained release polymer as a carrier,
The imidazole carboxylic acid derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is incorporated into pellets or microcapsules of these sustained-release polymers, and the pellets or microcapsules should be treated. It can be surgically implanted in tissue. Examples of the sustained-release polymer include ethylene vinyl acetate, polyhydromethacrylate, polyacrylamide, polyvinylpyrrolidone, methylcellulose, polyethylene glycol, lactic acid polymer, lactic acid / glycolic acid copolymer, and the like. Certain lactic acid polymers, lactic acid / glycolic acid copolymers and the like can be mentioned.

When the pharmaceutical composition of the present invention is used for actual treatment, the dose of the active ingredient, an imidazole carboxylic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, is administered. Is the patient's weight, age, gender,
It is appropriately determined depending on the degree of the disease, but in the case of oral administration, it is generally in the range of 0.1 to 1000 mg per adult per day, and in the case of parenteral administration, it is generally 0.01 to 300 per adult per day.
It can be administered once or several times in the mg range.

The dose of the active ingredient, the imidazolecarboxylic acid derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, depends on the kind of the disease to be treated, the condition of the patient and the treatment. Depending on the difference in the effects, it can be increased or decreased as appropriate.

[0052]

EXAMPLES The contents of the present invention will be described in more detail with reference to the following Reference Examples and Examples, but the present invention is not limited to these contents.

Reference Example 1 (E) -3,4,5-Trimethoxycinnamic acid chloride 3,4,5-Trimethoxycinnamic acid (10.00 g) and thionyl chloride (6.1 ml) in toluene (100 m
l) Add N, N-dimethylformamide (0.1m
l) was added and the mixture was stirred at 80 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and hexane was added to the residue.
(E) -3,4,5-Trimethoxycinnamic acid chloride (10.30 g) was obtained.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 3.911 (s, 3H), 3.91
7 (s, 3H), 3.918 (s, 3H), 6.55
(D, J = 15.4 Hz, 1H), 6.80 (s, 2
H), 7.76 (d, J = 15.4 Hz, 1H)

REFERENCE EXAMPLE 2 A solution of ethyl 2-methoxypropionate (15.00 g) in tetrahydrofuran (10 ml) was added to a suspension of lithium aluminum hydride (7.05 g) in tetrahydrofuran (150 ml) under ice-cooling. And stirred at room temperature for 2 hours.
Water was gradually added under ice-cooling, then concentrated hydrochloric acid (40 ml) and diethyl ether were added, and the precipitate was filtered off. The filtrate was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3-methoxypropanol (4.04 g).

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.7-1.95 (m, 2H),
2.35-2.6 (br, 1H), 3.3-3.85
(M, 7H)

Reference Example 3 The following compound was produced in the same manner as in Reference Example 2. 3-ethoxypropanol

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.15-1.35 (m, 3H),
1.75-1.95 (m, 2H), 3.4-3.9
(M, 6H)

Reference Example 4 2-Ethoxyethyl cyanoacetate (8.20 g) in diethyl ether (50 m)
l) Phosphorus pentachloride (19.20 g) was added to the solution over 5 minutes under ice-cooling, and the mixture was heated under reflux for 30 minutes. After that, the reaction solution was concentrated under reduced pressure to obtain an oily substance. 2-ethoxyethanol (8.29 g) was dissolved in diethyl ether (50 ml), and N, N-dimethylaniline (11.6 m) was added thereto.
l) was added at room temperature. The oily substance obtained above was added to this solution under ice cooling, and the mixture was heated under reflux for 2 hours and subsequently stirred at room temperature for 3 days. After adding water to the reaction solution, the organic layer was separated,
The aqueous layer was extracted with diethyl ether. Combine the organic layers, 1
The extract was washed successively with normal hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2-ethoxyethyl cyanoacetate (11.60 g).

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.22 (t, J = 7.0 Hz, 3
H), 3.51 (s, 2h), 3.54 (q, J = 7.5.
0 Hz, 2H), 3.6-3.75 (m, 2H), 4.
3-4.4 (m, 2H)

Reference Example 5 The following compound was produced in the same manner as in Reference Example 4. 2-methoxyethyl cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 3.39 (s, 3H), 3.51
(S, 2H), 3.63 (t, J = 4.6 Hz, 2
H), 4.36 (t, J = 4.6 Hz, 2H)

1,3-diethoxy-2-propyl cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.19 (t, J = 7.0 Hz, 6
H), 3.4-3.65 (m, 10H), 5.15-
5.3 (m, 1H)

2- (4-methoxyphenyl) cyanoacetic acid
ethyl

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 2.93 (t, J = 7.0 Hz, 2
H), 3.41 (s, 2H), 3.79 (s, 3H),
4.37 (t, J = 7.0 Hz, 2H), 6.85
(D, J = 8.6 Hz, 2H), 7.14 (d, J =
8.6Hz, 2H)

Cyclopentyl cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.4-2.0 (m, 8H);
41 (s, 2H), 5.2-5.35 (m, 1H)

4-tetrahydropyranyl cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.65-2.05 (m, 4H),
3.47 (s, 2H), 3.5-3.65 (m, 2
H), 3.85-4.0 (m, 2H), 5.0-5.1.
5 (m, 1H)

3-ethoxypropyl cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.15 to 1.25 (m, 3H),
1.85-2.0 (m, 2H), 3.35-3.6
(M, 6H), 4.33 (t, J = 6.4 Hz, 2H)

3-tetrahydrofuranyl cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 2.0-2.35 (m, 2H),
3.49 (s, 2H), 3.8-4.05 (m, 4
H), 5.35-5.5 (m, 1H)

1-methoxy-2-propyl cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.29 (d, J = 6.5 Hz, 3
H), 3.37 (s, 3H), 3.4-3.55 (m,
4H), 5.1-5.25 (m, 1H)

3-methoxypropyl cyanoacetate

1H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.9-2.05 (m, 2H),
3.3-3.6 (m, 7H), 4.25-4.4 (m,
2H)

Cyclohexyl cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.2-1.95 (m, 10H),
3.43 (s, 2H), 4.8-4.95 (m, 1H)

Reference Example 6 2-Ethoxyethyl hydroxyiminocyanoacetate 2-Ethoxyethyl cyanoacetate (11.60 g) and sodium nitrite (6.12 g) were added to water (34 ml), and then acetic acid (34 ml) was added under ice-cooling. (5.83 ml) over 5 minutes and stirred at room temperature for 5.5 hours. Concentrated hydrochloric acid (9.74 ml) was added to the reaction mixture with stirring, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2-ethoxyethyl hydroxyiminocyanoacetate (13.70 g).

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.10 (t, J = 7.0 Hz, 3
H), 3.47 (q, J = 7.0 Hz, 2H), 3.5
5-3.75 (m, 2H), 4.3-4.45 (m, 2
H), 14.9-15.35 (br, 1H).

Reference Example 7 The following compounds were produced in the same manner as in Reference Example 6. 2-methoxyethyl hydroxyimino cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 3.47 (s, 3H), 3.7 −
3.85 (m, 2H), 4.45-4.6 (m, 2
H), 12.0-13.6 (br, 1H)

1,3-diethoxy-2-propyl hydroxyiminocyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.21 (t, J = 7.0 Hz, 6
H), 3.45-3.8 (m, 8H), 5.3-5.4.
5 (m, 1H)

2- (4-methoxyphenyl) ethyl hydroxyimino cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 2.95-3.05 (m, 2H),
3.80 (s, 3H), 4.51 (t, J = 7.0H)
z, 2H), 6.75-6.95 (m, 2H), 7.0.
5-7.25 (m, 2H)

4-tetrahydropyranyl hydroxyimino cyanoacetate

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.5-2.05 (m, 4H),
3.4-3.9 (m, 4H), 5.0-5.2 (m, 1
H), 14.7-15.4 (m, 1H)

Cyclopentyl hydroxyiminocyanoacetate

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.4-2.05 (m, 8H),
5.2-5.4 (m, 1H), 14.7-15.5 (b
r, 1H)

3-Ethoxypropyl hydroxyiminocyanoacetate

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.09 (t, J = 7.0 Hz, 3
H), 1.8-1.95 (m, 2H), 3.2-3.6.
(M, 4h), 4.32 (t, J = 6.4 Hz, 2
H), 14.5-15.6 (br, 1H).

3-tetrahydrofuranyl hydroxyimino cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 2.1-2.45 (m, 2H),
3.9-4.2 (m, 4H), 5.5-5.7 (m, 1
H), 7.1-7.25 (m, 1H)

1-methoxy-2-propyl hydroxyiminocyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.36 (d, J = 6.5 Hz, 3
H), 3.43 (s, 3H), 3.5-3.7 (m, 2
H), 5.25-5.45 (m, 1H)

3-methoxypropyl hydroxyiminocyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.95-2.1 (m, 2H),
3.39 (s, 3H), 3.5-3.65 (m, 2
H), 4.46 (t, J = 6.4 Hz, 2H), 11.
05-12.7 (br, 1H)

Cyclohexyl hydroxyimino cyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.1-2.05 (m, 10H),
4.9-5.15 (m, 1H), 10.5-11.6
(M, 1H)

REFERENCE EXAMPLE 8 2-Ethoxyethyl 2-aminocyanoacetate Mercuric chloride (492 mg) was dissolved in water (48 ml), and an aluminum foil (1.23 g) cut into 1 cm square was added thereto.
Was added. After stirring at room temperature for 1 minute, water was removed by decantation. In the same operation, insolubles were removed from water (48
ml × 2), methanol (48 ml × 2) and diethyl ether (48 ml × 2). Diethyl ether (37 ml) was added to the insoluble matter, the atmosphere in the reaction vessel was replaced with argon gas, and a solution of 2-ethoxyethyl hydroxyiminocyanoacetate (7.03 g) in diethyl ether (26 ml) was added under ice-cooling. (2.77 ml) was added dropwise, and the mixture was heated under reflux for 30 minutes. The reaction mixture was filtered through celite, and the insolubles were washed with diethyl ether. The filtrate and the washing were concentrated under reduced pressure to obtain 2-ethoxyethyl 2-aminocyanoacetate (3.78 g).

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.1-1.3 (m, 3H), 2.
12 (brs, 2H), 3.4-3.8 (m, 4H),
4.3-4.55 (m, 3H)

Reference Example 9 The following compound was produced in the same manner as in Reference Example 8. 2-methoxyethyl 2-aminocyanoacetate

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 3.0-3.4 (m, 5H),
57 (t, J = 4.4 Hz, 2H), 4.15-4.3
5 (m, 2H), 4.84 (s, 1H)

1,3-diethoxy-2-propyl 2-aminocyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.1-1.3 (m, 6H), 1.
7-2.4 (br, 2H), 3.35-3.7 (m, 8
H), 4.49 (s, 1H), 5.2-5.35 (m,
1H)

2- (4-methoxyphenyl) ethyl 2-aminocyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.5-2.0 (br, 2H),
2.9-3.05 (m, 2H), 3.79 (s, 3
H), 4.3-4.55 (m, 3H), 6.8-6.9.
(M, 2H), 7.1-7.2 (m, 2H)

Cyclopentyl 2-aminocyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.5-2.2 (m, 10H),
4.39 (brs, 1H), 5.25-5.5 (m, 1
H)

4-Tetrahydropyranyl 2-aminocyanoacetate

1H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.7-2.1 (m, 6H);
5-4.05 (m, 4H), 4.4-4.55 (m, 1
H), 5.0-5.2 (m, 1H)

3-ethoxypropyl 2-aminocyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.1-1.3 (m, 3H), 1.
8-1.9 (m, 2H), 2.3-2.95 (br, 2
H), 3.4-3.55 (m, 2H), 3.62 (t,
J = 5.7 Hz, 2H), 3.78 (t, J = 5.6H)
z, 2H), 4.3-4.5 (m, 1H)

3-aminocyanoacetic acid 3-tetrahydrofuranyl

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.8-2.35 (m, 4H),
3.7-4.1 (m, 4H), 4.35-4.6 (m, 4H)
1H), 5.4-5.55 (m, 1H)

2-aminocyanoacetic acid 1-methoxy-2-
Propyl

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.25-1.35 (m, 3H),
1.8-2.9 (br, 2h), 3.3-3.6 (m,
5H), 4.45 (s, 0.44H), 4.47 (s,
0.56H), 5.15-5.3 (m, 1H)

Cyclohexyl 2-aminocyanoacetate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.2-2.2 (m, 12H),
4.42 (s, 1H), 4.85-5.0 (m, 1H)

Reference Example 10 Ethyl 5 (4) -amino-4 (5)-(2-ethoxyethoxycarbonyl) imidazole-2-carboxylate 2-ethoxyethyl 2-aminocyanoacetate (3.78)
g) was dissolved in ethanol (44 ml), and ethyl ethoxyiminoacetate (6.38 g) was added thereto, followed by heating under reflux for 20 hours. After the reaction solution was concentrated under reduced pressure, diethyl ether was added to the obtained residue. The precipitated crystals are collected by filtration and washed with diethyl ether to give 5 (4).
Ethyl-amino-4 (5)-(2-ethoxyethoxycarbonyl) imidazole-2-carboxylate (2.44
g) was obtained.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.23 (t, J = 7.0 Hz, 3
H), 1.41 (t, J = 7.1 Hz, 3H), 3.5
7 (q, J = 7.0 Hz, 2H), 3.73 (t, J =
4.7 Hz, 2H), 4.3-4.5 (m, 4H),
4.7-5.2 (br, 2H), 9.9-11.0 (b
r, 1H)

Reference Example 11 The following compounds were produced in the same manner as in Reference Example 10. 5 (4) -amino-4 (5)-(1,3-diethoxy-
Ethyl 2-propoxycarbonyl) imidazole-2-carboxylate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.19 (t, J = 7.0 Hz, 6
H), 1.25-1.55 (m, 3H), 3.4-3.
6 (m, 4H), 3.67 (d, J = 5.0 Hz, 4
H), 4.2-4.55 (m, 2H), 5.02 (br
s, 1H), 5.2-6.3 (br, 2H), 10.0
-11.3 (br, 0.83H), 11.7-12.4
(Br, 0.17H)

5 (4) -amino-4 (5)-[2- (4
-Methoxyphenyl) ethoxycarbonyl] imidazole-2-carboxylate

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.29 (t, J = 7.1 Hz, 3
H), 2.8-3.05 (m, 2H), 3.72 (s,
3H), 4.15-4.45 (m, 4H), 5.61
(Brs, 0.24H), 5.89 (s, 1.76)
H), 6.7-6.95 (m, 2H), 7.1-7.3.
5 (m, 2H), 12.39 (brs, 1H)

5 (4) -Amino-4 (5)-(4-tetrahydropyranyloxycarbonyl) imidazole-2
-Ethyl carboxylate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.42 (t, J = 7.1 Hz, 3
H), 1.6-2.15 (m, 4H), 3.4-4.1.
(M, 4H), 4.3-4.6 (m, 2H), 4.7-
5.9 (m, 3H), 9.7-10.8 (br, 1H)

Ethyl 5 (4) -amino-4 (5)-(3-ethoxypropoxycarbonyl) imidazole-2-carboxylate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.18 (t, J = 7.0 Hz, 3
H), 1.34 (t, J = 7.1 Hz, 3H), 1.9.
5-2.1 (m, 2H), 3.47 (q, J = 7.0H
z, 2H), 3.54 (t, J = 6.0 Hz, 2H),
4.3-4.5 (m, 4H), 5.35-6.2 (b
r, 2H)

5 (4) -Amino-4 (5)-(3-tetrahydrofuranyloxycarbonyl) imidazole-2
-Ethyl carboxylate

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.31 (t, J = 7.1 Hz, 3
H), 1.9-2.3 (m, 2H), 3.65-3.9.
5 (m, 4H), 4.28 (q, J = 7.1 Hz, 2
H), 5.3-5.45 (m, 1H), 5.6-6.1.
(Br, 2H), 12.3-13.8 (br, 1H)

5 (4) -Amino-4 (5)-(1-methoxy-2-propoxycarbonyl) imidazole-2-
Ethyl carboxylate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.1-1.5 (m, 6H), 3.
36 (s, 3H), 3.4-3.6 (m, 2H), 4.
2-4.5 (m, 2H), 5.2-5.4 (m, 1
H), 5.6-6.6 (br, 2H)

Ethyl 5 (4) -amino-4 (5) -cyclopentyloxycarbonylimidazole-2-carboxylate

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.29 (t, J = 7.1 Hz, 3
H), 1.45-2.0 (m, 8H), 4.26 (q,
J = 7.1 Hz, 2H), 5.15-5.3 (m, 1
H), 5.86 (brs, 2H), 11.9-13.1.
(Br, 1H)

Ethyl 5 (4) -amino-4 (5)-(2-methoxyethoxycarbonyl) imidazole-2-carboxylate

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.30 (t, J = 7.1 Hz, 3
H), 3.29 (s, 3H), 3.60 (t, J = 4.
7 Hz, 2H), 4.15-4.4 (m, 4H), 5.
6-5.75 (br, 0.2H), 5.95 (s, 1.
8H), 12.42 (s, 0.9H), 13.20-1
3.40 (br, 0.1H)

Ethyl 5 (4) -amino-4 (5) -cyclohexyloxycarbonylimidazole-2-carboxylate

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.1-2.0 (m, 13H),
4.27 (q, J = 7.1 Hz, 2H), 4.7-4.
9 (m, 1H), 5.55-5.8 (br, 0.29
H), 5.89 (s, 1.71H), 12.40 (s,
0.86H), 13.1-13.4 (br, 0.14
H)

Reference Example 12 Ethyl 5 (4) -amino-4 (5)-(3-methoxypropoxycarbonyl) imidazole-2-carboxylate 3-methoxypropyl hydroxyiminocyanoacetate (2.85 g) was added to water (20 ml). Then, saturated aqueous sodium hydrogen carbonate (16 ml) and sodium hydrosulfite (6.73 g) were added, and the mixture was stirred at 35 ° C for 1 hour. An excessive amount of sodium chloride was added to the reaction solution, and the mixture was sequentially extracted with methylene chloride and ethyl acetate, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Ethanol (20 ml) and ethyl ethoxyiminoacetate (1.91 g) were added to the obtained residue, and the mixture was heated under reflux for 1 day and then stirred at room temperature for 19 hours. The precipitate was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by aminopropylated silica gel column chromatography (elution solvent: methylene chloride / methanol = 20/1) to give 5 (4)- Amino-4
(5) Ethyl- (3-methoxypropoxycarbonyl) imidazole-2-carboxylate (161 mg) was obtained.

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.30 (t, J = 7.1 Hz, 3
H), 1.8-2.0 (m, 2H), 3.25 (s, 3
H), 3.44 (t, J = 6.2 Hz, 2H), 4.2
1 (t, J = 6.5 Hz, 2H), 4.28 (q, J =
7.1 Hz, 2H), 5.8-6.1 (br, 2H),
12.15-12.6 (br, 1H)

Reference Example 13 2-ethoxyethyl 5 (4) -amino-2-propylcarbamoylimidazole-4 (5) -carboxylate 5 (4) -amino-4 (5)-(2-ethoxyethoxycarbonyl) imidazole Ethyl-2-carboxylate (5
00 mg) was dissolved in ethanol (5 ml), and sodium cyanide (9 mg) and propylamine (3.
The mixture was stirred in a sealed tube at 80 ° C. for 15 hours. After the solvent was distilled off under reduced pressure, the obtained residue was purified by aminopropylated silica gel column chromatography (elution solvent: dichloromethane / methanol = 30/1) to give 5 (4) -amino-2-propylcarbamoylimidazole. 2-ethoxyethyl-4 (5) -carboxylate (506 mg) was obtained.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.97 (t, J = 7.4 Hz, 3
H), 1.22 (t, J = 7.0 Hz, 3H), 1.5
-1.7 (m, 2H), 3.25-3.45 (m, 2
H), 3.56 (q, J = 7.0 Hz, 2H), 3.6
5-3.8 (m, 2H), 4.35-4.5 (m, 2
H), 4.75-5.35 (br, 2H), 7.29.
(Brs, 1H)

Reference Example 14 The following compounds were produced in the same manner as in Reference Example 13. 5 (4) -amino-2-propylcarbamoylimidazole-4 (5) -carboxylic acid 1,3-diethoxy-2-
Propyl

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.97 (t, J = 7.4 Hz, 3
H), 1.18 (t, J = 7.0 Hz, 6H), 1.5
-1.7 (m, 2H), 3.3-3.6 (m, 6H),
3.67 (d, J = 5.1 Hz, 4H), 4.85 −
5.2 (br, 2H), 5.29 (quintet, J
= 5.1 Hz, 1H), 7.25-7.4 (m, 1H)

5- (4) -amino-2-propylcarbamoylimidazole-4 (5) -carboxylate 2- (4-methoxyphenyl) ethyl

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.97 (t, J = 7.4 Hz, 3
H), 1.5-1.75 (m, 2H), 2.9-3.1.
(M, 2H), 3.3-3.45 (m, 2H), 3.7
9 (s, 3H), 4.4-4.6 (m, 2H), 4.6
5-5.15 (br, 2H), 6.75-7.0 (m,
2H), 7.1-7.4 (m, 3H)

5-methoxyethyl 5 (4) -amino-2-propylcarbamoylimidazole-4 (5) -carboxylate

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 0.84 (t, J = 7.4 Hz, 3
H), 1.4-1.6 (m, 2H), 3.05-3.2.
(M, 2H), 3.28 (s, 3H), 3.58 (t,
J = 4.7 Hz, 2H), 4.2-4.35 (m, 2
H), 5.78 (brs, 2H), 8.2-8.4.
(M, 1H), 12.05-12.3 (br, 1H)

5- (4-) amino-2-propylcarbamoylimidazole-4 (5) -carboxylic acid 4-tetrahydropyranyl

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.98 (t, J = 7.4 Hz, 3
H), 1.5-2.1 (m, 6H), 3.3-3.45.
(M, 2H), 3.9-4.1 (m, 2H), 4.7-
5.3 (m, 3H), 7.1-7.25 (m, 1H)

5- (4-) amino-2-propylcarbamoylimidazole-4 (5) -ethoxypropyl carboxylate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.97 (t, J = 7.4 Hz, 3
H), 1.19 (t, J = 7.0 Hz, 3H), 1.5
-1.7 (m, 2H), 1.9-2.1 (m, 2H),
3.3-3.4 (m, 2H), 3.49 (q, J = 7.
0 Hz, 2H), 3.55 (t, J = 6.0 Hz, 2
H), 4.40 (t, J = 6.4 Hz, 2H), 4.6.
−5.7 (br, 2H), 7.2-7.5 (br, 1
H)

5 (4) -Amino-2-ethylcarbamoylimidazole-4 (5) -methoxypropyl carboxylate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.23 (t, J = 7.3 Hz, 3
H), 1.9-2.15 (m, 2H), 3.33 (s,
3H), 3.35-3.7 (m, 4H), 4.39
(T, J = 6.4 Hz, 2H), 5.0-5.7 (b
r, 2H), 7.4-7.75 (br, 1H)

5- (4-) amino-2-ethylcarbamoylimidazole-4 (5) -carboxylic acid 3-tetrahydrofuranyl

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.07 (t, J = 7.1 Hz, 3
H), 1.9-2.3 (m, 2H), 3.1-3.3.
(M, 2H), 3.65-3.9 (m, 4H), 5.3
−5.4 (m, 1H), 5.65−5.9 (br, 2
H), 8.3-8.45 (m, 1H), 11.9-1
2.6 (br, 1H)

5 (4) -Amino-2-ethylcarbamoylimidazole-4 (5) -carboxylic acid 1-methoxy-
2-propyl

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.24 (t, J = 7.3 Hz, 3
H), 1.25-1.45 (m, 3H), 3.25-
3.7 (m, 7H), 4.65-4.95 (br, 1
H), 5.15-5.5 (m, 2H), 7.0-7.2.
(Br, 0.5H), 7.35-7.6 (br, 0.5
H), 9.4-12.9 (br, 1H)

Cyclopentyl 5 (4) -amino-2-propylcarbamoylimidazole-4 (5) -carboxylate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.97 (t, J = 7.4 Hz, 3
H), 1.5-2.1 (m, 10H), 3.3-3.5.
(M, 2H), 4.6-4.9 (br, 2H), 5.3
-5.5 (m, 1H), 7.0-7.2 (m, 1H)

Cyclohexyl 5 (4) -amino-2-methylcarbamoylimidazole-4 (5) -carboxylate

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.1-2.0 (m, 10H),
2.71 (d, J = 4.5 Hz, 3H), 4.7-4.
9 (m, 1H), 5.4-5.6 (br, 0.4H),
5.71 (s, 1.6H), 8.1-8.35 (m, 1
H), 12.15 (brs, 0.8H), 12.6-1
3.1 (br, 0.2H)

Cyclopentyl 5 (4) -amino-2-methylcarbamoylimidazole-4 (5) -carboxylate

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.5-2.1 (m, 8H), 2.
9-3.05 (m, 3H), 4.6-4.9 (br,
1.4H), 5.2-5.5 (m, 1.6H), 7.0
−7.2 (br, 0.7H), 7.3 to 7.5 (br,
0.3H), 9.95-10.3 (br, 0.7H),
11.8-12.0 (br, 0.3H)

5 (4) -Amino-2-ethylcarbamoylimidazole-4 (5) -carboxylate 1,3-diethoxy-2-propyl

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 0.9-1.2 (m, 9H);
1-3.65 (m, 10H), 5.1-5.25 (m,
1H), 5.55-5.95 (br, 2H), 8.2-
8.45 (m, 1H), 11.7-12.55 (br,
1H)

Example 1 (E) -2-propylcarbamoyl-5 (4)-(3,
4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxylate 2-ethoxyethyl (compound 1) 5 (4) -amino-2-propylcarbamoylimidazole-4 (5) -carboxylate 2-ethoxy Ethyl (49
5 mg) was dissolved in pyridine (10 ml).
4,5-trimethoxycinnamic acid chloride (668 mg)
Was added and stirred at 110 ° C. for 2 hours. After evaporating the solvent under reduced pressure, the obtained residue was purified by aminopropylated silica gel column chromatography (eluent: dichloromethane / methanol = 30/1) to obtain (E) -2-propylcarbamoyl-5 (4). )-(3,4,5-Trimethoxycinnamoylamino) imidazole-4 (5) -carboxylate 2-ethoxyethyl (291 mg) was obtained.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.98 (t, J = 7.4 Hz, 3
H), 1.24 (t, J = 7.0 Hz, 3H), 1.5
-1.75 (m, 2H), 3.3-3.45 (m, 2
H), 3.61 (q, J = 7.0 Hz, 2H), 3.7
5-4.0 (m, 11H), 4.45-4.65 (m,
2H), 6.49 (d, J = 15.5 Hz, 1H),
6.80 (s, 2H), 7.1-7.25 (m, 1
H), 7.74 (d, J = 15.5 Hz, 1H), 9.
66 (s, 1H), 11.75-12.25 (br, 1
H)

Example 2 The following compounds were produced in the same manner as in Example 1. (E) -2-Ethylcarbamoyl-5 (4)-(3,
4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxylate 1-methoxy-2-propyl (compound 2)

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.24 (t, J = 7.3 Hz, 3
H), 1.44 (d, J = 6.5 Hz, 3H), 3.3
5-3.75 (m, 7H), 3.91 (s, 3H),
3.92 (s, 6H), 5.3-5.45 (m, 1
H), 6.48 (d, J = 15.5 Hz, 1H), 6.
80 (s, 2H), 7.1-7.25 (m, 1H),
7.73 (d, J = 15.5 Hz, 1H), 9.76
(S, 1H), 11.4-12.25 (br, 1H)

(E) -2-Ethylcarbamoyl-5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxylic acid 3-tetrahydrofuranyl (compound 3)

¹ H-NMR (400 MHz, DMSO-
d ₆ ) δ ppm: 1.10 (t, J = 7.2 Hz, 3
H), 1.9-2.35 (m, 2H), 3.2-3.4.
(M, 2H), 3.6-3.95 (m, 13H), 5.
3-5.5 (br, 1H), 6.9-7.25 (m, 3
H), 7.45-7.7 (m, 1H), 8.55-8.
65 (br, 0.3H), 8.70 (brs, 0.7
H), 9.75-9.95 (br, 0.3H), 10.
22 (brs, 0.7H), 12.89 (brs, 0.
7H), 13.75-14.0 (br, 0.3H)

(E) -2-Ethylcarbamoyl-5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxylate 3-methoxypropyl (compound 4)

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.25 (t, J = 7.3 Hz, 3
H), 2.0-2.2 (m, 2H), 3.38 (s, 3
H), 3.4-3.65 (m, 4H), 3.91 (s,
3H), 3.92 (s, 6H), 4.50 (t, J =
6.3 Hz, 2H), 6.54 (d, J = 15.5H)
z, 1H), 6.81 (s, 2H), 7.1-7.2.
(M, 1H), 7.74 (d, J = 15.5 Hz, 1
H), 9.80 (s, 1H), 12.03 (brs, 1
H)

(E) -2-Propylcarbamoyl-5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxylate 2-methoxyethyl (compound 5)

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.98 (t, J = 7.4 Hz, 3
H), 1.55-1.7 (m, 2H), 3.3-3.4.
5 (m, 2H), 3.47 (s, 3H), 3.7-3.
85 (m, 2H), 3.90 (s, 3H), 3.92
(S, 6H), 4.5-4.65 (m, 2H), 6.4
8 (d, J = 15.5 Hz, 1H), 6.81 (s, 2
H), 7.1-7.25 (m, 1H), 7.73 (d,
J = 15.5 Hz, 1H), 9.68 (s, 1H), 1
2.00 (brs, 1H)

(E) -2-propylcarbamoyl-5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxylate 3-ethoxypropyl (compound 6)

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.98 (t, J = 7.4 Hz, 3
H), 1.19 (t, J = 7.0 Hz, 3H), 1.5
5-1.75 (m, 2H), 2.11 (quinte
t, J = 6.2 Hz, 2H), 3.3-3.45 (m,
2H), 3.52 (q, J = 7.0 Hz, 2H), 3.
61 (t, J = 6.0 Hz, 2H), 3.91 (s, 3
H), 3.93 (s, 6H), 4.51 (t, J = 6.
5Hz, 2H), 6.52 (d, J = 15.5 Hz, 1
H), 6.81 (s, 2H), 7.1-7.2 (m, 1
H), 7.73 (d, J = 15.5 Hz, 1H), 9.
78 (s, 1H), 11.99 (brs, 1H)

(E) -2-Propylcarbamoyl-5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxylic acid 4-tetrahydropyranyl (compound 7)

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.99 (t, J = 7.4 Hz, 3
H), 1.6-2.2 (m, 6H), 3.3-3.7.
(M, 4H), 3.91 (s, 3H), 3.92 (s,
6H), 4.0-4.15 (m, 2H), 5.1-5.
3 (m, 1H), 6.47 (d, J = 15.5 Hz, 1
H), 6.80 (s, 2H), 7.1-7.2 (m, 1
H), 7.73 (d, J = 15.5 Hz, 1H), 9.
74 (brs, 1H), 11.96 (brs, 1H)

(E) -2-Propylcarbamoyl-5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -cyclopentyl carboxylate (compound 8)

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.99 (t, J = 7.4 Hz, 3
H), 1.5-2.2 (m, 10H), 3.3-3.5.
(M, 2H), 3.90 (s, 3H), 3.92 (s,
6H), 5.35-5.5 (m, 1H), 6.48.
(D, J = 15.5 Hz, 1H), 6.80 (s, 2
H), 7.1-7.2 (m, 1H), 7.72 (d, J
= 15.5 Hz, 1H), 9.79 (s, 1H), 1
1.93 (s, 1H)

(E) -2-Propylcarbamoyl-5
(4)-(3,4,5-Trimethoxycinnamoylamino) imidazole-4 (5) -carboxylate 1,3-diethoxy-2-propyl (compound 9)

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.98 (t, J = 7.4 Hz, 3
H), 1.21 (t, J = 7.0 Hz, 6H), 1.5
5-1.75 (m, 2H), 3.3-3.85 (m, 1
0H), 3.90 (s, 3H), 3.92 (s, 6
H), 5.3-5.5 (m, 1H), 6.47 (d, J
= 15.5 Hz, 1H), 6.80 (s, 2H), 7.
1-7.25 (m, 1H), 7.74 (d, J = 15.
5Hz, 1H), 9.70 (s, 1H), 11.7-1
2.3 (br, 1H)

(E) -2-propylcarbamoyl-5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -carboxylate 2- (4-methoxyphenyl) ethyl (compound 10)

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 0.99 (t, J = 7.4 Hz, 3
H), 1.5-1.75 (m, 2H), 3.07 (t,
J = 7.5 Hz, 2H), 3.3-3.5 (m, 2
H), 3.75 (s, 3H), 3.91 (s, 3H),
3.93 (s, 6H), 4.57 (t, J = 7.5H)
z, 2H), 6.40 (d, J = 15.5 Hz, 1
H), 6.75-6.9 (m, 4H), 7.1-7.2.
5 (m, 3H), 7.72 (d, J = 15.5 Hz, 1
H), 9.45-9.65 (br, 1H), 11.7-
12.25 (br, 1H)

(E) -2-Methylcarbamoyl-5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -cyclohexyl carboxylate (Compound 11)

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.1-1.7 (m, 6H), 1.
8-2.15 (m, 4H), 2.99 (d, J = 5.1)
Hz, 3H), 3.90 (s, 3H), 3.92 (s,
6H), 4.95-5.1 (m, 1H), 6.48.
(D, J = 15.5 Hz, 1H), 6.79 (s, 2
H), 7.05-7.2 (m, 1H), 7.72 (d,
J = 15.5 Hz, 1H), 9.80 (s, 1H), 1
1.94 (brs, 1H)

(E) -2-Methylcarbamoyl-5
(4)-(3,4,5-trimethoxycinnamoylamino) imidazole-4 (5) -cyclopentyl carboxylate (Compound 12)

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.55-2.15 (m, 8H),
2.99 (d, J = 5.1 Hz, 3H), 3.90
(S, 3H), 3.92 (s, 6H), 5.35-5.
5 (m, 1H), 6.49 (d, J = 15.5 Hz, 1
H), 6.80 (s, 2H), 7.1-7.25 (m,
1H), 7.72 (d, J = 15.5 Hz, 1H),
9.78 (s, 1H), 11.9-12.05 (br,
1H)

(E) -2-Ethylcarbamoyl-5
(4)-(3,4,5-Trimethoxycinnamoylamino) imidazole-4 (5) -carboxylate 1,3-diethoxy-2-propyl (compound 13)

¹ H-NMR (400 MHz, CDC
l ₃ ) δ ppm: 1.1-1.4 (m, 9H), 3.
35-3.85 (m, 10H), 3.90 (s, 3
H), 3.92 (s, 6H), 5.3-5.5 (m, 1
H), 6.47 (d, J = 15.5 Hz, 1H), 6.
80 (s, 2H), 7.1-7.25 (m, 1H),
7.74 (d, J = 15.5 Hz, 1H), 9.70
(S, 1H), 11.8-12.15 (br, 1H)

Example 3 Inhibition of Human Capillary Endothelial Cell Proliferation Culture of Human Capillary Endothelial Cells Normal Human Skin Capillary Endothelial Cells (Cell System)
ms Corporation) in an endothelial cell culture medium (MVE medium, Cell Systems Corpo).
(Ration Co., Ltd.). During the logarithmic growth phase, the culture medium is removed and a phosphate buffered saline solution (PBS
(-)) Was gently added to wash the cells. Then the PB
Except for S (-), 0.1% EDTA containing 0.02%.
A 25% trypsin solution was appropriately added, and the state of the cells was observed with a phase contrast microscope. While the cells were becoming spherical, an equal volume of MVE medium was added to the trypsin solution to stop the action of trypsin. The cells were detached from the culture plate by pipetting with a narrow Pasteur pipette. The cell suspension was transferred to a Spitz tube, MVE medium was added, pipetting was vigorously performed about 20 times with a Pasteur pipette, and centrifuged at 100 to 110 G for 1 minute. The supernatant was discarded, a new MVE medium was added, and pipetting was performed with a Pasteur pipette to prepare a cell suspension. A part of the cell suspension was taken, and the number of viable cells was counted with a phase contrast microscope using a hemocytometer. The cell concentration was 2.5 × 10 ⁴ cells /
ml and used for experiments.

Preparation of Test Reagent The test compound was dissolved in dimethyl sulfoxide (DMSO) and adjusted to various concentrations.

Experimental Procedure 200 μl of the cell suspension was added to a collagen-coated 96-well plate (manufactured by Iwaki Glass), and cultured at 37 ° C. in a 5% carbon dioxide gas-95% gas phase. One day after the culture, the culture solution was removed, and the cells were washed with PBS (-). After that, 200 μl of a new culture solution (MVE medium containing 10% FBS) and 1 μl of dimethyl sulfoxide (DMSO) were added to the control group, and 200 μl of a new culture solution (serum-free MVE medium) and 1 μl of dimethyl sulfoxide (DMSO) were added to the drug administration group.
Medium) and 1 μl of dimethyl sulfoxide (DMSO) solution of the test compound at various concentrations were added, and the cells were further cultured for 1 day. One day after the drug treatment, bromodeoxyuridine (BrdU, final concentration 10 μM) was added to the culture solution, and the cells were further cultured for 4 hours. After completion of the culture, the amount of BrdU incorporated into the cells was measured using an ELISA kit (Amersham).
And the cultivation ability was determined.

Judgment of effect The amount of BrdU incorporation in the control group was 100%, and that in the unstimulated group was 0%.
%, The 50% inhibitory concentration (I
_C50 ) was determined.

[0202] Results showing the various test compound _{an IC 50} value in Table 1 below.

[0202]

[Table 1]

Example 4 Acute Toxicity Test Male ICR mice were grouped into groups of 4 and fasted for 4 hours.
(E) -2-Ethylcarbamoyl-5 (4)-(3,
3,5-Trimethoxycinnamoylamino) imidazole-4 (5) -carboxylate 3-tetrahydrofuranyl was administered orally at a dose of 300 or 1000 mg / kg. As a result, no death cases were observed in all the administration groups 24 hours after administration.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 A61K 31/00 643D // C07D 233/90 C07D 233/90 C (72) Inventor Yoshiyoshi Nonaka Isao 1164-9 Toyoshina, Toyoshina-cho, Minamiazumi-gun, Nagano Pref. -1 Fragrance Smelody A101 (72) Inventor Nobuhiko Fushimi 89-6 Okada Shimookada, Matsumoto-shi, Nagano F-term (reference) 4C086 AA01 AA02 BC38 MA01 MA04 NA14 ZA36

Claims (1)

[Claims] 1. A compound of the general formula Wherein one of A and B in the formula is a general formula: (Wherein 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 cycloalkylalkoxy group, an aralkyloxy group, a lower acyl group, a mono- or di-lower alkyl-substituted amino group or A lower alkoxycarbonyl group, R ²
And R ³ may be the same or different, and include a hydrogen atom,
A halogen atom, a lower alkyl group, a lower alkoxy group, a cycloalkyl lower alkoxy group or an aralkyloxy group), and the other is a mono- or di-hydroxy lower alkoxycarbonyl group, a mono- or di-lower alkoxy lower alkoxycarbonyl group A hydroxyaryl lower alkoxycarbonyl group, a lower alkoxyaryl lower alkoxycarbonyl group or a cycloalkyloxycarbonyl group optionally having an oxygen atom in the ring, R ⁴ is a lower alkyl group, and R ⁵ is a hydrogen atom Or a lower alkyl group, or R ⁴ and R ⁵ may be combined with each other to form an alicyclic amino group] or a pharmacologically acceptable salt thereof. Characterized by containing as an active ingredient Newborn inhibitors.