JP2002193947A - Benzimidazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound used as an antagonist for VEGF receptor so as to treat disease concerned with vascularization induced by VEGF and to improve unhealthy condition induced by VEGF. SOLUTION: This compound is represented by formula (1) [wherein, R1 is hydrogen or a 1-6C alkyl, R2 is hydrogen atom or formula (2) (wherein, R4 is hydrogen or a 1-6C alkyl), and n is an integer of 0 to 2], and contains an allowable salt for medicine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a VEGF receptor antagonist which inhibits the binding of VEGF, a specific growth factor of vascular endothelial cells, to a receptor.

[0002]

2. Description of the Related Art VEGF (vascular endothelial growt)
h factor) is a growth factor with extremely high specificity for vascular endothelial cells, and VEGF and its receptor play a central role in physiological angiogenesis such as development and development and placental formation. VElt receptors include Flt-1 (fms-
like tyrosine kinase) and KDR (kinase insert do)
main containing receptor has been reported (Advanc
es in Cancer Research, Vol. 67, pp. 281-3.
16, p. 1995). VEGF and its receptor are not only physiological angiogenesis, but also diabetic retinopathy, rheumatoid arthritis, solid tumors (Advances in Cancer Research, 67, 281-316, 1995), Basedow Disease (hyperthyroidism) (J. Clin. Invest., No. 96)
Vol., Pp. 1295-1302, 1995), arteriosclerosis (Arterioscler. Thromb. Vasc. Biol., 19).
Vol. 131, pp. 139, 1999) also play a central role in pathological angiogenesis seen in such diseases, suggesting that they are deeply involved in the development of such diseases. ing. In addition, VEGF and its receptor are not only responsible for angiogenesis, but also for pathological diseases such as a decrease in tumor immune function due to suppression of maturation of dendritic cells (Nature Medicine, Vol. 2, pp. 1096-1103, 1996). It has been suggested that it is also involved in the symptoms. Therefore, substances that inhibit the binding of VEGF to its receptor are useful for treating various diseases in which pathological angiogenesis due to VEGF is involved, and for treating VGF.
It is thought that EGF is useful for ameliorating pathological symptoms.

[0003]

SUMMARY OF THE INVENTION The present invention is directed to the treatment of diseases involving angiogenesis induced by VEGF and to the treatment of VGF.
VE for ameliorating pathological symptoms induced by EGF
A GF receptor antagonist is provided.

[0004]

The compound of the present invention has the following formula (1)

[0005]

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[Wherein, R ¹ represents a hydrogen atom or 1 carbon atom
-6, wherein R ² is a hydrogen atom or the following formula (2)

[0007]

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(Wherein R ⁴ is a hydrogen atom or a group having 1 carbon atom)
-6 is an alkyl group. ), And n is an integer of 0 to 2. Or a pharmaceutically acceptable salt thereof.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the number of carbon atoms is 1-
The alkyl group of 6 means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, such as a methyl group,
Ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, cyclopentyl, cyclobutylmethyl, 1-ethylpropyl Group, hexyl group, isohexyl group, cyclohexyl group, cyclopentylmethyl group, 1-
An ethylbutyl group and the like can be mentioned.

In the present invention, the alkyl group having 14 to 20 carbon atoms means a linear or branched alkyl group having 14 to 20 carbon atoms, such as a tetradecyl group,
13-methyltetradecyl group, octadecyl group, 17-
Examples thereof include a methyloctadecyl group, an icosyl group, and an 18-methylnonadecyl group.

The pharmaceutically acceptable salts in the present invention include, for example, salts with mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, and the like. Examples thereof include salts with organic acids such as benzenesulfonic acid, salts with amines such as trimethylamine and methylamine, and salts with metal ions such as sodium ion, potassium ion and calcium ion.

In the formula (1), R ¹ is preferably a hydrogen atom, and R ² is preferably a carboxyphenyl group. R ³ is preferably an octadecyl group, and n is preferably 0 or 2.

The compound of the present invention can be produced by a method represented by the following reaction formula. In the formula, R ¹ , R ² and R ³ are as defined above, R is a hydrogen atom or a lower alkyl group, halo is a halogen atom and m is 1 or 2.

[0014]

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When R ² is not a hydrogen atom, the nitro compound of the formula (3) and R ² —NH ₂ are reacted in a suitable solvent at 0 ° C. to 120 ° C. in the presence of a base and in the presence or absence of a catalyst. Stir at temperature to obtain the compound of formula (4). As the base, triethylamine, diisopropylethylamine,
Organic bases such as pyridine and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, potassium hydride and the like are used. As the catalyst, a metal such as copper or a metal salt is used. As the solvent, a solvent inert to the reaction, such as N, N-dimethylformamide, is used.

Next, the compound of formula (5) is obtained by reducing the nitro group of the compound of formula (4) to an amino group. As the reduction method, ammonium chloride, reduction using a metal such as iron or tin and a metal salt in the presence of an acid such as hydrochloric acid or acetic acid, palladium-carbon, Raney nickel, catalytic reduction using a catalyst such as platinum oxide, palladium- Reduction with ammonium formate in the presence of a carbon catalyst. Examples of the solvent include solvents inert to the reaction, such as methanol, ethanol, and isopropyl alcohol.

Next, the compound of the formula (5) is condensed with the compound of the formula (6) wherein A is a single bond and R is a hydrogen atom to obtain a compound of the formula (7). As the condensing agent, 1- [3-
Reagents commonly used in the production of amides from amines and carboxylic acids, such as (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, are used. As the solvent, N, N-
A solvent inert to the reaction such as dimethylformamide is used. Alternatively, a carboxylic acid of the formula (6) wherein A is a single bond and R is a hydrogen atom is converted into an acid halide or a mixed acid anhydride by a generally used method, The compound of formula (7) can also be obtained by reacting. As the base, pyridine, triethylamine or the like is used. Examples of the solvent include solvents inert to the reaction, such as methylene chloride. Further, a carboxylic acid ester of the formula (6) and a compound of the formula (5), wherein A is a carbonyl group, m is 1 and R is not a hydrogen atom, are prepared at 100 ° C. to 200 ° C. The compound of the present invention of formula (8) is obtained by stirring at a temperature between
Examples of the solvent include solvents inert to the reaction, such as xylene.

Next, the compound of the formula (7) is reacted in the presence of a base to obtain a compound of the present invention of the formula (9). As the base, sodium hydroxide, potassium hydroxide, calcium hydroxide or the like is used, and as the solvent, a mixed solvent of water, methanol, ethanol or tetrahydrofuran is exemplified. The compound of the formula (8) in which R ¹ is an alkyl group and R ² is an alkoxycarbonylphenyl group is hydrolyzed by a usual method for hydrolyzing an ester group, R ¹ is a hydrogen atom, and R ² is Formula (8) which is a carboxyphenyl group
Of the present invention.

When R ² is a hydrogen atom, the compound of the formula (10) is condensed with the carboxylic acid of the formula (11) to obtain a compound of the formula (12). As a condensing agent, such as 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole are generally used in producing an amide from an amine and a carboxylic acid. Use reagents. As the solvent, a solvent inert to the reaction, such as N, N-dimethylformamide, is used.
Alternatively, after converting the carboxylic acid of the formula (11) into an acid halide or a mixed acid anhydride by a generally used method, the compound of the formula (1)
The compound of formula (12) can also be obtained by reacting the compound of formula (0) with a base in the presence of a base. As the base, pyridine, triethylamine or the like is used. Examples of the solvent include solvents inert to the reaction, such as methylene chloride. Next, the compound of the formula (12) is stirred at a temperature between 100 ° C. and 200 ° C. in the presence or absence of a suitable solvent to obtain the compound of the present invention of the formula (13). Examples of the solvent include solvents inert to the reaction, such as xylene. R ¹
The compound of the formula (13) in which is an alkyl group can be hydrolyzed by a usual method of hydrolyzing an ester group to lead to the compound of the present invention of the formula (13) in which R ¹ is a hydrogen atom.

The VEGF receptor antagonist of the present invention comprises a compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprises any pharmaceutically acceptable carrier, diluent or Contains pharmaceutical preparations containing excipients. The compounds according to the invention can be administered orally or parenterally. The dosage form is a tablet, capsule, granule, powder, powder, troche, ointment, cream, emulsion, suspension, suppository, injection, etc. (The method prescribed in the 12th revised Japanese Pharmacopoeia). These dosage forms can be appropriately selected depending on the condition, age and purpose of treatment of the patient. In the preparation of various dosage forms, conventional excipients (eg, crystalline cellulose, starch, lactose, mannitol, etc.), binders (eg, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), lubricants (eg, stearin Magnesium acid, talc, etc.),
Disintegrators (eg, calcium carboxymethyl cellulose) and the like can be used. The dose of the compound of the present invention is 1 to 2000 per day when treating an adult.
mg once or several times a day. This dosage can be appropriately increased or decreased depending on the age, weight and condition of the patient.

[0021]

EXAMPLES [Example 1] (1) Anhydrous potassium carbonate was added to a solution of 1.03 g of ethyl 3-aminobenzoate and 50 ml of methyl 4-fluoro-3-nitrobenzoate in 50 ml of N, N-dimethylformamide.
854 mg was added and the mixture was stirred at 80 ° C for 1 hour and at 120 ° C for 11 hours. Water was added to the reaction solution and extracted with ethyl acetate.
The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 4: 1) to give 4- [N- (3-
Ethoxycarbonylphenyl)] methyl -3-aminobenzoate (oil) 894 mg was obtained.

(2) 894 mg of the compound obtained in the above (1)
Was suspended in methanol (25 ml), and 10% palladium-carbon (89 mg) was added thereto.
Stirred for hours. The reaction solution was filtered to remove the catalyst, and the filtrate was evaporated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 1: 1) to give methyl 3-amino-4- [N- (3-ethoxycarbonylphenyl)] aminobenzoate (melting point: 128 to 100%). 237 mg).

(3) 230 m of the compound obtained in the above (2)
g, a mixture of 461 mg of 3- [4- (octadecyloxy) phenyl] propionic acid, 134 mg of 1-hydroxybenzotriazole hydrate and 280 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride To 150 ml of N, N-dimethylformamide.
Stirred at 0 ° C. for 3.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluted with hexane: ethyl acetate: chloroform = 4: 1: 3), and recrystallized from ethyl acetate to obtain the following compound. Methyl 4- [N- (3-ethoxycarbonylphenyl)] amino-3- {3- [4- (octadecyloxy) phenyl] propionylamino} benzoate (melting point: 13
(3.5-135 DEG C.) 345 mg are obtained.

[0024]

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(4) Compound 156 obtained in the above (3)
An aqueous sodium hydroxide solution (87 mg of sodium hydroxide, 3 ml of water) was added to a mixture in which mg was suspended in 3 ml of ethanol, and the mixture was stirred at 50 ° C. for 30 minutes and at 70 ° C. for 30 minutes. The reaction solution was acidified by adding 5% hydrochloric acid, and the precipitated solid was filtered and washed with water. The obtained solid was dried under reduced pressure to obtain 135 mg of the following compound 1 (melting point: 194 to 199 ° C).

[0026]

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Example 2 (1) 3.85 g of 3-aminobenzoic acid, 4-fluoro-
5.21 g of 3-nitrobenzoic acid, 156 mg of copper powder and 7.77 g of anhydrous potassium carbonate were added to 200 ml of N, N-dimethylformamide.
The mixture was suspended at 100 ° C. for 7 hours and at 140 ° C. for 5 hours.
Stirred for hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Crude product obtained by evaporating the solvent under reduced pressure
10 g was directly used for the next reaction. 7.98 g of methyl iodide was added to a mixture of 10 g of the crude product and 7.77 g of anhydrous potassium carbonate suspended in 200 ml of N, N-dimethylformamide, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 3: 1) to obtain 4- [N- (3-methoxycarbonylphenyl)].
Methyl amino-3-nitrobenzoate (melting point: 145.5)
１４147 ° C.) to obtain 827 mg.

(2) The compound obtained in the above (1) was reacted in the same manner as in Example 1 (2) to give 3-amino-
Methyl 4- [N- (3-methoxycarbonylphenyl)] aminobenzoate (melting point: 142-146 ° C) was obtained.

(3) 547 mg of the compound obtained in the above (2)
And 3- [4- (octadecyloxy) phenyl] -3-
Ethyl oxopropionate 838 mg mixture at 140 ° C
For 25.5 hours. The obtained crude product was purified by silica gel column chromatography [eluted with hexane: chloroform: ethyl acetate = 5: 3: 1], and recrystallized from ethyl acetate to obtain the following compound 2 (melting point: 85-8).
8 ° C.) 300 mg were obtained.

[0030]

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Example 3 1.8 g of 3- [4- (octadecyloxy) phenyl] propionic acid chloride was added to a solution of 745 mg of methyl 3,4-diaminobenzoate and 907 mg of triethylamine in 50 ml of methylene chloride. Was dissolved in 20 ml of methylene chloride under ice-cooling.
The mixture was stirred at room temperature for 10.5 hours, at 50 ° C for 4 hours and at 60 ° C for 3 hours. The reaction mixture was added with 5% hydrochloric acid, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (chloroform: ethyl acetate =
(Eluted at 10: 1) to give 4-amino-3- {3
-[4- (octadecyloxy) phenyl] propionylamino dibenzoate methyl (melting point: 158 to 160.5)
C) 1.2 g.

At 140 ° C., 1.06 g of the compound obtained above
Stir for 6 hours. The crude product was purified by silica gel column chromatography (eluted with chloroform: ethyl acetate = 10: 1) to give the following compound 3 (melting point: 107-10)
(9.5 ° C.) 587 mg were obtained.

[0033]

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Example 4 A solution prepared by dissolving 776 mg of methyl 2,3-diaminobenzoate and 945 mg of triethylamine in 50 ml of methylene chloride was charged with 2.04 g of 3- [4- (octadecyloxy) phenyl] propionic acid chloride. Was added at room temperature to a solution of
19 hours at room temperature, 4 hours at 40 ° C. and reflux for 3 hours. The reaction mixture was added with 5% hydrochloric acid, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.3 g of a crude product.

1.3 g of the obtained crude product was added at 140 ° C. to 13 g
Stirred for hours. The crude product was purified by silica gel column chromatography (eluted with chloroform: ethyl acetate = 10: 1) to give the following compound 4 (melting point: 91-93 ° C.)
977 mg were obtained.

[0036]

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Example 5 To a mixture of 231 mg of compound 2 suspended in 3 ml of ethanol was added an aqueous solution of sodium hydroxide (141 mg of sodium hydroxide, 3 ml of water) to give a mixture.
Stirred at C for 2 hours. The reaction solution was acidified by adding 5% hydrochloric acid, and the precipitated solid was filtered and washed with water. The obtained solid was dried under reduced pressure to give Compound 5 (melting point: 197 to 201).
C) 200 mg.

[0038]

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Example 6 Compound 6 (melting point: 202-230 ° C.) and compound 7 (melting point: 168-200 ° C.) were obtained from compound 3 and compound 4 in the same manner as in Example 5.
180 ° C).

[0040]

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[0041]

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[Test Example] Reference (Cell Growth & Differen)
The following tests were performed according to the method described in Tiation, Vol. 7, pp. 213-221, 1996). NIH3T3 cells (7 × 10 ⁴ cells / well) in which KDR was forcibly expressed were seeded on a 24-well collagen-coated plate, and 10% calf serum and 200 μg / well.
Dulbecco's modified Eagle's containing ml Geneticin G418
The cells were cultured in a medium (DMEM) at 37 ° C. for 24 hours in a 5% carbon dioxide gas atmosphere. The cells were added to buffer A [10
mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesu
lfonic acid) and 0.1% BSA (bovine serum albumin)] at 4 ° C for 30 minutes. Then, the medium was added to buffer B (10 mM HEPES and 0.5% BS in DMEM).
A), and the test compounds prepared by dissolving each test compound in dimethyl sulfoxide, diluting to a predetermined concentration with buffer B, and [ ¹²⁵ I] -VEGF (final concentration: 25 pM) are added. Then, a binding reaction was performed at 4 ° C. for 90 minutes.
After the reaction was completed, the cells were washed three times with ice-cold buffer A. Subsequently, 0.5 ml of 0.5 M NaOH was added to each well, and the cells were thawed at room temperature for 30 minutes. The radioactivity of the cell lysate in each well was measured using a gamma counter, and [ ¹²⁵ I] -V
The total binding amount of EGF was calculated. Non-specific binding of [ ¹²⁵ I] -VEGF was measured by a competition assay in the presence of 10 nM unlabeled VEGF, and [ ¹²⁵ I] -V was determined.
The specific binding amount of [ ¹²⁵ I] -VEGF was calculated from the difference from the total binding amount of EGF. The binding inhibition rate of the test compound was calculated by the following equation.

[0043]

(Equation 1)

From this value, the 50% binding inhibitory concentration (IC ₅₀ ) of the test compound was calculated. Table 1 shows the results.

[0045]

[Table 1]

[0046]

Industrial Applicability The compound of the present invention has an activity of inhibiting the binding of a ligand to a VEGF receptor, and inhibits angiogenesis by inhibiting VEGF-dependent vascular endothelial cell proliferation, It is considered that the reduced immune function is normalized by releasing the suppression of maturation of dendritic cells. Accordingly, the compounds of the present invention may be used for diabetic retinopathy, rheumatoid arthritis, solid tumors, Graves' disease,
It is expected to be a therapeutic agent for diseases involving angiogenesis induced by VEGF, such as arteriosclerosis. Further, the compound of the present invention is expected to have an effect of improving pathological symptoms induced by the action of VEGF such as a decrease in the immune function of cancer patients.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 27/02 A61P 27/02 29/00 101 29/00 101 35/00 35/00 43/00 111 43 / 00 111 C07D 235/18 C07D 235/18 (72) Inventor Tetsuo Takayama 3--24-1, Takada, Toshima-ku, Tokyo Inside Taisho Seiyaku Co., Ltd. (72) Inventor Masakazu Sato 3--24, Takada, Toshima-ku, Tokyo No. 1 Taisho Pharmaceutical Co., Ltd. (72) Inventor Takehiro Yamagishi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Masashi Shibuya 5374-18-601 Shiba, Kawaguchi City, Saitama Prefecture F-term (reference) 4C086 AA01 AA02 AA03 BC39 MA01 MA04 NA14 ZA45 ZA96 ZB15 ZB26 ZC06 ZC42

Claims (3)

[Claims] [Claim 1] The following formula (1) Wherein R ¹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ² is a hydrogen atom or a compound represented by the following formula (2): (Wherein R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), and n is an integer of 0 to 2. ]
Or a pharmaceutically acceptable salt thereof. 2. In the formula (1), R ¹ is a hydrogen atom, R ² is a carboxyphenyl group, R ³ is an octadecyl group, and n is 0 or 2. A compound according to 1 or a pharmaceutically acceptable salt thereof. 3. A VEGF receptor antagonist comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.