JP2002193922A - Substituted benzoic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound used as a VEGF receptor antagonist for the treatment of diseases which the vascularization induced by VEGF participates in and the improvement of morbid symptoms induced by the VEGF. SOLUTION: The compound represented by formula (1) R1 is hydrogen atom or a 1-6C alkyl group; R2 is hydrogen atom, hydroxy group or a group represented by formula R4S (R4 is a 1-6C alkyl group); R3 is a 14-20C alkyl group; X is oxygen atom or a group represented by the formula: R5N [R5 is hydrogen atom, a 1-6C alkyl group, a group represented by the formula: R6CO (R6 is hydrogen atom, a 1-6C alkyl group, a 2-6C alkoxyalkyl group, a 2-6C alkoxycarbonylalkyl group or 2-furyl group) or R7SO2 (R7 is a 1-6C alkyl group)]; and n is an integral number of 1 to 3} and its medicinally acceptable salt are included.

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 not only reduce angiogenesis, but also decrease tumor immune function by suppressing maturation of dendritic cells (Nature Medicine, Vol. 2, p. 1096-
(Page 1103, 1996). Therefore, VEGF
A substance that inhibits the binding of to and its receptor is considered to be useful for treatment of various diseases in which pathological angiogenesis by VEGF is involved and improvement of pathological symptoms by VEGF.

[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
Provided is a compound used as a GF receptor antagonist.

[0004]

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

[0005]

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## STR1 ## wherein R ¹ is a hydrogen atom or a carbon atom
-6 an alkyl group, R ² is (wherein, R ⁴ is an alkyl group having a carbon number of 1-6.) Hydrogen atom, a hydroxyl group or the formula R ⁴ S is a group represented by, R ³ Represents 14-carbon atoms.
X is an oxygen atom or a group represented by the formula R ⁵ N
[Wherein, R ⁵ is a hydrogen atom, an alkyl group having 1-6 carbon atoms, a formula R ⁶ CO (where R ⁶ is a hydrogen atom, 1-carbon atoms)
An alkyl group having 6 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms, an alkoxycarbonylalkyl group having 2 to 6 carbon atoms, or a 2-furyl group. Or a group represented by the formula R
⁷ SO ₂ (wherein, R ⁷ is an alkyl group having 1 to 6 carbon atoms). A group represented by
n is an integer of 1 to 3. And a pharmaceutically acceptable salt thereof.

[0007]

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, an 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,
Octadecyl group, 17-methyloctadecyl group, 17,
Examples include a 17-dimethyloctadecyl group, a nonadecyl group, an eicosanyl group, and the like.

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

In the above formula (1), R ¹ is preferably a hydrogen atom, and R ³ is preferably an octadecyl group.

The compound of the above formula (1) can be produced by a method represented by the following reaction formula. Where R ¹ ,
R ² , R ³ and n are as defined above, halo is a halogen atom, A is a halogen atom, a methanesulfonyloxy group and a para-toluenesulfonyloxy group, and R and R ′ are R ⁵ excluding a hydrogen atom .

[0012]

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A compound of the formula (2) and R-halo (for example, a salt
Acetyl chloride or methanesulfonyl chloride)
The reaction is carried out in the presence of a base, and the amide compound of the formula (3)
Obtainable. The base here is triethyl
Examples include amines and pyridine. As the solvent, salt
Solvents that are inert to the reaction, such as methylene
You. Or R is R⁶Corresponding carvone when it is CO
Acid anhydride [(R⁶CO)_TwoO] and a compound of formula (2)
Reaction in the presence of R⁶A compound of formula (3) which is CO
Can be obtained. The base and solvent used are the same as above.
It is like. R is R ⁶Corresponding carvone when it is CO
Acid R⁶COOH is used in a commonly used method without mixed acid.
After conversion to water, the compound is reacted with the compound of formula (2) in the presence of a base.
R is also⁶A compound of formula (3) which is CO
Can be obtained. Triethylamine as the base
And pyridine. As a solvent, methyl chloride
A solvent inert to the reaction such as ren is used. Or
R is R⁶Corresponding carboxylic acid R when CO⁶COO
H is condensed with a compound of formula (2) to form R⁶An expression that is CO
The amide compound of (3) can be obtained. As a condensing agent
1- [3- (dimethylamino) propyl] -3-e
Tylcarbodiimide hydrochloride and 1-hydroxybenzotri
Amides from amines and carboxylic acids, such as azoles
Reagents generally used for the production are used. As a solvent
N, N-dimethylformamide or methylene chloride
An inert solvent or the like is used for any reaction.

The alkylation reaction of the amide compound of the formula (3) with the compound of the formula (4) is carried out in the presence of a strong base to obtain the compound of the present invention of the formula (5). Examples of the base include sodium hydride, potassium hydride, calcium hydride, and the like, and a solvent inert to the reaction such as N, N-dimethylformamide is used.

The compound of the formula (6) can be obtained by reacting the compound of the formula (5) wherein R is an acetyl group in an alcohol solvent such as methanol in the presence of a strong acid such as sulfuric acid.

An amine compound of the formula (6) is represented by R-halo, the corresponding carboxylic acid or acid anhydride when R is R ⁶ CO;
In the presence or absence of a mixed acid anhydride or diketene and a base,
By reacting in the presence or absence of a condensing agent, the compounds of the present invention represented by formulas (7) and (8) can be obtained. Examples of the base include triethylamine, pyridine, potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, calcium hydride and the like. As the condensing agent, 1- [3- (dimethylamino) propyl] -3-
Reagents commonly used in preparing amides from amines and carboxylic acids, such as ethyl carbodiimide hydrochloride and 1-hydroxybenzotriazole, are used. As the solvent, a solvent inert to the reaction such as N, N-dimethylformamide or methylene chloride is used.

The etherification reaction of the compound of the formula (9) with the compound of the formula (10) is carried out in the presence of a base to obtain the compound of the present invention of the formula (11). Examples of the base include potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, calcium hydride and the like. As the solvent, a solvent inert to the reaction, such as N, N-dimethylformamide, is used.

The compound of the present invention in which R ¹ is an alkyl group is hydrolyzed by a usual method for hydrolyzing an ester group, and the compound represented by the formula (5), (6) or (7) wherein R ¹ is a hydrogen atom. ), Formulas (8) and (11).

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 forms are tablets, capsules, granules,
Powders, powders, troches, ointments, creams, emulsions,
Suspensions, suppositories, injections, etc., all of which are conventional formulation techniques (for example, the method prescribed in the 12th revised Japanese Pharmacopoeia)
Can be manufactured by These dosage forms are:
It can be appropriately selected according to the patient's symptoms, age and purpose of treatment. In the preparation of various dosage forms, conventional excipients (eg, crystalline cellulose, starch, lactose,
Mannitol), binders (eg, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), lubricants (eg, magnesium stearate, 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.

[0020]

EXAMPLES [Example 1] (1) Methyl 5-amino-2-methylthiobenzoate
7.0 g and triethylamine 7.18 g in methylene chloride 100
4.35 g of acetic anhydride was added to the solution dissolved in ml under ice-cooling, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, 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 recrystallized from chloroform and methyl 5-acetamido-2-methylthiobenzoate (melting point: 175-178 ° C) 7.35
g was obtained.

(2) 10.0 g of 4-hydroxybenzyl alcohol and 26.9 g of 1-bromooctadecane were added to N, N
-22.3 g of anhydrous potassium carbonate was added to the solution dissolved in dimethylformamide, and the mixture was stirred at 80 ° C for 2.5 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 recrystallized from chloroform-methanol to give 4- (octadecyloxy) benzyl alcohol (melting point: 84 to 86.5 ° C).
5 g were obtained.

(3) 15.0 g of the compound obtained in the above (2)
Was suspended in methylene chloride (200 ml), and triethylamine (5.47 g) and methanesulfonyl chloride (6.05) were added to the mixture.
After stirring at room temperature for 14.5 hours, 2.0 g of triethylamine and methanesulfonyl chloride were further added.
1.8 g was added, and the mixture was stirred at room temperature for 1 hour. Saturated saline was added to the reaction solution, 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 purified by silica gel column chromatography (eluted with hexane: ethyl acetate: chloroform = 20: 1: 1), and then 4- (octadecyloxy) benzyl chloride (melting point) : 57.5-59.0 ° C) 18.5 g was obtained.

2.0 g of the compound obtained in the above (1) was added to N, N-
To a solution dissolved in 50 ml of dimethylformamide was added 401 mg of oily sodium hydride (60%) under ice-cooling to obtain a solution.
After stirring for 5 minutes, the compound obtained in the above reaction formula (3) 3.63
g at room temperature and stirred at 50 ° C. for 30 minutes.
Stir for 4 hours. Dilute hydrochloric acid 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 subjected to silica gel column chromatography (eluted with hexane: ethyl acetate: chloroform = 3: 1: 1).
After purification, the following compound 1 (melting point: 52-53 ° C.) 2.7
5 g were obtained.

[0024]

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Example 2 1.0 g of methanesulfonyl chloride was added to a solution of 1.5 g of methyl 5-amino-2-methylthiobenzoate and 1.2 g of triethylamine dissolved in 15 ml of methylene chloride under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After stirring, 1.0 g of methanesulfonyl chloride was further added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Saturated saline was added to the reaction solution, 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 (hexane:
After purification with ethyl acetate: chloroform = 1: 1: 1), 1.07 g of methyl 2-methylthio-5-methanesulfonamidobenzoate (melting point: 150 to 157 ° C.) was obtained.

To a solution of 700 mg of the compound obtained above in 10 ml of N, N-dimethylformamide was added 112 mg of oily sodium hydride (60%) under ice-cooling, followed by stirring for 20 minutes. 1.1 g of the compound obtained in (14) was added at room temperature, and the mixture was stirred at 60 ° C for 2.5 hours. Water was added to the reaction solution, 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 purified by silica gel column chromatography (eluted with hexane: ethyl acetate: chloroform = 2: 1: 1), and the compound 2 shown below (melting point: 116.5-5) 118 ° C) 1.
24 g were obtained.

[0027]

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Example 3 Compounds 3 to 6 shown in Table 1 were obtained by the same operation as in Examples 1 and 2.

[0029]

[Table 1]

Example 4 Compound 7 (melting point: 50-51 ° C.) was obtained from ethyl 3-acetamidobenzoate by the same operation as in Examples 1 and 2.

[0031]

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Example 5 To a mixture of 3.03 g of compound 4 suspended in 50 ml of methanol was added 3 ml of concentrated sulfuric acid to obtain a mixture.
After heating under reflux for 5 hours, 2 ml of concentrated sulfuric acid was further added, and the mixture was further heated under reflux for 5 hours. After methanol was distilled off, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. 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 (hexane: ethyl acetate: chloroform = 3: 1: 1 to 1:
After purification by elution (sequentially at 1: 1), 1.37 g of the following compound 8 (melting point: 80.5-83 ° C.) was obtained.

[0033]

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Example 6 By the same procedure as in Example 5, the following compound 9 was obtained from compound 7 (melting point: 69.5).
７１71 ° C.).

[0035]

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Example 7 695 mg of compound 8 was converted to N, N-
To a solution dissolved in 15 ml of dimethylformamide was added 77 mg of oily sodium hydride (60%), and the mixture was added
After stirring for 10 minutes, 110 μl of methyl iodide was added at room temperature to give 5
After stirring at 0 ° C. for 1.5 hours, the mixture was stirred at room temperature for 22 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 subjected to silica gel column chromatography (hexane: ethyl acetate:
After purification with chloroform = 4: 1: 1), 340 mg of the following compound 10 (melting point: 60-64 ° C.) was obtained.

[0037]

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Example 8 To a solution of 600 mg of compound 8 and 312 mg of triethylamine in 15 ml of methylene chloride was added 164 mg of 2-furoyl chloride under ice-cooling, and the mixture was stirred for 45 minutes. Floyl chloride 50
mg was added and the mixture was stirred at room temperature for 14 hours. Saturated saline was added to the reaction solution, 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 purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 2: 1), and the following compound 11 (melting point: 85.5-89 ° C.) 700 mg was obtained.

[0039]

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Example 9 Compounds 12 to 15 shown in Table 2 were obtained in the same manner as in Example 8.

[0041]

[Table 2]

Example 10 600 mg of methyl 2,5-dihydroxybenzoate and the compound 1.4 obtained in Example 1 (3)
To a solution of 1 g in 15 ml of N, N-dimethylformamide was added 1.14 g of anhydrous potassium carbonate, and the mixture was stirred at 60 ° C. for 3 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 = 20: 1: 1), and the compound 16 (melting point: 79.5-5) was obtained. 82 ℃) 60
0 mg was obtained.

[0043]

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Example 11 By the same operation as in Example 10, compounds 17 to 19 shown in Table 3 were obtained.

[0045]

[Table 3]

Example 12 A solution prepared by dissolving 650 mg of compound 1 in 7 ml of tetrahydrofuran and 7 ml of ethanol was added to an aqueous solution of sodium hydroxide (435 ml of sodium hydroxide).
g, water 5 ml) and stirred at 50 ° C. for 1 hour. The reaction solution was acidified by adding 10% hydrochloric acid, and the precipitated solid was filtered and washed with water. The obtained solid was dried under reduced pressure to obtain 555 mg of the following compound 20 (melting point: 124-128 ° C).

[0047]

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Example 13 A mixture of 600 mg of compound 2 suspended in 7 ml of tetrahydrofuran and 7 ml of ethanol was added to an aqueous solution of sodium hydroxide (sodium hydroxide 380).
mg, 5 ml of water) and 3 ml of tetrahydrofuran, and the mixture was stirred at 50 ° C. for 1 hour. The reaction solution was acidified by adding 10% hydrochloric acid, and the precipitated solid was filtered and washed with water. The obtained solid was dried under reduced pressure to give the following compound 21 (melting point: 18
545 mg).

[0049]

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[Embodiment 14] Embodiments 12 and 13
By the same operation as described above, compounds 22 to 33 shown in Table 4 and compounds 34 to 37 shown in Table 5 were obtained.

[0051]

[Table 4]

[0052]

[Table 5]

[Test Example] Literature (Cell Growth & Differentiation, Vol. 7, 213)
Page-221, 1996), the following test was carried out. NIH3T3 cells (7 × 10 ⁴ cells / well) in which KDR was forcibly expressed were seeded on a 24-well collagen-coated plate,
5% in Dulbecco's modified Eagle's medium (DMEM) containing 10% calf serum and 200 μg / ml Geneticin G418
The cells were cultured at 37 ° C. for 24 hours in a% carbon dioxide atmosphere. The cells were added to buffer A [10 mM HEPES (N-2-hydroxye
thylpiperazine-N'-2-ethanesulfonic acid) and 0.1% BSA
(bovine serum albumin)] at 4 ° C. for 30 minutes. Then, the medium was changed to buffer B (DM
EM containing 10 mM HEPES and 0.5% BSA), and dissolve each test compound in dimethyl sulfoxide.
Test solution prepared by diluting to the specified concentration with [ ¹²⁵ I] -VE
GF (final concentration 25 pM) was added and 90 ° C at 4 ° C.
The binding reaction was allowed to run for minutes. After the reaction was completed, the cells were washed three times with ice-cold buffer A. Continue 0.5M for each well
0.5 ml of NaOH was added and the cells were thawed at room temperature for 30 minutes. The radioactivity of the cell lysate in each well was measured with a gamma counter to calculate the total binding amount of [ ¹²⁵ I] -VEGF.
Non-specific binding of [ ¹²⁵ I] -VEGF was determined by 10 nM unlabeled VE.
It was measured by a competition assay in the presence of GF, and the difference from the total binding amount of [ ¹²⁵ I] -VEGF was determined as [
The specific binding amount of ¹²⁵ I] -VEGF was calculated. The binding inhibition rate of the test compound was calculated by the following equation.

[0054]

(Equation 1)

From this value, the 50% binding inhibitory concentration (IC ₅₀ ) of the test compound was calculated. Table 6 shows the results.

[0056]

[Table 6]

[0057]

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. In addition, the compounds of the present invention include VEGF,
It is expected to improve the pathological symptoms induced by the action of.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/10 101 A61P 9/10 101 27/02 27/02 29/00 101 29/00 101 35/00 35/00 43/00 111 43/00 111 C07C 69/92 C07C 69/92 229/60 229/60 233/07 233/07 C07D 307/68 C07D 307/68 (72) Inventor Tetsuo Takayama Toshima-ku, Tokyo 3-24-1, Takada Taisho Pharmaceutical Co., Ltd. (72) Inventor Masakazu Sato 3-24-1, Takada, Toshima-ku, Tokyo Inside (72) Inventor Takehiro Yamagishi 3, Takada, Toshima-ku, Tokyo 24-1, Taisho Seiyaku Co., Ltd. 4C206 AA01 AA 02 AA03 DA17 DB15 DB17 DB43 GA02 GA32 JA47 MA01 MA04 NA14 ZA33 ZA45 ZA96 ZB15 ZB26 ZC06 ZC42 4H006 AA01 AB20 BJ50 BN30 BP30 BT32 BU46 BV25 TA05 TB04 TB61

Claims (3)

[Claims] [Claim 1] The following formula (1) In the formula, R ¹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ² is a hydrogen atom, a hydroxyl group, or a formula R ⁴ S (where R ⁴ is an alkyl group having 1 to 6 carbon atoms) Wherein R ³ is an alkyl group having 14 to 20 carbon atoms, X is an oxygen atom or a formula R ⁵ N wherein R ⁵ is a hydrogen atom, a carbon atom of 1 -6 alkyl group of the formula R ⁶ CO
(In the formula, R ⁶ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms, an alkoxycarbonylalkyl group having 2 to 6 carbon atoms or 2-
It is a furyl group. Or a group represented by the formula R ⁷ SO ₂ (where R ⁷ is an alkyl group having 1 to 6 carbon atoms). And n is an integer of 1 to 3. Or a pharmaceutically acceptable salt thereof. 2. The compound or a pharmaceutically acceptable salt thereof according to claim ¹ , wherein in the formula (1), R ¹ is a hydrogen atom and R ³ is an octadecyl group. 3. VE comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
GF receptor antagonist.