JPH0458458B2 - - Google Patents

Description

[Detailed description of the invention]

OBJECT OF THE INVENTION: The purpose of this invention is to develop novel organic compounds useful as medicines and provide them to the therapeutic community. Conventional technology: Cancer treatment methods can be broadly divided into surgical therapy and chemotherapy that directly or indirectly kills cancer cells, but a third method is to promote differentiation of cancer cells to eliminate cancer. An interesting method has been discovered. [Proc.Natl.Acad.USA 77 2936 (1980), J.
Med.Chem. 25 1269 (1982), Blood, 62 709 (1983).
Cell Engineering 2 No. 12 (1983). ] General formula according to German Patent Publication No. 28 54 354 It has been reported that benzoic acid derivatives shown in the following are pharmacologically valuable compounds and can be used for local or systemic treatment of benign or malignant tumors and prevention of the above-mentioned diseases. The compounds are also suitable for the systemic or local treatment of acne, acne, other skin diseases involving thickened or pathologically altered keratosis, as well as allergic and inflammatory diseases. Structure of the invention: The present invention is based on the general formula (): (In the formula, R ₁ and R ₂ independently represent lower intermediate alkyl,
In addition, both can be combined to form a 5- to 6-membered cycloalkyl group that may have a lower alkyl group, and R ₃ is a hydroxyl group, a lower alkoxy group, -NR ₄ R ₅ group (in the formula, R ₄ and R ₅ independently represent a hydrogen atom or a lower alkyl group), and X is

【formula】

[Formula]-N =N-

【formula】

【formula】

[Formula] (wherein R ₆ and R ₇ independently represent a hydrogen atom or a lower alkyl group) The benzoic acid derivative represented by It has been found that these compounds can be used in the treatment of cancer according to the third method described above. That is, the cancer cell differentiation induction test for the compound of the present invention uses human acute promyelocytic leukemia HL60 cells to determine differentiation into granulocytes based on nuclear morphology and nitroblue-tetrazolium (NBT) reducing ability. The method was as follows. HL-60 cells containing 5% fetal bovine serum
Subculture in RPMI1640 medium, adjust the dilution with the same medium so that the number of cells in the logarithmic growth phase is 3 x 10 ⁴ /ml, then add the test drug at a predetermined concentration, and culture the cells for 5 days. Fixed, Wright−
Perform Giemsa staining to determine nuclear morphology. In addition, cells obtained by the same treatment were centrifuged and mixed with RPMI containing 5% serum to maintain a constant cell number.
Dilute in medium and add 200ng TPA, 0.1%
Incubate at 37 °C for 20 min in the presence of NBT. Next, the cells colored black are counted using a microscope, and the percentage of cells capable of reducing NBT is calculated. The compound of the present invention is characterized in that benzoic acid and an alkyl-substituted phenyl group are bonded via an X group. At that time, the X group

【formula】

[Formula]-N =N-

【formula】

【formula】

[Formula] In which R ₁ and R ₂ are preferably of medium size, in particular isopropyl groups,
Butyl group, cyclopentyl group and R ₁ and
It is preferable that R ₂ together represent a 5 or 5-membered cyclic alkyl group. On the other hand, almost no effect is observed when both R ₁ and R ₂ are hydrogen atoms. Hydrogen atoms and methyl groups are particularly effective as R ₆ and R ₇ . Thus, R ₃ is preferably a hydroxyl group or a methoxy group. The compound represented by the general formula () of the present invention is characterized in that (a) the group X in the general formula () is -CO-C(R ₆ )=CH
(b) By condensing a compound showing a group with a corresponding acetophenone derivative and a terephthalaldehyde acid ester or a derivative thereof in the presence of a base, (b)

[Formula] By oxidizing a compound in which the corresponding X group is -C(R ₆ )=C(R ₇ )- group using an epoxidizing agent, (c) X is -N=N - group by condensing the corresponding derivative of aniline with p-nitrosobenzoic acid in the presence or absence of an acid catalyst (d) Compounds where X is -N(O)=N- (e) By condensing enylhydroxyamine and p-nitrosobenzoic acid or its derivative in the same manner as in section (c),
(f) X is a -N(R ₆ )-C(O)- group by condensing the compound with the corresponding nitrosobenzene derivative and parahydroxyaminobenzoic acid or a derivative thereof in the same manner as in section (c). (g) Compounds _where Manufactured by acylation with benzoic acid or a derivative thereof, or a corresponding reactive derivative of benzoic acid (acid halogen or ester, etc.) using a conventional method, and optionally hydrolyzing the compound thus obtained. can do. When a differentiation induction test was attempted using the compounds of the present invention (Table 1) using the method described above, all of these compounds exhibited activity at concentrations of 10 ^-6 mol or less. Among them, particularly strong compounds, such as compounds in which R ₁ and R ₂ are ethyl group, t-butyl group, or both together form a 6-membered cyclic alkyl group, are 10 ^- It shows activity even at ⁸ to 10 ^-10 mol. Reference example 176 mg (1 mmol) of p-tert.-butylacetophenone and 164 mg (1 mmol) of terephthalaldehyde acid methyl ester are dissolved in 8 ml of ethanol, 10 ml of 1N caustic soda is added, and the mixture is stirred overnight at room temperature. After the reaction is completed, the reaction solution is made acidic with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water until the pH reached 7, dehydrated with anhydrous sodium sulfate, and the solvent was distilled off to obtain the formula (R ₁ = t-butyl; R ₂ =
The desired compound (H, X=COCH=CH-; R ₃ =OH) is obtained. Melting point 245-246℃ (yield 75.2%) Analysis result C ₂₀ H ₂₀ H ₃ Calculated value (%) C; 77.90, H; 6.54 Experimental value (%) C; 77.62, H; 6.43 Obtained as above The methyl ester was quantitatively obtained by adding an ethereal solution of diazomethane in methanol to the prepared carboxylic acid. Melting point: 119-120.5°C Example 1 Similarly, in formula (), R ₁ and R ₂ are -C
(CH ₃ ) ₂ CH ₂ CH ₂ C (CH ₃ ) ₂ −, and X is =
It was possible to obtain a compound in which R ₃ is OH and OCH ₃ with a CO·CH=CH− group. Example 2 100 mg (0.287 mmol) of p-[(E)-2-(5,
Dissolve 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]benzoic acid methyl ester in 5 ml of chloroform,
Add 50 mg (0.289 mmol) of m-chloroperbenzoic acid in chloroform and reflux for 2 hours. After the raw materials have disappeared, the reaction solution is cooled and insoluble materials are removed by filtration, washed sequentially with a 1N aqueous sodium carbonate solution, a 1N aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the epoxy compound. () Formula (R ₁ and R ₂ are -C(CH ₃ ) ₂ CH ₂ CH ₂ C
(CH ₃ ) ₂ − and X is

[Formula] group, R ₃ = OCH ₃ ) is obtained. Melting point 163-166℃ (yield 92.0%) This epoxy body (ester) was dissolved in ethanol.
After hydrolysis with 1N caustic soda and neutralization with hydrochloric acid,
The corresponding carboxylic acid was obtained by extraction with ethyl acetate, evaporation of the solvent, and recrystallization from ethyl acetate. Melting point 215-216℃ Elemental analysis As C ₂₃ H ₂₆ O ₃ Calculated value (%) C; 78.82, H; 7.48 Experimental value (%) C; 79.03, H; 7.74 Example 3 5,5,8,8-tetra Methyl-5,6,7,
By nitrating 8-tetrahydronaphthalene (1.2 g) with nitric acid-sulfuric acid in sulfuric acid,
A 2-nitro derivative was obtained. mp.71-72℃ (0.9g,
recrystallized from methanol). This nitro compound was catalytically reduced in alcohol using Pd-C as a catalyst, and 2-amino-5,5,8,8-tetramethyl-5,6,
7,8-tetrahydronaphthalene was obtained. mp.72
~73°C (recrystallized from hexane). This amino compound (0.2 g) was dissolved in acetic acid (10 ml), trichloroacetic acid (0.1 g) was added, and a small excess of 4-nitrosobenzoic acid ethyl ester was mixed.
Leave at room temperature for 2 hours. By distilling off methanol and recrystallizing from methanol, the melting point is 118.5.
~119.5°C azo compound (R ₁ , R ₂ = -C
( _CH3 ) _2CH2CH2C ( _CH3 ) _2- , _{R3 = OCH3} , _X =
-N=N-) 0.32 g is obtained. Elemental analysis C ₂₂ H ₂₆ N ₂ O ₂ Calculated value C; 75.40, H; 7.48, N; 7.99 Experimental value C; 75.28, H; 7.29, N; 7.81 Hydrolysis of the above azo compound with 1N caustic soda in methanol However, in the same manner as in Example 2, the corresponding carboxylic acid could be obtained by post-treatment. Melting point: 287-288°C Example 4 The nitro compound (100 mg) obtained in Example 3 was dissolved in hydrous tetrahydrofuran (30 ml), and aluminum amargal (300 mg of aluminum foil and HgCl ₂ 5
% aqueous solution) to give the corresponding hydroxyamine derivative. Without purification, this was reacted with a small excess of p-nitrosobenzoic acid methyl ester to form the azoxy derivative (R ₁ ,
R ₂ = -C (CH ₃ ) ₂ CH ₂ CH ₂ C (CH ₃ ) ₂ -, R ₃ =
OCH ₃ , X=-N=N(O)-) is obtained. mp.114〜
115°C (recrystallized from hexane) ΓMASS: M ⁺ =366 Example 5 2-Amino-5,5, obtained in Example 3
8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalene (1 mmol) and terephthalic acid chloride monomethyl ester (1.1 mmol) are reacted in pyridine at room temperature, with quantitative yield, the general formula () ( R ₁ , R ₂ =-C(CH ₃ ) ₂ CH ₂ CH ₂ C
A compound represented by ( _CH3 ) _2- , X=NH-CO-, R= _OCH3 ) was obtained. Melting point 211-212°C (recrystallized from methylene chloride hexane). This product was dissolved in methanol, reacted with 1N caustic soda at room temperature for 2 hours, neutralized with dilute hydrochloric acid, extracted with ethyl acetate, the solvent was distilled off, and the resulting crystals were re-crystallized from ethyl acetate-hexane.
mp.205.5~206.5℃ () In the formula (R ₁ , R ₂ = -C
( _CH3 ) _2CH2CH2C ( _CH3 ) _{2- , X} =-NH-CO-,
A terephthalic acid amide derivative represented by R ₃ =OH) was obtained. Example 6 3,4-diethylbenzoic acid chloride (1.1 m
mol) to 4-aminobenzoic acid methyl ester (1
mmol) in 10 ml of anhydrous pyridine at room temperature for 5 hours. Add water and extract with chloroform, wash with dilute hydrochloric acid and then water, and distill off the chloroform.
The product was recrystallized from methanol and given the formula (R ₁ , R ₂ = Et, X = -CO-NH-, R ₃ = OCH ₃ )
Obtain mp.162-165℃. Yield quantitative. The compounds shown in the following table were synthesized in the same manner. The symbols in the synthesis method columns (a) to (f) in the table indicate that the synthesis methods (a) to (f) described in the specification were used for the synthesis, respectively.

【table】

[Table] ｜

_CH3O

【table】

Claims (1)

[Claims] 1 General formula (): (In the formula, R ₁ and R ₂ independently represent lower intermediate alkyl,
In addition, both can be combined to form a 5- to 6-membered cycloalkyl group that may have a lower alkyl group, and R ₃ is a hydroxyl group, a lower alkoxy group, -NR ₄ R ₅ group (in the formula, R ₄ and R ₅ independently represent a hydrogen atom or a lower alkyl group), and X is [Formula] [Formula] -N = N- [Formula] [Formula] [Formula _] A benzoic acid derivative represented by R ₇ independently represents a hydrogen atom or a lower alkyl group.