JPS6176440A - Benzoic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1-R5 are H, alkyl or adjacent two groups together form a 5- or 6-membered cycloalkyl; R1-R5 are not H at the same time; R6 is H, alkoxy or NR7R8 (R7 and R8 are H or alkyl); X is group of formula II - formula VI, N=N, etc.]. USE:A differentiation inducing agent for cancer cell, especially leukemia cell. PREPARATION:A compound of formula I wherein X is group of formula II can be prepared by reacting the corresponding acetophenone derivative with a terephthalaldehydric acid ester or its derivative in the presence of a base. The product can be converted to another compound of formula I wherein X is group of formula III by oxidizing with an epoxidizing agent. A compound of formula I wherein X is N=N is obtained by the condensation of the corresponding aniline derivative with p-nitrosobenzoic acid ester.

Description

DETAILED DESCRIPTION OF THE INVENTION Object of the Invention: The present invention aims to develop a novel organic compound for fJ' as a medicine and provide it to the therapeutic community.

Conventional technology: Cancer treatment methods can be roughly divided into surgical therapy and chemotherapy that directly or indirectly kills cancer cells.
As a method for this, an interesting method has been discovered that promotes differentiation of cancer cells and makes them cancerous. [(a) Proc, N
atl, Acad, Sc1. USA 7J-293G
(1980) (b) J, Med, Chemr, 25
'12Ei9 (1982), Blood, fi27
09(+983), (C) Cell Engineering 2 No.
12 (1983).

(d) Tl(E RECINOI[lS Vol,l
-2, M, B, 5porn et alACADEM
IC' PRESS 1984 [Vitamin A acid] - Reference (d) and German Patent Publication 2.8
It has been reported that benzoic acid derivatives represented by the formula 54354 and the like 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: Now, general formula (I) In the formula, R□+ R2, R3+ R4+ and R5 represent a hydrogen atom or a lower intermediate alkyl, and two adjacent ones thereof together represent 5 to 6 A membered cycloalkyl group can be formed, but not all of them must be hydrogen atoms at the same time, R6 is a hydroxyl group, a lower alkoxy group, -NR7R8 group (in the formula, R7 and R8 are hydrogen atoms) or a lower alkyl group), and X means Hu, is a compound which morphologically and functionally promotes the differentiation of cancer cells, especially leukemia cells, and 1. It was found that it can be used for cancer treatment by the third method of L.

That is, the compound of the present invention was used in a cancer cell differentiation induction test using human acute promyelocytic leukemia HL80 cells, in which differentiation into granulocytes was determined by nuclear morphology and nitroblue tetrazolium (NBT) reducing ability. I did it, and the method is as follows.

HL-60 cells were placed in RPMI IB containing 5% tallow serum.
Subcultured in 4O medium, the number of cells in logarithmic growth phase was 3.
The cells are diluted with the same medium to give a concentration of X104/■1, then a predetermined concentration of the test drug is added, and after culturing for 5 days, the cells are fixed and subjected to flight-Glemsa staining to determine the morphology of the nucleus.

In addition, cells obtained by the same treatment were centrifuged, diluted with RPM I medium containing 5% serum to a constant cell number, added with 200 ng of TPA, and incubated in the presence of 0.1% NBT for 20 minutes. Incubate at 37°C. Next, the cells colored black are counted using a microscope, and the percentage of cells with NBT reduction ability is calculated.

The compound of the present invention is characterized in that benzoic acid and an alkyl-substituted phenyl group are bonded through an X group. In this case, those in which the X group is 0- and R3 and R4 have a particularly medium size are preferred, in particular isopropyl, butyl,
Those with a cyclopentyl group and those where R3 and R together are a 5- or 6-membered cyclic alkyl group are preferred. On the other hand, almost no effect is observed when both R and R are hydrogen atoms.

It is valid. Thus, R is preferably a hydroxyl group or a methoxy group.

The compound represented by the general formula (I) of the present invention includes (a) a compound in which the group X of the general formula (I) represents 100-C(R)=CsB-M, a corresponding acetophenone derivative and a terephthalaldehyde acid ester; or a derivative thereof in the presence of a base, and by oxidizing a compound exhibiting a corresponding c) Compounds in which or a compound in which -N=N(0)- can be prepared by condensing the corresponding phenylhydroxyamine with varanitrosobenzoic acid or a derivative thereof in the same manner as in section (C). (0)- group or -N(0)=N-
By condensing the compound with the corresponding nitrosobenzene derivative and parahydroxyaminobenzoic acid or its derivative in the same manner as in section (C), (f) X is a -N (R7)-C(0)- group. Certain compounds can be prepared by acylating the corresponding aniline derivative with a reactive derivative of terephthalic acid (such as an acid halide or ester) (g) Compounds where It can be produced by acylation with a corresponding reactive derivative of benzoic acid (acid halogen or ester, etc.) by a conventional method, and then hydrolyzing the compound thus obtained, if desired. .

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 mol or less. Among them, particularly strong compounds are listed in Table 1, such as Compound No., L 2,
8.9+ 10.11+30.34.35.39.5
0, 55.58, 60.62, etc. (see Table 2).

Disaster-1 178 mg (1 mmol) of p-tert,-butylacetophenone,! =184 g (1a+mol) of terephthalaldehyde acid methyl ester are dissolved in 81 g of ethanol, 10 ml of IN caustic soda is added, and the mixture is stirred overnight at room temperature. After reaction route T, 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, then diluted with anhydrous sulfuric acid), dehydrated with IJum, and the solvent was distilled off to obtain the formula (I) (R3=t-butyl; X=C0CH=C
The target compound where H-; R6=OH is obtained. Melting point 245
~246°C (yield 75.2%) Analysis result C2oH2o03 Calculated value (%) C; 77.90, H; 6.54
Experimental value C%) C: 11.82, H: 6.43 By adding an ether solution of diazomethane in methanol to the carboxylic acid obtained as above, methyl ester was quantitatively obtained.

Melting point 119-120.5°C Fruit] l juice □ (□ 100 mg ((1,287 mmol) of I) - [(
E)-2-(5,6゜7.8-tetrahydro-5,5,
Dissolve 8,8-tetramethyl-2-naphthyl)ethenylcobenzoic acid methyl ester in 51 chloroform,
Add 0+wg (0.2B9 mmol) of m-chloroperbenzoic acid to a solution of chloroform and reflux for 2 hours.

After the raw materials have disappeared, the reaction solution is cooled, insoluble matter is filtered off, washed sequentially with IN aqueous sodium carbonate solution, 18 aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the epoxy compound. (I) Formula 1 Formula %) X is a -CH-CH- group, R=OCH3) is obtained.

Melting point 163-166°C (yield 92.0%) This epoxy substance (ester) was hydrolyzed with IN caustic soda in ethanol, neutralized with hydrochloric acid, extracted with ethyl acetate, the solvent was distilled off, and the epoxy compound (ester) was extracted with ethyl acetate. The corresponding carboxylic acid was obtained by reconsolidation.

Melting point 215-216°C Elemental analysis Calculated value as CHO (%) C; 7B, 82, H; 7.48 Experimental value (%) C; 79.03, H; 7.74 cusp □ 1 5.5 , 8,8-tetramethyl-5,6,7,8=tetrahydronaphthalene (1.2 g) was nitrated with nitric acid-sulfuric acid in sulfuric acid to obtain the 2-2) o derivative. mp, 71-72°C (recrystallized from 0,9 gl methanol). This nitro compound was catalytically reduced in alcohol using Pd-C as a catalyst, and 2-amino-5,5,8,8-
Tetramethyl-5,8,7,8-tetrahydronaphthalene was obtained. rrl, 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 methyl 4-nitrosobenzoate was added. Mix the esters and leave at room temperature for 2 hours. By distilling off methanol and recrystallizing from methanol, the melting point is 118.5 to 119.5.
°C azo compound (R3, R4 nee C(CH3)pl
2CH2,C(CH3)2-1R6=OcH3゜X=
-N=N-) 0.32 g is obtained.

Elemental analysis CHNO Calculated value C; 75.40, H; 7.48, N
; 7.99 experimental value C; 75.2B, H;
7.29, N; 7.8+ by hydrolyzing the azo compound described above with IN caustic soda in methanol and working up as in Example 2. We were able to obtain carboxylic acid. Melting point: 287-288°C Safety-1 The nitro compound (100 mg) obtained in Example 3 was dissolved in hydrous tetrahydrofuran (30 ml), and aluminum amalgam (aluminum foil 300+wg and gc125
% aqueous solution) to give the corresponding hydroxylamine derivative. This was reacted with a slight excess of p-nitrosobenzoic acid methyl ester without tl preparation to form an azoxy-conductor R6-OCH3,
=N (0)-) is obtained.

mp, 114-115'C (recrystallized from hexane). MASS: M = 386 actual m 2-amino-5,5°8.8- obtained according to Example 3
Tetramethyl-5,R3,7,8-tetrahydronaphthalene (1 mmol) is reacted with terephthalic acid chloride monomethyl ester (1,1 meal) in pyridine at room temperature, with quantitative yield, general formula % formula % (shown A compound was obtained.

Melting point 211-2126C (recrystallized from methylene chloride hexane).

This product was dissolved in methanol, reacted with IN caustic soda at room temperature for 2 hours, neutralized with dilute hydrochloric acid, extracted with ethyl acetate, the solvent was distilled off, and the obtained crystals were reconsolidated from ethyl acetate-hexane. .

205.5 to 206.5'C in formula (I) (R3, R4
Ni-C(CI+3)2CH2CH2C(CH3)2-1
A terephthalic acid amide derivative represented by X=-NH-Co-1R=OH) was obtained.

Fruit 119-J 3,4-diethylbenzoic acid chloride (1,1 mmol
) to 4-aminobenzoic acid methyl ester (io+mo
1) in 10 ml of anhydrous pyridine at room temperature for 5 hours. Add water, extract with chloroform, wash with dilute hydrochloric acid and then water, and distill off the chloroform. The product was recrystallized from methanol to form the formula (1) (R3, R4=E t1X=-
GO-NH-1R6=OCH3)mp, 162-165
Obtain °C. Yield quantitative.

Many compounds were synthesized in the same way, among which No.
Compounds Nos. 1 to 67 (including those of the above examples) are collectively displayed in Table 1. The symbols a) to g) in the synthesis method column in the table are respectively synthetic method a described in claim 1.
)-g) were used in the synthesis of these compounds.

15iHEt EtHHCf(-N(-ii,
-Cl8H19ND3. Last H20'259・shi260・
5°" C17) (□-PD3)"ω
1IICl, 7) (□P3103.5-105f1
1C□♂□9rc131071-106f++
(:,, throat (□, ND3 269. E sea)
271ftIC18H□9m3165.5-167.5
f11C18H19NO3AmorphfI
IC20H2P323o-231,5f1' C2
1H25]'031B3-184.5 f”
C2♂23) D3. ! ) (20244, 5-246
fIIC21H25NO3165-166,5f■C2
OH2, :P3256. shi258.5 f11
C21H25No3151-152 f■C
20H23ND3220.5-221.5f”C
2□H25No3137.5-138 fC
□9H2oN202248-248.5015) (14
N202115-116・5C14H12N20219
1-193・5C17H□8N20291.5-92 018H2ON2024″″′5 C17H18N202215-216 C22) (26N202118・5-119・5C23
)'I2603215-216bC19H200319
9-200,5bC22H26N203114-115
d, e procedural amendment October 24, 1982

Claims (3)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, R_1, R_2, R_3, R_4, and R_5 represent a hydrogen atom, a low intermediate alkyl, and two adjacent Both of them can be combined to form a 5- to 6-membered cycloalkyl group, but all of them must not be hydrogen atoms at the same time, and R_6 is a hydroxyl group, lower alkoxy group, -NR_7R_8 group (in the formula R_7 and R
_8 represents a hydrogen atom or a lower alkyl group), and X is ▲a mathematical formula, a chemical formula, a table, etc.▼, ▲a mathematical formula, a chemical formula,
There are tables, etc. ▼, -N=N-, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_7 and R_8 represent a hydrogen atom or a lower alkyl group), a benzoic acid derivative represented by (2) (a) Group X in general formula (I) is -CO-C(R_
6) By condensing a compound showing =CR_8- group with the corresponding acetophenone derivative and terephthalaldehyde acid ester or its derivative in the presence of a base, (b) By oxidizing the compound in which the corresponding X group is -C(R_7)=C(R_8)- group using an epoxidizing agent, (c) Compounds in which X is -N=N- group are converted into corresponding compounds. (d) X is an -N(O)=N- group or -N=N(O)-
(e) X is -N=N(O)- group or -N(O )=N-
(f) X is a -N(R_7)-C(O)- group by condensing the compound with the corresponding nitrosobenzene derivative and parahydroxyaminobenzoic acid or its derivative in the same manner as in section (c). (g) Compounds where X is -C(O)-N(R_7)- can be prepared by acylating the corresponding aniline derivative with a reactive derivative of terephthalic acid (such as an acid halide or ester). or a derivative thereof, with a corresponding reactive derivative of benzoic acid (acid halogen or ester, etc.) by a conventional method, and the compound thus obtained is hydrolyzed as desired. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1, R_2, R_3, R_4, R_5, R_
6 and X have the above meanings) (3) An agent for inducing differentiation of cancer cells, particularly leukemia cells, characterized by containing a benzoic acid derivative represented by general formula (I)