JPS6253981A - Novel benzoic acid derivative - Google Patents

Abstract

NEW MATERIAL:A benzoic acid derivative shown by the formula I[R is alkyl; R1 is halogen; R2 is H, methyl or ethyl; X is O, S, =SO2, =SO, =NH, =N-CH3 or =N<+>(CH3)2; Y is -CONR3-, -NR3CO-, -COCR3=CR3-, -CR3=CR3CO-, -N=N-, -N=N(O)-, -N(O)=N- or group shown by the formula II (R3 is H, methyl or ethyl)]. EXAMPLE:Terephthalic acid(4,4-dimethylchromanyl)amidomethyl ester. USE:A remedy for diseases such as cartilaginous disease, dermatosis such as psoriasis, malignant disease such as leukemina, etc., caused by stagnation or abnormality of differentiation. PREPARATION:For example, a corresponding acetophenone is condensed with a terephthalaldehydric acid ester or its derivative in the presence of a base to give a compound shown by the formula I wherein Y is -CO-CR3=CH- group.

Description

DETAILED DESCRIPTION OF THE INVENTION Object of the Invention: Cartilage degenerative diseases, dermatological diseases such as psoriasis, and malignant diseases such as leukemia are considered to be diseases caused by stagnant or abnormal differentiation.

This invention provides novel organic compounds of pharmaceutical value that enable the treatment of these diseases in humans and animals.

BACKGROUND OF THE INVENTION It is already known that there are interesting methods for promoting the differentiation of cancer cells and causing them to develop cancer.

(a) J, Med, Chem, 25 1289 (1
982), (b) Cancer Research (S
apple,)4!12469s-2475s (c)
BLOOD of J, A, S, of Hemato
logy 64 709-721 (1983) (d
)Experientla 34 1105-1246
(e) Cell Engineering 2° No. 12 (1983) - These documents also report that retinoids and their related compounds exhibit characteristic effects in the treatment of tumors and integumentary areas.

In German Publication No. 28 54 354 p-((E
)-2-(5,G,7.8-tetrahydro-9,5,8
, 8-tetramethyl-2-naphthyl)buhenyl)benzoic acid is a pharmacologically valuable compound that can be used in the systemic and local treatment of benign or malignant tumors and in the prevention of the above-mentioned diseases. has been reported.

The compounds are also suitable for the systemic or local treatment of acne, pimples, other skin diseases involving thickened or pathologically altered keratosis, as well as allergic and inflammatory diseases.

In addition, it has been reported in 7 Meri 6 Patent Application Ser. No. 511037 that homologs of the above compounds have the effect of inhibiting cartilage degeneration when administered to mammals suffering from joint diseases.

Structure of the invention: In the formula, R is an alkyl group having 1 to 4 carbon atoms, in particular a methyl group or an ethyl group, R□ is a halogen atom,
R is a hydrogen atom, a methyl group or an ethyl group; X is an oxygen atom, a sulfur atom, a =S02, = group; and Y is a group of the following formula -CONR- -NR3CO-

The compound represented by the general formula (I) of the present invention can be produced as follows.

(a) Group Y of the following general formula (I) 100-CR3=CH
By condensing a compound showing a - group with a corresponding acetophenone derivative and a terephthalaldehyde acid ester or its derivative in the presence of a base, a compound in which the corresponding Y group shows a CR===CR group can be converted into an epoxidizing agent. By oxidizing using (c) Y is -N =
Compounds that are N-groups can be prepared by condensing the corresponding derivative of anidine with varanitrosobenzoic acid ester in the presence or absence of an acid catalyst (d) where Y is an -N(0)=N- group or - N=N (O)
- group can be obtained by condensing the corresponding phenylhydroxyamine and varanitrosobenzoic acid or its derivatives in the same manner as in section (C). 0)=N
- group with the corresponding nitrosobenzene derivative and parahydroxyaminobenzoic acid or its derivative (C)
(f) Compounds in which Y is -NR-Go- group can be obtained by acylating the corresponding aniline derivative with a reactive derivative (acid halide or ester, etc.) of terephthalic acid (g ) Compounds in which Y is -Co-NR- are produced by acylating para-aminobenzoic acid or its ester with the corresponding reactive derivative of benzoic acid (acid halide or ester, etc.) by a conventional method; The compound obtained is hydrolyzed as desired.

Hereinafter, the method for producing the compound of the present invention will be explained with reference to Examples, but the compound of the present invention is not limited to these production methods, and can be easily produced by experts by methods known per se or other methods. .

Example-1 Teleflu-dimethyl cumanlu
Arado Methyl Ester 6-Amino-4,4-dimethylchroman 0゜177g
(1 mmol) was dissolved in benzene 10-1, 1 ml (excess) of pyridine and 0.2 g (1,01 ml) of terephthalic acid monomethyl ester chloride were sequentially added, and the mixture was stirred at room temperature for 3.5 hours. Add 50 ml of water to the reaction solution, and extract 3 times with 75 ml of ethyl acetate.

The extract was sequentially mixed with 100 layers of hydrochloric acid, 100 layers of water, 100 layers of saturated sodium bicarbonate, 100 layers of water, and 1 layer of saturated saline.
After washing with 00 ml of water and drying with magnesium sulfate, the solvent was distilled off to obtain 0.352 g of a pale yellow oil. By recrystallizing this from benzene-hexane, 0.29 g
The title compound was obtained as pale yellow needles.

m, p, 129-130°C NMR (CDCI) δ1.35 (s, 8),
δ1.84 (t, 2.J=5L δ3.95 (s.

3), 64.20 (t, 2.J=5), 66.77
(d, 1.J=2), 67.89 (d, 2.J=9)
, δ7. 92 (broads, 1), δ8.
11 (d, 2.J=9) IR3380cg+-1 (NH), 1715 (ester), IE375 (amide), 815 (p-) Elemental analysis calculated value C70, 78%, H6, 23%, N 4.1
3% actual value C70, 64%, HG, 28%, N
4.01% Similarly, 6-amino-4,4 as a raw material
The corresponding alkylamide compound was obtained by using 6-ethylamino-4,4-dimethylchroman obtained in Reference Example 1 instead of -dimethylchroman.

4.354g of 4-dimethylchroman was added to 8ni1 of acetic anhydride.
Dissolve in 61% nitric acid 3. A solution of Ool (1.5 equivalents) in 9 ml of acetic anhydride was stirred at 0°C for 10 min.
Drops over 50 minutes After 50 minutes saturated soda water 200 II
Pour into 1 liter and extract with 400ml of dichloromethane.

Wash twice with 200ml of water and once with 100 sets of saturated saline,
Dry over magnesium sulfate, remove solvent under reduced pressure, 5.32
7 g of brown crystals were obtained. Separation by column chromatography (eluent dichloroethane/n-hexane) yielded 2.811 g of pale yellow crystals of 4,4-dimethyl-6-nitrochroman (yield 50.5% from 4°4-dimethylchroman). ), 2.004 g (yield 36.0%) of a red oil of 4,4-dimethyl-8-nitrochroman, and 312 g of a mixture were obtained. 4,4-Dimethyl-θ-nitrochroman was recrystallized from hexane to yield 2.581 g (4
6.4%) pale yellow crystals were obtained.

4,4-dimethyl-6-nitrochroman thus obtained 1. ．． Dissolve 438g in 120ml of ethanol,
Add 0.75 g of Pd-carbon (ethanol 301),
Hydrogen catalytic reduction is carried out for 2 and a half hours. Pd-carbon was filtered off and evaporated under reduced pressure to obtain 1.514 g of a brown oil. This was separated using a column (dichloroethane/hexane (2:1)) and 6-amino-4,4-dimethylchroman 0.589
8 g (yield 48.0% from 4°4-dimethyl-6-nitrochroman), 0.25 g (17.8%) of 6-ethylamino-4,4-dimethylchroman, 0.25 g (17.8%) of mixture.
5850g was obtained.

6-amino-4,4-dimethylchroman light brown oil NMR (CDCI) δ1.31 (s, 6)
, δ1.82 (t, 2. J=El), δ3.1
4 (s.

2, NH2), δ4.0B (t, 2.J=6), δ
6.3-6. Et5 (m, 3) 6-ethylamino-4,4-dimethylchroman brown oil NMR (CDCI') 61.31 (t, 3
．． J=7), δ1.35 (s, 6), δ1.7
7 (t.

2, J=5), 62.74 (s, 1), δ3.07
(q, 2. J=7Lδ4.04 (t, 2
．． J=5), δ6.2-8.8 (m, 3) real [
-Terefluor-dimethyl 0.188 g (0.495 mmol) of the methyl ester obtained in Example 1 was added to 4.
Dissolved in 5 ml of methanol and added 1.85N caustic potassium 0.
4 ml (74 mmol) was added dropwise, then 2 ml of water was added, stirred for 16 hours (at room temperature), neutralized with IN hydrochloric acid, and extracted with ethyl acetate (2 x 50 sl). Add this to 150w of water
11 Wash with 100 ml of saturated lucium chloride, dry with sodium sulfate, and evaporate under reduced pressure. Pale yellow crystals of terephthalic acid (N-4,4-dimethyl-6-chromanyl)amide 0.180
g (99.3% yield from methyl ester) was obtained. Of this, 148 mg was recrystallized from ethyl acetate-hexane to obtain 94 mg of pale yellow crystals (yield: 58.3%).

m, p, 230.5-231.5° CNMRδ1
．． 35 (s, 8), δ1.84 (tt2, J=
5), 64. 17 (t, 2. J=5), δ5
．． 2 (broad Sr 1), δ6.73 (
d, 1°J=9Lδ7.38 (dd, 1.J=9
．． J=3), δ7.69 (d, 1.J=3), δ7.
97 (d, 2. J=9), δ8. 11 (
d, 2. J=9), 69.32 (s, 1) IR3320cm+-1,3000(broad), 1
72011675.820 Elemental analysis value C, H1gNO4 Calculated value C70, 14%, H5, 89%, N 4.31
% actual value C[i9.82%, C5,92%,
C4,QEi% Ester 200 mg (1,036 + mol) of 6-amino-4,4-dimethylthiochroman synthesized in Reference Example 2 and 205 mg (1,0 mol) of terephthalic acid chloride monomethyl ester.
36 mmol) was added with 1 ml of 101 pyridine in anhydrous benzene, and reacted at room temperature for 1.5 hours with stirring. Add water to the reaction solution and extract with ethyl acetate. 0.2 organic layer
Wash with an aqueous solution of N nitric acid steel until the blue color disappears, and then sequentially with water, saturated bicarbonate water, water, and saturated saline. After dehydration over magnesium sulfate and evaporation of the solvent, 317 mg of the title compound was obtained as pale yellow crystals (86.2%). Recrystallization from methanol gave 248 mg (67.4%) of pale yellow needle crystals. It was crystallized again from benzene to obtain colorless needle crystals.

m, 1), 185-187° C Elemental analysis value C2°H2□N03S Calculated value CC7,59%, C5,9G%, N3
．． 94% actual value CC7, 55%, 85.98%,
N3.67% NMR (60MHz CDCl) δ
1.29s (6H), δ1.8E3m (2H), δ3
．． 00s (2H), δ3.90s (3H), δ6.
97d (IH, J=8.5Hz), δ7゜29dd
(IH, J”8.5Hz, J=2Hz), δ7.89d
(IH, J=2Hz), 67.81d (IH, J=
8.5Hz), δ8.01d (IH, J=8.5Hz)
, δ8.08s (IH)IR(KBr)16EtO(
amide), 1691.1279 c++-' Reference ■-2-dimethyl--3 g of 4,4-dimethyl-6-acetylthiochroman (
13,6ff1mol), H2NOH@HC11゜4
1 g (20.4 mmol) was dissolved in 30 ml of ethanol, pyridine 61 was added thereto, and the mixture was refluxed for 5 minutes. The solvent was distilled off, the solution was dissolved in 200 ml of dichloromethane, washed with water (80 sl), hydrochloric acid (2N, 80+alX2) and brine (80 sl), and dehydrated with sodium sulfate.

The solvent was distilled off to obtain 3.08g of pale yellow crystals (96°4%
)Obtained. This was recrystallized in benzene/hexane to obtain 2.786 g of colorless needle crystals (87.2%).

m, p, 108-109°C Elemental analysis value C, Hl, 7NO8 Calculated value CC8,27%, 87.28%, C5,9
5% actual value C68, 27%, 87.38%, N 5.
73% of the above oxime 2.330 g (9,915 mm
ol) in 70 ml of dry ether and cooled to -10°C with aqueous brine. While stirring this,
1.725 g of thionyl chloride dissolved in ether of sl
(11,90 o 1/1.2 equivalents) was slowly added over 10 minutes. The reaction solution changed from white to yellow to red and a precipitate appeared. After stirring for 30 minutes at -10'C, add brine, add dichloromethane (100ml x 3 times) and extract water (501ml).
l) After washing with saline solution (50 sl) and dehydrating with sodium sulfate,
After evaporation of the solvent, 2.283 g (97.1%) of ocher crystals were obtained.
get. This was recrystallized from benzene/hexane to obtain 1.780 g of acetamide derivative (78,
4%).

m, p, 131-132° C Elemental analysis values C engineering, H engineering, NO3 Calculated values CG6.38%, H7,28%, N 5.
95% Actual -1 value 0 8G, 27%, H7, 31%
, N 5.71% 1.730 g of the above acetamide (7
, 3E3 of) to 60 ml of Claisen alkali (8
8g of caustic potash dissolved in 133ml of water and diluted to 250ml with methanol, 6.29mol/I)
The mixture was dissolved in water and refluxed for 1 hour. Add dichloromethane 1001 and adjust the pH to >7 with hydrochloric acid, then dichloromethane (100
Extract with m+x3), wash with water (50+sl), and dehydrate with sodium sulfate. The solvent was distilled off to obtain 1.318 g (9
2.6%) was obtained. Recrystallization from benzene/hexane gives brown needle-like crystals of 4,4-dimethyl-6-amino-thiochroman.

m, p, 61.5° C calculated value CC8, 37%, C7, 82%, N 7.25
% Actual value CC8, 13%, 87.91%, N 7.
00% 150 g of methyl ester obtained in Example 3 (0,
Dissolve 423 Dragon 01) in 5111 ethanol and add 2N
Add 3.1 parts of caustic soda and stir at room temperature overnight. I in the reaction solution
Add N-hydrochloric acid to bring the pH to <7, then extract with ethyl acetate.

The organic layer was washed with water and saturated saline, and dehydrated with magnesium sulfate. The solvent is distilled off to obtain the title compound as light brown crystals. 145 mg (100%).

Recrystallized from ethyl acetate/hexane to give 6 pale yellow needles.
8.8+++g (47.7%) was obtained.

m, p, 214-215°C Elemental analysis value C engineering. 8. N03S Calculated value CGG, 85%, H5, [i1%, N 4.1
0% actual value C611i, 83%, H5, 85%, N3
．． 8H% NMR (100MHz, CDCl) δ1.
37s (8H), δ1.97m (2H), 63.05
m (2H), δ7. OOd (IH, J=4.8H
z), δ7.38dd (IH, J=4°8 Hz +
J = 2 Hz), δ7.78d (IH,
J"2H2), 67.96 (2H, J=4..8Hz
), δ8.12d (2H, J=4.8Hz) IR(K
Br) 1670 (amide) 1B40.1522.12
83 am-1 RU 1 Hyo U Yu L (L Tue) 208 mg (1 mmol) of 4,4-dimethylchroman-6-carboxylic acid obtained in Reference Example 3 below was dissolved in benzene 7+1, and thionyl chloride 6+al (large excess)
and reflux for 6 hours. After distilling off benzene and thionyl chloride and adding 8ml of benzene and 71ml of pyridine to the residue, methyl 4-ami7benzoate (1,06ml) was added.
After stirring at room temperature for 3.5 days, a small amount of 4-dimethylaminopyridine was added, stirring at room temperature for 21 hours, and refluxing for further 9 hours. After diluting the reaction solution with 30 ml of ethyl acetate, the organic layer was washed in this order with water, 2N hydrochloric acid, water, IN-soda carbonate, water, and saturated brine. After dehydration with magnesium sulfate and concentration, 213n+g of crude crystals (0,570no++ol
).

Crude yield 66%. After recrystallization (benzene-hexane), 187 mg of the title compound are obtained as white crystals.

m, p, 175°C NMR (CDCI) δ1.40 (s, 8. C(CH3)2), δ1
．． 91 (t, J=8Hz, 2, CH2C(CH3
S, δ3゜92 (S, 3. C00CH,),
G4.40 (t, J=2.5Hz, ILδ7.70
(d, J=9Hz.

2), δ7.79 (d, J=2.5Hz, 1), G7
．． 82 (s, 1.C0NH), G8.05
(d.

J=9Hz, 2) IR (KBr) 1710cm-11655cm-1
Elemental analysis value C2゜H2o04NC1Φ1/4H20 calculated value CG3.49%, H5, 4%, N3.70%
Actual value CC3.24%, G5.37%, N3
．． 44% altitude exposed 2.84g (1,85a+mo
l) 30 peng! Suspend it in water and add 1.83 potassium carbonate to it.
g (1°32 mmol) and caustic potash 0.530 g
(3,83m+++o l ) mixed aqueous solution M20+sl
Add slowly and shake vigorously while heating occasionally to make a homogeneous suspension and filter. This filtrate was heated to 55-59°C, and 4°4-dimethyl-6-acetylchroman 533
mg (2, 81 mmol) was added and stirred for 1 hour. After destroying the excess chlorine in the reaction solution and making it acidic by adding dilute hydrochloric acid,
Extracted with ether. The organic layer is washed with water and saturated brine, dried over magnesium sulfate, and concentrated. After recrystallization (acetic acid-hexane), 388 mg (1,52 m Peng o1) of white needles4. 4-dimethyl-8-chloro-chroman-6
- Obtain carboxylic acid. Yield 58%.

m, p, 218-219° C Elemental analysis value C engineering, H engineering, 03C1 Calculated value C59.88%, 85.44% Actual value C5
9.75%, H5.43% 40 mg (0.11 mmol) of the methyl ester obtained in Example 5, 2 al of ethyl alcohol N, caustic soda 2 + 11 were added, and the mixture was stirred at room temperature for 9 hours.

Add IN hydrochloric acid to the reaction solution to adjust the pH to <7, and add 10% ethyl acetate.
Extract 3 times with 1. The organic layer was washed with water and saturated saline, and after dehydration with magnesium sulfate, 71! By condensation, 39 mg (0.1 1++ usol') of crude crystals of the title compound were obtained. Crude yield: 100%.

After recrystallization (acetic acid ethyl hexane), 23 mg of white crystals are obtained.

m. p. 275-278°C NMR (CD OD) δ1.41 (s, 6.C (CH)), δ1.91
(t, J=5Hz, 2, CH2C(CH3)2)
, G4.

36 (t, J=5Hz.2, CH　O), G7.

78 (d.J-8.5Hz.2), 67, 82 (cL
J==3Hz, IL67, 92 (d, J=
3Hz+1), δ7.99 (d.J=8.5Hz.

IR (KBr) 1690cm-1, 1880cm
-1' Elemental analysis value C19H□804NCI Total Wfa C 63.43%, ) (5.04%
．． N 3.89% Actual value C G3.2[,
G5.07II&, N 3.69%1 300++ g (0.802
+smol) is dissolved in 30+l acetic acid containing 329 mg (5 equivalents) of sodium acetate, 600 mg of Pd-charcoal is added, and catalytic reduction is carried out for 4 and a half hours. Filter the reaction solution through double filter paper. The residue is washed with 20σ1 benzene. The filtrate is 8
After diluting with 0 ml of water, neutralize with saturated bicarbonate water (pH 8).
degree) and extracted three times with 100 ml of acetic acid. Combine the washing liquid and extract, wash with water and saturated saline, dehydrate with magnesium sulfate, and concentrate. Crude crystals of the title compound 2 8 1 mg (0
．． 7 7 0+a+nol) is obtained. Crude yield 96%,
After recrystallization (from benzene-hexane) 231 mg of white crystals are obtained.

m. 1), 172° C NMR (CDCI) δ1, 39 (sr 6+ C (CH3)2),
δ1.89 2 (s, 3.COOCB9,G
4. 26 (t, J=6Hz, 2, CH20), G
8. 84 (d. J=8Hz.L H-8), 6
7, 53 (dd. J = 8 Hz, J = 3 H
z + 1 + H − 7), δ7.72(
d. J:=8.5Hz, 2), 67, 90 (d.

J=3Hz+L H-5), δ7.91 (sr
LCONH), δ8.05 (d.J=8.5Hz.

IR (KBr) 1695cm-,', 1 6 7
0cm-1 elemental analysis value CHON・I/8HO calculated value C70, 31%, HG, 27%, N 4.1
0% actual value C70, 30%, HEi, 27%, N 3
．． 89% 180 mg of methyl ester obtained in Example 7 (0,5
32 mmol) was dissolved in 4 ml of ethyl alcohol, 2N caustic soda 2111 was added, and the mixture was stirred at room temperature for 21 hours.

After the same post-treatment as in Example 6, crude crystals of the title compound I
7 mg (0,513 imol) of Ei is obtained. Crude yield 96%, recrystallized (from ethyl acetate-hexane) to 1
12 mg of white crystals are obtained.

m, 1), 243-245" C NMR (CD OD) 61, 40 (s, 6. C (C horse) 2), δ1.8
7 (t, J=5Hz, 2, CHfJ(CG3)
p, 64°26 (t, J=5H2,2,CH20), G
8°82 (d, J=8Hz, 1.8-8), δ7.6
8 (dd, J=8Hz, J=3Hz, 1.8-7),
δ7.80 (d, J=8Hz, 2), δ7.97 (
d, J”3Hz, 1.8-5), 68.00(
d, J=8Hz, 2) IR (KBr) 1680cm-1,1655cm-
1 element analysis value CHON calculated value (: 70.14%, 85.89%, N
4.31% actual value C1li9.99%, H5,88%
, N4.50% 1,1-dioxo- obtained in Reference Example 4
4,4-dimethylthiochromancarboxylic acid 994.0m
A small amount of thionyl chloride and 0.8 cc of DMF were added to g while stirring on a water bath, and the mixture was reacted for 1 hour. TLC(
After confirming the completion of the reaction using 1% ethyl acetate/hexane, thionyl chloride was distilled off at room temperature under reduced pressure, and benzene was added to remove as much thionyl chloride as possible by azeotropy.

To this, methyl p-aminobenzoate 891. E3mg (
Add 0.3cc (1 equivalent) of pyridine dissolved in 3Qcc of benzene on a water bath while stirring.
, 50 mg of 4-(N,N-dimethylamino)pyridine was added and reacted for 1 hour. After confirming the completion of the reaction by TLC (dichloromethane), dichloromethane was added to the reaction solution to dissolve the precipitate, and water was added to the saturated solution. Sodium bicarbonate, 2N
Wash with hydrochloric acid and dehydrate with sodium sulfate. The solvent was distilled off to obtain 1.173 g of white powder (yield 77.5%). This was recrystallized from ethyl acetate/hexane to give the title compound as white needle crystals, 251.4 mg (m, 1), 230-2
31°C) was obtained.

NMR (CDC1/DMSO) δ1.17 (s, 8H, C(CH3)2), G2°CH25), G3.55 (s, 3H, C00CH3
), δ7.8 (m, 7 H+ A r −H),
δ9.64 (s, IH, NH) Elemental analysis value calculation value CG2.00%, H5,4H%, N3.82%
Actual value (: G1.7H%, 85.38%,
N 3.34% In the same manner, using the sulfoxide compound obtained in Reference Example 4 instead of the sulfone compound as a raw material, the corresponding sulfoxide target compound was obtained.

Suspend 13.50 g of highly bleached powder in 53 cc of warm water, 12.4 Etg of potassium carbonate, 3.56 g of caustic potassium and 2 f3 c of water.
Add the solution dissolved in C little by little while mixing well, and add K
An OCI solution (g equivalent) was prepared. 4゜4-dimethyl-
The KOCI solution was added to 3.00 g of 6-acetyl-thiochroman while stirring on a water bath, reacted for 80 minutes, and further reacted overnight at room temperature. After confirming that the reaction was almost completed by TLC, add 3.7 ml of acidic sodium sulfite.
g/14 cc of water was added, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was extracted with 2N sodium bicarbonate. This was neutralized with 2N hydrochloric acid and extracted with acetic acid. The organic layer was dehydrated with sodium sulfate and the solvent was distilled off to obtain 3.03 g (yield 87.5%) of a white powder mainly composed of sulfone compounds (m,
p, 193-195'C) was obtained.

MS:M”=254 NMR (CDCI DMSO) δL 47 (s, 8H, C(CH3)2), 62
゜4 (m, 2H, CCHC), G3. 5 (m,
2H, CH8), G8. O(m, 3H, Ar
-H) Depending on the conditions, the corresponding sulfoxide was mainly obtained.

Example - 111.3 mg of the ester obtained in Example 9 was added with 4 methanol.
cc, IQ% caustic soda lcc is added, and the mixture is stirred at room temperature for 20 hours. After confirming the disappearance of the raw material ester by TLC (dichloromethane), a saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is washed with dichloromethane. The mixture was neutralized with 2N hydrochloric acid, extracted with ethyl acetate, dehydrated with sodium sulfate, and the solvent was distilled off to obtain 112.7 mg of white powder (yield: 100%).

This was recrystallized from ethyl acetate/hexane and white needle crystals 61
．． 8 mg was obtained. (Yield 54.8%) m, p, 293-294°C NMR(CI)C13・DMSO) δ1.5 (s, 6H, C(CH) L δ2.2(
m, 2H, CCHCLδ3- 5 (m+ 28IC
HlS), G8 (m, 7H+ Ar H), G
9゜2 (s, IH) Practical History - Part 1 Azobenzenecarbon - Conductor CH3C
o2H 6-amino 4,4-dimethylchroman 1 obtained in Reference Example 1
10 mg (0.62 smol) and 94 mg of methyl p-nitrosobenzoate (0.62 mmol) were added to 5 m of acetic acid.
1 and stirred overnight at room temperature in the dark.

Pour the reaction solution into water, extract with ether, and add the organic layer to water for 18 hours.
Wash three times with sodium bicarbonate, water and saturated brine, dehydrate over magnesium sulfate, and evaporate the solvent. The product was purified by silica gel column chromatography to obtain 124 mg of azo methyl ester (yield: 64.4%). Recrystallized from hexane to produce orange phosphorus flakes. m, 1), 142-143°
C NMR (100MHz t CD CI3) δ1.4
3s (6H), δ1.90t (2H, J=6Hz)
, 63.98s (3H), 64.29℃ (2H1J
=6H2), δB, 90d (LH.

J=9Hz), δ7.72dd (IH, J=2゜9H
2), δ7.88d (2H, J=8.5Hz), δ7
．． 95d (IH, J=2Hz), δ8.15d (
2H, J=8.5Hz) Elemental analysis value C19H2゜N2O3 Calculated value C70, 35%, H8, 22%, N 8.64
% Actual value C70, 23%, 88.17%, N
8.77% 90 mg of the above methyl ester (0,29
mmol) in 3 ml ethanol. Under Ar substitution, 2N caustic soda 21+11 was added, and the mixture was stirred overnight at room temperature in the dark. IN hydrochloric acid was added to the reaction solution to adjust the pH to <7, and the precipitate was extracted with ethyl acetate. The organic layer was washed with water until the pH became 7, and then dehydrated with magnesium sulfate. The solvent was distilled off to give 75 mg of azocarboxylic acid (yield: 187°3%).
get. Recrystallization from ethyl acetate gave orange needle crystals.

m, p, 285-286°CO NMR (100MHz, CD OD) δ1.43s
(6H), δ1.90t (2H, J= 5 Hz)
, δ4.29t (2H,, I"5Hz), δ6.8
8d (IH, J=9Hz), 67.69dd (IH
, J=2.9Hz), δ7.88d(2H, J-8,5
Hz), δ7.96d (IH.

J=2Hz), δ8.13d (2H, J=8.5Hz
) Elemental analysis (ilIC18H18N203 calculated value CG9
．． EiG%, 85.85%, N 9.03% Actual value CG 9.93%, 85.92%, N 9.20% Similarly, the corresponding azocarboxylic acid methyl ester of X=S m, p, 182. 5-163.5°C1 and the corresponding azocarboxylic acid m, 1), 27B.

5-278°C was synthesized.

Tendo J1-Lz Chalcone Carvone 9゛-ketone body 1
15 mg (0.52 mmol) and terephthalaldehyde m+so I) were dissolved in 5 parts ethanol, 1 part fat, and 2
Add N caustic soda and stir overnight. IN hydrochloric acid was added to the reaction solution to adjust the pH to <7, and the precipitate was extracted with ethyl acetate. The organic layer was washed with water until the pH reached 7, dehydrated with magnesium sulfate, and the solvent was distilled off to obtain the desired chalcone carboxylic acid 15.
0 mg (yield 78.4%) is obtained. Recrystallize from ethyl acetate/hexane to obtain pale yellow prism crystals.

m. p. 217-218.5° CONMR (1
0 0 MHz, C D 30 D) δ1.
39s (E3H), 61.9-2.1m (2H), δ
3. O-3.2m (2H), δ7.18d (IH.J
=8Hz), 67, 77dd (IH.

J=2+8Hz), δ7.80s (2H), δ7
.

82d (2H.J=8Hz), δ8.06d (2
H, J=8Hz), δB. 11d (IH, J=2Hz
).

Similarly, the corresponding compound of X=0, m. p. 22
Obtain 3-225°C.

Claims (3)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R is an alkyl group having 1 to 4 carbon atoms, especially a methyl group or an ethyl group, R_1 is a halogen atom, and R_2 is Hydrogen atom, methyl group or ethyl group, X is oxygen atom, sulfur atom, =SO_2, =SO, =NH, =N
-CH_3, or =N^+(CH_3)_2 groups, and Y is a group of the following formula -CONR_3- -NR_3CO- -COCR_3=CR_3- -CR_3=CR_3CO- -N=N- -N=N(O)- -N(O)=N- ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_3 is a hydrogen atom, a methyl group or an ethyl group, and may be different from each other.) Benzoic acid derivative represented by (2) (a) The group Y in the following general formula (I) is -CO-CR
By condensing a compound showing a _3=CH- group with a corresponding acetophenone derivative and a terephthalaldehyde acid ester or its derivative in the presence of a base, (b) Y represents a ▲mathematical formula, chemical formula, table, etc.▼ group. By oxidizing a compound in which the corresponding Y group is a CR_3■CR_3 group using an epoxidizing agent, (c) a compound in which Y is a -N=N group can be obtained by oxidizing the corresponding aniline derivative in the presence of an acid catalyst or By condensation with para-nitrosobenzoic acid ester in the absence of
(e) Y is -N=N(O)- group or -N(O )=N-
By condensing the compound which is a group with the corresponding etrosobenzene derivative and parahydroxyaminobenzoic acid or its derivative in the same manner as in section (c), (f) Compounds in which Y is -NR_3-CO- group correspond. By acylating an aniline derivative with a reactive derivative of terephthalic acid (such as an acid halide or ester), (g) a compound in which Y is -CO-NR_3- can be converted to para-aminobenzoic acid or its ester with the reactivity of the corresponding benzoic acid. General formula (I) characterized in that it is produced by acylation with a derivative (acid halide or ester, etc.) by a conventional method, and the compound thus obtained is hydrolyzed as desired ▲Mathematical formula, chemical formula, table etc.▼ In the formula, R is an alkyl group having 1 to 4 carbon atoms, especially a methyl group or an ethyl group, R_1 is a halogen atom, R_2 is a hydrogen atom, a methyl group or an ethyl group, X is an oxygen atom, Sulfur atom, =SO_2, =SO, =NH, =N
-CH_3, or =N^+(CH_3)_2 groups, and Y is a group of the following formula -CONR_3- -NR_3CO- -COCR_3=CR_3- -CR_3=CR_3CO- -N=N- -N=N(O)- -N(O)=N- ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_3 is a hydrogen atom, a methyl group, or an ethyl group and may be different from each other.) A benzoic acid derivative represented by manufacturing method (3) An agent for inducing differentiation of cancer cells, particularly leukemia cells, characterized by containing a benzoic acid derivative represented by general formula (I)