JPH02247185A - Novel benzoic acid derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 is H, OH or lower alkanoyl; R2 is H or lower alkyl; x is -CONH-, -COO-, -OCO- or -COH=C(OH)-; n is 1 or 2]. EXAMPLE:4-[3,5-Bis(trimethylsilyl)phenylcarboxamide]benzoic acid. USE:A differentiation inducing substance for cancer cell, especially leukemia cell. A remedy for psoriasis. A remedy for immunological disease and inflammatory disease. PREPARATION:A compound of formula I wherein X is -CONH- can be produced by converting a benzoic acid derivative of formula n to its reactive derivative (acid halide, mixed acid anhydride, etc.), condensing the compound with p- aminobenzoic acid or its ester derivative and optionally hydrolyzing the resultant compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel benzoic acid derivative useful as a pharmaceutical and a method for producing the same.

Conventional technology Cancer treatment methods can be roughly divided into surgical therapy and scientific therapy that directly or indirectly kills cancer cells, but a third method is to promote differentiation of cancer cells and eliminate cancer. An interesting method has been discovered.

[(a) Proc, Natl, Acad, Sci, V
SA 772936 (1980)(b) J, Med
, Chem, 25]-269 (1982), B], o
od, 62709 (1983) (c) Cell Engineering 2 N
o,]-2(1,98:3)(d) THE RECI
NOIDS Vol, 1-2. M, B, 5porn e
tal ACADEMIC PRESS 1984 These documents report that retinoic acid (vitamin A acid) and its related compounds exhibit characteristic effects in the treatment of tumors and dermatology. Furthermore, German publication 2854354 states that P-((E)-2-(5,6,7
It has been reported that ,8,-teihelahydro5,5,8,8-te1-ramethyl-2-naphthyl)propenyl)benzoic acid can be used for the systemic and local treatment of benign or malignant tumors and for the prevention of the above-mentioned diseases. ing.

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

Furthermore, JP-A-61-22046.61-22047.61
-76440 has the general formula (V) (in the formula R□ lR2'
lR3'lR4' l and R5' represent a hydrogen atom or a lower/intermediate alkyl group, and two adjacent ones thereof can be taken together to form a 5- to 6-membered cycloalkyl group. However, all of them cannot be hydrogen atoms at the same time, and R6' is a hydroxyl group, a lower alkoxy group,
N R7'RB' group (in the formula, R7' and R8' represent a hydrogen atom or a lower alkyl group), and X' is
-C)I=CI+-, -NHCO-, -CON)I-,
-C0CH=CB-, -N=N-. It has been reported that the benzoic acid derivatives shown in ) and their related compounds similarly exhibit extremely strong physiological activity, and related compounds have also been reported in JP-A No. 62-215581. These documents describe methods for measuring the activity of these compounds using human acute promyelocytic leukemia HL-60 cells and the activities of these compounds. Then, R
As 2rR3' and R4', those having a medium size are particularly advantageous, and in particular, isopropyl groups, butyl groups, and those which together form a 5- or 6-membered cyclic alkyl group are preferred. It is also explained that hydrogen atoms and methyl groups are particularly effective as R,' and R8', and that R6' is preferably a hydroxyl group or a me-1-oxy group.

The object of the present invention is to develop another compound that has the possibility of alleviating the side effects of the above-mentioned known compounds and expanding the therapeutic area, thus enriching the technology. There is a particular thing.

Now, the above-mentioned problem for converting gp to -CON H-, -COO-, -0CO- or C0CH=C(OH)-, and n represents 1 or 2), or a pharmacologically acceptable derivative thereof It has been found that this can be achieved with salt.

In the compound represented by general formula (I), examples of the lower alkanoyl group represented by R□ include acetyl,
Examples of the lower alkyl group represented by R2 include propionyl, butyryl, etc., and examples of the lower alkyl group represented by R2 include methyl, ethyl,
Examples include n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl, and tert-butyl groups.

The compound represented by general formula (I) can form a salt with a base, and the present invention provides pharmaceutically acceptable salts of general formula (I), such as metal salts such as sodium, potassium, and calcium salts, ammonium salts, etc. Salts and methylamine, ethylamine, 1-lymethylamine, triethylamine, pyridine.

Contains salts with organic bases such as picoline, arginine, and lysine.

The novel benzoic acid derivative represented by general formula (I) of the present invention is produced by the following method. That is, (a) a compound in which the group X of general formula (I) represents -CONH- is a benzoic acid represented by the following general formula (II) (wherein R1 and n represent the same meanings as above). The derivative is converted into its reactive derivative (acid halide, mixed acid anhydride, etc.) by a conventional method, and then condensed with P-aminobenzoic acid or its ester derivative in the presence or absence of a base in an inert organic solvent. It can be manufactured by

Examples of the base used in this condensation reaction include pyridine, picoline, lutidine, N-methylpiperidine, N-methylmorpholine, trimethylamine, triethylamine, potassium carbonate, and sodium carbonate. Any inert organic solvent may be used as long as it does not inhibit the reaction, such as ether, benzene, toluene, ethyl acetate, tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl sulfoxide, N, N- Examples include dimethylformamide, and the reaction temperature ranges from 0°C to the reflux temperature of the solvent used.

(b) A compound in which the bracket X of general formula (I) represents -C○○- is obtained by converting the benzoic acid derivative represented by the general formula (n) by a conventional method to its reactive derivative (acid halide, mixed acid It can be produced by converting the compound into anhydride, etc.) and then condensing it with P-hyaloxyben, C1 aromatic acid or its ester derivative in an inert organic solvent in the presence or absence of a base.

Base used in this condensation reaction, inert organic solvent,
and the reaction temperature is above ii! Follow method (a).

(c) Compounds in which the group X of general formula (I) is 1○CO-.

(In the formula, R1 and n represent the same meanings as above.) A phenol derivative represented by the formula (wherein R1 and n represent the same meanings as above) is mixed with a reactive derivative of terephthalic acid or its ester derivative (acid halide, mixed acid anhydride, etc.) in the presence of a base or in the absence of a base. It can be produced by condensation in the presence of an inert organic solvent.

Base used in this condensation reaction, inert organic solvent,
The reaction temperature is the same as in method (a) above.

(d) A compound in which the group X in the general formula (■) is 100CR=C(OH) and R1 is a hydroxyl group at the 2-position is a compound according to the following general formula (IV).
It can be produced by rearranging the terephthalic acid derivative represented by the formula (wherein R2 and n have the same meanings as defined above) in a solvent (Baker-Pen-Talaman rearrangement) in the presence of an alkali catalyst.

The alkali catalyst used in this rearrangement reaction is
Examples include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium alcoholade, sodium hydride, etc. Any solvent may be used as long as it does not inhibit the reaction, such as methanol. .

Examples include ethanol, acetone, benzene, toluene, pyridine, etc., and the reaction temperature ranges from 0°C to the reflux temperature of the solvent used.

The compound obtained as follows may be further hydrolyzed if desired. This hydrolysis reaction is carried out using an alkali catalyst, such as sodium hydroxide, potassium hydroxide, carbonate 1-
It is carried out in a conventional manner using potassium carbonate and potassium carbonate.

It should be noted that the compounds represented by the general formulas (II) and (1-cho) which were used as starting materials in the method of the present invention are new compounds, with some exceptions, and the manufacturing method thereof is described in Reference Examples.

Representative examples of the active compound represented by the general formula (I) produced in the manner described above include the compounds listed below.

4-(3-trimethylsilylphenylcarboxamide)
Benzoic acid 1-(3-1~limethylsilyl phenyl lupoxamide) Methyl benzoate 4- [3,5-bis(trimethylsilyl)phenylcarboxami-1-]benzoic acid 4- [3,5-bis(trimethylsilyl)] Methyl phenylcarboxamitocobenzoate 4-(3-1-limethylsilylphenylcarboxy)methylbenzoate 4-[3,5-bis(1-limethylsilyl)phenylcarboxy]methylbenzoate 4-(2-acetyl- 4-trimethylsilylphenoxycarbonyl) methyl benzoate 4-(2-acetyl-5-trimethylsilylphenoxycarbonyl) methyl benzoate 4-[1-hydroxy-3-(2-hyroxy-4-
1] Limethylsilylphenyl)-3-oxo-1-propenyl]benzoic acid 4-[1-hydroxy-3-(2-hydroxy-4-1
-methylsilylphenyl)-3-oxo-1-propenyl]methylbenzoate 4-[1-hydroxy-3-(2-hydroxy-5-1
~limethylsilylphenyl)-3-okine-proper]benzoic acid 4-[1-hydroxy-3-(2-hydroxy-5-1
Methyl helimethylsilylphenyl)-3-oxo-1-propenyl]benzoate The compound represented by the general formula (I) of the present invention morphologically and functionally promotes the differentiation of cancer cells, particularly leukemia cells. Treatment of proliferative and immunological malignant skin diseases accompanied by keratinization and inflammation, such as cancer, leukemia, T-cell malignancy, and dry cast.
It is useful for treating immune diseases such as rheumatism and suppressing immune rejection during organ transplants.

The compounds of the present invention can be used in the treatment of cancers such as T-cell leukemia, acute myeloid leukemia, neuroblastoma, squamous cell carcinoma, etc., by systemic administration, injection or oral administration at doses lower than 5111 g/kg per day, especially at doses lower than 0.5 g/kg per day. 001-1 mg/kg/day, and for skin diseases such as psoriasis, alone or in combination with other drugs such as anthralin, topical corticosteroids, selective UV therapeutic agents, etc. , 0.1-], Omg/g/day, as an ointment cream, etc.

The present invention will be explained below with reference examples and examples.
The invention is not limited to these specific details.

Reference Example 1 2.0 g (14 mmol) of 3.5-bis(1 helimethylsilyl)benzoic acid highly bleached powder, 1.38 g of potassium carbonate (
], Ommol), potassium hydroxide 0.40g (7,1
A suspension of 2 mmol) in water (40 ml) was heated at 65°C for 30 min.
Stir for a minute and filter. The filtrate was mixed with 0.53 g (2 mmol) of 3',5'-bis(trimethylsilyl)acetophenone.
) and heated under reflux for 7.5 hours while stirring. After cooling,
After adding 3 ml of IN aqueous sodium bisulfite solution to destroy the chlorine, the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over Glauber's salt, the solvent was distilled off, and the residue was purified using a silica gel column (eluent: n-hexane/ethyl acetate 2:1 to 1:1). 0.27 g of white powder was obtained (yield 51z).

m, p, 300°C or higher'IH-NMII Spectrum 1~L δ(CDC1a)p
pm: 0, 32 (1811, s), 7.138
(ill, t: J = l, 1llz), 8.
24 (211, d: J=1, ], IIz) MS:
266 (M”) Example 1 4-[3,5-bis(1-limethylsilyl)phenylcarboxamitocobenzoic acid a) 4-[3,5-bis(1-limethylsilyl)phenylcarboxamitocobenzoic acid 1-]benzoic acid Methyl 3,5-bis(trimethylsilyl)benzoic 11(1,0
6% (4nono1), 1.05 g of calcium carbonate, and 104 ml of dry benzene were mixed with 0.64 ml (8.8 mmol) of thionyl chloride and N under stirring at room temperature.

N-dimethylformamide 0.34 ml (4.4 mmo
l) was added. After stirring at room temperature for 3 hours, calcium carbonate was filtered off, and the filtrate was concentrated under reduced pressure. Dissolve the residue in 25 ml of dry tetrahydrofuran and add 1 to 1 ethylamine.
．． 23ml (8,8nonol) and 665mg (4,4nonol) of methyl P-aminobenzoate were added, and the mixture was stirred at room temperature overnight. After making the mixture weakly acidic with 0.5N hydrochloric acid, it was extracted with methylene chloride. The extract was washed with water and saturated brine, dried over Glauber's salt, and then the solvent was distilled off. The residue was purified with a silica gel column (eluent: n-hexane/i!ethyl acid 5:1) to obtain 1.34 g of pale yellow crystals (
Yield 84〆).

m, p, 191-192°C MS spectrum m/z: 399 (M dimension)' II-NM
R spectrum δ (CDCl2) ppm: 0.3
1 (18H, s), 3.90 (3H, s), 7.7
4 (211,d:J-8,8tlz), 7.83(
Ill, t: J-1, 1Hz), 7.96 (2H
, d: J4, 1llz), 8.04 (2H,
d: J=8.8Hz), 8.1.4 (IH, br
-s)b)4-[3,5-bis(trimethylsilyl)
Phenylcarboxamitocobenzoate 4=[3,5-bis(trimethylsilyl)phenylcarboxamitocobenzoate methyl 22 mg (0,055 mm
ol) was dissolved in 6 ml of ethanol, 3 ml of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. 0.5
The mixture was made weakly acidic with N-hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and then the solvent was distilled off. The residue was recrystallized from ethyl acetate-〇-hexane to obtain the title compound as a colorless prism.
m [obtained (yield 661).

m, p, 276-280'C (decomposition) MS spectrum m/z: 385 (M'')'H-NMR spectrum 1-
δ(CDCl2)ppm: 0.33(1811,s
), 7.78 (2tl, d:J=8.8Hz), 7
．． 84 (111, brs), 7.94 (211,
d: J=0.9Hz), 8.14 (2H, d:
J=8, 8Hz) Example 2 Methyl 4-[3,5-bis(1-limethylsilyl)phenylcale5boxy]benzoate 3,5-bis(1-helimethylsilyl)anbu, folic acid 665
+ n bar (2.5 mmol), calcium carbonate 670 m (
H, dry benzene 62.5 m], thionyl chloride 0.4x1 (5.5 m1nol), N,
N-dimethylformamide 0,21ml (2,75m
mol) was added.

After stirring at room temperature for 3 hours, the returned calcium oxide was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 17.5 ml of dry tetrahydrofuran (THF), 0.77 ml (5.5 mmol) of triethylamine and 418 mg (2.75 mmol) of methyl P-hydroxybenzoate were added, and the mixture was stirred at room temperature for one day. After making the mixture weakly acidic with 0.5N hydrochloric acid, it was extracted with methylene chloride. The extract was washed with water and saturated brine, dried over Glauber's salt, the solvent was distilled off, and the residue was purified with a silica gel column (eluent: n-hexane/ethyl acetate lo: 1) to give white crystals with 0. 93g was obtained (yield 93%). This was recrystallized from aqueous methanol to obtain 0.79 g of the title compound in the form of colorless needles (yield 79%).
.

m, p, 81-82℃ MS Spec I-le m/Z: 400 (8mm, 385(M")
-15) "H-NMR spectrum 1~ru δ (CDCl2)
ppm: 0.33 (188, s), 3.93 (31
+, s), 7.30 (2H, d: J=8.81
1z), 7.91(1)1. t: J=0.9t
lz), 8.13(211,d:J=8.811z
), 8.30 (ltl, d:J=0.9Hz) Reference example 2 2'-hydroxy-5'-1~limethylsilylace1~
Phenone a) 2-(5-bromo-2-1-limethylsilyloxyphenyl)-2-methyl-1,3-dioxolene 2-(5
-bromo-2-hyroxyphenyl)-2-methyl-
3.11 g (12 mmol) of 1,3-dioxolene was added to T
Dissolved in 24 ml of HF and stirred with water cooling, add 1.84 ml (13,2 mmol) of triethylamine, followed by 1.68 ml (13,2 mmol) of 1-limethylsilyl chloride.
1. ) was added dropwise. After stirring at room temperature for 2 hours, filter
The filtrate was concentrated under reduced pressure to obtain 4.0 g of crude product.

b) 2'-hydroxy-5r h-lymethylsilylacetophenone magnesium 321 mg (13,2 nunol), methyl iodide 0.07 ml, dry T HF 1.321 I
The mixture was heated to reflux and, after cooling, diluted with 3.96 ml of 1-lye THF. A solution of 40 g of 2-(5-bromo-2-trimethylsilyloxyphenyl)-2-methyl-1,3-dioxolene obtained above in dry THF (9.6 ml) was added dropwise to this mixture under reflux. , and further heated under reflux for 2 hours. After cooling, 1.68 ml (13.2 mmol) of 1-limethylsilyl chloride
．． ) was added and heated again for 3 hours. Water was added to the reaction mixture and extracted with ether.

The extract was washed with water and saturated brine, dried over Glauber's salt, and then concentrated under reduced pressure. The residue contained 721 m of acetic acid and 10.8 m of water.
g (600 mmoi), P P T SO, 46 g (
1.8 mmo'J-) was added thereto, and the mixture was heated under reflux for 3 hours.

After cooling, it was concentrated under reduced pressure, and the residue 'a' was dissolved in ether. The mixture was washed with water, a 1-lium hydrogen carbonate aqueous solution, and saturated brine, dried over Glauber's salt, and then concentrated under reduced pressure. Dilute the residue with silica gel (eluent: n-hexane/ethyl acid 20:1)
1.66 g of pale yellow liquid was obtained (yield 67%).
).

MS spectrum m/z: 208 (M+), 1.93
(K''-15)' H-NMR spectrum 1-rule δ(CO
Cl, ) ppm: 0.28 (911,s), 2.
65 (311, S), 6.96 (III, d: J
-7,9l-1z), 7.59(iH,dd:J
=7.9. ],, 81Jz), 7°84(Il
l, d: J = 1.8 Hz), 12.31 (IN, s
) Example 3 Methyl 4-(2-acetyl-4-1-limethylsilylphenoxycarbonyl)benzoate -) to THF
20 m], and under water-cooling stirring, add 0.0 m of triethylamine.
61m], (4,1nuno1.), followed by terephthalic acid monomethyl ester chloride l; 874mg (4,1nuno1.);
4111 mol) was added. After stirring for 1 hour at room temperature,
It was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water, an aqueous solution of 1-lium bicarbonate, and saturated brine, and then dried over Glauber's salt.

It was concentrated under reduced pressure, and the residue was purified using a silica gel column (eluent: n-hexane/ethyl acetate 5:1) to give white crystals J.
.

25g was obtained (yield 85z).

m, p, 33.5-90°5°C MS level m/z: 370 (Ken)"+1-NM
R spectrum δ (CDCl2) ppm: 0.32
(911,s), 2.55 (3H,s), 3.97
(311,s), 7.22(+, H, d: J near,
7Hz), 7.73 (LH, dd: J=7°7,
1.511z), 7.97 (], H, d: J=1
．． 5Hz), g, 16 (211, d: J=8.
811z), g, 29(2+1.d: J=8.81
1z) Example 4 4-[1-hydroxy-3-(2-hydroxy-5-trimethylsilylphenyl)-3-oxo-1-propenyl]benzoic acid a) 4-[1-hydroxy-3-(2-hydroxy -5
Methyl trimethylsilylphenyl)-3-oxo-1-propenyl]benzoate 740 mg (2 mmol)
) To 14 ml of tr-pyridine was added 280 mg (5 mm.1) of pulverized potassium hydroxide while stirring at room temperature. After stirring overnight at room temperature, the reaction was dissolved in cold 20% aqueous acetic acid (5%
5m1. ) poured inside. The extract was extracted with ethyl acetate, washed with water and saturated brine, and dried over Glauber's salt. It was concentrated under reduced pressure, and the residue was purified with a silica gel column (eluent: RL-hexane/ethyl acetate 5:1) to obtain 200 mg of yellow crystals (
Yield 27″1).

m, p, 129.5-13180 MS spectrum m/z: 370 (M”)”+1-N)
IR spectrum δ(CD'C13)PPm'0,3
1(9)1. s), 3.96 (311, s)
, 6.88 (IN, s), 7.00 (Ill,
d: J=7.911z), 7.61 (III, dd
: J=7.9, 1.311z), 7.85(III,
d:J=1.3+Iz), 7.97(2H, d:,]
=8.8Hz), 8.17(2H, d: +4.8H
z), 12.04 (LH,s), 15.44
(LH, 5) b) 4=[i-hydroxy-3-(2-hydroxy-5
1-helimethylsilylphenyl)-3-oxo-1-propenyl]benzoic acid 4-[1-hydroxy-3-(2-hydroxy-5-1
~Methyl silyl phenyl)-3-oxo-1-probel]benzoate 148 mg (0.4 mmol 1.)
was dissolved in 20 ml of ethanol, and 2 ucl of 2N aqueous 1-lium hydroxide solution was added while stirring at room temperature. After stirring for 1 hour at room temperature, 10% hydrochloric acid was added to adjust the pH to 4. The extract was extracted with ethyl acetate, washed with water and saturated brine, and then dried over magnesium sulfate. It was concentrated under reduced pressure, and the residue was recrystallized from methanol to obtain 72 mg of the title compound as yellow needles (
Yield 51z).

m, p, 207-209°C MS spec 1~le z: 356 (Ari' II-N)
IR Spec 1 Hel δ (CDCl2) ppm: 0.2
6 (911, s), 6.84-8°30 (8t+, m) Reference example 3 2'-hydroxy-4'-1-limethylsilylacetophenone a) 2-(4-bromo-2-trimethyl silyloxyphenyl)-2-methyl-1,3-dioxolene 1-(4-
Bromo-2-hydroxyphenyl)-2-methyl-1,
3.11 g (12 mniol) of 3-dioxolene was added to T
fW IN to 24 ml of HF, under water-cooled stirring, add 1.84 ml (13.2 mmol) of 1-ethylamine, followed by 1. ．． 68m1 (13,
2n+mo1. ) was added dropwise. After stirring at room temperature for 3 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 4.0 g of a crude product.

b) 2'-Hydroxy-4'-1-limethylsilylacetophenone Magnesium 321 mH (1,3,2 mmol.), Methyl iodide 0.07 resistance.

A mixture of dry THF 1.32n+]- was heated to reflux and after cooling, dry THF 3.96m
Diluted with 1. The above-obtained 2
-(4-Bromo-2-1helimethylsilyloxyphenyl)-2-methyl-", 4.0 g of 3-dioxolene in a volume of dry TI The mixture was heated to reflux. After cooling, 1.68 ml (13,211+11o1) of 1-lymethylsilyl chloride was added, and the mixture was heated again for 2 hours.

After cooling, water was added to the reaction solution and extracted with ether.

The extract was washed with water and saturated brine, dried over Glauber's salt, and then concentrated under reduced pressure. Add 1 to 72 ml of acetic acid to the residue, water], 0.8
m1. (600mmo], ), P P T S 0.4
6 g (1.8 mmol) was added and heated under reflux for 4 hours. After cooling, the mixture was neutralized with 10% hydrogen carbonate and thulium, and concentrated under reduced pressure.

The residue was dissolved in ether, washed with water, an aqueous solution of hydrogen carbonate, and saturated brine, and then dried over Glauber's salt. It was concentrated under reduced pressure, and the residue was purified with a silica gel column (eluent: 11-hexane/ethyl acetate 1.5:1) to give a pale yellow liquid 1.
．． 08EX was obtained (yield 43z).

MS spec 1~le m/z: 208 (M”), 1.93
(M'-1,5)'-H-NMR spectrum δ(C
DC1,) ppm: 0, 27 (911,s), 2
．． 63 (:llI, s), 7.03 (il
l, dd: J=7.911z, 1.311z),
7゜14 (II(,d:J4.311z), 7
．． 69 (Ill, d: J=7.911z), 1
2.15(III, s) Example 5 Methyl 4-(2-acetyl-5-trimethylsilylphenoxycarbonyl)benzoate 2'-H-1-Roxy 4'-trimethylsilylace1-
832 mg (4 mmol) of phenone was added to T I-(F 2
Dissolved in 0 ml of ethylamine and 0.0 ml of 1 to ethylamine under water-cooling and stirring.
61ml (4,4+nmol) followed by 74Il1g (4,4+nmol) of terephthalic acid monomethyl ester chloride III
4nun○1) was added. After stirring at room temperature for 1 day, it was filtered and the filtrate was concentrated under reduced pressure. Add ethyl acetate to the residue,
After washing with water, aqueous sodium bicarbonate solution, and saturated brine, it was dried over Glauber's salt.

It was concentrated under reduced pressure, and the residue was purified by a silica gel column (eluent: n-hexane/ethyl acetate 5:1) to obtain 1.40 g of a pale yellow viscous liquid (yield 95%).

MS spectrum m/z: 370 (M”) 1-11-N
MR spectrum δ (CDCl2) ppm: 0.3
], (song, s), 2.54 (3It, s), 3.
98 (311, s), 7.34 (Ill, d:J
=I, IHz), 7.51 (II(, dd:
J=7゜5.1, 1.1(z), 7.84 (]
, +l, d: J=7.511z), 8.16(
2H, d:J:9.0Hz), 8.30(2fl,
d: J=9.01lz) Example 6 4-[1-hyroxy-3-(2-hydroxy-4-
1-limethylsilylphenyl)-3-oxo-1-probel]benzoic acid a) 4-[1-hydroxy-3-(2-hydroxy-41-limethylsilylphenyl)-3-oxo-1- propenylconic acid, methyl sulfonate 4-(2-acetyl-51-lymethylsilylphenoxycarbonyl)ammonium, methyl sulfate 740 mg (2 mmol)
) was dissolved in 4 ml of pyridine I, and 280 mg (5 mmol 1.) of pulverized potassium hydroxide was added thereto while stirring under water cooling.

After stirring for 1.5 h under water cooling, the reaction solution was cooled to 20%
Poured into aqueous acetic acid solution (55ml). The extract was extracted with ethyl acetate, washed with water and saturated brine, and then dried over sodium sulfate. Concentrate under reduced pressure and transfer the residue to a silica gel column (eluent: n-
Purified with hexane/ethyl acetate 5:1), yellow crystals 51
0 mg was obtained (yield 69I).

m, p, 152 (54°C MS spec I~le m/z: 370 (M”) Jl-NM
Rsubek[・ru δ(CDCl2)ppm: 0.29(
911, s), 3.96 (3) 1. s), 6.89(]
-11, s), 7.06 (III, dd: J near, 9° 0.911z), 7.17 (11+, d: J = 0.91
1z), 7°73 (Ill, d:J=7.911z),
7.97 (211, d: J=8.811z), 8.
15(211,d:, ]=8.811z), I
], 91 (Ill, s), 15.41 (], I
+, s) b) 4-[1-hyroxy-3-(2-hyroxy-4 trimethylsilylphenyl)-3-oxo-1-propenyl]benzoic acid 4-[1-hydroxy-3-(2 - Hi1ku Logisi 5 -
370 mg of 1-limethylsilylphenyl)-3-oxo-1-propenyl]benzoic acid (Imn+o, 1.) was dissolved in 60 ml of ethanol, and 5 ml of 2N aqueous sodium hydroxide solution was added while stirring at room temperature.

After stirring overnight at room temperature, 10% hydrochloric acid was added to adjust the pH to 8.

Concentrate under reduced pressure, add water to the residue, and prepare P with 10% hydrochloric acid.

The precipitated crystals were collected by filtration and recrystallized from N,N-dimethylformamide and ethanol to obtain the title compound as yellow plate-like crystals.
5 mg was obtained (yield: 49z).

m, p, 288-291°C (resolved) MS spectrum m/z: 356 (M”)' II-NMR Subek 1
~le δ(T)MSQ-d')ppIIG O,27(
911, s), 7.00-8.24 (8tl, m) Patent applicant: Mine Shuto - Agent: Patent attorney Sunagawa Fifth Department procedural amendment (voluntary)

Claims (5)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 represents a hydrogen atom, a hydroxyl group, or a lower alkanoyl group, R_2 represents a hydrogen atom or a lower alkyl group, and X represents a group - CONH-, -COO-, -OCO-
or -COH=C(OH)-, and n represents 1 or 2. ) and pharmacologically acceptable salts thereof. (2)a) In the general formula (I), the group X is -CONH-
For compounds that are, the following general formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R_1 represents a hydrogen atom, a hydroxyl group, or a lower alkanoyl group, and n represents 1 or 2. b) X by converting the benzoic acid derivative represented by
is -COO-, the above general formula (I
By converting the benzoic acid derivative represented by I) into its antiderivative (acid halide, mixed acid anhydride, etc.) and condensing it with p-hydroxybenzoic acid or its ester derivative, c) X is -OCO-. For compounds, the following general formula (III) ▲Mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R_1 represents a hydrogen atom, hydroxyl group, or lower alkanoyl group, and n represents 1 or 2.) By condensing the phenol derivative represented by with a reactive derivative (acid halide, mixed acid anhydride, etc.) of terephthalic acid or its ester derivative, d) X is -COCH=C(OH)- and R_1 is the 2nd position. For compounds that are hydroxyl groups, the following general formula (IV) ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼ (IV) (In the formula, R_2 represents a hydrogen atom or a lower alkyl group, and n represents 1 or 2.) By rearranging the terephthalic acid derivative shown in the presence of an alkali catalyst. General formula (I) ▲There are numerical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 is a hydrogen atom, represents a hydroxyl group or a lower alkanoyl group, R_2 represents a hydrogen atom or a lower alkyl group, X represents -CONH-, -COO-, -OCO- or -COCH=C(OH)-, and n represents 1 or 2. A method for producing a benzoic acid derivative represented by: (3) An agent for inducing differentiation of cancer cells, particularly leukemia cells, which comprises a benzoic acid derivative of general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. (4) A therapeutic agent for psoriasis characterized by containing a benzoic acid derivative of general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. (5) A therapeutic agent for immune and inflammatory diseases characterized by containing a benzoic acid derivative of general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.