JPH05247007A - New benzoxazole compound - Google Patents

Abstract

PURPOSE:To provide the subject new compound useful as a new type of antineoplastic agent having antibacterial activity for both gram-positive and gram-negative bacteria as well as antineoplastic activity. CONSTITUTION:The objective compound of formula I (R1 is H or lower alkyl; R2 is H, CH3 or benzyl), e.g. a compound of formula I-1. The compound of the formula I-1 can be obtained in high yield by ester interchange reaction of a compound of formula a using a halogenating agent such as thionyl chloride through the established process followed by reaction of the resulting compound of formula b with methyl 2-amino-3-hydroxybenzoate. A compound of formula I-2 can easily be obtained by catalytic hydrogenation of the compound of the formula I-1.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION This invention relates to novel benzoxazole compounds, and more particularly to 2,4'-bibenzoxazole compounds. The compound of the present invention is a compound having antitumor activity and antibacterial activity.

[0002]

2. Description of the Related Art Up to now, many attempts have been made to develop anticancer agents, but the diversity of cancers and the high toxicity of the anticancer agents used have become problems, and the development of new anticancer agents has been increasing. Is waiting. Some of the anti-cancer agents already proposed are occupied by extracts from plants and antibiotics.

By the way, compounds having a benzoxazole skeleton, which has been awaited for its interest in exhibiting various physiological activities, are calcimicin (Calcim) as an antibiotic.
ycin) (eg MO Chaney et al., JA
m. Chem. Soc. , 96 , 1932 (1974))
And cezomycin (eg LD
avid et al. Antibiotics. , 35 , 1
409 (1982)), and as a substance having a cell-killing effect, milliamines (for example, D. Uemura et al., Bull. Chem.
Soc. Japan, 50 , 2005 (1977)) is known. These compounds are structurally interesting in that they have a carboxyl group and a group derived therefrom at the 4-position of the benzoxazole bone nucleus (J. He.
thermocycle. Chem. , 27 , 335 (19
90)).

However, at present, no compound having such a bone nucleus has been put to practical use as an anticancer agent, an antitumor agent or an antibacterial agent.

[0005]

In recent years, antibiotics which have been used as antibacterial agents and antitumor agents have a problem that tumor cells become drug resistant as well as emergence of resistant bacteria due to their use. Is becoming Therefore, an object of the present invention is to provide a compound belonging to a unique class which is predicted not to show cross resistance with them.

[0006]

[Means for Solving the Problems] In order to achieve the above object, the present inventors have extensively screened useful compounds from soil-isolated bacteria and conducted synthetic research on various compounds. It was found that a strain belonging to Streptoverticillium , which is one of the above, produces a benzoxazole compound exhibiting antitumor activity and antibacterial activity, and that this compound and a series of derivatives can be easily chemically synthesized.

Therefore, according to the present invention, the following formula [I]

[0008]

[Chemical 2]

The above object is achieved by providing a benzoxazole compound represented by the formula ( ₁₎ wherein R ₁ represents a hydrogen atom or a lower alkyl group, and R ₂ represents a hydrogen atom, a methyl group or a benzyl group. To be done. The term lower alkyl group used in the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms. Therefore, the substituent R ₁ of the compound of the present invention may include a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a hexyl group, and the like. From the viewpoint of physiological activity or synthesis, hydrogen atom, methyl group, ethyl group, propyl group and isopropyl group are preferable.

When the R ₁ group is a hydrogen atom (that is, the compound of formula [I] has a free carboxyl group), the compound of the present invention is further provided as an alkali addition salt thereof. sell. Examples of the compound used to form such a salt include various inorganic or organic alkaline compounds, and preferably used in the production of a pharmaceutically acceptable salt in the technical field to which a drug belongs. Those known per se can be mentioned.

Although a part of the compound of the present invention can be obtained from the soil-isolated strain as described above, it can be easily obtained in a large amount by chemical synthesis according to the reaction scheme shown below.

[0012]

[Chemical 3]

(In the above formula, Et ₃ N represents triethylamine and PPTS represents pyridinium p-toluenesulfonate.) In the above reaction scheme, the compound represented by the formula (a) is known, and for example, the above-mentioned S may be used. ． W. Go
ldstein et al. Heterocycl. Ch
em. , 27 , pp. 335-336 (1990), and can be produced in high yield.

The reaction from the compound (a) to the compound (b) is a transesterification reaction which is known per se, and can be proceeded in good yield with a halogenating agent such as thionyl chloride.
The reaction from compound (b) to (c) is carried out by the above Goldst method.
Published by ein et al., eg, 2-amino-
The reaction can be carried out according to the reaction conditions from methyl 3-hydroxybenzoate to the compound (a), and the target compound [I-1] can also be obtained in high yield. The target compound corresponds to the compound of the present invention in which R ₁ represents a methyl group and R ₂ represents a benzyl group. R ₂ represents a benzyl group by subjecting this compound as a starting material to hydrolysis or transesterification of the methoxycarbonyl group (carboxylic acid ester group) at the 4-position of the benzoxazole ring,
Various compounds of the present invention can be prepared.

In the reaction of compound [I-1] to [I-2], for example, the benzyl group can be easily removed by ordinary catalytic hydrogenation, and thus R _{1 of the} present invention represents a methyl group. , R ₂ represents a hydrogen atom. Further, by utilizing the phenolic hydroxyl group of this compound, etherification or esterification known per se can be carried out.

[0016] Thus compounds of the invention provided, to the murine melanoma B16 cells showed inhibitory activity of the proliferation at low concentrations, still further, Staphylococcus aureus (Staphylococcus aureu
s ), Pseudomonas aeruginosa ( Pseudom )
onas aeruginosa ) and other antibacterial activities against gram-positive and gram-negative bacteria.

[0017]

EXAMPLES Compounds of formula shown in producing the above reaction scheme of the compound of Example 1 present invention (b) 1.20 g
(3.3 mmol), methyl 2-amino-3-hydroxybenzoate 0.50 g (3.0 mmol), triethylamine 0.33 g (3.3 mmol), and pyridinium p-toluenesulfonate 0.20 g (0.80 mmol). And were refluxed in 50 ml of xylene for 16 hours. The reaction solution was cooled to room temperature, diluted with 200 ml of ethyl acetate, and then washed with 100 ml of water. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain an oily crude product. By silica gel radial chromatography, eluting with hexane to hexane / ethyl acetate (7: 3), the fraction containing the target compound was concentrated and then purified to give the compound [I-
1] was obtained. This compound was reduced by catalytic hydrogenation using palladium black as a catalyst to give a compound [I-
2] was obtained. (Mp _{^{217~219 ℃) 1 HNMR (CDC1 3}} ) δ4.17 (3H, s, CO
_{OCH 3), 7.00 (1H,} dd, 19-H), 7.
15 (1H, d, 17-H), 7.4-7.5 (3H,
m, 5-H, 12-H, 18-H), 7.72 (1H,
d, 11-H), 7.82 (1H, d, 6-H), 8.
01 (1H, d, 20-H), 8.07 (1H, d, 4
-H), 8.31 (1H, d, 13-H), 11.9.
(1H, br, OH) UV λmax (MeOH) 249, 263, 271,
314, 325, 348, 365, 420 nm (log ε
4.32, 4.30, 4.30, 4.46, 4.51,
4.44, 4.27, 3.17) IR νmax 1725 cm ^-1 HRMS m / z 386.0913 (C ₂₂ H ₁₄ N ₂ O).
₅ , calculated value: 386.0903) In addition, as shown in the above NMR data, for example, 19-
Numbers such as H represent carbon positions represented by the following structural formulas.

[0018]

[Chemical 4]

Example 2Hydrolysis and etherification (1) Compound [I-2] in pyridine with sodium hydroxide
When the mixture is added and left at room temperature, the corresponding free carboxylic acid
R in the compound formula [I]₁Represents a hydrogen atom, R ₂But water
(Representing an elementary atom) was obtained. The production of carboxylic acid is¹
1 H NMR (CDCl₃) To the disappearance of the δ 4.17 absorption
Therefore, it is confirmed. (2) Compound [I-1] was added to dry acetone in potassium carbonate.
Reaction with methyl iodide in the presence of
An ether compound in which an acid group is methylated (R in formula [I]
₁Represents a methyl group, R₂Represents a methyl group)
Was given. (Melting point 145 to 147 ° C.)¹ 1 H NMR (CDCl₃) Δ 4.09 (s, 3, OC
H₃) IR λmax 1710 cm^-1 HRMS m / z 400.1067 (C_{twenty three}H₁₆N₂O
_Five, Calculated value; 400.1059) Example 3UK-1 against mouse melanoma cell B16
Activity Mouse melanoma cells B16, which are skin cancer cells, were
5 × 10 on a 5 mm dish^FourCells were inoculated. Medium is 1
2 ml of MEM medium containing 0% serum was used. On each dish
Add various concentrations of UK-1 as an ethanol solution,
The inhibitory effect on cell proliferation after 2 hours was examined. Number of cells
The measurement of heme was carried out by treating cells dispersed by trypsin treatment.
It was performed by counting with a cytometer.

As a result, the drug concentration IC ₅₀ value, which was 50% of the control (no drug added) cell number, was about 0.5 μg / ml. Example 4 Antibacterial activity of demethylated compound of compound [I-2] The antibacterial activity of demethylated compound of compound [I-2] against Staphylococcus aureus NCTC8530 and Pseudomonas aeruginosa IFO3080 was examined by the broth dilution method. That is, 1 platinum loop of the test bacterium was taken from the slant, and 10 ml of 3 sterilized
Incubation was carried out at 37C overnight in a test tube containing a% broth liquid medium to give an inoculum. This was diluted with a sterilized 3% broth liquid medium so that the number of bacteria was 10 ⁶ / ml, and 5 ml of this was dispensed into a sterilized test tube. After adding the above-mentioned compounds of various concentrations prepared in advance in a 2-fold dilution series with ethanol and culturing at 37 C for 20 hours, the presence or absence of proliferation was determined by the change in turbidity. as a result,
The minimum inhibitory concentration (MIC) is Staphylococcus aurcu.
s) 3.13 μg / ml against NCTC8530, and Pseudomonas aeruginosa (Pscudomo)
6.25 μg / ml against N. acruginosa) IFO 3080.

[0021]

INDUSTRIAL APPLICABILITY According to the present invention, there is provided a benzoxazole compound belonging to a new type which has never been used as an anticancer agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C12R 1: 625) 7804-4B

Claims (1)

[Claims] 1. The formula: (In the above formula, R ₁ represents a hydrogen atom or a lower alkyl group, and R ₂ represents a hydrogen atom, a methyl group, or a benzyl group), and a benzoxazole compound and a salt thereof.