JPH06199857A - 5-deazaflave-6,9-quinone derivative and its production - Google Patents

Abstract

PURPOSE:To provide a novel compound useful as a circulating automatic reduction-oxidation catalyst or as a carcinostatic agent. CONSTITUTION:The compound of formula I (R<1> is H, (substituted) lower alkyl or aryl; R<2> is (substituted)alkyl, R<3> is H, lower alkyl, lower alkoxy, halogen), e.g. 10-butyl-8-methoxy-3-methyl-5-deazaflavo-6,9-quinone. The compound of formula I is obtained by stirring a 5-deazaflavin derivative of formula II (R<4> is lower alkoxy; the position of R<3> is the 7 or 8 position of the 5-deazaflavin ring) and ceric ammonium nitrate in a solvent at room temperature for 1-10hrs. The ceric ammonium nitrate is used in an amount of 2-10 equivalents per equivalent of the compound of formula II. Amine compounds, alcohol and thiol compounds can be oxidized with a small amount of the compound of formula I.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a 5-deazaflavo-6,9-quinone derivative which is useful as a circulating auto redox catalyst and also has an antitumor effect.

[0002]

2. Description of the Related Art A 5-deazaflavin derivative in which the nitrogen at the 5-position of riboflavin is equivalently converted to CH is known as a compound having a circulating auto-redox catalyst action [F. Yo
neda et al. Chem. Soc. , Perkin
Trans. Pt. 1, page 1836 (1981
Year) and F. Yoneda et al., Chem. Lett. ，
Pp. 1467 (1979)]. This action is
When a deazaflavin derivative is reacted with amines, alcohols or thiols, hydrogen atoms are removed from these compounds to form a dihydro form, which is easily oxidized in air to return to the original 5-deazaflavin derivative. That is.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a compound having a novel skeleton which has an excellent cyclic autoredox catalytic action.

[0004]

Means for Solving the Problems As a result of intensive investigations by the present inventors, the inventors have focused their attention on the circulating autoredox catalytic action of the 5-deazaflavin derivative and the electron transfer action of coenzyme ubiquinone (coenzyme Q), and A completely new fused tricyclic skeleton (5-deazaflavo)
An attempt was made to synthesize a compound having a 6,9-quinone skeleton). However, the synthesis of 5-deazaflavo-6,9-quinone skeleton is not easy, and it is difficult to synthesize 5-deazaflavo-6,9-quinone skeleton with various oxidizing agents
-Oxidation of the deazaflavin skeleton did not lead to successful synthesis. In such a situation, it was found that 5-deazaflavo-6,9-quinone skeleton can be specifically synthesized by using ceric ammonium nitrate (hereinafter referred to as CAN) as an oxidant, and further, The present invention has been completed by finding that a specific compound having a skeleton solves the above problems.

That is, the present invention uses the formula

[0006]

(In the formula, R ¹ is a hydrogen atom, an “aryl group,
A halogen atom, a lower alkoxy group, a hydroxyl group or a carboxyl group, which may be substituted with a lower alkyl group or an aryl group, and R ² is substituted with an "aryl group, a halogen atom, a lower alkoxy group, a hydroxyl group or a carboxyl group" And R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom. ) 5-deazaflavo represented by
6,9-quinone derivative, and the present invention is

[0008]

(In the formula, R ¹ , R ² and R ³ have the same meanings as described above, and R ⁴ represents a lower alkoxy group, provided that the position of R ³ is the 7-position or 8-position of the 5-deazaflavin ring. The present invention is a method for producing a compound of formula (I), which comprises reacting CAN with a 5-deazaflavin derivative represented by Here, the lower alkyl group in the compound of the formula (I) means a straight or branched chain having 1 to 4 carbon atoms. The alkyl group refers to a straight or branched chain having 1 to 16 carbon atoms. The lower alkoxy group refers to a linear or branched chain having 1 to 4 carbon atoms. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The aryl group is a monovalent group of an aromatic hydrocarbon which may be substituted with the lower alkyl group, the lower alkyl group, the halogen atom or a trifluoromethyl group, for example, a phenyl group, a p-chlorophenyl group, Examples include p-bromophenyl group, p-trifluoromethylphenyl group, p-methoxyphenyl group, toluyl group, xylyl group, mesityl group, cumenyl group and naphthyl group.

Next, a method for producing the compound of formula (I) of the present invention will be explained. That is, in a liquid obtained by suspending a compound of formula (II), which can be produced by the method described in JP-A-3-81276, page 837 (production method A), in a solvent, 2 equivalents to the compound of formula (II) are added. An aqueous solution in which 10 equivalents of CAN was dissolved was added at 0 ° C., the mixture was stirred at room temperature for 1 hr to 10 hr, and then extracted, dried and purified (recrystallized as necessary) by a conventional method to obtain the compound of formula (I The compound of 1) can be manufactured. Here, as the solvent, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, or the like can be used.

[0011]

Since the compound of the formula (I) of the present invention has an excellent cyclic auto-redox catalytic action on amines, alcohols or thiols, a small amount of the compound of the formula (I) can be used. It can oxidize large amounts of amines, alcohols or thiols. Therefore, it has become possible to avoid using a large amount of an organic oxidant that causes pollution. In addition, the compound of formula (I) also has a carcinostatic action, and is therefore useful as a carcinostatic agent.

[0012]

EXAMPLES The present invention will be described in more detail with reference to examples. Example 1 10-Butyl-8-methoxy-3-methyl-5-deaza
Production of flavo-6,9-quinone (Compound 1) (1) 3-methyl-6-butylaminouracil (900
mg, 4.6 mmol) and 2,3,4-trimethoxybenzaldehyde (1.26 g, 1.4 eq.) in DMF.
The liquid suspended in (2 ml) was heated for 4 hours. After cooling, the precipitated crystal was separated by filtration and recrystallized from ethanol to obtain 1.0 g of 10-butyl-8,9-dimethoxy-3-methyl-5-deazaflavin. m. p. > 300 ° C NMR (CDCl ₃ , 200 MHz) δ (ppm);
8.73 (s, 1H), 7.65 (d, 1H, J = 8.
8 Hz), 7.18 (d, 1H, J = 8.8 Hz),
4.08 (s, 3H), 3.92 (s, 3H), 3.4
6 (s, 3H), 0.94 (t, 3H, J = 7.3H
z)

(2) A solution prepared by suspending 200 mg of the compound obtained in (1) in acetonitrile (10 ml) was added with CAN.
An aqueous solution (6 ml) of (3.5 g) was slowly added at 0 ° C. The mixture was stirred at room temperature for 2 hours. After completion of stirring, the mixture was extracted with methylene chloride, dried over sodium sulfate, and methylene chloride was distilled off. The residue was purified by silica gel column chromatography to obtain the title compound. m. p. > 300 ° C. (decomposition) NMR (CDCl ₃ , 200 MHz) δ (ppm);
9.12 (s, 1H), 6.21 (s, 1H), 3.9
6 (s, 3H), 3.46 (s, 3H), 1.01 (d
d, 3H, J = 7.5Hz, 7.1Hz)

Examples 2 to 16 (1) The corresponding compound was used in place of 3-methyl-6-butylaminouracil in Example (1), and in Examples 11 to 13, 2,3,4-tri 2,3-dimethoxy-5-bromobenzaldehyde was used instead of methoxybenzaldehyde, and 2,3-dimethoxy-5-bromobenzaldehyde was used in Examples 14 to 16.
Instead of 3,4-trimethoxybenzaldehyde 2,
Example 1 using 3-dimethoxybenzaldehyde
The compounds shown in Table 1 were obtained in substantially the same manner as in (1).

[0015]

[Table 1]

(2) Using the compounds obtained in (1), the compounds shown in Table 2 were obtained in substantially the same manner as in Example 1 (2).

[0017]

[Table 2]

(Hereinafter, the compounds obtained in Examples 2 to 16 will be referred to as Compounds 2 to 16, respectively.) Test Example 1 [Circulating auto redox catalyst action test] 5-deazaflavo-6 produced in Examples 2 to 10 , 9-
Quinones and 10-hexyl-8,9-dimethoxy-3-methyl-5-deazaflavin, benzoquinone and naphthoquinone (these are referred to as Controls 1 to 3) (0.1 mmol) and a benzylamine aqueous solution (benzylamine) as controls. : Water = 1: 1, 5 ml) was exposed to air and mixed at 60 ° C. for 48 hours. Reaction mixture 5
% Hydrochloric acid and extracted with chloroform. The obtained benzaldehyde was measured by liquid gas chromatography. The results are shown in Table 3.

[0019]

[Table 3]

Test Example 2 [Anticancer test] A culture solution containing various cultured tumor cells (2 × 10 ³ cells) and a test compound was added to a 96-well plate (NUNC, 01-6700).
Add to each well of 8) so that the volume becomes 200 μl.
Culturing was carried out for 72 hours under% CO ₂ -95% air. After culturing,
MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide]
25 μl of the solution (2 mg / ml) was added to each well, and the cells were further incubated for 4 hours at 37 ° C. under 5% CO ₂ -95% air. After removing the culture solution, 200 μl of dimethylsulfoxide was added to each well to dissolve the formed MTT-formazan, and the absorbance at 540 nm was measured using a microplate photometer, which was used as an index of cell number. The inhibition rate was calculated by the following formula, and the concentration of the test compound that inhibited 50% (IC ₅₀ value) was determined.

[0021]

[Equation 1]

Various tumor cell lines were cultured in RPMI 1640 medium (Nissui Pharmaceutical) containing 10% FCS. The obtained IC ₅₀ value (μg / ml) is shown in Table 4.

[0023]

[Table 4]

[0024]

Claims (2)

[Claims] 1. A formula (In the formula, R ¹ represents a hydrogen atom, a lower alkyl group or an aryl group which may be substituted with an “aryl group, a halogen atom, a lower alkoxy group, a hydroxyl group or a carboxyl group”, and R ² represents an “aryl group, a halogen group”. atom, a lower alkoxy group, optionally substituted by hydroxyl or carboxyl group "may indicate an alkyl group, R ³ is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom.) represented by 5- Deazafurabo -6, 9-
Quinone derivative. 2. A formula (In the formula, R ¹ , R ² and R ³ have the same meanings as described above, and R ⁴ represents a lower alkoxy group. However, the position of R ³ is the 7-position or 8-position of the 5-deazaflavin ring.) The formula is characterized by reacting a 5-deazaflavin derivative represented by (In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) A process for producing a 5-deazaflavo-6,9-quinone derivative.