JPH0414089B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel tropolone compound, a copper complex thereof, or an antitumor drug containing the same as an active ingredient. That is, the present invention is based on the general formula:

【formula】

【formula】 or

[Formula] (wherein, R ¹ is H or a C ₁ to C ₃ lower alkyl group,
Tropolone compound represented by R ² is a C ₁ to C ₃ lower alkyl group, a phenyl group substituted with a methoxy group or a halogen group, or an unsubstituted phenyl group, and R ³ is a C ₁ to _{C 3} lower alkyl group or a copper complex thereof, or an antitumor drug containing the same as an active ingredient. The compound of the present invention is novel and can be produced by the method shown in the following reaction formula. or That is, when a mixture of a tropolone compound such as 4-isopropyltropolone (hinokitiol) and benzaldehyde diethyl acetal is heated, 3-(α-ethoxybenzyl)-6-
Isopropyltropolone ( ) and α,α-bis(6-isopropyl-2-hydroxy-3-tropolyl)toluene ( ) are obtained. Furthermore, when tropolone and 1-ethoxyisochroman are heated and reacted in the same manner, 3-(1-isochromanyl)tropolone () is obtained. These tropolone compounds can be converted into copper complex salts by conventional methods. The compounds obtained by the above method have strong antitumor effects and are expected to be used as pharmaceuticals. EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 Preparation of 3-(α-ethoxybenzyl)-6-isopropyltropolone (I-a) (wherein ^R1 = isopropyl group, ^R2 = phenyl group, ^R3 = ethyl group). A mixture of 5.9 g of benchaldehyde diethyl acetal and 4.5 g of 4-isopropyltropolone was heated and melted at 160-170 DEG C. for 6 hours in an argon stream. Next, the reaction mixture was separated and purified using silica gel column chromatography, and a viscous oil (bp=140
℃/0.005 mmHg) (Ia) 1 g (12%) was obtained. NMR (CDCl ₃ ) σ: 1.24 (6H, d, J = 7Hz),
1.25 (3H, t, J=7Hz), 2.85 (1H, m), 3.58
(2H, q, J=7Hz), 6.12 (1H, s), 6.93−
7.68 (7H, m), 7.95 (1H, d, J=10Hz), 9.26
(1H, broad). MS: m/e: 298 (M ⁺ ). Anal.
Calcd _{C19H22O3 :} C, _76.48 :H, 7.423.
Foud: C, 76.52: H, 7.48. Example 2 3-(α-ethoxy-4-methylbenzyl)-6
-isopropyltropolone (Ib) (wherein,
Production of R ¹ = isopropyl group, R ² = 4-betyl phenyl group, R ³ = ethyl group) 4-methylbenzaldehyde ethyl acetal (6.4 g, 33 mmol) and hinokitiol (2.8 g,
(17 mmol) was heated and stirred at 150° C. for 6 hours in an argon stream. The reaction mixture was separated and purified by silica gel chromatography to obtain compound (I-b) (bp=160-170℃/0.005) as a viscous liquid.
mmHg) was obtained (1.3 g (25%)). NMR (CDCl ₃ ) σ: 1.20 (3H, t, J = 7Hz),
1.38 (6H, d, J=7Hz), 2.29 (3H, s), 2.60
-3.20 (1H, m), 3.51 (1H, q, J=7Hz),
5.97 (1H, s), 6.70−8.00 (7H, broad), 8.70−
9.30 (1H, broad). MS: m/e: 312 (M ⁺ ).
Anal.Calcd C ₂₀ H ₂₄ O ₃ :C, 76.89:H,
7.74 Found: C, 76.87: H7.80. Example 3 3-(α-ethoxy-4-methoxybenzyl)-
6-isopropyltropolone (I-c) (wherein,
Production of R ¹ = isopropyl group, R ² = 4-methoxyphenyl group, R ³ = ethyl group) A mixture of 4-methoxybenzaldehyde diethyl acetal (5.5 g, 26 mmol) and hinokitiol (4 g, 24 mmol) was heated with argon. in airflow
Heated at 150°C for 10 hours. The reaction mixture was separated and purified using silica gel column chromatography.
1.5 g (18.5%) of a viscous liquid (Ic) was obtained.
(bp=180℃/0.005mmHg). NMR (CDCl ₃ ) σ: 1.30 (6H, d, J = 7Hz),
1.30 (3H, t, J=7Hz), 2.85 (1H, m), 3.58
(2H, q, J=7Hz), 3.80 (3H, s), 6.08 (1H,
s), 6.70−7.60 (7H, m), 8.05 (1H, d, J=
10Hz). MS: m/e: 328 (M ⁺ ). Anal.Calcd
_{C20H24O4 :} C, _73.14 :H, 7.37Foud:C,
73.32H, 7.50. Example 4 α,α-bis(6-isopropyl-2-hydroxy-3-tropolyl)toluene (-a)
(In the formula, R ¹ = isopropyl group, R ² = phenyl group) Following the elution of I-a by silica gel column chromatography according to the method of Example 1, from the second elution part
mp.199-200℃ crystal (-a) 3.16g (28%)
I got it. NMR (CDCl ₃ )σ: 1.27 (12H, d, J=7
Hz), 2.48−3.26 (2H, s), 6.76 (1H, s), 6.82
−7.44 (10H, m), 9.53 (2H, broad). MS:
m/e: 416 (M ⁺ ). Anal.Calcd C ₂₇ H ₂₈ O ₄ :C,
77.86:H, 6.78Foud:C, 77.79:H, 6.82. Example 5 α,α-bis(6-isopropyl-2-hydroxy-3-tropolyl)-4-methoxytoluene (-a) (wherein R ¹ =isopropyl group, R ²
= 4-methoxyphenyl group) Production of hinokitiol (4 g, 24 mmol) and anisaldehyde diethyl acetal (2.5 g, 12 mmol)
mol) was heated at 180° C. for 2 hours under a stream of argon. After the reaction, it was dissolved in hot methanol and cooled to precipitate crystals. The crystals were collected by filtration, the mother liquor was concentrated, and the crystals were separated by column chromatography using silica gel to precipitate crystals. Recrystallize from ethanol together with the crystals collected by filtration before.
Crystals (-b) with mp.204-205℃ were obtained [yield 1.8
g (33.6%)]. NMR (CDCl ₃ )σ: 1.30 (12H, d, J=7
Hz), 2.48−3.24 (2H, m), 3.85 (3H, s) 6.56
(1H, s), 6.60−7.51 (10H, m), 9.02 (2H,
broad). MS: m/e: 446 (M ⁺ ). Anal.Calcd
_{C27H30O5 :} C, _75.31 :H, 6.77Foud:C,
75.42:H, 6.75. Example 6 α,α-bis(6-isopropyl-2-hydroxy-3-tropolyl)-4-methyltoluene (-c) (wherein R ¹ = isopropyl group, R ² =
Production of methylphenyl group) Hinokitiol (3.28g, 20mmol) and 4-
A mixture of methylbenzaldehyde diethyl acetal (2.4 g, 12 mmol) was heated at 180° C. for 6 hours under a stream of argon. Petroleum ether was added to the reaction solution, and the precipitated crystals were collected by filtration, and the mother liquor was separated by column chromatography using silica gel. Crystals were obtained from the portion eluted with a mixed solution of petroleum ether and ethyl acetate. Combined with the crystals collected earlier and recrystallized from benzene, mp.231-233
1.60 g (37.2%) of crystals (-c) were obtained. NMR (CDCl ₃ ) σ: 1.28 (12H, d, J=6
Hz), 2.37 (3H, s), 2.50−3.30 (2H, m), 6.65
(1H, s), 6.70−7.50 (10H, broad), 9.00−9.72
(2H, broad). MS: m/e: 430 (M ⁺ ). Anal.
Calcd _{C28H30O4 :} C, _78.10 :H, 7.04.
Found: C, 78.19: H, 7.11. Example 7 α,α-bis(6-isopropyl-2-hydroxy-3-tropolyl)-4-chlorotoluene (-c) (wherein R ¹ = isopropyl group, R ² =
Production of hinokitiol (3.28 g, 20 mmol) and 4-fluorophenyl group)
A mixture of chlorobenzaldehyde diethyl acetal (2.57 g, 12 mmol) was heated at 180° C. for 6 hours under a stream of argon. Petroleum ether was added to the reaction mixture, and the precipitated crystals were collected by filtration, and the mother liquor was separated by column chromatography using silica gel. Petroleum ether-ethyl acetate (32:1)
It was eluted with a mixed solvent of , and crystals were precipitated. Recrystallize from benzene together with the crystals filtered earlier,
Crystals (-d) with mp.227-228℃ were obtained [yield 1.6
g (35%)] NMR (CDCl ₃ ) σ: 1.14 (12H, d, J = 8
Hz), 2.35−3.15 (2H, m), 6.62 (1H, s), 6.67
−7.55 (10H, broad), 9.05−9.70 (2H, broad).
MS: m/e: 451 (M ⁺ ). Anal.Calcd
_{C27H27O4Cl :} C, _71.90 :H, 6.05. Found:C,
71.66:H, 5.98. Example 8 α,α-bis(6-isopropyl-2-hydroxy-3-tropolyl)-4-methoxytoluene-copper complex salt (Ib-Cu) (wherein R ¹ = isopropyl group, R ² = 4-methoxy -b (0.5g, 1.12m) obtained by the method of Example 5
mol) in 30 ml of chloroform, a suspension of copper acetate (0.5 g, 2.2 mmol) in a small amount of water was added thereto, and the mixture was stirred for 2 hours. Separate the chloroform layer, wash with water, dry, and concentrate the solvent.
0.49g (85%) of green crystals with mp.300°C or higher were obtained. Anal.Calcd C ₂₉ H ₂₈ O ₅ :Cu:C, 70.29:H,
5.83. Found: C, 70.41: H, 5.91. Example 9 Production of 3-(1-isochromanyl)-6-isopropyltropolone (-a) (in the formula, R ¹ = isopropyl group) 1-ethoxyisochroman 8.15 g (45 mmol)
and 5 g (30 mmol) of hinokitiol were heated and melted at 150-160° C. for 8 hours in an argon stream. The reaction mixture was separated and purified using silica gel column chromatography, and 4.13 g (46%) of crystals (-a) with a mp. of 135-138°C was obtained from the benzene eluate. NMR (CDCl ₃ ) σ: 1.23 (6H, d, J = 7Hz),
2.50−3.50 (3H, m), 3.80−4.45 (2H, m), 6.62
(1H, s), 6.72−7.40 (7H, m), 7.50 (1H, d,
J=10Hz), 9.30 (1H, broad). MS: m/e:
296 (M ⁺ ). Anal.Calcd C ₁₉ H ₂₀ O ₃ :C, 77.00:
H, 6.80. Found: C, 77.23: H, 6.92. Example 10 3-(1-isochromanyl)tropolone(-
b) Production of (in the formula, R ¹ =H) 1-ethoxyisochromane 2.9 g (16 mmol)
and 1.3 g (10 mmol) of tropolone were heated and melted at 150-160° C. for 15 hours in an argon stream. The reaction mixture was separated and purified using silica gel column chromatography, and crystals at mp.175-178°C were obtained from the eluate of a mixed solvent of petroleum ether and ethyl acetate (-b)
1.25g (46%) was obtained. NMR ( _CDCl3 ) σ: 2.53−3.51 (2H, m), 3.80
−4.54 (2H, m), 6.65 (1H, s), 6.73−7.71
(7H, m), 9.03−9.65 (1H, broad). MS: m/
e: 245 (M ⁺ ). Anal.Calcd C ₁₆ H ₁₄ O ₃ :C,
75.57:H, 5.55. Found: C, 75.61: H, 5.51 Example 11 3-(1-isochromanyl)-6-isopropyltropolone-copper complex salt (-a-Cu) (in the formula, R ¹
= isopropyl group) 1g of the compound-a obtained in Example 9 and 0.8g of copper acetate
g was dissolved in 50 ml of methanol and 50 ml of chloroform, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with chloroform, the chloroform layer was separated, washed with water, dried, and the solvent was concentrated to obtain 1 g (83%) of green crystals (-a-Cu) with mp.290° or higher. . Antitumor Test KB-Cell Proliferation Inhibition Test This test uses KBB cells as minimal
The experiment was carried out using medium (MEM)-10% Calf Serm medium and cultured at 37°C in a 5% carbon dioxide incubator. First, on the first day, 2 KB cells were
Dilute to contain ×10 ⁴ /ml, and add 3 ml to 60
Planted in mm watch glass. Then, on the second day, test substances were added at 100, 30, 10, 3, and 1 μg/ml, respectively, and cultured in the same manner. Finally, cells that survived on the fourth day were removed from the watch glass using trypsin, and the number of cells was counted. At this time, the concentration of the drug required to actually inhibit cell proliferation by 50% compared to the control without the addition of the drug (ED ₅₀ ) was determined, and the drug and cancer cell proliferation inhibitory effect were determined. expressed. The results are shown in Table 1. Life extension effect test on tumor-bearing mice After transplanting ¹⁰⁶ P388 tumor cells into each group of 6 CDF mice, the test drug was administered intraperitoneally to the mice on the 1st and 5th day. did. The survival effect was evaluated as the ratio (T/C%) of the survival days of the treated group to the survival days of the untreated group. The results are shown in Table 1 above.

【table】

【table】

Claims (1)

[Claims] 1. General formula: [Wherein, R ₁ represents H or a C ₁ to C ₃ lower alkyl group; Q is [Formula] (wherein, R ² is a C ₁ to _{C 3} lower alkyl group, a methoxy group, or a halogen group Substituted phenyl group or unsubstituted phenyl group, R ³ represents a C ₁ to C ₃ lower alkyl group), (However, R ¹ and R ² are as defined already.)
Or, a tropolone compound or its copper complex compound represented by [Formula]]. 2 General formula: [Wherein, R ₁ represents H or a C ₁ to C ₃ lower alkyl group; Q is [Formula] (wherein, R ² is a C ₁ to _{C 3} lower alkyl group, a methoxy group, or a halogen group Substituted phenyl group or unsubstituted phenyl group, R ³ represents a C ₁ to C ₃ lower alkyl group), (However, R ¹ and R ² are as defined already.)
Or, an antitumor drug containing [Formula]] as an active ingredient.