JPS6257175B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a novel method for producing tropolone derivatives. The above derivative has antitumor activity and is expected to be used as an antitumor agent. Conventional technology Formula (), (In the formula, R ¹ is hydrogen or a lower alkyl group, R ²
is an aryl or substituted aryl group, R ⁴ is a lower alkyl group)
By reacting the groups () and acetal (), the reaction formula; (wherein R ¹ , R ² and R ⁴ are as defined above) is disclosed by the applicant. (Chem.Pharm.Bull., Volume 31, No. 8,
2952 pages, 1983; J.Chem.Soc.Perkin Trans,
1301 pages, 1984; J.Med.Chem., vol. 27, 1749 pages,
1984; JP-A-59-134720 and JP-A-59
-Refer to Publication No. 134744). For ^{example , R 1} is isopropyl group, R ² is paramethoxyphenyl group, R ⁴
Monotropolone derivatives where is an ethyl group ()
Then, a bistropolone derivative of the formula () in which R ¹ is an isopropyl group and R ² is a paramethoxyphenyl group could be obtained. Problems to be Solved by the Invention and Means for Solving the Problems It has now been discovered that a novel tropolone derivative having antitumor activity can be produced using a monotropolone derivative () as a raw material. The present invention aims to provide novel tropolone derivatives having antitumor activity. The novel tropolone derivative according to the present invention has the general formula: (In the formula, R ¹ is hydrogen or a lower alkyl group, R ²
is an aryl or substituted aryl group, and R ³ is a substituted aryl group or a substituted or unsubstituted heterocyclic group selected from the group consisting of coumarin, pyran, quinoline, indole, and flavone residues. As is well known in tropolone chemistry, the tropolone compound has tautomers. It is to be understood that the present invention includes tautomers of these compounds or mixtures thereof. The tropolone derivative according to the present invention has the formula (), (In the formula, R ¹ and R ² are as described above,
Produced by reacting a monotropolone derivative represented by the formula (R ⁴ is a lower alkyl group) with a compound represented by the formula (), R ³ H () (wherein R ³ is as described above) be done. general formula, In the tropolone derivative of the present invention represented by
R ¹ is hydrogen or a lower alkyl group, usually a C ₁ -C ₃ alkyl group, preferably an isopropyl group, and R ²
is an aryl or substituted aryl group, preferably p
-methoxyphenyl group. Substituted aryl groups represented by the R ³ group include hydroxy, oxo, alkyloxy, alkyl and alkenyl groups.
Aryl groups substituted by more than one group, e.g. 2-
Groups such as hydroxy 1,4-naphthoquinone, eugenol, 4-t-butylcatechol, p-hydroquinone, 1,4-dihydroxynaphthalene, 2-methyl-1,4-naphthoquinone, α-naphthol, preferably 2-hydroxynaphthoquinone ,
4-t-butylcatechol, p-hydroquinone,
2-methyl-1,4-naphthoquinone, etc., and the heterocyclic group represented by the R ³ group is a monocyclic or polycyclic, unsubstituted or hydroxy, oxo, hydroxy group containing oxygen or nitrogen as a heteroatom. A heterocyclic group substituted by one or more groups such as methyl, for example 4-hydroxycoumarin, kojic acid, 8-hydroxyquinoline, indole,
It is a group such as flavone. The tropolone derivative represented by the above general formula can be obtained by heating the monotropolone derivative () and the compound represented by the formula () to a high temperature to obtain the reaction formula: (wherein R ¹ , R ² , R ³ and R ⁴ are as defined above). The monotropolone derivative ( ) used in the present invention is produced from hinokitiol ( ) and acetal ( ) as described above, and R ¹ is an isopropyl group, R ² is a para-methoxyphenyl group, and R ⁴ is an ethyl group. It is preferable, but not limited to this. The compound represented by the formula () used in the present invention has ^OR4 in the monotropolone derivative ()
Compounds that can be substituted with R ³ groups to produce tropolone derivatives of the present invention, such as 2-hydroxynaphthoquinone, eugenol, 4-t-butylcatechol, p-hydroquinone, 2-methyl-1,4
- substituted aryl compounds such as naphthoquinone, or e.g. 4-hydroxycoumarin, kojic acid,
It is an unsubstituted or substituted heterocyclic compound such as 8-hydroxyquinoline, indole, or flavone. The monotropolone derivative of formula () and the compound of formula () can be used in approximately equimolar ratio,
Alternatively, the compound of formula () can be used in excess of an equimolar ratio, for example 1.2 moles or more of the compound of formula () to 1 mole of the compound of formula (). The mixture of the formula () and the compound of formula () is heated in the absence of a solvent or in the presence of a solvent. When a solvent is not used, the mixture is melted by heating at a high temperature, for example 120 DEG to 180 DEG C., for a suitable period of time, for example 1 to 10 hours. When a solvent is used, the reaction is carried out in the presence of a catalyst by heating under reflux at 100 to 180° C. for 1 to 6 hours. Examples of the solvent used include xylene, toluene, cymene, and hexamethylphosphoric triamide (HMPA). Further, as a catalyst, for example, sodium hydride or potassium tert-butoxide can be suitably used. Note that the used solvent can be removed under reduced pressure after the reaction is completed. The reaction product can be purified by recrystallization from a suitable solvent or mixed solvent, such as methanol, ether, ethyl acetate, ethyl acetate and chloroform. Alternatively, elute by silica gel column chromatography using an appropriate eluent,
It can then be recrystallized from a solvent as described above. Effects of the Invention The compound of the present invention exhibits strong antitumor effects in antitumor tests, and is expected to be used as an antitumor drug. The KB-cell growth inhibition test and the survival effect test on cancer-bearing mice conducted in the antitumor test are as follows. Anti-tumor test KB - Cell growth inhibition test KB cells in Eagle's minimal essential medium
(MEM)-10% Calf Serm medium and cultured at 37°C in a 5% carbon dioxide incubator. On the first day, KB cells were diluted to contain 2 x 10 ⁴ cells/ml, and 3 ml of this was planted in a 60 mm watch glass. On the second day, the test drug was administered at 100, 30 and 10, respectively.
3. It was added at a concentration of 1 μg/ml and cultured in the same manner. 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 inhibit cell proliferation (ED ₅₀ ) by 50% compared to the control without the addition of the drug was determined, and the cancer cell proliferation inhibitory effect of the drug was determined. expressed. Table 1 shows the results.
It was shown to. Test for prolonging survival of cancer-bearing mice. After transplanting ¹⁰⁶ P388 tumor cells into each group of 6 CDF mice, the first
On the fifth day, the test drug was intraperitoneally administered to the mice. 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 the table.

【table】

【table】

[Table] Example 1 Preparation of 3-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-4-hydroxycoumarin (6a). 1 g (3.0 mmol) of 3-(α-ethoxy-4-methoxybenzyl)-6-isopropyltropolone (3) produced by the reaction of hinokitiol and anisaldehyde diethyl acetal and 0.59 g (3.6 mmol) of 4-hydroxycoumarin (5a) ) mixture with
It was melted at 120°C for 4 hours. When the crude crystals precipitated after the reaction are recrystallized from methanol, the mp is 203-204℃.
0.6g (44%) of 6a was obtained. Elemental analysis: C, 72.37; H, 5.41 NMR (DMSO-D ₆ ) δ: 1.25 (6H, d, J = 7
Hz), 2.65-3.15 (1H, m), 3.77 (3H, S),
6.22 (2H, S), 6.70-8.20 (11H, m), MSm/
e: 412 (M ⁺ ) Example 2 2-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-3-hydroxy-6-hydroxymethyl-4-oxopyran ( 6b) Manufacture. Compound (3) 1.0g (3.0mmol) and kojic acid 0.52g
(3.6 mmol) was melted at 140°C for 3 hours. After the reaction, the precipitated crystals were recrystallized from methanol. 0.4 g (31%) of 6b with mp 143-145°C was obtained. Elemental analysis: C, 67.86; H, 5.67. NMR (DMSO-D ₆ ) δ: 1.21 (6H, d, J = 7
Hz), 2.80-3.20 (1H, m), 3.79 (3H, S),
4.32 (2H, S), 5.50-6.00 (1H, b), 6.46
(1H, S), 6.85-7.50 (7H, m), MSm/e:
424 (M ⁺ ) Example 3 Preparation of 2-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-3-hydroxynaphthoquinone (6c). A mixture of 1 g (3.0 mmol) of compound (3) and 0.63 g (3.6 mmol) of 2-hydroxynaphthoquinone was
Melt at ℃ for 6 hours. After the reaction, the mixture was purified by silica gel column chromatography. That is, when the crystals obtained by elution with a mixed solvent of petroleum ether: ethyl acetate = 10:1 are recrystallized from a mixed solvent of methanol: dichloromethane = 5:1, mp185 is obtained.
0.34g (27%) of 6c at ~187°C was obtained. Elemental analysis values: C, 73.41; H, 5.32. NMR (CDCl ₃ ) δ: 1.22 (6H, d, J=7
Hz), 2.60-3.30 (1H, m), 3.79 (3H, S),
6.47 (1H, S), 6.70−8.30 (11H, m), 8.50−
9.00 (2H, S), MSm/e: 424 (M ⁺ ). Example 4 2-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-4-allyl-methoxyphenol (6d)
Manufacturing of. Compound (3) 1g (3mmol) and eugenol 0.6g
(3.6 mmol) was melted at 160°C for 3 hours. The reaction mixture was purified by silica gel column chromatography. That is, when the crystals obtained by elution with a mixed solvent of hexane: ethyl acetate = 5:1 are recrystallized from ethyl acetate, 6d of mp233℃ is obtained.
0.15g (11%) was obtained. Elemental analysis values: C, 75.02; H, 6.83. NMR (CF ₃ COOH) δ: 1.45 (6H, d, J=
7Hz), 3.30 (3H, d, J = 7Hz), 3.98 (6H,
S), 4.21~5.21 (2H, m), 5.45~6.25 (1H,
m), 6.62 (1H, S), 6.20-9.0 (9H, m),
MSm/e: 446 (M ⁺ ). Example 5 Preparation of 6-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-4-tert-butylcatechol (6e). A mixture of 1 g (3 mmol) of compound (3) and 0.61 g (3.6 mmol) of 4-tert-butylcatechol was heated at 160°C.
It was melted for 2 hours. The reaction mixture was purified by silica gel column chromatography. That is, when the crystals obtained by elution with a mixed solvent of hexane: ethyl acetate = 3:1 are recrystallized from ether, mp96
0.82 g (60%) of 6e at ~99°C was obtained. Elemental analysis values: C, 74.65; H, 7.22. NMR (CDCl ₃ ) δ: 1.26 (9H, S), 1.30
(6H, d, J=7Hz), 2.59~3.14 (1H, m),
3.82 (3H, S), 6.41 (1H, S), 6.72-7.94
(9H, m), MSm/e: 448 (M ⁺ ). Example 6 Preparation of 5-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-8-hydroxyquinoline (6f). A mixture of 1.5 g (4.6 mmol) of compound (3) and 0.8 g (5.5 mmol) of 8-hydroxyquinoline was dissolved in 25 ml of anhydrous xylene, and 0.1 g of potassium tert-butoxide and 0.1 g of hexamethylphosphoric acid triamide were added to this mixture. The mixture was heated under reflux for 5 hours to react. After the reaction, xylene was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. That is, when the crystals obtained by elution with a mixed solvent of hexane: ethyl acetate = 9:1 are recrystallized from a mixed solvent of ethyl acetate: chloroform = 1:3, 0.55 g (29%) of 6f at mp212-214°C is obtained.
Obtained. Elemental analysis values: C, 75.96; H, 5.78; N, 3.05. NMR (CDCl ₃ ) δ: 1.47 (6H, d, J=7
Hz), 2.62-3.61 (1H, m), 4.00 (3H, S),
6.50~7.70 (11H, m), 8.02~8.42 (1H, m),
8.92 (1H, d, J=6Hz), 9.30 (2H, b),
MSm/e: 427 (M ⁺ ). Example 7 Preparation of 3-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-indole (6 g). Compound (3) 1.5g (4.6mmol) and indole 0.65g
(5.5 mmol) was dissolved in 25 ml of anhydrous xylene, and this was added with potassium tert-butoxide.
0.1 g and 0.1 g of hexamethylphosphoric triamide were added, and the mixture was heated under reflux for 5 hours. After the reaction, xylene was distilled off under reduced pressure and the residue was purified by silica gel column chromatography. That is, when the crystals obtained by elution with a mixed solvent of hexane: ethyl acetate = 9:1 are recrystallized from ethyl acetate,
0.65g (35%) of 6g of mp162°C was obtained. Elemental analysis values: C, 78.23; H, 6.23; N, 3.53. NMR (CDCl ₃ ) δ: 1.27 (6H, d, J=7
Hz), 2.45-3.24 (1H, m), 3.83 (3H, S),
6.49 (1H, S), 6.60-7.95 (12H, m), 8.45
(1H, S), 9.55 (1H, b), MSm/e: 399 (M
⁺ ). Example 8 Preparation of 2-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-hydroquinone (8). A mixture of 1.0 g (3.0 mmol) of compound (3) and 0.66 g (6.0 mmol) of p-hydroquinone was melted at 130°C for 2 hours. The reaction mixture was purified by silica gel column chromatography. That is, when the crystals obtained by elution with a mixed solvent of hexane: ethyl acetate = 10:1 are recrystallized from ethyl acetate, mp145 is obtained.
0.35g (30%) of -150°C crystals were obtained. Elemental analysis value: C, 72.73; H, 6.56 NMR (CDCl ₃ + DMSO-d ₆ ) δ: 1.27 (6H,
d, J=7Hz), 2.55-3.06 (1H, m), 3.80
(3H, S), 6.20-7.55, 7.55-8.60 (14H, m) MSm/e = 392 (M ⁺ ). Example 9 Preparation of 2-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-1,4-dihydroxynaphthalene (9). 2 g (6.0 mmol) of compound (3) and 1.18 g (7.3 mmol) of 1,4-dihydroxynaphthalene were dissolved in 50 ml of dry xylene and heated under reflux for 6 hours. After the reaction, xylene was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. That is, when the crystals eluted with a mixed solvent of ethyl acetate:hexane=1:10 were recrystallized from ethyl acetate, 0.33 g (17%) of crystals with an mp of 160-162°C was obtained. Elemental analysis values: C, 76.15; H, 5.92 MSm/e = 442 (M ⁺ ). Example 10 Preparation of 6-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-5,7-dihydroxyflavone (10). 1 g (3.0 mmol) of compound (3) and 0.85 g (3.3 mmol) of 5.7-dihydroxyflavone in 20 ml of xylene
The mixture was stirred and heated under reflux for 1 hour. Xylene was distilled off from the reaction mixture under reduced pressure, and the residue was separated and purified by silica gel column chromatography. That is, when the crystals eluted with a mixed solvent of ethyl acetate: hexane = 1:15 are recrystallized from a mixture of ethyl acetate and tetrahydrofuran, mp183-
0.24g (28%) of crystals at 185°C were obtained. Elemental analysis value: C, 73.79; H, 5.32 NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 7
Hz), 2.65-3.20 (1H, m), 3.75 (3H, S),
6.28−8.42 (14H, m), 8.96 (1H, b), 10.76
(1H, b), 13.62 (1H, b), MSm/e=536
(M ⁺ ). Example 11 Preparation of 2-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-3-methyl-1,4-naphthoquinone (11). Compound (3) 1g (3.0mmol) and 2-methyl-1,
4-dihydroxynaphthalene 0.52g (3.0mmol)
was dissolved in 20 ml of dry xylene and heated under reflux for 2 hours. After the reaction, xylene was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography. That is, ethyl acetate:hexane=1:
The compound becomes a yellowish powder when eluted with a mixed solvent of 10
0.38g (28%) was obtained. NMR (CDCl ₃ ) δ: 1.21 (6H, d, J=7
Hz), 2.20 (3H, S), 2.50-3.20 (1H, m),
3.74 (3H, S), 6.00 (1H, S), 6.60−8.20
(11H, m), 8.90 (1H, b) MSm/e=454
(M ⁺ ). Example 12 Preparation of 2-[α-(2-hydroxy-6-isopropyltropon-3-yl)-4-methoxybenzyl]-α-naphthol (11). Compound (3) 3.0g (9.0mmol) and α-naphthol
A mixture of 0.97g (13.5mmol) was heated under reflux at 160°C for 1 hour. The reaction mixture was separated and purified by silica gel column chromatography. That is, when the crystals eluted with a mixed solvent of ethyl acetate: hexane = 1:9 are recrystallized from ether, mp141-
1.03 (27%) of crystals at 143°C were obtained. Elemental analysis value: C, 75.89; H, 6.05 NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 7
Hz), 2.61-3.08 (1H, m), 3.78 (3H, S),
6.70 (1H, S), 6.86-8.78 (13H, m), 9.22
(2H,b) MSm/e=426(M ⁺ ).

Claims (1)

[Claims] 1. General formula: (In the formula, R ¹ is hydrogen or a lower alkyl group, R ²
is an aryl or substituted aryl group, R ³ is a substituted aryl group, or a substituted or unsubstituted heterocyclic group selected from the group consisting of coumarin, pyran, quinoline, indole and flavone residues) A method for producing a derivative, which has the formula (): (In the formula, R ¹ and R ² are as described above,
R ⁴ is a lower alkyl group) A monotropolone derivative represented by the formula (): R ³ H () (wherein R ³ is as described above) is subjected to a thermal reaction. The above-mentioned manufacturing method is characterized. 2. The method according to claim 1, wherein the heating reaction is carried out without a solvent. 3. The method according to claim 1, wherein the heating reaction is carried out in the absence of a solvent and in the presence of a catalyst.