WO2001053302A1

WO2001053302A1 - 5H-QUINOXALINO[2,3-b]NAPHTHO[2,1][1,4]OXAZIN-5-ONE AND INTERMEDIATE FOR THE PREPARATION THEREOF

Info

Publication number: WO2001053302A1
Application number: PCT/JP2001/000261
Authority: WO
Inventors: Tadashi Katoh; Fusae Miyata; Kaoru Yamada; Sadamu Yoshida
Original assignee: Sagami Chemical Research Center; Toppan Printing Co., Ltd.
Priority date: 2000-01-24
Filing date: 2001-01-17
Publication date: 2001-07-26
Also published as: AU2001227046A1

Abstract

5H-Quinoxalino[2,3-b]naphtho[2,1][1,4]oxazin-5-one (1) exhibiting cytotoxicity to malignant tumor cells and being expected to be useful as an antitumor drug (or an anticancer drug); and an intermediate (2) for the preparation thereof.

Description

Specification

5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazin-5-one and its production intermediates

The present invention relates to a novel 5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazin-5-one which exhibits cytotoxicity and is expected to be used as an antitumor agent and its production For intermediates. Background art

There is a strong demand from society for the development of superior antitumor agents, and the creation of new cytotoxic compounds has a very important role in the development of superior antitumor agents. In general, the antitumor activity and antitumor spectrum of a compound largely depend on its chemical structure, so that a cytotoxic compound having a novel structure different from known ones can be used to develop antitumor agents currently in practical use. There is great potential for the development of antitumor agents with better characteristics. Disclosure of the invention

An object of the present invention is to provide a novel cytotoxic 5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazin-5-one, and to produce the compound. To provide useful intermediates.

In view of the above problems, the present inventors have conducted intensive studies, and as a result, have found that 5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazine represented by the following formula (1) It has been found that 5-one has cytotoxicity, and the present invention has been completed.

That is, the present invention provides the following formula (1)

5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazin-5-one represented by the following formula:

The present invention provides a production intermediate of 5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazin-5-one represented by the above formula (1) .

Hereinafter, the present invention will be described in more detail. BEST MODE FOR CARRYING OUT THE INVENTION

The compound represented by the formula (1) of the present invention is, for example, commercially available triamino-2-naphthol assalt (3)

From the following synthesis process _c

(First step)

In this step, a base is allowed to act on triamino-2-naphthol salt (3) to obtain a compound of formula (4) This is to produce triamino-2-naphthol represented by the formula: As the base, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, ammonia, triethylamine, ethyldiisopropylamine, pyridine, pyrrolidine, piperidine and the like are used. Solvents include water; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol. Solvents; ether solvents such as getyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, and 1,4-dioxane; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, and chloroform; pentane, hexane, Hydrocarbon solvents such as cyclohexane, benzene, and toluene; aprotic polar solvents such as ethyl acetate, acetate nitrile, propionitol, acetone, nitromethane, N, N-dimethylformamide, and dimethyl sulfoxide It is also possible to mix two or more of the above solvents. Absent. The reaction can take place between 0 and the melt flow.

(Second step)

In this step, 1-amino-2-naphthol represented by the formula (4) is reacted with 2,3-dichloroquinoxaline represented by the formula (5) under a base, and 5H represented by the formula (2) -Quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazine. Examples of the base used include lithium hydrogen hydride, sodium hydride, potassium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropyl pyramide, lithium hexamethyldisilazide, sodium carbonate, Potassium carbonate, cesium carbonate, triethylamine, ethyldiisopropylamine, pyridine and the like are used. Examples of the solvent include ether solvents such as getyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, and 1,4-dioxane; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, and chloroform. Hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene and toluene; Ν, Ν-dimethylformamide, dimethylsulfoxy An aprotic polar solvent such as a solvent is used, and two or more of the above solvents may be mixed. The reaction can be carried out between 0 ° C and the reflux temperature of the solvent.

(Third step)

In this step, the 5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazine represented by the formula (2) is oxidized, and the 5H-quinoxalino [1,4] oxazine represented by the formula (1) is oxidized. Quinoxalino [2,3-b] naphtho [2,1] [1,4] This is intended to produce oxazin-5-one. The reaction involves the reaction of oxygen-N ,, '-bis (salicylidene) ethylenediaminocobalt (II) (sarcomin), oxygen- 2,2,6,6-tetramethylpiperinidyl-Ν-oxide radical (TEMPO) ) —Copper (II) chloride, sodium ditrosodisulfonate (Flemish: ^), cesium ammonium nitrate (CAN), benzeneselenic anhydride, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), silver oxide (1), lead oxide (IV), potassium permanganate, potassium ferricyanide, or the like. Solvents include ether solvents such as Jethyl ether, diisopropyl propyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane; halogen hydrocarbon hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform. Solvents: Hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, and toluene; aprotic polar solvents such as acetonitrile, propionitrile, acetone, nitromethane, N, N-dimethylformamide, and dimethyl sulfoxide It may be used, and two or more of the above solvents may be mixed. The reaction can be carried out between -20 ° C and the reflux temperature of the solvent.

The 5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazin-5-one represented by the above formula (1) obtained as described above A growth inhibitory activity test was performed to confirm that this compound exhibited cytotoxicity and had use as an antitumor agent.

Hereinafter, the present invention will be described in detail with reference examples, examples, and test examples, but it goes without saying that the present invention is not limited to these. Example Poem 1

To a mixed solution (100 ml) of triamino-2-naphthyl salt (1.00 g, 5.11 mol) in methanol / ethyl acetate (1/10) was added a saturated aqueous solution of sodium hydrogen carbonate (100 ml) at room temperature. 3¾ and a half for 5 minutes. The reaction mixture was extracted with ethyl acetate (100 ml X3), and the extract was washed with saturated saline (100 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by silica gel chromatography- (ethyl acetate: hexane = 1: 1) to give triamino-2-naphthol (0.753 g, 87 °) as a white powder.

IR (KBr, Le cm— '): 3387 (s), 3315 (s), 3047 (m), 2924 (m), 2787 (w), 2625 (w), 2582 (w), 1655 (m), 1604 (m), 1575 (m), 1512 (s), 1481 (w), 1460 (w), 1444 (m), 1394 (m), 1363 (s), 1334 (s), 1277 (s), 1257 (m), 1226 (w), 1192 (m), 1149 (w), 1074 (w), 1020 (w), 939 (m), 866 (s), 856 (s), 800 (s), 767 (s), 742 (m), 696 (w), 640 (w), 597 (w), 536 (w), 499 (w), 484 (w).

_{Ή-NMR (500MHz, CDC1 3} ) 6: 3.75-3.88 (2H, br, NH 2), 5.27 (1H, s, OH), 7.09 (2H, d, J = 7.8Hz), 7.29-7.38 (2H, m), 7.42-7.50 (1H, m), 7.76 (1H, d, J = 7.3Hz), 7.80 (1H, d, J = 7.8Hz).

EIMS (m / Z): 159 (M ⁺ ), 133, 114, 103, 77, 65, 51.

Anal.Calcd. For C, ₀ H ₉ N0: C, 75.45; H, 5.70; N, 8.80 ¾.

Found: C, 75.59; H, 5.61; N, 8.92%. Example 1

60% solution of 1-amino-2-naphthyl (478 mg, 3.OOmiol) and 2,3-dichloroquinoxaline (622 mg, 3.00 benzyl) in N, N-dimethylformamide (20 ml) at 0 ° C Sodium hydride (420 mg, 10.5 mmol) was added in small portions, and the mixture was stirred at 60 ° C for 30 minutes under an argon atmosphere. Diisopropyl ether (20 ml) and water (100 ml) were added to the reaction mixture, the mixture was stirred at 0 ° C for 30 minutes, and the deposited precipitate was filtered. The product was washed successively with disopropyl ether (100 ml) and water (100 ml), and then decompressed under reduced pressure to give 5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazine (269 mg , 90%) as a yellow powder.

Melting point: 279-281.

IR (KBr, cm- ¹ ): 3196 (w), 3055 (w), 2926 (w), 2854 (w), 1628 (w), 1608 (m), 1587 (s), 1574 (m), 1543 (m), 1520 (w), 1481 (s), 1456 (s), 1406 (s), 1338 (w), 1304 (s), 1284 (w), 1269 (m), 1201 (m), 1143 (w), 1120 (w), 1087 (w), 1001 (w), 979 (w), 945 (w), 927 (w), 866 (w), 866 (w), 794 (m), 763 (s), 736 (m), 652 (w), 601 (m), 557 (w), 538 (m), 499 (w).

Ή-NMR (500 MHz, CDC1 :,) δ: 7.05 (1H, s, NH), 7.20 (1H, d, J = 8.6 Hz), 7.38 (1H, t, J = 7.2 Hz), 7.42-7.49 ( 3H, m), 7.51 (1H, d, J = 7.2Hz), 7.57 (1H, t, J = 7.2Hz), 7.62 (1H, d, J = 8.0Hz), 7.70 (1H, d, J = 8.6 Hz), 7.80 (1H, d, J = 8.0Hz).

EIMS (m / Z): 285 (M +), 142, 129, 111, 97, 85, 83, 71, 69, 57, 55, 43, 41.

Anal.Calcd. For Ο, βΗ ,, Ν., Ο: C, 75.78; H, 3.89; N, 14.73%.

Found: C, 75.62; H, 3.98; N, 14.46%. Example 2

5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazine (852 mg, 2.99 benzyl) and ぴ '-bis (salicylidene) ethylenediaminocobalt (Π) (sarcomine) (194 mg, 0.597 mmol) in N, N-dimethylformamide (36 ml) was stirred at room temperature under an oxygen atmosphere for 1 hour. Dichloromethane (400 ml) was added to the reaction mixture, which was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a residue. The resulting residue was purified using silica gel chromatography (dichloromethane) and recrystallized from ethyl acetate to give 5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] Oxazin-5-one (725 mg, 81%) was obtained as orange crystals.

Melting point: 288-290 ° C.

IR (KBr, cm- ¹ ): 3036 (w), 1641 (s), 1595 (m), 1568 (s), 1496 (w), 1464 (w), 1400 (w), 1379 (w), 1361 (w), 1332 (m), 1309 (s), 1277 (w), 1244 (s), 1213 (m), 1170 (m), 1141 (w), 1126 (), 1111 (w), 1082 (w), 1005 (), 902 (w), 817 (), 785 (m), 765 (s), 711 (m), 671 (w), 625 (w), 607 (w), 520 (w ), 495 (w).

Ή-NMR (500 MHz, CDC1,) δ: 6.68 (1H, s), 7.79-7.90 (4H, m), 8.05 (1H, dd, J = l.0, 8.3 Hz), 8.26 (1H, dd, J = l.0, 8.3Hz), 8.28-8.32 (1H, m), 8.88-8.92 (1H, m)

EIMS (m / Z): 299 (M ⁺ ), 284, 227, 163, 113, 101, 75.

_{.. Anal Calcd for C, 8} H 9 N 3 0 2: C, 72.24; H, 3.03; N, 14.04%.

Found: C, 72.05; H, 2.78; N, 13.96%. Test Example 1 (Malignant tumor cell growth inhibition test)

Mouse lymphoid leukemia cells (P388) were added to RPMI-1640 medium containing 10% fetal calf serum supplemented with 5 ml of 2-hydroxyethyl disulfide and 100 mg / ml of kanamycin sulfate, and the cultured cells were grown to lxl (T cells / ml). The 5H-quinoxalino of the present invention [2,3- b] naphtho [2, 1] [1, 4] Okisajin - and添Ka卩5- one (1) to a predetermined concentration, C0 ₂ incubator (C0 ₂ 5%, humidity 100, 37 ° C) For 4 days. To measure the number of viable cells by the MTT colorimetric method, it was determined for 50% cell growth inhibition marrow from the growth inhibition rate relative to the control group _{_{(IC 5 Q), IC 5}} . The value was 18 g / ml. Industrial applicability

The compound of the present invention is a cytotoxic substance having a completely different chemical structure from that of the existing ulcer agent, and is expected to be used as an antitumor agent having a new mechanism of action.

Claims

The scope of the claims

1. The following equation (1)

5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazin-5-one represented by:

2. The following equation (2)

5H-quinoxalino [2,3-b] naphtho [2,1] [1,4] oxazine represented by