KR100508559B1 - NOVEL 6,11-DIHYDRO-QUINOXALINO[2,3-g]PHTHALAZINE-6,11-DIONE DERIVATIVES, INTERMEDIATES AND PROCESS FOR MAKING THE SAME - Google Patents

Abstract

The present invention relates to a novel compound represented by the following formula (1), an intermediate thereof, and a method for preparing the same, and the compound may be used for the purpose of preventing, treating or assisting in treating various cancer diseases.

[Formula 1]

In the formula, the definition of R ₁ is as defined in the specification of the present invention.

Description

Novel 6,11-dihydro-quinoxalino [2,3-g] phthalazine-6,11-dione derivatives, intermediates thereof and preparation methods thereof NOVEL 6,11-DIHYDRO-QUINOXALINO [2,3- g] PHTHALAZINE-6,11-DIONE DERIVATIVES, INTERMEDIATES AND PROCESS FOR MAKING THE SAME}

The present invention provides pharmaceutically active novel 6,11-dihydro-quinoxalino [2,3-g] phthalazine-6,11-dione derivatives, pharmaceutically acceptable salts thereof and certain of these derivatives. An intermediate and a method for producing the same.

Quinone derivatives have been widely used in medicine and the like for centuries as compounds having various physiological activities [Calndra, JC, Adams, ECJ Am. Chem. Soc. 72 (10), 4804, 1950 ; Lutz, RE, et al., JWJ Org. Chem. 14, 982, 1949 ; Pratt, YT, Drake, NLJ Am. Chem. Soc. 77 (1), 37, 1955 ; Porter, TH, et al., J. Med. Chem. 14 (11), 1029, 1972 ; Pratt, YT, Drake, NLJ Am. Chem. Soc. 82 (5), 1155, 1960 ; Crosby, AH, Lutz, REJ Am. Chem. Soc. 78 (6), 1233, 1956 ; Katoh, A., et al., Heterocycles 34 (10), 1965, 1992 ]. For example, these compounds have important physiological activities such as enzyme inhibitors, antibacterial agents, antifungal agents, and anticancer agents, and have been reported to play important roles in electron transfer and oxidative phosphorylation in physiological metabolism [Morton, RA Ed. Biochemistry of Quinones, 1965 ].

In addition, since linkage expansion occurs easily by intramolecular cyclization through nucleophilic addition reaction and nucleophilic substitution reaction, it functions as a useful intermediate in the synthesis of pharmaceuticals. Among them, heterocyclic quinone compounds containing nitrogen as a cyclic element in a heterocyclic structure have strong electron affinity [Camilleri, P., Odell, BJ Chem. Soc. Perkin Trans., 1671, 1987 ] is known to have excellent anticancer and biological activity [Akutagerwa, M., et al., J. Chem. Soc. Common. 19, 1290, 1985 ; Skibo, EB, et al., J. Med. Chem. 37 (1), 78, 1994 ; Helissey, P., Renault, SG Anti-cancer Drug Desine 9, 51, 1994 ; Giorgio-Renault, S., et al., J. Med. Chem. 34 (1), 38, 1991 ; Fox, MA, Voynick, Taj Org. Chem. 46 (7), 1235, 1981 ].

1

However, a compound of 2-methyl-1-substituted-naphtho [2,3-d] imidazole-4,9-dione, which is a naphthoquinone derivative, and 2-methyl-1-substituted-imidazo [4, In the case of 5-g] quinolinedione derivatives, the cytotoxic effect was not so good [J. Med. Chem. (1996) 39, 1447; Bioorg. Med. Chem. (2000), 8, 2079].

Gastric adenocarcinoma in the case of 2-methyl-4,9-dihydro-1- (4-bromophenyl) -1H-imidazo [4,5-g] -quinoxaline-4,9-dione Although the cytotoxic effect was superior to cisplatin or doxorubicin, which is currently used as an anticancer agent, the cell line has only a limited cytotoxic effect on human gastric cancer cell lines [HWYoo, et al., J. Med. Chem. (1998), 41, 4716.

On the other hand, Cyke et al., In the relationship between the structure of the heterocyclic quinone compound and its anticancer activity, the number and position of nitrogen as a cyclic constituent in the heterocyclic structure play an important role, and in the dichloroquinone compound, naphthalene, quinoline, iso It was found that DNA cleavage activity was increased in the order of quinoline, diazanaphthalene and the like [IAShaikh, et. al., J. Med. Chem. (1986), 29 (8), 1335].

In light of these results, the present inventors found a new heterocyclic quinone-based compound based on phthalazine, which is expected to exhibit effective anticancer activity among diazanaphthalene analogues, and completed the present invention.

The present invention seeks to provide pharmaceutically active novel quinoxalino [2,3-g] phthalazine-6,11-dione derivatives, pharmaceutically acceptable salts thereof, intermediates of these compounds and methods for their preparation. do.

The present invention provides a compound represented by the formula (1), a pharmaceutically acceptable salt thereof.

In the above formula, R ₁ may be one selected from the group consisting of hydrogen, lower alkyl group and lower alkoxy group.

Throughout the formulas and throughout the specification relating to the present invention, the term "lower alkyl group" used in the definition of R ₁ means a straight or branched chain alkyl group consisting of 1 to 6 carbon atoms, for example methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl Or 1-ethyl-2-methylpropyl group. Among them, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl groups are preferred, and methyl, ethyl, n-propyl or n-butyl groups are most preferred.

In addition, the term "lower alkoxy group" used in the definition of R ₁ means a straight or branched chain alkoxy group composed of 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy Or a hexyloxy group. Among them, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary butoxy or tert-butoxy groups are preferred, and methoxy or ethoxy groups are most preferred.

Preferred compounds among the compounds represented by Formula 1 are compounds represented by the following Formula 2.

In the formula, the definition of R ₁ is the same as in formula (1).

Specific examples of the preferred compound represented by Formula 2 are as follows.

Viii) 6,11-dihydro-quinoxalino [2,3-g] phthalazine-6,11-dione

Ii) 6,11-dihydro-2-methyl-quinoxalino [2,3-g] phthalazine-6,11-dione

Viii) 6,11-dihydro-2-methoxy-quinoxalino [2,3-g] phthalazine-6,11-dione

Viii) 6,11-dihydro-2-ethyl-quinoxalino [2,3-g] phthalazine-6,11-dione

Viii) 6,11-dihydro-2-ethoxy-quinoxalino [2,3-g] phthalazine-6,11-dione

Viii) 6,11-dihydro-2-n-propyl-quinoxalino [2,3-g] phthalazine-6,11-dione

Viii) 6,11-dihydro-2-n-butyl-quinoxalino [2,3-g] phthalazine-6,11-dione

Throughout the specification of the present invention, the heterocyclic quinone compound means a compound including a structure in which one or more heterocycles are condensed with the quinone ring in the quinone ring. In addition, condensation herein means a bond in a fused form where the ring and the ring share one side.

The compound of the present invention has a condition as a DNA intercalater described below due to the structure of the compound based on phthalazine as a backbone.

Iii) three or four condensed rings in the plane

Ii) Heterocycles containing two or more nitrogen elements as ring members in a single ring

Iii) conjugated carbonyl groups present in the para position on the quinone nucleus

B-DNA insertion occurs when the chromophore of the insert, that is, the planar condensed ring structure, is sandwiched between two base pairs. At this time, there is no change in the primary structure and the secondary structure of DNA, but in the tertiary structure, a change occurs to accommodate the planar insert. That is, as the insertion material and the DNA form a complex, the distance between the two base pairs of the double helix (double helix) increases, the length of the tertiary helix structure is somewhat longer than the original structure, and the phenomenon that the helix is released. As a result, it appears to exert anticancer activity by inhibiting cell growth in S phase by inhibiting the action of RNA synthase and gyrase (gyrase, topo-isomerase) [Moore, MH, Kennard, OJ Mol. Biol. 206, 693, 1987 ; Pindur, U., Haber, M., Sattler, KJ Chem. Educa. 70 (4), 263, 1993].

On the other hand, hydrogen bonding energy and van der Waals energy play an important role in the insertion material forming a stable complex with double helix DNA [Kennard, O., Hunter, WN Angew. Chem. Int. Ed. Engl. 30, 1245, 1991 ]. That is, when nitrogen is included as a ring member in the heterocyclic structure as in the compound of the present invention, the nitrogen element forms a hydrogen bond with DNA, thereby making the insertion complex more stable, and the conjugated carbonyl group present in the quinone nucleus is also DNA. Hydrogen bonds with and appear to contribute to the stability of the insert complex.

Therefore, the number and position of nitrogen in the heterocyclic structure of the compound of the present invention is very important in relation to the cytotoxic effect. The compounds based on phthalazine of the present invention seem to be more effective in showing intercalation activity in the number of nitrogen or mutual positions of nitrogen, as compared to compounds consisting of quinoline or quinoxaline structures.

In addition, in the case of two conjugated carbonyl groups present on the quinone nucleus, it is more preferable to form a stable DNA insertion complex at the para position than at the ortho position.

In particular, as the compound maintains a planar structure by a plurality of condensed rings, it is easier to align and stack with double-stranded DNA by van der Waals forces under the influence of π electrons of the condensed ring, thereby forming a more stable insertion complex. . However, as the number of condensed rings increases, not only DNA insertion itself becomes difficult due to the increase in molecular size, but also the self-stacking tendency increases, thereby decreasing the DNA affinity of the insert. Therefore, for more preferable DNA insertion activity, it is preferable that three or four rings are condensed (molecular size of about 3-4 mm long and 6-8 mm long).

The present invention also provides an intermediate represented by the formula (3).

In the formula, the definition of R ₁ is the same as in formula (1).

Among the intermediates represented by Chemical Formula 3, particularly preferable compounds for preparing the compounds of the present invention are those represented by the following Chemical Formula 4.

In the formula, the definition of R ₁ is the same as in formula (1).

The invention also provides a process for the preparation of the compounds of the invention and their intermediates.

The preparation method of the compound of the present invention and the intermediate thereof is as follows.

[Figure 2]

In the figure, the definition of R ₁ is the same as in formula (1).

Hereinafter, a method of preparing the compound of the present invention and an intermediate thereof will be described in detail.

Viii) The starting material 6,7-dichloro-5,8-phthalazinedione is dissolved in alcohol, preferably ethanol, and then suitable arylamine is selected and added dropwise at 0-50 占 폚, preferably at room temperature. The specific examples of the arylamine used is aniline, o - toluidine, m - toluidine, p - toluidine, o - not. Dean, m - not. Din, p - not. Aberdeen, 2-ethyl aniline, 3-ethyl aniline, 4- Ethylaniline, o -phenetidine, m -phenetidine, p -phenetidine, 4-n-propylaniline, 4-n-butylaniline, 4-n-pentylaniline or 4-n-hexylaniline It is not limited thereto. The molar ratio of 6,7-dichloro-5,8-phthalazinedione and arylamine used above is preferably 1: 1 to 1: 3, preferably 1: 1.5 to 1: 2.5. The mixture is reacted at 0-50 ° C., preferably at room temperature, for a time sufficient for reaction, preferably 3-7 hours, to yield a 6-arylamino-7-chloro-5,8-phthalazinedione compound. .

If necessary to obtain the compound, it may be subjected to a post-treatment process such as extraction or purification after the reaction. As a preferable example of the post-treatment process, after the reaction is completed, the precipitate formed by adding water to the reaction solution is filtered, and the filtrate is extracted with ethyl acetate, dried and concentrated, and then combined with the precipitate obtained above. . In addition, it may be further subjected to a general purification step such as washing with cold alcohol of the same kind as the alcohol solvent used in the reaction process.

Ii) Next, 6-arylamino-7-chloro-5,8-phthalazinedione obtained in the above process is dissolved in an alcohol, preferably ethanol, and NaN ₃ (sodium azide) is preferably added thereto. Is dissolved in a small amount of water and added dropwise. The mixture is reacted for a sufficient time, preferably while heating and stirring for 6-24 hours to give a 6,11-dihydro-quinoxalino [2,3-g] -phthalazine-6,11-dione compound. do. The molar ratio of 6-arylamino-7-chloro-5,8-phthalazinedione and NaN ₃ used in the above reaction can be 1: 1 to 1: 2, most preferably about 1: 1.5.

If necessary to obtain the compound, it may be subjected to a post-treatment process such as extraction or purification after the reaction. As a preferred example of the post-treatment process, after the reaction is completed, the reaction mixture is removed under reduced pressure, extracted with water and ethyl acetate, the organic layer is dried and concentrated, and then washed with cold alcohol of the same type as the reaction solvent. Or a general purification process such as separation by column chromatography.

Pharmaceutically acceptable salts of the compounds of the invention are, for example, acid addition salts of the phthalazinedione derivatives of the invention that are sufficiently basic, for example inorganic or organic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Acid addition salts with methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, citric acid, lactic acid or maleic acid). In addition, suitable pharmaceutically acceptable base-addition salts of the phthalazinedione derivatives of the present invention that are sufficiently acidic include alkali metal salts such as lithium, sodium or potassium salts; Alkaline earth metal salts such as calcium or magnesium salts; Ammonium salts; Or salts with organic bases that provide physiologically acceptable cations, for example with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine. All such salts fall within the scope of the present invention and they can be prepared by conventional methods. For example, they can be prepared by contacting acidic and basic groups in a suitable aqueous, non-aqueous or partially aqueous medium, generally in a stoichiometric ratio. The salts are appropriately recovered by filtration, preferably by filtration after precipitation with a non-solvent that is an etheric or hydrocarbon solvent, evaporation of the solvent, or lyophilization in the case of an aqueous solvent.

Since the compounds of the present invention exhibit DNA insertion activity, they can all be used for the prophylaxis, treatment or treatment of hyperproliferation (eg cancer) in mammals, especially humans. In particular, the pharmaceutical composition containing the compound of the present invention or a salt thereof as an active ingredient can be used for various benign or malignant human tumors (lung cancer, ovarian cancer, skin cancer, melanoma cancer, central nerve cancer, colon cancer, kidney cancer, liver cancer, bladder cancer, breast cancer). , Stomach cancer, uterine cancer, prostate cancer, colon cancer, vulvar cancer, thyroid cancer, sarcoma, gliomas, various head and neck tumors, etc.). Activity against the benign disease is described in J. Invest. Dermatol. (1992), 98, 296] can be determined using standard assays.

A pharmaceutical composition (hereinafter referred to as "the composition of the present invention") comprising the compound of the present invention or a salt thereof as an active ingredient is prepared in unit dose form or formulated using a pharmaceutically acceptable carrier or excipient or in a multi-dose container. It may be prepared by incorporation, and may be administered orally, parenterally or topically, once or several times.

As used herein, the term “parenteral” includes, without limitation, subcutaneous, intravenous, arterial or infusion techniques. The term "topical" also includes inhalation spray and rectal administration, as well as administration by conventional routes such as mucous membranes and skin of the mouth and nose.

The compositions of the present invention may be in solid, semisolid or liquid dosage form (e.g. in the form of tablets, capsules, pills, powders, suppositories, solutions, elixirs, syrups, suspensions, creams, sugar tablets, pastes and sprays) Can be. As is known in the art, the route of administration of the phthalazine derivatives described herein is selected according to the type of composition to be used. In general, it is preferred to use unit dosage forms of the inhibitors described herein to facilitate the treatment and administration of the correct dose of the active compound. In general, the compounds having a therapeutic effect of the present invention are present in a dosage form that is sufficient to provide a desired level of concentration, i.

The dosage of the composition of the present invention is generally administered in a single or multidose form in an amount of about 0.01 to 100 mg / kg per day based on the active ingredient, but may be determined differently depending on the health condition or pathological findings of the individual.

For oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may contain various disintegrants such as starch, preferably potato or tapioca starch, alginic acid and certain silicate complexes, polyvinyl pyrrolidone, It can be used with binders such as sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are sometimes very useful for tableting. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules. Preferred materials related to this include high molecular weight polyethylene glycols as well as lactose or lactose. If oral administration of an aqueous suspending agent or elixir is desired, the essential active ingredients contained therein are various sweetening or flavoring agents, colorants or pigments and, if desired, emulsifying and / or suspending agents as well as water, ethanol, propylene glycol, It can be used in combination with diluents such as glycerin and various similar mixtures.

For parenteral administration, various substances can be used as carriers, adjuvants and vehicles in the compositions of the present invention as useful in the pharmaceutical sector. Injections, such as oily solutions, suspensions or emulsions, may be formulated by known techniques using the necessary suitable dispersing or wetting agents and suspending agents. Sterile injectables may also be used, for example, sterile nonpyrogenic or parenterally acceptable non-toxic diluents or solvents such as 1,3-butanediol. Other acceptable vehicles and solvents that may be used include 5% Textose Injection, Ringer's Injection and Sodium Chloride Injection. Sterile, nonvolatile oils are also commonly used as solvents or suspending media. Any mixed nonvolatile oil may be used for this purpose, including synthetic mono-, di- or triglycerides. Fatty acids such as oleic acid may also be used in the preparation of injectable compositions.

Rectal suppositories of the compositions of the present invention can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter, polyethylene glycol, etc., which is solid at room temperature but liquid at body temperature and thus melts in the rectum to release the drug.

In addition, the composition of the present invention may be administered locally, and for this use, it is preferable to administer the cream, salves, jelly, paste, ointment, and the like according to standard pharmaceutical practice.

The following examples illustrate the preparation of starting materials for carrying out the invention and the compounds of the invention and their intermediates, which are intended to illustrate the invention and are not intended to limit the scope of the invention.

Example 1 6,11-dihydro-quinoxalino [2,3-g] phthalazine-6,11-dione

1-1) Preparation of 6,7-dichloro-5,8-phthalazine dione

The starting material of this example, 6,7-dichloro-5,8-phthalazinedione, is described in J.S.Kim, et al., Bull.Korean Chem. Soc. (2002), 23 (10), 1425].

3

The figure schematically shows a method for preparing 6,7-dichloro-5,8-phthalazinedione, which will be described in more detail, in which phthalazine (Merck, Germany) (20.0 g, 0.15 mol) is concentrated in sulfuric acid (150 ml After dissolving in), potassium nitrate (73.2 g, 0.72 mol) was added to the solution at 0 ° C. in small portions, and heated again for 2 days while maintaining 55-60 ° C. The mixture was diluted with water at 0 ° C., then neutralized with sodium hydroxide solution and the precipitate was filtered to give 5-nitrophthalazine.

The methanol (1L) solution of HONH ₂ HCl (62.0g, 0.89mol) was slowly added to the 5-nitrophthalazine (26.0g, 0.15mol) ethanol (1.5L) solution at 50-55 ° C. for 3 hours. And stirred. The reaction mixture was cooled with ice water and the resulting precipitate was filtered to give 5-nitro-8-aminophthalazine.

5-Nitro-8-aminophthalazine (14.2 g, 74.7 mmol) obtained above was dissolved in methanol (700 ml), and then FeCl ₃ (70.0 mg, 0.43 mmol) and charcoal (4.50) were added to the solution. g) joined. The mixture was refluxed for 5 hours and filtered using celite to give 5,8-diaminophthalazine.

The 5,8-diaminophthalazine (7.09g, 44.3mmol) obtained above was dissolved in concentrated hydrochloric acid (90.0ml), and then several times each part of NaClO ₃ (6.08g, 49.6mmol) was added to the solution at 0 ° C. Subscribed across. The reaction mixture was stirred for 1 hour at room temperature, cooled by addition of water and the precipitate was filtered to give 6,7-dichloro-5,8-phthalazinedione.

1-2) Preparation of 6,11-dihydro-quinoxalino [2,3-g] phthalazine-6,11-dione

1-2-a) 6-phenylamino-7-chloro-5,8-phthalazinedione

After dissolving 6,7-dichloro-5,8-phthalazinedione (500 mg, 2.19 mmol) in ethanol (20 ml), aniline (0.4 ml, 4.37 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 5 hours, and then water was added to filter the resulting precipitate. The filtrate was extracted with ethyl acetate, dried and concentrated, combined with the precipitate obtained above, and washed with cold ethanol to give a purple solid (600 mg, 96%).

Melting Point: 245 ~ 246 ℃

¹ H-NMR (CDCl ₃ ): δ 9.93 (s, 1 H), 9.78 (s, 1 H), 7.72 (br. S, 1 H), 7.40 (t, J 7.6 Hz, 2H), 7.30 (t, J 7.6 Hz, 1H), 7.11 (d, J 7.6 Hz, 2H)

IR (CH ₂ Cl ₂ ): 3289, 1684, 1553 cm ^-1

1-2-b) 6,11-dihydro-quinoxalino [2,3-g] phthalazine-6,11-dione

NaN ₃ (200 mg, 3.08 mmol) dissolved in 6-phenylamino-7-chloro-5,8-phthalazinedione (570 mg, 2.0 mmol) in ethanol (50 ml) and dissolved in a small amount of water in the solution. Was added dropwise, and the reaction mixture was heated and stirred overnight. The mixture was removed under reduced pressure and extracted with water and ethyl acetate. The organic layer was dried and concentrated, washed with cold ethanol or separated by column chromatography to obtain a brown solid (150 mg, 23%).

Melting Point:> 300 ℃

¹ H-NMR (DMSO d6): δ 9.36 (s, 2H), 7.71 (m, 2H), 7.31 (m, 2H)

IR (CH ₂ Cl ₂ ): 1697 cm ^-1

Elemental Analysis: Calcd for C ₁₄ H ₆ N ₄ O ₂ : C, 64.12; H, 2.31; N, 21.37

           Found: C, 63.62; H, 2.50; N, 20.71

Example 2 6,11-dihydro-2-methyl-quinoxalino [2,3-g] phthalazine-6,11-dione

2-a) 6- (4-methylphenylamino) -7-chloro-5,8-phthalazinedione

6,7-dichloro-5,8-phthalazinedione and p -toluidine (468 mg, 4.37 mmol) were reacted according to the method of Example 1-2-a) of Example 1 to a purpleish color (610 mg, 93%). Got.

Melting Point: 218 ~ 219 ℃

¹ H-NMR (CDCl ₃ ): δ 9.85 (d, J 0.8 Hz, 1H), 9.70 (d, J 0.8 Hz, 1H), 7.63 (br, s, 1H), 7.12 (d, J 8.4 Hz, 2H ), 6.94 (d, J 8.4 Hz, 2H), 2.32 (s, 3H)

IR (CH ₂ Cl ₂ ): 3219, 1686, 1552 cm ^-1

2-b) 6,11-dihydro-2-methyl-quinoxalino [2,3-g] phthalazine-6,11-dione

6- (4-methylphenylamino) -7-chloro-5,8-phthalazinedione (600 mg, 2.0 mmol) was reacted with NaN ₃ according to the method of Example 1-2-b) to give a brown solid ( 93 mg, 16%).

Melting Point:> 300 ℃

¹ H-NMR (DMSO d6): δ 9.99 (s, 2H), 8.32 (d, J 8.4 Hz, 1H), 8.22 (br s, 1H), 7.99 (dd, J 8.4 and 1.6 Hz, 1H), 2.65 (s, 3H)

IR (CH ₂ Cl ₂ ): 1703cm ^-1

Elemental Analysis: Calcd for C ₁₅ H ₈ N ₄ O ₂ : C, 65.22; H, 2.92; N, 20.28

           Found: C, 65.10; H, 3.02; N, 19.72

Example 3 6,11-dihydro-2-methoxy-quinoxalino [2,3-g] phthalazine-6,11-dione

3-a) 6- (4-methoxyphenylamino) -7-chloro-5,8-phthalazinedione

According to the method of 1-2-a) of Example 1, 6,7-diclo-5,8-phthalazinedione was reacted with p -anizidine (538 mg, 4.37 mmol) to give a mauve solid (640 mg, 93 %) Was obtained.

Melting Point: 179 ~ 180 ℃

¹ H-NMR (CDCl ₃ ): δ 9.85 (d J 0.8 Hz, 1H), 9.70 (d, J 0.8 Hz, 1H), 7.60 (br s, 1H), 7.00 (dd, J 6.8 and 2.4 Hz, 2H ), 6.84 (dd, J 6.8 and 2.4 Hz, 2H), 3.78 (s, 3H)

IR (CH ₂ Cl ₂ ): 3289, 1681, 1637, 1552 cm ^-1

3-b) 6,11-dihydro-2-methoxy-quinoxalino [2,3-g] phthalazine-6,11-dione

6- (4-methoxyphenylamino) -7-chloro-5,8-phthalazinedione (630mg, 2.0mmol) was reacted with NaN ₃ according to the method of Example 1-2-b) and browned. Solid (110 mg, 19%) was obtained.

Melting Point:> 300 ℃

¹ H-NMR (DMSO d6): δ 9.97 (s, 2H). 8.31 (d, J 9.2 Hz, 1H), 7.75-7.82 (m, 2H), 4.04 (s, 3H)

IR (CH ₂ Cl ₂ ): 1692 cm ^-1

Elemental Analysis: Calcd for C ₁₅ H ₈ N ₄ O ₃ : C, 61.65; H, 2.76; N, 19.17

           Measurement: C, 61.31; H, 2.78; N, 18.81

Example 4 6,11-dihydro-2-ethyl-quinoxalino [2,3-g] phthalazine-6,11-dione

4-a) 6- (4-ethylphenylamino) -7-chloro-5,8-phthalazinedione

6,7-dichloro-5,8-phthalazinedione and 4-ethylaniline (529mg, 4.37mmol) were reacted according to the method of Example 1-2-a) of Example 1 to give a mauve solid (650mg, 95%). )

Melting Point: 152 ~ 153 ℃

¹ H-NMR (CDCl ₃ ): δ 9.90 (d, J 1.2 Hz, 1H), 9.74 (d, J 1.2 Hz, 1H), 7.66 (br s, 1H), 7.19 (d, J 8.4 Hz, 2H) , 7.01 (d, J 8.4 Hz, 2H), 2.66 (q, J 7.6 Hz, 2H), 1.24 (t, J 7.6 Hz, 3H)

IR (CH ₂ Cl ₂ ): 3213, 1686, 1552 cm ^-1

4-b) 6,11-dihydro-2-ethyl-quinoxalino [2,3-g] phthalazine-6,11-dione

Brown solid by reacting 6- (4-ethylphenylamino) -7-chloro-5,8-phthalazinedione (630 mg, 2.0 mmol) with NaN ₃ according to the method of Example 1-2-b) (80 mg, 14%) was obtained.

Melting Point:> 300 ℃

¹ H-NMR (DMSO d6): δ 10.03 (s, 2H), 8.38 (d, J 8.8 Hz, 1H), 8.26 (br s, 1H), 8.08 (br d, J 8.8 Hz, 1H), 2.99 ( q, J 7.6 Hz, 2H), 1.37 (t, J 7.6 Hz, 3H)

IR (CH ₂ Cl ₂ ): 1697 cm ^-1

Elemental Analysis: Calcd for C ₁₆ H ₁₀ N ₄ O ₂ : C, 66.20; H, 3.47; N, 19.30

           Found: C, 65.87; H, 3.36; N, 18.98

Example 5 6,11-dihydro-2-ethoxy-quinoxalino [2,3-g] phthalazine-6,11-dione

5-a) 6- (4-ethoxyphenylamino) -7-chloro-5,8-phthalazinedione

6,7-dichloro-5,8-phthalazinedione and p-phenetidine (599 mg, 4.37 mmol) were reacted according to the method of Example 1-2-a) of Example 1 to give a mauve solid (690 mg, 96 %) Was obtained.

Melting Point: 191 ~ 192 ℃

¹ H-NMR (CDCl ₃ ): δ 9.89 (d, J 1.2 Hz, 1H), 9.73 (d, J 1.2 Hz, 1H), 7.64 (br s, 1H), 7.04 (dd, J 6.8 and 2.0 Hz, 2H), 6.86 (dd, J 6.8 and 2.0 Hz, 2H), 4.04 (q, J 6.8 Hz, 2H), 1.42 (t, J 6.8 Hz, 3H)

IR (CH ₂ Cl ₂ ): 3257, 1695, 1639, 1553, 1520 cm ^-1

5-b) 6,11-dihydro-2-ethoxy-quinoxalino [2,3-g] phthalazine-6,11-dione

6- (4-ethoxyphenylamino) -7-chloro-5,8-phthalazinedione (660 mg, 2.0 mmol) was reacted with NaN ₃ according to the method of Example 1-2-b), and yellow. A solid (210 mg, 34%) was obtained.

Melting Point:> 300 ℃

¹ H-NMR (DMSO d6): δ 10.01 (s, 2H), 8.33 (d, J 9.2 Hz, 1H), 7.71-7.95 (m, 2H), 4.37 (q, J 6.9 Hz, 2H), 1.47 ( t, J 6.9 Hz, 3H)

IR (CH ₂ Cl ₂ ): 1703cm ^-1

Elemental Analysis: Calcd for C ₁₆ H ₁₀ N ₄ O ₃ : C, 62.74; H, 3.29; N, 18.29

           Found: C, 63.19; H, 3.26; N, 18.06.

Example 6 6,11-dihydro-2-n-propyl-quinoxalino [2,3-g] phthalazine-6,11-dione

6-a) 6- (4-n-propylphenylamino) -7-chloro-5,8-phthalazinedione

6,7-dichloro-5,8-phthalazinedione and 4-n-propylaniline (0.65ml, 4.37mmol) were reacted according to the method of Example 1-2-a) of Example 1 , 95%).

Melting Point: 146 ~ 147 ℃

¹ H-NMR (CDCl ₃ ): δ 9.89 (d, J 1.2 Hz, 1H), 9.74 (d, J 1.2 Hz, 1H), 7.67 (br s, 1H), 7.16 (d, J 8.4 Hz, 2H) , 7.00 (d, J 8.4 Hz, 2H), 2.60 (t, J 7.2 Hz, 2H), 1.61-1.66 (m, 2H), 0.93 (t, J 6.8 Hz, 3H)

IR (CH ₂ Cl ₂ ): 3207, 1686, 1632, 1552 cm ^-1

6-b) 6,11-dihydro-2-n-propyl-quinoxalino [2,3-g] phthalazine-6,11-dione

6- (4-n-propylphenylamino) -7-chloro-5,8-phthalazinedione (660 mg, 2.0 mmol) was reacted with NaN ₃ according to the method of Example 1-2-b). A yellow solid (120 mg, 20%) was obtained.

Melting Point:> 300 ℃

¹ H-NMR (DMSO d6): δ 9.99 (s, 2H), 8.33 (d, J 8.8 Hz, 1H), 8.21 (br s, 1H), 8.03 (br d, J 8.8 Hz, 1H), 2.90 ( t, J 7.6 Hz. 2H), 1.75 (m, 2H), 0.94 (t, J 7.2 Hz, 3H)

IR (CH ₂ Cl ₂ ): 1703cm ^-1

Elemental Analysis: Calcd for C ₁₇ H ₁₂ N ₄ O ₂ : C, 67.10; H, 3.97; N, 18.41

           Found: C, 67.09; H, 4.06; N, 18.57

Example 7 6,11-dihydro-2-n-butyl-quinoxalino [2,3-g] phthalazine-6,11-dione

7-a) 6- (4-n-butylphenylamino) -7-chloro-5,8-phthalazinedione

6,7-dichloro-5,8-phthalazinedione and 4-n-butylaniline (0.96ml, 4.37mmol) were reacted according to the method of Example 1-2-a) of Example 1 , 94%).

Melting Point: 153 ~ 154 ℃

¹ H-NMR (CDCl ₃ ): δ 9.90 (d, J 0.8 Hz, 1H), 9.75 (d, J 0.8 Hz, 1H), 7.66 (br s, 1H), 7.16 (d, J 8.0 Hz, 2H) , 7.00 (d, J 8.0 Hz, 2H), 2.62 (t, J 7.6 Hz, 2H), 1.55-1.64 (m, 2H), 1.31-1.37 (m, 2H), 0.92 (t, J 7.2 Hz, 3H )

IR (CH ₂ Cl ₂ ): 3213, 1687, 1552 cm ^-1

7-b) 6,11-dihydro-2-n-butyl-quinoxalino [2,3-g] phthalazine-6,11-dione

6- (4-n-butylphenylamino) -7-chloro-5,8-phthalazinedione (680 mg, 2.0 mmol) was reacted with NaN ₃ according to the method of Example 1-2-b). A yellow solid (140 mg, 22%) was obtained.

Melting Point:> 300 ℃

¹ H-NMR (DMSO d6): δ 9.99 (s, 2H), 8.33 (d, J 8.8 Hz, 1H), 8.21 (br s, 1H), 8.03 (br d, J 8.8 Hz, 1H), 2.93 ( t, J 7.6 Hz, 2H), 1.71 (m, 2H), 1.34 (m, 2H), 0.91 (t, J 7.2 Hz, 3H)

IR (CH ₂ Cl ₂ ): 1699 cm ^-1

Elemental Analysis: Calcd for C ₁₈ H ₁₄ N ₄ O ₂ : C, 67.91; H, 4.43; N, 17.60

           Found: C, 68.01; H, 4.42; N, 17.61

The present invention provides novel quinoxalino [2,3-g] phthalazine-6,11-dione-based compounds, pharmaceutically acceptable salts thereof, intermediates for preparing the compounds and methods for their preparation, The compounds or salts thereof are useful for the prevention, treatment and treatment of various cancer diseases since they inhibit DNA proliferation by exhibiting DNA insertion activity.

Claims (6)

A compound represented by the formula (1) or a pharmaceutically acceptable salt thereof. [Formula 1] In the above formula, R ₁ is _{one selected} from the group consisting of hydrogen, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms. The compound or salt thereof according to claim 1, wherein the compound is represented by Chemical Formula 2. [Formula 2] In the above formula, R ₁ is _{one selected} from the group consisting of hydrogen, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms. The method of claim 2, wherein R ₁ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, methoxy, ethoxy, n -A compound or a pharmaceutically acceptable salt thereof, characterized in that it is one kind selected from the group consisting of propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, secondary butoxy group and tertiary butoxy group. delete i) reacting the 6,7-dichloro-5,8-phthalazinedione and arylamine compounds in a molar ratio of 1: 1 to 1: 3; and ii) adding sodium azide to the product of the step in a molar ratio of 1: 1. To 1 to 2 to prepare a 6,11-dihydro-quinoxalino [2,3-g] phthalazine-6,11-dione derivative comprising the step of reacting. delete