KR20160009392A - Novel quinoxaline derivatives and use thereof - Google Patents

Abstract

In the present invention, provided are a compound represented by the chemical formula 1 or pharmaceutically acceptable salts thereof, a manufacturing method thereof, a pharmaceutical composition for preventing or treating cancer, and a food composition comprising the same. According to the present invention, the compound can be usefully used for preventing or treating cancer, by having excellent effects in promoting the increase of cAMP and the activities of cAMP response element (CRE) in cells. In the chemical formula 1, the definition of R_1 to R_6 is the same as defined in the specification.

Description

Novel quinoxaline derivatives and uses thereof < RTI ID = 0.0 >

The present invention relates to a novel quinoxaline derivative or a pharmaceutically acceptable salt thereof, a process for producing the quinoxaline derivative, a pharmaceutical composition and a food composition for preventing or treating cancer comprising the same.

Generally, the substances used as anticancer drugs have considerable toxicity, and thus they can not selectively remove only cancer cells. Therefore, it is required to develop a less toxic and effective anticancer drug to prevent the development of cancer, have.

The term "chemotherapeutic agent" refers to a chemotherapeutic agent other than surgery or radiation therapy among the methods used to treat malignant tumors, and refers to a substance that inhibits the synthesis of nucleic acids and exhibits anticancer activity. Chemotherapeutic agents are largely classified into antimetabolites, alkylating agents, antimitotic drugs, and hormones. Methotrexate, 6-mercaptopurine, 6-thioguanine, and 5-fluorouracil, Cytarabine, are examples of metabolic antagonists that inhibit the metabolism required for cancer cell proliferation. As an alkylating agent that has an anticancer effect by modifying the structure of DNA and introducing an alkyl group into guanine of DNA and cutting the chain, there are nitrogens mustad compounds (chlorambucil, cyclophosphamide), ethylene imine compounds (thiotepa), alkyl sulfonate compounds busulfan, nitrousurea carmustine, and triacene compounds (dacarbazine). As mitotic phase specificity drugs, mitotic inhibitors that inhibit mitosis by inhibiting mitosis by inhibiting mitosis include anticancer drugs such as actinomycin D, doxorubicin, bleomycin, mitomycin, vincristine, vinblastine Alkaloids, taxoids, which are mitotic inhibitors including taxane rings, and the like. In addition, hormones such as corticosteroids or progesterone and platinum-containing compounds such as cisplatin are used as anticancer drugs.

However, the biggest problem with chemotherapy is drug resistance, which is a major factor that ultimately causes treatment failure, despite the initial successful response to chemotherapy. Therefore, it is urgently required to develop a new chemotherapeutic agent capable of reducing drug resistance. cAMP level regulating mechanism has been emerging as a method for the development of a variety of existing new chemotherapeutic agents and it is believed that the substance that regulates the level of cAMP can act as a selective anticancer agent for cancer cells. cAMP is a secondary messenger that is very important for the signal transduction of GPCR (G-protein coupled receptor) and is used for GPCR functional assay. Initially, cAMP was known to phosphorylate serine 43 of Raf-1 and inhibit Erk1 / 2 activity, resulting in inhibition of cell growth. However, Raf-1 was not the absolute target of cAMP as a result of the cell growth being still inhibited when the Raf-1 mutation that was not responsive to cAMP was expressed and cAMP levels were increased. In addition, recent studies have shown that the action of cAMP is more complex and regulates diverse signal transduction and regulates cell growth as well as various other intracellular physiological functions. Increased levels of cAMP have been reported to inhibit ovarian cancer cell growth (Experimental Cell Research 273, 11, 95-106, Oncogene 1999, 18-9, 1755-1763) (International Journal of Gynecological Cancer 2008, 18-6). In a 2008 report of BMC cancer, we found that low levels of cAMP in colorectal cancer may stimulate cell growth and cAMP levels may inhibit cell growth (BMC Cancer 2008 8: 320). In other words, it can be seen that the promotion and inhibition of cell growth is caused by the balance of various signals controlling cAMP concentration.

cAMP is regulated by the adenylate cyclase activity in the cell membrane and regulates the expression of the cAMP response element (CRE) in the promoter by expressing the transcription factor cAMP response element binding protein (CREB) do. Therefore, drugs that increase cAMP level and promote CRE activity will block the cell proliferation pathways, so that an effective anticancer drug development can be expected.

Thus, the present inventors have made efforts to modify the 2-amino substituted-3-substituted quinoxaline core skeleton in order to develop a novel anticancer agent that promotes cAMP increase / CRE activity. As a result, Substituted 2-amino-substituted 3-substituted quinoxaline-based compound, and confirmed that the compound can be utilized as a cancer treatment agent, thereby completing the present invention.

The present invention provides a novel quinoxaline derivative or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for treating cancer comprising the same.

In order to solve the above problems, the present invention provides a quinoxaline derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In this formula,

,

또는

이고,R ₁ is

,

or

ego,

Wherein, A ₁ is hydrogen or C _{1 -6} alkyl,

A ₂ is a single bond or C _{1 -6} alkylene,

A ₃ is selected from the group consisting of pyrrolidinyl, morpholino, amino, benzeneyl, benzo [d] [1,3] diazoyl, naphthalenyl, C _{3 -6} cycloalkyl, C _{1 -6} alkyl, piperidinyl, quinoxaline Amino or phenylmethanamino, < RTI ID = 0.0 >

Wherein A ₃ is substituted or unsubstituted with one or more substituents selected from the group consisting of C _{1 -6} alkyl, C _{1 -6} alkoxy, halogen, phenyl C _{1 -6} alkylene and C _{1 -6} alkylcarboxy, ,

B is a pyrrolidinyl, a piperidinyl or a C _{1 -6} alkyl, carboxy,

R ₂ is hydrogen, C _{1 -6} alkoxy or halogen,

R ₃ to R ₆ are each independently hydrogen, C _{1 -6} alkyl, C _{1 -6} alkoxy, halogen or nitro,

n is an integer of 0 to 10;

Preferably, A < ₁ > is hydrogen, methyl or ethyl,

A ₂ is a single bond, methyl, ethylpropyl or pentyl,

A ₃ is pyrrolidinyl substituted or unsubstituted with methyl;

             Morpholino;

            Amino substituted or unsubstituted with one or more substituents selected from the group consisting of methyl and ethyl;

             Benzenyi which is unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, methoxy and chloro;

             Benzo [d] [l, 3] diazolyl;

             Naphthalenyl;

C _{3 -6} cycloalkyl;

             Isobutyl;

            Piperidinyl substituted or unsubstituted with one or more substituents selected from the group consisting of benzyl and tert-butylcarboxy;

            Quinoxalin-2-amino; or

            Phenylmethanamino which is unsubstituted or substituted by methoxy,

B may be pyrrolidinyl, piperidinyl or methylcarboxy.

Preferably, each of R ₃ to R ₆ may independently be hydrogen, methyl, methoxy, fluoro, chloro or nitro.

Preferably, n is 0 to 8, more preferably 0 to 6, still more preferably 0 to 4, still more preferably 0 to 3, still more preferably 0 to 2, still more preferably 0 to 1 Lt; / RTI >

Representative examples of the compound represented by the above formula (1) are as follows:

1) 3-Chloro-5-methyl-N- (2- (1-methylpyrrolidin- 2- yl) ethyl) quinoxaline-

2) 3-Chloro-5,8-dimethoxy-N- (2- (1-methylpyrrolidin-2- yl) ethyl) quinoxalin-

3) N- (1-benzylpiperidin-4-yl) -3-chloro-5-methoxyquinoxalin-

4) 3-Chloro-7-methyl-N- (2-morpholinoethyl) quinoxalin-

5) 2-Chloro-6-methoxy-3- (4- (pyrrolidin- 1 -yl) piperidin- 1 -yl) quinoxaline,

6) 3,6-dimethoxy-N- (2-morpholinoethyl) quinoxalin-2-amine,

7) N ¹ - (3,6-dimethoxy quinoxalin- ² -yl) -N ² , N ² -dimethylethane-1,2-diamine,

8) 2-Methoxy-3- (4- (pyrrolidin-1-yl) piperidin- 1 -yl) quinoxaline,

9) N- (2,4-dimethoxybenzyl) -3-methoxy-7-nitroquinoxalin-

10) N- (2,4-dimethoxybenzyl) -3,6-dimethoxyquinoxalin-2-amine,

11) N-benzyl-7-fluoro-3-methoxyquinoxalin-2-amine,

12) Synthesis of N- (benzo [d] [1,3] diol-5-ylmethyl) -6-fluoro-3-methoxyquinoxalin-

13) N- (4-chlorobenzyl) -6-fluoro-3-methoxyquinoxalin-

14) 6-Fluoro-3-methoxy-N- (naphthalen-2-ylmethyl) quinoxalin-

15) N- (2-chlorobenzyl) -7-fluoro-3-methoxyquinoxalin-

16) Methyl 1- (6-fluoro-3-methoxyquinoxalin-2-yl) piperidine-4-

17) N-benzyl-6-chloro-3-methoxyquinoxalin-2-amine,

18) 6-Chloro-N- (cyclohexylmethyl) -3-methoxyquinoxalin-2-amine,

19) 2-Methoxy-6-nitro-3- (pyrrolidin-1-yl) quinoxaline,

20) 6-Fluoro-N-isobutyl-3-methoxyquinoxalin-2-amine,

21) N ^1, N ¹ - diethyl -N4- (6- fluoro-3-methoxy kwinok utilizing 2-yl) pentane-1,4-diamine,

22) N- (1-benzylpiperidin-4-yl) -3,7-dichloroquinoxalin-

23) 3- (1,4'-Bipiperidin-1'-yl) -2,6-dichloroquinoxalin,

24) N ¹ - (3,7-dichloroquinoxalin-2-yl) -N ³ , N ³ -dimethylpropane-1,3-diamine,

25) 3,7-Dichloro-N- (2- (1-methylpyrrolidin-2-yl) ethyl) quinoxalin-

26) 7-Fluoro-3-methoxy-N- (2- (piperidin- 1- yl) ethyl) quinoxalin-

27) 3- (1,4'-Bipiperidin-1'-yl) -2-methoxy-6-

28) 3-Chloro-6,7-dimethyl-N- (2- (1-methylpyrrolidin- 2- yl) ethyl) quinoxalin-

29) 3-Chloro-6,7-dimethyl-N- (3-morpholinopropyl) quinoxalin-

30) N ⁴ - (3-chloro-6,7-methoxy quinoxalin-2-yl) -N ¹ , N ¹ -diethylpentane-

31) N ¹ - (3-methoxy-7-nitroquinoxalin- ² -yl) -N ² , N ² -dimethylethane-

32) N ¹ , N ¹ -diethyl-N ² - (3-methoxy-7-methoxyquinoxalin- ² -yl) -N ² -methylethan-

^{33) N 1, N 1,} N 2 - ethyl -N ² - (3- methoxy-7-methoxy-ethane-1,2-diamine kwinok-2-yl) utilizing,

34) 3-Methoxy-7-nitro-N- (2- (pyrrolidin- 1 -yl) ethyl) quinoxalin-

35) 3-Methoxy-N- (2-morpholinoethyl) -7-methoxyquinoxalin-

36) N- (1-Benzylpiperidin-4-yl) -3-chloroquinoxalin-

37) tert-Butyl 4- (3-chloro-5-methoxyquinoxalin-2-ylamino) piperidine-

38) N ¹ -methyl-N ¹ , N ² -di (quinoxalin-2-yl) ethane-1,2-

39) N ¹ - (3- methoxybenzyl) -N ² - methyl -N ² - ethane-1,2-diamine (2-yl) utilizing kwinok,

40) N- (Benzo [d] [1,3] diol-5-ylmethyl) -6-chloro-3- methoxyquinoxalin-

41) 6-Chloro-N- (4-chlorobenzyl) -3-methoxyquinoxalin-

42) 6-Chloro-3-methoxy-N- (naphthalen-2-ylmethyl) quinoxalin-

43) 6-Chloro-N- (2-chlorobenzyl) -3-methoxyquinoxalin-

44) 6-Chloro-3-methoxy-N-phenethyl quinoxalin-

45) 6-Chloro-3-methoxy-N- (4-methyl) quinoxalin-

46) 6-Chloro-N- (cyclopropylmethyl) -3-methoxyquinoxalin-2-amine,

47) 6-Chloro-3-methoxy-N- (2-methyl) quinoxalin-

48) 3-Chloro-6,7-dimethyl-N- (2- (1-methylpyrrolidin- 2- yl) ethyl) quinoxalin-

49) 3-Chloro-7-methyl-N- (2-morpholinoethyl) quinoxalin-

50) 3,5,7-Trichloro-N- (2- (pyrrolidin-1-yl) ethyl) quinoxalin-2-amine.

The compound represented by Formula 1 according to the present invention may form a salt, particularly a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are not particularly limited, such as acid addition salts, as are commonly used in the art (J. Pharm. Sci., 66, 1 (1977)). Preferred pharmaceutically acceptable acid addition salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, orthophosphoric acid or sulfuric acid; Or organic acids such as, for example, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid.

In addition, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, a compound represented by the formula (1) is dissolved in an excess of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, the non-soluble compound salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. At this time, it is preferable to prepare metal salts, in particular, sodium salts, potassium salts or calcium salts, and these metal salts can be reacted with a suitable salt (for example, nitrate).

In addition, the compounds represented by Formula 1 according to the present invention include all possible stereoisomers, including pharmaceutically acceptable salts thereof, as well as possible solvates and hydrates thereof, which can be prepared therefrom. The solvates, hydrates and stereoisomers of the compound represented by the formula (1) can be prepared from the compound represented by the formula (1) using conventional methods.

The compound represented by the formula (1) according to the present invention may be prepared in a crystalline form or in an amorphous form, and may be optionally hydrated or solvated when prepared in crystalline form. In the present invention, compounds containing various amounts of water as well as stoichiometric hydrates of the compound represented by the formula (1) may be included. Solvates of the compounds of formula (I) according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

In another aspect, the present invention provides a process for producing a compound represented by the above formula (1).

Specifically, the present invention provides, as an embodiment, a process for producing a compound represented by the following general formula (1), comprising the step of reacting a compound represented by the following formula (2) with a compound represented by the following formula And a method for producing a compound represented by formula (1-1).

[Formula 1-1]

(2)

[Formula 3-1]

[Formula 3-2]

[Formula 3-3]

In this formula,

R _{1 ,} R ₃ to R _{6 ,} A ₁ to A ₃ , B and n are the same as defined in Formula 1,

X is halogen.

In the present invention, the reaction molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3-1, 3-2, or 3-3 may be 1: 1 to 4, preferably 1: 1 to 2 Lt; / RTI > If the reaction molar ratio is out of the above range, there is a disadvantage in that it is economically inefficient because the excess amount of the compound remains unreacted in a large amount.

In the present invention, dimethyl sulfoxide may be used as the solvent in Step 1-1. However, any solvent capable of dissolving the compound represented by Chemical Formulas 2, 3-1, 3-2 or 3-3 may be used without limitation .

In the present invention, the reaction temperature of step 1-1 is preferably 10 ° C to 50 ° C, more preferably 15 ° C to 30 ° C. However, the compound of formula 2-1 and 3- 2 or 3-3, can be included in the reaction temperature without limitation.

In the present invention, the reaction time of step 1-1 is preferably 10 minutes to 6 hours, more preferably 30 minutes to 2 hours. If the reaction time is shorter than 10 minutes, there is a disadvantage in that the yield of the product is lowered due to the presence of unreacted materials. If the reaction time is longer than 6 hours, there is a disadvantage in that the yield is lowered due to side reaction.

Specifically, the present invention includes, as another embodiment, a process (step 1-2) of reacting a compound represented by the following formula (4) with a compound represented by the following formula (3-1), (3-2) or Which comprises reacting a compound represented by the following general formula

[Formula 1-2]

[Formula 3-1]

[Formula 3-2]

[Formula 3-3]

[Chemical Formula 4]

In this formula,

R _{1 ,} R ₃ to R _{6 ,} A ₁ to A ₃ , B and n are the same as defined in Formula 1,

X is halogen.

In the present invention, the reaction molar ratio of the compound represented by Formula 4 to the compound represented by Formula 3-1, 3-2, or 3-3 may be 1: 1 to 4, preferably 1: 1 to 2 Lt; / RTI > If the reaction molar ratio is out of the above range, there is a disadvantage in that it is economically inefficient because the excess amount of the compound remains unreacted in a large amount.

In the present invention, dimethyl sulfoxide may be used as the solvent in Step 1-2. However, any solvent which can dissolve the compound represented by Chemical Formula 4, 3-1, 3-2 or 3-3 may be used without limitation .

In the present invention, the reaction temperature of step 1-2 is preferably 10 ° C to 50 ° C, more preferably 15 ° C to 30 ° C. However, the reaction of the compound of formula 4 and 3- 2 or 3-3, can be included in the reaction temperature without limitation.

In the present invention, the reaction time of step 1-2 is preferably 10 minutes to 6 hours, more preferably 30 minutes to 2 hours. If the reaction time is shorter than 10 minutes, there is a disadvantage in that the yield of the product is lowered due to the presence of unreacted materials. If the reaction time is longer than 6 hours, there is a disadvantage in that the yield is lowered due to side reaction.

The method of the present invention may further comprise the step (1-3) of reacting the compound represented by the following general formula (1-2) with sodium methoxide after the step 1-2. A process for producing a compound represented by the general formula (1-3) is provided.

[Formula 1-2]

[Formula 1-3]

In this formula,

R ₁ And R ₃ to R ₆ are as defined in Formula 1,

X is halogen.

In the present invention, the reaction molar ratio of the compound represented by Formula 1-2 to sodium methoxide may be 1: 1 to 4, preferably 1: 1. If the reaction molar ratio is out of the above range, there is a disadvantage in that it is economically inefficient because the excess amount of the compound remains unreacted in a large amount.

In the present invention, in the step 1-3, tetrahydrofuran, methanol or a mixed solvent thereof may be used as the solvent, but any solvent which can dissolve the compound represented by the above formula 1-2 or sodium methoxide may be used without limitation have.

In the present invention, the reaction temperature in the above step 1-3 is preferably 10 ° C to 50 ° C, more preferably 15 ° C to 30 ° C. However, the reaction between the compound represented by the above formula 1-2 and sodium methoxide Can be included in the reaction temperature without limitation.

In the present invention, the reaction time of step 1-3 is preferably 5 minutes to 1 hour, more preferably 10 minutes to 30 minutes. If the reaction time is shorter than 5 minutes, there is a disadvantage in that the yield of the product is lowered due to the presence of unreacted materials. If the reaction time is longer than 1 hour, there is a disadvantage in that a side reaction is present and the yield is lowered.

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof. Specifically, the composition may be a pharmaceutical composition for cancer prevention or treatment, which promotes cAMP (cyclic adenosine monophosphate) increase and cAMP response element (CRE) activity in cells.

The compounds according to the present invention have an excellent effect of promoting the increase of cAMP and the activity of cAMP response element (CRE) in cells, and thus they can be usefully used for the treatment of cancer diseases. Adenosine monophosphate (AMP) is produced by the adenylate cyclase activity in the cell membrane and expresses the cAMP response element (CRE) in the promoter by expressing the transcription factor cAMP response element binding protein (CREB) ≪ / RTI > Therefore, the novel quinoxaline derivative of the present invention, which promotes CRE activity by increasing cAMP, inhibits cell proliferation and can be used for the prevention or treatment of cancer.

In one embodiment of the present invention, the level of intracellular cAMP was measured using a PerkinElmer LANCE cAMP kit, and a novel quinoxaline derivative that inhibits TR-FRET signal by 65% or more was firstly selected (FIG. 1 and Table 2 ). As a result, it was found that the quinoxaline derivative significantly increased intracellular cAMP.

In addition, in one embodiment of the present invention, HT29 cells of the colon cancer cell line were treated with the compound represented by Formula 1 to perform a WST assay (Takara, cat No. MK400). As a result, in Experimental Example 1-1, (Fig. 3). In addition, it was confirmed that the quinoxaline derivatives produced inhibited the growth of colon cancer cells by about 60% or more (Fig. 3). From the above results, it was found that the quinoxaline derivative significantly inhibited the growth of cancer cells by increasing cAMP in cancer cells.

In addition, in an embodiment of the present invention, through the CRE-Luciferase reporter assay, the novel quinoxaline derivative of the present invention shows a marked increase in the activity of the CRE luciferase reporter as compared with the positive control, Could know. From the above results, it was confirmed that the quinoxaline derivative of the present invention has an excellent effect of promoting the activity of the CRE promoter by increasing intracellular cAMP, and thus can be used for the prevention or treatment of cancer (FIGS. 4 and 5).

In one embodiment of the present invention, a novel quinoxaline derivative, 3-chloro-5,8-dimethoxy-N- (2- (1-methylpyrrolidin- In order to confirm the tumor growth inhibitory effect of the amine (drug # 2), the colon cancer cell line HT29 was subcutaneously injected into nude mice, and the compound was injected, and the size of the colon cancer tumor was reduced ( 6). From the above results, it was confirmed that the novel quinoxaline derivative of the present invention has an excellent effect for the prevention or treatment of cancer.

The term "prophylactic " used in the present invention means any action that inhibits or delays a cancerous disease by the administration of a pharmaceutical composition comprising the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof.

As used herein, the term "treatment" as used herein refers to all treatments for improving or ameliorating symptoms of cancer by administering a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof it means.

Wherein the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, Endometrioid cancer, thyroid cancer, pituitary cancer, adenocarcinoma, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, endometrial cancer, endometrial carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, (CNS), primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, pituitary adenoma, and the like, including, but not limited to, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, kidney cell carcinoma, But is not limited thereto.

The pharmaceutical composition comprising the compound of formula (I) according to the present invention may further comprise an appropriate carrier, excipient or diluent according to a conventional method. Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories or sterilized injection solutions according to a conventional method.

In detail, when formulating, it can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like which are usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, Can be mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of liquid formulations for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Examples of the non-aqueous solution and suspension include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Examples of the suppository base include withexol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The dosage of the compound of formula (I) according to the present invention may vary depending on the patient's age, body weight, sex, dosage form, health condition and disease severity. Based on the adult patient weighing 70 kg But it is not limited to 0.01 mg to 5000 mg per day, and may be administered once to several times a day at intervals of time according to the judgment of a doctor or pharmacist.

The pharmaceutical dosage forms of the compounds according to the invention may also be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in suitable aggregates.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.

In another aspect, the present invention provides a method for preventing or treating cancer, which comprises administering to a subject an effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The terms "prevention "," treatment ", and "cancer" of the present invention are as described above.

The term "individual" of the present invention means any animal, including a human being who has invented or can develop the inflammatory disease or allergic disease, such as a monkey, a cow, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, Or guinea pig, and the pharmaceutical composition of the present invention may be administered to an individual to effectively prevent or treat the disease. The pharmaceutical composition of the present invention can be administered in parallel with existing therapeutic agents.

The term "administering" of the present invention means providing the patient with the desired substance in any suitable manner, and the administration route of the composition of the present invention may be administered through any conventional route so long as it can reach the target tissue have. But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oleic acid), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), an emulsifier, a buffer for pH control, a microbial growth inhibitor And a pharmaceutical carrier such as a preservative (e.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

According to the present invention, known drugs used for preventing or treating various known diseases other than the compound represented by the above-mentioned formula (1) or its pharmaceutically acceptable salts as an active ingredient are added according to the kind of diseases to be prevented or treated As described herein.

The composition of the present invention is administered in a pharmaceutically effective amount.

The term " pharmaceutically effective amount " as used herein means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, Factors well known in the art and other medical fields including, but not limited to, the severity of the disease, the severity, the activity of the drug, the sensitivity to the drug, the mode of administration, the time of administration, the route of administration and rate of release, Can be determined accordingly. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specific dosages are as described above.

In addition, the cancer prevention or treatment method of the present invention can be used in combination with surgery, radiation therapy, hormone therapy, chemotherapy, and methods using a biological response modifier.

In another aspect, the present invention provides a food composition for preventing or improving cancer, which comprises a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.

As used herein, the term " food " refers to any product, including but not limited to meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice creams, Beverages, vitamin complexes, functional foods, and health foods, all of which include foods in a conventional sense.

The term "functional food " of the present invention is the same term as " food for special health use (FoSHU) ", and includes medical and medical effects It means high food. The term "functional" as used herein means that the structure and function of the human body have a beneficial effect on health uses such as controlling nutrients or physiological actions. The functional food of the present invention can be prepared by a method commonly used in the art and can be prepared by adding raw materials and ingredients that are usually added in the art. In addition, the formulations of the above-mentioned functional foods can also be produced without limitation as long as the formulations are recognized as functional foods. The composition for food of the present invention can be manufactured in various forms, and unlike general pharmaceuticals, it has the advantage that there is no side effect that may occur when a drug is used for a long period of time, and is excellent in portability, Functional foods can be ingested as adjuvants to promote the effects of cancer prevention or improvement.

In the present invention, the term " health food "refers to a food having an active health promotion or promotion effect as compared to a general food, and a health supplement food refers to a food for health assistance. Accordingly, the terms functional food, health food, and health supplement are used.

The term "prophylactic" as used herein is as described above, and "improvement" means any act in which the cancerous condition is alleviated or changed by administration of the composition of the present invention.

The compound represented by Formula 1 is contained in an amount of 0.01 to 100% by weight, more preferably 1 to 80% by weight based on the total weight of the food composition. When the food is a beverage, it may be contained in a proportion of 1 to 30 g, preferably 3 to 20 g based on 100 ml, but is not limited thereto.

In addition, the composition may contain additional ingredients which are commonly used in food compositions and which can improve odor, taste, vision and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid and the like. In addition, it may include minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu) It may also include amino acids such as lysine, tryptophan, cysteine, valine, and the like.

In addition, the composition can be used in combination with a preservative (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate), a disinfectant (such as bleaching powder and highly bleached white powder, sodium hypochlorite), an antioxidant (butylhydroxy anisole (BHA) (Sodium hypophosphate), bleach (sodium sulfite), seasoning (sodium MSG glutamate, etc.), sweeteners (hemicellulose, cyclamate, saccharin, A food additive such as a flavor (vanillin, lactones), a swelling agent (alum, D-tartrate, potassium hydrogen), an emulsifier, a thickening agent (glue), a covering agent, a gum base agent, a foam inhibitor, and food additives. The additives may be selected and used in appropriate amounts depending on the type of food.

The compound represented by formula (I) according to the present invention is excellent in the effect of promoting the increase of cAMP and the activity of cAMP response element (CRE) in cells, and thus can be effectively used for prevention or treatment of cancer.

Figure 1 shows the cAMP standard and the TR-FRET signal to determine the number of cells to use in the experiment.
FIG. 2 is a graph showing cAMP levels of cells using fluorescent dye (TR-FRET) using DMSO as a control drug and 1000 drugs
FIG. 3 is a graph showing the inhibition effect on cell growth of quinoxaline derivatives that increase cAMP.
4 is a graph showing the activity of the CRE promoter which is changed by cAMP of the quinoxaline derivative of the present invention.
FIG. 5 is a graph showing CRE-Luc (CRE-Luciferase) reporter activity according to the dose of the quinoxaline derivative of the present invention.
Figure 6 is a graph showing the decrease in colorectal cancer after administration of 3-chloro-5,8-dimethoxy-N- (2- (1-methylpyrrolidin-2-yl) ethyl) quinoxalin- It is a photograph of a tumor.

Hereinafter, the present invention will be described in more detail with reference to the following Production Examples and Examples. However, the following Preparation Examples and Examples are for illustrating the present invention, but the scope of the present invention is not limited thereto.

Example  1. 3- Chloro -5- methyl -N- (2- (1- Methylpyrrolidine Yl) ethyl) Quinoxaline - Of the amine (drug # 1)  Produce

(106.5 mg, 0.5 mmol) was dissolved in dimethyl sulfoxide (2.0 ml), and then 2- (1-methylpyrrolidin-2-yl) -Amine (128.2 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and saturated sodium chloride solution, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate, 10/1, v / v) to obtain the title compound (96.0 mg, 63%). NMR and mass spectrometry The results were as follows.

_{^{1 H NMR (300MHz, CDCl 3}} ) 1.74-1.79 (m, 4H), 1.91-1.98 (m, 2H), 2.19-2.22 (m, 1H), 2.40 (s, 3H), 4.42-4.45 (m, 1H ), 2.62 (s, 3H), 3.14-3.16 (m, IH), 3.58-3.61 (m, IH), 3.77-3.80 (m, IH), 7.23-7.25 , ≪ / RTI > 1H), 7.53 (br s, 1H), 7.62-7.63 (m, 1H); MS (ESI) m / z 305.8 ([M + H] < ⁺ >).

Example  2. 3,6- Dimethoxy -N- (2- Morpholinoethyl ) Quinoxaline -2- Of the amine (drug # 6)  Produce

Example  2-1. 3- Chloro -6- Methoxy -N- (2- Morpholinoethyl ) Quinoxaline -2- Amine  Produce

2-morpholinoethanamine (128.2 mg, 1.0 mmol) was added at room temperature after 2,3-dichloro-6-methoxyquinoxaline (106.5 mg, 0.5 mmol) was dissolved in dimethyl sulfoxide And stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and saturated sodium chloride solution, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate, 10/1, v / v) to obtain the title compound (98.5 mg, 61%).

Example  2-2. 3,6- Dimethoxy -N- (2- Morpholinoethyl ) Quinoxaline -2- Of the amine (drug # 6)  Produce

Amine (96.8 mg, 0.3 mmol) was dissolved in tetrahydrofuran (3 ml), and the solution was added with 25 wt.% Solution of triethylamine in methanol at room temperature % Sodium methoxide solution (64.8 mg, 0.3 mmol), and the mixture was stirred at room temperature for 20 minutes. After completion of the reaction, methylene chloride, distilled water and saturated sodium chloride solution were used. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 2/1, v / v) to obtain the title compound (86.0 mg, 90% Mass spectrometry (MS) analysis results were as follows.

_{^{1 H NMR (300MHz, CDCl 3}} ) 2.59 (br s, 4H), 2.85 (br s, 2H), 3.69 (br s, 2H), 3.79 (br s, 4H), 3.89 (s, 3H), 4.12 ( s, 3H), 7.05 (dd, J = 8.9 and 2.8 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H); MS (ESI) m / z 319.4 ([M + H] < ⁺ >).

Example  3 to 50. Quinoxaline  Preparation of derivatives

The compounds of Examples 3 to 50 were prepared in the same manner as in Example 1 or Example 2 except that the reactants were appropriately changed in consideration of the structure of the compound to be prepared. The physical properties of the above compounds are summarized in Table 1.

¹ H NMR spectra were recorded at Bruker Avance 200 MHz, 300 MHz, and 500 MHz and chemical shifts (δ) were recorded in ppm relative to TMS as an internal standard. All specimens were dissolved in DMSO-d ₆ and CDCl ₃ unless otherwise specified. MS data was recorded on a Micromass Quattro Micro model.

Experimental Example  1. In cancer cells cAMP  Increase effect and inhibition effect of cancer cell growth

Experimental Example  1-1. cAMP  Level measurement ( TR - FRET assay )

The TRCE-FRET assay was performed using the PerkinElmer LANCE cAMP kit and the level of intracellular cAMP was measured using the measured TR-FRET signal. As the cAMP concentration in the sample increased, the 665 nm signal decreased, while as the cAMP concentration in the sample decreased, the 665 nm signal increased. 1, the cAMP standard and the number of cells to be used in the experiment were determined. The level of intracellular cAMP was measured by the following experimental method, and a drug which inhibits TR-FRET signal by 65% or more was firstly selected.

1) To the assay plate, 5 μl of cAMP standard or cAMP inducer forskolin (1 μM) was added or added to dispense the novel quinoxaline derivative of the present invention.

2) 5 μl of cell suspension (1000 cells) was added.

3) The reaction was allowed to proceed at room temperature for 30 minutes.

4) 5 μl of Europium-Streptavidin (Eu-SA) / Biotin-cAMP (B-cAMP) tracer was added.

5) 5 μl of U Light - anti - cAMP antibody was added.

6) The reaction was allowed to take place at room temperature for 1-24 hours.

7) TR-FRET signal was measured.

The TR-FRET signal was measured through the above-described experimental method to confirm the level of cAMP. Figure 2 is a graphical representation of intracellular cAMP levels and is representative of a primary screening of 1000 drugs. In detail, DMSO was used as a control for the drug, and the cells were treated with drugs 1 to 84 of 1000 drugs, and the level of cAMP was measured by measuring the TR-FRET signal. 50 drugs were found to be the lowest level of TR-FRET signaling in the primary screening and as cAMP-modulating drugs.

The inhibition rate of the TR-FRET signal measured by the above experimental method is shown in Table 2 below.

Quinoxaline
Derivative No. TR-FRET signal inhibition rate (%) Quinoxaline
Derivative No. TR-FRET signal inhibition rate (%) 2 73 28 80 3 65 40 79 4 70 42 68 7 68 44 65 10 71 46 67 11 66 48 79 26 68 49 72 27 88 50 84

As can be seen from Table 2, the quinoxaline derivative according to the present invention showed a TR-FRET signal inhibition rate of at least 65%. As a result, it was found that the quinoxaline derivative significantly increased intracellular cAMP.

Experimental Example  1-2. Cell growth inhibition experiment

The normal cell line was the WI38 cell line and the cancer cell line was HT29 cell line. The same cell number was seeded in a 96-well dish and adhered for 12 hours. A sample treated with control DMSO and a drug-treated sample were subjected to a WST assay (Takara, cat No. MK400) with the time as T0. Cells were seeded in a 96-well plate containing 10 μl of wst. After appropriate time, the change in color of the medium was measured using a spectrophotometer. (24 hours after attachment of the cells to the plate), and the degree of cell growth inhibition or cell death was quantified in the sample treated with the drug compared to the control (FIG. 3).

As a result, it was confirmed that the quinoxaline derivative in which cAMP was increased in Experimental Example 1-1 inhibited the growth of colon cancer cells by about 60% or more. From the above results, it was found that the quinoxaline derivative of the present invention significantly inhibited the growth of cancer cells by increasing cAMP in cancer cells.

Experimental Example  2. CRE Lucifer Reyes  Reporter Analysis ( CRE - Luciferase reporter assay )

The effect of the novel quinoxaline derivative of the present invention on the cAMP level was examined using a stable cell line into which CRE-Luciferase (CRE-Luc) reporter and control Renilla Luciferase DNA were inserted saw. Twelve hours after the treatment of the compound, forskolin was further treated for 4 hours, and 20 μl (per 96 wells) of cell lysis buffer (Promega for luciferase assay) was treated to prepare samples. 10 μl Was reacted with luciferin (10 μl) to measure the activity of each reporter through a luminometer. Thereafter, a stop buffer was added to the luminescent material to measure the activity of the reporter The activity of the Renilla enzyme was also measured. The values for each of these reporter activities were divided by the value of Renilla activity of each sample, and then expressed as the ratio of the activity of the test group (the above compound) to the control group (DMSO treatment). The mean values of three independent experiments are shown in FIG. In addition, the activity of the reporter by the concentration of each drug is shown in FIG.

As a result, since the activity of CRE luciferase reporter is significantly increased as compared with that of positive control group, the novel quinoxaline derivative of the present invention has an excellent effect of promoting the activity of CRE promoter by increasing intracellular cAMP, Or can be used for treatment.

Experimental Example  3. Rat xenotransplantation ( Mouse xenograft ) Experiment

In order to observe the tumor growth inhibitory effect of the novel quinoxaline derivatives of the present invention, 9 × 10 ⁶ cells were subcutaneously injected into nude mice of the colon cancer cell line HT29. The tumor size ranged from 70 to 100 mm ³ Mice were injected with 20 mg / kg of the drug into the blood vessels for 5 days a week. The mice were injected for 5 days each week for 3 weeks until tumors of mice injected with negative control (DMAC 10% + 10% Tween 80 + distilled water 80%) were 1000 mm ³ , and tumors were then removed.

As a result, as shown in FIG. 6, 3-chloro-5,8-dimethoxy-N- (2- (1-methylpyrrolidin- 2- yl) ethyl) quinoxalin- The size of colon cancer tumors was reduced.

From the above results, it was confirmed that the novel quinoxaline derivative of the present invention has an excellent effect for the prevention or treatment of cancer.

Meanwhile, the novel compounds represented by Formula 1 according to the present invention can be formulated into various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation example  1. Purification (direct pressurization)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Formulation example  2. Tablet (wet assembly)

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation example  3. Powder and Capsule

After sieving 5.0 mg of the active ingredient, 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate were mixed. The mixture was filtered through a hard No. 5 gelatin capsules.

Formulation example  4. Injection

Injections were prepared by adding 100 mg of the active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO _{4 12} H ₂ O and 2974 mg of distilled water.

Formulation example  5. Manufacture of health food

1000 mg of active ingredient

Vitamin mixture quantity

70 비 of vitamin A acetate

Vitamin E 1.0 mg

0.13 mg of vitamin B1

0.15 mg of vitamin B2

0.5 mg of vitamin B6

0.2 g of vitamin B12

10 mg of vitamin C

10 μg of biotin

Nicotinic acid amide

50 엽 of folic acid

Calcium pantothenate 0.5 mg

Mineral mixture quantity

1.75 mg ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

15 mg of potassium phosphate monobasic

Secondary calcium phosphate 55 mg

90 mg of potassium citrate

Calcium carbonate 100 mg

24.8 mg of magnesium chloride

Although the composition ratio of the above-mentioned vitamin and mineral mixture is relatively mixed with a suitable ingredient for health food, the compounding ratio may be arbitrarily modified, and the above ingredients may be mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are to be considered in all respects as illustrative and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.

Claims (11)

1. A compound represented by the following formula (1): < EMI ID =
[Chemical Formula 1]

In this formula,
R ₁ is

,

or

ego,
Wherein, A ₁ is hydrogen or C _{1 -6} alkyl,
A ₂ is a single bond or C _{1 -6} alkylene,
A ₃ is selected from the group consisting of pyrrolidinyl, morpholino, amino, benzeneyl, benzo [d] [1,3] diazoyl, naphthalenyl, C _{3 -6} cycloalkyl, C _{1 -6} alkyl, piperidinyl, quinoxaline Amino or phenylmethanamino, < RTI ID = 0.0 >
Wherein A ₃ is substituted or unsubstituted with one or more substituents selected from the group consisting of C _{1 -6} alkyl, C _{1 -6} alkoxy, halogen, phenyl C _{1 -6} alkylene and C _{1 -6} alkylcarboxy, ,
B is a pyrrolidinyl, a piperidinyl or a C _{1 -6} alkyl, carboxy,
R ₂ is hydrogen, C _{1 -6} alkoxy or halogen,
R ₃ to R ₆ are each independently hydrogen, C _{1 -6} alkyl, C _{1 -6} alkoxy, halogen or nitro,
n is an integer of 0 to 10;
The method according to claim 1,
Wherein A < ₁ > is hydrogen, methyl or ethyl,
A ₂ is a single bond, methyl, ethylpropyl or pentyl,
A ₃ is pyrrolidinyl substituted or unsubstituted with methyl;
Morpholino;
Amino substituted or unsubstituted with one or more substituents selected from the group consisting of methyl and ethyl;
Benzenyi which is unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, methoxy and chloro;
Benzo [d] [l, 3] diazolyl;
Naphthalenyl;
C _{3 -6} cycloalkyl;
Isobutyl;
Piperidinyl substituted or unsubstituted with one or more substituents selected from the group consisting of benzyl and tert-butylcarboxy;
Quinoxalin-2-amino; or
Phenylmethanamino which is unsubstituted or substituted by methoxy,
And B is pyrrolidinyl, piperidinyl or methylcarboxy, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Wherein R < ₂ > is hydrogen, methoxy, or chloro; or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Wherein each of R ₃ to R ₆ is independently hydrogen, methyl, methoxy, fluoro, chloro or nitro; or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
The compound
1) 3-Chloro-5-methyl-N- (2- (1-methylpyrrolidin- 2- yl) ethyl) quinoxaline-
2) 3-Chloro-5,8-dimethoxy-N- (2- (1-methylpyrrolidin-2- yl) ethyl) quinoxalin-
3) N- (1-benzylpiperidin-4-yl) -3-chloro-5-methoxyquinoxalin-
4) 3-Chloro-7-methyl-N- (2-morpholinoethyl) quinoxalin-
5) 2-Chloro-6-methoxy-3- (4- (pyrrolidin- 1 -yl) piperidin- 1 -yl) quinoxaline,
6) 3,6-dimethoxy-N- (2-morpholinoethyl) quinoxalin-2-amine,
7) N ¹ - (3,6-dimethoxy quinoxalin- ² -yl) -N ² , N ² -dimethylethane-1,2-diamine,
8) 2-Methoxy-3- (4- (pyrrolidin-1-yl) piperidin- 1 -yl) quinoxaline,
9) N- (2,4-dimethoxybenzyl) -3-methoxy-7-nitroquinoxalin-
10) N- (2,4-dimethoxybenzyl) -3,6-dimethoxyquinoxalin-2-amine,
11) N-benzyl-7-fluoro-3-methoxyquinoxalin-2-amine,
12) Synthesis of N- (benzo [d] [1,3] diol-5-ylmethyl) -6-fluoro-3-methoxyquinoxalin-
13) N- (4-chlorobenzyl) -6-fluoro-3-methoxyquinoxalin-
14) 6-Fluoro-3-methoxy-N- (naphthalen-2-ylmethyl) quinoxalin-
15) N- (2-chlorobenzyl) -7-fluoro-3-methoxyquinoxalin-
16) Methyl 1- (6-fluoro-3-methoxyquinoxalin-2-yl) piperidine-4-
17) N-benzyl-6-chloro-3-methoxyquinoxalin-2-amine,
18) 6-Chloro-N- (cyclohexylmethyl) -3-methoxyquinoxalin-2-amine,
19) 2-Methoxy-6-nitro-3- (pyrrolidin-1-yl) quinoxaline,
20) 6-Fluoro-N-isobutyl-3-methoxyquinoxalin-2-amine,
21) N ^1, N ¹ - diethyl -N4- (6- fluoro-3-methoxy kwinok utilizing 2-yl) pentane-1,4-diamine,
22) N- (1-benzylpiperidin-4-yl) -3,7-dichloroquinoxalin-
23) 3- (1,4'-Bipiperidin-1'-yl) -2,6-dichloroquinoxalin,
24) N ¹ - (3,7-dichloroquinoxalin-2-yl) -N ³ , N ³ -dimethylpropane-1,3-diamine,
25) 3,7-Dichloro-N- (2- (1-methylpyrrolidin-2-yl) ethyl) quinoxalin-
26) 7-Fluoro-3-methoxy-N- (2- (piperidin- 1- yl) ethyl) quinoxalin-
27) 3- (1,4'-Bipiperidin-1'-yl) -2-methoxy-6-
28) 3-Chloro-6,7-dimethyl-N- (2- (1-methylpyrrolidin- 2- yl) ethyl) quinoxalin-
29) 3-Chloro-6,7-dimethyl-N- (3-morpholinopropyl) quinoxalin-
30) N ⁴ - (3-chloro-6,7-methoxy quinoxalin-2-yl) -N ¹ , N ¹ -diethylpentane-
31) N ¹ - (3-methoxy-7-nitroquinoxalin- ² -yl) -N ² , N ² -dimethylethane-
32) N ¹ , N ¹ -diethyl-N ² - (3-methoxy-7-methoxyquinoxalin- ² -yl) -N ² -methylethan-
^{33) N 1, N 1,} N 2 - ethyl -N ² - (3- methoxy-7-methoxy-ethane-1,2-diamine kwinok-2-yl) utilizing,
34) 3-Methoxy-7-nitro-N- (2- (pyrrolidin- 1 -yl) ethyl) quinoxalin-
35) 3-Methoxy-N- (2-morpholinoethyl) -7-methoxyquinoxalin-
36) N- (1-Benzylpiperidin-4-yl) -3-chloroquinoxalin-
37) tert-Butyl 4- (3-chloro-5-methoxyquinoxalin-2-ylamino) piperidine-
38) N ¹ -methyl-N ¹ , N ² -di (quinoxalin-2-yl) ethane-1,2-
39) N ¹ - (3- methoxybenzyl) -N ² - methyl -N ² - ethane-1,2-diamine (2-yl) utilizing kwinok,
40) N- (Benzo [d] [1,3] diol-5-ylmethyl) -6-chloro-3- methoxyquinoxalin-
41) 6-Chloro-N- (4-chlorobenzyl) -3-methoxyquinoxalin-
42) 6-Chloro-3-methoxy-N- (naphthalen-2-ylmethyl) quinoxalin-
43) 6-Chloro-N- (2-chlorobenzyl) -3-methoxyquinoxalin-
44) 6-Chloro-3-methoxy-N-phenethyl quinoxalin-
45) 6-Chloro-3-methoxy-N- (4-methyl) quinoxalin-
46) 6-Chloro-N- (cyclopropylmethyl) -3-methoxyquinoxalin-2-amine,
47) 6-Chloro-3-methoxy-N- (2-methyl) quinoxalin-
48) 3-Chloro-6,7-dimethyl-N- (2- (1-methylpyrrolidin- 2- yl) ethyl) quinoxalin-
49) 3-Chloro-7-methyl-N- (2-morpholinoethyl) quinoxalin-
50) is selected from the group consisting of 3,5,7-trichloro-N- (2- (pyrrolidin-1-yl) ethyl) quinoxalin-2-amine. Acceptable salt.
Reacting a compound represented by the following formula (2) with a compound represented by the following formula (3-1), (3-2) or (3-3)
[Formula 1-1]

(2)

[Formula 3-1]

[Formula 3-2]

[Formula 3-3]

In this formula,
R _{1 ,} R ₃ to R _{6 ,} A ₁ to A ₃ , B and n are as defined in claim 1,
X is halogen.
Reacting a compound represented by the following formula (4) with a compound represented by the following formula (3-1), (3-2) or (3-3)
[Formula 1-2]

[Formula 3-1]

[Formula 3-2]

[Formula 3-3]

[Chemical Formula 4]

In this formula,
R _1, R ₃ to R _6, A ₁ to A ₃ , B and n are as defined in claim 1,
X is halogen.
A process for producing a compound represented by the following Formula 1-3, which comprises reacting a compound represented by the following Formula 1-2 with sodium methoxide:
[Formula 1-2]

[Formula 1-3]

In this formula,
R ₁ And R ₃ to R ₆ are as defined in claim 1,
X is halogen.
A pharmaceutical composition for preventing or treating cancer, comprising a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
10. The method of claim 9,
Wherein the composition promotes the increase of cAMP in the cell and the activity of the cAMP response element (CRE).
A food composition for preventing or improving cancer, comprising the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

Images