KR101071359B1 - 2-methyl-2-alkyl-6-amido-2h-benzopyran derivatives having anti-cancer activity - Google Patents

Abstract

The present invention provides novel 2-methyl-2-alkyl-6-amido-2 H -benzopyran derivatives having a good NF-ĸB target gene expression inhibitory activity, pharmaceutically acceptable salts thereof, methods for preparing the compounds, and It relates to the use of this compound as an anticancer agent.

Description

2-methyl-2-alkyl-6-amido-2H-benzopyran derivatives having anti-cancer activity}

The present invention provides novel 2-methyl-2-alkyl-6-amido-2 H -benzopyran derivatives having a good NF-ĸB target gene expression inhibitory activity, pharmaceutically acceptable salts thereof, methods for preparing the compounds, and An anticancer agent comprising the compound as an active ingredient.

The term "anticancer agent" refers to chemotherapeutic agents other than surgery or radiation therapy among the methods used to treat malignant tumors, and most of them show anticancer activity by inhibiting the synthesis of nucleic acids. Chemotherapeutic agents are broadly classified into antimetabolites, alkylating agents, antimitotic drugs, and hormones. Metabolic antagonists that inhibit metabolic processes necessary for the proliferation of cancer cells include folate derivatives (methotrexate), purine derivatives (6-mercaptopurine, 6-thioguanine), and pyrimidine derivatives (5-fluorouracil, Cytarabine). Alkylating agents that introduce anti-cancer effects by introducing alkyl groups into DNA guanine and modifying the structure of the DNA and cleaving the chains, include nitrogen mustard compounds (chlorambucil, cyclophosphamide), ethyleneimine compounds (thiotepa), alkylsulfonate compounds ( busulfan), nitrosourea compounds (carmustine), triazane compounds (dacarbazine). Mitosis inhibitors that inhibit mitosis by blocking mitosis as a specific period of mitosis, include anticancer drugs such as actinomycin D, doxorubicin, bleomycin, mitomycin, and plants such as vincristine and vinblastine. Alkaloids, taxoids including mitosis inhibitors including taxane rings, and the like. In addition, hormones such as corticosteroids and progesterone and platinum-containing compounds such as cisplatin are used as anticancer agents.

In general, the substances used as anticancer drugs have considerable toxicity and cannot selectively remove only cancer cells. Therefore, there is an urgent need for development of low-toxic and effective anticancer drugs to prevent cancer as well as treatment after cancer. Do. In addition, one of the biggest problems with chemotherapeutic agents is drug resistance, which is a major factor that eventually causes treatment failure despite the initial successful response by anticancer drugs.

In this context, NF-ĸB has recently received much attention as a target for developing effective and safe anticancer drugs and overcoming drug resistance, and has been found to discover effective organic small molecules that inhibit the expression of NF-ĸB target genes, and to prevent and treat cancer. Efforts have been made to develop anticancer drugs. [M. Karin et al., Nature Reviews Cancer 2002, 2, 301-310; B. Haefner, Drug Discovery Today 2002, 7, 653-663; C. Nakanishi et al., Nature Reviews Cancer 2005, 5, 297-309; S. Olivier et al., Biochemical Pharmacology 2006, 1054-1068; J. Adams, Drug Discovery Today 2003, 8, 307-315; A. Albini et al., Nature Reviews Cancer 2007, 7, 139-147].

As a prior invention related to the present invention, 2-methyl-2- (oxymethyl) -6- (ureido) -2 H- benzopyran compound having NF-ĸB target gene expression inhibitory activity was synthesized and published by the present inventors. It has been. [Korea Patent Registration No.954,611]

[Formula A]

In formula (A), R ¹ represents a hydrogen atom or an acyl group of C ₁ -C ₆ ; R ² represents an aryl or heteroaryl group selected from phenyl, pyridinyl, isoxazolyl, thiazolyl, triazolyl, benzothiazolyl, benzisothiazolyl, and thiadiazolyl, A is a hydrogen atom, Halogen atom, C ₁ -C ₆ alkyl group, or C ₁ -C ₆ alkoxy group.

The compound 2-methyl -2 H disclosed compound and the above-described prior art invention of the invention, but similar in that it has a viscosity benzopyran skeleton structure, the overall chemical structures and substituents are different from each other in the position C2 and C6 are all different from one .

Therefore, the compound represented by the formula (1) characterized by the present invention is a compound of a novel structure that has not been disclosed in the related prior art, and has an excellent NF-ĸB target gene expression inhibitory activity as an anticancer agent for cancer prevention and treatment Can be utilized.

The present invention relates to novel 6-alkyl of 2-methyl-2-amido -2 H - there is provided a benzopyran derivative.

It is another object of the present invention to provide a method for preparing the above-mentioned novel compound.

In addition, the present invention has another object to provide a pharmaceutical use using the novel compound as an anticancer agent, because the novel compound has an NF-ĸB target gene expression inhibitory activity.

The present invention is excellent NF-ĸB target gene expression inhibitory activity to having a 2-alkyl-6-amino 2-methyl FIG -2 represented by the following formula 1 H - is a benzopyran derivative in its features.

[Formula 1]

In Chemical Formula 1,

A is a hydrogen atom; Halogen atom; C ₁ -C ₅ alkyl group; Or a C ₁ -C ₅ alkoxy group, R ₁ is a hydrogen atom; Acetyl group; C ₁ -C ₅ alkyl group; Or a C ₆ -C ₁₀ aryl C ₁ -C ₅ alkyl group, R ₂ is a C ₁ -C ₅ alkyl group; C ₃ -C ₈ cycloalkyl group; C ₂ -C ₅ alkenyl group; C ₆ -C ₁₀ aryl group; Or a 5- to 7-membered heteroaryl group including a hetero atom selected from oxygen or sulfur, and the aryl or heteroaryl used in the definition of R ₁ and R ₂ is halo, nitro, amino, hydroxy, acetamido, respectively. , Mono (C ₁ -C ₅ alkyl) amino, di (C ₁ -C ₅ alkyl) amino, C ₂ -C ₅ acyl, C ₁ -C ₅ alkyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ 0 to 3 substituents selected from alkoxy, C ₁ -C ₅ haloalkoxy and C ₁ -C ₅ alkylthio may be substituted.

In addition, the compound represented by Chemical Formula 1 according to the present invention may also exist in the form of a solvate (for example, a hydrate).

In addition, the compound represented by Chemical Formula 1 according to the present invention may have one or more asymmetric centers, and in the case of such compounds, enantiomers or diastereomers may be present. Accordingly, the present invention includes each isomer or a mixture of these isomers.

Since the novel compounds according to the present invention have excellent NF-ĸB target gene expression inhibitory activity, it is useful for developing new anticancer drugs for cancer prevention and treatment.

The substituents used in the compound definition according to the present invention will be described in more detail as follows.

The term "halogen atom" in the present invention means fluorine, chlorine, bromine and iodine atoms.

In the present invention, the alkyl group of C ₁ -C ₅ is methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, t -butyl, n -pentyl, i -pentyl, neopentyl or an aliphatic saturated hydrocarbon group having 1 to 5 carbon atoms including t -pentyl and the like.

In the present invention, the term "C ₃ -C ₈ cycloalkyl group" is an aliphatic having 3 to 8 carbon atoms including cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclobutylmethyl, cyclohexyl, and the like. It means a saturated hydrocarbon group.

In the present invention, the "C ₁ -C ₅ haloalkyl group" means a C ₁ -C ₅ alkyl group in which a hydrogen atom is substituted by one or more halogen atoms, such as a trifluoromethyl group.

In the present invention, "C ₁ -C ₅ alkoxy group" means methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, i -butoxy, t -butoxy , C ₁ -C ₅ refers to a hydroxy group substituted with a hydrogen atom by a substituent selected from an alkyl group.

In the present invention, "C ₁ -C ₅ haloalkoxy group" means a C ₁ -C ₅ alkoxy group in which a hydrogen atom is substituted by one or more halogen atoms, such as a difluoromethoxy group.

In the present invention, "C ₁ -C ₅ alkylthio group" means a mercapto group in which a hydrogen atom is substituted by a substituent selected from a C ₁ -C ₅ alkyl group.

The term "aryl group" in the present invention means a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group including phenyl, naphthyl, anthranilyl, phenanthryl, and the like. In addition, the aryl group may be substituted or unsubstituted by a substituent, and the substituted aryl group may be halo, nitro, amino, hydroxy, acetamido, mono (C ₁ -C ₅ alkyl) amino, di (C ₁ -C ₅ alkyl) amino, C ₂ -C ₅ acyl, C ₁ -C ₅ alkyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ haloalkoxy, C ₁ -C ₅ alkylthio It may be substituted by 1 to 3 substituents selected from among.

In the present invention, the "heteroaryl group" refers to pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxa Diazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, benzofurazanyl, dibenzofuranyl, Isobenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, dibenzothiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolinyl And monocyclic, bicyclic, or tricyclic aromatic heterohydrocarbon groups including quinoxalinyl, phthalazinyl, chinolinyl, quinazolinyl, and the like. In addition, the heteroaryl group may be substituted or unsubstituted by a substituent, and the substituted heteroaryl group may be halo, nitro, amino, hydroxy, acetamido, mono (C ₁ -C ₅ alkyl) amino, di (C ₁ -C ₅ alkyl) amino, C ₂ -C ₅ acyl, C ₁ -C ₅ alkyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ haloalkoxy, C ₁ -C ₅ alkyl It may be substituted by 1 to 3 substituents selected from thio and the like.

In the compound represented by Formula 1 according to the present invention, More preferably, A is a hydrogen atom; Or a C ₁ -C ₅ alkyl group, R ₁ is a hydrogen atom; An alkyl group of C ₁ -C ₅ ; Benzyl groups; Or C ₁ -C represents a substituted benzyl with 1 to 3 substituents selected from the group consisting of alkyl and alkoxy of C ₁ -C _{5 5,} wherein R ₂ is C ₁ -C ₅ alkyl group; C ₃ -C ₈ cycloalkyl group; C ₂ -C ₅ alkenyl group; Phenyl group; Halo, nitro, amino, acetamido, mono (C ₁ -C ₅ alkyl) amino, di (C ₁ -C ₅ alkyl) amino, C ₂ -C ₅ acyl, C ₁ -C ₅ alkyl, C ₁ -C A phenyl group substituted with 1 to 3 substituents selected from ₅ haloalkyl, and C ₁ -C ₅ alkoxy; Naphthyl group; Furanyl group; Thiophene group; Or a benzo [ d ] [1,3] dioxol group.

In the compound represented by Chemical Formula 1 according to the present invention, particularly preferably, A represents a hydrogen atom, a methyl group, an ethyl group, or a propyl group, and R ₁ represents a hydrogen atom, a methyl group, an ethyl group, a benzyl group, or 2-methic. A methoxybenzyl group, 3-methoxybenzyl group, or 4-methoxybenzyl group, R ₂ represents a methyl group, an ethyl group, a propyl group, a t -butyl group, a cyclopropyl group, a cyclohexyl group, a vinyl group, an allyl group, Phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,4-dichlorophenyl group, 2,4-difluorophenyl group , 2,4,6-trichlorophenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 4-nitrophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-acetylphenyl group, 3- Cetylphenyl group, 4-acetylphenyl group, 2-aminophenyl group, 3-aminophenyl group, 4-aminophenyl group, 2-dimethylaminophenyl group, 3-dimethylaminophenyl group, 4-dimethylaminophenyl group, 2-acetamidophenyl group, 3- It is a compound which shows an acetamidophenyl group, a 4-acetamidophenyl group, a naphthyl group, a naphthyl group, a furanyl group, a thiophenyl group, or a benzo [ d ] [1,3] dioxol group.

More specifically exemplified by the compound represented by Formula 1 according to the present invention are as follows:

2-propyl-2-methyl -6- (t- butylamido) -2 H - benzopyran,

2-propyl-2-methyl-6-cyclo propyl amido -2 H - benzopyran,

2-propyl-2-methyl -6- (t- butylamido) -7-methyl -2 H - benzopyran,

2-propyl-2-methyl-6-cyclo propyl amido-7-methyl -2 H - benzopyran,

2-phenylethyl-2-methyl-6-cyclo propyl amido -2 H - benzopyran,

2-phenylethyl-2-methyl -6- (t- butylamido) -2 H - benzopyran,

2-phenylethyl-2-methyl-6-cyclo propyl amido-7-methyl -2 H - benzopyran,

2-phenylethyl-2-methyl-6-cyclo hexyl-amido -2 H - benzopyran,

2- (4-methoxy-phenylethyl) -2-methyl-6-cyclo propyl amido -2 H - benzopyran,

2- (4-methoxy-phenylethyl) -2-methyl -6- (t- butylamido) -2 H - benzopyran,

2- (4-methoxy-phenylethyl) -2-methyl-6-cyclo hexyl-amido -2 H - benzopyran,

2-propyl-2-methyl-6- (furan-2-ylamido) -2 H -benzopyran,

2-ethyl-2-phenyl-6- (furan-2-yl amido) -2 H - benzopyran,

2- (4-methoxy-phenylethyl) -2-methyl-6- (furan-2-yl amido) -2 H - benzopyran,

2-propyl-2-methyl-6- (furan-2-yl amido) -7-methyl -2 H - benzopyran,

2-ethyl-2-phenyl-6- (furan-2-yl amido) -7-methyl -2 H - benzopyran,

2-phenylethyl-2-methyl-6- (thiophen-2-yl amido) -7-methyl -2 H - benzopyran,

2-propyl-2-methyl-6- (4-fluorophenyl) amido -2 H - benzopyran,

2-propyl-2-methyl-6- (4-chlorophenyl) amido -2 H - benzopyran

2-propyl-2-methyl-6- (4-nitrophenyl) amido -2 H - benzopyran,

2-propyl-2-methyl-6- (4-methylphenyl) amido -2 H - benzopyran,

2-propyl-2-methyl-6- (2-trifluoromethylphenyl) amido -2 H - benzopyran,

2-propyl-2-methyl-6- (2,4,6-trichloro-phenyl) amido -2 H - benzopyran,

2-propyl-2-methyl-6- (naphthalene-1-yl) amido -2 H - benzopyran,

2-phenylethyl-2-methyl-6-phenyl-amido -2 H - benzopyran,

2-ethyl-2-phenyl-6- (2-fluoro-phenyl) amido -2 H - benzopyran,

2-ethyl-2-phenyl-6- (2-chlorophenyl) amido -2 H - benzopyran,

2-ethyl-2-phenyl-6- (4-fluorophenyl) amido -2 H - benzopyran,

2-ethyl-2-phenyl-6- (4-chlorophenyl) amido -2 H - benzopyran,

2-ethyl-2-phenyl-6- (4-nitrophenyl) amido -2 H - benzopyran,

2-ethyl-2-phenyl-6- (4-methylphenyl) amido -2 H - benzopyran,

2-phenylethyl-2-methyl-6- (naphthalene-1-yl) amido -2 H - benzopyran,

2-ethyl-2-phenyl-6- (2-trifluoromethylphenyl) amido -2 H - benzopyran,

2-phenylethyl-2-methyl-6- (2,4,6-chlorophenyl) amido -2 H - benzopyran,

2- (4-methoxy-phenylethyl) -2-methyl-6- (2-chlorophenyl) amido -2 H - benzopyran,

2- (4-methoxy-phenylethyl) -2-methyl-6- (4-chlorophenyl) amido -2 H - benzopyran,

2- (4-methoxy-phenylethyl) -2-methyl-6- (2-fluorophenyl) amido -2 H - benzopyran,

2- (4-methoxy-phenylethyl) -2-methyl-6- (4-nitrophenyl) amido -2 H - benzopyran,

2- (4-methoxy-phenylethyl) -2-methyl-6- (4-methylphenyl) amido -2 H - benzopyran,

2- (4-methoxy-phenylethyl) -2-methyl-6- (2-trifluoromethylphenyl) amido -2 H - benzopyran,

2- (4-methoxy-phenylethyl) -2-methyl-6- (naphthalene-1-yl) amido -2 H - benzopyran,

2-propyl-2-methyl-6- (4-acetylphenyl) amino-7-methyl -2 H - benzopyran,

2-propyl-2-methyl-6- (4-fluorophenyl) amino-7-methyl -2 H - benzopyran,

2-propyl-2-methyl-6- (4-chlorophenyl) amido-7-methyl-2 H -benzopyran,

2-propyl-2-methyl-6- (2,4,6-trichloro-phenyl) amido-7-methyl -2 H - benzopyran,

2-propyl-2-methyl-6- (4-nitrophenyl) amino-7-methyl -2 H - benzopyran,

2-propyl-2-methyl-6- (4-methylphenyl) amido-7-methyl -2 H - benzopyran,

2-propyl-2-methyl-6- (3-ethynyl-phenyl) amido-7-methyl -2 H - benzopyran,

2-propyl-2-methyl-6- (2-trifluoromethylphenyl) amido-7-methyl-2 H -benzopyran,

2-propyl-2-methyl-6- (4-methoxyphenyl) amido-7-methyl -2 H - benzopyran,

2-propyl-2-methyl-6- (benzo [d] [1,3] dioxolane-5-yl) amido-7-methyl -2 H - benzopyran,

2-propyl-2-methyl-6- (4-acetamido-phenyl) amido-7-methyl -2 H - benzopyran,

2-propyl-2-methyl -6- (3- N, N- dimethylaminophenyl) -2-methyl-7-amido H - benzopyran,

2-ethyl-2-phenyl-6- (4-fluorophenyl) amino-7-methyl -2 H - benzopyran,

2-ethyl-2-phenyl-6- (4-chlorophenyl) amino-7-methyl -2 H - benzopyran,

2-phenyl-2-ethyl-6- (4-acetylphenyl) amino-7-methyl -2 H - benzopyran,

2-ethyl-2-phenyl-6- (4-methylphenyl) amido-7-methyl -2 H - benzopyran,

2-phenylethyl-2-methyl -6- (4- (t- butylphenyl) amido-7-methyl -2 H - benzopyran,

2-phenylethyl-2-methyl-6- (4-trifluoromethylphenyl) amido-7-methyl-2 H -benzopyran,

2-phenylethyl-2-methyl -6- (4- N, N- dimethylaminophenyl) -2-methyl-7-amido H - benzopyran.

On the other hand, the present invention includes a method for producing a compound represented by the formula (1). The preparation method according to the present invention comprises a total of two steps of preparation as shown in Scheme 1 below:

Scheme 1

In Scheme 1, A, R ₁ , and R ₂ are each as defined above.

The first step in the preparation method according to Scheme 1 is a process for preparing an amine compound represented by Chemical Formula 3 by reducing the nitro compound represented by Chemical Formula 2.

The nitro compound represented by Formula 2 used as a raw material in the reduction reaction is J. Med. Chem. It can be prepared using the method disclosed in 2001, 44, 4207-4215 or a general organic synthesis method. The reduction reaction is carried out in the presence of a tin (Sn) compound such as tin chloride (SnCl ₂ ) or tin chloride dihydrate (SnCl ₂ 2H ₂ O). As the reduction solvent, for example, ethyl acetate, dichloromethane, toluene, methanol, ethanol, tetrahydrofuran, acetonitrile, dimethylformamide, and the like can be used. The reduction reaction temperature is maintained at a boiling point range of room temperature to a solvent, specifically, at a temperature range of 20 ° C. to 150 ° C., and preferably a reflux reaction is performed at a boiling point of the solvent. The reduction reaction time is generally 5 to 24 hours, preferably 15 to 24 hours.

In the second step, the amine compound represented by Chemical Formula 3 is acylated with an acyl halide represented by R ₂ -C (O) X (where X is a halogen), and is represented by Chemical Formula 1. Process for preparing the compound.

The acylating agent uses, for example, pivaloyl chloride, cyclopropoyl chloride, 2-furanoyl chloroid, 4-fluorobenzoyl chloride and the like as the acyl chloride compound. In addition, the acylation reaction can be carried out in the presence of a conventional organic base, for example, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 2,6- Lutidine, 1,8-diazabicyclo [5.4.0] -undeth-7-ene (DBU), and the like. The acylation reaction solvent is a conventional organic solvent, for example, dichloromethane, toluene, methanol, ethanol, tetrahydrofuran, acetonitrile, dimethylformamide and the like. The acylation reaction temperature is in the boiling point range of 0 ° C. to the solvent, preferably in the temperature range of 20 ° C. to 150 ° C., and preferably in the temperature range of 50 ° C. to 150 ° C. The reduction reaction time is generally 5 to 24 hours, preferably 10 to 24 hours.

In order to confirm the production of the intermediate compound or the target compound produced by the preparation method according to the scheme 1 was separated and purified by a multi-column chromatography equipment (Quad ^{3 +} ; Biotage, USA), the structure by NMR and Mass spectrum Analyzed.

On the other hand, since the compound represented by the formula (1) according to the present invention has excellent NF-ĸB target gene expression inhibitory activity can be usefully used as an anticancer agent.

Therefore, the present invention includes a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient contains a pharmaceutical composition effective as an agent for preventing and treating various cancers caused by abnormal growth of cells.

Pharmaceutically acceptable salts in the present invention can be prepared by conventional methods in the art. Pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like; Formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gustyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin) Salts with the same organic acid; Salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline and the like; Salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like; Metal salts by reaction with alkali metals such as sodium and potassium; Or salts with ammonium ions.

In addition, the pharmaceutical composition of the present invention can be added to the compound represented by the formula (1) or pharmaceutically acceptable salts thereof by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient, etc. as a conventional formulation in the pharmaceutical field It can be formulated. For example, it can be prepared by oral or parenteral administration such as tablets, capsules, troches, solutions, suspensions, and the like, and can be used for the prevention and treatment of various types of tumors.

Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.

In addition, the dosage of the compound represented by Formula 1 according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, based on an adult patient with a weight of 70 kg In general, 0.01 mg to 5000 mg per day, and may be dividedly administered once to several times a day at regular intervals according to the judgment of a doctor or pharmacist.

The present invention as described above will be described in more detail based on the following Examples and Experimental Examples, but the present invention is not limited thereto.

Example Synthesis of Compound

Example 1. 2-propyl-2-methyl-6- ( t- butylamido) -2 H -benzopyran

a) 2-propyl-2-methyl-6-amino-2 H -benzopyran (Formula 3)

2-propyl-2-methyl-6-nitro-2 H -benzopyran (3.10 g, 13.3 mmol) was dissolved in ethyl acetate (40 mL), followed by addition of SnCl ₂ 2H ₂ O (6.00 g, 26.6 mmol). After refluxing for 3 hours and the reaction was completed, it was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure, purified by silica gel column chromatography ( n -hexane: ethyl acetate, 5: 1 v / v) to 2-propyl-6-amino-2-methyl -2 H -benzopyran (2.57 g, 95%) was obtained.

MS (ESI) 202 [M + H] ⁺ .

b) 2-propyl-2-methyl-6- ( t- butylamido) -2 H -benzopyran (Formula 1)

2-propyl-6-amino-2-methyl-2 H -benzopyran (2.18 g, 10.7 mmol) was dissolved in dichloromethane (30 mL), followed by pivaloyl chloride (1.54 g, 12.8 mmol) and pyridine ( 1.27 g, 16.1 mmol) were added and stirred at room temperature for 2 hours. After the completion of the reaction, the mixture was washed with water, the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure, purified by silica gel column chromatography ( n -hexane: ethyl acetate, 6: 1 v / v) to obtain the desired 2-propyl. 2-methyl -6- (t- butylamido) -2 H - to give a benzopyran (2.40 g, 78%).

MS (ESI) 288 [M + H] ⁺ .

Example 2 2-propyl-2-methyl-6-cyclo propyl amido -2 H - benzopyran

Example 1 (a) and 2-propyl-6-amino-2-methyl -2 H obtained in the same way - the benzopyran in Example 1, was reacted with cyclo pro foil chloride in the same manner as in (b) the compound Got it.

Example 3 2-Propyl-2-methyl -6- (t- butylamido) -7-methyl -2 H - benzopyran

Example 1 (a) obtained in the same manner as 2-propyl-2-methyl-6-amino-7-methyl -2 H - benzopyran of Example 1, pivaloyl chloride and the reaction in the same manner as in (b) To obtain the compound.

Example 4 2-Propyl-2-methyl-6-cyclo propyl amido-7-methyl -2 H - benzopyran

Example 1 (a) and 2-propyl-2-methyl-6-amino-7-methyl -2 H obtained in the same way - the benzopyran in Example 1, was reacted with cyclo pro foil chloride in the same manner as in (b) The compound was obtained.

Example 5: 2-phenyl-2-methyl-6-cyclo propyl amido -2 H - benzopyran

Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same way - the benzopyran in Example 1 (b) and reacted with a cycle profile foil chloride in the same manner as the compound Got.

Example 6 2-phenyl-2-methyl -6- (t- butylamido) -2 H - benzopyran

Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same way - the benzopyran in Example 1 (b) to avoid reaction with the same procedure just as with the chloride compound Got.

Example 7. 2-phenylethyl-2-methyl-6-cyclopropylamido-7-methyl-2 H -benzopyran

Example 1 (a) and 2-phenyl-2-methyl-6-amino-7-methyl -2 H obtained in the same way - the benzopyran in Example 1 (b) with a cycle profile foil chloride in the same manner Reaction to obtain the compound.

Example 8 2-Phenyl-2-methyl-6-cyclo hexyl-amido -2 H - benzopyran

Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same way - the benzopyran in Example 1 (b) and reacted with a cyclo hexyl soil chloride in the same manner as the compound Got.

Example 9. 2- (4-methoxy-phenylethyl) -2-methyl-6-cyclo propyl amido -2 H - benzopyran

Example 1 2- (4-methoxy-phenylethyl) -2-amino-2-methyl-6-H obtained in the same manner as in (a) - cyclo pro foil in the same manner benzopyran, as in Example 1 (b) Reaction with chloride afforded the compound.

Example 10. 2- (4-methoxy-phenylethyl) -2-methyl -6- (t- butylamido) -2 H - benzopyran

Example 1 (a) obtained in the same manner as 2- (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - pivaloyl a benzopyran, in the same manner as in Example 1 (b) Reaction with chloride afforded the compound.

Example 11 2- (4-methoxy-phenylethyl) -2-methyl-6-cyclo hexyl-amido -2 H - benzopyran

Example 1 (a) and 2 obtained in the same manner as (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - cyclo hexyl soil a benzopyran, in the same manner as in Example 1 (b) Reaction with chloride afforded the compound.

Example 12. 2-propyl-2-methyl-6- (furan-2-ylamido) -2 H -benzopyran

Example 1 (a) and 2-propyl, obtained by the same procedure 2-amino-6-methyl -2 H - a benzopyran, Example 1 (b) by the same method 2-Pugh pyrano a reaction with the chloride and the The compound was obtained.

Example 13. 2-phenylethyl-2-methyl-6- (furan-2-ylamido) -2 H -benzopyran

Example 1 (a) 2- amino-6-phenyl-2-methyl -2 H obtained in the same manner as in-the-benzopyran, in the same manner as in Example 1 (b) 2- Pew pyrano one is reacted with chloride The compound was obtained.

Example 14. 2- (4-methoxy-phenylethyl) -2-methyl-6- (furan-2-yl amido) -2 H - benzopyran

Example 1 (a) and 2 obtained in the same manner as (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - benzopyran performed, for example, 1 (b) in the same manner as 2-Pugh Reaction with ranoyl chloride afforded the compound.

Example 15. 2-propyl-2-methyl-6- (furan-2-ylamido) -7-methyl-2 H -benzopyran

Example 1 (a) and 2-propyl, obtained by the same procedure 2-amino-6-methyl -2 H - a benzopyran, Example 1 (b) by the same method 2-Pugh pyrano a reaction with the chloride and the The compound was obtained.

Example 16. 2-ethyl-2-phenyl-6- (furan-2-yl amido) -7-methyl -2 H - benzopyran

Example 1 (a) and 2-phenyl-2-methyl-6-amino-7-methyl -2 H obtained in the same way - the benzopyran, in the same manner as in Example 1 (b) 2-Wallis one Llano Reaction with chloride afforded the compound.

Example 17. 2-phenyl-ethyl-2-methyl-6- (thiophen-2-yl amido) -7-methyl -2 H - benzopyran

Example 1 (a) 2-phenylethylamine obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - benzopyran for Example 1, 2-Im Opaque Russo in the same way as (b) Reaction with chloride afforded the compound.

Example 18. 2-Propyl-2-methyl-6- (4-fluorophenyl) amido -2 H - benzopyran

Example 1 (a) 2- profile obtained in the same manner as 2-amino-6-methyl -2 H - a benzopyran, Example 1 (b) by the same procedure as a reaction with benzoyl chloride and the 4-fluoro The compound was obtained.

Example 19. 2-Propyl-2-methyl-6- (4-chlorophenyl) amido -2 H - benzopyran

Example 1 (a) and 2-propyl obtained in the same manner as 2-methyl-6-amino -2 H - a benzopyran, Example 1 (b) by the same manner as reaction with 4-chlorobenzoyl chloride and the compound Got.

Example 20 2-propyl-2-methyl-6- (4-nitrophenyl) amido -2 H - benzopyran

Example 1 (a) and 2-propyl obtained in the same manner as 2-methyl-6-amino -2 H - a benzopyran, Example 1 (b) by the same manner as reaction with 4-nitrobenzoyl chloride and the compound Got.

Example 21. 2-Propyl-2-methyl-6- (4-methylphenyl) amido -2 H - benzopyran

Example 1 (a) and 2-propyl obtained in the same manner as 2-methyl-6-amino -2 H - a benzopyran, Example 1 (b) by the same manner as reaction with 4-methylbenzoyl chloride, and the compound Got.

Example 22. 2-Propyl-2-methyl-6- (2-trifluoromethylphenyl) amido -2 H - benzopyran

Example 1 (a) obtained in the same manner as 2-propyl-6-amino-2-methyl -2 H - benzopyran to Example 1 (b) and the same method as methyl chloride and reaction with 2-trifluoromethyl To obtain the compound.

Example 23. 2-Propyl-2-methyl-6- (2,4,6-trichloro-phenyl) amido -2 H - benzopyran

Example 1 (a) 2- profile obtained in the same manner as 2-amino-6-methyl -2 H - benzopyran to Example 1 (b) to the 2,4,6-trichloroethane in the same manner methylbenzoyl Reaction with chloride afforded the compound.

Example 24. 2-Propyl-2-methyl-6- (naphthalene-1-yl) amido -2 H - benzopyran

Example 1 2-Propyl-2-methyl-6-amino -2 H obtained in the same manner as in (a) - the benzopyran in Example 1, is reacted with a 1-naphthyl chloride by the same method as (b) The compound was obtained.

Example 25. 2-phenylethyl-2-methyl-6-phenylamido-2 H -benzopyran

Example 1 2-phenyl-2-methyl-6-amino -2 H obtained in the same manner as in (a) - the benzopyran in Example 1 (b) is reacted with benzoyl chloride in the same manner as to give the compound .

Example 26. 2-ethyl-2-phenyl-6- (2-fluoro-phenyl) amido -2 H - benzopyran

Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same way - the benzopyran in Example 1, was reacted with benzoyl chloride 2-fluoro in the same way as (b) The compound was obtained.

Example 27. 2-ethyl-2-phenyl-6- (2-chlorophenyl) amido -2 H - benzopyran

Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same manner - the benzopyran in Example 1 (b) by the same manner as the reaction with 2-chlorobenzoyl chloride and the The compound was obtained.

Example 28. 2-ethyl-2-phenyl-6- (4-fluorophenyl) amido -2 H - benzopyran

Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same way - the benzopyran in Example 1, was reacted with 4-fluoro benzoyl chloride in the same manner as in (b) The compound was obtained.

Example 29. 2-ethyl-2-phenyl-6- (4-chlorophenyl) amido -2 H - benzopyran

Example 1 (a) and the same manner as 2-phenylethyl-amino-2-methyl-6 H -2 obtained at the same manner a benzopyran, as in Example 1 (b) 4- chloro-benzoyl chloride was reacted with the The compound was obtained.

Example 30. 2-ethyl-2-phenyl-6- (4-nitrophenyl) amido -2 H - benzopyran

Example 1 (a) the same manner as 2-phenylethyl-2-methyl-6-amino -2 H obtained and at the same manner a benzopyran, as in Example 1 (b) 4- nitrobenzoyl chloride is reacted with the The compound was obtained.

Example 31. 2-ethyl-2-phenyl-6- (4-methylphenyl) amido -2 H - benzopyran

Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same manner - the benzopyran in Example 1 (b) by the same manner as reaction with 4-methylbenzoyl chloride and the The compound was obtained.

Example 32. 2-phenyl-ethyl-2-methyl-6- (naphthalene-1-yl) amido -2 H - benzopyran

Example 1 (a) the same procedure 2-ethyl-2-phenyl-6-amino-2, obtained by the H - benzopyran to Example 1 (b) and reaction with chloride in the same manner as 1-naphthyl To obtain the compound.

Example 33. 2-ethyl-2-phenyl-6- (2-trifluoromethylphenyl) amido -2 H - benzopyran

Example 1 (a) and 2-phenyl-2-methyl-6-amino -2 H obtained in the same manner-benzo pyran-methyl-a, as in Example 1 (b) and 2-trifluoromethyl-benzoyl chloride in the same manner as Reaction to obtain the compound.

Example 34. 2-phenyl-ethyl-2-methyl-6- (2,4,6-chlorophenyl) amido -2 H - benzopyran

Example 1 (a) and 2-phenylethylamine obtained in the same manner as 2-amino-6-methyl -2 H - benzopyran to Example 1 (b) in the same manner as 2,4,6-chlorobenzoyl chloride And the compound was obtained.

Example 35. 2- (4-methoxy-phenylethyl) -2-methyl-6- (2-chlorophenyl) amido -2 H - benzopyran

Example 1 (a) and 2 obtained in the same manner as (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - benzopyran performed, for example, 1 (b) in the same manner as 2-chloro Reaction with benzoyl chloride afforded the compound.

Example 36. 2- (4-methoxy-phenylethyl) -2-methyl-6- (4-chlorophenyl) amido -2 H - benzopyran

Example 1 (a) and 2 obtained in the same manner as (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - a benzopyran, Example 1 (b) in the same manner as 4-chloro Reaction with benzoyl chloride afforded the compound.

Example 37. 2- (4-methoxy-phenylethyl) -2-methyl-6- (2-fluorophenyl) amido -2 H - benzopyran

Example 1 (a) and 2 obtained in the same manner as (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - benzopyran performed, for example, 2-fluoro-1 in the same way as (b) Reaction with robenzoyl chloride gave the compound.

Example 38. 2- (4-methoxy-phenylethyl) -2-methyl-6- (4-nitrophenyl) amido -2 H - benzopyran

Example 1 (a) and 2 obtained in the same manner as (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - a benzopyran, in the same manner as in Example 1 (b) 4-nitro Reaction with benzoyl chloride afforded the compound.

Example 39. 2- (4-methoxy-phenylethyl) -2-methyl-6- (4-methylphenyl) amido -2 H - benzopyran

Example 1 (a) obtained in the same manner as 2- (4-methoxy-phenylethyl) -2-amino-2-methyl-6 H - a benzopyran, in the same manner as in Example 1 (b) 4-methyl Reaction with benzoyl chloride afforded the compound.

Example 40. 2- (4-methoxy-phenylethyl) -2-methyl-6- (2-trifluoromethylphenyl) amido -2 H - benzopyran

Example 1 (a) 2- obtained in the same way as (4-methoxyphenyl-ethyl) -2-methyl-6-amino -2 H - 2- tree benzopyran, by the same method as in Example 1 (b) Reaction with fluoromethylbenzoyl chloride afforded the compound.

Example 41. 2- (4-methoxy-phenylethyl) -2-methyl-6- (naphthalene-1-yl) amido -2 H - benzopyran

Example 1 (a) obtained in the same manner as 2- (4-methoxyphenyl ethyl) -2-methyl-6-amino -2 H - 2- naphthyl a benzopyran, in the same manner as in Example 1 (b) Reaction with tyloyl chloride afforded the compound.

Example 42. 2-propyl-2-methyl-6- (4-acetylphenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) obtained in the same manner as 2-propyl-2-methyl-6-amino-7-methyl -2 H - a benzopyran, Example 1 (b) in the same manner as 4-acetyl chloride and the reaction To obtain the compound.

Example 43. 2-propyl-2-methyl-6- (4-fluorophenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) and 2-propyl obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - benzopyran to Example 1 (b) in the same manner as 4-fluoro-benzoyl chloride And the compound was obtained.

Example 44. 2-propyl-2-methyl-6- (4-chlorophenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) and 2-propyl-2-methyl-6-amino-7-methyl -2 H obtained in the same manner at the same manner a benzopyran, as in Example 1 (b) 4- chlorobenzoyl chloride with Reaction to obtain the compound.

Example 45. 2-propyl-2-methyl-6- (2,4,6-trichlorophenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) and 2-propyl obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - a benzopyran, Example 1 (b) in the same manner as 2,4,6 Reaction with trichlorobenzoyl chloride afforded the compound.

Example 46. 2-propyl-2-methyl-6- (4-nitrophenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) and 2-propyl-2-methyl-6-amino-7-methyl -2 H obtained in the same manner benzo pyran conducted, Example 1 4-nitrobenzoyl in the same way as (b) chloride and Reaction to obtain the compound.

Example 47. 2-propyl-2-methyl-6- (4-methylphenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) and 2-propyl-2-methyl-6-amino-7-methyl -2 H obtained by the same method - carried out benzopyran, Example 1 4-methylbenzoyl in the same way as (b) chloride and Reaction to obtain the compound.

Example 48. 2-propyl-2-methyl-6- (3-ethynylphenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) and 2-propyl obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - benzopyran to Example 1 (b) in the same manner as 4-ethynyl-benzoyl chloride Reaction with gave the compound 3

Example 49. 2-propyl-2-methyl-6- (2-trifluoromethylphenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) and 2-propyl obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - benzopyran to Example 1 (b) to a 2-trifluoromethyl in the same way methyl Reaction with benzoyl chloride afforded the compound.

Example 50. 2-propyl-2-methyl-6- (4-methoxyphenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) 2- propyl-2-methyl-6-amino-7-methyl -2 H obtained in the same manner as in-the-benzopyran, in the same manner as in Example 1 (b) 4- methoxybenzoyl chloride And the compound was obtained.

Example 51. 2-Propyl-2-methyl-6- (benzo [d] [1,3] dioxolane-5-yl) amido-7-methyl -2 H - benzopyran

Example 1 (a) 2- profile obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - in the same way a benzopyran, as in Example 1 (b) 3,4- di high The compound was obtained by reacting with lerofuranobenzoyl chloride.

Example 52. 2-propyl-2-methyl-6- (4-acetamidophenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) 2- profile obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - a benzopyran, in the same manner as in Example 1 (b) 4- acetamido-benzoyl Reaction with chloride afforded the compound.

Example 53. 2-propyl-2-methyl-6- (3- N, N- dimethylaminophenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) and 2-propyl obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - benzopyran to Example 1 3- N, in the same way as (b) N- Reaction with dimethylaminobenzoyl chloride afforded the compound.

Example 54. 2-phenylethyl-2-methyl-6- (4-fluorophenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) and 2-phenylethylamine obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - a benzopyran, Example 1 (b) in the same manner as 4-fluoro-benzoyl chloride And the compound was obtained.

Example 55. 2-phenylethyl-2-methyl-6- (4-chlorophenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) 2- phenyl obtained in the same manner as ethyl-2-methyl-6-amino-7-methyl -2 H - a benzopyran, Example 1 (b) in the same manner as 4-chlorobenzoyl chloride And the compound was obtained.

Example 56. 2-phenylethyl-2-methyl-6- (4-acetylphenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) 2- phenylethyl obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - a benzopyran, in the same manner as in Example 1 (b) 4- acetyl chloride And the compound was obtained.

Example 57. 2-phenylethyl-2-methyl-6- (4-methylphenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) 2- phenylethyl obtained in the same manner as 2-methyl-6-amino-7-methyl -2 H - a benzopyran, in the same manner as in Example 1 (b) 4- methylbenzoyl chloride And the compound was obtained.

Example 58. 2-phenyl-2-methyl -6- (4- (t- butylphenyl) amido-7-methyl -2 H - benzopyran

Example 1 (a) 2- phenyl-2-methyl-6-amino-7-methyl -2 H obtained in the same way as - in the same way a benzopyran, as in Example 1 (b) 4- (t- Reaction with butyl) benzoyl chloride afforded the compound.

Example 59. 2-phenylethyl-2-methyl-6- (4-trifluoromethylphenyl) amido-7-methyl-2 H -benzopyran

Example 1 (a) and 2-phenyl-2-methyl-6-amino-7-methyl -2 H obtained in the same way - the benzopyran in Example 1 (b) and in the same manner as 4-trifluoromethyl Reaction with methylbenzoyl chloride afforded the compound.

Example 60. 2-phenyl-2-methyl -6- (4- N, N- dimethylaminophenyl) -2-methyl-7-amido H - benzopyran

Example 1 2-phenyl-2-methyl-6-amino-7-methyl -2 H obtained in the same manner as in (a) - in the same way a benzopyran, as in Example 1 (b) 4- N, N -dimethylamino by reaction with benzoyl chloride to give the above compound.

The structure and analysis data of the compounds synthesized by the preparation method according to the above embodiment are shown in Table 1 below.

¹ H NMR spectra were recorded at Bruker Avance 500 MHz and chemical shifts ( δ ) were recorded in ppm relative to TMS as an internal standard. MS data were recorded on Micromass's Quattro Micro model.

Example rescue Molecular Weight MS
[M + H] ^{+ 1} H NMR (500 MHz, CDCl ₃ ) (δ, ppm)
One

287.4
288
2

271.4
272
3

301.4 302
4

285.4 286
5

333.4
334
6

349.5
350
7

347.5
348

8

375.5

376 7.36-7.07 (m, 7H), 7.73 (d, 1H, J = 8.6 Hz), 6.36 (d, 1H, J = 9.8 Hz), 5.62 (d, 1H, J = 9.8 Hz), 2.81-2.71 (m , 2H), 2.27-2.04 (m, 1H), 2.01-1.72 (m, 6H), 1.58-1.46 (m, 4H), 1.43 (s, 3H), 1.35-1.30 (m, 2H)
9

363.5
365
10

379.5
380
11

405.5
406
12

297.4
298

13

359.4
360
14

389.5
390
15

311.4
312
16

373.5
374

17

404.82

405 7.60 (d, 1H, J = 3.9 Hz), 7.59 (br-s, 1H, NH), 7.51 (d, 1H, J = 4.8 Hz), 7.38 (d, 1H, J = 2.4 Hz), 7.26-7.23 (m, 2H), 7.18-7.16 (m, 4H), 7.10 (dd, 1H, J = 4.8 Hz, J = 3.9 Hz), 6.76 (d, 1H, J = 8.7 Hz), 6.37 (d, 1H, J = 9.9 Hz), 5.63 (d, 1H, J = 9.9 Hz), 2.78-2.73 (m, 2H), 2.03-1.97 (m, 2H), 1.44 (s, 3H)
18

325.4
326
19

341.8
342
20

352.4
353
21

321.4
322
22

375.4
376
23

410.7
411
24

357.5
358

25

369.5

370 7.84 (d, 2H, J = 8.4 Hz), 7.78 (s, 1H), 7.52-7.45 (m, 3H), 7.42 (d, 1H, J = 2.4 Hz), 7.25-7.23 (m, 2H), 7.20 -7.16 (m, 3H), 6.77 (d, 1H, J = 8.4 Hz), 6.37 (d, 1H, J = 9.9 Hz), 5.63 (d, 1H, J = 9.9 Hz), 2.78-2.74 (m, 2H), 2.03-1.99 (m, 2H), 1.44 (s, 3H)

26

387.5

388 8.34 (br-s, 1H, NH), 8.17-8.14 (m, 1H), 7.49 (m, 1H), 7.44 (d, 1H, J = 2.4 Hz), 7.30-7.23 (m, 4H), 7.20- 7.13 (m, 4H), 6.78 (d, 1H, J = 8.7 Hz), 6.40 (d, 1H, J = 9.9 Hz), 5.64 (d, 1H, J = 9.9 Hz), 2.81-2.72 (m, 2H ), 2.08-1.94 (m, 2H), 1.45 (s, 3H)
27

403.9
413
28

387.5
388
29

403.9
404
30

414.5
415
31

383.5
384
32

419.5
429
33

437.5
438
34

472.8
473
35

433.9
434

36

433.9
434
37

417.5
418
38

444.5
445
39

413.5
414
40

467.5
468
41

449.6
450
42

363.5
364
43

339.4
340
44

355.9
356
45

424.8
425
46

366.4
367
47

335.5
336

48

347.5
348
49

389.4
390
50

351.4
352
51

365.5
366
52

378.5
379
53

364.5
365
54

401.5
402
55

417.9
428

56

425.5

426 8.05 (d, 2H, J = 8.8 Hz), 7.97 (d, 2H, J = 8.8 Hz), 7.56 (s, 1H), 7.43 (s, 1H), 7.27-7.18 (m, 5H), 6.69 (s , 1H) 6.38 (d, 1H, J = 10.0 Hz), 5.60 (d, 1H, J = 10.0 Hz), 2.80-2.75 (m, 2H), 2.66 (s, 3H), 2.27 (s, 3H), 2.05-1.98 (m, 2H), 1.44 (s, 3H)
57

397.5
398
58

439.6
440

59

451.5
452

60

426.6

427 7.84 (d, 2H, J = 8.8 Hz), 7.44 (s, 2H), 7.26-7.16 (m, 5H), 6.80 (d, 1H, J = 8.8 Hz), 6.67 (s, 1H), 6.38 (d , 1H, J = 10.0 Hz) 5.58 (d, 1H, J = 10.0 Hz), 3.05 (s, 6H), 2.82-2.69 (m, 2H), 2.26 (s, 3H), 2.05-1.95 (m, 2H ), 1.44 (s, 3 H)

[Experimental Example] Pharmacological Activity Confirmation Experiment

In addition, the pharmacological activity of the novel compounds represented by Formula 1 according to the present invention was tested by the method of the following experimental example.

Experimental Example 1. Inhibitory Activity of NF-ĸB Target Gene Expression

The NF-kB transcriptional regulatory activity of the test compound was measured by the following method. NF-kB / A549 cells were cultured by treating hygromycin 100 ug / mL in RPMI medium containing 10% FBS. After incubating the cells in 96 well plates (10 ⁴ / well) for 24 hours, the compound was treated with PMA 10 ng / mL after 1 hour and then maintained at 37 ° C. and 5% carbon dioxide for 6 hours. Cultured in a cell culture. After rinsing with phosphate buffer solution (PBS), the activity of luciferase was evaluated using Dual Glo Luciferase Assay System (Promega) by adding phosphate buffer solution. A liminometer (Victor II) was used for the measurement.

Some of the pharmacological activity results according to Experimental Example 1 are shown in Table 2 below.

Experimental Compound NF-κB target gene expression inhibitory activity
(% inhibition at 2.5 uM) Example 2 92.6 Example 4 102.34 Example 12 101.24 Example 17 102.22 Example 26 100.18 Example 32 101.23 Example 42 101.89 Example 43 103.35 Example 44 105.27 Example 52 102.06 Example 60 102.08

Experimental Example 2 In Vitro Cancer Cell Proliferation Inhibition Activity

In vitro activity on cancer cells was evaluated in the following manner. 100 μL (1 × 10 ⁵ / mL) of the cell suspension diluted in complete medium was added to a 96 well plate, test compound dissolved in DMSO solution was incubated in a humidified 37 ° C. CO ₂ incubator for 48 to 96 hours. A well in which only cancer cells were cultured without the test compound was used as a control, and 2 mL of MTS [3- (4,5-dimethylthiazol-2-yl) -5- (3 was added to 100 μL of phenazinemethosulfate. -Carboxymethoxyphenyl) -3- (4-sulfophenyl) -2 H -tetrazolium)] test solution for cancer cells by mixing the solution and measuring the absorbance of the reaction product formazan at 490/650 nm of each well Cancer cell growth inhibition (%).

[Equation 1]

Some of the pharmacological activity results according to Experimental Example 2 are shown in Table 3 below.

Experimental Compound Cancer cell proliferation inhibitory activity
(IC ₅₀ , μM) Example 2 0.20 Example 4 0.32 Example 12 1.23 Example 43 0.11 Example 44 0.09 Example 52 2.27

[Formulation example]

On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in 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 1.Tablet (Direct Press)

After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized into tablets.

Formulation 2. Tablet (Wet Granulation)

After sifting 5.0 mg of the active ingredient, 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 then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

Formulation 3. Powders and Capsules

After sifting 5.0 mg of active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. Filled in 5 gelatin capsules.

Formulation 4. Injection

Injectables were prepared by containing 100 mg of the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ 12H ₂ O and 2974 mg of distilled water.

Claims (7)

To 2-methyl-2-alkyl-6-amido -2 H represented by the following formula (1) - a compound selected from the salts acceptable benzopyran derivative and its pharmaceutically
[Formula 1]

In Chemical Formula 1,
A is a hydrogen atom; Halogen atom; C ₁ -C ₅ alkyl group; Or a C ₁ -C ₅ alkoxy group,
R ₁ is a hydrogen atom; Acetyl group; C ₁ -C ₅ alkyl group; Or a C ₆ -C ₁₀ aryl C ₁ -C ₅ alkyl group,
R ₂ is a C ₁ -C ₅ alkyl group; C ₃ -C ₈ cycloalkyl group; C ₂ -C ₅ alkenyl group; C ₆ -C ₁₀ aryl group; Or a 5 to 7 membered heteroaryl group containing a hetero atom selected from oxygen or sulfur,
Aryl or heteroaryl used in the above R ₁ and R ₂ definitions are halo, nitro, amino, hydroxy, acetamido, mono (C ₁ -C ₅ alkyl) amino, di (C ₁ -C ₅ alkyl) amino A substituent selected from C ₂ -C ₅ acyl, C ₁ -C ₅ alkyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ haloalkoxy, C ₁ -C ₅ alkylthio 0 to 3 can be substituted,
However, a compound in which A is a hydrogen atom, R ₁ is a hydrogen atom and R ₂ is a C ₁ -C ₅ alkyl group at the same time is excluded.
The method according to claim 1,
A is a hydrogen atom; Or C ₁ -C ₅ alkyl group,
R ₁ is a hydrogen atom; An alkyl group of C ₁ -C ₅ ; Benzyl groups; Or it represents a benzyl substituted with one to three substituents selected from alkoxy of C ₁ -C ₅ alkyl and C ₁ -C ₅ a,
R ₂ is a C ₁ -C ₅ alkyl group; C ₃ -C ₈ cycloalkyl group; C ₂ -C ₅ alkenyl group; Phenyl group; Halo, nitro, amino, acetamido, mono (C ₁ -C ₅ alkyl) amino, di (C ₁ -C ₅ alkyl) amino, C ₂ -C ₅ acyl, C ₁ -C ₅ alkyl, C ₁ -C A phenyl group substituted with 1 to 3 substituents selected from ₅ haloalkyl, and C ₁ -C ₅ alkoxy; Naphthyl group; Furanyl group; Thiophene group; Or a benzo [ d ] [1,3] dioxol group,
A compound wherein A is a hydrogen atom, R ₁ is a hydrogen atom, and R ₂ is a C ₁ -C ₅ alkyl group.
The method according to claim 1,
A represents a hydrogen atom, a methyl group, an ethyl group, or a propyl group,
R ₁ represents a hydrogen atom, a methyl group, an ethyl group, a benzyl group, 2-methoxybenzyl group, 3-methoxybenzyl group, or 4-methoxybenzyl group,
R ₂ is methyl, ethyl, propyl, t -butyl, cyclopropyl, cyclohexyl, vinyl, allyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluoro Rophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,4-dichlorophenyl group, 2,4-difluorophenyl group, 2,4,6-trichlorophenyl group, 2-trifluoromethylphenyl group, 3 -Trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 4-nitrophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxy Methoxyphenyl group, 2-acetylphenyl group, 3-acetylphenyl group, 4-acetylphenyl group, 2-aminophenyl group, 3-aminophenyl group, 4-aminophenyl group, 2-dimethylaminophenyl group, 3-dimethylaminophenyl group, 4-dimethylaminophenyl group , 2-acetamidophenyl group, 3-acetamidophenyl group, 4-acetamidophenyl group, naphthyl group, naphthyl group, furanyl group, cy Indicates the pen group, or benzo [d] [1,3] dioxolanyl seam,
A compound wherein A is a hydrogen atom, R ₁ is a hydrogen atom, and R ₂ is a methyl group, an ethyl group, a propyl group, or a t -butyl group.
The method according to claim 1,
2-propyl-2-methyl -6- (t- butylamido) -2 H - benzopyran,
2-propyl-2-methyl-6-cyclo propyl amido -2 H - benzopyran,
2-propyl-2-methyl -6- (t- butylamido) -7-methyl -2 H - benzopyran,
2-propyl-2-methyl-6-cyclo propyl amido-7-methyl -2 H - benzopyran,
2-phenylethyl-2-methyl-6-cyclo propyl amido -2 H - benzopyran,
2-phenylethyl-2-methyl -6- (t- butylamido) -2 H - benzopyran,
2-phenylethyl-2-methyl-6-cyclo propyl amido-7-methyl -2 H - benzopyran,
2-phenylethyl-2-methyl-6-cyclo hexyl-amido -2 H - benzopyran,
2- (4-methoxy-phenylethyl) -2-methyl-6-cyclo propyl amido -2 H - benzopyran,
2- (4-methoxy-phenylethyl) -2-methyl -6- (t- butylamido) -2 H - benzopyran,
2- (4-methoxy-phenylethyl) -2-methyl-6-cyclo hexyl-amido -2 H - benzopyran,
2-propyl-2-methyl-6- (furan-2-ylamido) -2 H -benzopyran,
2-ethyl-2-phenyl-6- (furan-2-yl amido) -2 H - benzopyran,
2- (4-methoxy-phenylethyl) -2-methyl-6- (furan-2-yl amido) -2 H - benzopyran,
2-propyl-2-methyl-6- (furan-2-yl amido) -7-methyl -2 H - benzopyran,
2-ethyl-2-phenyl-6- (furan-2-yl amido) -7-methyl -2 H - benzopyran,
2-phenylethyl-2-methyl-6- (thiophen-2-yl amido) -7-methyl -2 H - benzopyran,
2-propyl-2-methyl-6- (4-fluorophenyl) amido -2 H - benzopyran,
2-propyl-2-methyl-6- (4-chlorophenyl) amido -2 H - benzopyran
2-propyl-2-methyl-6- (4-nitrophenyl) amido -2 H - benzopyran,
2-propyl-2-methyl-6- (4-methylphenyl) amido -2 H - benzopyran,
2-propyl-2-methyl-6- (2-trifluoromethylphenyl) amido -2 H - benzopyran,
2-propyl-2-methyl-6- (2,4,6-trichloro-phenyl) amido -2 H - benzopyran,
2-propyl-2-methyl-6- (naphthalene-1-yl) amido -2 H - benzopyran,
2-phenylethyl-2-methyl-6-phenyl-amido -2 H - benzopyran,
2-ethyl-2-phenyl-6- (2-fluoro-phenyl) amido -2 H - benzopyran,
2-ethyl-2-phenyl-6- (2-chlorophenyl) amido -2 H - benzopyran,
2-ethyl-2-phenyl-6- (4-fluorophenyl) amido -2 H - benzopyran,
2-ethyl-2-phenyl-6- (4-chlorophenyl) amido -2 H - benzopyran,
2-ethyl-2-phenyl-6- (4-nitrophenyl) amido -2 H - benzopyran,
2-ethyl-2-phenyl-6- (4-methylphenyl) amido -2 H - benzopyran,
2-phenylethyl-2-methyl-6- (naphthalene-1-yl) amido -2 H - benzopyran,
2-ethyl-2-phenyl-6- (2-trifluoromethylphenyl) amido -2 H - benzopyran,
2-phenylethyl-2-methyl-6- (2,4,6-chlorophenyl) amido -2 H - benzopyran,
2- (4-methoxy-phenylethyl) -2-methyl-6- (2-chlorophenyl) amido -2 H - benzopyran,
2- (4-methoxy-phenylethyl) -2-methyl-6- (4-chlorophenyl) amido -2 H - benzopyran,
2- (4-methoxy-phenylethyl) -2-methyl-6- (2-fluorophenyl) amido -2 H - benzopyran,
2- (4-methoxy-phenylethyl) -2-methyl-6- (4-nitrophenyl) amido -2 H - benzopyran,
2- (4-methoxy-phenylethyl) -2-methyl-6- (4-methylphenyl) amido -2 H - benzopyran,
2- (4-methoxy-phenylethyl) -2-methyl-6- (2-trifluoromethylphenyl) amido -2 H - benzopyran,
2- (4-methoxy-phenylethyl) -2-methyl-6- (naphthalene-1-yl) amido -2 H - benzopyran,
2-propyl-2-methyl-6- (4-acetylphenyl) amino-7-methyl -2 H - benzopyran,
2-propyl-2-methyl-6- (4-fluorophenyl) amino-7-methyl -2 H - benzopyran,
2-propyl-2-methyl-6- (4-chlorophenyl) amido-7-methyl-2 H -benzopyran,
2-propyl-2-methyl-6- (2,4,6-trichloro-phenyl) amido-7-methyl -2 H - benzopyran,
2-propyl-2-methyl-6- (4-nitrophenyl) amino-7-methyl -2 H - benzopyran,
2-propyl-2-methyl-6- (4-methylphenyl) amido-7-methyl -2 H - benzopyran,
2-propyl-2-methyl-6- (3-ethynyl-phenyl) amido-7-methyl -2 H - benzopyran,
2-propyl-2-methyl-6- (2-trifluoromethylphenyl) amido-7-methyl-2 H -benzopyran,
2-propyl-2-methyl-6- (4-methoxyphenyl) amido-7-methyl -2 H - benzopyran,
2-propyl-2-methyl-6- (benzo [d] [1,3] dioxolane-5-yl) amido-7-methyl -2 H - benzopyran,
2-propyl-2-methyl-6- (4-acetamido-phenyl) amido-7-methyl -2 H - benzopyran,
2-propyl-2-methyl -6- (3- N, N- dimethylaminophenyl) -2-methyl-7-amido H - benzopyran,
2-ethyl-2-phenyl-6- (4-fluorophenyl) amino-7-methyl -2 H - benzopyran,
2-ethyl-2-phenyl-6- (4-chlorophenyl) amino-7-methyl -2 H - benzopyran,
2-phenyl-2-ethyl-6- (4-acetylphenyl) amino-7-methyl -2 H - benzopyran,
2-ethyl-2-phenyl-6- (4-methylphenyl) amido-7-methyl -2 H - benzopyran,
2-phenylethyl-2-methyl -6- (4- (t- butylphenyl) amido-7-methyl -2 H - benzopyran,
2-phenylethyl-2-methyl-6- (4-trifluoromethylphenyl) amido-7-methyl-2 H -benzopyran, and
2-phenylethyl-2-methyl -6- (4- N, N- dimethylaminophenyl) -2-methyl-7-amido H - benzopyran
Compounds characterized in that selected from.
A pharmaceutical composition for treating and preventing cancer, comprising the compound of any one of claims 1 to 4 as an active ingredient.
An anticancer agent characterized in that it contains a compound of any one of the claims 1 to 4.
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