KR100784850B1 - Chroman-2-carboxylic acid arylamide derivatives, method of the same and nf-kappab inhibitor comprising thereby - Google Patents

Abstract

A novel chroman-2-carboxylic acid amide derivative compound and a pharmaceutical composition comprising the same are provided to act as an inhibitor of NF-kappaB, thereby capable of preventing or treating diseases related to the NF-kappaB such as multiple myeloma, rheumatoid arthritis, and cancer. A chroman-2-carboxylic acid amide derivative is represented by the formula(1-a) or (1-b). In the formula(1-a), each R1, R2, R3, R4 and R5 is same or different and is independently H, hydroxy, C1-4 alkoxy, C1-4 alkyl, trifluoromethyl, halogen, or nitro. In the formula(1-b), each R1, R2, R3, R4 and R5 is same or different and is independently H, hydroxy, C1-4 alkoxy, C1-4 alkyl, trifluoromethyl, halogen, or nitro, provided that all R1 to R5 being H, or R1 and R3 to R5 being H and R2 being nitro, or R1 to R3 and R5 being H and R4 being nitro are excluded. A method for preparing the chroman-2-carboxylic acid amide derivative of the formula(1-a) comprises the steps of: (a) treating 2-hydroxyacetone phenone and oxalic acid diester under a base and then treating them with an acid to prepare a compound represented by the formula(2-a); (b) subjecting the compound of the formula(2-a) to a catalytic reduction under an ethanol-acetic acid solvent and a Pd/C catalyst to prepare a compound represented by the formula(3-a); (c) treating the compound of the formula(3-a) with potassium hydroxide to prepare a compound represented by the formula(4-a); and (d) treating the compound of the formula(4-a) with an amine compound to prepare the compound of the formula(1-a). A pharmaceutical composition for preventing or treating multiple myeloma, rheumatoid arthritis, or cancer comprises the chroman-2-carboxylic acid amide derivative or a pharmaceutically acceptable salt thereof as an effective ingredient and a pharmaceutically acceptable carrier.

Description

CHROMAN-2-CARBOXYLIC ACID ARYLAMIDE DERIVATIVES, METHOD OF THE SAME AND NF-κB INHIBITOR COMPRISING THEREBY}

[Technical Field]

The present invention relates to a novel chroman-2-carboxylic acid arylamide derivative, a preparation method thereof, and a pharmaceutical composition containing the same. The inhibitor may be used as a composition for preventing or treating a disease associated with NF-κB, and preferably relates to a composition for preventing or treating at least one disease selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer.

[Private Technology]

Most human diseases are caused by a combination of abnormal elements and substances produced by gene expression during or when the disease occurs. Such diseases include autoimmune disease including autoimmune arthritis, glomerulonephritis, asthma, inflammatory bowel disease (IBD), and sepsis Septic shock, Lung Fibrosis, carcinogenesis, or cancer, and Acquired Immune Deficiency Syndrome (AIDS). Generally, these genes are inactive or very insignificant in biological or physical processes. However, under certain conditions, such as exposure to environmental pollution, the expression of these genes increases exponentially with preexisting genetic elements. These genetic elements are nuclear, an essential transcription factor that regulates gene expression of cytokines, chemokines, growth factors, adhesion molecules, and acute phase proteins. regulated by factor-κB (NF-κB) (Li, Q. et al . , Nat. Rev. Immunol., 2: 724-34. 2002; Young, MR, et al . , Trends Mol. Med., 9: 36-41, 2003; Haefner, B., Drug Discov. today, 7: 653-63, 2002).

NF-κB was first identified as a transcriptional activator specific for B cells of the κ-light chain gene of immunoglobulins. NF-κB has since been identified in a variety of cells and is known to be activated by many factors. Such NF-κB has been widely studied in various fields such as immunology, molecular biology, biochemistry, genetics, cell biology and developmental biology.

NF-κB exists in the cytoplasm of most cells and is in the form of homo-dimers and heterodimers as a bond between groups of structurally similar proteins (Baldwin, AS et al. al ., Annu . Rev. Immunol , 14 : 649-683 (1996) ; Kopp, EB et al ., Adv . Immunol , 58 : 1-27 (1995)). Each element of this group of proteins contains a protected amino terminus, called the Rel-Homology Domain (RHD), which contains a DNA-binding domain and a dimerization domain. And nuclear localization signals (NLS). In mammals, in particular, NF-κB is composed of five proteins, p65 (RelA), RelB, c-Rel, p50 / p105 (NF-κB1) and p52 / p100 (NF-κB2). p65 (RelA), RelB and c-Rel are produced as active proteins that cause transcription, and p50 / p105 (NF-κB1) and p52 / p100 (NF-κB2) are synthesized from precursors of 105 kDa and 100 kDa, respectively. These 105kDa and 100kDa precursors undergo several processes to turn into smaller active forms, p50 and p52, which cause transcription. Typical NF-κB has dimer forms of p65 (RelA) and p50 / p105 (NF-κB1). However, it has also been reported that various dimer forms exist that include other Rels (Michael, JM et. al ., Immunol. Today , 19: 80-88 (1998).

In the cytoplasm, NF-κB is in an inactive form by binding to IκBa, IκBb, IκBe, IκBg, Bcl3, and the precursor proteins p100 and p105, known as inhibitory proteins (Simon, TW et al ., Semin . Cancer Biol . 8 : 75-82 (1997). All known IκBs contain ankyrin repeat domains with various types of 30-33 amino acid sequences, and the special interaction between ankyrin repeat domains and RHD clearly characterizes the binding between NF-κB and IκB. In other words, the IκB group regulates the DNA binding of NF-κB and the subcellular localization of the Rel-NF-κB protein by blocking NLS located near the carboxyl terminus of RHD of NF-κB (Thomas, H. et. al . , Cell . 68 : 1121-1133 (1992).

One factor that regulates the binding of NF-κB and IκB is IκB kinase (IKK). By activation of IKK, the N-terminus of IκB is phosphorylated and the release of IκB is regulated. This IKK contains two kinase subunits of IKKα (IKK1) and IKKβ (IKK2) and regulatory subunits that are NEMO (NF-κB essential modifier) or IKKγ (Rothwarf, DM et al . , Sci , STKE , 5 : re1. (1999)). In the general NF-κB pathway, IKKβ phosphorylates two N-terminal serine residues of IκB. In particular, IκBα is phosphorylated at serine residues 32 and 36 and IkBβ at serine residues 19 and 23. The role of IKKα is not clear in the general pathway of NF-κB, but recent studies are thought to modulate gene expression by altering histone phosphorylation in the nucleus. But another NF-κB pathway is dependent on IKKα, which phosphorylates p100 and induces p52.

Each of the IκBs phosphorylated by this IKK complex is ubiquitated by ubiquitin ligase, such as SCF (or SCRF), to be degraded in the proteasome. When IκB is broken down, NF-κB is activated and moved into the nucleus by NLS to express genes. There is a difference in path by so many external signals that actually activate NF-κB. However, most pathways are the same in terms of enhancing the transcriptional capacity of NF-kB by activating IKK and releasing IkB. Among the studies of interest, pathways that activate IKK by external signals include TNFR, TLR / IL-1R, TCR and BCR (Matthew, SH et. al . , Genes Dev . 18 : 2195-2224 (2004).

NF-κB is a cytokine, chemokine, adhesion molecule, acute phase proteins, anti-microbial peptide, cell surface receptor, inducible Activates the transcriptional stages of genes expressing nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) (Barnes, PJ et. al . , N. Engl . J. Med . 366 : 1066-1071 (1997); Xie, Q et al . , J. Biol . Chem . 269 : 4705-4708 (1994); Yamamoto, K. et al . , J. Biol. Chem . 270 : 31315-31320 (1995)).

Stimulants that activate NF-κB are external substances such as toxic substances, bacteria, viruses, ultraviolet rays, ionizing radiation, etc. As internal substances, cytokines, inflammatory mediators, growth factors, and oxygen deficiency are known (Delhase, M. et al., Nature, 406: 367-8 (2000); Mercurio, F. et al., curr.Opin.Cell Biol., 11: 226-32 (1999).

Therefore, abnormal NF-κB activation is known to be associated with the cause or malignancy of refractory diseases and cancer diseases accompanied by various inflammatory diseases including myeloma, arthritis, arterial stenosis, and asthma (Aradhya, S et al., Curr. Opin.Genet. Dev., 11: 300-7, 2001; Orlowski, RZ et al., Trnds Mol.Med., 8: 385-9 (2002)).

Bortezomib, an inhibitor of 26S proteasome that is involved in NF-κB activation, is an anticancer agent for multiple myeloma and has been approved by the US Food and Drug Administration for clinical use (Dispenzieri, A., N. Engl). J. Med., 352: 2546-8 (2005)).

Therefore, the inventors of the present invention have derived chromaman-2-carboxylic acid arylamide derivatives by establishing the preparation method based on the fact that inhibiting NF-κB activation can be used as a useful pharmaceutical composition for the prevention and treatment of inflammation and cancer diseases. In addition, the present invention was completed by confirming that they strongly inhibited NF-κB activation.

In order to meet the above demands, the present invention is useful for the prevention or treatment of multiple myeloma, rheumatoid arthritis and cancer due to inhibition of NF-kB activation, a compound having few side effects, a method for preparing the compound and an effective multiple containing the same It is an object to provide a composition for preventing or treating myeloma, rheumatoid arthritis and cancer.

In order to achieve the above object, the present invention provides a novel Chroma-based derivative compound, a preparation method thereof and an NF-kB inhibitor containing the same as an active ingredient. The inhibitor may be used as a composition for preventing or treating a disease associated with NF-kB, and preferably relates to a composition for preventing or treating at least one disease selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer.

Hereinafter, the present invention will be described in more detail.

In one aspect of the invention, the present invention relates to a novel Chroma-based derivative compound. The Chroma-based derivative compound may be a compound having a structure of Formula 1-a or Formula 1-b, and may be a pharmaceutically acceptable salt thereof:

In the above formula,

R ₁ to R ₅ may be the same as or different from each other, and each independently may be H, hydroxy, alkoxy having C1 to C4, alkyl having C1 to C4, trifluoromethyl, halogen or nitro group.

In the above formula,

R ₁ to R ₅ may be the same or different and each independently may be H, hydroxy, alkoxy having C1 to C4, alkyl having C1 to C4, trifluoromethyl, halogen or nitro group.

The alkoxy may be preferably a methoxy group, the alkyl may be preferably a methyl group, and the halogen may be preferably a chloro group.

Preferred compounds of the invention are chroman-2-carboxylic acid phenylamide, chroman-2-carboxylic acid (2-hydroxy-phenyl) -amide, chroman-2-carboxylic acid (3-hydroxy-phenyl) -amide, chroma Mann-2-carboxylic acid (4-hydroxy-phenyl) -amide, chromman-2-carboxylic acid (2-methoxy-phenyl) -amide, chroman-2-carboxylic acid (3-methoxy-phenyl) -amide, Chromman-2-carboxylic acid (4-methoxy-phenyl) -amide, chromman-2-carboxylic acid ortho-tolylamide, chromman-2-carboxylic acid meta-tolylamide, chromman-2-carboxylic acid para-tolylamide , Chroman-2-carboxylic acid (3-trifluoromethyl-phenyl) -amide, chroman-2-carboxylic acid (4-trifluoromethyl-phenyl) -amide, chroman-2-carboxylic acid (3- Chloro-phenyl) -amide, chroman-2-carboxylic acid (4-chloro-phenyl) -amide, chroman-2-carboxylic acid (3-nitro-phenyl) -amide, chroman-2-carboxylic acid (4-nitro- Phenyl) -Amy , 6-hydroxy-7-methoxy-chroman-2-carboxylic acid (2-hydroxy-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid (3-hydroxy- Phenyl) -amide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid (4-hydroxy-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid (2 -Methoxy-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid (3-methoxy-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-2 -Carboxylic acid (4-methoxy-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid ortho-tolylamide, 6-hydroxy-7-methoxy-chroman-2- Carboxylic acid meta-tolylamide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid para-tolylamide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid (3-trifluoromethyl -Phenyl) -amide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid (4-trifluoromethyl-phenyl) -amide, 6-hydroxy-7-meth Cy-Chroman-2-carboxylic acid (2-chloro-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-carboxylic acid (3-chloro-phenyl) -amide, 6-hydroxy-7 -Methoxy-chroman-2-carboxylic acid (4-chloro-phenyl) -amide, and the substituents of the preferred compound may be as shown in Table 1 below.

6th 7th R ₁ R ₂ R ₃ R ₄ R ₅ KAL-1201 H H H H H H H KAL-1202 H H OH H H H H KAL-1203 H H H OH H H H KAL-1204 H H H H OH H H KAL-1205 H H OCH ₃ H H H H KAL-1206 H H H OCH ₃ H H H KAL-1207 H H H H OCH ₃ H H WAL-1031 H H CH ₃ H H H H WAL-1032 H H H CH ₃ H H H WAL-1029 H H H H CH ₃ H H WAL-1037 H H H CF ₃ H H H WAL-1043 H H H H CF ₃ H H WAL-1201 H H H Cl H H H WAL-1202 H H H H Cl H H WAL-1036 H H H NO ₂ H H H WAL-1041 H H H H NO ₂ H H KAL-1119 OH OCH3 OH H H H H KAL-1184 OH OCH3 H OH H H H KAL-1135 OH OCH3 H H OH H H KAL-1188 OH OCH3 OCH ₃ H H H H KAL-1187 OH OCH3 H OCH ₃ H H H KAL-1136 OH OCH3 H H OCH ₃ H H KAL-1200 OH OCH3 CH ₃ H H H H KAL-1196 OH OCH3 H CH3 ₃ H H H KAL-1191 OH OCH3 H H CH ₃ H H KAL-1195 OH OCH3 H CF ₃ H H H KAL-1190 OH OCH3 H H CF ₃ H H KAL-1198 OH OCH3 Cl H H H H KAL-1194 OH OCH3 H Cl H H H KAL-1120 OH OCH3 H H Cl H H

The most preferred compound of the present invention is 6-hydroxy-7-methoxy-chroman-2-carboxylic acid (4-chloro-phenyl) -amide (KAL-1120).

The present invention also provides a method for preparing the compound of Formula 1-a or Formula 1-b.

The compounds of the present invention may be prepared by the method shown in the following schemes, but are not limited to these examples. The following schemes represent the preparation steps of representative compounds of the present invention, and other compounds may be prepared by appropriate changes in reagents and starting materials known to those skilled in the art.

The method for preparing the compound of Formula 1-a may be as described in Scheme 1 below, and the method for preparing the compound of Formula 1-b may be as described in Scheme 2 below.

The preparation method according to Scheme 1 is as follows.

In more detail, the production method according to Scheme 1,

(a) treating 2-hydroxyacetonephenone and oxalic acid diester under base and acid treatment to prepare a compound of formula 2-a (WAL-1001 of the above scheme);

(b) subjecting the compound of formula 2-a to catalytic reduction under an ethanol-acetic acid solvent and a Pd / C catalyst to prepare a compound of formula 3-a (WAL-1003 in the above scheme);

(c) treating the compound of Formula 3-a with potassium hydroxide to prepare a hydrolyzed compound of Formula 4-a (WAL-1004 of the above scheme); And

(d) treating the compound represented by Chemical Formula 4-a with an amine compound to produce a chroman-2-carboxylic acid amide derivative represented by Chemical Formula 1-a according to claim 1; Refers to a method for producing a derivative.

In the step (a), preferably, 2-hydroxyacetonephenone and oxalic acid diester are added to the sodium ethoxide solution, followed by reaction under reflux under a nitrogen stream. Prepared by weak acidic acid and then obtained by column chromatography,

In the step (b), the compound of formula 2-a may be dissolved in ethanol and reacted under acetic acid and hydrogen gas under Pd / C catalyst, and the compound of formula 3-a may be obtained through filtration and chromatography. The Pd / C catalyst may be preferably 7% to 12% of Pd / C catalyst, most preferably 10% of Pd / C catalyst,

Step (c) may be obtained by dissolving the compound of Chemical Formula 4-a in water and adding potassium hydroxide, followed by reaction. The reaction is preferably 75 ° C. to 99 ° C., more preferably 80 ° C. to 95 ° C., Most preferably at 90 ° C.,

In the step (d), the chroman-2-carboxylic acid is dissolved in anhydrous tetrahydrofuran, and then reacted by addition of N, N-carbonyldiimidazole, and then an amine compound is added and reacted under a nitrogen stream.

The amine compound is a phenylamine, aminophenol, methoxyphenylamine, tolyl corresponding to derivatives KAL-1201, KAL-1202, KAL-1205, WAL-1031, WAL-1037, WAL-1201 and WAL-1036, which are final compounds. Amines, trifluoromethylphenylamine, chlorophenylamine, nitrophenylamine and the like.

The preparation method according to Scheme 2 is as follows.

More specifically, the production method according to Scheme 2,

(a) preparing a compound of formula 2-b by subjecting methoxyhydroquinone and acetic acid to a Friedel-Crafts acylation reaction under a zinc chloride catalyst;

(b) preparing a compound of formula 2-b, wherein the compound of formula 2-b and dihydropyran (DHP) are protected with a hydroxy group under a pyridium paratoluenesulfonate (PPTs) catalyst;

(c) reacting the compound of Formula 3-b with diethyl ester of oxalate under a base and acid-treated to prepare a compound of Formula 4-b, which is cyclized;

(d) subjecting the compound of Formula 4-b to catalytic reduction under an ethanol-acetic acid solvent and a Pd / C catalyst to prepare a compound of Formula 5-b;

(e) treating the compound of Formula 5-b with potassium hydroxide to prepare a hydrolyzed compound of Formula 6-b; And

(f) treating the compound represented by Chemical Formula 6-b with an amine compound to prepare a chromaman-2-carboxylic acid amide derivative represented by Chemical Formula 1-b according to claim 1;

It refers to a method for producing a chromaman-2-carboxylic acid amide derivative, characterized in that it comprises a.

In the step (a), preferably acetic acid and lower lead chloride are added and reacted at 125 ° C to 150 ° C, preferably 135 ° C to 145 ° C, most preferably 140 ° C and a nitrogen stream, followed by heating with methoxyhydroquinone. It may be carried out by, the heating temperature is preferably 110 ℃ to 159 ℃, more preferably 120 ℃ to 150 ℃, most preferably 145 ℃,

In the step (b), after dissolving the compound of Formula 2-b and pyridium-para-toluenesulfonate in anhydrous dichloromethane, 3,4-dihydro-2H-pyran is added to the solution, and then 15 ° C. To 30 ° C., preferably 20 ° C. and under a stream of nitrogen to stir until the material is dissolved,

In the step (c), preferably, 2-hydroxyacetonephenone and oxalic acid diester are added to the sodium ethoxide solution, followed by reaction under reflux under a nitrogen stream, and the chemical formula 4-b weakly acidifies the reaction product. It can be obtained through column chromatography after preparing with

In the step (d), the compound of formula 4-b may be dissolved in ethanol and reacted under acetic acid and hydrogen gas under Pd / C catalyst, and the compound of formula 5-b may be obtained through filtration and chromatography. The Pd / C catalyst may be preferably 7% to 12% of Pd / C catalyst, most preferably 10% of Pd / C catalyst,

The step (e) may be obtained by dissolving the compound of Chemical Formula 5-b in water and adding potassium hydroxide to react the same.

In step (f), 6-hydroxy-7-methoxy-chroman-2-carboxylic acid represented by Chemical Formula 6-b is dissolved in anhydrous tetrahydrofuran, and then reacted by adding N, N-carbonyldiimidazole. , An amine compound can be added and reacted under a stream of nitrogen,

The amine compound is aminophenol, methoxyphenylamine, tolylamine, trifluoromethylphenylamine, chlorophenyl corresponding to derivatives KAL-1119, KAL-1188, KAL-1200, KAL-1195, and KAL-1198, which are final compounds. Amines and the like.

In another aspect of the present invention, the present invention also provides a pharmaceutical composition for inhibiting NF-kB activation comprising the compound of Formula 1-a or Formula 1-b or a pharmaceutically acceptable salt thereof as an active ingredient.

The present inventors measured the amount of secretory alkaline phosphatase (SEAP) produced with NF-kB when treated with the relative fluoresecnce unit (RFU). It was confirmed that NF-kB activation can be suppressed.

Since NF-kB is translocated into the nucleus and induces a transcription process in the nucleus, the pharmaceutical composition of the present invention which inhibits NF-kB activation is transcribed in the nucleus and is a cytokine, chemokine, and adhesion molecule. Activation of the transcriptional stages of acute phase proteins, anti-microbial peptides, cell surface receptors, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) genes. It has been confirmed that it is possible to prevent or treat any one or more diseases selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer that can be affected by the gene.

Therefore, the pharmaceutical composition for inhibiting NF-kB activation may preferably be a composition for preventing or treating any one or more diseases selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer.

The Chromane derivative-based compound may be used alone in the composition, and may further include other pharmacologically acceptable carriers or excipients. In this case, the Chromann derivative-based compound in the composition may be 0.1 to 99.9% by weight, but the preferred content is appropriately adjusted according to the method of use and method of use of the composition.

When used as the medicament, the composition may be prepared by mixing the chroman derivative of Formula 1-a or Formula 1-b with a pharmaceutically acceptable carrier or excipient or diluting with a diluent according to conventional methods. Examples of pharmaceutically acceptable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The pharmaceutical composition may further include fillers, extenders, disintegrants, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives or surfactants.

The formulation of the composition may vary depending on the method of use and may be formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. In general, the formulations are PLASTERS, GRANULES, LOTIONS, POWDERS, SYRUPS, LIQUIDS AND SOLUTIONS, AEROSOLS, OINTMENTS ), FRUIDEXTRACTS, ELIXIR, EMULSIONS, SUSPENSIONS, INFUSIONS, SACHET, TABLETS, PILLS, INJECTIONS, soft or hard It may be in the form of a capsule (CAPSULES) and pills (PILLS).

When the composition is used as a medicament, the administration method may be oral or parenteral, and may be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular.

The dosage of the composition can be determined in consideration of the age, sex, severity, condition of the patient, absorption of the active ingredient in the body, inactivation rate and the drug used in combination, and 0.5 mg based on the daily active ingredient It can be administered from / kg (body weight) to 50 mg / kg (body weight), it may be administered once or divided into several times.

Hereinafter, preferred embodiments of the present invention are described. However, the following examples are only preferred embodiments of the present invention, and the present invention is not limited to the following examples.

Example  1: Manufacture of raw materials

Example  1-1: 4-oxo-4H- Chromen -2- Carboxylic acid  Ethyl ester ( WAL -1001)

Sodium (164 mg, 7.13 mmol) was added to ethanol (7 ml) in a 25 ml round flask to make a sodium ethoxide solution. Then, 2-hydroxyacetophenone (200 mg, 1.47 mmol) was added thereto, followed by heating. mg, 3.82 mmol) was slowly added and refluxed under a nitrogen stream for 2 hours. After the reaction was completed, the reaction was cooled at 20 ℃, concentrated under reduced pressure and dissolved in water. The solution was prepared slightly acidic with 6N hydrochloric acid. Extraction was carried out using dichloromethane, and the extracted solvent was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrated material under reduced pressure was dissolved in ethanol (50 ml), c-hydrochloric acid (1 ml) was added, and the mixture was stirred at 20 ° C for 24 hours. After stirring, column chromatography was conducted to obtain WAL-1001.

Yield: 90%, 287 mg

m.p. : 73 to 75 ℃

IR (KBr): 3066.26, 1734, 1646, 1466, 1267, 777 cm ^-1

1 H NMR (CDCl ₃ .300 MHz) d 8.21 (d, 1H, J = 8.02 Hz, Ar- H ), 7.75 (t, 1H, J = 7.77 Hz, Ar- H ), 7.63 (d, 1H, J = 8.39 Hz, Ar- H ), 7.46 (t, 1H, J = 7.53 Hz, Ar- H ), 7.13 (s, 1H, OCC H C), 4.47 (m, 2H, J = 7.14 Hz, OC H ₂ CH ₃ ), 1.44 (t, 1H, J = 7.14 Hz, OCH ₂ C H ₃ )

Example  1-2: Croman -2- Carboxylic acid  Ethyl ester ( WAL -1003)

Dissolve 4-oxo-4H-chromen-2-carboxylic acid ethyl ester (WAL-1001) (600 mg, 2.75 mmol) in ethanol and place it in a 100 ml round flask and add Pd / C (120 mg) and acetic acid (2 ml). And stirred for one day under hydrogen stream. Filtration with Celite removed the solids and the filtrate was concentrated and purified by flash column chromatography (silica gel 230-400 mesh, Merck 9385) to give the product as a brown oil.

Yield: 98%, 556 mg

IR (KBr): 2979, 1753, 1488, 1193, 1114, 754 cm ^-1

1 H NMR (CDCl 3 .300 MHz) d 7.03 (t, 1H, J = 7.64 Hz, Ar-H) 6.95 (d, 1H, J = 7.34 Hz, Ar- H ), 6.85 (d, 1H, J = 8.09 Hz , Ar- H ), 6.78 (t, 1H, J = 7.36 Hz, Ar- H ), 4.63 (d, 1H, J = 7.47 Hz, OC H CH ₂ CH ₂ ), 4.17 (m, 2H, J = 7.13 Hz, OC H ₂ CH ₃ ), 2.81 to 2.62 (m, 2H, OCHCH ₂ C H ₂ ), 2.25 to 2.03 (m, 2H, OCHC H ₂ CH ₂ ), 1.21 (t, 3H, J = 7.13 Hz, OCH ₂ C H ₃ )

Example  1-3: Croman -2- Carboxylic acid  ( WAL Preparation of 1004)

In a 25 ml round flask, chromman-2-carboxylic acid ethyl ester (WAL-1003) (231 mg, 1.12 mmol) was dissolved in water (10 mL) and potassium hydroxide (251 mg, 4.48 mmol) was added. Stirred. After stirring, 1N hydrochloric acid was added to make the pH neutral, and extracted with ethyl acetate. The solvent was concentrated under reduced pressure and then purified by flash column chromatography (silica gel 230-400 mesh, Merck 9385).

Yield: 97%, 194 mg

m.p. : 95 to 98 ° C

IR (KBr): 2926, 1719, 1244, 1094, 750 cm ^-1

1 H NMR (CDCl ₃ .300 MHz) d 7.15 (t, 1H, J = 7.68 Hz, Ar- H ), 7.07 (d, 1H, J = 7.33 Hz, Ar- H ), 6.93 (d, 1H, J = 8.41 Hz, Ar- H ), 6.91 (t, 1H, J = 7.37 Hz, Ar- H ), 4.76 (d, 1H, J = 8.31 Hz, OC H CH ₂ CH ₂ ), 2.94-2.78 (m, 2H , OCHCH ₂ C H ₂ ), 2.41 ~ 2.16 (m, 2H, OCHC H ₂ CH ₂ )

Example  1-4: 1- (2,5-dihydroxy-4- Methoxyphenyl )- Ethanon  ( KAL -1014) Produce

Zinc chloride (3.30 g, 24.2 mmol) and acetic acid (3.30 g, 55.0 mmol) were added to a 50 ml round flask, and the mixture was stirred at 140 ° C. and a nitrogen stream. Add methoxyhydroquinone (2.8 g, 20.0 mmol) to it and heat it until it starts to boil and keep it no higher than 159 ° C. Then, 40 mL of d -hydrochloric acid (1: 3) was added thereto, and extracted with dichloromethane. The solvent was concentrated under reduced pressure and purified by flash column chromatography (silica gel 230-400 mesh, Merck 9385) to give a yellow solid.

Yield: 45%, 1.64 g

m.p. 144.6 to 146.3 ° C

IR (KBr): 3297, 1508, 1272, 1061 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.20 (s, 1H, Ar- H ), 6.44 (s, 1H, Ar- H ), 3.93 (s, 3H, OC H ₃ ), 2.53 (s, 3H, COC H ₃ )

Example  1-5: 1- [2-hydroxy-4- Methoxy -5- ( Tetrahydropyran -2- Iloxy )- Phenyl ] -Ethanone ( KAL -1023)

In a 150 ml round flask, 1- (2,5-dihydroxy-4-methoxyphenyl) -ethanone (KAL-1014) (1.50 g, 8.23 mmol) and pyridinium-para-toluenesulfonate (60.0 mg, 0.239 mmol) was dissolved in anhydrous dichloromethane (50 mL) and stirred. To this was slowly added 3,4-dihydro-2 H -pyran (2.10 g, 25.0 mmol) to anhydrous dichloromethane (30 mL). After stirring until the material was dissolved at 20 ° C. and under a nitrogen stream, the reaction was terminated by TLC. Extracted twice with water (40 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (silica gel 230-400 mesh, Merck 9385) to give a brownish yellow liquid product.

Yield: 91%, 2.00 g

IR (KBr): 2943, 1631, 1258, 1029 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.42 (s, 1H, Ar- H ), 6.44 (s, 1H, Ar- H ), 5.23 (t, 1H, J = 3.1 Hz, OC H ), 4.07 to 3.99 (m, 2H, OCHC H ₂ ), 3.87 (s, 3H, OC H ₃ ), 2.53 (s, 3H, COC H ₃ ), 2.01 to 1.62 (m, 6H, OCHC H ₂ C H ₂ C H ₂ )

Example  1-6: 6-hydroxy-7- Methoxy -4-oxo-4H- Croman -2- Carboxylic acid  Ethyl ester ( KAL -1060)

Sodium (1.10 g, 47.8 mmole) was added to ethanol (50 mL) to form a sodium ethoxide solution, then 1- [2-hydroxy-4-methoxy-5- (tetrahydropyran-2-yloxy) -phenyl ] -Ethanone (KAL-1023) (2.5 g, 9.39 mmole) and oxalic acid diethyl ester (4.10 g, 28.1 mmole) were slowly added and reacted under a nitrogen stream for 2 hours. After the reaction was cooled to 20 ℃ and concentrated under reduced pressure and extracted with water (30 mL) and dichloromethane (50 mL). The extracted solvent was dried over anhydrous sodium sulfate, and the solid obtained by concentrating under reduced pressure was dissolved in ethanol (80 mL), and then c -hydrochloric acid (1 mL) was added, followed by stirring at 20 ° C for 24 hours. After stirring, the solid was filtered using a filter paper, and then dried to obtain a yellow solid.

Yield: 66% 1.64 g

m. p. : 197.7 ℃

IR (KBr): 3175, 1637, 1465, 1265 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.62 (s, 1H, Ar- H ), 7.07 (s, 1H, Ar- H ), 7.05 (s, 1H, COC H ), 4.45 (q, 2H, J = 7.1 Hz, COOC H ₂ CH ₃ ), 4.03 (s, 3H, OC H ₃ ), 1.43 (t, 3H, J = 7.1 Hz, COOCH ₂ C H ₃ )

Example  1-7: 6-hydroxy-7- Methoxy - Croman -2- Carboxylic acid  Preparation of Ethyl Ester (KAL-1061)

6-hydroxy-7-methoxy-4-oxo-4H-chroman-2-carboxylic acid ethyl ester (KAL-1060) (1.90 g, 7.19 mmol) was dissolved in ethanol and placed in a 100 ml round flask and Pd / C ( 120 mg) and acetic acid (2 ml) were added and stirred under a stream of hydrogen for one day. Filtration with Celite removed the solids and the filtrate was concentrated and purified by flash column chromatography (silica gel 230-400 mesh, Merck 9385) to give the product as a brown oil.

Yield: 98%, 1.78 g

IR (KBr): 3230, 1250 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 6.58 (s, 1H, Ar- H ), 6.51 (s, 1H, Ar- H ), 4.62 (d, 1H, J = 8.4 Hz, OC H COO), 4.22 ( q, 2H, J = 7.1 Hz, COOC H ₂ CH ₃ ), 3.83 (s, 3H, OC H ₃ ), 2.76 to 2.66 (m, 2H, OCHCH ₂ C H ₂ ), 2.26 to 2.11 (m, 2H, OCHC H ₂ CH ₂ ), 1.30 (t, 3H, J = 7.1 Hz, COOCH ₂ C H ₃ )

Example  1-8: 6-hydroxy-7- Methoxy - Croman -2- Carboxylic acid  ( KAL -1071)

In a 25 ml round flask, chromoman-2-carboxylic acid ethyl ester (KAL-1061) (1.80 g, 7.41 mmol) was dissolved in water (10 mL) and potassium hydroxide (1.60 g, 28.5 mmol) was added. Stirred. After stirring, 1N hydrochloric acid was added to make the pH neutral, and extracted with ethyl acetate. The solvent was concentrated under reduced pressure and then purified by flash column chromatography (silica gel 230-400 mesh, Merck 9385).

Yield: 99%, 1.59 g

m. p. : 158.2 ℃

IR (KBr): 3458, 1717, 1514, 1203 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 6.61 (s, 1H, Ar- H ), 6.49 (s, 1H, Ar- H ), 4.66 (d, 1H, J = 8.9 Hz, OC H COO), 3.84 ( , 3H, OC H ₃ ), 2.76 to 2.66 (m, 2H, OCHCH ₂ C H ₂ ), 2.26 to 2.11 (m, 2H, OCHC H ₂ CH ₂ )

Example 2 Chroman - 2 - carboxylic Acid Preparation of phenylamide (KAL -1201)

Chromman-2-carboxylic acid (WAL-1004) (110 mg, 0.533 mmol) was added to a 50 ml round flask and dissolved with 10 ml of anhydrous tetrahydrofuran, followed by N, N-carbonyldiimidazole (151 mg 0.931 mmol). After the reaction at 20 ° C. for 1 hour, phenylamine (87.6 mg, 0.941 mmol) was added thereto, and the mixture was stirred at 20 ° C. and nitrogen stream for 12 hours. After concentration under reduced pressure the reaction is complete, stirring, into water N 1 - was extracted by using hydrochloric acid and then with an appropriate pH 3 to 4, dichloromethane. Water was removed with Na ₂ SO ₄ , concentrated under reduced pressure, and purified by flash column chromatography (silica gel 230-400 mesh, Merck 9385) to obtain the derivative KAL -1201 .

Yield: 96% 130 mg

m. p. : 100 to 102 ° C

IR (KBr): 3256, 1667, 1112, 749 cm ^-1

1 H NMR (CDCl 3, 300 MHz) d 7.65 (d, 2H, J = 7.78 Hz, Ar- H ), 7.35 (t, 2H, J = 7.88 Hz, Ar- H ), 7.17 (d, 1H, J = 7.27 Hz, Ar- H ), 7.13 (t, 2H, J = 6.48 Hz, Ar- H ), 7.01 (d, 1H, J = 7.99 Hz, Ar- H ), 6.87 (t, 1H, J = 7.35 Hz, Ar- H ), 4.68 (d, 1H, J = 7.11 Hz, O CH CH ₂ CH ₂ ), 2.80 (m, 2H, OCHCH ₂ C H ₂ ), 2.30 (m, 2H, OCHC H ₂ CH ₂ )

Amide (KAL -1202) - chroman-2-carboxylic acid (2-hydroxy-phenyl) Example 3

The derivative was carried out in the same manner as in Example 2, except that 92.0 mg (0.843 mmol) of 2-aminophenol was used instead of phenylamine. KAL -1202 was obtained.

Yield: 78%, 118 mg

m. p. : 199 ℃

IR (KBr): 3391.21, 3101.94, 1663.30, 1550.49, 1237.11 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.14 (d, 1H, J = 23.7 Hz, Ar- H ), 7.09 (d, 1H, J = 7.71 Hz, Ar- H ), 7.08 (t, 1H, J = 7.71 Hz, Ar- H ), 7.05 (d, 1H, J = 3.28 Hz, Ar- H ), 7.04 (t, 1H, J = 3.74 Hz, Ar- H ), 6.96 (d, 1H, J = 7.72 Hz , Ar- H ), 6.88 (t, 1H, J = 8.43 Hz, Ar- H ), 6.82 (t, 1H, J = 7.88 Hz, Ar- H ), 4.64 (d, 1H, J = 7.51 Hz, OC H CH ₂ CH ₂ ), 2.83 (m, 2H, OCHCH ₂ C H ₂ ), 2.45 to 2.07 (m, 2H, OCHC H ₂ CH ₂ )

Example  4: Croman -2- Carboxylic acid  (3-hydroxy- Phenyl )- Amide  ( KAL Preparation of

The derivative KAL- 1203 was obtained in the same manner as in Example 2 except that 92.0 mg (0.843 mmol) of 3-aminophenol was used instead of phenylamine.

Yield: 86%, 131 mg

m. p. : 175 ℃

IR (KBr): 3200.29, 2923.56, 1551.45, 1223.61 cm ^-1

1 H NMR (CDCl 3, 300 MHz) d 7.23 (s, 1H, Ar- H ), 7.19 (d, 1H, J = 7.96 Hz, Ar- H ), 7.12 (t, 1H, J = 8.19 Hz, Ar- H ), 6.98 (t, 1H, J = 4.30 Hz, Ar- H ), 6.97 (d, 1H, J = 5.44 Hz, Ar- H ), 6.76 (d, 1H, J = 7.88 Hz, Ar- H ), 6.67 (t, 1H, J = 4.97 Hz, Ar- H ), 6.62 (d, 1H, J = 3.25 Hz, Ar- H ), 4.70 (d, 1H, J = 4.6 Hz, OC H CH ₂ CH ₂ ) , 2.97 to 2.84 (m, 2H, OCHCH ₂ C H ₂ ), 2.54 to 2.11 (m, 2H, OCHC H ₂ CH ₂ )

The crude amide (KAL -1204) - chroman-2-carboxylic acid (4-hydroxy-phenyl) Example 5

Derivatives were carried out in the same manner as in Example 2, except that 38.0 mg (0.348 mmol) of 4-aminophenol was used instead of phenylamine. Obtained KAL -1204

Yield: 87%, 54 mg

m. p. : 165 ℃

IR (KBr): 3255.25, 2923.56, 1661.37, 1568.81, 1230.36 cm ^-1

H NMR (CDCl 3, 300 MHz) d 7.46 (d, 2H, J = 8.86 Hz, Ar- H ), 7.19 (d, 1H, J = 7.14 Hz, Ar- H ), 7.12 (t, 1H, J = 6.90 Hz, Ar- H ), 6.97 (d, 1H, J = 2.73 Hz, Ar- H ), 6.93 (t, 1H, J = 4.98 Hz, Ar- H ), 6.84 (d, 2H, J = 8.82 Hz, Ar- H ), 4.63 (m, 1H, J = 4.21 Hz, OC H CH ₂ CH ₂ ), 2.89 (m, 2H, OCHCH ₂ C H ₂ ), 2.51 to 2.11 (m, 2H, OCHC H ₂ CH ₂ )

Amide (KAL -1205) - chroman-2-carboxylic acid (2-methoxy-phenyl) Example 6

The derivative KAL- 1205 was obtained in the same manner as in Example 2 except for using 89.6 mg (0.728 mmol) of 2-methoxyphenylamine instead of phenylamine.

Yield: 87%, 138 mg

m. p. : 90 ℃

IR (KBr): 3362, 1678, 1538, 1230 cm ^-1

1 H NMR (CDCl ₃ .300 MHz) d 8.42 (d, 1H, J = 7.89 Hz, Ar- H ), 7.18 (t, 1H, J = 7.57 Hz, Ar- H ), 7.10 (d, 1H, J = 9.25 Hz, Ar- H ), 7.08 (t, 1H, J = 7.00 Hz, Ar- H ), 6.99 (d, 1H, J = 7.82 Hz, Ar- H ), 6.98 (t, 1H, J = 7.28 Hz , Ar- H ), 6.92 (d, 1H, J = 7.94 Hz, Ar- H ), 6.90 (d, 1H, J = 8.01 Hz, Ar- H ), 4.63 (d, 1H, J = 9.24 Hz, OC H CH ₂ CH ₂ ), 3.87 (s, 3H, OC H ₃ ), 2.98 to 2.78 (m, 2H, OCHCH ₂ C H ₂ ), 2.54 to 2.05 (m, 2H, OCHC H ₂ CH ₂ )

Amide (KAL -1206) - chroman-2-carboxylic acid (3-methoxy-phenyl) Example 7

The derivative KAL- 1206 was obtained in the same manner as in Example 2 except for using 89.6 mg (0.728 mmol) of 3-methoxyphenylamine instead of phenylamine.

Yield: 93%, 147 mg

m. p. : 82 ℃

IR (KBr): 3402, 1698, 1532, 1218 cm ^-1

1 H NMR (CDCl ₃ .300 MHz) d 7.38 (s, 1H, Ar- H ), 7.26 (d, 1H, J = 5.12 Hz, Ar- H ), 7.18 (t, 1H, J = 7.3 Hz, Ar- H ), 7.10 (t, 1H, J = 7.23 Hz, Ar- H ), 7.06 (d, 1H, J = 7.6 Hz, Ar- H ), 6.98 (d, 1H, J = 7.41 Hz, Ar- H ) , 6.95 (t, 1H, J = 7.26 Hz, Ar- H ), 6.95 (t, 1H, J = 7.26 Hz, Ar- H ), 6.71 (d, 1H, J = 8.18 Hz, Ar- H ), 4.64 (d, 1H, J = 9.73 Hz, OC H CH ₂ CH ₂ ), 3.83 (s, 3H, OC H ₃ ), 2.97 to 2.81 (m, 2H, OCHCH ₂ C H ₂ ), 2.56 to 2.05 (m, 2H, OCHC H ₂ CH ₂ )

Amide (KAL -1207) - chroman-2-carboxylic acid (4-methoxy-phenyl) Example 8

The derivative KAL - 1207 was obtained in the same manner as in Example 2 except that 176 mg (1.43 mmol) of 4-methoxyphenylamine was used instead of phenylamine.

Yield: 89.6%, 242 mg

m. p. : 97 ℃

IR (KBr): 3255, 1662, 1513, 1233 cm ^-1

1 H NMR (CDCl ₃ .300 MHz) d 7.50 (d, 2H, J = 8.96 Hz, Ar- H ), 7.17 (t, 1H, J = 7.77 Hz, Ar- H ), 7.11 (d, 1H, J = 7.4 Hz, Ar- H ), 6.97 (d, 1H, J = 4.7 Hz, Ar- H ), 6.95 (t, 1H, J = 3.64 Hz, Ar- H ), 6.89 (d, 2H, J = 9.03 Hz , Ar- H ), 4.63 (d, 1H, J = 9.77 Hz, OC H CH ₂ CH ₂ ), 3.81 (s, 3H, OC H ₃ ), 3.00-2.77 (m, 2H, OCHCH ₂ C H ₂ ) , 2.56 to 2.05 (m, 2H, OCHC H ₂ CH ₂ )

Example 9 Chromane -2- carboxylic Acid Ortho-tolyl Preparation of amide (WAL -1031)

The derivative WAL - 1031 was obtained in the same manner as in Example 2 except that 79.0 mg (0.737 mmol) of ortho-tolylamine was used instead of phenylamine.

Yield: 67%, 100 mg

m. p. : 101 ℃

IR (KBr): 3415, 1679, 1458, 1126 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 8.0 (d, 1H, J = 8.1 Hz.Ar- H ), 8.23 (d, 1H, J = 4.9 Hz, Ar- H ), 7.15 (t, 2H, J = 8.2 Hz, Ar- H ), 7.1 (t, 2H, J = 5.5 Hz, Ar- H ), 6.96 (d, 2H, J = 8.0 Hz, Ar- H ), 4.55 (d, 1H, J = 4.6 Hz , OC H ), 2.9 (m, 2H, OCHCH ₂ C H ₂ ) 2.30 (m, 2H, OCHC H ₂ ), 2.2 (s, 1H, Ar-C H ₃ )

Example 10 Chromman -2- carboxylic Acid Preparation of Meta - tolylamide ( WAL- 1032)

The derivative WAL- 1032 was obtained in the same manner as in Example 2 except for using 79.0 mg (0.737 mmol) of meta-tolylamine instead of phenylamine.

Yield: 81%, 120 mg

m. p. : 95 ℃

IR (KBr): 3311, 1668, 1593, 1230 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.50 (d, 2H, J = 8.31 Hz, Ar- H ), 7.20 (t, 1H, J = 8.0 Hz, Ar- H ) 7.18 (d, 2H, J = 7.89 Hz, Ar- H ), 7.10 (d, 1H, J = 7.07 Hz, Ar- H ), 6.75 (t, 1H, J = 5.03 Hz, Ar- H ), 6.70 (d, 1H, J = 6.9 Hz, Ar- H), 4.67 (d, 1H, J = 6.72 Hz, O CH), 2.85 (m, 2H, OCHCH 2 C H 2), 2.47 (s, 1H, Ar-C H 3), 2.21 (m, 2H, OCHC H ₂ )

Preparation of tolylamide (WAL -1029) - chroman-2-carboxylic acid p-: Example 11

The derivative WAL- 1029 was obtained in the same manner as in Example 2 except for using 163 mg (1.52 mmol) of para-tolylamine instead of phenylamine.

Yield: 6.4%, 20 mg

m. p. : 104 ℃

IR (KBr): 3249, 1672, 1495, 1230 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.45 (s, 1H, Ar- H ), 7.37 (d, 2H, J = 7.20 Hz, Ar- H ), 7.25 (t, 1H, J = 8.21 Hz, Ar- H ), 7.18 (d, 1H, J = 7.48 Hz, Ar- H ), 7.10 (d, 1H, J = 7.37 Hz, Ar- H ), 6.95 (t, 2H, J = 7.25 Hz, Ar- H ) , 4.62 (d, 1H, J = 9.63 Hz, O CH ), 2.85 (m, 2H OCHCH ₂ C H ₂ ), 2.30 (d, 3H, Ar-C H ₃ ), 2.13 (m, 2H, OCHC H ₂ )

Example 12: chroman-2-carboxylic acid (3-trifluoromethyl-phenyl) - amide (WAL-1037)

Derivative WAL - 1037 was obtained in the same manner as in Example 2 except for using 118 mg (0.732 mmol) of 3-trifluoromethylphenylamine instead of phenylamine.

Yield: 78%, 140 mg

m. p. : 65 ℃

IR (KBr): 3335, 1673, 1532, 1224 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.92 (s, 1H, Ar- H ), 7.82 (d, 1H, J = 7.99 Hz, Ar- H ), 7.48 (t, 1H, J = 7.80 Hz, Ar- H ), 7.40 (d, 1H, J = 8.89 Hz, Ar- H ), 7.19 (t, 1H, J = 7.60 Hz, Ar- H ), 7.1 (d, 1H, J = 6.75 Hz, Ar- H ) , 6.98 (d, 1H, J = 5.19 Hz, Ar- H ), 6.97 (d, 1H, J = 6.38 Hz, Ar- H ), 6.87 (t, 1H, J = 7.30 Hz, Ar- H ), 4.62 (d, 1H, J = 6.07 Hz, OC H ), 2.80 (m, 2H, OCHCH ₂ C H ₂ ), 2.2 (m, 2H, OCHC H ₂ )

Example 13: Preparation of chroman-2-carboxylic acid (4-trifluoromethyl-phenyl) - amide (WAL-1043)

The derivative WAL- 1043 was obtained in the same manner as in Example 2 except for using 118 mg (0.732 mmol) of 4-trifluoromethylphenylamine in place of phenylamine.

Yield: 67%, 120 mg

m. p. : 80 ℃

IR (KBr): 3329, 1748, 1519, 1117 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.80 (d, 2H, J = 8.47 Hz, Ar- H ), 7.62 (d, 2H, J = 8.48 Hz, Ar- H ), 7.20 (t, 1H, J = 8.83 Hz, Ar- H ), 7.10 (d, 1H, J = 6.69 Hz, Ar- H ), 7.05 (d, 1H, J = 6.75 Hz, Ar- H ), 7.0 (d, 1H, J = 4.93 Hz , Ar- H ), 6.87 (t, 1H, J = 7.25 Hz, Ar- H ), 4.65 (d, 1H, J = 7.17 Hz, O CH ), 8.58 (m, 2H, OCHCH ₂ C H ₂ ) 2.28 (m, 2H, OCHC H ₂ )

Amide (WAL -1201) - chroman-2-carboxylic acid (3-chlorophenyl): Example 14

The derivative WAL - 1201 was obtained in the same manner as in Example 2 except that 96.6 mg (0.757 mmol) of 3-chlorophenylamine was used instead of phenylamine.

Yield: 51%, 74 mg

m. p. : 94 ℃

IR (KBr): 3322, 1676, 1538, 1236 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 8.31 (s, 1H, Ar- H ), 7.37 (d, 1H, J = 7.78 Hz, Ar- H ), 7.18 (t, 1H, J = 8.04 Hz, Ar- H ), 7.11 (d, 1H, J = 8.01 Hz, Ar- H ), 7.03 (t, 1H, J = 5.93 Hz, Ar- H ), 7.02 (d, 1H, J = 6.56 Hz, Ar- H ) , 6.89 (d, 1H, J = 8.24 Hz, Ar- H), 6.86 (t, 1H, J = 7.37 Hz, Ar- H), 4.54 (d, 1H, J = 9.75 Hz, O CH), 2.91 to 2.70 (m, 2H, OCHCH ₂ C H ₂ ) 2.46 to 1.98 (m, 2H, OCHC H ₂ )

Example 15: chroman-2-carboxylic acid (4-chloro-phenyl) amide (WAL -1202)

The derivative WAL -1202 was obtained in the same manner as in Example 2 except for using 86.8 mg (0.680 mmol) of 4-chlorophenylamine instead of phenylamine.

Yield: 61%, 80 mg

m. p. : 100 ℃

IR (KBr): 3322, 1673, 1532, 1224 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.49 (d, 2H, J = 8.69 Hz, Ar- H ), 7.24 (d, 2H, J = 8.69 Hz, Ar- H ), 7.10 (t, 1H, J = 7.67 Hz, Ar- H ), 7.03 (d, 1H, J = 7.28 Hz, Ar- H ), 6.89 (d, 1H, J = 9.09 Hz, Ar- H ), 6.87 (t, 1H, J = 8.28 Hz , Ar- H ), 4.55 (d, 1H, J = 9.79 Hz, OC H ), 2.92 to 2.71 (m, 2H, OCHCH ₂ C H ₂ ) 2.48 to 1.96 (m, 2H, OCHC H ₂ )

Example 16: chroman-2-carboxylic acid (3-nitro-phenyl) amide (WAL -1036)

The derivative WAL- 1036 was obtained in the same manner as in Example 2 except that 100 mg (0.724 mmol) of 3-nitrophenylamine was used instead of phenylamine.

Yield: 94%, 157 mg

m. p. : 142 ℃

IR (KBr): 3316, 1679, 1532, 1488 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 8.25 (s, 1H, Ar- H ), 8.10 (t, 2H, J = 4.45 Hz, Ar- H ), 7.54 (t, 1H, J = 8.22 Hz, Ar- H ), 7.20 (d, 1H, J = 7.43 Hz, Ar- H ), 7.15 (d, 1H, J = 7.09 Hz, Ar- H ), 7.0 (d, 1H, J = 7.61 Hz, Ar- H ) , 6.82 (d, 1H, J = 7.33 Hz, Ar- H ), 4.75 (d, 1H, J = 7.24 Hz, O CH ), 2.75 (m, 2H, OCHCH ₂ C H ₂ ), 2.25 (m, 2H , OCHC H ₂ )

Amide (WAL -1041) - chroman-2-carboxylic acid (4-nitrophenyl): Example 17

A derivative WAL - 1041 was obtained in the same manner as in Example 2 except that 100 mg (0.724 mmol) of 4-nitrophenylamine was used instead of phenylamine.

Yield: 42%, 70 mg

m. p. : 181 ℃

IR (KBr): 3440, 1698, 1538, 1329 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 8.40 (d, 2H, J = 9.04 Hz, Ar- H ), 7.80 (d, 2H, J = 9.05 Hz, Ar- H ), 7.30 (t, 1H, J = 8.50 Hz, Ar- H ), 7.0 (d, 1H, J = 7.92 Hz, Ar- H ), 6.95 (t, 1H, J = 8.35 Hz, Ar- H ) 4.65 (d, 1H, J = 7.20 Hz, O CH ), 3.0 (m, 2H, OCHCH ₂ C H ₂ ), 2.22 (m, 2H, OCHC H ₂ )

Example 18 Preparation of 6-hydroxy-7 -methoxy - chroman - 2- carboxylic acid (2-hydroxy-phenyl) -amide ( KAL- 1119)

6-hydroxy-7-methoxy-chroman-2-carboxylic acid ( KAL -1071 ) (300 mg, 1.34 mmol) was added to a 50 ml round flask and dissolved in anhydrous tetrahydrofuran (25 mL), followed by N, N-carbonyldiimidazole (325 mg, 2.00 mmol) was added and reacted at 20 ° C. for 1 hour. 2-aminophenol (219 mg, 2.01 mmol) was added to the compound obtained by the reaction, followed by stirring at 20 ° C. and a nitrogen stream. Then, the mixture was concentrated under reduced pressure, water was added, titrated to pH 3 to 4 with 1 N hydrochloric acid, and extracted with dichloromethane. Water was removed with sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (silica gel 230-400 mesh, Merck 9385) to obtain the derivative KAL- 1119 .

Yield: 18%, 77 mg

m. p. : 153.4 ℃

IR (KBr): 3422, 1640, 1515, 1250 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.15 (d, 1H, J = 7.6 Hz, Ar- H ), 7.06 (t, 2H, J = 8.9 Hz, Ar- H ), 6.90 (d, 1H, J = 7.2 Hz, Ar- H ), 6.65 (s, 1H, Ar- H ), 6.52 (s, 1H, Ar- H ), 4.64 (d, 1H, J = 9.8 Hz, OC H ), 3.89 (s, 3H , OC H ₃ ), 2.86 to 2.74 (m, 2H, OCHCH ₂ C H ₂ ), 2.47 to 2.02 (m, 2H, OCHC H ₂ CH ₂ )

Example 19 Preparation of 6-hydroxy-7 -methoxy - chroman -2- carboxylic acid (3-hydroxy-phenyl) -amide ( KAL- 1184)

A derivative KAL- 1184 was obtained in the same manner as in Example 18 except for using 219 mg (2.01 mmol) of 3-aminophenol instead of 2-aminophenol.

Yield: 28%, 120 mg

m. p. : 207.3 ℃

IR (KBr): 3346, 1661, 1511, 1269 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.47 (s, 1H, Ar- H ), 7.20 (t, 1H, J = 8.2 Hz, Ar- H ), 6.92 (d, 1H, J = 7.2 Hz, Ar- H ), 6.66 (d, 1H, J = 8.0 Hz, Ar- H ), 6.64 (s, 1H, Ar- H ), 6.52 (s, 1H, Ar- H ), 4.55 (d, 1H, J = 9.9 Hz, OC H ), 3.89 (s, 3H, OC H ₃ ), 2.84 to 2.72 (m, 2H, OCHCH ₂ C H ₂ ), 2.48 to 2.05 (m, 2H, OCHC H ₂ CH ₂ )

Example 20 Preparation of 6-hydroxy-7 -methoxy - chroman -2- carboxylic acid (4-hydroxy-phenyl) -amide ( KAL- 1135)

The derivative KAL- 1135 was obtained in the same manner as in Example 18 except that 146 mg (1.34 mmol) of 4-aminophenol was used instead of 2-aminophenol.

Yield: 28%, 80 mg

m. p. : 172.3 ℃

IR (KBr): 3375, 1661, 1513, 1195 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.44 (d, 2H, J = 8.8 Hz, Ar- H ), 6.84 (d, 2H, J = 8.3 Hz, Ar- H ), 6.59 (s, 1H, Ar- H ), 6.51 (s, 1H, Ar- H ), 4.55 (d, 1H, J = 9.8 Hz, OC H ), 3.88 (s, 3H, OC H ₃ ), 2.87 to 2.66 (m, 2H, OCHCH ₂ C H ₂ ), 2.48 to 2.04 (m, 2H, OCHC H ₂ CH ₂ )

Example 21 Preparation of 6-hydroxy-7 -methoxy - chroman - 2- carboxylic acid (2-methoxy-phenyl) -amide ( KAL- 1188)

The derivative KAL - 1188 was obtained in the same manner as in Example 18 except for using 247 mg (2.01 mmol) of 2-methoxyphenylamine instead of 2-aminophenol.

Yield: 30%, 132 mg

m. p. : 115.4 ℃

IR (KBr): 3384, 1674, 1509, 1266 cm ^-1

1 H NMR (CD ₃ OD, 300 MHz) d 8.21 (d, 1H, J = 8.0 Hz, Ar- H ), 7.17 (t, 1H, J = 8.2 Hz, Ar- H ), 7.05 (d, 1H, J = 7.7 Hz, Ar- H ), 6.97 (t, 1H, J = 7.5 Hz, Ar- H ), 6.61 (s, 1H, Ar- H ), 6.56 (s, 1H, Ar- H ), 4.65 (d , 1H, J = 8.6 Hz, OC H CO), 3.91 (s, 3H, OC H ₃ ), 3.88 (s, 3H, OC H ₃ ) 2.81 to 2.69 (m, 2H, OCHCH ₂ C H ₂ ), 2.34 To 2.10 (m, 2H, OCHC H ₂ CH ₂ )

Example 22 Preparation of 6-hydroxy-7 -methoxy - chroman -2- carboxylic acid (3-methoxy-phenyl) -amide ( KAL- 1187)

The derivative KAL - 1187 was obtained in the same manner as in Example 18 except for using 247 mg (2.01 mmol) of 3-methoxyphenylamine instead of 2-aminophenol.

Yield: 41%, 180 mg

IR (KBr): 3384, 1673, 1511, 1265 cm ^-1

1 H NMR (CD ₃ OD, 300 MHz) d 7.38 (s, 1H, Ar- H ), 7.24 (t, 1H, J = 7.6 Hz, Ar- H ), 6.90 (d, 1H, J = 6.5 Hz, Ar H ), 6.68 (d, 1H, J = 6.2 Hz, Ar- H ), 6.64 (s, 1H, Ar- H ), 6.53 (s, 1H, Ar- H ), 4.55 (d, 1H, J = 9.9 Hz, OC H ), 3.89 (s, 3H, OC H ₃ ), 3.80 (s, 3H, OC H ₃ ) 2.91 to 2.67 (m, 2H, OCHCH ₂ C H ₂ ), 2.51 to 1.99 (m, 2H , OCHC H ₂ CH ₂ )

Example 23 Preparation of 6-hydroxy-7 -methoxy - chroman -2- carboxylic acid (4-methoxy-phenyl) -amide ( KAL- 1136)

A derivative KAL- 1136 was obtained in the same manner as in Example 18 except for using 165 mg (1.34 mmol) of 4-methoxyphenylamine instead of 2-aminophenol.

Yield: 30%, 89 mg

m. p. : 152.8 ℃

IR (KBr): 3304, 1661, 1513, 1238 cm ^-1

1 H NMR (CDCl ³ , 300 MHz) δ 7.49 (d, 2H, J = 9.0 Hz, Ar- H ), 6.89 (d, 2H, J = 8.9 Hz, Ar- H ), 6.64 (s, 1H, Ar- H ), 6.51 (s, 1H, Ar- H ), 4.54 (d, 1H, J = 4.8 Hz, OC H ), 3.88 (s, 3H, OC H ₃ ), 3.80 (s, 3H, OC H ₃ ) 2.84 to 2.72 (m, 2H, OCHCH ₂ C H ₂ ), 2.47 to 2.03 (m, 2H, OCHC H ₂ CH ₂ )

Example 24 6-hydroxy-7 -methoxy - chroman -2- carboxylic acid Ortho-tolyl Preparation of amide (KAL-1200)

The derivative KAL- 1200 was obtained in the same manner as in Example 18 except for using 215 mg (2.01 mmol) of ortho-tolylamine instead of 2-aminophenol.

Yield: 11%, 47 mg

m. p. : 140.1 ℃

IR (KBr): 3248, 1666, 1515, 1160 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.48 (d, 1H, J = 7.2 Hz, Ar- H ), 7.26 (d, 1H, J = 7.1 Hz, Ar- H ), 7.21 (t, 1H, J = 7.5 Hz, Ar- H ), 7.17 (t, 1H, J = 7.1 Hz, Ar- H ), 6.64 (s, 1H, Ar- H ), 6.56 (s, 1H, Ar- H ), 4.68 (d, 1H, J = 8.8 Hz, OC H ), 3.85 (s, 3H, OC H ₃ ), 2.82 to 2.72 (m, 2H, OCHCH ₂ C H ₂ ), 2.36 to 2.14 (m, 2H, OCHC H ₂ CH ₂ ), 2.20 (s, 3H, Ar-C H ₃ )

Example 25 6-hydroxy-7 -methoxy - chroman -2- carboxylic acid Preparation of Meta - tolylamide (KAL-1196)

The derivative KAL- 1196 was obtained in the same manner as in Example 18 except for using 215 mg (2.01 mmol) of meta-tolylamine instead of 2-aminophenol.

Yield: 24%, 102 mg

m. p. : 146.4 ℃

IR (KBr): 3249, 1671, 1515, 1163 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.46 (s, 1H, Ar- H ), 7.38 (d, 1H, J = 8.0 Hz, Ar- H ), 7.24 (t, 1H, J = 8.2 Hz, Ar- H ), 7.00 (d, 1H, J = 7.4 Hz, Ar- H ), 6.64 (s, 1H, Ar- H ), 6.52 (s, 1H, Ar- H ), 4.55 (d, 1H, J = 9.9 Hz, OC H ), 3.89 (s, 3H, OC H ₃ ), 2.84 to 2.72 (m, 2H, OCHCH ₂ C H ₂ ), 2.50 to 2.02 (m, 2H, OCHC H ₂ CH ₂ ), 2.36 (s , 3H, Ar-C H ₃ )

Example 26 Preparation of 6-hydroxy-7 -methoxy - chroman -2- carboxylic acid para- tolylamide (KAL-1191)

The derivative KAL - 1191 was obtained in the same manner as in Example 18 except for using 215 mg (2.01 mmol) of para-tolylamine instead of 2-aminophenol.

Yield: 19%, 81 mg

m. p. : 169.5 ℃

IR (KBr): 3302, 1668, 1514 cm ^-1

1 H NMR (CD ₃ OD, 300 MHz) d 7.48 (d, 2H, J = 8.4 Hz, Ar- H ), 7.15 (d, 2H, J = 8.4 Hz, Ar- H ), 6.63 (s, 1H, Ar H ), 6.52 (s, 1H, Ar- H ), 4.54 (d, 1H, J = 10 Hz, OC H ), 3.89 (s, 3H, OC H ₃ ), 2.84 to 2.72 (m, 2H, OCHCH ₂ C H ₂ ), 2.50 to 2.02 (m, 2H, OCHC H ₂ CH ₂ ), 2.33 (s, 3H, Ar-C H ₃ )

Example 27 Preparation of 6-hydroxy-7 -methoxy - chroman -2- carboxylic acid (3-trifluoromethyl-phenyl) -amide ( KAL- 1195)

A derivative KAL- 1195 was obtained in the same manner as in Example 18 except for using 323 mg (2.01 mmol) of 3-trifluoromethylamine instead of 2-aminophenol.

Yield: 12%, 61 mg

m. p. : 187.1 ℃

IR (KBr): 3396, 1686, 1513, 1329 cm ^-1

1 H NMR (CD ₃ OD, 300 MHz) d 8.00 (s, 1H, Ar- H ), 7.79 (d, 1H, J = 8.3 Hz, Ar- H ), 7.44 (t, 1H, J = 7.9 Hz, Ar H ), 7.32 (d, 1H, J = 8.4 Hz, Ar- H ), 6.55 (s, 1H, Ar- H ), 6.43 (s, 1H, Ar- H ), 4.47 (d, 1H, J = 10 Hz, OC H ), 3.73 (s, 3H, OC H ₃ ), 2.74 to 2.60 (m, 2H, OCHCH ₂ C H ₂ ), 2.28 to 1.91 (m, 2H, OCHC H ₂ CH ₂ )

Example 28 Preparation of 6-hydroxy-7 -methoxy - chroman -2- carboxylic acid (4-trifluoromethyl-phenyl) -amide ( KAL- 1190)

A derivative KAL -1190 was obtained in the same manner as in Example 18 except that 323 mg (2.01 mmol) of 4-trifluoromethylamine was used instead of 2-aminophenol.

Yield: 27%, 133 mg

m. p. : 160.3 ℃

IR (KBr): 3312, 1685, 1509, 1117 cm ^-1

1 H NMR (CD ₃ OD, 300 MHz) δ 7.89 (d, 2H, J = 8.5 Hz, Ar- H ), 7.67 (d, 2H, J = 8.6 Hz, Ar- H ), 6.66 (s, 1H, Ar H ), 6.56 (s, 1H, Ar- H ), 4.59 (d, 1H, J = 10 Hz, OC H ), 3.86 (s, 3H, OC H ₃ ), 2.88 to 2.69 (m, 2H, OCHCH ₂ C H ₂ ), 2.42 to 2.04 (m, 2H, OCHC H ₂ CH ₂ )

Example 29 Preparation of 6-hydroxy-7 -methoxy - chroman - 2- carboxylic acid (2-chloro-phenyl) -amide ( KAL- 1198)

The derivative KAL - 1198 was obtained in the same manner as in Example 18 except that 128 mg (1.00 mmol) of 2-chlorophenylamine was used instead of 2-aminophenol.

Yield: 13%, 30 mg

m. p. : 148.5 ℃

IR (KBr): 3378, 1698, 1513, 1273 cm ^-1

1 H NMR (CD3OD, 300 MHz) d 8.14 (d, 1H, J = 8.2 Hz, Ar- H ), 7.50 (d, 1H, J = 8.1 Hz, Ar- H ), 7.36 (t, 1H, J = 7.8 Hz, Ar- H ), 7.20 (t, 1H, J = 7.8 Hz, Ar- H ), 6.61 (s, 1H, Ar- H ), 6.56 (s, 1H, Ar- H ), 4.70 (d, 1H , J = 8.9 Hz, OC H ), 3.85 (s, 3H, OC H ₃ ), 2.82 to 2.73 (m, 2H, OCHCH ₂ C H ₂ ), 2.36 to 2.10 (m, 2H, OCHC H ₂ CH ₂ )

Example 30 Preparation of 6-hydroxy-7 -methoxy - chroman -2- carboxylic acid (3-chloro-phenyl) -amide ( KAL- 1194)

The derivative KAL- 1194 was obtained in the same manner as in Example 18 except that 256 mg (2.01 mmol) of 3-chlorophenylamine was used instead of 2-aminophenol.

Yield: 17%, 78 mg

m. p. : 143.5 ℃

IR (KBr): 3288, 1514, 1198 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.54 (s, 1H, Ar- H ), 7.30 (d, 1H, J = 8.1 Hz, Ar- H ), 7.10 (t, 1H, J = 8.1 Hz, Ar- H ), 6.94 (d, 1H, J = 8.0 Hz, Ar- H ), 6.47 (s, 1H, Ar- H ), 6.34 (s, 1H, Ar- H ), 4.37 (d, 1H, J = 10 Hz, OC H ), 3.71 (s, 3H, OC H ₃ ), 2.67 to 2.55 (m, 2H, OCHCH ₂ C H ₂ ), 2.32 to 1.83 (m, 2H, OCHC H ₂ CH ₂ )

Example 31 Preparation of 6-hydroxy-7 -methoxy - chroman -2- carboxylic acid (4-chloro-phenyl) -amide ( KAL- 1120)

The derivative KAL- 1120 was obtained in the same manner as in Example 18 except that 256 mg (2.01 mmol) of 4-chlorophenylamine was used instead of 2-aminophenol.

Yield: 20%, 88 mg

m. p. : 131.1 ℃

IR (KBr): 3324, 1678, 1508, 1166 cm ^-1

1 H NMR (CDCl ₃ , 300 MHz) d 7.56 (d, 2H, J = 8.7 Hz, Ar- H ), 7.31 (d, 2H, J = 8.7 Hz, Ar- H ), 6.64 (s, 1H, Ar- H ), 6.51 (s, 1H, Ar- H ), 4.54 (d, 1H, J = 9.9 Hz, OC H ), 3.88 (s, 3H, OC H ₃ ), 2.85 to 2.73 (m, 2H, OCHCH ₂ C H ₂ ), 2.49 to 2.01 (m, 2H, OCHC H ₂ CH ₂ )

Example  32: NF Inhibitory Effect on -κB Activation

As described below for the biological efficacy of the target compound obtained from the preparation method, the inhibitory effect of NF-κB was measured through Test Example 1, and was calculated as a concentration (IC ₅₀ ) showing a 50% inhibitory effect accordingly.

Macrophage with pNF-κB-SEAP-NPT (Moon, KY et al., Anal. Biochem. 292; 17-21 (2001)), a plasmid capable of detecting expression of reporter genes dependent on NF-κB activation Samples were pretreated to RAW264.7 cells (TIB-71, American Type Culture Collection (ATCC)) for 2 hours and stimulated for 24 hours using glycolipid (LPS, 1 ug / ml). The amount of secreted alkaline phosphatase (SEAP) produced in conjunction with the activation of NF-κB was determined using the supernatant obtained by centrifugation of the cell culture medium after the stimulation was terminated with a relative fluoresecnce unit (RFU). (Moon, KY et al., Anal. Biochem. 292; 17-21 (2001)). As shown in Table 2, the effect of the sample was calculated as the concentration (IC ₅₀ ) showing a 50% inhibitory effect.

No. IC ₅₀ (μM) KAL-1201 8.2 KAL-1202 > 100 KAL-1203 21.5 KAL-1204 18.3 KAL-1205 27.8 KAL-1206 23.8 KAL-1207 16.8 WAL-1031 18.3 WAL-1032 16.3 WAL-1029 18.8 WAL-1037 18.4 WAL-1043 10.5 WAL-1201 16.8 WAL-1202 3.2 WAL-1036 20.4 WAL-1041 16.4 KAL-1119 21.8 KAL-1184 > 100 KAL-1135 > 100 KAL-1188 43.9 KAL-1187 > 100 KAL-1136 > 100 KAL-1200 > 100 KAL-1196 48.7 KAL-1191 32.0 KAL-1195 10.9 KAL-1190 52.0 KAL-1198 62.0 KAL-1194 21.1 KAL-1120 6.0

The novel Chromann derivative compound of the present invention and the pharmaceutical composition containing the same act as an inhibitor of NF-kB, and at least one disease selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer, which is a disease associated with NF-κB. It relates to a composition for the prophylaxis or treatment of.

Claims (12)

Chromman-2-carboxylic acid amide derivative having the structure of Formula 1-a or Formula 1-b or a pharmaceutically acceptable salt thereof: (Formula 1-a)

Wherein R1, R2, R3, R4 and R5 may be the same or different from each other and are independently H, hydroxy, alkoxy having C1 to C4, alkyl having C1 to C4, trifluoromethyl, halogen or nitro group. (Formula 1-b)

Wherein R1, R2, R3, R4 and R5 may be the same or different from each other and are independently H, hydroxy, alkoxy having C1 to C4, alkyl having C1 to C4, trifluoromethyl, halogen or nitro group. However, all of R1 to R5 are H, R1 and R3 to R5 are H, R2 is a nitro group, R1 to R3 and R5 are H, and R4 is a nitro group. The method of claim 1, The chroman-2-carboxylic acid amide derivative Chromman-2-carboxylic acid phenylamide, chroman-2-carboxylic acid (2-hydroxy-phenyl) -amide, chroman-2-carboxylic acid (3-hydroxy-phenyl) -amide, chroman-2-carboxylic acid ( 4-hydroxy-phenyl) -amide, chroman-2-carboxylic acid (2-methoxy-phenyl) -amide, chroman-2-carboxylic acid (3-methoxy-phenyl) -amide, chroman-2-carboxylic acid (4-methoxy-phenyl) -amide, chroman-2-carboxylic acid ortho-tolylamide, chroman-2-carboxylic acid meta-tolylamide, chroman-2-carboxylic acid para-tolylamide, chroman-2- Carboxylic Acid (3-Trifluoromethyl-phenyl) -amide, Chroman-2-carboxylic Acid (4-Trifluoromethyl-phenyl) -amide, Chroman-2-carboxylic Acid (3-Chloro-phenyl) -amide, Chromate Mann-2-carboxylic acid (4-chloro-phenyl) -amide, chromman-2-carboxylic acid (3-nitro-phenyl) -amide, chroman-2-carboxylic acid (4-nitro-phenyl) -amide, 6-hydride Roxy-7-methoxy-Chroman 2-carboxylic acid (2-hydroxy-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid (3-hydroxy-phenyl) -amide, 6-hydroxy-7-meth Methoxy-chroman-2-carboxylic acid (4-hydroxy-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-carboxylic acid (2-methoxy-phenyl) -amide, 6-hydroxy -7-methoxy-chroman-2-carboxylic acid (3-methoxy-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-carboxylic acid (4-methoxy-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid ortho-tolylamide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid meta-tolylamide, 6-hydroxy-7- Methoxy-chroman-2-carboxylic acid para-tolylamide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid (3-trifluoromethyl-phenyl) -amide, 6-hydroxy-7- Methoxy-chroman-2-carboxylic acid (4-trifluoromethyl-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-carboxylic acid (2-chloro Rho-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid (3-chloro-phenyl) -amide, 6-hydroxy-7-methoxy-chroman-2-carboxylic acid ( 4-chloro-phenyl) -amide selected from the group consisting of Chromman-2-carboxylic acid amide derivative or a pharmaceutically acceptable salt thereof. (a) treating 2-hydroxyacetonephenone and oxalic acid diester under base and acid treatment to prepare a compound of formula 2-a; (b) subjecting the compound of Formula 2-a to catalytic reduction under an ethanol-acetic acid solvent and a Pd / C catalyst to prepare a compound of Formula 3-a; (c) treating the compound of Formula 3-a with potassium hydroxide to prepare a hydrolyzed compound of Formula 4-a; And (d) treating the compound of Formula 4-a with an amine compound to prepare a chroman-2-carboxylic acid amide derivative of Formula 1-a of claim 1; Method for producing a chroman-2-carboxylic acid amide derivative, comprising a. [Formula 2-a]

[Formula 3-a]

[Formula 4-a]

The amine compound of claim 3, wherein the amine compound is any one selected from the group consisting of phenylamine, aminophenyl, methoxyphenylamine, tolylamine, trifluoromethylphenylami, chlorophenylamine, and nitrophenylamine. Process for the preparation of carboxylic acid amide derivatives. (a) subjecting methoxyhydroquinone and acetic acid to a Friedel-Crafts acylation reaction under a zinc chloride catalyst to prepare a compound of formula 2-b; (b) preparing a compound of formula 2-b, wherein the compound of formula 2-b and dihydropyran (DHP) are protected with a hydroxy group under a pyridium paratoluenesulfonate (PPTs) catalyst; (c) reacting the compound of Formula 3-b with diethyl ester of oxalate under a base and acid-treated to prepare a compound of Formula 4-b, which is cyclized; (d) subjecting the compound of Formula 4-b to catalytic reduction under an ethanol-acetic acid solvent and a Pd / C catalyst to prepare a compound of Formula 5-b; (e) treating the compound of Formula 5-b with potassium hydroxide to prepare a hydrolyzed compound of Formula 6-b; And (f) treating the compound represented by Chemical Formula 6-b with an amine compound to prepare a chromaman-2-carboxylic acid amide derivative represented by Chemical Formula 1-b according to claim 1; Method for producing a chroman-2-carboxylic acid amide derivative, comprising a. [Formula 2-b]

[Formula 3-b]

[Formula 4-b]

[Formula 5-b]

[Formula 6-b]

The amine compound of claim 5, wherein the amine compound is any one selected from the group consisting of phenylamine, aminophenyl, methoxyphenylamine, tolylamine, trifluoromethylphenylamido, chlorophenylamine and nitrophenylamine. Process for the preparation of carboxylic acid amide derivatives. delete A composition for the prophylaxis or treatment of multiple myeloma comprising the chromoman-2-carboxylic acid amide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. A composition for the prophylaxis or treatment of rheumatoid arthritis comprising the chromoman-2-carboxylic acid amide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier A composition for the prophylaxis or treatment of cancer comprising the chromman-2-carboxylic acid amide derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. Prevention of any one or more diseases selected from the group consisting of multiple myeloma, rheumatoid arthritis and cancer, wherein the content of the chromman-2-carboxylic acid amide derivative of claim 1 or a pharmaceutically acceptable salt thereof is 0.1 to 99% by weight based on the total composition; or Therapeutic composition. The method according to any one of claims 8 to 11, The composition is a formulation selected from the group consisting of a warning agent, granules, rochers, powders, syrups, liquids, aerosols, ointments, liquid extracts, emulsions, suspensions, immersions, tablets, injections, capsules and pills , Multiple myeloma, rheumatoid arthritis and cancer for the prevention or treatment of any one or more diseases selected from the group consisting of.