KR101693033B1 - Novel Chlorogenic Acid Derivatives and Composition for Treating Inflammatory Disease Comprising the Same - Google Patents

Abstract

The present invention relates to a novel chlorogenic acid derivative compound having an anti-inflammatory activity and an anti-inflammatory composition comprising it as an active ingredient. The chlorogenic acid derivative compounds of the present invention inhibit the overproduction of nitric oxide (NO) induced by treatment in macrophages to LPS. The chlorogenic acid derivative compounds of the present invention inhibit the activation of NF-κB, an important signal transduction mediator, in oxidative stress and inflammation-promoting pathways. The chlorogenic acid derivative compound of the present invention is highly likely to be developed as a therapeutic agent for various inflammatory diseases by inhibiting nitric oxide and production and activation of NF-κB.

Description

TECHNICAL FIELD The present invention relates to a novel chlorogenic acid derivative and a composition for treating inflammatory diseases comprising the same as an effective ingredient.

The present invention relates to a novel chlorogenic acid derivative and a composition for treating an inflammatory disease comprising the same as an effective ingredient.

Lipopolysaccharide (LPS), a lipid-polysaccharide complex compound, is an endotoxin O-antigen found in the cell wall of gram negative bacteria, bacterial LPS is typically a lipid A (endotoxin), a non- Saccharide, and polysaccharide (O-antigen). The lipid moiety (lipid A) complexes with the core polysaccharide moiety through a glucoside bond. The core moiety is linked to an O-chain polysaccharide having a high degree of immunogenicity and variability consisting of a repeated oligosaccharide unit, i.e., the O-antigen site, which is the third external site. The last part of the LPS molecule acts as a bacterial serogroup-specific function to activate multiple transcription factors. The most important finding is the fact that the plasma membrane protein TLR4 acts as a lipid A signaling receptor in animal cells. TLR4 belongs to the congenital immunoreceptor family. The recognition of LPS by TLR4 induces MyD88-dependent activation of NF-κB (nuclear factor-kappa B) and mitogen-activated protein kinase (MAPK), both proinflammatory transcription factors.

Nitric oxide (NO) is an important intracellular and intercellular signaling molecule involved in the regulation of various physiological mechanisms in the immune system. NO reacts with superoxide (O2) to generate peroxynitrite ions, and the resulting ions induce excessive inflammatory activity and cause septicemia, ulcerative colitis, arthritis, (SLE), and Sjogren's syndrome (SS) (2-4). Reactive oxygen species (ROS) and nitric oxide (NO) NO) plays a crucial physiological role as an intermediate mediator of the signal transduction process, but excessive production of endogenous and / or exogenous ROS and NO is implicated in the pathogenesis of inflammatory diseases and cancer NF- is activated by extracellular signals such as tumor necrosis factor alpha, interleukin-1, lipopolysaccharide (LPS), ultraviolet light, reactive oxygen species (ROS) and phorbol esters (Israel et al., 1989; Michie NF-κB, a redox-sensitive transcription factor, can be activated by oxidative stress and inflammatory mediators. When NF-κB is activated , IκB is phosphorylated by IκB kinase (IKK) complex and IκB is ubiquitinated and degraded (Hacker and Karin, 2006; Hayden and Ghosh, 2004). Free NF-κB isolated from IκB migrates to the nucleus NF-κB is involved in the pathogenesis of chronic inflammatory diseases and various cancers of the human body (Perkins, 2007; Yamamoto and Gaynor, 2001), and transcription of genes involved in cell growth regulation, apoptosis, immune response, inflammation and cancer in the nucleus (Makarov, 2000; Mayo and Baldwin, 2000; Rayet and Gelinas, 1999). Thus, inhibitors of NF-κB function are expected to be useful as anti-inflammatory and anti-cancer agents. Gravinol, a proanthocyanidin isolated from grape seeds, is a potent antioxidant and has anti-inflammatory activity through NF-κB inhibition in hyperglucose-induced renal tubular epithelial cells [2,3]. Bioflavonoids Antioxidants, especially pycnogenol, reduce inflammation through inhibition of NF-κB activity [4]. Curcumin inhibits oxidative stress and inflammation of the retina via NF-κB inactivation in diabetic patients [5]. Chroman derivatives exhibit potent inhibitory activity against NF-κB.

To identify new compounds with structural similarity, the chroman skeleton was changed to caffeic acid. A new derivative series was synthesized to determine the activity against NF-κB and cytotoxicity against various cell lines. The inhibitory activity of NO derivatives on mouse macrophage RAW264.7 cells was affected by the length and size of the alkyl moiety and the undecyl caffeate showed the strongest inhibitory activity against NO production. Also, in each experiment using undecanol, caffeic acid, undecanol + caffeic acid, and undecyl caffeate, the linkage between caffeic acid and alkyl chains was shown to be important for activity gave. Amide and ketone derivatives have been shown to exhibit inhibitory activity against NO production as well as ester and ether functionalities [1]. Various compounds have been reported to inhibit LPS-induced NO production and NF-κB activation in RAW 264.7 macrophages 1).

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

1: Uwai K, Osanai Y, Imaizumi T, Kanno S, Takeshita M, Ishikawa M. Inhibitory effect of the alkyl side chains on caffeic acid analogues on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages. Bioorg Med Chem. 2008 Aug 15; 16 (16): 7795-803. Epub 2008 Jul 8. 1: Kwak JH, Won SW, Kim TJ, Yi W, Choi EH, Kim SC, Park H, Roh E Jung JK Hwang BY Hong JT Kim Y Cho J Lee H. Synthesis and nuclear factor-kappaB inhibitory activities of 6- or 7-methylchroman-2-carboxylic acid N- (substituted) phenylamides. Arch Pharm Res. 2009 Feb; 32 (2): 167-75. Epub 2009 Mar 13. [1] Ma Q. Transcriptional responses to oxidative stress: pathological and toxicological implications. Pharmacol Ther 2010; 125: 376-93. [2] Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res 2011; 21: 103-15. [3] Kim YJ, Kim YA, Yokozawa T. Attenuation of oxidative stress and inflammation by gravinol in high glucose-exposed renal tubular epithelial cells. Toxicology 2010; 270: 106-11. [4] Peng Q, Wei Z, Lau BH. Pycnogenol inhibits tumor necrosis factor-alpha-induced nuclear factor kappa B activation and adhesion molecule expression in human vascular endothelial cells. Cell Mol Life Sci 2000; 57: 834-41. [5] Kowluru RA, Kanwar M. Effects of curcumin on retinal oxidative stress and inflammation in diabetes. Nutr Metab (Lond) 2007; 4: 8.

The present inventors have made extensive efforts to develop a therapeutic agent for inflammatory diseases having an effective anti-inflammatory activity by inhibiting the production of excessive nitric oxide (NO) and inhibiting the activity of the transcription factor NF-κB. As a result, it has been confirmed that the novel chlorogenic acid derivatives synthesized by the present inventors have an anti-inflammatory activity by very effectively inhibiting over-production of nitric oxide and activation of NF-κB, thereby completing the present invention.

Therefore, an object of the present invention is to provide novel chlorogenic acid derivatives.

Another object of the present invention is to provide a composition for the prevention, treatment or amelioration of an inflammatory disease comprising the chlorogenic acid derivative as an active ingredient.

The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, there is provided a chlorogenic acid derivative compound represented by the following formula (1) to (5): or a pharmaceutically acceptable acid addition salt thereof.

이고; 상기 치환된 페닐은 직쇄 또는 분지쇄의 C₁-C₆ 알킬, -NO₂, 및 할로겐에 의해 치환된 직쇄 또는 분지쇄의 C₁-C₆ 알킬로 이루어지는 그룹에서 선택된 하나 이상의 치환기로 치환된 페닐이고; 상기 치환된 벤질은 직쇄 또는 분지쇄의 C₁-C₆ 알킬, C₁-C₃ 알콕시, 할로겐, -SO₂NH₂, 및 할로겐에 의해 치환된 직쇄 또는 분지쇄의 C₁-C₆ 알킬로 이루어지는 그룹에서 선택된 하나 이상의 치환기로 치환된 벤질(단, 2-메틸벤질, 2-메톡시벤질, 및 4-메톡시벤질은 제외)이다. Wherein R is C ₃ -C ₈ cycloalkyl, substituted phenyl, substituted benzyl or

ego; Said substituted phenyl is phenyl substituted with one or more substituents selected from the group consisting of straight or branched C ₁ -C ₆ alkyl, -NO ₂ , and straight or branched C ₁ -C ₆ alkyl substituted by halogen ego; Wherein said substituted benzyl is a straight chain or branched chain C ₁ -C ₆ alkyl substituted by C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy, halogen, -SO ₂ NH _2, halogen, and straight chain or branched chain Benzyl substituted with one or more substituents selected from the group consisting of (excluding 2-methylbenzyl, 2-methoxybenzyl, and 4-methoxybenzyl).

Wherein R ₁ and R ₂ are independently hydroxyl or acetate;

이다. 단, R₁ 및 R₂가 각각 히드록실이고, R₃ 는 시클로헥실인 화합물 제외한다. R ₃ is C ₃ -C ₈ cycloalkyl or

to be. Provided that R ₁ and R ₂ are each hydroxyl and R ₃ is cyclohexyl.

In Formula 3, R is benzyl substituted by halogen or straight or branched C ₁ -C ₆ alkyl substituted by halogen.

Wherein R is benzyl or substituted benzyl, and the substituted benzyl is benzyl substituted by halogen or straight chain or branched C ₁ -C ₆ alkyl substituted by halogen.

As used herein, the term "alkyl" means a straight or branched saturated aliphatic hydrocarbon group of the specified number of carbon atoms and includes, for example, methyl, ethyl, propyl, isobutyl, pentyl, hexyl, heptyl, octyl, Tridecyl, and the like. C ₁ -C ₄ alkyl represents an alkyl group having 1 to 4 carbon atoms, and includes not only n-propyl and n-butyl, but also branched isopropyl, isobutyl and t-butyl.

As used herein, the term "cycloalkyl" refers to a non-aromatic saturated monocyclic, fused bicyclic or bridged cyclic, cyclic hydrocarbon group containing the specified number of cyclic carbon atoms. For example, C ₃ -C ₆ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

As used herein, the term "alkoxy" means a radical formed by the removal of hydrogen from an alcohol of the specified carbon number. For example, C ₁ -C ₃ alkoxy includes methoxy, ethoxy and propoxy.

As used herein, the term " halogen " refers to a halogen group element substituent and includes, for example, fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

As used herein, the term "straight-chain or branched alkyl substituted by halogen" means alkyl as defined above wherein at least one hydrogen atom is replaced by halogen, for example, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ CF ₂ CF _3, and the like.

The term "pharmaceutically acceptable acid addition salts" is used herein to refer to those salts formed with inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, p-toluenesulfonic acid and the like.

According to one embodiment of the present invention, the chlorogenic acid derivative compound of the present invention is a compound of any one of the following compounds:

(1S, 3S, 4R, 5R, E) -3- {3- (3,4-dihydroxyphenyl) acryloyloxy)} 1,4,5-trihydroxycyclohexanecarboxylic acid;

(1 S, 3 S, 4 R, 5 R) - methyl -3 - [{(E) -3-yl (3,4-hydroxyphenyl) acrylic} oxy] -1,4,5- tree Hydroxycyclohexanecarboxylate;

(E) -N -cyclohexyl-3- (3,4-dihydroxyphenyl) acrylamide;

(E) -N -cyclopentyl-3- (3,4-dihydroxyphenyl) acrylamide;

(E) -4- {3- (cyclohexyloxy) -3-oxoprop-1-en-1-yl} 1,2-phenylene diacetate;

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) phenyl 4- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) phenyl 3- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- isopropyl-phenyl) acrylamide;

(E) - N - (4- butylphenyl) -3- (3,4-hydroxyphenyl) acrylamide;

(E) -3- (3,4- dihydroxyphenyl) - N - (3- nitrophenyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- nitrophenyl) acrylamide;

(E) - N - (4- (4- bromo-phenyl) -3-methyl -1H- pyrazol-5-yl) -3- (3,4-hydroxyphenyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-4- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- methylbenzyl) acrylamide;

(E) - N - (4- chlorobenzyl) -3- (3,4-hydroxyphenyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- sulfamoyl-benzyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-3- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-2- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-2- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - (3- methylbenzyl) acrylamide;

(E) - N - (2- chloro-benzyl) -3- (3,4-hydroxyphenyl) acrylamide;

(E) - N - (3- chloro-benzyl) -3- (3,4-hydroxyphenyl) acrylamide; And

N -benzyl-2- (3,4-dimethoxyphenyl) thiazol-4-amine.

According to another aspect of the present invention, there is provided an anti-inflammatory composition comprising a chlorogenic acid derivative compound represented by the following formula (1) to (6) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient: to provide:

[Chemical Formula 1]

이고; Wherein R is C ₃ -C ₈ cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl or

ego;

Said substituted phenyl being optionally substituted with one or more substituents selected from the group consisting of straight or branched C ₁ -C ₆ alkyl, -NO ₂ , and straight or branched C ₁ -C ₆ alkyl substituted by halogen ego;

Wherein said substituted benzyl is a straight chain or branched chain C ₁ -C ₆ alkyl substituted by C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy, halogen, -SO ₂ NH _2, halogen, and straight chain or branched chain Benzyl substituted with one or more substituents selected from the group consisting of

(2)

Wherein R ₁ and R ₂ are independently hydroxyl or acetate;

이다. R ₃ is C ₃ -C ₈ cycloalkyl or

to be.

(3)

Wherein R is benzyl or substituted benzyl, and the substituted benzyl is benzyl substituted by halogen or halogen-substituted straight-chain or branched C ₁ -C ₆ alkyl.

[Chemical Formula 4]

Wherein R is benzyl or substituted benzyl, and the substituted benzyl is benzyl substituted by halogen or straight chain or branched C ₁ -C ₆ alkyl substituted by halogen.

[Chemical Formula 5]

[Chemical Formula 6]

Wherein R is piperidinyl.

The contents of the derivative compounds of the above Chemical Formulas (1) to (5), which are effective ingredients of the anti-inflammatory composition of the present invention, are the same as those described in the above-mentioned derivative compounds.

According to one embodiment of the present invention, the chlorogenic acid derivative compound which is an effective component of the anti-inflammatory composition of the present invention is a compound of any one of the following compounds:

(1S, 3S, 4R, 5R, E) -3- {3- (3,4-dihydroxyphenyl) acryloyloxy)} 1,4,5-trihydroxycyclohexanecarboxylic acid;

(1 S, 3 S, 4 R, 5 R) - methyl -3 - [{(E) -3-yl (3,4-hydroxyphenyl) acrylic} oxy] -1,4,5- tree Hydroxycyclohexanecarboxylate;

(E) -N -cyclohexyl-3- (3,4-dihydroxyphenyl) acrylamide;

(E) - N -benzyl-3- (3,4-dihydroxyphenyl) acrylamide;

(E) -3- (3,4-dihydroxyphenyl) -N -phenylacrylamide;

(E) -N -cyclopentyl-3- (3,4-dihydroxyphenyl) acrylamide;

(E) -3- (3,4-dihydroxyphenyl) -1- (piperidin-1-yl) prop-2-en-1-one;

(E) -4- {3- (cyclohexyloxy) -3-oxoprop-1-en-1-yl} 1,2-phenylene diacetate;

(E) -cyclohexyl 3- (3,4-dihydroxyphenyl) acrylate;

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) phenyl 4- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) phenyl 3- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- isopropyl-phenyl) acrylamide;

(E) - N - (4- butylphenyl) -3- (3,4-hydroxyphenyl) acrylamide;

(E) -3- (3,4- dihydroxyphenyl) - N - (3- nitrophenyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- nitrophenyl) acrylamide;

(E) - N - (4- (4- bromo-phenyl) -3-methyl -1H- pyrazol-5-yl) -3- (3,4-hydroxyphenyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-4- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- methylbenzyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- methoxybenzyl) acrylamide;

(E) - N - (4- chlorobenzyl) -3- (3,4-hydroxyphenyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- sulfamoyl-benzyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-3- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - (2- methoxybenzyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - (2- methylbenzyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-2- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-2- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - (3- methylbenzyl) acrylamide;

(E) - N - (2- chloro-benzyl) -3- (3,4-hydroxyphenyl) acrylamide;

(E) - N - (3- chloro-benzyl) -3- (3,4-hydroxyphenyl) acrylamide;

4- [2- (benzylamino) thiazol-4-yl} benzene-1,2-diol; And

N -benzyl-2- (3,4-dimethoxyphenyl) thiazol-4-amine.

The chlorogenic acid derivative compound of the present invention inhibits excessive production of nitric oxide (NO) induced by LPS treatment in immune cells and has an activity of inhibiting the activation of NF-κB, so that it is very effective in prevention, treatment or improvement of inflammatory diseases Valid.

According to one embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating an inflammatory disease, which comprises the chlorogenic acid derivative represented by any one of Chemical Formulas 1 to 6 as an active ingredient.

In the present invention, the inflammatory diseases are atopic dermatitis, psoriasis, sinusitis, rhinitis, conjunctivitis, asthma, dermatitis, inflammatory collagen vascular disease, glomerulonephritis, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease, sepsis, septic shock, pulmonary fibrosis, Inflammatory bowel disease, inflammatory bowel disease, type 1 diabetes, type 2 diabetes, arthritis, rheumatoid arthritis, reactive arthritis, osteoarthritis, inflammatory bowel disease, inflammatory bowel disease, chronic inflammatory disease due to inflammatory osteolysis, viral or bacterial infection, , Lyme disease, Borreliosis, Neurogenic-Borrelia, Tuberculosis, Alzheimer's disease, Alzheimer's disease, Alzheimer's disease, Alzheimer's disease, Alzheimer's disease, Sarcoidosis, lupus, albuminous lupus, tuberculous lupus, lupus nephritis, systemic lupus erythematosus, macular Chronic pain syndrome, chronic fatigue syndrome, chronic fatigue immunodeficiency syndrome, myalgic encephalomyelitis, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, autistic spectrum disorders, attention deficit disorder, and attention deficit hyperactivity disorder Deficient hyperactivity disorder, and the like.

The pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration or the like.

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The daily dosage of the pharmaceutical composition of the present invention is, for example, 0.001-100 mg / kg.

The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

According to another embodiment of the present invention, there is provided a functional food composition for improving inflammatory diseases, which comprises, as an active ingredient, a chlorogenic acid derivative represented by any one of Chemical Formulas 1 to 6 above.

The functional food composition of the present invention includes components that are ordinarily added during the manufacture of food, and includes, for example, proteins, carbohydrates, fats, nutrients, and seasonings. For example, in the case of a drink, a sweetener or a natural carbohydrate may be added as an additional ingredient in addition to the chlorogenic acid derivative as an active ingredient. For example, natural carbohydrates include monosaccharides (e.g., glucose, fructose, etc.); Disaccharides (e.g., maltose, sucrose, etc.); oligosaccharide; Polysaccharides (e.g., dextrin, cyclodextrin and the like); And sugar alcohols (e.g., xylitol, sorbitol, erythritol, etc.). As the sweetening agent, natural sweetening agents (e.g., tau Martin and stevia extract) and synthetic sweetening agents (e.g., saccharin, aspartame, etc.) can be used.

The features and advantages of the present invention are summarized as follows:

(i) The chlorogenic acid derivative compounds of the present invention inhibit the overproduction of nitric oxide (NO) induced by LPS treatment in macrophages.

(Ii) The chlorogenic acid derivative compounds of the present invention inhibit the activation of NF-κB, an important signal transduction mediator, in oxidative stress and inflammation-promoting pathways.

(Iii) The chlorogenic acid derivative compound of the present invention is highly likely to be developed as a therapeutic agent for various inflammatory diseases by inhibiting nitric oxide production and NF-κB activation.

Fig. 1 shows an example of a compound showing an activity of inhibiting NO production and NF-kB activation induced by LPS.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Synthesis method

1. Synthesis method 1

HOBt (1.0 eq) and EDCI (1.0 eq) in DMF were added to a solution of caffeic acid (1.0 eq), and the mixture was stirred at room temperature for 20 minutes. Amine (1.0 eq) was added to the solution, and the mixture was stirred at room temperature for 20 minutes. The mixture was treated with DIPEA (2.0 eq) at ambient temperature and the reaction mixture was stirred at ambient temperature for 16 hours. After dissolving the mixture into EtOAc, H ₂ O, 1N-HCl, and brine (brine), dried the organic layer with MgSO ₄ filtered and concentrated in vacuo. The product was loaded onto silica gel and purified by column chromatography (EA in HX conditions).

2. Synthesis method 2

Caffeic acid (300 mg, 1.67 mmol) in benzene (3 mL) was stirred at room temperature. The mixture was treated with SOCl ₂ (0.666 mL, 9.13 mmol) and stirred at 50 < 0 > C for 4 hours. The solvent was concentrated and used directly in the next reaction without purification. K ₂ CO ₃ (207 mg, 1.50 mmol) in CH ₃ CN (2 mL) was stirred at room temperature. The mixture was treated with 1-methylimidazole (0.00800 mL, 0.100 mmol), TMEDA (0.0150 mL, 0.100 mmol) and amine at ambient temperature. CH ₃ CN (2 mL) in the (E) -3- (3,4-dihydroxy-phenyl) acryloyl chloride was added to the solution at room temperature, the reaction mixture was stirred at room temperature for 14 hours. The mixture was dissolved in EtOAc (3 X 5 mL), MeOH (3 X 5 mL) and the solvent was concentrated. The product was loaded onto silica gel and purified by column chromatography (EA in HX conditions).

3. Synthesis Method 3

A solution of chlorogenic acid (100 mg, 0.280 mmol) and Pd / C (30.0 mg) in EtOH was stirred at room temperature. H ₂ The gas was added at ambient temperature and the reaction mixture was stirred at ambient temperature for 14 hours. The Pd / C was removed by filtration, and the filtrate was concentrated in vacuo. The product was loaded onto silica gel and purified by column chromatography (EA in HX conditions).

4. Synthesis Method 4

A solution of chlorogenic acid in MeOH (200 mg, 0.560 mmol) was stirred at room temperature. TMSCHN ₂ (0.420 mL, 0.840 mmol) was added to the solution and the reaction mixture was stirred at ambient temperature for 15 hours. The mixture was filtered and concentrated in vacuo. The product was loaded onto silica gel and purified via column chromatography (EA in HX conditions).

5. Synthesis method 5

A solution of caffeic acid (300 mg, 1.67 mmol) in pyridine was stirred at room temperature. DMAP (4.89 mg, 0.0400 mmol) was added to the solution and the reaction mixture was stirred at 0 < 0 > C. Ac ₂ O (1.08 mL, 16.7 mmol) was then added to the solution and the reaction mixture was stirred at ambient temperature for 13 hours. The solvent was concentrated.

(E) -3- (3,4-diacetoxyphenyl) acrylic acid in benzene was stirred at room temperature. The mixture was treated with SOCl ₂ (0.205 mL, 3.50 mmol) and stirred at 50 < 0 > C for 3 h. After 3 h, the SOCl ₂ was removed under vacuum and the residue was dissolved in DCM. The reaction mixture was then treated with DMAP (8.55 mg, 0.0699 mmol) and the mixture was stirred at room temperature. Cyclohexanol (0.0740 mL, 0.699 mmol) was added to the solution and the reaction mixture was stirred at ambient temperature for 12 hours. The solvent was concentrated in vacuo. The product was loaded onto silica gel and purified via column chromatography (EA in HX conditions).

6. Synthetic method 6

(E) -4- (3- (cyclohexyloxy) -3-oxoprop-1-phenyl) -1,2-phenylene diacetate (47.8 mg, 0.138 mmol) in THF was stirred at room temperature. The reaction mixture was treated with a _{2% Na 2 CO 3 (1.00} mL) and MeOH (2.00 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was adjusted to pH 1 with 1 N HCl, washed with H ₂ O and extracted with diethyl ether. After the organic layer was dried using MgSO _4, filtered and concentrated under vacuum. The product was loaded onto silica gel and purified using column chromatography (EA in HX conditions).

7. Synthetic method 7

Potassium thiocyanate (1.0 eq) was added to a solution of 1,2-dimethoxybenzene (1.15 eq) in methanesulfonic acid in an ice-cooled water bath. After stirring at room temperature for 4.3 hours, the reaction mixture was poured into chilled water. The precipitate was filtered and the filtrate was dried to obtain a crude product. The crude product was recrystallized from ethyl acetate. The aqueous filtrate was extracted with dichloromethane. The combined residue and recrystallization mother liquor was purified by SiO ₂ column chromatography (EA in HX conditions).

Bromoacetonitrile (0.14 mL, 2.00 mmol) was dissolved in 10 mL of dichloromethane and 3,4-dimethoxybenzothioamide (395 mg, 2.00 mmol) was added. The mixture was stirred under reflux overnight. After cooling, the precipitated solids were extracted with CH ₂ Cl ₂ and dried using MgSO ₄ . The combined residues SiO ₂ Purified by column chromatography (EA in HX conditions).

(1.0 eq) and R-bromide (0.8-1.0 eq) were dissolved in acetone. K ₂ CO ₃ (3.0 eq) was added to the solution. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the resulting residue was purified by chromatography (EA in HX conditions).

8. Synthetic method 8

Potassium thiocyanate (1.0 eq) was added to a solution of benzylamine hydrochloride (1.5 eq) in THF. The mixture was stirred under reflux overnight. After cooling the mixture, and the precipitated solid extracted with EtOAc and dried using MgSO _4. The residue was purified using SiO ₂ column chromatography (EA in HX conditions).

Thioacetamide (1.0 eq) was added to 2-chloro-l- (3,4-dihydroxyphenyl) ethanone (1.0 eq) in EtOH and the mixture was refluxed overnight. After removal of the solvent, the precipitated solids were extracted with EtOAc and NaHCO ₃ . After the organic layer was dried using MgSO _4, filtered and concentrated under vacuum.

Synthesis Example of Compound

One. Synthetic example  1: (1S, 3S, 4R, 5R, E) -3- {3- (3,4- Dihydroxyphenyl ) Acryloyloxy )} 1,4,5-trihydroxycyclohexanecarboxylic acid

Chlorogenic acid (300 mg, 0.85 mmol) and Pd / C (85 mg) were dissolved in EtOH (3 mL) and H ₂ gas was introduced. After stirring at room temperature for 14 hours, it was filtered and concentrated.

Yield: 67.1%; ^{1 H NMR (MeOD, 500 MHz} ) δ 6.59 (d, 1H, J = 10.8 Hz, Ar- H), 6.58 (s, 1H, Ar- H), 6.55 (dd, 1H, J = 8.1, 2.1 Hz, Ar- H), 5.22 (m, 1H, OC H CH 2), 4.00 (m, 1H, C H OH), 3.53 (m, 1H, C H OH), 2.71 (t, 2H, J = 7.7 Hz, _{Ar-C H 2 CH 2)} , 2.52 (td, 2H, J = 7.5, 3.3 Hz, Ar-CH 2 C H 2), 1.95 (m, 4H, C H 2 CC H 2); ¹³ C NMR (MeOD, 100 MHz) ? 176.0, 173.0, 144.8, 143.2, 132.2, 119.2, 115.1, 115.0, 72.2, 70.7, 70.1, 39.0, 36.9, 36.0, 30.0, 38.4; MS m / z (MH) ^- calculated for C ₁₆ H ₂₀ O ₉ 355.3. found: 355.1; IR (neat) 3350, 1716, 1278, 1198 cm < ^-1 >

2. Synthetic example  2: (1 S , 3 S , 4 R , 5 R ) - methyl -3 - [{(E) -3- (3,4- Dihydroxyphenyl ) Acryloyl} oxy] -1,4,5-trihydroxycyclohexanecarboxylate

Chlorogenic acid (200 mg, 0.56 mmol) was dissolved in MeOH, TMSCHN ₂ (0.42 mL, 0.84 mmol) was added dropwise and the mixture was stirred at room temperature for 15 hours. After 15 hours, the solvent was removed and purified by column chromatography.

Yield: 51.9%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.51 (d, 1H, J = 15.8 Hz, Ar-C H CH), 7.03 (s, 1H, Ar- H), 6.93 (d, 1H, J = 8.0 Hz, Ar- H), 6.77 (d, 1H, J = 8.0 Hz, Ar- H), 6.20 (d, 1H, J = 15.9 Hz, Ar-CHC H), 5.27 (t, 1H, J = 2.4 Hz, C (O) OC H), 4.12 (m, 1H, C H OH), 3.72 (m, 1H, C H OH), 3.68 (s, 3H, OC H 3), 2.01 (m, 4H, C H 2 CC H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 174.0, 166.9, 148.3, 145.5, 126.2, 121.6, 115.1, 113.7, 113.6, 74.4, 70.1, 52.5, 51.5, 45.8, 36.6, 27.9, 23.1; MS m / z (M + H ) - calculated for C 17 H 20 O 9 369.3. found: 369.1; IR (neat) 3387, 1700, 1269, 1159 cm < ^-1 >

3. Synthesis Example 3: Synthesis of (E) - N -Cyclohexyl-3- (3,4-dihydroxyphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (165 mg, 1.22 mmol) and EDCI (234 mg, 1.22 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, cyclohexylamine (0.12 mL, 1.0 mmol) was added dropwise and the mixture was stirred at room temperature for 20 minutes. After 20 minutes DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCI and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 10.9%; ^{1 H NMR (MeOD, 500 MHz} ) δ 7.38 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.00 (s, 1H, Ar- H) 6.90 (dd, 1H, J = 8.2, 2.0 Hz , Ar- H), 6.77 (d , 1H, J = 8.2 Hz, Ar- H), 6.36 (d, 1H, J = 15.7 Hz, Ar-CHC H), 3.76 (m, 1H, NHC H CH 2) , 1.80 (m, 5H, NHC 6 H 5), 1.38 (m, 5H, NHC 6 H 5); ¹³ C NMR (MeOD, 100 MHz) ? 166.9, 147.3, 145.3, 140.6, 127.0, 120.63, 117.3, 115.0, 113.6, 48.4, 32.5, 25.3, 24.8; MS m / z (M + H ) - calculated for C 15 H 19 NO 3 262.3. found: 262.3; IR (NaTe) 3280, 1649, 1579, 1522, 1445 cm < ^-1 >

4. Synthesis Example 4: Synthesis of (E) - N -Benzyl-3- (3,4-dihydroxyphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (165 mg, 1.22 mmol) and EDCI (234 mg, 1.22 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, benzylamine (0.12 mL, 1.0 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 minutes DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCI and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 52.3%; NMR H ¹ (MeOD, 500 MHz) δ 7.46 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.34 (m, 4H, Ar- H), 7.27 (m, 1H, Ar- H), 7.03 (s, 1H, Ar- H ), 6.94 (dd, 1H, J = 8.2, 2.1 Hz, Ar- H), 6.78 (d, 1H, J = 8.2 Hz, Ar- H), 6.43 (d, 1H , J = 15.6 Hz, Ar- CHC H), 4.50 (s, 2H, NHC H 2); ¹³ C NMR (MeOD, 100 MHz) ? 167.8, 147.4, 145.3, 141.2, 138.6, 128.2, 127.2, 126.9, 126.8, 120.7, 116.8, 115.0, 113.7, 42.9; MS m / z (M + Na) ^- calculated for C ₁₆ H ₁₅ NO ₃ 270.3. found: 270.2; IR (neat) 3285, 1650, 1598, 1524, 1448 cm ^-1

5. Synthesis Example 5: (E) -3- (3,4-Dihydroxyphenyl) - N - phenylacrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (165 mg, 1.22 mmol) and EDCI (234 mg, 1.22 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, aniline (0.10 mL, 1.0 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 minutes DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCI and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 7.06%; ^{1 H NMR (MeOD, 500 MHz} ) δ 7.81 (d, 1H, J = 8.5 Hz, Ar-C H CH), 7.67 (d, 1H, J = 8.3 Hz, Ar-CHC H), 7.67 (d, 1H , J = 8.1 Hz, Ar- H ), 7.57 (d, 1H, J = 8.1 Hz, Ar- H), 7.25 (t, 2H, J = 8.0 Hz, Ar- H), 7.03 (t, 1H, J = 7.4 Hz, Ar- H), 6.99 (s, 1H, Ar- H), 6.72 (d, 1H, J = 8.2 Hz, Ar- H), 6.49 (d, 1H, J = 15.6 Hz, Ar- H ); ¹³ C NMR (MeOD, 100.6 MHz) ? 166.0, 147.6, 145.4, 142.0, 128.5, 128.4, 126.9, 123.8, 121.0, 119.9, 117.4, 115.1, 113.8; MS m / z (M + H ) - calculated for C 15 H 13 NO 3 256.3. found: 256.2; IR (neat) 3266, 1596, 1535, 1439, 1250 cm < ^-1 >

6. Synthetic example  6: (E) - N - Cyclopentyl -3- (3,4- Dihydroxyphenyl ) Acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (165 mg, 1.22 mmol) and EDCI (234 mg, 1.22 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, cyclopentylamine (0.10 mL, 1.0 mmol) was added and the mixture was stirred at room temperature for 20 minutes. DIPEA (0.38 mL, 2.22 mmol) was then added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 7.29%; ^{1 H NMR (Acetone, 500 MHz} ) δ 7.36 (d, 1H, J = 15.6 Hz, Ar-C H CH), 7.03 (s, 1H, Ar- H), 6.91 (dd, 1H, J = 8.0, 2.1 Hz, Ar- H), 6.82 ( d, 1H, J = 8.2 Hz, Ar- H), 6.39 (d, 1H, J = 15.6 Hz, Ar-CHC H), 4.24 (m, 1H, NHC H CH 2 ), 1.93 (m, 2H, NHCHC ₂ H ₂ ), 1.70 (m, 2H, NHCHC ₂ H ₂ ), 1.61 (m, 2H, NHCHCH ₂ C H ₂ ), 1.50 (m, 2H, NHCHCH ₂ C H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.4, 147.3, 145.3, 140.1, 127.0, 120.6, 117.2, 115.0, 113.6, 51.1, 32.3, 23.4; MS m / z (M + H ) - calculated for C 14 H 17 NO 3 248.3. found: 248.3; IR (neat) 3258, 2950, 1650, 1278 cm < ^-1 >

7. Synthetic example  7: (E) -3- (3,4- Dihydroxyphenyl ) -1- (piperidin-1-yl) Professional 2-en-1-one

Caffeic acid (200 mg, 1.11 mmol), HOBt (165 mg, 1.22 mmol) and EDCI (234 mg, 1.22 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes piperidine (0.10 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1N-HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography (EtOAc: n-Hexane: MeOH = 1: 2: 7%).

Yield 5.47%; ^{1 H NMR (MeOD, 500 MHz} ) δ 6.84 (s, 1H, Ar- H), 6.71 (m, 2H, Ar-C H CH), 6.54 (d, 1H, J = 12.5 Hz, Ar- H), 5.85 (d, 1H, J = 12.5 Hz, Ar- H), 3.61 (t, 2H, J = 5.6 Hz, NC H 2 CH 2), 3.40 (t, 2H, J = 5.6 Hz, NC H 2 CH 2 ), 1.58 (m, 4H, C H ₂ CH ₂ ), 1.28 (m, 2H, CH ₂ C H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 166.7, 147.4, 145.3, 143.2, 127.2, 120.7, 115.1, 113.9, 113.5, 46.8, 43.2, 24.2; MS m / z (M + H ) - calculated for C 14 H 17 NO 3 248.3. found: 248.3; IR (neat) 3439, 2932, 1561, 1432, 1262 cm < ^{-1 &}

8. Synthetic example  8: (E) -4- {3- ( Cyclohexyloxy ) -3- Oxoprop -1-en-1-yl} 1,2- Phenyl Randy acetate

Caffeic acid (300 mg, 1.67 mmol) was dissolved in distilled pyridine and DMAP (4.89 mg, 0.04 mmol) was added. After cooling to 0 ℃ dropwise to _{Ac 2 O (1705 mg, 16.7mmol} ). After stirring at room temperature for 16 hours, the solvent was removed and the product was recrystallized from EtOAc / n-hexane to give the product. The resultant was dissolved in benzene (3 mL), SOCl ₂ (0.25 mL, 3.50 mmol) was added dropwise, and the mixture was stirred at 50 ° C for 3 hours. After removal of the solvent, the residue was dissolved in CH ₂ Cl ₂ , DMAP (8.55 mg, 0.07 mmol) and cyclohexanol (0.074 mL, 0.70 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After 16 hours, the solvent was removed and purified by column chromatography.

Yield 8.23%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.59 (d, 1H, J = 16.0 Hz, Ar-C H CH), 7.40 (dd, 1H, J = 8.4, 2.0 Hz, Ar-H), 7.35 (d, 1H, J = 1.9 Hz, Ar -H), 7.20 (d, 1H, J = 8.4 Hz, Ar-H), 6.37 (d, 1H, J = 16.0 Hz, Ar-C H CH), 4.88 (m, 1H, Ar-OC H), 2.30 (s, 3H, OC H 3), 2.29 (s, 3H, OC H 3), 1.90 (m, 2H, OCHC H 2), 1.76 (m, 2H, OCHC H 2 ), 1.42 (m, 6H, OCHC H ₂ C H ₂ C H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 168.0, 168.0, 166.0, 143.4, 142.4, 142.3, 133.5, 126.3, 123.9, 122.7, 120.1, 72.9, 31.7, 25.5, 25.4, 24.1, 23.8, 20.6, 20.6; MS m / z (M + Na ) - calculated for C 19 H 22 O 6 369.4. found: 369.3; IR (neat) 2937, 1774, 1707, 1178 cm < ^-1 >

Synthesis Example 9: Synthesis of (E) -cyclohexyl 3- (3,4-dihydroxyphenyl) acrylate

(E) -4- (3- (cyclohexyloxy) -3-oxoprop-1-enyl) -1,2-phenylene diacetate was dissolved in THF, MeOH was added to 2% Na ₂ CO ₃ Solution. After stirring at room temperature for 4 h, it was extracted with water, 6 N HCl and diethyl ether.

Yield 4.12%; ^{1 H NMR (MeOD, 500 MHz} ) δ 7.53 (d, 1H, J = 15.9 Hz, Ar-C H CH), 7.04 (s, 1H, Ar- H), 6.95 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.79 ( d, 1H, J = 8.1 Hz, Ar- H), 6.25 (d, 1H, J = 15.9 Hz, Ar-CHC H), 4.82 (m, 1H, OC H CH 2 ) 1.92 (m, 2H, OCHC H ₂ ), 1.79 (m, 2H, OCHC H ₂ ), 1.49 (m, 6H, OCHC H ₂ C H ₂ C H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.4, 148.1, 145.4, 145.1, 126.4, 121.5, 115.1, 114.3, 113.7, 72.5, 60.1, 31.4, 25.1, 23.4, 13.0; ^{MS m / z (MH) -} calculated for C 15 H 18 O 4 261.3. found: 261.0; IR (neat) 3301, 2941, 1683, 1025 cm < ^-1 >

10. Synthetic example  10: (E) -3- (3,4- Dihydroxyphenyl ) - N -(4-( Trifluoromethyl ) Phenyl) acrylamide

To a flask with two necks was added K ₂ CO ₃ (207 mg, 1.5 mmol), 1-methylimidazole (0.008 mL, 0.1 mmol), TMEDA (0.015 mL, 0.1 mmol) and 3- (trifluoromethyl) Aniline (161 mg, 1.0 mmol) was added and dissolved in CH ₃ CN (1 mL), and the reaction was allowed to proceed at 0 ° C in an ice bath. (E) -3- (3,4-dihydroxyphenyl) acryloyl chloride (210 mg, 1.5 mmol) was dissolved in CH ₃ CN (1 mL) and stirred. After 12 h, it was extracted with EtOAc, concentrated and purified by column chromatography.

Yield 6.05%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.84 (d, 2H, J = 8.4 Hz, Ar- H), 7.61 (d, 2H, J = 8.7 Hz, Ar- H), 7.55 (d, 1H, J = 15.6 Hz, Ar-C H CH ), 7.06 (d, 1H, J = 2.0 Hz, Ar- H), 6.96 (dd, 1H, J = 8.2, 2.1 Hz, Ar- H), 6.78 (d, 1H, J = 8.2 Hz, Ar- H ), 6.55 (d, 1H, J = 15.6 Hz, Ar-CHC H ); ¹³ C NMR (MeOD, 100 MHz) ? 166.2, 147.9, 145.4, 142.9, 142.4, 126.7, 125.6, 125.6, 121.2, 119.3, 116.9, 115.1, 113.8, 60.1; MS m / z (M + H ) - calculated for C 16 H 12 FNO 3 324.3. found: 324.2

IR (neat) 3276, 1651, 1590, 1517, 1115 cm < ^{-1 &}

11. Synthetic example  11: (E) -3- (3,4- Dihydroxyphenyl ) - N - (3- ( Trifluoromethyl ) Phenyl) acrylamide

A flask with two necks was charged with K ₂ CO ₃ (TEA) (0.015 mL, 0.1 mmol) and 3- (trifluoromethyl) aniline (161.12 mg, 1.0 mmol) ₃ CN (1 mL), and then reacted in an ice water bath at 0 ° C. (E) -3- (3,4-dihydroxyphenyl) acryloyl chloride (210 mg, 1.5 mmol) was dissolved in CH ₃ CN (1 mL) and stirred. After 12 h, it was extracted with EtOAc, concentrated and purified by column chromatography.

Yield 7.26%; ^{1 H NMR (MeOD, 400 MHz} ) δ 8.11 (s, 1H, Ar- H), 7.80 (d, 1H, J = 8.24 Hz, Ar- H), 7.54 (d, 1H, J = 15.6 Hz, Ar- C H CH), 7.49 (t , 1H, J = 8.1 Hz, Ar- H), 7.35 (d, 1H, J = 7.8 Hz, Ar- H), 7.06 (s, 1H, Ar- H), 6.96 ( (d, 1H, J = 8.2, 2.0 Hz, Ar- H ), 6.78 (d, 1H, J = 8.2 Hz, Ar- H ), 6.53 (d, 1H, J = 15.6 Hz, Ar-CHC H ); ¹³ C NMR (MeOD, 100 MHz) ? 166.2, 147.9, 145.4, 142.7, 139.7, 129.3, 126.7, 122.8, 121.1, 119.8, 119.8, 116.8, 116.0, 115.1, 113.8, 60.1; ^{MS m / z (MH) -} calculated for C 16 H 12 FNO 3 322.2. found: 322.0; IR (neat) 3273, 2839, 1661, 1599, 1550 cm < ^{-1 &}

12. Synthetic example  12: (E) -3- (3,4- Dihydroxyphenyl ) - N -(4- Isopropylphenyl ) Acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-isopropylaniline (0.15 mL, 1.11 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 13.6%; _{^{1 H NMR (CDCl 3, 500}} MHz) δ 7.56 (d, 2H, J = 8.5 Hz, Ar- H), 7.52 (d, 1H, J = 15.6 Hz, Ar-C H CH), 7.21 (d, 2H , J = 8.5 Hz, Ar- H ), 7.08 (d, 1H, J = 2.0 Hz, Ar- H), 6.97 (dd, 1H, J = 8.1, 2.0 Hz, Ar- H), 6.80 (d, 1H , J = 8.2 Hz, Ar- H ), 6.56 (d, 1H, J = 15.6 Hz, Ar-CHC H), 2.88 (m, 1H, C H (CH 3) 2), 1.26 (s, 3H, CHC H ₃ ), 1.25 (s, 3H, CH ₃ H ₃ ); ¹³ C NMR (MeOD, 100 MHz) ? 164.4, 146.1, 143.8, 143.1, 140.3, 134.9, 125.4, 124.7, 119.4, 118.4, 115.9, 113.6, 112.2, 32.0, 21.5; ^{MS m / z (MH) -} calculated for C 18 H 19 NO 3 296.4. found: 296.0; IR (neat) 3210, 2960, 1650, 1568, 1459 cm < ^{-1 &}

13. Synthesis Example 13: Synthesis of (E) - N - (4-butylphenyl) -3- (3,4-dihydroxyphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-butyl aniline (0.18 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h and extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 16.6%; _{^{1 H NMR (CDCl 3, 400}} MHz) δ 7.54 (d, 2H, J = 8.3 Hz, Ar- H), 7.52 (d, 1H, J = 15.5 Hz, Ar-C H CH), 7.14 (d, 2H , J = 8.4 Hz, Ar- H ), 7.08 (d, 1H, J = 1.6 Hz, Ar- H), 6.96 (dd, 1H, J = 8.2, 1.6 Hz, Ar- H), 6.80 (d, 1H , J = 8.1 Hz, Ar- H ), 6.56 (d, 1H, J = 15.6 Hz, Ar-CHC H), 2.58 (t, 2H, J = 7.6 Hz, Ar-C H 2 CH 2), 1.59 ( _{m, 2H, Ar-CH 2} C H 2 CH 2), 1.36 (m, 2H, Ar-CH 2 CH 2 C H 2), 0.95 (t, 3H, J = 7.6 Hz, Ar-CH 2 CH 2 CH ₂ C H ₃ ); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 169.8, 151.5, 149.3, 145.8, 142.6, 140.2, 132.3, 130.9, 124.9, 123.9, 121.3, 119.0, 117.7, 38.6, 37.5, 25.9, 16.9; ^{MS m / z (MH) -} calculated for C 19 H 21 NO 3 310.4. found: 310.2

IR (neat) 3315, 2925, 1652, 1602, 1437 cm < ^-1 >

14. Synthetic example  14: (E) -3- (3,4- Dihydroxyphenyl ) - N - (3- Nitrophenyl ) Acrylamide

To a two necked flask was added K ₂ CO ₃ (207 mg, 1.5 mmol), 1-methylimidazole (0.008 mL, 0.1 mmol), TMEDA (0.015 mL, 0.1 mmol) and 4- nitroaniline (138 mg, 1.0 mmol) was dissolved in CH ₃ CN (1 mL), and the reaction was allowed to proceed at 0 ° C in an ice water bath. (E) -3- (3,4-dihydroxyphenyl) acryloyl chloride (210 mg, 1.5 mmol) was dissolved in CH ₃ CN (1 mL) and stirred. After 12 h, it was extracted with EtOAc, concentrated and purified by column chromatography.

Yield 12.7%; ^{1 H NMR (MeOD, 500 MHz} ) δ 8.76 (s, 1H, Ar- H), 7.94 (d, 2H, J = 8.2 Hz, Ar- H), 7.57 (d, 1H, J = 15.7 Hz, Ar- C H CH), 7.54 (dd , 1H, J = 16.3, 7.9 Hz, Ar- H), 7.07 (s, 1H, Ar- H), 6.97 (d, 1H, J = 8.2 Hz, Ar- H), 6.79 (d, 1H, J = 8.1 Hz, Ar- H), 6.53 (d, 1H, J = 15.5 Hz, Ar-CHC H); ¹³ C NMR; ^{MS m / z (MH) -} calculated for C 15 H 12 N 2 O 5 299.3. found: 299.1; IR (neat) 3348, 2923, 1600, 1527, 1350 cm < ^{-1 &}

15. Synthetic example  15: (E) -3- (3,4- Dihydroxyphenyl ) - N -(4- Nitrophenyl ) Acrylamide

To a two necked flask was added K ₂ CO ₃ (207 mg, 1.5 mmol), 1-methylimidazole (0.008 mL, 0.1 mmol), TMEDA (0.015 mL, 0.1 mmol) and 4- nitroaniline (138 mg, 1.0 mmol) were dissolved in CH ₃ CN (1 mL), and the reaction was allowed to proceed at 0-5 ° C in an ice water bath. (E) -3- (3,4-dihydroxyphenyl) acryloyl chloride (210 mg, 1.5 mmol) was dissolved in CH ₃ CN (1 mL) and stirred. After 12 h, it was extracted with EtOAc, concentrated and purified by column chromatography.

Yield 10.2%; ^{1 H NMR (MeOD, 400 MHz} ) δ 8.22 (d, 2H, J = 9.3 Hz, Ar- H), 7.89 (d, 2H, J = 9.4 Hz, Ar- H), 7.58 (d, 1H, J = 15.5 Hz, Ar-C H CH ), 7.07 (d, 1H, J = 2.0 Hz, Ar- H), 6.97 (dd, 1H, J = 8.3, 2.0 Hz, Ar- H), 6.78 (d, 1H, J = 8.1 Hz, Ar- H) , 6.55 (d, 1H, J = 15.5 Hz, Ar-CHC H); ¹³ C NMR; ^{MS m / z (MH) -} calculated for C 19 H 21 NO 3 299.3. found: 299.0; IR (neat) 3329, 2950, 1673, 1501, 1331 cm < ^{-1 &}

16. Synthetic example  16: (E) - N - (4- (4- Bromophenyl ) -3- methyl -1H- Pyrazole -5-yl) -3- (3,4-dihydroxyphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 5-amino-4- (4-bromophenyl) -3-methylpyrazole (280 mg, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ , concentrated under reduced pressure and purified by recrystallization (EtOAc: n- Hexane).

Yield 12.7%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.69 (d, 1H, J = 15.8 Hz, Ar-C H CH), 7.51 (d, 1H, J = 15.8 Hz, Ar-CHC H), 7.49 (dd, 2H , J = 8.4, 1.9 Hz, Ar- H), 7.20 (d, 1H, J = 8.6Hz, Ar- H), 7.19 (dd, 1H, J = 8.4, 1.9 Hz, Ar- H), 7.09 (d , 1H, J = 2.0 Hz, Ar- H), 6.99 (dd, 1H, J = 8.4, 1.9 Hz, Ar- H), 6.74 (d, 1H, J = 8.2 Hz, Ar- H), 2.14 (s , 3H, C H ₃ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.4, 151.4, 148.9, 148.1, 147.0, 145.6, 131.6, 131.2, 130.3, 126.7, 122.3, 119.7, 115.2, 114.2, 113.1, 101.5, 11.9; ^{MS m / z (MH) -} calculated for C 19 H 16 BrN 3 O 3 413.3. found: 413.8; IR (neat) 2923, 1678, 1391, 637 cm < ^-1 >

17. Synthetic example  17: (E) -3- (3,4- Dihydroxyphenyl ) - N -(4-( Trifluoromethyl ) benzyl ) Acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4- (trifluoromethyl) benzylamine (0.16 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 76.0%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.74, 7.61 (d, d 5H, J = 7.2, 7.2 Hz, Ar- H), 7.20 (s, 1H, Ar- H), 7.06 (d, 1H, J = 7.6 Hz, Ar- H), 6.93 (d, 1H, J = 7.6 Hz, Ar- H), 6.61 (d, 1H, J = 14.8 Hz, Ar- H), 4.69 (s, 2H, Ar-C H ₂ NH); ^{13 C NMR (MeOD, 100 MHz} ) δ 168.0, 147.5, 145.3, 143.4, 141.5, 129.1, 128.8, 127.6, 126.8, 125.7, 125.0, 125.0, 125.0, 123.0, 120.8, 116.6, 115.1, 113.7, 60.1, 42.3, 13.1; ^{MS m / z (MH) -} calculated for C 17 H 14 F 3 NO 3 336.3. found: 336.1

IR (neat) 3299, 2926, 1649, 1589, 1442, 1112 cm -1

18. Synthesis Example 18: (E) -3- (3,4-Dihydroxyphenyl) - N - (4-methylbenzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-methylbenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl, and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 87.0%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.62 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.36 (d, 2H, J = 7.6 Hz, Ar- H), 7.29 (d, 2H, J = 7.7 Hz, Ar- H) , 7.21 (s, 1H, Ar- H), 7.09 (d, 1H, J = 8.2 Hz, Ar- H), 6.95 (d, 1H, J = 8.1 Hz, Ar- H ), 6.60 (d, 1H, J = 15.6 Hz, Ar-CHC H ), 4.60 (s, 2H, NHC H ₂ ), 2.47 (s, 3H, Ar-C H ₃ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.7, 147.4, 145.3, 141.0, 136.6, 135.5, 128.8, 127.2, 126.9, 120.7, 116.9, 115.0, 113.7, 42.6, 19.7; MS m / z (M + H ) - calculated for C 17 H 17 NO 3 284.3. found: 284.2; IR (neat) 3314, 2923, 1645, 1577, 1457 cm < ^{-1 &}

19. Synthetic example  19: (E) -3- (3,4- Dihydroxyphenyl ) - N - (4-methoxybenzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-methoxybenzylamine (0.15 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 87.8%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.62 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.39 (d, 2H, J = 8.0 Hz, Ar- H), 7.21 (s, 1H, Ar- H), 7.08 (d, 1H, J = 8.2 Hz, Ar- H), 7.02 (d, 2H, J = 8.0 Hz, Ar- H), 6.95 (d, 1H, J = 8.1 Hz, Ar- H ), 6.59 (d, 1H, J = 15.6 Hz, Ar-CHC H ), 4.57 (s, 2H, NHC H ₂ ), 3.91 (s, 3H, Ar-OC ₃ H ); ¹³ C NMR (MeOD, 100 MHz) ? 167.7, 159.1, 147.4, 145.3, 141.1, 130.6, 128.6, 126.9, 120.7, 116.9, 115.0, 113.7, 113.5, 54.3, 42.4; MS m / z (M + H ) - calculated for C 17 H 17 NO 4 300.3. found: 300.1; IR (neat) 3488, 3326, 2927, 1646, 1029 cm < ^{-1 &}

20. Synthetic example  20: (E) - N -(4- Chlorobenzyl ) -3- (3,4- Dihydroxyphenyl ) Acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-chlorobenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 86.6%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.42 (d, 1H, Ar-C H CH), 7.30 (m, 4H, Ar- H), 7.01 (d, 1H, J = 2.0 Hz, Ar- H), 6.90 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 8.2 Hz, Ar- H), 6.39 (d, 1H, J = 15.6 Hz, Ar-CHC H) , 4.44 (s, 2H, NHC H ₂ ); _{^{13 C NMR (CDCl 3, 100}} MHz) δ 170.2, 149.8, 147.7, 143.7, 139.9, 134.9, 131.2, 130.6, 129.2, 123.2, 119.1, 117.4, 116.1, 44.5; MS m / z (M + H) ^- calculated for C ₁₆ H ₁₄ ClNO ₃ 304.7. found: 304.1; IR (neat) 3467, 2926, 1652, 1591, 1456, 605 cm -1

21. Synthetic example  21: (E) -3- (3,4- Dihydroxyphenyl ) - N -(4- Sulfamoylbenzyl ) Acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-aminobenzylbenzenesulfonamide (207 mg, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 89.5%; 1H NMR (MeOD, 400 MHz) δ 7.84 (s, 2H, J = 8.4 Hz, Ar- H), 7.45 (d, 2H, J = 8.4 Hz, Ar- H), 7.43 (d, 1H, J = 15.9 Hz, Ar-C H CH) , 7.01 (d, 1H, J = 2.0 Hz, Ar- H), 6.91 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.76 (d, 1H, J = 8.2 Hz, Ar- H), 6.42 (d, 1H, J = 15.7 Hz, Ar-CHC H), 4.53 (s, 2H, NHC H 2); ¹³ C NMR (MeOD, 100 MHz) ? 168.0, 147.5, 145.3, 143.5, 142.4, 141.5, 127.6, 127.5, 126.0, 120.9, 116.6, 115.1, 113.7, 42.3; MS m / z (M + H ) - calculated for C 16 H 16 N 2 O 5 S; 349.4. found: 349.1; IR (neat) 3347, 1648, 1274, 1151 cm < ^-1 >

22. Synthetic example  22: (E) -3- (3,4- Dihydroxyphenyl ) - N - (3- ( Trifluoromethyl ) Ben V) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 3- (trifluoromethyl) benzylamine (0.16 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 80.2%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.61 (s, 1H, Ar- H), 7.53 (m, 3H, Ar- H), 7.43 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.01 (d, 1H, J = 2.0 Hz, Ar- H), 6.91 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 15.6 Hz, Ar-CHC H) , 4.54 (s, 2H, NHC H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.9, 147.5, 145.3, 141.5, 140.3, 131.0, 129.0, 126.8, 123.8, 123.8, 123.6, 123.5, 120.8, 116.5, 115.1, 113.7, 42.3; ^{MS m / z (MH) -} calculated for C 17 H 14 F 3 NO 3 336.3. found: 336.1

IR (neat) 3195, 2924, 1649, 1580, 1440, 1114 cm -1

23. Synthetic example  23: (E) -3- (3,4- Dihydroxyphenyl ) - N - (2-methoxybenzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 2-methoxybenzylamine (0.15 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 5.74%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.40 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.24 (m, 2H, Ar- H), 6.99 (d, 1H, J = 2.0 Hz, Ar- H), 6.95 (d, 1H, J = 7.9 Hz, Ar- H), 6.89 (m, 2H, Ar- H), 6.74 (d, 1H, J = 8.2 Hz, Ar- H), 6.42 ( d, 1H, J = 15.7 Hz , Ar-CHC H), 4.46 (s, 2H, NHC H 2), 3.85 (s, 3H, OC H 3); ¹³ C NMR (MeOD, 100 MHz) ? 167.8, 157.4, 147.4, 145.3, 141.0, 128.4, 128.3, 127.0, 126.1, 120.7, 120.0, 117.0, 115.0, 113.7, 110.0, 54.4, 38.3; MS m / z (M + H ) - calculated for C 17 H 17 NO 4 300.3. found: 300.2; IR (neat) 3258, 1652, 1524, 1247 cm < ^-1 >

24. Synthesis Example 24: (E) -3- (3,4-Dihydroxyphenyl) - N - (2-methylbenzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 2-methylbenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 7.19%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.42 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.24 (t, 1H, J = 4.3 Hz, Ar- H), 7.15 (m, 3H, Ar- H), 6.99 (d, 1H, J = 1.0 Hz, Ar- H), 6.90 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 8.2 Hz, Ar- H), 6.41 (d, 1H, J = 15.7 Hz, Ar-CHC H), 4.46 (s, 2H, NHC H 2), 2.33 (s, 3H, ArC H 3); ¹³ C NMR (MeOD, 100 MHz) ? 167.7, 147.4, 145.3, 141.1, 136.0, 136.0, 129.9, 127.7, 127.1, 126.9, 125.7, 120.7, 116.8, 115.0, 113.7, 41.1, 17.7; ^{MS m / z (MH) -} calculated for C 17 H 17 NO 3 282.3. found: 282.1; IR (neat) 3275, 2928, 1652, 1596, 1523 cm < ^-1 >

25. Synthetic example  25: (E) -3- (3,4- Dihydroxyphenyl ) - N -(2-( Trifluoromethyl ) benzyl ) Acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 2- (trifluoromethyl) benzylamine (0.16 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 7.13%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.68 (d, 1H, J = 8.0 Hz, Ar- H), 7.58 (m, 2H, Ar- H), 7.45 (d, 1H, J = 15.6 Hz, Ar- C H CH), 7.43 (m , 1H, Ar- H), 7.02 (d, 1H, J = 2.0 Hz, Ar- H), 6.92 (dd, 1H, J = 8.0, 2.0 Hz, Ar- H), 6.76 (d, 1H, J = 8.4 Hz, Ar- H ), 6.45 (d, 1H, J = 15.6 Hz, Ar-CHC H ), 4.68 (s, 2H, NHC H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 170.0, 147.5, 145.4, 141.6, 136.9, 132.1, 129.4, 129.0, 127.2, 126.8, 125.6, 125.6, 125.5, 120.1, 116.5, 115.1, 113.7, 39.4; MS m / z (M + Na ) - calculated for C 17 H 17 F 3 NO 3 360.3. found: 360.2; IR (neat) 3279, 2924, 1653, 1598, 1116 cm < ^-1 >

26. Synthetic example  26: (E) -3- (3,4- Dihydroxyphenyl ) - N -(2-( Trifluoromethyl ) Ben V) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 3,4-dimethoxybenzylamine (0.17 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 67.2%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.42 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.00 (m, 1H, J = 2.0 Hz, Ar- H), 6.89 (m, 4H, Ar- H), 6.75 (d, 1H, J = 8.2 Hz, Ar- H), 6.39 (d, 1H, J = 15.6 Hz, Ar- H), 4.40 (s, 2H, NHC H 2), 3.81 ( s, 3H, OC ₃ H ₃ ), 3.79 (s, 3H, OC ₃ H ₃ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.7, 149.2, 148.4, 147.4, 145.3, 141.1, 131.5, 126.9, 120.7, 119.9, 116.9, 115.0, 113.7, 111.6, 111.4, 55.1, 55.0, 42.7; ^{MS m / z (MH) -} calculated for C 18 H 19 NO 5 328.4. found: 328.1; IR (neat) 2927, 1653, 1591, 1514, 1024 cm <" ^{1 &}

27. Synthesis Example 27: (E) -3- (3,4-Dihydroxyphenyl) - N - (3-methylbenzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 3-methylbenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 67.1%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.42 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.18 (t, 1H, J = 7.5 Hz, Ar- H), 7.12 (s, 1H, Ar- H), 7.06 (m, 2H, Ar- H), 7.00 (d, 1H, J = 2.0 Hz, Ar- H), 6.90 (dd, 1H, J = 8.3, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 8.2 Hz, Ar- H), 6.40 (d, 1H, J = 15.7 Hz, Ar-CHC H), 4.42 (s, 2H, NHC H 2), 2.30 (s, 3H, Ar-C H _3); ¹³ C NMR (MeOD, 100 MHz) ? 167.8, 147.4, 145.3, 141.2, 138.5, 137.9, 128.1, 127.9, 127.5, 126.9, 124.3, 120.1, 116.9, 115.1, 113.7, 42.9, 20.1; MS m / z (M + H ) - calculated for C 17 H 17 NO 3 284.3. found: 284.3; IR (neat) 3314, 2924, 1649, 1583, 1441 cm < ^{-1 &}

28. Synthetic example  28: (E) - N -(2- Chlorobenzyl ) -3- (3,4- Dihydroxyphenyl ) Acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 2-chlorobenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 79.6%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.42 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.38 (m, 2H, Ar- H), 7.28 (m, 2H, Ar- H), 7.01 (d, 1H, J = 2.0 Hz, Ar- H), 6.91 (dd, 1H, J = 8.5, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 8.2 Hz, Ar- H), 6.43 (d, 1H, J = 15.7 Hz, Ar-CHC H), 4.56 (s, 2H, NHC H 2); ¹³ C NMR (MeOD, 100 MHz) ? 167.9, 147.5, 145.4, 141.4, 135.7, 133.0, 129.1, 129.0, 128.4, 126.8, 126.7, 120.8, 116.5, 115.0, 113.7, 40.8; MS m / z (M + H) ^- calculated for C ₁₆ H ₁₄ ClNO ₃ 304.7. found: 304.2; IR (neat) 3327, 1649, 1585, 1443, 749 cm < ^{-1 &}

29. Synthetic example  29: (E) - N - (3- Chlorobenzyl ) -3- (3,4- Dihydroxyphenyl ) Acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 3-chlorobenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 53.1%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.43 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.32 (s, 1H, Ar- H), 7.29 (d, 1H, J = 7.5 Hz, Ar- H), 7.24 (m, 2H, Ar- H), 7.01 (d, 1H, J = 2.0 Hz, Ar- H), 6.91 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 8.2 Hz, Ar- H ), 6.40 (d, 1H, J = 15.7 Hz, Ar-CHC H ), 4.46 (s, 2H, NHC H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.9, 147.5, 145.3, 141.4, 141.2, 134.0, 129.7, 127.2, 126.9, 126.8, 125.5, 120.8, 116.6, 115.1, 113.7, 42.3; MS m / z (M + H) ^- calculated for C ₁₆ H ₁₄ ClNO ₃ 302.7. found: 302.1; IR (neat) 3196, 2925, 1647, 1535, 1440, 1183 cm < ^{-1 &}

30. Synthetic example 30: 4 -[2-( Benzylamino ) Thiazol-4-yl} benzene-l, 2- Dior

(322 mg, 1.73 mmol) was dissolved in EtOH (10 mL). To the mixture was added 1-benzylthiourea (287 mg, 1.73 mmol) Lt; RTI ID = 0.0 > reflux. ≪ / RTI > After 12 hours, the mixture was extracted with EtOAc and NaHCO _3. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 72.1%; ≪ ¹ > H NMR (MeOD, 400 MHz); ¹³ C NMR (MeOD, 100 MHz); MS m / z (M + H ) - calculated for C 16 H 14 N 2 O 2 S 298.36. found: IR (neat) cm ^-1

31. Synthesis Example 31: N -Benzyl-2- (3,4-dimethoxyphenyl) thiazol-4-amine

Amine (91.7 mg, 0.39 mmol) was dissolved in acetone (2 mL), and K ₂ CO ₃ (80 mg, 1.17 mmol) was added thereto. Benzyl bromide was slowly added dropwise and stirred for 4 hours. After 4 hours, the acetone was removed and purified by column chromatography.

Yield 76.4%; ≪ ¹ > H NMR (MeOD, 400 MHz); ¹³ C NMR (MeOD, 100 MHz); MS m / z (M + H ) - calculated for C 18 H 18 N 2 O 2 S 326.4. found: IR (neat) cm ^-1

The derivative compounds of the present invention synthesized in the above examples are summarized as follows.

[Chemical Formula 1]

derivative R 3  Cyclohexyl 4  benzyl 5  Phenyl 6  Cyclopentyl 10  4- (trifluoromethyl) phenyl 11  3- (trifluoromethyl) phenyl 12  4-isopropylphenyl 13  4-butylphenyl 14  3-nitrophenyl 15  4-nitrophenyl 16

17  4- (trifluoromethyl) benzyl 18  4-methylbenzyl 19  4-methoxybenzyl 20  4-chlorobenzyl 21  4-Sulfamoylbenzyl 22  3- (Trifluoromethyl) benzyl 23  2-methoxybenzyl 24  2-methylbenzyl 25  2- (Trifluoromethyl) benzyl 26  3,4-dimethoxybenzyl 27  3-methylbenzyl 28  2-chlorobenzyl 29  3-chlorobenzyl

(2)

derivative R1 R2 R3 2 Hydroxyl Hydroxyl

8 acetate acetate Cyclohexyl 9 Hydroxyl Hydroxyl Cyclohexyl

(3)

derivative R 30 benzyl

[Chemical Formula 4]

derivative R 31 benzyl

[Chemical Formula 5: Derivative 1]

[Chemical Formula 6]

derivative R 7 Piperidinyl

Active experiment example

Experimental Example 1: Culture of RAW 264.7 macrophages

RAW 264.7 macrophages were cultured in DMEM medium containing 10% FBS in mouse macrophages.

Experimental Example 2: Analysis of NO production amount

RAW 264.7 macrophages were diluted with DMEM medium containing 10% FBS and dispensed into 96 well-plates at 5 X 10 ⁵ cells / ml per well. 1 μg / ml LPS and samples were treated by concentration. 100 μl of griess reagent (griess A: griess B = 1: 1) was added to 100 μl of the supernatant and incubated for 10 minutes at room temperature. The absorbance was measured at 540 nm NO production amount was quantified.

Experimental Example 3: Cytotoxicity analysis (MTT analysis)

NO, and mitogen analysis, the remaining medium was discarded, 200 ml of fresh medium was added, and the mixture was stabilized for 1 hour. MTT reagent was added so as to be 0.5 mg / ml, and then cultured in a 37 ° C incubator. When 70% of the cells formed crystals, all of the medium was removed, and 100 ml of DMSO was added to dissolve the crystals. Then, the absorbance was measured at 550 nm.

Experimental Example 4: Analysis of NF-kB activity

To measure the activity of NF-κB, we used RAW264.7 macrophages in which expression of SEAP (seceretory alkaline phosphatase) was induced by the NF-κB response element. RAW264.7 cells were treated with LPS for 24 hours under the presence or absence of a sample containing the derivative compound synthesized in the examples, and SEAP activity was measured.

Experimental Example 5: NO production inhibitory activity and NF-κB activation inhibitory activity

compound Cytotoxicity
(IC ₅₀ , uM) NO generation
(IC ₅₀ , uM) NF-κB
SEAP analysis
(IC ₅₀ , uM) Ex vivo model The inhibition rate at 1 mg / kg LPS-treated group mac No production Chlorogenic acid > 1000 > 30 72% Intraperitoneal vasodilation Derivative 1 - > 1000 > 30 0% normal Derivative 2 - 673 > 30 81% Intraperitoneal vasodilation Derivative 3 > 30 15.1 4.0 4% Intraperitoneal vasodilation Derivative 4 - 22.2 4.5 10% Intraperitoneal vasodilation Derivative 5 - 21.4 5.8 40% Intraperitoneal vasodilation Derivative 6 NO toxicity > 30 > 30 Derivative 7 NO toxicity > 30 > 30 Derivative 8 > 10 2.8 1.5 16% Intraperitoneal vasodilation Derivative 9 > 30 16.0 Derivative 10 Derivative 11 > 3 1.6 Derivative 12 > 3 1.9 Derivative 13 > 1 0.6 The derivative 14 > 3 1.4 Derivative 15 > 3 3.8 Derivative 16 > 3 1.5 Derivative 17 > 30 1.7 0.9 Derivative 18 > 30 3.2 2.5 Derivative 19 5.2 4.0 Derivative 20 > 10 1.7 0.6 Derivative 21 NO toxicity > 30 > 30 The derivative 22 > 10 1.5 0.8 Derivative 23 NO toxicity 17.0 The derivative 24 NO toxicity 9.6 Derivative 25 > 30 5.7 The derivative 26 Derivative 27 The derivative 28 Derivative 29 Derivative 30 Derivative 31

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (7)

The following chlorogenic acid derivative compound or a pharmaceutically acceptable acid addition salt thereof:
(E) -4- {3- (cyclohexyloxy) -3-oxoprop-1-en-1-yl} 1,2-phenylene diacetate.
delete A pharmaceutical composition for the treatment or prevention of an inflammatory disease comprising the following chlorogenic acid derivative compound or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, wherein the chlorogenic acid derivative compound is used for the production of NO (Nitric Oxide) or NF-kB wherein the inflammatory disease is septicemia, sepsis shock, ulcerative colitis, arthritis, lupus, or Sjogren ' s syndrome.
(E) -4- {3- (cyclohexyloxy) -3-oxoprop-1-en-1-yl} 1,2-phenylene diacetate; or
(E) -cyclohexyl 3- (3,4-dihydroxyphenyl) acrylate.
delete delete The present invention provides a functional food composition for improving inflammatory diseases, which comprises the following chlorogenic acid derivative compound or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, wherein the chlorogenic acid derivative compound is a functional food composition for improving the production of NO (Nitric Oxide) wherein said inflammatory disease is septicemia, sepsis shock, ulcerative colitis, arthritis, lupus, or Sjogren ' s syndrome.
(E) -4- {3- (cyclohexyloxy) -3-oxoprop-1-en-1-yl} 1,2-phenylene diacetate; or
(E) -cyclohexyl 3- (3,4-dihydroxyphenyl) acrylate.
delete

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