KR101651208B1 - Novel Chlorogenic Acid Derivatives and Anti-Inflammatory and Skin Whitening Composition Comprising the Same - Google Patents

Abstract

The present invention relates to a novel chlorogenic acid derivative compound having an anti-inflammatory activity and a skin whitening activity, the use of the compound and a process for producing the compound. The compounds of the present invention inhibit the NF-kB activation pathway and inhibit the activity of alpha -MSH (alpha -Malanocyte-Stimulating Hormone), thereby having both anti-inflammatory activity and whitening activity. The compound of the present invention can be developed as a therapeutic agent for inflammatory diseases and as a skin lightening agent.

Description

[0001] The present invention relates to a chlorogenic acid derivative compound and an antiinflammatory and skin whitening composition containing the same as an effective ingredient.

The present invention relates to a chlorogenic acid derivative compound and an anti-inflammatory and skin whitening composition comprising the compound as an active ingredient.

Sepsis refers to a state of systemic inflammatory response syndrome (SIRS) caused by infection of microorganisms. It has been accepted that the cause is caused by an increase in the expression of an inflammatory factor caused by the inflammatory reaction of the host by the infection rather than simply by the infection (1, 2). (ROS), reactive nitrogen species (RNS), and the like, as mediators that act as inflammatory mediators, including cytokines, chemokines, adhesion molecules, reactive oxygen species (3-9). These immunomodulators protect the host by activating the immune response to foreign substances, bacteria, and antigenic substances they produce, but if excessive amounts are produced, inflammatory diseases such as SIRS, sepsis, and septic shock will occur .

NF-κB is an important transcription factor that regulates the genetic expression of immunomodulatory factors associated with sepsis. Increased NF-κB activity and increased concentration in the nucleus are associated with high mortality of sepsis and side effects of treatment. Animal model experiments showed that inhibition of NF-κB activity was associated with decreased inflammatory response and decreased organ dysfunction compared to the control group. This fact supports the fact that NF-κB plays a central role in the signaling pathway leading to sepsis, and that the regulation of NF-κB activity is a therapeutic target for sepsis (10-12). NF-κB is composed of a dimer of the Relish (Rel) family. (P65 / 100), and they are commonly used for binding to dimers, DNA, and IκB (inhibior). of NF-κB) molecules (13, 14).

The activation mechanism of NF-kB is as follows. The interaction of NF-kB with a specific binding sequence of a gene promoter is induced by various stimuli. Examples of stimuli include endotoxin, products of gram-positive bacteria, cytokines, T and B cell mitogens, oxidants, and physicochemical stimuli (6, 7, 15). This stimulation phosphorylates the IκB molecule bound to the p65 (Rel A): p50 dimer and the phosphorylated IκB is degraded by ubiquitination. As a result, the liberated p65 (Rel A): p50 dimer migrates from the cytoplasm to the nucleus and acts as a transcription factor in the nucleus. The dimer migrated into the nucleus binds to a specific promoter sequence related to the inflammatory response and promotes the transcription of inflammatory mediators (3). Phosphorylation and degradation of IκB, which acts as an initiator in the activation pathway of NF-κB, is mediated by IκB kinase (IKK), an upper kinase of NF-κB. The IKK complex, an upper kinase of NF-κB, is composed of three components α, β and γ. IKKα is involved in the noncanonical activation pathway of NF-κB, and IKKβ plays an essential role in the canonical activation pathway. On the other hand, IKKγ (NEMO) is known to regulate noncatalytic subunit (16-18).

CAPE (Caffeic acid phenethyl ester) is an active ingredient of propolis ingredient of honeycomb, and it is known to have anti-inflammatory, anticancer, immunomodulating and whitening effects (24). Previous studies have concluded that both CGA and CAPE inhibit the NF-κB activation pathway, but their mechanism of action is different. CGA inhibits phosphorylation and degradation of IκB, thereby inhibiting the activation of p65 (Rel A): p50 dimer from cytoplasm to nucleus and activation of NF-κB (25). However, CAPE does not inhibit phosphorylation and degradation of IκB, but it blocks the NF-κB activation pathway by blocking the migration of p65 (Rel A) to the nucleus (24).

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.

Korean Patent No. 10-0962827 Korean Patent No. 10-1176699 Korean Patent Publication No. 10-2008-0079324

1. Shu, F. L .; Asr B. M. Am J Physiol Lung Cell Mol Physiol. 2006, 290, 622-645. 2. Cohen J. Nature. 2002, 420, 885-891. 3. Edward, A. The Journal of Infectious Diseases. 2003, 187, 364-369. 4. Senftleben, U .; Karin, M. Crit Care Med. 2002, 30, 18-26. 5. Tak, P. P .; Firestein, G. S. J Clin Invest. 2001, 107, 7-11. 6. Ulevitch, R. J. Crit Care Med. 2001, 29, 8-12. 7. Zhang, G .; Ghosh, S. J Clin Invest. 2001, 107, 9-13. 8. Abraham, E. Crit Care Med. 2000, 28, 100-104. 9. May, M. J .; Ghosh, S. Immunol Today. 1998, 19, 80-88. 10. Udalova, I. A .; Knight, J. C .; Vidal, V .; Nedospasov, S. A .; Kwiatkowski, D. J Biol Chem. 1998, 273, 21178-86. 11. Kunsch, C .; Rosen, C. A. Mol Cell Biol. 1993, 13, 6137-46. 12. Hiscott, J .; Marois, J .; Garoufalis, Mol Cell Biol. 1993, 13, 6231-40. 13. Baeuerle, P. A .; Baltimore, D. Cell. 1996, 87, 13-20. 14. Ghosh, S .; May, M.J .; Kopp, E. B. Annu Rev Immunol. 1998, 16, 225-60. 15. Beutler, B. Endotoxin, Curr Opin Microbiol. 2000, 3, 23-8. 16. Lee, M. S .; Journal of Korean Endocrinology Society. 2006, 21, 352-363. 17. DiDonato, J. A .; Hayakawa, M .; Rothwarf, D. M .; Zandi, E .; Karin, M. Nature. 1997, 388, 548-554. 18. Lin, A .; Karin, M. Semin Cancer Biol. 2003, 13, 107-114. 19. Yuexin, X .; Jingwen, C .; Xiao, Y .; Weiwei, Tao .; Fengrong J .; Zhimin Y .; Chang, L. Inflamm. Res. 2010, 59, 871-877. 20. Kono, Y .; Kobayashi, K .; Tagawa, S .; Adachi, K .; Ueda, A .; Sawa, Y. Biochim Biophys Acta. 1997, 1335, 335-42. 21. Kasai, H .; Fukada, S .; Yamaizumi, Z .; Sugie, S.; Mori, H. Food Chem Toxicolm. 2000, 38, 467-71. 22. Dos, S. M. D .; Almeida, M. C .; Lopes, N. P .; De S. G. E. Biol Pharm Bull. 2006, 29, 2236-40. 23. Feng, R .; Lu, Y .; Bowman, L. L .; Qian, Y .; Castranova, V .; Ding, M. J Biol Chem. 2005, 280, 27888-95. 24. Natarajan, K .; Sanjaya, S.; Terrence, R .; Burke, J. R .; Dezider, G .; Bharat, B. A. Proc. Natl. Acad. Sci. 1996, 93, 9090-9095. 25. Hwang, S. J .; Kim, Y. W .; Park, Y. H. Lee, H. J .; Kim, K. W. Inflamm. Res. 2013, DOI 10.1007 / s00011-013-0674-4. 26. Toshihiro, A .; Kohta, K .; Masashi, O .; Hiroyukiya .; Masahiro, M .; Ayako, Y .; Eri O .; Makoto, F .; Harukuni, T .; Jizaemon, F. CHEMISTRY & BIODIVERSITY. 2013, 10, 313-327. 27. Igor, P .; Marko, Z .; Stojan, S. Tetrahedron Lett. 2008, 64, 5191-5199. 28. Arbuj, S. S .; Waghmode, S. B .; Ramaswamy, A. V. Tetrahedron Lett. 2007, 48, 1411-1415. 29. B. Narayana, B. V. Ashalatha, K. Vijaya Raj, N. Suchetha Kumari, Phosphorus, Sulfur, and Silicon. 2006, 181, 1381-1389. 30. Sudershan, R. G .; David, Y. S. Synthetic Communications ㄾ. 2008, 38, 401-410. 31. Herr, R. J .; Kuhler, J. L .; Meckler, H .; Opalka, C. J. Synthesis. 2000, 11, 1569-1574. 32. Yu, H. E .; Oh, S. J .; Ryu, J. K .; Kang, J. S .; Hong, J. T .; Jung, J. K .; Han, S. B .; Seo, S. Y .; Kim, Y. H .; Park, S. K .; Kim, H. M .; Lee, K. H. Phytother. Res, 2013, DOI: 10.1002 / ptr.5033.

The present inventors have sought to find a compound having an anti-inflammatory activity capable of treating an inflammatory disease and having a whitening activity that can inhibit the synthesis of melanin. As a result, we have successfully synthesized chlorogenic acid derivatives modified with the functional group of chlorogenic acid, and found that these synthesized derivatives inhibit the NF-κB activation pathway and inhibit the activity of α-MSH (α-Melanocyte-Stimulating Hormone) The present inventors have completed the present invention by experimentally confirming that the whitening activity is simultaneously present.

Accordingly, an object of the present invention is to provide a novel chlorogenic acid derivative compound.

Another object of the present invention is to provide an anti-inflammatory composition comprising the compound as an active ingredient.

It is still another object of the present invention to provide a skin whitening composition comprising the compound as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for treating or preventing melanin pigment hyperproliferative disorder, which comprises the above compound as an active ingredient.

It is still another object of the present invention to provide a method for producing the above compound.

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 compound represented by the following general formula (1) or (2).

Wherein R is a straight or branched C ₁ -C ₃ alkyl substituted with fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), hydrogen (H), fluorine (F) Chlorine (Cl), bromine (Br) or iodine (I).

Wherein R is a straight or branched C ₁ -C ₃ alkyl substituted with fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), hydrogen (H), fluorine (F) Chlorine (Cl), bromine (Br) or iodine (I).

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 ₃ alkyl represents an alkyl group having 1 to 3 carbon atoms, and includes not only linear n-propyl but also branched isopropyl.

As used herein, the term "straight or branched C ₁ -C ₃ alkyl substituted by fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) Means alkyl as defined, 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.

According to a preferred embodiment of the present invention, the compound of formula (1) or (2) is any one of the following compounds:

4- (benzo [d] [1,3] dioxol-5-yl) -N-benzothiazol-2-amine;

4- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (trifluoromethyl) benzyl) thiazol-2-amine;

4- (benzo [d] [1,3] dioxol-5-yl) -N- (3- (trifluoromethyl) benzyl) thiazol-2-amine;

4- (benzo [d] [1,3] dioxol-5-yl) -N- (4- (trifluoromethyl) benzyl) thiazol-2-amine;

4- (benzo [d] [1,3] dioxol-5-yl) -N- (2-chlorobenzyl) thiazol-2-amine;

4- (benzo [d] [1,3] dioxol-5-yl) -N- (3-chlorobenzyl) thiazol-2-amine;

4- (benzo [d] [1,3] dioxol-5-yl) -N- (4-chlorobenzyl) thiazol-2-amine;

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

4- (2 - ((2- (trifluoromethyl) benzyl) amino) thiazol-4-yl) benzene-1,2-diol;

4- (2 - ((3- (trifluoromethyl) benzyl) amino) thiazol-4-yl) benzene-1,2-diol;

4- (2 - ((4- (trifluoromethyl) benzyl) amino) thiazol-4-yl) benzene-1,2-diol;

4- (2 - ((2-chlorobenzyl) amino) thiazol-4-yl) benzene-1,2-diol;

4- (2 - ((3-chlorobenzyl) amino) thiazol-4-yl) benzene-1,2-diol; And

4- (2 - ((4-chlorobenzyl) amino) thiazol-4-yl) benzene-1,2-diol.

According to another aspect of the present invention, there is provided an anti-inflammatory composition comprising the compound of Formula 1 or Formula 2 as an active ingredient.

The compounds of the present invention have anti-inflammatory activity by inhibiting the NF-kB activation pathway.

The composition of the present invention may be provided in the form of a pharmaceutical composition for the treatment or prevention of inflammatory diseases.

In the present invention, the inflammatory disease is selected from the group consisting of atopic dermatitis, psoriasis, sinusitis, rhinitis, conjunctivitis, asthma, dermatitis, inflammatory collagen vascular disease, glomerulonephritis, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease, sepsis, septic shock, Inflammatory bowel disease, inflammatory bowel disease, type 1 diabetes, type 2 diabetes, arthritis, rheumatoid arthritis, reactive arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, Myocarditis, endocarditis, pericarditis, cystic fibrosis, Hashimoto's thyroiditis, Graves' disease, leprosy, syphilis, Lyme disease, Borreliosis, neurogenic-borrelia, Tuberculosis, sarcoidosis, lupus, homosexual lupus, tuberculous lupus, lupus nephritis, systemic lupus erythematosis, Or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prophylaxis of atopic dermatitis, irritable bowel syndrome, irritable bowel syndrome, Crohn's disease, Schwann disease, fibromyalgia, chronic fatigue syndrome, chronic fatigue immunodeficiency syndrome, Attention deficit 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 dose of the pharmaceutical composition of the present invention is, for example, 0.001 to 1000 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.

The composition of the present invention may be provided in the form of a food composition for the improvement of inflammatory diseases.

The food composition of the present invention includes components that are ordinarily added during the manufacture of food products, 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.

According to another aspect of the present invention, there is provided a skin whitening composition comprising the compound as an active ingredient.

The compounds of the present invention have skin whitening activity by inhibiting the activity of? -MMH (α-Melanocyte-Stimulating Hormone).

According to a preferred embodiment of the present invention, the compound of the present invention is contained in the composition of the present invention in an amount of 0.0001 to 30% by weight, more preferably 0.001 to 30% by weight, still more preferably 0.01 - 30% by weight.

The skin whitening composition of the present invention may be provided in the form of a cosmetic composition.

The cosmetic composition of the present invention may be prepared into any of the formulations conventionally produced in the art, and may be prepared, for example, as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, But are not limited to, cleansing, oils, powder foundations, emulsion foundations, wax foundations and sprays. More specifically, it can be prepared in the form of a soft lotion, a nutritional lotion, a lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.

When the formulation of the present invention is a paste, a cream, a lotion, or a gel, an animal oil, vegetable oil, wax, paraffin, starch, tracer, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide Can be used.

In the case where the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. Especially, in the case of a spray, a mixture of chlorofluorohydrocarbons, propane / Propane or dimethyl ether.

When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives, or ethoxylated glycerol fatty acid esters.

The ingredients included in the cosmetic composition of the present invention include, in addition to the active ingredient and the carrier ingredient, the ingredients conventionally used in cosmetic compositions and include conventional ingredients such as antioxidants, stabilizers, solubilizers, vitamins, May include adjuvants.

According to another aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prophylaxis of a melanin pigment hyperproliferative disorder.

As used herein, the term " hyperpigmentation of melanin pigment "means darkening or darkening of melanin compared to other areas due to excessive increase of melanin in specific areas of the skin or nail. The melanin pigment hyperpigmentation disorder includes, but is not limited to, spots, freckles, senile pigment, or solar lentigines.

The contents of the pharmaceutical composition in the present invention are not described in the same way as those described in the pharmaceutical composition for the treatment or prevention of inflammatory diseases.

The pharmaceutical composition of the present invention can be administered orally or parenterally. In the case of parenteral administration, the composition can be administered by local application to the skin, intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, . In view of the fact that the pharmaceutical composition of the present invention is applied for the treatment or prevention of a melanin pigment hyperpigmentation disease, it is preferable that the composition is topically applied to the skin.

According to a preferred embodiment of the present invention, the pharmaceutical composition of the present invention has an external preparation for skin. The external preparation for skin is not particularly limited and is preferably a powder, a gel, an ointment, a cream, a lotion, a liquid or an aerosol formulation.

According to another aspect of the present invention, the present invention provides a process for preparing a compound represented by the above formula (1), comprising the steps of:

(i) synthesizing compound 3 from compound 4 according to the following reaction scheme a;

[Reaction Scheme a]

(Ii) synthesizing compound 2 from compound 3 according to the following reaction scheme b; And

[Reaction Scheme b]

(Iii) synthesizing compound 1 from compound 2 according to the following reaction scheme c.

[Reaction Scheme c]

Wherein R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of straight or branched C ₁ -C ₆ alkyl substituted with fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) C ₃ alkyl, is hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).)

According to another aspect of the present invention, the present invention provides a process for preparing a compound represented by the above formula (2), comprising the steps of:

(i) synthesizing compound 7 from compound 8 and compound 6 from compound 7 according to the following reaction formula d; And

[Scheme d]

Wherein R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of straight or branched C ₁ -C ₆ alkyl substituted by fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) C ₃ alkyl, is hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).)

(Ii) synthesizing compound 5 from compound 6 according to the following reaction scheme e.

[Reaction Scheme e]

Wherein R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of straight or branched C ₁ -C ₆ alkyl substituted with fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) C ₃ alkyl, is hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).)

The present invention relates to a novel chlorogenic acid derivative compound having an anti-inflammatory activity and a skin whitening activity, the use of the compound and a process for producing the compound. The compounds of the present invention inhibit the NF-kB activation pathway and inhibit the activity of alpha -MSH (alpha -Malanocyte-Stimulating Hormone), thereby having both anti-inflammatory activity and whitening activity. The compound of the present invention can be developed as a therapeutic agent for inflammatory diseases and as a skin lightening agent.

1 is a schematic diagram of a synthetic design of the chlorogenic acid derivative of the present invention.

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

I. Design and Synthesis of Compounds

1. Design of compounds

Chlorogenic acid (CGA) has a structure in which caffeic acid (A) and quinic acid (B) are linked by an ester bond. To improve the pharmacokinetics and ADME of CGA, derivatives of A and B were converted to other functional groups. A portion of caffeic acid was converted to a structure in which thiazole was introduced in consideration of drug-likeness properties, and the structure of catechol was replaced with dioxolane, Respectively. Quinic acid, part B, is substituted with an aromatic ring introduced with an electron withdrawing group (EWG) at ortho, meta and para positions to identify structure- . In order to synthesize the derivatives in consideration of the above two aspects, it is designed as shown in Fig.

2. Synthesis of Compound

2-1. Retro-Synthesis of Class I Derivatives

[Reaction Scheme 1]

As shown in Reaction Scheme 1, the 4- (benzo [d] [1,3] dioxol-5-yl) -N-benzylthiazol-2-amine derivatives (1) Through the benzylation, the aminothiazole (2) was thought to be obtained through the formation of thiols through the cyclization of bromoanthanone (3). Bromoethane (3) was expected to be obtained via the a-bromination of acetophenone (4).

2-2. Retro-Synthesis of Class II Derivatives

[Reaction Scheme 2]

As shown in Reaction Scheme 2, the 4- (2- (benzylamino) thiazol-4-yl) benzene-1,2-diol derivative (5) can be obtained by cyclization of benzylthiourea (6) , And benzylthiourea (6) was thought to be synthesized from benzylamine (8) through thiourea formation.

2-3. Synthesis of Class I Derivatives

[Reaction Scheme 3]

As shown in Reaction Scheme 3, 3,4- (methylenedioxy) acetophenone (4) was dissolved in acetonitrile by the method reported in literature for the synthesis of Class I derivatives of chlorogenic acid derivatives, NBS (1.5 eq ) And p-toluenesulfonic acid (0.1 eq) were reacted at room temperature for 24 hours to obtain desired compound 3 in a yield of 76.4% (27, 28).

[Reaction Scheme 4]

To obtain 4- (benzo [d] [1,3] dioxol-5-yl) thiazol-2-amine (2) as shown in Scheme 4, bromoethanone (3 ) And thiourea (2.0 eq) were dissolved in anhydrous THF under a nitrogen stream and reacted at 66-80 ° C for 24 hours to obtain the desired compound 2 in a yield of 41.3% (29).

[Reaction Scheme 5]

As shown in Scheme 5, aminothiazole (2) and NaH (3.0 eq) were dissolved in anhydrous THF under a nitrogen stream. After 1 hour, a benzyl bromide derivative (1.5 eq) was added and reacted for 10 minutes to obtain a total of 7 4- (benzo [d] [1,3] dioxol-5-yl) -N- (substituted benzyl) thiazole- 2-amine derivatives (compound 1a - 1 g) were obtained (Tables 1 and 30 below).

Compound 1a-1g R ₁ R ₂ R ₃ yield(%) 1a H H H 21.2 1b CF ₃ H H 16.9 1c H CF ₃ H 17.2 1d H H CF ₃ 16.7 1e Cl H H 17.6 1f H Cl H 17.4 1g H H Cl 17.1

2-4. Synthesis of Class II Derivatives

[Reaction Scheme 6]

As shown in Reaction Scheme 6, Compound 7, which is a salt form, was synthesized by reacting benzylamine derivative (8) with HCl in order to synthesize a class II type derivative in the chlorogenic acid derivative. Compound 7 was dissolved in anhydrous THF under a nitrogen stream and then reacted with KSCN (2.0 eq) at 66-80 ° C for 24 hours to obtain a total of 7 benzylthiourea derivatives (compounds 6a to 6g) (Table 2, 31)

Compound 6a-6g R ₁ R ₂ R ₃ yield(%) 6a H H H 19.1 6b CF ₃ H H 12.4 6c H CF ₃ H 11.5 6d H H CF ₃ 10.9 6e Cl H H 17.6 6f H Cl H 10.5 6g H H Cl 11.6

[Reaction Scheme 7]

As shown in Scheme 7, the benzylthiourea derivative (6) was dissolved in ethanol, and 2-chloro-3 ', 4'-dihydroxyacetophenone (1.0 eq) was added thereto at 78-80 ° C (Compound 5a-5g) was obtained (Table 3, 30) by reacting the compound of the present invention for 24 hours to obtain a total of 7 4- (2- (substituted (benzyl) amino) thiazol-4-yl) benzene- .

Compound 5a-5g R ₁ R ₂ R ₃ yield(%) 5a H H H 34.4 5b CF ₃ H H 32.6 5c H CF ₃ H 34.5 5d H H CF ₃ 31.8 5e Cl H H 30.5 5f H Cl H 21.4 5g H H Cl 16.7

3. Synthesis Example of Compound

3-1. Synthesis methods and materials

IR (Infrared) spectra were measured using a Jasco FT / IR 4100 and expressed in cm ^-1 . Mass spectra and HPLC chromatograms were measured using an Agilent 1290 Infinity HPLC system and an Agilent 6460 triple quadrupole mass spectrometer using a Jetstream ™ ESI ion source LC-MS / MS. ^{The 1} H NMR and ¹³ C NMR spectra were measured on a Bruker DPX 400 MHz Spectrometer and a Bruker AVANCE 500 MHz Spectrometer. The chemical shifts were expressed in ppm (parts per million) and the coupling constants in Hz (herts). Silica gel (230-400 mesh, Merk) for column chromatography was used, and Kieselgel 60 F254 plate (Merk) was used for TLC (Thin Layer Chromatography). The reagents and solvents used in this experiment were not subjected to any secondary purification steps but commercial products were used. THF (tetrahydrofuran), an anhydrous solvent used during the reaction, was distilled using sodium hydroxide and benzophenone.

3-2. Synthetic example

Synthesis of 1- (benzo [d] [1,3] dioxol-5-yl) -2-bromoethanone (3)

3,4 (methylenedioxy) acetophenone (2.00 g, 12.2 mmol) and p - toluenesulfonic acid monohydrate (p -TsOH) (0.164 g, 1.22 mmol) was dissolved in a CH ₃ CN (100 mL). N -Bromosuccinimide (NBS) (3.25 g, 18.3 mmol) was added thereto, followed by reaction at room temperature for 24 hours under a nitrogen stream. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane, and extracted with H ₂ O 3 times. The dichloromethane layer was separated, dried over anhydrous Na ₂ SO ₄ , and concentrated to give Compound 3. ^{Yield: 76.4%, 1 H NMR (} CDCl 3, 400 MHz) d 7.53 (dd, J = 8.20, 1.80 Hz, 1H, Ar- H), 7.41 (d, J = 1.70 Hz, 1H, Ar- H), 6.86 (d, J = 8.15 Hz , 1H, Ar- H), 6.06 (s, 2H, OC H 2 O), 4.61 (s, 2H, COC H 2 Br)

Synthesis of 4- (benzo [d] [1,3] dioxo-5-yl) thiazol-2-amine (2)

(3.00 g, 12.3 mmol) was dissolved in ethanol (150 ml) and then thiourea (1.88 g, 12.3 mmol) was added to the solution. 24.7 mmol), and the mixture was reacted at 66-80 ° C for 24 hours in a stream of nitrogen. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO ₄ and purified by column chromatography (THF: Hexane = 1: 3). Yield: 41.3%. ^{1 H NMR (MeOD, 400 MHz} ) d 7.26 (dd, J = 8.08, 1.72 Hz, 1H, Ar- H) 7.20 (d, J = 1.68 Hz, 1H, Ar- H), 6.79 (d, J = 8.12 Hz, 1H, Ar- H), 6.64 (s, 1H, CC H SCNH 2), 5.93 (s, 2H, OC H 2 O)

Synthesis of 4- (benzo [d] [1,3] dioxol-5-yl) -N-benzylthiazol-

Amine (2) (1.00 g, 4.54 mmol) and NaH (0.164 g, 6.82 mmol) were dissolved in THF (15 ml) And then allowed to react at room temperature for 1 hour under a nitrogen stream. Benzyl bromide (1.17 g, 6.82 mmol) was then slowly added dropwise at room temperature and allowed to react for 10 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto. The ethyl acetate layer was separated and dried over anhydrous Na ₂ SO _4, and then to column chromatography (Ethyl acetate: Hexane = 1: 5) to give the compound 1a with. ^{Yield: 21.2%, 1 H NMR (} CDCl 3, 400 MHz) d 7.30 (m, 7H, Ar- H), 6.76 (d, J = 8.08 Hz, 1H, Ar- H), 6.51 (s, 1H, CC _{H SCNH 2), 5.93 (s} , 2H, OC H 2 O), 4.45 (s, 2H, NC H 2 C 6 H 6) 13 C NMR (CDCl 3, 100 MHz) 169.4, 150.9, 147.8, 147.2, 137.7 , 129.4, 128.9, 128.6, 127.7, 119.3, 108.4, 106.7, 101.1, 99.7, 49.8. IR (neat) 3204, 1548, 864 cm -1 MS m / z [M + H] + C 17 H 14 N 2 O 2 S detected: 311.0872, Δm (ppm): 1.70.

Synthesis of 4- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (trifluoromethyl) benzyl) thiazol-

A mixture of 4- (benzo [d] [1,3] dioxol-5-yl) thiazol- 2 -amine ( 2 ) (1.00 g, 4.54 mmol) and NaH (0.164 g, 6.82 mmol) And then allowed to react at room temperature for 1 hour under a nitrogen stream. Then 2- (trifluoromethyl) benzyl bromide (1.63 g, 6.82 mmol) was slowly added dropwise at room temperature and allowed to react for 10 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO _4, and then purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to obtain Compound 1b. Yield ^{16.9%, 1 H NMR (CDCl} 3, 400 MHz) d 7.66 (m, 2H, Ar- H), 7.48 (t, J = 7.60 Hz, 1H, Ar- H), 7.35 (t, J = 7.60 Hz , 1H, Ar- H), 7.26 (d, J = 8.00 Hz, 1H, Ar- H), 7.21 (s, 1H, Ar- H), 6.69 (d, J = 8.05 Hz, 1H, Ar- H) , 6.48 (s, 1H, CC H SCNH ₂ ), 5.90 (s, 2H, OC H ₂ O), 4.67 (s, 2H, NC H ₂ C ₆ H ₆ ) ¹³ C NMR (CDCl ₃ , 100 MHz) , 148.7, 145.4, 144.8, 134.0, 129.8, 126.9, 126.5, 125.0, 123.6, 123.6, 117.4, 105.8, 104.2, 98.6, 97.3, 43.6, 43.6. IR (neat) 3744, 3210, 2897, 2355, 1550, 1358, 865 cm -1 MS m / z [M + H] + C 18 H 13 F 3 N 2 O 2 S detected: 379.0747, Δm (ppm): -6.30

Synthesis of 4- (benzo [d] [1,3] dioxol-5-yl) -N- (3- (trifluoromethyl) benzyl) thiazol-

A mixture of 4- (benzo [d] [1,3] dioxol-5-yl) thiazol- 2 -amine ( 2 ) (1.00 g, 4.54 mmol) and NaH (0.164 g, 6.82 mmol) And then allowed to react at room temperature for 1 hour under a nitrogen stream. Then 3- (trifluoromethyl) benzyl bromide (1.63 g, 6.82 mmol) was slowly added dropwise at room temperature and allowed to react for 10 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO ₄ , and purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to give compound 1c. Yield ^{17.2%, 1 H NMR (CDCl} 3, 400 MHz) d 7.68 (s, 1H, Ar- H), 7.61 (dd, J = Hz, 2H, Ar- H), 7.50 (t, J = Hz, 1H , Ar- H), 7.34 (d , J = Hz, 1H, Ar- H), 7.29 (s, 1H, Ar- H), 6.83 (d, J = Hz, 1H, Ar- H), 6.57 (s 1H, CC H SCNH ₂ ), 5.99 (s, 2H, OC H ₂ O), 4.61 (s, 2H, NC H ₂ C ₆ H ₆ ), ¹³ C NMR (CDCl ₃ , 100 MHz) 147.9, 147.3, 138.9, 130.9, 129.2, 124.5, 124.5, 124.4, 124.4, 119.1, 108.3, 106.6, 101.1, 99.93, 49.24, 30.9. IR (neat) 3740, 3202, 2896, 1550, 1323, 865 cm ^-1 , MS m / z [M + H] ⁺ C ₁₈ H ₁₃ F ₃ N ₂ O ₂ S detected: 379.0734, 2.98.

Synthesis of 4- (benzo [d] [1,3] dioxol-5-yl) -N- (4- (trifluoromethyl) benzyl) thiazol-

A mixture of 4- (benzo [d] [1,3] dioxol-5-yl) thiazol-2-amine (2) (1.00 g, 4.54 mmol) and NaH (0.164 g, 6.82 mmol) And then allowed to react at room temperature for 1 hour under a nitrogen stream. Then 4- (trifluoromethyl) benzyl bromide (1.63 g, 6.82 mmol) was slowly added dropwise at room temperature and allowed to react for 10 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO ₄ and then purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to give compound 1d. Yield 16.7%; _{^{1 H NMR (CDCl 3, 400}} MHz) d 7.60 (d, J = 8.12 Hz, 2H, Ar- H), 7.49 (d, J = 8.08 Hz, 2H, Ar- H), 7.31 (dd, J = 8.12 , 1.72 Hz, 1H, Ar- H ) 7.29 (s, 1H, Ar- H), 6.79 (d, J = 8.08 Hz, 1H, Ar- H), 6.55 (s, 1H, CC H SCNH 2), 5.96 (s, 2H, OC H ₂ O), 4.58 (s, 2H, NC H ₂ C ₆ H ₆ ); _{^{13 C NMR (CDCl 3, 100}} MHz) 168.9, 151.1, 147.9, 147.3, 142.0, 130.1, 129.8, 129.3, 127.8, 125.7, 125.6, 119.9, 108.4, 106.7, 101.1, 100.0, 49.1; IR (neat) 3743, 3200, 2898, 1550, 1422, 936 cm < ^{-1 &} gt ;; MS m / z [M + H ] + C 18 H 13 F 3 N 2 O 2 S detected: 379.0724, Δm (ppm): -0.42.

Synthesis of 4- (benzo [d] [1,3] dioxol-5-yl) -N- (2-chlorobenzyl) thiazol-

A mixture of 4- (benzo [d] [1,3] dioxol-5-yl) thiazol-2-amine (2) (1.00 g, 4.54 mmol) and NaH (0.164 g, 6.82 mmol) And then allowed to react at room temperature for 1 hour under a nitrogen stream. 2-Chlorobenzyl bromide (1.40 g, 6.82 mmol) was then slowly added dropwise at room temperature and allowed to react for 10 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO _4, and then purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to obtain Compound 1e. Yield 17.6%; _{^{1 H NMR (CDCl 3, 400}} MHz) d 7.46 (m, 1H, Ar- H), 7.35 (m, 1H, Ar- H), 7.29 (dd, J = 8.08, 1.68 Hz, 1H, Ar- H) , 7.22 (m, 3H, Ar- H), 6.74 (d, J = 8.08 Hz, 1H, Ar- H), 6.50 (s, 1H, CC H SCNH 2), 5.94 (s, 2H, OC H 2 O ), 4.57 (s, 2H, NC H ₂ C ₆ H ₆ ); ¹³ C NMR (CDCl ₃ , 100 MHz) 169.3, 150.4, 147.9, 147.4, 135.0, 133.5, 129.6, 129.5, 129.0, 128.8, 127.0, 120.0, 108.4, 106.7, 101.1, 99.6, 47.5; IR (neat) 3844, 3742, 2894, 1548, 1351, 809 cm < ^{-1 &} gt ;; MS m / z [M + H] ⁺ C ₁₇ H ₁₃ ClN ₂ O ₂ S detected: 345.0467,? M (ppm): -2.45.

Synthesis of 4- (benzo [d] [1,3] dioxol-5-yl) -N- (3-chlorobenzyl) thiazol-

A mixture of 4- (benzo [d] [1,3] dioxol-5-yl) thiazol-2-amine (2) (1.00 g, 4.54 mmol) and NaH (0.164 g, 6.82 mmol) And then allowed to react at room temperature for 1 hour under a nitrogen stream. 3-Chlorobenzyl bromide (1.40 g, 6.82 mmol) was then slowly added dropwise at room temperature and allowed to react for 10 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO _4, and then purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to give compound 1f. Yield 17.4%; _{^{1 H NMR (CDCl 3, 400}} MHz) d 7.26 (m, 6H, Ar- H), 6.76 (d, J = 8.12 Hz, 1H, Ar- H), 6.51 (s, 1H, CC H SCNH 2), 5.94 (s, 2H, OC H ₂ O), 4.42 (s, 2H, NC H ₂ C ₆ H ₆ ); _{^{13 C NMR (CDCl 3, 100}} MHz) 169.3, 151.1, 147.9, 147.2, 140.0, 134.5, 130.0, 129.4, 127.8, 125.6, 119.9, 108.3, 106.6, 101.1, 99.8, 49.2; IR (neat) 3207, 2892, 1550, 1350, 808, 780 cm < ^{-1 &} gt ;; MS m / z [M + H] ⁺ C ₁₇ H ₁₃ ClN ₂ O ₂ S detected: 345.0468,? M (ppm): -2.49.

Synthesis of 4- (benzo [d] [1,3] dioxol-5-yl) -N- (4-chlorobenzyl) thiazol-

A mixture of 4- (benzo [d] [1,3] dioxol-5-yl) thiazol-2-amine (2) (1.00 g, 4.54 mmol) and NaH (0.164 g, 6.82 mmol) And then allowed to react at room temperature for 1 hour under a nitrogen stream. 4-Chlorobenzyl bromide (1.40 g, 6.82 mmol) was then slowly added dropwise at room temperature and allowed to react for 10 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO _4, and then purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to obtain 1 g of a compound. Yield 17.1%; _{^{1 H NMR (CDCl 3, 400}} MHz) d 7.28 (m, 6H, Ar- H), 6.76 (d, J = 8.08 Hz, 1H, Ar- H), 6.51 (s, 1H, CC H SCNH 2), 5.93 (s, 2H, OC H ₂ O), 4.43 (s, 2H, NC H ₂ C ₆ H ₆ ); _{^{13 C NMR (CDCl 3, 100}} MHz) 168.9, 151.0, 147.9, 147.3, 136.2, 133.5, 129.3, 129.0, 120.0, 108.4, 106.6, 101.1, 99.9, 49.1, 29.7; IR (neat) cm- ¹ ; MS m / z [M + H] ⁺ C ₁₇ H ₁₃ ClN ₂ O ₂ S detected: 345.0468,? M (ppm): -2.50.

Synthesis of 1-benzylthiourea (6a)

HCl was slowly added dropwise to the benzylamine (8a) in an ice bath to synthesize benzylamine-HCl (7a) in a salt form. Then, benzylamine-HCl (7a) (1.00 g, 6.96 mmol) was dissolved in THF (15 ml) together with potassium thiocyanate (1.35 g, 1.40 mmol) and the mixture was stirred at 66-80 ° C for 24 hours Lt; / RTI > Concentrated under reduced pressure after the reaction was finished, which was extracted twice with ethyl acetate and H ₂ O. The ethyl acetate layer was separated, re-extracted with 1N HCl solution and brine, dried over anhydrous Na ₂ SO ₄ , and purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to obtain Compound 6a. Yield: 19.1%; _{^{1 H NMR (CDCl 3, 400}} MHz) d 7.22 - 7.39 (m, 5H, Ar- H), 5.54 (s, 2H, NHC H 2 C 6 H 6).

Synthesis of 1- (2- (trifluoromethyl) benzyl) thiourea (6b)

HCl was slowly added dropwise to the 2- (trifluoromethyl) benzylamine (8b) in an ice bath to synthesize salt 2- (trifluoromethyl) benzylamine-HCl (7b). Then, 2-trifluoromethyl) benzylamine HCl (7b) (1.00 g, 4.73 mmol) was dissolved in THF (15 ml) together with potassium thiocyanate (0.918 g, 9.45 mmol) -The reaction was carried out at 80 ° C for 24 hours. After the reaction was over, the mixture was concentrated under reduced pressure, and extracted twice with ethyl acetate and H ₂ O. The ethyl acetate layer was separated, re-extracted with 1N HCl solution and brine, dried over anhydrous Na ₂ SO ₄ , and purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to obtain compound 6b. Yield: 12.4%.

Synthesis of 1- (3- (trifluoromethyl) benzyl) thiourea (6c)

HCl was slowly added dropwise to 3- (trifluoromethyl) benzylamine (8c) in an ice water bath to synthesize 3- (trifluoromethyl) benzylamine-HCl (7c) in salt form. Then, 3- (trifluoromethyl) benzylamine-HCl (7c) (1.00 g, 4.73 mmol) was dissolved in THF (15 ml) together with potassium thiocyanate (0.918 g, 9.45 mmol) At 66-80 < 0 > C for 24 hours. When the reaction was completed, the reaction mixture was concentrated under reduced pressure and extracted twice with ethyl acetate and H ₂ O. The ethyl acetate layer was separated, re-extracted with 1N HCl solution and brine, dried over anhydrous Na ₂ SO ₄ , and purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to obtain compound 6c. Yield: 11.5%.

Synthesis of 1- (4- (trifluoromethyl) benzyl) thiourea (6d)

HCl was slowly added dropwise to 4- (trifluoromethyl) benzylamine (8d) in an ice bath to synthesize 3- (trifluoromethyl) benzylamine HCl (7d) in the form of salt. Then, 3- (trifluoromethyl) benzylamine HCl (7d) (1.00 g, 4.73 mmol) was dissolved in THF (15 ml) together with potassium thiocyanate (0.918 g, 9.45 mmol) And reacted at 66-80 ° C for 24 hours. After the reaction was over, the mixture was concentrated under reduced pressure, and extracted twice with ethyl acetate and H ₂ O. The ethyl acetate layer was separated, re-extracted with 1N HCl solution and brine, dried over anhydrous Na ₂ SO ₄ , and purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to obtain compound 6d. Yield: 10.9%.

Synthesis of 1- (2-chlorobenzyl) thiourea (6e)

HCl was slowly added dropwise to the 2-chlorobenzylamine (8e) in an ice bath to synthesize 2-chlorobenzylamine-HCl (7e) in the form of salt. Then 2-chlorobenzylamine HCl (7e) (1.00 g, 5.62 mmol) was dissolved in THF (15 ml) along with potassium thiocyanate (1.09 g, 11.23 mmol) and then stirred at 66-80 ° C And reacted for 24 hours. After completion of the reaction, it was concentrated under reduced pressure, and extracted twice with ethyl acetate and H ₂ O. The ethyl acetate layer was separated, re-extracted with 1N HCl solution and brine, dried over anhydrous Na ₂ SO ₄ , and purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to obtain Compound 6e. Yield: 17.6%; _{^{1 H NMR (CDCl 3, 400}} MHz) d 7.20 - 7.39 (m, 4H, Ar- H), 5.59 (s, 2H, NHC H 2 C 6 H 6).

Synthesis of 1- (3-chlorobenzyl) thiourea (6f)

HCl was slowly added dropwise to the 3-chlorobenzylamine (8f) in an ice bath to synthesize 3-chlorobenzylamine-HCl (7f) in the form of salt. Then, 2-chlorobenzylamine HCl (7f) (1.00 g, 5.62 mmol) was dissolved in THF (15 ml) together with potassium thiocyanate (1.09 g, 11.23 mmol) and then at 66-80 ° C And reacted for 24 hours. When the reaction was completed, the reaction mixture was concentrated under reduced pressure and extracted twice with ethyl acetate and H ₂ O. The ethyl acetate layer was separated, re-extracted with 1N HCl solution and brine, dried over anhydrous Na ₂ SO ₄ , and purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to obtain compound 6f. Yield: 10.5%; _{^{1 H NMR (CDCl 3, 400}} MHz) d 7.12 - 7.32 (m, 4H, Ar- H), 5.50 (s, 2H, NHC H 2 C 6 H 6).

1- (4-chlorobenzyl) thiourea (6 g)

HCl was slowly added dropwise to 4-chlorobenzylamine (8 g) in an ice water bath to synthesize 3-chlorobenzylamine-HCl (7 g) in a salt form. Then, 2-chlorobenzylamine.HCl (7 g) (1.00 g, 5.62 mmol) was dissolved in THF (15 ml) together with potassium thiocyanate (1.09 g, 11.23 mmol) and then at 66-80 ° C And reacted for 24 hours. After the reaction was over, the mixture was concentrated under reduced pressure, and extracted twice with ethyl acetate and H ₂ O. The ethyl acetate layer was separated, re-extracted with 1N HCl solution and brine, dried over anhydrous Na ₂ SO ₄ and purified by column chromatography (Ethyl acetate: Hexane = 1: 5) to obtain 6 g of the compound. Yield: 11.6%.

Synthesis of 4- (2- (benzylamino) thiazol-4-yl) benzene-1,2-diol (5a)

1-benzylthiourea (6a) (100 mg, 0.600 mmol) was dissolved in ethanol (15 mL), 2-chloro-1- (3,4- dihydroxyphenyl) ethanone (112 mg, 0.600 mmol) And the mixture was reacted at 66-80 占 폚 under a stream of nitrogen for 24 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and extracted with NaHCO ₃ saturated solution three times. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO ₄ and purified by column chromatography (5% MeOH in Dichloromethane) to give compound 5a. Yield: 34.4%; ^{1 H NMR (MeOD, 400 MHz} ) d 7.38 (m, 2H, Ar- H), 7.33 (m, 2H, Ar- H), 7.23 (m, 2H, Ar- H), 7.12 (m, 1H, Ar H ), 6.75 (d, J = 8.25 Hz, 1 H, Ar- H ), 6.52 (s, 1H, CC H SCNH ₂ ), 4.48 (s, 2H, NC H ₂ C ₆ H ₆ ); ¹³ C NMR (MeOD, 100 MHz) 169.9, 151.0, 144.9, 144.8, 138.6, 128.1, 127.4, 127.3, 126.9, 117.6, 114.9, 113.1, 98.6, 30.2; IR (neat) 3861, 3389, 1547 cm < ^{-1 &} gt ;; MS m / z [M + H] ⁺ C ₁₆ H ₁₄ N ₂ O ₂ S detected: 299.0861,? M (ppm): -3.93.

Synthesis of 4- (2 - ((2- (trifluoromethyl) benzyl) amino) thiazol-4-yl) benzene-1,2-diol (5b)

(100 mg, 0.427 mmol) was dissolved in ethanol (15 mL), and then 2-chloro-1- (3,4-dihydroxyphenyl) Ethanone (79.7 mg, 0.427 mmol), and the mixture was reacted at 66-80 ° C for 24 hours under a nitrogen stream. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, saturated NaHCO ₃ solution was added, and extracted three times. Dried after separation the ethyl acetate layer over anhydrous Na ₂ SO ₄ and purified by column chromatography (5% MeOH in Dichloromethane) to give Compound 5b. Yield: 32.6%; ^{1 H NMR (MeOD, 400 MHz} ) d 7.62 (t, J = 8.00 Hz, 2H, Ar- H), 7.50 (t, J = 7.56 Hz, 1H, Ar- H), 7.33 (t, J = 7.44 Hz , 1H, Ar- H), 7.15 (d, J = 2.40 Hz, 1H, Ar- H), 7.04 (dd, J = 8.20, 2.08 Hz, 1H, Ar- H), 6.66 (d, J = 8.20 Hz , 1H, Ar- H ), 6.48 (s, 1H, CC H SCNH ₂ ), 4.67 (s, 2H, NC H ₂ C ₆ H ₆ ); ¹³ C NMR (MeOD, 100 MHz) 169.3, 151.1, 144.9, 144.7, 137.4, 132.0, 128.8, 127.4, 127.0, 126.5, 125.4, 122.9, 117.6, 114.9, 113.1, 98.3, 44.7; IR (neat) 3367, 1543, 1436, 1308 cm < ^{-1 &} gt ;; MS m / z [M + H] ⁺ C ₁₇ H ₁₃ F ₃ N ₂ O ₂ S detected: 367.0735,? M (ppm): -3.43.

Synthesis of 4- (2 - ((3- (trifluoromethyl) benzyl) amino) thiazol-4-yl) benzene-1,2-diol (5c)

(100 mg, 0.427 mmol) was dissolved in ethanol (15 mL) and then 2-chloro-1- (3,4-dihydroxyphenyl) thiourea (6c) Ethanone (79.7 mg, 0.427 mmol), and the mixture was reacted at 66-80 ° C for 24 hours under a nitrogen stream. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and purified by column chromatography (5% MeOH in Dichloromethane) to obtain Compound 5c. Yield: 34.5%; ^{1 H NMR (MeOD, 400 MHz} ) d 7.62 (s, 1H, Ar- H), 7.66 (d, J = 7.32 Hz, 1H, Ar- H), 7.53 (m, 2H, Ar- H), 7.22 ( d, J = 2.04 Hz, 1H , Ar- H), 7.11 (dd, J = 8.24, 2.04 Hz, 1H, Ar- H), 6.75 (d, J = 8.24 Hz, 1H, Ar- H), 6.56 ( s, 1 H, CC H SCNH ₂ ), 4.60 (s, 2H, NC H ₂ C ₆ H ₆ ); ¹³ C NMR (MeOD, 100 MHz) 169.4, 151.05, 144.9, 144.8, 140.5, 131.0, 130.6, 128.9, 127.4, 124.0, 123.9, 123.6, 117.6, 114.9, 113.0, 98.3, 29.4; IR (neat) 3745, 3366, 1550, 1445, 1326 cm < ^{-1 &} gt ;; MS m / z [M + H ] + C 17 H 13 F 3 N 2 O 2 S detected: 367.0736, Δm (ppm): -3.65.

Synthesis of 4- (2 - ((4- (trifluoromethyl) benzyl) amino) thiazol-4-yl) benzene-1,2-diol (5d)

(100 mg, 0.427 mmol) was dissolved in ethanol (15 mL) and then 2-chloro-1- (3,4-dihydroxyphenyl) thiourea (6d) Ethanone (79.7 mg, 0.427 mmol), and the mixture was reacted at 66-80 ° C for 24 hours under a nitrogen stream. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto and extracted three times. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and purified by column chromatography (5% MeOH in Dichloromethane) to give compound 5d. Yield: 31.8%; ^{1 H NMR (MeOD, 400 MHz} ) d 7.53 (m, 4H, Ar- H), 7.14 (d, J = 2.08 Hz, 1H, Ar- H), 7.03 (dd, J = 8.24, 2.08 Hz, 1H, H ), 6.67 (d, J = 8.24 Hz, 1 H, Ar- H ), 6.49 (s, 1H, CC H SCNH ₂ ), 4.54 (s, 2H, NC H ₂ C ₆ H ₆ ); ¹³ C NMR (MeOD, 100 MHz) 169.4, 151.6, 151.0, 145.3, 145.0, 144.8, 143.6, 127.3, 126.2, 122.5, 122.2, 117.6, 114.9, 114.8, 114.6, 113.1, 45.5; IR (neat) 3366, 1675, 1596, 1543, 1428, 1320 cm < ^{-1 &} gt ;; MS m / z [M + H] ⁺ C ₁₇ H ₁₃ F ₃ N ₂ O ₂ S detected: 367.0737,? M (ppm): -3.82.

Synthesis of 4- (2 - ((2-chlorobenzyl) amino) thiazol-4-yl) benzene-1,2-diol (5e)

(100 mg, 0.498 mmol) was dissolved in ethanol (15 mL) and then 2-chloro-1- (3,4-dihydroxyphenyl) ethanone (93.0 mg , 0.498 mmol), and the mixture was reacted at 66-80 ° C for 24 hours in a nitrogen stream. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and purified by column chromatography (5% MeOH in Dichloromethane) to obtain Compound 5e. Yield: 30.5%; ^{1 H NMR (MeOD, 400 MHz} ) d 7.50 (m, 1H, Ar- H), 7.40 (m, 1H, Ar- H), 7.26 (m, 3H, Ar- H), 7.11 (dd, J = 8.24 , 2.08 Hz, 1H, Ar- H ), 6.74 (d, J = 8.24 Hz, 1H, Ar- H), 6.56 (s, 1H, CC H SCNH 2), 4.63 (s, 2H, NC H 2 C 6 H ₆ ); ¹³ C NMR (MeOD, 100 MHz) 169.38, 150.94, 144.9, 144.8, 135.9, 133.1, 129.1, 129.0, 128.4, 127.3, 126.7, 117.6, 114.9, 113.1, 46.0; IR (neat) 3743, 3366, 1543, 1437, 751 cm < ^{-1 &} gt ;; MS m / z [M + H] ⁺ C ₁₆ H ₁₃ ClN ₂ O ₂ S detected: 333.0451,? M (ppm): 2.41.

Synthesis of 4- (2 - ((3-chlorobenzyl) amino) thiazol-4-yl) benzene-1,2-diol (5f)

After dissolving 1- (3-chlorobenzyl) thiourea (6f) (100 mg, 0.498 mmol) in ethanol (15 mL), 2-chloro-1- (3,4- dihydroxyphenyl) ethanone , 0.498 mmol), and the mixture was reacted at 66-80 ° C for 24 hours in a nitrogen stream. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, saturated NaHCO ₃ solution was added, and extracted three times. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and purified by column chromatography (5% MeOH in Dichloromethane) to give compound 5f. Yield: 21.4%; ^{1 H NMR (MeOD, 400 MHz} ) d 7.41 (s, 1H, Ar- H), 7.23 (m, 4H, Ar- H), 7.11 (dd, J = 8.24, 2.08 Hz, 1H, Ar- H), 6.75 (d, J = 8.16 Hz, 1 H, Ar- H ), 6.55 (s, 1H, CC H SCNH ₂ ), 4.51 (s, 2H, NC H ₂ C ₆ H ₆ ); ¹³ C NMR (MeOD, 100 MHz) 169.5, 150.9, 145.0, 144.8, 141.3, 134.0, 129.6, 127.3, 127.0, 126.9, 117.6, 115.0, 113.1, 104.2, 61.8, 13.8; IR (neat) 3743, 3347, 1547, 778 cm < ^{-1 &} gt ;; MS m / z [M + H] ⁺ C ₁₆ H ₁₃ ClN ₂ O ₂ S detected: 333.0455,? M (ppm): 1.01.

Synthesis of 4- (2 - ((4-chlorobenzyl) amino) thiazol-4-yl) benzene-1,2-diol (5 g)

(100 mg, 0.498 mmol) was dissolved in ethanol (15 mL), and then 2-chloro-1- (3,4-dihydroxyphenyl) ethanone (93.0 mg , 0.498 mmol), and the mixture was reacted at 66-80 ° C for 24 hours in a nitrogen stream. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and saturated NaHCO ₃ solution was added thereto. The ethyl acetate layer was separated, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and purified by column chromatography (5% MeOH in Dichloromethane) to obtain 5 g of a compound. Yield: 6.7%; ^{1 H NMR (MeOD, 400 MHz} ) d 7.35 (m, 4H, Ar- H), 7.21 (s, 1H, Ar- H), 7.11 (m, 1H, Ar- H), 6.75 (d, J = 8.16 1H, Ar- H ), 6.54 (s, 1H, CC H SCNH ₂ ), 4.50 (s, 2H, NC H ₂ C ₆ H ₆ )

¹³ C NMR (MeOD, 100 MHz) 169.6, 150.5, 150.4, 145.0, 144.8, 137.4, 127.1, 124.8, 117.5, 114.9, 113.0, 99.0, 67.5, 53.4, 29.5, 25.1; IR (neat) 3744, 3311, 1610, 1514, 1438, 779 cm < ^{-1 &} gt ;; MS m / z [M + H] ⁺ C ₁₆ H ₁₃ ClN ₂ O ₂ S detected: 333.0464,? M (ppm): -1.48.

Ⅱ. Measurement of biological activity of compounds

To evaluate the anti - inflammatory activity of chlorogenic acid derivatives and the whitening - related activity through inhibition of melanogenesis, two activities were evaluated. The anti-inflammatory activity was investigated through the NF-κB activation inhibitory activity, and the whitening-related activity was examined through the inhibition of melanin formation by the α-MSH inhibitory activity.

In order to determine the inhibitory activity of NF-κB activation, the inhibitory activity of NF-κB activation of each derivative was evaluated by IC ₅₀ value for an animal model in which an inflammatory response was induced by LPS (Lipopolysaccharide). Compounds 1b, 1d, 1e, 5b, and 5e showed relatively high activity as compared to those in which the IC ₅₀ value of chlorogenic acid was 30 μM or less. Particularly, compound 1d showed 40-fold higher inhibitory activity of NF-κB activation than chlorogenic acid. The derivatives except these five derivatives showed lower activity than the control (CGA), but almost all compounds showed inhibitory activity.

In order to measure the whitening-related activity, the melanin production inhibitory activity due to the? -MSH inhibitory activity was evaluated by measuring the IC ₅₀ value. As a result of the activity evaluation, the overall trend was similar to the inhibitory activity of NF-κB activation. In other words, it was confirmed that the order of inhibition of NF-κB activation remained unchanged, and almost all of the compounds showed inhibitory activity although they were low in activity as a whole.

The synthesized chlorogenic acid derivatives have anti-inflammatory activity by inhibiting NF-κB activation, and inhibited melanin production by inhibiting the activity of α-MSH.

compound rescue NF-κB IC ₅₀ values (μM) α-MSH IC ₅₀ value (μM) 1a

- 11.05 1b

15.85 9.60 1c

42.85 15.35 1d

0.75 0.90 1e

2.90 12.75 1f

67.50 12.30 1g

60.25 37.80

compound rescue NF-κB IC ₅₀ values (μM) α-MSH IC ₅₀ value (μM) 5a

1.90 2.10 5b

3.35 9.60 5c

2.60 1.70 5d

- 32.55 5e

2.40 2.00 5f

- - 5g

9.50 7.40

Ⅲ. Review

In this study, chlorogenic acid (CGA), which is expected to be applicable to inflammatory diseases such as sepsis due to its anti - inflammatory activity, was selected as a target substance and its derivatives were synthesized into two classes. Subsequently, NF-κB activation and α-MSH inhibitory activity of the synthesized derivatives were evaluated. To improve pharmacokinetics and ADME of CGA, derivatives of caffeic acid and quinic acid were synthesized. Caffeic acid was converted into a structure in which thiazole was introduced in consideration of drug-likeness property, and a catechol structure was substituted with dioxolane to confirm its importance. Quinic acid was replaced with an aromatic ring introduced with CF3 and Cl as an electron withdrawing group (EWG) in ortho, meta and para positions to investigate the structure-activity relationship . Compounds 1b, 1d, 1e, 5b, and 5e showed relatively high activity when compared to those in which the IC ₅₀ value of chlorogenic acid was 30 μM or less as a result of evaluating NF-κB activation inhibitory activities of the derivatives. Particularly, compound 1d showed 40-fold higher inhibitory activity against NF-κB than chlorogenic acid. Derivatives other than these five derivatives also showed lower activity than the control (CGA), but almost all compounds showed inhibitory activity. As a result of the whitening activity evaluation, the overall tendency was similar to the inhibitory activity of NF-κB activation. In other words, it was confirmed that the order of inhibition of NF-κB activation remained unchanged, and almost all of the compounds showed inhibitory activity although they were low in activity as a whole. In terms of structure activity relationship (SAR), derivatives of the Electron Withdrawing Group (EWG) are substituted with othro positions in the meta and para positions It can be confirmed that it exhibits higher activity than the substituted derivatives.

Taken together, the synthesized CGA derivatives had overall NF-κB inhibitory activity and α-MSH inhibitory activity, among which derivatives were found to have higher activities than CGA. It was confirmed that the synthesized CGA derivatives could be developed as anti - inflammatory and whitening active ingredients.

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 (13)

A compound represented by the following formula (1).
[Chemical Formula 1]

Wherein R is a straight or branched C ₁ -C ₃ alkyl substituted with fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), hydrogen (H), fluorine (F) Chlorine (Cl), bromine (Br) or iodine (I).
A compound according to claim 1, wherein the compound of formula (1) is any one of the following compounds:
4- (benzo [d] [1,3] dioxol-5-yl) -N-benzothiazol-2-amine;
4- (benzo [d] [1,3] dioxol-5-yl) -N- (2- (trifluoromethyl) benzyl) thiazol-2-amine;
4- (benzo [d] [1,3] dioxol-5-yl) -N- (3- (trifluoromethyl) benzyl) thiazol-2-amine;
4- (benzo [d] [1,3] dioxol-5-yl) -N- (4- (trifluoromethyl) benzyl) thiazol-2-amine;
4- (benzo [d] [1,3] dioxol-5-yl) -N- (2-chlorobenzyl) thiazol-2-amine;
4- (benzo [d] [1,3] dioxol-5-yl) -N- (3-chlorobenzyl) thiazol-2-amine; And
4- (benzo [d] [1,3] dioxol-5-yl) -N- (4-chlorobenzyl) thiazol-2-amine.
delete delete delete A cosmetic composition for skin whitening comprising a compound represented by the following formula (1) or (2) as an active ingredient:
[Chemical Formula 1]

Wherein R is a straight or branched C1-C3 alkyl substituted with fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), hydrogen (H), fluorine (F), chlorine Cl), bromine (Br) or iodine (I).

(2)

In Formula 2, R is a linear or branched C1-C3 alkyl substituted with fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), hydrogen (H), fluorine (F) Cl), bromine (Br) or iodine (I).
delete The cosmetic composition according to claim 6, wherein the cosmetic composition is in the form of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation or spray Lt; RTI ID = 0.0 > of: < / RTI >
delete A pharmaceutical composition for treating or preventing a melanin pigment hyperproliferative disorder, comprising a compound represented by the following formula (1) or (2) as an active ingredient, wherein the melanin pigment hyperpigmentation disease is selected from the group consisting of spots, freckles, wherein the composition is solar lentigines.
[Chemical Formula 1]

Wherein R is a straight or branched C1-C3 alkyl substituted with fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), hydrogen (H), fluorine (F), chlorine Cl), bromine (Br) or iodine (I).

(2)

In Formula 2, R is a linear or branched C1-C3 alkyl substituted with fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), hydrogen (H), fluorine (F) Cl), bromine (Br) or iodine (I).
[Claim 11] The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition has an external preparation for skin of a powder, gel, ointment, cream, lotion, liquid or aerosol formulation.
A process for producing a compound represented by the general formula (1) of claim 1, comprising the steps of:
(i) synthesizing compound 3 from compound 4 according to the following reaction scheme a;
[Reaction Scheme a]

(Ii) synthesizing compound 2 from compound 3 according to the following reaction scheme b; And
[Reaction Scheme b]

(Iii) synthesizing compound 1 from compound 2 according to the following reaction scheme c:
[Reaction Scheme c]

Wherein R is a straight or branched C ₁ -C ₃ alkyl substituted with fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) Fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). delete

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