KR101488583B1 - New compounds having skin whitening activity and medical use thereof - Google Patents

Abstract

The present invention relates to novel compounds having skin whitening activity and medicinal uses thereof, and the compounds according to the present invention have a skin whitening activity inhibiting tyrosinase, and therefore, they can be used as skin whitening pharmaceutical compositions, cosmetic compositions or health functional foods .

Description

TECHNICAL FIELD [0001] The present invention relates to a novel compound having skin whitening activity and a medical use thereof,

The present invention relates to novel compounds having skin whitening activity and their medical uses.

The color of human skin is determined by the amount of melanin, carotene and hemoglobin, among which melanin is the most crucial factor. The melanin pigment is a phenolic polymer substance having a complex form of black pigment and protein. It plays a role of blocking ultraviolet rays, and a person who lacks the melanin pigment is very sensitive to sunlight and is likely to burn, and skin cancer is likely to occur at a young age. On the other hand, ultraviolet rays and carcinogens of short wavelength form harmful free radicals in the skin, but melanin plays a useful role to protect proteins and genes by removing such free radicals. Thus, a high amount of melanin means that it has an effective countermeasure to protect the skin from physical or chemical toxicants.

Melanin is produced by a complex process from tyrosine by the action of tyrosinase in the pigment cells. At this time, melanin produced is transferred to skin cells, and melanin is lost with epidermal detachment and disappearing circulation. This process of melanin production is a naturally occurring phenomenon and does not result in excessive production of melanin in normal skin. However, when the skin responds to external stimuli such as ultraviolet rays, environmental pollution, stress, or the like, melanin is excessively produced and is not discharged out of the skin. It is transferred to keratinocyte and accumulates in the skin surface layer to become stain, freckles, Not only does it cause serious cosmetic problems, it also promotes skin aging and skin cancer.

On the other hand, the prevention of melanin pigmentation in the skin has been mainly studied in the following four perspectives. First, to regulate tyrosinase activity, the main enzyme of melanin synthesis, antagonists against tyrosinase synthesis inhibitors or tyrosinase substrates are developed. Secondly, a substance exhibiting toxicity to melanocytes is developed in order to lower the function of melanocyte, which is the place of melanin biosynthesis in animals. Third, a dopa reducing material is developed to prevent the oxidation of dopa, an intermediate metabolite of the melanin synthesis pathway. Finally, a first enzyme tyrosinase, a melanin producing mechanism, and dopachrome tautomerase (DOPA chrome), a second enzyme that catalyzes the conversion of 5,6-dihydroxyindole-2-carboxyic acid into DHICA DOPA chrome tautomerase) and the activity of a third enzyme that catalyzes the conversion of DHICA to indole-5,6-quinone-2-carboxylic acid .

In recent years, oriental women prefer white, clean skin like white whiting, and since they use it as an important criterion of beauty, they are actively developing a whitening agent to treat skin pigmentation abnormalities and meet beauty needs.

In the development of a whitening agent, there is known a method of decolorizing by reducing the produced melanin pigment and a method of inhibiting the activity of tyrosinase, an enzyme that forms a melanin pigment. However, it is known that the whitening agent using tocopherol or vitamins used for reducing the melanin pigment has a very small discoloring effect of the melanin pigment. Accordingly, inhibitors that inhibit the activity of tyrosinase and inhibit the production of melanin pigment have been attracting attention.

As a whitening ingredient in the conventional cosmetics field, for example, substances inhibiting tyrosinase enzyme activity such as kojic acid and arbutin, hydroquinone, L-ascorbic acid, And derivatives thereof and various plant extracts have been used. However, the use thereof is limited due to poor stability in the prescription system and coloration, generation of odor, efficacy at a living body level, unclear effects, and safety problems. In addition, Kojisan inhibits enzyme activity by adsorbing copper ions present in the active site of tyrosinase. However, it has been proved that it causes instability, skin side effects, and liver cancer as a result of recent animal tests. Vitamin C and its derivatives are difficult to use as raw materials for cosmetics because of their good oxidative instability. Hydroquinone has excellent whitening effect on the skin, but it does not cause skin irritation such as allergenicity, toxicity to melanocytes, It is highly irritating to the public and is recently prohibited to use as a carcinogen. In addition, arbutin is a derivative in which hydroquinone is conjugated with glucopyranoside. As a result, hydroquinone is less toxic to human body, and inhibits the synthesis of melanin pigment, resulting in an increase in melanin pigmentation However, it has a disadvantage in that it is partially decomposed by skin enzymes. Therefore, it is urgent to develop a safe alternative whitening agent which has excellent efficacy and few side effects even in small amounts.

Korean Patent Laid-Open Publication No. 2006-0031007 discloses a cosmetic composition for preventing skin aging and whitening using a chondroma extract and a compound isolated therefrom, but discloses a compound having completely different chemical structure from the compound of the present invention .

It is an object of the present invention to provide novel compounds having skin whitening activity and medicinal uses thereof.

In order to achieve the above object, the present invention provides a compound represented by the following general formula (1), an isomer thereof and a mixture thereof:

[Chemical Formula 1]

Wherein each of R ¹ to R ⁴ may be the same or different and is any one of H, OH, halogen, C 1 to C 4 alkyl or C 1 to C 4 alkoxy, and X and Y may be H or CH ₃ .

More specifically, the compound (2 Z) -2- (4- hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H ) -one, (2 Z) -2- (4- methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (4- hydroxy-3-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one , (2 Z) -2- (3- hydroxy-4-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3-ethoxy-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (3,4- dihydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3- bromo-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (2,4- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one , (2 Z) -2- (3,4- dimethoxy-ben Vinylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (2 Z) -2- (4- hydroxy-3,5- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one, (2 Z) -2- (3,4,5- trimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (4- hydroxy-benzylidene ) Benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one and ( Z ) -2- (2- hydroxybenzylidene) benzo [ d ] thiazolo [ a] imidazole -3 (2 H) - one, (Z) -2- (4- methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one , (Z) -2- (4- hydroxy-3-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3-hydroxy-4-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3-ethoxy -4 -hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2,4- dihydroxy-benzylidene) benzo [d ] Thiazolo [ 3,2- a] -3 (2 H) imidazol-on, (Z) -2- (3,4- dihydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole- 3 (2 H) - one, (Z) -2- (3- bromo-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one , (Z) -2- (2,4- dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3, 4-dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3,4- dimethoxy-benzylidene) benzo [d ] Thiazolo [3,2- a ] imidazol-3 ( 2H ) -one and ( Z ) -2- (3,5- dibromo-4-hydroxybenzylidene) benzo [ d ] thiazolo [ 3,2- a] imidazole -3 (2 H) - one and (Z) -2- (3,4,5- trimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] already (2 H ) -one. ≪ / RTI >

The compounds according to the present invention may be provided in the form of their pharmaceutically acceptable salts, wherein the pharmaceutically acceptable salts thereof include hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, A salt of any one selected from the group consisting of maleic acid salts, maleic acid salts, gluconic acid salts, succinic acid salts, formic acid salts, trifluoroacetic acid salts, oxalic acid salts, fumaric acid salts, methanesulfonic acid salts, benzenesulfonic acid salts, para toluenesulfonic acid salts and camphorsulfonic acid salts .

The present invention also provides a skin whitening composition comprising the above-mentioned compound as an active ingredient. The composition may be provided in the form of a cosmetic composition, a pharmaceutical composition or a health functional food.

The pharmaceutical compositions may further comprise suitable carriers, excipients or diluents conventionally used in the manufacture of pharmaceutical compositions.

Examples of the carrier, excipient or diluent which can be used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.

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

In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose sucrose), lactose, gelatin, and the like.

In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of suppository bases include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like.

The amount of the compound which is an active ingredient of the pharmaceutical composition according to the present invention may vary depending on the age, sex, body weight and disease of the patient, but is preferably 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / Or several times.

Further, the dose of the compound according to the present invention may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.

The pharmaceutical composition may be administered to mammals such as rats, mice, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intratracheal, intrauterine or intracerebroventricular injections.

The compound according to the present invention has a stability of not less than 2 g / kg of 50% lethal dose (LC ₅₀ ) and can be used in the pharmaceutical composition of the present invention.

In addition, the cosmetic composition may contain, in addition to the compound according to the present invention as an active ingredient, conventional additives such as stabilizers, solubilizers, vitamins, pigments and flavors, and carriers.

The cosmetic composition may be prepared in any form conventionally produced in the art and may be in the form of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, oil, powder foundation, emulsion foundation, Wax foundation, spray, and the like. However, the present invention is not limited thereto. More specifically, it can be manufactured in the form of a sun cream, a flexible lotion, a convergent lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a pack, a spray or a powder.

When the formulation is a paste, cream or gel, an animal oil, a vegetable oil, a wax, a paraffin, a starch, a tracer, a cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as a carrier component .

When the formulation is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, chlorofluorohydrocarbons, propane / Or propellants such as dimethyl ether.

When the formulation is a solution or an emulsion, a solvent, a solubilizing 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, - butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid esters of sorbitan.

When the formulation is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspension such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, a microcrystalline cellulose , Aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

The health functional food may be provided in the form of a powder, a granule, a tablet, a capsule, a syrup or a drink. The health functional food may be used together with food or food additives other than the compound according to the present invention, Can be suitably used according to the method of The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.

The effective dose of the compound contained in the health functional food may be used in accordance with the effective dose of the pharmaceutical composition, but may be less than the above range for the purpose of health and hygiene or long-term intake for health control purposes , It is clear that the active ingredient can be used in an amount exceeding the above range since there is no problem in terms of safety.

There is no particular limitation on the kind of the above health functional food and examples thereof include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, , Drinks, alcoholic beverages and vitamin complexes.

Since the compounds according to the present invention have skin whitening activity inhibiting tyrosinase, they can be usefully used as a skin whitening pharmaceutical composition, a cosmetic composition or a health functional food.

Figure 1 shows the tyrosinase inhibitory activity of the compounds according to the invention. ND means that no inhibitory activity was detected.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

< Example  1> 6 (7) -Methyl- [1,3] thiazolo [3,2- a ] Benzimidazole-3 (2 H ) -One [6 (7) -methyl- [1,3] thiazolo [3,2- a ] benzimidazole-3 (2 H ) -one] Synthesis of (9)

[Reaction Scheme 1]

(a) CS ₂ , NaOH, H ₂ O, EtOH, reflux, 5 h; (b) NaOAc, Ac ₂ O, reflux, 5 min; (c) NaOAc, AcOH, 80 &lt; 0 &gt; C, 1-3 days.

One. 5- methyl -One H - Benzo [ d ] Imidazole -2- Thiol  [5- methyl -1H- benzo [d] imidazole-2-thiol] (8)

3,4-Diaminotoluene (65.48 mmol, 8.0 g) was dissolved in water (12 mL), ethanol (80 mL) and sodium hydroxide (NaOH) (1.16 equivalents, 3.03 g ) Mixed solution. Carbon disulfide (CS ₂ ) (1.16 eq., 4.58 mL) is slowly added dropwise to the reaction mixture at 0 ° C and refluxed for 5 hours. After cooling the reaction mixture to room temperature, the charcoal is gradually added in portions and refluxed for 10 minutes. The reaction mixture is poured into hot water and the insoluble solid is filtered off. The filtrate is treated with 50% acetic acid and stored in the refrigerator. The resulting solid was filtered and washed with excess water to obtain Compound 8.

Brown solid; Reaction time 5 hours; Yield 55.8%;

^{1 H NMR (500MHz, DMSO- d} 6) δ 12.38 (brs, 1 H), 7.00 (d, 1 H, J = 8.0 Hz), 6.93 (s, 1 H), 6.92 (d, 1 H, J = 8.0 Hz), 2.32 (s, 3 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) ? 168.4, 133.1, 132.3, 130.9, 123.9, 110.3, 109.8, 21.6.

2. 6 (7) - methyl - [l, 3] thiazolo [3,2- a ] Benzimidazole -3 (2 H ) -One [6 (7) - methyl - [1,3] thiazolo [3,2- a ] benzimidazole-3 (2 H ) -one] Synthesis of (9)

5-methyl -1 H - benzo [d] imidazol-2-one (8) (5-methyl- 1 H -benzo [d] imidazole-2-thiol) (18.27 mmol, 3 g), bromoacetic acid ( bromoacetic acid (1.0 eq, 2.53 g) and sodium acetate (1.0 eq, 1.5 g) in acetic anhydride (30 mL) was refluxed for 5 minutes. To the reaction mixture was added 1 M sodium hydroxide aqueous solution (1 M NaOH aqueous solution) and then extracted with methylene chloride. The organic layer was evaporated after drying with MgSO ₄ and filtered. The resulting residue was purified by silica gel column chromatography using ethyl acetate and methylene chloride as developing solvent to obtain thiazolobenzimidazole compound 9 as a regioisomer mixture.

Light yellow solid; Reaction time 5 minutes; Yield 34.8%;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.70 (d, 1 H, J = 8.4 Hz), 7.65 (d, 1 H, J = 0.8 Hz), 7.40 (d, 1 H, J = 8.0 Hz), 7.32 (d, 1 H, J = 0.8 Hz), 7.11 (dd, 1 H, J = 0.8, 8.4 Hz), 7.04 (dd, 1 H, J = 0.8, 8.4 Hz), 4.27, 4.26 (each s, 4 H), 2.40 (s, 6 H); _{^{13 C NMR (100MHz, CDCl 3}} ) δ 164.9, 164.7, 158.6, 157.2, 150.3, 147.9, 136.3, 134.4, 130.3, 128.1, 127.3, 125.1, 119.4, 118.7, 112.9, 112.1, 39.1, 39.1, 22.0, 21.8.

3. 2- (substituted Benzylidene ) -6 (7) - methyl - [l, 3] thiazolo [3,2- a ] Benzimidazole -3 (2 H ) -One [2- ( substituted benzylidene ) -6 (7) - methyl - [1,3] thiazolo [3,2- a ] benzimidazole-3 (2 H ) -one] (9a-9k) Synthesis of

A mixture of thiazolobenzimidazolone (0.29 - 0.39 mmol), substituted benzaldehydes (1.0 - 1.1 eq) and sodium acetate (3.0 eq.) In acetic acid Lt; RTI ID = 0.0 &gt; 80 C. &lt; / RTI &gt; After water was added to the reaction mixture, the resulting precipitate was filtered and washed with water to obtain the target compounds 9a-9k as a positional isomer mixture.

1) (2 Z) -2- ( 4- hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(2 Z ) -2- (4-Hydroxybenzylidene) -6 (7) -methylbenzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 9a]

Green solid; Reaction time 20 hours; Yield 61.9%; Melting point> 300 ℃;

^{1 H NMR (500 MHz, DMSO-} d 6) δ 10.42 (brs, 2 H), 7.94 (s, 1 H), 7.93 (s, 1 H), 7.75 (d, 1 H, J = 8.0 Hz), 7.71 (d, 1 H, J = 1.0 Hz), 7.57 and 7.56 (each d, each 2 H, J = 8.0 Hz), 7.49 (d, 1 H, J = 8.0 Hz), 7.41 (s, 1 H) , 7.17 (dd, 1 H, J = 1.0, 8.5 Hz), 7.13 (d, 1 H, J = 8.0 Hz), 6.94 and 6.94 (each d, each 2 H, J = 8.0 Hz), 2.42 (s, 3 H), 2.38 (s, 3 H); ^{13 C NMR (100MHz, DMSO- d} 6) δ 161.3, 160.0, 159.9, 153.9, 153.1, 149.2, 146.9, 137.1, 137.0, 135.8, 134.3, 133.6, 130.9, 128.7, 127.2, 125.5, 124.2, 120.7, 119.8, 119.3, 117.2, 113.0, 112.4, 21.9, 21.8.

2) (2 Z) -2- (4- methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(2 Z ) -2- (4-Methoxybenzylidene) -6 (7) -methylbenzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 9b]

Light yellow solid; Reaction time 3 days; Yield 70.2%; Melting point 208.5 - 209.4 캜;

¹ H NMR (500 MHz, CDCl ₃ ) ? 7.98 (s, 1H), 7.97 (s, 1H), 7.87 (d, 1H, J = 8.5 Hz), 7.83 (each d, each 2 H, J = 8.0 Hz), 7.52 (d, 1 H, J = 9.0 Hz), 7.44 (s, 1 H), 7.17 (d, 1 H, J = 8.0 Hz), 7.13 ( (d, 1H, J = 8.0 Hz), 7.01 and 7.01 (each d, each 2H, J = 9.0 Hz), 3.86 ); _{^{13 C NMR (100MHz, CDCl 3}} ) δ 162.0, 160.1, 159.9, 153.7, 152.9, 149.2, 146.9, 136.8, 136.7, 136.1, 134.6, 132.7, 130.7, 128.5, 127.1, 125.7, 125.3, 122.0, 119.8, 119.1, 115.1, 113.2, 112.5, 55.7, 22.0, 21.8.

3) (2 Z) -2- ( 4- hydroxy-3-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H imidazole) -one [(2 Z) -2- (4 -Hydroxy-3-methoxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one; 9c]

Green solid; Reaction time 24 hours; Yield 58.2%; Melting point 213.6 - 214.3 캜;

^{1 H NMR (500MHz, DMSO- d} 6) δ 10.10 (s, 2 H), 7.97 (s, 1 H), 7.96 (s, 1 H), 7.77 (d, 1 H, J = 8.5 Hz), 7.73 (s, 1 H), 7.50 (d, 1 H, J = 8.5 Hz), 7.44 (s, 1 H), 7.28 (s, 2 H), 7.19 (d, 2 H, J = 8.0 Hz), 7.18 (d, 1 H, J = 8.0 Hz), 7.14 (d, 1 H, J = 8.5 Hz), 6.96 (d, 2 H, J = 8.5 Hz), 3.84 (s, 6 H), 2.43 (s, 3 H), 2.39 (s, 3 H); ^{13 C NMR (100MHz, DMSO- d} 6) δ 160.0, 159.9, 150.8, 149.2, 148.8, 147.0, 137.4, 135.8, 134.4, 130.9, 128.7, 127.3, 125.5, 125.3, 124.7, 121.0, 119.9, 119.4, 117.0, 115.3, 113.0, 112.4, 56.4, 21.9, 21.8.

4) (2 Z) -2- ( 3- hydroxy-4-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one [(2 Z) -2- (3 -Hydroxy-4-methoxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one; 9d]

Green solid; Reaction time 24 hours; Yield 56.8%; Melting point 229.8 - 230.9 캜;

^{1 H NMR (500MHz, DMSO- d} 6) δ 9.60 (brs, 2 H, 7.91 (s, 1 H), 7.90 (s, 1 H), 7.77 (d, 1 H, J = 8.0 Hz), 7.73 ( s, 1 H), 7.51 ( d, 1 H, J = 8.0 Hz), 7.44 (s, 1 H), 7.20 (m, 3 H), 7.15 (d, 1 H, J = 8.0 Hz), 7.14 ( s, 2 H), 7.09 ( d, 2 H, J = 8.5 Hz), 3.84 (s, 6 H), 2.43 (s, 3 H), 2.40 (s, 3 H); 13 C NMR (100MHz, DMSO - d ₆ ) ? 159.9, 159.8, 153.9, 153.1, 151.3, 149.2, 147.8, 147.0, 137.2, 137.0, 135.8, 134.4, 130.9, 128.7, 127.3, 126.0, 125.5, 124.9, 121.9, 119.9, 119.4, 116.7, 113.2 , 113.0, 112.4, 56.4, 21.9, 21.8.

5) (2 Z) -2- (3-ethoxy-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one [(2 Z) -2- (3 -Ethoxy-4-hydroxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one; 9e]

Green solid; Reaction time 24 hours; Yield 50.5%; Melting point 200.2 - 200.8 캜;

^{1 H NMR (500MHz, DMSO- d} 6) δ 10.02 (s, 2 H), 7.95 (s, 1 H), 7.94 (s, 1 H), 7.76 (d, 1 H, J = 8.5 Hz), 7.72 (s, 1H), 7.50 (d, 1H, J = 8.0 Hz), 7.43 (s, 1H), 7.24 J = 8.5 Hz), 6.96 (d, 2H, J = 8.0 Hz), 4.09 (q, 4H, J = 7.0 Hz), 2.42 (t, 6H, J = 7.0 Hz); ^{13 C NMR (100MHz, DMSO- d} 6) δ 160.0, 159.8, 153.8, 153.0, 151.1, 149.2, 147.9, 147.0, 137.4, 137.3, 135.8, 134.3, 130.9, 128.7, 127.2, 125.5, 125.3, 124.7, 120.9, 119.9, 119.4, 117.1, 116.2, 113.0, 112.4, 64.6, 21.9, 21.8, 15.3.

6) (2 Z) -2- ( 3,4- dihydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(2 Z ) -2- (3,4-Dihydroxybenzylidene) -6 (7) -methylbenzo [ d ] thiazolo [3,2- a ] imidazol-3 (2 H ) -one; 9f]

Green solid; Reaction time 24 hours; Yield 55.2%; Melting point 284.0 - 285.2 DEG C;

^{1 H NMR (500MHz, DMSO- d} 6) δ 9.77 (brs, 4 H), 7.88 (s, 1 H), 7.87 (s, 1 H), 7.76 (d, 1 H, J = 8.0 Hz), 7.72 (s, 1 H), 7.50 (d, 1 H, J = 8.5 Hz), 7.43 (s, 1 H), 7.17 (d, 1 H, J = 8.5 Hz), 7.14 (d, 1 H, J = 8.0 Hz), 7.13 (s, 2 H), 7.08 (d, 2 H, J = 7.5 Hz), 6.90 (d, 2 H, J = 7.5 Hz), 2.43 (s, 3 H), 2.39 (s, 3 H); ^{13 C NMR (100MHz, DMSO- d} 6) δ 160.0, 159.9, 153.9, 153.2, 150.2, 149.2, 147.0, 146.7, 137.5, 137.4, 135.8, 134.3, 130.9, 128.7, 127.2, 125.5, 125.3, 124.6, 120.5, 119.8, 119.3, 117.3, 117.1, 113.0, 112.4, 21.9, 21.8.

7) (2 Z) -2- ( 3- bromo-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one [(2 Z) -2- (3 -Bromo-4-hydroxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one; 9g]

Light yellow solid; Reaction time 24 hours; Yield 61.2%; Melting point 260.9 - 261.8 캜;

¹ H NMR (500 MHz, DMSO- d ₆ ) ? 11.28 (s, 2H), 7.93 (s, 1H), 7.92 , J = 8.0 Hz), 7.70 (s 1 H), 7.53 (d, 2 H, J = 8.5 Hz), 7.49 (d, 1 H, J = 8.5 Hz), 7.42 (s, 1 H), 7.16 ( d, 1 H, J = 8.5 Hz), 7.12 (d, 1 H, J = 8.0 Hz), 7.11 (d, 2 H, J = 8.0 Hz), 2.41 (s, 3 H), 2.38 (s, 3 H); ^{13 C NMR (100MHz, DMSO- d} 6) δ 159.7, 159.6, 157.5, 153.6, 152.8, 149.2, 146.9, 136.7, 135.9, 135.5, 135.4, 134.5, 131.4, 130.9, 128.7, 127.3, 125.9, 125.6, 122.6, 119.9, 119.4, 117.7, 113.0, 112.4, 111.0, 21.9, 21.8.

8) (2 Z) -2- ( 2,4- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [ (2 Z ) -2- (2,4-Dimethoxybenzylidene) -6 (7) -methylbenzo [ d ] thiazolo [3,2- a ] imidazol-3 (2 H ) -one; 9h]

Light yellow solid; Reaction time 30 hours; Yield 45.0%; Melting point 217.8 - 218.3 캜;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.34 (s, 2 H), 7.86 (d, 1 H, J = 8.0 Hz), 7.82 (s, 1 H), 7.49 (d, 1 H, J = 8.8 Hz ), 7.47 (d, 2 H , J = 8.8 Hz), 7.42 (s, 1 H), 7.14 (d, 1 H, J = 7.6 Hz), 7.10 (d, 1 H, J = 8.4 Hz), 6.59 (d, 2H, J = 2.0, 8.8 Hz), 6.44 (d, 2H, J = 2.0 Hz), 3.89 , 2.45 (s, 3 H); _{^{13 C NMR (100MHz, CDCl 3}} ) δ 164.0, 160.6, 160.4, 160.2, 149.2, 146.9, 135.9, 134.4, 132.5, 132.4, 131.5, 130.8, 128.6, 127.0, 125.1, 121.7, 119.7, 119.0, 115.5, 113.2, 112.4, 105.9, 98.8, 55.8, 22.0, 21.8.

9) (2 Z) -2- ( 3,4- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [ (2 Z ) -2- (3,4-Dimethoxybenzylidene) -6 (7) -methylbenzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 9i]

Yellow solid; Reaction time 30 hours; Yield 43.8%; Melting point 199.2 - 199.7 캜;

¹ H NMR (400 MHz, CDCl ₃ ) ? 7.94 (s, 1H), 7.93 (s, 1H), 7.85 (d, 1H, J = 8.4 Hz) , 1 H, J = 8.0 Hz ), 7.43 (s, 1 H), 7.20 (d, 2 H, J = 8.4 Hz), 7.15 (d, 1 H, J = 8.0 Hz), 7.11 (d, 1 H , J = 8.0 Hz), 7.06 (s, 2 H), 6.94 (d, 2 H, J = 8.4 Hz), 3.95 (s, 6 H), 3.92 (s, 6 H), 2.47 (s, 3 H ), 2.45 (s, 3 H); _{^{13 C NMR (100MHz, CDCl 3}} ) δ 160.0, 159.8, 153.5, 152.8, 151.8, 149.6, 149.3, 147.0, 136.9, 136.8, 136.1, 134.7, 130.7, 128.5, 127.2, 126.0, 125.4, 125.1, 122.4, 119.9, 119.2, 113.3, 112.8, 112.5, 111.7, 56.3, 56.2, 22.0, 21.8.

10) (2 Z) -2- ( 4- hydroxy-3,5-dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazol-3 (2 H) - one [(2 Z) -2- (4 -Hydroxy-3,5-dimethoxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one ; 9j]

Dark yellow solid; Reaction time 24 hours; Yield 55.6%; Melting point 247.2 - 247.8 캜;

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.46 (brs, 2 H), 7.91 (s, 1 H), 7.90 (s, 1 H), 7.72 (d, 1 H, J = 8.4 Hz), 7.67 (s 1 H), 7.46 ( d, 1 H, J = 8.4 Hz), 7.39 (s, 1 H), 7.13 (d, 1 H, J = 8.4 Hz), 7.09 (d, 1 H, J = 8.4 Hz), 6.94 (s, 4H), 3.81 (s, 12H), 2.38 (s, 3H), 2.35 (s, 3H); ^{13 C NMR (100MHz, DMSO- d} 6) δ 159.8, 159.7, 153.8, 153.0, 149.2, 148.9, 146.9, 140.0, 137.6, 137.5, 135.8, 134.4, 130.8, 128.6, 127.2, 125.5, 123.5, 121.2, 119.9, 119.4, 113.0, 112.4, 109.0, 56.8, 21.9, 21.8.

11) (2 Z) -2- ( 3,4,5- trimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one [(2 Z) -2- (3,4,5 -Trimethoxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one; 9k]

Light yellow solid; Reaction time 23 hours; Yield 65.4%; Melting point 131.4 - 132.2 DEG C;

¹ H NMR (400 MHz, CDCl ₃ ) ? 7.94 (s, 1H), 7.93 (s, 1H), 7.86 (d, 1H, J = 8.4 Hz) , 1 H, J = 8.4 Hz ), 7.44 (s, 1 H), 7.17 (d, 1 H, J = 8.4 Hz), 7.12 (d, 1 H, J = 8.4 Hz), 6.81 (s, 4 H ), 3.93 (s, 12 H), 3.91 (s, 6 H), 2.48 (s, 3 H), 2.46 (s, 3 H); _{^{13 C NMR (100MHz, CDCl 3}} ) δ 159.7, 159.6, 153.9, 153.4, 152.6, 149.3, 147.0, 140.9, 136.9, 136.8, 136.3, 134.9, 130.7, 128.5, 128.5, 127.3, 125.5, 124.2, 120.0, 119.3, 113.3, 112.5, 107.9, 61.3, 56.5, 22.0, 21.8.

< Example  2> Benzo [ d ]tea Azulo [3,2- a ] Imidazole -3 (2 H ) -One [Benzo [ d ] thiazolo [3,2- a ] imidazol-3 (2 H ) -one] Synthesis of (10)

[Reaction Scheme 2]

(a) NaOAc, AcOH, 85 ° C, 12-30 hours

(0.03 mol, 5.0 g), bromoacetic acid (1.5 eq., 6.90 g) and sodium acetate (3.0 eq., 8.2 g) were added to a solution of 1 H- benzo [ d ] imidazole- The mixture was refluxed in acetic acid (50 mL) solvent over night. Water was added to the reaction mixture, followed by filtration and washing with water. The filtrate solid was recrystallized from ethanol to give the above compound 10 in 68% yield.

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.83 (d, 1 H, J = 7.6 Hz), 7.56 (d, 1 H, J = 8.0 Hz), 7.34 (t, 1 H, J = 8.0 Hz) , 7.29 (t, 1H, J = 7.6 Hz), 4.58 (s, 2H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) ? 166.7, 159.9, 150.0, 130.5, 126.2, 124.1, 119.2, 112.5, 40.4.

1. 2- (substituted Benzylidene ) Benzo [ d ] Thiazolo [3,2- a ] Imidazole -3 (2 H ) -One [2- (& benzylidene ) benzo [ d ] thiazolo [3,2- a ] imidazole -3 (2 H ) - one ] Derivative (10a-10n) Synthesis of

A mixture of thiazoloimidazolone (5.2 mmol), various benzaldehyde (1.0-1.1 equivalents) and sodium acetate (NaOAc) (1.57 mmol) was added to a solution of acetic acid (1.0 mL) Lt; RTI ID = 0.0 &gt; 85 C &lt; / RTI &gt; for 12-30 hours. The reaction mixture was cooled to room temperature and then water was added. The resulting precipitate was filtered and washed with water to obtain the desired compound (10a-10n).

1) (Z) -2- (4- hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- (4- hydroxybenzylidene benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10a]

Reaction time overnight; Yield 55.3%;

^{1 H NMR (500MHz, DMSO- d} 6) δ 10.46 (s, 1 H), 7.99 (s, 1 H), 7.92 (d, 1 H, J = 8.0 Hz), 7.64 (d, 1 H, J = 8.0 Hz), 7.60 (d, 2 H, J = 8.5 Hz), 7.38 (t, 1 H, J = 8.0 Hz), 7.34 (t, 1 H, J = 8.0 Hz), 6.95 (d, 2 H, J = 8.5 Hz); ¹³ C NMR (100 MHz, DMSO- d ₆ ) ? 161.3, 160.1, 154.0, 148.9, 137.2, 133.7, 130.8, 126.2, 124.6, 124.3, 120.8, 119.8, 117.2, 113.0.

2) (Z) -2- (2- hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- (2- hydroxybenzylidene benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10b]

Reaction time 2 days; Yield 35.6%;

^{1 H NMR (500MHz, DMSO- d} 6) δ 12.92 (brs, 1 H), 8.39 (s, 1 H), 7.71 (d, 1 H, J = 8.0 Hz), 7.63 (t, 1 H, J = 8.0 Hz), 7.49-7.45 (m, 3 H), 7.36 (t, 1H, J = 8.0 Hz), 7.12 (m, 2H).

3) (Z) -2- (4- methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- (4- methoxybenzylidene benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10c]

Reaction time overnight; Yield 82.2%;

_{^{1 H NMR (500MHz, CDCl 3}} ) δ 8.04 (d, 1 H, J = 8.0 Hz), 8.01 (s, 1H), 7.67 (d, 1 H, J = 8.0 Hz), 7.57 (d, 2 H, J = 9.0 Hz), 7.38 ( t, 1 H, J = 8.0 Hz), 7.33 (d, 1 H, J = 8.0 Hz), 7.02 (d, 2 H, J = 9.0 Hz), 3.88 (s, 3 H); _{^{13 C NMR (100MHz, CDCl 3}} ) δ 162.1, 160.1, 153.8, 149.1, 137.1, 132.8, 130.8, 126.0, 125.7, 124.3, 121.9, 119.7, 115.2, 113.1, 55.8.

4) (Z) -2- (4- hydroxy-3-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(Z) -2 - (4-hydroxy-3-methoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10d]

Yellow solid; Reaction time overnight; Yield 61.3%;

^{1 H NMR (400MHz, DMSO- d} 6) δ 10.13 (s, 1 H), 7.96 (s, 1 H), 7.88 (d, 1 H, J = 7.6 Hz), 7.61 (d, 1 H, J = 7.6 Hz), 7.34 (t, 1 H, J = 7.6 Hz), 7.30 (t, 1 H, J = 7.6 Hz), 7.25 (d, 1 H, J = 1.6 Hz), 7.17 (dd, 1 H, J = 1.6, 8.4Hz), 6.95 (d, 1H, J = 8.4Hz), 3.82 (s, 3H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) ? 160.0, 154.0, 150.9, 148.9, 148.7, 137.5, 130.7, 126.2, 125.3, 124.6, 124.5, 120.9, 119.8, 117.0, 115.2, 112.9, 56.3.

5) (Z) -2- (3- hydroxy-4-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(Z) -2 - (3-hydroxy-4-methoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10e]

Yellow solid; Reaction time overnight; Yield 60.8%;

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.60 (s, 1 H), 7.90 (s, 1 H), 7.89 (d, 1 H, J = 8.0 Hz), 7.62 (d, 1 H, J = 8.0 Hz), 7.38 (t, 1H, J = 8.0 Hz), 7.31 (t, 1H, J = 8.0 Hz), 7.18 (d, 1H, J = 8.4 Hz), 7.12 , 7.06 (d, 1H, J = 8.4 Hz), 3.81 (s, 3 H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) ? 160.0, 154.0, 151.3, 148.9, 147.7, 137.1, 130.8, 126.2, 125.9, 124.9, 124.6, 121.8, 119.8, 116.6, 113.1, 113.0, 56.4.

6) (Z) -2- (3- ethoxy-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(Z) -2 - (3-ethoxy-4-hydroxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10f]

Yellow solid; Reaction time overnight; Yield 45.1%;

^{1 H NMR (400MHz, DMSO- d} 6) δ 10.05 (s, 1 H), 7.96 (s, 1 H), 7.90 (d, 1 H, J = 8.0 Hz), 7.63 (d, 1 H, J = 8.0 Hz), 7.36 (t, 1H, J = 8.0 Hz), 7.32 (t, 1H, J = 8.0 Hz), 7.25 (d, 1H, J = 2.0 Hz), 7.18 J = 2.0, 8.4 Hz), 6.95 (d, 1H, J = 8.4 Hz), 4.07 (q, 2H, J = 7.2 Hz), 1.34 (t, 3 H, J = 7.2 Hz); ¹³ C NMR (100 MHz, DMSO- d ₆ ) ? 160.0, 154.0, 151.1, 148.9, 147.9, 137.5, 130.8, 126.2, 125.3, 124.7, 124.6, 120.9, 119.9, 117.1, 116.3, 113.0, 64.6, 15.3.

7) (Z) -2- (2,4- dihydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- ( 2,4-dihydroxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10g]

Reaction time overnight; Yield 42.1%;

^{1 H NMR (500MHz, DMSO- d} 6) δ 12.19 (brs, 1 H), 10.9 (s, 1 H), 8.41 (s, 1 H), 7.59 (d, 1 H, J = 8.5 Hz), 7.42 (m, 2 H), 7.14 (t, 1 H, J = 7.5 Hz), 7.12 (t, 1 H, J = 7.5 Hz), 6.82 (dd, 1 H, J = 2.5, 8.5 Hz), 6.77 ( d, 1H, J = 2.5 Hz); ^{13 C NMR (125MHz, DMSO- d} 6) δ 162.8, 159.3, 156.2, 149.9, 149.6, 147.6, 130.8, 130.6, 122.5, 122.1, 114.3, 114.0, 112.9, 112.3, 102.6, 102.3.

8) (Z) -2- (3,4- dihydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- ( 3,4-dihydroxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10h]

Reaction time overnight; Yield 58.2%;

^{1 H NMR (500MHz, DMSO- d} 6) δ 9.99 (brs, 1 H), 9.57 (brs, 1 H), 7.92 (d, 1 H, J = 8.0 Hz), 7.90 (s, 1 H), 7.65 (d, 1H, J = 8.0 Hz), 7.38 (t, 1H, J = 8.0 Hz), 7.34 (t, 1H, J = 8.0 Hz), 7.14 1 H, J = 8.5 Hz), 6.91 (d, 1H, J = 8.5 Hz); ¹³ C NMR (100 MHz, DMSO- d ₆ ) ? 160.1, 154.1, 150.1, 148.9, 146.7, 137.6, 130.8, 126.2, 125.4, 124.6, 124.5, 120.5, 119.8, 117.3, 117.1, 112.9.

9) (Z) -2- (3- bromo-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(Z) -2 - (3-bromo-4-hydroxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10i]

Reaction time 2 days; Yield 68.7%;

^{1 H NMR (400MHz, DMSO- d} 6) δ 11.31 (s, 1 H), 7.96 (s, 1 H), 7.90 (m, 2 H), 7.63 (d, 1 H, J = 8.0 Hz), 7.56 (d, 1 H, J = 8.0 Hz), 7.36 (t, 1 H, J = 8.0 Hz), 7.32 (t, 1 H, J = 8.0 Hz), 7.10 (d, 1 H, J = 8.8 Hz) ; ¹³ C NMR (100 MHz, DMSO- d ₆ ) ? 159.8, 157.6, 153.8, 148.9, 136.8, 135.6, 131.4, 130.8, 126.3, 125.9, 124.7, 122.6, 119.9, 117.7, 113.0, 111.0.

10) (Z) -2- (2,4- dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- (2 , 4-dimethoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10j]

Reaction time overnight; Yield: 63.0%;

_{^{1 H NMR (500MHz, CDCl 3}} ) δ 8.39 (s, 1 H), 8.05 (d, 1 H, J = 7.5 Hz), 7.67 (d, 1 H, J = 7.5 Hz), 7.52 (d, 1 H , J = 8.5 Hz), 7.37 (t, 1 H, J = 7.5 Hz), 7.32 (t, 1 H, J = 7.5 Hz), 6.62 (d, 1 H, J = 8.5 Hz), 6.48 (s, 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.1, 161.7, 160.7, 160.4, 154.3, 148.9, 132.9, 131.6, 125.9, 124.1, 121.5, 119.5, 115.4, 113.0, 105.9, 98.8, 55.9, 55.8.

11) (Z) -2- (3,4- dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - -2- ( 3 -on [(Z) , 4-dimethoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10k]

Reaction time overnight; Yield 50.2%;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.01 (d, 1 H, J = 7.6 Hz), 7.98 (s, 1 H), 7.66 (d, 1 H, J = 7.6 Hz), 7.37 (t, 1 H , J = 7.6 Hz), 7.32 (t, 1 H, J = 7.6 Hz), 7.22 (dd, 1 H, J = 1.6, 8.8 Hz), 7.07 (d, 1 H, J = 1.6 Hz), 6.96 ( d, 1H, J = 8.8Hz), 3.95 (s, 3H), 3.93 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) ? 160.0, 153.6, 151.9, 149.7, 148.9, 137.3, 130.7, 126.1, 126.0, 125.2, 124.4, 122.2, 119.7, 113.1, 112.8, 111.7, 56.3, 56.2.

12) (Z) -2- (4- hydroxy-3,5-dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- (4-hydroxy-3,5-dimethoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10l]

Reaction time overnight; Yield 68.4%;

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.50 (s, 1 H), 7.95 (s, 1 H), 7.89 (d, 1 H, J = 7.6 Hz), 7.62 (d, 1 H, J = 7.6 Hz), 7.34 (t, 1H, J = 7.6 Hz), 7.30 (t, 1H, J = 7.6 Hz), 6.97 (s, 2H), 3.82 (s, 6H); ¹³ C NMR (100 MHz, DMSO- d ₆ ) ? 159.9, 153.9, 149.0, 149.0, 140.1, 137.7, 130.8, 126.2, 124.6, 123.5, 121.3, 119.9, 112.9, 109.0, 56.8.

13) (Z) -2- (3,5- dibromo-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z ) -2- (3,5-dibromo-4-hydroxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10m]

Reaction time 24 hours; Yield 79.9%;

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.72 (brs, 1 H), 8.02 (s, 2 H), 7.93 7.87 (m, 2 H), 7.66 (d, 1 H, J = 8.0 Hz), 7.39 7.32 (m, 2H).

14) (Z) -2- (3,4,5- trimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(Z) -2 - (3,4,5-trimethoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10n]

Reaction time 3 days; Yield 78.4%;

_{^{1 H NMR (500MHz, CDCl 3}} ) δ 8.03 (d, 1 H, J = 7.5 Hz), 7.98 (s, 1 H), 7.68 (d, 1 H, J = 7.5 Hz), 7.39 (t, 1 H , J = 7.5 Hz), 7.34 (t, 1H, J = 7.5 Hz), 6.84 (s, 2H), 3.94 (s, 6H), 3.93 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) ? 159.7, 153.9, 153.4, 149.0, 140.9, 137.2, 130.6, 128.5, 126.2, 124.5, 124.1, 119.9, 113.1, 107.9, 61.3, 56.5.

< Experimental Example  1> Tyrosinase inhibitory effect

Mushroom-derived tyrosinase was used as an enzyme source in this experiment. The tyrosinase activity was slightly modified and the activity was determined according to a known method ( Life Sci . , 1999, 65, 241-246). That is, 20 μl of a 1000-unit aqueous solution of mushroom-derived tyrosinase was added to a 96-well microplate (Nunc, Denmark), and a total of 200 μl of the assay mixture containing 1 mM L-tyrosine and 50 mM phosphate buffer Prepared. The assay mixture was incubated at 25 &lt; 0 &gt; C for 30 minutes. After incubation, the amount of dopachrome produced in the reaction mixture was measured at ₄₉₂ nm (OD ₄₉₂ ) using a microplate reader (Hewlett Packard).

When the degree of inhibition of kojic acid was set at 100, the degree of inhibition of the synthesized compounds was shown as a relative value. Compounds 9b, 9f, 10e, 10f and 10h showed better inhibitory activity than kojic acid, which is a positive control group, as a result of measuring tyrosinase inhibitory activity of a total of 25 compounds synthesized. Compounds 10k and 10n showed slightly lower inhibitory activity than kojic acid (Fig. 1).

< Experimental Example  2> Toxicity experiment

Compound 9f was suspended in 0.5% methylcellulose solution in male Balb / c mice, and single oral doses of 0.5g / kg, 1g / kg and 2g / kg were administered once, and the survival rate and body weight of mice were examined for 7 days.

After this administration, we observed the mortality of the animal, clinical symptoms, weight change, hematologic test and blood biochemical test, and autopsied the visceral organs and thoracic organs were observed.

As a result, no clinical symptoms or dead animals were found in all animals, and no toxic changes were observed in weight changes, blood tests, blood biochemical tests, and autopsy findings.

As a result, the compounds of the present invention did not show toxic changes to 2 g / kg in rats, and thus, the oral LD 50 was found to be a safe substance of 2 g / kg or more.

Hereinafter, formulation examples of the composition containing the compound 9f according to the present invention will be described, but the present invention is not intended to be limited thereto but is specifically described.

< Prescription example  1 > Prescription example

&Lt; Prescription Example 1-1 > Preparation of powder

20 mg of Compound 9f, 100 mg of lactose and 10 mg of talc were mixed and filled in an airtight container to prepare a powder.

&Lt; Prescription Example 1-2 > Preparation of tablets

20 mg of Compound 9f, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate were mixed and tableted according to a conventional preparation method.

&Lt; Prescription Example 1-3 > Preparation of capsules

10 mg of Compound 9f, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate were mixed, and the above components were mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.

&Lt; Prescription Example 1-4 > Preparation of injection

Compound 9f (10 mg), sterile distilled water suitable amount for injection, and pH adjuster were mixed, and the contents were adjusted to the above contents in accordance with the usual injection preparation method (2 ml) per ampoule.

&Lt; Prescription Example 1-5 > Preparation of ointment preparation

Compound 9f 10 mg, PEG-4000 250 mg, PEG-400 650 mg, white petrolatum 10 mg, p-hydroxybenzoic acid methyl 1.44 mg, p-hydroxybenzoyl propyl 0.18 mg and remaining amount of purified water were mixed and the ointment was prepared according to the usual ointment preparation method Respectively.

< Prescription example  2> Cosmetics  Of the composition Prescription example

&Lt; Prescription Example 2-1 > Production of nutrition lotion

3.0 parts by weight of propylene glycol, 0.1 part by weight of carboxy polymer, purified water of a small amount of preservative and remaining amount were heated to 80 to 85 ° C while stirring and mixing, and then charged into a manufacturing part. Then, an emulsifying agent was allowed to act. 1.0 part by weight of Polysorbate 60, 0.5 parts by weight of sesquioleate, 10.0 parts by weight of liquid paraffin, 1.0 part by weight of sorbitan stearate, 0.5 part by weight of glycerin monostearate as a parent type, 1.5 parts by weight of stearic acid, 1.0 part by weight of glyceryl stearate / PEG-400 stearate, And 0.2 parts by weight of amine were heated to 80 to 85 DEG C and then emulsified. After the emulsification was completed, the mixture was thermally cooled to 50 DEG C with stirring using an agitator, and a trace amount of fragrance was added thereto. After cooling to 45 DEG C, a trace amount of pigment was added. Compound 9f was added at 35 DEG C, .

&Lt; Prescription Example 2-2 > Preparation of nutritional cream

0.3 parts by weight of carboxy polymer, 5.0 parts by weight of butylene glycol, 3.0 parts by weight of glycerin and the remaining amount of purified water were heated to 80 to 85 캜 while stirring and mixing, 2.0 parts by weight, glyceryl monostearate 2.0 parts by weight, polyoxyethylene sorbitan monostearate 0.5 part by weight, sorbitan sesquioleate 0.5 part by weight, glyceryl monostearate / glyceryl stearate / polyoxyethylene stearate 1.0 part by weight of wax, 4.0 parts by weight of liquid paraffin, 4.0 parts by weight of squalane, and 4.0 parts by weight of caprylic / capric triglyceride were heated to 80 to 85 ° C. and 0.5 part by weight of triethanolamine was added thereto to emulsify . After the emulsification was completed, the mixture was cooled to 35 DEG C while stirring with an agitator, and then Compound 9f was added thereto, followed by cooling to 25 DEG C and aging.

<Prescription Example 2-3> Manufacture of Wash Foam

30.0 parts by weight of TEA-cocoyl glutamate, 10.0 parts by weight of disodium laureth sulfosuccinate glycerin, 10.0 parts by weight of glycerin, 2.0 parts by weight of cocamide DEA, 1.0 part by weight of PEG-120 methyl glucoside diolate, 20, 0.5 part by weight of PEG-150 pentaerythrityl tetrastearate, 0.05 part by weight of tetrasodium EDTA and a trace amount of preservative were sequentially added to the preparation part, and the mixture was heated to 60 to 65 占 폚 and stirred for 15 minutes. After the stirring, a portion of the purified water was added, and the mixture was stirred for 30 minutes. Then, a portion of the purified water was slowly added thereto, stirred for 30 minutes, cooled to 35 ° C, cooled to 25 ° C by adding Compound 9f and perfume, .

< Prescription example  3> Health supplement

<Prescription Example 3-1> Preparation of Health Functional Foods

Compound 9f 1 mg Vitamin A acetate 70, Vitamin E 1.0 mg Vitamin B 1 0.13 mg Vitamin B 2 0.15 mg Vitamin B 6 0.5 mg Vitamin B 12 0.2 mg Vitamin C 10 mg Biotin (Ferrous sulfate 1.75 mg, zinc oxide 0.82 mg, magnesium carbonate 25.3 mg, potassium phosphate monobasic 15 mg, calcium phosphate dibasic calcium phosphate 0.5 mg), and fumaric acid 55 mg, potassium citrate (90 mg), calcium carbonate (100 mg) and magnesium chloride (24.8 mg) were mixed to prepare granules, and a health functional food was prepared according to a conventional method.

&Lt; Prescription Example 3-2 > Preparation of health drink

To the mixture was added 1 mg of Compound 9f, 1000 mg of citric acid, 100 g of oligosaccharide, 2 g of a plum concentrate, 1 g of taurine and purified water to make a total of 900 mL. The above components were mixed according to a conventional health drink manufacturing method, After stirring and heating at 85 ° C for a period of time, the resulting solution was filtered and sterilized by sealing in a 2 L container which was then sterilized and then refrigerated.

Claims (6)

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

In this formula,
X is hydrogen, Y is CH ₃ , R ¹ to R ⁴ may be the same or different and are any one of H, OH, halogen, C 1 to C 4 alkyl or C 1 to C 4 alkoxy;
X is CH _3, Y is hydrogen, R ¹ to R ⁴ may be the same or different, each, H, OH, halogen, alkoxy of any one of C1 to C4 alkyl or C1 to C4;
X and Y are hydrogen, and three substituents including R ¹ of R ¹ to R ⁴ are hydrogen and the remaining one substituent is either OH or C1 to C4 alkoxy;
X and Y are hydrogen, R ³ is OH, two substituents of R ¹ , R ² and R ⁴ are hydrogen, and the remaining one substituent is any of C 2 to C 4 alkoxy, OH or Br;
X and Y are hydrogen, R ³ is OH, one substituent of R ¹ , R ² and R ⁴ is hydrogen and the remaining two substituents are Br;
X and Y are hydrogen, R ³ is C 1 to C 4 alkoxy, and R ¹ , R ² or R ⁴ may be the same or different and is selected from the group consisting of hydrogen and C 1 to C 4 alkoxy. The method according to claim 1, wherein the compound is (2 Z) -2- (4- hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H ) -one, (2 Z) -2- (4- methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (4- hydroxy-3-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one , (2 Z) -2- (3- hydroxy-4-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3-ethoxy-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (3,4- dihydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3- bromo-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (2,4- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one , (2 Z) -2- (3,4- dimethoxy- Tired den) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (2 Z) -2- (4- hydroxy -3,5 -dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one, (2 Z) -2- (3,4,5 -trimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one, (Z) -2- (4- hydroxy-benzyl vinylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (4- methoxy-benzylidene) benzo [d] thiazolo [3,2 - a] imidazole -3 (2 H) - one, (Z) -2- (3-ethoxy-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (Z) -2- (2,4- dihydroxy-benzylidene) benzo [d] thiazolo [3,2- a] -3 (2 H ) imidazol-on, (Z Dihydroxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one, ( Z ) -2- 4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2,4- dimethoxy-benzylidene) benzo [ d ] thiazolo [3,2- a ] Imidazol -3 (2 H) - one, (Z) -2- (3,4- dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3,5- dibromo-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one and (Z ) -2- (3,4,5-trimethoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one. . A pharmaceutical composition for skin whitening comprising a compound represented by the following formula (1) as an active ingredient:
[Chemical Formula 1]

Wherein each of R ¹ to R ⁴ may be the same or different and is any one of H, OH, halogen, C 1 to C 4 alkyl or C 1 to C 4 alkoxy, and X and Y are H or CH ₃ . The method according to claim 3, wherein the compound is (2 Z) -2- (4- hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H ) -one, (2 Z) -2- (4- methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (4- hydroxy-3-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one , (2 Z) -2- (3- hydroxy-4-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3-ethoxy-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (3,4- dihydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3- bromo-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (2,4- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one , (2 Z) -2- (3,4- dimethoxy- Tired den) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (2 Z) -2- (4- hydroxy -3,5 -dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one, (2 Z) -2- (3,4,5 -trimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one, (Z) -2- (4- hydroxy-benzyl vinylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2- hydroxy-benzylidene) benzo [d] thiazolo [3,2 - a] imidazole -3 (2 H) - one, (Z) -2- (4- methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (4- hydroxy-3-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2 - (3-hydroxy-4-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3-ethoxy- 4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2,4- dihydroxy-benzylidene) benzo [ d] thiazole [3,2- a] -3 (2 H ) imidazol-on, (Z) -2- (3,4- dihydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3- bromo-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2,4- dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3 , 4-dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (4-hydroxy-3,5-dimethoxy benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3,5- dibromo-4-hydroxy-benzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one and ( Z ) -2- (3,4,5-trimethoxybenzylidene) benzo [ d ] thiazolo [3 , 2- a ] imidazol-3 (2 H ) -one. A cosmetic composition for skin whitening comprising a compound represented by the following formula (1) as an active ingredient:
[Chemical Formula 1]

Wherein each of R ¹ to R ⁴ may be the same or different and is any one of H, OH, halogen, C 1 to C 4 alkyl or C 1 to C 4 alkoxy, and X and Y are H or CH ₃ . The method according to claim 5, wherein the compound is (2 Z) -2- (4- hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H ) -one, (2 Z) -2- (4- methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (4- hydroxy-3-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one , (2 Z) -2- (3- hydroxy-4-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3-ethoxy-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (3,4- dihydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3- bromo-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (2,4- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one , (2 Z) -2- (3,4- dimethoxy- Tired den) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (2 Z) -2- (4- hydroxy -3,5 -dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one, (2 Z) -2- (3,4,5 -trimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one, (Z) -2- (4- hydroxy-benzyl vinylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2- hydroxy-benzylidene) benzo [d] thiazolo [3,2 - a] imidazole -3 (2 H) - one, (Z) -2- (4- methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (4- hydroxy-3-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2 - (3-hydroxy-4-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3-ethoxy- 4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2,4- dihydroxy-benzylidene) benzo [ d] thiazole [3,2- a] -3 (2 H ) imidazol-on, (Z) -2- (3,4- dihydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3- bromo-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2,4- dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3 , 4-dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (4-hydroxy-3,5-dimethoxy benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3,5- dibromo-4-hydroxy-benzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one and ( Z ) -2- (3,4,5-trimethoxybenzylidene) benzo [ d ] thiazolo [3 , 2- a ] imidazol-3 (2 H ) -one.

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