CN109369637A - The novel derivative of kojic acid of one kind thiadiazoles containing 1,3,4- and its application - Google Patents

The novel derivative of kojic acid of one kind thiadiazoles containing 1,3,4- and its application Download PDF

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CN109369637A
CN109369637A CN201811293631.1A CN201811293631A CN109369637A CN 109369637 A CN109369637 A CN 109369637A CN 201811293631 A CN201811293631 A CN 201811293631A CN 109369637 A CN109369637 A CN 109369637A
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CN109369637B (en
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谢文林
刘仁志
梅期红
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Hunan University of Science and Technology
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin

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Abstract

The invention discloses one kind to contain the novel derivative of kojic acid of 1,3,4- thiadiazoles and its application, and structural formula is as shown in the formula (I),In formula (I), substituent R is H ,-CH3,‑CF3,‑CH2CH3,‑OCH3,F,Cl,Br,‑COCH3,‑OH,‑COOH,‑SO3H,‑C6H5Or substituted-phenyl.(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1 of benzene invention, 3,4- thiadiazoles -2- base) -3- Activities of Arylacrylamide Compounds to tyrosinase have certain inhibitory activity, can be used for preparing skin-lightening cosmetic and drug.And its synthetic method is simple, and material is easy to get.

Description

The novel derivative of kojic acid of one kind thiadiazoles containing 1,3,4- and its application
Technical field
It is a kind of novel (E)-N- (5- ((5- hydroxyl the present invention relates to a kind of novel derivative of kojic acid of thiadiazoles containing 1,3,4- Base -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- bases) -3- Activities of Arylacrylamide Compounds is new Tyrosinase inhibitor, be applied to medicine, food, filed of daily-use chemical industry as melanin inhibitor or whitening agent.More specifically For, the present invention provides (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) first sulphur as tyrosinase inhibitor Base) -1,3,4- thiadiazoles -2- base) -3- Activities of Arylacrylamide Compounds preparation method and pharmaceutical composition comprising them Object.
Background technique
Tyrosinase (EC 1.14.18.1, Tyrosinase) is a kind of metalloenzyme of cupric, be distributed widely in microorganism, In animals and plants and human body.Tyrosinase is primarily involved in two reaction process: catalysis l-tyrosine hydroxylating be changed into L-3,4 dihydroxyphenylalanine and It aoxidizes L-3,4 dihydroxyphenylalanine and forms DOPA quinone, DOPA quinone forms melanin after series reaction.Tyrosinase has weight in organism The physiological function wanted, meanwhile, it is also related with the generation of diseases such as the melanin over-deposit such as human body freckle, foxiness, and and elder brother The husking of worm and the browning of fruits and vegetables have much relations.In the various organisms of nature, the phenols chemical combination containing numerous species Under tyrosinase catalysis series of chemical occurs for object, these phenolic compounds, eventually leads to the change of fruit, victual Color.Therefore, by inhibiting the catalytic activity of tyrosinase that can improve the pigmentation of skin and preventing the brown of water fruits and vegetables Become.
Kojic acid (kojic Acid) also known as kojic acid.External much researchs and test result confirm over the past decade, bent Acid has very strong inhibiting effect and safe and nontoxic to the generation of human skin melanin, will not generate hickie sequelae.Cause And in supplying toner, facial mask, lotion, frost, the beauty that can effectively treat freckle, age spot, pigmentation, acne has been made Albefaction cosmetic, and become international popular advanced cosmetics, it is deep by consumer, especially there is color spot to take a disease young women Like.But since kojic acid is unstable, to light, thermo-responsive, be easily oxidized in air, in addition, kojic acid easily with many gold Belong to ion chelating, especially can generate yellow colored complex with Fe chelating, this makes the skin-whitening product prepared with kojic acid exist It places in use process and often gradually becomes yellowish-brown.And many results of study show, the derivative of some kojic acids not only have compared with Good stability, is not susceptible to oxidation stain, and its ability inhibited tyrosinase activity is more more significant than kojic acid.Therefore The research and development of various derivative of kojic acid become the research hotspot for scientists.
Summary of the invention
The purpose of the present invention is to provide a kind of novel derivative of kojic acid of thiadiazoles containing 1,3,4-, and this kind of compound is to junket Propylhomoserin enzyme has certain inhibitory activity, the pigmentation and whitening applied to skins such as prevention and treatment color spot, freckle, senile plaques.This The purpose of invention also includes providing the composition containing such noval chemical compound.
Above-mentioned purpose of the invention is achieved by following scheme: one kind novel kojic acid of thiadiazoles containing 1,3,4- spreads out Biology, structural formula are as shown in the formula (I):
In formula (I), substituent R is H ,-CH3, -CF3, -CH2CH3, -OCH3, F, Cl, Br, -COCH3, -OH, - COOH, -SO3H, -C6H5Or substituted-phenyl.
Described one kind contains the preparation method of 1,3, the 4- novel derivative of kojic acid of thiadiazoles, reaction formula are as follows:
Specific step is as follows:
(1) reaction flask equipped with kojic acid is placed in ice bath, thionyl chloride is then slowly added dropwise into reaction flask and magnetic force stirs It mixes, TLC tracks reaction process.After reaction, petroleum ether is added into reaction solution, a large amount of solids are precipitated, filters, dries solid Intermediate product 2- chloromethyl -5- hydroxyl -4H- pyrans -4- ketone 1 can be obtained with ethyl alcohol recrystallization afterwards.
(2) by above-mentioned intermediate product 2- chloromethyl -5- hydroxyl -4H- pyrans -4- ketone 1 and -5 sulfydryl -1,3,4- of 2- amino Thiadiazoles is dissolved in ethyl alcohol, and triethylamine is added dropwise, and is heated to reflux, and TCL tracks reaction process.After reaction, it is cooled to room Temperature, is precipitated solid, and solid N,N-dimethylformamide and Diethyl ether recrystallization both obtain intermediate product 5- (5- hydroxyl -4- oxo - Pyrans -2- base) methyl mercapto -2- amino -1,3,4- thiadiazoles 2.
(3) by above-mentioned intermediate product 5- (5- hydroxyl -4- oxo-pyrans -2- base) methyl mercapto -2- amino -1,3,4- thiophene Diazole 2 is added in reaction flask, while substituted cinnamic acid, 1- hydroxy benzo triazole (HOBt) and 1- ethyl-(3- dimethyl is added Aminopropyl) carbodiimide hydrochloride (EDCI), n,N-Dimethylformamide, magnetic agitation, to all are dissolved under ice bath After solid dissolution, N-methylmorpholine is added dropwise, then the reaction was continued at room temperature, and TCL judges reaction end.It is added after reaction Distilled water, is precipitated solid, and solid obtains target product (E)-N- (5- ((5- hydroxyl -4- oxo-through column chromatographic isolation and purification 4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- bases) -3- aryl acrylamide derivative (I), i.e., it is a kind of to contain 1,3, The novel derivative of kojic acid of 4- thiadiazoles.
A kind of application of the novel derivative of kojic acid of thiadiazoles containing 1,3,4- in terms of preparing skin-lightening cosmetic.
A kind of application of the novel derivative of kojic acid of thiadiazoles containing 1,3,4- in preparation whitening pharmaceutical preparations.
Beneficial effects of the present invention: being experimentally confirmed, and one kind of the invention is derivative containing the novel kojic acid of 1,3,4- thiadiazoles Object has certain tyrosinase inhibitory activity, and one of they or composition can be used for preparing skin-lightening cosmetic and drug. And synthetic method is simple, and material is easy to get, and provides a kind of new development approach to solve cosmetics and the pharmaceuticals of whitening.
Specific embodiment
Below by compound experiment example and activity experiment example, the present invention is described in further detail.
In order to better understand the present invention, preparation (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) is now provided Methyl mercapto) -1,3,4- thiadiazoles -2- bases) -3- Activities of Arylacrylamide Compounds embodiment, the present invention includes but not only limits In this preparation method.It should (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- Base) the i.e. described novel derivative of kojic acid of one kind thiadiazoles containing 1,3,4- of -3- Activities of Arylacrylamide Compounds.
Embodiment 1:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- is (to first Phenyl) acrylamide (Ia) synthesis.
First the reaction flask equipped with kojic acid (21.0 mmol) is placed in ice bath, 40ml thionyl chloride is then slowly added dropwise and arrives In reaction flask and magnetic agitation, TLC track reaction process.After reaction, petroleum ether is added into reaction solution, is precipitated a large amount of solid Body filters, and intermediate product 2- chloromethyl -5- hydroxyl -4H- pyrans -4- ketone 1 can be obtained with ethyl alcohol recrystallization after drying solid.
Weigh above-mentioned 1 2- chloromethyl -5- hydroxyl -4H- pyrans -4- ketone (10mmol) of intermediate and -5 sulfydryl of 2- amino - 1,3,4- thiadiazoles (10mmol) is dissolved in 30ml ethyl alcohol, and triethylamine (12mmol) then is added dropwise, is heated to reflux, and TCL tracking is anti- Answer process.It is cooled to room temperature after reaction, solid is precipitated, after this solid n,N-Dimethylformamide and Diethyl ether recrystallization Intermediate product 5- (5- hydroxyl -4- oxo-pyrans -2- base) methyl mercapto -2- amino -1,3,4- thiadiazoles 2.
Again by above-mentioned intermediate 5- (5- hydroxyl -4- oxo-pyrans -2- base) methyl mercapto -2- amino -1,3,4- thiadiazoles 2 (2.0 mmol) is dissolved in 15ml n,N-Dimethylformamide, under ice bath, addition p-methylphenyl acrylic acid (2.0mmol), 1- hydroxy benzo triazole (HOBt) (2.0mmol) and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (2.0mmol), magnetic agitation are added dropwise N-methylmorpholine (6.0mmol) after all solids dissolution, continue in ice Bath is lower to react 1h, then the reaction was continued at room temperature 12h, and TCL tracks reaction process.It is added after reaction into reaction solution Distilled water, is precipitated white solid, filtering, and column chromatography for separation obtains target product (E)-N- (5- ((5- hydroxyl -4- oxo -4H- Pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- bases) -3- (p-methylphenyl) acrylamide, chemical structural formula such as formula (Ia) shown in, yield: 75.2%.
1HNMR (500 MHz, DMSO) δ : 8.60 (s, 1H), 7.81 (d, J = 16.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.44 (s, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 16.0 Hz, 1H), 6.47 (s, 1H), 4.28 (s, 2H), 2.35 (s, 3H); 13CNMR (125 MHz, DMSO)δ : 172.11, 171.28, 165.02, 163.90, 150.08, 147.91, 147.69, 141.76, 140.87, 131.46, 130.12, 129.27, 115.73, 115.25, 35.94, 21.57 ; IR (KBr) v: 3290, 3104, 1729, 1668, 1629, 1514, 1412, 1361, 1322, 1207, 1157 cm-1; HRMS (ESI, m/ z) calcd for [C18H16N3O4S2]+ (M+H)+ 402.0577, found 402.0572.
Embodiment 2:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (4- first Oxygen phenyl) acrylamide (Ib) synthesis.
The preparation method of the present embodiment is in addition to replacing p-methylphenyl acrylic acid with p-methoxyphenyl acrylic acid, remaining is the same as implementation Example 1 finally obtains white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles - 2- yl) -3- (4- anisyl) acrylamide, shown in chemical structural formula such as formula (Ib), yield: 77.1%.
1HNMR (500 MHz, DMSO) δ : 8.59 (s, 1H), 7.81 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.44 (s, 2H), 7.02 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 15.5Hz, 1H), 6.47 (s, 1H), 4.28 (s, 2H), 3.34 (s, 3H); 13CNMR (125 MHz, DMSO) δ:172.17, 171.27, 164.97, 164.04, 162.15, 150.05, 147.71, 140.90, 131.17, 126.80 , 115.72, 114.97, 113.53, 55.87, 35.94 ; IR (KBr) v: 3349, 3110, 1733, 1653, 1504, 1418, 1328, 1255, 1201, 1128, 1030 cm-1; HRMS (ESI, m/z) calcd for [C18H16N3O5S2]+ (M+H)+ 418.0526, found 418.0527.
Embodiment 3:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (3- fluorine Phenyl) acrylamide (Ic) synthesis.
The preparation method of the present embodiment is in addition to replacing p-methylphenyl acrylic acid with 3- fluorophenyl acrylic acid, remaining same embodiment 1, finally obtain white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- Base) -3- (3- fluorophenyl) acrylamide, shown in chemical structural formula such as formula (Ic), yield: 74.8%.
1HNMR (500 MHz, DMSO) δ: 8.63 (s, 1H), 7.85 (d, J = 16.0 Hz, 1H), 7.75 (d, J = 10.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.50 (q, J = 8.0 Hz, 1H), 7.45 (s, 2H), 7.31 (td, J = 8.5, 2.0 Hz, 1H), 6.96 (d, J = 16.5 Hz, 1H), 6.48 (s, 1H), 4.29 (s, 2H); 13CNMR (125 MHz,DMSO ) δ :171.99, 171.28, 165.09, 163.86, 163.58, 161.92, 150.12, 147.68, 146.47, 140.81, 136.68, 136.61, 131.48, 131.41, 125.77, 118.34 , 118.17, 118.06, 115.74, 115.42, 115.24, 35.94; IR (KBr) v: 3287, 3079, 1736, 1644, 1631, 1583, 1505, 1409, 1239, 1195, 1136 cm-1; HRMS (ESI, m/z) calcd for [C17H13FN3O4S2]+ (M+H)+ 406.0326, found 406.0329.
Embodiment 4:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (3- first Oxygen phenyl) acrylamide (Id) synthesis.
The preparation method of the present embodiment is in addition to replacing p-methylphenyl acrylic acid with 3- anisyl acrylic acid, remaining is the same as implementation Example 1 finally obtains white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles - 2- yl) -3- (3- anisyl) acrylamide, shown in chemical structural formula such as formula (Id), yield: 78.2%.
1HNMR (500 MHz, DMSO) δ: 8.62 (s, 1H), 7.82 (d, J = 16.0 Hz, 1H), 7.45 (s, 2H), 7.41 (s, 1H), 7.37 (d, J = 5.0 Hz, 2H), 7.05 (s, 1H), 6.91 (d, J = 16.0 Hz, 1H), 6.48 (s, 1H), 4.29 (s, 2H), 3.33 (s, 3H); 13CNMR (125MHz, DMSO)δ: 172.05, 171.27, 165.05, 163.78, 160.12, 150.10, 147.84, 147.69 , 140.84, 135.56, 130.51, 121.89, 117.68, 116.79, 115.74, 113.81, 55.76, 35.93; IR (KBr) v: 3317, 3125, 1709, 1651, 1605, 1518, 1417, 1281, 1193, 1126,929 cm-1; HRMS (ESI, m/z) calcd for [C18H16N3O5S2]+ (M+H)+ 418.0526, found 418.0529.
Embodiment 5:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (4- fluorine Phenyl) acrylamide (Ie) synthesis.
The preparation method of the present embodiment is in addition to replacing p-methylphenyl acrylic acid with 4- fluorophenyl acrylic acid, remaining same embodiment 1, finally obtain white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- Base) -3- (4- fluorophenyl) acrylamide, shown in chemical structural formula such as formula (Ie), yield: 73.6%.
1HNMR (500 MHz, DMSO) δ: 8.62 (s, 1H), 7.90 (dd, J = 8.0, 5.5 Hz, 2H), 7.87 (d, J = 16.0 Hz, 1H), 7.45 (s, 2H), 7.30 (t, J = 8.5 Hz, 2H), 6.85 (d, J = 16.0 Hz, 1H), 6.48 (s, 1H), 4.29 (s, 2H); 13CNMR (125 MHz, DMSO) δ: 172.06, 171.27, 165.14, 165.05, 163.74 , 163.16, 150.09, 147.69, 146.66, 140.84, 131.70, 130.85, 116.63, 116.45, 116.28, 115.74, 35.94; IR (KBr) v: 3298, 3109, 1733, 1644, 1631, 1508, 1409, 1320, 1201, 1146, 835 cm-1; HRMS (ESI, m/ z) calcd for [C17H13FN3O4S2]+ (M+H)+ 406.0326, found 406.0332.
Embodiment 6:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (4- tri- Trifluoromethylphenyl) acrylamide (If) synthesis.
For the preparation method of the present embodiment in addition to replacing p-methylphenyl acrylic acid with 4- trifluoromethyl acrylic acid, remaining is same Embodiment 1 finally obtains white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiophenes Diazole -2- base) -3- (4- trifluoromethyl) acrylamide, shown in chemical structural formula such as formula (If), yield: 65.1%.
1HNMR (500 MHz, DMSO) δ: 8.64 (s, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.94 (d,J = 16.0 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.45 (s, 2H), 7.04 (d, J = 16.5 Hz, 1H), 6.49 (s, 1H), 4.29 (s, 2H); 13CNMR (125 MHz, DMSO) δ: 171.95, 171.28, 165.12, 163.42, 150.13, 147.67, 146.00, 140.79, 138.11, 129.86, 126.26, 119.36, 115.75, 35.94; IR (KBr) v: 3287, 3097, 1728, 1640, 1513, 1411, 1326, 1203, 1130, 1068, 941, 832 cm-1; HRMS (ESI, m/z) calcd for [C18H13F3N3O4S2]+ (M+ H)+ 456.0294, found 456.0298.
Embodiment 7:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (2- bromine Phenyl) acrylamide (Ig) synthesis.
The preparation method of the present embodiment is in addition to replacing p-methylphenyl acrylic acid with 2- bromophenyl acrylic acid, remaining same embodiment 1, finally obtain white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- Base) -3- (2- bromophenyl) acrylamide, shown in chemical structural formula such as formula (Ig), yield: 69.6%.
1HNMR (500 MHz, DMSO) δ : 8.65 (s, 1H), 8.05 (dd, J = 12.0, 3.5 Hz, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.49-7.40 (m, 4H), 6.94 (d, J = 15.5 Hz, 1H), 6.49 (s, 1H), 4.29 (s, 2H); 13CNMR (125 MHz, DMSO) δ :171.44, 170.78, 164.62, 162.87, 149.69, 147.15, 144.53, 140.26, 133.33, 132.85, 132.68, 128.77, 128.40, 125.00, 119.07, 115.26, 35.45; IR (KBr) v: 3286, 3094, 1738, 1643, 1512, 1410, 1316, 1203, 1153, 941, 754 cm-1; HRMS (ESI, m/z) calcd for [C17H13BrN3O4S2]+ (M+H)+ 465.9525, found 465.9527.
Embodiment 8:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- phenyl third The synthesis of acrylamide (Ih).
The preparation method of the present embodiment is in addition to replacing p-methylphenyl acrylic acid with phenylacrylic acid, remaining is with embodiment 1, most Obtain white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base)-afterwards 3- Phenyl Acrylamide, shown in chemical structural formula such as formula (Ih), yield: 75.1%.
1HNMR (500 MHz, DMSO) δ : 8.62 (s, 1H), 7.85 (d, J = 16.0 Hz, 1H), 7.81 (d, J = 7.5 Hz, 2H), 7.47 (s, 2H), 7.46 (s, 1H), 7.45 (s, 2H), 6.87 (d, J = 16.0 Hz, 1H), 6.48 (s, 1H), 4.29 (s, 2H); 13CNMR (125 MHz, DMSO) δ: 172.06, 171.28 , 165.04, 163.77, 150.10, 147.90, 147.69, 140.85, 134.15, 131.58, 129.49 , 129.25, 116.43, 115.75, 35.94; IR (KBr) v : 3286, 3083, 1734, 1629, 1502, 1405, 1197, 1132 cm-1; HRMS (ESI, m/z) calcd for [C17H14N3O4S2]+ (M+H)+ 388.0420, found 388.0422.
Embodiment 9:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (3- first Phenyl) acrylamide (Ii) synthesis.
The preparation method of the present embodiment is in addition to replacing p-methylphenyl acrylic acid with 3- tolyl acrylic acid, remaining same embodiment 1, finally obtain white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- Base) -3- (3- tolyl) acrylamide, shown in chemical structural formula such as formula (Ii), yield: 76.4%.
1HNMR (500 MHz, DMSO) δ : 8.62 (s, 1H), 7.80 (d, J = 16.0 Hz, 1H), 7.63 (s, 1H), 7.60 (d, J = 7.0 Hz, 1H), 7.45 (s, 2H), 7.35 (t, J =7.5, 1H), 7.29 (d, J = 7.0 Hz, 1H), 6.84 (d, J = 16.0 Hz, 1H), 6.48 (s, 1H), 4.29 (s, 2H), 2.34 (s, 3H); 13CNMR (125 MHz, DMSO) δ : 172.07, 171.27, 165.03, 163.80 , 150.10 , 148.03, 147.68, 140.85, 138.79, 134.08, 132.30, 129.68, 129.37, 126.49, 116.19, 115.74, 35.94, 21.30; IR (KBr) v : 3296, 3087, 1734, 1665, 1631, 1502, 1411, 1314, 1197, 1132 cm-1; HRMS (ESI, m/z) calcd for [C18H16N3O4S2]+ (M+H)+ 402.0577, found 402.0581.
Embodiment 10:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (4- chlorine Phenyl) acrylamide (Ij) synthesis.
The preparation method of the present embodiment is in addition to replacing p-methylphenyl acrylic acid with 4- chlorphenyl acrylic acid, remaining same embodiment 1, finally obtain white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- Base) -3- (4- chlorphenyl) acrylamide, shown in chemical structural formula such as formula (Ij), yield: 76.2%.
1HNMR (500 MHz, DMSO) δ: 8.62 (s, 1H), 7.86 (s, 1H), 7.84 (d, J = 6.0 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.45 (s, 2H), 6.90 (d, J = 16.0 Hz, 1H), 6.48 (s, 1H), 4.29 (s, 2H); 13CNMR (125 MHz, DMSO) δ :172.01, 171.27, 165.07, 163.64, 150.10, 147.68, 146.47, 140.82, 136.15, 133.12, 130.97, 129.54, 117.24, 115.74, 35.94; IR (KBr) v: 3294, 3101, 1730, 1641, 1513, 1407, 1315, 1203, 1150, 1093, 941, 817cm-1; HRMS (ESI, m/z) calcd for [C17H13ClN3O4S2]+ (M+ H)+ 422.0031, found 422.0040.
Embodiment 11:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (3- bromine Phenyl) acrylamide (Ik) synthesis.
The preparation method of the present embodiment is in addition to replacing p-methylphenyl acrylic acid with 3- bromophenyl acrylic acid, remaining same embodiment 1, finally obtain white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- Base) -3- (3- bromophenyl) acrylamide, shown in chemical structural formula such as formula (Ik), yield: 70.3%.
1HNMR (500 MHz, DMSO) δ: 8.63 (s, 1H), 8.08 (s, 1H), 7.83 (t, J = 8.0 Hz, 2H), 7.66 (d, J = 7.0 Hz, 1H), 7.45 (s, 2H), 7.41 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.48 (s, 1H), 4.29 (s, 2H); 13CNMR (125 MHz, DMSO) δ : 171.98, 171.27, 165.08 , 163.54 , 150.12, 147.66, 146.20, 140.80 , 136.63, 134.02, 131.70, 131.49, 128.17, 122.86 , 118.14 , 115.75, 35.94; IR (KBr) v: 3410, 3271, 3105, 1735, 1655, 1616, 1514, 1413, 1307, 1200, 1135, 939, 777cm-1; HRMS (ESI, m/z) calcd for [C17H13BrN3O4S2]+ (M+H)+ 465.9525, found 465.9528.
Embodiment 12:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (3- chlorine Phenyl) acrylamide (Il) synthesis.
The preparation method of the present embodiment is in addition to replacing p-methylphenyl acrylic acid with 3- chlorphenyl acrylic acid, remaining same embodiment 1, finally obtain white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- Base) -3- (3- chlorphenyl) acrylamide, shown in chemical structural formula such as formula (Il), yield: 72.1%.
1HNMR (500 MHz, DMSO) δ: 8.63 (s, 1H), 7.96 (s, 1H), 7.84 (d, J = 16.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.5 Hz, 2H), 6.98 (d, J = 16.5 Hz, 1H), 6.48 (s, 1H), 4.29 (s, 2H); 13CNMR (125 MHz, DMSO) δ: 171.49, 170.78, 164.58, 163.05, 149.62, 147.18, 145.75, 140.31, 135.87, 133.81, 130.74, 130.62, 128.28, 127.36, 117.67, 115.25, 35.44; IR (KBr) v: 3406, 3166, 3271, 1731, 1648, 1496, 1412, 1308, 1203, 1153cm-1; HRMS (ESI, m/z) calcd for [C17H13ClN3O4S2]+ (M +H)+ 422.0031, found 422.0037.
Embodiment 13:
(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (4- bromine Phenyl) acrylamide (Im) synthesis.
The preparation method of the present embodiment is in addition to replacing p-methylphenyl acrylic acid with 4- bromophenyl acrylic acid, remaining same embodiment 1, finally obtain white solid (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- Base) -3- (4- bromophenyl) acrylamide, shown in chemical structural formula such as formula (Im), yield: 69.9%.
1HNMR (500 MHz, DMSO) δ: 8.62 (s, 1H), 7.83 (d, J = 16.0 Hz, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.45 (s, 2H), 6.92 (d, J = 16.0 Hz, 1H), 6.48 (s, 1H), 4.29 (s, 2H); 13CNMR (125 MHz, DMSO) δ : 171.51 , 170.77 , 164.57 , 163.14 , 149.60 , 147.17 , 146.08 , 140.32 , 132.94 , 131.97 , 130.66 , 124.57 , 116.80 , 115.24 , 35.44 ; IR (KBr) v: 3290, 3096, 1731, 1643, 1511, 4109, 1315, 1202, 1145, 1070, 940, 816 cm-1; HRMS (ESI, m/z) calcd for [C17H13BrN3O4S2]+ (M+H)+ 465.9525, found 465.9530.
The activity experiment method and result of above compound is given below.
The tyrosinase that a certain amount of vigor is 6680 U/mg is dissolved in the phosphate buffer solution of 0.1 M of pH=6.8, After being added compound oscillation about one minute of various concentration, substrate L-3,4- dihydroxy benzenes is added in constant temperature 20 minutes at 30 DEG C Alanine (L-DOPA) tests OD at the nm of λ=475 after mixing475Time course curve calculates enzymatic activity by curve: enzyme Relative activity=K/K0*100% .
Experimental data is handled using expert data processing software Microcal Origin Professional, with reaction process line Straight slope be reaction speed, which is set as ordinate, is that abscissa is mapped using inhibitor concentration, it is available Inhibitor to the inhibition IC of tyrosinase50Value, K0The straight slope of reaction process line when for without inhibitor.Test result It is shown in Table 1.
As it can be seen from table 1 kojic acid thioether analog derivative (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) - 1,3,4- thiadiazoles -2- base) -3- substituted acrylamide all has certain inhibitory activity to tyrosinase.Wherein (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (2- bromophenyl) acrylamide; (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (4- chlorphenyl) Acrylamide;(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiadiazoles -2- base) -3- (3- bromophenyl) acrylamide;(E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) -1,3,4- thiophene two Azoles -2- base) -3- (3- chlorphenyl) acrylamide and (E)-N- (5- ((5- hydroxyl -4- oxo -4H- pyrans -2- base) methyl mercapto) - 1,3,4- thiadiazoles -2- base) -3- (4- bromophenyl) acrylamide is better than positive control to the inhibitory activity effect of tyrosinase Object kojic acid, their IC50Value is respectively 11.32 μM, 14.90 μM, 6.49 μM, 8.48 μM, 9.54 μM.

Claims (3)

1. one kind contains 1,3, the 4- novel derivative of kojic acid of thiadiazoles, which is characterized in that its structural formula is as shown in the formula (I):
In formula (I), substituent R is H ,-CH3, -CF3, -CH2CH3, -OCH3, F, Cl, Br, -COCH3, -OH, - COOH, -SO3H, -C6H5Or substituted-phenyl.
2. a kind of novel derivative of kojic acid of thiadiazoles containing 1,3,4- as described in claim 1 is in terms of preparing skin-lightening cosmetic Using.
3. a kind of answering in preparation whitening pharmaceutical preparations of the novel derivative of kojic acid of thiadiazoles containing 1,3,4- as described in claim 1 With.
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