CN117820251B - Bis-alpha-keto acid amide compound and composition thereof - Google Patents
Bis-alpha-keto acid amide compound and composition thereof Download PDFInfo
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- CN117820251B CN117820251B CN202410233124.8A CN202410233124A CN117820251B CN 117820251 B CN117820251 B CN 117820251B CN 202410233124 A CN202410233124 A CN 202410233124A CN 117820251 B CN117820251 B CN 117820251B
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- tyrosinase
- acid amide
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 21
- 150000004716 alpha keto acids Chemical class 0.000 claims abstract description 6
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- 150000003839 salts Chemical class 0.000 claims description 4
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 102000003425 Tyrosinase Human genes 0.000 abstract description 18
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- 230000000694 effects Effects 0.000 abstract description 10
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of chemical synthesis, in particular to a double alpha-keto acid amide compound and a composition thereof; the structural general formula is shown in formula I;
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a double alpha-keto acid amide compound and a composition thereof.
Background
The skin contains melanocytes which metabolize the food intake and the self-synthesized amino acid "tyrosine" to melanin by self-carried tyrosinase. Skin cells such as melanosomes transport melanin from the basal skin to the epidermis to resist external damage such as ultraviolet rays. The more melanin in the epidermis, the darker the skin tone of the person.
Melanogenesis is a complex pathway involving a combination of enzymatic and chemical catalytic reactions. Melanin is synthesized and secreted mainly by melanocytes. Melanocytes aggregate with surrounding keratinocytes to form dendritic structures. Melanosomes are specialized organelles of melanocytes that contain melanin particles therein, and synthesis, storage and transport of the melanin particles are all performed in the melanosomes. After melanogenesis, it is transferred from the dendritic tip of melanocytes to keratinocytes. Melanocytes produce two types of melanin: eumelanin and pheomelanin. Among these, the melanogenesis process starts with the oxidation of tyrosine to dopaquinone by Tyrosinase (TYR), and the formation of dopaquinone is a rate limiting step in melanin synthesis. The dopaquinone can be further converted in the presence of cysteine or glutathione after formation to finally produce pheomelanin, or can be intramolecular internalized and further oxidized through the cyclopamine to produce dopachrome and finally converted to eumelanin under the action of tyrosine related proteins TRP-1, TRP-2. Among these, although three enzymes, TYR, TRP-1 and TRP-2, are all involved in the melanogenesis pathway, TYR is the only essential enzyme for melanogenesis, inhibition of this enzyme activity will directly affect the rate and amount of melanin synthesis, and reduction of pigmentation is the main direction of research on current market whiteners.
A number of topical products are currently available for the treatment of pigmentation disorders, which contain a number of different active ingredients to reduce melanin production and/or distribution. Among them, hydroquinone, kojic acid, arbutin, etc. are more common. However, the current common technical solutions often present a safety risk that is not negligible, such as hydroquinone may cause exogenous brown yellow disease and permanent skin leukoplakia. Arbutin as a derivative of hydroquinone, the risk of which under certain conditions releases hydroquinone is also not negligible. While kojic acid has been controversially used due to its potential endocrine disrupting properties.
Among the many pathways, the most effective is the inhibition of tyrosinase activity, as it is the production data for direct synthesis of melanin. The structure of the molecules is similar to that of tyrosine, so that the molecules can deceive tyrosinase and smoothly combine with tyrosinase. And they are not easily detached after being combined with tyrosinase. Thus, tyrosinase is tightly held, and cannot turn tyrosine into melanin.
The earliest tyrosinase inhibitor was hydroquinone, however its side effects were relatively large and resulted in a susceptibility to pigmentation disorders. And thus are prohibited from being added to cosmetics in many countries. On the basis of the novel tyrosinase inhibitor, researchers continuously search for safer and efficient tyrosinase inhibitors to meet the brightening demands of consumers. After decades of development, researchers have found tyrosinase inhibitors that are more effective, including phenethyl resorcinol and lu-n-furo. The former is derived from the German raw material Shimadzu and is widely added to many products. However, the side effects are also very large, the skin care product has irritation and carcinogenicity, and the risk of drug-induced vitiligo and drug-induced chloasma caused by excessively inhibiting tyrosinase function is also caused.
Therefore, development of a novel whitening product which is safe, efficient and convenient to apply is an urgent need.
Disclosure of Invention
The purpose of the invention is that: provided are bis-alpha-keto acid amide compounds and compositions thereof.
In order to solve the technical problems, the technical scheme adopted in the invention is as follows:
The structural general formula of the double alpha-keto acid amide compound is shown as formula I;
wherein R1 is a C0-C6 linear or branched alkyl group.
Further, the compounds exist in free form, or as well as pharmaceutically acceptable salts.
Further, the pharmaceutically acceptable salts include sodium, potassium and calcium salts.
A composition containing the above-mentioned bis-alpha-keto acid amide compound.
Further, the addition amount of the double alpha-keto acid amide compound in the composition is 0.000001 to 20 percent of the total weight of the preparation.
Advantageous effects
(1) The compound provided by the invention can effectively inhibit the activity of tyrosinase and inhibit the synthesis of melanin, and has a good skin whitening effect.
(2) Compared with the prior art, the compound has the advantages that the molecular space structure is greatly changed, the acting target points with tyrosinase are increased, the stability and the safety of the compound are obviously improved, the dissolution performance is improved, and a better effect is realized.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
4- (2, 4-Dimethoxyphenyl) -1, 3-thiazol-2-amine is also prepared in a convenient manner by the method disclosed (document US 2011/02300886) or directly using a commercial reagent.
Example 1:
Under the protection of nitrogen, 4- (2, 4-dimethoxy phenyl) -1, 3-thiazole-2-amine (1.5 g) is dispersed in dry dichloromethane (30 mL), cooled to-5-10 ℃, and a dichloromethane solution (2.0M, 19 mL) of boron tribromide is dropwise added and the reaction is carried out for 24 hours under the heat preservation. After completion of the reaction, the mixture was quenched with methanol, concentrated and dispersed with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium bicarbonate and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated, filtered and washed with a small amount of cold isopropyl acetate, dried in vacuo at 20-30 ℃ to give 0.72g of 4- (2-aminothiazol-4-yl) benzene-1, 3-diol as an off-white solid which was used directly in the subsequent reaction without purification.
Example 2:
Oxalic acid (0.20 g) was dispersed in dry acetonitrile (15 mL), followed by DIPEA (0.86 g) and HATU (1.69 g), stirred at room temperature for 30 min, then 4- (2-aminothiazol-4-yl) benzene-1, 3-diol (0.93 g) was added and the reaction 12-24 h was stirred. After the reaction is completed, 1N NaOH (15 mL) is added, and the mixture is stirred at 5-15 ℃ overnight, and the obtained yellow mixed solution is neutralized to pH 5-6 by using 1N HCl. Extraction was performed using ethyl acetate (3×20 mL). After the organic phases were combined and concentrated, the crude product was purified using prepHPLC (ACCQPREP HP150, welch Ultimate Polar-RP 5 μm 21.2x150 mm, (a) 0.1% TFA aq., (B) CH3 CN) and the product collected and lyophilized to give N1, N2-bis (4- (2, 4-dihydroxyphenyl) thiazol-2-yl) oxalamide 0.69 g as a white powder. ESI-MS: m/z 485.4 [ M+H ] +;1H NMR (400 MHz, DMSO-d 6):
14.11(s,2H),11.27(s,2H),9.69(s,2H),7.68(s,2H),7.45(m,2H),6.47(m,2H),6.38(m,2H)。
example 3:
Succinic acid (0.31 g) was dispersed in dry acetonitrile (15 mL), followed by DIPEA (1.02 g) and HATU (2.00 g), stirred at room temperature for 30 min, then 4- (2-aminothiazol-4-yl) benzene-1, 3-diol (1.09 g) was added and the reaction 12-24 h was stirred. After the reaction is completed, 1N NaOH (15 mL) is added, and the mixture is stirred at 5-15 ℃ overnight, and the obtained yellow mixed solution is neutralized to pH 5-6 by using 1N HCl. Extraction was performed using ethyl acetate (3×20 mL). After the organic phases were combined and concentrated, the crude product was purified using prep-HPLC (ACCQPREP HP, welch Ultimate Polar-RP 5 μm 21.2X150 mm, (A) 0.1% TFA aq., (B) CH 3 CN) and the product was collected and lyophilized to give N1, N4-bis (4- (2, 4-dihydroxyphenyl) thiazol-2-yl) butanediamide 0.68 g as a white powder. ESI-MS: m/z 499.5 [ M+H ] +;1H NMR (400 MHz, DMSO-d 6):
12.09(s,2H),11.27(s,2H),9.67(s,2H),7.66(s,2H),7.42(m,2H),6.42(m,2H),6.33(m,2H),2.50(s,2H)。
Example 4:
Glutaric acid (0.21 g) was dispersed in dry acetonitrile (15 mL), followed by addition of DIPEA (0.62 g) and HATU (1.21 g), stirring at room temperature for 30min, adding 4- (2-aminothiazol-4-yl) benzene-1, 3-diol (0.66 g) and stirring for reaction 12-24 h. After the reaction is completed, 1N NaOH (15 mL) is added, and the mixture is stirred at 5-15 ℃ overnight, and the obtained reddish brown mixed solution is neutralized to pH 5-6 by using 1N HCl. Extraction was performed using ethyl acetate (3×20 mL). After the organic phases were combined and concentrated, the crude product was purified using column chromatography (silica gel, dichloromethane-methanol) to give 0.38g of N1, N5-bis (4- (2, 4-dihydroxyphenyl) thiazol-2-yl) glutaramide as an off-white solid. ESI-MS: m/z 513.5 [ M+H ] +;1H NMR (400 MHz, DMSO-d 6):
12.11(s,2H),11.24(s,2H),9.67(s,2H),7.64(s,2H),7.40(m,2H),6.39(m,2H),6.31(m,2H),2.34(m,4H),2.03(m,2H)
Example 5:
Adipic acid (0.28 g) was dispersed in dry acetonitrile (15 mL), followed by DIPEA (0.74 g) and HATU (1.46 g), stirred at room temperature for 30 min, then 4- (2-aminothiazol-4-yl) benzene-1, 3-diol (0.80 g) was added and the reaction 12-24 h was stirred. After the reaction is completed, 1N NaOH (15 mL) is added, and the mixture is stirred at 5-15 ℃ overnight, and the obtained reddish brown mixed solution is neutralized to pH 5-6 by using 1N HCl. Extraction was performed using ethyl acetate (3×20 mL). The organic phases were combined and concentrated, and the crude product was purified by column chromatography (silica gel, dichloromethane-methanol) to give N1, N6-bis (4- (2, 4-dihydroxyphenyl) thiazol-2-yl) hexanediamide 0.48 g as a white solid .ESI-MS:m/z 527.6 [M+H]+;1H NMR(400 MHz, DMSO-d6): 12.12(s,2H),11.26(s,2H),9.65(s,2H),7.59(s,2H),7.29(m,2H),6.35(m,2H),6.28(m,2H),2.34(m,4H),1.99(m,4H)
Validity test:
The inhibition activity of tyrosinase by the compounds was reported with reference to the prior art (Journal of biochemical and biophysical methods, 1994, 28 (3): 173-183.) using the modified MBTH method. The inhibition of human tyrosinase by compounds was determined by oxidation of levodopa to levodopa quinone by human tyrosinase using 3-methyl-2-benzothiazolinone (MBTH) as chromogenic reagent, further generating a colored product from MBTH reacting with dopa quinone, terminating the reaction and measuring the specific absorption of the generated product at 505 nm.
Application examples:
according to the mass fractions of the components in the formulation examples in the following table, the required emulsion can be prepared by referring to the following formulation production process steps.
Table formulation example
The preparation method comprises the following steps:
taking the formulation 1 as an example,
Polyglycerol-3-methylglucdistearate, hydrogenated polydecene, oleyl erucic acid ester, ethyl palmitate, polydimethylsiloxane, methyl parahydroxybenzoate and butylhydroxytoluene are added as oil phases, the oil phases are heated to be dissolved by a liquid preparation tank, and cyclopenta-dimethicone is added and stirred for dispersion.
Adding water, glycerol, propylene glycol, butanediol, dipropylene glycol, betaine salicylate, EDTA trisodium, ammonium acryloyldimethyl taurate/behenpolyether-25 methacrylate cross-linked polymer and carbomer into a water phase liquid preparation tank, heating and stirring until the components are completely dissolved.
Pumping water phase into emulsifying kettle, adding oil phase, stirring, homogenizing, and stirring.
Cooling, and adding mixture of glycerol polymethacrylate, C12-C15 alcohol benzoate and aminomethylpropanol. After thoroughly mixing, a mixture of N, N-bis (4- (2, 4-dihydroxyphenyl) thiazol-2-yl) malonamide, essence, bis-diethoxydiglycol cyclohexane-1, 4-dicarboxylate, phenoxyethanol was added. And (3) cooling to room temperature after fully homogenizing, and standing to obtain the required emulsion.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of the invention should be assessed as that of the appended claims.
Claims (5)
1. The double alpha-keto acid amide compound is characterized in that: the structural general formula is shown in formula I;
;
wherein R1 is a C0-C6 linear or branched alkyl group.
2. The bis- α -ketoacid amides according to claim 1, characterized in that: the compounds exist in free form, or as well as pharmaceutically acceptable salts.
3. The bis- α -ketoacid amides according to claim 2, characterized in that: the pharmaceutically acceptable salts include sodium, potassium and calcium salts.
4. A composition comprising the bis- α -ketoacid amide-based compound according to any one of claims 1 to 3.
5. The composition of claim 4, wherein: the addition amount of the double alpha-keto acid amide compound in the composition is 0.000001 to 20 percent of the total weight of the composition.
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US4501750A (en) * | 1981-01-13 | 1985-02-26 | Mitsui Toatsu Kaguku Kabushiki Kaisha | Thiazole compounds, a process for preparing same and a pharmaceutical composition containing the thiazole compounds |
CN1349990A (en) * | 1996-07-19 | 2002-05-22 | 武田药品工业株式会社 | Heterocyclic compound, its preparation and use |
US6596746B1 (en) * | 1999-04-15 | 2003-07-22 | Bristol-Myers Squibb Company | Cyclic protein tyrosine kinase inhibitors |
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US4501750A (en) * | 1981-01-13 | 1985-02-26 | Mitsui Toatsu Kaguku Kabushiki Kaisha | Thiazole compounds, a process for preparing same and a pharmaceutical composition containing the thiazole compounds |
CN1349990A (en) * | 1996-07-19 | 2002-05-22 | 武田药品工业株式会社 | Heterocyclic compound, its preparation and use |
US6596746B1 (en) * | 1999-04-15 | 2003-07-22 | Bristol-Myers Squibb Company | Cyclic protein tyrosine kinase inhibitors |
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