CN116375601A - Anti-melanoma compound and preparation method and application thereof - Google Patents

Anti-melanoma compound and preparation method and application thereof Download PDF

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CN116375601A
CN116375601A CN202310651878.0A CN202310651878A CN116375601A CN 116375601 A CN116375601 A CN 116375601A CN 202310651878 A CN202310651878 A CN 202310651878A CN 116375601 A CN116375601 A CN 116375601A
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melanoma
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dmso
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CN116375601B (en
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黄永学
李松
杨川
龚瑜
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Chengdu Tailaikang Technology Co ltd
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Abstract

The invention discloses an anti-melanoma compound, a preparation method and application thereof, and relates to the field of organic synthesis. The anti-melanoma compound provided by the invention is a medicament with high curative effect on malignant melanoma chemotherapy, is also suitable for research and evaluation of psoriasis medicaments, and provides a new clinical medicament for treating melanoma and psoriasis by synthesis of the anti-melanoma compound.

Description

Anti-melanoma compound and preparation method and application thereof
Technical Field
The invention relates to the field of organic synthesis, in particular to an anti-melanoma compound, and a preparation method and application thereof.
Background
Melanoma is a malignant tumor originated from melanocytes and is represented by black or gray asymmetric patches, nodules or tumors and the like appearing on affected parts, and the application of drugs is an auxiliary treatment method, and common drugs comprise chemotherapy drugs, molecular targeting drugs and immune drugs. Malignant melanoma is similar to most tumor treatment methods, including early stage operation treatment, medium and late stage operation combined with radiotherapy and chemotherapy, and novel comprehensive treatment methods such as immunotherapy and targeted therapy. The disease has a long course and requires long-term continuous treatment.
The chemotherapeutic medicine can kill tumor cells, inhibit the growth and reproduction of tumor cells, and prolong the survival time of patients. The common chemotherapeutics include taxol, cisplatin, temozolomide, dacarbazine, carboplatin, etc.
Currently, there is a lack of efficient chemotherapeutics for malignant melanoma. Melanoma is highly resistant to chemotherapy. Dacarbazine has long been the first drug to be treated in chemotherapy, but its response rate is still poor, and the drug has never shown any survival advantage when used in metastatic melanoma. The precursor drug temozolomide of the dacarbazine is orally taken, and has certain effect on the metastasis of the central nervous system. Combination chemotherapy regimens are mostly used for single-drug unresponsive metastatic malignant melanoma, with multiple combination chemotherapy regimens, but combination chemotherapy does not improve overall survival in patients.
Disclosure of Invention
The invention aims to provide an anti-melanoma compound, a preparation method and application thereof, wherein 2-aminobenzoyl hydrazine and dimethyl butynedioate are used as starting materials, and a chemotherapeutic drug compound with high curative effect on malignant melanoma is synthesized through 3-step reaction.
The technical scheme adopted by the invention is as follows:
an anti-melanoma compound, which is a compound with a structure shown in a general formula (1) or each stereoisomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
Figure SMS_1
;
r' is selected from hydrogen, halogen, hydroxy, nitro, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, OPO (OR) 1 )(OR 2 )，O-(CH 2 ) n -NR 3 R 4 Sulfonyl, NR 5 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein n is 1-10; r is R 1 And R is 2 Independently selected from hydrogen, C 1 ~C 10 Alkyl, benzyl; r is R 3 ~R 6 Independently selected from hydrogen, C 1 ~C 10 An alkyl group.
Further, the R' is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, OPO (OR) 1 )(OR 2 )，O-(CH 2 ) n -NR 3 R 4 Sulfonyl, NR 5 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein n is 1-7; r is R 1 And R is 2 Independently selected from hydrogen, C 1 ~C 7 Alkyl, benzyl; r is R 3 ~R 6 Independently selected from hydrogen, C 1 ~C 7 An alkyl group.
Further, n is 1-4; r is R 1 And R is 2 Independently selected from hydrogen, C 1 ~C 4 Alkyl, benzyl; r is R 3 ~R 6 Independently selected from hydrogen, C 1 ~C 4 An alkyl group.
An anti-melanoma compound selected from the following compounds:
Figure SMS_15
Figure SMS_4
Figure SMS_12
Figure SMS_7
Figure SMS_13
Figure SMS_9
Figure SMS_18
Figure SMS_6
Figure SMS_14
Figure SMS_2
Figure SMS_10
Figure SMS_5
Figure SMS_17
Figure SMS_8
Figure SMS_16
Figure SMS_3
Figure SMS_11
。
the 25 anti-melanoma compounds prepared herein are numbered sequentially by Arabic numerals for convenience of the following description.
The preparation method of the anti-melanoma compound comprises the following steps:
1) Preparing a compound A from 2-aminobenzoyl hydrazine and dimethyl butynedioate in a methanol solvent;
2) Synthesizing a compound B by the compound A prepared in the step 1) and amino acid protected by Fmoc protecting groups under the action of a condensing reagent and alkali;
3) Removing Fmoc protecting groups from the compound B prepared in the step 2) under the action of alkali to prepare an anti-melanoma compound;
the reaction general formula is as follows:
Figure SMS_19
。
the Fmoc protecting group is 9-fluorenylmethoxycarbonyl, is extremely stable to acidic conditions, and realizes the protection of amino groups by generating carbamate with the amino groups; fmoc protecting groups are easily deprotected under alkaline conditions.
Typical protecting amino acids for Fmoc protecting groups are Fmoc-Cl, fmoc-Ala-OH, fmoc-Vla-OH, fmoc-Leu-OH, fmoc-Ile-OH, fmoc-Phe-OH, fmoc-Trp (Boc) -OH, fmoc-Pro-OH, fmoc-Met-OH, fmoc-Gyl-OH and Fmoc-Ser (tBu) -OH, fmoc-Thr (tBu) -OH, fmoc-Tyr (tBu) -OH, and the Fmoc protecting groups used in the present invention are various derivatives of Fmoc-L-Tyr-OH.
Further, R is
Figure SMS_20
And R' is selected from the substituent groups.
Further, the Fmoc protecting group is selected from various derivatives of fluorenylmethoxycarbonyl-L-tyrosine.
Further, in the step 2), the base is selected from one or more of diisopropylethylamine, triethylamine and N-methylmorpholine, and the condensing agent is selected from one or more of HATU, DIC, EDCI, HBTU, BOP, pyBOP.
Further, in the step 3), the base is selected from one or more of diisopropylamine, triethylamine and N-methylmorpholine.
The application of the anti-melanoma compound prepared by the preparation method is the application of the anti-melanoma compound in medicines for treating melanoma or psoriasis.
The anti-melanoma compound or stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or eutectic pharmaceutical composition of the anti-melanoma compound can contain pharmaceutically acceptable auxiliary materials, is a chemotherapeutic drug for malignant melanoma, and can also be used for treating psoriasis.
The "melanoma" includes, but is not limited to, superficial diffuse melanoma, nodular melanoma, freckle-like melanoma, and shoulder freckle-like melanoma.
The "psoriasis" includes, but is not limited to, psoriasis vulgaris, psoriasis arthrosis, psoriasis rubra variant, and psoriasis pustulosa.
The term "pharmaceutically acceptable" as used herein is meant to include any material which does not interfere with the effectiveness of the biological activity of the active ingredient and which is not toxic to the host to which it is administered.
The pharmaceutically acceptable auxiliary materials are the general names of all additional materials except the main drugs in the medicine, and the auxiliary materials have the following properties: (1) no toxic or side effect to human body; (2) The chemical property is stable, and is not easily influenced by temperature, pH, preservation time and the like; (3) No incompatibility with the main medicine, and no influence on the curative effect and quality inspection of the main medicine; (4) does not interact with the packaging material. Adjuvants in the present invention include, but are not limited to, fillers (diluents), lubricants (glidants or anti-adherents), dispersants, wetting agents, binders, conditioning agents, solubilizing agents, antioxidants, bacteriostats, emulsifiers, disintegrants, and the like. The binder comprises syrup, acacia, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose or hydroxypropyl methylcellulose), gelatin slurry, syrup, starch slurry or polyvinylpyrrolidone; the filler comprises lactose, sugar powder, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salt (such as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; the lubricant comprises aerosil, magnesium stearate, talcum powder, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol and the like; disintegrants include starch and its derivatives (e.g., sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone, microcrystalline cellulose, etc.; the wetting agent comprises sodium dodecyl sulfate, water or alcohol, etc.; the antioxidant comprises sodium sulfite, sodium bisulphite, sodium metabisulfite, dibutyl benzoic acid and the like; the bacteriostat comprises 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol and the like; the regulator comprises hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate, buffer (including sodium dihydrogen phosphate and disodium hydrogen phosphate), etc.; the emulsifier comprises polysorbate-80, sorbitan without acid, pluronic F-68, lecithin, soybean lecithin, etc.; the solubilizer comprises Tween-80, bile, glycerol, etc. The term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention with acids or bases that are suitable for use as medicaments. The acid base is a broad Lewis acid base. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and the like; acidic amino acids such as aspartic acid and glutamic acid.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention can likewise be used in injectable formulations. Wherein the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (refers to a stamped tablet or a machine pressed tablet prepared by a sterile operation method for medicines), and is dissolved by water for injection when in use for subcutaneous or intramuscular injection.
Wherein the powder for injection contains at least an excipient in addition to the above-mentioned compounds. The excipients described in the present invention, which are components intentionally added to a drug, should not have pharmacological properties in the amounts used, however, the excipients may aid in processing, dissolution or dissolution of the drug, delivery by targeted route of administration, or stability.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
"alkyl" refers to an aliphatic hydrocarbon group, and to a saturated hydrocarbon group. The alkyl moiety may be a straight chain alkyl group or a branched alkyl group. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.
The C1-Cn used in the invention comprises C1-C2, C1-C3 … … C1-Cn, n is an integer more than one; the prefix as a substituent means minimum and maximum values of the number of carbon atoms in the substituent, for example, "C1-C6 alkyl" means a straight-chain or branched alkyl group having one to 6 carbon atoms.
"sulfonyl" is of formula-S (=o) 2 R has a chemical structure of-S (=O) when two connecting ends 2 (CH 2 ) a -wherein R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, and the like, a being a natural number.
"phosphoryl" is a chemical structure having the formula-P (=o) RR', which when two linking ends are present is-P (=o) R (CH 2 ) a Wherein R, R' can be independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, amino, and the like, and a is a natural number.
"benzyl" is of formula C 6 H 5 -CH 2 The chemical structure is a benzyl-containing functional group.
The alkyl group, amino group, sulfonyl group, phosphoryl group, benzyl group and the like described herein may be unsubstituted alkyl group, amino group, sulfonyl group, phosphoryl group, benzyl group and the like, and may be substituted alkyl group, amino group, sulfonyl group, phosphoryl group, benzyl group and the like.
In the above, unless already indicated, the term "substituted" means that the mentioned groups may be substituted by one or more additional groups, each and independently selected from alkyl, hydroxy, alkoxy, nitro, acyl, halogen, aminoalkyl, amino, benzyl and the like.
The IC50 refers to the concentration of the inhibitor when the "cell activity" is inhibited by half, and in terms of apoptosis, it can be understood that a certain drug induces apoptosis of tumor cells at a concentration of 50%, which is referred to as 50% inhibition concentration, i.e. the concentration corresponding to the ratio of apoptotic cells to total cell number equal to 50%, and the IC50 value can be used to measure the ability of the drug to induce apoptosis, i.e. the stronger the induction ability, the lower the value, and also can reversely indicate the tolerance of a certain cell to the drug.
HPV-16 immortalized epidermal keratinocytes are human immortalized keratinocytes stably expressed by human papilloma virus HPV 16E 6/E7 genes, and are commonly used for the research of simulating fast proliferation cells such as melanoma, silver snow disease and the like. In the present invention, the cells are used to evaluate the activity of a compound in inhibiting cell proliferation.
Methotrexate: an organic compound with chemical formula of C 20 H 22 N 8 O 5 The anti-folate compound is mainly used as an anti-folate antineoplastic, and can inhibit the synthesis of tumor cells by inhibiting the dihydrofolate reductase, thereby inhibiting the growth and the reproduction of the tumor cells.
The invention has the beneficial effects that:
1. the invention takes 2-aminobenzoyl hydrazine and butynedioic acid dimethyl ester as initial raw materials, synthesizes the chemotherapeutic drug compound with high curative effect on malignant melanoma through 3 steps of reactions, and has simple synthetic route, mild condition and easily obtained raw materials.
2. The anti-melanoma compound synthesized by the invention provides a new clinical medicine for treating melanoma and psoriasis, and can be taken orally or externally.
Detailed Description
The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described herein are only some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to fall within the scope of the invention.
Unless otherwise specified in the examples, the reaction temperature was room temperature (20℃to 30 ℃).
The reagents used in the examples were obtained commercially, unless otherwise specified.
In the present invention, the structure of the compounds is determined by Mass Spectrometry (MS) and/or nuclear magnetic resonance (1 HNMR) equipment. The chemical abbreviations have the following meanings:
fmoc: fluorenylmethoxycarbonyl;
DMSO: dimethyl sulfoxide;
Na 2 S 2 O 5 : sodium metabisulfite;
DCM: dichloromethane;
HATU: o- (7-azabenzotriazol-1-yl) -N, N' -tetramethylurea hexafluorophosphate;
eq: equivalent weight;
DMF: n, N-dimethylformamide;
NaI: sodium iodide;
HCl: hydrochloric acid;
the synthetic general formula of the anti-melanoma compound is as follows:
Figure SMS_21
；
the R is
Figure SMS_22
The R' is selected from the substituent groups as described above.
The Fmoc protecting groups used in the present invention protect amino acids, except compounds 12, 18, 19, which are commercially available.
Example 1
Synthesis of protected amino acid-N-fluorenylmethoxycarbonyl-L-tyrosyl sulfonate sodium salt of Compound 12:
5.16g Fmoc-L-Tyr-OH,240mlDMF,300ml dioxane was added together to the reaction vessel, 6.09g pyridine sulfur trioxide was added with stirring, and the temperature was raised to 80℃for reaction for 3 hours. 300ml of water, 3X100ml of ethyl acetate were added, the product was extracted, ethyl acetate was concentrated off, the residue was dissolved in methanol, 6.9g of sodium methoxide was added, stirred overnight, the precipitated solid was filtered off, the liquid fraction was concentrated to remove methanol, ethyl acetate was added to the residue, and the precipitated solid was collected and dried to give 4.5g (product yield 70%).
1H NMR (300 MHz, DMSO)δ12.74(br, 1H), 7.89(d, J = 7.9Hz, 2H), 7.75-7.65(m, 3H), 7.35-7.42 (m, 4H), 7.08-7.14(m, 4H), 4.06-4.26 (m, 4H), 2.75-3.10(m, 2H)；
Mass spectrometry: 484.1 (M+H+).
Example 2
Synthesis of protected amino acid N-fluorenylmethoxycarbonyl-L-tyrosine bis-benzyl phosphate of Compound 19:
20g of Fmoc-L-Tyr-OH were dissolved in 200ml of THF, 6.4g of N-methylmorpholine and 9.2g of t-butyldimethylchlorosilane were added and stirred at room temperature for 2 hours. Then, 10.2g of tetrazole and 17g of diphenyl N, N' -diisopropylphosphoramidite were added to the reaction mixture, and the mixture was stirred for 2 hours, followed by TLC monitoring the completion of the reaction. Then controlling the temperature (lower than 20 ℃) and dropwise adding 19.2ml of 70 percent tertiary butyl hydroperoxide, reacting for 2 hours after the completion of the dropwise adding, and then dropwise adding 10 percent Na 2 S 2 O 5 The reaction was quenched with 77ml of solution. Ethyl acetate (3×500 ml) was added to the reaction mixture, the extract was concentrated under reduced pressure to remove ethyl acetate, and then 10g of N-fluorenylmethoxycarbonyl-L-tyrosine dibenzyl phosphate was obtained by silica gel column chromatography in 85% yield.
1H NMR (300 MHz, DMSO). Delta. 11.98 (br, 1H), 7.88 (d, J=7.9 Hz, 2H), 7.60-7.65 (m, 3H), 7.00-7.51 (m, 18H), 5.03 (m, 4H), 4.16-4.20 (m, 4H), 2.75-3.15 (m, 2H); mass spectrometry: 664.20 (M+H+).
Example 3
Synthesis of protected amino acid-N-fluorenylmethoxycarbonyl-O-benzyl-L-phosphotyrosine of Compound 18:
10g of N-fluorenylmethoxycarbonyl-L-tyrosine dibenzyl phosphate obtained in example 2 was dissolved in 300ml of acetone, and then 15g of NaI was added thereto, the reaction solution was heated under reflux for 2 hours, the reaction solution was cooled, and the solid was precipitated by filtration. The obtained solid was dissolved in 2ml of aqueous hcl, the ethyl acetate extract was added, the extract was washed, and the ethyl acetate was concentrated under reduced pressure after drying, and then 7g of N-fluorenylmethoxycarbonyl-O-benzyl-L-phosphotyrosine was obtained by silica gel column chromatography in a yield of 81%.
1H NMR (300 MHz, DMSO). Delta. 11.98 (br, 1H), 11.0 (br, 1H), 7.88 (d, J=7.9 Hz, 2H), 7.60-7.65 (m, 3H), 7.00-7.51 (m, 13H), 5.03 (m, 2H), 4.16-4.20 (m, 4H), 2.75-3.15 (m, 2H); mass spectrometry: 574.16 (M+H+).
Example 4
Synthesis of compound a:
to methanol (10 mL) was added 2-aminobenzoyl hydrazine (6.85 mM, 1.03 g), and the mixture was stirred until clear, followed by slow dropwise addition of dimethyl butynedioate (6.85 mM). After 5 minutes, the mixed solution was filtered to give a yellow crude product. Recrystallisation from methanol, filtration and washing with a small amount of methanol gives compound a (0.83 g, 42%) after drying.
1H NMR (300 MHz, DMSO) delta 7.52 (dd, j=7.9, 1.4 Hz, 1H), 7.25 (ddd, j=8.4, 7.2, 1.5 Hz, 1H), 6.80 (dd, j=8.3, 0.8 Hz, 1H), 6.63-6.54 (m, 1H), 3.90 (s, 2H), 3.81-3.58 (m, 7H), 3.19 (d, j=5.2 Hz, 1H); mass spectrometry: 293.2 (M+H+).
Example 5
Synthesis of compound B:
compound A (10 mmol,1.0 eq) and Fmoc-protected amino acid (10 mmol,1.0 eq) were dissolved in DCM (15 v/w), HATU (12 mmol, 1.2 eq) and diisopropylethylamine (30 mmol,3.0 eq) were then added, after stirring overnight at RT, 5% aqueous citric acid (10 v/w) was added, the layers were stirred, the lower organic phase was separated, dried over anhydrous sodium sulphate, filtered, the organic phase concentrated under reduced pressure and the residue was chromatographed over silica gel to give Compound B.
The compounds B1-B25 correspond to the compounds before Fmoc protecting groups of anti-melanoma compounds 1-25 are removed respectively, and yield and nuclear magnetic resonance data of the compounds B1-B25 are obtained according to the synthesis general method of the compound B:
compound B1 (yield 75%)
1 H NMR (300 MHz, DMSO) δ 8.05(br, 1H), 7.02-7.87(m, 19H), 4.95(m, 1H) 4.36-4.41 (m, 3H), 3.68 (s, 6H), 3.28-3.54 (m, 2H), 2.68 (m, 2H), mass spectrometry: 663.24 (M+H) + )。
Compound B2 (yield 70%)
1 H NMR (300 MHz, DMSO). Delta.8.10 (br, 1H), 7.05-7.90 (m, 18H), 4.92 (m, 1H), 4.30-4.45 (m, 3H), 3.65 (s, 6H), 3.30-3.56 (m, 2H), 2.68 (m, 2H); mass Spectrometry: 681.68 (M+H) + )。
Compound B3 (yield 75%)
1 H NMR (300 MHz, DMSO). Delta.8.06 (br, 1H), 7.03-7.85 (m, 18H), 4.94 (m, 1H), 4.32-4.43 (m, 3H), 3.62 (s, 6H), 3.32-3.58 (m, 2H), 2.69 (m, 2H); mass Spectrometry: 698.13 (M+H) + )。
Compound B4 (yield 78%)
1 H NMR (300 MHz, DMSO). Delta.8.02 (br, 1H), 7.02-7.84 (m, 18H), 4.93 (m, 1H), 4.30-4.41 (m, 3H), 3.60 (s, 6H), 3.30-3.56 (m, 2H), 2.67 (m, 2H); mass Spectrometry: 742.58 (M+H) + )。
Compound B5 (yield 76%)
1 H NMR (300 MHz, DMSO). Delta.8.01 (br, 1H), 7.01-7.83 (m, 18H), 4.92 (m, 1H), 4.31-4.42 (m, 3H), 3.61 (s, 6H), 3.32-3.58 (m, 2H), 2.68 (m, 2H); mass Spectrometry: 789.58 (M+H) + )。
Compound B6 (yield 80%)
1 H NMR (300 MHz, DMSO). Delta.8.01 (br, 1H), 7.01-7.83 (m, 18H), 5.35 (br, 1H), 4.90 (m, 1H), 4.30-4.41 (m, 3H), 3.63 (s, 6H), 3.33-3.59 (m, 2H), 2.67 (m, 2H), mass spectrometry: 679.69 (M+H) + )。
Compound B7 (yield 75%)
1 H NMR (300 MHz, DMSO). Delta.8.02 (br, 1H), 7.01-7.83 (m, 18H), 6.27 (br, 2H), 4.91 (m, 1H), 4.31-4.42 (m, 3H), 3.62 (s, 6H), 3.34-3.60 (m, 2H), 2.68 (m, 2H), mass spectrometry: 678.70 (M+H) + )。
Compound B8 (yield 79%)
1 H NMR (300 MHz, DMSO) δ 8.01(br, 1H), 7.02-7.85(m, 18H), 4.92(m, 1H), 4.32-4.44(m, 3H), 3.61(s, 6H), 3.35-3.61(m, 2H), 266 (m, 2H); mass Spectrometry: 708.69 (M+H) + )。
Compound B9 (yield 80%)
1 H NMR (300 MHz, DMSO). Delta.8.01 (br, 1H), 7.02-7.85 (m, 18H), 4.92 (m, 1H), 4.32-4.44 (m, 3H), 3.83 (s, 3H), 3.60 (s, 6H), 3.33-3.58 (m, 2H), 2.65 (m, 2H), mass spectrometry: 691.71 (M+H) + )。
Compound B10 (yield 76%)
1 H NMR (300 MHz, DMSO). Delta.8.02 (br, 1H), 7.05-7.88 (m, 18H), 4.93 (m, 1H), 4.35-4.47 (m, 3H), 4.10 (s, 3H), 3.62 (s, 6H), 3.32-3.58 (m, 2H), 2.67 (m, 2H), 1.30 (m, 3H), mass spectrometry: 707.74 (M+H) + )。
Compound B11 (yield 78%)
1 H NMR (300 MHz, DMSO). Delta.8.01 (br, 1H), 7.03-7.85 (m, 18H), 4.91 (m, 1H), 4.32-4.44 (m, 3H), 3.60 (s, 6H), 3.35-3.61 (m, 2H), 2.66 (m, 2H), 1.42 (s, 9H), mass spectrometry: 735.79 (M+H) + )。
Compound B12: (yield 75%)
1H NMR (300 MHz, DMSO). Delta.6.90-7.87 (m, 19H), 4.06-4.39 (m, 4H), 3.90 (s, 2H), 3.68 (s, 6H), 2.75-3.10 (m, 2H), 2.1 (br, 1H); mass spectrometry: 759.19 (M+H+).
Compound B13 (yield 73%)
1 H NMR (300 MHz, DMSO). Delta.11.99 (br, 2H), 8.01 (br, 1H), 7.02-7.85 (m, 18H), 4.92 (m, 1H), 4.32-4.44 (m, 3H), 3.61 (s, 6H), 3.35-3.61 (m, 2H), 2.66 (m, 2H), mass spectrometry: 759.67 (M+H) + )。
Compound B14 (yield 78%)
1 H NMR (300 MHz, DMSO). Delta. 11.98 (br, 2H), 8.02 (br, 1H), 7.01-7.84 (m, 18H), 4.91 (m, 1H), 4.31-4.43 (m, 3H), 3.78 (s, 3H), 3.61 (s, 6H), 3.35-3.61 (m, 2H), 2.68 (m, 2H); mass Spectrometry: 773.69 (M+H) + )。
Compound B15 (yield 75%)
1 H NMR (300 MHz, DMSO) δ 12.02(br, 1H), 8.01(br, 1H), 7.03-7.87(m, 18H), 4.92(m, 1H), 4.33-4.45(m, 3H), 4.06(m, 2H), 3.61(s, 6H), 3.35-3.61(m,2H) 2.68 (m, 2H), 1.32 (m, 3H), mass spectrum: 787.72 (M+H) + )。
Compound B16 (yield 72%)
1 H NMR (300 MHz, DMSO). Delta.8.03 (br, 1H), 7.05-7.89 (m, 18H), 4.91 (m, 1H), 4.32-4.46 (m, 3H), 3.75 (s, 6H), 3.63 (s, 6H), 3.36-3.63 (m, 2H), 2.69 (m, 2H); mass Spectrometry: 787.72 (M+H) + )。
Compound B17 (yield 80%)
1 H NMR (300 MHz, DMSO). Delta.8.02 (br, 1H), 7.04-7.87 (m, 18H), 4.92 (m, 1H), 4.33-4.45 (m, 3H), 4.05 (m, 2H), 3.63 (s, 6H), 3.35-3.61 (m, 2H), 2.68 (m, 2H), 1.30 (m, 3H), mass spectrometry: 815.77 (M+H) + )。
Compound B18 (yield 75%)
1H NMR (300 MHz, DMSO). Delta. 11.98 (br, 1H), 6.92-7.90 (m, 24H), 5.08 (s, 2H), 4.08-4.41 (m, 4H), 3.90 (s, 2H), 3.68 (s, 6H), 2.73-3.12 (m, 2H); mass spectrometry: 849.25 (M+H+).
Compound B19 (yield 72%)
1H NMR (300 MHz, DMSO) delta 6.95-7.95 (m, 29H), 5.10 (s, 4H), 4.07-4.40 (m, 4H), 3.91 (s, 2H), 3.70 (s, 6H), 2.75-3.15 (m, 2H); mass spectrometry: 939.91 (M+H+).
Compound B20 (yield 80%)
1 H NMR (300 MHz, DMSO). Delta.8.11 (br, 1H), 7.05-7.90 (m, 18H), 4.91 (m, 1H), 4.30-4.45 (m, 3H), 3.63 (s, 6H), 3.30-3.56 (m, 2H), 2.68 (s, 2H), 2.36 (s, 3H); mass Spectrometry: 677.71 (M+H) + )。
Compound B21 (yield 75%)
1 H NMR (300 MHz, DMSO). Delta.8.12 (br, 1H), 7.02-7.88 (m, 18H), 4.90 (m, 1H), 4.28-4.43 (m, 3H), 3.60 (s, 6H), 3.31-3.50 (m, 2H), 2.70 (s, 2H), 2.60 (m, 2H), 1.22 (m, 3H), mass spectrometry: 691.74 (M+H) + )。
Compound B22 (yield 72%)
1 H NMR (300 MHz, DMSO). Delta.8.10 (br, 1H), 7.04-7.92 (m, 18H), 4.95 (m, 1H), 4.31-4.48 (m, 3H), 4.1 (br, 1H), 3.60 (s, 6H), 3.31-3.57 (m, 2H), 2.68 (s, 5H), mass spectrometry: 692.73 (M+H) + )。
Compound B23 (yield 76%)
1 H NMR (300 MHz, DMSO). Delta.8.12 (br, 1H), 7.06-7.94 (m, 18H), 4.95 (m, 1H), 4.31-4.48 (m, 3H), 4.0 (br, 1H), 3.60 (s, 6H), 3.31-3.57 (m, 4H), 2.68 (s, 2H), 1.28 (m, 3H); mass Spectrometry: 707.76 (M+H) + )。
Compound B24 (yield 82%)
1 H NMR (300 MHz, DMSO). Delta.8.10 (br, 1H), 7.05-7.93 (m, 18H), 4.94 (m, 1H), 4.31-4.48 (m, 3H), 3.60 (s, 6H), 3.31-3.57 (m, 2H), 3.05 (s, 6H), 2.68 (s, 2H); mass Spectrometry: 706.76 (M+H) + )。
Compound B25 (yield 76%)
1 H NMR (300 MHz, DMSO). Delta.8.12 (br, 1H), 7.01-7.90 (m, 18H), 4.96 (m, 1H), 4.30-4.45 (m, 3H), 3.62 (s, 6H), 3.30-3.60 (m, 6H), 2.68 (s, 2H), 1.18 (m, 6H), mass spectrometry: 734.81 (M+H) + )。
Example 6
Synthesis of anti-melanoma compounds:
dissolving a compound B in DMF (dimethyl formamide) with the volume being 5 times, adding diisopropylamine with the volume being 2 times, reacting for 2 hours at room temperature, adding water with the volume being 15 times, adding ethyl acetate with the volume being 10 times, stirring for 10 minutes, standing for layering, separating an ethyl acetate phase, extracting the water phase with ethyl acetate for 2 times, combining the ethyl acetate phases, adding anhydrous sodium sulfate for drying, filtering, concentrating the ethyl acetate, adding petroleum ether/ethyl acetate for crystallization, filtering and drying to obtain the anti-melanoma compound.
According to the synthesis method of the anti-melanoma compounds, anti-melanoma compounds 1 to 25 are prepared respectively, and yield and nuclear magnetic resonance data are obtained respectively as follows:
anti-melanoma Compound 1 (yield 85%)
1H NMR (300 MHz, DMSO). Delta.7.01-7.90 (m, 11H), 5.12 (br, 2H), 4.08-4.29 (m, 1H), 3.60 (s, 6H), 3.29-3.54 (m, 2H), 2.70 (m, 2H); mass spectrometry: 441.45 (M+H+).
Anti-melanoma Compound 2 (yield 88%)
1H NMR (300 MHz, DMSO). Delta.7.05-7.95 (m, 10H), 5.15 (br, 2H), 4.10-4.30 (m, 1H), 3.62 (s, 6H), 3.35-3.59 (m, 2H), 2.72 (m, 2H); mass spectrometry: 459.44 (M+H+).
Anti-melanoma Compound 3 (yield 83%)
1H NMR (300 MHz, DMSO). Delta.7.03-7.92 (m, 10H), 5.13 (br, 2H), 4.09-4.31 (m, 1H), 3.61 (s, 6H), 3.30-3.55 (m, 2H), 2.71 (m, 2H); mass spectrometry: 475.89 (M+H+).
Anti-melanoma Compound 4 (yield 85%)
1H NMR (300 MHz, DMSO). Delta.7.04-7.94 (m, 10H), 5.14 (br, 2H), 4.11-4.32 (m, 1H), 3.60 (s, 6H), 3.32-3.57 (m, 2H), 2.70 (m, 2H); mass spectrometry: 520.35 (M+H+).
Anti-melanoma Compound 5 (yield 88%)
1H NMR (300 MHz, DMSO). Delta.7.02-7.92 (m, 10H), 5.15 (br, 2H), 4.13-4.34 (m, 1H), 3.61 (s, 6H), 3.30-3.55 (m, 2H), 2.71 (m, 2H); mass spectrometry: 567.35 (M+H+).
Anti-melanoma Compound 6 (yield 85%)
1H NMR (300 MHz, DMSO). Delta.7.01-7.91 (m, 10H), 5.35 (br, 1H), 5.11 (br, 2H), 4.12-4.32 (m, 1H), 3.63 (s, 6H), 3.31-3.56 (m, 2H), 2.74 (m, 2H); mass spectrometry: 457.45 (M+H+).
Anti-melanoma Compound 7 (yield 80%)
1H NMR (300 MHz, DMSO). Delta.7.02-7.91 (m, 10H), 6.27 (br, 2H), 5.12 (br, 2H), 4.11-4.31 (m, 1H), 3.62 (s, 6H), 3.32-3.57 (m, 2H), 2.75 (m, 2H); mass spectrometry: 456.48 (M+H+).
Anti-melanoma Compound 8 (yield 85%)
1H NMR (300 MHz, DMSO). Delta.7.01-7.90 (m, 10H), 5.11 (br, 2H), 4.10-4.30 (m, 1H), 3.61 (s, 6H), 3.31-3.56 (m, 2H), 2.76 (m, 2H); mass spectrometry: 486.45 (M+H+).
Anti-melanoma Compound 9 (yield 84%)
1H NMR (300 MHz, DMSO). Delta.7.00-7.91 (m, 10H), 5.12 (br, 2H), 4.12-4.32 (m, 1H), 3.85 (s, 3H), 3.62 (s, 6H), 3.32-3.57 (m, 2H), 2.77 (m, 2H); mass spectrometry: 471.48 (M+H+).
Anti-melanoma Compound 10 (yield 85%)
1H NMR (300 MHz, DMSO). Delta.7.02-7.92 (m, 10H), 5.13 (br, 2H), 4.15-4.35 (m, 1H), 4.05 (m, 2H), 3.62 (s, 6H), 3.33-3.58 (m, 2H), 2.75 (m, 2H), 1.33 (m, 3H); mass spectrometry: 485.5 (M+H+).
Anti-melanoma Compound 11 (yield 80%)
1H NMR (300 MHz, DMSO). Delta.7.03-7.92 (m, 10H), 5.12 (br, 2H), 4.11-4.30 (m, 1H), 3.63 (s, 6H), 3.31-3.56 (m, 2H), 2.77 (m, 2H), 1.42 (s, 9H); mass spectrometry: 513.55 (M+H+).
Anti-melanoma Compound 12 (yield 82%)
1H NMR (300 MHz, DMSO). Delta.6.91-7.90 (m, 11H), 5.15 (br, 2H), 4.06-4.39 (m, 1H), 3.91 (s, 2H), 3.65 (s, 6H), 2.72-3.12 (m, 2H), 2.2 (br, 1H); mass Spectrometry: 537.12 (M+H+).
Anti-melanoma Compound 13 (yield 85%)
1H NMR (300 MHz, DMSO). Delta.12.01 (br, 2H), 7.01-7.90 (m, 10H), 5.13 (br, 2H), 4.10-4.30 (m, 1H), 3.61 (s, 6H), 3.31-3.56 (m, 2H), 2.76 (m, 2H); mass spectrometry: 537.43 (M+H+).
Anti-melanoma Compound 14 (yield 86%)
1H NMR (300 MHz, DMSO). Delta.11.95 (br, 1H), 7.05-7.95 (m, 10H), 5.12 (br, 2H), 4.11-4.31 (m, 1H), 3.78 (s, 3H), 3.61 (s, 6H), 3.32-3.57 (m, 2H), 2.75 (m, 2H); mass spectrometry: 551.46 (M+H+).
Anti-melanoma Compound 15 (yield 88%)
1H NMR (300 MHz, DMSO). Delta.11.99 (br, 1H), 7.03-7.94 (m, 10H), 5.15 (br, 2H), 4.12-4.32 (m, 1H), 4.05 (m, 2H), 3.63 (s, 6H), 3.33-3.59 (m, 2H), 2.76 (m, 2H), 1.31 (m, 3H); mass spectrometry: 565.48 (M+H+).
Anti-melanoma Compound 16 (yield 85%)
1H NMR (300 MHz, DMSO). Delta.7.05-7.95 (m, 10H), 5.16 (br, 2H), 4.15-4.38 (m, 1H), 3.80 (s, 6H), 3.65 (s, 6H), 3.33-3.59 (m, 2H), 2.78 (m, 2H); mass spectrometry: 565.48 (M+H+).
Anti-melanoma Compound 17 (yield 83%)
1H NMR (300 MHz, DMSO). Delta.7.02-7.93 (m, 10H), 5.13 (br, 2H), 4.13-4.35 (m, 1H), 3.82 (m, 4H), 3.64 (s, 6H), 3.31-3.57 (m, 2H), 2.71 (m, 2H), 1.28 (m, 6H); mass spectrometry: 593.53 (M+H+).
Anti-melanoma Compound 18 (yield 83%)
1H NMR (300 MHz, DMSO). Delta.11.90 (br, 1H), 6.95-7.95 (m, 15H), 5.25 (br, 2H), 5.10 (s, 2H), 4.10-4.40 (m, 1H), 3.90 (s, 2H), 3.68 (s, 6H), 2.73-3.12 (m, 2H); mass spectrometry: 627.18 (M+H+).
Anti-melanoma Compound 19 (yield 85%)
1H NMR (300 MHz, DMSO). Delta.6.95-7.95 (m, 20H), 5.30 (br, 2H), 5.13 (s, 4H), 4.10-4.35 (m, 1H), 3.90 (s, 2H), 3.72 (s, 6H), 2.75-3.17 (m, 2H); mass spectrometry: 717.22 (M+H+).
Anti-melanoma Compound 20 (yield 88%)
1H NMR (300 MHz, DMSO). Delta.7.01-7.95 (m, 10H), 5.25 (br, 2H), 4.10-4.30 (m, 1H), 3.62 (s, 6H), 3.35-3.59 (m, 2H), 2.72 (m, 2H), 2.34 (s, 3H); mass spectrometry: 455.48 (M+H+).
Anti-melanoma Compound 21 (yield 87%)
1H NMR (300 MHz, DMSO). Delta.7.00-7.96 (m, 10H), 5.20 (br, 2H), 4.11-4.28 (m, 1H), 3.61 (s, 6H), 3.36-3.60 (m, 2H), 2.70 (m, 2H), 2.61 (m, 2H), 1.23 (m, 3H); mass spectrometry: 469.50 (M+H+).
Anti-melanoma Compound 22 (yield 84%)
1H NMR (300 MHz, DMSO). Delta.7.02-7.95 (m, 10H), 5.23 (br, 2H), 4.10-4.30 (m, 1H), 4.01 (br, 1H), 3.62 (s, 6H), 3.35-3.59 (m, 2H), 2.72 (s, 5H); mass spectrometry: 470.49 (M+H+).
Anti-melanoma Compound 23 (yield 90%)
1H NMR (300 MHz, DMSO). Delta.7.04-7.97 (m, 10H), 5.21 (br, 2H), 4.11-4.31 (m, 1H), 4.00 (br, 1H), 3.61 (s, 6H), 3.35-3.59 (m, 4H), 2.68 (s, 2H), 1.29 (m, 3H); mass spectrometry: 484.52 (M+H+).
Anti-melanoma Compound 24 (yield 85%)
1H NMR (300 MHz, DMSO). Delta.7.01-7.94 (m, 10H), 5.21 (br, 2H), 4.10-4.30 (m, 1H), 3.63 (s, 6H), 3.35-3.59 (m, 2H), 3.06 (s, 6H), 2.72 (s, 2H); mass spectrometry: 484.52 (M+H+).
Anti-melanoma Compound 25 (yield 88%)
1H NMR (300 MHz, DMSO). Delta.7.00-7.92 (m, 10H), 5.19 (br, 2H), 4.12-4.32 (m, 1H), 3.62 (s, 6H), 3.30-3.59 (m, 6H), 2.70 (s, 2H), 1.18 (m, 6H); mass spectrometry: 512.57 (M+H+).
Biological activity assessment:
b16 (murine melanoma cells) and HPV-16 immortalized epidermal keratinocytes derived from American ATCC.
Compound C was evaluated for biological activity using B16 (murine melanoma cells) and HPV-16 immortalized epidermal keratinocytes, and methotrexate was used as a control group, and the MTT activity test experiment was performed:
1) Cell concentration was adjusted to 0.5x10 in 96-well plates 5 -1x10 5 Individual/ml, 5% CO at 37℃ 2 Culturing in a constant temperature incubator for 24 hours;
2) The experimental group was in an incubator for 72 hours;
3) Using MTT, absorbance at 595nm was read.
The results are shown in Table 1:
TABLE 1 biological Activity evaluation of B16 and HPV-16 immortalized epidermal keratinocytes against melanoma Compounds 1-25
Figure SMS_23
As can be seen from table 1, all of the anti-melanoma compounds 1, 6, 7, 8, 11-19 of the present invention showed a strong ability of cells to induce apoptosis for B16; compounds 1-7, 9-11 and 17-25 of the invention show strong apoptosis-inducing capacity for HPV-16, and show that the anti-melanoma compound has an inhibiting effect on melanoma.

Claims (10)

1. An anti-melanoma compound, characterized in that the compound has a structure as shown in a general formula (1) or each stereoisomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
Figure QLYQS_1
；
r' is selected from hydrogen, halogen, hydroxy, nitro, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, OPO (OR) 1 )(OR 2 )，O-(CH 2 ) n -NR 3 R 4 Sulfonyl, NR 5 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein n is 1-10; r is R 1 And R is 2 Independently selected from hydrogen, C 1 ~C 10 Alkyl, benzyl; r is R 3 ~R 6 Independently selected from hydrogen, C 1 ~C 10 An alkyl group.
2. The anti-melanoma compound of claim 1 wherein R' is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, nitro, C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, OPO (OR) 1 )(OR 2 )，O-(CH 2 ) n -NR 3 R 4 Sulfonyl, NR 5 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein n is 1-7; r is R 1 And R is 2 Independently selected from hydrogen, C 1 ~C 7 Alkyl, benzyl; r is R 3 ~R 6 Independently selected from hydrogen, C 1 ~C 7 An alkyl group.
3. The anti-melanoma compound according to claim 2, wherein n has a value of 1 to 4; r is R 1 And R is 2 Independently selected from hydrogen, C 1 ~C 4 Alkyl, benzyl; r is R 3 ~R 6 Independently selected from hydrogen, C 1 ~C 4 An alkyl group.
4. An anti-melanoma compound according to any one of claims 1 to 3, which is selected from the group consisting of:
Figure QLYQS_8
Figure QLYQS_3
Figure QLYQS_12
Figure QLYQS_7
Figure QLYQS_16
Figure QLYQS_9
Figure QLYQS_13
、
Figure QLYQS_6
、
Figure QLYQS_17
、
Figure QLYQS_2
、
Figure QLYQS_10
、
Figure QLYQS_5
Figure QLYQS_11
、
Figure QLYQS_14
、
Figure QLYQS_18
、
Figure QLYQS_4
、
Figure QLYQS_15
、
Figure QLYQS_19
、
Figure QLYQS_20
。
5. a method of preparing an anti-melanoma compound according to claim 1 comprising the steps of:
1) Preparing a compound A from 2-aminobenzoyl hydrazine and dimethyl butynedioate in a methanol solvent;
2) Synthesizing a compound B by the compound A prepared in the step 1) and amino acid protected by Fmoc protecting groups under the action of a condensing reagent and alkali;
3) Removing Fmoc protecting groups from the compound B prepared in the step 2) under the action of alkali to prepare an anti-melanoma compound;
the reaction general formula is as follows:
Figure QLYQS_21
。
6. the method for preparing an anti-melanoma compound according to claim 5, wherein R is
Figure QLYQS_22
R' is selected from the substituent groups of any one of claims 1-4.
7. The method for preparing an anti-melanoma compound according to claim 5, wherein the amino acid selected as the Fmoc protecting group is various derivatives of fluorenylmethoxycarbonyl-L-tyrosine.
8. The method for producing an anti-melanoma compound according to claim 5, wherein the base in step 2) is one or more selected from diisopropylethylamine, triethylamine, and N-methylmorpholine, and the condensing agent is one or more selected from HATU, DIC, EDCI, HBTU, BOP, pyBOP.
9. The method for producing an anti-melanoma compound according to claim 5, wherein the base in step 3) is one or more selected from diisopropylamine, triethylamine, and N-methylmorpholine.
10. The use of an anti-melanoma compound prepared by the preparation method according to any one of claims 5 to 9, in the manufacture of a medicament for the treatment of melanoma or psoriasis.
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