Conjugate compounds containing 13-cis-retinoic acid and ascorbic acid

Abstract

This invention relates to a conjugate compound containing 13-cis-retinoic acid and vitamin C, and a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier. Because this compound has much better water solubility than retinoic acid, it reduces the effective dose of retinoic acid and minimizes side effects. This compound increases the efficiency of 13-cis-retinoic acid and the concentration that passes from the cell membrane into the cell. This compound is useful in the treatment of cancers such as pancreatic cancer.

Description

[Technical Field]

[0001] The present invention relates to a conjugate compound comprising 13-cis-retinoic acid and vitamin C, and a pharmaceutically acceptable salt thereof. The present invention also relates to a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier. [Background technology]

[0002] All-trans retinoic acid (ATRA), also known as tretinoin, and isotretinoin (13-cis-retinoic acid) are orally active vitamin A derivatives. Due to their specific effects on cell proliferation, differentiation, and apoptosis, as well as their low toxicity, 13-cis-retinoic acid and ATRA are promising compounds for the treatment of various cancers. Retinoic acid receptors in human cell nuclei have been discovered by biochemists and found not to be mutated in cancer cells; therefore, retinoic acid may exert its anticancer effects in many malignancies. For example, in children with high-risk neuroblastoma, treatment with 13-cis-retinoic acid has been found to reduce the risk of cancer recurrence after high-dose chemotherapy and stem cell transplantation. ATRA is being studied in combination with other drugs for various cancers and precancerous lesions. Numerous clinical trials using ATRA as part of combination therapy are currently underway [Kocher, HM, Basu, B., Froeling, FEM et al. Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer. Nat Commun 11, 4841 (2020)]. For example, ATRA and various interferons (IFNs) have been shown to enhance the effects of both drugs, resulting in growth inhibition and cell death in tumor cell lines. Nevertheless, to unlock the therapeutic potential of retinoic acid, many studies highlight the need for a better understanding of the mechanisms blocking retinoic acid signaling and retinoic acid regulatory gene expression in cancers such as acute myeloid leukemia (AML). Combination therapies targeting multiple gene silencing mechanisms may be the most effective strategy to mediate the reactivation of ATRA-sensitive gene expression and differentiation of AML cells, as well as the general anticancer activity of ATRA.Currently, the identification of a class of proteins that regulate gene expression through histone and DNA modification is driving the development of new therapeutic drugs called epigenetic drugs that alter chromatin structure. However, these epigenetic modifiers have been shown to be only partially effective against various cancers when used alone.

[0003] Vitamin A is a fat-soluble vitamin and an essential nutrient for humans. It is a group of organic compounds that include retinol, retinal (also known as retinaldehyde), retinoic acid, and several provitamin A carotenoids (especially beta-carotene). Retinoic acid is a metabolite of vitamin A1 (all-trans-retinol). Isotretinoin (13-cis-retinoic acid) is an orally active vitamin A derivative.

[0004] Vitamin C (ascorbic acid, also known as ascorbate) is a water-soluble vitamin found in citrus fruits and other fruits and vegetables. Vitamin C is an essential nutrient involved in tissue repair, collagen formation, and the enzymatic production of certain neurotransmitters. It is required for the function of several enzymes and is important for the function of the immune system. Vitamin C also functions as an antioxidant. [Brief explanation of the drawing]

[0005] [Figure 1] Figure 1 shows examples of the synthesis of conjugate compounds of formulas A1 and A2 that do not have a protecting group. [Figure 2] Figure 2 shows an example of the synthesis of a conjugate compound of formula A2 having a protecting group. Here, the protecting group 2-methoxyethoxymethyl ether (MEM) was used as an example. Other protecting groups may also be used. [Figure 3] Figure 3 shows an example of the synthesis of the conjugate compound of formula A1 used in this study. [Modes for carrying out the invention]

[0006] definition As used herein, a “pharmaceutically acceptable salt” is a salt that retains the desired biological activity of the parent compound without imparting undesirable toxic effects. The forms of pharmaceutically acceptable salts include various crystalline polymorphs as well as amorphous forms of various salts. Pharmaceutically acceptable salts can be formed with metal or organic counterions and include, but are not limited to, alkali metal salts such as sodium or potassium; alkaline earth metal salts such as magnesium or calcium; and ammonium salts or tetraalkylammonium salts, i.e., NX4+ (wherein X is C1-4).

[0007] Abbreviation HATU, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate DIPEA, N,N-diisopropylethylamine DMAP, 4-dimethylaminopyridine DCC, N,N'-Dicyclohexylcarbodiimide NHS, N-hydroxysuccinimide THF, tetrahydrofuran DMF, Dimethylformamide Ac, acetate ACN, acetonitrile Bn, benzyl ether BOM, benzyloxymethyl acetal Bz, benzoate MEM, 2-methoxyethoxymethyl ether MEMCl, 2-methoxyethoxymethyl chloride MOM, Methoxymethylacetal MOP, Methoxypropyl Acetal Nap, 2-naphthylmethyl ether NMR, Nuclear Magnetic Resonance PMB, 4-Methoxybenzyl ether TBDMS, tert-Butyldimethylsilyl ether TBDPS, tert-Butyldiphenylsilyl ether TBS, tert-Butyldimethylsilyl ether TES, Triethylsilyl ether THP, Tetrahydropyranyl acetal TIPS, Triisopropylsilyl ether TMS, Trimethylsilyl ether Troc, 2,2,2-Trichloroethyl carbonate

[0008] Conjugate compounds containing 13-cis-retinoic acid and ascorbic acid The present invention relates to conjugate compounds of Formulas A1 and A2 containing 13-cis-retinoic acid and vitamin C (ascorbic acid). The 13-cis-retinoic acid in the conjugate compounds provides therapeutic activity, and the vitamin C in the conjugate compounds increases the water solubility of the compounds and greatly reduces the effective dose of 13-cis-retinoic acid in the compounds for treating diseases.

[0009] [Chemical formula]

[0010] Preparation of Compounds of Formula A1 and Formula A2 Figures 1 and 2 show examples of different schemes (with or without protecting groups) for synthesizing conjugate compounds of Formulas A1 and A2.

[0011] As shown in Figure 1, to form retinoic acid chloride (Compound 2), while stirring at room temperature, (COCl)2 and CH2Cl2 in catalytic amount of dimethylformamide (DMF) are added to a solution of retinoic acid (1). Then, distillation is carried out under reduced pressure to remove unreacted (COCl)2 and DMF, and retinoic acid chloride (Compound 2) is obtained.

[0012] In some embodiments, compounds represented by formulas A1 and A2 can be directly synthesized by combining retinoic acid or retinoic acid chloride with vitamin C (Figure 1). For example, a solution of vitamin C is mixed with either retinoic acid (compound 1) or retinoic acid chloride (compound 2) in the presence of a catalytic system of N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP), or N-hydroxysuccinimide (NHS) is added at room temperature. After the reaction is complete, the solution is concentrated under reduced pressure to obtain the target compound in solid form.

[0013] In some embodiments, compounds of formula A2 can be synthesized using protecting groups (Figure 2). For example, isopropylidene ascorbic acid (compound 3) is dissolved in dichloromethane solution, then N,N-diisopropylethylamine (DIPEA) is added, followed by the addition of 2-methoxyethoxymethyl chloride (MEMCl) to form compound 4, in which the C2 and C3 hydroxyl groups of the ascorbic acid ring are protected by a 2-methoxyethoxymethyl ether (MEM) protecting group. Compound 4 is then dissolved in 80% ethaneic acid (HOAc) and reacted at 50°C for 2 hours. After the reaction is complete, the solution is concentrated under reduced pressure to remove the ethaneic acid. The resulting residue (compound 5) and retinoic acid chloride (compound 2) are further dissolved in DMF, and DCC and DMAP are added at room temperature. The mixture is then stirred for 2 hours to form compound 6.

[0014] Subsequently, the protecting group can be removed by treatment with a suitable deprotecting agent. For example, the removal of the MEM protecting group in compound 6 was achieved by reacting compound 6 with anhydrous zinc bromide (ZnBr2) in CH2Cl2 or HCl / dioxane at room temperature for 2 hours. After the reaction was complete, the solution was concentrated and dried. The residue was then purified to obtain the compound of formula A2.

[0015] Suitable protecting groups for this method include, but are not limited to, 2,2,2-trichloroethyl carbonate (Troc), 2-methoxyethoxymethyl ether (MEM), 2-naphthylmethyl ether (Nap), 4-methoxybenzyl ether (PMB), acetate (Ac), benzoate (Bz), benzyl ether (Bn), benzyloxymethyl acetal (BOM), methoxymethyl acetal (MOM), methoxypropyl acetal (MOP), methyl ether, tetrahydropyranyl acetal (THP), triethylsilyl ether (TES), triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBS or TBDMS), and tert-butyldiphenylsilyl ether (TBDPS).

[0016] Pharmaceutical composition The present invention provides a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a conjugate compound of formula A1 or A2 or a pharmaceutically acceptable salt thereof.

[0017] In one embodiment, the compound is incorporated into any acceptable carrier, including a cream, gel, lotion, or other type of suspension that stabilizes the compound and allows it to be delivered to the affected area by topical application. In another embodiment, the pharmaceutical composition may be in the form of tablets, capsules, granules, fine particles, powders, syrups, suppositories, injectable solutions, patches, etc. The pharmaceutical compositions described above can be prepared by conventional methods.

[0018] Pharmacopoeia-acceptable carriers, which are inert components, can be selected by those skilled in the art using conventional criteria. Pharmaceutically acceptable carriers include, but are not limited to, non-aqueous-based solutions, suspensions, emulsions, microemulsions, micelle solutions, gels, and ointments. Pharmaceutically acceptable carriers also include physiological saline and aqueous electrolyte solutions; ionic and nonionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and dextrose. agents); pH adjusters and buffers such as hydroxides, phosphates, citrates, acetates, and borate salts; and trolamine; antioxidants such as bisulfite, sulfite, metabisulfite, thiosulfite, ascorbic acid, acetylcysteine, cysteine, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, and ascorbyl palmitate salts, acids, and / or bases; surfactants such as phospholipids, including but not limited to lecithin, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol; poloxam It may also contain, but is not limited to, polyethers such as polysorbates (including poloxamine, polysorbate 80, polysorbate 60, and polysorbate 20), polyethylene glycol, and polypropylene glycol; polyvinyls such as polyvinyl alcohol and povidone; cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose and their salts; petroleum derivatives such as mineral oil and white petrolatum; fats such as lanolin, peanut oil, palm oil, and soybean oil; mono-, di-, and triglycerides; polymers of acrylic acid such as carboxypolymethylene gel and hydrophobically modified crosslinked acrylate copolymers; polysaccharides such as dextran and glycosaminoglycans such as sodium hyaluronate.Other pharmaceutically acceptable carriers include xanthan gum, carrageenan, Avicel RC-591 (a mixture with microcrystalline cellulose), and polyethylene glycol. Alternatively, the active compound may be dissolved or suspended in a pharmaceutically acceptable lipid preparation, such as those described by Kalepu et al. (Acta Pharmaceutica Sinica B, 3:361-372, 2013), for example, vegetable oil, coconut oil, or castor oil.

[0019] Such pharmaceutically acceptable carriers may be preserved against bacterial contamination using well-known preservatives, including but not limited to benzalkonium chloride, ethylenediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, or they may be formulated as non-preserved formulations for single or multiple use.

[0020] For example, tablet or capsule formulations of a compound may contain other excipients that are not biologically active and do not react with the compound. Excipients for tablets or capsules may include fillers, binders, lubricants and glidants, disintegrants, wetting agents, and release rate regulators. Binders are important for tablet formulations as they promote the adhesion of the formulation particles. Examples of excipients for tablets or capsules include, but are not limited to, carboxymethylcellulose, cellulose, ethylcellulose, hydroxypropylmethylcellulose, methylcellulose, karaya gum, starch, tragacanth gum, gelatin, magnesium stearate, titanium dioxide, poly(acrylic acid), and polyvinylpyrrolidone. For example, tablet formulations may contain inert components such as colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and / or titanium dioxide. Capsule formulations may contain inert components such as gelatin, magnesium stearate, and / or titanium dioxide.

[0021] For example, a patch formulation of the compound may contain several inert components such as 1,3-butylene glycol, dihydroxyaluminum aminoacetate, disodium edetate, D-sorbitol, gelatin, kaolin, methylparaben, polysorbate 80, povidone, propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water. The patch formulation may also contain skin permeability enhancers such as lactic acid esters or diethylene glycol monoethyl ether.

[0022] Topical formulations containing compounds may be in the form of gels, creams, lotions, liquids, emulsions, ointments, sprays, solutions, and suspensions. Examples of inactive components in topical formulations include, but are not limited to, (emollient / permeation enhancer), diethylene glycol monoethyl ether (emollient / permeation enhancer), DMSO (solubility enhancer), silicone elastomer (rheology / texture modifier), caprylic / capric triglyceride (emollient), octisalete (emollient / UV filter), silicone fluid (emollient / diluent), squalene (emollient), sunflower oil (emollient), and silicone dioxide (thickener).

[0023] In one embodiment, the concentration of a conjugate compound containing 13-cis-retinoic acid and vitamin C, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition may be, but is not limited to, 0.1 μM to 10 mM, 0.1 μM to 1 mM, 0.1 μM to 500 μM, 0.1 μM to 250 μM, 0.1 μM to 100 μM, 0.1 μM to 50 μM, 1 μM to 10 mM, 1 μM to 1 mM, 1 μM to 500 μM, 1 μM to 250 μM, 1 μM to 100 μM, 1 μM to 50 μM, 10 μM to 10 mM, 10 μM to 1 mM, 10 μM to 500 μM, 10 μM to 250 μM, 10 μM to 100 μM, or 10 μM to 50 μM.

[0024] How to use This conjugate compound is useful for treating cancers such as pancreatic cancer, lung cancer, colorectal cancer, ovarian cancer, adrenal cancer, bone cancer, brain cancer, breast cancer, gallbladder cancer, head and neck cancer, kidney cancer, laryngeal cancer, liver cancer, prostate cancer, parathyroid cancer, skin cancer, gastric cancer, and thyroid cancer.Further examples of cancers suitable for treatment with this conjugate compound include cholangiocarcinoma, acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and in situ carcinoma, Ewing's sarcoma, epidermoid carcinoma, giant cell tumor, glioblastoma multiforme, hairy-cell tumor, intestinal ganglioneuroma, hyperplastic corneal nerve tumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, malignant carcinoid, malignant melanoma, and malignant hypercalcemia. This includes hypercalcemia, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteosarcoma, pheochromocytoma, polycythemia vera, primary brain tumor, small-cell lung tumor, squamous cell carcinoma of both ulcerating and papillary types, hyperplasia, seminoma, soft tissue sarcoma, retinoblastoma, rhabdomyosarcoma, renal cell tumor, focal skin lesions, reticular sarcoma, and Wilm's tumor.

[0025] The method of the present invention comprises the step of administering a compound of formula A1 or formula A2 to a cancer patient in an amount effective for treating cancer. As used herein, “effective amount” means an amount effective for treating cancer by improving the pathological condition or alleviating the symptoms of cancer.

[0026] The pharmaceutical compositions of the present invention can be administered by systemic administration or local administration. Local administration includes topical administration and inhalation. Systemic administration includes oral, parenteral (intravenous, intramuscular, subcutaneous, or rectal, etc.), and other systemic administration routes. In systemic administration, the active compound first reaches the plasma and then distributes to the target tissue. Intravenous administration is the preferred administration route of the present invention.

[0027] The dosage of the composition can be varied based on the stage of cancer and the individual response of each patient. For systemic administration, the plasma concentration of the active compound delivered may vary. However, generally, 1 × 10⁻⁶ is used. -10 ~1 × 10 -4 moles / liter, preferably 1 × 10⁻⁶ -8 ~1 × 10 -5 It is expressed as moles per liter.

[0028] In one embodiment, the pharmaceutical composition is administered intravenously to the subject. The dose for intravenous bolus injection or intravenous infusion is generally 0.03 to 20 mg / kg / day, preferably 0.03 to 10 mg / kg / day.

[0029] In one embodiment, the pharmaceutical composition is administered orally to a subject. The dosage for oral administration is generally at least 0.1 mg / kg / day and less than 100 mg / kg / day. For example, the dosage for oral administration is 0.1 to 100 or 0.5 to 50 mg / kg / day for a human subject. For example, the dosage for oral administration is 20 to 1000 mg / day or 100 to 2000 mg / day for a human subject, preferably 20 to 500, 25 to 200, 50 to 500, 50 to 200, 100 to 600, 100 to 400, 100 to 800, 200 to 800, 400 to 800, 400 to 1200, 500 to 2000, or 800 to 2000 mg / day.

[0030] In one embodiment, the pharmaceutical composition is administered subcutaneously to the subject. The dosage for subcutaneous administration is generally 0.3 to 20 mg / kg / day, preferably 0.3 to 3 mg / kg / day.

[0031] In one embodiment, the pharmaceutical composition is administered by inhalation. Methods of inhalation include liquid instillation, inhalation as a pressurized fluid formulation via a metered-dose inhaler or equivalent, inhalation of an aerosolized solution via a nebulizer, inhalation of a dry powder, and introducing a soluble or dry substance into an airflow during mechanical ventilation. The surface concentration of the active compound delivered by inhalation may vary, but is generally 1 × 10⁻⁶. -10 ~1 × 10 -4 moles / liter, preferably 1 × 10⁻⁶ -8 ~1 × 10 -5 It is expressed as moles per liter.

[0032] Those skilled in the art will recognize that a wide variety of delivery mechanisms are also suitable for the present invention.

[0033] This method is useful when treating mammals such as humans, horses, and dogs. The present invention is particularly useful when treating humans.

[0034] The following examples further illustrate the present invention. These examples are merely intended to illustrate the present invention and should not be construed as limiting.

Example

[0035] Example 1 Synthesis of Compound A1

[0036] Figure 3 summarizes one scheme for the synthesis of Compound A1.

[0037] <​​​​​​​​​​​​​H NMR (400 MHz, DMSO-d6): δ 12.52 (br s, 1H), 7.62 (d, J = 15.2 Hz, 1H), 7.21-7.14 (m, 1H), 6.35-6.29 (m, 2H), 6.25-6.21 (m, 1H), 5.86 (s, 1H), 5.01-4.78 (m, 3H), 3.80 (t, J = 7.0 Hz, 2H), 3.47-3.45 (m, 2H), 1.69 (s, 3H), 2.017 (s, 5H), 1.693 (s, 3H), 1.58-1.56 (m, 1H), 1.45-1.44 (m, 1H), 1.02 (s, 6H).

[0039] Example 2: Cytotoxicity of compound A1 against cancer cell lines

[0040] Objective: To test the cytotoxic effects of compound A1 on three cancer cell lines in vitro.

[0041] [Table A1]

[0042] @ All cell lines used in this study are derived from human patients. * All complete culture media were prepared by adding fetal bovine serum to a final concentration of 10%, without the addition of antibiotics.

[0043] [Table A2]

[0044] procedure Cells were cultured in the prescribed growth medium containing 10% FBS and maintained in a humidified incubator at 37°C with 5% CO2. Compound A2 was weighed and dissolved in a 1 / 4 (v / v) ratio DMSO / EtOH mixed solvent to a final concentration of 200 mM on the day of treatment. One day before treatment, cells in the logarithmic growth phase were harvested and counted, yielding 5 × 10⁶ cells. 3 Cells were seeded at a density of 100 mL / well in 96-well plates. After overnight incubation, 100 mL of fresh medium prepared at a continuous concentration of 40 to 1000 μM was gently added to the assumed wells, and the working concentration was then reduced to 20 to 500 μM. A control plate without formula A2 was performed using the same procedure as above, but with the addition of 100 mL of fresh medium prepared at the same solvent volume. All plates were gently mixed and incubated for the next 24 hours.

[0045] On the day of cell viability detection, 50 mL of MTT working solution was added to the tested wells and incubated at 37°C for 3 hours. Absorbance spectroscopy readings were recorded at a wavelength of 540 nm. Readings from blank wells (wells containing only cell culture medium without cells) and negative control wells (wells containing cells and culture medium without formula A2 and solvent treatment) were recorded and used for calibration. After subtracting the blank values ​​from all OD540 readings, cell viability was calculated using the following formula.

[0046] Cell viability (%) = [OD540(sample) / OD540(negative control in sample plate)] / [OD540(control) / OD540(negative control in control plate)] × 100%

[0047] The concentration of compound A, which inhibits cell survival by up to 50%, was measured using the online tool "Quest Graph™ IC50 Calculator" (AAT Bioquest, Inc., 26 June 2024, www.aatbio.com / tools / ic50-calculator).

[0048] result Tables 1-3 show the cell viability calculated using various A1 concentrations. The values ​​were averaged from six replication wells. These cell viability values ​​were further used to determine the IC of each cell line. 50 The concentration was estimated (Table 4).

[0049] [Table 1]

[0050] [Table 2]

[0051] [Table 3]

[0052] [Table 4]

[0053] [Table 5]

[0054] For comparison, using the A549 cell line, the IC of 13-cisretinoic acid was observed. 50 It is 518.23 μM. On the other hand, the IC of formula A1 50 The concentration is 197.34 μM, indicating that formula A1 is more effective than 13-cisretinoic acid in inhibiting the proliferation of the A549 cell line.

[0055] Example 3: Synthesis of Compound A2 (Prophetic Example)

[0056] Formula A2 is manufactured according to Figure 2.

[0057] To form retinoic acid chloride, a catalytic amount of (COCl)2 and CH2Cl2 in dimethylformamide (DMF) is added to a solution of (2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexa-1-en-1-yl)nonano-2,4,6,8-tetraenoic acid while stirring at room temperature. Then, under reduced pressure distillation is performed to remove unreacted (COCl)2 and DMF to obtain retinoic acid chloride (compound 2).

[0058] Compound A2 is synthesized using a protecting group. R)-5-((S)-1,2-dihydroxyethyl)-3,4-dihydroxyfuran-2(5H)-one (1,500 mg, 1.14 mmol) is dissolved in dichloromethane solution (5 ml), then N,N-diisopropylethylamine (DIPEA) is added, followed by 2-methoxyethoxymethyl chloride (300 mg, 1.32 mmol) (MEMCl). The reaction mixture is stirred at room temperature in the dark for 16 hours. After the reaction is complete, compound 4 is formed, and the C2 and C3 hydroxyl groups of its ascorbic acid ring are protected by a 2-methoxyethoxymethyl ether (MEM) protecting group.

[0059] Next, compound 4 is dissolved in 80% ethane acid (HOAc) and reacted at 50°C for 4 hours. After the reaction is complete, the solution is concentrated under reduced pressure to remove the ethane acid. The resulting compound 5 and retinoic acid chloride (compound 2) are further dissolved in DMF (5 ml), and DCC (172 mg, 1.19 mmol) and DMAP (210 mg, 1.36 mmol) are added at room temperature. The mixture is stirred for 4 hours to form compound 6.

[0060] Subsequently, the protecting group is removed by treatment with an appropriate deprotecting agent, anhydrous zinc bromide (ZnBr2), in CH2Cl2 or HCl / dioxane at room temperature for 4 hours. After the reaction is complete, the mixture is diluted with water (10 mL) and extracted with Â1 (10 mL × 3). The combined organic layer is concentrated under reduced pressure to obtain the residue. The residue is purified by preliminary HPLC. The residue is then purified to obtain compound A2.

[0061] The above describes preferred embodiments of the present invention, and it should be understood that modifications can be made without departing from the scope of the invention as described in the claims.

Claims

1. A compound having the structure of formula A2 or A1, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】

2. The compound according to claim 1, which is formula A2.

3. The compound according to claim 1, which is formula A1.

4. A pharmaceutical composition comprising the compound described in claim 1 and a pharmaceutically acceptable carrier thereof.

5. A method for treating cancer, comprising administering the compound described in claim 1 to a subject in need thereof.

6. The method according to claim 3, wherein the compound is administered by intravenous administration.

7. The method according to claim 3, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

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