Multi-target tamibarotene derivative and its preparation method and application

Abstract

The invention provides a multiple target point type Tamibarotene derivative as well as a preparation method and an application thereof. Particularly, RAR (retinoic acid receptor) agonist Tamibarotene is connected with antineoplastic drug hydroxycarbamide, fluorouracil and lenalidomide on sales through ester bonds or amido bonds respectively to obtain three multiple target point mutual prodrugs. The invention provides a method for preparing the compound and the application of the compound in preparing antineoplastic drugs, particularly drugs for curing various leukemias. The invention further relates to a drug combination of the compound.

Description

Technical field

[0001] The present invention relates to the field of medicinal chemistry, in particular to a multi-target type Tamibarotene derivative and a preparation method thereof, as well as the medical use of these compounds, especially the use in the preparation of anti-tumor drugs. Background technique

[0002] Retinoic acid receptors are a subfamily of the nuclear receptor (nuclear receptors, NR) superfamily. It consists of 2 types of receptors, namely retinoic acid receptors (RARs) and retinoic acid X receptors (retinoid). Xreceptors, RXRs), RARs and RXRs include three subtypes of α, β and γ respectively. Retinoids are the general term for more than 4000 natural and synthetic compounds. They are related to the metabolite of vitamin A (retinol) in structure and function: all-trans-retinoic acid (ATRA) related. Retinoic acid compounds have a wide range of biological effects, and play an important role in maintaining normal body functions, anti-tumor, treating skin disea...

Examples

Embodiment 1

[0063] Example 1: N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-((ureaoxy)carbonyl)benzamide ( 1) Preparation

[0064] Tamibarotene (AM80) (0.35g, 1mmol) was dissolved in anhydrous tetrahydrofuran, and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.21 g, 1.1mmol), add pentafluorophenol (0.20g, 1.1mmol) previously dissolved in N,N-dimethylformamide. The reaction was carried out at room temperature for 12 hours, and the reaction was monitored by TLC. After the reaction is completed, the solvent is evaporated for later use. First dissolve hydroxyurea (0.08g, 1mmol) in N,N-dimethylformamide, add N-methylmorpholine (12mL) to dissolve the upper pentafluorophenol ester in anhydrous dioxane, Drop into the N,N-dimethylformamide reaction solution. React at room temperature for 12h. It was directly passed through the column (EA / PE=5 / 1) to obtain a white solid 1 (0.11 g, 27%). ESI-MS m / z:410.5(M+H) + , 1 H-NMR(600MHzDMSO-d 6 ):δ1.24-1.25(m,12H), 1.64-1.66(m,4H)...

Embodiment 2

[0065] Example 2: (5-Fluoro-2,4-dioxy-3,4-dihydropyrimidine-1(2H)-yl)methyl-4-((5,5,8,8-tetramethyl -Preparation of 5,6,7,8-tetrahydro-2-naphthyl)carbamoyl)benzoate (3)

[0066] 5-Fluorouracil (5-FU) (1.3g, 10mmol) was mixed with 3mL of 37% aqueous formaldehyde solution, stirred at 60°C for 2h, and evaporated under reduced pressure to remove water to obtain a colorless viscous oil. The obtained oil was dissolved in anhydrous acetonitrile, and AM80 (3.51 g, 10 mmol), dicyclohexylcarbodiimide (2.3 g, 11 mmol), and an appropriate amount of 4-dimethylaminopyridine were added. After 24 hours, TLC monitored the reaction to be complete, the solvent was evaporated, ethyl acetate was added to dissolve, and the organic phase was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. It was dried over anhydrous magnesium sulfate, filtered and evaporated to remove the solvent, and the residue was separated with a silica gel column (dichlorometh...

Embodiment 3

[0067] Example 3: N 1 -(2-(2,6-Piperidinedione-3-yl)-1-oxoisoindolin-4-yl)-N 4 Preparation of (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)terephthalamide (5)

[0068] Tamibarotene (AM80) (0.35g, 1mmol) was dissolved in 20mL of thionyl chloride, two drops of DMF were added dropwise, and the mixture was stirred and refluxed at 75°C for 2h. The solvent was evaporated to obtain compound 4 as a yellow oily compound. In the future, Nalidomide (0.26g, 1mmol) was dissolved in the pyridine solution, and the tetrahydrofuran solution of compound 4 was added dropwise under ice bath. Remove the ice bath temperature response. After 24 hours, TLC monitored the reaction to be complete, the solvent was evaporated, ethyl acetate was added to dissolve, and the organic phase was washed with water, 1M hydrochloric acid, and saturated sodium chloride. It was dried over anhydrous magnesium sulfate, filtered and evaporated to remove the solvent, and the residue was separated with a silica gel c...

Technical field

[0001] The present invention relates to the field of medicinal chemistry, in particular to a multi-target type Tamibarotene derivative and a preparation method thereof, as well as the medical use of these compounds, especially the use in the preparation of anti-tumor drugs. Background technique

[0002] Retinoic acid receptors are a subfamily of the nuclear receptor (nuclear receptors, NR) superfamily. It consists of 2 types of receptors, namely retinoic acid receptors (RARs) and retinoic acid X receptors (retinoid). Xreceptors, RXRs), RARs and RXRs include three subtypes of α, β and γ respectively. Retinoids are the general term for more than 4000 natural and synthetic compounds. They are related to the metabolite of vitamin A (retinol) in structure and function: all-trans-retinoic acid (ATRA) related. Retinoic acid compounds have a wide range of biological effects, and play an important role in maintaining normal body functions, anti-tumor, treating skin disea...

Examples

Embodiment 1

[0063] Example 1: N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-((ureaoxy)carbonyl)benzamide ( 1) Preparation

[0064] Tamibarotene (AM80) (0.35g, 1mmol) was dissolved in anhydrous tetrahydrofuran, and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.21 g, 1.1mmol), add pentafluorophenol (0.20g, 1.1mmol) previously dissolved in N,N-dimethylformamide. The reaction was carried out at room temperature for 12 hours, and the reaction was monitored by TLC. After the reaction is completed, the solvent is evaporated for later use. First dissolve hydroxyurea (0.08g, 1mmol) in N,N-dimethylformamide, add N-methylmorpholine (12mL) to dissolve the upper pentafluorophenol ester in anhydrous dioxane, Drop into the N,N-dimethylformamide reaction solution. React at room temperature for 12h. It was directly passed through the column (EA / PE=5 / 1) to obtain a white solid 1 (0.11 g, 27%). ESI-MS m / z:410.5(M+H) + , 1 H-NMR(600MHzDMSO-d 6 ):δ1.24-1.25(m,12H), 1.64-1.66(m,4H)...

Embodiment 2

[0065] Example 2: (5-Fluoro-2,4-dioxy-3,4-dihydropyrimidine-1(2H)-yl)methyl-4-((5,5,8,8-tetramethyl -Preparation of 5,6,7,8-tetrahydro-2-naphthyl)carbamoyl)benzoate (3)

[0066] 5-Fluorouracil (5-FU) (1.3g, 10mmol) was mixed with 3mL of 37% aqueous formaldehyde solution, stirred at 60°C for 2h, and evaporated under reduced pressure to remove water to obtain a colorless viscous oil. The obtained oil was dissolved in anhydrous acetonitrile, and AM80 (3.51 g, 10 mmol), dicyclohexylcarbodiimide (2.3 g, 11 mmol), and an appropriate amount of 4-dimethylaminopyridine were added. After 24 hours, TLC monitored the reaction to be complete, the solvent was evaporated, ethyl acetate was added to dissolve, and the organic phase was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. It was dried over anhydrous magnesium sulfate, filtered and evaporated to remove the solvent, and the residue was separated with a silica gel column (dichlorometh...

Embodiment 3

[0067] Example 3: N 1 -(2-(2,6-Piperidinedione-3-yl)-1-oxoisoindolin-4-yl)-N 4 Preparation of (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)terephthalamide (5)

[0068] Tamibarotene (AM80) (0.35g, 1mmol) was dissolved in 20mL of thionyl chloride, two drops of DMF were added dropwise, and the mixture was stirred and refluxed at 75°C for 2h. The solvent was evaporated to obtain compound 4 as a yellow oily compound. In the future, Nalidomide (0.26g, 1mmol) was dissolved in the pyridine solution, and the tetrahydrofuran solution of compound 4 was added dropwise under ice bath. Remove the ice bath temperature response. After 24 hours, TLC monitored the reaction to be complete, the solvent was evaporated, ethyl acetate was added to dissolve, and the organic phase was washed with water, 1M hydrochloric acid, and saturated sodium chloride. It was dried over anhydrous magnesium sulfate, filtered and evaporated to remove the solvent, and the residue was separated with a silica gel c...

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