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CN-121974921-A - Camptothecin derivative, pharmaceutical composition and application thereof

CN121974921ACN 121974921 ACN121974921 ACN 121974921ACN-121974921-A

Abstract

The invention discloses a novel camptothecin compound or a stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the camptothecin compound or the stereoisomer or the pharmaceutically acceptable salt and application of the camptothecin compound or the stereoisomer or the pharmaceutically acceptable salt as an antitumor drug. Wherein R 1 、R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, mercapto, sulfone, sulfoxide, nitro, substituted or unsubstituted amine, carboxyl, amide, deuteroalkyl, C 1‑6 alkyl, C 1‑6 alkoxy, C 1‑6 haloalkyl, C 2‑6 alkenyl, C 2‑6 alkynyl, and C 3‑6 cycloalkyl, C 3‑6 heterocyclyl, aryl, or heteroaryl, or R 1 and R 2 、R 2 and R 3 are each linked to adjacent carbon atoms to form a 5-7 membered cycloalkyl or heterocycloalkyl, said 5-7 membered cycloalkyl or heterocycloalkyl optionally substituted with one or more halogen or deuterium atoms, alkyl, alkoxy. The compound has good antitumor effect.

Inventors

  • WEI MANMAN
  • WANG CHAOHUI
  • CHEN JIANXIN

Assignees

  • 上海臻格生物技术有限公司

Dates

Publication Date
20260505
Application Date
20260305

Claims (10)

  1. 1. A camptothecine compound is characterized in that the structure is as follows: , Wherein, the R 1 、R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, mercapto, sulfone, sulfoxide, nitro, substituted or unsubstituted amine, carboxyl, amide, deuterated alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl, C 3-6 heterocyclyl, aryl, or heteroaryl; Or R 1 and R 2 、R 2 and R 3 are each linked to adjacent carbon atoms to form a 5-7 membered cycloalkyl or heterocycloalkyl; the 5-7 membered cycloalkyl or heterocycloalkyl is optionally substituted with one or more halogen or deuterium atoms, alkyl, alkoxy.
  2. 2. The camptothecin compound according to claim 1, wherein, W is 、 、 Or (b) ; R 4 and R 5 are each independently selected from hydrogen, deuterium, halogen, and R 4 and R 5 are not simultaneously hydrogen atoms; R 6 is selected from hydrogen, halogen, deuterated alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 2-6 alkynyl; R 7 is selected from the group consisting of hydrogen, deuterated alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl, acyl, Or (b) ; R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, deuterated alkyl, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; x is selected from CH 2 、N-R 10 , O, S, sulfoxide or sulfone; Y is selected from O, S; R 10 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl or heteroaryl; m, n are each independently selected from 0, 1, 2, and m, n are not simultaneously 0.
  3. 3. The camptothecin compound according to claim 1, wherein, Preferably R 1 is hydrogen, halogen; preferably R 2 is methyl, deuterated methyl, halogen; Preferably, R 1 and R 2 together with the atoms to which they are attached form a 5-6 membered heterocyclic group containing 1 or 2 oxygen atoms as ring atoms, said 5-6 membered heterocyclic group being optionally substituted with one or more halogens; Preferably R 1 and R 2 together with the atoms to which they are attached form Or (b) ; Preferably R 3 is hydrogen, halogen.
  4. 4. The camptothecin compound according to claim 2, wherein, Preferably X is CH 2 , O, S; Preferably R 4 and R 5 are F; Preferably R 6 is hydrogen, F; Preferably R 7 is hydrogen, methyl; Preferably R 8 and R 9 are hydrogen, F; Preferably Y is O, S.
  5. 5. The camptothecin compound according to any one of claims 1 or 2, which is selected from the following compounds, or stereoisomers thereof, or pharmaceutically acceptable salts thereof: ; 。
  6. 6. the camptothecine compound according to any one of claims 1 or 2, which is characterized in that it can be used as a pharmaceutical composition comprising camptothecine compound and pharmaceutically acceptable auxiliary materials.
  7. 7. The camptothecins according to any one of claims 1 or 2, characterized in that it is used in the preparation of a medicament for preventing or treating topoisomerase I related diseases.
  8. 8. The camptothecine compound according to any one of claims 1 or 2, which is characterized in that it can be used for preparing antitumor drugs.
  9. 9. A process for the preparation of camptothecins according to any one of claims 1 or 2, comprising the steps of: ; step 1 Synthesis of N- (4-bromo-3-fluorophenyl) acetamide (Compound 002-1), SM-3 (5 g, 26.31 mmol) and triethylamine (7.16 ml, 52.62 mmol) were dissolved in dichloromethane (10 mL), and acetyl chloride (2.06 ml, 28.95 mmol) was slowly added dropwise at room temperature and stirred overnight at room temperature. The reaction was monitored by LCMS, the reaction was dried and concentrated, and the crude product was purified by silica gel chromatography over a gradient of 0% -50% ethyl acetate/petroleum ether to give compound 002-1 (5.22 g, 22.6 mmol, 85.8%). MS m/z (ESI) =232.02 [ M+1] + ; Step 2 Synthesis of N- (3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acetamide (Compound 002-2), Compound 002-1 (1 g, 4.3 mmol) and bis (pinacolato) diboron (1.64 g, 6.46 mmol) were dissolved in 1.4-dioxane (40 mL), potassium acetate (1.01 g, 10.75 mmol) and DPPF palladium dichloride (314 mg, 0.43 mmol) were added at ambient temperature and stirred overnight at 90 °. The reaction was monitored by LCMS. The reaction was dried and concentrated and the crude product was purified by silica gel chromatography over a gradient of 0% -50% ethyl acetate/petroleum ether to give compound 002-2 (960 mg, 3.4, mmol, 80%). MS M/z (ESI) = 280.14 [ m+1] + ; step 3:N synthesis of- (3-fluoro-4-deuterated methylphenyl) acetamide (compound 002-3), Compound 002-2 (960 mg, 3.4 mmol) and deuterated methyl iodide (3 g, 17.2 mmol) were dissolved in a mixed solvent of DMF/water (22 ml, 10:1), and potassium carbonate (1.78 g, 10.2 mmol) and triorthophenylphosphine (261 mg, 0.68 mmol), tris (dibenzylideneacetone) dipalladium (393 mg, 0.34 mmol) were added at room temperature, and stirred at 70 ° overnight. The reaction was monitored by LCMS, cooled to room temperature, filtered, the filtrate was added with water and extracted with ethyl acetate (40 ml x 3), the combined organic phases, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel chromatography over a gradient of 0% -50% ethyl acetate/petroleum ether to give compound 002-3 (496 mg, 22.6 mmol, 85%). MS M/z (ESI) = 171.10 [ m+1] + ; Step 4 Synthesis of N- (2-bromo-5-fluoro-4-deuterated methylphenyl) acetamide (Compound 002-4), Compound 002-3 (1 g, 5.88 mmol) was dissolved in acetonitrile (10 mL), cooled to zero degrees, NBS (1.55 g, 5.87 mmol) was added in portions and stirred overnight at room temperature. Pouring into ice saturated sodium bicarbonate solution, diluting with ethyl acetate, saturated saline washing, drying with anhydrous sodium sulfate, filtering, concentrating, purifying the crude product with silica gel chromatographic column with gradient of 0% -50% ethyl acetate/petroleum ether to obtain compound 002-4 (500 mg, 2.0 mmol, 35%); step 5 Synthesis of tert-butyl 5- (2-acetamido-4-fluoro-5-deuterated methylbenzoyl) -3, 3-difluoropiperidine-1-carboxylate (Compound 002-5), Sodium hydride (96 mg, 4 mmol) was dissolved in tetrahydrofuran (8 mL) under a nitrogen atmosphere at 0 o C, a tetrahydrofuran solution of the compound 002-4 (500 mg,2 mmol) was slowly added dropwise to the reaction solution, stirred at 0 o C for 1 hour, the reaction solution was cooled to-78 o C, a tetrahydrofuran solution of n-butyllithium (2.5 ml, 3.8 mmol, 1.6M) was added dropwise, the reaction was kept for-78 o C for 1 hour, and then a tetrahydrofuran (2 mL) solution of the compound 001-2 (513 mg, 1.66 mmol) was added dropwise at-78 o C, and stirred at room temperature for 3 hours. The reaction was monitored by LCMS, quenched by addition of saturated aqueous ammonium chloride (10 mL), extracted with ethyl acetate (3X 30 mL), the combined organic phases washed with saturated brine (20 mL), dried and concentrated, and the crude product purified by silica gel chromatography over a gradient of 0% -50% ethyl acetate/petroleum ether to give compound 002-5 (180 mg, 0.43 mmol, 26% yield) MS M/z (ESI): 318.2 [ M-100] + ; step 6 (2-amino-4-fluoro-5-deuterated methylphenyl) (5, 5-difluoropiperidin-3-yl) methanone (compound 002-6), Compound 002-5 (180 mg, 0.43 mmol) was dissolved in 6M aqueous hydrochloric acid (2 mL) and 4M dioxane hydrochloride solution (2 mL) and stirred at 95 ° for 2 hours. Cooling to room temperature, adding ammonia water to adjust to alkalescence (pH to 7-8), and concentrating under reduced pressure to obtain crude compound 002-6 (118 mg) MS m/z (ESI) =276.3 [ M+1] + ; Step 7 synthesis of (S) -11- ((. R) -5, 5-difluoropiperidin-3-yl) -4-ethyl-8-fluoro-4-hydroxy-9-deuterated methyl-1H-pyrano [3',4':6,7] indolizino [1,2-b ] quinoline-3, 14 (4H, 12H) -dione and (S) -11- ((. S) -5, 5-difluoropiperidin-3-yl) -4-ethyl-8-fluoro-4-hydroxy-9-deuterated methyl-1H-pyrano [3',4':6,7] indolizino [1,2-b ] quinoline-3, 14 (compound 2a and compound 2 b), The crude compound 002-6 (118 mg) was dissolved in toluene (20 mL) at room temperature, p-toluenesulfonic acid monohydrate (163 mg, 0.96 mmol) and SM-2 (113 mg, 0.48 mmol) were added and stirred for 12 hours at 110 °. Monitoring the reaction by LCMS, concentrating under reduced pressure, and purifying the crude product by high performance liquid chromatography to obtain the compound 2a (2.4 mg, 4.78 μmol)：MS m/z（ESI）：= 503.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.37 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 10.8 Hz, 1H), 7.32 (s, 1H), 6.53 (s, 1H), 5.66–5.38 (m, 4H), 4.01 (s, 1H), 3.21–3.11 (m, 2H), 3.05–2.90 (m, 2H), 2.83–2.70 (m, 1H), 2.62–2.53 (m, 1H), 1.93–1.80 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H); And a compound 2b (1.6 mg, 3.18 μmol)：MS m/z（ESI）：= 503.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.38 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 10.8 Hz, 1H), 7.32 (s, 1H), 6.53 (s, 1H), 5.66–5.38 (m, 4H), 4.02 (s, 1H), 3.23–3.11 (m, 2H), 3.06–2.89 (m, 2H), 2.82–2.70 (m, 1H), 2.60–2.54 (m, 1H), 1.94–1.81 (m, 2H), 0.87 (t, J= 7.2 Hz, 3H).
  10. 10. A process for the preparation of camptothecins according to any one of claims 1 or 2, comprising the steps of: ; step 1, synthesizing 2-bromo-4-chloro-5-fluoroaniline (compound 003-1), Compound SM-4 (14.6 g, 100 mmol) was dissolved in acetonitrile (100 mL), N-bromosuccinimide (17.8 g, 100 mmol) was slowly added under ice bath, the reaction was monitored by LCMS with stirring at room temperature for 2 hours, quenched under ice bath with aqueous sodium thiosulfate (200 mL), extracted with dichloromethane (2×200 mL) and the combined organic phases washed with saturated brine (200 mL), dried and concentrated. The crude product was purified by silica gel chromatography column, gradient 20% -50% ethyl acetate/petroleum ether, to give compound 003-1 (21 g,93.56 mmol). MS M/z (ESI) = 223.92 [ m+h ] + ; Step 2 Synthesis of N- (2-bromo-4-chloro-5-fluorophenyl) acetamide (Compound 003-2), Dissolving compound 003-1 (21 g,93.56 mmol) in acetic acid (100 mL), slowly adding acetic anhydride (13.36 mL, 141.31 mmol) under ice bath, stirring at room temperature for 2 hours, precipitating solid, monitoring the reaction by LCMS, filtering, spinning the solid as product, pulping the mother liquor with petroleum ether, filtering, and combining the solids to obtain compound 003-2 (20 g,75.05 mmol) MS M/z (ESI) = 265.93 [ M+H ] + ; Step 3 Synthesis of tert-butyl 5- (2-acetamido-5-chloro-4-fluorobenzoyl) -3, 3-difluoropiperidine-1-carboxylate (Compound 003-3), Sodium hydride (125 mg, 3.12, mmol, 60% purity) was placed in a three-necked flask, tetrahydrofuran (5 mL) was added under nitrogen and ice bath, then compound 003-2 (413 mg, 1.56, mmol) was added, and the reaction was stirred under ice bath for 0.5 hours. The reaction solution was cooled to-78 ℃, n-hexane solution of n-butyllithium (1.9 mL, 3.12 mmol, 1.6M) was slowly added dropwise, the reaction was stirred at-78 ℃ for 1 hour, then tetrahydrofuran (5 mL) solution of compound 001-2 (400 mg,1.30 mmol) was slowly added at-78 ℃ and warmed to room temperature, the reaction was carried out for 5 hours, and the reaction was monitored by LCMS. Saturated aqueous ammonium chloride (20 mL) was added, extracted with ethyl acetate (2×20 mL), the combined organic phases were washed with saturated brine (20 mL), dried and concentrated, and the crude product was purified by silica gel chromatography over a gradient of 10% -50% ethyl acetate/petroleum ether to give compound 003-3 (50 mg,0.11 mmol): MS M/z (ESI) = 435.12 [ m+h ] + ; Step 4 Synthesis of N- (4-chloro-2- (5, 5-difluoropiperidine-3-carbonyl) -5-fluorophenyl) acetamide (compound 003-4), Dissolving compound 003-3 (50 mg,0.11 mmol) in 1, 4-dioxane solution of hydrochloric acid (1 mL, 4 mmol, 4M), stirring and reacting for 0.5 hours, adding aqueous hydrochloric acid solution (0.5 mL, 6M), heating to 90 ℃ for 1 hour, monitoring the reaction by LCMS, regulating the reaction solution to be slightly alkaline (pH to 7-8) by ammonia water, concentrating to obtain crude compound 003-4, and directly carrying out the next reaction; Step 5 (S) -9-chloro-11- ((. Cndot.) -5, 5-difluoropiperidin-3-yl) -4-ethyl-8-fluoro-4-hydroxy-1H-pyrano [3',4':6,7] indolizino [1,2-b ] quinoline-3, 14 (4H, 12H) -dione and (S) -9-chloro-11- ((. Cndot.) -5, 5-difluoropiperidin-3-yl) -4-ethyl-8-fluoro-4-hydroxy-1H-pyrano [3',4':6,7] indolizino [1,2-b ] quinoline-3, 14 (4H, 12H) -dione (Compound 3a and Compound 3 b), The crude compound 003-4 was dissolved in toluene (5 mL), and compound SM-2 (26 mg, 0.10 mmol) and p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol) were added and reacted at 110 ℃ for 48 hours. Monitoring the reaction by LCMS, purifying the crude product by reverse phase High Performance Liquid Chromatography (HPLC) gradient purification with 20% -40% acetonitrile/buffer (0.1% formic acid aqueous solution) to obtain the compound 3a (1.9 mg, 3.65 μmol)：MS m/z（ESI）：= 520.12 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 10.0 Hz, 1H), 7.34 (s, 1H), 6.57 (s, 1H), 5.73–5.24 (m, 4H), 4.10–3.86 (m, 1H), 3.22–3.10 (m, 2H), 3.07–2.70 (m, 4H), 1.92–1.78 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H); Obtaining the compound 3b (2.4 mg, 4.62 μmol)：MS m/z（ESI）：= 520.12 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 10.0 Hz, 1H), 7.35 (s, 1H), 6.56 (s, 1H), 5.69–5.34 (m, 4H), 4.10–3.88 (m, 1H), 3.21–3.08 (m, 2H), 3.06–2.71 (m, 4H), 1.97–1.77 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H).

Description

Camptothecin derivative, pharmaceutical composition and application thereof Technical Field The invention relates to a camptothecine derivative, a pharmaceutical composition and application thereof, belonging to the field of antitumor drug preparation. Background Camptothecin (CPT) is a very important natural product, mainly found in the skin and fruit of camptotheca acuminata. The compound is extracted and separated from camptotheca acuminata in 1966 for the first time, and has stronger in vitro anti-tumor activity. Related mechanism researches show that camptothecine has the activity of inhibiting topoisomerase I, and can be combined with a complex of the topoisomerase I and DNA to form a stable ternary complex, so that topoisomerase I-mediated DNA fragmentation is blocked, and further processes of DNA replication, transcription, repair and the like are blocked, so that cell cycle retardation and apoptosis are caused. The camptothecin derivative can increase water solubility by introducing water-soluble groups or preparing prodrugs, thereby improving drug properties. A number of camptothecine derivatives with greatly improved solubility are now marketed in batches, for example three camptothecine derivatives, topotecan (Topotecan), irinotecan (Irinotecan), belotecan (Belotecan) and the like, which are approved for the clinical treatment of colon cancer, small cell lung cancer and ovarian cancer. However, through a great deal of early clinical experiments, the problem of low oral bioavailability caused by low solubility and poor chemical stability of camptothecine as an anti-tumor drug is found, and toxic and side effects such as emesis and bone marrow suppression are accompanied, so that the clinical application of camptothecine is finally hindered. Therefore, improving the physicochemical properties and activity and safety of camptothecins is still a problem to be solved. With the successful marketing of ADC DS-8201 in 2019, the optimization and transformation of anticancer natural product camptothecine derivatives gradually become hot. After DS-8201, camptothecin payload has led to numerous company simulations due to low toxicity, better bystander effect and faster metabolism, and various large companies and research institutions have developed a large number of camptothecin derivatives on the basis of the camptothecin payload. With the differences in ADC targets, conjugation modes, etc., there is an urgent need to develop camptothecin derivatives with different killing activities, more optimal physicochemical properties and safety for screening and optimization of ADC toxins to construct optimal ADCs. The invention aims to provide a novel camptothecin compound or a stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the camptothecin compound or the stereoisomer or the pharmaceutically acceptable salt and application of the camptothecin compound and the stereoisomer or the pharmaceutically acceptable salt as an anti-tumor drug. Disclosure of Invention The invention aims to provide a novel camptothecin compound or a stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the camptothecin compound or the stereoisomer or the pharmaceutically acceptable salt and application of the camptothecin compound and the stereoisomer or the pharmaceutically acceptable salt as an anti-tumor drug. The terms of the present invention are defined and described as follows: Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Unless stated to the contrary, the terms used in the specification and claims have the following meanings. Herein ""Means a ligation site. The term "stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers and diastereomers. The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Particular geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the definition of compounds of the invention. The compounds of the invention may have one or more chiral centers which are independently present, "" indicates that the absolute configuration of the chiral center is not determined, but the corresponding compound itself is already a chiral pure enantiomer or diastereomer after isolation or preparation. The term "alkyl" refers to a hydrocarbon group