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CN-121991086-A - Bis (2-chloroethyl) carbamate modified SN-38 derivative and preparation method and application thereof

CN121991086ACN 121991086 ACN121991086 ACN 121991086ACN-121991086-A

Abstract

The invention belongs to the technical field of traditional Chinese medicine modernization, and mainly relates to a novel camptothecin derivative, a preparation method and medical application thereof. Specifically, the invention is based on structural optimization of the camptothecine which is the active ingredient of the traditional Chinese medicine, and chemical modification is carried out on 7-ethyl-10-hydroxycamptothecin (SN-38) through bis (2-chloroethyl) carbamate groups, so as to design and synthesize a novel derivative which simultaneously contains nitrogen mustard pharmacophore and camptothecine parent nucleus. And further introducing phosphate groups into alcohol hydroxyl groups or forming inorganic acid salts through phosphorylation modification or salification reaction, and finally obtaining the target compound shown in the formula I. The in-vitro and in-vivo experiments prove that the SN-38 derivative related to the invention has the advantages of improving the anti-tumor effect, improving the stability of the medicament, reducing the toxic and side effects of the medicament and the like.

Inventors

  • WANG ZENGTAO
  • WANG TIANTIAN
  • HAN XIAORUI
  • He Mengni
  • WANG XIUMEI
  • PENG MENGYAO

Assignees

  • 江西中医药大学

Dates

Publication Date
20260508
Application Date
20250930

Claims (6)

  1. 1. A bis (2-chloroethyl) carbamate modified SN-38 derivative has a structural general formula shown in a formula (I): Wherein R is selected from H, phosphate group (PO 3 H 2 ), sodium phosphate salt (PO 3 Na 2 ) and the like, XH is pharmaceutically acceptable acid such as hydrochloric acid (HCl), sulfuric acid (H 2 SO 4 ), phosphoric acid (H 3 PO 4 ), hydrobromic acid (HBr), nitric acid (HNO 3 ), citric acid (C 6 H 8 O 7 ), maleic acid (C 4 H 4 O 4 ), tartaric acid (C 4 H 6 O 6 ), methanesulfonic acid (CH 3 SO 3 H), acetic acid (CH 3 COOH), fumaric acid (C 4 H 4 O 4 ), succinic acid (C 4 H 6 O 4 ), malic acid (C 4 H 6 O 5 ), benzoic acid (C 7 H 6 O 2 ), lactic acid (C 3 H 6 O 3 ), glutamic acid (C 5 H 9 NO 4 ), aspartic acid (C 4 H 7 NO 4 ) and the like.
  2. 2. A bis (2-chloroethyl) carbamate modified SN-38 derivative of formula (I), an enantiomer, a racemate, or a mixture thereof, or a pharmaceutically acceptable salt, hydrate, and solvate thereof, wherein the compound is selected from the group consisting of: Table 1:
  3. 3. the method for preparing the SN-38 derivative according to claim 1 or 2, wherein the synthetic route of the method is as follows:
  4. 4. The method for preparing the SN-38 derivative according to claim 1 or 2, wherein the target compounds 1,2-HX, 3 and 4 are synthesized by carbamate reaction, hydrochloride reaction, phosphate reaction and neutralization salt formation reaction in sequence by taking SN-38 as a starting material. The preparation method comprises the steps of (1) reacting SN-38 with bis (2-chloroethyl) carbamoyl chloride (BCCC or corresponding carbamic acid and the like serving as raw materials) in a halogenated hydrocarbon solvent (such as dichloromethane and chloroform) at room temperature for 12-24 hours in the presence of alkali (such as triethylamine, pyridine or analogues thereof) and a catalyst (such as DMAP or derivatives thereof), extracting and carrying out column chromatography to obtain a compound 1, (2) reacting the compound 1 with concentrated hydrochloric acid or other inorganic acid (such as sulfuric acid and hydrobromic acid) or organic acid (such as citric acid, maleic acid, tartaric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, malic acid, benzoic acid, lactic acid, glutamic acid, aspartic acid and the like) in an alcohol ether mixed solvent (such as methanol/diethyl ether and ethanol/isopropyl ether) at room temperature for 0.5-2 hours, precipitating acid salt to obtain a compound 2-HX, (3) reacting the compound 1 with a phosphorylating reagent (such as P 2 O 5 、POCl 3 or tetraethyl phosphate) in an inert solvent (such as dioxane and toluene) at 60-100 ℃ for 60-100 hours, and carrying out a step-8 DEG, and carrying out a step-8-phase reaction with a polar phosphoric acid and carrying out a sodium salt precipitation reaction with a polar phosphoric acid compound (such as ethanol) in a water-8-alkaline solution, and carrying out step 4-alkaline aqueous solution, and carrying out purification. The method can efficiently prepare the series of SN-38 derivatives by optimizing the reaction conditions (including but not limited to catalyst types, solvent selection, temperature control and purification modes), and the protection scope of the method covers reasonable alternatives of the reaction parameters in the steps.
  5. 5. A bis (2-chloroethyl) carbamate modified SN-38 derivative of claim 1 or 2, wherein the inhibitor comprises a compound of any one of claims 1-2, enantiomers, diastereomers, racemates, and mixtures thereof, and pharmaceutically acceptable salts, crystalline hydrates, and solvates thereof.
  6. 6. A pharmaceutical composition comprising (a) a therapeutically effective amount of one or more of the compounds of claim 1, enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, and (B) a pharmaceutically acceptable carrier for the compounds of claim 1. In another preferred embodiment, the pharmaceutical composition optionally further comprises a pharmaceutically acceptable adjuvant selected from the group consisting of binders, fillers, diluents, disintegrants, suspending agents, slow (controlled) release agents, lyoprotectants, coating agents, enteric materials, lubricants, glidants, anti-adherents, sweeteners, flavoring agents, plasticizers, opacifiers, solubilizers, humectants, solvents, tonicity modifiers, colorants, pigments, surfactants, emulsifiers, water-soluble matrices, fat-soluble matrices, porogens, gels, preservatives, buffers, chelating agents, antioxidants, or combinations thereof. The preparation method is characterized by being used for preparing and treating the medicines related to the cancer. In another preferred embodiment, the cancer-related disease is selected from the group consisting of liver cancer, lung cancer, breast cancer, stomach cancer, colorectal cancer, esophageal cancer, cervical cancer, ovarian cancer, bladder cancer, pancreatic cancer, acute and chronic granulocytic leukemia, chorioallantoic cancer, and the like.

Description

Bis (2-chloroethyl) carbamate modified SN-38 derivative and preparation method and application thereof Technical Field The invention belongs to the technical field of modernization of traditional Chinese medicines, and mainly relates to a novel camptothecin derivative, a preparation method and medical application thereof, in particular to a technical scheme for improving water solubility, stability and antitumor activity of a medicine by introducing bis (2-chloroethyl) carbamate and salt groups. Background The camptothecine is a natural antitumor active ingredient extracted from the traditional Chinese medicine camptotheca acuminata (Camptotheca acuminata), and the derivative SN-38 has remarkable antitumor potential as a topoisomerase I inhibitor, but is limited by bottleneck problems of extremely low water solubility, excessively fast in vivo metabolism, remarkable toxic and side effects and the like, so that the application of the camptothecine in clinical preparation development is severely restricted. The invention is based on the structural optimization of the camptothecine which is the active ingredient of the traditional Chinese medicine, and carries out chemical modification on 7-ethyl-10-hydroxycamptothecin (SN-38) through bis (2-chloroethyl) carbamate groups, thereby designing and synthesizing a novel derivative which simultaneously contains nitrogen mustard pharmacophore and camptothecine parent nucleus. And further introducing phosphate groups into alcohol hydroxyl groups or forming acid salts through phosphorylation modification or salt forming reaction, and finally obtaining the target compound shown in the formula I. In vivo and in vitro experiments prove that the novel camptothecin derivative disclosed by the invention has the advantages of improving the anti-tumor effect, improving the drug stability, reducing the toxic and side effects of the drug and the like. By searching, no patent publication related to the present patent application has been found. Disclosure of Invention The invention aims to provide novel SN-38 derivatives modified by bis (2-chloroethyl) carbamate and a preparation method thereof, so as to solve the problem of limited clinical application of the conventional SN-38 caused by low water solubility, insufficient bioavailability and toxicity. Meanwhile, the synergistic effects of enhanced antitumor activity, optimized physicochemical properties and reduced toxic and side effects are realized by combining SN-38 with nitrogen mustard pharmacophore and introducing acid/salt modification, so that more efficient and safe candidate medicaments for treating malignant tumors such as cervical cancer, liver cancer, colon cancer and the like are provided. The invention discloses a novel diagnosis and treatment prodrug molecule based on SN-38, which has a structural general formula shown in formula I: Wherein R is selected from H, phosphate group (PO 3H2), sodium phosphate salt (PO 3Na2) and the like, XH is pharmaceutically acceptable acid such as hydrochloric acid (HCl), sulfuric acid (H 2SO4), phosphoric acid (H 3PO4), hydrobromic acid (HBr), nitric acid (HNO 3), citric acid (C 6H8O7), maleic acid (C 4H4O4), tartaric acid (C 4H6O6), methanesulfonic acid (CH 3SO3 H), acetic acid (CH 3 COOH), fumaric acid (C 4H4O4), succinic acid (C 4H6O4), malic acid (C 4H6O5), benzoic acid (C 7H6O2), lactic acid (C 3H6O3), glutamic acid (C 5H9NO4), aspartic acid (C 4H7NO4) and the like. A method for synthesizing an SN-38 derivative as described above, which method has the following synthetic route: The method is characterized by comprising the steps of (1) reacting SN-38 with bis (2-chloroethyl) carbamoyl chloride (BCH, or corresponding carbamic acid and the like serving as raw materials) in a halogenated hydrocarbon solvent (such as dichloromethane and chloroform) at room temperature for 12-24 hours in the presence of alkali (such as triethylamine, pyridine or analogues thereof) and a catalyst (such as DMAP or derivatives thereof), extracting and column-chromatography to obtain a compound 1, (2) reacting the compound 1 with concentrated hydrochloric acid or other inorganic acid (such as sulfuric acid and hydrobromic acid) or organic acid (such as citric acid, maleic acid, tartaric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, malic acid, benzoic acid, lactic acid, glutamic acid, aspartic acid and the like) in an alcohol ether mixed solvent (such as methanol/diethyl ether and ethanol/isopropyl ether) for 0.5-2 hours, precipitating acid salt to obtain a compound 2-HX, (3) reacting the compound 1 with a phosphorylating reagent (such as P 2O5、POCl3 or tetraethyl pyrophosphate) in an inert solvent (such as dioxane and toluene) at 60-100 ℃ in steps of 6-48 ℃ for 60 ℃ respectively, precipitating the compound with water-48 ℃ in a polar solvent (such as ethanol) and drying to obtain a sodium salt (such as ethanol) and drying the compound (4) in the presence of a polar sodium salt).