52 results about "Camptothecin derivative" patented technology

The invention relates to application of a topoisomerase inhibitor and a conjugate thereof. Specifically, the inventor provides a class of camptothecin derivatives, linker conjugates and antibody-drug conjugates with novel structures, and the camptothecin derivatives, linker conjugates and antibody-drug conjugates have excellent anti-tumor activity and good lipophilicity. In-vitro and in-vivo experiments show that the drug conjugate containing the camptothecin derivative disclosed by the invention has an improved anti-tumor curative effect and high safety, and has an application prospect in the field of cancer treatment.

The present invention relates to an antibody-drug conjugate represented by formula (I) having an oxacycloalkyl-substituted camptothecin derivative as a drug toxic moiety, wherein the definitions of each group in the formula are as described in the specification, and the antibody-drug conjugate has a significant antitumor effect. [Formula 1] JPEG2026502963000098.jpg54170

Disclosed are new anti-HER2 ADCs conjugated to camptothecin derivatives as toxins for therapeutic use. The antitumor effects of the ADCs of Formula (PL-A) (e.g., compounds MB-2a and MB-3a (trastuzumab meditecan)) render these compounds useful for treating cell proliferative diseases such as cancers.

Disclosed are new anti-HER2 ADCs conjugated to camptothecin derivatives as toxins for therapeutic use. The antitumor effects of the ADCs of Formula (PL-A) (e.g., compounds MB-2a and MB-3a (trastuzumab meditecan)) render these compounds useful for treating cell proliferative diseases such as cancers.

Provided is a novel camptothecin derivative or a conjugate thereof, and a preparation method therefor and an application thereof in medicine. Specifically, provided is a compound represented by general formula (A) or a ligand-drug conjugate thereof, a preparation method therefor, and an application of the ligand-drug conjugate and a pharmaceutical composition thereof in the preparation of a drug for the treatment of cancer or immunological diseases.

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. According to the structure, R1, R2 and R3 are independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, sulfydryl, sulfuryl, sulfoxide, nitro, substituted or unsubstituted amido, carboxyl, acylamino, deuterated alkyl, C1-6 alkyl, C1-6 alkoxy, C1-6 halogenated alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 heterocyclic radical, aryl or heteroaryl; or R1 and R2 as well as R2 and R3 are respectively connected with adjacent carbon atoms to form 5-7-membered cycloalkyl or heterocycloalkyl; the 5-to 7-membered cycloalkyl or heterocyclic cycloalkyl is optionally substituted by one or more halogens or deuterium atoms, alkyl and alkoxy. The compound has a good anti-tumor effect.

This invention provides an irinotecan-conjugated polypeptide compound, its preparation method, and its application, belonging to the field of biomedical technology. Irinotecan (Dxd) is the active pharmaceutical ingredient. Irinotecan belongs to the topoisomerase I inhibitor class—camptothecin derivatives—and is a semi-synthetic small molecule chemotherapeutic drug capable of directly killing cancer cells in the active division phase and inhibiting tumor growth. TYLCTACDYTHH is a highly effective PDPN-targeting peptide that can effectively target the PDPN site in human glioblastoma. In vitro and in vivo experimental results show that the conjugated compound of this invention can significantly inhibit the proliferation of primary glioblastoma cells and effectively inhibit the growth of intracranial orthotopic xenografts in NOD-SCID mice, demonstrating good anti-tumor activity. This compound shows promise for targeted therapy of glioblastoma and has the potential to prolong patient survival.

The anti-cancer use of a camptothecin derivative which demonstrates a surprising resistance to the degrading effects of Human Serum Albumin ("HSA") in vivo is disclosed. Since HSA represents about half of serum protein in human blood, previous camptothecins generally worked poorly or not at all in vivo due to inactivation by HSA among other factors. Since NSS-01 is similar in mechanism of action to other camptothecins, and as demonstrated herein has both: (i) greater anti-tumor activity against various human cancers and (ii) less toxicity at therapeutic dosing - than topotecan and irinotecan; and without wishing to be bound by theory, NSS-01 demonstrated desirable antitumor activity against adenocarcinomas, it therefore should demonstrate desirable antitumor activity against other cancers that are susceptible to Topoisomerase I inhibitors.

Provided are a C9-substituted camptothecin derivative and a conjugate thereof. Specifically disclosed is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The camptothecin derivative and the conjugate thereof have a good cell killing effect.

The invention relates to a topoisomerase inhibitor as well as a conjugate and application thereof. Specifically, the invention discloses a camptothecin derivative with a brand new structure, a linker conjugate and an antibody-drug conjugate. Experimental results show that by using the camptothecin derivative with high lipophilicity, the anti-tumor effect of the ADC drug can be remarkably improved, so that linker conjugates and cytotoxic small molecules are expected to be applied to the field of biological medicines.

The invention relates to a camptothecin derivative and a conjugate thereof as well as a preparation method and medical application of the camptothecin derivative and the conjugate. The invention relates to a novel camptothecin compound derivative, a ligand drug conjugate containing the camptothecin compound derivative, a pharmaceutical composition containing the conjugate, and application of the conjugate in cancer treatment.

The invention provides a camptothecin derivative and an antibody-drug conjugate thereof. The compound is high in activity, small in toxicity and good in affinity, the direct targeted killing effect on tumor cells is achieved through the compound and an antibody drug conjugate, and the antibody drug conjugate containing the antibody is remarkable in cell killing effect and has the very high tumor inhibition rate.

In particular, antibody-drug conjugates (ADCs) that bind to the B7-H3 antigen are provided. Furthermore, pharmaceutical compositions and therapeutic methods for treating cancer using the ADCs provided herein are disclosed. This disclosure provides ADCs comprising an anti-B7-H3 antibody conjugated to a camptothecin derivative toxin or a duostatin derivative toxin via a linker moiety. In embodiments, the anti-B7-H3 antibody binds to B7-H3 expressing cancer cells, enabling selective uptake of the ADC into the cancer cells.

The present invention relates to the technical field of camptothecin derivative preparation, particularly to a camptothecin derivative synthesis method, which uses 2-nitroacetophenone and isopropylamine as raw materials, and the camptothecin derivative is obtained through a Mannich reaction, a methylsulfonylation reaction, a nitro reduction reaction and a ring closing reaction. According to the synthetic method of the camptothecin derivative, the complex camptothecin derivative is split into two segments 1-(2-aminophenyl)-3-(N-isopropyl-N-methylsulfonylamino) propan-1-one and a compound V which are easy to prepare, and finally, a plurality of rings and chemical bonds are constructed simultaneously through one-step efficient ring closing reaction. The yield attenuation caused by progressive multiplication of the yield in the traditional linear synthesis is avoided, and the total yield is improved.

The present invention provides a novel camptothecin derivative compound, a pharmaceutically acceptable salt, a stereoisomer, or a prodrug thereof, and a method for preparing same and use thereof. The compound has a structure represented by formula (I) and has good anticancer activity.

The application belongs to the technical field of organic synthesis and medicine, and particularly relates to 20(S)-10,11-difluoromethylenedioxy camptothecin derivatives, a preparation method and application thereof. The derivative is a compound with a structure shown in formula (I), stereoisomers and pharmaceutically acceptable salt forms. The novel 20(S)-10,11-difluoromethylenedioxy camptothecin derivative can be used for preparing and synthesizing camptothecin drugs for preventing or treating tumors. The compound has good anti-inflammatory activity, in-vivo and in-vitro anti-tumor activity and cell transmembrane transport capacity. The preparation method is easy to operate, the post-treatment is simple, the reaction starting material is cheap and easy to obtain, the reaction substrate has strong designability, the reaction efficiency is high, and the practicability is strong.

The present invention relates to an antibody-drug conjugate represented by formula (I) having a haloalkyl-substituted camptothecin derivative as a drug toxic moiety, wherein the definitions of each group in the formula are as described in the specification, and the antibody-drug conjugate has a significant antitumor effect. [Formula 1] JPEG2026501617000115.jpg57170

The invention belongs to the technical field of organic synthesis and medicines, and particularly relates to an aminated 20 (S)-10, 11-difluoromethylenedioxy camptothecin derivative as well as a preparation method and application thereof. The derivative is a compound with a structure as shown in a formula (I), and in the formula (I), R is shown in the description; wherein X is an integer from 3 to 10, and n is an integer from 3 to 10; and Z is selected from (amido substitution). The novel aminated 20 (S)-10, 11-difluoromethylenedioxy camptothecin derivative provided by the invention has good in-vivo and in-vitro anti-tumor activity, and can be used for preparing and synthesizing camptothecin drugs for preventing or treating tumors, the preparation method is easy to operate, the post-treatment is simple and convenient, the initial raw materials of the reaction are cheap and easy to obtain, the designability of the reaction substrate is strong, and the method is suitable for industrial production. The reaction efficiency is relatively high, and the practicability is relatively high.

The present invention discloses camptothecin derivatives and their ligand-drug conjugates, which provide superior antitumor camptothecin-based ADC drugs with higher safety and efficacy, and can better meet clinical needs.

The invention belongs to the technical field of tumor immunotherapy, and particularly relates to a response type self-assembly prodrug nanoparticle and a preparation method and application thereof.The self-assembly prodrug nanoparticle SIN / CPT-NPs is constructed by combining a camptothecin derivative CPT-C, a GSH response type NO prodrug SIN-C and mPEG2000-DSPE, and the preparation method comprises the steps that mPEG2000-DSPE and prodrugs CPT-C and SIN-C are dissolved in chloroform, then the solution is added into a reaction kettle, the reaction kettle is heated, the reaction kettle is heated, and the reaction kettle is cooled to the room temperature to obtain the response type self-assembly prodrug nanoparticle SIN / CPT-NPs; the preparation method comprises the following steps: firstly, preparing an SIN-CPT-coated NPs by using a three-dimensional micro-fluidic chip to form a uniform lipid film in a rotary evaporator, then adding ultrapure water to carry out hydration and ultrasonic treatment to obtain a nano suspension, removing unencapsulated drugs and large particles through centrifugal separation, and collecting supernate to obtain SIN / CPT-coated NPs. According to the SIN-CPT-coated NPs, drug release is specifically triggered through tumor microenvironment GSH, DNA damage, STING pathway activation and ICD effect are synchronously induced, and the SIN-CPT-coated NPs are prepared. DC maturation and CD8 + T cell infiltration are driven to form a chemotherapy-immune synergistic anti-tumor closed loop.

The application relates to antibody-drug conjugates, pharmaceutical compositions comprising the antibody-drug conjugates, and medicinal uses of the antibody-drug conjugates for treating diseases such as cancer. In one embodiment, the antibody-drug conjugate is formed with an anti-human ROR1 antibody and a camptothecin derivative.

This invention provides an antibody-drug conjugate in which a compound of Formula 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, hydrate, solvate, or isotopically labeled analogue thereof is linked to an anti-Nectin-4 antibody via a linker. The antibody-drug conjugate according to this invention can selectively exhibit the activity of the compound of Formula 1 on cancer cells expressing Nectin-4.

Provided are an intermediate for synthesizing a camptothecin derivative, a preparation method therefor, and the use thereof. An intermediate A can be obtained from 3-fluoro-4-methylaniline by means of acylation, bromination, and cross-coupling reactions. The intermediate A can be used for preparing an intermediate B to further prepare exatecan mesylate. The intermediate compound B can be obtained from the intermediate A by means of a rearrangement reaction, and exatecan mesylate can be obtained from the intermediate compound B by means of deprotection for acetamido and amino at the a site, a condensation reaction, and a hydrolysis reaction. The reaction starting materials have a low price, the reaction conditions of each step are moderate, the operation is simple, and the yield is high, such that the intermediate is suitable for industrial production.

Disclosed are a compound of formula (I'), an antibody-drug conjugate (ADC) of the compound, and a pharmaceutical composition comprising the compound and / or an ADC of the compound. The compound is useful for the treatment, prevention, or improvement of diseases or disorders such as cancer. JPEG2026513350000146.jpg5758

The invention provides novel methods for preparing camptothecin derivatives and their synthetic precursors.

An antitumor pharmaceutical camptothecin derivative and an antibody-drug conjugate thereof. By means of a series of molecular structure modifications, an optimal camptothecin antitumor drug is obtained, so as to be more suitable as a drug for antibody conjugation.

The present invention relates to the technical field of drug synthesis, and provides a dideuterated camptothecin derivative as shown in general formula Q and a preparation method therefor and in vitro biological activity and use thereof. The compound is a topoisomerase I inhibitor, and can be used for preparing a drug for treating various diseases in the field related to anti-tumor.

The present application relates to a kind of preparation of new indole camptothecin derivatives and its use in antitumor, the structure of the compound general formula is shown as follows.In vitro cytotoxic activity screening results show that new indole camptothecin derivatives have broad-spectrum antitumor activity, to human hepatoma cell (HepG2), human non-small cell lung cancer cell (A549), human colon cancer cell (SW480), human intrahepatic cholangiocarcinoma cell (RBE), human breast cancer cell (MCF-7), human pancreatic cancer cell (BxPC3), human bladder cancer cell (T24), human bladder cancer cell (umuc3) show strong inhibitory activity. Among them, the antitumor activity of compound D-18 is most outstanding, and shows strong inhibition to the 8 tumor cell lines measured, IC 50 The range is 0.2585-10.69 μM, significantly better than the control drug irinotecan, and comparable to topotecan activity. Therefore, indole camptothecin derivatives are expected to be developed into a new antitumor drug.

This invention provides an antibody-drug conjugate in which a compound of Formula 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, hydrate, solvate, or isotopically labeled analogue thereof is linked to an anti-c-Met antibody via a linker. The antibody-drug conjugate according to this invention can selectively exhibit the activity of the compound of Formula 1 on c-Met-expressing cancer cells.

The invention relates to a method for preparing a camptothecin derivative and an intermediate of the camptothecin derivative, and belongs to the field of medicine synthesis. The invention relates to a preparation method of a compound 4, and a reaction formula is shown in the specification. The preparation method comprises the following steps: a method I: when X is selected from Cl, X is selected from Br or I; the method comprises the following steps: (1) carrying out Friedel-Crafts acylation reaction on a compound 1 and a compound 2 to prepare a compound 3; (2) carrying out substitution reaction on the compound 3 to prepare a compound 3a; (3) carrying out hydrolysis reaction on the compound 3a to prepare a compound 4; method II: when X is selected from Br or I; the method comprises the following steps: (1) carrying out Friedel-Crafts acylation reaction on a compound 1 and a compound 2 to prepare a compound 3; and step (2), carrying out hydrolysis reaction on the compound 3 to prepare a compound 4. The method is mild in process condition and simple to operate, one-step reaction is carried out through ingenious conception, hydrolysis of halogen and an amino protecting group is realized at the same time, the yield can reach more than 90%, and the purity can reach more than 99%.