TECHNICAL FIELD

The present invention relates to an anti-tumor drug compound, in particular, to the preparation and use of an immune-stimulating soluble doxorubicin-conjugated complex.

TECHNICAL BACKGROUND

We have previously published the invention. Aspartame targets the activated doxorubicin derivative (Patent No. 201210573744.3). EMC-AANL-DOX binds albumin through the EMC group to form a large coupling in the blood. Molecules that specifically recognize activated compounds in tumors through aspartase. Based on this patent, through further compound screening and systematic biological research, we have developed immunosuppressive cell targeting and soluble doxorubicin-conjugated complexes. New compounds with curative effect.

SUMMARY OF INVENTION

The technical problem to be solved by the present invention is to overcome the above-mentioned shortcomings, and research and design an immune-stimulating soluble doxorubicin-conjugated complex. Due to the combination of appropriate compound linker, the toxicity of cytotoxic drugs is reduced, and targeted aggregation in the tumor micro-environment can stimulate the immune system and activate efficiently.

The present disclosure provides a compound having the following structure or a pharmaceutically acceptable salt thereof:

In one or more embodiments, the compound can be prepared by the following methods, but is not limited to these preparation methods, including the following steps:

Step 1: Preparation of tripeptide-PABC or tetrapeptide: coupling amino acid residues and isolating the formed tripeptide-PABC or tetrapeptide, that is, C-A;

Step 2: Preparation of MI-S: selecting a compound suitable for the MI-S group of this patent, and performing condensation or cyclization to obtain MI-S with a carboxyl group at one end;

Step 3: Preparation of MI-S-C-A: Intermediate (MI-S-C-A) obtained by coupling C-A obtained in step 1 and MI-S obtained in step 2 with amino and carboxyl groups;

Step 4. Covalently combine the carboxyl or hydroxyl activation product of the A-terminus of the compound MI-S-C-A obtained in step 3 with the amino group of the optional drug to form Immune-stimulating Soluble doxorubicin-conjugated complexes.

The present invention also provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof disclosed herein, and a pharmaceutically acceptable carrier.

In one or more embodiments, the cancer is selected from the group consisting of: liver cancer, kidney cancer, thyroid cancer, colorectal cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, rectal cancer, esophageal cancer, lung cancer (e.g., bronchial lung cancer, Including undifferentiated small cell and non-small cell), nasopharyngeal cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, uterine cancer, ovarian cancer, testicular cancer, blood cancer (such as chronic or acute leukemia, including lymphocytic And granulocytic leukemia), malignant lymphoma, fibrosarcoma, soft tissue sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, nephroblastoma, neuroblastoma, thyroid cancer and squamous cell carcinoma of the head and neck.

The invention also provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of an immunotherapeutic medicament.

In one or more embodiments, the immunotherapeutics can be used to stimulate the proliferation of T cells and invasion of lesions, inhibit tumor-associated macrophages, and/or promote stimulation of immune responses.

The experimental design idea of the present invention is to first synthesize a large number of compounds with different structures, and then use these compounds to study the working mechanism of the asparagine peptide endonuclease. Since the active center of the asparaginide endonuclease is located at the bottom of the balloon-like indentation, the substrate peptide needs to be close to the enzyme active center at the bottom of the balloon to be activated. At this time, the molecular structure connecting the adjacent end of the substrate peptide directly determines its activation efficiency. Based on this, we screened different C groups and found that the asparagine peptide endonuclease preferably recognizes the ALA-ALA-ASN sequence and cleaves the ASN amide bond, and at the same time the amino acids on both sides of the ALA-ALA-ASN sequence Residues or groups have a great influence on the binding force of the compound to the enzyme protein, that is, the screening of A, MI-S, we linked different synthetic A and MI-S groups to doxorubicin and then screened for activation efficiency under the conditions of tumor tissue or asparagine endonuclease. In the end, a Doxorubicin conjugates complex QHL-087 with reduced toxicity of Doxorubicin and increased solubility, targeted aggregation of tumor sites, and significantly enhanced activation characteristics was obtained.

Through experimental screening and determination, the added functional groups do not affect drug release and improve activation efficiency. Therefore, compared with the previous generation of doxorubicin derivative, the immuno-stimulant soluble doxorubicin derivative increases anti-tumor effect.

It was found through experimental measurement that: 1. Doxorubicin-conjugated complex of the present invention can aggregate in the tumor micro-environment 2. the Doxorubicin-conjugated complex of the present invention has increased water solubility 3. the MI-S group in the Doxorubicin-conjugated complex of the present invention the effect of the difference on activation efficiency is very large. The longer the chain length of MI-S, the steric relationship is not conducive to the combination of the compound and the enzyme, and the activation efficiency is reduced. The chain length of MI-S is too short or all are alkanes. When the base chain is used, the binding ability to A is insufficient, and the solubility of the compound cannot be improved.

Thus, the compound of the present invention has the characteristics of water solubility, long half-life, and high activation. Compared with doxorubicin, epirubicin, and comparative patented invention, the compound of the present invention reduces the toxicity of the compound and improves the anti-tumor effect. Curative effect, more dosage forms can be prepared at the same time, and it has very good application prospects.

