WO2019192454A1 - 新型小分子免疫激动剂和免疫靶向化合物及其应用 - Google Patents
新型小分子免疫激动剂和免疫靶向化合物及其应用 Download PDFInfo
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- WO2019192454A1 WO2019192454A1 PCT/CN2019/080945 CN2019080945W WO2019192454A1 WO 2019192454 A1 WO2019192454 A1 WO 2019192454A1 CN 2019080945 W CN2019080945 W CN 2019080945W WO 2019192454 A1 WO2019192454 A1 WO 2019192454A1
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Definitions
- the present invention relates to a series of small molecule immunoagonists which are homologues and their immunotargeting compounds which are coupled with targeted drugs and their applications, and which belong to the interdisciplinary field of medicinal chemistry and immunology.
- TLRs Toll-like receptors
- TLR7 can be activated by synthetic small molecule compounds, induces immune regulation in the body, and plays an important role in antiviral and antitumor effects (Huju Chi, Chunman Li, Flora Sha Zhao, Li Zhang, Tzi Bun Ng, Guangyi Jin and Ou Sha. Anti-tumor Activity of Toll-Like Receptor 7 Agonists.Front Pharmacol.2017 May 31;8:304.doi:10.3389/fphar.2017.00304).
- TKI thyroid kinase inhibitor
- TKI tyrosine kinase inhibitor
- TKI antagonizes the immune cell activation of TLR7 agonists and inhibits the production of immune-activated cytokines (Scientific Reports, 2016 Dec 21; 6: 39598. doi: 10.1038/srep39598).
- An object of the present invention is to provide a series of small molecule immunoagonists having immunostimulating action and applications thereof, and to provide an immunotargeting compound obtained by coupling the above small molecule immunoagonist with a targeting drug and application.
- a first aspect of the invention relates to a small molecule immunoagonist of formula (I) or an isomer or pharmaceutically acceptable salt thereof:
- a 1 represents O or C
- a 2 represents a nitro group, an amino group, an isocyanate group, an alkyleneamino group, an alkylene isocyanate group or a group selected from the group consisting of the formula (II) or the formula (III):
- R 1 and R 2 each independently represent (CH 2 ) p (NH) q , wherein p is 0, 1 or 2, and q is 0, 1 or 2;
- R 3 represents O or S
- the carbon atom in the (CH 2 ) s near the carbonyl group may be substituted with a group selected from the group consisting of -NHBoc, amino group, -NHFmoc, Or forming a double bond with another carbon atom;
- R 5 represents a hydroxyl group, an alkoxy group, a hydroxylamine group, a vinyl group or a group selected from the group consisting of:
- R 6 represents an alkyl group or a group selected from the group consisting of:
- the isomer is an isomer or an enantiomer.
- the invention relates to a small molecule immunoagonist of formula (I) or an isomer or pharmaceutically acceptable salt thereof:
- a 1 represents O or C
- a 2 represents a nitro group, an amino group, an isocyanate group, a C 1 -C 6 alkyleneamino group, a C 1 -C 6 alkylene isocyanate group or a group selected from the formula (II) or the formula (III):
- R 1 and R 2 each independently represent (CH 2 ) p (NH) q , wherein p is 0 or 1, q is 0 or 1;
- R 3 represents O or S
- the carbon atom near the carbonyl group may be substituted with a group selected from the group consisting of -NHBoc, amino group, -NHFmoc, Or forming a double bond with another carbon atom;
- R 5 represents a hydroxyl group, a C 1 -C 6 alkoxy group, a hydroxylamine group, a vinyl group or a group selected from the group consisting of:
- R 6 represents a C 1 -C 6 alkyl group or a group selected from the group consisting of:
- the invention relates to a small molecule immunoagonist of formula (I) or an isomer or pharmaceutically acceptable salt thereof:
- a 1 represents O or C
- a 2 represents a nitro group, an amino group, an isocyanate group, a methyleneamino group, a methylene isocyanate group or a group selected from the group consisting of the formula (II) or the formula (III):
- R 1 and R 2 each independently represent (CH 2 ) p (NH) q , wherein p is 0 or 1, q is 0 or 1;
- R 3 represents O or S
- the carbon atom near the carbonyl group may be substituted with a group selected from the group consisting of -NHBoc, amino group, -NHFmoc, Or forming a double bond with another carbon atom;
- R 5 represents a hydroxyl group, a methoxy group, a hydroxylamine group, a vinyl group or a group selected from the group consisting of:
- R 6 represents a methyl group or a group selected from the group consisting of:
- the invention relates to a small molecule immunoagonist of formula (I), or an isomer thereof or a pharmaceutically acceptable salt thereof, which is a SZU series of compounds selected from the group consisting of the following structural formulas (see Table 1 below) Or a pharmaceutically acceptable salt thereof: SZU-104, SZU-105, SZU-107, SZU-108, SZU-109, SZU-110, SZU-111, SZU-112, SZU-113, SZU-115, SZU-118, SZU-120, SZU-127, SZU-128, SZU-129, SZU-131, SZU-132, SZU-133, SZU-134, SZU-135, SZU-136, SZU-137, SZU- 138, SZU-139, SZU-140, SZU-142, SZU-143, SZU-144, SZU-145, SZU-149, SZU-104, S
- a second aspect of the invention relates to an immunotargeting compound or a pharmaceutically acceptable salt thereof, which comprises a small molecule immunoagonist or an addition product thereof with a thiol-containing polypeptide such as glutathione and a targeting drug or antibody
- a thiol-containing polypeptide such as glutathione
- the valence coupling is formed, and its general formula is expressed as follows:
- TLA represents a small molecule immunoagonist or an addition product thereof with a thiol-containing polypeptide such as glutathione;
- Tar represents a targeting drug or antibody;
- n and m each independently represent a value between 1 and 5;
- Representative of a linking chain which is a linear or branched alkane or polyethylene glycol chain, the two ends of which are directly covalently linked to TLA and/or Tar or covalently linked to TLA and/or Tar by other groups.
- the small molecule immunoagonist comprises the small molecule immunoagonist of the first aspect of the invention and a compound selected from the group consisting of:
- the small molecule immunoagonist is a SZU series of compounds selected from the following (specific structural formulas are shown in Table 1 below) or a pharmaceutically acceptable salt thereof: SZU-102, SZU-104, SZU- 105, SZU-106, SZU-107, SZU-108, SZU-109, SZU-110, SZU-111, SZU-112, SZU-113, SZU-115, SZU-118, SZU-120, SZU-127, SZU-128, SZU-129, SZU-131, SZU-132, SZU-133, SZU-134, SZU-135, SZU-136, SZU-137, SZU-138, SZU-139, SZU-140, SZU- 142, SZU-143, SZU-144, SZU-145, SZU-149, SZU-158, SZU-159, SZU-
- the TLA is a compound selected from the group consisting of: SZU-103-GSH, SZU-114-GSH, SZU-117-GSH, SZU-122-GSH, SZU-127-GSH, SZU-133-GSH, SZU-138-GSH or SZU-144-GSH.
- the Tar is selected from at least one of the following: Dasatinib, Imatinib, Saracatinib, Ponatinib, Nilotinib, Danusertib, AT9283 Degrasyn, Bafetinib, kw-2449, nyp-bhg712, dcc-2036, GZD824.
- GNF-2 GNF-2, PD173955, GNF-5, Bosutinib, Gefitinib, Erlotinib, Sunitinib, Ruxolitinib, Tofacitinib, Lapatinib, Vandetanib, Sorafenib, Sunitinib, Axitinib, Nintedanib, Regorafenib, Pazopanib, Lenvatinib, Crizotinib, Ceritinib, Cabozantinib, DWF, Afatinib, Ibrutinib, Niraparib, Palbociclib, B43, KU004, Foreinib, KRCA-0008, PF-06439015, PF-06463922, Canerlinib, GSA-10, GW2974, GW583340, W24002, CP-380736, D2667, Mubritinib, PD153035, PD168393, Pelitin
- the Tar is selected from at least one of the group consisting of a TKI, an EGFR inhibitor, a KRAS inhibitor, a BRAF inhibitor, a BTK inhibitor, a BRD4 inhibitor, a PD-L1 inhibitor, a PD- 1 inhibitor, OX40 agonist, PARP inhibitor or CDK4/6 inhibitor.
- the other group comprises an amide, an alkoxy bond, an alkylthio bond, a substituted amine group, a quaternary ammonium salt, a heterocyclic ring formed by a cilck reaction, an amino acid group which can be dissociated by a protease, a urea group Group or thiourea group.
- the immunotargeting compound or a pharmaceutically acceptable salt thereof is a SZU series compound selected from the following (specific structural formula is shown in Table 4 below) or a pharmaceutically acceptable salt thereof: SZU-116, SZU-119, SZU-124, SZU-125, SZU-146, SZU-147, SZU-168, SZU-169, SZU-174, SZU-175, SZU-176, SZU-177, SZU-178, SZU- 179, SZU-180, SZU-181, SZU-158-PD-L1, SZU-158-OX40, SZU-158-PD-1 or SZU-136-miRNA21.
- a third aspect of the invention relates to the small molecule immunoagonist of the formula (I) according to the first aspect of the invention, or an isomer or pharmaceutically acceptable salt thereof, the compounds SZU-101, SZU-103, SZU-114, Use of SZU-117, SZU-122 and SZU-130 (see Table 2 for specific structural formula) and the immunotargeting compound of the second aspect of the invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for participating in immunomodulation .
- a fourth aspect of the invention relates to the small molecule immunoagonist of the formula (I) according to the first aspect of the invention, or an isomer or pharmaceutically acceptable salt thereof, the compounds SZU-101, SZU-103, SZU-114, SZU-117, SZU-122 and SZU-130 and the immunotargeting compound of the second aspect of the invention or a pharmaceutically acceptable salt thereof, in the preparation of an antitumor drug, an antiviral drug and a drug for targeting a scavenging protein use.
- the invention also relates to the use of the compound SZU-136-miRNA21 and analogs thereof for the preparation of a medicament for immunologically targeting RNA.
- the compound SZU-136-miRNA21 and its analogs serve as immunologically targeted small molecule RNAs.
- the medicament may be in various dosage forms, including solid preparations, liquid preparations, complexes of the drug with various carriers, or crystalline water complexes of the drug.
- the invention also relates to the use of the compounds SZU-179, SZU-180 and SZU-181 for the preparation of anti-AIDS and anti-hepatitis B drugs.
- the compounds SZU-179, SZU-180 and SZU-181 are used as antiviral immunotargeting compounds.
- the invention further relates to the use of the compounds SZU-161 and SZU-162 for determining the degree of coupling of small molecule immunoagonist-conjugated protein drugs and cells.
- the compounds SZU-161 and SZU-162 act as small molecule immunoagonists with specific ultraviolet absorption.
- the invention further relates to the use of the compounds SZU-116 and SZU-124 for observing the cellular uptake and in vivo distribution of a research protein or a targeted drug, wherein the compounds SZU-116 and SZU-124 are coupled to a protein or a targeting agent.
- the compounds SZU-116 and SZU-124 are used as optical tracing properties of small molecule immuno-agonist chromogenic indicators. When coupled with proteins or targeted drugs, they can display the cellular absorption and in vivo distribution of proteins or targeted drugs in real time. .
- the invention also relates to the use of the compounds SZU-114, SZU-117, SZU-122, SZU-127, SZU-133, SZU-138, SZU-143 in the preparation of a medicament having immunotargeting bifunctionality, wherein the compound SZU- 114.
- SZU-117, SZU-122, SZU-127, SZU-133, SZU-138, SZU-143 are coupled to a targeting drug or antibody.
- the small molecule immunoagonists of the invention have immunological activation by themselves.
- the combination of TKI and TLR7 immunoagonists results in TKI antagonizing immune cell activation of TLR7 agonists and inhibiting the production of immune activated cytokines.
- the inventors covalently coupled the TKI targeting drug with the TLR7 small molecule immunoagonist, it was unexpectedly found that such covalently coupled compounds not only maintained or improved the immune activation of small molecule immunoagonists, but also improved The anti-tumor effect of the targeted drug.
- Such immunotargeting compounds obtained by the method of the invention are of great significance for the long-term and efficient treatment of tumors.
- the structural formulas of the compounds SZU-103, SZU-114, SZU-117, SZU-122 and SZU-130 and preparation methods thereof are disclosed in Chinese Patent Application CN107281483A.
- the structural formula of the compounds SZU-102 and SZU-106 and the preparation method thereof are disclosed in Chinese Patent Application No. CN106267188A, wherein the compound SZU-102 is the compound 1 therein, and the compound SZU-106 is the compound 19 therein.
- some of the small molecule immunoagonists in Tables 1 and 2 can form an adduct with a thiol-containing polypeptide such as glutathione (GSH), which is capable of targeting glutathione transferase, synergistic chemotherapy drugs, irreversible TKI targeted drugs and other irreversible targeted drugs to improve the treatment of the disease, eliminate drug resistance, and activate the immune effect.
- GSH glutathione
- thiol-containing compounds include, for example, 2-methylamine ethanethiol and SZU-033T Wait.
- the small molecule immunoagonists in Tables 1 and 2 and the partial small molecule immunoagonists in Table 3 and the compounds formed by GSH can be coupled with a targeting agent to obtain a bifunctional immunotargeting compound having an immunotargeting effect.
- the immunotargeting compounds are shown in Table 4 below:
- Small molecule immunoagonists (exemplified by SZU-137) are coupled to the second route of targeted drug synthesis:
- the same method as described above is also applicable to the formation of an immunotargeting compound by coupling with SZU-144 or SZU-133 and a targeting drug.
- the linker may also be a simple linear alkane or may be replaced according to various needs.
- a carboxyl-containing small molecule immunoagonist (eg, SZU-138) can couple a antibody to form a soluble functional protein polypeptide conjugate by an addition reaction and a coupling reaction, which can form a salt due to a dimethylamino group.
- the formation of an ionized positive charge is beneficial to improve the therapeutic effect and water solubility, thereby solving the solubility problem of the coupled product.
- carboxyl group-containing small molecule immunoagonist can also be coupled to two different targeted drugs to form a dual targeting immune compound.
- Small molecule immunoagonists using SZU-171 as an example are coupled with the third route of targeted drug synthesis:
- the product formed by small molecule immunoagonists and glutathione can also be coupled with two different targeted drugs to improve efficacy.
- the targeted drug may be various TKI drugs and various tumor targeting drugs, and may also be antibodies such as CD3 antibody, PD-1 antibody, OX40 antibody, CD19 antibody, CD20 antibody, HER2 antibody, MUC1 antibody and various tumors. Protein antibodies and antibodies to pathogens, etc.
- the coupling chain therein may be various alkane chains or alkoxy chains, etc., and may be adjusted according to the needs of dissolution and metabolism optimization.
- the above double-conjugated immunotargeting compound has the advantages of forming two positive ion amino groups (amino salt-HN + -, -NH + 3 ), high solubility, and the double target can be adjusted and optimized as needed; for example, targeting 1 For T cell CD3 antibody or CD122 antibody, targeting 2 is a tumor cell HER2 inhibitor, which can promote the infiltration of T cells into the tumor microenvironment, enhance the anti-tumor effect, activate the immune TLR7 receptor, and generate targeted immune memory. .
- Small molecule immuno-agonists (exemplified by SZU-166, which is a unique isocyanate small molecule immunoagonist with the advantage of mild quantitative coupling addition with amino compounds).
- SZU-115 and SZU-160 are novel small molecule immunoagonists with click reactive groups. Their functions basically include two points. 1) After coupling with macromolecules and biologically active substances, the click reaction is followed by a coloring indication. The agent optically traces the coupled product, for example, after coupling the protein or after targeting the drug, observing the cellular absorption and distribution of the protein or the targeted drug.
- SZU-115 can also connect antibodies and targeted drugs at the same time, reduce the off-target effect of antibodies, enhance targeted drug effects, and activate anti-tumor immunity:
- Compound SZU-136 and compound SZU-160 have similar effects and application effects.
- the SZU-139 in the present invention is produced by SZU-136 reacting with a ribose click:
- miRNA21 small molecule immunoagonists coupled to small RNAs
- miRNA21 plays an important role in tumorigenesis and development (Cell Death Dis.2018 Feb 13;9(2):219.doi :10.1038/s41419-017-0243-9; Proc Natl Acad Sci US A.2015 Jun 30;112(26):E3355-64.doi:10.1073/pnas.1504630112;Cancer Lett.2017 May 1;393:86- 93.doi:10.1016/j.canlet.2017.02.019; https://en.wikipedia.org/wiki/MIRN21 ), the use of small molecule immuno-agonists to conjugate disease-causing miRNAs can guide the immune system to cut off the source of the disease , blocking changes in related proteins and the occurrence of related diseases.
- the alkynyl immuno agonist can be replaced by SZU-115.
- the carboxyl group of SZU-115 can be coupled with Argonaute to form a complex, interfere with the formation of miRNA and Argonaute complex, and lead to immune cell endosomes under the action of TLR7 agonist, resulting in Immune elimination and memory:
- miRNAs produced by the human body especially miRNAs released by tumor cells, generally have no immune-inducing ability, and exogenous antisense oligonucleotide RNA
- the target miRNA can be specifically recognized, it is mostly immunogenic and is eliminated, or is rapidly degraded in the body.
- the above method can be used to form pathogenic autologous miRNAs into immunogenic miRNAs that are recognized by natural immunity. The same method is equally applicable to other pathogenic miRNAs such as miRNA30c and the like.
- the effect of tumors and other diseases confers dual function (bifunctional targeting drugs) of the targeted drug, which is enhanced by immunological anti-tumor factors (such as IFN- ⁇ ) and pathogenic targeting sites.
- immunological anti-tumor factors such as IFN- ⁇
- pathogenic targeting sites The inhibition of the two functions is synergistic.
- the present invention relates to a novel highly effective targeted drug that combines functions into one.
- a reasonable role of the immunotargeting compounds of the present invention is to eliminate pathogenic targets (proteins) by the immune pathway, as shown in FIG.
- an immunotargeting compound formed by a small molecule immunoagonist coupled with a targeted drug can overcome drug resistance and improve therapeutic effect.
- the acid-type small molecule immuno-agonist lysine-derived compounds SZU-104, SZU-105, SZU-112, and SZU-113 are amino acid derivatives having immunoagonist activity, and can be prepared as needed in the preparation of immune antigen polypeptides.
- the site of insertion of the polypeptide (or antibody) is positioned to achieve the purpose of localization coupling:
- SZU-161 and SZU-162 as small molecule immunoagonists for coupled protein drugs, have specific UV absorption peaks (342 nM), which can be used as a general method for determining the coupling degree of small molecule immunoagonist-conjugated protein drugs:
- Determination method 1) Determine the light absorption intensity of SZU-161 at 342 nM at different concentrations, and make a standard curve of concentration and absorbance to obtain the concentration-absorbance relationship; 2) Determine the coupled protein after coupling protein The absorbance at 342 nM at the concentration can be obtained by substituting the relationship to obtain the relative concentration of SZU-161 in the conjugate.
- SZU-162 has the same application effect.
- immunocytokines represent Cytokine (including IFN- ⁇ , IL-12, IL-6, TNF- ⁇ , etc.), and their concentration can be used to indicate the level of activation of immune cells by the compound.
- FIG 1 shows the immunocytokine (IL-6) activation effect of the SZU-GSH series of compounds.
- Figure 2 shows the distribution of fluorescently labeled SZU-116 in cells.
- FIG. 3 shows the immunocytokine (IFN- ⁇ ) activation effects of SZU-102, 103, 106, 107, 108, 110, 111, 114, 115, 116, 117, 118.
- SZU-101 and R848 are standard controls, which are internationally recognized standard immunosuppressive small molecule immunoagonists, the same below.
- FIG. 4 shows the immunocytokine (IFN- ⁇ ) activation effects of SZU-143, 144, 146, 147, 149. Where con is the PBS blank control, the same below.
- Figure 5 shows the immunocytokine (IL-12) activation effects of SZU-143, 144, 146, 147, 149.
- Figure 6 shows the immunocytokine (TNF- ⁇ ) activation effect of SZU-143, 144, 146, 147, 149.
- Figure 7 shows the immunocytokine (IL-6) activation effects of SZU-143, 144, 146, 147, 149.
- Figure 8 shows the immunocytokine (IFN- ⁇ ) activation effects of SZU-145, 158, 104, 109, 112, 124.
- Figure 9 shows the immunocytokine (IL-12) activation effects of SZU-145, 158, 104, 109, 112, 124.
- Figure 10 shows the immunocytokine (TNF- ⁇ ) activation effects of SZU-145, 158, 104, 109, 112, 124.
- Figure 11 shows the immunocytokine (IL-6) activation effects of SZU-145, 158, 104, 109, 112, 124.
- Figure 12 shows the effect of each immunocytokine activation of SZU-125.
- FIG. 13 shows the immunocytokine (IFN- ⁇ ) activation effect of SZU-105.
- FIG. 14 shows the immunocytokine (IL-12) activation effect of SZU-105.
- FIG. 15 shows the immunocytokine (IFN- ⁇ ) activation effect of SZU-113.
- FIG 16 shows the immunocytokine (IL-12) activation effect of SZU-113.
- FIG 17 shows the immunocytokine (IL-12) activation effect of SZU-119.
- FIG. 18 shows the immunocytokine (IL-6) activation effect of SZU-119.
- FIG 19 shows the immunocytokine (IFN- ⁇ ) activation effect of SZU-120.
- FIG. 20 shows the immunocytokine (IL-6) activation effect of SZU-120.
- 21 to 54 show the respective immunocytokine activation effects of the small molecule immunoagonists SZU-122 and 127-142 of the present invention, respectively.
- Figure 55 shows the effect of SZU-102, 119, 125, 146, 147, 169, 174, 175, 168, 176, 177, 179 activating immune cells to produce IFN- ⁇ .
- Figure 56 shows the effect of SZU-102, 119, 125, 146, 147, 169, 174, 175, 168, 176, 177, 179 activating immune cells to produce IL-12.
- Figure 57 shows the in vivo anti-tumor (CT26) activity of novel immunotargeting compounds: Veh (not administered control), A (SZU-177), B (SZU-175), C (SZU-174), D ( SZU-147), E (SZU-176).
- CT26 in vivo anti-tumor
- Figure 58 shows in vivo anti-tumor (B16) activity effects of novel immunotargeting compounds: Veh (unadministered control), G (PD-L1 antibody), H (SZU-178), I (SZU-158-PD- L1), J (SZU-158-OX40), K (PD-1 antibody), L (SZU-158-PD-1).
- Figure 59 shows that JQ1 inhibits TLR7 agonist activity of SZU-101; SZU-119 retains the immunocytokine eliciting activity of TLR7 agonists.
- Figure 60 shows that JQ1 inhibits TLR7 agonist activity of SZU-101; SZU-119 retains the immunocytokine eliciting activity of TLR7 agonists.
- Figure 61 shows that SZU-119 retains CD274 (PD-L1) inhibitory activity of JQ1 on B16 cells.
- the "control” refers to a blank control.
- Figure 62 shows the effect of SZU-163 and SZU-166 activating immune cells to produce IFN- ⁇ .
- Figure 63 shows the effect of SZU-180 and SZU-136-miRNA21 activating immune cells to produce IFN- ⁇ .
- Figure 64 shows the anti-tumor (4T1) survival effect of PD-1 antibody, PD-L1 antibody, OX40 antibody and their SZU-158 conjugate, and SZU-178.
- Figure 65 shows the effect of PD-1 antibody, PD-L1 antibody, OX40 antibody and their SZU-158 conjugate and SZU-178 activating immune cells to produce IFN- ⁇ .
- Figure 66 shows the effect of SZU-181 activating immune cells to produce IFN- ⁇ .
- Figure 67 shows the effect of SZU-106, SZU-158, and SZU-160 activating immune cells to produce IFN- ⁇ , wherein the "control" is a PBS blank control.
- Figure 68 shows the effect of SZU-106, SZU-158, and SZU-160 activating immune cells to produce IL-6, wherein "control" is a blank control.
- Figure 69 is a graphical representation of the effect of TLR7 small molecule immunoagonists and human autologous miRNAs coupled to immunologically target interfering with agonist proteins to eliminate their associated pathogenic effects.
- Fig. 70 is a view showing the action of the immunotargeting compound in the present invention for removing a pathogenic target (protein) by an immunological route.
- the synthesis method of the compound of the present invention is exemplified as follows.
- the synthesis method exemplified may enlighten a person skilled in the art to carry out the synthesis of the novel compound of the present invention, but the synthesis of the novel compound in the present invention is not limited to the exemplified synthesis method.
- the SZU-030T obtained in the previous step was dissolved in 10 mL of anhydrous tetrahydrofuran (THF), and 484 mg of triphenylphosphine was added thereto under ice-cooling, and the mixture was stirred at room temperature overnight, and the reaction was monitored by LC-MS. After completion of the reaction, 20 mL of water was added, stirring was continued for 30 min, filtered under reduced pressure, washed twice with water and dried to yield s.
- THF anhydrous tetrahydrofuran
- the preparation method was the same as that of SZU-116 except that the SZU-017T was replaced by FITC to obtain a grass green semi-solid.
- the preparation method is the same as SZU-103-GSH except that SZU-138 is used instead of SZU-103, and glutathione is replaced by 2-dimethylaminoethanethiol to obtain a white solid.
- ESI-MS: m/z 562.2 [M +H] + .
- the same method can be used to prepare SZU-159, except that SZU138 is replaced by SZU-144 and 2-dimethylaminoethanethiol at room temperature for 24 hours to obtain SZU-159.
- Bromine was slowly added dropwise to the acetic acid solution of SZU-151. After stirring overnight, neutralized with NaHCO 3 and the reaction liquid. To the obtained viscous compound, a little ethanol is added. The remaining bromine was removed by adding a sodium thiosulfate solution. After suction filtration and drying of the obtained solid, a 10% NaOH solution was added, filtered again, and dried under reduced pressure. Purification by preparative liquid chromatography gave bromide.
- SZU-134 was dissolved in DMSO, equimolar NHS and EDCI were added, and after stirring for 10 minutes, equimolar amount of direct purple N (OX40 agonist) was added. The reaction was sealed at room temperature for 3 days. The reactant was added with 20 times of water, and the precipitated solid was filtered, stirred with 2N NaOH and 10 ° C for 30 minutes, filtered, and the filtrate was acidified to pH 1 with 2N hydrochloric acid to precipitate solid product SZU-169, yield 52%, MS (ESI) : m/z: [M+2Na] 1616.64.
- the a reactant was dissolved in a small amount of DMF, and a single equivalent of sodium azide was added thereto, and the reaction was stirred at room temperature for 24 hours. 10 times by volume of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure to give the product b in a yield of 90%.
- Afatinib 100 mg and 50 mg b were dissolved in 15 mL of DMF, and a trace amount of NaI was added thereto, and reacted at 60 ° C for 24 hours; 100 mL of n-butanol was added to the reaction mixture, and the mixture was distilled under reduced pressure for at least a volume (about 5 mL). After cooling to room temperature, 50 mL of ethyl acetate was added to give a solid product c, which was dried in vacuo to give EtOAc (EtOAc): m.
- EtOAc EtOAc
- SZU-158 5 mg was taken, dissolved in 0.5 mL of DMSO, equimolar NHS and EDCI were added, and stirred at room temperature for 4 hours.
- the mixed reaction solution was filtered through a filter to obtain a SZU-158-PD-1 coupling product, which was lyophilized to give a white solid SZU-158-PD-1, 18 mg.
- the immunocytokine activity of SZU-158-PD-1 is shown in Figures 58 and 65, and the antibody functions are shown in Figures 58, 64 and 65).
- SZU-158 5 mg was taken, dissolved in 0.5 mL of DMSO, equimolar NHS and EDCI were added, and stirred at room temperature for 4 hours.
- the mixed reaction solution was filtered through a filter to obtain a SZU-158-PD-L1 coupling product, which was lyophilized to give a white solid SZU-158-PD-L1, 15 mg.
- the immunocytokine activity of SZU-158-PD-L1 is shown in Figures 58 and 65, and the antibody functions are shown in Figures 58, 64 and 65).
- the new immunotargeting compound formed by the SZU-158 conjugated antibody can form a salt due to the dimethylamino group to form a salted positive charge, which is beneficial to improve the therapeutic effect and water solubility.
- Vemu-1 is a precursor of Vemurafenib and is available from WuXi PharmaTech.
- Vemu-1 Dissolve Vemu-1 in DMF, add 2 times mole of triethylamine, cool to 0 ° C, add 1 time mole of vinylsulfonyl chloride, stir the mixture slowly to room temperature for 8 hours, add 10 times volume of ice water to the mixture. Stir well for 1 hour, adjust the pH to 8 with saturated Na 2 CO 3 , precipitate a solid, filter, wash twice with water, and dry to give Vemu-2.
- 1 g of Vemu-2 was dissolved in 30 mL of DMF, 0.33 g of mercaptoethylamine was added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure to give crude EtOAc (EtOAc). Product: 0.98 g, yield 85%, MS (ESI): m/z: [M+1] 552.04.
- the Osimertinib intermediate was purchased from WuXi PharmaTech.
- SZU-160 3.5 mg was taken, dissolved in 0.5 mL of DMSO, equimolar NHS and EDCI were added, and stirred at room temperature for 4 hours.
- the mixed reaction solution was filtered through a filter to obtain a SZU-160-PD-L1 antibody coupling product solution; 2.5 mg of Erlotinib, 2 mg of sodium ascorbate and 2 mg of copper sulfate were added, and the mixture was stirred at room temperature for 12 hours, and the reaction solution was filtered.
- the membrane was filtered and lyophilized to obtain a white solid SZU-178 (i.e., SZU-178 coupled with the complex of erlotinib and PD-L1 antibody SZU-160-Erlotinib-PD-L1), 12 mg.
- SZU-115-PD-L1-targeted drug ie complex formed by SZU-115 coupled PD-L1 antibody and targeting drug
- the method of coupling the PD-L1 antibody was the same as in the preparation of SZU-178, and the click reaction method was the same as in the preparation of SZU-179, and SZU-180 was obtained.
- the resulting product can be used to treat AIDS.
- lymphocyte separation solution containing mouse lymphocyte separation solution, and filtered through a 0.22 ⁇ m filter to obtain a cell suspension. Lymphocytes were obtained by centrifugation. The removed lymphocytes were placed in a 15 mL centrifuge tube and 10 mL of 1640 complete medium was added and mixed. Centrifuge at 250 g for 10 min and discard the supernatant.
- Spleen lymphocytes inoculated in 24-well plates were stimulated with different concentrations of the SZU series of small molecule immunoagonists and novel immunotargeting compounds of the invention, and the 24-well plates were transferred to the incubator, and the supernatant was gently aspirated after 24 hours. Samples tested for Elisa. Concentrations and concentration gradients are determined by the needs of each assay sample.
- Blocking 200 ⁇ l of the diluted blocking solution was added to each well, sealed with plastic wrap, and sealed at room temperature for one hour. The plate was washed three times with PBST and patted dry.
- the supernatant samples obtained by stimulating the spleen lymphocytes with different concentrations of the drug were added to the corresponding wells, and three replicate wells were set for each sample, and blank control wells and negative control wells were additionally set and labeled accordingly.
- the 96-well microtiter plate with the standard and sample was sealed with plastic wrap and incubated for 2 hours at room temperature or overnight at 4 °C. The liquid in the plate was aspirated, and the plate was washed three times with PBST and patted dry.
- the detection antibody was diluted to the desired concentration with a dilution buffer, 100 ⁇ l was added to each well, and incubated for 1 hour at room temperature. The liquid in the plate was aspirated, washed five times with PBST, and patted dry.
- TMB 3,3',5,5'-tetramethylbenzidine
- Termination After the color development was completed, 50 ⁇ l of the stop solution was added to each well, and the stop solution was 1 mol/L H 2 SO 4 .
- Detection The 96-well microtiter plate after termination was placed in a full-wavelength microplate reader, and the absorbance value was read at a wavelength of 450 nm. Export the data, make a standard curve with software, and derive a linear regression equation. The concentration of immune cells (INF- ⁇ , IL-6, etc.) produced by the immune cells was calculated. Please refer to the attached figure for the specific experimental results.
- PBS blank controls, immuno agonists or novel immunotargeting compounds were administered separately.
- the dose to be administered is determined according to actual needs (effective, safe dose principle), and each substance is dissolved in a suitable solvent, each dose is 100 ⁇ L; each group is administered intraperitoneally.
- Each group was administered on the 7th, 15th, 22nd, and 29th day after the tumor was implanted; and the tumor size was periodically measured. Mice were euthanized when the tumor reached 1500 mm 3 or greater than 15% of body weight. Tumor suppression and survival results are shown in Figures 57, 58 and 64. It can be seen that the novel immunotargeting compound treatment group of the present invention has a markedly enhanced antitumor effect.
- the biological activity test methods of the novel small molecule immunoagonists and novel immunotargeting compounds of the present invention are not limited to the above test methods, and other related known or recognized activity test methods can also be used.
- the related activity diagrams in the present invention are not limited to the one illustrated method, and the illustrated method can enlighten those skilled in the art to realize the application effects of the novel small molecule immunoagonists and novel immunotargeting compounds in the present invention. .
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Abstract
Description
Claims (20)
- 式(I)的小分子免疫激动剂或其异构体或药学上可接受的盐:其中A 1表示O或C;A 2表示硝基、氨基、异氰酸酯基、亚烷基氨基、亚烷基异氰酸酯基或选自式(II)或式(III)的基团:其中R 1和R 2各自独立地表示(CH 2) p(NH) q,其中p为0、1或2,q为0、1或2;R 3表示O或S;R 4表示(CH 2) x(C=O) y(NH) z[(CH 2) 2O] r(CH 2) s(C=C) t,其中x为0至5的整数,y为0、1或2,z为0、1或2,r为0、1、2或3,s为0至5的整数且t为0、1或2,其中当s≠0且t=0时,(CH 2) s中靠近羰基的碳原子可以被选自以下的基团取代:-NHBoc、氨基、-NHFmoc、 或与另一碳原子形成双键;R 5表示羟基、烷氧基、羟胺基、乙烯基或选自以下的基团:其中*表示连接至碳原子的位点;其中排除选自以下的化合物:
- 权利要求1的式(I)的小分子免疫激动剂或其异构体或药学上可接受的盐:其中A 1表示O或C;A 2表示硝基、氨基、异氰酸酯基、C 1-C 6亚烷基氨基、C 1-C 6亚烷基异氰酸酯基或选自式(II)或式(III)的基团:其中R 1和R 2各自独立地表示(CH 2) p(NH) q,其中p为0或1,q为0或1;R 3表示O或S;R 4表示(CH 2) x(C=O) y(NH) z[(CH 2) 2O] r(CH 2) s(C=C) t,其中x为0至5的整数,y为0或1,z为0或1,r为0、1、2或3,s为0至5的整数且t为0或1,其中当s≠0且t=0时,(CH 2) s中靠近羰基的碳原子可以被选自以下的基团取代:-NHBoc、氨基、-NHFmoc、 或与另一碳原子形成双键;R 5表示羟基、C 1-C 6烷氧基、羟胺基、乙烯基或选自以下的基团:其中*表示连接至碳原子的位点;其中排除选自以下的化合物:
- 权利要求2的式(I)的小分子免疫激动剂或其异构体或药学上可接受的盐:其中A 1表示O或C;A 2表示硝基、氨基、异氰酸酯基、亚甲基氨基、亚甲基异氰酸酯基或选自式(II)或式(III)的基团:其中R 1和R 2各自独立地表示(CH 2) p(NH) q,其中p为0或1,q为0或1;R 3表示O或S;R 4表示(CH 2) x(C=O) y(NH) z[(CH 2) 2O] r(CH 2) s(C=C) t,其中x为0至5的整数,y为0或1,z为0或1,r为0、1、2或3,s为0至5的整数且t为0或1,其中当s≠0且t=0时,(CH 2) s中靠近羰基的碳原子可以被选自以下的基团取代:-NHBoc、氨基、-NHFmoc、 或与另一碳原子形成双键;R 5表示羟基、甲氧基、羟胺基、乙烯基或选自以下的基团:其中*表示连接至碳原子的位点;其中排除选自以下的化合物:
- 权利要求3的式(I)的小分子免疫激动剂,或其异构体或药学上可接受的盐,其为选自以下的SZU系列化合物或其药学上可接受的盐:SZU-104、SZU-105、SZU-107、SZU-108、SZU-109、SZU-110、SZU-111、SZU-112、SZU-113、SZU-115、SZU-118、SZU-120、SZU-127、SZU-128、SZU-129、SZU-131、SZU-132、SZU-133、SZU-134、SZU-135、SZU-136、SZU-137、SZU-138、SZU-139、SZU-140、SZU-142、SZU-143、SZU-144、SZU-145、SZU-149、SZU-158、SZU-159、SZU-160、SZU-161、SZU-162、SZU-163、SZU-166或SZU-171。
- 权利要求5的免疫靶向化合物或其药学上可接受的盐,其中所述小分子免疫激动剂为选自以下的SZU系列化合物或其药学上可接受的盐:SZU-102、SZU-104、SZU-105、SZU-106、SZU-107、SZU-108、SZU-109、SZU-110、SZU-111、SZU-112、SZU-113、SZU-115、SZU-118、SZU-120、SZU-127、SZU-128、SZU-129、SZU-131、SZU-132、SZU-133、SZU-134、SZU-135、SZU-136、SZU-137、SZU-138、SZU-139、SZU-140、SZU-142、SZU-143、SZU-144、SZU-145、SZU-149、SZU-158、SZU-159、SZU-160、SZU-161、SZU-162、SZU-163、SZU-166、SZU-171、SZU-101、SZU-103、SZU-114、SZU-117、SZU-122或SZU-130。
- 权利要求5的免疫靶向化合物或其药学上可接受的盐,其中所述TLA为选自以下的化合物:SZU-103-GSH、SZU-114-GSH、SZU-117-GSH、SZU-122-GSH、SZU-127-GSH、SZU-133-GSH、SZU-138-GSH或SZU-144-GSH。
- 权利要求5的免疫靶向化合物或其药学上可接受的盐,其中所述Tar选自以下的至少一种:Dasatinib,Imatinib,Saracatinib,Ponatinib,Nilotinib,Danusertib,AT9283Degrasyn,Bafetinib,kw-2449,nyp-bhg712,dcc-2036,GZD824.,GNF-2,PD173955,GNF-5,Bosutinib,Gefitinib,Erlotinib,Sunitinib,Ruxolitinib,Tofacitinib,Lapatinib,Vandetanib,Sorafenib,Sunitinib,Axitinib,Nintedanib,Regorafenib,Pazopanib,Lenvatinib,Crizotinib,Ceritinib,Cabozantinib,DWF,Afatinib,Ibrutinib,Niraparib,Palbociclib,B43,KU004,Foreinib,KRCA-0008,PF-06439015,PF-06463922,Canerlinib,GSA-10,GW2974,GW583340,W24002,CP-380736,D2667,Mubritinib,PD153035,PD168393,Pelitinib,PF-06459988,PF06672131,PF-6422899,PKI166,ReveromycinA, Tyrphostin 1,tyrphostin23,lyrphostin51,Tyrphostin,AG528,Tyrphostin,AG658,Tyrphostin,AG825,Tyrphostin,AG835,Tyrphostin,AG1478,Tyrphostin,RG13022,Tyrphostin,RG14620,B178,GSK1838705A,PD-161570,PD173074,SU-5402,Roslin2,Picropodophyllotoxin,PQ401,i-ome-tyrphostin,AG538,GNF5837,GW441756,Tyrphostin,AG879,DMPQ,jnj-10198409,PLX647,Trapidil,TyrphostinA9,Tyrhostin,AG370,Lestaurtinib,DMH4,Eldanamvcin,Genistein,Gw2580,HerbimycinA,Lavendustin,CMidostaurin,nvp-bhg712,PD158780,pd-166866,pf-0627334,PP2,RPL,SU11274,SU5614,Symadex,Tyrphostin,AG34,Tyrphostin,AG974,Tyrphostin,AG1007,UNC2881,Honokiol,SU1498,SKLB1002,cp-547632,jk-p3,KRN633,sc-1,ST638,SU 5416,Sulochrin,Tyrphostin,SU1498,rociletinib,Dacomitinib,Tivantinib,Neratinib,Masitinib,Vatalanib,Icotinib,xl-184,osi-930,AB1010,Quizartinib,AZD9291,Tandutinib,HM61713,Brigantinib,Vemurafenib(plx-4032),Semaxanib,AZD2171,Crenolanib,Damnacanthal,Fostamatinib,Motesanib,Radotinib,osi-027,Linsitinib,BIX02189,PF-431396,PND-1186,PF-03814735,PF-431396,sirollmus,temsirolimus,everolimus,deforolimus,Zotarolimus,BEZ235,INK128,Omipalisib,AZD8055,MHY1485,PI-103,KU-0063794,ETP-46464,GDC0349,XL388,WYE-354,WYE-132,GiSK1059615,WAY-600,PF-04691502,wYE-687,PP121,BGT226,AZD2o014,PP242,CH5132799,P529,GDC0980,GDC-0994,XMD82,Ulixertinib,FR180204,SCH772984,Trametinib,PD184352,PD98059,Selumetinib,PD325901,U0126,Pimasertinib,tak-733,AZD8330,Binimetinib,PD318088,SL-327,Refametinib,gdc-0623,Cobimetinib,b1-847325,Adaphostin,GNF2,PPYA,aim-100,ASP 3026,LFM,Toceranib,JQ1,Niraparib,Fuzuopali,palbociclib,ARS-853,ARS-1620,Chlorazol-violet N(直接紫N),miRNA-21,PreS,Zidovudine,Lenvatinib,LY-364947,ARS-1620或Reparixin,EGFR抑制剂,TKI,BRD4抑制剂,KRAS通路相关靶点抑制剂,BRAF抑制剂,BTK抑制剂,PARP抑制剂,PD-L1抑制剂(包括抗体、小分子),PD-1抑制剂(包括抗体、小分子),OX40激动剂(包括 抗体、小分子),CD122抗体,CD3抗体,CD19抑制剂,CD20抑制剂,MUC1抑制剂,MUC16抑制剂,CDK4/6抑制剂,TGF-β抑制剂,CXCR抑制剂,CCL和CXCL趋化因子抑制剂以及miRNA。
- 权利要求9的免疫靶向化合物或其药学上可接受的盐,其中所述Tar选自如下的至少一种:TKI、EGFR抑制剂、KRAS抑制剂、BRAF抑制剂、BTK抑制剂、BRD4抑制剂、PD-L1抑制剂、PD-1抑制剂、OX40激动剂、PARP抑制剂或CDK4/6抑制剂。
- 权利要求5的免疫靶向化合物或其药学上可接受的盐,其中所述其他基团包括酰胺、烷氧键、烷硫键、取代胺基、季胺盐、cilck反应形成的杂环、可用蛋白酶解离的氨基酸基团、脲基团或硫脲基团。
- 权利要求5的免疫靶向化合物或其药学上可接受的盐,其为选自以下的SZU系列化合物或其药学上可接受的盐:SZU-116、SZU-119、SZU-124、SZU-125、SZU-146、SZU-147、SZU-168、SZU-169、SZU-174、SZU-175、SZU-176、SZU-177、SZU-178、SZU-179、SZU-180、SZU-181、SZU-158-PD-L1、SZU-158-OX40、SZU-158-PD-1或SZU-136-miRNA21。
- 权利要求1至4中任一项的式(I)的小分子免疫激动剂或其异构体或药学上可接受的盐,化合物SZU-101、SZU-103、SZU-114、SZU-117、SZU-122和SZU-130以及权利要求5至13中任一项的免疫靶向化合物或其药学上可接受的盐在制备参与免疫调节的药物中的用途。
- 权利要求1至4中任一项的式(I)的小分子免疫激动剂或其异构体或药学上可接受的盐,化合物SZU-101、SZU-103、SZU-114、SZU-117、SZU-122和SZU-130以及权利要求5至13中任一项的免疫靶向化合物或其药学上可接受的盐在制备抗肿瘤药物、抗病毒药物和靶向清除蛋白的药物中的用途。
- 化合物SZU-136-miRNA21及其类似物在制备免疫靶向RNA的药物中 的用途。
- 化合物SZU-179、SZU-180和SZU-181在制备抗艾滋病和抗乙肝的药物中的用途。
- 化合物SZU-161和SZU-162在测定小分子免疫激动剂偶联蛋白药物和细胞的偶联度中的用途。
- 化合物SZU-116和SZU-124在观察研究蛋白或靶向药的细胞吸收和体内分布中的用途,其中化合物SZU-116和SZU-124与蛋白或者靶向药偶联。
- 化合物SZU-114、SZU-117、SZU-122、SZU-127、SZU-133、SZU-138、SZU-143在制备具有免疫靶向双功能的药物中的用途,其中化合物SZU-114、SZU-117、SZU-122、SZU-127、SZU-133、SZU-138、SZU-143与靶向药或抗体偶联。
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CN115192726A (zh) | 2022-10-18 |
US20210038605A1 (en) | 2021-02-11 |
WO2019192454A9 (zh) | 2020-01-16 |
JP2021519792A (ja) | 2021-08-12 |
CN108379591B (zh) | 2022-03-29 |
US20230148436A2 (en) | 2023-05-11 |
CN108379591A (zh) | 2018-08-10 |
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