WO2019095455A1 - Dérivés de pyridopyrimidine ou sels de ceux-ci, leur procédé de préparation, composition pharmaceutique et utilisations correspondantes - Google Patents

Dérivés de pyridopyrimidine ou sels de ceux-ci, leur procédé de préparation, composition pharmaceutique et utilisations correspondantes Download PDF

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WO2019095455A1
WO2019095455A1 PCT/CN2017/114611 CN2017114611W WO2019095455A1 WO 2019095455 A1 WO2019095455 A1 WO 2019095455A1 CN 2017114611 W CN2017114611 W CN 2017114611W WO 2019095455 A1 WO2019095455 A1 WO 2019095455A1
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compound
tumor
formula
pharmaceutically acceptable
acceptable salt
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廖学斌
贺磊
王志松
高燕
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清华大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of Toll-like receptors (TLRs), and in particular to pyridopyrimidine derivatives or salts thereof for use as TLR7 and/or TLR8 agonists, and preparation, pharmaceutical compositions and uses thereof For the preparation of a medicament for treating infectious diseases, respiratory diseases, immune related diseases, viral diseases or tumors.
  • TLRs Toll-like receptors
  • pyridopyrimidine derivatives or salts thereof for use as TLR7 and/or TLR8 agonists
  • preparation, pharmaceutical compositions and uses thereof For the preparation of a medicament for treating infectious diseases, respiratory diseases, immune related diseases, viral diseases or tumors.
  • Toll-like receptors are a family of receptors that are relatively conservative in evolution, including at least 13 members.
  • Ten species (TLR1-10) were found in humans, and TLRI, TLR2, TLR4, TLR5, TLR6, and TLR10 were expressed on the cell surface.
  • TLR3, TLR7, TLR8, and TLR9 are expressed in cells, mainly for monitoring and recognizing viral nucleic acids, TLR3 recognizes double-stranded RNA, and TLR7 and TLR8 recognize single-stranded RNA, and TLR9 recognizes unmethylated CG Coenzyme I regulates the response of bacterial DNA to certain viruses.
  • TLRs can specifically recognize pathogen-associated molecular patterns (PAMP), play an important role in both innate and acquired immunity, and are a bridge between natural immunity and acquired immunity.
  • PAMP pathogen-associated molecular patterns
  • TLR7 recognizes a single-stranded RNA that binds to a virus or a synthetic small-molecule steroid, recruits a specific adaptor protein, activates a series of signal cascades, initiates a high-level systemic adaptive immune response, and kills the virus. The cells thus completely eliminate the virus.
  • TLR7 agonists have been used to treat chronic viral infections such as hepatitis B and hepatitis C.
  • TLR7 agonists can induce more rapid and effective immune protection as an influenza vaccine adjuvant.
  • TLR7 agonists can not only directly stimulate pDC secretion of IFN- ⁇ , but also enhance the co-stimulatory and antigen-presenting ability of pDC.
  • Activated pDC promotes the proliferation of CD4+ T cells, further activates CD8+ T cells, kills Tumor cells, therefore, the role of TLR7 agonists as immunoadjuvants in the body recognition and killing of tumors is also gradually gaining attention.
  • the present invention provides a pyridopyrimidine derivative or a salt thereof, which is useful as a TLRs receptor agonist, has the characteristics of good selectivity, high activity, and good safety, and provides preparation of a pyridopyrimidine derivative or a salt thereof. Methods and pharmaceutical compositions and uses thereof.
  • the pyridopyrimidine derivative or a salt thereof provided by the present invention has a structural formula represented by the formula (I):
  • L represents a linking group which is absent or is a C 1 -C 6 alkylene group or a C 1 -C 6 alkenylene group, wherein the group may be optionally substituted by a C 1 -C 4 alkyl group;
  • R 1 represents Or halogen, wherein R 3 is selected from the group consisting of H, halogen, aminomethylene, (substituted amino) methylene or quaternary ammonium salts thereof, heterocyclic substituted methylene, azidomethylene, phosphonic acid methylene , diethyl phosphonate methylene, methoxy acyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CF 3 -, -COOH, -COOCH 3 , -CN, HO-CH 2 ;
  • R 2 represents -YR 4 , wherein Y represents N, S, O, R 4 represents C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and Y and R 4 in -YR 4 may also form a heterocyclic ring.
  • the heterocyclic ring may be morpholine or piperidine;
  • the substituted amino group may be dimethylamino, Leu-amino, Leu Ala Ala Asn-amino, (trifluoromethyl)methyleneamino, methylamino;
  • the quaternary ammonium salt is a quaternary ammonium hydrochloride
  • Halogen is fluorine or chlorine.
  • the L is a C 1 -C 6 alkylene group, preferably -CH 2 -.
  • the R 1 is
  • the R 2 is -NR 4 .
  • the compound of formula (I) is selected from the group consisting of
  • the pharmaceutically acceptable salts include hydrochlorides, sulfates, phosphates, carboxylates.
  • the nitrogen-containing organic compound is an alkylamine, piperidine, alkoxyamine, morpholine, preferably n-butylamine;
  • the sulfur-containing organic compound is an alkylthiol, preferably n-butyl mercaptan; and
  • the oxygen-containing organic compound is an alkyl group.
  • Alcohol preferably n-butanol.
  • the substituted benzyl bromide is preferably 3-methylbenzyl bromide.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a pyridopyrimidine derivative of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  • the pharmaceutically acceptable excipients include, but are not limited to, sweeteners, diluents, stabilizers, emulsifiers, dispersants, preservatives, colorants, flavor enhancers, surfactants, wetting agents, disintegrants , suspending agents, isotonic agents, solvents.
  • the pharmaceutical composition of the present invention can be prepared into tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels.
  • the route of administering the pyridopyrimidine derivative of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof includes, but is not limited to, oral, rectal, transmucosal, topical, transdermal, inhalation, parenteral , sublingual, intravaginal, intranasal, intramuscular, subcutaneous, intravenous administration.
  • the dose to be administered is 0.1 to 0.2 mg/kg, preferably 0.1 mg/kg, once a day.
  • the concentration of the agonist in the composition is from 0.1 to 0.2 mg/kg, preferably the concentration of the agonist is 0.1 mg/kg.
  • composition further comprises at least one additional therapeutic agent selected from the group consisting of a chemotherapeutic agent, an immunotherapy, an anti-angiogenic agent, a cytokine, a hormone, a polynucleotide, an antibody, an immunologically active fragment.
  • a chemotherapeutic agent selected from the group consisting of a chemotherapeutic agent, an immunotherapy, an anti-angiogenic agent, a cytokine, a hormone, a polynucleotide, an antibody, an immunologically active fragment.
  • the antibody includes, but is not limited to:
  • MDX-010 (Medarex, NJ, is a humanized anti-CTLA-4 antibody; SYNAGIS (MedImmune), a humanized anti-respiratory syncytial virus (RSV) Monoclonal antibody; HERCEPTIN (trastuzumab) (Genetech, California), which is a humanized anti-HER2 monoclonal antibody; humanized anti-CD18F(ab')2 (Genentech) CDP860, which is a humanized anti-CD18F(ab')2 (Celltech, UK); PRO542, which is an anti-HIVgp120 antibody fused to CD4 (Projenik/Gianzan Transgenic Company ( Progenics/Genzyme Transgenics)); Ostavir, a human anti-hepatitis B virus antibody (ProteinDesignLab/Novartis); PROTOVIRTM, a humanized anti-CMV IgG1 antibody (protein design laboratory / Novartis MAK-195 (SEGARD), which is mouse
  • the above antibodies are preferably a PD-1 antibody, a TIM-3 antibody, a PD-1 antibody, and a TIM-3 antibody.
  • the therapeutic agent may be an anticancer agent, including but not limited to: acevicin, arubicin, apodazole hydrochloride, acronin, adoline, adileuxolin, Hexamethyl melamine, ampomycin, ammine acetate, aminoglutethimide, ampicillin, anastrozole, aflatoxin, asparaginase, triamcin, azacitidine, azatidine , azomycin, bamastat, benzozide, bicalutamide, chlorpyrifos hydrochloride, dinifadil diformate, bicex, bleomycin sulfate, buquina sodium, Bromide, busulfan, actinomycin C, caprotestosterone, carbamide, carbemide, carboplatin, carmustine, carbofurin hydrochloride, dextromethorphan, siadifen Glutamate, chlorambucil, sirolimus, cis
  • anticancer agents include, but are not limited to, 5-ethynyl uracil, abiraterone, arubicin, acyl fulvene, adenocyclopentanol (adecypenol), adoline, aldileukin, ALL -TK antagonist, hexamethylene melamine, amoxirace, 2,4 dichlorophenoxyacetic acid (amidox), amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, ana rhopti Azole, andrographolide, angiogenesis inhibitor, antagonist D, antagonist G, Anrelix, anti-dorsalization protein 1, antiandrogen, prostate cancer, antiestrogens, antineoplaston , antisense oligodeoxynucleotide, glycine afedromycin, apoptosis gene modulator, apoptosis regulator, depurinated nucleic
  • a method of increasing a positive immune response in a body comprising: administering a therapeutically effective amount to a system or individual in need thereof A pyridopyrimidine derivative of the formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutical composition, or a pharmaceutical composition as described above, or a compound prepared according to the above method, thereby modulating TLR7 and/or TLR8.
  • a method of enhancing the effect of chemotherapy comprising administering to a system or individual in need thereof a therapeutically effective amount of a chemotherapeutic agent, simultaneously or subsequently, a therapeutically effective amount of a pyridopyrimidine derivative of formula (I) or a pharmaceutically acceptable salt thereof.
  • a method of enhancing immunotherapy comprising: administering to a system or individual in need thereof a therapeutically effective amount of a pyridopyrimidine derivative of formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutical composition, or a combination thereof
  • a pyridopyrimidine derivative of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition, or a combination thereof
  • Compounds, or compounds prepared according to the methods described above, are simultaneously or subsequently introduced into a system or individual into a chimeric antigen receptor T cell (CAR-T).
  • CAR-T chimeric antigen receptor T cell
  • Another aspect of the invention provides a method of treating or pre-paying a disease in a mammal comprising: administering to a system or individual in need thereof a therapeutically effective amount of a pyridopyrimidine derivative of formula (I) or a pharmaceutically acceptable salt thereof , pharmaceutical composition.
  • Another aspect of the invention provides a method of treating a cell proliferative disorder comprising: administering to a system or individual in need thereof a therapeutically effective amount of a pyridopyrimidine derivative of formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutical combination thereof
  • the cell proliferative disorder is lymphoma, osteosarcoma, melanoma, or a tumor of the breast, kidney, prostate, colorectum, thyroid, ovary, pancreas, neurons, lung, uterus or gastrointestinal tract.
  • the present invention provides a pyridopyrimidine derivative of the formula (I) or a pharmaceutically acceptable salt thereof for use as a TLRs receptor agonist for the preparation of a medicament for treating a disease or condition associated with TLRs activity .
  • TLRs are TLR7 and/or TLR8.
  • a pyridopyrimidine derivative of the formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for the preparation of a pharmaceutical preparation for up-regulating inflammation and cytokine-mediated pathway, T cell activation, withering
  • the pharmaceutical preparation increases the number of CD8+ T cells.
  • the pharmaceutical preparation increases the ratio of CD8+ T cells/Treg cells.
  • the pharmaceutical preparation enhances PDL-1 expression.
  • the pharmaceutical preparation increases the level of interleukin 2 and/or increases the level of interferon gamma and/or decreases the level of interleukin 10.
  • a pyridopyrimidine derivative of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof for the preparation of a downregulated Wnt signaling pathway formulation.
  • the expression level of ⁇ -catenin protein is down-regulated.
  • a pyridopyrimidine derivative of the formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for influencing macrophages preferably, affects the expression of mRNA levels of genes such as Il1b, Il6, Il12b, Tnf, Ifnb1, Cxcl1, Cxcl10 and Il10.
  • a pyridopyrimidine derivative of the formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above for use in the manufacture of a medicament for treating an infectious disease, an immune disease, a viral disease or a tumor application.
  • the above diseases are preferably asthma, cancer, HIV, HBV.
  • TNT and infectious diseases Petular immune activation in chronic origin interferons, acts via an "Tell-like receptor.
  • Antiviral Ther., 2012, 17, 4, P657-P667 A new era of targeting the ancient gatekeepers of the immune system: toll-like agonists in the treatment of allergic rhinitis and asthma.
  • virus Disease (.A nucleoside analog, 7-thia-8-oxoguanosine stimulates proliferation of thymocytes in vitro. Immunol.
  • TLR7 adjuvant activity of 3M-052 An imidazoquinoline designed For local activity without systemic cytokine induction.Vaccine,2011,29,33,P5434-P5442;Effective Innate and Adaptive Antimelanoma Immunity through Localized TLR7/8Activation,Immunol.,2014,193,9,P4722-P4731
  • TLR7 agonist provided by the present invention is verified by Indicated for treatment of the above diseases.
  • the above immune diseases are autoimmune diseases, including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, polymyositis, vasculitis, Wei Gina granuloma, sarcoidosis, ankylosing spondylitis, Wright syndrome, psoriatic arthritis, Behcet syndrome, etc.
  • the above viral diseases include, but are not limited to, Ebola virus disease, anthrax disease, condyloma acuminata, simple warts, plantar warts, respiratory syncytial virus (RSV), hepatitis B, hepatitis C, dengue virus, herpes simplex Viruses (eg HSV-I, HSV-II, CMV or VZV), susceptible soft palate, vaccinia, smallpox, lentivirus, human immunodeficiency virus (HIV), human papillomavirus (HPV), cytomegalovirus ( CMV), varicella-zoster virus (VZV), rhinovirus, enterovirus, adenovirus, influenza, parainfluenza, mumps virus, measles virus, papovavirus, flavivirus, retrovirus, arenavirus ( For example, LCM, Junin virus, Machupo virus, Guanarito virus and Lassa fever) and fibrillar virus (such as Ebola
  • Such tumors include, but are not limited to, human sarcoma and carcinoma, such as fibrosarcoma, myoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovial tumor , mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, papillary adenocarcinoma, Cyst adenocarcinoma, medullary carcinoma, bronchial carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryo
  • the tumor is colon cancer, bladder cancer, melanoma, meningioma, lung cancer, or pancreatic cancer.
  • Intravesical Toll-like receptor 7agonist R-837 Optimization of its formulation in an orthotopic mouse model of bladder cancer [J].
  • Melanoma Effectivee Innate and Adaptive Antimelanoma Immunity through Localized TLR7/8Activation. J.
  • a pyridopyrimidine derivative of the formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof for the preparation of a medicament for preventing tumor recurrence.
  • the pharmaceutical composition can cause persistent systemic immune memory to prevent recurrence.
  • the present invention has the following beneficial effects:
  • TLRs Toll-like receptors
  • the combination with PD-1 and Tim-3 antibodies can effectively enhance the anti-tumor effect of each other.
  • Combined medication group from the whole body The immune status enhances the body's immune response level and promotes the immune system's killing of the tumor.
  • “Pharmaceutically acceptable” means a material that does not adversely affect biologically or otherwise, for example, the material may be incorporated into a pharmaceutical composition for administration to a patient without causing any adverse biological effects or Any other ingredients in the composition interact in a detrimental manner.
  • pharmaceutically acceptable is used to mean a pharmaceutical carrier or excipient, it is meant that the carrier or excipient meets the required standards for toxicological and production testing or is included in the US Food and Drug Administration. A guide to inactive ingredients.
  • combination or “pharmaceutical combination” as used herein, refers to a product obtained by mixing or combining more than one active ingredient and comprising a combination of fixed and non-fixed combinations of the active ingredients.
  • TLR disease or "disease or condition associated with TLR activity” refers to any disease state associated with a toll-like receptor.
  • Figure 1 is an EC50 assay of agonist D018 in accordance with the present invention.
  • Figure 2 is a graph showing the growth of tumor volume in accordance with the present invention.
  • Figure 3 is a graph showing tumor volume of mice in each group of tumors on day 34 according to the present invention.
  • Figure 4 is a graph showing the detection of infiltrating lymphocytes in tumor tissues according to the present invention.
  • Figure 5 is a graph showing the number of CD 8+ T lymphocytes in each experimental group according to the present invention.
  • Figure 6 is a graph of the ratio of CD 8+ T/Treg ratios for each experimental group in accordance with the present invention.
  • Figure 7 is a graph showing the expression of PDL-1 in each experimental group according to the present invention.
  • Figure 8 is a graph showing the effect of secretion of cytokines in the serum of mice of each experimental group according to the present invention.
  • Figure 9 is a graph showing the effect of agonist D018 on the secretion of cytokines in macrophages according to the present invention.
  • Figure 10 is a graph showing the expression level of candidate genes by RT-PCR according to the present invention.
  • Figure 11 is a graph showing the expression of CCl4 and ⁇ -catenin by IHC according to the present invention.
  • Figure 12 is a graph showing the survival of tumors of different experimental groups of tumors in accordance with the present invention.
  • Figure 13 is a graph showing the effect of a combination according to the present invention on immune memory.
  • Figure 14 is a graph showing growth of tumor volume in combination with antibody PD-1 and TIM3 in accordance with the present invention.
  • Figure 15 is a graph showing the results of tumor inhibition experiments of Ag104Ld mice according to the present invention.
  • Figure 16 is a flow chart showing the infiltration of lymphocytes CD4T+ cells, CD8+ T cells and Treg cells in Ag104Ld mouse tumor tissue according to the present invention.
  • Figure 17 is a flow cytometric diagram of DC11 of CD11c+CD103+ in Ag104Ld mouse tumor tissue according to the present invention.
  • Figure 18 is a flow cytometric diagram of central memory type T cells in tumor tissue of Ag104Ld mice according to the present invention.
  • the starting materials and reagents employed in the present invention are all commercially available, and suppliers include, but are not limited to, Aldrich Chemical Company, Lancaster Synthesis Ltd. Among them, dimethylformamide, tetrahydrofuran and dioxane are all ultra-dry solvents purchased from the company, and stored in a glove box. Dichloromethane and acetone are separately taken from the solvent purification system, all for the water. The sensitive reaction glassware was first dried in an oven at 100 °C. The materials and reagents used without further processing are used directly unless otherwise stated.
  • the preparation method of the compound 3, the steps include:
  • the preparation method of the compound N21, the steps include:
  • the preparation method of the compound N23 and the compound N25, the steps include:
  • the compound 8 prepared in Example 2 was used as a raw material, and under a nitrogen atmosphere, a compound 8 (125.9 mg, 0.5 mmol) was dissolved in 5 mL of dry tetrahydrofuran under a nitrogen atmosphere, and 2-methoxybenzyl bromide was sequentially added. (150.8 mg, 0.75 mmol), zinc powder (98.1 mg, 1.5 mmol) and Ni(PPh3)2Cl2 (138.8 mg, 0.05 mmol), stirred at room temperature for 24 hours, concentrated under reduced pressure, silica gel column chromatography The reaction formula is:
  • the compound 8 prepared in Example 2 was used as a raw material, and under a nitrogen atmosphere, a compound 8 (125.9 mg, 0.5 mmol) was dissolved in 5 mL of dry tetrahydrofuran under a nitrogen atmosphere, and 4-methoxybenzyl bromide was sequentially added. (150.8mg, 0.75mmol), zinc powder (98.1mg, 1.5mmol) and Ni(PPh3)2Cl2 (138.8mg, 0.05mmol), stirred at room temperature for 24 hours, concentrated under reduced pressure, and obtained by silica gel column chromatography for:
  • the preparation method of the compound N26, the steps include:
  • the compound 8 prepared in Example 2 was used as a raw material, and under a nitrogen atmosphere, a compound 8 (125.9 mg, 0.5 mmol) was dissolved in 5 mL of dry tetrahydrofuran in a 25 mL sealed tube, followed by the addition of 2 -trifluoromethyl bromide.
  • Benzyl (0.75 mmol) zinc powder (98.1 mg, 1.5 mmol) and Ni(PPh3)2Cl2 (138.8 mg, 0.05 mmol) were stirred at room temperature for 24 hr.
  • the preparation method of the compound N32, the steps include:
  • the compound 8 prepared in Example 2 was used as a raw material, and under a nitrogen atmosphere, a compound 8 (125.9 mg, 0.5 mmol) was dissolved in 5 mL of dry tetrahydrofuran under a nitrogen-protected sealed tube, followed by the addition of 4-bromobenzylbenzoic acid.
  • the ester (0.75 mmol), zinc powder (98.1 mg, 1.5 mmol) and Ni(PPh3)2Cl2 (138.8 mg, 0.05 mmol) were stirred at room temperature for 24 hours, concentrated under reduced pressure and purified by silica gel column chromatography. :
  • the preparation method of the compound N33, the steps include:
  • the compound 8 prepared in Example 2 was used as a raw material, and under a nitrogen atmosphere, a compound 8 (125.9 mg, 0.5 mmol) was dissolved in 5 mL of dry tetrahydrofuran under a nitrogen atmosphere, and then 3-bromobenzylbenzoic acid was sequentially added.
  • the ester (0.75 mmol), zinc powder (98.1 mg, 1.5 mmol) and Ni(PPh3)2Cl2 (138.8 mg, 0.05 mmol) were stirred at room temperature for 24 hours, and concentrated under reduced pressure.
  • the preparation method of the compound N29, the steps include:
  • the compound 8 prepared in Example 2 was used as a raw material. Under a nitrogen atmosphere, a compound 8 (125.9 mg, 0.5 mmol) was dissolved in 5 mL of dry tetrahydrofuran under a nitrogen atmosphere, and then 3-bromobenzylbenzoic acid (0.75) was sequentially added. Mg), zinc powder (98.1 mg, 1.5 mmol) and Ni(PPh3)2Cl2 (138.8 mg, 0.05 mmol), stirred at room temperature for 24 hours, concentrated under reduced pressure and purified by silica gel column chromatography.
  • the preparation method of the compound N10, the steps include:
  • the preparation method of the compound N01, the steps include:
  • Example 8 The compound N10 obtained in Example 8 was used as a raw material, dissolved in 5 mL of dry tetrahydrofuran, and dimethylamine hydrochloride (2.5 mmol) and potassium carbonate (207 mg, 1.5 mmol) were added, and the reaction mixture was stirred at room temperature for 12 hours. Concentrate The mixture was extracted with DCM/H2O, and the organic layer was combined, dried over anhydrous sodium sulfate, and concentrated.
  • the preparation method of the compound N02, the steps include:
  • Example 8 1 ml of a 4 M hydrochloric acid dioxane solution was placed, and the compound N10 (72.9 mg, 0.2 mmol) obtained in Example 8 was added, stirred, and a white solid was precipitated, filtered, and recrystallized to give white crystal compound N02.
  • the preparation method of the compound N12, the steps include:
  • the preparation method of the compound N14, the steps include:
  • the preparation method of the compound N35, the steps include:
  • the preparation method of the compound N37, the steps include:
  • the preparation method of the compound N16 includes the following steps:
  • the preparation method of the compound N40 comprises the steps of: taking a 25 ml sealed tube, and loading a compound 5 (125.9 mg, 0.5 mmol), (1-bromoethyl)benzene (102 mg, 0.75 mmol), and zinc powder (98.1 mg) in a glove box. , 1.5mmol), Ni(PPh3)2Cl2 (32.7mg, 0.05mmol) and THF (5mL, 0.1M), without special order; the reaction is stirred at room temperature for 24h, and purified by silica gel column chromatography to give product light yellow solid N40
  • the formula is:
  • the preparation method of the compound N42, the steps include:
  • the preparation method of the compound S01, the steps include:
  • the preparation method of the compound O01, the steps include:
  • HEK-Blue TM hTLR7 HEK-Blue TM hTLR8 and control HEK-Blue Null2-k cells culture and detection reagents: DMEM (4.5g / l glucose), bovine serum FBS, streptomycin (50 ⁇ g / ml) Penicillin (50 U/ml) Blasticidin (10 mg/ml), ZeocinTM (10 mg/ml), Normocin (50 mg/ml), HEK-BlueTM Detection.
  • Basic medium DMEM + 10% FBS + streptomycin + penicillin + Normocin (100 ⁇ g / ml)
  • Cell preparation The frozen cells were quickly placed in a 37 ° C water bath, shaken occasionally, and completely thawed in 1 minute; the cells were transferred to 15 ml of pre-warmed basal medium and resuspended; 1000 r / min, centrifuged for 5 min.
  • HEK-BlueTMhTLR7 or HEK- BlueTMhTLR8 100 ⁇ g/ml Zeocin+Blasticidin (30 ⁇ g/ml), HEK-Blue Null2-k: 100 ⁇ g/ml Zeocin; change the solution twice a week; when the amount of cells reaches 70%-80%, gently pat the cells with PBS Fall off.
  • Activity detection step add 20 ⁇ l sample per well in a 96-well plate (set duplicate wells); add 20 ⁇ l positive control (eg: INF- ⁇ , 100 ng/ml); add 20 ⁇ l negative control (eg ddH2O); gently wash the cells with 5-10 ml PBS (T75 flask) preheated in advance; add 2-5 ml PBS (T75 flask) to culture Put the bottle back in the incubator for 1-2min, gently tap to make the cells fall off; cell count, not centrifugation; HEK-Blue hTLR cell volume is about 220,000/ml, 180 ⁇ l per well (about 40,000 cells), HEK-Blue The amount of Null2-k cells is about 280,000/ml, 180 ⁇ l per well (about 50,000 cells); resuspend the cells with HEK-BlueTM to adjust the number of cells, and the incubation time is too long to avoid the background being too dark or false positive; The °C incubator was cultured for 6-16 h
  • the concentration for 50% of maximal effect refers to the concentration that causes 50% of the maximum effect.
  • the experimental results showed that the half-maximal effect concentration of R848 was mTLR7 (75 nM), hTLR (773 nM) and the TLR agonist D018 (compound number N01) of the present invention: mTLR7 (33 nM), hTLR (15 nM) (see Fig. 1), EC50 Very good response to the efficacy of agonists, the smaller the value, the higher the efficacy.
  • MC38 intestinal cancer cells were used, and MC38 was cultured in DMEM medium containing 10% FBS, and cultured in an incubator at 5% CO 2 at 37 °C.
  • Conventional passage was digested with trypsin 0.25% Trypsin-EDTA (GIBCO: 25200-056) for 1-3 min.
  • the cell passage ratio was 1:3, and the cell density was less than 80% passage.
  • the cells were changed 2-3 times a week. The cells were passaged 3 days before the tumor was implanted, and a new culture medium was replaced one day before the injection.
  • 1 x 106 MC38 cells with a survival rate of 80% were injected subcutaneously into the right side of 6-8 week old female C57BL/6 mice.
  • the tumor size of the PD-1+D018 group was much smaller than that of the other groups.
  • the above data show that the agonist D018 and R848, PD-1 antibodies have inhibitory effects on tumors. Among them, agonist D018 has a better therapeutic effect on tumors than the agonist group R848 and PD-1 antibody groups, especially PD.
  • the tumor volume was maintained at a very low level after the combination of -1 and D018, and was significantly smaller than the other groups, indicating that PD-1+D018 had the best antitumor effect.
  • the tumor volume has been in slow growth or even growth arrest since the administration, so we believe that the antitumor effect of D018 is dose-dependent between 10-25 ⁇ g.
  • the D018-administered group had better antitumor effect and dose-dependent, indicating that the drug efficacy of the TLR7 agonist was significantly better than that of the commercial R848.
  • Tumor tissue infiltrating lymphocytes are composed of various immune cells (CD4+ T cells, CD8+ T cells, NK cells, NKT cells, etc.) and play a key role in tumor immunity.
  • D018 exert antitumor immunity mechanisms
  • the single-cell suspension fraction was subjected to flow staining of four colors of FITC-anti-CD4 antibody, labeled PE-FOXP3 antibody, labeled percp-anti-CD8 antibody, and labeled APC-anti-CD25 antibody, and the tumor was analyzed by flow cytometry.
  • Infiltrating lymphocyte components such as CD4+ T cells, CD8+ T cells, and Treg cells. Flow detection display (see Figure 4 for details).
  • CD8+ T lymphocytes also known as cytotoxic T lymphocytes (CTLs)
  • CTLs cytotoxic T lymphocytes
  • CD4+ T cells we set the number of CD4+ T cells in each mouse to 10,000, thus homogenizing each sample, and analyzing the number of CD8+ T cells in each group of PD-1+D018 (25 ⁇ g) and PD-1+R848 ( The number of CD8+T in the tumor tissue of the 25 ⁇ g group was significantly increased compared with the other groups (Fig.
  • CD8+ T cells are the key effector cells in tumor immunotherapy, and the number of them directly determines the intensity and prognosis of tumor immunity in mice. From the results, it can be seen that the effects of ⁇ PD-1 and D018 alone have a limited effect on the number of CD8+ T cells, but the combination of the two can significantly improve this state.
  • TLR7 can enhance the number of initial T cells and enhance Its exposure to mouse tumor antigens, but for some reason these T cells are rapidly inactivated, and when we add ⁇ PD-1 to mice, it can significantly prolong the number of effector T cells, so the combination of the two is greatly It improves the immune microenvironment of mouse tumors and enhances the immune rejection of tumors in mice.
  • the ratio of CD 8+T/Treg in the tumor tissues of PD-1+D018 (25 ⁇ g) group, PD-1+R848 (10 ⁇ g) group and PD-1+R848 (25 ⁇ g) group was higher (Fig. 6), and these three groups
  • the tumor growth rate in mice was also significantly slowed down.
  • effector T cells there are some inhibitory regulatory T cells, such as Treg cells.
  • Treg cells The current research shows that the immune microenvironment of tumors can not only look at the number of effector T cells, but also the microenvironment.
  • the ratio of medium effect T cells to Treg cells, such as increased ratio means that the immune microenvironment develops in the direction of inhibiting tumor growth. For example, a decrease in the ratio means that the microenvironment can promote tumor growth.
  • PD-1 is generally expressed on activated T cells, and its expression level is gradually increased as T cells are activated.
  • activated T cells encounter their ligand PD-L1, they cause T cell inactivation. Therefore, the expression level of PDL-1 in tumor tissues also affects the number and function of effector T cells in the tumor immune microenvironment. To this end, we examined the expression level of PD-L1 on the surface of tumor cells (see Figure 7 for details).
  • the increase in PD-L1 expression in the 25 ⁇ g group of ⁇ PD-1+D018 is not contradictory to previous results. More and more studies have shown that patients with increased PDL-1 expression have better clinical treatment after ⁇ PD-1 treatment. The effect may be related to the sensitivity of ⁇ PD-1 treatment after high expression of PD-L1.
  • mice After the mice were sacrificed, the whole blood was collected by a 21-gauge needle with a 1 ml syringe at a heart puncture, and allowed to stand at room temperature for 1 hour to cause agglomeration. Serum was collected after centrifugation at 3000 rpm. Serum was stored frozen (-80 ° C) after harvest. Mouse interleukin 2 (IL-2) was detected by ELISA, and the indexes of mouse IFN- ⁇ , TNF- ⁇ and IL-6 were detected, and each of the three sub-wells was sampled.
  • IL-2 Mouse interleukin 2
  • the reagents used were rewarmed at room temperature (18-25 ° C); the plate was washed: the coated enzyme plate was placed on the plate washer and rinsed 5 times with the washing solution; then the filter paper was lightly rubbed to remove excess liquid; Adding: Add 100 ul of cell culture supernatant sample per well, incubate at 37 ° C, incubate for 1 h; wash the plate: place the plate on the plate washer and rinse with the washing solution 5 times, then tap on the filter paper.
  • Detection Ab add 100 ul (1:200) diluted detection antibody per well; incubate at 37 ° C incubator for 1 h; wash plate: place the plate on the plate washer and rinse with wash solution 5 times Then, tap on the filter paper to remove excess liquid; add Aiding-HRP: add 100ul (1:1000) to dilute Aiding-HRP; place in 37 ° C incubator, incubate for 30 min; wash plate: place the microplate on the plate Rinse with the washing solution 5 times on the machine, then tap on the filter paper to remove excess liquid; substrate color development: add 100ul Substrate Solution F (protected from light) to each well for 15min; stop: add 100ul stop solution per well to stop the reaction; : OD value measured at 450 nm on a microplate reader within 30 min, according to the standard curve The regression equation calculates the concentration of cytokines in the sample.
  • Interleukin-2 was used as a cytokine to stimulate and maintain the proliferation of T cells. A significant increase in its level is critical for the functioning of effector cells in the tumor immune microenvironment.
  • the level of interleukin-6 in the combination group was significantly higher than that in the control group, which stimulated the proliferation, differentiation, and function of cells involved in the immune response.
  • the level of interferon gamma in the combination group is relatively high, and the interferon has antiviral, immunomodulatory and antitumor properties.
  • the combination of the negative immunomodulatory interleukin 10 levels of inflammation and immunosuppressive factors in the combination group was the lowest in each group. To sum up, the combination group tends to increase the body's immune response level from the systemic immune status and promote the immune system's killing of tumors.
  • Macrophages were derived from wild-type C57BL/6 bone marrow cells, which were taken out and cultured in conditioned medium containing M-CSF for 5 days. At the end of the incubation period, adherent cells were collected and re-plated for cell experiments.
  • Real-time quantitative PCR analysis of wild-type C57BL/6 bone marrow-derived macrophages under different time and different doses of D018, R848 and Poly (I:C) stimulation Il1b, Il6, Il12b, Tnf, Ifnb1, Cxcl1, Cxcl10 and Il10 The mRNA levels of the genes were normalized to each sample using the housekeeping gene GAPDH.
  • D018 stimulated BMDMs to produce the highest level of tnf compared to the other two stimulators at 0.023 ⁇ g/ml, indicating that D018 has the lowest dose activity or the highest activity.
  • D018 (0.023 ⁇ g/ml) or R848 (10 ⁇ g/ml) reached the highest point after 1 hour of stimulation of BMDMs, and the level of the factor began to fall from the 6th hour.
  • the Ifnb1, Cxcl1, and Cxcl10 tri-cytokines are generally more active than D848, while R848 is more active when stimulating Il10.
  • RNA concentration was determined by NanoDrop (ND-lOOO) UV spectrophotometer. The RNA concentration was not less than 40 ng/m. Purity requirements 0D260/280 are greater than 1.8. 5 g of each sample was taken, and a single-stranded cDNA library was synthesized by reverse transcription using ReversetranscriptTM kit (Invitrogen). Perform high-throughput sequencing.
  • the invention carried out RNA-seq on the tumors of each group of mice, and the results showed that the combination of drugs caused a series of changes in the gene expression of mouse tumors, up-regulating the inflammatory and cytokine-mediated pathways.
  • the number of genes that are beneficial to tumor immunotherapy, such as T cell activation, apoptotic signaling pathway, and B cell activation pathway, and the down-regulation of Wnt signaling pathway on the other hand promote the infiltration of immune cells into tumor tissues. At this prompt we verified using the real-time PCR method.
  • the specific steps are as follows: 1 dewaxing: the tissue chip is immersed in xylene for 20 minutes, and replaced with fresh xylene; 2 rehydration: the tissue slice after dewaxing is soaked in 100% ethanol for 5 minutes twice, 95 % ethanol, 90% ethanol, 80% ethanol, 70% ethanol, distilled water were soaked for 5 minutes ⁇ 1 time; 3 antigen repair: the antigen repair solution was citric acid-sodium citrate buffer, and the antigen repair solution was heated to boiling at microwave high temperature.
  • the slice is placed, and then heated by microwave high heat for 5 minutes, supplemented with distilled water to restore the volume, and then heated with microwave high temperature for 5 minutes, naturally cooled to room temperature; 4 removal of endogenous peroxidase: freshly configured 3% H2O2, Drops, incubate for 10 minutes at room temperature in the dark; 5 blocking: block with normal sheep serum working solution for 20 minutes at room temperature; 6 primary antibody reaction: drop with 10 ⁇ g/mL rabbit anti-human PHF23 primary antibody (diluted in PBS), 37 ° C Incubate for 1 hour, control group with PBS instead of primary antibody; PBS wash for 5 minutes ⁇ 3 times; 7 secondary antibody reaction: HRP-goat anti-rabbit antibody diluted 1:200 (diluted with PBS), react at room temperature for 30 minutes; 8 PBS wash for 5 minutes ⁇ 3 times; 9 diaminobiphenylamine (DAB) develops color, Tablets, the reaction results were observed; 10 hematoxylin nucleus, bluing water; Up-drafting of
  • part of it is to reduce the inhibition of Ccl4 gene by decreasing the expression of ⁇ -catenin, so that more Ccl4 can promote its infiltration of DC cells into tumor tissue and activate T cells.
  • Ccl4 chemotactic cytokine receptor promotes the infiltration of DC and T cells into tumor tissues, which makes DC cells have more opportunities to contact tumors, and better promotes tumor antigens to T cells of lymphoid tissues, making tumor specificity in the circulatory system. As the number of lymphocytes increases, the body enters a virtuous cycle of tumor-specific immunity and accelerates the body's removal of tumor tissue.
  • mice IgG Isotype control, ⁇ PD-1, R848 25 ⁇ g, ⁇ PD-1+R84810 ⁇ g, ⁇ PD-1+R848 25 ⁇ g, D018 25 ⁇ g, ⁇ PD-1+D018 10 ⁇ g, ⁇ PD-1+D018 25 ⁇ g 8 groups.
  • Each group of 10 mice after tumor growth in tumor-bearing mice reached 100mm3, PD-1 monoclonal antibody was treated with 200 ⁇ g/mouse every 3 days, and TLR7 agonist was given an immunotherapy every 7 days, divided into 10 ⁇ g.
  • Two dose groups with 25 ⁇ g.
  • the tumors of other groups were reduced to different extents, and the ⁇ PD-1+D018 25 ⁇ g group started the tumor volume from the treatment. It has been in a state of slow growth or even growth stagnation, which has a p value ⁇ 0.001 compared with the control group.
  • D018 and R848, the single-administered group and the combined treatment group have obvious effects of inhibiting tumor growth, and the combined administration has a more obvious anti-tumor effect, and the anti-tumor effect has a significant dose between 10-25 ⁇ g. Dependence.
  • the D018-administered group had better anti-tumor effect and dose-dependent. It was found that the survival rate of IgG Isotype control at 33 days in the MC38 group was 0% at 41 days, and ⁇ PD-1 was 40% at D41. %, ⁇ PD-1+D018 is 100%. This indicates that the drug efficacy of the TLR7 agonist of the present invention is significantly better than that of the commercial R848.
  • the contralateral side of the primary vaccination was inoculated with 1 x 106 MC38 cells.
  • mice that were first vaccinated grew very rapidly, and those who rejected MC38 tumors after combination therapy completely resisted the stress of MC38 cells.
  • mice were divided into IgG Isotype control, ⁇ Tim-3, D018, ⁇ PD-1+D018, ⁇ Tim-3+D018, ⁇ PD-1+D018+ ⁇ Tim-3 groups, 10 mice in each group, and the tumor was small.
  • the tumors of the mice were randomly sorted into the above 6 groups after they reached 100 mm3.
  • the PD-1 mAb was treated with 200 ⁇ g/dose every 3 days, and the TLR7 agonist was given an immunotherapy every 7 days, and the tumor size was measured once every 3 days with a vernier caliper.
  • tumors of mice in other administration groups were reduced to different extents, among which ⁇ PD-1+D018, ⁇ PD-1+D018+ ⁇ Tim-
  • the tumor volume of the three groups from the time of self-administration treatment was always in a state of slow growth or even growth stagnation, which was significantly different from the control group.
  • the simple administration of ⁇ Tim-3 showed no obvious therapeutic effect, but its combined treatment with D018 significantly improved the ability to inhibit tumor volume. Therefore, the combination of D018 with ⁇ PD-1 and ⁇ Tim-3 antibodies and the combination therapy of the three have obvious inhibitory effects on tumor growth, and the combination of the two immunoassay sites has the most obvious antitumor effect.
  • Ag104Ld fiber cells were used, cultured in DMEM medium containing 10% FBS, and cultured in an incubator at 5% CO 2 at 37 °C. Conventional passage was digested with trypsin 0.25% Trypsin-EDTA (GIBCO: 25200-056) for 1-3 min. After passage, the cells were changed 2-3 times a week. The cells were passaged 3 days before the tumor was implanted, and a new culture medium was replaced one day before the injection. 1 ⁇ 10 5 Ag104Ld cells with a survival rate of 80% were injected subcutaneously into the right side of 6-8 week old female CH1 mice.
  • the cytometry analysis of the components of the tumor-infiltrating lymphocytes, such as CD4+ T cells, CD8 + T cells, and Treg cells was shown by flow cytometry (see Figure 16 for details).
  • Flow cytometry of CD103 + was analyzed by flow cytometry with CD45 antibody, CD103 antibody, CD11c antibody, and flow-through detection was shown (see Figure 17 for details).
  • CD8 + T cells are the key effector cells in tumor immunotherapy, and the number of them directly determines the intensity and prognosis of tumor immunity in mice.
  • the ratio of CD8 + T cells/Treg cells also increased significantly, and the tumor growth rate of these two groups was also significantly slowed down.
  • DC is a full-time presentation of antigen-presenting cells that initiates a primary immune response to T lymphocytes. Studies have shown that DC expresses multiple phenotypic molecules and CD11c is one of its specific markers.
  • CD103 + DC is a major regulatory DC subpopulation that transports antigen from the lamina intestinal mucosa to the lymph nodes and mesenteric lymph nodes, and stimulates the expression of the homing molecule ⁇ 4 ⁇ 7 integrin by activated T lymphocytes, thereby mediating T lymphocyte regression. Nest to the site of antigen invasion.
  • T cells After T cells are activated by specific antigenic substances, they proliferate and differentiate to form two types of cells that are functionally different, namely T immune effector cells and memory T cells. Among them, memory T cells will mobilize the defense mechanism in memory in the next antigen invasion, and destroy the target cells again.
  • Memory T cells also include central memory T cells (Tcm) and effector memory T cells (Tem).
  • Tcm biomarkers are CD62L and CD44 double positive cells, which means that Tcm can pass through the lymphatic shield, return to the lymph nodes, and be in a state activated by the antigen. Tcm cells have self-more The new and replication ability, which lasts for a long time in the body, can play a long-term anti-tumor effect.
  • Tcm cells can be quantitatively monitored to provide a reference for clinical standardized treatment.

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Abstract

La présente invention concerne des dérivés de pyridopyrimidine ou des sels de ceux-ci, un procédé de préparation associé, une composition pharmaceutique et leurs utilisations, en particulier un nouveau composé agoniste de TLR et des sels pharmaceutiquement acceptables ou une composition du composé. L'invention concerne également un procédé de préparation des substances selon l'invention et des utilisations desdites substances pour la préparation de médicaments destinés au traitement de maladies infectieuses, de maladies du système respiratoire, de maladies immunologiques et de maladies virales ou de tumeurs. La présente invention a de bonnes valeurs d'application clinique.
PCT/CN2017/114611 2017-11-17 2017-12-05 Dérivés de pyridopyrimidine ou sels de ceux-ci, leur procédé de préparation, composition pharmaceutique et utilisations correspondantes WO2019095455A1 (fr)

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EP4122931A4 (fr) * 2020-03-18 2024-04-17 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Forme cristalline d'un agoniste de tlr8
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CN115607550A (zh) * 2021-07-14 2023-01-17 清华大学 一种tlr7/8激动剂在抑制hiv中的应用
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