WO2020248908A1 - Immunomodulateur bifonctionnel, sel pharmaceutiquement acceptable et composition pharmaceutique associée - Google Patents

Immunomodulateur bifonctionnel, sel pharmaceutiquement acceptable et composition pharmaceutique associée Download PDF

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Publication number
WO2020248908A1
WO2020248908A1 PCT/CN2020/094580 CN2020094580W WO2020248908A1 WO 2020248908 A1 WO2020248908 A1 WO 2020248908A1 CN 2020094580 W CN2020094580 W CN 2020094580W WO 2020248908 A1 WO2020248908 A1 WO 2020248908A1
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compound
substituted
bifunctional
unsubstituted
cancer
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PCT/CN2020/094580
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English (en)
Chinese (zh)
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唐士兵
曾少高
米琦·丹尼尔·托特雷拉
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中国科学院广州生物医药与健康研究院
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Priority to CN202080018398.5A priority Critical patent/CN113557236B/zh
Publication of WO2020248908A1 publication Critical patent/WO2020248908A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • This application belongs to the technical field of medicine, and relates to a bifunctional immunomodulator and a pharmaceutically acceptable salt and pharmaceutical composition thereof.
  • Immunotherapy refers to a treatment method that achieves the purpose of treatment by inducing, enhancing or suppressing immune response.
  • significant progress has been made in the treatment of various diseases, especially cancer, and has become the most advanced drug therapy in addition to chemotherapy and targeted therapy.
  • Important treatment options In the process of cancer occurrence and development, cancer cells have evolved various protective mechanisms to avoid the recognition and killing of the body's immune system, that is, cancer immune escape.
  • the more in-depth study of cancer immune escape signaling pathway is PD-1/PD-L1 (Programmed death 1/Programmed death-ligand 1).
  • PD-1/PD-L1 Programmed death 1/Programmed death-ligand 1
  • many drugs have entered clinical applications.
  • the monoclonal antibodies Pembrolizumab (Keytruda, Merck) and Nivolumab (Opdivo, Bristol-Myers Squibb) have become blockbuster drugs for the treatment of various cancers.
  • the PD-1/PD-L1 interaction is a negative signaling pathway that regulates the immune response.
  • Cancer cells or stromal cells in the cancer microenvironment inhibit T cells through high expression of PD-L1 protein and PD-1 protein on the immune T cell membrane The function and promote its apoptosis.
  • PD-1/PD-L1 modulators such as the monoclonal antibody Pembrolizumab, disrupt the interaction between PD-L1 on cancer cells and T cell PD-1, block the negative regulatory function of the pathway, and reactivate T cells to cancer
  • the immune response of the cells restores the vitality of T cells to achieve the purpose of killing cancer cells to treat cancer. Therefore, the PD-1/PD-L1 interaction has been widely studied and has played an important role in the clinical treatment of cancer in recent years.
  • the TGF- ⁇ (transforming growth factor- ⁇ ) signaling pathway is widely involved in a variety of cellular processes, including cell growth, differentiation, migration and adhesion, apoptosis, etc., in the embryonic development and tissue and organ formation, tissue repair, immune supervision and Play an important role in adult homeostasis.
  • the TGF- ⁇ signaling pathway is very complex, and the TGF- ⁇ /SMAD pathway has been extensively studied.
  • the TGF- ⁇ /SMAD pathway consists of three subtypes ( ⁇ 1, ⁇ 2, ⁇ 3) of free ligands that bind to cell surface type I and type II TGF- ⁇ transmembrane serine/threonine kinase receptors to form heterologous complexes Activating receptor-specific SMAD protein (R-SAMD), R-SAMD combines with common SMAD (co-SMAD) to enter the nucleus and interact with other cytokines to mediate gene transcription.
  • Abnormal TGF- ⁇ signaling pathway can lead to many diseases, such as cancer occurrence and metastasis, tissue fibrosis, cartilage dysplasia, abnormal inflammatory response, and pulmonary hypertension.
  • tumor cells and intratumoral stromal cells generally promote the immune escape and metastasis of cancer through high expression of TGF- ⁇ , leading to cancer deterioration and increasing the difficulty of cancer treatment.
  • Tumor immunotherapy has made a lot of progress in all aspects, but various drugs still have many shortcomings. The most prominent is that the effective response rate of patients is very low. For example, for various solid tumors, PD-1/PD-L1 drugs are only effective for 10-20% of patients. Therefore, it is urgent to improve the existing PD-1/PD-L1 drugs to increase the remission rate and survival rate of patients.
  • the TGF- ⁇ signaling pathway is generally highly expressed in the tumor microenvironment at the same time. Therefore, while inhibiting the PD-1/PD-L1 pathway, blocking the tumor microenvironment TGF- ⁇ pathway can theoretically promote PD-1 /PD-L1 drug effect. Based on this design concept, German Merck has developed a new type of tumor immune drug M7824.
  • M7824 is a bifunctional fusion protein, which is formed by the fusion of an IgG1 monoclonal antibody targeting PD-L1 protein and the extramembrane domain of TGF- ⁇ receptor type II. Therefore, the protein can inhibit both the PD-1/PD-L1 interaction and the TGF- ⁇ signaling pathway, which can significantly promote the killing of tumor cells by immune cells. Furthermore, one drug targeting two pathways with different functions at the same time may overcome the resistance of tumor cells to single pathway therapies, and greatly improve drug benefits and reduce the side effects of combined drugs.
  • Existing experimental data and clinical results have confirmed that M7824 is effective in a variety of solid tumors.
  • bifunctional fusion proteins targeting PD-1/PD-L1 and TGF- ⁇ signaling pathways have been disclosed in some patents, such as WO2006074451A2, WO2009152610A1, WO2011109789A2, WO2013164694A1, WO2014164427A1, WO2015077540A2, WO2015118175A2, WO2018205985A1, etc., but PD-1 There are no reports on the bifunctional small molecule immunomodulators of PD-L1 and TGF- ⁇ signaling pathway.
  • small molecules Compared with protein drugs, small molecules have many unique advantages: relatively stable, can be taken orally, and convenient to use; product quality is easy to control, and batch stability is good; the production process, transportation and storage are relatively easy, and the cost is low; and it is less likely to produce immune crossover reaction. Therefore, the study of bifunctional small molecule immunomodulators is a better choice for immunotherapy and will achieve better therapeutic effects. In view of the fact that there are no dual-functional small molecules that target PD-1/PD-L1 and TGF- ⁇ signaling pathways, this situation needs to be resolved urgently.
  • this application provides a dual-function immunomodulator having a structure as shown in formula I:
  • R 1 is selected from
  • R 2 and R 3 are each independently selected from hydrogen, halogen, cyano (-CN), substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, trifluoromethyl or ethylene base.
  • R 4 is selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C3-C7 cyclic hydrocarbon group, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted Substituted C1-C4 alkyl acyl, substituted or unsubstituted C1-C4 alkylsulfonyl, substituted or unsubstituted C1-C4 alkyl acyl methylene, substituted or unsubstituted benzyl, substituted or unsubstituted Aroyl acyl methylene, substituted or unsubstituted 5-7 membered ring heteroarylmethylene or substituted or unsubstituted 5-7 membered ring heteroaroyl methylene.
  • R 5 and R 6 are each independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, trifluoromethyl, substituted or unsubstituted Substituted C1-C4 alkyl acyl, substituted or unsubstituted C1-C4 alkylsulfonyl, substituted or unsubstituted C1-C4 alkyl acyl methylene, substituted or unsubstituted benzyl, substituted or unsubstituted Aroyl acylmethylene, substituted or unsubstituted 5-7 membered ring heteroarylmethylene or substituted or unsubstituted 5-7 membered ring heteroaryl acylmethylene, or R 5 and R 6 are connected with Pyrazole forms a 5-7 membered ring.
  • the It means that R 5 and R 6
  • R 7 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, aryl or 5-7 membered heteroaryl.
  • A is selected from a C1-C16 alkyl group, a C1-C16 polyethylene glycol alkoxy group, a C1-C16 sulfur atom or nitrogen atom-containing alkyl group, or a C1-C16 amino acid-containing alkyl group; wherein, A It is connected to the benzylidene group through a CN bond, and is connected to the benzene ring of the quinoline ring through an oxygen atom, and the connection position is the 7 or 8 position of the quinoline ring.
  • the bifunctional immunomodulator provided in this application includes a benzyl phenyl ether molecular skeleton that simultaneously blocks the interaction of PD-1/PD-L1 and a 4-(4-pyrazole) quinoline molecular skeleton that blocks the TGF- ⁇ signaling pathway , The two are connected by molecular chain fragments. Therefore, the dual-function immunomodulator provided in this application can simultaneously block the PD-1/PD-L1 interaction and the TGF- ⁇ signaling pathway.
  • the alkyl group refers to a linear or branched saturated or unsaturated alkyl group
  • C1-C6 alkyl includes C1-C6 linear alkyl, C3-C6 branched alkyl , C2-C6 linear alkene groups, C3-C6 branched alkene groups, and alkynyl groups.
  • the alkoxy group is -OR-, where R is an alkyl group.
  • the trifluoromethyl group is -CF 3 .
  • alkyl acyl group refers to -C(O)R, where R is an alkyl group.
  • alkylsulfonyl group refers to -S(O) 2 R, wherein R represents an alkyl group.
  • alkylacylmethylene refers to -CH 2 C(O)R, where R represents an alkyl group.
  • arylacylmethylene refers to -CH 2 C(O)Ar, where Ar represents an aryl group.
  • heteroarylmethylene group refers to -CH 2 A 1 , where A 1 represents a heteroaryl group.
  • heteroaryl acyl methylene group refers to -CH 2 C(O)A 1 , where A 1 represents a heteroaryl group.
  • polyethylene glycol alkoxy group refers to -(CH 2 -CH 2 -O) n -, where n ⁇ 1.
  • the alkyl group containing sulfur atom or nitrogen atom refers to containing S or N in the main chain of the alkyl group.
  • amino acid-containing alkoxy group refers to amino acids such as glycine, proline, alanine, etc. Structure, where R represents the side chain of an amino acid, and n ⁇ 1.
  • substitution means that one or more hydrogens on the carbon are substituted, but does not include the original heteroatoms.
  • substituted or unsubstituted alkylsulfonyl refers to Except for the sulfonyl group, other hydrogen atoms on the carbon atoms of the alkyl group are substituted.
  • the C1-C3 can be C1, C2, or C3.
  • the C1-C6 can be C1, C2, C3, C4, C5, or C6.
  • the C3-C7 can be C3, C4, C5, C6, or C7.
  • the C1-C4 can be C1, C2, C3, or C4.
  • the 5-7 membered ring may be a 5-membered ring, a 6-membered ring or a 7-membered ring.
  • the C1-C16 may be C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, or C16, etc.
  • the 7 or 8 positions of the quinoline ring are as follows:
  • the modulator has a structure as shown in Formula II:
  • M is selected from a C1-C16 alkyl group, a C1-C16 polyethylene glycol alkoxy group, a C1-C16 sulfur atom or nitrogen atom-containing alkyl group, or a C1-C16 amino acid-containing alkyl group; oxygen
  • the connection position of the atom and the quinoline derivative is the 7 or 8 position of the quinoline ring.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the same ranges as described above.
  • the R 2 is methyl.
  • the substituents are selected from halogen (-X), hydroxyl (-OH), amino (-NH 2 ), nitro (-NO 2 ), mercapto (-SH), cyano Group (-CN), C1-C3 alkylsulfonyl (-R-SO 3 H), C1-C3 alkoxy (-OR) or substituted heteroaromatic methoxy group.
  • the R 3 is selected from methyl, trifluoromethyl, fluorine, chlorine, bromine, cyano, methanesulfonyl or trifluoromethanesulfonyl.
  • the methylsulfonyl group is -S(O) 2 -CH 3 .
  • the trifluoromethanesulfonyl group is -S(O) 2 -CF 3 .
  • R 4 is selected from methyl, methoxy, benzyl, benzyloxy, ortho or meta cyanobenzyloxy, pyridinemethyleneoxy, or ortho or meta cyanopyridinemethyleneoxy base.
  • the structural formula of the ortho-cyanobenzyloxy group is The meta-cyanobenzyloxy group is The ortho-cyanopyridinemethyleneoxy group is Meta-cyanopyridinemethyleneoxy is Indicates the position where the group is attached.
  • R 5 and R 6 are connected and form a 5-6 membered ring with pyrazole.
  • the bifunctional regulator is selected from
  • this application provides a preparation method of the bifunctional immunomodulator according to the first aspect, the preparation method includes the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and M have the same ranges as described above.
  • the molar ratio of compound A and compound B is 1:1;
  • the reagent for the condensation reduction reaction is sodium cyanoborohydride
  • the added amount of sodium cyanoborohydride is more than 2 times the molar added amount of compound B;
  • the reaction temperature of the condensation reduction reaction is 10-30°C, and the reaction time is 12-48h;
  • the preparation method of the compound A is as follows:
  • the molar ratio of the compound C to the compound D is (1.1-1.3):1, such as 1.15:1, 1.2:1, 1.25:1, and the like.
  • the reagent for the substitution reaction is any one of sodium hydrogen, sodium hydroxide, potassium hydroxide or sodium carbonate.
  • the reaction temperature of the substitution reaction is 25°C or more, such as 30°C, 40°C, 45°C, 50°C, 55°C, etc.
  • the reaction time is 2h or more, such as 2.5h, 3h, 4h, 5h, etc.
  • the reagent is first added to the compound D solution and mixed, and then compound C is added to the compound D solution for substitution reaction.
  • the adding temperature of the reagent is below 0°C, such as -1°C, -2°C, -5°C, -10°C and the like.
  • the preparation method of the compound C is as follows:
  • the preparation method of the compound D is as follows:
  • step (a) is the reduction reaction of the carboxyl group, namely: -COOH ⁇ -CH 2 OH, and the reduction is carried out using borane.
  • step (b) is the reaction of -Br with R 1 boron reagent.
  • step (c) is the bromination reaction of the hydroxyl group, that is, -OH ⁇ -Br.
  • step (d) is an R 3 derivatization reaction such as chlorination.
  • the preparation method of the compound B includes deprotecting the amine group protected by the tert-butoxycarbonyl group, and the reagent used for the deprotection of the amine group is an acidic reagent.
  • step (e) and step (f) are condensation reactions.
  • the reaction of step (e) is carried out in the presence of an organic base or an inorganic base.
  • the organic base is preferably triethylamine
  • the inorganic base is preferably sodium hydroxide, cesium carbonate or sodium bicarbonate.
  • reaction in step (e) is carried out in the presence of a condensing agent.
  • the reaction of step (f) is carried out in the presence of an inorganic base
  • the inorganic base is preferably sodium hydrogen, sodium hydroxide, cesium carbonate or sodium bicarbonate.
  • the application provides an enantiomer, diastereomer or pharmaceutically acceptable salt of the bifunctional immunomodulator according to the first aspect.
  • Enantiomers in this application refer to chiral molecules that are optically mirror images of each other and cannot overlap; diastereomers refer to all stereoisomers that are not enantiomers, that is, those that do not have a mirror image relationship. Optical isomers.
  • the pharmaceutically acceptable salt is an acid addition salt or a base addition salt.
  • reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid can prepare a pharmaceutically acceptable acid addition salt of the bifunctional immunomodulator of the present application.
  • the acid addition salt includes hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate, ethanesulfonate, tosylate, benzenesulfonate, acetic acid Salt, maleate, tartrate, succinate, citrate, benzoate, ascorbate, salicylate, malonate, adipate, caproate, arginine, Any one or a combination of at least two of fumarate, nicotinate, phthalate, or oxalate.
  • the free acid form is reacted with a pharmaceutically acceptable inorganic or organic base to prepare the bifunctional immunomodulator of the present application in a pharmaceutically acceptable base addition.
  • a salt
  • the base addition salt includes lithium salt, sodium salt, potassium salt, barium salt, calcium salt, magnesium salt, aluminum salt, iron salt, ferrous salt, copper salt, zinc salt, or the bifunctional immune
  • the modifier is a salt composed of morpholine, diethylamine, triethylamine, isopropylamine, trimethylamine, lysine or histidine.
  • this application provides a pharmaceutical composition, the pharmaceutical composition comprising the bifunctional immunomodulator described in the first aspect or the enantiomers of the bifunctional immunomodulator described in the third aspect, Diastereomers or pharmaceutically acceptable salts and pharmaceutically acceptable carriers.
  • the pharmaceutically acceptable carrier can be in liquid, semi-liquid or solid form, formulated in a manner suitable for the administration route used, and can be used for in vivo treatment and has biocompatibility.
  • the pharmaceutical composition can be administered according to the following modes of administration: oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, oral, intranasal, liposome, etc. kind of form.
  • the oral pharmaceutical composition can be solid, gel or liquid.
  • solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders.
  • the preparation may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners, and flavoring agents.
  • binders include, but are not limited to, microcrystalline cellulose, glucose solution, gum arabic, gelatin solution, sucrose and starch paste;
  • examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate , Stearic acid;
  • examples of diluents include but are not limited to lactose, sucrose, starch, mannitol, dicalcium phosphate;
  • examples of glidants include but are not limited to silicon dioxide;
  • disintegrants include but are not limited to Sodium carboxymethyl cellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, and carboxymethyl cellulose.
  • the pharmaceutical composition of the present application is administered parenterally, generally by injection, including subcutaneous, intramuscular or intravenous injection.
  • the injection can be made into any conventional form, such as a liquid solution or suspension, a solid form suitable for dissolving or suspending in a liquid before injection, or an emulsion.
  • pharmaceutically acceptable carriers that can be used in the injections of this application include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifiers, chelating agents And other pharmaceutically acceptable substances.
  • aqueous carriers include Sodium Chloride Injection, Ringer's Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringer's Injection;
  • non-aqueous carriers include fixed oils of plant origin, Cottonseed oil, corn oil, sesame oil, and peanut oil;
  • antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.;
  • isotonic agents include sodium chloride and glucose; buffers include phosphate And citrate.
  • composition of the present application can also be prepared into a sterile freeze-dried powder injection by dissolving the compound in a sodium phosphate buffer solution, which contains glucose or other suitable excipients, and then dissolving the solution under standard conditions known to those skilled in the art. Sterile filtration followed by freeze drying to obtain the desired formulation.
  • this application provides the bifunctional immunomodulator according to the first aspect or the enantiomers, diastereomers or pharmaceutically acceptable
  • the accepted salt is used in the preparation of dual inhibitors of PD-1/PD-L1 and TGF- ⁇ .
  • the dual-function immunomodulator provided in this application can inhibit the PD-1/PD-L1 pathway while blocking the TGF- ⁇ signaling pathway.
  • this application provides the bifunctional immunomodulator according to the first aspect or the enantiomers, diastereomers or pharmaceutically acceptable
  • the diseases related to the PD-1/PD-L1 and/or TGF- ⁇ signaling pathway include cancer, infectious diseases or autoimmune diseases.
  • the diseases related to the PD-1/PD-L1 and/or TGF- ⁇ signaling pathway include multiple myeloma, melanoma, glioma, glioblastoma, leukemia, sarcoma, smooth muscle Tumor, mesothelioma, breast cancer, cervical cancer, lung cancer, stomach cancer, rectal cancer, colon cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer , Bacterial infection, viral infection, chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhage nephritis syndrome, primary bile Liver cirrhosis, multiple cerebrospinal sclerosis, rheumatoid arthritis, dermatomyositis, poly
  • the bifunctional immunomodulator provided in this application can inhibit the PD-1/PD-L1 pathway while blocking the TGF- ⁇ signaling pathway
  • the bifunctional immunomodulator provided in this application can be used to prepare application drugs.
  • the main role of drugs is to treat or prevent diseases related to PD-1/PD-L1 signaling pathway or/and TGF- ⁇ signaling pathway.
  • the bifunctional immunomodulator provided in this application includes a benzyl phenyl ether molecular skeleton that simultaneously blocks the interaction of PD-1/PD-L1 and 4-(4-pyrazole)quine that blocks the TGF- ⁇ signaling pathway
  • the morpholino molecular skeleton, the two are connected by molecular chain fragments. Therefore, the dual-function immunomodulator provided in this application can simultaneously block the PD-1/PD-L1 interaction and the TGF- ⁇ signaling pathway.
  • the pharmaceutically acceptable salt of the bifunctional immunomodulator provided in this application contains one or more bifunctional immunomodulators. Therefore, it has a good application effect in preparing medicines for treating and/or preventing diseases related to PD-1/PD-L1 and/or TGF- ⁇ signaling pathway.
  • the starting materials and reaction reagents used in the following examples are all commercially available products.
  • the reagents and solvents used in the experiment are handled according to the specific conditions of the reaction.
  • Petroleum ether PE
  • dichloromethane DCM
  • EA ethyl acetate
  • THF tetrahydrofuran
  • MeOH N,N-dimethylformamide
  • DME ethylene glycol dimethyl ether
  • DMA N,N-dimethylacetamide
  • DIEA N,N-diisopropylethylamine
  • TAA triethylamine
  • DCC dicyclohexylcarbodiimide
  • DMAP 4- N,N-dimethylaminopyridine
  • HOBt 1-hydroxybenzotriazole
  • HOBt 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • EDC ⁇ HCl di-tert-butyl dicarbonate
  • the analysis data of the samples are measured by the following instruments: NMR is measured by Bruker AMX-400 and Bruker AMX-500 nuclear magnetic resonance instruments, TMS (tetramethylsilane) is the internal standard, and the chemical shift unit is ppm, the coupling constant unit is Hz; the mass spectrum is measured by an Agilent1200/MSD mass spectrometer.
  • TLC silica gel plate is HSGF-254 thin-layer chromatography prefabricated plate produced by Yantai Chemical Plant; petroleum ether boiling range 60-90°C; UV lamp is used , Iodine cylinder and phosphomolybdic acid, etc.
  • a bifunctional immunomodulator its chemical structure is as follows:
  • the preparation method is as follows:
  • Dissolve compound 1-4 (5.4g, 0.029mol) in 150mL of dry ether, add 60% sodium hydrogen (1.8g, 0.045mol) at 0°C, stir for about 30min until no gas is generated, protect it with argon, Add compound 1-3 (9.0g, 0.035mol) in 100mL of dry tetrahydrofuran solution dropwise, raise to 55°C and stir overnight after the dropwise addition is complete. After TLC detects that there is no raw material, filter to remove the insoluble matter, and evaporate the low boiling point solvent under reduced pressure. The remaining mixture was poured into stirring ice water, and a large amount of white solid was precipitated. After suction filtration, the filter cake was washed once with petroleum ether and suction filtered to obtain the white solid compound 1-5 (7.0 g, yield 65.8%).
  • the crude compound 1-7 (4.2g, 0.017mol) was dissolved in 150mL of dry dichloromethane, and 1-hydroxybenzotriazole (2.3g, 0.017mol), N-tert-butoxycarbonylethylenediamine ( 2.7g, 0.017mol), triethylamine (3.4g, 0.034mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.0g, 0.017mol), room temperature After stirring overnight, the reaction solution was added with 150 mL saturated aqueous ammonium chloride solution, and then extracted with 200 ⁇ 3 mL ethyl acetate.
  • the crude compound 1-8 (3.0g, 7.6mmol) was dissolved in 50mL of dry tetrahydrofuran, triethylamine (1.2g, 11.4mmol) was added at room temperature, protected by argon, and methanesulfonyl chloride (1.1g, 9.5 mmol), kept at 0°C and stirred for 10 min, then warmed to room temperature and stirred overnight.
  • the reaction solution was added with 50 mL of saturated aqueous ammonium chloride solution, and then extracted with 100 ⁇ 3 mL of ethyl acetate.
  • Dissolve compound 1-10 (0.35g, 0.5mmol) in 10mL of dichloromethane, add an equal volume of trifluoroacetic acid at 0°C, and stir overnight at room temperature. After TLC detects that there is no raw material, the solvent and excess reagents are evaporated under reduced pressure After adding methanol to dissolve, add sodium bicarbonate (0.13g, 1.5mmol) and stir for 30 minutes. After filtering to remove the solid, the filtrate is concentrated and purified by column chromatography to obtain the crude compound 1-11 as a yellow solid. The molecular weight is identified by mass spectrometry. Go directly to the next step.
  • a bifunctional immunomodulator its chemical structure is as follows:
  • the preparation method is as follows:
  • the tert-butanol was evaporated under reduced pressure, the aqueous layer was extracted once with 50 mL of n-pentane, the aqueous layer was slowly added with cold 10% sodium bisulfate aqueous solution, adjusted to pH 1-2, and then extracted with 250 ⁇ 3 mL of ethyl acetate.
  • Dissolve compound 2-5 (0.28g, 0.35mmol) in 10mL of DMF, add an equal volume of trifluoroacetic acid at 0°C, and stir at room temperature for 5h. After TLC detects that there is no raw material, the solvent and excess reagents are evaporated under reduced pressure. After the methanol was dissolved, sodium bicarbonate (0.13 g, 1.5 mmol) was added and stirred for 30 min. After the solid was removed by filtration, the filtrate was concentrated to obtain the crude compound 2-6 as a yellow oil. After the molecular weight was identified by mass spectrometry, proceed directly to the next step.
  • a bifunctional immunomodulator its chemical structure is as follows:
  • the preparation method is as follows:
  • a bifunctional immunomodulator its chemical structure is as follows:
  • the preparation method is as follows:
  • Dissolve compound 4-2 (0.25g, 0.53mmol) in 10mL of tetrahydrofuran, add an equal volume of saturated methanolic hydrogen chloride solution at 0°C, and stir overnight at room temperature. After TLC detects that there is no raw material, the solvent and excess reagents are evaporated under reduced pressure After adding methanol to dissolve, add sodium bicarbonate (0.13g, 1.5mmol) and stir for 30 minutes. After filtering to remove the solid, the filtrate is concentrated to obtain the crude product of compound 2-6 as a yellow oil. The molecular weight is identified by mass spectrometry and the next step is directly carried out.
  • Dissolve compound 4-4 (0.18g, 0.53mmol) in 10mL of DMF, add an equal volume of saturated methanolic hydrogen chloride solution at 0°C, stir at room temperature overnight, after TLC detects no raw materials, evaporate the solvent and excess reagents under reduced pressure After adding ethyl acetate to dissolve, add sodium bicarbonate (0.13g, 1.5mmol) and stir for 30min. After filtering to remove the solid, the filtrate is concentrated to obtain the crude compound 4-5 as a yellow oil. After the molecular weight is identified by mass spectrometry, proceed directly to the next step .
  • a bifunctional immunomodulator its chemical structure is as follows:
  • Compound 5 can be synthesized via a similar route to compound 1.
  • a bifunctional immunomodulator its chemical structure is as follows:
  • Compound 6 can be synthesized via a similar route to compound 1.
  • a bifunctional immunomodulator its chemical structure is as follows:
  • Compound 7 can be synthesized via a similar route to compound 3.
  • a bifunctional immunomodulator its chemical structure is as follows:
  • Compound 8 can be synthesized via a similar route to compound 4.
  • a bifunctional immunomodulator its chemical structure is as follows:
  • a bifunctional immunomodulator its chemical structure is as follows:
  • compound 10 the enantiomer of compound 4 can be synthesized by a similar route.
  • Test Example 1 Test of the inhibitory effect of the compounds of the present application and comparative examples on PD-L1 protein at the cellular level
  • Experimental principle Use a cell line with high expression of PD-L1 protein, add DMSO or compound to incubate for a certain period of time, then add PE-Labeled Human PD-1 protein, and then use flow cytometry to detect whether the cells are labeled with PD-1 protein. In order to determine whether the tested compound is consistent with the interaction of PD-L1 and PD-1 protein.
  • the specific test procedure is as follows: first add the prepared compound (20 mM DMSO solution) to PBS, and dilute it to 1 mM. After counting the CR1-PDL1 cells with high expression of PDL1, adjust the cells to 5x10 5 /100 ⁇ l, and then spread the cells (100 ⁇ l) into a 96-well plate.
  • Test Example 2 Test of the inhibitory effect of the compounds of the present application and comparative examples on the TGF- ⁇ signal pathway at the cellular level
  • the TGF- ⁇ signaling pathway is directly related to the phagocytic ability of macrophages.
  • the signaling pathway is inhibited, the phagocytic ability of macrophages is significantly enhanced. Therefore, the phagocytic ability of macrophages can be improved by detecting the compound treatment.
  • the above test compound inhibits the activity of the TGF- ⁇ signaling pathway.
  • the specific test procedure is: spread macrophages at 50,000 cells/well in a 24-well plate, add compound and anti-CD47 antibody after 24 hours, and add TGF- ⁇ protein after 2 hours.
  • L1210 tumor cells labeled with CFSE fluorescently labeled were added to the macrophage wells at 200,000 cells/well. After incubating for 2 hours at 37°C, they were photographed under a fluorescence microscope to calculate the phagocytosis rate ( The number of phagocytic tumor cells in each field/total number of macrophages in each field ⁇ 100%).

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Abstract

L'invention concerne un immunomodulateur bifonctionnel, un sel pharmaceutiquement acceptable et une composition pharmaceutique associée. Le modulateur a une structure représentée par la formule I. L'immunomodulateur bifonctionnel comprend un squelette moléculaire d'éther de phényle benzyle qui bloque l'interaction PD-1/PD-L1, et un squelette moléculaire de 4-(4-pyrazole)quinoléine qui bloque une voie de signalisation de TGF-β. Les deux squelettes moléculaires sont reliés par l'intermédiaire de fragments de chaîne moléculaire. L'immunomodulateur bifonctionnel peut bloquer simultanément l'interaction PD-1/PD-L1 et une voie de signalisation de TGF-β.
PCT/CN2020/094580 2019-06-10 2020-06-05 Immunomodulateur bifonctionnel, sel pharmaceutiquement acceptable et composition pharmaceutique associée WO2020248908A1 (fr)

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