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WO2017198194A1 - Acide boronique et composé ester borate et ses applications - Google Patents

Acide boronique et composé ester borate et ses applications Download PDF

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Publication number
WO2017198194A1
WO2017198194A1 PCT/CN2017/084924 CN2017084924W WO2017198194A1 WO 2017198194 A1 WO2017198194 A1 WO 2017198194A1 CN 2017084924 W CN2017084924 W CN 2017084924W WO 2017198194 A1 WO2017198194 A1 WO 2017198194A1
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compound
crystal form
compound according
group
drug
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Chinese (zh)
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广兵
阳泰
董韧涵
刘进
覃传军
谢建
彭向阳
钟月玲
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Chengdu Origin Biotechnology Ltd Co
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Chengdu Origin Biotechnology Ltd Co
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    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • 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
    • A61K31/69—Boron compounds
    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the invention belongs to the field of chemical medicines, and in particular relates to an antitumor compound and a pharmaceutical composition thereof.
  • Ubiquitin-proteasome pathway-mediated protein degradation is an important mechanism by which the body regulates intracellular protein levels and functions. Once the proteasome exceeds normal levels, it causes a decrease in growth inhibition, a decrease in apoptosis, and promotes angiogenesis, thereby causing various tumor diseases, and thus the proteasome is an important target for drugs such as cancer. Proteasome inhibitors inhibit tumor cell growth and promote apoptosis by blocking cellular proteasome degradation.
  • MM Multiple myeloma
  • MM is a plasma cell carcinoma found in the bone marrow.
  • multiple myeloma a group of plasma cells or myeloma cells are transformed into cancer cells and proliferate, resulting in a higher than normal number of plasma cells.
  • plasma cells migrate extensively in the body, it is likely to involve most of the bones in the body, which may lead to compression fractures, osteolytic lesions and related pain.
  • Multiple myeloma can cause several serious health problems, involving red blood cell counts in the bones, immune system, kidneys, and individuals. Some of the more common symptoms include bone pain and fatigue.
  • Mantle cell lymphoma follicular lymphoma is a relatively common non-Hodgkin's lymphoma.
  • Mantle cell lymphoma accounts for 6% of non-Hodgkin's lymphoma, and the first-line treatment regimen does not achieve a completely satisfactory result.
  • Follicular lymphoma accounts for 22% of non-Hodgkin's lymphoma, and despite various treatments, there is still unmet clinical need.
  • Lung cancer, colon cancer, breast cancer, kidney cancer, cervical cancer, nasopharyngeal cancer, etc. are also high-risk tumor types. Although there are already a large number of therapeutic drugs and means, high-value therapeutic drugs in this field are still unmet clinical needs.
  • Ixazomib (boric acid moiety).
  • WO 2012/177835 discloses derivatives of the following structures of Ixazomib: (code name Ixazomib DEA)
  • Bilgicer et al (Journal of Medicinal Chemistry, 2014, 57:5282) reported different prodrugs of bortezomib, the prodrug of which was designed to form hydroxyl groups in boric acid structural units into various cyclic esters.
  • the prior art discloses the above-mentioned boric acid cyclic ester as a prodrug, and the release of the boric acid moiety is effective.
  • the present invention provides a compound of the formula (I) or a crystalline form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or boric anhydride:
  • ring A represents one of the following structures:
  • R 1 is selected from H or C 1-6 alkyl
  • R 2 is selected from C 1-6 alkyl
  • R 3 and R 4 are selected from hydrogen, or R 3 and R 4 together with the inserted oxygen and boron atoms form an optionally substituted 5-20 membered ring, the ring further comprising 0-2 selected from nitrogen and oxygen. Or a ring hetero atom of sulfur.
  • R 1 is selected from H.
  • R 2 is selected from isopropyl.
  • X 1 and X 2 are selected from hydroxyl, or X 1 and X 2 together form a portion of the acid functional groups formed by removing a hydrogen atom esterifying agent.
  • X 1 and X 2 are selected from a hydroxyl group.
  • the borating agent is selected from the group consisting of compounds containing at least one hydroxyl group or at least one carboxyl group.
  • the borating agent is a borate esterifying agent containing N atoms.
  • the ring formed is a 5-12 membered ring.
  • the borating agent is selected from the group consisting of a monosaccharide or a polyhydric alcohol.
  • the borating agent is selected from the group consisting of C 4-10 saturated borating agents, wherein the sum of the number of hydroxyl groups and carboxyl groups is 2 to 4.
  • the borating agent is selected from the group consisting of mannitol, citric acid, malic acid, tartaric acid, glucose, diethanolamine, dipropanolamine, triethanolamine, tripropanolamine, 3-((2-hydroxyethyl) Amino)-1-propanol, N-methyldiethanolamine, N-butyldiethanolamine, 2-((2-hydroxypropyl)amino)-1-propanol, diisopropanolamine and N,N Any one of bis(2-hydroxyethyl)glycine; or the boronic acid esterifying agent is optionally C1-6 alkyl, C3-C6 cycloalkyl, C2-C6 carboxyalkyl , C1-C6 hydroxyalkyl substitution.
  • ring A is selected from the following structures:
  • the borating agent is selected from the group consisting of dipropanolamine.
  • the borating agent is selected from the group consisting of diethanolamine.
  • the compound is one of the following compounds or one of its mannitol esters:
  • the compound is one of the following compounds:
  • the compound is one of the following compounds:
  • the present inventors have surprisingly found that the different substituents on the benzene ring and the cyclic esters of boric acid have higher anti-multiple myeloma cell activity, and thus have a good application prospect.
  • the present invention also discloses a novel synthetic route for the above compounds, as follows:
  • CN200780100142 discloses a method for synthesizing a compound similar to the patent; which uses TBTU or the like as a condensing agent to form an amide reaction of a substituted intermediate S1 of a substituted benzoic acid with glycine with an amino boronate S2, but the present inventors are surprised It has been found that the preparation of the compounds disclosed herein using the above-disclosed patents will result in the predominantly by-product S4-1, which is predominantly deboronated.
  • the TBTU is replaced with other such as DCC, EDCI.HCl, etc., or the reaction solvent system is changed, but the target intermediate is surprisingly less or completely unavailable. It indicates that the difference of the substituents on the benzene ring directly affects the feasibility of the preparation method and is non-obvious.
  • a method of activating a carboxyl group such as preparing an activated ester (herein, a mixed acid anhydride), can obtain a target in a high yield.
  • the carboxyl activating agent is selected from any one or more selected from the group consisting of ethyl chloroformate, propyl chloroformate and isobutyl chloroformate.
  • the key is to keep the system alkaline
  • the base may be selected from any one or more of N-methylmorpholine, triethylamine and N-ethyldiisopropylamine.
  • the salt of the compound represented by S2 is a trifluoroacetate or a hydrochloride.
  • the present invention also provides the use of the compound, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a solvate thereof, or a boric anhydride, for the preparation of an antitumor drug or a proteasome inhibitor.
  • proteasome inhibitor drug is a proteasome chymotrypsin-like protease inhibitor drug or a proteasome caspase-like protease inhibitor drug.
  • the antitumor drug is a drug for preventing and/or treating plasmacytoma.
  • the plasmacytoma is multiple myeloma.
  • the compounds of the present invention also exhibit inhibitory effects against a variety of other cancers.
  • the antitumor drug is a drug for preventing and/or treating lymphoma.
  • the medicament is a medicament for preventing and/or treating non-Hodgkin's lymphoma.
  • the non-Hodgkin's lymphoma is a mantle cell lymphoma.
  • the non-Hodgkin's lymphoma is a follicular lymphoma.
  • the tumor is a mantle cell lymphoma or a follicular lymphoma.
  • the tumor is breast cancer, colon cancer, lung cancer, kidney cancer, cervical cancer, nasopharyngeal cancer.
  • the C 1 -C 6 alkyl group means a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkyl group, that is, a straight chain or a branch having 1 to 6 carbon atoms.
  • Alkyl of the chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, and the like.
  • the ring hetero atom refers to a boron atomating agent which is ring-formed with a boron atom or an oxygen atom, and a hetero atom other than a carbon atom in the ring-forming atom, excluding a substituent group on the ring. atom.
  • the boric acid compound in the present invention, it refers to a compound containing a boronic acid -B (OH) 2 moiety.
  • the boric acid compound can form an oligomeric anhydride by partially dehydrating the boric acid.
  • the boric anhydride refers to a compound formed by combining two or more boric acid compound molecules while losing one or more water molecules. When mixed with water, the boric anhydride compound is hydrated to release the free boric acid compound.
  • the boric anhydride may contain two, three, four or more boric acid units, and may have a cyclic or linear configuration. For example, the following ring structure:
  • n can be an integer from 0-10.
  • the borate esterifying agent refers to any compound having at least two functional groups, each of which can form a covalent bond with boron, such as a hydroxyl group and a carboxyl group.
  • boron such as a hydroxyl group and a carboxyl group.
  • mannitol, citric acid, malic acid, tartaric acid, glucose, aminodiethanol, aminodipropanol, triethanolamine, and tripropanolamine may be included.
  • the borate esterifying agent includes, in addition to the above, 3-((2-hydroxyethyl)amino)-1-propanol, N-methyldiethanolamine, N-butyldiethanolamine, 2- ((2-hydroxypropyl)amino)-1-propanol, diisopropanolamine and N,N-bis(2-hydroxyethyl)glycine, etc.; or, the borate esterifying agent is optionally C1 a -6 alkyl group, a C3-C6 cycloalkyl group, a C2-C6 carboxyalkyl group, a C1-C6 hydroxyalkyl group, or the like.
  • the present invention provides a compound of the formula (I) or a crystalline form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or boric anhydride:
  • ring A represents one of the following structures:
  • R 5 , R 6 , and R 7 are selected from the group consisting of H, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl;
  • R 1 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 cycloalkyl, alkoxy, benzyl; the C 1-6 alkyl, C 1-6 cycloalkyl, alkoxy, benzyl The base can be further substituted;
  • R 2 is selected from C 1-6 alkyl
  • R 3 and R 4 are selected from hydrogen, or R 3 and R 4 together with the inserted oxygen and boron atoms form an optionally substituted 5-20 membered ring, the ring further comprising 0-2 selected from nitrogen and oxygen. Or a ring hetero atom of sulfur.
  • R 1 is selected from H or benzyl.
  • R 2 is selected from isopropyl.
  • X 1 and X 2 are selected from a hydroxyl group, or X 1 and X 2 together form a portion after dehydrogenation of the two functional groups of the borate esterifying agent.
  • X 1 and X 2 are selected from a hydroxyl group.
  • the borating agent is selected from the group consisting of compounds containing at least one hydroxyl group or at least one carboxyl group.
  • the borating agent is a borate esterifying agent containing N atoms.
  • the ring formed is a 5-10 membered ring.
  • the borating agent is selected from the group consisting of a monosaccharide or a polyhydric alcohol.
  • the borating agent is selected from the group consisting of C 4-10 saturated borating agents, wherein the sum of the amounts of the hydroxyl group and the carboxyl group is 2-8.
  • the borating agent is selected from the group consisting of mannitol, citric acid, malic acid, tartaric acid, glucose, diethanolamine, dipropanolamine, triethanolamine, tripropanolamine, 3-((2-hydroxyethyl) Amino)-1-propanol, N-methyldiethanolamine, N-butyldiethanolamine, 2-((2-hydroxypropyl)amino)-1-propanol, diisopropanolamine and N,N Any one of bis(2-hydroxyethyl)glycine; or the boronic acid esterifying agent is optionally C1-6 alkyl, C3-C6 cycloalkyl, C2-C6 carboxyalkyl And a C1-C6 hydroxyalkyl group or the like.
  • the compound of the present invention may be one of the following structures:
  • the present inventors have surprisingly found that the different substituents of the benzene ring moiety, whether the boronic acid structural unit is esterified, and the different cyclic esters and different combinations in the above structure produce unexpected activity effects.
  • N-containing heterocyclic cyclic ester having a different boric acid structural unit although it may be slowly decomposed into a boric acid moiety, is not only a prodrug, but has an unexpected biological activity by itself.
  • the present invention also provides a pharmaceutical composition which is prepared by using the compound or a pharmaceutically acceptable salt thereof or boric anhydride as an active ingredient, together with a pharmaceutically acceptable adjuvant.
  • the pharmaceutically acceptable adjuvant is selected from any one or more of a diluent, a filler, a colorant, a glidant, a lubricant, a binder, a stabilizer, a suspending agent or a buffer.
  • the preparation is a tablet, a capsule, an oral solution, an injection, a transdermal agent, an aerosol solid preparation, a liposome preparation or a controlled release preparation.
  • the prodrugs are derivatives of the aforementioned compounds which may themselves have weak or no activity, but are converted to corresponding conditions under physiological conditions (for example by metabolism, solvolysis or otherwise) after administration. Biologically active form.
  • the key intermediates and compounds of the present invention are isolated and purified in a manner that is commonly used in organic chemistry for separation and purification.
  • One or more compounds of the invention may be used in combination with one another, or the compounds of the invention may be used in combination with any other active agent for the preparation of an anti-tumor or proteasome inhibitor. If a group of compounds is used, the compounds can be administered to the subject simultaneously, separately or sequentially.
  • the compound of the present invention can be combined with other drugs based on the principle of anti-tumor synergistic mechanism, including sequential administration or simultaneous administration, to improve anti-tumor efficacy, delay drug resistance, and reduce drug toxicity.
  • the combination of the present invention which comprises the compound of any of the preceding, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a solvate thereof, for simultaneous or separate administration of the same or different unit preparations Or a boric anhydride and an antitumor drug or a drug for adjuvant treatment of a tumor, and a pharmaceutically acceptable carrier.
  • the present invention also provides a method for preventing and/or treating a tumor, which comprises administering to a tumor patient a compound according to any one of the above, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a solvate thereof Or boric anhydride.
  • the tumor patient is a patient of plasmacytoma, lymphoma, breast cancer, colon cancer, lung cancer, kidney cancer, cervical cancer and/or nasopharyngeal cancer.
  • the patient is a multiple myeloma patient; the patient is a non-Hodgkin's lymphoma patient, and further a mantle cell lymphoma and/or follicular lymphoma patient.
  • the X-ray powder diffraction of the crystal form has characteristic peaks at 8.38, 11.4, 12.1, 13.29, 18.27, 19.62, 20.47, 23.32, and 24.74 degrees.
  • the relative intensity values of the characteristic peaks of the 2 ⁇ diffraction angle are:
  • the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the present invention also provides a crystal form of a borate compound, wherein the X-ray powder diffraction of the crystal form has a 2 ⁇ diffraction angle of 6.19, 7.98, 10.05, 14.73, 14.92, 17.16, 18.8, 20.03, 21.05 degrees. Characteristic peaks.
  • the relative intensity values of the characteristic peaks of the 2 ⁇ diffraction angle are:
  • the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the present invention also provides a crystal form of a borate ester compound having X-ray powder diffraction having characteristic peaks at 2.23, 12.53, 14.18, 17.06, 20.82, 21.46, 22.62 degrees in X-ray powder diffraction.
  • the relative intensity values of the characteristic peaks of the 2 ⁇ diffraction angle are:
  • the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the present invention also provides a crystal form of a borate compound in which X-ray powder diffraction has a 2 ⁇ diffraction angle of 10.59, 11.76, 13.19, 15.56, 17.76, 19.5, 20.26, 21.37, 22.2 degrees. Characteristic peaks.
  • the relative intensity values of the characteristic peaks of the 2 ⁇ diffraction angle are:
  • the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the present invention also provides a crystal form of a borate ester compound, X-ray powder diffraction of the crystal form, 2 ⁇ derivative
  • the shooting angles have characteristic peaks at 7.06, 10.61, 12.24, 14.9, 17.23, 20.21, 23.49, and 26.48 degrees.
  • the relative intensity values of the characteristic peaks of the 2 ⁇ diffraction angle are:
  • the crystal form has an X-ray powder diffraction pattern substantially as shown in FIG.
  • cytotoxic drugs such as carboplatin, cisplatin, irinotecan, paclitaxel, fluorouracil, cytarabine, lenalidomide, retinoic acid
  • Hormonal drugs such as dexamethas
  • the pharmaceutically acceptable excipient of the present invention means a substance which is contained in a dosage form in addition to the active ingredient.
  • the compound of the invention has good proteasome inhibitory activity and antitumor activity, and has low toxicity and excellent clinical application prospect.
  • alkyl includes a straight or branched alkyl group.
  • the term "compound of the present invention” means a compound represented by the formula (I).
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).
  • the term "pharmaceutically acceptable salt” means that the compound of the present invention and an acid or a base are suitable for use as a medicine. Salt of matter.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with an alkali metal.
  • Alkali metals suitable for forming salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, and the like.
  • the pharmaceutically acceptable excipient which has a certain physiological activity, but the addition of the ingredient does not change the dominance of the above-mentioned pharmaceutical composition in the course of the disease treatment, but only plays an auxiliary effect, and the auxiliary effect is only the ingredient
  • the use of known activities is an adjuvant treatment that is commonly used in the medical field. It is still within the scope of the present invention to use the above-mentioned excipients in combination with the pharmaceutical compositions of the present invention.
  • the compound of the present invention has an excellent therapeutic antitumor effect
  • the compound of the present invention and various crystal forms thereof, a pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and a compound containing the compound of the present invention are mainly active ingredients.
  • the pharmaceutical composition can be used for anti-tumor.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 1 to 20 mg of the compound of the invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and (A) humectant, for example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) an absorption accelerator such as a quaternary amine compound; (g) a wetting agent such as cetyl alcohol and glyceryl
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • Figure 1 is a mass spectrum of Compound 1-1-2.
  • Figure 2 is a mass spectrum of Compound 1-1-3.
  • Figure 3 is a mass spectrum of the compound I-2-2.
  • Figure 4 is an X-ray powder diffraction pattern of Compound 1-1-2.
  • Figure 5 is an X-ray powder diffraction pattern of Compound 1-1-3.
  • Figure 6 is an X-ray powder diffraction pattern of Compound 1-1-4.
  • Figure 7 is an X-ray powder diffraction pattern of Compound 1-1-5.
  • Figure 8 is an X-ray powder diffraction pattern of Compound I-2-2.
  • Figure 9 is an X-ray powder diffraction pattern of Compound I-2-3.
  • Figure 10 is a graph showing the results of hydrolysis experiments of Compound I-2-3 in PBS.
  • Figure 11 shows that the compounds I-1-3 and I-2-3 of the present invention can significantly inhibit the proteasome activity in tumor tissues of mouse multiple myeloma in vivo.
  • Figure 12 shows that the compounds I-1-3 and I-2-3 of the present invention are capable of inducing the formation of tumor apoptosis markers - Cleaved PARP and Cleaved Caspase-3 activated fragments.
  • Figure 13 is a mouse tumor tissue section: 1 negative control group; 2 oral Ixazomib-DEA group; 3 oral administration of compound I-1-3 of the present invention; 4 oral administration of compound I-2-3 of the present invention.
  • the starting material S1 is prepared by dehydrating the substituted benzoic acid and the glycine methyl ester to form an amide, and then hydrolyzing the methyl ester; the trifluoroacetate or hydrochloride intermediate of the S2 aminoborate is commercially available, and other synthetic
  • the reagents are all commercially available.
  • the target compounds obtained in the examples were all controlled to have a purity of 98% or more.
  • CN200780100142 discloses a synthesis method of a compound similar to the present invention, which uses TBTU or the like as a condensing agent to form an amide reaction of a condensed intermediate S1 of a substituted benzoic acid with glycine with an amino boronate S2, but the inventors have found
  • the compound disclosed in the present invention is prepared by the above-mentioned patent disclosure route, and the obtained product is mainly a by-product S4-1 of deboronate, and the specific operation is as follows:
  • the target product was not obtained by replacing the reaction solvent system or using other condensing agents such as EDCI.HCl, DCC, and the like.
  • WO2012/177835 also discloses a synthetic route, as shown below:
  • the inventors selected X as Cl, reacted the above starting material (S1-1) with thionyl chloride to prepare an acid chloride, and formed an amidation reaction with S2 under basic conditions. Attempts, the resulting product is extremely complex, with many by-products and no preparative value (HPLC monitoring target conversion is less than 10%).
  • the specific preparation method of the present invention is as follows: 3 g (10 mmol) of starting material (S-1-1) in 20 mL of dichloromethane solution, NMM (N-methylmorpholine) 2.6 g (26 mmol) is added, and the temperature is lowered to 5 degrees. After adding 1.34 g (12 mmol) of ethyl chloroformate, and reacting to obtain the activated ester intermediate M1-1, the mixture was filtered, and 4.69 g of S2 (12 mmol) was added to the filtrate, stirred at room temperature for 3 hours, and then quenched with ice water. The organic layer was dried and concentrated to give a pale yellow solid object S3-1.
  • chloroethyl chloroformate or butyl chloroformate (isobutyl ester) or the like is used instead of ethyl chloroformate, and NMM is replaced with other organic bases such as triethylamine or N-ethyldiisopropylamine. Similar results, the yields were all above 80%.
  • the intermediate obtained in the previous step 5.1 g of S3-1, 40 mL of methanol, 4.5 mL of 1N hydrochloric acid solution, 2.6 g of isobutylboric acid (2.5 eq), and 20 mL of n-hexane were stirred at room temperature overnight to give n-hexane.
  • the compound I-1-2 was obtained according to the above preparation process and was detected at a temperature of 20 to 25 ° C.
  • the crystal X-ray powder diffraction pattern is as shown in Fig. 4, and the characteristic data is as follows:
  • the boric acid raw material (I-1-1) 2.25 g (5.55 mmol) was dissolved in 45 ml of ethyl acetate, stirred at room temperature for 5 min, and then diethanolamine (S-3-3) 0.61 g (5.82 mmol) was added dropwise, dropwise. A white solid precipitated in the middle reaction solution. After completion of the dropwise addition, stirring was continued for 2 hours, and suction filtration was carried out to obtain 2.4 g of an I-1-3 compound in a yield of 91%.
  • the compound I-1-3 was obtained according to the above preparation process and was detected at a temperature of 20 to 25 ° C.
  • the crystal X-ray powder diffraction pattern is as shown in Fig. 5, and the characteristic data is as follows:
  • the compound I-1-4 was obtained according to the above preparation process and was detected at a temperature of 20 to 25 ° C.
  • the crystal X-ray powder diffraction pattern is as shown in Fig. 6, and the characteristic data is as follows:
  • the compound I-1-5 was obtained according to the above preparation process and was detected at a temperature of 20 to 25 ° C.
  • the crystal X-ray powder diffraction pattern is as shown in Fig. 7, and the characteristic data is as follows:
  • the synthesis route is similar to that in Example 1, and the main product is obtained by the amide method disclosed in the patent.
  • the amide group is linked by the mixed acid anhydride method as shown above to finally obtain the target compound I-2-1;
  • the preparation method of -1 mannitol ester and compound I-2-1 sodium salt is similar to that of Example 1.
  • the compound I-2-2 is obtained and detected at a temperature of 20 to 25 ° C.
  • the crystal X-ray powder diffraction pattern is as shown in Fig. 8.
  • the characteristic data is as follows:
  • the compound I-2-3 was obtained according to the above preparation process and was detected at a temperature of 20 to 25 ° C.
  • the crystal X-ray powder diffraction pattern is as shown in Fig. 9, and the characteristic data is as follows:
  • the synthesis route is similar to that in Example 1, and the main product is a boric acid removal by-product obtained by the condensing agent method disclosed in the patent; the target product I-3-1; I-3-1 mannitol ester is obtained by the mixed acid anhydride method as shown in the above figure. And the preparation method of the sodium salt of the I-3-1 compound is the same as in the first embodiment.
  • Example 1 As in the synthesis route of Example 1, similarly, the boring agent method disclosed in the patent is used to obtain a by-product of boric acid removal; the mixed acid anhydride method as shown above is used to obtain the target substance I-4-1; the preparation method of the mannitol ester is carried out in the same manner. example 1.
  • the synthesis route is similar to that in Example 1, and the main product is obtained by the amide method disclosed in the patent.
  • the amide group is linked by the mixed acid anhydride method as shown above to finally obtain the target compound I-5-1; the compound I-5.
  • the preparation method of -1 mannitol ester and compound I-5-1 sodium salt is similar to that of Example 1.
  • I-6-1, I-7-1, and I-10-1 are compounds disclosed in CN200780100142. Surprisingly, it was found that the iodine-containing compounds I-8-1 and I-9-1 on the benzene ring are extremely easy to decompose at room temperature, indicating that the difference in halogen substituents on the benzene ring directly affects the stability and preparation of the derivative. Sex.
  • the pharmaceutical capsule composition of Compound I-1-2 contains 3 g or 4 g of Compound I-1-2, 193 g or 192 g of microcrystalline cellulose, 4 g of micronized silica gel, and a total of 200 g and No. 2 hollow capsules.
  • the preparation method is:
  • the mixed powder was passed through a 120 mesh sieve, filled into No. 2 capsules and sealed, and a total of 1000 capsules were prepared.
  • Example 25 Pharmaceutical tablet composition of a compound of the invention
  • the pharmaceutical tablet composition of the compound I-2-2, the compound I-2-2 is 1 part by weight, the lactose is 0.1-0.5 part by weight, the hydroxypropylcellulose is 0.05-0.08 part by weight, and the sodium carboxymethyl starch is 0.008- 0.014 parts by weight, an appropriate amount of povidone K30, 0.01-0.05 parts by weight of magnesium stearate; tablets are prepared according to the above ratio, and each tablet contains 1-6 mg of each of 1-6.
  • Example 26 Pharmaceutical Injectable Composition of a Compound of the Invention
  • a pharmaceutical injection composition of the compound I-1-1 which contains 1 g of I-1-1 mannitol ester, 34 g of disodium hydrogen phosphate, and a sufficient amount of water for injection.
  • the preparation method is:
  • step b the solution obtained in step a is filtered, dispensed in 1000 bottles of 2mL vials, half-plugged;
  • compositions of the compounds I-2-1, I-3-1, and I-5-1 are the same as above.
  • the pharmaceutically acceptable liposome composition of Compound I-2-2 contains 5 g of Compound 1-1-2 and 6.7 g of lecithin, 3.3 g of cholesterol, 5 g of vitamin C, and a sufficient amount of PBS buffer solution (pH 7.4).
  • the preparation method is:
  • the dry film container obtained in c, b was added to a PBS buffer solution (pH 7.4) to 500 mL, and vitamin C was added thereto, followed by ultrasonication.
  • I-1-3, I-2-3 compound S1:S2 1:3 without hydrolysis reaction, after the hydrolysis reaction, S2 in the measured nuclear magnetic spectrum contains the benzene ring hydrogen of the hydrolyzed product, but S1 remains It is a characteristic hydrogen of I-1-3 and I-2-3 compounds.
  • the calculation formula of the three hydrogen integral areas of the benzene ring after hydrolysis is: S2-3S1. Therefore, the molar ratio of the borate ester to its hydrolyzate boric acid is calculated as: 3S1/S2-3S1, and the time to be decomposed to half is t1/2.
  • the boric acid ester compound As a prodrug, combined with the results of other activity experiments of the inventors, Not only the boric acid moiety of the compound of the present invention has a strong activity, but also the borate ester compound can exert an active effect (not only the former Medicine), which plays an important role in the therapeutic effect of non-oral routes of administration.
  • the test sample was dissolved in DMSO and stored at low temperature. Before the test, the stability of the sample was measured by HPLC to ensure the stability of the sample used in the present embodiment.
  • Experimental method The fluorescent substrate Suc-Leu-Leu-Val-Tyr-AMC (Try-AMC sequence) was used to detect the inhibitory activity of the sample on the proteasome ⁇ 5 subunit, and the inhibition of the enzyme activity by different compounds was observed. The hydrolysis of the proteasome ⁇ 5 subunit was observed. The Try-AMC sequence in the substrate releases AMC. Under the detection conditions of excitation wavelength 380 nm and emission wavelength 460 nm, the released AMC fluorescence absorption value can be detected, and the inhibitory activity of the compound on the enzyme can be observed and calculated.
  • the IC50 of inhibition of proteasome ⁇ 5 subunit activity by the test sample was calculated by Graphpad Prism 5.0, and the results were as follows:
  • the compound of the present invention has a good proteasome ⁇ 5 subunit-chymotrypsin-like protease inhibitory activity.
  • test sample was dissolved in DMSO and stored at low temperature. Test the stability of the sample by HPLC before the test.
  • the samples used in this embodiment were stable.
  • Multiple myeloma cells RPMI8226, U266, MM.1S, MM.1R (purchased from ATCC, USA) were added to a flat-bottom 96-well cell culture plate at 40,000 cells/well.
  • the highest concentration of the compound was 1 ⁇ M, Ixazomib Citrate, Ixazomib-DEA and Ixazomib were used as positive control groups. Dilute the drug concentration according to a 5-fold gradient.
  • the GI50 of the test sample against the proliferation inhibition activity of multiple myeloma cells was calculated by Graphpad Prism 5.0, and the results were as follows:
  • boric acid cyclic benzene ring substituents affects the compound's inhibition of the proliferation activity of multiple myeloma cells.
  • the order of activity is basically, diurylamine borate cyclic ester > triethanolamine cyclic ester of boric acid > diethanolamine cyclic ester of boric acid > citric acid cyclic ester of boric acid > boric acid compound ( Unesterified); substituents on the benzene ring, the order of activity is: 2-Cl-5-Br substitution >5-Cl-2-Br substitution >2,5-2-F-4-Cl substitution >4, 5-2-F-2-Cl substitution.
  • the compounds in Table 2-1 are all boric acid structures. It can be seen that Compounds I-1-1 and I-2-1 can effectively inhibit the proliferation of multiple myeloma cells, among which, in the inhibitory activity against MM1S, Compounds I-1-1 and I-2-1 were superior to the positive drug Ixazomib.
  • the compounds in Table 2-2 are all N-containing heterocyclic cyclic ester structures, and it can be seen that the compounds of the present invention are 1-1-2, I-1-3, I-2-2, and I-2-3. , I-2-5, I-3-2, I-3-3, I-4-2, and I-4-3 can effectively inhibit the proliferation of multiple myeloma cells, wherein compound I-1-2,
  • the inhibitory activities of I-1-3, I-2-2, I-2-3, I-2-5, and I-3-2 against all multiple myeloma cells were superior to the positive drug Ixazomib-DEA, Compound I. -3-3, I-4-2, and I-4-3 have better inhibitory activity against U266, MM1S, and MM1R than the positive drug Ixazomib-DEA.
  • the experimental results indicate the structure of the N-containing heterocyclic cyclic ester with 2-Cl-5-Br substitution, 5-Cl-2-Br substitution, 2,5-2-F-4-Cl substitution, 4,5-2-F
  • the compound formed by the substitution of -2-Cl has high inhibitory activity against multiple myeloma cells, among which, the structure containing N heterocyclic cyclic ester and 2-Cl-5-Br substituted, 5-Cl-2- are preferred.
  • Br replaces the compound formed by the complexation.
  • the compounds in Table 2-3 are all oxygen-containing heterocyclic cyclic ester structures, and it can be seen that the compounds of the present invention are 1-1-4, I-1-4-1, I-2-4, and I-3. -4, I-3-4-1, I-4-4, and I-4-4-1 can effectively inhibit the proliferation of multiple myeloma cells, among which, compounds I-1-4, I-1-4 -1, I-2-4 inhibited all of the multiple myeloma cells better than the positive drug IxazomibCitrate, compounds I-3-4, I-3-4-1, I-4-4, I-4 -4-1 has better inhibitory activity against MM1S than yang Sex drug IxazomibCitrate.
  • the experimental results indicate the structure of the oxygen-containing heterocyclic cyclic ester with 2-Cl-5-Br substitution, 5-Cl-2-Br substitution, 2,5-2-F-4-Cl substitution, 4,5-2-F
  • the compound formed by the substitution of -2-Cl has high inhibitory activity against multiple myeloma cells, and among them, an oxygen-containing heterocyclic cyclic ester structure and 2-Cl-5-Br substitution, 5-Cl-2- are preferred.
  • Br replaces the compound formed by the complexation.
  • MM.1S multiple myeloma cells were established using MM.1S multiple myeloma cells and severe combined immunodeficiency (SCID) mice: 3 ⁇ 10 7 MM.1S cells were resuspended in 100 ⁇ l of 1640 medium and mixed with 100 ⁇ l of Matrigel. The above 200 ⁇ l homogenate system was injected into the right abdomen of SCID mice (5 weeks old, female). After 6-7 days, a visible size (100 mm 3 ) was formed at the site of tumor injection, and the tumor was grown to a diameter of about 2 cm; the compounds of the present invention I-1-3, I-2-3 and the control compound Ixazomib-DEA were orally administered orally. (The compound was dissolved with 5% HP ⁇ CD at a dose of 10 mg/kg).
  • tissue homogenate was performed by adding 200 ⁇ l of pre-cooled 1640 medium per 0.1 g of tumor tissue (on ice operation, keeping the tissue homogenization operation at a low temperature). 25 ⁇ l of the homogenate sample was added to Promega Proteasome-Glo TM Chymotrypsin-Like (for ⁇ 5 subunit assay), Caspase-Like (for ⁇ 1 subunit assay) and Trypsin-Like (for ⁇ 2 subunit assay) assay kit.
  • 25 ⁇ l of detection reagent was provided for detecting proteasome 20S- ⁇ 5, ⁇ 1 and ⁇ 2 subunit inhibitory activities, respectively.
  • tissue homogenate was added according to 1 ml of protein lysate per 0.1 g of tumor tissue, and then supernatant was centrifuged at 12,000 rpm for western-blot operation, using rabbit anti-PARP, rabbit anti-Caspase- 3 and rabbit anti-Cleaved Caspase-3 antibody were detected.
  • the activity of proteasome 20S- ⁇ 5 and ⁇ 1 subunit (caspase-like active subunit) in tumor tissues was significantly inhibited.
  • This example demonstrates that the compounds of the present invention can directly reach tumor tissues, inhibit proteasome activity, and thereby induce tumor tissue apoptosis.
  • administration of the compounds of the present invention, I-1-3 and I-2-3 induced the formation of a tumor-apoptable marker-Cleaved PARP and a Cleaved Caspase-3 activating fragment.
  • the 20S- ⁇ 1 subunit inhibitory activity of the proteasome was superior to the positive control drug Ixazomib-DEA, and the difference was extremely significant (P ⁇ 0.0001).
  • the compound of the present invention can reach the tumor tissue orally, and exerts a more remarkable activity than the Ixazomib-DEA proteasome inhibitory activity, meaning that the compound of the present invention has Stronger apoptosis-inducing activity. Furthermore, the administration of the compounds of the present invention, I-1-3 and I-2-3, was more effective than the Ixazomib-DEA in inducing the expression of the tumor apoptosis markers Cleaved PARP and Cleaved Caspase-3 (see Figure 12).
  • the experimental results indicate that the compounds of the present invention, I-1-3, I-2-3, can be prepared as proteasome inhibitor drugs, especially proteasome chymotrypsin-like (proteasome 20S- ⁇ 5) protease inhibitor drugs and Proteasome caspase-like (proteasome 20S- ⁇ 1) protease inhibitor drug.
  • the in vivo model of multiple myeloma mice was established according to the method described in Example 31, and the tumor was grown to a diameter of about 2 cm; the compounds of the present invention I-1-3, I-2-3 and the control drug Ixazomib-DEA were orally administered orally. (The drug was dissolved with 5% HP ⁇ CD at a dose of 10 mg/kg). After 8 hours, the skin of the mice was peeled off, and the tumor tissues were taken out and fixed with 4% paraformaldehyde. The fixed tissue was dehydrated, embedded, and sliced, and the following operations were performed: the dewaxed sections were placed on a dyeing rack, and stained in a hematoxylin dyeing tank for 10-20 minutes.
  • Negative control group The number of tumor cells was large, and the growth was dense. Occasionally, the tumor cells were lysed, fragmented and disappeared, and the tumor cells showed a small amount of necrosis.
  • Ixazomib-DEA drugs the number of tumor cells is large, the growth is dense, the tumor cells are punctate or focal necrosis (the degree of tissue necrosis is ++), and the aggregated multiple tumor cells are concentrated and divided, and the necrotic area is occasionally seen. There are monocytes, neutrophil infiltration.
  • Oral administration of the compound of the present invention I-1-3 the number of tumor cells is small, the cells are arranged loosely, and the tumor cells are flaky necrosis (the degree of tissue necrosis is determined as +++), and most of the tumor cells are concentrated, divided, dissolved, and visible in the tissue. Protein-like substances and cell debris, a large number of neutrophils, plasma cells and monocytes can be seen in the necrotic area.
  • Oral administration of the compound of the present invention I-2-3 the number of tumor cells is small, the cells are arranged loosely, and the tumor cells are flaky necrosis (the degree of tissue necrosis is determined as +++), and most of the tumor cells are concentrated, divided, dissolved, and visible in the tissue. Protein Samples and cell debris, a large number of neutrophils, plasma cells and monocytes can be seen in the necrotic area.
  • this example demonstrates that the compounds of the present invention have superior apoptosis-inducing activity in tumor tissues in vivo than the control drug Ixazomib-DEA.
  • Example 33 TUNEL-POD method for detecting tumor tissue apoptosis in animals of the present invention
  • the in vivo model of multiple myeloma mice was established according to the above method, and the tumor was grown to a diameter of about 2 cm; the compounds of the present invention I-1-3, I-2-3 and the control drug Ixazomib-DEA were administered orally by gavage (drug 5) %HP ⁇ CD was dissolved at a dose of 10 mg/kg). After 8 hours, the skin of the mice was peeled off, and the tumor tissue was taken out.
  • the BA200Digital digital trinocular camera micro-camera system micro-camera system was used to collect the images of the slices. Each slice was observed at 100 times before the whole tissue, and then one region was selected 400 times according to the size and expression of the tissue. Each slice was read, counted under the microscope, and the positive rate was counted. The results are shown in Table 4 below:
  • the test sample was dissolved in DMSO and stored at low temperature. Prior to the test, the stability of the sample was measured by HPLC to ensure the stability of the sample used in this embodiment.
  • the mantle cell lymphoma line JVM-2 and the follicular lymphoma line SU-DHL-6 were added to a flat-bottom 96-well cell culture plate at 10,000 cells/well. The highest concentration of the compound was 50 ⁇ M and Ixazomib-DEA was used as a control group. Dilute the drug concentration according to a 5-fold gradient. After the compound was applied for 48 hours, 10 ⁇ l of CCK-8 was added, and after incubation for 6 hours, the 450 nM wavelength absorption value was measured by a microplate reader.
  • the GI50 of the test sample for the proliferation inhibition activity of the mantle cell lymphoma cells was calculated by Graphpad Prism 5.0, and the results are shown in Table 5 below:
  • the experimental results demonstrate that the compounds of the present invention, I-1-3, I-2-3, and I-5-3, have the effect of inhibiting lymphoma, especially for mantle cell lymphoma and follicularity in non-Hodgkin's lymphoma.
  • the inhibition of lymphoma is significant.
  • Example 35 Inhibitory activity of the compound of the present invention against HT-29 human colon cancer cell line, breast cancer cell MDA-MB-231, lung cancer cell NCI-H460 and renal cancer cell line
  • Collect HT-29 human colon cancer cells in logarithmic growth phase count, resuspend the cells with complete medium, adjust the cell concentration to the appropriate concentration (determined according to the cell density optimization test results), inoculate 96-well plates, add 100 ⁇ l of cell suspension per well. liquid.
  • the cells were incubated for 24 hours at 37 ° C, 100% relative humidity, 5% CO 2 incubator.
  • the test compound was diluted with the medium to the corresponding concentration of action set, and added to the 96-well plate at 25 ⁇ l/well.
  • the final concentration of the compound was diluted from 100 ⁇ M to 0 ⁇ M in 4 fold gradients.
  • the cells were incubated for 72 hours at 37 ° C in a 100% relative humidity, 5% CO 2 incubator.
  • Test compound IC50(nM) Test compound IC50(nM) I-1-1 4.90 I-1-3 5.34 I-2-1 3.14 I-2-3 3.77 I-5-1 9.12 I-6-1 50.40 I-7-1 82.33 I-10-1 61.21 Ixazomib 55.35 Ixazomib-DEA 53.26
  • Test compound IC50(nM) Test compound IC50(nM) I-1-3 12.60 I-1-1 15.10 I-2-3 10.20 I-2-1 13.14 I-5-1 13.23 I-6-1 68.71 I-7-1 133.24 I-10-1 145.75 Ixazomib 58.82 Ixazomib-DEA 56.77
  • Test compound IC50(nM) Test compound IC50(nM) I-1-1 50.10 I-1-3 22.38 I-2-1 49.33 I-2-3 26.12 1-5-1 32.29 1-6-1 220.40 1-7-1 255.41 1-10-1 247.82 Ixazomib 160.91 Ixazomib-DEA 202.47
  • the results show that the compounds of the present invention are compared to the control compounds Ixazomib, Ixazomib-DEA, I-6-1, I-7-1, I-10-1 to NCI-H460 lung cancer cell line, MDA-MB-231 breast cancer cell line.
  • the proliferation of renal cancer cell lines has a more significant inhibitory effect.
  • Example 36 Inhibitory activity of the compound of the present invention on human cervical cancer and nasopharyngeal carcinoma cells
  • the test sample was dissolved in DMSO and stored at low temperature. Before the test, the stability of the sample was measured by HPLC to ensure the stability of the sample used in the present embodiment.
  • the cervical cancer cell line HeLa cells were added to a flat-bottom 96-well cell culture plate at 2000 cells/well. After the cells were cultured for 24 hours, the test compound was added. The highest concentration of the compound is 10 ⁇ M.
  • Ixazomib-DEA, Ixazomib, I-6-1, I-7-1, and I-10-1 were used as a control group. Dilute the drug concentration according to a 5-fold gradient.
  • the GI50 of the test sample against the proliferation inhibition activity of the cervical cancer cell line HeLa cells was calculated by Graphpad Prism 5.0, and the results are shown in Table 10 below:
  • Test compound GI50(nM) Test compound GI50(nM) I-1-1 9.11 I-1-3 29.48 I-2-1 8.05 I-2-3 30.02 I-5-1 18.31 I-6-1 170.53 I-7-1 116.26 I-10-1 182.93 Ixazomib 32.84 Ixazomib-DEA 51.16
  • the compounds of the present invention had more significant inhibitory effects on the cervical cancer cell line HeLa cells than the compounds Ixazomib, Ixazomib-DEA, I-6-1, I-7-1, and I-10-1.
  • Test compound GI50(nM) Test compound GI50(nM) I-1-1 603.97 I-1-3 616.03 I-2-1 614.80 I-2-3 670.52 I-5-1 683.52 I-6-1 1691.49 I-7-1 1922.08 I-10-1 1743.61 Ixazomib 803.52 Ixazomib-DEA 862.56
  • the benzene ring halogen substituent has a large influence on the activity, although those skilled in the art can consider Cl, Br, and I as electronic isosters to be mutually substituted, but surprisingly
  • the present inventors have found that a halogen change of a substituent on a benzene ring, and a different combination thereof, can give an unexpected difference in antitumor activity.
  • I-1-1, I-1-3, I-2-1, I-2-3, and I-5-1 exhibited remarkably excellent antitumor activity.
  • Example 37 Determination of the effect of a compound of the invention on human hERG ion channels stably expressed in HEK293 cells using conventional patch clamps
  • the hERG ion channel steady-state expression HEK293 cells were transferred to a perfusion tank and perfused with extracellular fluid at room temperature, each cell being self-control.
  • Test compounds were all dissolved in DMSO and configured to a concentration gradient of 0.3 ⁇ M, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, 30 ⁇ M, 100 ⁇ M.
  • the compounds were all perfused using a perfusion system using their own gravity. Test at least two cells per concentration. After the current is stable (or 5 minutes), the change in current magnitude before and after the compound is compared to calculate the blocking effect of the compound.
  • the positive control Cisapride was subjected to an IC50 test at a concentration gradient of 1 nM, 3 nM, 10 nM, 30 nM, 100 nM.
  • the method is the same as the test compound.
  • the test electrodes were drawn with PC-10 (Narishige, Japan).
  • the cells were clamped at –80 mV, then depolarized to 40 mV with a square wave lasting 4 seconds, and then hyperpolarized to -40 mV with a square wave lasting 2 seconds to obtain the hERG tail current. This procedure is repeated every 20 seconds.
  • the hERG tail current is a pure hERG current.
  • test compound for human hERG ion channel blockade expression in HEK293 cells is perfused, and when the reaction is stable, the blocking strength is calculated.
  • Table 12 The IC50 values of the test compounds for human hERG ion channel blockade expression in HEK293 cells are shown in Table 12 below:
  • Test compound IC50 ( ⁇ M) Test compound IC50 ( ⁇ M) I-1-1 >100 I-1-3 >100 I-2-1 >100 I-2-3 >100 Ixazomib 59.94 Ixazomib-DEA 56.43 Cisapride (positive control) 0.011
  • the compounds created by the present invention have a weaker blocking effect on the ion channel.
  • the compounds of the present invention have good proteasome inhibitory activity and antitumor activity, especially I-1-1, I-1-3, I-2-1, I-2-3, and I-5-1.
  • Excellent anti-tumor activity superior to the existing compounds Ixazomib and Ixazomib-DEA, and the cardiotoxicity of I-1-1, I-1-3, I-2-1, I-2-3 is also extremely low, significantly lower than The existing compounds Ixazomib and Ixazomib-DEA have excellent clinical application prospects.

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Abstract

La présente invention concerne un composé tel que représenté par la formule (I). La présente invention concerne également un sel pharmaceutiquement acceptable du composé, un procédé pour le produire, ses utilisations, et une composition pharmaceutique associée. Le composé selon la présente invention fournit des effets inhibiteurs significatifs contre les cellules tumorales, est applicable dans la prévention et/ou le traitement des maladies liées aux tumeurs, plus précisément le cancer du sein, le cancer du côlon, le cancer du poumon, et le myélome multiple, et présente de larges perspectives d'application.
PCT/CN2017/084924 2016-05-19 2017-05-18 Acide boronique et composé ester borate et ses applications Ceased WO2017198194A1 (fr)

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Publication number Priority date Publication date Assignee Title
KR20210010579A (ko) * 2018-05-28 2021-01-27 쟝쑤 차이 타이 펑하이 파머큐티컬 컴퍼니 리미티드 펩타이드 보레이트 에스테르류 화합물의 합성 및 용도
EP3805237A4 (fr) * 2018-05-28 2021-08-18 Jiangsu Chia Tai Fenghai Pharmaceutical Co., Ltd. Synthèse et utilisations d'un composé peptidique d'ester de borate
KR102558265B1 (ko) * 2018-05-28 2023-07-20 쟝쑤 차이 타이 펑하이 파머큐티컬 컴퍼니 리미티드 펩타이드 보레이트 에스테르류 화합물의 합성 및 용도
US12157749B2 (en) 2018-09-14 2024-12-03 Chengdu Origin Biotechnology Limited Company Borate-based drug and use thereof
CN113876784A (zh) * 2021-09-27 2022-01-04 潍坊博创国际生物医药研究院 硼代亮氨酸类化合物的新用途
CN113876784B (zh) * 2021-09-27 2023-07-21 潍坊博创国际生物医药研究院 硼代亮氨酸类化合物的新用途

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