WO2018171816A1 - Dipeptide deutéré d'acide boronique ou composé ester de celui-ci, procédé de synthèse et application associés - Google Patents

Dipeptide deutéré d'acide boronique ou composé ester de celui-ci, procédé de synthèse et application associés Download PDF

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WO2018171816A1
WO2018171816A1 PCT/CN2018/087761 CN2018087761W WO2018171816A1 WO 2018171816 A1 WO2018171816 A1 WO 2018171816A1 CN 2018087761 W CN2018087761 W CN 2018087761W WO 2018171816 A1 WO2018171816 A1 WO 2018171816A1
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deuterated
compound
boronic acid
acid
pharmaceutically acceptable
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PCT/CN2018/087761
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English (en)
Chinese (zh)
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朱永强
雷萌
白恩赫
冯华云
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南京陵瑞医药科技有限公司
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/005—Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the field of drug synthesis, and particularly relates to a deuterated dipeptide boronic acid or an ester compound thereof, a synthesis method and use thereof.
  • the Ubiquitin-Proteasome Pathway is the main pathway for the degradation of intracellular protein systems and is involved in many physiologically important cellular processes including signal transduction, immune response, unfolded protein response and cell cycle. progress. This pathway has important relationships with cardiovascular and cerebrovascular diseases, cancer, and the pathogenesis of neurodegenerative diseases.
  • bortezomib PS-341
  • PS-341 the first proteasome inhibitor in 2003, was approved by the FDA for the treatment of recurrent myeloma.
  • the drug was approved for marketing in the European Union for multiple myeloma.
  • September 2005 the drug was introduced by Xi'an Yangsen and was first listed in Guangzhou, China.
  • the object of the present invention is to provide a novel class of compounds having proteasome inhibitory activity and better pharmacodynamic properties, as well as a synthesis method and use thereof.
  • the first aspect of the present invention discloses a deuterated dipeptide boronic acid or boric acid ester compound, or a crystal form thereof, or a pharmaceutically acceptable hydrate or solvate thereof, which has the structure of the following formula (a) Show,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, deuterium or halogen, or one or more deuterated or fully deuterated C 1 -C 4 alkyl groups; 1 , at least one of R 2 , R 3 , R 4 , R 5 , and R 6 is deuterated or deuterated;
  • the P group is selected from the following fragments:
  • B is a boron atom
  • Z 1 and Z 2 are independently selected from a hydroxyl group, a C 1-10 alkoxy group or an aryloxy group
  • the P group is a heterocyclic group containing N, S and/or O formed by the following fragment and other compounds,
  • B is a boron atom and the atom attached to formula (a) is B.
  • both R 1 and R 4 are halogen, and two of R 2 , R 3 , R 5 and R 6 and two hydrazines.
  • both R 1 and R 4 are chlorine, R 2 and R 3 are all hydrogen, and R 5 and R 6 are both hydrazine.
  • the P group is a boronic acid ester or anhydride group formed from the following fragment with an alpha-hydroxycarboxylic acid or a beta-hydroxycarboxylic acid,
  • B is a boron atom and the atom attached to formula (a) is B.
  • the P group is a borate group formed from a compound having two or more independent hydroxyl structures which are not on the same carbon atom,
  • B is a boron atom and the atom attached to formula (a) is B.
  • the deuterium isotope content of the deuterated substitution site is at least greater than the natural rhenium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%. More preferably greater than 95%, more preferably greater than 99%.
  • the compound of formula (I) contains at least one deuterium atom, more preferably two deuterium atoms.
  • R 1 and R 4 are selected from halogen; more preferably chlorine;
  • R 2 and R 3 are hydrogen
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, deuterium, deuterated methyl, deuterated ethyl, and halogen.
  • the borate moiety is a five-membered ring. In other embodiments, the borate moiety is a six-membered ring. In other embodiments, the borate moiety is a mixture of a five-membered ring and a six-membered ring.
  • the term "independently selected from” is that a plurality of groups are each selected from certain substituents, and that the groups are not related to each other, for example, "R 1 , R 2 are independently selected from hydrogen, deuterium or halogen. ",” means that R 1 is selected from hydrogen, deuterium or halogen, R 2 is selected from hydrogen, deuterium or halogen, and the R 1 and R 2 groups are not related to each other.
  • alpha-hydroxycarboxylic acid refers to a compound containing a hydroxyl group attached directly to a carbon atom relative to the alpha position of the carboxylic acid group.
  • alpha-hydroxycarboxylic acid is not intended to be limited to compounds having only one hydroxyl group and one carboxylic acid group.
  • ⁇ -hydroxycarboxylic acid refers to a compound containing a hydroxyl group attached directly to a carbon atom relative to the beta position of the carboxylic acid group.
  • ⁇ -hydroxycarboxylic acid is not intended to be limited to compounds having only one hydroxyl group and one carboxylic acid group.
  • the beta-hydroxy carboxylic acid is selected from the group consisting of malic acid, citric acid, 3-hydroxybutyric acid, beta-hydroxyisovaleric acid, and salicylic acid. In some other embodiments, the beta-hydroxy carboxylic acid is selected from the group consisting of malic acid, citric acid, 3-hydroxybutyric acid, beta-hydroxyisovaleric acid, tartaric acid, and salicylic acid. In certain embodiments, the beta-hydroxy carboxylic acid is citric acid. Some other non-limiting examples of beta-hydroxycarboxylic acids include glucoheptonic acid, maltoic acid, lactobionic acid, and galactosuccinic acid. Some other non-limiting examples of beta-hydroxycarboxylic acids include diquat, 1-hydroxy-2-naphthoic acid, and 3-hydroxy-2-naphthoic acid.
  • the alpha-hydroxy acid or beta-hydroxy acid is selected from the group consisting of glycolic acid, malic acid, hexahydromandelic acid, 2-hydroxyisobutyric acid, capric acid, mandelic acid, lactic acid, 3-hydroxy-butyric acid , ⁇ -hydroxyisovalerate, 2-hydroxy-3,3-dimethylbutyric acid, 2-hydroxy-3-methylbutyric acid,-hydroxyisohexanoic acid, tartaric acid, salicylic acid and benzoic acid.
  • the compound having two or more independent hydroxyl structures that are not on the same carbon atom is selected from the group consisting of diethanolamine, tartaric acid, alpha-D-glucose, D-ribose, and the like.
  • the structure of the formula (a) may be of the following two structures:
  • formula (a) may also be represented by formula (3) or (4):
  • the carbon atom to which the R 5 and R 6 groups in the compound of the present invention are attached may be a racemate or may be optically active.
  • the compound of interest is a preferred compound selected from the group consisting of;
  • a process for the preparation of the deuterated dipeptide boronic acid or borate ester compound, or a crystalline form thereof, or a pharmaceutically acceptable hydrate or solvate thereof comprising the following reaction process:
  • the P group is a heterocyclic group containing N, S and/or O formed by the following fragment and other compounds,
  • B is a boron atom and the atom attached to formula (a) is B.
  • a particularly preferred compound of the invention is ((R)-1-(2-(2,5-benzamide)-2,2-diacetylacetylamino)-3-methylbutyl)borate Ethanolamine ester (compound NNU-458).
  • Another particularly preferred compound of the invention is ((R)-1-(2-(2,5-benzamide)-2,2-dioxaacetylamino)-3-methylbutyl)boronic acid Phthalate
  • the present invention provides methods for their preparation.
  • the method includes:
  • NNU-455 can be reacted with decanoic acid in a similar manner to form NNU-459.
  • the compound (VIII) is produced by the following method:
  • the compound (VII) is reacted under the action of an inert solvent, heavy water, DMSO-d 6 and a base to form the compound (VIII).
  • the compound (VII) is produced by the following method:
  • the compound (VI) is produced by the following method:
  • the compound (IV) and the compound (V) are dehydrated and condensed by a condensing agent and a base to form the compound (VI).
  • the compound (IV) is obtained by the following method:
  • the compound (III) is obtained by the following method:
  • the base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, potassium hydroxide, sodium hydroxide or a combination.
  • a peptide condensing agent commonly used in the above reaction is N,N-dicyclohexyl-carbodiimide (abbreviated as DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. (abbreviated as EDC.HCl), 1-hydroxybenzotriazole (abbreviated as HOBt) or isobutyl chloroformate.
  • DCC N,N-dicyclohexyl-carbodiimide
  • EDC.HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • HOBt 1-hydroxybenzotriazole
  • isobutyl chloroformate isobutyl chloroformate.
  • each reaction temperature is carried out at -20 to 100 °C.
  • a method of preparing a pharmaceutical composition comprising the steps of: administering a pharmaceutically acceptable carrier to a compound of the first aspect of the invention, or a pharmaceutically acceptable crystalline form thereof The hydrate or solvate is mixed to form a pharmaceutical composition.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable hydrate or a solvent Compound.
  • the pharmaceutical composition is an injection, a sachet, a tablet, a pill, a powder or a granule.
  • the pharmaceutical composition further comprises an additional therapeutic agent, which is a medicament for cancer, cardiovascular disease, inflammation, immune disease, kidney disease, angiogenesis, prostate disease.
  • an additional therapeutic agent which is a medicament for cancer, cardiovascular disease, inflammation, immune disease, kidney disease, angiogenesis, prostate disease.
  • the therapeutic agents include, but are not limited to, 5-fluorouracil, AV412, avastin (bevacizumab), bexarotene, bortezomib, ossification Calcitriol, canertinib, capecitabine, carboplatin, celecoxib, cetuximab, CHR-2797, cis Platinum (cisplatin), dasatinib, digoxin, enzastaurin, erlotinib, etoposide, everolimus, fulvestrant Fulvestrant), gefitinib, 2,2-difluorodeoxycytidine, genistein, imatinib, irinotecan , lapatinib, lenalidomide, letrozole, leucovorin, matuzumab, oxaliplatin, paclitaxel Paclitaxel), panitumumab, pegfilgrastin, peglated al
  • a compound as described in the first aspect of the invention or a crystalline form, a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the preparation of a proteasome inhibiting substance Pharmaceutical composition.
  • the compounds are useful for the treatment and prevention of diseases associated with proteasome targets.
  • the pharmaceutical composition is for treating and preventing a disease: cancer, cardiovascular disease, inflammation, immune disease, kidney disease, angiogenesis, or prostate disease.
  • the cancer includes, but is not limited to, multiple myeloma, non-small cell lung cancer, uterine cancer, rectal, brain cancer, head cancer, neck cancer, skin cancer, prostate cancer, breast Cancer, solid tumor, kidney cancer, blood cancer, liver cancer, stomach cancer, or pancreatic cancer.
  • a method of treatment comprising the step of administering a compound of the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable hydrate or solvent, to a subject in need of treatment
  • the composition, or the pharmaceutical composition described in the third aspect of the invention is administered to inhibit the proteasome.
  • the disease comprises cancer, cardiovascular disease, inflammation, immune disease, kidney disease, angiogenesis or prostate disease.
  • the deuterated dipeptide boronic acid and boric acid ester of the present invention have more excellent pharmacokinetic and/or pharmacodynamic properties than the undeuterated compound, and thus are more suitable as a compound for inhibiting proteasome. It is further suitable for the preparation of a medicament for treating cancer and related diseases.
  • the present invention has been completed on this basis.
  • NNU-459 also showed better activity than the control compound MLN-9708 on the IC 50 (nM) of tumor cell line U266, RPMI-8266 and breast cancer cell line MAD-MB-231. .
  • deuterated refers to the replacement of one or more hydrogens in a compound or group by deuterium. Deuterated can be monosubstituted, disubstituted, polysubstituted or fully substituted. The terms “one or more deuterated” are used interchangeably with “one or more deuterated”.
  • the deuterated substitution of germanium in the unknown isotope content is at least greater than the natural rhenium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%. More preferably greater than 95%, more preferably greater than 99%.
  • the compound of the formula contains at least one deuterium atom, more preferably two deuterium atoms.
  • compound of the invention refers to a compound of formula (a).
  • the term also encompasses various crystalline forms, pharmaceutically acceptable hydrates or solvates of the compounds of formula (a).
  • the preparation methods of the undeuterated dipeptide boronic acid and its esters used in the present invention are known.
  • the dipeptide boronic acid and its ester corresponding to the deuterated can be used as the starting material of the corresponding deuterated boric acid compound. Synthesize using the same route.
  • a preferred preparation procedure is as follows.
  • compositions and methods of administration are provided.
  • the compound of the present invention has excellent inhibitory activity against proteasome, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable hydrate or solvate thereof, and pharmaceutical composition containing the compound of the present invention as a main active ingredient It can be used to treat, prevent, and alleviate diseases mediated by the proteasome.
  • the compounds of the invention are useful in the treatment of diseases such as cancer, cardiovascular disease, obesity, diabetes and the like.
  • 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 10 to 200 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.
  • “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.
  • carrier used interchangeably herein and include any and all solvents, diluents and other liquid carriers, dispersion or suspension aids, surfactants, pH adjusters, Isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., are suitable for the particular dosage form desired.
  • any conventional carrier medium is incompatible with a compound of the invention, for example, by causing any undesirable biological effects or interaction with any other component of the pharmaceutical composition to render the compound ineffective or ineffective, or to produce a hazardous substance, its use is It is considered to be within the scope of the invention.
  • Pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, carbonates, magnesium hydroxide and aluminum glycine, Sorbic acid or potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, pyrogen-free water, salts or electrolytes such as protamine sulfate, disodium phosphate, disodium hydrogen phosphate, sodium chloride and zinc salts, colloidal dioxide Silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, polyethylene-polyoxypropylene block polymer, lanolin, sugars such as lactose, glucose, sucrose and mannitol, starches such as corn starch and potato starch, cellulose And derivatives thereof such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, powdered tragacanth; malt
  • compositions of the present invention can be prepared by methods well known in the art, such as conventional granulation, mixing, dissolving, encapsulating, lyophilizing or emulsifying methods and the like.
  • the compositions can be produced in a variety of forms including granules, pellets or granules, powders, including freeze-dried, spin-dried or spray-dried powders, amorphous powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, mashes, and mixtures. Suspending agent or solution.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and according to a preferred embodiment, the composition of the present invention is formulated for administration to a mammal, preferably to a human.
  • These pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable kit.
  • the term "digestive administration" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic and intracranial injection or infusion techniques.
  • the composition is administered orally, intravenously or subcutaneously.
  • the formulations of the invention can be designed to be short acting, fast release or long lasting. Additionally, the compounds can be administered in a local rather than systemic manner, such as at the site of a tumor (eg, by injection).
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butanediol, cyclodextrin, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin , tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters, sorbitan and mixtures thereof.
  • the oral compositions may also contain adj
  • 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, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants , 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; An absorption accelerator, for example, a quaternary amine compound; (g) a wetting agent, for example, cetylene glycol
  • 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.
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • Injectable preparations for example, sterile injectable aqueous or oily suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, a compound sodium chloride injection, and an isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium, and any of the ⁇ RTIgt; Further, a fatty acid such as oleic acid is used for the preparation of an injection.
  • the injectable preparation may be sterilized by, for example, filtration through a bacterial retention filter or by incorporating a sterilizing agent in the form of a sterile solid composition which may be dissolved or dispersed in sterile water or otherwise before use.
  • sterile injectable media Compositions formulated for parenteral administration may be administered by bolus injection or by timed bolus injection, or may be administered by continuous infusion.
  • Dosage forms for topical or transdermal administration of a compound of the invention include ointments, powders, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers which may be required.
  • Ophthalmic formulations, ear drops and eye drops are also considered to be within the scope of the invention.
  • the present invention contemplates the use of transdermal patches that have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the invention provides pharmaceutical compositions of the compounds and other excipients described herein. In some other embodiments, the invention provides pharmaceutical compositions of a compound of NNU-455 and other excipients described herein. In other embodiments, the invention provides a pharmaceutical composition comprising a decanoate (NNU-459) and diethanolamine (NNU-458) of NNU 455 and other excipients described herein.
  • the pharmaceutical formulations of the present invention are prepared by using excipients having low or low moisture content and using dry or non-aqueous formulation methods to provide a stable solid oral dosage form of the active compound.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the compound of the present invention has excellent inhibitory property against a proteasome.
  • the dosage can be varied and a long acting formulation can be formed, which can also improve the suitability in the form of a long acting formulation.
  • Substituting hydrazine for the hydrogen atom in the compound, due to its isotope effect, can increase the drug concentration of the compound in the animal to improve the efficacy of the drug.
  • Step III Take the compound obtained in Step III (129mg, 0.31mmol) was dissolved with 2.5mLMeOH, was added LiOH ⁇ H 2 O (39mg, 0.92mmol) and H 2 O (0.8mL), TLC detection, reaction was complete after 2h.
  • the organic phase was dried, the aqueous phase was extracted with diethyl ether (2 ⁇ 1 mL), and aqueous hydrochloric acid was added dropwise to pH 2-3 to yield a large white solid, ethyl acetate.
  • -N-(2,5-dichlorobenzoyl)glycine 106 mg, yield 86.0%, mp 169.3-170.8 °C.
  • the compound VII (500 mg, 1.38 mmol) was dissolved in 16 ml of anhydrous tetrahydrofuran, potassium carbonate (191.4 mg, 1.38 mmol), DMSO-d6 (3.75 ml), and water (2.5 ml) were added, and the reaction was stirred for 5 hours in an oil bath at 65 ° C. . After the completion of the reaction by LC-MS, the tetrahydrofuran was evaporated under reduced pressure, and a small amount of water was added and the mixture was extracted with ethyl acetate. The organic phase was washed twice with water and brine, and the solvent was evaporated. Pure product 278mg, yield 55.6%.
  • the citric acid (192.12 mg, 0.39 mmol) was dissolved in 2 mL of ethyl acetate, and the temperature was raised to 74 ° C. After the decanoic acid was completely dissolved, Compound VII (363.03 mg, 0.36 mmol) dissolved in 1 mL of ethyl acetate was added. Slowly cool to 60 ° C, react for 3 h, then slowly cool to 25 ° C overnight. The reaction was detected by TLC, filtered, and the cake was vacuum dried to give a pure product (yield: 90.0 mg).
  • Two groups were administered with 0.100 mg ⁇ mL -1 NNU-459 and MLN-9708 in the tail vein at a dose of 0.500 mg ⁇ kg -1 , respectively, before administration and 10 min, 20 min, 30 min, 1 h, 2 h, 4 h after administration.
  • blood was collected from the jugular vein by about 0.200mL, placed in a test tube containing EDTA-K 2 , centrifuged at high speed (7800 ⁇ g) for 5 min, and the plasma was separated and stored at -15 ° C to -35 ° C. . Used to compare the pharmacokinetic differences between NNU-459 and MLN-9708 administered intravenously.
  • the other two groups were administered 0.150 mg ⁇ mL -1 NNU-459 and MLN-9708 at a dose of 1.50 mg ⁇ kg -1 , respectively, before administration and 5 min, 10 min, 20 min, 30 min, 1 h, 2 h after administration.
  • blood was collected from the jugular vein by about 0.200mL, placed in a test tube containing EDTA-K 2 , and centrifuged at high speed (7800 ⁇ g) for 15 minutes, and the plasma was separated at -15 ° C ⁇ -35 °C save. Used to compare the pharmacokinetic differences between NNU-459 and MLN-9708 administered orally.
  • the compound of the present invention has better pharmacokinetics in animals and thus has better pharmacodynamics and therapeutic effects.
  • the metabolism of the compounds of the present invention in organisms is altered by deuteration. This leads to a reduction in the first-pass effect.
  • the dosage can be varied and a long acting formulation can be formed, which can also improve the suitability in the form of a long acting formulation.
  • the pharmacokinetic effect is also altered by deuteration because the deuterated compound completely forms another hydrate membrane such that the distribution in the organism is significantly different from the undeuterated compound.
  • Example 4 Liver microsome stability experiment of NNU-455 and MLN-2238
  • NNU-455 and MLN-2238 of NNU-459 and MLN-9708 was determined in liver microsomes of different species.
  • Human liver microsome working solution (2 ⁇ ) 0.3 mL of human liver microsome stock solution (20 mg/mL) was added to 5.7 mL of phosphate buffer to obtain a working solution of 1.0 mg/mL.
  • Rat liver microsome working solution (2 ⁇ ) 0.3 mL of rat liver microsome stock solution (20 mg/mL) was added to 5.7 mL of phosphate buffer to obtain a working solution of 1.0 mg/mL.
  • Mouse liver microsome working solution (2 ⁇ ) 0.3 mL of mouse liver microsome stock solution (20 mg/mL) was added to 5.7 mL of phosphate buffer to obtain a working solution of 1.0 mg/mL.
  • Canine liver microsome working solution (2 ⁇ ) 0.3 mL of canine liver microsome stock solution (20 mg/mL) was added to 5.7 mL of phosphate buffer to obtain a working solution of 1.0 mg/mL.
  • v. Monkey liver microsome working solution (2 ⁇ ) 0.3 mL of monkey liver microsome stock solution (20 mg/mL) was added to 5.7 mL of phosphate buffer to obtain a working solution of 1.0 mg/mL.
  • Working solution of the test article (10 ⁇ ) firstly prepare a 10 mM stock solution with DMSO, then dilute to 100 ⁇ M with 50% methanol-water, and then dilute to a working solution at a concentration of 10 ⁇ M with a phosphate buffer.
  • Stop Solution 100 ng/mL tolbutamide was formulated with methanol as a stop solution containing an internal standard.
  • the matrix required for the reaction was added in the order of Table 1 below, and the test article was made in 3 parallels at each time point, and the positive control was made in 3 parallels at each time point.
  • the concentration of the compound at different incubation time points is expressed as Aa/Ai (the ratio of the compound to the peak area of the internal standard mass spectrometry signal).
  • the residual rate is obtained by dividing the concentration of each compound at each time point by the concentration at time 0, and the calculation formula is as follows:
  • Vd is the apparent partition coefficient
  • the detection solution used in this patent is a single-solution cell proliferation assay kit from Promega; the cells used are U266, RPMI8226.
  • the experimental system is 110 ⁇ L, which contains 90 ⁇ L of cell suspension, 10 ⁇ L of detection solution, and 10 ⁇ L of drug (inhibitor).
  • the final concentration is 4.54 ⁇ 10 -8 M to 1.77 ⁇ 10 -9 M, and the last concentration is 0 M. It is 5 ⁇ 10 -7 M to 1.95 ⁇ 10 -8 M, and the last concentration is 0M.
  • the specific experimental process is as follows:
  • the drug was accurately weighed and dissolved in DMSO to 10 -2 M.
  • the dilution configuration U266 was 1 ⁇ 10 4 /well
  • the RPMI 8226 was 1 ⁇ 10 4 /well.
  • NNU-459, NNU-458 are similar to the IC 50 MLN-9708, showed the same activity or better inhibition of tumor.
  • the medicament of the present invention may take, but is not limited to, the following pharmaceutical composition:
  • Dosage per unit dose (mg) Dosage (%w/w or w/w) The compound 4 1.3 Microcrystalline cellulose 231.8 77.3 Pregelatinized starch 60 20 Silica 1.2 0.4 Magnesium stearate 3 1 Content weight 300 100
  • Dosage per unit dose (mg) Dosage (%w/w or w/w)
  • the medicament 4 1.3 Microcrystalline cellulose 246.8 82.3 Mannitol 45 15 talcum powder 1.2 0.4 Magnesium stearate 3 1 Content weight 300 100
  • Dosage per unit dose (mg) Dosage (%w/w or w/w) The compound 3 1.5 Microcrystalline cellulose 150 75 corn starch 45 22.5 Magnesium stearate 2 1 Content weight 200 100
  • Dosage per unit dose (mg) Dosage (%w/w or w/w) The compound 3 1.5 Mannitol 120 60 lactose 45 37.5 Magnesium stearate 2 1 Content weight 200 100
  • Mannitol 100 50 Microcrystalline cellulose 95 47.5 Magnesium stearate 2 1 Content weight 200 100
  • Dosage per unit dose (mg) Dosage (%w/w or w/w) The compound 2.3 1.15 Microcrystalline cellulose 195 97.5 talcum powder 0.7 0.35 Magnesium stearate 2 1 Content weight 200 100
  • Dosage per unit dose (mg) Dosage (%w/w or w/w) The compound 2.3 1.15 Silicified microcrystalline cellulose 155 77.5 Mannitol 40 20 talcum powder 0.7 0.35 Magnesium stearate 2 1 Content weight 200 100
  • the above pharmaceutical composition was uniformly mixed in a usual manner, and then placed in an opaque white gelatin capsule.
  • the compound includes the compound NNU-455 and its phthalate ester (NNU-459) and diethanolamine ester (NNU-458).

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Abstract

La présente invention concerne un dipeptide deutéré d'acide boronique ou un composé ester de celui-ci, ou une forme cristalline, un hydrate ou un solvate pharmaceutiquement acceptable de celui-ci, la structure de celui-ci étant représentée par la formule (a), dans laquelle : R 1, R2, R3, R4, R5 et R6 sont indépendamment choisis parmi l'hydrogène, le deutérium, ou l'halogène, ou un groupe alkyle choisi parmi plusieurs groupes alkyle en C1-C4 deutérés ou entièrement deutérés; et au moins l'un parmi R1, R2, R3, R4, R5 ou R6 est deutéré ou est du deutérium. Le composé de la présente invention peut inhiber efficacement les protéasomes, et peut traiter ou prévenir de manière efficace un cancer, une maladie cardiovasculaire, une inflammation, une maladie immunitaire, une maladie rénale, une angiogenèse ou une maladie de la prostate.
PCT/CN2018/087761 2017-03-23 2018-05-22 Dipeptide deutéré d'acide boronique ou composé ester de celui-ci, procédé de synthèse et application associés WO2018171816A1 (fr)

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JP6802899B2 (ja) * 2016-07-25 2020-12-23 深▲セン▼市塔吉瑞生物医▲薬▼有限公司Ｓｈｅｎｚｈｅｎ ＴａｒｇｅｔＲｘ，Ｉｎｃ． 置換ボロン酸化合物、該化合物を含む医薬組成物およびその使用
CN106916177B (zh) * 2017-03-23 2019-04-23 南京陵瑞医药科技有限公司 一种氘代的二肽硼酸或其酯类化合物及其合成方法与用途
CN108794516A (zh) * 2017-04-26 2018-11-13 上海时莱生物技术有限公司 硼酸和硼酸酯类化合物及其制备方法和用途
WO2019020099A1 (fr) * 2017-07-28 2019-01-31 成都地奥九泓制药厂 Composé de borate et procédé de synthèse et utilisations de ce composé
CN113603713A (zh) * 2017-12-05 2021-11-05 深圳市塔吉瑞生物医药有限公司 一种取代的硼酸酯化合物的制备方法及其晶型
CN109053782B (zh) * 2018-08-09 2020-01-17 潍坊博创国际生物医药研究院 多功能靶向免疫小分子抗癌药枸橼酸Bestazomib及其制备方法与应用
CN110357787A (zh) * 2019-08-02 2019-10-22 苏州艾和医药科技有限公司 依沙佐米合成工艺研究
CN113105486B (zh) * 2021-02-24 2023-08-15 南京师范大学 一种硼酸酯类化合物及其药学上可接受的盐、其制备方法及其用途

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