WO2022171151A1 - 一种smtp-7衍生物及其用途 - Google Patents

一种smtp-7衍生物及其用途 Download PDF

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WO2022171151A1
WO2022171151A1 PCT/CN2022/075740 CN2022075740W WO2022171151A1 WO 2022171151 A1 WO2022171151 A1 WO 2022171151A1 CN 2022075740 W CN2022075740 W CN 2022075740W WO 2022171151 A1 WO2022171151 A1 WO 2022171151A1
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deuterium
compound
pharmaceutically acceptable
acceptable salt
formula
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PCT/CN2022/075740
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English (en)
French (fr)
Inventor
祝令建
于秀招
刘晓武
贲培培
陈磊
孔祥林
黄建
孙飘扬
Original Assignee
上海森辉医药有限公司
上海盛迪医药有限公司
江苏恒瑞医药股份有限公司
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Priority to EP22752311.5A priority Critical patent/EP4293028A4/en
Priority to US18/546,071 priority patent/US20240190896A1/en
Priority to CN202280008550.0A priority patent/CN116669723A/zh
Publication of WO2022171151A1 publication Critical patent/WO2022171151A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • 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 present disclosure belongs to the field of medicine, and relates to a SMTP-7 derivative and use thereof.
  • SMTP-7 (TMS-007, Stachybotrys microspore triprenyl phenol-7) was extracted from a mold (Stachybotrys microspora) on a special fallen leaf on Iriomote Island, Okinawa Prefecture in 2000. Vitamin E is similar. It has a novel mechanism of action to break down blood clots and is thought to inhibit local inflammation at the site of the thrombus. In addition, SMTP-7 also has anti-tumor angiogenesis activity, antioxidant activity and tissue regeneration promoting activity (WEIMIN H, SHIGEKI O, et al. J. Antibiot., 2000, 53(3): 241-247).
  • Plasminogen is the precursor of plasmin, which can be activated to generate plasmin. This is a protease that hydrolyzes many proteins, including thrombin. After binding to plasminogen, SMTP-7 changes its molecular conformation and is more easily activated by plasminogen activator. So SMTP-7 itself does not activate plasminogen function, it just makes the activation process easier. This unique combination of action of SMTP-7 makes SMTP-7 a best-in-class thrombolytic drug for the treatment of acute ischemic stroke (AIS), which is comparable to existing standard thrombolytic drugs.
  • AIS acute ischemic stroke
  • Ratio has the potential to extend the therapeutic window (although many antihypertensive, lipid-lowering, and anticoagulant drugs can prevent stroke, the only therapeutic drugs currently used for ischemic stroke are recombinant tissue plasminogen activator (rt-PA, A teplase), whose main component is a glycoprotein, containing 526 amino acids).
  • rt-PA tissue plasminogen activator
  • the SMTP molecule induces a conformational change in plasminogen, resulting in an increased rate of plasminogen binding to fibrin, and ultimately activation of plasmin. Additionally, SMTP induces self-cleavage of plasmin to provide angiogenic human angiostatin-like fragments. This activity is believed to be the mechanism for the anti-angiogenic and anti-tumor effects of SMTP molecules. Furthermore, SMTP-induced increases in activated plasminogen may control local extracellular proteolysis, leading to tissue remodeling, wound healing, and tissue regeneration.
  • the disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • R 27 is selected from deuterium
  • R 28 is selected from deuterium
  • R 36 is selected from deuterium
  • R 37 is selected from deuterium.
  • R 26 is selected from deuterium
  • R 38 is selected from deuterium
  • R 24 is selected from deuterium
  • R 25 is selected from deuterium
  • R 39 is selected from deuterium
  • R 40 is selected from deuterium.
  • R 29 in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from deuterium.
  • R 30 is selected from deuterium
  • R 31 is selected from deuterium
  • R 34 is selected from deuterium
  • R 35 is selected from deuterium
  • R 16 is selected from deuterium
  • R 17 is selected from deuterium
  • R 47 is selected from deuterium
  • R 48 is selected from deuterium.
  • R 12 is selected from deuterium
  • R 13 is selected from deuterium
  • R 14 is selected from deuterium
  • R 50 is selected from deuterium
  • R 51 is selected from deuterium
  • R 52 is selected from deuterium
  • R 23 is selected from deuterium
  • R 41 is selected from deuterium
  • R 32 is selected from deuterium
  • R 33 is selected from deuterium
  • R 30 is selected from deuterium
  • R 31 is selected from deuterium
  • R 32 is selected from deuterium
  • R 33 is selected from deuterium
  • R 34 is selected from deuterium
  • R 35 is selected from deuterium. is selected from deuterium.
  • R 29 is selected from deuterium
  • R 30 is selected from deuterium
  • R 31 is selected from deuterium
  • R 32 is selected from deuterium
  • R 33 is selected from deuterium
  • R 34 is selected from deuterium.
  • R35 is selected from deuterium.
  • R 1 is selected from deuterium
  • R 2 is selected from deuterium
  • R 3 is selected from deuterium
  • R 4 is selected from deuterium
  • R 5 is selected from deuterium
  • R 6 is selected from deuterium
  • R 58 is selected from deuterium
  • R 59 is selected from deuterium
  • R 60 is selected from deuterium.
  • R 61 is selected from deuterium
  • R 62 is selected from deuterium
  • R 63 is selected from deuterium
  • R 1 is selected from deuterium
  • R 2 is selected from deuterium
  • R 3 is selected from deuterium
  • R 4 is selected from deuterium
  • R 5 is selected from deuterium
  • R 6 is selected from deuterium.
  • R58 is selected from deuterium
  • R59 is selected from deuterium
  • R60 is selected from deuterium
  • R61 is selected from deuterium
  • R62 is selected from deuterium
  • R63 is selected from deuterium.
  • R 7 is selected from deuterium
  • R 57 is selected from deuterium
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned compound represented by formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.
  • the present disclosure also provides a method for preventing and/or treating cardiovascular and cerebrovascular diseases by administering to the patient a therapeutically effective amount of the aforementioned compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the disease is selected from thromboembolic diseases.
  • the disease is selected from myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortocoronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral Arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.
  • the present disclosure also provides the use of the compound represented by the aforementioned formula I or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases.
  • the disease is selected from thromboembolic diseases.
  • the disease is selected from myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortocoronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral Arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.
  • the present disclosure also provides a compound of formula I or a pharmaceutically acceptable salt thereof for preventing and/or treating cardiovascular and cerebrovascular diseases.
  • the disease is selected from thromboembolic diseases.
  • the disease is selected from myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortocoronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral Arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.
  • the pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts.
  • the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of this disclosure.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both Two configurations.
  • the bond The configuration is not specified, i.e. it can be either the Z configuration or the E configuration, or both.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton transfer such as keto-enol and imine-enamine, lactam-lactam isomerizations .
  • An example of a lactam-lactam equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically-labeled compounds of the present disclosure which are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic weight or mass number different from that normally found in nature.
  • isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) of deuterium (ie, at least 45 % of deuterium incorporated).
  • the compounds of the present disclosure are at least 3500 times (52.5% deuterium incorporated at each designated deuterium atom), at least 4000 times ( 60% deuterium incorporated), at least 4500 times (67.5% deuterium incorporated), at least 5000 times (75% deuterium incorporated), at least 5500 times (82.5% deuterium incorporated), at least 6000 times (90% deuterium incorporated) , at least 6333.3 times (95% deuterium incorporation), at least 6466.7 times (97% deuterium incorporated), at least 6600 times (99% deuterium incorporated), or at least 6633.3 times (99.5% deuterium incorporated).
  • the present disclosure also includes compounds of formula (I) in various deuterated forms.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to relevant literature to synthesize the compound of formula (I) in deuterated form.
  • Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients Form.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable excipient” or “acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, Glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • an “effective amount” or “therapeutically effective amount” as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • experimental methods without specific conditions are generally based on conventional conditions or conditions suggested by raw material or commodity manufacturers.
  • Reagents with no specific source indicated are conventional reagents purchased in the market.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the MS was measured with an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS instrument (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.
  • HPLC preparations used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying the compound, and the volume of the solvent
  • TLC thin layer chromatography
  • the ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • Stachybotrys microspora IFO30018 was inoculated into seed medium (4% glucose, 0.5% soybean poise, 0.3% dry broth, 0.3% yeast extract, 0.01% defoamer, pH 5.8), cultured 4 days.
  • the seed broth was re-inoculated into fermentation medium ( 5 % sucrose, 0.1% yeast extract, 0.3% NaNO3, 0.1% K2HPO4 , 0.05% MgSO4.7H2O , 0.05% KCl , 0.00025% CoCl2.6H 2 O, 0.0015% FeSO 4 ⁇ 7H 2 O, 0.00065% CaCl 2 ⁇ 2H 2 O, 0.01% defoamer, pH 5.8), after culturing for 4 days, L-ornithine was added to continue culturing for 1 day to complete the fermentation.
  • the fermentation broth was extracted with methanol.
  • the extract was concentrated by rotary evaporation and extracted with ethyl acetate. After dehydration with anhydrous sodium sulfate, it was filtered, concentrated, dried and solidified.
  • the cured product was dissolved in methanol, and pretreated and prepared using a reversed-phase filler.
  • the target product is obtained through steps such as ethyl acetate extraction.
  • Compound 1 was prepared according to the method of Example 1 by using ⁇ -deuterated L-ornithine (prepared according to Example 2).
  • Stachybotrys microspora IFO30018 was inoculated into seed medium (4% glucose, 0.5% soybean poise, 0.3% dry broth, 0.3% yeast extract, 0.01% defoamer, pH 5.8), cultured 4 days.
  • the seed broth was re-inoculated into fermentation medium ( 5 % sucrose, 0.1% yeast extract, 0.3% NaNO3, 0.1% K2HPO4 , 0.05% MgSO4.7H2O , 0.05% KCl , 0.00025% CoCl2.6H 2 O, 0.0015% FeSO 4 ⁇ 7H 2 O, 0.00065% CaCl 2 ⁇ 2H 2 O, 0.01% defoamer, pH 5.8), after culturing for 4 days, add ⁇ -deuterated L-ornithine for 1 day , to end fermentation.
  • the fermentation broth was extracted with methanol.
  • the extract was concentrated by rotary evaporation and extracted with ethyl acetate. After dehydration with anhydrous sodium sulfate, it was filtered, concentrated, dried and solidified.
  • the cured product was dissolved in methanol, and pretreated and prepared using a reversed-phase filler.
  • the target compound was obtained through steps such as ethyl acetate extraction.
  • each sample was collected through the jugular vein or other suitable blood collection methods, anticoagulated with heparin sodium, and placed on ice immediately after collection.
  • the samples were collected before administration and 5min, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 10h, and 24h after administration. Blood samples were collected at 10 time points.
  • the collected blood samples were placed in a heparin anticoagulant blood collection tube, and the plasma was separated by centrifugation (centrifugation force 6800 g, centrifugation for 6 min, 2-8° C.). Plasma samples were stored in a -80°C freezer prior to analysis.
  • the blood concentration of each test substance is detected, and the quality control samples are analyzed at the same time as the samples are analyzed, and the accuracy of the quality control samples exceeding 66.7% is required to be between 80-120%.
  • the target product compound 2 was prepared by referring to the method of Example 1.
  • Compound 3b is a racemate, and after chiral preparation, 2.2 g of target compound 3c is obtained as a configuration monomer.
  • the target product compound 3 was prepared by referring to the method of Example 1.
  • the target product compound 4 was prepared by referring to the method of Example 1.
  • the embolic stroke model was prepared with reference to literature methods (J Cereb Blood Flow Metab, 1997, 17(2): 123-135.). 0.1 mL of rat blood was taken, immediately inhaled into a PE50 tube, placed at room temperature for 2 hours, and then stored at 4°C for 22 hours. The thrombus was pushed out into 30 mL of normal saline and washed 3 times for 5 min each time. Cut emboli with a length of 5mm and put them in a special PE50 tube at the end of the suction tube for use.
  • the rats were fixed on the operating table in a supine position, the skin was incised at the midline of the neck, the right common carotid artery was dissociated, and the branches of the internal carotid artery were isolated and clamped. Cut a small incision at the common carotid artery, push the embolus in the catheter into the brain with 0.4 mL of normal saline, carefully withdraw the cannula, ligate the common carotid artery, and suture the skin.
  • the neurological function score was performed 1 hour after the modeling. Those with a score of ⁇ 8 were successfully established.
  • the rats were divided into sham operation group, model control group, test drug group (5, 10, 20 mg/kg), and control drug group. (10 mg/kg), 10 rats in each group.
  • the sham operation group and the model control group were given normal saline
  • the test drug group was given compound 1 (1 mg/ml, prepared with normal saline (2mM NaOH solution to adjust the pH to about 9.2)
  • the control drug group was given SMTP-7 (1 mg/ml, Physiological saline (pH adjusted to about 9.2 with 2 mM NaOH solution).
  • 10% of the liquid volume was injected intravenously, and the remaining 90% was infused for 30 minutes. The end point of the test was 24h after the drug.
  • the degree of behavioral disturbance of animals was observed and scored before administration and 24 hours after treatment.
  • the scoring criteria are as follows:
  • the brain was collected by cardiac perfusion, and the brain tissue was frozen in a -20 °C refrigerator, and sliced from front to back, each slice with a thickness of 2 mm. Sections with bleeding were scored as 1 point, and the sum of the scores of each section was the total bleeding score of each animal.
  • the brain was collected by cardiac perfusion, and the brain tissue was frozen in a -20 °C refrigerator, and sliced from front to back, each slice with a thickness of 2 mm.
  • the brain tissue sections were placed in 2% red tetrazolium (TTC) solution and incubated at 37°C for 5 min.
  • TTC red tetrazolium
  • the infarcted tissue was white, and the non-infarcted tissue was red.
  • the cerebral infarct size was measured by Image J software, and the percentage of the infarct size in the whole brain area was calculated.
  • compound 1 and SMTP-7 both had significant improvements, and compound 1 was better than SMTP-7 at the same dose of 10 mg/kg (about 37% lower), and the probability of more severe infarction was higher. Low.
  • Compound 1 can improve neurological function and cerebral infarction size after cerebral infarction, and has a lower risk of bleeding.

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Abstract

本公开涉及一种SMTP-7衍生物及其用途。具体而言，提供了一种式I所示化合物或其可药用盐，其中各基团如说明书中所定义。

Description

一种SMTP-7衍生物及其用途 技术领域
本公开属于医药领域，涉及一种SMTP-7衍生物及其用途。
背景技术
SMTP-7(TMS-007,Stachybotrys microspore triprenyl phenol-7)于2000年提取自冲绳县西表岛一种特殊落叶上的霉菌(Stachybotrys microspora)，是一种小分子纤溶酶原激活剂，结构与维生素E类似。其具有一种新颖的分解血凝块的作用机制，同时被认为能够抑制血栓部位的局部炎症。此外，SMTP-7还具有抗肿瘤血管生成活性、抗氧化性及促进组织再生活性(WEIMIN H,SHIGEKI O,et al.J.Antibiot.,2000,53(3):241-247)。
Figure PCTCN2022075740-appb-000001
纤溶酶原是纤溶酶前体，激活后可以生成纤溶酶。这是一个蛋白酶，可以水解很多蛋白、包括血栓蛋白。SMTP-7与纤溶酶原结合后改变其分子构象，更容易被纤溶酶原激活剂激活。所以SMTP-7本身并无激活纤溶酶原功能，只是令激活过程更加容易。SMTP-7这种独特的组合作用使SMTP-7有望成为一款治疗急性缺血性卒中(AIS)同类最佳的(best-in-class)溶栓药物，与现有的标准溶栓药物相比具有延长治疗窗口的潜力(虽然很多降压、降脂、抗凝药可以预防中风，但治疗性药物现在只有用于缺血性中风的重组组织纤溶酶原激活剂(rt-PA，阿替普酶)，其主要成分是糖蛋白，含526个氨基酸)。
SMTP分子诱导纤溶酶原的构象变化，导致纤溶酶原结合血纤蛋白的速度加快，并最终激活得到纤溶酶。另外，SMTP诱导纤溶酶的自剪切，以提供血管生成人血管抑制素样片段。该活性被认为是SMTP分子的抗血管生成和抗肿瘤作用的机制。此外，SMTP诱导的激活纤溶酶原的增加可能会控制局部细胞外蛋白水解，从而导致组织重塑，伤口愈合和组织再生。
发明内容
本公开(The disclosure)提供了式I所示化合物或其可药用盐，
Figure PCTCN2022075740-appb-000002
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 33、R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41、R 42、R 43、R 44、R 45、R 46、R 47、R 48、R 49、R 50、R 51、R 52、R 53、R 54、R 55、R 56、R 57、R 58、R 59、R 60、R 61、R 62和R 63各自独立地为氢或氘，且R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 33、R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41、R 42、R 43、R 44、R 45、R 46、R 47、R 48、R 49、R 50、R 51、R 52、R 53、R 54、R 55、R 56、R 57、R 58、R 59、R 60、R 61、R 62和R 63中至少一个是氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 27选自氘，R 28选自氘，R 36选自氘，R 37选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 26选自氘，R 38选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 24选自氘，R 25选自氘，R 39选自氘，R 40选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 29选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 30选自氘，R 31选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 34选自氘，R 35选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 16选自氘，R 17选自氘，R 47选自氘，R 48选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 12选自氘，R 13选自氘，R 14选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 50选自氘，R 51选自氘，R 52选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 23选自氘，R 41选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 32选自氘，R 33选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 30选自氘，R 31选自氘，R 32选自氘，R 33选自氘，R 34选自氘，R 35选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 29选自氘，R 30选自氘，R 31选自氘，R 32选自氘，R 33选自氘，R 34选自氘，R 35选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 1选自氘，R 2选自氘，R 3选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 4选自氘，R 5选自氘，R 6选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 58选自氘，R 59选自氘，R 60选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 61选自氘，R 62选自氘，R 63选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 1选自氘，R 2选自氘，R 3选自氘，R 4选自氘，R 5选自氘，R 6选自氘，R 58选自氘，R 59选自氘，R 60选自氘，R 61选自氘，R 62选自氘，R 63选自氘。
在一些实施方案中，式I所示化合物或其可药用盐中R 7选自氘，R 57选自氘。
另一方面，一些实施方案提供的式I所示化合物或其可药用盐为
Figure PCTCN2022075740-appb-000003
式I所示典型化合物，包括但不限于：
Figure PCTCN2022075740-appb-000004
Figure PCTCN2022075740-appb-000005
本公开中还提供了一种药物组合物，包括至少一种治疗有效量的前述式I所示化合物或其可药用的盐以及药学上可接受的赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述式I所示化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述式I所示化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述式I所示化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有1％-99％的前述式I所示化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有2％-98％的前述式I所示化合物或其可药用的盐。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物 含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
本公开还提供一种预防和/或治疗心脑血管疾病的方法，其通过向所述患者施用治疗有效量的前述式I所示化合物或其可药用的盐。在一些实施方案中，所述疾病选自血栓栓塞性疾病。在一些实施方案中，所述疾病选自心肌梗塞、心绞痛、血管成型术或主动脉冠状动脉分流术后的再阻塞和再狭窄、弥散性血管内凝血、中风、短暂的局部缺血发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。
本公开还提供如前述式I所示化合物或其可药用的盐或前述药物组合物在制备用于预防和/或治疗心脑血管疾病的药物中的用途。在一些实施方案中，所述疾病选自血栓栓塞性疾病。在一些实施方案中，所述疾病选自心肌梗塞、心绞痛、血管成型术或主动脉冠状动脉分流术后的再阻塞和再狭窄、弥散性血管内凝血、中风、短暂的局部缺血发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。
本公开还提供一种用于预防和/或治疗心脑血管疾病的前述式I所示化合物或其可药用盐。在一些实施方案中，所述疾病选自血栓栓塞性疾病。在一些实施方案中，所述疾病选自心肌梗塞、心绞痛、血管成型术或主动脉冠状动脉分流术后的再阻塞和再狭窄、弥散性血管内凝血、中风、短暂的局部缺血发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。
另一方面，本公开中所述化合物可药用盐选自无机盐或有机盐。
另一方面，本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本公开所述化合物的化学结构中，键
Figure PCTCN2022075740-appb-000006
表示未指定构型，即如果化学结 构中存在手性异构体，键
Figure PCTCN2022075740-appb-000007
可以为
Figure PCTCN2022075740-appb-000008
或者同时包含
Figure PCTCN2022075740-appb-000009
Figure PCTCN2022075740-appb-000010
两种构型。本公开所述化合物的化学结构中，键
Figure PCTCN2022075740-appb-000011
并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2022075740-appb-000012
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少3000倍的丰度的氘(即，至少45％的氘掺入)。在某些实施方式中，本公开的化合物对于各个指定的氘原子的丰度为氘的天然丰度的至少3500倍(在各个指定的氘原子处52.5％的氘掺入)、至少4000倍(60％氘掺入)、至少4500倍(67.5％氘掺入)、至少5000倍(75％氘掺入)、至少5500倍(82.5％氘掺入)、至少6000倍(90％氘掺入)、至少6333.3倍(95％氘掺入)、至少6466.7倍(97％氘掺入)、至少6600倍(99％氘掺入)或至少6633.3倍(99.5％氘掺入)。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”或“可接受的赋形剂”包括但不限于任何已经被美国食品 和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本公开中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制本公开的范围。
本公开实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)。
waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。
手性HPLC分析测定使用Agilent 1260DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化 学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1：SMTP-7制备
Figure PCTCN2022075740-appb-000013
将小孢葡萄穗霉(Stachybotrys microspora)IFO30018接种至种子培养基(4％葡萄糖、0.5％大豆泊、0.3％干燥肉汤、0.3％酵母提取物、0.01％消泡剂，pH5.8)，培养4天。种子培养液再接种至发酵培养基(5％蔗糖、0.1％酵母提取物、0.3％NaNO3、0.1％K 2HPO 4、0.05％MgSO 4·7H 2O、0.05％KCl、0.00025％CoCl 2·6H 2O、0.0015％FeSO 4·7H 2O、0.00065％CaCl 2·2H 2O、0.01％消泡剂，pH5.8)，培养4天后，添加L-鸟氨酸继续培养1天，结束发酵。
利用甲醇提取发酵液。对提取液进行旋蒸浓缩，再使用乙酸乙酯提取。用无水硫酸钠脱水后，过滤、浓缩、干燥固化。
用甲醇溶解固化物，利用反相填料进行预处理和制备。再经过乙酸乙酯萃取等步骤，获得目标产物。
实施例2：δ-氘代-L-鸟氨酸制备(化合物1e)
Figure PCTCN2022075740-appb-000014
(S)-2-(双(叔丁氧基羰基)氨基)-4-氰基丁酸苄酯(化合物1b)
将化合物1a(参照Synlett,2016,vol.27,2，309–312制备，74.8g，234.9mmol)溶解于乙腈(750mL)中，加入Boc 2O(76.9g，352.4mmol)，加入DMAP(2.9g，23.5mmol)，然后在45℃条件下反应1-1.5小时，旋蒸除掉溶剂，粗品经柱层析纯化得95g目标化合物2b(纯度99.4％，收率100％)，MS(ESI)m/z 441.2[M+Na] +。
化合物1c和1d
将化合物1b(4.18g,10mmol)溶解于EA(100mL)(超干)和D 2O(20mL)，加入PtO 2(204mg)，置换D 2，并在D 2保护下30℃(外温)反应40h，反应基本结束，分液，水相用EA洗涤后，直接冻干得固体1.87g，将固体溶解到乙腈(5ml)和乙酸乙酯(20ml)中，室温搅拌，过滤，滤饼用乙酸乙酯洗涤，油泵干燥得化合物1c和1d的混合物1.54g(收率46％)。
δ-氘代-L-鸟氨酸(化合物1e)
将化合物1c和1d混合物(195mg，0.58mmol)溶解在6M盐酸水溶液中，室温反应2h，反应基本完全，旋蒸除掉溶剂，油泵干燥至恒重得到120mg浅黄色固体产物化合物1e(收率100％，纯度97.25％)。
HNMR(D 2O,400M):1.95～1.94(m,4H),2.91～2.98(m,0.027H)，3.96(t,J＝6.4Hz,1H).
实施例3：δ-氘代SMTP-7的制备(化合物1)
Figure PCTCN2022075740-appb-000015
采用δ-氘代L-鸟氨酸(按照实施例2制备)参照实施例1方法制备化合物1。
将小孢葡萄穗霉(Stachybotrys microspora)IFO30018接种至种子培养基(4％葡萄糖、0.5％大豆泊、0.3％干燥肉汤、0.3％酵母提取物、0.01％消泡剂，pH5.8)，培养4天。种子培养液再接种至发酵培养基(5％蔗糖、0.1％酵母提取物、0.3％NaNO3、0.1％K 2HPO 4、0.05％MgSO 4·7H 2O、0.05％KCl、0.00025％CoCl 2·6H 2O、0.0015％FeSO 4·7H 2O、0.00065％CaCl 2·2H 2O、0.01％消泡剂，pH5.8)，培养4天后，添加δ-氘代L-鸟氨酸继续培养1天，结束发酵。
利用甲醇提取发酵液。对提取液进行旋蒸浓缩，再使用乙酸乙酯提取。用无水硫酸钠脱水后，过滤、浓缩、干燥固化。
用甲醇溶解固化物，利用反相填料进行预处理和制备。再经过乙酸乙酯萃取等步骤，获得目的物。
1H NMR(400MHz,DMSO-d6)δ13.07–12.66(br.,1H),9.79(s,1H),9.73(s,1H),6.66(s,1H),6.62(s,1H),5.28–5.09(m,3H),5.07–4.95(m,2H),4.72(dd,J＝9.9,5.7Hz,1H),4.26–4.05(m,4H),3.73(dd,J＝13.0,6.9Hz,2H),2.82(dt,J＝17.0,4.8Hz,2H),2.48–2.38(m,2H),2.17–2.05(m,4H),2.04–1.95(m,4H),1.95–1.81(m,6H),1.66–1.46(m,23H),1.18(s,3H),1.15(s,3H).
测试例1：大鼠体内药代动力学研究
1.1供试品的制备
分别称取适量SMTP-7和化合物1，依次加入终体积2％DMSO、98％生理盐水，涡旋超声使充分混匀后，得到浓度为1mg/mL的澄清溶液，以备用。
1.2动物
SD大鼠，年龄6-8周，体重约180-220g
1.3方案
Figure PCTCN2022075740-appb-000016
1.4样品采集
经颈静脉或其它适合采血方式，每个样品采集约0.20mL，肝素钠抗凝，采集后马上放置冰上。采集给药前及给药后5min、0.25h、0.5h、1h、2h、4h、6h、10h、24h。共10个时间点血样。将收集的血液样本置于肝素抗凝型采血管中，离心分离血浆(离心力6800g，离心6min，2-8℃)。血浆样本在分析前存放于-80℃冰箱内。
1.5生物分析和数据处理
检测各受试物血药浓度，分析样品的同时进行质控样品的分析，并要求超过 66.7％的质控样品的准确度在80-120％之间。
进行血浆药物浓度-时间曲线绘制时，BLQ均记为0。进行药代参数计算时，给药前的浓度按照0计算；Cmax之前的BLQ(包括“No peak”)按照0计算；C max之后出现的BLQ(包括“No peak”)一律不参与计算。通过不同时间点的血药浓度数据，采用Phoenix WinNonlin 7.0软件的非房室模型统计矩法计算以下药代动力学参数：AUC (0-t)、AUC (0-∞)、T 1/2、MRT、C max、T max等参数。
实验结果：
组别 T 1/2(h) T max(h) C max(ng/ml) AUC (0-t)(h*ng/ml) MRT (0-t)
1 6.689±0.178 0.08±0.00 26,311.98±6,236.41 8,009.467±1,832.168 0.465±0.080
2 8.94±0.61 0.08±0.00 19,078.40±4,312.75 11,287.80±1,377.70 3.06±0.25
结论：相比于SMTP-7，化合物1在SD大鼠静脉注射给药后体现了更长的半衰期，更低的C max。
实施例4：α-氘代-L-鸟氨酸的制备
Figure PCTCN2022075740-appb-000017
α-氘代-2-((叔丁氧羰基)氨基)-4-氰基丁酸(化合物2c)
氮气保护下，化合物1b(按照实施例1制备，25.0g，59.8mmol)，加入MeOD125mL搅拌溶解，加入无水碳酸钾(41.3g，299.0mmol)，20-30℃反应16h，反应基本结束，体系直接浓缩得到粗品化合物2c。MS(ESI)m/z 252.1[M+Na] +。
α-氘代-2-((叔丁氧羰基)氨基)-4-氰基丁酸苄酯(化合物2d)
化合物2c粗品(25.0g，59.8mmol)，加入无水乙腈150mL，加入BnBr(15.3g，89.7mmol)，氮气保护，20-30℃反应6h，反应基本完全，过滤，滤饼乙腈洗涤，滤液浓缩，粗品经柱层析得到6.8g目标化合物2d，手性HPLC检测为消旋体(两步收率35.7％)，MS(ESI)m/z 343.1[M+Na]+。
α-氘代-(S)-2-((叔丁氧羰基)氨基)-4-氰基丁酸苄酯(化合物2e)
将上述制备获得的6.8g化合物2d外消旋产品经手性拆分，得到3.6g的化合物2e。
仪器：MGⅡpreparative SFC(SFC-14)，手性柱：ChiralPak AY，250×30mm I.D.,5 μm，流动相A：二氧化碳，流动相B：甲醇(0.1％氨水)、梯度15％，流速：60ml/min，背压：100bar，柱温：38℃，检测波长：220nm，分离时长：约6min。
HNMR(CDCl3,400M)：1.44(s,9H),1.58～1.65(m,1H),1.97～2.04(m,1H),2.23～2.28(m,1H),,2.38～2.46(m,1H),5.17～5.20(m,2H),7.36～7.38(m,5H).
α-氘代-(S)-5-氨基-2-((叔丁氧基羰基)氨基)戊酸(化合物2f)
称取化合物2e(3.5g，10.9mmol)，加入70mL乙酸乙酯溶解，加入纯净水700mL，加入PtO 2(224mg，0.9mmol)，抽换氢气，20-30℃反应16h，反应基本完全，过滤，滤液分液，收集水相，水相水洗，冻干得到目标化合物2f粗品约1.6g，加入20mL乙酸乙酯和2mL乙腈，打浆，过滤，固体抽干，得到纯品约1.5g(收率58.6％)。MS-ESI:m/z 236.1[M+H]+。
HNMR(D2O,400M):1.44(s,9H),1.58～1.80(m,4H),2.93～2.98(m,2H).
α-氘代-L-鸟氨酸(化合物2g)
称取化合物2f(1.5g，6.4mmol)，加入6M HCl约10mL搅拌溶解，20-30℃反应2h，反应基本完全，反应液直接冻干，得到化合物2g粗品1.2g，加入20mL乙腈打浆，过滤，得到固体1.1g纯品(收率83.9％)。MS-ESI:m/z 134.1[M+H]+。
HNMR(D2O,400M):1.67～2.01(m,4H),2.98～3.01(m,2H).
实施例5：α-氘代SMTP-7的制备(化合物2)
Figure PCTCN2022075740-appb-000018
采用α-氘代L-鸟氨酸(按照实施例4制备)参照实施例1方法制备获得目标产物化合物2。
实施例6：β-氘代-L-鸟氨酸(化合物3e)的制备
β-氘代-L-鸟氨酸(化合物3e)
Figure PCTCN2022075740-appb-000019
化合物3b
将化合物3a(3.8g,15.4mmol，参考Journal of the American Chemical Society,2017,vol.139,39,13830-13836制备)、无水碳酸钾(10.6g，77mmol)溶于60mL无水乙腈中；加入BnBr(5.3g，30.8mmol)，10-20℃反应16小时；过滤，除不溶物，有机相EA洗涤，滤液浓缩得到粗品柱层析(PE:EA＝10:1)得到4.8g目标化合物3b(纯度93.3％，收率97％)。
MS-ESI:m/z 343.1[M+Na] +
1HNMR(CDCl 3,400M):1.45(s,9H),4.36-4.40(m,1H),5.17-5.24(s,2H),7.27-7.40(m,5H).
化合物3c
化合物3b为消旋体，手性制备后得到构型单体2.2g目标化合物3c。
化合物3d
化合物3c(2.2g,6.9mmol)，加入EA和水搅拌溶解，加入PtO2(0.3g，1.3mmol)，体系抽换氢气三次，10-20℃反应16小时，过滤，水相加入EA约50mL分液，收集水相，减压浓缩，油泵拉干得到粗品，加入20mL乙酸乙酯和2mL乙腈10-20℃打浆，过滤，EA洗涤，收集固体干燥得到1.2g目标化合物3d。
MS-ESI:m/z 235.1[M+H] +
化合物3e
化合物3d(1.2g,5.1mmol)溶于12mL 6M盐酸水溶液中，10-20℃反应4小时，直接油泵减压浓缩得1.05g目标化合物3e(收率100％)。
MS-ESI:m/z 135.1[M+H] +
1HNMR(CDCl 3,400M):1.67-1.81(m,2H),1.91-1.93(m,0.1H),2.95-2.32(m,2H),3.98(s,1H).
实施例7：β-氘代SMTP-7的制备(化合物3)
Figure PCTCN2022075740-appb-000020
采用β-氘代L-鸟氨酸(按照实施例6制备)参照实施例1方法制备获得目标产物化合物3。
实施例8：γ-氘代-L-鸟氨酸的制备(化合物4c)
Figure PCTCN2022075740-appb-000021
化合物4b
将化合物4a(2.2g，6.4mmol，参考Journal of the American Chemical Society,2018,vol.140,23,7116–7126制备)溶解于四氢呋喃(50mL)中，加入Boc 2NH(2.1g，9.6mmol)和三苯基膦(5.0g，19.1mmol)，冷却至0℃，缓慢滴加DEAD(3.3g，19.1mmol)，完毕后回到室温搅拌过夜，加膦酸缓冲液淬灭反应，用乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，有机相浓缩并柱层析纯化(EA:PE＝1:20)得目标产物1.7g产品化合物4b(收率50％)。
1H NMR(500MHz,CDCl 3)δ4.87(dd,J＝9.5,5.0Hz,1H),3.70(s,3H),3.59(d,J＝3.1Hz,2H),2.09(dd,J＝14.2,4.7Hz,1H),1.88–1.81(m,1H),1.49(d,J＝3.3Hz,36H).
化合物4c
将化合物4b(1.7g,3.2mmol)和4M盐酸水溶液(30mL)加入到100mL封管中，加热到90度(外温)反应16小时。冷却至室温后浓缩，油泵干燥得500mg化合物4c(收率92％)。
MS-ESI:m/z 135.1[M+H] +
1H NMR(500MHz,D2O)δ3.99(t,J＝6.3Hz,1H),3.03(s,2H),1.97(qd,J＝14.5,6.5Hz,2H).
实施例9：γ-氘代SMTP-7的制备(化合物4)
Figure PCTCN2022075740-appb-000022
采用γ-氘代L-鸟氨酸(按照实施例8制备)参照实施例1方法制备获得目标产物化合物4。
测试例2：大鼠体内药代动力学研究
1.1供试品的制备
分别称取适量SMTP-7、化合物2、化合物3和化合物4，加入生理盐水(2mM NaOH溶液调节pH至约9.2)，涡旋超声使充分混匀后，得到浓度为1mg/mL的澄清溶液，以备用。
1.2动物
SD大鼠，年龄6-8周，体重约180-240g
1.3方案
Figure PCTCN2022075740-appb-000023
参照测试例1方法检测大鼠体内药代动力学AUC (0-t)、AUC (0-∞)、T 1/2、MRT、C max、T max等参数。
实验结果：大鼠静脉注射给药后，SMTP-7、化合物2和化合物3的T 1/2和AUC差异性不大，化合物4的T 1/2和AUC低于SMTP-7。
测试例3：大鼠血栓栓塞
1.1脑梗塞模型制备
脑梗塞模型参照文献方法制备栓塞性卒中模型(J Cereb Blood Flow Metab,1997,17(2):123-135.)。取大鼠血0.1mL，立即吸入PE50管中，室温放置2h后，4℃保存22h。将血栓推出至30mL生理盐水中，洗涤3次，每次5min。切 取长度为5mm栓子，吸入管末端特制的PE50管中备用。
大鼠异氟烷气体麻醉后，仰卧位固定于手术台上，颈正中线切开皮肤，游离右侧颈总动脉，并分离颈内动脉分支翼额用动脉夹闭。在颈总动脉处剪一小口，将上述导管内栓子用0.4mL生理盐水推入颅内后，小心抽出插管，结扎颈总动脉，缝合皮肤。
2.2分组和给药
造模结束1h进行神经功能评分，≥8分者为造模成功，并将大鼠分为假手术组、模型对照组、受试药组组(5、10、20mg/kg)、对照药物组(10mg/kg)，每组10只大鼠。假手术组与模型对照组给予生理盐水、受试药组给予化合物1(1mg/ml，生理盐水(2mM NaOH溶液调节pH至约9.2)配制)，对照药物组给予SMTP-7(1mg/ml，生理盐水(2mM NaOH溶液调节pH至约9.2)配制)。造模结束1h后立即静脉给药，先推注药液量的10％，剩余90％输注30min。试验终点为药后24h。
神经功能评分
分别于给药前、治疗后24h观察动物行为障碍的程度并进行评分。评分标准如下：
MCAO大鼠神经功能损害程度评分标准
Figure PCTCN2022075740-appb-000024
Figure PCTCN2022075740-appb-000025
脑出血测定
24h评分采血结束后，心脏灌流取脑，将脑组织置于-20℃冰箱内冷冻后，由前向后进行切片，每片厚度为2mm。切片有出血即记1分，各切片的分数总和为每个动物的出血总分。
脑梗死范围测定
24h评分采血结束后，心脏灌流取脑，将脑组织置于-20℃冰箱内冷冻后，由前向后进行切片，每片厚度为2mm。将脑组织切片置2％红四氮唑(TTC)溶液中，37℃孵育5min，梗死组织呈白色，非梗死组织为红色。采用Image J软件进行脑梗死面积测定，并计算梗死面积占全脑面积的百分比。
脑梗死面积百分比％＝脑梗死面积/全脑面积×100％
数据分析方法
计量资料以
Figure PCTCN2022075740-appb-000026
表示，采用T-TEST两两比较，P<0.05有统计学差异。
实验结果：
表1：行为学评分和脑梗死面积
Figure PCTCN2022075740-appb-000027
备注：#表示相对于假手术组，*表示相对于模型组。
表2：脑出血评分
Figure PCTCN2022075740-appb-000028
Figure PCTCN2022075740-appb-000029
行为学方面，相同给药剂量下(10mg/kg)，化合物1和SMTP-7相对于模型组均有改善且改善程度相当。
脑梗死面积方面，相较于模型组，化合物1和SMTP-7均具有显著改善，且同10mg/kg剂量下化合物1优于SMTP-7(降低约37％)，发生较严重梗死的概率较低。
脑出血方面，相较于模型组，化合物1和SMTP-7各剂量组均有改善，10mg/kg剂量下，化合物1(10％)给药后脑出血发生概率更低于SMTP-7(20％)，而且SMTP-7出现脑出血评分≥3的情况(10％)，提示给予SMTP-7后脑部有更高的出血转化风险，这对临床缺血性脑卒治疗是不利的。
结论：化合物1对脑梗塞后的神经功能、脑梗死面积均有改善作用，同时具有较低的出血风险。

Claims (25)

  1. 式I所示的化合物或其可药用盐，
    Figure PCTCN2022075740-appb-100001
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 33、R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41、R 42、R 43、R 44、R 45、R 46、R 47、R 48、R 49、R 50、R 51、R 52、R 53、R 54、R 55、R 56、R 57、R 58、R 59、R 60、R 61、R 62和R 63各自独立地为氢或氘，且R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 33、R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41、R 42、R 43、R 44、R 45、R 46、R 47、R 48、R 49、R 50、R 51、R 52、R 53、R 54、R 55、R 56、R 57、R 58、R 59、R 60、R 61、R 62和R 63中至少一个是氘。
  2. 根据权利要求1所示的化合物或其可药用盐，其中R 27选自氘，R 28选自氘，R 36选自氘，R 37选自氘。
  3. 根据权利要求1或2所示的化合物或其可药用盐，其中R 26选自氘，R 38选自氘。
  4. 根据权利要求1-3任一项所述的化合物或其可药用盐，其中R 24选自氘，R 25选自氘，R 39选自氘，R 40选自氘。
  5. 根据权利要求1-3任一项所述的化合物或其可药用盐，其中R 29选自氘。
  6. 根据权利要求1-5任一项所述的化合物或其可药用盐，其中R 30选自氘，R 31选自氘。
  7. 根据权利要求1-6任一项所述的化合物或其可药用盐，其中R 34选自氘，R 35选自氘。
  8. 根据权利要求1-7任一项所述的化合物或其可药用盐，其中R 16选自氘，R 17选自氘，R 47选自氘，R 48选自氘。
  9. 根据权利要求1-8任一项所述的化合物或其可药用盐，其中R 12选自氘，R 13选自氘，R 14选自氘。
  10. 根据权利要求1-9任一项所述的化合物或其可药用盐，其中R 50选自氘，R 51选自氘，R 52选自氘。
  11. 根据权利要求1-10任一项所述的化合物或其可药用盐，其中R 23选自氘，R 41选自氘。
  12. 根据权利要求1-11任一项所述的化合物或其可药用盐，其中R 32选自氘，R 33选自氘。
  13. 根据权利要求1-5或12任一项所述的化合物或其可药用盐，其中R 30选自氘，R 31选自氘，R 32选自氘，R 33选自氘，R 34选自氘，R 35选自氘。
  14. 根据权利要求1-13任一项所述的化合物或其可药用盐，其中R 1选自氘，R 2选自氘，R 3选自氘。
  15. 根据权利要求1-14任一项所述的化合物或其可药用盐，其中R 4选自氘，R 5选自氘，R 6选自氘。
  16. 根据权利要求1-15任一项所述的化合物或其可药用盐，其中R 58选自氘，R 59选自氘，R 60选自氘。
  17. 根据权利要求1-16任一项所述的化合物或其可药用盐，其中R 61选自氘，R 62选自氘，R 63选自氘。
  18. 根据权利要求17所述的化合物或其可药用盐，其中R 1选自氘，R 2选自氘，R 3选自氘，R 4选自氘，R 5选自氘，R 6选自氘，R 58选自氘，R 59选自氘，R 60选自氘，R 61选自氘，R 62选自氘，R 63选自氘。
  19. 根据权利要求1-18任一项所述的化合物或其可药用盐，其中R 7选自氘，R 57选自氘。
  20. 根据权利要求1所述的化合物或其可药用盐，其为
    Figure PCTCN2022075740-appb-100002
  21. 式I所示化合物或其可药用盐，选自：
    Figure PCTCN2022075740-appb-100003
    Figure PCTCN2022075740-appb-100004
  22. 根据权利要求1-21任一项所述的化合物或其盐，其中氘原子的丰度为氘的天然丰度的至少4000倍，优选至少5500倍，更优选至少6000倍。
  23. 一种药物组合物，包括至少一种治疗有效量的如权利要求1-22任一项所述的化合物或其可药用的盐以及药学上可接受的赋形剂。
  24. 一种预防和/或治疗心脑血管疾病的方法，其通过向所述患者施用治疗有效量的如权利要求1-22任一项所述的化合物或其可药用盐，或权利要求23所述的药物组合物，所述疾病优选血栓栓塞性疾病，更优选心肌梗塞、心绞痛、血管成型术或主动脉冠状动脉分流术后的再阻塞和再狭窄、弥散性血管内凝血、中风、短暂的局部缺血发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。
  25. 权利要求1-22任一项所述的化合物或其可药用盐，或权利要求23所述的药物组合物在制备用于预防和/或治疗心脑血管疾病的药物中的用途，所述疾病优选血栓栓塞性疾病，更优选心肌梗塞、心绞痛、血管成型术或主动脉冠状动脉分流术后的再阻塞和再狭窄、弥散性血管内凝血、中风、短暂的局部缺血发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118084942A (zh) * 2024-04-26 2024-05-28 深圳创元生物医药科技有限公司 一种甲基化smtp-7的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117164597B (zh) * 2023-11-02 2024-02-09 深圳创元生物医药科技有限公司 一种smtp-0合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102115478A (zh) * 2010-05-14 2011-07-06 上海海洋大学 一种呋喃并吲哚类化合物及其制备方法和应用
WO2012115209A1 (ja) * 2011-02-24 2012-08-30 国立大学法人東京農工大学 可溶性エポキシドハイドロラーゼ阻害剤
CN106946910A (zh) * 2017-03-22 2017-07-14 上海海洋大学 一种吡喃骈吲哚乙酰化衍生物及其制备方法和应用
WO2020184691A1 (ja) * 2019-03-12 2020-09-17 学校法人昭和大学 薬剤及び該薬剤を用いて糖尿病合併症を治療又は予防する方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102115478A (zh) * 2010-05-14 2011-07-06 上海海洋大学 一种呋喃并吲哚类化合物及其制备方法和应用
WO2012115209A1 (ja) * 2011-02-24 2012-08-30 国立大学法人東京農工大学 可溶性エポキシドハイドロラーゼ阻害剤
CN106946910A (zh) * 2017-03-22 2017-07-14 上海海洋大学 一种吡喃骈吲哚乙酰化衍生物及其制备方法和应用
WO2020184691A1 (ja) * 2019-03-12 2020-09-17 学校法人昭和大学 薬剤及び該薬剤を用いて糖尿病合併症を治療又は予防する方法

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
HU, W. M. ET AL.: "SMTP (Stachybotrys microspora triprenyl phenol) enhances clot clearance in a pulmonary embolism model in rats", THROMBOSIS JOURNAL, vol. 10, no. 2, 9 January 2012 (2012-01-09), XP021118694, ISSN: 1477-9560, DOI: 10.1186/1477-9560-10-2 *
J CEREB BLOOD FLOW METAB, vol. 17, no. 2, 1997, pages 123 - 135
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 139, no. 39, 2017, pages 13830 - 13836
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 140, no. 23, 2018, pages 7116 - 7126
SAWADA, H. ET AL.: "SMTP-7, a novel small-molecule thrombolytic for ischemic stroke: a study in rodents and primates", JOURNAL OF CEREBRAL BLOOD FLOW & METABOLISM, vol. 34, no. 2, 31 December 2014 (2014-12-31), XP055953671, ISSN: 0271-678X, DOI: 10.1038/jcbfm.2013.191 *
See also references of EP4293028A4
SHIBATA, K. ET AL.: "A novel finding of a low-molecular-weight compound, SMTP-7, having thrombolytic and anti-inflammatory effects in cerebral infarction of mice", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, vol. 382, no. 3, 3 August 2010 (2010-08-03), XP019838869, ISSN: 0028-1298 *
SYNLETT, vol. 27, no. 2, 2016, pages 309 - 312
WEIMIN HSHIGEKI O ET AL., ANTIBIOT., vol. 53, no. 3, 2000, pages 241 - 247

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118084942A (zh) * 2024-04-26 2024-05-28 深圳创元生物医药科技有限公司 一种甲基化smtp-7的制备方法

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