+

WO2018131950A1 - Dérivé de nucléoside carbocyclique et agent antiviral le comprenant - Google Patents

Dérivé de nucléoside carbocyclique et agent antiviral le comprenant Download PDF

Info

Publication number
WO2018131950A1
WO2018131950A1 PCT/KR2018/000644 KR2018000644W WO2018131950A1 WO 2018131950 A1 WO2018131950 A1 WO 2018131950A1 KR 2018000644 W KR2018000644 W KR 2018000644W WO 2018131950 A1 WO2018131950 A1 WO 2018131950A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
mmol
reduced pressure
under reduced
Prior art date
Application number
PCT/KR2018/000644
Other languages
English (en)
Korean (ko)
Inventor
정낙신
신영섭
김규동
윤지성
김홍래
김혜옥
쿠마 사후프라모드
리테오간도 에스. 나타샤 리마
코바시코바크리스티나
클라라 포스츄마씨.
에릭 스나이더제이.
허머트제이. 마틴 반
Original Assignee
퓨쳐메디신 주식회사
서울대학교산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020170005061A external-priority patent/KR20180083094A/ko
Priority claimed from KR1020170063574A external-priority patent/KR20180128252A/ko
Application filed by 퓨쳐메디신 주식회사, 서울대학교산학협력단 filed Critical 퓨쳐메디신 주식회사
Publication of WO2018131950A1 publication Critical patent/WO2018131950A1/fr

Links

Images

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/167—Purine radicals with ribosyl as the saccharide radical
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to carbocyclic nucleoside derivatives and antiviral agents comprising the same.
  • Virus is a representative cause of numerous intractable diseases that threaten human health, and invests enormous capital to prevent or treat them worldwide.
  • intractable RNA viruses such as Chikungunya Virus, SARS virus, MERS virus, and Zika virus have caused serious risks to humans, thus inhibiting their proliferation.
  • antiviral agents can inhibit the virus through various mechanisms (mechanism), two of which are known to be effectively used to suppress the virus.
  • the first is to inhibit S-adenosylhomocysteine (hereafter SAH) hydrolase.
  • SAH S-adenosylhomocysteine
  • SAH hydrolase is a tetramer type enzyme that uses NAD + as a coenzyme. It reversibly hydrolyzes SAH into adenosine (Ado) and homocysteine (Hcy). In addition to nucleosides, it is an important enzyme for the methylation of substances like histamine and norepinephrine.
  • SAH hydrolase causes the accumulation of SAH, and the excess SAH in turn inhibits S-adenosylmethionine (AdoMet) -dependent transmethylase and capping of viral mRNAs, thereby reducing the protein required for virus replication. It can't be made properly, resulting in an antiviral effect.
  • AdoMet S-adenosylmethionine
  • SAH hydrolase is considered an essential component in the development of a broad spectrum antiviral agent, as most animal DNA viruses, as well as RNA viruses, require methylation enzymes (viral mRNA guanosine N7-methytransferases, O-2′-methytransferase) for mRNA capping. do. In other words, the development of RNA virus therapeutics and the development of SAH hydrolase inhibitors seem to have a high correlation.
  • the second is to inhibit viral RNA polymerase.
  • RNA viruses replicate by inserting Nucleoside-5'-triphosphate (NTP), a substrate, into an RNA chain by RNA polymerase.
  • NTP Nucleoside-5'-triphosphate
  • substances that inhibit RNA polymerase may also act as antiviral agents, and are converted to triphosphate in the body to selectively inhibit viral RNA polymerase or directly inserted into the viral RNA chain, thereby resulting in chain termination. ) It is thought that the development of effective antiviral agents is possible.
  • an antiviral agent functions as an inhibitor of RNA polymerase against normal cells as well as viruses, it is difficult to increase its selectivity because it may be toxic to normal cells.
  • the problem to be solved by the present invention is that it has a function of inhibiting SAH hydrolase, and can effectively suppress the virus, but has little toxicity in the body, and is very suitable for the inhibition of the virus and the prevention and treatment of viral diseases. It is to provide a novel carbocyclic nucleoside derivative that can be utilized.
  • Carbocyclic nucleoside derivative or a pharmaceutically acceptable salt thereof according to an embodiment of the present invention for solving the above problems is represented by the following formula (A).
  • n 1 or 2
  • R1 and R2 are each independently hydrogen or fluorine
  • B is the following formula B-1 or B-2
  • P is hydrogen or phosphoamidate group to be
  • X1 is a chlorine, a hydroxyl group (OH group), an amino group or an alkylamino group
  • Y1 is hydrogen or an amino group.
  • the alkylamino group is a monoalkylamino group (-NHR) such as -NHMe or -NHEt or a dialkylamino group (-NR2) such as -NMe2, -NMeEt or -NEt2)
  • X2 is a hydroxyl group or an amino group
  • Y2 is hydrogen, methyl group or halogen
  • Formula A may be the following Formula a.
  • R 2 in Formula A may be fluorine.
  • Formula a may be the following Formula 5a, 5b or 5c.
  • Formula A may be the following Formula b.
  • R 1 may be fluorine.
  • Formula b may be the following Formula 15a or Formula 15b.
  • An antiviral agent comprising a carbocyclic nucleoside derivative or a pharmaceutically acceptable salt thereof according to another embodiment of the present invention for solving the above problems is represented by the following formula (A).
  • n 1 or 2
  • R1 and R2 are each independently hydrogen or fluorine
  • B is the following formula B-1 or B-2
  • P is hydrogen or phosphoamidate group to be
  • X1 is a chlorine, a hydroxyl group (OH group), an amino group or an alkylamino group
  • Y1 is hydrogen or an amino group.
  • the alkylamino group is a monoalkylamino group (-NHR) such as -NHMe or -NHEt or a dialkylamino group (-NR2) such as -NMe2, -NMeEt or -NEt2)
  • X2 is a hydroxyl group or an amino group
  • Y2 is hydrogen, methyl group or halogen
  • Formula A may be the following Formula a.
  • R 2 in Formula A may be fluorine.
  • Formula a may be the following Formula 5a, 5b or 5c.
  • Formula A may be the following Formula b.
  • R 1 may be fluorine.
  • Formula b may be the following Formula 15a or Formula 15b.
  • the present invention is expected to be developed as a new antiviral agent with little toxicity in the body, which can contribute to the development of the new drug development field, a representative national knowledge-based business in the future, can be expected to improve the public health It is, of course, expected to contribute to economic development.
  • Carbocyclic nucleoside derivatives according to one embodiment of the present invention may be represented by the following formula (A).
  • n 1 or 2
  • R 1 and R 2 are each independently hydrogen or fluorine
  • B is the following formula B-1 or B-2
  • P is hydrogen or phosphoamidate It may be a flag.
  • X1 may be a chlorine, a hydroxyl group, an amino group, or an alkylamino group
  • Y1 may be hydrogen or an amino group
  • the alkylamino group may be a monoalkylamino group (-NHR) such as -NHMe or -NHEt or a dialkylamino group (-NR2) such as -NMe2, -NMeEt or -NEt2.
  • -NHR monoalkylamino group
  • -NR2 dialkylamino group
  • X2 may be a hydroxyl group or an amino group
  • Y2 may be hydrogen, a methyl group, or a halogen.
  • n may be 1 in Formula A, and P may be hydrogen. That is, the carbocyclic nucleoside derivative represented by Formula A may be a carbocyclic nucleoside derivative represented by Formula A below.
  • n is 1, P is hydrogen or a phosphoramidate group, and B may be Chemical Formula B-1. More specifically, the carbocyclic nucleoside derivative represented by Chemical Formula a may be a compound represented by Chemical Formula 5a, a compound represented by 5b, or a compound represented by Chemical Formula 5c.
  • n is 2, and P may be hydrogen. That is, the carbocyclic nucleoside derivative represented by Formula A may be a carbocyclic nucleoside derivative represented by Formula b below.
  • R1 may be fluorine
  • B may be Formula B-1.
  • the carbocyclic nucleoside derivative represented by Formula b may be a compound represented by Formula 15a or a compound represented by Formula 15b.
  • Carbocyclic nucleoside derivatives represented by Formula A may be provided in the form of a pharmaceutically acceptable salt.
  • salts are acid addition salts formed with various pharmaceutically acceptable organic or inorganic acids.
  • Suitable organic acids include, for example, tetracarboxylic acid, phosphonic acid, sulfonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid, Maleic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfuric acid, and the like can be used. Or phosphoric acid may be used.
  • the present invention is not limited thereto, and the carbocyclic nucleoside derivatives of the present invention may be provided in the form of all salts, hydrates, and solvates that may be prepared by conventional methods.
  • An antiviral agent according to an embodiment of the present invention may include the above-described carbocyclic nucleoside derivative as an active ingredient.
  • An antiviral agent refers to a pharmaceutical composition that can be used not only to inhibit the activity, replication, etc. of a virus, but also to prevent and / or treat all diseases caused by a virus.
  • the virus is, for example, Chikungunya Virus (CHIKV), Samryki Forrest Virus (SFV), MERS virus (Middle East Respiratory Syndrome Coronavirus (MERS-CoV), SARS Virus (Severe Acute) RNA viruses such as Respiratory Syndrome Coronavirus (SARS-CoV), Equine Arteritis Virus (EAV), Mouse Hepatitis Virus (MHV), Sindbis Virus (SINV), and the like.
  • CHCV Chikungunya Virus
  • SFV Samryki Forrest Virus
  • MERS virus Middle East Respiratory Syndrome Coronavirus
  • SARS Virus severe Acute RNA viruses
  • SARS-CoV Respiratory Syndrome Coronavirus
  • EAV Equine Arteritis Virus
  • MHV Mouse Hepatitis Virus
  • SINV Sindbis Virus
  • the antiviral agent including the carbocyclic nucleoside derivative described above may be a pharmaceutical composition that effectively inhibits a virus by using the main mechanism of inhibiting SAH hydrolase.
  • the antiviral agent may be administered systemically or locally, and formulated with excipients (or diluents) such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like, which are generally used for oral or parenteral administration. Can be.
  • excipients or diluents
  • fillers extenders, binders, wetting agents, disintegrants, surfactants, and the like
  • Solid dosage forms for oral administration may include tablets, pills, powders, granules, capsules, and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose ( sucrose, lactose, gelatin and the like can be mixed and prepared.
  • excipients such as starch, calcium carbonate, sucrose ( sucrose, lactose, gelatin and the like can be mixed and prepared.
  • lubricants such as magnesium stearate, talc and the like can also be used.
  • Liquid formulations for oral administration include, for example, suspensions, solutions, emulsions, syrups, and the like, and liquid formulations include various excipients, for example, wetting agents, in addition to water, liquid paraffin, which are commonly used simple diluents, Sweeteners, fragrances, preservatives and the like.
  • Formulations for parenteral administration may include injections, emulsions, inhalants, suppositories, and the like.
  • Injectables may include sterile aqueous solvents, non-aqueous solvents and suspending agents, such as propylene glycol, polyethylene glycol, vegetable oils such as olive oil, esters such as ethyl oleate, and the like, suppositories being based on witepsol, Macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
  • the antiviral agents of the invention may also be formulated in ointments or creams for topical application.
  • the preferred dosage of the antiviral agent depends on a number of factors, including the condition and weight of the patient, the extent of the disease, the form of the drug, the route and duration of administration, and can be appropriately selected by those skilled in the art.
  • the route of administration may also vary depending on the condition of the patient and its severity.
  • carbocyclic nucleoside derivatives of the present invention have antiviral efficacy against RNA viruses and at the same time have biocompatible properties with little or no toxicity in the body (see Experimental Examples), inhibition of viruses and prevention of viral diseases and / Or as a pharmaceutical composition well suited for treatment.
  • the compound of formula 1 (6 g, 24.8 mmol) synthesized in Preparation Example 1 was dissolved in anhydrous THF, and chlorotriethylsilane (TESCl) (16.7 mL, 99.2 mmol) was added dropwise and cooled to -78 ° C. To the cooled mixture was slowly added dropwise 1.0 M lithium bis (trimethylsilyl) amide / THF solution (LiHMDS 1.0 M solution in THF) (50 mL, 50 mmol), followed by stirring the reaction well under the same conditions for 30 minutes to obtain silyl enol ether. It makes me angry.
  • THF chlorotriethylsilane
  • the reaction mixture was terminated with an aqueous saturated ammonium chloride (NH 4 Cl) solution, the aqueous layer was extracted with ethyl acetate, and the organic layer was separated. The separated organic layer was sufficiently washed with water and brine, dried over magnesium sulfate (MgSO 4), and the residual solid was removed by filtration under reduced pressure, and then concentrated under reduced pressure. This concentrated residue is taken up in anhydrous DMF and then cooled to 0 ° C.
  • NH 4 Cl aqueous saturated ammonium chloride
  • the compound of formula 2a (3.33 g, 12.8 mmol) obtained in Preparation Example 2-1 was dissolved in methanol, and then cooled sufficiently to 0 ° C or less. To the cooled solution is added sodium borohydride (NaBH 4) (1.45 g, 38.4 mmol) slowly. After stirring the reaction under the same conditions and confirming the reaction termination by TLC, the reaction mixture was terminated with a saturated aqueous solution of ammonium chloride (NH 4 Cl), the aqueous layer was extracted with ethyl acetate and the organic layer was separated. The separated organic layer was washed with water and brine sufficiently, dried over magnesium sulfate (MgSO4), removed under reduced pressure, and concentrated under reduced pressure.
  • NaBH 4 sodium borohydride
  • the intermediate (2.54 g, 76%) obtained by separating the produced alcohol compound by silica gel chromatography was dissolved in anhydrous pyridine and cooled to 0 ° C.
  • Anhydrous trifluoromethanesulfonic anhydride (3.26 ml, 19.36 mmol) was added dropwise to the cooled mixture, followed by stirring for 30 minutes under the same conditions to trifluoromethylsulfonated.
  • the reaction mixture was terminated with a saturated aqueous solution of ammonium chloride (NH 4 Cl), the aqueous layer was extracted with ethyl acetate, and the organic layer was separated.
  • the separated organic layer was washed with water and brine sufficiently, dried over magnesium sulfate (MgSO4), removed under reduced pressure, and concentrated under reduced pressure.
  • the resulting trifluoromethylsulfonated compound and sodium azide (NaN 3) (1.89 g, 29.04 mmol) are mixed with anhydrous DMF, and then agitated by stirring at 60 ° C. under heating. After stirring for about 4 hours, the reaction was terminated by TLC, and the reaction was terminated with water.
  • the aqueous layer was extracted with ethyl acetate, and the organic layer was separated.
  • the separated organic layer was washed with water and brine sufficiently, dried over magnesium sulfate (MgSO4), removed under reduced pressure, and concentrated under reduced pressure.
  • the obtained azide compound is separated and purified through silica gel chromatography and the like, and the obtained compound (4.07 g, 42%) is dissolved in methanol.
  • An appropriate amount of palladium / carbon is added to the solution, and the reaction vessel is hydrogen-substituted to carry out a hydrogenation reaction to reduce the azide group to an amine group.
  • the reaction vessel is hydrogen-substituted to carry out a hydrogenation reaction to reduce the azide group to an amine group.
  • Lithium borohydride (LiBH4) is used instead of sodium borohydride (NaBH4) in the alcoholation of ketones, and 10 equivalents of sodium azide is used in the azide reaction and the temperature is raised to 100 ° C. In addition, the stirring time should be increased to about 15 hours.
  • the compound of formula 4a (220 mg, 0.54 mmol) synthesized in Preparation Example 4-1 was dissolved in tert-butanol, and then transferred to a stainless steel bomb reactor. After saturated ammonia / tert-butanol (third butanol) was added dropwise to the mixture, the reaction vessel was sealed and stirred at 120 ° C. for about 15 hours. After confirming that the reaction was terminated by TLC, the reaction mixture was diluted with methanol and concentrated under reduced pressure. The concentrated residue is dissolved in THF, and then dropwise added a solution of trifluoroacetic acid (TFA) and water in a 2: 1 mixture.
  • TFA trifluoroacetic acid
  • the compound of formula 4b (21 mg, 0.0527 mmol) synthesized in Preparation Example 4-2 was dissolved in methanol, and heated to 80 ° C. under acidic conditions such as a mixed solution of trifluoroacetic acid and water (1: 1). After stirring for about 15 hours, the reaction was terminated by TLC or the like and concentrated under reduced pressure. The concentrated residue was separated and purified by silica gel chromatography to obtain the compound of Chemical Formula 5d (10 mg, 67%) having the following 1H NMR spectrum.
  • the compound of formula 4a (113 mg, 0.283 mmol) synthesized in Preparation Example 4-1 was dissolved in ethanol and then transferred to a glass seal bomb. 40% methylamine aqueous solution was added dropwise to the mixture, and the reaction vessel was sealed and stirred at room temperature for 2 hours. After confirming that the reaction was terminated by TLC, the reaction mixture was concentrated under reduced pressure. The concentrated residue is dissolved in THF, and then dropwise added a solution of trifluoroacetic acid (TFA) and water in a 2: 1 mixture. After stirring the reaction mixture for 50 to 30 hours, the reaction was terminated by TLC and concentrated under reduced pressure. The concentrated residue was separated and purified by silica gel chromatography to obtain the compound of Chemical Formula 6a (66 mg, 67%) having the following 1H NMR spectrum.
  • TFA trifluoroacetic acid
  • N, N-di (tertbutyl carboxylic acid) (N, N-diBoc) -ized intermediate (8 mg, 0.015 mmol) and N-tertbutyl carboxylic acid ( N-Boc) intermediate (13 mg, 0.029 mmol) can be obtained.
  • the reaction mixture was terminated with a saturated aqueous solution of ammonium chloride (NH 4 Cl), the aqueous layer was extracted with ethyl acetate, and the organic layer was separated. The separated organic layer was washed with water and brine sufficiently, dried over magnesium sulfate (MgSO4), removed under reduced pressure, and concentrated under reduced pressure. The concentrated residue can be separated and purified through silica gel chromatography or the like to obtain a precursor (10 mg, 0.0215 mmol) that has not reacted with the intermediate (15 mg, 0.0215 mmol).
  • NH 4 Cl saturated aqueous solution of ammonium chloride
  • MgSO4 magnesium sulfate
  • the reacted intermediate (15 mg, 0.0215 mmol) is suspended in an aqueous formic acid solution (50 v / v%) and stirred at room temperature for about 8 hours to proceed with the protecting group removal reaction. After confirming that the reaction was terminated by TLC, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified through silica gel chromatography, obtaining a compound of Formula 7b (12 mg, 100%) having the following 1H NMR spectrum. .
  • Methyl 3-methoxyacrylate (20 mL, 186 mmol) was added to a 2 M aqueous sodium hydroxide solution (103 ml) and stirred at room temperature for 2 hours to completely dissolve.
  • the reaction mixture is completely acidified with 2M aqueous hydrochloric acid solution and filtered to collect the precipitated solid.
  • the solid organic acid obtained above is dissolved in water and neutralized with a 2 M aqueous sodium hydroxide solution to obtain an organic acid in the form of sodium salt. This is also dried in a reduced pressure desiccator with phosphorus pentoxide (phosphorus (V) oxide) 3 days.
  • the dried organic sodium salt (6.20 g, 50 mmol) was made into a suspension with anhydrous diethyl ether, and then thionyl chloride (5.45 mL, 75 mmol) was added dropwise and heated under reflux for 4 hours. Let it be. Thereafter, the reaction mixture is stirred at 30 ° C. for about 15 hours to acid chloride. The reaction mixture is cooled to room temperature and filtered under reduced pressure while washing with anhydrous diethyl ether. The filtrate was concentrated under reduced pressure under nitrogen gas, and the concentrated residue was distilled under reduced pressure to obtain an organic acid chloride (3.08 g, 51%).
  • the dried silver cyanate (8.44 g, 56.32 mmol) was made into a suspension with benzene and heated to reflux for 30 minutes.
  • the obtained organic acid chloride (1.45 g, 12.03 mmol) was added dropwise to the prepared suspension and heated to reflux for 30 minutes to obtain isocyanate, which precipitated the reaction suspension without any other procedure, and then the supernatant was added to the next reaction. Use it.
  • the compound of formula 3a (2.572 g, 9.84 mmol) synthesized in Preparation Example 3-1 was dissolved in DMF and cooled sufficiently to below -20 ° C.
  • the isocyanic acid (45 mL, 19.68 mmol) synthesized above was added dropwise to the reaction mixture and stirred for about 15 hours while being slowly heated to room temperature.
  • the reaction was terminated by TLC, washed with methylene chloride, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure.
  • an azeotrope mixed with toluene, ethanol, etc. is concentrated sufficiently under reduced pressure to solidify the residue, and the solidified residue is separated and purified by silica gel chromatography to obtain urea derivative (2.903 g, 76%) as an intermediate. have.
  • the compound of Formula 8a (100 mg, 0.384 mmol) synthesized in Preparation Example 8-1 was dissolved in methylene chloride, and then pyridine (0.21 mL, 2.57 mmol) was added dropwise and cooled to 0 ° C.
  • Benzoyl chloride (0.27 mL, 2.31 mmol) was added dropwise to the cooled reaction mixture, which was then slowly heated to room temperature and stirred for about 15 hours. After confirming that the reaction was terminated by TLC, the reaction was terminated with water, the aqueous layer was extracted with methylene chloride, and the organic layer was separated.
  • the residue obtained by concentrating the washed organic layer under reduced pressure is dissolved in 1,4-dioxane and transferred to a sealable reaction vessel, and saturated ammonia water is then added at a rate of 20 v / v% of the solution. After the reaction mixture was stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The concentrated residue can be separated and purified by silica gel chromatography to obtain an intermediate (42 mg, 26%) converted to cytosine.
  • the cytosine intermediate (42 mg, 0.0735 mmol) was dissolved in methanol, transferred to a sealable reaction vessel, saturated aqueous ammonia / methanol solution was added, stirred at room temperature for 2 days, and the reaction mixture was concentrated under reduced pressure.
  • the concentrated residue was diluted with a small amount of water and extracted about 10 times with methylene chloride to remove residual benzoyl adduct.
  • the compound of formula 9a having the following 1H NMR spectrum (17 mg, 85%) was
  • the reaction mixture was terminated with a saturated aqueous solution of ammonium chloride (NH 4 Cl), the aqueous layer was extracted with ethyl acetate, and the organic layer was separated. The separated organic layer was washed with water and brine sufficiently, dried over magnesium sulfate (MgSO4), removed under reduced pressure, and concentrated under reduced pressure. The concentrated residue was separated and purified through silica gel chromatography to obtain a precursor (25 mg, 0.083 mmol) that did not react with the intermediate (28 mg, 0.0495 mmol).
  • NH 4 Cl saturated aqueous solution of ammonium chloride
  • MgSO4 magnesium sulfate
  • the reacted intermediate (28 mg, 0.0495 mmol) is suspended in an aqueous formic acid solution (50 v / v%) and stirred at room temperature for about 8 hours to proceed with the protecting group removal reaction. After confirming that the reaction was terminated by TLC, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the compound of Chemical Formula 10a having the following 1H NMR spectrum (24 mg, 90%). .
  • Copper bromide dimethylsulfide complex (933mg, 4.54mmol) was dissolved in anhydrous THF (300ml) and 1.0M vinylmagnesium bromide 1.0M solution in THF (69.3ml) at -78 ° C. , 69.3 mmol) and hexamethylphosphoramide (HMPA) (33.4 ml, 192 mmol) were added.
  • Di-cyclopentenone (5 g, 32.4 mmol) and chlorotrimethylsilane (TMSCl) (20.6 ml, 162 mmol) were dissolved together in anhydrous THF (180 ml) and then slowly added dropwise to the reaction flask at -78 ° C. Stirred for 2 h.
  • the first intermediate (4.7 g, 26.0 mmol) was dissolved in methanol (100 mL) and sodium borohydride (NaBH 4) (1.1 g, 28.6 mmol) was added at 0 ° C.
  • NaBH 4 sodium borohydride
  • the reaction mixture was stirred at the same temperature for 30 minutes, neutralized with water and a small amount of acetic acid, the aqueous layer was extracted with ethyl acetate, and the organic layer was separated.
  • the separated organic layer was sufficiently washed with water and brine, dried over magnesium sulfate (MgSO 4), and the residual solid was removed by filtration under reduced pressure, and then concentrated under reduced pressure.
  • the concentrated residue was separated and purified through silica gel chromatography to obtain a second intermediate (4.6 g, 97%).
  • the second intermediate (4.6 g, 25.2 mmol) was dissolved in DMF (30 mL), followed by imidazole (8.6 g, 126.2 mmol) and chlorotertbutyldiphenylsilane (TBDPSCl) (10.4 g, 37.8 mmol). Add at 0 ° C.
  • the reaction mixture was stirred at room temperature for 1 hour, water was added, the mixture was extracted with diethyl ether, and the organic layer was separated. The separated organic layer was sufficiently washed with water and brine, dried over magnesium sulfate (MgSO 4), and the residual solid was removed by filtration under reduced pressure, and then concentrated under reduced pressure. The concentrated residue was separated and purified through silica gel chromatography to obtain a third intermediate (10.2 g, 92%).
  • the separated organic layer was sufficiently washed with water and brine, dried over magnesium sulfate (MgSO 4), and the residual solid was removed by filtration under reduced pressure, and then concentrated under reduced pressure.
  • the concentrated residue was separated and purified through silica gel chromatography to obtain a fourth intermediate (7.5 g, 72%).
  • the fifth intermediate (3.3 g, 16.3 mmol) was dissolved in methylene chloride (40 mL), and then 4-dimethylaminopyridine (DMAP) (0.2 g, 1.6 mmol) and triethylamine (6.8 mL, 48.9) at 0 ° C. mmol) and chlorotertbutyldiphenylsilane (TBDPSCl) (4.9 g, 17.9 mmol) were added.
  • DMAP 4-dimethylaminopyridine
  • TBDPSCl chlorotertbutyldiphenylsilane
  • the compound of formula 11 (4.2 g, 9.5 mmol) synthesized in Preparation Example 11 was dissolved in anhydrous THF, and chlorotriethylsilane (TESCl) (16.7 mL, 99.2 mmol) was added dropwise and cooled to -78 ° C. To the cooled mixture was slowly added dropwise 1.0M lithium bis (trimethylsilyl) amide / THF solution (LiHMDS 1.0M solution in THF) (50mL, 50mmol), and the reaction was stirred under the same conditions for 30 minutes to carry out silyl enol etherification.
  • THF chlorotriethylsilane
  • the reaction mixture was added with saturated aqueous ammonium chloride (NH 4 Cl) solution, the aqueous layer was extracted with ethyl acetate, and the organic layer was separated. The separated organic layer was sufficiently washed with water and brine, dried over magnesium sulfate (MgSO 4), and the residual solid was removed by filtration under reduced pressure, and then concentrated under reduced pressure. This concentrated residue was taken up in anhydrous acetonitrile and then cooled to 0 ° C.
  • saturated aqueous ammonium chloride NH 4 Cl
  • MgSO 4 magnesium sulfate
  • the compound of formula 12a (2.5 g, 5.4 mmol) synthesized in Preparation Example 12-1 was dissolved in methanol, and then cooled to -40 ° C.
  • Sodium borohydride (NaBH 4) (1.45 g, 38.4 mmol) was slowly added to the cooled solution.
  • the reaction was terminated by TLC, and then saturated ammonium chloride (NH 4 Cl) aqueous solution was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, and the organic layer was separated.
  • the separated organic layer was washed with water and brine sufficiently, dried over magnesium sulfate (MgSO 4), removed from the residual solid by filtration under reduced pressure, and concentrated under reduced pressure.
  • the intermediate (2.54 g, 76%) obtained by separating and purifying the alcohol compound produced through silica gel chromatography was dissolved in anhydrous pyridine and cooled to 0 ° C.
  • Anhydrous trifluoromethanesulfonic anhydride (3.26ml, 19.36mmol) was added dropwise to the cooled mixture, followed by stirring for 30 minutes under the same conditions to trifluoromethylsulfonated.
  • the compound of formula 13b (250 mg, 0.52 mmol) synthesized in Preparation Example 13-2 was dissolved in 1,4-dioxane (50 mL), and then 4,6-dichloro-5-formamidopi Limidine (120 mg, 0.65 mmol) and trimethylamine (0.55 ml, 3.86 mmol) were added. After the reaction mixture was heated to reflux for 2 days, the reaction was terminated by TLC, and the reaction mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain an intermediate. Diethoxymethyl acetate (5 mL) was added to the intermediate, followed by stirring at 140 ° C. for about 12 hours.
  • the intermediate (70 mg, 0.22 mmol) was dissolved in tert-butanol, and then transferred to a stainless steel bomb reactor. Saturated ammonia / terbutanol was added dropwise to this mixture, and then the reaction vessel was sealed and stirred at 120 ° C. for 15 hours. After confirming that the reaction was terminated by TLC, the reaction mixture was diluted with methanol and concentrated under reduced pressure. The concentrated residue was separated and purified by silica gel chromatography to obtain a compound of formula 15a (55 mg, 84.6%) having a 1H NMR spectrum as follows.
  • a compound of Formula 14b (100 mg, 0.3 mmol) synthesized in Preparation Example 14-2 other than the compound of Formula 14a was used as a starting material, except that the mixture was stirred at 90 ° C. for about 3 hours during the amination reaction.
  • the same procedure as in Preparation Example 15-1 was carried out to obtain a compound of Formula 15b (30 mg, 32%) having the following 1H NMR spectrum.
  • the purified intermediate (55 mg, 0.17 mmol) was dissolved in methanol and then transferred to a stainless steel bomb reactor. Methylamine aqueous solution (40w / v%) was added dropwise to this mixed solution, and then the reaction vessel was sealed and stirred at 80 to 5 hours. After confirming that the reaction was terminated by TLC, the reaction mixture was concentrated under reduced pressure. The concentrated residue was separated and purified by silica gel chromatography to obtain a compound of formula 16a (37 mg, 68%) having a 1H NMR spectrum as follows.
  • the purified intermediate (50 mg, 0.158 mmol) was dissolved in 1,4-dioxane and 1 N HCl (3 mL) was added dropwise at room temperature. The reaction mixture was heated to reflux and stirred for about 14 hours, after which the reaction was terminated by TLC and concentrated under reduced pressure. The concentrated residue was separated and purified by silica gel chromatography to obtain the compound of formula 17 having the following 1H NMR spectrum (33 mg, 70%).
  • Methyl 3-methoxyacrylate (20 mL, 186 mmol) was added to a 2 M aqueous sodium hydroxide solution (103 ml), and stirred at room temperature for 2 hours to completely dissolve.
  • the reaction mixture was completely acidified with 2M aqueous hydrochloric acid solution and filtered to collect the precipitated solid.
  • the solid organic acid obtained above was dissolved in water and neutralized with a 2 M aqueous sodium hydroxide solution to obtain an organic acid in the form of sodium salt. This is also dried in a reduced pressure desiccator with phosphorus pentoxide (phosphorus (V) oxide) 3 days.
  • the dried organic sodium salt (6.20 g, 50 mmol) was made into a suspension with anhydrous diethyl ether, and then thionyl chloride (5.45 mL, 75 mmol) was added dropwise and heated under reflux for 4 hours. I was. Thereafter, the reaction mixture is stirred at 30 ° C. for about 15 hours to acid chloride. The reaction mixture is cooled to room temperature and filtered under reduced pressure while washing with anhydrous diethyl ether. The filtrate was concentrated under reduced pressure under nitrogen gas, and the concentrated residue was purified by distillation under reduced pressure to obtain an organic acid chloride (3.08 g, 51%).
  • the dried silver cyanate (8.44g, 56.32mmol) is made into a suspension with benzene and heated under reflux for 30 minutes.
  • the obtained organic acid chloride (1.45 g, 12.03 mmol) was added dropwise to the prepared suspension and heated to reflux for 30 minutes to obtain isocyanate, which precipitated the reaction suspension without any other procedure, and then the supernatant was used for the next reaction. It was.
  • the compound of formula 13a (0.2 g, 0.41 mmol) synthesized in Preparation Example 13-1 was dissolved in DMF and cooled sufficiently to below -20 ° C.
  • the isocyanic acid (45 mL, 19.68 mmol) synthesized above was added dropwise to the reaction mixture and stirred for about 15 hours while being slowly heated to room temperature.
  • the reaction was terminated by TLC, washed with methylene chloride, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. At this time, an azeotrope is made with toluene, ethanol, etc., and concentrated under reduced pressure to make the residue solid. Then, the solidified residue is separated and purified by silica gel chromatography to obtain urea derivative (2.903 g, 76%) as an intermediate. .
  • CHIKV Chikungunya Virus
  • SFV Semliki Forrest Virus
  • Compound of Formula 15a synthesized in Preparation Example 15-1 was diluted to 200 ⁇ M in Iscove's modified Dulbecco's medium (IMDM) containing 1% FCS (fetal calf serum) and antibiotics. Vero E6 cells were cultured in 96-well plates to contain 2 ⁇ 10 4 cells per well. After incubating the cells overnight at 37 ° C., 50 ⁇ l of the compound dilution was injected into each well, and mixed with 100 ⁇ l of Eagle's minimal essential medium (EMEM) containing 2% FCS and 50 ⁇ l of the CHIKV inoculum.
  • IMDM Iscove's modified Dulbecco's medium
  • FCS fetal calf serum
  • Vero E6 cells were cultured in 96-well plates to contain 2 ⁇ 10 4 cells per well. After incubating the cells overnight at 37 ° C., 50 ⁇ l of the compound dilution was injected into each well, and mixed with 100 ⁇ l
  • CPE virus-induced cytopathic effect
  • side effects of the compound at 3 dpi day postinfection
  • Cytotoxicity by compound treatment was confirmed by culturing the cells in the same manner as above except that the normal medium was injected instead of the virus inoculum.
  • EC50 50% effective concentration
  • CC50 50% cytotoxic concentration
  • Table 1 shows the EC50, CC50 and SI values calculated by the above method.
  • the carbocyclic nucleoside derivatives of the present invention have a low EC50 for the RNA viruses CHIKV and SFV and a high CC50 for the host cell, thus preventing and treating viral inhibition and viral diseases. It can be seen that it can be utilized as a pharmaceutical composition very suitable for.
  • a reaction mixture (250 ⁇ l) of 50 mM sodium phosphate (pH 8.0) and AdoHcy hydrolase (2 ⁇ M as monomer; 5 ⁇ M as tetramer) was synthesized in Preparation Example 15-1 and Preparation Example 15-2, respectively.
  • One of the compounds of Formula 15b was preincubated at 37 ° C. for 10 minutes. After preincubation, 100 ⁇ M of AdoHcy was added to initiate the reaction and allowed to proceed for 20 minutes. The reaction mixture was then further incubated in 200 ⁇ M DTNB, and the maximum absorbance at 412 nm of the product TNB (5-thio-2-nitrobenzoic acid) was measured with a spectrophotometer.
  • the carbocyclic nucleoside derivative of the present invention since the carbocyclic nucleoside derivative of the present invention has a low IC50 value for SAH hydrolase, it is suitable as a pharmaceutical composition having an antiviral effect through the SAH hydrolase inhibition mechanism. It can be seen that it can be used as.
  • DMEM Dulbecco's modified Eagle's Medium
  • FCS foetal calf serum
  • 2 mM L-glutamine penicillin 100 IU / ml
  • streptomycin 100 g / ml was used to incubate at 37 ° C, 5% carbon dioxide conditions in a thermo-hygrostat.
  • Vero cell lines were described above using a combination of Eagle's Minimum Essential Medium (EMEM; Lonza) with 8% FCS, 2 mM L-glutamine, penicillin 100 IU / ml and streptomycin 100 g / ml Cultured under the same conditions.
  • EMEM Eagle's Minimum Essential Medium
  • the HuH7 cell line contains a medium containing 8% FCS, 2 mM L-glutamine, penicillin 100 IU / ml, streptomycin 100 ⁇ g / ml and 1x non-essential amino acids (NEAA; Lonza) in MDEM. Cultured under the same conditions as described above.
  • MRC-5 cell line was subjected to the same conditions described above using a medium containing 8% FCS, 2 mM L-glutamine, penicillin 100 IU / ml, streptomycin 100 ⁇ g / ml, 1 ⁇ NEAA in EMEM Incubated at.
  • EMEM and 25 mM N-2-Hydroxyethylpiperazine-N ''-2-ethanesulfonic acid in 2% FCS, mM L-glutamine, penicillin 100 IU / ml, streptomycin (streptomycin) ) 100 ⁇ g / ml combined medium was used.
  • CHIKV LS3 infectious agents were produced by the method described in PLOS ONE 8 (2013): e71047 published by the Scholte group.
  • Zika virus (ZIKV) strain SL1602 was developed by Sci. Rep. (2017) isolated from infected travelers returning from Suriname by the method described in in press.
  • Middle east respiratory syndrome coronavirus strain EMC / 2012 was developed by Dr. Fakeeh Hospital of Jeddah, Saudi Arabia. It was isolated from Soliman's patient tissue (2012, Van Boheemen group) and provided at the Erasmus Medical Center in Rotterdam, The Netherlands.
  • Severe acute respiratory syndrome coronavirus SARS- CoV; strain Frankfurt 1
  • test substance was dissolved in DMSO and used at 20 mM and 10 ⁇ M.
  • VeroE6 cell lines were inoculated at 100 ⁇ l volume into each well to reach 5,000 cells / well (CHIKV) in 96-well clusters.
  • Vero (CCL81) cell lines were inoculated at 96-well clusters to 5,000 cells / well (ZIKV).
  • Vero, HuH7 and MRC-5 cell lines were inoculated in 96-well clusters at 20,000, 10,000 and 15,000 cells / well, respectively.
  • VeroE6 cell lines were seeded at 96 cells / well in 96-well clusters.
  • Each cell is identical to CHIKV (MOI 0.005), ZIKV (MOI 0.050), MERS-CoV (MOI 0.01 in HuH7, MOI 0.005 in Vero and MOI 0.03 in MRC-5 cells) or SARS-CoV (MOI 0.01) Infected with quadruplicate.
  • the evaluation material was treated in the same manner with diluted media, and the cytotoxicity test (CC50 evaluation) was performed simultaneously.
  • the virus was subjected to colorimetric viability assays using CellTiter 96® AQueous® One Solution Cell Proliferation Assay (MTS) reagent (Promega).
  • MTS Cell Proliferation Assay
  • Absorbance was measured using a Berthold Mithras LB 940 plate reader at 495 nm and normalized to cells that were not treated with infectious agents and analytes.
  • CC50 measurements were normalized to cells not treated with infectious agents and test substances.
  • EC50 values were determined using a non-linear regression method using Graphpad Prism.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de nucléoside carbocyclique représenté par la formule chimique A ou un sel pharmaceutiquement acceptable de celui-ci, et un agent antiviral le comprenant.
PCT/KR2018/000644 2017-01-12 2018-01-12 Dérivé de nucléoside carbocyclique et agent antiviral le comprenant WO2018131950A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR1020170005061A KR20180083094A (ko) 2017-01-12 2017-01-12 카보사이클릭 뉴클레오사이드 유도체 및 이를 포함하는 항바이러스제
KR10-2017-0005061 2017-01-12
KR10-2017-0063574 2017-05-23
KR1020170063574A KR20180128252A (ko) 2017-05-23 2017-05-23 카보사이클릭 뉴클레오사이드 유도체 및 이를 포함하는 항바이러스제

Publications (1)

Publication Number Publication Date
WO2018131950A1 true WO2018131950A1 (fr) 2018-07-19

Family

ID=62840619

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2018/000644 WO2018131950A1 (fr) 2017-01-12 2018-01-12 Dérivé de nucléoside carbocyclique et agent antiviral le comprenant

Country Status (1)

Country Link
WO (1) WO2018131950A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113929724A (zh) * 2021-11-02 2022-01-14 周雨恬 一种核苷类化合物及其药物组合物和用途
EP4272747A4 (fr) * 2021-02-26 2024-10-23 Future Medicine Co., Ltd. Composition pharmaceutique contenant un dérivé de nucléoside carbocyclique pour la prévention et le traitement du coronavirus 19

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4605659A (en) * 1985-04-30 1986-08-12 Syntex (U.S.A.) Inc. Purinyl or pyrimidinyl substituted hydroxycyclopentane compounds useful as antivirals

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4605659A (en) * 1985-04-30 1986-08-12 Syntex (U.S.A.) Inc. Purinyl or pyrimidinyl substituted hydroxycyclopentane compounds useful as antivirals

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
COOLS, M. ET AL.: "Mechanism of Antiviral and Cytotoxic Action of (±)-6' beta-fluoroansteromycin. a Potent Inhibitor of S-Adenosylhomocysteine Hydrolase", MOLECULAR PHARMACOLOGY, vol. 39, no. 6, June 1991 (1991-06-01), pages 718 - 724 *
YANG, M. ET AL.: "5'-Homoaristeromycin. Synthesis and Antiviral Activity against Orthopox Virus", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 15, 3 January 2005 (2005-01-03), pages 149 - 151, XP027800848 *
YANG, M. ET AL.: "6'-Methyl-5'-homoaristeromycin: A Structural Variation of the Anti-orthopox Vims Candidate 5'-homoaristeromycin", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 21, 2013, pages 4374 - 4377 *
YIN, X.-Q. ET AL.: "Chiral Syntheses of 6'beta-fluoroaristeromycin, 6'-beta-fluoro-5'-noraristeromycin and Aristeromycin", TETRAHEDRON LETTERS, vol. 46, 19 September 2005 (2005-09-19), pages 7535 - 7538, XP002680404 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4272747A4 (fr) * 2021-02-26 2024-10-23 Future Medicine Co., Ltd. Composition pharmaceutique contenant un dérivé de nucléoside carbocyclique pour la prévention et le traitement du coronavirus 19
CN113929724A (zh) * 2021-11-02 2022-01-14 周雨恬 一种核苷类化合物及其药物组合物和用途
CN113929724B (zh) * 2021-11-02 2024-05-31 周雨恬 一种核苷类化合物及其药物组合物和用途

Similar Documents

Publication Publication Date Title
WO2021040356A1 (fr) C-nucléosides, c-nucléotides et leurs analogues, équivalents et promédicaments de ceux-ci pour l'inhibition de l'ectonucléotidase
WO2019112344A1 (fr) Nouveau dérivé de pyrimidine ayant pour effet d'inhiber la croissance de cellules cancéreuses, et composition pharmaceutique contenant celui-ci
AU2019310508B2 (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and pharmaceutical composition comprising the same
WO2019078522A1 (fr) Composé induisant la dégradation de la protéine céréblon, procédé de préparation associé, et composition pharmaceutique pour la prévention ou le traitement du cancer le contenant en tant que principe actif
WO2021137646A1 (fr) Dérivé de pyrrolobenzodiazépine et conjugué ligand-lieur associé
WO2016032209A2 (fr) N-(pyrrolidin-3-yl)-7h-pyrrolo[2,3-d]pyrimidine-4-amine substituée utilisée en tant qu'inhibiteur de la janus kinase
WO2018080127A1 (fr) Composition pharmaceutique pour la prévention et le traitement de la stéatohépatite non alcoolique, de la fibrose hépatique et de la cirrhose du foie, comprenant des dérivés d'adénosine
WO2014109530A1 (fr) Dérivé 2-(phényléthynyl)thiéno[3,4-b]pyrazine, et composition pharmaceutique comprenant ce dérivé et destinée à la prévention ou au traitement du cancer
WO2023033551A1 (fr) Analogue de coiffe d'arnm et son utilisation
WO2018131950A1 (fr) Dérivé de nucléoside carbocyclique et agent antiviral le comprenant
WO2017034245A1 (fr) Inhibiteur sélectif de la janus kinase 1 et utilisation pharmaceutique associée
WO2016093554A2 (fr) Nouveau dérivé de 4-(aryl)-n-(2-alkoxythiéno[3,2-b]pyrazin-3-yl)-pipérazine-1-carboxamide et effet antiprolifératif de celui-ci
WO2022196858A1 (fr) Dérivé d'acide aminé, son procédé de préparation et composition pharmaceutique pour le traitement de l'hépatite comprenant ledit dérivé
WO2012060482A1 (fr) Dérivé de carboxamide de pyrrolopyrimidinone inhibant les cdk ou sel pharmaceutiquement acceptable de celui-ci, et composition pharmaceutique contenant ce dérivé comme principe actif et destinée à prévenir ou à traiter un carcinome hépatocellulaire
WO2022177307A1 (fr) Composition de stimulateur de gène d'interféron comprenant un dérivé de benzimidazole en tant que principe actif
WO2018169252A1 (fr) Dérivé de n-benzyl-n-phénoxyl-carbonyl-phénylsulfonamide et composition pharmaceutique comprenant celui-ci
WO2021172871A1 (fr) Nouveau dérivé d'imidazole ayant une activité inhibitrice de protéine kinase, et son utilisation
WO2021201352A1 (fr) Nouveau dérivé de benzimidazole, son procédé de préparation et son utilisation en tant qu'agent anticancéreux
WO2015016511A1 (fr) Nouveau dérivé de biphényle, et son procédé de préparation
WO2017115914A1 (fr) Inhibiteur de la phosphorylation de ppary et composition pharmaceutique le comprenant
WO2020190073A1 (fr) Composition pharmaceutique comprenant un nouveau composé hétérocyclique azolopyrimidine en tant que principe actif
WO2015115796A1 (fr) Dérivé pegylé de 7-déshydrocholestérol
WO2017052322A1 (fr) Dérivé d'adénosine, procédé de préparation associé, et composition pharmaceutique le contenant en tant que principe actif pour la prévention ou le traitement du cancer
WO2023027236A1 (fr) Micelle comprenant un composé conjugué de benzimidazole-hydrate de carbone, son procédé de préparation et son utilisation en tant qu'agent anticancéreux ou agent antiviral
WO2016144087A1 (fr) Dérivé de n-phényl-n'-phénoxycarbonyl-phénylsulfonhydrazide et composition pharmaceutique le contenant

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18739348

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 16.10.2019)

122 Ep: pct application non-entry in european phase

Ref document number: 18739348

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载