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WO2019141096A1 - Composé d'urée substitué, son procédé de préparation et son utilisation - Google Patents

Composé d'urée substitué, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2019141096A1
WO2019141096A1 PCT/CN2019/070390 CN2019070390W WO2019141096A1 WO 2019141096 A1 WO2019141096 A1 WO 2019141096A1 CN 2019070390 W CN2019070390 W CN 2019070390W WO 2019141096 A1 WO2019141096 A1 WO 2019141096A1
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Prior art keywords
group
compound
alkyl
membered
nitrogen
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Ceased
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PCT/CN2019/070390
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English (en)
Chinese (zh)
Inventor
刘金明
何婷
蔡家强
王利春
王晶翼
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Publication of WO2019141096A1 publication Critical patent/WO2019141096A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the adenosine receptor is a G protein-coupled receptor (GPCRs), and the family of receptors mainly includes four receptors A1, A2a, A2b and A3. Among them, the A2a and A2b receptors are coupled to the Gs protein that activates adenylate cyclase, and stimulate the production of intracellular cyclic adenosine monophosphate (cAMP).
  • GPCRs G protein-coupled receptor
  • A2a and A2b receptors are coupled to the Gs protein that activates adenylate cyclase, and stimulate the production of intracellular cyclic adenosine monophosphate (cAMP).
  • adenosine A2a receptor antagonists have a good application prospect in the pharmaceutical industry as a tumor therapeutic drug.
  • adenosine A2a receptors are also associated with Parkinson's disease, Alzheimer's disease, AIDS cerebral palsy, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, multiple system atrophy, cerebral ischemia , attention deficit hyperactivity disorder, sleep disorders, anxiety disorders, mood disorders, epilepsy, neuralgia, migraine and other diseases.
  • Corvus' CPI-444 is a compound that antagonizes the adenosine A2a receptor and is currently in Phase I clinical studies. The indication is a tumor. Prior to this, CPI-444 was used in clinical trials for the treatment of central nervous system diseases. .
  • WO 01/62233 and WO2002014282 A1 disclose that an aminopyridine compound has an antagonistic effect on the adenosine A2a receptor, and discloses a therapeutic agent which can be used as a drug for Parkinson's disease or Alzheimer's disease.
  • R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, R 8 R 9 NC 1-6 alkyl-, 5-6 a heterocyclic group -C 1-6 alkyl-, 5-6 membered heteroaryl-C 1-6 alkyl- and 5-6 membered heteroaryl, wherein said heterocyclic group and heteroaryl group are optionally Substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, amino, C 1-6 alkyl and C 1-6 alkoxy;
  • R 3 is C 1-6 alkyl or C 3-6 cycloalkyl
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen and halogen;
  • R 8 and R 9 are each independently selected from hydrogen and C 1-6 alkyl.
  • R 8 and R 9 are as defined herein.
  • a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a piperazinyl group.
  • a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof wherein: R 8 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof wherein: R 9 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, which is selected from:
  • Hal 1 and Hal 2 are each independently the same or different halogens, such as Cl, Br or I;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined above.
  • Step A Compound II-1 is reacted with a halogenating agent to obtain Compound II-2;
  • substitution reaction of compound II-1 with a halogenating agent gives compound II-2.
  • the substitution reaction is preferably carried out in a solvent in the presence of a strong base.
  • the strong base may be LiHMDS, NaHMDS, LDA, n-butyllithium, t-butyllithium or the like, preferably n-butyllithium.
  • the halogenating agent may be N-bromosuccinimide, N-iodosuccinimide, bromine and iodine, preferably iodine.
  • the base may be an inorganic base such as potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium phosphate.
  • the coupling reaction is carried out in a suitable organic solvent, which may be selected from the group consisting of 1,4-dioxane and N,N-dimethylformamide, for example 1,4-dioxane Six rings.
  • the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere.
  • the coupling reaction is carried out at a suitable temperature, which may be from 70 to 100 ° C, preferably 80 ° C.
  • the coupling reaction is carried out for a suitable period of time, which may be from 1 to 8 hours, preferably 3 hours.
  • Hal 1 and Hal 2 are each independently the same or different halogens, such as Cl, Br or I;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined above.
  • Step A Compound III-1 is reacted with IN-a to obtain compound III-2;
  • Hal 1 is halogen, such as Cl, Br or I, preferably Br;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined above.
  • Compound IV-1 is reacted with DMF-DMA to give compound IV-2.
  • This reaction is preferably carried out under solvent free conditions. However, the reaction can also be carried out in a solvent which can dissolve the raw material to some extent without inhibiting the reaction, such as 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone. , benzene or toluene, etc.
  • the reaction temperature is usually from room temperature to 120 ° C, preferably 80 ° C.
  • the reaction time is usually from 6 to 24 hours, preferably 12 hours.
  • Step B Compound IV-2 is reacted with hydrazine to give compound IV-3;
  • Compound IV-3 is reacted with a halogenating agent in a solvent to give compound IV-4.
  • the halogenating agent used may be N-bromosuccinimide or bromine, preferably N-bromosuccinimide.
  • the solvent to be used is long as it does not inhibit the reaction and can dissolve the raw material to some extent, such as N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, tetrahydrofuran, 1,4-dioxane.
  • the ring and dimethoxyethane and the like are preferably N,N-dimethylformamide.
  • the reaction temperature is usually -20 ° C to room temperature, preferably 0 ° C to room temperature.
  • the reaction time is usually from 1 to 24 hours, preferably from 12 hours.
  • Step D Compound IV-4 is reacted with IN-b to give compound IV-5;
  • Compound V-1 is reacted with an oxidizing agent in a solvent to obtain Compound V-2.
  • the oxidizing agent used may be selenium dioxide, potassium permanganate, sodium periodate, hydrogen peroxide or the like, preferably selenium dioxide.
  • the reaction can be carried out to a certain extent in a solvent which can dissolve the raw materials without inhibiting the reaction, such as 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone or the above organic
  • a mixed solvent of a solvent and water preferably a mixed solvent of 1,4-dioxane and water.
  • the reaction temperature is usually from room temperature to 120 ° C, preferably 110 ° C.
  • the reaction time is usually from 3 to 14 hours, preferably 5 hours.
  • Step F Compound V-6 is reacted with compound IN-e to obtain compound V-7;
  • Compound V-6 is coupled with compound compound IN-e to give compound V-7.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst such as tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium dichloride dichloromethane complex.
  • the base may be an inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogencarbonate or sodium hydrogencarbonate, preferably cesium carbonate.
  • the coupling reaction is carried out in a suitable organic solvent or a mixed solvent of an organic solvent and water, which may be selected from 1,4-dioxane, N,N-dimethylformamide or the like.
  • a mixed solvent of an organic solvent and water for example, a mixed solvent of 1,4-dioxane and water.
  • the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere.
  • the coupling reaction is carried out at a suitable temperature, which may be from 70 to 100 ° C, preferably 80 ° C.
  • the coupling reaction is carried out for a suitable period of time, which may be from 1 to 24 hours, such as 8 hours.
  • Step G Compound V-7 is reacted with compound IN-f to obtain compound V-8;
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
  • the MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • the instrument model used was Agilent 1260, the column was Waters XBridge Prep C18 OBD (19 mm ⁇ 150 mm ⁇ 5.0 ⁇ m); the column temperature was 25 ° C; the flow rate was 20.0 mL / min; the detection wavelength was 214 nm; the elution gradient was as follows:
  • the microwave reaction was carried out using a Biotage Initiator + (400 W, RT ⁇ 300 ° C) microwave reactor.
  • the second step preparation of 5-chloro-3-fluoro-4-(5-methylfuran-2-yl)pyridin-2-amine
  • Example 13 1-(5-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of -yl)-3-(2-morpholin-4-yl-ethyl)-urea (Compound 13)
  • Example 36 1-(6-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)-1, Preparation of 2,4-triazin-3-yl)-3-methylurea (Compound 36)
  • Cell culture medium Ham's F12 medium (Gibco, 11765054) containing 10% fetal bovine serum, 200 ⁇ g/ml Zeocin and 100 ⁇ g/ml Hygromycin B
  • Kit cAMP Assay Kit (CISBIO 62AM4PEC)
  • CHO-K1 cells stably expressing the ADORA2a receptor i.e., adenosine A2a receptor
  • ADORA2a receptor i.e., adenosine A2a receptor
  • test compound was diluted with DMSO to prepare a 10 mM stock solution of the test compound, and the stock solution was diluted with the experimental buffer to obtain a test compound solution of different working concentrations.
  • the positive working concentration of the positive agonist NECA was 10 ⁇ M; the positive antagonist ZM241385 was the highest working concentration of 1 ⁇ M, and was further diluted to different concentrations with the experimental buffer.
  • Plate 1 was added to 5 ⁇ l of the diluted positive agonist NECA, and 5 ⁇ l of the assay buffer was added to the wells and incubated for 0.5 hours at room temperature. After the detection reagent in the kit was added according to the instructions of the CISBIO kit, the incubation was continued for 1 hour, and the fluorescent signal was read by the PheraStar microplate reader to obtain the original data.
  • Compound number IC 50 (nM) range 1 10 ⁇ IC 50 ⁇ 30 2 30 ⁇ IC 50 ⁇ 100 3 IC 50 ⁇ 3 4 10 ⁇ IC 50 ⁇ 30 5 30 ⁇ IC 50 ⁇ 100 6 10 ⁇ IC 50 ⁇ 30
  • Table 1 indicates that the compounds of the present application have a good inhibitory effect on intracellular cAMP of the downstream signal factor of the A2a receptor at the cellular level.
  • the compounds of the present application were administered to male SD rats by intravenous (IV) and gavage (PO), respectively, to examine the pharmacokinetic characteristics.
  • IV and PO were administered at a dose of 1 mg/kg and 5 mg/kg, respectively, and the vehicle of IV was a mixture of 5% DMSO, 5% Solutol (polyethylene glycol-15 hydroxystearate) and 90% physiological saline, PO The solvent was 0.5% MC (sodium methylcellulose).
  • 3 rats were administered IV in parallel in the IV-administered group, before administration (0 h) and 0.083, 0.25, 0.5, 1, 2, 4, 6 and 8 h after administration, respectively. The blood was collected in parallel at the time point.
  • the exposure amount (AUC last ) of the compound 8 and the compound 34 of the present application administered by IV at a dose of 1 mg/kg was 431 h*ng/mL and 490 h*ng/mL, respectively.
  • the corresponding maximum plasma concentrations ( Cmax ) were 665 ng/mL and 547 ng/mL, respectively, indicating that Compound 8 and Compound 34 of the present application have excellent drug exposure in rats by IV administration.

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  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé d'urée substitué, son procédé de préparation et son utilisation. Plus particulièrement, l'invention concerne un composé d'urée substitué ou un sel pharmaceutiquement acceptable, un stéréoisomère, une substance polymorphe, un solvate, un N-oxyde, un composé marqué par un isotope, un métabolite ou un promédicament de celui-ci. L'invention concerne également un procédé de préparation du composé, un intermédiaire, une composition pharmaceutique comprenant le composé, et des utilisations thérapeutiques associées. Le composé ou la composition pharmaceutique de celui-ci est capable d'inhiber l'activité du récepteur A2a de l'adénosine et peut être utilisé pour traiter ou prévenir une maladie associée au récepteur A2a de l'adénosine, en particulier pour traiter une tumeur.
PCT/CN2019/070390 2018-01-19 2019-01-04 Composé d'urée substitué, son procédé de préparation et son utilisation Ceased WO2019141096A1 (fr)

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CN201810051542 2018-01-19

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Cited By (1)

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CN113166119A (zh) * 2018-12-28 2021-07-23 四川科伦博泰生物医药股份有限公司 取代芳基化合物及其制备方法和用途

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CN103664908A (zh) * 2013-12-10 2014-03-26 苏州大学 一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物

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Publication number Priority date Publication date Assignee Title
CN1602196A (zh) * 2001-12-10 2005-03-30 弗·哈夫曼-拉罗切有限公司 作为腺苷调节剂的2－氨基苯并噻唑脲
CN1791600A (zh) * 2003-05-19 2006-06-21 弗·哈夫曼-拉罗切有限公司 用作腺苷受体的配体的苯并噻唑衍生物
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113166119A (zh) * 2018-12-28 2021-07-23 四川科伦博泰生物医药股份有限公司 取代芳基化合物及其制备方法和用途
CN113166119B (zh) * 2018-12-28 2024-01-05 四川科伦博泰生物医药股份有限公司 取代芳基化合物及其制备方法和用途

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