WO2023280181A1 - 用作dhodh抑制剂的1,2,4-三唑酮衍生物及其制备方法和用途 - Google Patents
用作dhodh抑制剂的1,2,4-三唑酮衍生物及其制备方法和用途 Download PDFInfo
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- WO2023280181A1 WO2023280181A1 PCT/CN2022/104004 CN2022104004W WO2023280181A1 WO 2023280181 A1 WO2023280181 A1 WO 2023280181A1 CN 2022104004 W CN2022104004 W CN 2022104004W WO 2023280181 A1 WO2023280181 A1 WO 2023280181A1
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- 239000012312 sodium hydride Substances 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 229960000331 teriflunomide Drugs 0.000 description 1
- UTNUDOFZCWSZMS-YFHOEESVSA-N teriflunomide Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC=C(C(F)(F)F)C=C1 UTNUDOFZCWSZMS-YFHOEESVSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- 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
- 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
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the invention belongs to the field of medicinal chemistry, and more specifically, relates to a novel 1,2,4-triazolone derivative, a preparation method thereof and the application of the compound.
- Dihydroorotate dehydrogenase (Dihydroorotate Dehydrogenase, DHODH) is an iron-containing flavin-dependent enzyme, mainly present in the inner mitochondrial membrane, and is the key enzyme for the de novo synthesis of pyrimidine nucleotides.
- Pyrimidine nucleotides are the backbone components of DNA and RNA.
- Orotic acid is a precursor for the synthesis of pyrimidine nucleotides.
- DHODH catalyzes the dehydrogenation of dihydroorotic acid, converting it into orotic acid. Therefore, inhibiting DHODH can block the de novo synthesis of pyrimidine, resulting in obstacles to DNA and RNA synthesis.
- Intracellular pyrimidine nucleotides are mainly derived from de novo and salvage synthesis pathways.
- pyrimidine nucleotides are mainly derived from the salvage, also known as regenerative, synthesis pathway that directly converts free pyrimidine bases to pyrimidine nucleotides.
- the salvage pathway also known as regenerative, synthesis pathway that directly converts free pyrimidine bases to pyrimidine nucleotides.
- the pyrimidine nucleotides generated by the salvage pathway cannot maintain cell function or survival. Therefore, DHODH-dependent de novo synthesis of pyrimidine nucleotides is critical for the survival of these cells.
- Inhibiting the activity of DHODH can selectively prevent such cells from requiring a large amount of pyrimidine nucleotides, thereby hindering the synthesis of biological macromolecules such as DNA, RNA, and glycoproteins, and inhibiting cell function or growth.
- DHODH inhibitors targeting abnormally activated T and B cells and rapidly dividing cancer cells for the purpose of treating cancer, viral infection, autoimmune diseases (rheumatoid arthritis and multiple sclerosis)
- the research and development of DHODH has achieved initial results.
- the DHODH small molecule inhibitors Leflunomide/Teriflunomide and Buquina have been approved for the treatment of rheumatoid arthritis and multiple sclerosis.
- these inhibitors have high fat solubility and poor selectivity, and long-term use will cause serious side effects. Therefore, finding new DHODH inhibitors with high efficiency and low side effects for the treatment of immune-related diseases and tumors has become a current research hotspot.
- the present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
- n 0, 1 or 2;
- X is CH or N
- R 1 is aryl or heteroaryl, which can be substituted by one or more of the following groups: halogen, NH 2 , C1-C3 alkyl, C1-C3 alkoxy or Halogenated C1-C3 alkyl;
- R2 is H or F ;
- R 3 is C1-C3 alkyl
- R 4 is C1-C6 alkyl, C3-C8 cycloalkyl or halogenated C1-C6 alkyl.
- R 1 is: Wherein R a , R b , R c , R d and Re are independently H, F, Cl, Me, Et, OMe, CHF 2 , CF 3 or NH 2 .
- R 3 is Me.
- R 4 is Me, Et, CF 3 ,
- the above-mentioned compound or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are selected from one of the following structures:
- Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.
- Another object of the present invention provides the compound represented by the general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition Application in the preparation of medicines for treating tumors and other related diseases; wherein, the tumors are preferably solid tumors and hematological tumors.
- the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.
- the compounds described herein are according to methods well known in the art.
- the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below.
- the compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.
- the present invention also provides a preparation method of the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following method A or method B:
- Method A comprises the following steps: first, compound A1 and compound A2 are reacted under strong basic conditions to generate compound A3, compound A3 is further reacted with compound A4 under the action of strong base to generate compound A5, and compound A5 and compound A6 are subjected to a coupling reaction to generate the target Compound A7.
- Method B comprises the following steps: first, the carboxyl group of compound B1 undergoes a chlorination reaction to generate acid chloride compound B2, compound B2 is further reacted with isopropanol under the action of a strong base to generate compound B3, compound B3 and compound A6 generate compound B4 under alkaline conditions , Compound B4 is reacted under strongly basic conditions, and then reacted with compound A2 to obtain compound B5, and compound B5 is reacted with a suitable raw material A4 to obtain target compound B6.
- “Pharmaceutically acceptable” here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.
- the term "pharmaceutically acceptable salt” refers to a form of a compound which does not cause significant irritation to the organism to which it is administered and which does not abolish the biological activity and properties of the compound.
- the pharmaceutically acceptable salt is obtained by reacting the compound of general formula (1) with an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and other inorganic acids, formic acid, acetic acid , propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
- an acid such as hydrochloric acid, hydrobromic acid, hydro
- references to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs.
- Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
- Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein.
- the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol.
- the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.
- compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms.
- the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms.
- Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.
- the compounds of general formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomeric forms, and cis-trans isomeric forms occur.
- Each chiral center or axial chirality will independently give rise to two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
- the present invention is meant to include all such isomeric forms of these compounds.
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
- compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
- radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
- heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.
- alkyl means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
- Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 ) CH , iPr , nPr , iBu , nBu or tBu .
- cycloalkyl means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic.
- cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of cycloalkyl groups can be optionally oxidized to form oxo or sulfide groups. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
- cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group.
- cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinenyl, norcarpanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.
- alkoxy means an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
- Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxyl.
- alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
- Preferred alkoxy groups are selected from OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.
- aryl refers to a hydrocarbon aromatic group, aryl is monocyclic or polycyclic, eg a monocyclic aryl ring fused with one or more carbocyclic aromatic groups.
- aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.
- heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl is monocyclic or polycyclic.
- a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
- heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H- Pyrrolo[2,3-b]pyridyl,
- halogen refers to fluorine, chlorine, bromine or iodine.
- halo or halogen substitution
- appearing before the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Substituted by F or Cl.
- membered ring includes any ring structure.
- member is meant to indicate the number of skeletal atoms that make up the ring.
- cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
- cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
- fragment refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to molecules.
- keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
- acceptable means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
- treatment includes alleviating, suppressing or improving the symptoms or conditions of a disease; inhibiting the development of complications; improving or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom.
- a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
- Active ingredient refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1).
- the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers.
- the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
- the present invention is meant to include all such isomeric forms of these compounds.
- composition a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
- administered, administering, or administration means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound Wait.
- the present invention provides methods of treating diseases including, but not limited to, conditions involving DHODH (such as cancer) using compounds of general formula (1) or pharmaceutical compositions of the present invention.
- a method for treating cancer comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1) to an individual in need thereof.
- the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer , head and neck cancer, stomach cancer, mesothelioma or all cancer metastases.
- the compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts .
- safe and effective amount means: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
- the safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.
- “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity .
- “Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
- Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
- cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
- gelatin such as stearic acid, magnesium stearate
- calcium sulfate such as soybean oil, sesame oil,
- the compounds of the present invention When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
- Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, from such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
- coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, from such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
- Examples of usable embedding components are polymeric substances and waxy substances.
- the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
- inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
- compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
- Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
- the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
- the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
- a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
- the dosage is usually 1-2000 mg, preferably 50-1000 mg.
- factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
- 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in ⁇ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
- AlMe3 stands for trimethylaluminum
- Ar stands for argon
- CDCl3 stands for deuterated chloroform
- (COCl) 2 stands for oxalyl chloride
- Cs2CO3 stands for cesium carbonate
- DCM stands for dichloromethane
- Dioxane represents 1,4-dioxane
- DMF represents N,N-dimethylformamide
- DMSO represents dimethyl sulfoxide
- EA or EtOAc represents ethyl acetate
- h represents hours
- IPA represents isopropanol
- KF stands for potassium fluoride
- KHMDS stands for potassium bis(trimethylsilyl)amide
- LC-MS stands for liquid chromatography-mass spectrometry
- Me 3 OBF 4 stands for trimethyloxonium tetrafluoroborate
- MeOH stands for methanol
- mL stands for milliliter
- min stands for minute
- MS stands for mass
- 2-Chloro-6-fluoroaniline (6.11g, 42.0mmol) and dry DCM (60mL) were added to a 250mL three-necked flask, and after Ar displacement protection, trimethylaluminum (42mL, 1M in n-Heptane, 42mmol ), after dropping, the mixture was stirred at room temperature for 2h. Then 1-5 (3.62g, 10.5mmol) was added, and the mixture was replaced by Ar, then raised to 50°C and stirred for 3h.
- Embodiment 2-53 the synthesis of compound 2-53
- the target compound 2-53 was obtained according to the similar synthesis method in Example 1.
- Target compounds 55-59 were obtained according to the similar synthesis method in Example 54 using different starting materials.
- the reference compound used in the present invention is BAY-2402234, whose synthesis method refers to patent WO2018077923, and its structure is as follows:
- Embodiment 60 The compound of the present invention is to the mensuration of DHODH enzymatic activity
- the cascade reaction is used to determine its ability to catalyze the oxidation of the natural substrate DHO (dihydroorotate) to orotate and reduce coenzyme Q at the same time.
- the enzymatic activity of DHODH was detected indirectly by measuring the ability of coenzyme Q to reduce the chromogenic substrate DCIP.
- the reaction substrate DHO was added to start the reaction, and the enzyme activity was measured by detecting the depletion of DCIP by measuring the absorption at 600nm at regular intervals.
- the inhibition rate of DHODH enzyme activity of different concentrations of compounds was calculated, and the IC50 value of the half effective inhibitor concentration was calculated.
- the screening results are shown in Table 3.
- THP-1 cells were planted in a 384-well plate (Fisher 142762), 3000 cells per well, and on the second day, a compound diluted in a gradient was added. After adding the compound for 72 hours, CellTiter-Lumi (Beiyuntian C0068XL) was added to measure the ATP content in the cells. The cell growth was evaluated, and the IC 50 of the compound for inhibiting cell growth was calculated. The screening results are shown in Table 3.
- MV-4-11 cells were planted in a 384-well plate (Fisher 142762), 3000 cells per well, and on the second day, the compound was added in a gradient dilution. After adding the compound for 72 hours, CellTiter-Lumi (Beiyuntian C0068XL) was added to measure the ATP content in the cells. content, evaluate the cell growth, and calculate the IC 50 of the compound for inhibiting cell growth. The screening results are shown in Table 3.
- CellTiter-Lumi Beiyuntian C0068XL
- the compound of the present invention is to the inhibitory activity of DHODH enzyme, and the antiproliferative activity of THP-1 cell and MV-4-11 cell
- the compound of the present invention inhibits DHODH enzyme and also has strong anti-proliferation activity on tumor cells THP-1 and MV-4-11. And compared with the control compound, the inhibitory activity of the compound of the present invention on MV-4-11 cells has been greatly improved.
- Compound adopts intravenous injection and oral gavage administration, intravenous injection dosage is 2mg/kg, oral administration dosage is 10mg/kg (0.5% CMC-Na suspension), selects 15 ICR mice, male, each Mice were collected at 3 discrete time points, with 3 mice per time point. The sampling time points were before administration, 5min, 15min, 30min, 1h, 3h, 5h, 8h, 12h and 24h after administration, and about 80 ⁇ L of blood was collected from the orbit or heart at each time point after administration.
- compound 1 has good oral bioavailability, and good oral absorption properties are of great significance in improving the efficacy of drugs, reducing drug dosage, and saving costs.
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Abstract
Description
Claims (8)
- 如权利要求1或2所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物,其中所述通式(1)中,R 3为Me。
- 一种药物组合物,其特征在于,其含有药学上可接受的赋形剂或载体,以及如权利要求1-5中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
- 一种如权利要求1-5中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求6所述的药物组合物在制备预防或治疗肿瘤的药物中的应用。
- 如权利要求7所述的应用,其中所述肿瘤包括实体瘤和血液瘤。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2014128669A2 (en) * | 2013-02-25 | 2014-08-28 | Aurigene Discovery Technologies Limited | Trisubstituted benzotriazole derivatives as dihydroorotate oxygenase inhibitors |
CN110023302A (zh) * | 2016-10-27 | 2019-07-16 | 拜耳股份有限公司 | 用作dhodh抑制剂的2,4,5-三取代的1,2,4-三唑酮 |
CN110248937A (zh) * | 2016-10-27 | 2019-09-17 | 拜耳股份有限公司 | 4,5-环状1,2,4-三唑酮 |
WO2020144638A1 (en) * | 2019-01-11 | 2020-07-16 | Janssen Biotech, Inc. | Dihydroorotate dehydrogenase inhibitors |
WO2021038490A1 (en) * | 2019-08-29 | 2021-03-04 | Janssen Biotech, Inc. | Substituted urea dihydroorotate dehydrogenase inhibitors |
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- 2022-07-05 WO PCT/CN2022/104004 patent/WO2023280181A1/zh active Application Filing
- 2022-07-05 CN CN202280047403.4A patent/CN117616026A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2014128669A2 (en) * | 2013-02-25 | 2014-08-28 | Aurigene Discovery Technologies Limited | Trisubstituted benzotriazole derivatives as dihydroorotate oxygenase inhibitors |
CN110023302A (zh) * | 2016-10-27 | 2019-07-16 | 拜耳股份有限公司 | 用作dhodh抑制剂的2,4,5-三取代的1,2,4-三唑酮 |
CN110248937A (zh) * | 2016-10-27 | 2019-09-17 | 拜耳股份有限公司 | 4,5-环状1,2,4-三唑酮 |
WO2020144638A1 (en) * | 2019-01-11 | 2020-07-16 | Janssen Biotech, Inc. | Dihydroorotate dehydrogenase inhibitors |
WO2021038490A1 (en) * | 2019-08-29 | 2021-03-04 | Janssen Biotech, Inc. | Substituted urea dihydroorotate dehydrogenase inhibitors |
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