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WO2021179884A1 - Dérivé d'acide oléanolique ayant un cycle c à structure diénique conjuguée, son procédé de préparation et son utilisation - Google Patents

Dérivé d'acide oléanolique ayant un cycle c à structure diénique conjuguée, son procédé de préparation et son utilisation Download PDF

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WO2021179884A1
WO2021179884A1 PCT/CN2021/076726 CN2021076726W WO2021179884A1 WO 2021179884 A1 WO2021179884 A1 WO 2021179884A1 CN 2021076726 W CN2021076726 W CN 2021076726W WO 2021179884 A1 WO2021179884 A1 WO 2021179884A1
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compound
pharmaceutically acceptable
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丁晔
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to an oleanolic acid derivative compound for preventing and treating inflammation-related diseases and tumor-related diseases, and a preparation method and application thereof.
  • Natural terpenoids and derivatives have unique chemical structures and biologically active properties, and are one of the important sources for the development of new small molecule drugs.
  • Paclitaxel from Bristol-Myers Squibb and Docetaxel from Sanofi although they have very similar taxane terpenoid structures, have their own characteristics in terms of pharmacokinetics, safety, and clinical application. Features [Practical Medicines and Clinics, 2010,4,281-283].
  • oleanane terpenoids such as oleanolic acid
  • have a wide range of biological activities such as antioxidant and anti-inflammatory.
  • Oleanolic acid is approved in my country for the adjuvant treatment of clinical liver diseases (such as hepatitis).
  • oleanolic acid has weak anti-inflammatory and other biological activities, high fat solubility and poor water solubility, and other shortcomings, which limit its clinical application.
  • the drug has not been approved for marketing by the United States, Europe and other drug regulatory authorities.
  • a series of derived oleanolic acid derivatives such as RTA401, RTA402 and RTA408, are compounds with strong biological activity [J.Med.Chem.2000,43,4233-4246]. Such compounds can be cytoprotective agents and inhibitors of cell inflammatory processes at low concentrations, and inhibit cell proliferation and promote apoptosis at high concentrations [Nat. Rev. Cancer, 2007, 7, 357-369]. Studies have shown that the mechanism of action of this type of compound is also very complicated, and there are many potential targets.
  • Keap1-NRF2 Multiple inflammation-related targets and signaling pathways including Keap1-NRF2 have been proven [Nat.Rev.Cancer,2007,7,357–369; J.Am.Soc.Nephrol.2012,1663-1673; PLOS ONE,2014, 9,e98896] participate in it.
  • the first type of compounds is mainly focused on the A ring, the preferred candidate compound RTA401 (also known as CDDO, Bardoxolone), namely 2-cyano-3,12-dioxole-1,9(11)-two Ene-28-acid; and RTA402 (also known as CDDO-Me, Bardoxolone methyl), which is 2-cyano-3,12-dioxole-1,9(11)-diene-28-methyl acid .
  • RTA401 also known as CDDO, Bardoxolone
  • RTA402 also known as CDDO-Me, Bardoxolone methyl
  • RTA402 is not a simple methyl ester prodrug of RTA401.
  • Reata Company advances both RTA401 and RTA402 into clinical trials and applies them in different indications. For example, in clinical trial NCT00322140, RTA401 was used to treat solid tumors and lymphomas, and in clinical trial NCT03749447, RTA402 was used to treat chronic kidney disease.
  • the C ring is also a key area that affects the activity and druggability of the compound.
  • the C ring of oleanane also has unique chemical properties.
  • the ethylenic bond of ring A of RTA402 can be reduced by catalytic hydrogenation at atmospheric pressure, while the ethylenic bond of ring C is very stable to catalytic hydrogenation.
  • Reata Company conducts special research on the C ring, such as saturating unsaturated ethylenic bonds [CN102164941B]. Although the safety of the compound is improved, the biological activity is reduced, and it has not been selected for clinical research so far.
  • the present invention provides an oleanane compound with a C ring having a conjugated diene rigid structure, its preparation method and its application.
  • the present invention provides a class of compounds of general formula (I) or pharmaceutically acceptable salts thereof:
  • Z -COOR 2 , -CONR 2 R 3 , or -NR 2 R 3 ;
  • R 1 is independently taken from hydrogen, or alkyl (C ⁇ 8), alkyl ether group, or halogen substituted form of at least one hydrogen atom of any one of these groups;
  • R 2 and R 3 are independently taken from hydrogen, or alkyl (C ⁇ 8), cycloalkyl (C ⁇ 8), spiroalkyl (C ⁇ 8), alkenyl (C ⁇ 8), alkynyl ( C ⁇ 8), aryl (C ⁇ 8), heteroaryl (C ⁇ 8, where at least one of the ring atoms is nitrogen, oxygen or sulfur), aralkyl (C ⁇ 8), alkyl ether group, or these At least one hydrogen atom of any one of the groups is substituted by halogen, hydroxyl, amino, or carboxyl.
  • the compound is further defined as a type of compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:
  • Z -COOR 1 , -CONR 1 R 2 , or -NR 1 R 2 ;
  • R 1 and R 2 are independently taken from hydrogen, or alkyl (C ⁇ 8), cycloalkyl (C ⁇ 8), spiroalkyl (C ⁇ 8), alkenyl (C ⁇ 8), alkynyl ( C ⁇ 8), aryl (C ⁇ 8), heteroaryl (C ⁇ 8, where at least one of the ring atoms is nitrogen, oxygen or sulfur), aralkyl (C ⁇ 8), alkyl ether group, or these At least one hydrogen atom of any one of the groups is substituted by halogen, hydroxyl, amino, or carboxyl.
  • the compound is further defined as a type of compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:
  • Z -COOR 1 , -CONR 1 R 2 , or -NR 1 R 2 ;
  • R 1 and R 2 are independently taken from hydrogen, or alkyl (C ⁇ 8), cycloalkyl (C ⁇ 8), spiroalkyl (C ⁇ 8), alkenyl (C ⁇ 8), alkynyl ( C ⁇ 8), aryl (C ⁇ 8), heteroaryl (C ⁇ 8, where at least one of the ring atoms is nitrogen, oxygen or sulfur), aralkyl (C ⁇ 8), alkyl ether group, or these At least one hydrogen atom of any one of the groups is substituted by halogen, hydroxyl, or amino.
  • the compound is further defined as a type of compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof:
  • Z -COOCH 3 , -CONHCH 2 CF 3 or -NHCOCF 2 CH 3 ;
  • R 1 is taken from alkyl (C ⁇ 8), cycloalkyl (C ⁇ 8), spiroalkyl (C ⁇ 8), alkenyl (C ⁇ 8), alkynyl (C ⁇ 8), aryl ( C ⁇ 8), heteroaryl (C ⁇ 8, wherein at least one of the ring atoms is nitrogen, oxygen or sulfur), aralkyl (C ⁇ 8), alkyl ether group, or at least one of any of these groups
  • the compound is further defined as a type of compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof:
  • Z -COOCH 3 , -CONHCH 2 CF 3 or -NHCOCF 2 CH 3 ;
  • R 1 is taken from alkyl (C ⁇ 8), cycloalkyl (C ⁇ 8), alkenyl (C ⁇ 8), alkynyl (C ⁇ 8), aryl (C ⁇ 8), heteroaryl ( C ⁇ 8, where at least one of the ring atoms is nitrogen, oxygen or sulfur), aralkyl (C ⁇ 8), alkyl ether group, or halogen, hydroxyl, or amino substitution of at least one hydrogen atom of any of these groups form.
  • Non-limiting examples of the compounds provided in the present disclosure include compounds according to the chemical formula shown below, and pharmaceutically acceptable salts thereof:
  • some compounds can be selected by the following synthesis method (1) to construct a C-ring conjugated diene structure:
  • some compounds can also be selected to construct the C-ring conjugated diene structure by the following synthesis method (2):
  • some compounds can also be selected to construct the C-ring conjugated diene structure by the following synthesis method (3):
  • the above-mentioned compounds themselves, or optical isomers, and pharmaceutically acceptable salts possess anti-inflammatory activity at low concentration (nM) and anti-tumor activity at high concentration ( ⁇ M).
  • the above-mentioned compounds themselves, or optical isomers, and pharmaceutically acceptable salts have applications in the treatment of inflammatory-related diseases, tumors and other diseases.
  • the amount of the compound itself, or an optical isomer, or a pharmaceutically acceptable salt in the application is about 0.01 mg to about 1000 mg, about 0.1 mg to about 200 mg, about 1 mg to about 100 mg, and about 5 mg to about 5 mg. About 30 mg, about 10 mg to about 20 mg, about 12 mg to about 18 mg, or about 15 mg.
  • the present invention also provides a pharmaceutical composition.
  • the compound disclosed herein can be administered as a pure chemical, but is preferably administered as a pharmaceutical composition. Therefore, the present invention provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain the compound or salt as the sole active agent, and may also contain at least one other active agent.
  • the compounds disclosed in the present invention can be injected, orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, by oral cavity, rectal, as an ophthalmic solution, or via a dosage unit formulation containing conventional pharmaceutical carriers.
  • the pharmaceutical composition can be formulated into any pharmaceutical form, such as: injection, aerosol, cream, gel, pill, capsule, tablet, syrup, transdermal patch, or ophthalmic solution.
  • Some dosage forms such as tablets and capsules can be subdivided into appropriate dosage unit dosage forms containing appropriate amounts of active ingredients such as effective amounts for the desired purpose.
  • Injection preparations preferably include injections, powder injections, etc., and are preferably injected intravenously, intramuscularly or locally.
  • Carriers include excipients and diluents, and must have sufficiently high purity and very low toxicity to make them suitable for administration to the patient to be treated.
  • the carrier may be inert or it may have medicinal benefits on its own.
  • the types of carriers include, but are not limited to: binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents Agent, and wetting agent.
  • Some carriers can be listed in more than one category, for example, vegetable oils can be used as lubricants in some formulations and as diluents in others.
  • Exemplary pharmaceutical carriers include sugar, starch, cellulose, malt, gelatin, talc and vegetable oils.
  • An optional active agent may be included in the pharmaceutical composition, which does not substantially affect the activity of the compound of the present invention.
  • Optical isomers are compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space. It includes “diastereomers” and “enantiomers”.
  • Alkyl includes both branched and straight chain saturated aliphatic hydrocarbon groups, and has a specified number of carbon atoms, generally 1 to about 12 carbon atoms.
  • alkyl (C ⁇ 8) as used herein denotes an alkyl group having 1 to 8 carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, tert-butyl, n-pentyl, and sec-pentyl.
  • Cycloalkyl includes monocyclic, bicyclic or tricyclic alkyl groups, which usually have 3 to 12 carbon atoms. Cycloalkyl (C ⁇ 8) refers to having 3 to 8 carbon atoms, such as 3 to 8, or 3 to 4, 3 to 5, 3 to 6, or 3 to 7 carbon atoms. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic and tricyclic ring systems include both bridged cycloalkyls and fused rings, such as, but not limited to, bicyclic [2.1.1] hexane and the like.
  • Cycloalkyl groups can be substituted or unsubstituted.
  • the substituted cycloalkyl group may be substituted one or more times with non-hydrogen and non-carbon groups as defined above.
  • substituted cycloalkyl groups may also include those rings substituted with straight or branched chain alkyl groups as defined above.
  • Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, for example, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6- Disubstituted cyclohexyl, which may be substituted with substituents such as those listed above.
  • Alkenyl (C ⁇ 8) “alkenyl” refers to straight and branched hydrocarbon chains that include one or more unsaturated carbon-carbon bonds. The carbon-carbon bonds can occur at any stable point along the chain.
  • the alkenyl group (C ⁇ 8) described herein generally has 2 to 8 carbon atoms, such as C 2 -C 8 , C 2 -C 6 , and C 2 -C 4 alkenyl. In some embodiments, the alkenyl group includes one, two, or three carbon-carbon double bonds.
  • Alkenyl groups can be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, for example, but not limited to, mono-, di- or tri-substituted alkenyl groups substituted with substituents such as those listed above.
  • Aryl is a cyclic aromatic hydrocarbon that does not contain heteroatoms.
  • the aryl group described herein includes monocyclic, bicyclic and tricyclic ring systems.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptyl, diphenyl, fluorenyl, phenanthryl, anthracenyl, indenyl, dihydroindenyl, pentacyclopentadienyl, and naphthyl.
  • the aryl group contains 6-14 carbon atoms in the ring portion of the group, and in other embodiments, it contains 6-12 carbon atoms or even 6-10 carbon atoms.
  • aryl groups are phenyl and naphthyl.
  • aryl includes those groups that contain fused rings, such as fused aryl-aliphatic ring systems (e.g., indenyl, tetrahydronaphthyl, etc.).
  • fused aryl-aliphatic ring systems e.g., indenyl, tetrahydronaphthyl, etc.
  • aryl also includes substituted aryl groups. Groups such as tolyl are called substituted aryl groups. Representative substituted aryl groups can be mono-substituted and substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-substituted, 3-substituted, 4-substituted, 5-substituted, or 6-substituted phenyl or naphthyl, which can be substituted by such as those listed above
  • the substituents and other substituents are substituted.
  • the aryl group is a phenyl group, which may be substituted or unsubstituted.
  • the substituted phenyl group has one or two substituents.
  • the substituted phenyl has one substituent.
  • Heteroaryl means a stable 5- or 6-membered monocyclic or polycyclic ring containing 1 to 4, or preferably 1 to 3 heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon.
  • heteroaryl groups include, but are not limited to: pyridinyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, Azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]phenylthio, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl , And 5,6,7,8-tetrahydroisoquinoline.
  • Alkynyl includes straight and branched chain alkyl groups as defined above, except that there is at least one triple bond between two carbon atoms.
  • the alkynyl group (C ⁇ 8) has 2-8 carbon atoms, and in some embodiments, 2-8, 2-6, or 2-4 carbon atoms.
  • the alkynyl group includes one, two, or three carbon-carbon triple bonds. Examples include but are not limited to -C ⁇ CH, -C ⁇ CCH 3 , -CH 2 C ⁇ CCH 3 , -C ⁇ CCH 2 CH(CH 2 CH 3 ) 2 and so on.
  • Alkynyl groups can be substituted or unsubstituted.
  • Representative substituted alkynyl groups may be mono-substituted or substituted more than once, for example, but not limited to, mono-, di- or tri-substituted alkynyl groups substituted with substituents such as those listed above .
  • Alkyl is an alkyl group as defined above, wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to the aryl group as defined above.
  • the aralkyl group (C ⁇ 8) has 7 to 8 carbon atoms.
  • Aralkyl groups can be substituted or unsubstituted.
  • the substituted aralkyl group can be substituted in the alkyl part, the aryl part, or both the alkyl and aryl parts of the group.
  • Representative aralkyl groups include, but are not limited to, benzyl and phenethyl.
  • Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.
  • Alkyl ether group refers to any alkyl group as defined above in which at least one carbon-carbon bond is replaced with a carbon-oxygen bond.
  • the carbon-oxygen bond can be on the terminal (as in an alkoxy group) or the carbon-oxygen bond can be internal (ie, C-O-C).
  • Alkyl ethers contain at least one carbon-oxygen bond, but may include more than one carbon-oxygen bond.
  • polyethylene glycol (PEG) is included within the meaning of alkyl ether.
  • alkyl ether groups are optionally substituted.
  • the alkyl ether is substituted with an alcohol or phosphate ester.
  • spiroalkyl refers to a structure composed of two cycloalkyl moieties with exactly one atom in common. Examples include, but are not limited to, spiro[2.3]hexyl, spiro[2.5]octane and the like.
  • halogen refers to bromine, chlorine, fluorine, or iodine.
  • hydroxyl may refer to -OH or its ionized form -O - .
  • amino refers to a functional group having a nitrogen atom and 1 to 2 hydrogen atoms.
  • Amino groups are generally used herein to describe primary, secondary, or tertiary amines, and those skilled in the art can determine their identity in view of the context in which the term is used in this disclosure.
  • the term “amine” or “amine group” or “amino group” means a functional group containing a nitrogen atom derived from ammonia (NH 3 ).
  • the amine group may be a primary amine, which means that the nitrogen is bonded to two hydrogen atoms and a substituent that includes a substituted or unsubstituted alkyl or aryl group or an aliphatic or aromatic group.
  • the amine group may be a secondary amine, which means that the nitrogen is bonded to one hydrogen atom and two substituents, the substituents including substituted or unsubstituted alkyl or aryl groups or aliphatic or aromatic groups, This is defined as follows.
  • the amine group may be a tertiary amine, which means that the nitrogen is bonded to three substituents, which include substituted or unsubstituted alkyl or aryl groups or aliphatic or aromatic groups.
  • the amine group may also be a quaternary amine, which means that the designated amine group is bonded to the fourth group to form a positively charged ammonium group.
  • Carboxyl refers to the -C(O)OH group or its ionized form: -C(O)O - .
  • “Pharmaceutically acceptable salt” or “salt of a compound” is a derivative of the disclosed compound, wherein the parent compound is modified by preparing a non-toxic acid or base addition salt thereof, and also refers to these compounds and these salts
  • Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues such as carboxylic acids; etc., and include one or more Combinations of the above salts.
  • Pharmaceutically acceptable salts include non-toxic salts and quaternary ammonium salts such as parent compounds formed from non-toxic inorganic or organic acids.
  • non-toxic acid salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, Cesium salt, etc.; alkaline earth metal salt such as: calcium salt, magnesium salt, etc., and a combination including one or more of the above-mentioned salts.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.
  • other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, Cesium salt, etc.
  • alkaline earth metal salt such as: calcium salt, magnesium salt, etc., and a combination including one or more of the above-mentioned salts.
  • Organic salts include compounds such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, catabolic acid, maleic acid, hydroxymaleic acid, benzene Acetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid , Ethane disulfonic acid, oxalic acid, isethionic acid, HOOC-(CH 2 )n-COOH (where n is 0 to 4) and other organic acid salts; organic amine salts, such as: triethylamine salt, Pyridine
  • Figure 1 shows the co-crystal structure analysis and structural modification prediction of the BTB region protein of RTA401 and the target protein Keap1.
  • Fig. 2 is an MS spectrum of a representative compound 1 having a C ring of a conjugated diene structure.
  • Fig. 3 is a 1 H NMR spectrum of a representative compound 1 having a C ring of a conjugated diene structure.
  • Fig. 4 is an MS spectrum of the representative compound 7 with the C ring of the substituted conjugated diene structure.
  • Fig. 5 is a 1 H NMR chart of a representative compound 7 having a ring C of a conjugated diene structure with a substituent.
  • Fig. 6 is the rigid structure region (gray region) of the C ring core of the conjugated diene structure with substituents.
  • the embodiment of the present invention provides an oleanane compound with a C ring of a conjugated diene rigid structure, and a synthesis method and biological activity screening thereof.
  • the fine structure of the compound C ring has an extremely important influence on the activity of the compound.
  • the available data show that, without the enol-like conjugated structure, OA-26 reduces the anti-inflammatory activity of RTA401 compound by 1000 times [J.Med.Chem.2000,43,4233-4246].
  • the structure of the compound C ring is affected by the large steric hindrance of the surrounding multi-ring rigid structure, which makes its reactivity significantly passivated.
  • the C-cyclic ethylenic bond of oleanolic acid (OA) does not react at all under atmospheric catalytic hydrogenation conditions.
  • the A-ring ethylenic bond of OA-20 can be reduced quantitatively, but the C-ring ethylenic bond can not be reacted at all, and the final compound is OA-19. Therefore, it can be seen that the C ring possesses the unique chemical properties of natural terpenoid products.
  • Synthetic reagents and conditions a) hydrogen, palladium on carbon, tetrahydrofuran, normal pressure and normal temperature, 24 to 48 hours.
  • Synthetic reagents and conditions a) benzyl chloride, potassium carbonate, N,N-dimethylformamide, 55°C, 5 hours; b) acetic anhydride, pyridine, 0°C ⁇ room temperature, 4 hours; c) 30% hydrogen peroxide , Formic acid, dichloromethane, room temperature, 24 hours; d) bromine, hydrobromic acid, acetic acid, 50 °C ⁇ room temperature, 24 hours; e) potassium hydroxide, methanol, reflux, 54 minutes; f) Jones reagent, acetone, 0°C ⁇ room temperature, 20 minutes; g) ethyl formate, sodium methoxide, dichloromethane, 0°C ⁇ room temperature, 12 hours; h) hydroxylamine hydrochloride, ethanol, reflux, 1 hour; i) zinc amalgam reagent, acetone, Room temperature, 4 hours; j) Sodium methoxide, ether, methanol, 0°C ⁇ room
  • the white solid (2.1 g, 3.74 mmol) obtained in the previous step was dissolved in a mixed solution of methanol (60 mL) and ether (125 mL), sodium methoxide (6.38 g, 118 mmol) was added at 0°C, and the reaction was carried out at room temperature for 45 minutes.
  • the reaction solution was diluted with dichloromethane (50 mL), and the organic layer was washed 3 times with 5% dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a pale yellow solid OA-10 ( 2.0g, 95%).
  • Synthesis reagents and conditions a) hydrogen, palladium on carbon, tetrahydrofuran, normal pressure and room temperature, 1 to 2 hours; b) methyl iodide, potassium carbonate, acetone, room temperature, 4 hours; c) zinc amalgam reagent, acetone, room temperature, 4 Hours; d) sodium methoxide, ether, methanol, 0°C ⁇ room temperature, 1 hour; e) 2,3-dichloro-5,6-dicyanoquinone, benzene, reflux, 20 minutes.
  • OA-8 was used as the starting material to prepare OA-11, and the preparation method was completed according to the previous study [CN102070697A].
  • Compound OA-11 (1.05g, 2.1mmol) was dissolved in acetone (50mL), potassium carbonate (3.0g, 21mmol) was added and suspended in the solution, stirred vigorously for 2 hours, and slowly added dropwise methyl iodide (0.85g, 6mmol), react at room temperature for 5 hours.
  • the reaction solution was filtered, the filtrate was concentrated, and dichloromethane (50mL) was diluted.
  • Synthetic reagents and conditions a) zinc amalgam reagent, acetone, room temperature, 4 hours; b) sodium methoxide, ether, methanol, 0°C ⁇ room temperature, 1 hour; c) 2,3-dichloro-5,6-di Cyano-p-benzoquinone, benzene, reflux, 20 minutes; d)i. Oxalyl chloride, anhydrous dichloromethane, 0°C ⁇ room temperature, 12 hours; ii. NH 2 CH 2 CF 3 , triethylamine, anhydrous dichloride Methane, 0°C ⁇ room temperature, 4 hours.
  • Dissolve compound 3 (1.4g, 3.04mmol) in anhydrous dichloromethane (5mL), add oxalyl chloride (3.86g, 30.4mmol) at 0°C, stir, return to room temperature, react overnight, spin dry to obtain a pale yellow solid , Directly into the next reaction.
  • the solid obtained in the previous step was dissolved in anhydrous dichloromethane (5mL).
  • Trifluoroethylamine (0.36g, 3.64mmol) and triethylamine (0.92g, 9.12mmol) were added at 0°C, stirred, returned to room temperature, and reacted.
  • Synthesis reagents and conditions a) Sodium methoxide, ether, methanol, 0°C ⁇ room temperature, 1 hour; b) 2,3-Dichloro-5,6-dicyano-p-benzoquinone, benzene, reflux, 20 minutes; c) Acetic anhydride, concentrated sulfuric acid, p-toluenesulfonic acid, room temperature, 2 hours.
  • Synthesis reagents and conditions a) Sodium methoxide, ether, methanol, 0°C ⁇ room temperature, 1 hour; b) 2,3-Dichloro-5,6-dicyano-p-benzoquinone, benzene, reflux, 20 minutes; c) Acetic anhydride, concentrated sulfuric acid, p-toluenesulfonic acid, room temperature, 2 hours.
  • Synthesis reagents and conditions a) methyl iodide, potassium carbonate, acetone, room temperature, 4 hours; b) acetic anhydride, concentrated sulfuric acid, p-toluenesulfonic acid, room temperature, 2 hours.
  • the preparation of OA-21 from compound OA-20 was completed by referring to the method of preparing OA-12 from OA-11 in Example 2 of the present invention.
  • the preparation of compound 7 from compound OA-21 is completed by referring to the method of preparing compound 5 from OA-18 in Example 4 of the present invention.
  • MS[M+H] + of compound 7 calcd for C 34 H 46 NO 5 , 548.3; found 548.5; MS [M+NH 4 ] + : calcd for C 34 H 49 N 2 O 5 , 565.4; found 565.6.
  • Synthesis reagents and conditions a) i. Oxalyl chloride, anhydrous dichloromethane, 0°C ⁇ room temperature, 12 hours; ii.NH 2 CH 3 , triethylamine, anhydrous dichloromethane, 0°C ⁇ room temperature, 4 hours B) i. Oxalyl chloride, anhydrous dichloromethane, 0°C ⁇ room temperature, 12 hours; ii. NH 2 CH 2 CF 3 , triethylamine, anhydrous dichloromethane, 0°C ⁇ room temperature, 4 hours; c )i. Oxalyl chloride, anhydrous dichloromethane, 0°C ⁇ room temperature, 12 hours; ii.
  • the preparation of OA-22, OA-23 and OA-24 from compound OA-20 was completed by referring to the method of preparing compound 4 from compound 3 in Example 3 of the present invention.
  • the preparation of compounds 8, 9 and 10 from compounds OA-22, OA-23 and OA-24, respectively, was completed with reference to the method for preparing compound 5 from OA-18 in Example 4 of the present invention.
  • Synthesis reagents and conditions a) Acetic anhydride, concentrated sulfuric acid, p-toluenesulfonic acid, room temperature, 2 hours.
  • Compound OA-25 was prepared from OA-20 with reference to CN104395332B.
  • the preparation of compound 11 from compound OA-25 was completed by referring to the method of preparing compound 5 from OA-18 in Example 4 of the present invention.
  • MS[M+H] + of compound 11 calcd for C 35 H 47 F 2 N 2 O 4 , 597.4; found 597.4.
  • Synthesis reagents and conditions a) Anhydrous tetrahydrofuran, lithium diisopropylamine solution, chloroacetic anhydride, -78°C, 2-4 hours.
  • Synthetic reagents and conditions a) Anhydrous tetrahydrofuran, lithium diisopropylamide solution, isobutyryl chloride, -78°C, 2-4 hours.
  • compound 13 was prepared from compound OA-21 in a small amount. MS[M+H] + of compound 13: calcd for C 36 H 50 NO 5 , 576.3; found 576.4.
  • Synthetic reagents and conditions a) Anhydrous tetrahydrofuran, lithium diisopropylamide solution, isobutyryl chloride, -78°C, 2-4 hours.
  • compound 14 was prepared from compound OA-21. MS[M+H] + of compound 14: calcd for C 36 H 48 NO 6 ,590.3; found 590.3.
  • the results of the determination of the inhibition of IFN ⁇ -induced nitric oxide production by RAW264.7 mouse macrophages by several compounds of the present invention were carried out with reference to the document J. Med. Chem. 2000, 43, 4233-4246. 20,000 cells/well were seeded in RPMI1640 medium and 0.5% FBS in a 96-well plate, and incubated at 37° C. and 5% CO 2. DMSO or test compound and recombinant mouse IFN ⁇ were treated together for 48 hours. Griess reagent is used to react with nitric oxide in the medium and detected at 550 nM. In this way, the anti-inflammatory biological activity of the compound was initially screened.
  • a "-" means IC 50 is greater than 100nM
  • IC 50 is between 10 and 100nM
  • b OA-26 is a known compound, prepared according to the document J. Med. Chem. 2000, 43, 4233-4246.
  • Example 14 Based on the screening model in Example 14, before adding DMSO or test compound 7 or 12, add a known cell esterase inhibitor (for example, 1mmol/L Paraoxon) [J.Appl.Toxicol.2005,25,562–67] , And then also use Griess reagent to react with nitric oxide in the medium and detect at 550nM. In this way, the interaction between the esterase inhibitor and the test compound is tested.
  • the results show (see Table 2), which represents that the anti-inflammatory biological activity produced by compounds 7 and 12 is completely independent of the presence of esterase.
  • a "-" means IC 50 is greater than 100nM
  • IC 50 is between 10 and 100nM
  • Human pancreatic cancer PANC-1 cells were seeded in a 96-well plate at a density of 3000 cells/well with 100 ⁇ L of culture medium. Add the required drug concentration to the culture medium, shake and mix, and each drug concentration is at least three replicate holes. After 72 hours, discard the culture medium, add 60 ⁇ L of 50% TCA to each well, let stand for 60 minutes at 4°C, wash with deionized water, and dry naturally; add 60 ⁇ L of 0.4% SRB to each well, and keep it at room temperature away from light.
  • the cell proliferation inhibition rate (%) (1-OD experimental group /OD solvent group )*100%.
  • the experimental results are shown in Table 3 below.
  • Most of the compounds can inhibit the proliferation of human pancreatic cancer PANC-1 cells at the micromolar level.
  • the electron-withdrawing substituent side chain can significantly enhance the anti-tumor biological activity of the compound.
  • compound 11 And 12 compared with RTA402, the biological activity has a significant difference (P ⁇ 0.05).
  • a "-" means IC 50 is greater than 100 ⁇ M
  • IC 50 is between 10 and 100 ⁇ M
  • b OA-26 is a known compound, prepared according to the document J. Med. Chem. 2000, 43, 4233-4246.
  • the toxicity of compounds 7 and 12 at the IC 50 concentration level of anti-tumor and anti-inflammatory on human normal cells representative LO2 hepatocytes was investigated.
  • the logarithmic growth phase cells were seeded in a 96-well plate (100 ⁇ L/well) at a cell density of 8 ⁇ 10 3 cells per well, and placed in a cell incubator for culture.
  • different concentrations of test compounds were added to the culture medium, and each group had 4 multiple wells. Put the cells back into the CO 2 incubator for culture.
  • test compound After 24 hours, discard the cell culture medium, add 200 ⁇ L of medium containing 10% MTT (5mg/mL), continue incubating for 4 hours in the 37°C incubator, discard the medium containing MTT, and then add 150 ⁇ L of DMSO to each well , Shake for 8min to fully dissolve the formed formazan.
  • the results are shown in Table 4.
  • the test compound has little inhibitory activity against normal cells at the concentration level of anti-tumor (1-10 ⁇ M), and has good tumor cell/normal cell selectivity; while at the concentration of anti-inflammatory activity (Around 10 nM), no inhibitory activity was seen at all.
  • compounds 7 and 12 the toxicity to human normal cells is slightly reduced or equivalent, and there is no significant inhibitory effect on human normal cells at therapeutic concentrations.
  • a "-" means that the inhibition rate is less than or equal to 0%, and there is no cell proliferation inhibition at all.

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Abstract

La présente invention relève du domaine de la chimie pharmaceutique, et concerne en particulier un dérivé d'acide oléanolique ayant un cycle C à structure diénique conjuguée, son procédé de préparation et son utilisation. En particulier, la présente invention concerne également une composition pharmaceutique contenant une quantité efficace du dérivé ou un sel pharmaceutiquement acceptable de celui-ci, et un véhicule pharmaceutiquement acceptable ; de plus, le dérivé ou le sel pharmaceutiquement acceptable de celui-ci peut être utilisé pour traiter des maladies associées à une inflammation et a une activité antitumorale, et la sécurité du composé est améliorée ou équivalente.
PCT/CN2021/076726 2020-03-09 2021-02-18 Dérivé d'acide oléanolique ayant un cycle c à structure diénique conjuguée, son procédé de préparation et son utilisation Ceased WO2021179884A1 (fr)

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CN120349366A (zh) * 2025-03-07 2025-07-22 国科大杭州高等研究院 五环三萜类衍生物、制备方法及其医药用途

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