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WO2021008014A1 - Modulateur du récepteur x hépatique spiro(3,3'-phénylpyrrolidine oxyindole) et son procédé de préparation et son application - Google Patents

Modulateur du récepteur x hépatique spiro(3,3'-phénylpyrrolidine oxyindole) et son procédé de préparation et son application Download PDF

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WO2021008014A1
WO2021008014A1 PCT/CN2019/116017 CN2019116017W WO2021008014A1 WO 2021008014 A1 WO2021008014 A1 WO 2021008014A1 CN 2019116017 W CN2019116017 W CN 2019116017W WO 2021008014 A1 WO2021008014 A1 WO 2021008014A1
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alkyl
compound
cooh
independently
halogenated
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陈浩
顾琼
陈子扬
张子振
徐峻
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Mw Cannabis Pharmaceutical Inc
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Mw Cannabis Pharmaceutical Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to the field of biomedicine. Specifically, the present invention relates to a spiro (3,3'-phenylpyrrolidine oxyindole) liver X receptor modulator and its preparation method and application.
  • Liver X receptor is a ligand-dependent transcription factor that combines with retinol X receptor (RXR) to form a heterodimer form: LXR/RXR. This dimer is activated by the ligand. It can be combined with the LXR response element (LXRE) on the target gene to regulate the transcription process of the target gene.
  • LXR includes two subtypes, LXR ⁇ and LXR ⁇ . LXR ⁇ is distributed in the liver, small intestine, fat and immune function macrophages, while LXR ⁇ is widely distributed throughout the body. It is generally believed that LXR ⁇ selective agonists can avoid the side effects of fatty liver.
  • LXR As a nuclear receptor activated by oxidized sterols, LXR plays an important role in fat, cholesterol, sugar metabolism and inflammation.
  • LXR synthetic agonists include GW3965 and TO901317. Development of LXR agonists, which can be used to treat glioblastoma and other cancers, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson's, Alzheimer's disease, multiple sclerosis, atopic dermatitis, rheumatoid joints Lead compound for inflammation and osteoporosis.
  • LXR ⁇ agonists due to the strong metabolism of GBM cells and the large demand for cholesterol, LXR ⁇ agonists lead to reduced cholesterol uptake and increased efflux, which interferes with the intracellular energy metabolism pathway, leading to Malignant tumor apoptosis. Therefore, LXR agonists are a new way to fight glioblastoma.
  • liver X receptor modulator Through a large number of experimental studies, the inventors proposed a new liver X receptor modulator. Surprisingly, they found that it has significant liver X receptor agonist activity, and is effective against cancers such as glioblastoma and atherosclerosis. , Dyslipidemia, Metabolic Syndrome, Parkinson, Alzheimer's Disease, Multiple Sclerosis, Atopic Dermatitis, Rheumatoid Arthritis and Osteoporosis have significant curative effects, and their application prospects are very broad.
  • the present invention proposes a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, or tautomer of a compound represented by formula (I) Isomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • A is a bond, -(C(R 7 ) 2 ) n1 -, -(C(R 7 ) 2 ) n1 -NR 8 -(C(R 7 ) 2 ) n1 -, -(C(R 7 ) 2 ) n1 -O-(C(R 7 ) 2 ) n1 -,-(C(R 7 ) 2 ) n1 -S-(C(R 7 ) 2 ) n1 -,
  • X 1 and X 2 are independently C(R 7 ) 2 , O, S or NR 8 ;
  • R 3 is H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, oxo or C 1-6 alkyl;
  • Each R 4 , R 5 , and R 6 is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH or C 1-6 alkyl;
  • Each R 7 , R 8 , R 8a , R 8b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, C 1-6 alkyl Or halogenated C 1-6 alkyl;
  • n1, m2, n1, and n2 are independently 0, 1, 2, 3, or 4.
  • the aforementioned compound may further include at least one of the following additional technical features:
  • the heteroaryl group composed of C 6-10 aryl and 5-10 atom
  • each R 4 , R 5 , and R 6 is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH or C 1 -4 alkyl;
  • Each R 7 , R 8 , R 8a , R 8b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, C 1-4 alkyl Or halogenated C 1-4 alkyl.
  • each R 4 , R 5 , R 6 is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, methyl , Ethyl, n-propyl, isopropyl, tert-butyl or n-butyl;
  • Each R 7 , R 8 , R 8a , R 8b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, methyl, ethyl, N-propyl, isopropyl, tert-butyl, n-butyl, trifluoromethyl, 1-chloroethyl, difluoromethyl, 2-fluoroethyl or 3,3,3-trifluoropropyl.
  • n3 0, 1, 2, 3, 4 or 5.
  • it is a compound represented by formula (IV-1) or (IV-2), or a stereoisomer of a compound represented by formula (IV-1) or (IV-2), geometric isomer Forms, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • R 9 is H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, or C 1-6 alkyl.
  • R 9 is H, D, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -COOH, or C 1-4 alkyl.
  • the present invention is a compound represented by formula (IV-1-a), (IV-1-b), (IV-2-a) or (IV-2-b), or formula (IV- 1-a), (IV-1-b), (IV-2-a) or (IV-2-b) stereoisomers, geometric isomers, tautomers, nitroxides Compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate of a compound having one of the following structures , Metabolite, pharmaceutically acceptable salt or its prodrug:
  • the present invention proposes a pharmaceutical composition comprising the aforementioned compound.
  • the aforementioned pharmaceutical composition may further include at least one of the following additional technical features:
  • the pharmaceutical composition further includes a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.
  • the pharmaceutical composition further includes an additional therapeutic agent for the treatment of glioblastoma, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson's, Alzheimer's Drugs for disease, multiple sclerosis, atopic dermatitis, rheumatoid arthritis, osteoporosis, or a combination thereof.
  • the additional therapeutic agent is temozolomide, formustine, statins (lovastatin, simvastatin), fibrates (clofibrate, liberate, bezafibrate) ), trihexyphenidyl, aspirin, non-steroidal anti-inflammatory drugs (diclofenac, nabumetone, meloxicam) or any combination thereof.
  • the present invention proposes the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicine for stimulating liver X receptors.
  • the liver X receptor is LXR ⁇ .
  • the present invention proposes the use of the compound described above or the pharmaceutical composition described above in the preparation of a kit for stimulating liver X receptors for scientific research .
  • the liver X receptor is LXR ⁇ .
  • the present invention proposes the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicine for the treatment or prevention of glioblastoma and atherosclerosis , Dyslipidemia, metabolic syndrome, Parkinson's, Alzheimer's disease, multiple sclerosis, atopic dermatitis, rheumatoid arthritis, osteoporosis drugs or their combination.
  • the present invention proposes that the compound described above or the pharmaceutical composition described above can be used in the treatment or prevention of glioblastoma, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson, Use in Alzheimer's disease, multiple sclerosis, atopic dermatitis, rheumatoid arthritis, osteoporosis, or a combination thereof.
  • the present invention proposes to treat or prevent glioblastoma, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson's, Alzheimer's disease, multiple sclerosis, atopic
  • Figure 1 is a schematic diagram of the liver X receptor agonistic activity of compounds according to embodiments of the present invention.
  • Figure 2 is a schematic diagram of the anti-glioblastoma activity of compound 3a-1 according to an embodiment of the present invention
  • Figure 3 is a schematic diagram of the anti-glioblastoma mechanism of compound 3a-1 according to an embodiment of the present invention, and control represents control.
  • Stereoisomers refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • Chiral refers to a molecule that can not overlap with its mirror image; and “achiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomers refer to two isomers of a compound that cannot be superimposed but are mirror images of each other.
  • Diastereoisomers refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more chiral centers.
  • the prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (for example, carbon, etc.) of the compound disclosed in the present invention can exist in a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration form exist.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)- configuration, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the present invention can be used as one of the possible isomers or their mixtures, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms).
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may have E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may have a cis or trans configuration.
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • racemate of any final product or intermediate obtained can be resolved into optical enantiomers by methods familiar to those skilled in the art by known methods, for example, by performing diastereomeric salts of the obtained Separate.
  • the racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • keto-enol tautomerism include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • C 1 -C 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses contained in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses contained in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses contained in the examples.
  • a class of compounds can be understood that the term “optionally substituted” and the term “substituted or unsubstituted” can be used interchangeably. Generally speaking, the term “optionally” whether or not preceded by the term “substituted” means that one or more hydrogen atoms in a given structure may be substituted or unsubstituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have a substituent at each substitutable position of the group. When more than one position
  • alkyl as used in the present invention includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, wherein the alkyl groups can be independently optionally substituted with one or more substituents described in the present invention.
  • the alkyl group contains 1-10 carbon atoms, in other embodiments, the alkyl group contains 1-8 carbon atoms, and in other embodiments, the alkyl group contains 1-6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu , -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-
  • haloalkyl refers to the case where the alkyl group may be substituted by one or more identical or different halogen atoms, the halogen atom being F, Cl, Br or I. Where the alkyl group has the meaning as described in the present invention, such examples include, but are not limited to, trifluoromethyl, 1-chloroethyl, difluoromethyl, 2-fluoroethyl, 3,3,3 -Trifluoropropyl, etc.
  • hydroxy-substituted alkyl group refers to the case where the alkyl group may be substituted by one or more hydroxy groups. Where the alkyl group has the meaning as described in the present invention, such examples include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, dihydroxymethyl, 2-hydroxyethyl, 3,3,3- Trihydroxypropyl, etc.
  • amino refers to -NH 2 .
  • alkoxy refers to an alkyl group, as defined in the present invention, connected to the main carbon chain through an oxygen atom.
  • alkyl group as defined in the present invention, connected to the main carbon chain through an oxygen atom.
  • examples include, but are not limited to, methoxy, ethoxy, propoxy and the like.
  • cycloalkyl refers to a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms.
  • the bicyclic or tricyclic ring system may include fused rings, bridged rings, and spiro rings.
  • the cycloalkyl group contains 3-10 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in another embodiment, the cycloalkyl group contains 3-6 carbon atoms. carbon atom.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group is optionally substituted with one or more substituents described in this invention.
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, at least one of which is aromatic of.
  • the aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group.
  • aryl can be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracene.
  • the aryl group is optionally substituted with one or more substituents described in the present invention.
  • heteroaryl means a monocyclic, bicyclic and tricyclic ring system containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, at least one of which is aromatic, And at least one ring contains one or more heteroatoms.
  • the heteroaryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the heteroaryl group.
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring”, “aromatic heterocycle” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described in the present invention.
  • the 5-10 atom heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • the ring system formed by the substituent R'connected to the central ring by a bond represents that the substituent R'can be substituted at any substitutable or any reasonable position on the ring.
  • formula a represents that any position on the B'ring that may be substituted can be substituted by R', as shown in formula b, formula c and formula d.
  • each R 7 can be the same or different, and they are mutually expressing The specific items may also be the same or different; the specific options of each n1 may be the same or different, and the specific items expressed between each other may also be the same or different; for example, in formula (I), each R 4
  • the specific options of R 5 or R 6 may be the same or different, and the specific items expressed by R 4 , R 5 and R 6 may also be the same or different.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergies or similar inappropriate reactions, such as gastrointestinal upset, dizziness, and the like.
  • pharmaceutically acceptable refers to those approved by a federal regulatory agency or a national government or listed in the US Pharmacopeia or other generally recognized pharmacopoeia for use in animals, more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered.
  • These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Water and aqueous solutions Saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, especially injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • “Hydrate” in the present invention refers to the compound or its salt provided by the present invention, which also includes water bound by non-covalent intermolecular forces in chemical or non-chemical quantities. It can also be said that solvent molecules are formed by water. Associate.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • esters in the present invention means that the compound represented by formula (I) to formula (IV) containing a hydroxyl group can form an ester that is hydrolyzable in vivo.
  • esters are, for example, pharmaceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent alcohol.
  • the groups of hydrolyzable esters in the compound represented by formula (I)-(IV) containing hydroxyl include, but are not limited to, phosphoric acid group, acetoxymethoxy group, 2,2-dimethylpropionyloxy group Methoxy, alkanoyl, benzoyl, benzylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl, etc.
  • N-oxide in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), in which, for example, the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as methylene chloride .
  • MCPBA m-chloroperoxybenzoic acid
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I) to formula (IV) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • T. Higuchi and V. Stella Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.
  • the present invention includes isotopically-labeled compounds, which are equivalent to the compounds described in formula (I)-formula (IV), but one or more of the atoms have an atomic mass or mass number different from those common in nature. Replaced.
  • isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotope-labeled compounds represented by formula (I)-formula (IV) of the present invention and their prodrugs can generally be prepared in this way.
  • Metal refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, acylating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • compositions can be prepared by the active ingredient and a pharmaceutically acceptable carrier.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known to us in the field, as described in the literature: S.M. Berge et al., describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977.
  • non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, Nitrate, etc., and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citric acid Salt, benzoate, mandelate, methanesulfonate, ethanesulfonate, tosylate, sulfosalicylate, etc., or obtained by other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate Salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate , Laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, Pectinate, persul
  • the present invention also contemplates the quaternary ammonium salt formed by any compound containing the N group.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, aluminum salt and the like.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and C 1 -8 Sulfonates and aromatic sulfonates.
  • Amine salts such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl reduced glucose Amine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine And tris(hydroxymethyl)aminomethane; alkaline earth metal salts such as but not limited to barium, calcium and magnesium; transition metal salts such as but not limited to zinc.
  • alkaline earth metal salts such as but not limited to barium, calcium and magnesium
  • transition metal salts such as but not limited to zinc.
  • the "effective amount” or “effective dose” of the compound or pharmaceutically acceptable composition of the present invention refers to an effective amount for treating or reducing the severity of one or more conditions mentioned in the present invention.
  • the compounds and compositions can be administered in any amount and route of administration to effectively treat or reduce the severity of the disease. The exact amount required will vary according to the patient's condition, which depends on race, age, general condition of the patient, severity of infection, special factors, method of administration, etc.
  • the compound or composition can be administered in combination with one or more other therapeutic agents, as discussed in this invention.
  • One of the objectives of the present invention is to provide new compounds with significant liver X receptor modulating activity.
  • the second objective of the present invention is to provide a novel drug that has significant treatment for glioblastoma and other cancers, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson, Alzheimer's disease, multiple sclerosis, atopic Dermatitis, rheumatoid arthritis, osteoporosis compounds.
  • the third objective of the present invention is to provide a method for preparing the liver X receptor modulator.
  • the fourth object of the present invention is to provide the compound in the treatment of glioblastoma and other cancers, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson, Alzheimer's disease, multiple sclerosis, atopic Application in dermatitis, rheumatoid arthritis, osteoporosis.
  • the present invention provides a method for preparing the spiro (3,3'-phenylpyrrolidine oxyindole) liver X receptor modulator, which comprises the following steps: dissolving tryptamine and isobutyraldehyde in dichloromethane, in an acidic environment
  • the Pictet-Spengler reaction occurs in the medium to obtain intermediate 1a; 1a is dissolved in tetrahydrofuran and rearranged under the action of N-bromosuccinimide to obtain intermediate 1b; 1b is dissolved in dichloromethane and triethylamine is added.
  • intermediate 1c React with di-tert-butyl dicarbonate to obtain intermediate 1c; 1c is dissolved in toluene, add cuprous iodide, N,N-dimethylethylenediamine, potassium carbonate, and react with m-chloroiodobenzene to obtain intermediate 1d; 1d Dissolve in 2,4,-dioxane, add bis(dibenzylideneacetone) palladium, dual pinacol borate, and potassium acetate to react in a nitrogen atmosphere to obtain intermediate 1e; 1e and bromo R a fragment occurs suzuki coupling reaction to give intermediate 1f; 1f deprotected under acidic conditions, with an anhydride of R b containing, acid chloride obtained according spiro (3,3-phenyl-pyrrolidin-oxindole ) Hepatic X receptor modulators.
  • the compound provided by the present invention has significant liver X receptor agonistic activity and anti-glioblastoma activity, and can be used to treat glioblastoma and other cancers, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson, Al Lead compound for Zheimer's disease, multiple sclerosis, atopic dermatitis, rheumatoid arthritis, and osteoporosis.
  • the compound provided by the present invention was used to screen out liver X receptor agonists on HEK293T cells using reporter gene method, and tested the anti-glioblastoma activity of the compound in U87EGFRvIII cells, and found that LXR ⁇ selective agonist 3a- 1 has the best anti-glioblastoma activity. Research on its anti-glioblastoma mechanism has shown that the compound up-regulates low-density lipoprotein-induced degradation factor (IDOL) by stimulating LXR ⁇ , and promotes IDOL-mediated degradation.
  • IDOL low-density lipoprotein-induced degradation factor
  • LDLR Low-density lipoprotein receptor
  • ABSC ATP binding cassette transporter
  • the present invention has the following beneficial effects:
  • the compound provided by the present invention has easy-to-obtain raw materials, simple preparation, and has significant liver X receptor agonistic activity and anti-glioblastoma activity.
  • the spiro (3,3'-phenylpyrrolidine oxyindole) class Liver X receptor modulators are used in the preparation of prevention and treatment of glioblastoma and other cancers, atherosclerosis, dyslipidemia, metabolic syndrome, Parkinson, Alzheimer's disease, multiple sclerosis, atopic dermatitis, It has great application prospects in rheumatoid arthritis and osteoporosis.
  • reaction solution was washed with saturated ammonium chloride and sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude intermediate 1d, which was purified by silica gel column chromatography to obtain the pure product.
  • Example 2 Liver X receptor activity test of the compound obtained in Example 1
  • HEK293T cells human embryonic kidney cells
  • DMEM high glucose
  • fetal bovine serum 10% fetal bovine serum and 1% double antibody at 37°C and 5% CO 2 .
  • HEK293T cells were seeded in 96-well plates with a cell density of 2 ⁇ 10 4 cells/well. After 24 hours, transfection was performed according to Lipofectamine TM 3000 reagent instructions. The specific transfection steps are as follows:
  • the results were analyzed using Renilla luciferase activity to correct the firefly luciferase activity.
  • the compounds with better LXR activity at 1 ⁇ M are 2g, 2h, 2i, 2m, 3a, and the compounds 2a, 2c, 2d, 2f, and 2j are slightly less active.
  • the compounds 2g, 2h, 2i, 2m, 3a with better LXR activity at 1 ⁇ M were selected for chiral resolution, and then the LXR transcription activity was tested by the dual luciferase reporter gene experiment.
  • the agonistic activity of the compound LXR has the following law: R, R configuration>racemate> S, S configuration.
  • 3a-1 has LXR ⁇ selectivity and the highest LXR ⁇ agonistic efficiency.
  • Table 1 Liver X receptor agonistic activity and anti-glioblastoma activity of the compounds
  • NA no activity is shown in the test range.
  • NT means not detected.
  • HA1800 cells normal astrocytes
  • HEK293T cells embryonic kidney cells
  • DMEM high glucose
  • HA1800, U87EGFRvIII, U251, and A172 cells were seeded in a 96-well plate with DMEM (high sugar) medium containing 1% lipoprotein-free serum and 1% double antibody.
  • the cell density was 1.5 ⁇ 10 3 cells/well, 24 After hours, add medicine for 7 days.
  • CCK-8 kit for detection that is, add 10 ⁇ L of CCK-8 solution to each well, incubate for 1 to 4 hours and then use a multifunctional microplate reader to measure the absorbance at 450nm.
  • the anti-glioblastoma activity of the compound obtained in Example 1 is shown in Table 1.
  • the 8 compounds have anti-glioblastoma activity on U87EGFRvIII cells, all of which are racemates and their R, R configurations.
  • the anti-glioblastoma activity of the compound has the following law: R, R configuration>racemate>S, S configuration, which is consistent with the compound's LXR ⁇ activity law.
  • the compound 3a-1 with the best activity on U87EGFRvIII cells was selected, and further activity was confirmed in U251 and A172 cells, and the toxicity of the compound on normal astrocyte HA1800 was tested. As shown in Figure 2, compound 3a-1 showed good activity on the three glioblastoma cells and was less toxic to normal astrocyte HA1800.
  • 3a-1 In order to explore the anti-glioblastoma mechanism of compound 3a-1, the liver X receptor downstream gene expression, low-density lipoprotein uptake, cholesterol efflux, intracellular cholesterol content and siRNA silencing LXR ⁇ or LXR ⁇ or After LXR ⁇ , 3a-1 has anti-glioblastoma activity.
  • the cells were inoculated in a 6-well plate with DMEM (high glucose) medium containing 5% fetal bovine serum and 1% double antibody.
  • the cells were cultured to about 80% coverage, the medium was changed to DMEM (high sugar) medium containing 1% lipoprotein serum and 1% double antibody, and the test compound was added for 48 hours.
  • the cells were washed twice with PBS, total RNA was extracted with RNAiso plus reagent, 1 ⁇ g of total RNA was reverse transcribed into cDNA using ReverTra Ace qPCR RT Master Mix, and PCR amplification was performed using SYBR Green Realtime PCR Master Mix.
  • the cells were seeded in a 6-well plate with DMEM (high glucose) medium containing 5% fetal bovine serum and 1% double antibody, and the cell density was 1 ⁇ 10 5 cells/well. After overnight incubation, change to DMEM (high glucose) medium containing 1% lipoprotein-free serum and 1% double antibody, and add 2 ⁇ g/mL Dil-LDL and test compound for 48 hours. The cells were washed twice with PBS, fixed with 4% paraformaldehyde solution for 30 minutes, and then stained with DAPI dye at a concentration of 0.5 mg/mL for 10 minutes. After washing twice with PBS, the cell imaging system was used to take pictures.
  • DMEM high glucose
  • the cells were inoculated in a 96-well plate with DMEM (high glucose) medium containing 5% fetal bovine serum and 1% double antibody, and the cell density was 4 ⁇ 10 4 cells/well. Add 0.5 ⁇ M 22-NBD-cholesterol and test compound for 24 hours. After the cells were washed twice with sterilized PBS, they were cultured in serum-free DMEM (high sugar) medium, and 15 ⁇ g/mL ApoA1 was added to incubate for 4 hours. The cells were washed twice with PBS, 40 ⁇ L of RIPA lysis buffer was added, and shaken at room temperature for 20 minutes. A multifunctional microplate reader was used to measure the fluorescence intensity of the cell culture medium and cell lysate of each well (excitation light: 485nm, emission light: 535nm).
  • the cells were inoculated into a 10 cm petri dish with DMEM (high glucose) medium containing 5% fetal bovine serum and 1% double antibody.
  • the cells were cultured to about 60% coverage, the medium was changed to DMEM (high sugar) medium containing 1% lipoprotein-free serum and 1% double antibody, and the test compound was added for 48 hours.
  • the cells were washed twice with PBS, 400 ⁇ L RIPA Lysis Solution was added to each dish, and ultrasonically lysed 10 times, 1 second each time, with 1 second interval. After measuring the protein concentration with BCA protein quantification kit, add 250 ⁇ L methanol and 750 ⁇ L chloroform, vortex and shake.
  • siRNA scramble transfers 50nM siRNA scramble, siRNA GAPDH, siRNA LXR ⁇ or siRNA LXR ⁇ into U87EGFRvIII cells with Lipofectamine TM 3000 reagent in DMEM (high glucose) medium containing 1% lipoprotein serum and 1% double antibody for 24 hours.
  • DMEM high glucose
  • the cells were harvested for RT-PCR and CCK-8 experiments.
  • compound 3a-1 can up-regulate liver X receptor target genes ABCA1, IDOL, ABCG1, ApoE and SREBP-1c. Among them, compound 3a-1 can up-regulate IDOL, inhibit low-density lipoprotein uptake, up-regulate ABCA1, promote cholesterol efflux, and ultimately reduce intracellular cholesterol content and kill cholesterol-dependent glioblastoma cells.
  • LXR ⁇ When LXR ⁇ is silenced, the antiglioblastoma activity of compound 3a-1 is still maintained; when LXR ⁇ is silenced, the antiglioblastoma activity of compound 3a-1 is greatly reduced, indicating that compound 3a-1 can pass through LXR ⁇ instead of LXR ⁇ , Play an anti-glioblastoma effect.
  • the compound of the present invention has significant liver X receptor agonistic activity and anti-glioblastoma activity, and can be used as the treatment of glioblastoma and other cancers, atherosclerosis, dyslipidemia, metabolic syndrome, Lead compounds for Parkinson's disease, Alzheimer's disease, multiple sclerosis, atopic dermatitis, rheumatoid arthritis, and osteoporosis.
  • Its anti-glioblastoma mechanism is: activating LXR ⁇ , up-regulating the downstream gene IDOL of liver X receptor, and inhibiting the uptake of low-density lipoprotein; up-regulating the downstream gene ABCA1 of liver X receptor, promoting the efflux of cholesterol, both of them It causes the cholesterol content in the cell to decrease and kills glioblastoma cells that depend on cholesterol.

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Abstract

L'invention concerne modulateur du récepteur X hépatique spiro(3,3'-phénylpyrrolidine oxyindole), un procédé de préparation et une application de celui-ci, le modulateur du récepteur étant spécifiquement un composé représenté par la formule (I), ou un stéréoisomère, un isomère géométrique, un tautomère, un oxyde d'azote, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable, ou un promédicament du composé représenté par la formule (I).
PCT/CN2019/116017 2019-07-18 2019-11-06 Modulateur du récepteur x hépatique spiro(3,3'-phénylpyrrolidine oxyindole) et son procédé de préparation et son application Ceased WO2021008014A1 (fr)

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