WO2020007342A1 - Application de composé de phosphate de biphényle en tant qu'antagoniste de gpr84 - Google Patents

Application de composé de phosphate de biphényle en tant qu'antagoniste de gpr84 Download PDF

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WO2020007342A1
WO2020007342A1 PCT/CN2019/094702 CN2019094702W WO2020007342A1 WO 2020007342 A1 WO2020007342 A1 WO 2020007342A1 CN 2019094702 W CN2019094702 W CN 2019094702W WO 2020007342 A1 WO2020007342 A1 WO 2020007342A1
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unsubstituted
substituted
alkyl
alkylene
aryl
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南发俊
谢欣
肖瑜峰
张庆
陈林海
方友臣
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Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/67—Phosphorus compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to the application of biphenyl phosphate ester compounds.
  • GPR84 G protein-coupled receptor 84
  • it has GPR84 antagonistic activity and can competitively inhibit GPR84.
  • Activation of this receptor by agonists can be used for the treatment of related diseases caused by high GPR84 expression or excessive excitability, such as multiple sclerosis, inflammatory bowel disease, liver fibrosis, pulmonary fibrosis, arthritis Wait.
  • biphenyl phosphate compounds As a type of chemical catalyst widely used in asymmetric catalysis, biphenyl phosphate compounds have been successfully implemented since 2004 when Akiyama and Terada independently reported asymmetric Maninch reactions catalyzed by chiral phosphate compounds. Such reactions as Mannich reaction, Picter-Spengler reaction, aza-Diels-Alder reaction, Friedel-Crafts reaction, and high enantioselective catalysis of aza-Ene reaction.
  • GPR84 G protein-coupled receptor 84
  • C9-C14 medium-chain fatty acid receptor first discovered by Wittenberger and others in 2001.
  • GPR84 is mainly expressed in bone marrow and peripheral blood leukocytes (including neutrophils). Cells, eosinophils, basophils) and adipocytes.
  • GPR84 expression in monocytes / macrophages is up-regulated, and medium-chain fatty acids can significantly up-regulate the expression of the IL-12p40 subunit in the macrophage cell line RAW264.7 via GPR84, and regulate Th1 Cellular immune response promotes inflammation and plays an important role in the occurrence of inflammatory diseases such as multiple sclerosis (MS), inflammatory bowel disease, and arthritis.
  • MS multiple sclerosis
  • inflammatory bowel disease inflammatory bowel disease
  • the occurrence of metabolic diseases such as obesity and diabetes is closely related to chronic inflammation.
  • macrophages invade adipose tissue, they can promote the occurrence of inflammatory responses by secreting cytokines.
  • GPR84 expression in fat cells will increase, indicating that GPR84 is also involved Cross-regulation between fatty acid metabolism and the immune system.
  • GPR84 can promote inflammation, it plays an important role in the occurrence of inflammation-related diseases. Therefore, by inhibiting the activity of the GPR84 through a GPR84 antagonist, it can treat inflammation-related diseases, such as multiple sclerosis, inflammatory bowel disease, arthritis, and the like.
  • the purpose of the present invention is to provide the use of a novel biphenyl phosphate ester compound.
  • Y is O or S;
  • X is O or S;
  • M is H, or an ion of the following metals: Li, Na, K, Ca, Mg, Cu, Fe, Zn, Al, Mn, or a conjugate acid of the following bases: NH 3 , arginine, betaine, caffeine , Choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethyl Morpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, hydrazone, poly Amine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently hydrogen, substituted or unsubstituted C 1 to C 6 alkyl, substituted or unsubstituted C 1 to C 6 silyl, substituted or unsubstituted C 3 to C 6 cycloalkyl, substituted or unsubstituted C 6 to C 16 aryl, substituted or unsubstituted 3-20 membered heteroaryl; or R 1 , R 2 Any two of R 3 , R 4 and R 4 form a substituted or unsubstituted C 3 to C 6 cyclic hydrocarbon, a substituted or unsubstituted C 6 to C 10 aromatic ring, or a substituted or unsubstituted 3 -12-membered heteroaryl ring; or any two of R 5 , R 6 , R 7 , and R 8 and the connected C to form a substituted or unsubstituted C 3
  • L is unsubstituted, bonded, substituted or unsubstituted C 1 to C 6 alkylene, or between L and R 4 and connected C, and L and R 8 and connected C are independently substituted or unsubstituted C 3 -C 7 cyclic hydrocarbons;
  • substitution means having one or more substituents selected from the group consisting of: C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkylamino, C 6 to C 16 aryl, halogen , Hydroxyl, amino, -COOC 1 to C 6 alkyl, -COOH.
  • R 1 is hydrogen, substituted or unsubstituted C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 6 cycloalkyl, or substituted or unsubstituted C 6 to C 16 aromatic.
  • R 1 is hydrogen, substituted or unsubstituted C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 6 cycloalkyl, or substituted or unsubstituted C 6 to C 16 aromatic.
  • substitution means having one or more substituents selected from the group consisting of: C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkylamino, C 6 to C 16 aryl, halogen , Hydroxyl, amino, -COOC 1 to C 6 alkyl, -COOH.
  • R 5 is hydrogen, substituted or unsubstituted C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 6 cycloalkyl, substituted or unsubstituted C 6 to C 16 aromatic A substituted or unsubstituted 3-12 membered heterocyclic ring; a substituted or unsubstituted C 6 to C 10 aromatic ring is formed between R 5 and R 6 and the connected C,
  • substitution means having one or more substituents selected from the group consisting of: C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkylamino, C 6 to C 16 aryl, halogen , Hydroxyl, amino, -COOC 1 to C 6 alkyl, -COOH.
  • R 1 and R 5 are each independently hydrogen, substituted or unsubstituted C 1 to C 6 alkyl, substituted or unsubstituted C 6 to C 16 aryl, or substituted or unsubstituted 4 -6-membered heteroaryl, the substitution means having one or more substituents selected from the group consisting of phenyl, C 1 to C 4 alkoxy, C 1 to C 4 alkyl, fluorine, chlorine, bromine , -N (C 1 to C 4 alkyl) (C 1 to C 4 alkyl), C 6 to C 16 aryl, hydroxyl, amino, -COOC 1 to C 6 alkyl, -COOH.
  • R 3 and R 4 form a substituted or unsubstituted C 3 to C 6 cyclic hydrocarbon, a substituted or unsubstituted C 6 to C 10 aromatic ring, or a substituted or unsubstituted C 3 to R. 3-10 membered heterocyclic ring;
  • substitution means having one or more substituents selected from the group consisting of: C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkylamino, C 6 to C 16 aryl, halogen , Hydroxyl, amino, -COOC 1 to C 6 alkyl, -COOH.
  • R 7 and R 8 form a substituted or unsubstituted C 3 to C 6 cyclic hydrocarbon, a substituted or unsubstituted C 6 to C 10 aromatic ring, or a substituted or unsubstituted C and C 8 . 3-10 membered heterocyclic ring;
  • substitution means having one or more substituents selected from the group consisting of: C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkylamino, C 6 to C 16 aryl, halogen , Hydroxyl, amino, -COOC 1 to C 6 alkyl, -COOH.
  • a benzene ring is formed between R 1 and R 2 and the connected C.
  • a benzene ring is formed between R 5 and R 6 and the connected C.
  • benzo C 3 -C 6 cycloalkyl or naphthyl is formed between R 3 and R 4 and the connected benzene ring.
  • R 3 and R 4 may be fused to be unsubstituted, substituted or unsubstituted C 3 to C 6 and cycloalkyl, substituted or unsubstituted C 6 to C 10 and aryl, substituted or unsubstituted. Substituted C 3 to C 10 heteroaryl.
  • R 7 and R 8 are unsubstituted, substituted or unsubstituted C 3 to C 6 cycloalkyl, substituted or unsubstituted C 6 to C 10 aryl, substituted or unsubstituted And C 3 to C 10 heteroaryl.
  • L is none, a bond, or a C 1 -C 4 alkylene group; or between L and R 4 and the connected C, and L and R 8 and the connected C are each independently and the ring is C 3 -C 7 cyclic hydrocarbon.
  • L is none, a bond, or a C 1 -C 4 alkylene group; or between L and R 4 and a connected benzene ring, and L and R 8 and a connected benzene ring each independently form a benzene And C 3 -C 6 cycloalkyl.
  • the C1-C6 alkylamino group includes, but is not limited to, NHCH 3 , N (CH 3 ) (CH 2 CH 3 ), NHCH 3 , NH (CH 2 CH 3 ), N (CH 3 ) (CH 2 CH 2 CH 3 ), N (CH 2 CH 3 ) (CH 2 CH 2 CH 3 ), N (CH 3 ) 2 , N (CH 2 CH 3 ) 2 or N (CH 2 CH 2 CH 3 ) 2 .
  • the substituent on the substituted aryl group is selected from the following group:
  • the compound is:
  • each ring and substituent described in Formula I is independently a corresponding group in each specific compound described in the specification.
  • the compound is a racemic compound or a chiral compound.
  • each chiral carbon is independently an R configuration or an S configuration.
  • the disease is multiple sclerosis, inflammatory bowel disease, arthritis, pulmonary fibrosis or liver fibrosis.
  • a method for treating a related disease caused by high expression of GPR84 receptor or excessive excitability and administering a compound of the present invention or a pharmaceutically acceptable salt to a patient in need.
  • the disease is multiple sclerosis, inflammatory bowel disease, arthritis, pulmonary fibrosis or liver fibrosis.
  • the biphenyl phosphate compounds of the present invention have previously been reported more as chiral catalyzed ligand molecules, and their reports on GPR84 biological activity testing are currently unavailable. Through in-depth research on these compounds, this was discovered for the first time creatively.
  • a class of compounds has unexpectedly high antagonistic activity against GPR84.
  • the result of this GPR84 antagonistic activity is the first such discovery report in the world to date, which is very innovative. It is expected to become a new drug that can treat inflammation-related diseases such as multiple sclerosis, inflammatory bowel disease, arthritis, liver fibrosis, and pulmonary fibrosis.
  • biphenyl phosphate compounds have a high antagonistic activity on the GPR84 target and can competitively inhibit the receptors caused by GPR84 agonists.
  • Activation which can be used to prepare drugs for treating related diseases caused by high expression of GPR84 receptor or excessive excitability, including diseases such as multiple sclerosis, inflammatory bowel disease, arthritis, liver fibrosis, pulmonary fibrosis, etc. . Based on this, the present invention has been completed.
  • C 6 -C 10 means having 6-10 carbon atoms
  • C 3 -C 6 means having 3-6 carbon atoms, and so on.
  • integers 0-4 refer to 0, 1, 2, 3, 4; 6-10 carbon atoms refer to 6, 7, 8, 9, 10 carbon atoms, and so on.
  • a 3-10 member means a ring having 3-10 ring atoms.
  • alkyl refers to a saturated linear or branched hydrocarbon group; for example, -CH 3 or -CH (CH 3 ) 2 ; alkylene refers to a saturated hydrocarbon group that formsally removes the remaining two monovalent hydrogens, including but not It is limited to methylene (-CH 2- ), ethylene (-CH 2 CH 2- ), and the like.
  • Alkoxy refers to -O- (alkyl), including but not limited to -OCH 3 , -OCH 2 CH 3 and the like.
  • Cycloalkyl refers to a saturated cyclic hydrocarbon group, such as cyclohexyl.
  • Heterocyclic refers to heterocycloalkyl or heteroaryl ring
  • heterocycloalkyl refers to a saturated cyclic hydrocarbon group containing at least one heteroatom (such as N, O, or S);
  • heteroaryl ring or heteroaryl refers to containing at least one heteroatom A heteroatom aromatic ring.
  • a cyclic hydrocarbon means a saturated, unsaturated cyclic hydrocarbon group.
  • Aryl or aromatic ring refers to a full-carbon monocyclic or fused polycyclic ring having a conjugated ⁇ -electron system, and includes phenyl (Ph), naphthyl, fluorenyl, anthracenyl, and phenanthryl.
  • Possible substituents include, but are not limited to: C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 6 alkylamino, C 2 -C 10 alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, C 1 -C 20 heterocycloalkyl, C 1 -C 20 heterocycloalkenyl, C 1 -C 10 Alkoxy, C 6 -C 16 aryl, aryloxy, heteroaryl, heteroaryloxy, amino, hydroxyl, halogen, mercapto, cyano, nitro, carboxyl and carboxylate groups and the like.
  • the GPR84 antagonist provided by the present invention is a compound having the structure of Formula I:
  • the compound of formula I described in the present invention is a compound prepared in the examples.
  • the present invention also provides pharmaceutically acceptable salts thereof, including salts obtained by reacting a compound of formula I with an inorganic base or an organic base compound.
  • Salts derived from inorganic bases include, but are not limited to: aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, Zinc salt and so on. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts obtained from pharmaceutically acceptable organic non-toxic bases including but not limited to salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ions Exchange resins such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol , Ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucosamine, Porphyrin, piperazine, piperidine, amidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • the reaction is carried out in pyridine; the reaction temperature is 60 ° C to 100 ° C; the reaction time is about 1 to 24 hours; after the reaction is completed, it is extracted with solvents such as AcOEt, Et 2 O, CH 2 Cl 2 , CHCl 3 , washed with saturated brine, and After drying, the solvent was removed under reduced pressure at low temperature.
  • solvents such as AcOEt, Et 2 O, CH 2 Cl 2 , CHCl 3
  • S2 reacts with NaH and chloromethyl methyl ether in tetrahydrofuran to obtain S3 at room temperature, the reaction time is 4-12 hours;
  • S3 reacts with n-butyl lithium and halogen element under tetrahydrofuran to obtain S4 and S5 (for S4, the halogen element is 1 -1.5 equivalents, halogen simple substance for S5 and 2.5-3.5 equivalents), the reaction temperature is 0 °C ⁇ 25 °C, the reaction time is 4-12 hours;
  • S4, S5 and boric acid compounds are in tetratriphenylphosphonium palladium, sodium carbonate
  • the intermediate was refluxed under DME for 10-24 hours to obtain the intermediate, and the intermediate was deprotected by hydrochloric acid / THF to obtain S6; S6 was obtained by the method described in route one to obtain P2.
  • S7 can be obtained according to the method described in line 2. After reacting S7 with n-butyllithium and a halogenated compound in THF, S4 can be obtained by deprotection of hydrochloric acid / THF, and S4 can be obtained by the method described in line 1.
  • the raw material P1 was dissolved in EA, and an alkali (a conjugate base of M, a hydroxide of M, or a carbonate of M) was added and washed twice.
  • the aqueous layer was back-extracted with EA, the EA layer was concentrated, and the crude product was subjected to silica gel column chromatography.
  • the product P2 is obtained.
  • M is a cation of the following metals: Li, Na, K, Ca, Mg, Cu, Fe, Zn, Al, Mn;
  • Conjugated acids of or below NH 3 , arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- Dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine Acid, methylglucosamine, morpholine, piperazine, piperidine, hydrazone, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc .; others The definition of each substituent is as described above.
  • a compound of formula I can competitively inhibit the activation of the receptor caused by an agonist of GPR84, and can be used to prepare a drug for the treatment of related diseases caused by high expression of GPR84 receptor or excessive excitability.
  • the diseases include multiple sclerosis, inflammatory bowel disease, arthritis, liver fibrosis, and pulmonary fibrosis.
  • a pharmaceutical composition contains a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • “Pharmaceutically acceptable carrier”, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers or gel substances which are suitable for human use and There must be sufficient purity and low enough toxicity. "Compatibility” here means that each component in the composition can blend with the active ingredient of the present invention (the compound of formula I or a pharmaceutically acceptable salt thereof) and each other without significantly reducing the active ingredient Effect.
  • Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • solid lubricants such as stearic acid, Magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol
  • the compounds and pharmaceutical compositions of the present invention can be in a variety of forms, and can be administered orally or parenterally in the form of injections, such as capsules, tablets, granules, solutions, powders, powders, or syrups.
  • the compounds and pharmaceutical compositions may be present in a suitable solid or liquid carrier and in a suitable sterilizing device for injection or instillation.
  • the above formulations can be prepared by conventional pharmaceutical methods.
  • the compounds and pharmaceutical compositions of the present invention are useful for clinical use in mammals, including humans and animals, and can be administered via the oral, nasal, or gastrointestinal tract.
  • the most preferred route of administration is oral.
  • NMR was measured by Mercury-VX 300M, Mercury-VX400M or AVANCE-III 500M instrument manufactured by Varian
  • NMR calibration ⁇ H 7.26ppm (CDCl 3 ), 2.50ppm (DMSO-d 6 ), 3.15ppm (CD 3 OD); reagents are mainly provided by Shanghai Chemical Reagent Company; TLC thin-layer chromatography silica gel plate is produced by Shandong Yantai Huiyou Silica Gel Development Co., Ltd., model HSGF 254; Chemical plant branch production, model zcx-11, 200-300 mesh.
  • the raw material G1 (100 mg, 0.54 mmol) was dissolved in dry pyridine (1.5 mL), and heavy distilled POCl 3 (250 uL, 2.68 mmol) was added dropwise under the protection of N 2 , and the reaction was performed at 60 ° C. for 5 h.
  • the raw material G1 was purchased from a reagent company.
  • G1 200 mg, 0.57 mmol was dissolved in anhydrous THF, and 0.95 ml of a n-butyllithium hexane solution (1.5 mmol) was added at 0 ° C. After 3 hours of reaction at room temperature, the solution was added at -78 ° C 1-iodopropane (272mg, 1.6mmol), warmed to room temperature for 1h the reaction was quenched with water, extracted with EA, dried over anhydrous Na 2 SO 4.
  • Compound G1 was synthesized according to the literature (US2013 / 204014).
  • Compound XYF616S (110mg, 0.18mmol) was dissolved in 5mL of methanol solution, and an aqueous solution of LiOH (43mg, 1.8mmol) was added. The mixture was reacted at reflux for 4h, cooled to room temperature, and 1M hydrochloric acid solution was added.
  • a GPR84 antagonistic activity test of the compounds of the present invention was performed.
  • a human-derived GPR84 cell line was obtained by transfecting a plasmid encoding the GPR84 and G ⁇ 16 proteins in a HEK293 cell line.
  • the fluorescent dye Fluo-4AM was purchased from Invitrogen.
  • Intracellular Ca 2+ is a very important second messenger of G protein coupled receptor signaling pathway. When GPR84 coupled with G ⁇ 16 protein and agonist are combined, the intracellular Ca 2+ concentration can be significantly increased.
  • Fluo-4 is a Ca 2+ ion-specific fluorescent probe that can quantitatively bind to Ca 2+ ions and emit fluorescence. Therefore, the fluorescence detection method is used to detect the agonistic or antagonistic activity of the compound in a 96-well or 384-well flat-bottomed microtiter plate.
  • GPR84 antagonists Detection of the inhibitory effect of GPR84 antagonists on receptors: After GPR84 cells are incubated with the fluorescent dye Fluo-4, they are added with different concentrations of antagonist compounds and incubated for a period of time to occupy the binding site (antagonistic binding site) of the agonist to GPR84. A certain concentration of agonist (6-OAU) is added to compete with the antagonist for binding sites. At the same time, it is excited by a light source with a wavelength of 485nm and the change of the fluorescence intensity of the dye caused by the change of the calcium ion concentration in the cell is detected. PRISM software calculated half-maximum inhibition concentration (IC 50).
  • Formulated HBSS 0.4g / L KCl (5.4mM), 0.12g / L Na 2 HPO 4 ⁇ 12H 2 O (0.3mM), 0.06g / L KH 2 PO 4 (0.4mM), 0.35g / L NaHCO 3 ( 4.2mM), 0.14g / L CaCl 2 (1.3mM), 0.10g / L MgCl 2 ⁇ 6H 2 O (0.5mM), 0.05g / L MgSO 4 (0.6mM), 8.0g / L NaCl (137mM), Weigh out the above components and dissolve them with ultrapure water, adjust the pH to 7.4 with hydrochloric acid or NaOH solution, filter, and store at 4 ° C for one month.
  • Preparation of calcium buffer solution first prepare 560mM D-glucose (100X) water-soluble storage solution, 250mM 1,2-diphenyl-4- (2-phenylsulfinyl) ethyl-3,5-pyrazolidinedione ( 1000X) storage solution.
  • Formulation of dyes First, prepare 3% Cremophor EL (100X) PBS-dissolved storage solution and 2mM Fluo-4 (1000X) DMSO-dissolved storage solution, and then prepare 1 ⁇ L of 2mM Fluo-4AM and 10 ⁇ L of each dye per ml. Mix 3% Cremophor EL, then dilute with 1mL calcium buffer and mix.
  • the cells were seeded at a density of 40,000 cells / well onto a 96-well cell culture plate, and the culture was continued for more than 24 hours to make the cell density to 80-90% for experimental detection. Aspirate the culture medium in the wells of the cells to be tested, add 40 ⁇ L / well of freshly prepared dye, and place in a 37 ° incubator at a constant temperature for 40 to 50 minutes.
  • Formulate compounds during cell incubation (this step can also be prepared in advance): freshly prepare calcium buffer before the experiment to dilute the compound used as an antagonist to 1.5 times the final working concentration, and dilute the compound used as an agonist to the final work 3 times the concentration (if the compound is dissolved in DMSO, the DMSO concentration should not exceed 1% in the final work).
  • the dye After the incubation step is completed, the dye is sucked up and discarded. After washing with calcium buffer solution, change to 50 ⁇ L of calcium buffer solution containing different concentrations of antagonists and incubate for another 10 min.
  • a FlexStation III microplate detector uses a FlexStation III microplate detector to add 25 ⁇ L / well of calcium buffer containing a certain concentration (generally an effective concentration of the agonist EC 80 or so) to the stimulus. At the same time, stimulate with a 485nm light source and detect cells at the 525nm band. Changes in the fluorescence intensity of the dye caused by changes in the internal calcium ion concentration.

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Abstract

L'invention concerne l'application d'un composé de phosphate de biphényle, servant à préparer un antagoniste de GPR84, utilisé en tant qu'antagoniste de GPR84 ou dans la préparation d'un médicament destiné à traiter une maladie associée à une expression élevée ou une excitabilité excessivement élevée du récepteur GPR84 ; la structure dudit composé de phosphate de biphényle est représentée par la formule générale I ; les définitions de chaque substituant sont telles que décrites dans la description et les revendications. Selon l'invention, il est attendu que les composés de phosphate de biphényle, en tant qu'antagonistes du récepteur GPR84, deviennent un nouveau type de médicament permettant de traiter des maladies associées à l'inflammation, telles que la sclérose en plaques, la maladie intestinale inflammatoire, l'arthrite, la fibrose hépatique et la fibrose pulmonaire.
PCT/CN2019/094702 2018-07-06 2019-07-04 Application de composé de phosphate de biphényle en tant qu'antagoniste de gpr84 Ceased WO2020007342A1 (fr)

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