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WO2022164239A1 - Composé dérivé de pyrazole-carboxamide et utilisation associée - Google Patents

Composé dérivé de pyrazole-carboxamide et utilisation associée Download PDF

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WO2022164239A1
WO2022164239A1 PCT/KR2022/001522 KR2022001522W WO2022164239A1 WO 2022164239 A1 WO2022164239 A1 WO 2022164239A1 KR 2022001522 W KR2022001522 W KR 2022001522W WO 2022164239 A1 WO2022164239 A1 WO 2022164239A1
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methyl
chlorophenyl
dichlorophenyl
pyrazole
carboxamide
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Korean (ko)
Inventor
배수열
김보경
이지혜
김영훈
박철영
양혜경
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Pharminogen Inc
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Pharminogen Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel pyrazole-carboxamide derivative compound and its use for the prevention or treatment of related diseases based on an antagonist/inverse agonist effect specific to cannabinoid receptor 1 thereof.
  • the endocannabinoid system is composed of endocannabinoids, receptors, transporters, and enzymes, and plays an important role in a wide variety of physiological processes. have. (Howlett, AC, Annu. Pharmacol. Toxicol . 1995, 35, 607-634; Pacher, P. et. al, FEBS J. 2013, 280, 1918-1943; Lu, Y. et. al, Can. J. Physiol. Pharmacol . 2017, 95, 311-327).
  • CB1 and CB2 Two different subtypes of the human cannabinoid receptor (subtypes, CB1 and CB2) have been isolated, all of which belong to the G protein coupled receptor superfamily.
  • Cannabinoid receptor CB1 together with CB2 receptor and endocanabinoid ligand (endocanabinoid: ex. anandamide, 2-AG, etc.), constitutes an endocanabinoid system that plays an important role in maintaining energy homeostasis.
  • the CB1 receptor is mainly distributed in the central nervous system including the brain of mammals including humans and is known to be involved in energy metabolism and appetite regulation. known to be involved.
  • rimonabant SR141716A
  • SR141716A The selective CB1 receptor antagonist, rimonabant (SR141716A)
  • rimonabant inhibited the activity of CB1 receptors in the central nervous system (CNS) and was withdrawn from the market due to serious side effects such as depression and suicidal ideation (Christensen, R. et al., Lancet , 2013, 23, 4751). -4760).
  • appetite regulation by CB1 receptors is not limited to CB1 receptors present in the brain, but appetite is also regulated by CB1 receptors present in peripheral tissues. It has already been verified by many research results (Tam J. et al., Cell Metab . 2012, 16(2), 167-179).
  • CB1 receptor-activator-based type 2 diabetes treatment agent that does not pass through the blood-brain barrier and minimizes side effects by specifically controlling only the activity of CB1 receptors in peripheral tissues.
  • peripheral tissue-specific CB1 receptor inhibitors have been developed by several research groups (Chorvat, R. et al. Bioorg. Med. Chem. Lett . 2013, 23, 4751-4760; Kunos, G. et al., Br. J. Pharmacol . 2011, 163, 1423-1431).
  • Representative peripheral tissue-specific CB1 receptor inhibitors with high potential for success recently developed are AM6545 and JD5037.
  • the first candidate, AM6545 was developed by Dr. Developed/reported by the Kunos group.
  • AM6545 was developed through modification of the existing CB1 receptor inhibitor, Rimonabant, and showed a high affinity for the CB1 receptor compared to its parent, rimonabant, while its ability to cross the blood vessel-brain barrier was 14 times lower. It also did not affect the various behavioral effects mediated by CB1 receptors present in the brain.
  • AM6545 improves insulin resistance, fatty liver, and leptin resistance in type 2 diabetes, improves glucose homeostasis and plasma lipid profile, and increases adiponectin production regardless of the weight loss effect. For the first time, it showed the possibility of developing peripheral tissue-specific CB1 receptor inhibitors for the treatment of type 2 diabetes (Tam J. et al., J. Clin Invest . 2010, 120(8), 2953-2966).
  • JD5037 a second peripheral tissue-specific CB1 receptor inhibitor candidate developed by US venture company Jenrin Discovery, also has a low ability to cross the blood-brain barrier, and various behavioral effects mediated by CB1 receptors in the brain similar to AM6545. It had no effect on type 2 diabetes by improving insulin and leptin resistance and plasma lipid profile (Tam J. et al., Cell Metab . 2012, 16(2)). , 2953-2966).
  • a compound having an antagonist/inverse agonist effect specific for selectively peripheral CB1 receptors is effective in various diseases such as diabetes, metabolic disease, dyslipidemia, alcoholic liver disease or non-alcoholic liver disease without side effects related to the central nervous system. drugs can be developed.
  • It is also an object of the present invention to provide a pharmaceutical composition comprising the novel compound and a pharmaceutically acceptable carrier.
  • an object of the present invention is based on the specific inhibitory effect of the novel compound on cannabinoid receptor 1 (CB1), the compound, its isomer, its solvate or a pharmaceutically acceptable salt thereof It is to provide a pharmaceutical composition for the prevention or treatment of diseases caused by overexpression or overactivity of cannabinoid receptor 1, including.
  • 'halogen' refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), unless otherwise specified.
  • alkyl' refers to a saturated, straight-chain or branched hydrocarbon radical represented by C n H 2n+1 , and specifically, between 1 and 6, respectively, 1 to refers to a saturated, straight-chain or branched hydrocarbon radical containing between 8, 1-10, or 1-20 carbon atoms.
  • these radicals include, but are not limited to, the methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, heptyl, octyl radicals.
  • the term 'C 1 -C 6 alkyl' refers to a linear or branched hydrocarbon residue having 1 to 6 carbon atoms, unless otherwise specified. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • 'cycloalkyl' or 'cycloalkyl' denotes a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound.
  • the term 'C 3 -C 6 cycloalkyl' refers to a cyclic hydrocarbon residue having 3 to 6 carbon atoms, unless otherwise specified. Examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • aryl refers to mono- or poly-cyclic carbocy having 2 to 30 carbon atoms, 6 to 14 carbon atoms, or 1 to 6 carbon atoms, having one or more aromatic rings, fused or non-fused. refers to a click ring system, and examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, andracenyl, and the like.
  • heteroaryl as used herein, unless otherwise stated, includes atoms other than carbon and one or more heteroatoms.
  • the heteroatoms are atoms selected from the group consisting of O, N, Se and S. may include one or more.
  • the number of carbon atoms is not particularly limited, but preferably has 2 to 30, 6 to 14, or 1 to 6 carbon atoms, and the heteroaryl group may be monocyclic or polycyclic.
  • heteroaryl group examples include a thiophene group, a furanyl group, a pyrrole group, an imidazolyl group, a thiazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a bipyridyl group, a pyrimidyl group, a triazinyl group, a triazinyl group Jolyl group, acridyl group, pyridazinyl group, pyrazinyl group, quinolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, pyridopyrimidyl group, pyridopyrazinyl group, pyrazinopyrazinyl group , isoquinolinyl group, indolyl group, carbazolyl group, benzoxazolyl group, benzimidazolyl group, benzo
  • R 1 is H or halogen
  • R 2 is H, halogen or CN
  • R 3 and R 4 are each independently H or halogen
  • Q is substituted or unsubstituted aryl or heteroaryl
  • L is , , , , or ego
  • L 1 is C 1 -C 6 alkyl
  • R' and R'' may each independently be substituted with H or C 1 -C 3 alkyl
  • Het is a 4-6 membered aromatic or non-aromatic heterocyclic compound unsubstituted or substituted with haloalkyl, and contains N or O in 1 to 4 rings.
  • R 1 may be H or Cl.
  • R 2 may be H or CN.
  • R 3 may be Cl.
  • R 4 may be H or Cl.
  • aryl may be any one selected from the following structures;
  • the heteroaryl may be any one selected from the following structures:
  • X is hydrogen or halogen
  • L may be any one selected from the following structures:
  • L 1 is C 1 -C 3 alkyl
  • R' and R'' may be H.
  • Het may be a compound that is unsubstituted or substituted with haloalkyl, and is a 4-6 membered aromatic heterocyclic compound including N or O in 2 to 4 rings.
  • Het may be any one selected from the following structures:
  • Y is H or CX 3
  • X is halogen
  • the compound may be any one selected from the group consisting of the following compounds:
  • a pharmaceutical composition comprising the pyrazole-carboxamide derivative compound, an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pyrazole-carboxamide derivative compound, an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof including overexpression or hyperactivity of cannabinoid receptor 1 It provides a pharmaceutical composition for the prevention or treatment of diseases caused by
  • the cannabinoid receptor 1 ( To provide a method for preventing or treating diseases caused by overexpression or overactivation of cannabinoid receptor 1).
  • the pyrazole-carboxamide derivative compound for the preparation of a medicament for the prevention or treatment of diseases caused by overexpression or overactivity of cannabinoid receptor 1, the pyrazole-carboxamide derivative compound, an isomer thereof , a solvate thereof or a pharmaceutically acceptable salt thereof.
  • the disease caused by overexpression or overactivity of the cannabinoid receptor 1 may be one or more selected from the group consisting of diabetes, metabolic disease, dyslipidemia, alcoholic liver disease, and non-alcoholic liver disease, but is not limited thereto.
  • prevention refers to any action that inhibits or delays a disease caused by overexpression or overactivation of cannabinoid receptor 1.
  • treatment refers to any action in which the symptoms of an individual suspected of and onset of a disease caused by overexpression or overactivation of cannabinoid receptor 1 are improved or beneficially changed.
  • the "pharmaceutically acceptable” means exhibiting properties that are not toxic to cells or humans exposed to the composition.
  • the "pharmaceutically effective amount” means that the amount of the compound administered is effective in alleviating or reducing to some extent one or more symptoms of the disorder being treated, or delaying the onset of clinical markers or symptoms of a disease requiring prevention. means quantity.
  • a pharmacologically effective amount may have an effect of 1) reversing the rate of disease progression, 2) inhibiting further progression of the disease to some extent, and/or 3) alleviating to some extent one or more symptoms associated with the disease ( Preferably, it means an amount having the effect of removing).
  • a pharmacologically effective amount can be empirically determined by testing the compound in known in vivo and in vitro model systems for a disease in need of treatment.
  • the isomers may exist as R or S isomers, racemic compounds, diastereomeric mixtures, or individual diastereomers, depending on the presence of an asymmetric carbon center of the pyrazole-carboxamide derivative compound, all isomers and mixtures of these isomers are included within the scope of the present invention.
  • the solvate may comprise a stoichiometric or non-stoichiometric amount of a solvent that is bound by non-covalent intermolecular forces.
  • Preferred solvents include nonvolatile, nontoxic, or suitable solvents for human administration, for example, ethanol, methanol, propanol, methylene chloride, and the like, but are not limited thereto.
  • the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, inorganic ionic salts prepared from calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, Inorganic acid salts prepared with phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid , glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, mandelic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, Organic acid salts prepared from succinic acid
  • the pharmaceutically acceptable salt may be hydrochloric acid as the inorganic acid and methanesulfonic acid as the organic acid.
  • saline As the pharmaceutically acceptable carrier, saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components may be mixed and used, and if necessary, an antioxidant , buffers, bacteriostats, and other conventional additives may be added, but the present invention is not limited thereto.
  • the pharmaceutical composition or pharmaceutical composition may be provided as a pharmaceutical composition including an active ingredient alone, or one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the pharmaceutical composition or route of administration of the pharmaceutical composition is not limited thereto, but is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal.
  • the pharmaceutical composition or pharmaceutical composition may be administered orally or parenterally, and when administered parenterally, an injection method for external application or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection is selected.
  • an injection method for external application or intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection is selected.
  • oral administration can be preferably selected from the viewpoint of selecting a more effective absorption route.
  • the pharmaceutical composition or a preferred dosage of the pharmaceutical composition varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art. However, for a desirable effect, the composition is preferably administered at 0.01 to 1000 mg/kg/day, preferably 0.1 to 500 mg/kg/day, but is not limited thereto. The administration may be administered once a day, or divided into several administrations. The above dosages are not intended to limit the scope in any way.
  • the pharmaceutical composition or pharmaceutical composition When formulating the pharmaceutical composition or pharmaceutical composition, it is prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant usually used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral use include suspensions, solutions, emulsions, syrups, etc.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycero geratin and the like can be used.
  • the compound provided as an embodiment of the present invention may be prepared according to the following preparation method, but is not particularly limited thereto, and may be prepared by a method known in various literatures.
  • novel pyrazole-carboxamide derivative compounds of formula (1) may contain one or more asymmetric carbons, and thus racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereomers. It may exist as an isomer. Such isomers can be separated by conventional techniques, for example, column chromatography of the novel pyrazole carboxamide derivative compound of Formula 1 or resolution such as HPLC. Alternatively, stereoisomers of each of the compounds of Formula 1 can be stereospecifically synthesized using optically pure starting materials and/or reagents of known configurations.
  • the novel pyrazole-carboxamide derivative compound of Formula 1 can be prepared from pharmaceutically acceptable non-toxic acids derived from inorganic acids and organic acids.
  • the acids are acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloroic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, mucoic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like.
  • Citric acid, hydrobromoic acid, hydrochloroic acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid are particularly preferred.
  • novel pyrazole-carboxamide derivative compound provided as an aspect of the present invention exhibits antagonist/inverse agonist activity specific to cannabinoid receptor 1, thereby effectively preventing or treating related diseases. There are technical effects.
  • CB1 protein is an analysis result of the interaction between CB1 protein and taranabant, known as a CB1 inhibitor (Taranabant, inverse agonist).
  • 2 is a scatter plot showing docking energy score results for 102 compounds of synthetic candidate materials.
  • Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) pyrazine-2-carboxylate (2- 2f) was prepared similarly to the process described for compound (2-3a) above.
  • Methyl 5- (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxamido) -2-fluorobenzoate (2 -2o) was prepared similarly to the process described for compound (2-3a) above.
  • the organic layer was washed with 1N aqueous hydrochloric acid solution and purified water in that order, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure.
  • SBDD Structure-Based Drug Design
  • LBDD Ligand-Based Drug Design
  • the x-ray tertiary crystal structure (PDB code: 5U09) of the CB1 target protein was obtained from the Protein Data Bank (https://www.rcsb.org)
  • the Discovery Studio program DSSAULT SYSTEMS
  • the solvent molecules of the protein were removed, and a structure was obtained in which the protonation of the protein residue was calculated at pH 7.4, and a structure in which the ionization state was calculated based on pH 6.5 to 8.5 of the ligand.
  • CB1 protein is an analysis result of the interaction of CB1 protein with Taranabant (inverse agonist) known as a CB1 inhibitor, forming hydrogen bonds with Ser123 and Ser383, and forming strong hydrophobic pockets (Met103, Asp104, Ile105, Ile119, Phe170, Val196, Trp279). , Trp356, Ala380, Met384, Cys386).
  • Synthetic candidates 102 compounds were analyzed for binding forms between protein molecules and ligands using the Discovery Studio docking program. 40 kinds of final example compounds were discovered by analysis by docking energy score and visual inspection.
  • '- CDOCKER_INTERACTION_ENERGY' means protein-ligand binding energy and is calculated in kcal/mol units.
  • 'LigScore2' means protein-ligand binding affinity, and is calculated in pKi (-log Ki).
  • Table 5 below shows the protein-ligand binding energy (-CDOCKER_INTERACTION_ENERGY) and protein-ligand binding affinity (LigScore2) for the compounds selected by applying the CADD (Computer-Aided Drug Design) technology.
  • Example LigScore2 (pKi) -CDOCKER INTERACTION ENERGY (kcal/mol) One 7.66 64.44 2 7.50 66.71 3 7.25 61.21 4 7.37 67.51 5 7.61 68.04 6 7.53 62.99 7 6.98 54.00 8 6.84 55.05 9 6.87 56.02 10 7.28 58.61 11 7.63 64.28 12 7.51 61.12 13 6.36 45.53 14 4.88 28.99 15 7.62 61.68 16 7.22 54.93 17 7.24 60.38 18 7.19 55.00 19 7.75 64.89 20 7.65 65.14 21 7.53 62.01 22 7.67 64.25 23 5.81 43.57 24 7.14 56.10 25 6.80 56.23 26 7.12 56.20 27 6.95 57.47 28 7.14 56.99 29 7.31 57.98 30 7.52 57.80 31 7.32 59.86 32 6.96 63.64 33 7.04 62.99 34 6.81 61.35 35 6.87 58.03 36 6.78
  • a cAMP ELISA assay was performed using Rimonabant, an existing developed material, as a control.
  • CHO-GLP1R-CB1R cells were cultured for one day in DMEM medium containing 10% fetal bovine serum (FBS) and 1% antibiotics in an environment of 5% CO 2 37 °C. The next day, the cells were cultured in a medium without FBS for 30 minutes, and a CB1 inhibitor compound (including any one of the compounds of Examples 1 to 40) dissolved in DMSO was added and reacted for 30 minutes [compound final concentration ( ⁇ M)) : 0.1, 1, 2.5, 5, 10, 20]. 10 uM forskolin and 10 nM CP55,940 were added to the cells and incubated for 1 hour. After removing the solution, PBS and 0.1M HCl were added to wash the cells 3 times.
  • FBS fetal bovine serum
  • cAMP was measured using the Direct cAMP ELISA kit (Enzo Life Sciences, Lausen, Switzerland; Catalog # ADI-900-066). Absorbance was measured at 405 nm wavelength using an ELISA reader.
  • Example IC50 (Rimonabant) 2 2.56 (1.08) 3 1.13 (1.08) 4 7.09 (1.08) 5 5.6 (9.3) 6 6.7 (9.3) 7 0.52 (1.08) 8 0.85 (1.08) 9 0.49 (1.08) 10 0.48 (1.08) 12 1.12 (1.08) 13 0.48 (1.08) 14 0.66 (1.08) 16 1.25 (1.08) 17 10.4 (9.3) 18 2.55 (1.08) 19 2.9 (9.3) 37 1.56 (3.20) 38 3.54 (3.20) 39 4.25 (3.20) 40 2.75 (3.20)
  • the amount of the compound in the reaction mixture was quantified by LC-MS/MS after pretreatment of the liver microsome metabolic stability test result, and expressed as a percentage compared to the initial amount.
  • the blood-brain barrier (BBB) penetration test of the CB1 inhibitor compound was evaluated in ICR mice. All subjects were fasted for at least 16 hours prior to compound administration. A single dose (10 mg/kg) of a CB1 inhibitor compound (Examples 5, 6, 19) or rimonabant was suspended in 10 mL of a mixed solvent (4% DMSO; 8% Tween 80; 88% saline) and then orally administered to mice. . Mice were sacrificed 1, 2, and 4 hours after compound administration and analyzed. At each autopsy point, the mouse was anesthetized, and about 1 ml of blood was collected by laparotomy. The blood collected was immediately stored in an ice-cooled state (about 4°C).
  • a mixed solvent 4% DMSO; 8% Tween 80; 88% saline
  • CB1 inhibitor compounds Examples 5, 6, 19
  • rimonabant were measured using LC-MS/MS methods in mouse plasma and brain tissue collected to examine the BBB permeability of the drug.
  • the brain/plasma ratio of the compound 1, 2, and 4 hours after administration of the compound to the mouse is shown in Table 8 below.

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Abstract

Un exemple de la présente invention concerne un nouveau composé dérivé de pyrazole-carboxamide qui présente une activité antagoniste spécifique du récepteur cannabinoïde 1, et présente ainsi un effet technique de prévention ou de traitement efficace de maladies provoquées par la surexpression ou la suractivité du récepteur cannabinoïde 1, telles que le diabète, les maladies métaboliques, la dyslipidémie, la maladie hépatique alcoolique, les maladies hépatiques non alcooliques et des maladies analogues.
PCT/KR2022/001522 2021-01-28 2022-01-27 Composé dérivé de pyrazole-carboxamide et utilisation associée Ceased WO2022164239A1 (fr)

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JP2008285481A (ja) * 2007-04-20 2008-11-27 Mitsubishi Tanabe Pharma Corp 医薬組成物
WO2009033125A1 (fr) * 2007-09-07 2009-03-12 Jenrin Discovery Antagonistes/agonistes inverses de récepteur de cannabinoïde utiles pour traiter l'obésité
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