WO2020239050A1 - Composé de 2-(2-chloro-4-méthylphényl)quinazoline-4(3h)-cétone et son utilisation médicale - Google Patents

Composé de 2-(2-chloro-4-méthylphényl)quinazoline-4(3h)-cétone et son utilisation médicale Download PDF

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WO2020239050A1
WO2020239050A1 PCT/CN2020/093133 CN2020093133W WO2020239050A1 WO 2020239050 A1 WO2020239050 A1 WO 2020239050A1 CN 2020093133 W CN2020093133 W CN 2020093133W WO 2020239050 A1 WO2020239050 A1 WO 2020239050A1
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substituted
formula
arh
chloro
methylphenyl
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Chinese (zh)
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苏瑞斌
何新华
俞纲
张宪伟
曹燕卿
庄笑梅
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中国人民解放军军事科学院军事医学研究院
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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
    • A61K31/33—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention belongs to the field of pharmaceutical research, and specifically relates to 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compounds, a preparation method thereof, and its use for sedation, hypnosis, anticonvulsant, Use of antidepressant, anti-anxiety and other drugs.
  • GABA A receptors are important targets of sedative and hypnotics.
  • GABA A receptor agonists are the most widely used sedative and hypnotic drugs in clinical practice, including barbiturates such as Phenobarbital and Secobarbital ( Secobarbital) etc.; Benzodiazepine Drugs such as Diazepam, Clonazepam, Nitrazepam, Estazolam, Lorazepam, Midazolam, etc. ; Non-benzodiazepine Class drugs, such as Zolpidem (Zolpidem), Zopiclone (Zopiclone), Eszopiclone (Eszopiclone) and so on.
  • GABA A receptor belongs to the pentameric ligand-gated anion channel of the Cys ring receptor family. 19 genes encoding different subunits have been found in the human genome, including ⁇ 1-6 , ⁇ 1-3 , and ⁇ 1- 3. ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ 1-3 (previously called GABAc receptors) (Cold Spring Harbor Perspectives in Biology, 2012, 4(3): 829-841). Due to the different permutations and combinations of subunits, there are many different subtypes of GABA A receptors (Cell and Tissue Research, 2006, 326(2): 505-516.). The functions of different subtypes are different, and there are multiple drug action sites. According to the characteristics of GABA A receptors and the research progress of subunits, the design of GABA A receptor agonists can find new high-efficiency and low-toxicity sedative and hypnotic drugs.
  • R 1 and R 2 are each independently hydrogen, halogen atom, C1 to C15 linear or branched alkyl, halogen substituted C1 to C15 linear or branched alkyl, C1 to C15 alkoxy Group, C1 to C15 alkylamino, C2 to C20 alkenyl or C5 to C20 aryl;
  • W is C1 to C15 linear or branched alkyl, C2 to C20 alkenyl, saturated or unsaturated three to seven membered heterocyclic ring, saturated or unsaturated three to seven membered heterocyclic ring substituted C1 to C3 Alkyl, substituted or unsubstituted C3 to C20 cycloalkyl or substituted or unsubstituted C3 to C20 aryl.
  • the halogen atom is fluorine, chlorine or bromine.
  • the saturated or unsaturated three to seven heterocyclic ring contains 1 to 3 heteroatoms selected from O, S and N.
  • substituted or unsubstituted C3 to C20 cycloalkyl group means that there are 1 to 3 C1 to C6 alkyl groups or cyclic C5 to C6 aryl groups on the C3 to C20 cycloalkyl group.
  • substituted or unsubstituted C3 to C20 aryl group means that there are 1 to 3 C1 to C6 alkyl groups on the C3 to C20 aryl group.
  • R 1 and R 2 are each independently hydrogen, a halogen atom, a C1 to C10 linear or branched alkyl group, a halogen-substituted C1 to C10 linear or branched alkyl group, and a C1 to C10 alkane.
  • W is C1 to C10 linear or branched alkyl, C2 to C10 alkenyl, saturated or unsaturated five-membered or six-membered heterocycle, saturated or unsaturated five-membered or six-membered heterocycle substituted C1 or C2 alkyl group, substituted or unsubstituted C3 to C10 cycloalkyl group or substituted or unsubstituted C3 to C10 aryl group.
  • the saturated or unsaturated five-membered or six-membered heterocyclic ring contains 1 or 2 heteroatoms selected from O and S.
  • substituted or unsubstituted C3 to C10 cycloalkyl group means that there are 1 to 3 C1 to C3 alkyl groups or cyclic C5 to C6 aryl groups on the C3 to C10 cycloalkyl group.
  • substituted or unsubstituted C3 to C10 aryl group means that there are 1 to 3 C1 to C3 alkyl groups on the C3 to C10 aryl group.
  • R 1 and R 2 are each independently hydrogen, a halogen atom, a C1 to C6 linear or branched alkyl group, a halogen-substituted C1 to C6 linear or branched alkyl group, and a C1 to C6 alkyl group.
  • W is C1 to C6 linear or branched alkyl, C2 to C6 alkenyl, saturated or unsaturated five-membered or six-membered heterocycle, saturated or unsaturated five-membered or six-membered heterocycle substituted C1 or C2 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl or substituted or unsubstituted C3 to C8 aryl.
  • the saturated or unsaturated five-membered or six-membered heterocyclic ring contains 1 or 2 heteroatoms selected from O and S.
  • substituted or unsubstituted C3 to C10 cycloalkyl group refers to the presence of 1 or 2 C1 to C3 alkyl groups or cyclic C5 to C6 aryl groups on the C3 to C8 cycloalkyl group.
  • substituted or unsubstituted C3 to C10 aryl group means that there are 1 or 2 C1 to C3 alkyl groups on the C3 to C10 aryl group.
  • R 1 and R 2 are each independently hydrogen, a halogen atom, and the number of carbon atoms is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 straight chain or branched chain alkyl, the number of carbon atoms substituted by halogen atoms is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 straight chain Or branched chain alkyl, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 alkoxy group with carbon number C1 , C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 Alkylamino, with carbon number of C2, C3, C4, C5, C6, C7, C8 , C
  • W is selected from alkyl groups having carbon atoms of C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10, and carbon atoms of C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkenyl, saturated or unsaturated three to seven membered heterocyclic ring, saturated or unsaturated three to seven membered heterocyclic ring substituted C1, C2 or C3 alkyl, substituted or unsubstituted C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 ring Alkyl, or substituted or unsubstituted C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16,
  • R 1 and R 2 are each independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl or trifluoro Ethyl;
  • W is chlorophenyl, methylphenyl, ethylphenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl, methylcyclooctyl, Ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, ethylcycloheptyl, ethylcyclooctyl, furanyl, pyridyl, thienyl, pyrrolyl,
  • the compound represented by formula (I) according to the present invention is selected from the following compounds and pharmaceutically acceptable salts thereof:
  • Another aspect of the present invention relates to 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) or a pharmaceutically acceptable salt thereof for preparation
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of 2-(2-chloro-4-methylphenyl)quinazoline-4(3H) represented by formula (I) -Ketone compounds or pharmaceutically acceptable salts thereof as active ingredients and pharmaceutically acceptable excipients.
  • R 1 and R 2 in formula II have the same definition as formula I
  • W in W-NH 2 has the same definition as formula I.
  • R 1 and R 2 in III are the same as those in formula II, and the definition of W is the same as that of W in W-NH 2 ;
  • R 1 , R 2 , and W in formula IV have the same definition as formula III,
  • step 2) of the above method is specifically carried out in the presence of the NH 4 COOH-Pd/C system.
  • the target product 2-(2-chloro-4-methylphenyl)quinazoline is obtained -4(3H)-ketone compounds.
  • the specific reaction conditions of each step of amide condensation, reduction, Schiff base condensation can be carried out according to conventional designs in the art, for example, the amide condensation can refer to the literature (J.Org.Chem.27(11):3851-3855.
  • the reduction can refer to the literature (Bioorganic&Medicinal Chemistry Letters, 20(3), 1128-1133), the Schiff base condensation and heating ring combination, can refer to the literature (Advanced Synthesis&catalysis, 360(24): 4764 -4773) Preparation.
  • Figure 1 is a reaction scheme for preparing the compound of formula I in the present invention.
  • Figure 2 is a graph showing the drug metabolism conversion spectrum of the representative compound 9050 in rat liver microsomes.
  • the present invention uses WJ3008 as the lead compound to optimize the structure, and finds that the compound with the structure shown in formula (I) is a potent GABA A receptor agonist and has a good sedative and hypnotic effect.
  • the substitution of chlorine at position 10 in the molecule is very important to improve the efficacy, and the substitution of methyl at position 12 can avoid the side effects of muscle relaxation caused by the compound, and the methyl at position 12 can be rapidly metabolized into hydroxymethyl in liver microsomes.
  • Base accelerate the metabolic rate of the compound, and achieve the purpose of quick-acting and short-acting.
  • the "pharmaceutically acceptable salt” is a conventional non-toxic salt formed by the reaction of a compound of general formula (I) with an inorganic acid or an organic acid.
  • the conventional non-toxic salt can be prepared by reacting a compound of general formula (I) with an inorganic acid or an organic acid.
  • the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc.
  • the organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid , Malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p- Amino benzene sulfonic acid, 2-acetoxy benzoic acid and isethionic
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may exist in the form of its hydrate, solvate or prodrug. Therefore, hydrates, solvates or prodrugs of the compounds of the present invention or pharmaceutically acceptable salts thereof are also included in the scope of the present invention.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient.
  • Representative carriers include water, oil, Vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. For other information about the carrier, you can refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), and the content of this document is incorporated herein by reference.
  • the term "effective amount” or “therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • Ketone substitution does not occur on aromatic groups.
  • any variable such as R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • compositions which comprises a therapeutically effective amount of a compound represented by formula (I), and its stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, and hydrates And one or more of the crystal forms, and at least one excipient, diluent or carrier.
  • a pharmaceutical composition which comprises a therapeutically effective amount of a compound represented by formula (I), and its stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, and hydrates And one or more of the crystal forms, and at least one excipient, diluent or carrier.
  • a typical formulation is prepared by mixing the compound represented by formula (I) of the present invention and a carrier, diluent or excipient.
  • Suitable carriers, diluents or excipients are well known to those skilled in the art, including such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents , Water and other substances.
  • the specific carrier, diluent or excipient used will depend on the mode and purpose of the compound of the present invention.
  • the solvent is generally selected on the basis of the solvent considered by those skilled in the art to be safe and effective for administration to mammals.
  • safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble or miscible with water.
  • Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300) and the like.
  • the formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids, Coloring agents, sweetening agents, flavoring agents, flavoring agents or other known additives enable the drug to be manufactured or used in an acceptable form.
  • the two drugs or more drugs can be used separately or in combination, and are preferably administered in the form of a pharmaceutical composition.
  • the compound or pharmaceutical composition of formula (I) of the present invention can be administered separately or together in any known oral, intravenous, rectal, vaginal, transdermal, or other local or systemic administration form. Medicine to the subject.
  • compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids Agents, coloring agents, sweetening agents, flavoring agents, flavoring agents or other known additives, so that the pharmaceutical composition can be manufactured or used in an acceptable form.
  • the drug of the present invention is preferably administered by oral route.
  • Solid dosage forms for oral administration may include capsules, tablets, powder or granular formulations.
  • the compound or pharmaceutical composition of the present invention is mixed with at least one inert excipient, diluent or carrier.
  • Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginic acid Salt, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.; wetting agents such as glycerin, etc.; disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.; Solution blockers such as paraffin, etc.; absorption enhancers such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate Wait.
  • binders such as carboxymethyl cellulose,
  • the dosage form may also include buffering agents.
  • Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules, which use lactose and high molecular weight polyethylene glycol as excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, acetic acid Ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oils (such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.) ); Glycerin; Tetrahydrofurfuryl alcohol; Fatty acid esters of polyethylene glycol and sorbitan; or a mixture of several of these substances.
  • inert diluents commonly used in the art, such as water or other solvents
  • solubilizers and emulsifiers
  • composition may also include excipients, such as one or more of wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents and perfumes.
  • excipients such as one or more of wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension in addition to the compound or combination of the present invention, it may further contain a carrier such as a suspending agent, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline Cellulose, aluminum hydroxide, bentonite, agar and tragacanth, or a mixture of several of these substances.
  • a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline Cellulose, aluminum hydroxide, bentonite, agar and tragacanth, or a mixture of several of these substances.
  • the compound or pharmaceutical composition of the present invention can be administered in other topical dosage forms, including ointments, powders, sprays and inhalants.
  • the drug can be mixed with pharmaceutically acceptable excipients, diluents or carriers and any required preservatives, buffers or propellants under sterile conditions.
  • Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.
  • Another aspect of the present invention provides compounds represented by formula (I) and their tautomers, enantiomers, diastereomers, racemates, metabolic precursors, pharmaceutically acceptable salts, esters, Use of the prodrug or its hydrate or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases or symptoms related to the abnormal activity of GABA A.
  • the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can exist in suitable solid or liquid carriers or diluents. In addition, it is suitable for sterilization equipment for injection or drip.
  • the unit dose of the formulation formulation contains 0.05-200 mg of the compound of formula (I), preferably, the unit dose of the formulation formulation contains 0.1 mg-100 mg of the compound of formula (I).
  • the compounds and pharmaceutical compositions of the present invention can be used clinically on mammals, including humans and animals, and can be administered via oral, nose, skin, lung, or gastrointestinal tract. Most preferably it is oral.
  • the most preferred daily dose is 0.01-200 mg/kg body weight, taken at one time, or 0.01-100 mg/kg body weight in divided doses. Regardless of the method of administration, the individual's optimal dose should be determined based on the specific treatment. Usually start with a small dose and gradually increase the dose until the most suitable dose is found.
  • the present invention also proves that the compound involved in formula (I) can be rapidly metabolized in the body (the following reaction formula 2).
  • Animal experiments prove that the compound can take effect within 1 minute after intraperitoneal injection, and wake up after 2 hours, with spontaneous activity It has no effect and can be developed into a strong short-acting sedative and hypnotic drug to avoid residual effects the next day.
  • the materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.
  • the melting point is measured by YRT-3 melting point instrument.
  • 1 H-NMR and 13 C-NMR were measured by LSI-IST-005/JNM-ECA400 nuclear magnetic resonance instrument.
  • ESI-MS is measured by LSI-IST-003/G6230A mass spectrometer.
  • the thin layer chromatography plate adopts Merck GF254 fluorescent plate.
  • the ultraviolet high-pressure mercury lamp is provided by Shanghai Jiguang Special Lighting Appliance Factory.
  • the chemical reagents used are all chemically pure or analytically pure.
  • the first step is the preparation of 2-nitro-N-phenylbenzamide
  • the second step is the preparation of 2-amino-N-phenylbenzamide
  • the third step is the preparation of 2-(2-chloro-4-methylphenyl)-3-phenylquinazolin-4(3H)-one
  • reaction solution was transferred to a separatory funnel, 40 mL ethyl acetate was added, and the mixture was extracted twice with 20 mL saturated sodium chloride aqueous solution, and the aqueous phase was extracted once with 20 mL ethyl acetate.
  • the organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove nothing.
  • CCK8 was used to detect the toxicity of 36 compounds on Hep G2 cells, and each compound was tested at three concentrations of 30 ⁇ M, 10 ⁇ M, and 3 ⁇ M. Preliminary evaluation of the safety of the compound.
  • OD STSP Absorbance value of positive control well (cell + culture medium + Staurosporine)
  • Diazepam (DZP) and methaqualone (QUA) were used as positive control drugs, and the compounds in Table 2 were used as control drugs for pharmacodynamic study. After intraperitoneal injection of the compound, the induced behavioral effect was observed, and the rate of disappearance of the righting reflex in mice was recorded. The results are shown in Table 3 below.
  • the key structural feature of the present invention is that the substitution of chlorine at position 10 in formula (I) is very critical to the improvement of drug efficacy, and the substitution of methyl at position 12 can avoid the side effects of muscle relaxation caused by the compound before convulsions.
  • Chromatographic conditions Phenomenex C 18 (150mm ⁇ 2.1mm, 5 ⁇ m) column; mobile phase: water (containing 0.1% formic acid, A)-acetonitrile (containing 0.1% formic acid, B); gradient elution (0 ⁇ 30min, 98% ⁇ 2%A; 30.01min, 98%A; 30.01 ⁇ 35min, 98%A); column temperature 25°C; flow rate 0.3mL/min; injection volume 5 ⁇ L.
  • Electrospray ion source adopts positive scan mode, electrospray voltage is 2.8kV; sheath gas flow rate is 35arb; auxiliary gas flow rate is 10arb; capillary temperature is 320°C; full scan (Full scan): resolution: 70000; Scan range: 50-500m/z; secondary data dependent scan (Full MS/dd-MS2): resolution: 17500.
  • liver microsomes were pre-processed with the direct protein precipitation method.
  • In the incubation system take 50 ⁇ L each at 0min and 60min, add 200 ⁇ L acetonitrile, vortex for 1min, centrifuge at 4°C (13800 ⁇ g) for 10min, and take 100 ⁇ L of the supernatant. Sample analysis.
  • the total reaction volume of rat liver microsomes is 250 ⁇ L, and the final concentration of each component in the incubation system is (9050 is 50 ⁇ M, liver microsomal protein concentration is 1.185mg/mL, NADPH concentration is 1mM, incubated at 37°C), respectively, taken at 0 and 60 minutes 50 ⁇ L to 200 ⁇ L of ice-cold acetonitrile and mix to stop the reaction. Shake for 2 min, centrifuge at 4°C, 13 800 ⁇ g for 10 min, and quantitatively take 100 ⁇ L of the supernatant for analysis.
  • the representative compound 9050 is incubated in rat liver microparticles and can be quickly converted into hydroxylated metabolites (1h), which is consistent with the speculation of drug molecular design, as shown in Figure 2.
  • the next day residual effect is one of the main limitations of current sedative and hypnotic drugs.
  • the compound of the present invention has stronger pharmacological effects, faster metabolism, and reduces the residual effect of the next day. It is expected to be developed as a new type of high-efficiency and low-toxicity sedative and hypnotic drugs .
  • the preparation process of the compound is simple, the key step of the compound reaction is catalyzed by cheap metal copper, the yield is higher, the energy consumption is lower, and it is more environmentally friendly.

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Abstract

L'invention concerne un composé de 2-(2-chloro-4-méthylphényl)quinazoline-4(3H)-cétone représenté par la formule (I), son procédé de préparation et son utilisation dans, par exemple, des médicaments hypnotiques sédatifs, anticonvulsivants, antidépresseurs, anti-anxiété.
PCT/CN2020/093133 2019-05-29 2020-05-29 Composé de 2-(2-chloro-4-méthylphényl)quinazoline-4(3h)-cétone et son utilisation médicale WO2020239050A1 (fr)

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