WO2023054006A1 - Opioid receptor antagonist and pharmaceutical composition - Google Patents

Opioid receptor antagonist and pharmaceutical composition Download PDF

Info

Publication number
WO2023054006A1
WO2023054006A1 PCT/JP2022/034681 JP2022034681W WO2023054006A1 WO 2023054006 A1 WO2023054006 A1 WO 2023054006A1 JP 2022034681 W JP2022034681 W JP 2022034681W WO 2023054006 A1 WO2023054006 A1 WO 2023054006A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
opioid receptor
formula
opioid
Prior art date
Application number
PCT/JP2022/034681
Other languages
French (fr)
Japanese (ja)
Inventor
秀依 高橋
宏章 牧野
浩暢 有田
俊太郎 菊川
宰 富澤
正彦 舩田
健一 富山
Original Assignee
学校法人東京理科大学
国立研究開発法人国立精神・神経医療研究センター
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 学校法人東京理科大学, 国立研究開発法人国立精神・神経医療研究センター filed Critical 学校法人東京理科大学
Publication of WO2023054006A1 publication Critical patent/WO2023054006A1/en

Links

Images

Classifications

    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel opioid receptor antagonists and pharmaceutical compositions.
  • Fentanyl is a synthetic opioid ⁇ receptor agonist represented by the following formula, and is used as a narcotic analgesic to treat cancer pain. While fentanyl has a strong analgesic effect, it has a narrow safety margin and is prone to side effects.
  • naloxone, naltrexone, naldemedine, etc. which are opioid receptor antagonists, are known as therapeutic agents for side effects and addictive symptoms caused by opioid drugs.
  • opioid receptor antagonists have also been proposed (see, for example, Patent Document 1).
  • An object of the present invention is to provide a novel opioid receptor antagonist and pharmaceutical composition.
  • ⁇ 1> Containing as an active ingredient one atropisomer having an opioid receptor antagonistic action or a pharmacologically acceptable salt thereof among a pair of atropisomers possessed by the compound represented by the following formula (1) opioid receptor antagonists.
  • R 1 represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group, and may have a substituent.
  • Each R4 independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group.
  • R 1 in formula (1) is a heteroaryl group
  • R 2 and R 3 are each independently an alkyl group.
  • ⁇ 3> The opioid receptor antagonist according to ⁇ 1> or ⁇ 2>, which exhibits an antagonistic effect on opioid ⁇ receptors.
  • ⁇ 4> Contains, as the active ingredient, an atropisomer represented by the following formula (2) and having a positive specific rotation at 20°C with respect to the sodium D line when dissolved in chloroform, ⁇ 1> ⁇
  • ⁇ 5> Contains, as the active ingredient, an atropisomer represented by the following formula (3) and having a positive specific rotation at 20°C with respect to the sodium D line when dissolved in methanol, ⁇ 1> ⁇
  • ⁇ 6> Contains, as an active ingredient, one atropisomer having an opioid receptor antagonistic action or a pharmacologically acceptable salt thereof, out of the pair of atropisomers possessed by the compound represented by the following formula (1)
  • R 1 represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group, and may have a substituent.
  • Each R4 independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group.
  • novel opioid receptor antagonists and pharmaceutical compositions can be provided.
  • FIG. 4 shows dose-response curves when compound 3F (3F), compound 3L (3L), or fentanyl (FN) was added to opioid ⁇ receptor-expressing cells (CHO- ⁇ cells).
  • FIG. 4 shows dose-response curves of pretreatment of opioid ⁇ receptor-expressing cells (CHO- ⁇ cells) with compound 3F (3F) or naloxone (NLX) followed by addition of fentanyl.
  • FIG. 10 is a graph showing changes over time in the amount of locomotion every 10 minutes after administration of morphine (Mor) after administration of compound 3F (3F), naloxone (NLX), and saline (SAL) to mice. .
  • FIG. 1 shows dose-response curves when compound 3F (3F), compound 3L (3L), or fentanyl (FN) was added to opioid ⁇ receptor-expressing cells (CHO- ⁇ cells).
  • FIG. 4 shows dose-response curves of pretreatment of opioid ⁇ receptor-expressing cells
  • FIG. 10 shows total locomotion for 120 minutes after administration of morphine when mice were administered compound 3F (3F), naloxone (NLX), saline (SAL), and then morphine (Mor).
  • FIG. 4 shows dose-response curves when compound 5F (5F) or compound 5L (5L) was added to opioid ⁇ receptor-expressing cells (CHO- ⁇ cells).
  • FIG. 4 shows dose-response curves of pretreatment of opioid ⁇ receptor-expressing cells (CHO- ⁇ cells) with compound 5F (5F) or naloxone (NLX) followed by addition of fentanyl.
  • the opioid receptor antagonist according to the present embodiment is one atropisomer having opioid receptor antagonistic activity among a pair of atropisomers possessed by the compound represented by the following formula (1) (hereinafter referred to as "specific atropisomer isomer”) or a pharmacologically acceptable salt thereof as an active ingredient.
  • “Atropisomer” refers to structural isomers based on axial or planar chirality.
  • the compound represented by the above formula (1) is a bond between the carbon atom at position 1 in the benzene ring having R 2 and R 3 at positions 2 and 6 and the nitrogen atom at position 4 of the piperidine ring. It has a pair of atropisomers (Ra form and Sa form) derived from axial asymmetry due to restricted rotation of (carbon-nitrogen bond) due to steric hindrance.
  • the opioid receptor antagonist according to this embodiment contains one atropisomer having opioid receptor antagonistic activity or a pharmacologically acceptable salt thereof as an active ingredient.
  • the opioid receptor antagonist according to the present embodiment contains any atropisomer. good too.
  • R 1 represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group, and may have a substituent.
  • Each R4 independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group.
  • the alkyl group preferably has 1 to 20 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group, pentyl group, isopentyl group and hexyl group.
  • Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl and tricyclo[2.2.1.0 ] groups having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, such as heptyl groups.
  • the alkenyl group includes a vinyl group, allyl group, propenyl group, isopropenyl group, butenyl group, isobutenyl group, 1,3-butadienyl group, pentenyl group, hexenyl group, etc., having 2 to 20 carbon atoms, preferably 2 to 2 carbon atoms. Ten linear or branched groups are included.
  • the alkynyl group includes linear or branched groups having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, such as ethynyl group, propynyl group, butynyl group, pentynyl group and hexynyl group.
  • Aryl groups include monocyclic or 2- to 4-ring condensed polycyclic groups such as phenyl group, naphthyl group, anthryl group, phenanthryl group, pyrenyl group, fluorenyl group, indenyl group, acenaphthylenyl group, indanyl group and acenaphthenyl group. is mentioned.
  • Non-aromatic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolinyl, piperidyl, tetrahydropyridyl, homopiperidinyl, octahydroazocinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, and homopiperazinyl.
  • monocyclic nitrogen-containing groups such as groups, 2-piperazinonyl groups; monocyclic oxygen-containing groups such as tetrahydrofuranyl groups, tetrahydropyranyl groups and pyranyl groups; monocyclic nitrogen-containing/oxygen groups such as morpholinyl groups monocyclic nitrogen-sulfur groups such as a thiomorpholinyl group; Bicyclic oxygen-containing groups such as isochromanyl group, 1,3-benzodioxolyl group, 1,3-benzodioxanyl group, 1,4-benzodioxanyl group; 2,3-dihydrobenzothienyl group bicyclic sulfur-containing groups such as; [3.3]octyl group, 2-oxaspiro[3.3]octyl group, 6-aza-2-oxaspiro[3.3]octyl group, 1-azaspiro[4.5]decyl group, 1-oxaspiro[4 .5] a
  • Heteroaryl groups include monocyclic nitrogen-containing groups such as pyrrolyl, pyridyl, imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, and tetrazolyl; monocyclic nitrogen-containing groups such as furanyl; Oxygen-containing groups; monocyclic sulfur-containing groups such as thienyl; monocyclic nitrogen-containing and oxygen groups such as oxazolyl, isoxazolyl and oxadiazolyl groups; monocyclic groups such as thiazolyl, isothiazolyl and thiadiazolyl nitrogen/sulfur groups; Bicyclic nitrogen-containing groups such as a quinazolinyl group, quinoxalinyl group, naphthyridinyl group, pyrrolopyridyl group, imidazopyridyl group, pyrazolopyridyl group, pyridopyr
  • the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like.
  • R 1 to R 3 may have include an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a cyano group, a halogen atom, hydroxy group, amino group, nitro group, nitroxy group, mercapto group, cyanate group, thiocyanate group, isothiocyanate group, sulfo group, sulfamino group, sulfino group, sulfamoyl group, phospho group, phosphono group, boronyl group and the like.
  • the compound represented by formula (1) above has an acidic functional group or a basic functional group
  • the compound may be in the form of a salt.
  • the compound may be an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, etc.), It may be in the form of an ammonium salt or the like.
  • the compound represented by the above formula (1) when the compound represented by the above formula (1) has a basic functional group, the compound may be in the form of a salt with an inorganic acid such as hydrochloric acid or phosphoric acid, acetic acid, fumaric acid, methane It may be in the form of a salt with an organic acid such as sulfonic acid.
  • an inorganic acid such as hydrochloric acid or phosphoric acid, acetic acid, fumaric acid, methane
  • an organic acid such as sulfonic acid.
  • the specific atropisomer or a salt thereof which is the active ingredient of the opioid receptor antagonist according to the present embodiment, may exhibit an antagonistic effect on any type of opioid receptor, but at least on the opioid ⁇ receptor. It is preferable to show an antagonistic action against The antagonistic action of a specific atropisomer or a salt thereof on the opioid ⁇ receptor can be confirmed, for example, by measuring the 50% inhibitory concentration ( IC50 value) according to the method described in Test Example 1 below.
  • An example of a particularly preferred compound among the specific atropisomers is represented by the following formula (2) and has a positive specific rotation at 20° C. with respect to the sodium D line (wavelength 589 nm) when dissolved in chloroform.
  • a compound showing In formula (2) -Me represents a methyl group, and -Et represents an ethyl group. This compound exhibits a stronger opioid ⁇ receptor antagonistic activity than naloxone, as shown in Test Example 1 described later.
  • a particularly preferred compound among the specific atropisomers is represented by the following formula (3), and specific rotation at 20° C. with respect to the sodium D line (wavelength 589 nm) when dissolved in methanol is a positive value.
  • formula (3) -Me represents a methyl group. As shown in Test Example 3 described later, this compound exhibits a strong opioid ⁇ receptor antagonistic activity, though weaker than that of naloxone.
  • a specific atropisomer or a salt thereof, which is the active ingredient of the opioid receptor antagonist according to the present embodiment, can be obtained, for example, by optically resolving the racemate by chiral column chromatography or the like.
  • the opioid receptor antagonist according to the present embodiment of the pair of atropisomers possessed by the compound represented by the above formula (1), is different from the specific atropisomer, as long as it exhibits opioid receptor antagonistic activity. It may contain atropisomers or salts thereof. In this case, the enantiomeric excess of the specific atropisomer or salt thereof may be 0% ee or more, 20% ee or more, 40% ee or more, or 60% ee. 80% ee or more, 90% ee or more, or 95% ee or more.
  • the opioid receptor antagonist according to the present embodiment can contain ingredients other than the active ingredient, depending on the mode of use.
  • the opioid receptor antagonist according to this embodiment can contain a pharmacologically acceptable carrier.
  • the opioid receptor antagonist according to this embodiment may be used for medical purposes, or may be used for purposes other than medicine (research purposes, etc.).
  • the opioid receptor antagonist according to this embodiment is used for medical purposes, the dosage form, indications, etc. may be the same as those of the pharmaceutical composition described later.
  • the pharmaceutical composition according to this embodiment contains the above-described specific atropisomer or a pharmacologically acceptable salt thereof as an active ingredient.
  • the specific atropisomer or its salt, which is the active ingredient, has opioid receptor antagonistic activity. Therefore, the pharmaceutical composition according to this embodiment can be applied to symptoms requiring opioid receptor antagonism.
  • the pharmaceutical composition according to the present embodiment is used to improve or treat side effects of opioid drugs (constipation, nausea, vomiting, pruritus, hypotension, respiratory depression, delayed awakening, etc.) and toxic symptoms (respiratory depression, etc.). can be used for
  • the pharmaceutical composition according to this embodiment can also be used as a treatment adjuvant for alcoholism.
  • the pharmaceutical composition according to this embodiment preferably contains a pharmacologically acceptable carrier in addition to the active ingredient.
  • Pharmaceutically acceptable carriers include organic or inorganic carriers commonly used as pharmaceutical materials. This carrier is used as an excipient, lubricant, binder, disintegrant, etc. in solid formulations, and as a solvent, solubilizer, suspending agent, tonicity agent, buffer, etc. in liquid formulations. blended.
  • the pharmaceutical composition according to this embodiment may contain formulation additives such as preservatives, antioxidants and coloring agents.
  • the dosage form of the pharmaceutical composition according to this embodiment is not particularly limited. Dosage forms of the pharmaceutical composition include oral agents such as tablets, capsules, emulsions and suspensions; parenteral agents such as injections, drops, nasal drops and external preparations; and the like.
  • the dosage of the pharmaceutical composition according to this embodiment is appropriately determined according to the administration subject, administration route, symptoms, and the like.
  • Step 3 Optical resolution of compound 3 Since compound 3 is racemic, each atropisomer was separated and isolated by chiral high performance liquid chromatography (HPLC).
  • the atropisomer with a faster elution time is designated as compound 3F
  • the atropisomer with a later elution time is designated as compound 3L.
  • the enantiomeric excess of compound 3F was 97.9% ee
  • the enantiomeric excess of compound 3L was 96.9% ee.
  • the activation free energy value ⁇ G ⁇ between compound 3F and compound 3L was 126.7 kJ/mol (80° C., toluene).
  • [ ⁇ ] D 20 (3 L): ⁇ 4.43° (c 0.15, CHCl 3 )
  • ⁇ Test Example 1 Evaluation of in vitro opioid ⁇ receptor activity and opioid ⁇ receptor antagonistic activity of compound 3F and compound 3L>
  • Opioid ⁇ receptor-expressing cells (CHO- ⁇ cells) were suspended in a nutritive mixture/Ham's F-12 medium containing 10% FBS, and seeded in a 96-well plate at 5.0 ⁇ 10 4 cells/well. , 37° C., 5.0% CO 2 . After 24 hours, the medium was replaced with 100 ⁇ L/well of Component B (HBSS + 20 mM HEPES buffer, pH 7.4), and a calcium-sensitive fluorescent indicator (FLIPR Calcium 4 Assay kit, Molecular Devices) was used to measure intracellular Ca by drug stimulation. 2+ responses were measured.
  • Component B HBSS + 20 mM HEPES buffer, pH 7.4
  • FLIPR Calcium 4 Assay kit FLIPR Calcium 4 Assay kit, Molecular Devices
  • the fluorescence value was measured every 2 seconds for 90 seconds after addition of fentanyl, compound 3F, or compound 3L, which is an opioid ⁇ receptor agonist.
  • compound 3F or naloxone which is an opioid ⁇ receptor antagonist, was added, allowed to stand in the device for 30 minutes, then fentanyl (0.025 ⁇ M) was added, and the fluorescence value was similarly measured. was measured.
  • Flexstation 3 (Molecular Devices) was used for fluorescence measurement, and the measurement conditions were an excitation wavelength of 485 nm, a fluorescence wavelength of 525 nm, and a cutoff wavelength of 515 nm.
  • SOFTMAX PRO software (Molecular Devices) was used for data analysis.
  • FIG. 2 also shows dose-response curves when fentanyl was added after pretreatment with compound 3F (3F) or naloxone (NLX).
  • 3F 3F
  • NLX naloxone
  • Example 2 Evaluation of in vivo opioid receptor antagonism of compound 3F> To evaluate the in vivo opioid receptor antagonism of Compound 3F, behavioral pharmacological analysis in mice was performed. ICR male mice (Jcl, 20-25 g, CLEA Japan, Inc.) were used for behavioral pharmacological experiments.
  • SAL physiological saline
  • FIG. 3A shows the time course of the amount of exercise every 10 minutes after administration of morphine
  • FIG. 3B shows the total amount of exercise for 120 minutes after administration of morphine.
  • morphine administration significantly increased locomotion peaking at 30 minutes after administration, confirming the prokinetic action of morphine.
  • pretreatment with compound 3F or naloxone significantly inhibited the prokinetic effect of morphine ( ## p ⁇ 0.01). This result confirmed that compound 3F exhibited opioid receptor antagonism in vivo.
  • Step 3 Optical resolution of compound 5 Since compound 5 is racemic, each atropisomer was separated and isolated by chiral high performance liquid chromatography (HPLC).
  • the atropisomer with a faster elution time is designated as compound 5F
  • the atropisomer with a later elution time is designated as compound 5L.
  • the enantiomeric excess of compound 5F and compound 5L was 99.9% ee.
  • the activation free energy value ⁇ G ⁇ between compound 5F and compound 5L was 130.6 kJ/mol (80° C., toluene).
  • [ ⁇ ] D 20 (5 L): ⁇ 46.175° (c 1.00, MeOH)
  • ⁇ Test Example 3 Evaluation of in vitro opioid ⁇ receptor activity and opioid ⁇ receptor antagonistic activity of compound 5F and compound 5L>
  • Opioid ⁇ receptor-expressing cells (CHO- ⁇ cells) were suspended in a nutritive mixture/Ham's F-12 medium containing 10% FBS, and seeded in a 96-well plate at 5.0 ⁇ 10 4 cells/well. , 37° C., 5.0% CO 2 . After 24 hours, the medium was replaced with 100 ⁇ L/well of Component B (HBSS + 20 mM HEPES buffer, pH 7.4), and a calcium-sensitive fluorescent indicator (FLIPR Calcium 4 Assay kit, Molecular Devices) was used to measure intracellular Ca by drug stimulation. 2+ responses were measured.
  • Component B HBSS + 20 mM HEPES buffer, pH 7.4
  • FLIPR Calcium 4 Assay kit FLIPR Calcium 4 Assay kit, Molecular Devices
  • fluorescence values were measured every 2 seconds for 90 seconds after addition of compound 5F or compound 5L. Further, for opioid receptor antagonism, compound 5F or naloxone, which is an opioid ⁇ receptor antagonist, was added and allowed to stand in the device for 30 minutes. was added, and the fluorescence value was measured in the same manner. Flexstation 3 (Molecular Devices) was used for fluorescence measurement, and the measurement conditions were an excitation wavelength of 485 nm, a fluorescence wavelength of 525 nm, and a cutoff wavelength of 515 nm. SOFTMAX PRO software (Molecular Devices) was used for data analysis.
  • FIG. 5 Also shown in FIG. 5 is the dose-response curve when fentanyl was added after pretreatment with compound 5F (5F) or naloxone (NLX).
  • 5F compound 5F
  • NLX naloxone
  • IC 50 value 50% inhibitory concentration

Abstract

Provided are an opioid receptor antagonist, which contains, as an active ingredient, one atropisomer between a pair of atropisomers of a compound represented by formula (1), said atropisomer having an opioid receptor antagonistic action, or a pharmacologically acceptable salt thereof, and a pharmaceutical composition. In formula (1), R1 represents a heteroaryl group, etc. and R2 and R3 independently represent an alkyl group, etc.

Description

オピオイド受容体拮抗剤及び医薬組成物Opioid receptor antagonist and pharmaceutical composition
　本発明は、新規なオピオイド受容体拮抗剤及び医薬組成物に関する。 The present invention relates to novel opioid receptor antagonists and pharmaceutical compositions.
　フェンタニルは、下記式で表される合成オピオイドμ受容体作用薬であり、麻薬系の鎮痛薬としてがん性疼痛の治療等に使用されている。フェンタニルは、強い鎮痛作用を有する反面、安全域が狭く、副作用が出やすいという問題がある。 Fentanyl is a synthetic opioid μ receptor agonist represented by the following formula, and is used as a narcotic analgesic to treat cancer pain. While fentanyl has a strong analgesic effect, it has a narrow safety margin and is prone to side effects.
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
　近年、特に米国において、フェンタニル等のオピオイド系薬物の処方が増加する結果、多くの依存症患者を生み出し、過剰摂取による死亡が交通事故による死亡を上回るほど増加する状況となっている。また、違法に合成された新規オピオイド系薬物も次々に登場しており、過剰摂取による問題は深刻さを増す一方である。このような一連の問題はオピオイドクライシスと称され、大きな社会問題となっている。 In recent years, especially in the United States, the increase in prescriptions for opioid drugs such as fentanyl has resulted in the creation of many addicted patients, and the situation is such that overdose deaths exceed deaths in traffic accidents. In addition, illegally synthesized new opioid drugs are appearing one after another, and the problem of overdose is becoming more and more serious. Such a series of problems is called an opioid crisis, and has become a major social problem.
　現在、オピオイド系薬物による副作用や中毒症状に対する治療薬としては、オピオイド受容体拮抗薬であるナロキソン、ナルトレキソン、ナルデメジン等が知られている。また、その他のオピオイド受容体拮抗薬も幾つか提案されている（例えば、特許文献１参照）。 Currently, naloxone, naltrexone, naldemedine, etc., which are opioid receptor antagonists, are known as therapeutic agents for side effects and addictive symptoms caused by opioid drugs. In addition, some other opioid receptor antagonists have also been proposed (see, for example, Patent Document 1).
特開２０２０－１９６７３３号公報JP 2020-196733 A
　本発明は、新規なオピオイド受容体拮抗剤及び医薬組成物を提供することを課題とする。 An object of the present invention is to provide a novel opioid receptor antagonist and pharmaceutical composition.
　上記課題を解決するための具体的な手段には、以下の実施態様が含まれる。
＜１＞　下記式（１）で表される化合物が有する一対のアトロプ異性体のうち、オピオイド受容体拮抗作用を有する一方のアトロプ異性体又はその薬理学的に許容される塩を有効成分として含有するオピオイド受容体拮抗剤。 Specific means for solving the above problems include the following embodiments.
<1> Containing as an active ingredient one atropisomer having an opioid receptor antagonistic action or a pharmacologically acceptable salt thereof among a pair of atropisomers possessed by the compound represented by the following formula (1) opioid receptor antagonists.
Figure JPOXMLDOC01-appb-C000008
 ［式中、Ｒ１は、アルキル基、シクロアルキル基、アルケニル基、アルキニル基、アリール基、非芳香族複素環基、又はヘテロアリール基を示し、置換基を有していてもよい。Ｒ２及びＲ３はそれぞれ独立に、アルキル基、アルケニル基、アルキニル基、アリール基、カルバモイル基、ニトロ基、ハロゲン原子、又は－ＯＲ４、－Ｃ（＝Ｏ）Ｒ４、－Ｃ（＝Ｏ）ＯＲ４、－ＯＣ（＝Ｏ）Ｒ４、－ＮＲ４ ２、若しくは－ＳＲ４で表される基を示し、置換基を有していてもよい。Ｒ４はそれぞれ独立に、水素原子、アルキル基、シクロアルキル基、アルケニル基、アルキニル基、アリール基、非芳香族複素環基、又はヘテロアリール基を示す。］
Figure JPOXMLDOC01-appb-C000008
 [In the formula, R 1 represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group, and may have a substituent. R 2 and R 3 are each independently an alkyl group, alkenyl group, alkynyl group, aryl group, carbamoyl group, nitro group, halogen atom, or -OR 4 , -C(=O)R 4 , -C(=O ) represents a group represented by OR 4 , —OC(=O)R 4 , —NR 4 2 or —SR 4 and may have a substituent. Each R4 independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group. ]
＜２＞　前記式（１）中のＲ１がヘテロアリール基であり、Ｒ２及びＲ３がそれぞれ独立にアルキル基である、＜１＞に記載のオピオイド受容体拮抗剤。 <2> The opioid receptor antagonist according to <1>, wherein R 1 in formula (1) is a heteroaryl group, and R 2 and R 3 are each independently an alkyl group.
＜３＞　オピオイドμ受容体に対して拮抗作用を示す、＜１＞又は＜２＞に記載のオピオイド受容体拮抗剤。 <3> The opioid receptor antagonist according to <1> or <2>, which exhibits an antagonistic effect on opioid μ receptors.
＜４＞　下記式（２）で表され、且つ、クロロホルムに溶解したときのナトリウムＤ線に対する２０℃における比旋光度が正の値を示すアトロプ異性体を前記有効成分として含有する、＜１＞～＜３＞のいずれか１項に記載のオピオイド受容体拮抗剤。 <4> Contains, as the active ingredient, an atropisomer represented by the following formula (2) and having a positive specific rotation at 20°C with respect to the sodium D line when dissolved in chloroform, <1> ~ The opioid receptor antagonist according to any one of <3>.
Figure JPOXMLDOC01-appb-C000009
 ［式中、－Ｍｅはメチル基を示し、－Ｅｔはエチル基を示す。］
Figure JPOXMLDOC01-appb-C000009
 [In the formula, -Me represents a methyl group, and -Et represents an ethyl group. ]
＜５＞　下記式（３）で表され、且つ、メタノールに溶解したときのナトリウムＤ線に対する２０℃における比旋光度が正の値を示すアトロプ異性体を前記有効成分として含有する、＜１＞～＜３＞のいずれか１項に記載のオピオイド受容体拮抗剤。 <5> Contains, as the active ingredient, an atropisomer represented by the following formula (3) and having a positive specific rotation at 20°C with respect to the sodium D line when dissolved in methanol, <1> ~ The opioid receptor antagonist according to any one of <3>.
Figure JPOXMLDOC01-appb-C000010
 ［式中、－Ｍｅはメチル基を示す。］
Figure JPOXMLDOC01-appb-C000010
 [In the formula, -Me represents a methyl group. ]
＜６＞　下記式（１）で表される化合物が有する一対のアトロプ異性体のうち、オピオイド受容体拮抗作用を有する一方のアトロプ異性体又はその薬理学的に許容される塩を有効成分として含有する医薬組成物。 <6> Contains, as an active ingredient, one atropisomer having an opioid receptor antagonistic action or a pharmacologically acceptable salt thereof, out of the pair of atropisomers possessed by the compound represented by the following formula (1) A pharmaceutical composition for
Figure JPOXMLDOC01-appb-C000011
 ［式中、Ｒ１は、アルキル基、シクロアルキル基、アルケニル基、アルキニル基、アリール基、非芳香族複素環基、又はヘテロアリール基を示し、置換基を有していてもよい。Ｒ２及びＲ３はそれぞれ独立に、アルキル基、アルケニル基、アルキニル基、アリール基、カルバモイル基、ニトロ基、ハロゲン原子、又は－ＯＲ４、－Ｃ（＝Ｏ）Ｒ４、－Ｃ（＝Ｏ）ＯＲ４、－ＯＣ（＝Ｏ）Ｒ４、－ＮＲ４ ２、若しくは－ＳＲ４で表される基を示し、置換基を有していてもよい。Ｒ４はそれぞれ独立に、水素原子、アルキル基、シクロアルキル基、アルケニル基、アルキニル基、アリール基、非芳香族複素環基、又はヘテロアリール基を示す。］
Figure JPOXMLDOC01-appb-C000011
 [In the formula, R 1 represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group, and may have a substituent. R 2 and R 3 are each independently an alkyl group, alkenyl group, alkynyl group, aryl group, carbamoyl group, nitro group, halogen atom, or -OR 4 , -C(=O)R 4 , -C(=O ) represents a group represented by OR 4 , —OC(=O)R 4 , —NR 4 2 or —SR 4 and may have a substituent. Each R4 independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group. ]
＜７＞　下記式（２）で表され、且つ、クロロホルムに溶解したときのナトリウムＤ線に対する２０℃における比旋光度が正の値を示す化合物。 <7> A compound represented by the following formula (2) and showing a positive specific rotation at 20°C with respect to the sodium D line when dissolved in chloroform.
Figure JPOXMLDOC01-appb-C000012
 ［式中、－Ｍｅはメチル基を示し、－Ｅｔはエチル基を示す。］
Figure JPOXMLDOC01-appb-C000012
 [In the formula, -Me represents a methyl group, and -Et represents an ethyl group. ]
＜８＞　下記式（３）で表され、且つ、メタノールに溶解したときのナトリウムＤ線に対する２０℃における比旋光度が正の値を示す化合物。 <8> A compound represented by the following formula (3) and showing a positive specific rotation at 20°C with respect to the sodium D line when dissolved in methanol.
Figure JPOXMLDOC01-appb-C000013
 ［式中、－Ｍｅはメチル基を示す。］
Figure JPOXMLDOC01-appb-C000013
 [In the formula, -Me represents a methyl group. ]
　本発明によれば、新規なオピオイド受容体拮抗剤及び医薬組成物を提供することができる。 According to the present invention, novel opioid receptor antagonists and pharmaceutical compositions can be provided.
オピオイドμ受容体発現細胞（ＣＨＯ－μ細胞）に対して、化合物３Ｆ（３Ｆ）、化合物３Ｌ（３Ｌ）、又はフェンタニル（ＦＮ）を添加したときの用量反応曲線を示す図である。FIG. 4 shows dose-response curves when compound 3F (3F), compound 3L (3L), or fentanyl (FN) was added to opioid μ receptor-expressing cells (CHO-μ cells). オピオイドμ受容体発現細胞（ＣＨＯ－μ細胞）を化合物３Ｆ（３Ｆ）又はナロキソン（ＮＬＸ）で前処理した後、フェンタニルを添加したときの用量反応曲線を示す図である。FIG. 4 shows dose-response curves of pretreatment of opioid μ receptor-expressing cells (CHO-μ cells) with compound 3F (3F) or naloxone (NLX) followed by addition of fentanyl. マウスに化合物３Ｆ（３Ｆ）、ナロキソン（ＮＬＸ）、生理食塩水（ＳＡＬ）を投与した後、モルヒネ（Ｍｏｒ）を投与したときの、モルヒネ投与から１０分間毎の運動量の経時変化を示す図である。FIG. 10 is a graph showing changes over time in the amount of locomotion every 10 minutes after administration of morphine (Mor) after administration of compound 3F (3F), naloxone (NLX), and saline (SAL) to mice. . マウスに化合物３Ｆ（３Ｆ）、ナロキソン（ＮＬＸ）、生理食塩水（ＳＡＬ）を投与した後、モルヒネ（Ｍｏｒ）を投与したときの、モルヒネ投与から１２０分間の総運動量を示す図である。FIG. 10 shows total locomotion for 120 minutes after administration of morphine when mice were administered compound 3F (3F), naloxone (NLX), saline (SAL), and then morphine (Mor). オピオイドμ受容体発現細胞（ＣＨＯ－μ細胞）に対して、化合物５Ｆ（５Ｆ）又は化合物５Ｌ（５Ｌ）を添加したときの用量反応曲線を示す図である。FIG. 4 shows dose-response curves when compound 5F (5F) or compound 5L (5L) was added to opioid μ receptor-expressing cells (CHO-μ cells). オピオイドμ受容体発現細胞（ＣＨＯ－μ細胞）を化合物５Ｆ（５Ｆ）又はナロキソン（ＮＬＸ）で前処理した後、フェンタニルを添加したときの用量反応曲線を示す図である。FIG. 4 shows dose-response curves of pretreatment of opioid μ receptor-expressing cells (CHO-μ cells) with compound 5F (5F) or naloxone (NLX) followed by addition of fentanyl.
＜オピオイド受容体拮抗剤＞
　本実施形態に係るオピオイド受容体拮抗剤は、下記式（１）で表される化合物が有する一対のアトロプ異性体のうち、オピオイド受容体拮抗作用を有する一方のアトロプ異性体（以下、「特定アトロプ異性体」ともいう。）又はその薬理学的に許容される塩を有効成分として含有する。 <Opioid receptor antagonist>
The opioid receptor antagonist according to the present embodiment is one atropisomer having opioid receptor antagonistic activity among a pair of atropisomers possessed by the compound represented by the following formula (1) (hereinafter referred to as "specific atropisomer isomer”) or a pharmacologically acceptable salt thereof as an active ingredient.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　「アトロプ異性体」とは、軸性又は面性キラリティーに基づく構造異性体をいう。上記式（１）で表される化合物は、２，６位にＲ２及びＲ３が結合したベンゼン環における１位の炭素原子と、ピペリジン環の４位に結合した窒素原子との間の結合（炭素－窒素間結合）の回転が立体障害により制限されることにより、軸不斉由来の一対のアトロプ異性体（Ｒａ体及びＳａ体）を有する。本実施形態に係るオピオイド受容体拮抗剤は、この一対のアトロプ異性体のうち、オピオイド受容体拮抗作用を有する一方のアトロプ異性体又はその薬理学的に許容される塩を有効成分として含有する。上記式（１）で表される化合物が有する一対のアトロプ異性体の両方がオピオイド受容体拮抗作用を有する場合、本実施形態に係るオピオイド受容体拮抗剤は、いずれのアトロプ異性体を含有してもよい。 "Atropisomer" refers to structural isomers based on axial or planar chirality. The compound represented by the above formula (1) is a bond between the carbon atom at position 1 in the benzene ring having R 2 and R 3 at positions 2 and 6 and the nitrogen atom at position 4 of the piperidine ring. It has a pair of atropisomers (Ra form and Sa form) derived from axial asymmetry due to restricted rotation of (carbon-nitrogen bond) due to steric hindrance. Of the pair of atropisomers, the opioid receptor antagonist according to this embodiment contains one atropisomer having opioid receptor antagonistic activity or a pharmacologically acceptable salt thereof as an active ingredient. When both a pair of atropisomers possessed by the compound represented by the above formula (1) have opioid receptor antagonistic activity, the opioid receptor antagonist according to the present embodiment contains any atropisomer. good too.
　上記式（１）中、Ｒ１は、アルキル基、シクロアルキル基、アルケニル基、アルキニル基、アリール基、非芳香族複素環基、又はヘテロアリール基を示し、置換基を有していてもよい。Ｒ２及びＲ３はそれぞれ独立に、アルキル基、アルケニル基、アルキニル基、アリール基、カルバモイル基、ニトロ基、ハロゲン原子、又は－ＯＲ４、－Ｃ（＝Ｏ）Ｒ４、－Ｃ（＝Ｏ）ＯＲ４、－ＯＣ（＝Ｏ）Ｒ４、－ＮＲ４ ２、若しくは－ＳＲ４で表される基を示し、置換基を有していてもよい。Ｒ４はそれぞれ独立に、水素原子、アルキル基、シクロアルキル基、アルケニル基、アルキニル基、アリール基、非芳香族複素環基、又はヘテロアリール基を示す。 In the above formula (1), R 1 represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group, and may have a substituent. . R 2 and R 3 are each independently an alkyl group, alkenyl group, alkynyl group, aryl group, carbamoyl group, nitro group, halogen atom, or -OR 4 , -C(=O)R 4 , -C(=O ) represents a group represented by OR 4 , —OC(=O)R 4 , —NR 4 2 or —SR 4 and may have a substituent. Each R4 independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group.
　アルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｓｅｃ－ブチル基、イソブチル基、ｔｅｒｔ－ブチル基、ペンチル基、イソペンチル基、ヘキシル基等の炭素数１～２０、好ましくは炭素数１～１０の直鎖状又は分岐鎖状の基が挙げられる。 The alkyl group preferably has 1 to 20 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group, pentyl group, isopentyl group and hexyl group. is a linear or branched group having 1 to 10 carbon atoms.
　シクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、ビシクロ［２．２．１］ヘプチル基、ビシクロ［３．２．１］オクチル基、トリシクロ［２．２．１．０］ヘプチル基等の炭素数３～２０、好ましくは炭素数３～１０の基が挙げられる。 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl and tricyclo[2.2.1.0 ] groups having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, such as heptyl groups.
　アルケニル基としては、ビニル基、アリル基、プロペニル基、イソプロペニル基、ブテニル基、イソブテニル基、１，３－ブタジエニル基、ペンテニル基、ヘキセニル基等の炭素数２～２０、好ましくは炭素数２～１０の直鎖状又は分岐鎖状の基が挙げられる。 The alkenyl group includes a vinyl group, allyl group, propenyl group, isopropenyl group, butenyl group, isobutenyl group, 1,3-butadienyl group, pentenyl group, hexenyl group, etc., having 2 to 20 carbon atoms, preferably 2 to 2 carbon atoms. Ten linear or branched groups are included.
　アルキニル基としては、エチニル基、プロピニル基、ブチニル基、ペンチニル基、ヘキシニル基等の炭素数２～２０、好ましくは炭素数２～１０の直鎖状又は分岐鎖状の基が挙げられる。 The alkynyl group includes linear or branched groups having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, such as ethynyl group, propynyl group, butynyl group, pentynyl group and hexynyl group.
　アリール基としては、フェニル基、ナフチル基、アントリル基、フェナントリル基、ピレニル基、フルオレニル基、インデニル基、アセナフチレニル、インダニル基、アセナフテニル基等の単環式又は２～４環の縮合多環式の基が挙げられる。 Aryl groups include monocyclic or 2- to 4-ring condensed polycyclic groups such as phenyl group, naphthyl group, anthryl group, phenanthryl group, pyrenyl group, fluorenyl group, indenyl group, acenaphthylenyl group, indanyl group and acenaphthenyl group. is mentioned.
　非芳香族複素環基としては、アゼチジニル基、ピロリジニル基、ピロリニル基、ピペリジル基、テトラヒドロピリジル基、ホモピペリジニル基、オクタヒドロアゾシニル基、イミダゾリジニル基、イミダゾリニル基、ピラゾリジニル基、ピラゾリニル基、ピペラジニル基、ホモピペラジニル基、２－ピペラジノニル基等の単環式の含窒素基；テトラヒドロフラニル基、テトラヒドロピラニル基、ピラニル基等の単環式の含酸素基；モルホリニル基等の単環式の含窒素・酸素基；チオモルホリニル基等の単環式の含窒素・硫黄基；インドリニル基、イソインドリニル基、テトラヒドロキノリニル基、テトラヒドロイソキノリニル基、２，３－ジヒドロベンゾフラニル基、クロマニル基、クロメニル基、イソクロマニル基、１，３－ベンゾジオキソリル基、１，３－ベンゾジオキサニル基、１，４－ベンゾジオキサニル基等の２環式の含酸素基；２，３－ジヒドロベンゾチエニル基等の２環式の含硫黄基；ベンゾモルホリニル基、ジヒドロピラノピリジル基、ジヒドロジオキシノピリジル基、ジヒドロピリドオキサジニル基等の２環式の含窒素・酸素基；２－アザスピロ［３．３］オクチル基、２－オキサスピロ［３．３］オクチル基、６－アザ－２－オキサスピロ［３．３］オクチル基、１－アザスピロ［４．５］デシル基、１－オキサスピロ［４．５］デシル基等のヘテロ環式スピロ環基；などが挙げられる。 Non-aromatic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolinyl, piperidyl, tetrahydropyridyl, homopiperidinyl, octahydroazocinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, and homopiperazinyl. monocyclic nitrogen-containing groups such as groups, 2-piperazinonyl groups; monocyclic oxygen-containing groups such as tetrahydrofuranyl groups, tetrahydropyranyl groups and pyranyl groups; monocyclic nitrogen-containing/oxygen groups such as morpholinyl groups monocyclic nitrogen-sulfur groups such as a thiomorpholinyl group; Bicyclic oxygen-containing groups such as isochromanyl group, 1,3-benzodioxolyl group, 1,3-benzodioxanyl group, 1,4-benzodioxanyl group; 2,3-dihydrobenzothienyl group bicyclic sulfur-containing groups such as; [3.3]octyl group, 2-oxaspiro[3.3]octyl group, 6-aza-2-oxaspiro[3.3]octyl group, 1-azaspiro[4.5]decyl group, 1-oxaspiro[4 .5] a heterocyclic spirocyclic group such as a decyl group;
　ヘテロアリール基としては、ピロリル基、ピリジル基、イミダゾリル基、ピラゾリル基、ピラジニル基、ピリダジニル基、ピリミジニル基、トリアゾリル基、テトラゾリル基等の単環式の含窒素基；フラニル基等の単環式の含酸素基；チエニル等の単環式の含硫黄基；オキサゾリル基、イソオキサゾリル基、オキサジアゾリル基等の単環式の含窒素・酸素基；チアゾリル基、イソチアゾリル基、チアジアゾリル基等の単環式の含窒素・硫黄基；インドリル基、イソインドリル基、ベンズイミダゾリル基、インダゾリル基、ベンゾトリアゾリル基、テトラヒドロキノリル基、キノリル基、テトラヒドロイソキノリル基、イソキノリル基、キノリジニル基、シンノリニル基、フタラジニル基、キナゾリニル基、キノキサリニル基、ナフチリジニル基、ピロロピリジル基、イミダゾピリジル基、ピラゾロピリジル基、ピリドピラジル基、プリニル基、プテリジニル基等の２環式の含窒素基；ベンゾフラニル基、イソベンゾフラニル基等の２環式の含酸素基；ベンゾチエニル基等の２環式の含硫黄基；ベンゾオキサゾリル基、ベンゾイソオキサゾリル基、ベンゾオキサジアゾリル基等の２環式の含窒素・酸素基；ベンゾチアゾリル基、ベンゾイソチアゾリル基、ベンゾチアジアゾリル基、チアゾロピリジル基等の２環式の含窒素・硫黄基；などが挙げられる。 Heteroaryl groups include monocyclic nitrogen-containing groups such as pyrrolyl, pyridyl, imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, and tetrazolyl; monocyclic nitrogen-containing groups such as furanyl; Oxygen-containing groups; monocyclic sulfur-containing groups such as thienyl; monocyclic nitrogen-containing and oxygen groups such as oxazolyl, isoxazolyl and oxadiazolyl groups; monocyclic groups such as thiazolyl, isothiazolyl and thiadiazolyl nitrogen/sulfur groups; Bicyclic nitrogen-containing groups such as a quinazolinyl group, quinoxalinyl group, naphthyridinyl group, pyrrolopyridyl group, imidazopyridyl group, pyrazolopyridyl group, pyridopyrazyl group, purinyl group and pteridinyl group; Cyclic oxygen-containing group; Bicyclic sulfur-containing group such as benzothienyl group; Bicyclic nitrogen-containing/oxygen group such as benzoxazolyl group, benzoisoxazolyl group, benzoxadiazolyl group; bicyclic nitrogen-containing and sulfur groups such as a benzothiazolyl group, a benzisothiazolyl group, a benzothiadiazolyl group, and a thiazolopyridyl group;
　ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられる。 　The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like.
　Ｒ１～Ｒ３が有していてもよい置換基としては、アルキル基、シクロアルキル基、アルケニル基、アルキニル基、アリール基、非芳香族複素環基、ヘテロアリール基、シアノ基、ハロゲン原子、ヒドロキシ基、アミノ基、ニトロ基、ニトロキシ基、メルカプト基、シアネート基、チオシアネート基、イソチオシアネート基、スルホ基、スルファミノ基、スルフィノ基、スルファモイル基、ホスホ基、ホスホノ基、ボロニル基等が挙げられる。 Examples of substituents that R 1 to R 3 may have include an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a cyano group, a halogen atom, hydroxy group, amino group, nitro group, nitroxy group, mercapto group, cyanate group, thiocyanate group, isothiocyanate group, sulfo group, sulfamino group, sulfino group, sulfamoyl group, phospho group, phosphono group, boronyl group and the like.
　上記式（１）で表される化合物の中でも、Ｒ１がヘテロアリール基であり、Ｒ２及びＲ３がそれぞれ独立にアルキル基である化合物が好ましい。 Among the compounds represented by formula (1) above, compounds in which R 1 is a heteroaryl group and R 2 and R 3 are each independently an alkyl group are preferred.
　上記式（１）で表される化合物が酸性官能基又は塩基性官能基を有する場合、当該化合物は、塩の形態であってもよい。例えば、上記式（１）で表される化合物が酸性官能基を有する場合、当該化合物は、アルカリ金属塩（ナトリウム塩、カリウム塩等）、アルカリ土類金属塩（カルシウム塩、マグネシウム塩等）、アンモニウム塩等の形態であってもよい。また、上記式（１）で表される化合物が塩基性官能基を有する場合、当該化合物は、塩酸、リン酸等の無機酸との塩の形態であってもよく、酢酸、フマル酸、メタンスルホン酸等の有機酸との塩の形態であってもよい。 When the compound represented by formula (1) above has an acidic functional group or a basic functional group, the compound may be in the form of a salt. For example, when the compound represented by the above formula (1) has an acidic functional group, the compound may be an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, etc.), It may be in the form of an ammonium salt or the like. In addition, when the compound represented by the above formula (1) has a basic functional group, the compound may be in the form of a salt with an inorganic acid such as hydrochloric acid or phosphoric acid, acetic acid, fumaric acid, methane It may be in the form of a salt with an organic acid such as sulfonic acid.
　本実施形態に係るオピオイド受容体拮抗剤の有効成分である特定アトロプ異性体又はその塩は、オピオイド受容体のいずれのタイプに拮抗作用を示すものであってもよいが、少なくともオピオイドμ受容体に対して拮抗作用を示すものが好ましい。特定アトロプ異性体又はその塩のオピオイドμ受容体に対する拮抗作用は、例えば、後述する試験例１に記載する方法に従って５０％阻害濃度（ＩＣ５０値）を測定することにより確認することができる。 The specific atropisomer or a salt thereof, which is the active ingredient of the opioid receptor antagonist according to the present embodiment, may exhibit an antagonistic effect on any type of opioid receptor, but at least on the opioid μ receptor. It is preferable to show an antagonistic action against The antagonistic action of a specific atropisomer or a salt thereof on the opioid μ receptor can be confirmed, for example, by measuring the 50% inhibitory concentration ( IC50 value) according to the method described in Test Example 1 below.
　特定アトロプ異性体の中で特に好ましい化合物の一例としては、下記式（２）で表され、且つ、クロロホルムに溶解したときのナトリウムＤ線（波長５８９ｎｍ）に対する２０℃における比旋光度が正の値を示す化合物が挙げられる。式（２）中、－Ｍｅはメチル基を示し、－Ｅｔはエチル基を示す。この化合物は、後述する試験例１に示すとおり、ナロキソンよりも強力なオピオイドμ受容体拮抗作用を示す。 An example of a particularly preferred compound among the specific atropisomers is represented by the following formula (2) and has a positive specific rotation at 20° C. with respect to the sodium D line (wavelength 589 nm) when dissolved in chloroform. A compound showing In formula (2), -Me represents a methyl group, and -Et represents an ethyl group. This compound exhibits a stronger opioid μ receptor antagonistic activity than naloxone, as shown in Test Example 1 described later.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　また、特定アトロプ異性体の中で特に好ましい化合物の他の例としては、下記式（３）で表され、且つ、メタノールに溶解したときのナトリウムＤ線（波長５８９ｎｍ）に対する２０℃における比旋光度が正の値を示す化合物が挙げられる。式（３）中、－Ｍｅはメチル基を示す。この化合物は、後述する試験例３に示すとおり、ナロキソンよりは弱いものの、強力なオピオイドμ受容体拮抗作用を示す。 Further, another example of a particularly preferred compound among the specific atropisomers is represented by the following formula (3), and specific rotation at 20° C. with respect to the sodium D line (wavelength 589 nm) when dissolved in methanol is a positive value. In formula (3), -Me represents a methyl group. As shown in Test Example 3 described later, this compound exhibits a strong opioid μ receptor antagonistic activity, though weaker than that of naloxone.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　本実施形態に係るオピオイド受容体拮抗剤の有効成分である特定アトロプ異性体又はその塩は、例えば、ラセミ体をキラルカラムクロマトグラフィー等によって光学分割することにより得ることができる。 A specific atropisomer or a salt thereof, which is the active ingredient of the opioid receptor antagonist according to the present embodiment, can be obtained, for example, by optically resolving the racemate by chiral column chromatography or the like.
　本実施形態に係るオピオイド受容体拮抗剤は、オピオイド受容体拮抗作用を示す限り、上記式（１）で表される化合物が有する一対のアトロプ異性体のうち、特定アトロプ異性体とは異なる他方のアトロプ異性体又はその塩を含有していてもよい。この場合、特定アトロプ異性体又はその塩の鏡像体過剰率は、０％ｅｅ以上であってもよく、２０％ｅｅ以上であってもよく、４０％ｅｅ以上であってもよく、６０％ｅｅ以上であってもよく、８０％ｅｅ以上であってもよく、９０％ｅｅ以上であってもよく、９５％ｅｅ以上であってもよい。 The opioid receptor antagonist according to the present embodiment, of the pair of atropisomers possessed by the compound represented by the above formula (1), is different from the specific atropisomer, as long as it exhibits opioid receptor antagonistic activity. It may contain atropisomers or salts thereof. In this case, the enantiomeric excess of the specific atropisomer or salt thereof may be 0% ee or more, 20% ee or more, 40% ee or more, or 60% ee. 80% ee or more, 90% ee or more, or 95% ee or more.
　本実施形態に係るオピオイド受容体拮抗剤は、使用態様に応じて、有効成分以外の他の成分を含有することができる。例えば、本実施形態に係るオピオイド受容体拮抗剤は、薬理学的に許容される担体を含有することができる。 The opioid receptor antagonist according to the present embodiment can contain ingredients other than the active ingredient, depending on the mode of use. For example, the opioid receptor antagonist according to this embodiment can contain a pharmacologically acceptable carrier.
　本実施形態に係るオピオイド受容体拮抗剤は、医薬用途に用いるものであってもよく、医薬以外の用途（研究用途等）に用いるものであってもよい。本実施形態に係るオピオイド受容体拮抗剤を医薬用途に用いる場合、剤形、適応等は後述する医薬組成物と同様でよい。 The opioid receptor antagonist according to this embodiment may be used for medical purposes, or may be used for purposes other than medicine (research purposes, etc.). When the opioid receptor antagonist according to this embodiment is used for medical purposes, the dosage form, indications, etc. may be the same as those of the pharmaceutical composition described later.
＜医薬組成物＞
　本実施形態に係る医薬組成物は、上述した特定アトロプ異性体又はその薬理学的に許容される塩を有効成分として含有する。 <Pharmaceutical composition>
The pharmaceutical composition according to this embodiment contains the above-described specific atropisomer or a pharmacologically acceptable salt thereof as an active ingredient.
　有効成分である特定アトロプ異性体又はその塩は、オピオイド受容体拮抗作用を有する。このため、本実施形態に係る医薬組成物は、オピオイド受容体拮抗作用が必要とされる症状に適用することができる。例えば、本実施形態に係る医薬組成物は、オピオイド系薬物による副作用（便秘、悪心、嘔吐、掻痒、血圧降下、呼吸抑制、覚醒遅延等）や中毒症状（呼吸抑制等）を改善又は治療するために使用することができる。また、本実施形態に係る医薬組成物は、アルコール依存症の治療補助薬としても使用することができる。 The specific atropisomer or its salt, which is the active ingredient, has opioid receptor antagonistic activity. Therefore, the pharmaceutical composition according to this embodiment can be applied to symptoms requiring opioid receptor antagonism. For example, the pharmaceutical composition according to the present embodiment is used to improve or treat side effects of opioid drugs (constipation, nausea, vomiting, pruritus, hypotension, respiratory depression, delayed awakening, etc.) and toxic symptoms (respiratory depression, etc.). can be used for In addition, the pharmaceutical composition according to this embodiment can also be used as a treatment adjuvant for alcoholism.
　本実施形態に係る医薬組成物は、有効成分以外に、薬理学的に許容される担体を含有することが好ましい。薬理学的に許容される担体としては、製剤素材として慣用の有機又は無機の担体が挙げられる。この担体は、固形製剤においては、賦形剤、滑沢剤、結合剤、崩壊剤等として、液状製剤においては、溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤等として配合される。また、本実施形態に係る医薬組成物は、防腐剤、抗酸化剤、着色剤等の製剤添加物を含有していてもよい。 The pharmaceutical composition according to this embodiment preferably contains a pharmacologically acceptable carrier in addition to the active ingredient. Pharmaceutically acceptable carriers include organic or inorganic carriers commonly used as pharmaceutical materials. This carrier is used as an excipient, lubricant, binder, disintegrant, etc. in solid formulations, and as a solvent, solubilizer, suspending agent, tonicity agent, buffer, etc. in liquid formulations. blended. In addition, the pharmaceutical composition according to this embodiment may contain formulation additives such as preservatives, antioxidants and coloring agents.
　本実施形態に係る医薬組成物の剤形は特に制限されない。医薬組成物の剤形としては、錠剤、カプセル剤、乳剤、懸濁剤等の経口剤；注射剤、点滴剤、点鼻剤、外用剤等の非経口剤；などが挙げられる。 The dosage form of the pharmaceutical composition according to this embodiment is not particularly limited. Dosage forms of the pharmaceutical composition include oral agents such as tablets, capsules, emulsions and suspensions; parenteral agents such as injections, drops, nasal drops and external preparations; and the like.
　本実施形態に係る医薬組成物の投与量は、投与対象、投与経路、症状等に応じて適宜決定される。 The dosage of the pharmaceutical composition according to this embodiment is appropriately determined according to the administration subject, administration route, symptoms, and the like.
　以下、実施例によって本発明をより具体的に説明するが、本発明はこれらの実施例によって制限されるものではない。 The present invention will be described in more detail below with reference to examples, but the present invention is not limited by these examples.
＜合成例１：化合物３Ｆ及び化合物３Ｌの合成＞
（工程１：化合物２の合成） <Synthesis Example 1: Synthesis of Compound 3F and Compound 3L>
(Step 1: Synthesis of compound 2)
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　市販の１－（２－フェニルエチル）－４－ピペリドン（化合物１）（１．０１６ｇ，５ｍｍｏｌ）にエタノール（２０ｍＬ）を加えて溶解し、酢酸（３４３μＬ，６ｍｍｏｌ）及び２－エチル－６－メチルアニリン（１．３９４ｍＬ，１０ｍｍｏｌ）を加えた。反応溶液を加熱還流下で８０分間撹拌した後、２５℃に冷却し、シアノ水素化ホウ素ナトリウム（０．６２８ｇ，１０ｍｍｏｌ）をゆっくりと加えた。加熱還流下でさらに２１時間撹拌した後、２Ｎ　水酸化ナトリウム水溶液を加え、ロータリーエバポレーターで濃縮した。濃縮物を酢酸エチルにより抽出し、２Ｎ　水酸化ナトリウム水溶液及び飽和食塩水で洗浄した。Ｎａ２ＳＯ４を加えて乾燥させた後、濃縮した。粗生成物をカラムクロマトグラフィー（酢酸エチル／ジクロロメタン＝１／１）により精製し、化合物２を油状物質（収量：１．０３７ｇ；６４％）として得た。化合物２の物性値は以下のとおりである。 Ethanol (20 mL) was added to commercially available 1-(2-phenylethyl)-4-piperidone (compound 1) (1.016 g, 5 mmol) to dissolve it, and acetic acid (343 μL, 6 mmol) and 2-ethyl-6-methyl Aniline (1.394 mL, 10 mmol) was added. After the reaction solution was stirred under reflux for 80 minutes, it was cooled to 25° C. and sodium cyanoborohydride (0.628 g, 10 mmol) was slowly added. After further stirring for 21 hours while heating under reflux, 2N aqueous sodium hydroxide solution was added, and the mixture was concentrated using a rotary evaporator. The concentrate was extracted with ethyl acetate and washed with 2N sodium hydroxide aqueous solution and saturated brine. Na 2 SO 4 was added to dry and then concentrated. The crude product was purified by column chromatography (ethyl acetate/dichloromethane=1/1) to give compound 2 as an oil (yield: 1.037 g; 64%). The physical property values of compound 2 are as follows.
化合物２：
ＩＲ（ＡＴＲ）：３３７３ｃｍ－１（ＮＨ）；
１Ｈ　ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ３）：δ＝７．２８（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），７．１９（ｍ，３Ｈ），７．０２（ｄ，Ｊ＝７．２Ｈｚ，１Ｈ），６．９９（ｄ，Ｊ＝７．２Ｈｚ，１Ｈ），６．８６（ｔ，Ｊ＝７．２Ｈｚ，１Ｈ），２．９８（ｍ，３Ｈ），２．８０（ｍ，２Ｈ），２．６４（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），２．５９（ｍ，２Ｈ），２．２８（ｓ，３Ｈ），２．０３（ｔｄ，Ｊ＝１２．０，１．８Ｈｚ，２Ｈ），１．９５（ｍ，２Ｈ），１．５０（ｄｄｄ，Ｊ＝２４．０，１２．０，３．０Ｈｚ，２Ｈ），１．２３（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ）；
１３Ｃ　ＮＭＲ（１５０ＭＨｚ，ＣＤＣｌ３）：δ＝１４４．０，１４０．４，１３５．２，１２９．６，１２８．７，１２８．７，１２８．４，１２６．６，１２６．０，１２１．８，６０．５，５４．９，５３．１，３３．９，２４．５，１９．２，１４．４；
ＨＲＭＳ（ＥＳＩ）：ｍ／ｚ　ｃａｌｃｄ　ｆｏｒ　Ｃ２２Ｈ３１Ｎ２：３２３．２４８２（Ｍ＋Ｈ）＋，ｆｏｕｎｄ：３２３．２４８１． Compound 2:
IR (ATR): 3373 cm −1 (NH);
1 H NMR (600 MHz, CDCl 3 ): δ = 7.28 (t, J = 7.2 Hz, 2H), 7.19 (m, 3H), 7.02 (d, J = 7.2Hz, 1H) , 6.99 (d, J=7.2 Hz, 1 H), 6.86 (t, J=7.2 Hz, 1 H), 2.98 (m, 3 H), 2.80 (m, 2 H), 2 .64 (q, J=7.2Hz, 2H), 2.59 (m, 2H), 2.28 (s, 3H), 2.03 (td, J=12.0, 1.8Hz, 2H) , 1.95 (m, 2H), 1.50 (ddd, J=24.0, 12.0, 3.0 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H);
13 C NMR (150 MHz, CDCl 3 ): δ=144.0, 140.4, 135.2, 129.6, 128.7, 128.7, 128.4, 126.6, 126.0, 121. 8, 60.5, 54.9, 53.1, 33.9, 24.5, 19.2, 14.4;
HRMS (ESI) : m/z calcd for C22H31N2 : 323.2482 (M+H) <+> , found: 323.2481.
（工程２：化合物３の合成） (Step 2: Synthesis of Compound 3)
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　化合物２（１２９．０ｍｇ，０．４ｍｍｏｌ）をＤＭＦ（４ｍＬ）に溶解し、０℃に冷却した。その後、水素化ナトリウム（６０％　ｉｎ　ｏｉｌ）（２４ｍｇ，０．６ｍｍｏｌ）を加えた。反応溶液を２５℃で２５分間撹拌した後、２－フロイルクロリド（１１８μＬ，１．２ｍｍｏｌ）を加えた。２５℃で１８時間撹拌した後、２Ｎ　水酸化ナトリウム水溶液を加え、ジエチルエーテルにより抽出した。有機層を２Ｎ　水酸化ナトリウム水溶液及び飽和食塩水で洗浄し、Ｎａ２ＳＯ４を加えて乾燥させ、濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ジクロロメタン＝２／１）により精製し、化合物３を白色粉末（収量：１４４．５ｍｇ；８７％）として得た。化合物３の物性値は以下のとおりである。 Compound 2 (129.0 mg, 0.4 mmol) was dissolved in DMF (4 mL) and cooled to 0°C. Then sodium hydride (60% in oil) (24mg, 0.6mmol) was added. After the reaction solution was stirred at 25° C. for 25 minutes, 2-furoyl chloride (118 μL, 1.2 mmol) was added. After stirring at 25° C. for 18 hours, 2N aqueous sodium hydroxide solution was added and the mixture was extracted with diethyl ether. The organic layer was washed with 2N aqueous sodium hydroxide solution and saturated brine, dried by adding Na 2 SO 4 and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate/dichloromethane=2/1) to obtain compound 3 as a white powder (yield: 144.5 mg; 87%). The physical property values of compound 3 are as follows.
化合物３：
ｍｐ：１４１－１４２℃；
ＩＲ（ＡＴＲ）：１６３０ｃｍ－１（ＣＯ）；
１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ３）：δ＝７．３５（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），７．２６（ｄｔ，Ｊ＝１０．２，７．８Ｈｚ，３Ｈ），７．１８（ｍ，４Ｈ），７．１２（ｄ，Ｊ＝７．２Ｈｚ，１Ｈ），６．１２（ｄｄ，Ｊ＝３．６，１．８Ｈｚ，１Ｈ），５．２７（ｄｄ，Ｊ＝３．６，１．８Ｈｚ，１Ｈ），４．３１（ｔｔ，Ｊ＝１２．０，３．６Ｈｚ，１Ｈ），３．０４（ｍ，２Ｈ），２．７６（ｍ，２Ｈ），２．５４（ｍ，４Ｈ），２．２１（ｓ，３Ｈ），２．１７（ｔｄ，Ｊ＝１２．０，１．８Ｈｚ，２Ｈ），２．０４（ｄｄｔ，Ｊ＝２２．２，１２．０，３．６Ｈｚ，２Ｈ），１．５９（ｍ，２Ｈ），１．０７（ｔ，Ｊ＝７．８Ｈｚ，３Ｈ）；
１３Ｃ　ＮＭＲ（１５０ＭＨｚ，ＣＤＣｌ３）：δ＝１５９．６，１４７．４，１４４．４，１４３．５，１４０．３，１３７．９，１３７．８，１２８．７，１２８．７，１２８．６，１２８．３，１２６．５，１２６．０，１１４．８，１１１．０，６０．４，５７．０，５３．２，３３．８，３０．１，３０．０，２４．１，１９．１，１４．０；ｓｅｖｅｒａｌ　ｓｉｇｎａｌｓ　ｏｖｅｒｌａｐ；
ＨＲＭＳ（ＥＳＩ）：ｍ／ｚ　ｃａｌｃｄ　ｆｏｒ　Ｃ２７Ｈ３３Ｎ２Ｏ２：４１７．２５３７（Ｍ＋Ｈ）＋，ｆｏｕｎｄ：４１７．２５３７． Compound 3:
mp: 141-142°C;
IR (ATR): 1630 cm -1 (CO);
1 H-NMR (600 MHz, CDCl 3 ): δ=7.35 (d, J=1.8 Hz, 1 H), 7.26 (dt, J=10.2, 7.8 Hz, 3 H), 7.18 (m, 4H), 7.12 (d, J=7.2Hz, 1H), 6.12 (dd, J=3.6, 1.8Hz, 1H), 5.27 (dd, J=3. 6, 1.8Hz, 1H), 4.31 (tt, J = 12.0, 3.6Hz, 1H), 3.04 (m, 2H), 2.76 (m, 2H), 2.54 ( m, 4H), 2.21 (s, 3H), 2.17 (td, J = 12.0, 1.8 Hz, 2H), 2.04 (ddt, J = 22.2, 12.0, 3 .6 Hz, 2 H), 1.59 (m, 2 H), 1.07 (t, J = 7.8 Hz, 3 H);
13 C NMR (150 MHz, CDCl 3 ): δ=159.6, 147.4, 144.4, 143.5, 140.3, 137.9, 137.8, 128.7, 128.7, 128. 6, 128.3, 126.5, 126.0, 114.8, 111.0, 60.4, 57.0, 53.2, 33.8, 30.1, 30.0, 24.1, 19.1, 14.0; several signals overlap;
HRMS (ESI): m/z calcd for C27H33N2O2: 417.2537 (M+H)<+> , found : 417.2537 .
（工程３：化合物３の光学分割）
　化合物３はラセミ体であるため、キラル高速液体クロマトグラフィー（ＨＰＬＣ）により、各アトロプ異性体を分離及び単離した。ＨＰＬＣの分離条件は以下のとおりである。
－ＨＰＬＣ条件－
カラム：ＣＨＩＲＡＬＰＡＫ　ＩＧ（Φ＝４．６ｍｍ）
移動相：３０％エタノール／ヘキサン
流速：０．５ｍＬ／分
温度：２５℃
溶出時間：２５．７分、３０．８分 (Step 3: Optical resolution of compound 3)
Since compound 3 is racemic, each atropisomer was separated and isolated by chiral high performance liquid chromatography (HPLC). The HPLC separation conditions are as follows.
- HPLC conditions -
Column: CHIRALPAK IG (Φ=4.6mm)
Mobile phase: 30% ethanol/hexane Flow rate: 0.5 mL/min Temperature: 25°C
Elution time: 25.7 minutes, 30.8 minutes
　キラルＨＰＬＣにより分離及び単離された一対のアトロプ異性体のうち、溶出時間が早いアトロプ異性体を化合物３Ｆと表記し、溶出時間が遅いアトロプ異性体を化合物３Ｌと表記する。化合物３Ｆの鏡像体過剰率は９７．９％ｅｅであり、化合物３Ｌの鏡像体過剰率は９６．９％ｅｅであった。また、化合物３Ｆと化合物３Ｌとの間の活性化自由エネルギー値ΔＧ‡は１２６．７ｋＪ／ｍｏｌ（８０℃，トルエン）であった。化合物３Ｆ及び化合物３Ｌの比旋光度は以下のとおりである。
［α］Ｄ ２０（３Ｆ）：＋４．５０°（ｃ＝０．０３，ＣＨＣｌ３）
［α］Ｄ ２０（３Ｌ）：－４．４３°（ｃ＝０．１５，ＣＨＣｌ３） Of the pair of atropisomers separated and isolated by chiral HPLC, the atropisomer with a faster elution time is designated as compound 3F, and the atropisomer with a later elution time is designated as compound 3L. The enantiomeric excess of compound 3F was 97.9% ee, and the enantiomeric excess of compound 3L was 96.9% ee. Also, the activation free energy value ΔG ‡ between compound 3F and compound 3L was 126.7 kJ/mol (80° C., toluene). The specific rotations of compound 3F and compound 3L are as follows.
[α] D20 (3F): +4.50° (c= 0.03 , CHCl3 )
[α] D 20 (3 L): −4.43° (c=0.15, CHCl 3 )
＜試験例１：化合物３Ｆ及び化合物３Ｌのｉｎ　ｖｉｔｒｏにおけるオピオイドμ受容体作用及びオピオイドμ受容体拮抗作用の評価＞
　オピオイドμ受容体発現細胞（ＣＨＯ－μ細胞）を１０％　ＦＢＳ含有ｎｕｔｒｉｅｎｔ　ｍｉｘｔｕｒｅ／Ｈａｍ’ｓ　Ｆ－１２培地に懸濁し、５．０×１０４細胞／ウェルとなるように９６ウェルプレートに播種し、３７℃、５．０％　ＣＯ２の条件下にて培養した。２４時間後、培地を１００μＬ／ウェルのＣｏｍｐｏｎｅｎｔ　Ｂ（ＨＢＳＳ＋２０ｍＭ　ＨＥＰＥＳバッファー、ｐＨ７．４）に置換し、カルシウム感受性蛍光指示薬（ＦＬＩＰＲ　Ｃａｌｃｉｕｍ　４　Ａｓｓａｙ　ｋｉｔ、Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ社）を用いて、薬物刺激による細胞内Ｃａ２＋応答を測定した。具体的に、オピオイド受容体作用については、オピオイドμ受容体作用薬であるフェンタニル、化合物３Ｆ、又は化合物３Ｌを添加した後、２秒ごとに９０秒間に亘って蛍光値を測定した。また、オピオイド受容体拮抗作用については、化合物３Ｆ又はオピオイドμ受容体拮抗薬であるナロキソンを添加し、装置内に３０分間静置した後、フェンタニル（０．０２５μＭ）を添加し、同様に蛍光値を測定した。蛍光測定にはＦｌｅｘｓｔａｔｉｏｎ　３（Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ社）を使用し、測定条件は励起波長４８５ｎｍ、蛍光波長５２５ｎｍ、カットオフ波長５１５ｎｍとした。データの解析には、ＳＯＦＴＭＡＸ　ＰＲＯソフトウェア（Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ社）を使用した。 <Test Example 1: Evaluation of in vitro opioid μ receptor activity and opioid μ receptor antagonistic activity of compound 3F and compound 3L>
Opioid μ receptor-expressing cells (CHO-μ cells) were suspended in a nutritive mixture/Ham's F-12 medium containing 10% FBS, and seeded in a 96-well plate at 5.0×10 4 cells/well. , 37° C., 5.0% CO 2 . After 24 hours, the medium was replaced with 100 µL/well of Component B (HBSS + 20 mM HEPES buffer, pH 7.4), and a calcium-sensitive fluorescent indicator (FLIPR Calcium 4 Assay kit, Molecular Devices) was used to measure intracellular Ca by drug stimulation. 2+ responses were measured. Specifically, for opioid receptor action, the fluorescence value was measured every 2 seconds for 90 seconds after addition of fentanyl, compound 3F, or compound 3L, which is an opioid μ receptor agonist. In addition, for opioid receptor antagonism, compound 3F or naloxone, which is an opioid μ receptor antagonist, was added, allowed to stand in the device for 30 minutes, then fentanyl (0.025 μM) was added, and the fluorescence value was similarly measured. was measured. Flexstation 3 (Molecular Devices) was used for fluorescence measurement, and the measurement conditions were an excitation wavelength of 485 nm, a fluorescence wavelength of 525 nm, and a cutoff wavelength of 515 nm. SOFTMAX PRO software (Molecular Devices) was used for data analysis.
　化合物３Ｆ（３Ｆ）、化合物３Ｌ（３Ｌ）、又はフェンタニル（ＦＮ）を添加したときの用量反応曲線を図１に示す。図１から分かるように、フェンタニルを添加した場合には、濃度依存的に蛍光値の増加が確認され、５０％効果濃度（ＥＣ５０値）は４．７９×１０－９Ｍであった。化合物３Ｌを添加した場合にも、濃度依存的に蛍光値の増加が確認されたが、５０％効果濃度（ＥＣ５０値）は１．０９×１０－８Ｍでありフェンタニルよりも弱く、最大効果はフェンタニルの約６０％であった。この結果から、化合物３Ｌはオピオイドμ受容体部分作用薬であると考えられる。一方、化合物３Ｆを添加した場合には、蛍光値の増加は確認されなかった。 Dose-response curves for the addition of compound 3F (3F), compound 3L (3L), or fentanyl (FN) are shown in FIG. As can be seen from FIG. 1, when fentanyl was added, a concentration-dependent increase in fluorescence value was confirmed, and the 50% effective concentration (EC 50 value) was 4.79×10 −9 M. Even when compound 3L was added, a concentration-dependent increase in fluorescence value was confirmed, but the 50% effective concentration (EC 50 value) was 1.09×10 −8 M, which was weaker than fentanyl and had the maximum effect. was about 60% of fentanyl. This result suggests that Compound 3L is an opioid μ receptor partial agonist. On the other hand, when Compound 3F was added, no increase in fluorescence value was confirmed.
　また、化合物３Ｆ（３Ｆ）又はナロキソン（ＮＬＸ）で前処理した後、フェンタニルを添加したときの用量反応曲線を図２に示す。図２から分かるように、フェンタニルの効果は化合物３Ｆ及びナロキソンにより濃度依存的に抑制された。５０％阻害濃度（ＩＣ５０値）は、化合物３Ｆが３．２５×１０－８Ｍ、ナロキソンが１．６５×１０－７Ｍであり、化合物３Ｆの方がナロキソンよりも強力なオピオイドμ受容体拮抗作用を有していた。 FIG. 2 also shows dose-response curves when fentanyl was added after pretreatment with compound 3F (3F) or naloxone (NLX). As can be seen from FIG. 2, the effect of fentanyl was suppressed by compound 3F and naloxone in a dose-dependent manner. The 50% inhibitory concentration ( IC50 value) was 3.25×10 −8 M for compound 3F and 1.65×10 −7 M for naloxone, indicating that compound 3F is a more potent opioid μ receptor than naloxone. had an antagonistic effect.
＜試験例２：化合物３Ｆのｉｎ　ｖｉｖｏにおけるオピオイド受容体拮抗作用の評価＞
　化合物３Ｆのｉｎ　ｖｉｖｏにおけるオピオイド受容体拮抗作用を評価するため、マウスによる行動薬理学的解析を行った。行動薬理実験には、ＩＣＲ系雄性マウス（Ｊｃｌ、２０～２５ｇ、日本クレア（株））を使用した。 <Test Example 2: Evaluation of in vivo opioid receptor antagonism of compound 3F>
To evaluate the in vivo opioid receptor antagonism of Compound 3F, behavioral pharmacological analysis in mice was performed. ICR male mice (Jcl, 20-25 g, CLEA Japan, Inc.) were used for behavioral pharmacological experiments.
　３時間の環境適応後、行動薬理実験として、モルヒネの全身投与により誘発される行動変化に対する化合物３Ｆ又はオピオイド受容体拮抗薬であるナロキソンの効果を検討した。具体的には、赤外線センサー内蔵の自発運動量測定装置（ＡＣＴＩＭＯ－１００、バイオリサーチセンター（株））を用いて、モルヒネ（Ｍｏｒ）を１０ｍｇ／ｋｇの投与量で腹腔内投与した後の運動量を投与から１２０分間に亘って測定した。化合物３Ｆ（３Ｆ）の投与群（ｎ＝１２）は、モルヒネ投与の３０分前に化合物３Ｆを２ｍｇ／ｋｇの投与量で腹腔内投与した。ナロキソン（ＮＬＸ）の投与群（ｎ＝１２）は、モルヒネ投与の３０分前にナロキソンを２ｍｇ／ｋｇの投与量で腹腔内投与した。コントロールとしては、モルヒネ投与の３０分前に生理食塩水（ＳＡＬ）を腹腔内投与した投与群（ｎ＝１４）と、薬物の代わりに生理食塩水（ＳＡＬ）を腹腔内投与した投与群（ｎ＝１２）とを準備した。 After 3 hours of adaptation to the environment, as a behavioral pharmacological experiment, the effects of compound 3F or naloxone, an opioid receptor antagonist, on behavioral changes induced by systemic administration of morphine were examined. Specifically, using a locomotor activity measuring device (ACTIMO-100, Bio Research Center Co., Ltd.) with a built-in infrared sensor, morphine (Mor) was intraperitoneally administered at a dose of 10 mg/kg, and then the amount of exercise was administered. was measured over a period of 120 minutes. Compound 3F (3F) administration group (n=12) was intraperitoneally administered with compound 3F at a dose of 2 mg/kg 30 minutes before administration of morphine. In the naloxone (NLX) administration group (n=12), naloxone was administered intraperitoneally at a dose of 2 mg/kg 30 minutes before morphine administration. As controls, an administration group (n = 14) that was intraperitoneally administered with physiological saline (SAL) 30 minutes before administration of morphine, and an administration group (n = 14) that was intraperitoneally administered with physiological saline (SAL) instead of the drug (n = 12) were prepared.
　モルヒネ投与から１０分間毎の運動量の経時変化を図３Ａに示し、モルヒネ投与から１２０分間の総運動量を図３Ｂに示す。図３Ａ及び図３Ｂから分かるように、化合物３Ｆ又はナロキソンで前処置していない場合には、モルヒネ投与により、投与後３０分をピークとして運動量が有意に増加し、モルヒネによる運動促進作用が確認された（＊＊ｐ＜０．０１）。一方、化合物３Ｆ又はナロキソンで前処置した場合には、モルヒネによる運動促進作用が有意に抑制された（＃＃ｐ＜０．０１）。この結果から、化合物３Ｆがｉｎ　ｖｉｖｏでオピオイド受容体拮抗作用を示すことが確認された。 FIG. 3A shows the time course of the amount of exercise every 10 minutes after administration of morphine, and FIG. 3B shows the total amount of exercise for 120 minutes after administration of morphine. As can be seen from FIGS. 3A and 3B, in the absence of pretreatment with compound 3F or naloxone, morphine administration significantly increased locomotion peaking at 30 minutes after administration, confirming the prokinetic action of morphine. ( ** p<0.01). On the other hand, pretreatment with compound 3F or naloxone significantly inhibited the prokinetic effect of morphine ( ## p<0.01). This result confirmed that compound 3F exhibited opioid receptor antagonism in vivo.
＜合成例２：化合物５Ｆ及び化合物５Ｌの合成＞
（工程１：化合物４の合成） <Synthesis Example 2: Synthesis of Compound 5F and Compound 5L>
(Step 1: Synthesis of Compound 4)
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　市販の１－（２－フェニルエチル）－４－ピペリドン（化合物１）（２０３．１ｍｇ，１．００ｍｍｏｌ）にエタノール（５ｍＬ）を加えて溶解し、酢酸（６８μＬ，１．２ｍｍｏｌ）及び２－イソプロピル－６－メチルアニリン（３１０μＬ，２．０１ｍｍｏｌ）を加えた。反応溶液を加熱還流下で１時間撹拌した後、２５℃に冷却し、シアノ水素化ホウ素ナトリウム（１２６．１ｍｇ，２．０１ｍｍｏｌ）をゆっくりと加えた。加熱還流下でさらに１８時間撹拌した後、２Ｎ　水酸化ナトリウム水溶液を加え、ロータリーエバポレーターで濃縮した。濃縮物を酢酸エチルにより抽出し、２Ｎ　水酸化ナトリウム水溶液及び飽和食塩水で洗浄した。Ｎａ２ＳＯ４を加えて乾燥させた後、濃縮した。粗生成物をカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）により精製し、化合物４を油状物質（収量：２１４．０ｍｇ；６４％）として得た。化合物４の物性値は以下のとおりである。 Commercially available 1-(2-phenylethyl)-4-piperidone (compound 1) (203.1 mg, 1.00 mmol) was dissolved in ethanol (5 mL), and acetic acid (68 μL, 1.2 mmol) and 2-isopropyl -6-Methylaniline (310 μL, 2.01 mmol) was added. After the reaction solution was stirred under reflux with heating for 1 hour, it was cooled to 25° C. and sodium cyanoborohydride (126.1 mg, 2.01 mmol) was slowly added. After further stirring for 18 hours while heating under reflux, 2N aqueous sodium hydroxide solution was added and the mixture was concentrated by a rotary evaporator. The concentrate was extracted with ethyl acetate and washed with 2N sodium hydroxide aqueous solution and saturated brine. Na 2 SO 4 was added to dry and then concentrated. The crude product was purified by column chromatography (hexane/ethyl acetate=1/1) to give compound 4 as an oily substance (yield: 214.0 mg; 64%). The physical property values of compound 4 are as follows.
化合物４：
ＩＲ（ＡＴＲ）：３３７３ｃｍ－１（ＮＨ）；
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）：δ＝７．２８（ｍ，２Ｈ），７．１９（ｍ，３Ｈ），７．０９（ｄｄ，Ｊ＝７．３，１．４Ｈｚ，１Ｈ），６．９８（ｄｄ，Ｊ＝７．３，１．４Ｈｚ，１Ｈ），６．９１（ｔ，Ｊ＝７．３Ｈｚ，１Ｈ），３．２１（ｓｅｐ，Ｊ＝６．９Ｈｚ，１Ｈ），３．００（ｍ，２Ｈ），２．９１（ｔｔ，Ｊ＝１１．０，３．９Ｈｚ，１Ｈ），２．８０（ｍ，２Ｈ），２．５８（ｍ，２Ｈ），２．５１（ｂｒｓ，１Ｈ，ＮＨ），２．２８（ｓ，３Ｈ），１．９９（ｍ，４Ｈ），１．５１（ｍ，２Ｈ），１．２２（ｄ，Ｊ＝６．９Ｈｚ，６Ｈ）；
１３Ｃ　ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）：δ＝１４３．０，１４０．９，１４０．３，１３０．３，１２８．６，１２８．３，１２８，３，１２６．０，１２３．８，１２２．３，６０．５，５５．８，５３．１，３３．９，３３．７，２７．６，２４．０，１９．３；
ＨＲＭＳ（ＥＳＩ）：ｍ／ｚ　ｃａｌｃｄ　ｆｏｒ　Ｃ２３Ｈ３３Ｎ２：３３７．２６３８（Ｍ＋Ｈ）＋，ｆｏｕｎｄ：３３７．２６３７． Compound 4:
IR (ATR): 3373 cm −1 (NH);
1 H NMR (400 MHz, CDCl 3 ): δ=7.28 (m, 2H), 7.19 (m, 3H), 7.09 (dd, J=7.3, 1.4 Hz, 1H), 6 .98 (dd, J=7.3, 1.4 Hz, 1 H), 6.91 (t, J=7.3 Hz, 1 H), 3.21 (sep, J=6.9 Hz, 1 H), 3. 00 (m, 2H), 2.91 (tt, J = 11.0, 3.9Hz, 1H), 2.80 (m, 2H), 2.58 (m, 2H), 2.51 (brs, 1H, NH), 2.28 (s, 3H), 1.99 (m, 4H), 1.51 (m, 2H), 1.22 (d, J = 6.9 Hz, 6H);
13 C NMR (100 MHz, CDCl 3 ): δ=143.0, 140.9, 140.3, 130.3, 128.6, 128.3, 128, 3, 126.0, 123.8, 122. 3, 60.5, 55.8, 53.1, 33.9, 33.7, 27.6, 24.0, 19.3;
HRMS (ESI): m/z calcd for C23H33N2 : 337.2638 (M+H) <+> , found : 337.2637.
（工程２：化合物５の合成） (Step 2: Synthesis of Compound 5)
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　化合物４（２１４．０ｍｇ，０．６３５ｍｍｏｌ）をＤＭＦ（８ｍＬ）に溶解し、０℃に冷却した。その後、水素化ナトリウム（６０％　ｉｎ　ｏｉｌ）（７６．３ｍｇ，１．９１ｍｍｏｌ）を加えた。反応溶液を２５℃で２０分間撹拌した後、２－フロイルクロリド（１６２μＬ，１．９１ｍｍｏｌ）を加えた。２５℃で１４時間撹拌した後、２Ｎ　水酸化ナトリウム水溶液を加え、ジエチルエーテルにより抽出した。有機層を２Ｎ　水酸化ナトリウム水溶液及び飽和食塩水で洗浄し、Ｎａ２ＳＯ４を加えて乾燥させ、濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン（１％トリエチルアミン）／酢酸エチル＝１／１）により精製し、化合物５を白色粉末（収量：１０６ｍｇ；３８％）として得た。化合物５の物性値は以下のとおりである。 Compound 4 (214.0 mg, 0.635 mmol) was dissolved in DMF (8 mL) and cooled to 0°C. Then sodium hydride (60% in oil) (76.3 mg, 1.91 mmol) was added. After the reaction solution was stirred at 25° C. for 20 minutes, 2-furoyl chloride (162 μL, 1.91 mmol) was added. After stirring at 25° C. for 14 hours, 2N aqueous sodium hydroxide solution was added and the mixture was extracted with diethyl ether. The organic layer was washed with 2N aqueous sodium hydroxide solution and saturated brine, dried by adding Na 2 SO 4 and concentrated. The crude product was purified by silica gel column chromatography (hexane (1% triethylamine)/ethyl acetate=1/1) to obtain compound 5 as a white powder (yield: 106 mg; 38%). The physical property values of compound 5 are as follows.
化合物５：
ｍｐ：９４－９５℃；
ＩＲ（ＡＴＲ）：１６２６ｃｍ－１（ＣＯ）；
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）：δ＝７．３４（ｄ，Ｊ＝１．６Ｈｚ，１Ｈ），７．３１（ｔ，Ｊ＝７．１Ｈｚ，１Ｈ），７．２６（ｍ，２Ｈ），７．１９（ｍ，４Ｈ），７．１２（ｄ，Ｊ＝７．１Ｈｚ，１Ｈ），６．１４（ｄｄ，Ｊ＝３．０，１．６Ｈｚ，１Ｈ），５．３０（ｄ，Ｊ＝３．０Ｈｚ，１Ｈ），４．２３（ｔｔ，Ｊ＝１１．９，３．７Ｈｚ，１Ｈ），３．０２（ｍ，３Ｈ），２．７６（ｍ，２Ｈ），２．５７（ｍ，２Ｈ），２．２４（ｓ，３Ｈ），２．１７（ｔｄｄ，Ｊ＝１２．４，５．０，２．７Ｈｚ，２Ｈ），２．０５（ｍ，２Ｈ），１．６５（ｍ，２Ｈ），１．２５（ｄ，Ｊ＝６．９Ｈｚ，３Ｈ），０．８２（ｄ，Ｊ＝６．９Ｈｚ，３Ｈ）；
１３Ｃ　ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）：δ＝１５９．７，１４８．３，１４７．４，１４４．３，１４０．４，１３７．７，１３７．１，１２９．０，１２８．７，１２８．４，１２８．３，１２６．０，１２４．９，１１５．１，１１１．０，６０．３，５７．６，５３．３，５３．２，３３．７，２９．９，２８．２，２４．５，２４．２，１９．３；ｓｅｖｅｒａｌ　ｓｉｇｎａｌｓ　ｏｖｅｒｌａｐ；
ＨＲＭＳ（ＥＳＩ）：ｍ／ｚ　ｃａｌｃｄ　ｆｏｒ　Ｃ２８Ｈ３５Ｎ２Ｏ２：４３１．２６９３（Ｍ＋Ｈ）＋，ｆｏｕｎｄ：４３１．２６９５． Compound 5:
mp: 94-95°C;
IR (ATR): 1626 cm −1 (CO);
1 H NMR (400 MHz, CDCl 3 ): δ = 7.34 (d, J = 1.6 Hz, 1 H), 7.31 (t, J = 7.1 Hz, 1 H), 7.26 (m, 2 H) , 7.19(m, 4H), 7.12(d, J=7.1Hz, 1H), 6.14(dd, J=3.0, 1.6Hz, 1H), 5.30(d, J = 3.0 Hz, 1H), 4.23 (tt, J = 11.9, 3.7 Hz, 1H), 3.02 (m, 3H), 2.76 (m, 2H), 2.57 ( m, 2H), 2.24 (s, 3H), 2.17 (tdd, J = 12.4, 5.0, 2.7Hz, 2H), 2.05 (m, 2H), 1.65 ( m, 2H), 1.25 (d, J = 6.9Hz, 3H), 0.82 (d, J = 6.9Hz, 3H);
13 C NMR (100 MHz, CDCl 3 ): δ=159.7, 148.3, 147.4, 144.3, 140.4, 137.7, 137.1, 129.0, 128.7, 128. 4, 128.3, 126.0, 124.9, 115.1, 111.0, 60.3, 57.6, 53.3, 53.2, 33.7, 29.9, 28.2, 24.5, 24.2, 19.3; several signals overlap;
HRMS ( ESI): m/z calcd for C28H35N2O2 : 431.2693 (M+H) < + > , found: 431.2695.
（工程３：化合物５の光学分割）
　化合物５はラセミ体であるため、キラル高速液体クロマトグラフィー（ＨＰＬＣ）により、各アトロプ異性体を分離及び単離した。ＨＰＬＣの分離条件は以下のとおりである。
－ＨＰＬＣ条件－
カラム：ＣＨＩＲＡＬＰＡＫ　ＩＧ（Φ＝４．６ｍｍ）
移動相：３０％エタノール／ヘキサン
流速：０．５ｍＬ／分
温度：２５℃
溶出時間：２２．７分、３７．７分 (Step 3: Optical resolution of compound 5)
Since compound 5 is racemic, each atropisomer was separated and isolated by chiral high performance liquid chromatography (HPLC). The HPLC separation conditions are as follows.
- HPLC conditions -
Column: CHIRALPAK IG (Φ=4.6mm)
Mobile phase: 30% ethanol/hexane Flow rate: 0.5 mL/min Temperature: 25°C
Elution time: 22.7 minutes, 37.7 minutes
　キラルＨＰＬＣにより分離及び単離された一対のアトロプ異性体のうち、溶出時間が早いアトロプ異性体を化合物５Ｆと表記し、溶出時間が遅いアトロプ異性体を化合物５Ｌと表記する。化合物５Ｆ及び化合物５Ｌの鏡像体過剰率は９９．９％ｅｅであった。また、化合物５Ｆと化合物５Ｌとの間の活性化自由エネルギー値ΔＧ‡は１３０．６ｋＪ／ｍｏｌ（８０℃，トルエン）であった。化合物５Ｆ及び化合物５Ｌの比旋光度は以下のとおりである。
［α］Ｄ ２０（５Ｆ）：＋４４．４８３°（ｃ＝１．００，ＭｅＯＨ）
［α］Ｄ ２０（５Ｌ）：－４６．１７５°（ｃ＝１．００，ＭｅＯＨ） Of the pair of atropisomers separated and isolated by chiral HPLC, the atropisomer with a faster elution time is designated as compound 5F, and the atropisomer with a later elution time is designated as compound 5L. The enantiomeric excess of compound 5F and compound 5L was 99.9% ee. Also, the activation free energy value ΔG ‡ between compound 5F and compound 5L was 130.6 kJ/mol (80° C., toluene). The specific rotations of compound 5F and compound 5L are as follows.
[α] D 20 (5F): +44.483° (c=1.00, MeOH)
[α] D 20 (5 L): −46.175° (c=1.00, MeOH)
＜試験例３：化合物５Ｆ及び化合物５Ｌのｉｎ　ｖｉｔｒｏにおけるオピオイドμ受容体作用及びオピオイドμ受容体拮抗作用の評価＞
　オピオイドμ受容体発現細胞（ＣＨＯ－μ細胞）を１０％　ＦＢＳ含有ｎｕｔｒｉｅｎｔ　ｍｉｘｔｕｒｅ／Ｈａｍ’ｓ　Ｆ－１２培地に懸濁し、５．０×１０４細胞／ウェルとなるように９６ウェルプレートに播種し、３７℃、５．０％　ＣＯ２の条件下にて培養した。２４時間後、培地を１００μＬ／ウェルのＣｏｍｐｏｎｅｎｔ　Ｂ（ＨＢＳＳ＋２０ｍＭ　ＨＥＰＥＳバッファー、ｐＨ７．４）に置換し、カルシウム感受性蛍光指示薬（ＦＬＩＰＲ　Ｃａｌｃｉｕｍ　４　Ａｓｓａｙ　ｋｉｔ、Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ社）を用いて、薬物刺激による細胞内Ｃａ２＋応答を測定した。具体的に、オピオイド受容体作用については、化合物５Ｆ又は化合物５Ｌを添加した後、２秒ごとに９０秒間に亘って蛍光値を測定した。また、オピオイド受容体拮抗作用については、化合物５Ｆ又はオピオイドμ受容体拮抗薬であるナロキソンを添加し、装置内に３０分間静置した後、オピオイドμ受容体作用薬であるフェンタニル（０．０２５μＭ）を添加し、同様に蛍光値を測定した。蛍光測定にはＦｌｅｘｓｔａｔｉｏｎ　３（Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ社）を使用し、測定条件は励起波長４８５ｎｍ、蛍光波長５２５ｎｍ、カットオフ波長５１５ｎｍとした。データの解析には、ＳＯＦＴＭＡＸ　ＰＲＯソフトウェア（Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ社）を使用した。 <Test Example 3: Evaluation of in vitro opioid μ receptor activity and opioid μ receptor antagonistic activity of compound 5F and compound 5L>
Opioid μ receptor-expressing cells (CHO-μ cells) were suspended in a nutritive mixture/Ham's F-12 medium containing 10% FBS, and seeded in a 96-well plate at 5.0×10 4 cells/well. , 37° C., 5.0% CO 2 . After 24 hours, the medium was replaced with 100 µL/well of Component B (HBSS + 20 mM HEPES buffer, pH 7.4), and a calcium-sensitive fluorescent indicator (FLIPR Calcium 4 Assay kit, Molecular Devices) was used to measure intracellular Ca by drug stimulation. 2+ responses were measured. Specifically, for opioid receptor activity, fluorescence values were measured every 2 seconds for 90 seconds after addition of compound 5F or compound 5L. Further, for opioid receptor antagonism, compound 5F or naloxone, which is an opioid μ receptor antagonist, was added and allowed to stand in the device for 30 minutes. was added, and the fluorescence value was measured in the same manner. Flexstation 3 (Molecular Devices) was used for fluorescence measurement, and the measurement conditions were an excitation wavelength of 485 nm, a fluorescence wavelength of 525 nm, and a cutoff wavelength of 515 nm. SOFTMAX PRO software (Molecular Devices) was used for data analysis.
　化合物５Ｆ（５Ｆ）又は化合物５Ｌ（５Ｌ）を添加したときの用量反応曲線を図４に示す。図４から分かるように、化合物５Ｌを添加した場合には、濃度依存的に蛍光値の増加が確認されたが、５０％効果濃度（ＥＣ５０値）は６．７２×１０－９Ｍであり、試験例１のフェンタニルよりも弱かった。一方、化合物５Ｆを添加した場合には、蛍光値の増加は確認されなかった。 Dose-response curves for the addition of compound 5F (5F) or compound 5L (5L) are shown in FIG. As can be seen from FIG. 4, when compound 5L was added, a concentration-dependent increase in fluorescence value was confirmed, but the 50% effective concentration ( EC50 value) was 6.72×10 −9 M. , was weaker than fentanyl in Test Example 1. On the other hand, when compound 5F was added, no increase in fluorescence value was confirmed.
　また、化合物５Ｆ（５Ｆ）又はナロキソン（ＮＬＸ）で前処理した後、フェンタニルを添加したときの用量反応曲線を図５に示す。図５から分かるように、フェンタニルの効果は化合物５Ｆ及びナロキソンにより濃度依存的に抑制された。５０％阻害濃度（ＩＣ５０値）は、化合物５Ｆが２．６１×１０－６Ｍ、ナロキソンが１．８４×１０－７Ｍであり、化合物５Ｆの方がナロキソンよりも弱いものの、いずれも強力なオピオイドμ受容体拮抗作用を有していた。 Also shown in FIG. 5 is the dose-response curve when fentanyl was added after pretreatment with compound 5F (5F) or naloxone (NLX). As can be seen from FIG. 5, the effect of fentanyl was suppressed by compound 5F and naloxone in a dose-dependent manner. The 50% inhibitory concentration (IC 50 value) was 2.61×10 −6 M for compound 5F and 1.84×10 −7 M for naloxone. Although compound 5F was weaker than naloxone, both were potent. had significant opioid μ-receptor antagonism.

Claims (8)

  1. 　下記式（１）で表される化合物が有する一対のアトロプ異性体のうち、オピオイド受容体拮抗作用を有する一方のアトロプ異性体又はその薬理学的に許容される塩を有効成分として含有するオピオイド受容体拮抗剤。
    Figure JPOXMLDOC01-appb-C000001
     ［式中、Ｒ１は、アルキル基、シクロアルキル基、アルケニル基、アルキニル基、アリール基、非芳香族複素環基、又はヘテロアリール基を示し、置換基を有していてもよい。Ｒ２及びＲ３はそれぞれ独立に、アルキル基、アルケニル基、アルキニル基、アリール基、カルバモイル基、ニトロ基、ハロゲン原子、又は－ＯＲ４、－Ｃ（＝Ｏ）Ｒ４、－Ｃ（＝Ｏ）ＯＲ４、－ＯＣ（＝Ｏ）Ｒ４、－ＮＲ４ ２、若しくは－ＳＲ４で表される基を示し、置換基を有していてもよい。Ｒ４はそれぞれ独立に、水素原子、アルキル基、シクロアルキル基、アルケニル基、アルキニル基、アリール基、非芳香族複素環基、又はヘテロアリール基を示す。］     An opioid receptor containing, as an active ingredient, one of a pair of atropisomers of a compound represented by the following formula (1), which has an opioid receptor antagonistic action or a pharmacologically acceptable salt thereof. Body antagonist.
    Figure JPOXMLDOC01-appb-C000001
     [In the formula, R 1 represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group, and may have a substituent. R 2 and R 3 are each independently an alkyl group, alkenyl group, alkynyl group, aryl group, carbamoyl group, nitro group, halogen atom, or -OR 4 , -C(=O)R 4 , -C(=O ) represents a group represented by OR 4 , —OC(=O)R 4 , —NR 4 2 or —SR 4 and may have a substituent. Each R4 independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group. ]
  2. 　前記式（１）中のＲ１がヘテロアリール基であり、Ｒ２及びＲ３がそれぞれ独立にアルキル基である、請求項１に記載のオピオイド受容体拮抗剤。 The opioid receptor antagonist according to Claim 1, wherein R1 in said formula (1) is a heteroaryl group, and R2 and R3 are each independently an alkyl group.
  3. 　オピオイドμ受容体に対して拮抗作用を示す、請求項１又は２に記載のオピオイド受容体拮抗剤。 The opioid receptor antagonist according to claim 1 or 2, which exhibits an antagonistic effect on opioid μ receptors.
  4. 　下記式（２）で表され、且つ、クロロホルムに溶解したときのナトリウムＤ線に対する２０℃における比旋光度が正の値を示すアトロプ異性体を前記有効成分として含有する、請求項１～３のいずれか１項に記載のオピオイド受容体拮抗剤。
    Figure JPOXMLDOC01-appb-C000002
     ［式中、－Ｍｅはメチル基を示し、－Ｅｔはエチル基を示す。］     Claims 1 to 3, containing as the active ingredient an atropisomer represented by the following formula (2) and having a positive specific rotation at 20 ° C. with respect to the sodium D line when dissolved in chloroform. An opioid receptor antagonist according to any one of claims 1 to 3.
    Figure JPOXMLDOC01-appb-C000002
     [In the formula, -Me represents a methyl group, and -Et represents an ethyl group. ]
  5. 　下記式（３）で表され、且つ、メタノールに溶解したときのナトリウムＤ線に対する２０℃における比旋光度が正の値を示すアトロプ異性体を前記有効成分として含有する、請求項１～３のいずれか１項に記載のオピオイド受容体拮抗剤。
    Figure JPOXMLDOC01-appb-C000003
     ［式中、－Ｍｅはメチル基を示す。］     Claims 1 to 3, containing as the active ingredient an atropisomer represented by the following formula (3) and having a positive specific rotation at 20 ° C. with respect to the sodium D line when dissolved in methanol. An opioid receptor antagonist according to any one of claims 1 to 3.
    Figure JPOXMLDOC01-appb-C000003
     [In the formula, -Me represents a methyl group. ]
  6. 　下記式（１）で表される化合物が有する一対のアトロプ異性体のうち、オピオイド受容体拮抗作用を有する一方のアトロプ異性体又はその薬理学的に許容される塩を有効成分として含有する医薬組成物。
    Figure JPOXMLDOC01-appb-C000004
     ［式中、Ｒ１は、アルキル基、シクロアルキル基、アルケニル基、アルキニル基、アリール基、非芳香族複素環基、又はヘテロアリール基を示し、置換基を有していてもよい。Ｒ２及びＲ３はそれぞれ独立に、アルキル基、アルケニル基、アルキニル基、アリール基、カルバモイル基、ニトロ基、ハロゲン原子、又は－ＯＲ４、－Ｃ（＝Ｏ）Ｒ４、－Ｃ（＝Ｏ）ＯＲ４、－ＯＣ（＝Ｏ）Ｒ４、－ＮＲ４ ２、若しくは－ＳＲ４で表される基を示し、置換基を有していてもよい。Ｒ４はそれぞれ独立に、水素原子、アルキル基、シクロアルキル基、アルケニル基、アルキニル基、アリール基、非芳香族複素環基、又はヘテロアリール基を示す。］     A pharmaceutical composition containing, as an active ingredient, one atropisomer having opioid receptor antagonistic activity or a pharmacologically acceptable salt thereof among a pair of atropisomers possessed by a compound represented by the following formula (1): thing.
    Figure JPOXMLDOC01-appb-C000004
     [In the formula, R 1 represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group, and may have a substituent. R 2 and R 3 are each independently an alkyl group, alkenyl group, alkynyl group, aryl group, carbamoyl group, nitro group, halogen atom, or -OR 4 , -C(=O)R 4 , -C(=O ) represents a group represented by OR 4 , —OC(=O)R 4 , —NR 4 2 or —SR 4 and may have a substituent. Each R4 independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a non-aromatic heterocyclic group, or a heteroaryl group. ]
  7. 　下記式（２）で表され、且つ、クロロホルムに溶解したときのナトリウムＤ線に対する２０℃における比旋光度が正の値を示す化合物。
    Figure JPOXMLDOC01-appb-C000005
     ［式中、－Ｍｅはメチル基を示し、－Ｅｔはエチル基を示す。］     A compound represented by the following formula (2) and having a positive specific rotation at 20°C with respect to the sodium D line when dissolved in chloroform.
    Figure JPOXMLDOC01-appb-C000005
     [In the formula, -Me represents a methyl group, and -Et represents an ethyl group. ]
  8. 　下記式（３）で表され、且つ、メタノールに溶解したときのナトリウムＤ線に対する２０℃における比旋光度が正の値を示す化合物。
    Figure JPOXMLDOC01-appb-C000006
     ［式中、－Ｍｅはメチル基を示す。］     A compound represented by the following formula (3) and having a positive specific rotation at 20°C with respect to the sodium D line when dissolved in methanol.
    Figure JPOXMLDOC01-appb-C000006
     [In the formula, -Me represents a methyl group. ]
PCT/JP2022/034681 2021-09-28 2022-09-16 Opioid receptor antagonist and pharmaceutical composition WO2023054006A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021158379 2021-09-28
JP2021-158379 2021-09-28

Publications (1)

Publication Number Publication Date
WO2023054006A1 true WO2023054006A1 (en) 2023-04-06

Family

ID=85782503

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2022/034681 WO2023054006A1 (en) 2021-09-28 2022-09-16 Opioid receptor antagonist and pharmaceutical composition

Country Status (1)

Country Link
WO (1) WO2023054006A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60248670A (en) * 1984-04-09 1985-12-09 ビ−オ−シ−　インコ−ポレ−テツド N-aryl-n-(4-piperidinyl)amide, drug, composition and method
WO2006101245A1 (en) * 2005-03-23 2006-09-28 Nippon Chemiphar Co., Ltd. N-substituted-n-(4-piperidinyl) amide derivative
US20210396706A1 (en) * 2020-06-22 2021-12-23 The Florida International University Board Of Trustees Aptamer-based sensors for detection of fentanyl opioids

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60248670A (en) * 1984-04-09 1985-12-09 ビ−オ−シ−　インコ−ポレ−テツド N-aryl-n-(4-piperidinyl)amide, drug, composition and method
WO2006101245A1 (en) * 2005-03-23 2006-09-28 Nippon Chemiphar Co., Ltd. N-substituted-n-(4-piperidinyl) amide derivative
US20210396706A1 (en) * 2020-06-22 2021-12-23 The Florida International University Board Of Trustees Aptamer-based sensors for detection of fentanyl opioids

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DUFFY JONATHAN, URBAS AARON, NIEMITZ MATTHIAS, LIPPA KATRICE, MARGINEAN IOAN: "Differentiation of fentanyl analogues by low-field NMR spectroscopy", ANALYTICA CHIMICA ACTA, vol. 1049, 1 February 2019 (2019-02-01), AMSTERDAM, NL , pages 161 - 169, XP093054470, ISSN: 0003-2670, DOI: 10.1016/j.aca.2018.12.014 *
LAMY FRANCOIS R.; DANIULAITYTE RAMINTA; BARRATT MONICA J.; LOKALA USHA; SHETH AMIT; CARLSON ROBERT G.: "Listed for sale: Analyzing data on fentanyl, fentanyl analogs and other novel synthetic opioids on one cryptomarket", DRUG AND ALCOHOL DEPENDENCE, vol. 213, 12 June 2020 (2020-06-12), IR , XP086215752, ISSN: 0376-8716, DOI: 10.1016/j.drugalcdep.2020.108115 *
LURIE, I.S. ; IIO, R.: "Use of multiple-reaction monitoring ratios for identifying incompletely resolved fentanyl homologs and analogs via ultra-high-pressure liquid chromatography-tandem mass spectrometry", JOURNAL OF CHROMATOGRAPHY A, vol. 1216, no. 9, 27 February 2009 (2009-02-27), AMSTERDAM, NL, pages 1515 - 1519, XP025909474, ISSN: 0021-9673, DOI: 10.1016/j.chroma.2008.12.097 *
SINGH P., PAI U. B.: "EFFECT OF MOLECULAR SIZE ON OPIATE RECEPTOR AFFINITY OF FENTANYL DERIVATIVES & ALPHA1-AGONIST POTENCY OF 2-AMINOTETRALINS.", INDIAN JOURNAL OF CHEMISTRY, COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (C S I R), IN, vol. 22B., no. 10., 1 October 1983 (1983-10-01), IN , pages 1076 - 1078., XP000853930, ISSN: 0019-5103 *

Similar Documents

Publication Publication Date Title
CN102459202B (en) As the inhibitor isoxazoline of fatty acid amide hydrolase
US11352344B2 (en) Antagonists of the muscarinic acetylcholine receptor M4
AU2019294835A1 (en) Ligands to cereblon (CRBN)
ES2899694T3 (en) Novel compounds, their synthesis and their uses
CN103068384A (en) Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activites
AU2018257203B2 (en) Novel tetrahydronaphthyl urea derivatives
EP3697781B1 (en) Antagonists of the muscarinic acetylcholine receptor m4
CA3068842A1 (en) Antagonists of the muscarinic acetylcholine receptor m4
JP2020530451A (en) Antagonist of muscarinic acetylcholine receptor M4
CN101970436A (en) Azaindole compounds for treatment of central nervous system disorders
FR2593818A1 (en) ACYLAMINOMETHYL-3 IMIDAZO (1,2-A) PYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
WO2023054006A1 (en) Opioid receptor antagonist and pharmaceutical composition
WO2022129909A1 (en) Cannabinoid derivatives as pharmaceutically active compounds and method of preparation thereof
CA3217661A1 (en) Small molecule cyclin dependent kinase 4/6 (cdk4/6) and ikzf2 (helios) degraders and methods of use thereof
CN112574212B (en) Pyrimido five-membered nitrogen heterocyclic derivative, preparation method and medical application thereof
WO2022125614A1 (en) Phosphonates as inhibitors of enpp1 and cdnp
CA3012839A1 (en) Tetrahydroisoquinoline derivatives
KR20230041715A (en) Pyridine-1,5-diones exhibiting MNK inhibition and methods of use thereof
CA3178647A1 (en) Substituted tricyclic amides, analogues thereof, and methods using same
CN116963733A (en) Imidazole compounds as ENPP1 inhibitors
WO2022164842A1 (en) Competitive and noncompetitive inhibitors of the muscarinic acetylcholine receptor m5
AU2021404159A1 (en) Cannabinoid derivatives as pharmaceutically active compounds and method of preparation thereof
CN116600813A (en) Phosphonates as ENPP1 and CDNP inhibitors
CN116496270A (en) 4-aminopiperidine derivative and preparation method and application thereof
CN115703767A (en) Preparation method of 3-aryloxy-3-five-membered heteroaryl-propylamine compound

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22875877

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2023551319

Country of ref document: JP