WO2022014680A1 - 置換ピペリジン化合物及びその用途 - Google Patents
置換ピペリジン化合物及びその用途 Download PDFInfo
- Publication number
- WO2022014680A1 WO2022014680A1 PCT/JP2021/026649 JP2021026649W WO2022014680A1 WO 2022014680 A1 WO2022014680 A1 WO 2022014680A1 JP 2021026649 W JP2021026649 W JP 2021026649W WO 2022014680 A1 WO2022014680 A1 WO 2022014680A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- azabicyclo
- octane
- mmol
- Prior art date
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- 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
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- 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
Definitions
- the present invention relates to a substituted piperidine compound having orexin type 2 receptor activating activity, a pharmaceutically acceptable salt thereof, and a pharmaceutical use thereof.
- the present invention also relates to a pharmaceutical substance containing the compound as an active ingredient.
- Non-Patent Document 2 a gene mutation in OX2R has been reported as a cause of canine narcolepsy (Non-Patent Document 2), and orexin-deficient mice showed narcolepsy-like symptoms very similar to human or canine narcolepsy (Non-Patent Document 3). .. Furthermore, studies using transgenic mice in which orexin neurons have been denatured and double transgenic mice obtained by crossing these mice with orexin overexpressing transgenic mice show that narcolepsy-like symptoms appearing due to degeneration of orexin neurons. It was revealed that it disappears by continuous expression of orexin (Non-Patent Document 4).
- Non-Patent Document 4 studies on OX2R knockout mice have suggested that OX2R is important for maintaining arousal (Non-Patent Document 5). It has also been suggested that daytime sleepiness in Parkinson's disease patients is caused by the loss of orexin nerves (Non-Patent Document 6). In addition, it has been suggested that patients with sleep apnea syndrome have low plasma OX-A concentration levels (Non-Patent Document 7). Against this background, it has been suggested that the OX2R agonist may be a therapeutic agent for narcolepsy and other therapeutic agents for sleep disorders exhibiting hypersomnia (Non-Patent Document 8).
- compounds with OX2R agonistic activity include narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, consciousness disorders such as coma, narcolepsy syndrome with narcolepsy-like symptoms, and hypersomnia with daytime hypersomnia. It may be used as a therapeutic agent for hypersomnia syndrome (for example, Parkinson's disease, Gillan Valley syndrome and Kleinelevin syndrome).
- TAK-925 a compound having OX2R activating activity, has been subjected to a Phase 1 study (intravenous administration) in healthy subjects and narcolepsy patients.
- An object of the present invention is to provide a substituted piperidine compound or a pharmaceutically acceptable salt thereof having orexin type 2 receptor activating activity, and a pharmaceutical composition containing them.
- Narcolepsy in a subject comprising administering to the subject a pharmacologically effective amount of the compound according to any one of the above [1] to [5] or a pharmaceutically acceptable salt thereof.
- Orexin in a subject comprising administering to the subject a pharmacologically effective amount of the compound according to any one of the above [1] to [5] or a pharmaceutically acceptable salt thereof.
- a method for treating narcolepsy which comprises administering to a subject the compound according to any one of the above [1] to [5] or a pharmaceutically acceptable salt thereof.
- Cataplexy in a subject comprising administering to the subject a pharmacologically effective amount of the compound according to any one of the above [1] to [5] or a pharmaceutically acceptable salt thereof.
- Treatment method [16] The compound according to any one of the above [1] to [5] or a pharmaceutically acceptable salt thereof for use in the treatment of cataplexy.
- a therapeutic agent for hypersomnia syndrome containing the compound according to any one of the above [1] to [5] or a pharmaceutically acceptable salt thereof.
- a hypersomnia in a subject comprising administering to the subject a pharmacologically effective amount of the compound according to any one of the above [1] to [5] or a pharmaceutically acceptable salt thereof. How to treat hypersomnia syndrome.
- Substituted piperidine compounds represented by the formulas (I), (II), (III) and (IV) according to the present invention (hereinafter referred to as compounds (I), (II), (III) and (IV)) or.
- the pharmaceutically acceptable salt has olexin type 2 receptor activating activity as shown in the activity data in the pharmacological test examples below.
- the compounds (I), (II), (III) and (IV) of the present invention have orexin type 2 receptor activating activity and have potential as a therapeutic agent for narcolepsy.
- FIG. 1 is an ORTEP diagram showing the results of X-ray crystal structure analysis of the compound obtained in Example 1.
- FIG. 2 is an ORTEP diagram showing the results of X-ray crystal structure analysis of the compound obtained in Example 3 (a dimer to which two molecules of acetonitrile are added).
- FIG. 3 is an ORTEP diagram showing the results of X-ray crystal structure analysis of the compound obtained in Example 4.
- the compound according to the present invention may have a crystalline polymorph, but is not limited to any of them, and may be a single substance or a mixture of any of the crystalline forms, and according to the present invention.
- the compound also includes an amorphous substance, and the compound according to the present invention includes an anhydride and a solvate (particularly a hydrate).
- the present invention also includes isotope-labeled compounds of compounds (I), (II), (III) and (IV).
- Isotope-labeled compounds are compound (I), except that one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. It is the same as II), (III) and (IV).
- Isotopes that can be incorporated into compounds of the invention include, for example, hydrogen, carbon, nitrogen, oxygen, fluorine, phosphorus, sulfur, isotope iodine, and chlorine, 2 H, 3 H, 11 C, 14 C , 15 N, 18 O, 18 F, 32 P, 35 S, 123 I, and 125 I and the like.
- isotopically-labeled compounds for example those into which radioactive isotopes are incorporated such as 3 H and / or 14 C are useful in pharmaceutical and / or substrate tissue distribution assays.
- 3 H and 14 C are considered useful because of their ease of preparation and detection.
- Isotopes 11 C and 18 F are considered useful in PET (positron emission tomography), and isotopes 125 I are considered useful in SPECT (single photon emission computed tomography), all useful in brain imaging. Is. Substitution with heavier isotopes such as 2 H may cause certain therapeutic advantages such as reducing the increase or dosage requirements in vivo half-life greater metabolic stability, therefore, under certain circumstances It is considered useful.
- the isotope-labeled compounds are uniformly prepared by using readily available isotope-labeled reagents in place of the non-isotope-labeled reagents and following the procedures disclosed in the Examples below. Can be done.
- pharmaceutically acceptable salt is not particularly limited as long as it forms a salt with the compound according to the present invention, and specifically, for example, an inorganic acid salt or an organic acid salt. Alternatively, an acid addition salt such as an acidic amino acid salt can be mentioned.
- the term "pharmaceutically acceptable salt” as used herein means, as long as the salt is formed in an appropriate ratio, the acid in the formed salt with respect to one molecule of the compound is used.
- the number of molecules is not particularly limited, but preferably the acid is about 0.5 to about 2 molecules per molecule of the compound, and more preferably the acid is about 0.5, about 0.5 molecules per molecule of the compound. 1 or about 2 molecules.
- Preferred examples of the inorganic acid salt include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like
- preferred examples of the organic acid salt include, for example, acetate and succinate.
- Preferred examples of the acidic amino acid salt include aspartate, glutamic acid and the like.
- Compounds (I), (II), (III) and (IV) according to the present invention are salts of compounds (I), (II), (III) and (IV) or compounds (I), (II), (. When obtained as a hydrate of III) and (IV), it can be converted into a free form of the above compounds (I), (II), (III) and (IV) according to a conventional method.
- various isomers for example, optical isomers, rotational isomers, stereoisomers, etc.
- it can be purified and isolated by using recrystallization, diastereomeric salt method, enzymatic division method, and various chromatography (for example, thin layer chromatography, column chromatography, gas chromatography, etc.).
- the pharmaceutically acceptable additive is a compound selected from the compound groups (I), (II), (III) and (IV) or a pharmaceutically acceptable salt thereof. It can be manufactured by mixing with.
- the pharmaceutical composition according to the present invention can be produced according to a known method such as, for example, the method described in the 17th revised Japanese Pharmacopoeia general rules for preparation.
- the pharmaceutical composition according to the present invention can be appropriately administered to a patient according to its dosage form.
- the dose of the compound (I), (II), (III) and (IV) according to the present invention, or a pharmaceutically acceptable salt thereof is determined by the degree of symptom, age, sex, body weight, administration form / salt.
- about 30 ⁇ g to 10 g, preferably 100 ⁇ g to 5 g, and more preferably 100 ⁇ g to 1 g are orally administered daily by injection, although it varies depending on the type of the disease and the specific type of the disease.
- About 30 ⁇ g to 1 g, preferably 100 ⁇ g to 500 mg, and more preferably 100 ⁇ g to 300 mg are administered once or in several divided doses, respectively.
- orexin type 2 receptor agonist means a drug that binds to an orexin type 2 receptor and has an action of activating the orexin type 2 receptor in the same manner as an in vivo ligand.
- the compound of the present invention can be used as a chemical probe for capturing a target protein of a bioactive small molecule compound. That is, the compound of the present invention has a portion different from the structural portion essential for expressing the activity of the compound. Mass Spectrom. Soc. Jpn. Vol. 51, No. By introducing a labeling group, a linker, etc. by the method described in 52003, p492-498, WO2007 / 139149, etc., it can be converted into affinity chromatography, photoaffinity probe, or the like.
- Examples of the labeling group, linker and the like used for the chemical probe include the groups shown in the group consisting of the following (1) to (5).
- Photoaffinity labeling group for example, benzoyl group, benzophenone group, azido group, carbonyl azido group, diazilidine group, enone group, diazo group, nitro group, etc.
- chemical affinity group for example, the alpha carbon atom is halogen.
- Protein-labeled groups such as atomically substituted ketone groups, carbamoyl groups, ester groups, alkylthio groups, ⁇ , ⁇ -unsaturated ketones, Michael acceptors such as esters, and oxylan groups).
- Cleaving linkers such as —S—S—, —O—Si—O—, monosaccharides (glucose group, galactose group, etc.) or disaccharides (lactose, etc.), and oligopeptides that can be cleaved by enzymatic reaction.
- Phishing tag groups such as biotin, 3- (4,4-difluoro-5,7-dimethyl-4H-3a, 4a-diaza-4-bora-s-indasen-3-yl) propionyl group, (4) 125 I, 32 P , 3 H, radioactive labeling group, such as 14 C; fluorescein, rhodamine, dansyl, umbelliferone, 7-Nitorofurazaniru, 3- (4,4-difluoro-5,7-dimethyl -4H -3a, 4a-diaza-4-bora-s-indacen-3-yl) Fluorescent labeling groups such as propionyl groups; chemiluminescent groups such as lumiferin and luminol; detectable heavy metal ions such as lanthanoid metal ions and radium ions.
- Markers or (5) groups to be bonded to solid-phase carriers such as glass beads, glass beds, microtiter plates, agarose beads, agarose beds, polystyrene beads, polystyrene beds, nylon beads, nylon beds and the like.
- the probe prepared by introducing a labeling group or the like selected from the group consisting of the above (1) to (5) into the compound of the present invention according to the method described in the above document is a new drug discovery target. It can be used as a chemical probe for identifying labeled proteins useful for searching and the like.
- the compounds (I), (II), (III) and (IV) of the present invention can be produced, for example, by the methods described in the following examples, and the effects of the compounds are shown in the following test examples. It can be confirmed by the method described in. However, these are exemplary examples, and the present invention is not limited to the following specific examples in any case, and may be changed without departing from the scope of the present invention.
- room temperature in the following examples and production examples usually indicates about 10 ° C to about 35 ° C. % Indicates weight percent unless otherwise specified.
- the chemical shift of the proton nuclear magnetic resonance spectrum is recorded in ⁇ units (ppm) with respect to tetramethylsilane, and the coupling constant is recorded in Hertz (Hz).
- the pattern is represented by, for example, s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad, brs: broad singlet and the like.
- Mass spectrometry was performed using a Waters Corp. Acquity UPLC (R) or Acquity UPC 2 (R).
- the silica gel used is Merck's Silica Gel60 (70-230 mesh or 230-400 mesh ASTM) or Fuji Silysia Chemical's PSQ60B, or a prepack column ⁇ column: YAMAZEN's Hi-Flash TM Colon (Silica gel). ), Size; S (16 x 60 mm), M (20 x 75 mm), L (26 x 100 mm), 2 L (26 x 150 mm), 3 L (46 x 130 mm), or Biotage TM SNAP Ultra manufactured by Biotage. Silica Cartridge, size: 10 g, 25 g, 50 g ⁇ was used. In addition, preparative by supercritical fluid chromatography (SFC) was performed using Prep100q manufactured by Waters.
- SFC supercritical fluid chromatography
- NH silica gel For NH silica gel, use CHROMATOREX NH-DM2035 manufactured by Fuji Silysia Chemical Ltd., or prepack column ⁇ column: Hi-Flush TM (registered trademark) Column (Amino) manufactured by YAMAZEN, size; S (16 ⁇ 60 mm), M (20). X75 mm), L (26 x 100 mm), 2L (26 x 150 mm), 3L (46 x 130 mm), or Wako Pure Chemical Industries, Ltd.
- Presep TM registered trademark
- Luerlock NH2 (HC)
- Size Any of type M (14 g / 25 mL), type L (34 g / 70 mL), type 2 L (50 g / 100 mL), and type 3 L (110 g / 200 mL) ⁇ was used.
- the reaction mixture was added to a solution of potassium hydroxide (5.00 g, 89.1 mmol) in water (10.0 mL) at 0 ° C.
- Tetrahydrofuran (10.0 mL) and di-tert-butyl dicarbonate (CAS No. 24424-99-5) (478 mg, 2.19 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes.
- Ethyl acetate was added to the reaction mixture and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
- Residues include N, N-dimethylformamide (50.0 mL), 2-chloro-5-fluoropyrimidine (CAS No. 62802-42-0) (5.21 mL, 42.2 mmol) and potassium carbonate (7.29 g, 52). 0.8 mmol) was added, and the mixture was stirred at 80 ° C.
- the resulting solid was collected by filtration using a glass filter and washed with ethyl acetate / n-heptane (550 mL of 1: 3 mixed solution). The obtained solid was dried under reduced pressure to obtain the title compound (407 g).
- N, N-diisopropylethylamine (92 mL, 530 mmol) was added dropwise over 25 minutes under ice-cooling, and then the mixture was stirred under ice-cooling for 1 hour.
- the reaction mixture was then cooled to an internal temperature of -72 ° C. with a dry ice-ethanol bath.
- N-Bromosuccinimide (80 g, 448 mmol) was added at once and stirred under a dry ice-ethanol bath for 1 hour and 20 minutes. After adding 28-30% aqueous ammonia (800 mL, 6390 mmol) and tetrahydrofuran (1000 mL), the mixture was stirred under a water bath for 2 hours.
- the aqueous layer was extracted 3 times with ethyl acetate (500 mL).
- the obtained organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (silica gel 4 kg, 30-40% ethyl acetate / n-heptane) to obtain 132 g of a crude product.
- silica gel column chromatography sica gel 4 kg, 30-40% ethyl acetate / n-heptane
- the obtained compound was dissolved in methanol, and supercritical fluid chromatography using CHIRALPAK® IG / SFC (2 cm ⁇ 25 cm) manufactured by Dycel (mobile phase CO2: methanol (75:25), 120 bar, 40 ° C., A compound (75 mg) having a retention time of 9.11 minutes, mainly composed of a component to be eluted later, was obtained by fractionating 13 mg / 500 ⁇ L (methanol) at a flow rate of 70 mL / min).
- the obtained compound was dissolved in methanol, and supercritical fluid chromatography using CHIRALPAK® IG / SFC (2 cm ⁇ 25 cm) manufactured by Dycel (mobile phase CO2: methanol (75:25), 120 bar, 40 ° C., 4 mg / 100 ⁇ L (methanol) was fractionated at a flow rate of 70 mL / min) to obtain a compound (52 mg) having a retention time of 7.52 minutes, mainly composed of a component to be eluted later.
- the obtained compound was dissolved in methanol, and supercritical fluid chromatography using CHIRALPAK® IG / SFC (2 cm ⁇ 25 cm) manufactured by Dycel (mobile phase CO2: methanol (75:25), 120 bar, 40 ° C., At a flow rate of 70 mL / min), 7 mg / 500 ⁇ L (methanol) was fractionated at a time to obtain the title compound (31.3 mg) having a retention time of 7.18 minutes to be eluted later.
- the obtained single crystal was subjected to X-ray crystal structure analysis under the following conditions.
- the X-ray crystal structure of the title compound is shown in FIG.
- Analytical instrument XtaLAB PRO P200 MM007HF (Rigaku, Japan)
- Soft CrysAlisPro (Rigaku Oxford Diffraction)
- X-ray multi-layer mirror monochromated Cu-K ⁇ (40 kV / 30 mA)
- Measurement method ⁇ axis oscillation method
- Camera length 35 mm
- Measurement temperature -170 °C
- the obtained mother liquor was concentrated to 10 times the amount, and isopropyl acetate (10 times amount), 5N aqueous sodium hydroxide solution (4.65 ml, 23.269 mmol) and water (4 times amount) were added. After removing the aqueous layer, it was washed with water (4 times the amount). After concentrating to a 5-fold amount, add with isopropyl acetate (10-fold amount) and azeotrope to a 5-fold amount. (+)-Di-palator oil-D-tartrate (3.15 g, 8.144 mmol) was added to a solution of (30.2 mL) and isopropyl acetate (151 mL), and the mixture was stirred overnight at room temperature.
- (+)-Di-palator oil-D-tartaric acid (0.05 eq) and isopropyl acetate (10 eq) were added. The entire amount was recovered by concentration, neutralization with sodium hydroxide, and washing with pure water, and (+)-dipivaloyl-D-tartic acid (0.2 eq) isopropyl acetate (151 mL), acetonitrile (30.2 mL) and methanol (+)-Di-palator oil-D-tartrate (3.15 g, 8.144 mmol) was added to the (38 mL) solution, and the mixture was stirred overnight at room temperature.
- (+)-Di-palator oil-D-tartaric acid (0.05 equal amount) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours.
- (+)-Di-palator oil-D-tartaric acid (0.025 eq) and isopropyl acetate (10 eq) were added to the reaction mixture, and the mixture was stirred overnight at room temperature.
- the reaction mixture was filtered using acetonitrile (3 mL), and the obtained filtrate was subjected to supercritical fluid chromatography using CHIRALPAK® IA / SFC (3 cm x 25 cm) manufactured by Dycel (mobile phase CO2: methanol (75:25)). , 120 bar, 40 ° C., flow velocity: 100 mL / min), and 500 ⁇ L was fractionated at a time to obtain the title compound (22.2 mg) having a retention time of 7.55 minutes.
- Test Example 1-1 Evaluation of operational activity against OX1R and OX2R Human Embryonic Kidney cells 293 (HEK293) cells in which hOX1R and hOX2R were forcibly expressed were 10,000 cells in each well of a 384-well microplate (Greener). The seeds were seeded and cultured in high glucose DMEM (Fujifilm Wako Pure Chemical Industries) supplemented with 10% FBS (Thermo Scientific) and 1% Pencillin-Streptomycin (Fujifilm Wako Pure Chemical Industries) for 24 hours.
- DMEM Flujifilm Wako Pure Chemical Industries
- FBS Thermo Scientific
- Pencillin-Streptomycin Fejifilm Wako Pure Chemical Industries
- test compound was dissolved in DMSO so as to 10 mM, final concentration diluted in assay buffer such that 1x10 -7 M from 3x10 -10 M (final concentration 0.1% DMSO).
- Fluorescence value of well to which compound-free buffer was added was 0%, OX-A (Peptide Institute) The fluorescence value of the well to which 10 nM was added was calculated as 100%, and the 50% working concentration (EC50 value) was obtained from the fluorescence values when various concentrations of the test compound were added. Table 1 shows the operational activity values of each compound.
- Test Example 1-2 Evaluation of operational activity against OX1R and OX2R Human Embryonic Kidney cells 293 (HEK293) cells in which hOX1R and hOX2R were forcibly expressed were 10,000 cells in each well of a 384-well microplate (Greener). The seeds were seeded and cultured for 1 day in high glucose DMEM (Fujifilm Wako Pure Chemical Industries) supplemented with 10% FBS (Thermo Scientific) and 1% Pencillin-Streptomycin (Fujifilm Wako Pure Chemical Industries).
- high glucose DMEM Flujifilm Wako Pure Chemical Industries
- FBS Thermo Scientific
- Pencillin-Streptomycin Ferjifilm Wako Pure Chemical Industries
- assay buffer containing Calcium 4 day (Molecular Device Corporation) and 2.5 mM Probenecid (Sigma-Aldrich) (20 mM HEPES (Sigma-Aldrich), Hank's balanced salt solution (Gibco), 0.1% 30 ⁇ L of BSA (Sigma-Aldrich), 0.1% Pluronic F-127 (Biotium, Inc.) was added and incubated for 60 minutes. 30 ⁇ L of assay buffer containing the test compound was added and the reaction was initiated.
- test compound was dissolved in DMSO so as to 10 mM, final concentration diluted in assay buffer such that 1x10 -5 M from 3x10 -11 M (final concentration 0.1% DMSO).
- the fluorescence value of the well to which the buffer solution containing no compound was added was calculated as 0%, and the fluorescence value of the well to which OX-A (Peptide Institute) 10 nM was added was calculated as 100%.
- the 50% working concentration (EC50 value) was determined from the fluorescence value of. Table 2 shows the operational activity values of each compound.
- Test Example 2 Increase in locomotor activity
- Increase in locomotor activity in mice is one of the indicators of arousal action, along with an increase in arousal time, an increase in body temperature, and an increase in cardiovascular parameters.
- the arousal effect was evaluated by measuring the locomotor activity of mice.
- Male C57BL / 6NCrl mice (18-19 weeks old, Charles River Japan, 4 patients in each group) were used in the experiment.
- Spontaneous momentum was measured by irradiating infrared rays from the side of the measurement cage using a momentum measuring device (VersaMax Open Field, AccuScan Instruments, Inc.) and quantifying the number of times the mouse passed through the irradiation line.
- mice were placed in a measurement cage and acclimatized for 3 hours, after which the compound was orally administered (10 mg / kg). Spontaneous exercise was measured 2 hours after administration.
- mice were administered with a solution of the test compound in 0.1 moL / L hydrochloric acid containing 5% (v / v) DMSO and 5% (v / v) Kolliphor® EL.
- the control group only the above solvent containing no test compound was administered to the mice.
- the locomotor activity is expressed in% as the locomotor activity of the test compound-administered group when the locomotor activity of the control group is 100%.
- the compound of the present invention enhanced the locomotor activity of mice. That is, it was shown that the compound of the present invention has a wakefulness effect.
- Test Example 3 Awakening effect by oral administration of the compound of the present invention to wild-type mice in the dark period
- wild-type (WT) male mice of the C57BL / 6 strain were used.
- 13-week-old mice underwent electroencephalogram and electromyogram measurement electrode implantation surgery under isoflurane anesthesia. After the operation, after acclimatization to the lighting cycle and the experimental operation, the electroencephalogram and the electromyogram were measured, and the mice capable of normally recording the electroencephalogram and the electromyogram were used for the experiment.
- a solution of the solvent (0 mg / kg) or the compound of Example 1 in the solvent; 1, 3 or 10 mg / kg) was orally administered 30 to 15 minutes before extinguishing.
- a 0.1 moL / L hydrochloric acid solution containing 5% (v / v) DMSO and 5% (v / v) Kolliphor® EL was used as the solvent.
- the electroencephalogram and electromyogram were recorded for about 24 hours from 1 hour before the lights were turned off. Mice were used repeatedly with a washout period of 2 days or longer.
- the sleep stage was determined every 1 epoch (10 seconds) using sleep analysis software (SleepSign; Kissei Comtec Co., Ltd.).
- the time (sleep latency) until the first sleep (sleep of 8 epochs or more starting from non-REM sleep) appeared after the lights were turned off was measured.
- the number of cases in each administration group is 16, and the comparison between the solvent administration group (control group) and the compound administration group of Example 1 for sleep latency is the Dunnet after the survival time analysis considering the correspondence of the same individual as the experimental round. A type multiple comparison test was performed, and the significance level was set to 5% on both sides.
- the sleep latency of the mice administered with the solvent and 1, 3 and 10 mg / kg of the compound of Example 1 was 0.23 hours, 0.28 hours, 0.44 hours and 2.07 hours, respectively.
- sleep latency was significantly increased in the compound-administered group of Example 1 at 3 or 10 mg / kg as compared with the solvent-administered group. That is, when the compound of Example 1 was orally administered in the light period (ZT12), which is the beginning of the active period for mice, a dose-dependent prolongation of sleep latency was confirmed.
- mice Orexin-deficient mice (orexin / ataxin 3 mice) with the wakefulness effect and cataplex-like behavior-suppressing effect of the compound of the present invention.
- 3 mice orexin / ataxin-3 Tg / + (hereinafter referred to as "Tg mouse"), Hara et al., Neuron, 30, 345-54, 2001), littermate wild-type mouse (hereinafter "WT mouse”) ")
- WT mouse littermate wild-type mouse
- the solvent (0 mg / kg) or the sample (solution in which the compound of Example 1 was dissolved in the solvent; 0.3, 1, or 3 mg / kg) was orally administered 30 to 15 minutes before turning off the light.
- a 0.1 moL / L hydrochloric acid solution containing 5% (v / v) DMSO and 5% (v / v) Kolliphor® EL was used as the solvent.
- the electroencephalogram and electromyogram were recorded for about 24 hours from 1 hour before the lights were turned off.
- mice were used repeatedly with a washout period of 2 days or longer.
- the obtained EEG and EMG data of each mouse were used to determine the sleep stage for up to 4 hours per epoch (10 seconds) using sleep analysis software (SleepSign; Kissei Comtec Co., Ltd.).
- the cataplexy-like symptom in this experiment means a phenomenon in which REM sleep appears immediately after a wakefulness of 4 consecutive epochs or more (direct transitions from work to REM sleep (DREM)).
- DREM in mice is an analog of cataplexy in humans (Exp Neurol. 2009; 217: 46-54).
- the time until the first sleep (sleep of 8 consecutive epochs or more excluding DREM) appeared (sleep latency) and the time until the first DREM appeared (DREM latency) were measured.
- the number of examples is 8 in the solvent-administered group and 14 in the compound-administered group of Example 1.
- a Dunnet-type multiple comparison test after survival time analysis was performed in consideration of the correspondence of the same individual as in the experimental round, and the significance level was set to 5% on both sides.
- the comparison between the normal control group and the pathological control group for DREM latency was performed by survival time analysis considering the correspondence of the same individual as the experimental time.
- the comparison between the pathological control group and the compound-administered group of Example 1 was performed by performing a Dunnet-type multiple comparison test after survival time analysis in consideration of the correspondence between the experimental times and the same individual.
- the significance level was 5% on both sides.
- Sleep latency of Tg mice administered with the solvent and 0.3, 1 and 3 mg / kg of the compound of Example 1 was 0.21 hours, 0.31 hours, 0.64 hours, and 2.42 hours, respectively. Sleep latency was significantly increased in the compound-administered groups of Example 1 at 1 and 3 mg / kg. That is, when the compound of Example 1 was orally administered in the light period (ZT12), which is the beginning of the active period for mice, it was confirmed that the orexin-deficient mice had a dose-dependent prolongation of sleep latency from 1 mg / kg.
- the DREM latency during vehicle administration in WT mice was 4.00 hours.
- the DREM latency of the solvent and 0.3, 1 and 3 mg / kg of the compound of Example 1 in Tg mice was 1.16 hours, 1.50 hours, 2.26 hours and 4.00 hours, respectively.
- a significant and dose-dependent increase in DREM latency was confirmed as compared with the solvent administration group. That is, the cataplexy-like symptoms (DREM) exhibited by orexin-deficient mice were suppressed in a dose-dependent manner by administration of the compound of the present invention.
Abstract
Description
[1] 下記式(I)
下記式(II)
下記式(III)
及び
下記式(IV)
からなる群から選ばれる一つの化合物又はその薬剤学的に許容される塩。
[2] 下記式(I)
[3] 下記式(II)
[4] 下記式(III)
[5] 下記式(IV)
[6] 前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩を含有する医薬組成物。
[7] 前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩を含有するオレキシン2型受容体作動薬。
[8] 前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩を含有するナルコレプシーの治療剤。
[9] 前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩の薬理学的有効量を対象に投与することを含む、該対象におけるナルコレプシーの治療方法。
[10] 前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩の薬理学的有効量を対象に投与することを含む、該対象におけるオレキシン2型受容体の活性化方法。
[11] 前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩を対象に投与することを含む、ナルコレプシーの治療方法。
[12] ナルコレプシーの治療のための医薬組成物を製造するための前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩の使用。
[13] ナルコレプシーの治療に使用するための前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩。
[14] 前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩を含有するカタプレキシーの治療剤。
[15] 前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩の薬理学的有効量を対象に投与することを含む、該対象におけるカタプレキシーの治療方法。
[16] カタプレキシーの治療に使用するための、前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩。
[17] カタプレキシーの治療のための医薬組成物を製造するための前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩の使用。
[18] 前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩を含有する過眠症症候群の治療剤。
[19] 前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩の薬理学的有効量を対象に投与することを含む、該対象における過眠症症候群の治療方法。
[20] 過眠症症候群の治療に使用するための、前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩。
[21] 過眠症症候群の治療のための医薬組成物を製造するための前記[1]~前記[5]のいずれか一つに記載の化合物又はその薬剤学的に許容される塩の使用。
本発明に係る医薬組成物は、薬剤学的に許容される添加物を化合物群(I)、(II)、(III)及び(IV)から選ばれる化合物又はその薬剤学的に許容される塩と混和することにより製造することができる。本発明に係る医薬組成物は、例えば、第十七改正日本薬局方の製剤総則に記載の方法など既知の方法に従って製造することができる。
(1)光親和性標識基(例えば、ベンゾイル基、ベンゾフェノン基、アジド基、カルボニルアジド基、ジアジリジン基、エノン基、ジアゾ基及びニトロ基等)及び化学親和性基(例えば、アルファー炭素原子がハロゲン原子で置換されたケトン基、カルバモイル基、エステル基、アルキルチオ基、α、β-不飽和ケトン、エステル等のマイケル受容体、及びオキシラン基等)等のタンパク質標識基、
(2)-S-S-、-O-Si-O-、単糖(グルコース基、ガラクトース基等)又は二糖(ラクトース等)等の開裂可能なリンカー、及び酵素反応で開裂可能なオリゴペプチドリンカー、
(3)ビオチン、3-(4,4-ジフルオロ-5,7-ジメチル-4H-3a,4a-ジアザ-4-ボラ-s-インダセン-3-イル)プロピオニル基等のフィッシングタグ基、
(4)125I、32P、3H、14Cなどの放射性標識基;フルオレセイン、ローダミン、ダンシル、ウンベリフェロン、7-ニトロフラザニル、3-(4,4-ジフルオロ-5,7-ジメチル-4H-3a,4a-ジアザ-4-ボラ-s-インダセン-3-イル)プロピオニル基等の蛍光標識基;ルミフェリン、ルミノール等の化学発光基;ランタノイド金属イオン、ラジウムイオン等の重金属イオン等の検出可能なマーカー又は
(5)ガラスビーズ、ガラスベット、マイクロタイタープレート、アガロースビーズ、アガロースベッド、ポリスチレンビーズ、ポリスチレンベッド、ナイロンビーズ、ナイロンベッド等の固相担体と結合させる基等。
n-:ノルマル
tert-:ターシャリー
1H-NMR:プロトン核磁気共鳴スペクトルメトリー
MS:マススペクトルメトリー
HPLC:高速液体クロマトグラフィー
2-ブロモ-2-シクロプロピルアセトアミドの合成
MS(ESI)m/z:178[M+H]+
3-メトキシイソニコチノニトリルの合成
1H-NMR(400MHz,CDCl3)δ(ppm):4.06(s,3H),7.44(d,J=5.0Hz,1H),8.37(d,J=4.5Hz,1H),8.49(s,1H).
MS(ESI)m/z:135[M+H]+
(R)-2-ブロモ-3-メチルブタンアミドの合成
1H-NMR(400MHz,CDCl3)δ(ppm):1.01(d,J=6.3Hz,3H),1.07(d,J=6.8Hz,3H),2.34-2.39(m,1H),4.28(d,J=4.5Hz,1H),5.58(brs,1H),6.41(brs,1H).
MS(ESI)m/z:180[M+H]+
N-(tert-ブトキシカルボニル)-ノルトロピノン(CAS No.185099-67-6)(1.00g,4.44mmol)のメチル tert-ブチル エーテル(18.0mL)溶液に3-メトキシイソニコチノニトリル(1.19g,8.88mmol)とビス(ピナコラート)ジボロン(CAS No.73183-34-3)(2.25g,8.88mmol)を加え、16時間加熱還流した。反応混合物へ炭酸ナトリウム(2mol/L水溶液,20.0mL)を0℃で加え、0℃で20分攪拌した。反応混合物へ酢酸エチルを加え、有機層を分離した。有機層を無水硫酸マグネシウム上で乾燥し、ろ過し、減圧下に濃縮した。残渣をカラムクロマトグラフィー(シリカゲル、0-20%メタノール/酢酸エチル)で精製し、標記化合物(1.12g)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):1.48(s,9H),1.77(m,2H),1.94-1.99(m,2H),2.21-2.32(m,2H),2.37-2.48(m,1H),2.63-2.74(m,1H),2.78(s,1H),3.96(s,3H),4.22-4.29(m,1H),4.31-4.42(m,1H),7.28(d,J=5.4Hz,1H),8.22-8.25(m,2H).
MS(ESI)m/z:335[M+H]+
tert-ブチル (1R,3r,5S)-3-ヒドロキシ-3-(3-メトキシピリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(610mg,1.82mmol)に濃硫酸(1.60mL,30.0mmol)を加え、室温で40分攪拌した。反応混合物を水酸化カリウム(5.00g,89.1mmol)の水(10.0mL)溶液に0℃で加えた。反応混合物にテトラヒドロフラン(10.0mL)とジ-tert-ブチル ジカルボナート(CAS No.24424-99-5)(478mg,2.19mmol)を加え、室温で10分攪拌した。反応混合物へ酢酸エチルを加え、有機層を分離した。有機層を無水硫酸マグネシウム上で乾燥し、ろ過し、減圧下に濃縮した。残渣をカラムクロマトグラフィー(シリカゲル、5-100%酢酸エチル/n-ヘプタン)で精製し、標記化合物(420mg)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):1.46(s,9H),1.72-1.81(m,1H),1.97-2.03(m,2H),2.05-2.36(m,2H),2.94-3.26(m,1H),3.87(s,3H),4.21-4.61(m,2H),6.30(brs,1H),6.99(d,J=4.5Hz,1H),8.17(d,J=5.0Hz,1H),8.21(s,1H).
MS(ESI)m/z:317[M+H]+
tert-ブチル (1R,5S)-3-(3-メトキシピリジン-4-イル)-8-アザビシクロ[3.2.1]オクト-2-エン-8-カルボキシラート(400mg,1.26mmol)のメタノール(3.00mL)溶液に10%パラジウム炭素(川研ファインケミカル(株),AD,52.7%含水品,284mg,0.126mmol)を加え、水素雰囲気下、室温にて1時間攪拌した。反応液をセライト(登録商標)ろ過し、残渣を酢酸エチルで洗浄した。得られたろ液を減圧下濃縮しエンド体とエキソ体の混合物(エンド:エキソ=1:2,398mg)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):1.49(s,6H),1.50(s,3H),1.61-2.13(m,22/3H),2.40-2.45(m,2/3H),2.96-3.01(m,1/3H),3.47-3.59(m,2/3H),3.88(s,1H),3.90(s,2H),4.16-4.28(m,1H),4.34(brs,1H),7.04(d,J=4.5Hz,2/3H),7.06(d,J=5.0Hz,1/3H),8.13-8.23(m,2H).
MS(ESI)m/z:319[M+H]+
tert-ブチル (1R,5S)-3-(3-メトキシピリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(398mg,1.25mmol)のtert-ブタノール(4.00mL)溶液にカリウム tert-ブトキシド(281mg,2.50mmol)を加え、17時間加熱還流した。反応混合物へ酢酸エチルと飽和食塩水を加え、有機層を分離した。有機層を無水硫酸マグネシウム上で乾燥し、ろ過し、減圧下に濃縮し、標記化合物(385mg)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):1.49(s,9H),1.58-2.06(m,8H),3.49-3.56(m,1H),3.90(s,3H),4.24(brs,1H),4.34(brs,1H),7.04(d,J=5.0Hz,1H),8.17-8.19(m,2H).
MS(ESI)m/z:319[M+H]+
tert-ブチル (1R,3s,5S)-3-(3-メトキシピリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(11.2g,35.2mmol)の酢酸(100mL)溶液に10%パラジウム炭素(川研ファインケミカル(株),AD,52.7%含水品,7.91g,3.52mmol)を加え、水素雰囲気下、70℃で18時間攪拌した。反応液をセライト(登録商標)ろ過し、残渣を酢酸エチルで洗浄した。得られたろ液を減圧下濃縮した。残渣へ酢酸エチルと水酸化ナトリウム(2N)を加え、有機層を分離した。有機層をISOLUTE(登録商標) HM-Nで乾燥し、ろ過し、減圧下に濃縮した。残渣にN,N-ジメチルホルムアミド(50.0mL)、2-クロロ-5-フルオロピリミジン(CAS No.62802-42-0)(5.21mL,42.2mmol)と炭酸カリウム(7.29g,52.8mmol)を加え、80℃で40分攪拌した。反応混合物へ酢酸エチルと飽和食塩水を加え、有機層を分離した。有機層を無水硫酸マグネシウム上で乾燥し、ろ過し、減圧下に濃縮した。残渣をカラムクロマトグラフィー(シリカゲル、10-60%酢酸エチル/n-ヘプタン)で精製し、標記化合物(9.84g)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):1.19-1.30(m,3H),1.46(s,9H),1.46-1.65(m,6H),1.81-1.97(m,3H),2.68(d,J=14.5Hz,1H),2.71-2.81(m,1H),3.30(s,3H),3.35(brs,1H),4.08-4.31(m,2H),4.64-4.77(m,1H),5.04-5.18(m,1H),8.13(s,2H).
MS(ESI)m/z:421[M+H]+
tert-ブチル (1R,3s,5S)-3-(1-(5-フルオロピリミジン-2-イル)-3-メトキシピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(7.00g,16.6mmol)をダイセル製CHIRALPAK(登録商標)IC/SFC(3cm×25cm)を用いた超臨界流体クロマトグラフィー(移動相 CO2:メタノール(90:10)、120bar、40℃、流速:100mL/分)にて一回あたり100mgずつ分取し、後に溶出する保持時間8.45分の標記化合物(3.02g)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):1.17-1.29(m,3H),1.46(s,9H),1.46-1.66(m,6H),1.85-1.97(m,3H),2.68(d,J=15.0Hz,1H),2.75(td,J=12.9,3.2Hz,1H),3.30(s,3H),3.35(brs,1H),4.11-4.31(m,2H),4.66-4.76(m,1H),5.10(dt,J=14.4,2.6Hz,1H),8.13(s,2H).
MS(ESI)m/z:443[M+Na]+
(分析条件)ダイセル製CHIRALPAK(登録商標) IC-3(3.0mm×50mm)を用いた超臨界流体クロマトグラフィー(移動相 CO2:メタノール(85:15),40℃,流速:1.2mL/分,検出:UV(254nm))
(分析結果)標記化合物の保持時間は1.34分であり、光学純度は>99%eeであった。
tert-ブチル (1R,3s,5S)-3-((3S,4R)-1-(5-フルオロピリミジン-2-イル)-3-メトキシピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(1.00g,2.38mmol)にトリフルオロ酢酸(5.00mL,64.9mmol)を加え、室温で20分攪拌した。反応液を減圧下濃縮した。残渣に2N 水酸化ナトリウム水溶液を加え、酢酸エチル(3回)で抽出した。合わせた有機層を無水硫酸マグネシウム上で乾燥し、ろ過し、減圧下に濃縮し、標記化合物(620mg)を得た。
MS(ESI)m/z:321[M+H]+
テトラヒドロフラン(7000mL)にピバロイルクロリド(302mL,2470mmol)を室温で加えた。そこへシクロプロピル酢酸(238mL,2450mmol)を室温で加え、0℃で冷却した。トリエチルアミン(350mL)を10分かけて滴下したのち、トリエチルアミン(400mL,総量5340mmol)を加えて、0℃で76分撹拌した。反応混合物へ(S)-4-フェニルオキサゾリジン-2-オン(350g,2140mmol)を一度に加えたのち、塩化リチウム(109g,2570mmol)を一度に加えた。反応混合物を室温で18時間撹拌したのち、酢酸エチル(7000mL)と水(3500mL)を加え室温で40分撹拌した。有機層を分離し、5%炭酸水素ナトリウム水溶液(3500mL)と水(1750mL)で順次洗浄した。得られた有機層を1750mLまで濃縮した。酢酸エチル(2100mL)を加えて、1750mLまで濃縮する共沸操作を3回繰り返したのち、さらに酢酸エチル(1050mL)を加えて1750mLまで濃縮した。得られた濃縮液を撹拌し、n-ヘプタン(1000mL)を滴下した。生じた懸濁液を10分撹拌し、さらにn-ヘプタン(2500mL)を滴下した。その混合液を室温で終夜撹拌したのち、さらに0℃で3.5時間撹拌した。生じた固体をガラスフィルターを用いてろ取し、酢酸エチル/n-ヘプタン(1:3の混合溶液550mL)で洗浄した。得られた固体を減圧下乾燥することで標記化合物(407g)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):0.09-0.24(m,2H)0.46-0.58(m,2H)1.00-1.13(m,1H),2.74-2.83(m,1H),2.88-2.98(m,1H),4.25-4.32(m,1H),4.70(t,J=8.83Hz,1H),5.45(dd,J=8.83,3.85Hz,1H),7.28-7.43(m,5H).
(S)-3-(2-シクロプロピルアセチル)-4-フェニルオキサゾリジン-2-オン(100g,408mmol)のジクロロメタン(1000mL)溶液に、ジブチルボロントリフラートの1Mジクロロメタン溶液 (500mL,500mmol)を氷冷下40分かけて滴下し、10分間氷冷下で攪拌した。N,N-ジイソプロピルエチルアミン(92mL,530mmol)を氷冷下25分かけて滴下したのち1時間氷冷下で攪拌した。その後反応混合物をドライアイス-エタノールバスで内温-72℃まで冷却した。N-ブロモスクシンイミド(80g,448mmol)を一度に加え、ドライアイス-エタノールバスの下で1時間20分攪拌した。28-30%アンモニア水(800mL,6390mmol)とテトラヒドロフラン(1000mL)を加えたのち水浴下で2時間攪拌した。有機層と水層を分けた後、水層を酢酸エチル(500mL)で3回抽出した。得られた有機層を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(シリカゲル 4kg、30-40%酢酸エチル/n-ヘプタン)で精製し132gの粗生成物を得た。得られた粗生成物にtert-ブチルメチルエーテル(1440mL)を加え50℃で一時間攪拌し溶解させたのち。室温で1日攪拌した。生じた固体をろ過し、tert-ブチルメチルエーテル(200mL)で洗浄した。ろ液と洗浄液を合わせ、そこに酢酸エチル(700mL)と活性炭(精製白鷺,26g)を加え室温で30分攪拌した。セライト(登録商標)ろ過により活性炭を除去し、酢酸エチル(700mL)で活性炭を洗浄した。ろ液と洗浄液を合わせたのち、減圧下濃縮することで標記化合物(97.1g,含量65.9%)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):0.40-0.52(m,1H),0.63-0.73(m,1H),0.77-0.86(m,1H),0.86-0.97(m,1H),1.41-1.50(m,1H),3.59-3.83(m,1H),5.34-5.71(m,1H),5.94-6.30(m,1H).
MS(ESI)m/z:180[M+H]+
(分析条件)ダイセル製CHIRALPAK(登録商標) IA(0.46cm×25cm×2本)を用いたクロマトグラフィー(移動相 エタノール:n-ヘキサン(10:90),40℃,流速:0.8mL/分,検出:UV(210nm))
(分析結果)標記化合物の保持時間は24.5分であった。
(R)-2-シクロプロピル-2-((1R,3S,5S)-3-((3S,4R)-1-(5-フルオロピリミジン-2-イル)-3-メトキシピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-イル)アセトアミドの合成
1H-NMR(400MHz,CDCl3)δ(ppm):0.28-0.37(m,1H),0.45-0.52(m,1H),0.53-0.58(m,1H),0.60-0.68(m,1H),0.78(dd,J=8.8,4.3Hz,1H),1.20-1.27(m,2H),1.32-1.45(m,2H),1.46-1.52(m,2H),1.59-1.65(m,3H),1.70-1.80(m,2H),1.81-1.88(m,1H),2.08(d,J=9.1Hz,1H),2.68(dd,J=14.3,1.1Hz,1H),2.75(td,J=12.8,2.9Hz,1H),3.21-3.24(m,1H),3.30(s,3H),3.36(brs,1H),3.86-3.91(m,1H),4.65-4.76(m,1H),5.10(dt,J=14.2,2.4Hz,1H),5.14-5.24(m,1H),6.92-7.02(m,1H),8.14(s,2H).
MS(ESI)m/z:418[M+H]+
(分析条件)ダイセル製CHIRALPAK(登録商標) IA(0.46cm×15cm)を用いたクロマトグラフィー(移動相 エタノール:ヘキサン(20:80),40℃,流速:1mL/分,検出:UV(254nm))
(分析結果)標記化合物の保持時間は4.91分であり、光学純度は>99%eeであった。
実施例1で得られた標記化合物(2.97mg)をメタノール(1mL)に溶解した。そのうち500μLをバイアルに入れ、軽くキャップを閉めた(溶媒蒸発法)。1日後、バイアル中に標記化合物の単結晶を得た。得られた単結晶について、以下の条件でX線結晶構造解析を行った。標記化合物のX線結晶構造を図1に示す。
分析機器:XtaLAB PRO P200 MM007HF (Rigaku, Japan)
ソフト:CrysAlisPro (Rigaku Oxford Diffraction)
X線:multi-layer mirror monochromated Cu-Kα (40 kV/30 mA)
測定法:ω axis oscillation method
カメラ長:35 mm
測定温度:-170℃
(R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-フルオロピリミジン-2-イル)-3-メトキシピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-イル)-3-メチルブタンアミドの合成
1H-NMR(400MHz,CDCl3)δ(ppm):0.95(d,J=6.8Hz,3H),1.02(d,J=6.8Hz,3H),1.15-1.56(m,8H),1.75(td,J=10.8,6.1Hz,3H),1.86-2.10(m,2H),2.67(d,J=13.1Hz,1H),2.75(td,J=12.9,3.2Hz,1H),2.95(d,J=4.1Hz,1H),3.19-3.27(m,1H),3.30(s,3H),3.33-3.46(m,2H),4.70(dt,J=13.3,2.2Hz,1H),5.06-5.16(m,1H),5.30-5.36(m,1H),6.79(brd,J=5.0Hz,1H),8.14(s,2H).
MS(ESI)m/z:421[M+H]+
(R)-2-((1R,3S,5S)-3-((3S,4R)-1-(5-クロロピリミジン-2-イル)-3-エトキシピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-イル)-2-シクロプロピルアセトアミドの合成
tert-ブチル(1R,3s,5S)-3-(3-メトキシピリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(20g,62.8mmol)と10%パラジウム炭素(川研ファインケミカル製タイプAD,約50%含水品,6g)の酢酸(160mL)混合物を水素雰囲気下70℃で終夜攪拌した。ろ過によりパラジウム炭素を除去し、メタノール(10倍量)で洗浄後、ろ液をおよそ2倍量まで濃縮した。得られた濃縮液に酢酸イソプロピル(15倍量)とn-ヘプタン(3倍量)を加えた後、48%水酸化ナトリウム水溶液(54.7mL)で洗浄した。n-ヘプタン(100mL)を加え水(5倍量)で洗浄後、およそ5倍量まで濃縮した。得られた濃縮液に酢酸イソプロピル(5倍量)を加えて、およそ5倍量まで濃縮する共沸操作を2回繰り返すことでtert-ブチル(1R,3s,5S)-3-(3-メトキシピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(15.1g)を酢酸イソプロピル溶液として得た。
得られたtert-ブチル(1R,3s,5S)-3-(3-メトキシピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(7.55g,23.3mmol)と(+)-ジピバロイル-D-酒石酸(1.85g,5.82mmol)の酢酸イソプロピル(151mL)、アセトニトリル(30.2mL)及びメタノール(38mL)溶液に(-)-ジ-パラトルオイル-L-酒石酸(2.70g,6.98mmol)を加え、室温にて3日間攪拌して固体を得た。
得られた固体をろ取したのち、酢酸イソプロピルとアセトニトリルの混合溶液(9/1)で固体を洗浄した。得られた母液を10倍量まで濃縮し、酢酸イソプロピル(10倍量)、5N水酸化ナトリウム水溶液(4.65ml,23.269mmol)及び水(4倍量)を加えた。水層を除去したのち、水(4倍量)で洗浄した。5倍量まで濃縮後、酢酸イソプロピル(10倍量)で加えて5倍量まで共沸し、(+)-ジピバロイル-D-酒石酸(1.852g,5.817mmol)のメタノール(38mL)、アセトニトリル(30.2mL)及び酢酸イソプロピル(151mL)溶液に(+)-ジ-パラトルオイル-D-酒石酸(3.15g,8.144mmol)を加え、室温にて終夜攪拌した。(+)-ジ-パラトルオイル-D-酒石酸(0.05等量)と酢酸イソプロピル(10倍量)を加えた。濃縮、水酸化ナトリウムによる中和、純水による洗浄によって全量を回収し、(+)-ジピバロイル-D-酒石酸(0.2等量)の酢酸イソプロピル(151mL)、アセトニトリル(30.2mL)及びメタノール(38mL)溶液に(+)-ジ-パラトルオイル-D-酒石酸(3.15g,8.144mmol)を加え、室温にて終夜攪拌した。反応混合物に(+)-ジ-パラトルオイル-D-酒石酸(0.05等量)を加え、室温にて4時間攪拌した。反応混合物へ(+)-ジ-パラトルオイル-D-酒石酸(0.025等量)と酢酸イソプロピル(10倍量)を加え、室温にて終夜攪拌した。濃縮、水酸化ナトリウムによる中和、純水による洗浄によって全量を回収し、(+)-ジピバロイル-D-酒石酸(0.2等量)の酢酸イソプロピル(151mL)、アセトニトリル(30.2mL)及びメタノール(38mL)溶液に(+)-ジ-パラトルオイル-D-酒石酸(3.15g,8.14mmol)を加え、室温にて終夜攪拌した。酢酸イソプロピル(10倍量)を加えた。7時間後、生じた固体をろ取し酢酸イソプロピルで洗浄することで標記化合物(3.45g)を得た。
(分析条件)ダイセル製CHIRALPAK(登録商標) IA(0.46cm×25cm)を用いたクロマトグラフィー(移動相 エタノール:n-ヘキサン(20:80),40℃,流速:1.0mL/分,検出:UV(254nm))
(分析結果)標記化合物の保持時間は8.52分であり、光学純度は99.2%eeであった。
2,5-ジクロロピリミジン(288mg,1.93mmol)、tert-ブチル(1R,3s,5S)-3-((3S,4R)-3-メトキシピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート ヘミ(2S,3S)-2,3-ビス((4-メチルベンゾイル)オキシ)スクシナート(500mg,0.966mmol)と炭酸カリウム(267mg,1.93mmol)のN,N-ジメチルホルムアミド(10mL)を80℃で24時間攪拌した。室温まで冷却した後、水を加え酢酸エチルで3回抽出した。有機層を集めて濃縮した。得られた残渣をカラムクロマトグラフィー(シリカゲル、10-100%酢酸エチル/n-ヘプタン)で精製し、標記化合物(368mg)を得た
1H-NMR(400MHz,CDCl3)δ(ppm):1.24-1.27(m,2H),1.41-1.49(m,2H),1.46(s,9H),1.61(brs,4H),1.82-1.98(m,4H),2.68(d,J=14.04Hz,1H),2.75(td,J=12.91,3.17Hz,1H),3.30(s,3H),3.36(brs,1H),4.11-4.32(m,2H),4.68-4.80(m,1H),5.12(dt,J=14.27,2.61Hz,1H),8.16(s,2H).
tert-ブチル(1R,3s,5S)-3-((3S,4R)-1-(5-クロロピリミジン-2-イル)-3-メトキシピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(300mg,0.687mmol)と48%臭化水素酸(5mL)の混合物を室温で20分攪拌したのち、100℃で2.5時間加熱した。その後室温で終夜攪拌し、得られた反応混合物を減圧下濃縮した。得られた残渣にテトラヒドロフラン(10mL)と飽和炭酸水素ナトリウム水溶液を加え、そこにジ-tert-ブチルジカルボナート(165mg,0.755mmol)を室温で加えた。UPLCで反応の完結を確認したのち、酢酸エチルと水を加えて有機層を分離した。水層を酢酸エチルで再度抽出し、先に得られた有機層と合わせて無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた残渣を10%酢酸エチル/n-ヘプタンの混合溶媒で洗浄し、標記化合物(226mg)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):1.28-1.34(m,2H),1.46(s,9H),1.59-1.72(m,6H),1.75-1.97(m,4H),2.70-2.83(m,1H),2.91(dd,J=14.04,0.91Hz,1H),3.97-4.03(m,1H),4.09-4.34(m,2H),4.68-4.79(m,1H),4.81-4.91(m,1H),8.18(s,2H).MS(ESI)m/z:423[M+H]+
tert-ブチル(1R,3s,5S)-3-((3S,4R)-1-(5-クロロピリミジン-2-イル)-3-ヒドロキシピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(50mg,0.118mmol)のN,N-ジメチルホルムアミド(1mL)溶液に、氷冷下、水素化ナトリウム(60%、流動パラフィンに分散、7.09mg,0.177mmol)を加えた。30分攪拌したのち、ヨウ化エチル(0.019mL,0.236mmol)を加え室温で16時間攪拌した。反応液へ水と酢酸エチルを加えた後、有機層を分離して濃縮した。得られた残渣をカラムクロマトグラフィー(シリカゲル、1-20%酢酸エチル/n-ヘプタン)で精製し、標記化合物(42.5mg)を得た。
MS(ESI)m/z:451[M+H]+
tert-ブチル(1R,3s,5S)-3-((3S,4R)-1-(5-クロロピリミジン-2-イル)-3-エトキシピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(42.5mg,0.094mmol)をトリフルオロ酢酸(1mL)で30分処理したのち、濃縮した。得られた残渣をメタノールに溶かし、Waters Porapak Rxn(登録商標) CX(0.4g)上に供した。固相をメタノール(6mL)で洗浄した後、生成物をアンモニア(2mol/Lメタノール溶液,6mL)で溶離し、溶出液を減圧下濃縮した。得られた残渣、製造例5と同様の操作にて得られた(S)-2-ブロモ-2-シクロプロピルアセトアミド(51.6mg,0.188mmol)、炭酸カリウム(26.0mg,0.188mmol)及びアセトニトリル(2mL)の混合物を室温で17日間攪拌した。反応混合物をアセトニトリル(3mL)を用いてろ過し、得られたろ液をダイセル製CHIRALPAK(登録商標)IA/SFC(3cmx25cm)を用いた超臨界流体クロマトグラフィー(移動相 CO2:メタノール(75:25)、120bar、40℃、流速:100mL/分)にて一回あたり500μLずつ分取し、保持時間7.55分の標記化合物(22.2mg)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):0.26-0.38(m,1H),0.40-0.58(m,2H),0.59-0.68(m,1H),0.71-0.83(m,1H),0.98-1.92(m,12H),1.04(t,J=7.02Hz,3H),2.07(brd,J=9.06Hz,1H),2.61-2.81(m,2H),3.13-3.30(m,2H),3.45(brs,1H),3.61-3.75(m,1H),3.84-3.92(m,1H),4.66-4.76(m,1H),4.93-5.11(m,1H),5.17-5.32(m,1H),6.90-7.03(m,1H),8.16(s,2H).
MS(ESI)m/z:448[M+H]+
(分析条件)ダイセル製CHIRALPAK(登録商標) IA-3(0.46cm×25cm)を用いた超臨界流体クロマトグラフィー(移動相 CO2:メタノール(80:20),40℃,流速:1.2mL/分,検出:UV(257nm))
(分析結果)標記化合物の保持時間は2.19分であり、光学純度は>99.9%eeであった。
実施例3で得られた標記化合物(1.37mg)をアセトニトリル(600μL)に溶解した。そのうち200μLをバイアルに入れ、軽くキャップを閉めた(溶媒蒸発法)。1日後、バイアル中に標記化合物の単結晶(アセトニトリルが2分子付加した二量体の結晶)を得た。得られた単結晶について、以下の条件でX線結晶構造解析を行った。標記化合物のX線結晶構造を図2に示す。
分析機器:XtaLAB PRO P200 MM007HF (Rigaku, Japan)
ソフト:CrysAlisPro (Rigaku Oxford Diffraction)
X線:multi-layer mirror monochromated Cu-Kα (40 kV/30 mA)
測定法:ω axis oscillation method
カメラ長:35 mm
測定温度:-170℃
(R)-2-シクロプロピル-2-((1R,3S,5S)-3-((2S,4S)-1-(5-フルオロピリミジン-2-イル)-2-メチルピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-イル)アセトアミドの合成
13mmスクリューキャップ試験管に、エチル (1R,3s,5S)-3-(トシルオキシ)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(CAS No.2236076-85-8)(200mg,0.566mmol)、臭化ニッケル(II)エチレングリコールジメチルエーテル錯体(17.5mg,0.057mmol)、4,4-ジ-tert-ブチル-2,2-ジピリジル(15.2mg,0.057mmol)、ヨウ化カリウム(94.0mg,0.566mmol)及びマンガン(62.2mg,1.13mmol)を加えた。次いで、tert-ブチル (S)-2-メチル-4-(((トリフルオロメチル)スルホニル)オキシ)-3,6-ジヒドロピリジン-1(2H)-カルボキシラート(CAS No.876922-74-6)(195mg,0.566mmol)のN,N-ジメチルアセトアミド(4.0mL)溶液及び4-エチルピリジン(0.064mL,0.566mmol)を窒素気流下加えた。得られた混合物を窒素雰囲気下、80℃で12.5時間撹拌した。室温まで冷却した後、酢酸エチルで希釈した。不溶物を綿栓ろ過で除去し、溶出物を水及び酢酸エチルで分配した。水層を分取し、酢酸エチルで抽出した。有機層を合わせ、水で3回洗浄し減圧下濃縮し、カップリング反応生成物を粗生成物として得た。
得られた粗生成物のジクロロメタン(4.0mL)溶液に、トリフルオロ酢酸(1.0mL)を加え、室温で1時間撹拌した。反応混合物に窒素を吹き付けることで溶媒を留去し、残渣をメタノールで希釈した。得られたメタノール溶液をWaters PоraPak Rxn(登録商標) CX(20cc(2g)cartridge)上に供した。固相をメタノール(20.0mL)で洗浄した後、アンモニア(2Nメタノール溶液,20mL)で溶出させた。溶出液を減圧下濃縮することで、標記化合物の粗生成物(120mg)を得た。
MS(ESI)m/z:279[M+H]+
エチル (1R,3s,5S)-3-((S)-2-メチル-1,2,3,6-テトラヒドロピリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(120mg,0.431mmol)、10%パラジウム炭素(エヌ・イーケムキャット(株)、48.47%含水品、183mg,0.083mmol)及びメタノール(4.0mL)の混合物を水素雰囲気下、6.5時間撹拌した。不溶物をセライト(登録商標)ろ過で除き、減圧下濃縮することで還元体(113mg)をシス・トランスの混合物として得た。
MS(ESI)m/z:281[M+H]+
得られた還元体(113mg)、2-クロロ-5-フルオロピリミジン(0.048mL,0.517mmol)、炭酸セシウム(281mg,0.862mmol)及びN,N-ジメチルアセトアミド(2.0mL)の混合物を100℃で8時間撹拌した。混合物をカラムクロマトグラフィー(シリカゲル、0-30%酢酸エチル/n-ヘプタン)で精製し、標記化合物(82.0mg)をシス・トランスの混合物として得た。
MS(ESI)m/z:377[M+H]+
(分析条件)ダイセル製CHIRALPAK(登録商標) IF-3(3.0mm×50mm)を用いた超臨界流体クロマトグラフィー(移動相 CO2:メタノール(70:30),40℃,流速:1.2mL/分,検出:UV(210-400nm))
(分析結果)標記化合物の保持時間は1.02分であり、トランス体の保持時間は1.23分であった。シス:トランスは4:5(ピーク面積比)であり、光学純度は>99%eeであった。
得られたシス・トランスの混合物を、ダイセル製CHIRALPAK(登録商標)IF/SFC(3cmx25cm)を用いた超臨界流体クロマトグラフィー(移動相 CO2:メタノール(70:30)、120bar、40℃、流速:100mL/分)にて一回あたり10mgずつ分取し、先に溶出する保持時間5.55分の標記化合物(34.0mg)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):1.17(d,J=6.34Hz,3H),1.23(t,J=7.25Hz,3H),1.19-2.02(m,14H),3.09(ddd,J=13.70,10.99,5.66Hz,1H),4.10(q,J=7.10Hz,2H),4.17-4.30(m,3H),4.34(dd,J=13.59,7.25Hz,1H),8.13(s,2H).
MS(ESI)m/z:377[M+H]+
(分析条件)ダイセル製CHIRALPAK(登録商標) IF-3(3.0mm×50mm)を用いた超臨界流体クロマトグラフィー(移動相 CO2:メタノール(70:30),40℃,流速:1.2mL/分,検出:UV(245nm))
(分析結果)標記化合物の保持時間は1.02分であり、シス:トランスは>99:1であり、光学純度は>99%eeであった。
エチル (1R,3s,5S)-3-((2S,4S)-1-(5-フルオロピリミジン-2-イル)-2-メチルピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン-8-カルボキシラート(34mg,0.09mmol)と48%臭化水素酸(2.0mL)の混合物を100℃で1時間撹拌した。反応混合物に0℃で5N水酸化ナトリウム水溶液を加えて中和した。混合物をジクロロメタンで3回抽出し、有機層を無水硫酸マグネシウムで乾燥し減圧下濃縮することで標記化合物(21.7mg)を得た。
MS(ESI)m/z:305[M+H]+
(1R,3s,5S)-3-((2S,4S)-1-(5-フルオロピリミジン-2-イル)-2-メチルピペリジン-4-イル)-8-アザビシクロ[3.2.1]オクタン(5.00mg,0.016mmol)、炭酸カリウム(4.54mg,0.033mmol)、(S)-2-ブロモ-2-シクロプロピルアセトアミド(8.24mg,0.033mmol)及びアセトニトリル(1.0mL)の混合物を室温で7日間撹拌した。反応混合物に炭酸カリウム(4.54mg,0.033mmol)及び(S)-2-ブロモ-2-シクロプロピルアセトアミド(8.24mg,0.033mmol)を加え、さらに室温で3日間撹拌した。反応混合物に塩化アンモニウム水溶液を加えて反応を停止させた。混合物を酢酸エチルで抽出し、有機層を水で洗浄し減圧下濃縮することで粗生成物を得た。
得られた粗生成物をメタノールで希釈し、Waters PоraPak Rxn(登録商標) CX(6cc(400mg)cartridge)上に供した。固相をメタノール(6.0mL)で洗浄した後、アンモニア(2Nメタノール溶液,6mL)で溶出させた。溶出液を減圧下濃縮し、得られた残渣を薄層クロマトグラフィー(NH,ジクロロメタン)で精製することで標記化合物(3.74mg)を得た。
1H-NMR(400MHz,CDCl3)δ(ppm):0.25-0.36(m,1H),0.39-0.51(m,1H),0.51-0.59(m,1H),0.59-0.70(m,1H),0.70-0.84(m,1H),1.18(d,J=6.34Hz,3H),1.21-1.55(m,9H),1.61-1.95(m,5H),2.04(d,J=9.06Hz,1H),3.10(ddd,J=13.70,10.99,5.21Hz,1H),3.15-3.28(m,1H),3.80-3.94(m,1H),4.17-4.29(m,1H),4.35(dd,J=13.59,7.25Hz,1H),5.18(brs,1H),6.94(brs,1H),8.14(s,2H).
MS(ESI)m/z:402[M+H]+
実施例4で得られた標記化合物(0.81mg)をメタノール(600μL)に溶解した。そのうち200μLを入れたバイアルを、このバイアルよりひと回り大きく、tert-ブチルメチルエーテル2mLが入ったバイアルにゆっくり入れ、キャップを閉めた(蒸気拡散法)。12日後、バイアル中に標記化合物の単結晶を得た。得られた単結晶について、以下の条件でX線結晶構造解析を行った。標記化合物のX線結晶構造を図3に示す。
分析機器:XtaLAB PRO P200 MM007HF (Rigaku, Japan)
ソフト:CrysAlisPro (Rigaku Oxford Diffraction)
X線:multi-layer mirror monochromated Cu-Kα (40 kV/30 mA)
測定法:ω axis oscillation method
カメラ長:35 mm
測定温度:-170℃
実施例1~4の化合物を用いて、以下の薬理試験を行った。
hOX1R、hOX2Rを強制発現させたHuman Embryonic Kidney cells 293(HEK293)細胞を384ウェルのマイクロプレート(Greiner)の各ウェルに10,000個となるように播種し、10% FBS(サーモサイエンティフィック)及び1% Penicillin-Streptomycin(富士フイルム和光純薬)添加した高グルコースDMEM(富士フイルム和光純薬)で24時間培養した。培地を除去後、Calcium 4 dye(Molecular Device Corporation)及び2.5mM プロベネシド(シグマアルドリッチ)を含むアッセイ用緩衝液(20mM HEPES(シグマアルドリッチ)、Hank’s balanced salt solution(ギブコ)、0.1% BSA(シグマアルドリッチ)、0.1% Pluronic F-127(Biotium,Inc.))を40μL添加し、60分間インキュベートした。アッセイ用緩衝液20μLを更に添加した後に、被験化合物を含むアッセイ用緩衝液20μLを添加し、反応を開始した。反応による細胞内カルシウムイオン濃度の変化は、FDSS7000(浜松ホトニクス)を用いて、480nm及び540nmの二波長励起による蛍光強度比を蛍光値として測定することにより測定した。なお、被験化合物は10mMとなるようにDMSOに溶解し、最終濃度が3x10-10Mから1x10-7Mとなるようにアッセイ用緩衝液で希釈した(DMSOの最終濃度は0.1%)。化合物を含まない緩衝液を添加したウェルの蛍光値を0%、OX-A(ペプチド研究所)
10nMを添加したウェルの蛍光値を100%として算出し、種々の濃度の被験化合物を添加した際の蛍光値から、50%作動作用濃度(EC50値)を求めた。表1に各化合物の作動活性値を示した。
hOX1R、hOX2Rを強制発現させたHuman Embryonic Kidney cells 293(HEK293)細胞を384ウェルのマイクロプレート(Greiner)の各ウェルに10,000個となるように播種し、10% FBS(サーモサイエンティフィック)及び1% Penicillin-Streptomycin(富士フイルム和光純薬)添加した高グルコースDMEM(富士フイルム和光純薬)で1日培養した。培地を除去後、Calcium 4 dye(Molecular Device Corporation)及び2.5mM プロベネシド(シグマアルドリッチ)を含むアッセイ用緩衝液(20mM HEPES(シグマアルドリッチ)、Hank’s balanced salt solution(ギブコ)、0.1% BSA(シグマアルドリッチ)、0.1% Pluronic F-127(Biotium,Inc.))を30μL添加し、60分間インキュベートした。被験化合物を含むアッセイ用緩衝液30μLを添加し、反応を開始した。反応による細胞内カルシウムイオン濃度の変化は、FDSS7000(浜松ホトニクス)を用いて、480nm及び540nmの二波長励起による蛍光強度比を蛍光値として測定することにより測定した。なお、被験化合物は10mMとなるようにDMSOに溶解し、最終濃度が3x10-11Mから1x10-5Mとなるようにアッセイ用緩衝液で希釈した(DMSOの最終濃度は0.1%)。化合物を含まない緩衝液を添加したウェルの蛍光値を0%、OX-A(ペプチド研究所)10nMを添加したウェルの蛍光値を100%として算出し、種々の濃度の被験化合物を添加した際の蛍光値から、50%作動作用濃度(EC50値)を求めた。表2に各化合物の作動活性値を示した。
マウスにおける運動量の増加は、覚醒時間の増加、体温の上昇、心脈管系パラメータの増強などと共に、覚醒作用の指標の1つである。この試験例では覚醒作用を、マウスの自発運動量を測定することにより評価した。実験には、雄性のC57BL/6NCrlマウス(18-19週齢、日本チャールス・リバー、各群4例ずつ)を用いた。自発運動量は、運動量測定装置(VersaMaxオープンフィールド、AccuScan Instruments, Inc.)を使用して測定ケージの側部から赤外線を照射し、マウスが照射線を通過する回数を定量することで測定した。マウスを測定ケージに入れ3時間馴化させた後、化合物を経口投与した(10mg/kg)。自発運動量は、投与後2時間測定した。試験化合物投与群は、試験化合物を5%(v/v)DMSO及び5%(v/v)Kolliphor(登録商標) ELを含む0.1moL/L塩酸に溶解した溶液をマウスに投与した。対照群には、試験化合物を含まない上記溶媒のみをマウスに投与した。
実験動物は、C57BL/6系統の野生型(WT)雄性マウスを用いた。13週齢のマウスにイソフルラン麻酔下にて脳波及び筋電図測定用電極埋め込み手術を行った。手術後、照明サイクルや実験操作への馴化を経てから、脳波及び筋電図の測定を実施し、脳波及び筋電図が正常に記録できるマウスを実験に供した。溶媒(0mg/kg)または実施例1の化合物を溶媒に溶解した溶液;1、3または10mg/kg)を消灯の30~15分前に経口投与した。なお、溶媒は5%(v/v)DMSO及び5%(v/v)Kolliphor(登録商標) ELを含む0.1moL/L塩酸溶液を用いた。脳波及び筋電図は消灯1時間前から約24時間記録した。マウスは2日以上のウォッシュアウト期間を設け、繰り返し使用した。得られた各マウスの脳波及び筋電図データは、睡眠解析ソフトウェア(SleepSign;キッセイコムテック株式会社)を利用して、1エポック(10秒)ごとに睡眠ステージを判定した。1例ごとに消灯後に最初の睡眠(non-REM睡眠から始まる8エポック以上の睡眠)が現れるまでの時間(睡眠潜時)を計測した。各投与群の例数を16とし、睡眠潜時についての溶媒投与群(対照群)と実施例1の化合物投与群間の比較は実験回と同一個体の対応を考慮した生存時間解析後のDunnet型多重比較検定を行い、いずれも有意水準は両側5%とした。
実験動物は、C57BL/6系統を遺伝的背景とするオレキシン/アタキシン3マウス(orexin/ataxin-3 Tg/+(以下「Tgマウス」と表記)、Hara et al., Neuron, 30, 345-54, 2001)、コントロールとして同腹仔の野生型マウス(以下「WTマウス」と表記)を用いた。12週齢(±2週)のマウスにイソフルラン麻酔下にて脳波及び筋電図測定用電極埋め込み手術を行った。手術後、照明サイクルや実験操作への馴化を経てから、脳波及び筋電図測定を実施し、脳波及び筋電図が正常に記録できるマウスを実験に供した。溶媒(0mg/kg)または検体(実施例1の化合物を溶媒に溶解した溶液;0.3、1、または3mg/kg)を消灯の30~15分前に経口投与した。なお、溶媒は5%(v/v)DMSO及び5%(v/v)Kolliphor(登録商標) ELを含む0.1moL/L塩酸溶液を用いた。脳波及び筋電図は消灯1時間前から約24時間記録した。マウスは2日以上のウォッシュアウト期間を設け、繰り返し使用した。得られた各マウスの脳波及び筋電図データは、睡眠解析ソフトウェア(SleepSign;キッセイコムテック株式会社)を利用して、1エポック(10秒)ごとに最大4時間まで睡眠ステージを判定した。本実験でのカタプレキシー様症状とは、連続4エポック以上の覚醒状態の直後にREM睡眠が出現する現象(direct transitions from wake to REM sleep(DREM))を意味する。マウスのDREMは人でのカタプレキシーのアナログである(Exp Neurol. 2009;217:46-54)。1例ごとに消灯後に最初の睡眠(DREMを除き、連続8エポック以上の睡眠)が現れるまでの時間(睡眠潜時)及び最初のDREMが現れるまでの時間(DREM潜時)を計測した。例数は溶媒投与群は8で、実施例1の化合物投与群は14である。睡眠潜時についての病態対照群と化合物投与群間の比較は実験回と同一個体の対応を考慮した生存時間解析後のDunnet型多重比較検定を行い、いずれも有意水準は両側5%とした。また、DREM潜時についての正常対照群と病態対照群間の比較は、実験回と同一個体の対応を考慮した生存時間解析にて行った。上記の検定が有意であった場合の病態対照群と実施例1の化合物投与群間の比較は実験回と同一個体の対応を考慮した生存時間解析後のDunnet型多重比較検定を行い、いずれも有意水準は両側5%とした。
Claims (15)
- 下記式(I)
下記式(II)
下記式(III)
及び
下記式(IV)
からなる群から選ばれる一つの化合物又はその薬剤学的に許容される塩。 - 請求項1~5のいずれか一項に記載の化合物又はその薬剤学的に許容される塩を含有する医薬組成物。
- 請求項1~5のいずれか一項に記載の化合物又はその薬剤学的に許容される塩を含有するオレキシン2型受容体作動薬。
- 請求項1~5のいずれか一項に記載の化合物又はその薬剤学的に許容される塩を含有するナルコレプシーの治療剤。
- 請求項1~5のいずれか一項に記載の化合物又はその薬剤学的に許容される塩の薬理学的有効量を対象に投与することを含む、該対象におけるナルコレプシーの治療方法。
- ナルコレプシーの治療に使用するための、請求項1~5のいずれか一項に記載の化合物又はその薬剤学的に許容される塩。
- ナルコレプシーの治療のための医薬組成物を製造するための請求項1~5のいずれか一項に記載の化合物又はその薬剤学的に許容される塩の使用。
- 請求項1~5のいずれか一項に記載の化合物又はその薬剤学的に許容される塩を含有するカタプレキシーの治療剤。
- 請求項1~5のいずれか一項に記載の化合物又はその薬剤学的に許容される塩の薬理学的有効量を対象に投与することを含む、該対象におけるカタプレキシーの治療方法。
- カタプレキシーの予防又は治療に使用するための、請求項1~5のいずれか一項に記載の化合物又はその薬剤学的に許容される塩。
- カタプレキシーの治療のための医薬組成物を製造するための請求項1~5のいずれか一項に記載の化合物又はその薬剤学的に許容される塩の使用。
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US11760747B2 (en) | 2020-12-21 | 2023-09-19 | Alkermes, Inc. | Substituted piperidino compounds and related methods of treatment |
WO2024075825A1 (ja) * | 2022-10-07 | 2024-04-11 | キッセイ薬品工業株式会社 | シクロペンタン化合物 |
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US11542276B2 (en) | 2019-11-25 | 2023-01-03 | Alkermes, Inc. | Substituted macrocyclic compounds and related methods of treatment |
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WO2024075825A1 (ja) * | 2022-10-07 | 2024-04-11 | キッセイ薬品工業株式会社 | シクロペンタン化合物 |
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