WO2022191092A1 - Quinoline compound, hnmt inhibitor, and agent for preventing/treating adhd, narcolepsy, or alzheimer's disease - Google Patents

Quinoline compound, hnmt inhibitor, and agent for preventing/treating adhd, narcolepsy, or alzheimer's disease Download PDF

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WO2022191092A1
WO2022191092A1 PCT/JP2022/009571 JP2022009571W WO2022191092A1 WO 2022191092 A1 WO2022191092 A1 WO 2022191092A1 JP 2022009571 W JP2022009571 W JP 2022009571W WO 2022191092 A1 WO2022191092 A1 WO 2022191092A1
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ethyl acetate
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美枝子 有澤
雄朗 吉川
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国立大学法人東北大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton

Definitions

  • the present invention relates to quinoline compounds, HNMT inhibitors and medicaments for preventing or treating ADHD, Narcolepsy or Alzheimer's.
  • AD Alzheimer's disease
  • CaMKII calcium/calmodulin-dependent protein kinase II
  • Non-Patent Document 11 histamine H3 receptor (H3R) antagonists
  • H3R histamine H3 receptor
  • An object of the present invention is to provide a new method for increasing the concentration of histamine in the brain.
  • the present inventors have made intensive studies on a novel mechanism for increasing the concentration of histamine in the brain.
  • the research proceeded with an approach of increasing brain histamine concentration by inhibiting HNMT (Non-Patent Document 14).
  • Non-Patent Document 14 As a result of extensive trial and error with a wide variety of compounds, the inventors have found that the compound represented by general formula (I) or a salt thereof has HNMT inhibitory activity.
  • the present invention is based on such new findings. Accordingly, the present invention provides the following items: Item 1.
  • l represents an integer of 0 to 3.
  • m represents an integer of 0 to 3;
  • n represents an integer of 0-4.
  • X represents a halogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, an alkylamino group or an aminoalkyl group.
  • Y represents a hydroxyl group, an optionally substituted acyloxy group, a sulfate group, a thiol group or an optionally substituted amino group.
  • l is 2 or more, multiple X's may be the same or different.
  • m is 2 or more, multiple Y's may be the same or different.
  • HNMT inhibitor comprising a compound represented by the following general formula (I) or a salt thereof:
  • l represents an integer of 0 to 3.
  • m represents an integer of 0 to 3;
  • n represents 0-4.
  • X represents a halogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, an alkylamino group or an aminoalkyl group.
  • Y represents a hydroxyl group, an optionally substituted acyloxy group, a sulfate group, a carbamoyloxy group, a thiol group or an optionally substituted amino group.
  • l is 2 or more, multiple X's may be the same or different.
  • m is 2 or more, multiple Y's may be the same or different.
  • a medicament for preventing or treating ADHD, narcolepsy or Alzheimer's comprising a compound represented by the following general formula (I) or a salt thereof:
  • l represents an integer of 0 to 3.
  • m represents an integer of 0 to 3;
  • n represents an integer of 0-4.
  • X represents a halogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, an alkylamino group or an aminoalkyl group.
  • Y represents a hydroxyl group, an optionally substituted acyloxy group, a sulfate group, a carbamoyloxy group, a thiol group or an optionally substituted amino group.
  • l is 2 or more, multiple X's may be the same or different.
  • m is 2 or more, multiple Y's may be the same or different.
  • Section 4 when l is 1 or more, at least one X is a halogen, when m is 1 or more, at least one Y is a hydroxyl group or an optionally substituted acyloxy group, and n is 0 to 2
  • the present invention can provide a new method for increasing brain histamine levels through a new approach of inhibiting HNMT. Therefore, according to the present invention, various diseases and conditions that can be treated by HNMT inhibition can be ameliorated.
  • FIG. 1 shows the measurement results of intracerebral histamine concentration (corrected by tissue weight of cortex, diencephalon, brain stem and cerebellum) one hour after administration of 0.1 mmol (100 ⁇ mol)/kg of HA98 in Experimental Example 2.
  • 2 shows the measurement results (change over time) of histamine concentrations in the cortex, diencephalon, brainstem, and cerebellum after administration of 0.1 mmol (100 ⁇ mol)/kg of HA98 in Experimental Example 2.
  • FIG. 1 shows the measurement results of intracerebral histamine concentration (corrected by tissue weight of cortex, diencephalon, brain stem and cerebellum) one hour after administration of 0.1 mmol (100 ⁇ mol)/kg of HA98 in Experimental Example 2.
  • 2 shows the measurement results (change over time) of histamine concentrations in the cortex, diencephalon, brainstem, and cerebellum after administration of 0.1 mmol (100 ⁇ mol)/kg of HA98 in Experimental Example 2.
  • FIG. 1 shows the measurement results (change over time) of 1-methylhistamine concentrations in the cortex, diencephalon, brainstem, and cerebellum after administration of 0.1 mmol (100 ⁇ mol)/kg of HA98 in Experimental Example 2.
  • FIG. 2 shows the measurement results of cortical histamine concentration 2 hours after administration of DMSO or 3, 10, 30, 100 ⁇ mol/kg of HA98 in Experimental Example 2.
  • FIG. 2 shows the measurement results of histamine concentration in the diencephalon 2 hours after administration of DMSO or 3, 10, 30, 100 ⁇ mol/kg of HA98 in Experimental Example 2.
  • FIG. 2 shows the measurement results of histamine concentration in the brainstem 2 hours after administration of DMSO or 3, 10, 30, 100 ⁇ mol/kg of HA98 in Experimental Example 2.
  • FIG. 2 shows the measurement results of histamine concentration in the brainstem 2 hours after administration of DMSO or 3, 10, 30, 100 ⁇ mol/kg of HA98 in Experimental Example 2.
  • FIG. 2 shows the measurement results of cerebellar histamine concentration 2 hours after administration of DMSO or 3, 10, 30, 100 ⁇ mol/kg of HA98 in Experimental Example 2.
  • FIG. 2 shows the measurement results of histamine concentrations in the cortex, diencephalon, brainstem, and cerebellum 2 hours after administration of 0.1 mmol (100 ⁇ mol)/kg of HA102 in Experimental Example 2.
  • FIG. 2 shows the measurement results of 1M histamine concentrations in cortex, diencephalon, brainstem and cerebellum 2 hours after administration of 0.1 mmol (100 ⁇ mol)/kg of HA102 in Experimental Example 2.
  • FIG. 1M histamine concentrations in cortex, diencephalon, brainstem and cerebellum 2 hours after administration of 0.1 mmol (100 ⁇ mol)/kg of HA102 in Experimental Example 2.
  • FIG. 2 shows the measurement results of histamine concentrations in the cortex, diencephalon, brainstem and cerebellum 2 hours after administration of DMSO or 10 ⁇ mol/kg of HA104, HA105 and HA106 in Experimental Example 2.
  • FIG. 2 shows the measurement results of 1M histamine concentrations in cortex, diencephalon, brainstem and cerebellum 2 hours after administration of DMSO or 10 ⁇ mol/kg of HA104, HA105 and HA106 in Experimental Example 2.
  • l represents an integer of 0 to 3.
  • m represents an integer of 0 to 3;
  • n represents an integer of 0-4.
  • X represents a halogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, an alkylamino group or an aminoalkyl group.
  • Y represents a hydroxyl group, an optionally substituted acyloxy group, a sulfate group, a carbamoyloxy group, a thiol group or an optionally substituted amino group.
  • l is 2 or more, multiple X's may be the same or different.
  • m is 2 or more, multiple Y's may be the same or different.
  • dotted lines indicate the presence or absence of a bond. for example, represents a double bond or a single bond.
  • halogen includes fluorine, chlorine, bromine, iodine and the like, preferably chlorine and the like.
  • alkyl group refers to a linear or branched saturated hydrocarbon group, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, C1-C10 alkyl groups such as sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group and n-decyl group; C1-C8 alkyl groups are preferred, C1-C6 alkyl groups are more preferred, and C1-C3 alkyl groups are more preferred.
  • alkenyl group refers to a linear or branched hydrocarbon group having a carbon-carbon double bond.
  • the number of carbon-carbon double bonds per alkenyl group is, for example, 1 to 3, preferably 1, and the like.
  • alkenyl groups include vinyl, vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2- butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 1-hexenyl, 1-octenyl, 1-nonenyl, 1-dekenyl, 3,3
  • hydroxyalkyl group refers to an alkyl group having at least one hydroxyl group, for example, having 1 to 3 (preferably 1 to 2, more preferably 1) hydroxyl group, An alkyl group is mentioned.
  • Hydroxyalkyl groups include, for example, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxy-n-propyl group, 1-hydroxypropan-2-yl group, 1-hydroxy-n- butyl group, 1,4-dihydroxy-n-butyl group, 5-hydroxy-n-pentyl group, 2,3,4-trihydroxy-n-pentyl group, 6-hydroxy-n-hexyl group, 7-hydroxy- 1 to 3 (preferably 1 to 2, more preferably C1-C10 (preferably C1-C8, more preferably C1-C6, more preferably C1-C3) alkyl groups having 1).
  • alkoxy group in the present invention includes an alkoxy group in which the alkyl moiety is the aforementioned alkyl group. More specifically, alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and n-pentyloxy.
  • the "acyloxy group” includes a formyloxy group and an alkylcarbonyloxy group in which the alkyl moiety is the aforementioned alkyl group. More specifically, acyloxy groups include, for example, formyloxy, acetyloxy, propionyloxy, n-butyroyloxy, isobutyroyloxy, n-pentanoyloxy, and 3-methylbutanoyl.
  • alkylcarbonyloxy group in which the alkyl moiety is a C1-C10 alkyl group, etc., preferably formyloxy group, alkyl moiety is a C1-C8 alkyl group
  • alkylcarbonyloxy group and the like more preferably a formyloxy group, an alkylcarbonyloxy group in which the alkyl portion is a C1-C6 alkyl group, more preferably a formyloxy group, and an alkyl portion in which the C1-C3 Examples thereof include an alkylcarbon
  • Alkylamino group in the present invention means an amino group having one or two alkyl groups.
  • 1) preferably an amino group having 1 or 2 (e.g., 1) C1-C8 alkyl group, and the like, more preferably 1 or 1 C1-C6 alkyl group
  • examples thereof include amino groups having two (eg, one) groups, and more preferably amino groups having one or two (eg, one) C1-C3 alkyl groups.
  • aminoalkyl group refers to an alkyl group having at least one amino group, and includes, for example, the aforementioned alkyl groups having 1 to 2 (preferably 1) amino group.
  • aminoalkyl groups include aminomethyl group, 2-aminoethyl group, 1-aminoethyl group, 3-amino-n-propyl group, 1-aminopropan-2-yl group, 1-amino-n- butyl group, 1,4-diamino-n-butyl group, 5-amino-n-pentyl group, 6-amino-n-hexyl group, 7-amino-n-heptyl group, 8-amino-n-octyl group, C1-C10 (preferably C1-C8, more preferably C1-C6, C1-C3) alkyl groups are more preferred.
  • aryl group means a monovalent group formed by removing one hydrogen atom from an aromatic hydrocarbon ring.
  • the aryl group includes, for example, a C6-C14 aryl group such as a phenyl group, a biphenyl group, a naphthyl group, an anthracenyl group, etc., preferably a C6-C10 aryl group and the like, more preferably a phenyl group and the like. is mentioned.
  • arylalkyl group refers to an alkyl group having at least one aryl group, and includes, for example, the aforementioned alkyl groups having 1 to 3 (preferably 1) aryl group.
  • arylalkyl groups include benzyl, naphthylmethyl, biphenylmethyl, anthracenylmethyl, 2-phenylethyl, 1-phenylethyl, 2-anthracenylethyl, and 3-phenyl-n.
  • l represents an integer of 0-3, preferably 0-2. l is preferably 1 when X is halogen.
  • m represents 0-3, preferably 0-2, more preferably 0 or 1.
  • n represents an integer of 0-4, preferably 0-3, more preferably 0-2.
  • the group X is preferably present at the * or ** position (preferably at the ** position) in the following groups.
  • l is 2 to 3 (preferably 1 to 2)
  • at least one (or at least two) of the groups X is the position of * or ** (preferably ** position).
  • the group Y is preferably present at the * or ** position (preferably the * position) in the following groups.
  • the group represented by the general formula A may be simply referred to as group A.
  • the group represented by the general formula A' may be simply referred to as group A'.
  • the group A is a group A' and m is 2 to 3 (preferably 1 to 2)
  • at least one (or at least two) of the groups Y is the group A' It is preferably present at the * or ** position (preferably at the * position).
  • group A is a group
  • the group Y is preferably present at the * position in the following group.
  • the group represented by the general formula A''' may be simply referred to as group A'''.
  • one of the groups Y is the position of * in the group A''' preferably present in
  • the group A''' is preferably a double bond.
  • At least one X is preferably halogen.
  • at least one Y is preferably a hydroxyl group or an optionally substituted acyloxy group (more preferably an optionally substituted acyloxy group).
  • m is 2 or more, it is preferable that all Y are hydroxyl groups or acyloxy groups which may have substituents, but at least one Y may have a hydroxyl group or a substituent.
  • Y may have a group other than a hydroxyl group and an optionally substituted acyloxy group (for example, an alkyl group, etc.).
  • the plurality of Xs when l is 2 or more, the plurality of Xs may be the same or different, and when m is 2 or more, the plurality of Ys may be the same or different, as described above. is.
  • the group A is a group A'''.
  • the number of the substituents is not limited, but includes, for example, 1 to 3, preferably 1 to 2, more preferably 1.
  • the substituent is not particularly limited, and examples thereof include a heterocyclic group optionally having a substituent A, an aryl group optionally having a substituent A, and the like.
  • the heterocyclic group or aryl group has a substituent A
  • the number of substituents A per heterocyclic group or phenyl group is not limited, but is preferably 1 to 2, more preferably 1.
  • the substituent A is not particularly limited, but has a structure such that a heterocyclic group optionally having a substituent A or a phenyl group optionally having a substituent A interacts with a cysteine residue. preferably.
  • Substituent A includes, for example, a thiol group, an ⁇ , ⁇ -unsaturated carbonyl group, a cyano group, a carboxyl group, an ester group, an aminocarboxyl group and the like.
  • the acyloxy group has a substituent, the acyloxy group is preferably a formyloxy group.
  • the substituent of the acyloxy group is a cyanophenyl group
  • the position where the cyano group is substituted may be ortho, para or meta, but the para position is preferred.
  • the hydrocarbon group represented by the group RD in the above formula include an alkyl group, an alkenyl group, an aryl group, an arylalkyl group and the like.
  • the heterocyclic group includes, for example, a monocyclic or bicyclic 5- to 10-membered saturated or unsaturated ring having 1 to 3 heteroatoms of at least one selected from the group consisting of nitrogen, oxygen and sulfur. and a monovalent group obtained by removing one hydrogen atom from the ring of .
  • the heterocyclic group preferably has nitrogen as a heteroatom.
  • the heterocyclic group is preferably a monocyclic 5- to 7-membered ring, more preferably a 6-membered ring.
  • An unsaturated heterocyclic ring is preferable as the heterocyclic group.
  • pyrrolidinyl group tetrahydrothiophenyl group, thiophenyl group, tetrahydrofuranyl group, furanyl group, pyridinyl group, pyrazinyl group, piperidinyl group, piperazinyl group, triazinyl group, thiazinyl group, indolyl group, quinolinyl group, naphthyridinyl group, thienyl group, and the like.
  • the compound (I) or a salt thereof of the present invention is useful because it exhibits HNMT inhibitory activity not only in vitro but also in vivo. Specifically, studies have been conducted in the past with an approach of increasing brain histamine concentration by inhibiting HNMT, but conventional HNMT inhibitors are nonspecific and do not transfer to the brain. There was a problem that there was no such problem (Non-Patent Document 11). Under such circumstances, the compound (I) or a salt thereof of the present invention is useful because it has brain-localizing properties and can inhibit HNMT even in vivo.
  • compound (I) includes the compounds or salts thereof shown in Tables 1 and 2 below. In this specification, the following compounds are sometimes represented by coat numbers (HA No) shown in the tables.
  • Compound (I) can be produced by various methods, for example, by the method shown by the following reaction scheme. [Reaction formula-1]
  • Z represents a group obtained by protecting the group represented by Y with a protecting group.
  • A represents halogen.
  • Z represents a group obtained by protecting the group represented by Y with a protecting group.
  • Protective groups include, for example, a methoxymethyl group (MOM), a silyl group (R3Si), and an acetyl group.
  • MOM methoxymethyl group
  • R3Si silyl group
  • acetyl group an acetyl group.
  • groups Z include MOMO-, R3SiO-, AcO-, and the like.
  • compound 3 can be obtained by reacting compound 1 and compound 2 first.
  • Compound 1 and compound 2 can be produced according to the method described in Production Examples below.
  • the ratio of compound 1 and compound 2 to be used is not particularly limited, but for example, about 1 to 5 mol of the latter can be used per 1 mol of the former.
  • the reaction can be performed in the presence of sodium hydride, potassium carbonate, or the like.
  • Compound (I) can then be obtained by deprotecting compound 3.
  • the reaction can be carried out in the presence of hydrochloric acid, tetrabutylammonium fluoride, potassium carbonate, or the like.
  • Each reaction of the above reaction scheme is usually carried out using a solvent that does not adversely affect the reaction, such as water, triethylamine, methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane. , diethyl ether diglyme, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, acetic acid, and the like, in a mixed solvent thereof.
  • the reaction temperature of each reaction is not particularly limited, and the reaction is usually carried out at room temperature, under cooling or heating. Preferably, it is -78 to 150°C.
  • the reaction time of the nuclear reaction is also not particularly limited, but the reaction can be carried out, for example, for 1 to 30 hours.
  • solvates eg, hydrates, ethanolates, etc.
  • Preferred solvates include hydrates.
  • Each target compound obtained in each of the above reaction schemes can be obtained by, for example, cooling the reaction mixture, and then separating the crude reaction product by an isolation operation such as filtration, concentration, or extraction, followed by column chromatography, recrystallization, or the like. It can be isolated and purified from the reaction mixture by ordinary purification procedures.
  • HNMT Inhibitor and Preventive/Treatment Agent for ADHD, Narcolepsy or Alzheimer's The compound (I) or a salt thereof, which is the compound of the present invention, has an HNMT inhibitory action.
  • diseases treatable by HNMT inhibition can be prevented or treated.
  • the present invention provides a medicament containing compound (I) or a salt thereof.
  • Diseases that can be treated by HNMT inhibition include ADHD (attention deficit/hyperactivity disorder), narcolepsy, Alzheimer's disease, and the like (Non-Patent Documents 6 to 8). Histamine has also been reported to have a memory-enhancing effect (Reference No. 2), an antiepileptic effect (Reference No. 3), an appetite suppressing effect (Reference No. 4), an analgesic effect (Reference No. 5), and the like. Therefore, the medicament of the present invention can also be used for memory enhancement, antiepileptic, appetite suppression, analgesia, and the like.
  • salt means a pharmaceutically acceptable salt.
  • the salt of compound (I) includes acid addition salts and base salts.
  • Specific examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, and phosphate, oxalate, malonate, and succinic acid.
  • salts maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethane
  • examples include organic acid salts such as sulfonates, and acidic amino acid salts such as glutamate and aspartate.
  • Specific examples of salts with bases include alkali metal or alkaline earth metal salts such as sodium salts, potassium salts or calcium salts, salts with organic bases such as pyridine salts and triethylamine salts, and bases such as lysine and arginine. and salts with synthetic amino acids.
  • compound (I) or a salt thereof may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds that are active ingredients of the present invention.
  • compound (I) has isomers such as geometric isomers, stereoisomers, and optical isomers, these isomers are included in compound (I) unless otherwise specified.
  • Solvents that form solvates include water, alcohols such as ethanol and propanol, organic acids such as acetic acid, esters such as ethyl acetate, ethers such as tetrahydrofuran and diethyl ether, ketones such as acetone, and DMSO. exemplified.
  • various pharmaceutically acceptable carriers e.g., isotonic agents, chelating agents, stabilizing agents, agents, pH adjusters, preservatives, antioxidants, solubilizers, thickening agents, etc.
  • tonicity agents examples include sugars such as glucose, trehalose, lactose, fructose, mannitol, xylitol and sorbitol; polyhydric alcohols such as glycerin, polyethylene glycol and propylene glycol; sodium chloride, potassium chloride and calcium chloride; Inorganic salts etc. are mentioned.
  • chelating agents include edetate salts such as disodium edetate, disodium calcium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or salts thereof, and hexamethalin. acid sodium, citric acid, and the like.
  • edetate salts such as disodium edetate, disodium calcium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or salts thereof, and hexamethalin. acid sodium, citric acid, and the like.
  • stabilizers examples include sodium hydrogen sulfite.
  • pH adjusters include acids such as hydrochloric acid, carbonic acid, acetic acid, and citric acid, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate, and hydrogen carbonate. salts, alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, and bases such as trometamol;
  • antiseptics examples include sorbic acid, potassium sorbate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, paraoxybenzoate such as butyl parahydroxybenzoate, chlorhexidine gluconate, benzalkonium chloride, chloride quaternary ammonium salts such as benzethonium and cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, chlorhexidine and the like.
  • antioxidants include sodium hydrogen sulfite, dried sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherols, and the like.
  • solubilizing agents include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, D-mannitol, etc.
  • thickening agents include polyethylene glycol, methylcellulose, ethylcellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like.
  • the pharmaceutical composition may further contain a compound known to have a therapeutic effect on diseases that can be treated by HNMT inhibition, in addition to compound (I) or a salt thereof.
  • therapeutic agents for ADHD include methylphenidate, atomoxetine, guanfacine and the like.
  • Drugs for treating narcolepsy include, for example, modafinil, methylphenidate, pemoline and the like.
  • Alzheimer's drugs include, for example, donepezil, memantine, galantamine and the like.
  • the content of compound (I) or a salt thereof in the composition is not particularly limited, and in terms of the content of compound (I), for example, 90% by mass or more, 70% by mass or more, It can be appropriately set from conditions such as 50% by mass or more, 30% by mass or more, 10% by mass or more, 5% by mass or more, and 1% by mass or more.
  • the dosage form is not particularly limited, and for example, tablets, pills, capsules, powders, granules, syrups, sublingual preparations for oral administration; injections (intravenous injections, intramuscular injections, local injections, etc.), gargles , drops, external preparations (ointments, creams, patches, inhalants), and parenteral preparations such as suppositories.
  • injections intravenous injections, intramuscular injections, local injections, etc.
  • gargles drops
  • external preparations ointments, creams, patches, inhalants
  • parenteral preparations such as suppositories.
  • preferred are, for example, injections, orally administered drugs, external preparations, and the like.
  • the content of the compound (I) of the present invention in the formulation varies depending on the route of administration, patient age, body weight, symptoms, etc., and cannot be categorically defined. More preferably, the amount should be about 100 to 1000 mg. In the case of administration once a day, this amount should be contained in one preparation, and in the case of administration three times a day, one third of this amount should be contained in one preparation.
  • the pharmaceutical of the present invention is administered to patients such as mammals.
  • Mammals include humans, monkeys, mice, rats, rabbits, cats, dogs, pigs, cows, horses, sheep and the like.
  • HNMT inhibition means significant suppression of HNMT activity, specifically methylation of histamine, as compared to when compound (I) or a salt thereof was not administered. HNMT activity can be measured by the method described in Examples.
  • a borane-tetrahydrofuran complex solution (1.0 M tetrahydrofuran solution, 3.04 mL, 2.74 mmol) was added dropwise to a solution of 19 (700.0 mg, 2.11 mmol) in tetrahydrofuran (10 mL) at 0°C, and the mixture was stirred at room temperature for 3 hours.
  • Sodium perborate tetrahydrate and water were added, and the mixture was stirred at room temperature for a whole day and night.
  • HA104 Synthesis To a tetrahydrofuran solution (1.83 mL) of HA-98 (0.091 mmol, 30 mg) were added pyridine (0.27 mmol, 22.1 ⁇ L), acetic anhydride (0.27 mmol, 25.8 ⁇ L) and 4-dimethylaminopyridine (0.008 mmol, 1 mg). was added under ice-cooling, and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (10 mL) was added for dilution, 0.1 M hydrochloric acid aqueous solution (10 mL) was added to stop the reaction, and the mixture was extracted three times with ethyl acetate (10 mL).
  • Experimental example 1 Measurement of HNMT inhibitory activity by candidate compounds Human HNMT protein (50 nM), histamine (10 ⁇ M, Sigma-Aldrich), S-adenosylmethionine (10 ⁇ M, New England Biolabs), 1x MTase-glo Reagent (Promega) in buffer (20 mM Tris, 50 mM NaCl, 1 mM EDTA, 3 mM MgCl2, 0.1 mg/mL BSA, 1 mM DTT (all Fuji Film Wako Pure Chemical Industries), pH 8.0).
  • candidate compounds were added to final concentrations of 30 pM, 100 pM, 300 pM, 1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, and 1 ⁇ M for a total of 25
  • the mixture was made up to ⁇ L, dispensed into a 96-well plate (Corning), and reacted at 37°C for 1 hour.
  • 25 ⁇ L of MTase-glo Detection Solution Promega was added and reacted at 25° C. for 30 minutes.
  • the amount of luminescence was measured using Luminoskan Ascent (ThermoFisher Scientific) to determine the inhibitory activity.
  • IC50 values were calculated using Prism software (GraphPad).
  • mice Effects of candidate compounds on increasing histamine levels in the brain
  • SLC 8-week-old male C57BL6/J mice
  • candidate compounds were dissolved in DMSO (Sigma-Aldrich) and administered intraperitoneally to mice at concentrations of 3 ⁇ mol/kg, 10 ⁇ mol/kg, 30 ⁇ mol/kg and 100 ⁇ mol/kg.
  • the mice were euthanized by cervical dislocation, and the brain was divided into 4 parts, cortex, diencephalon, brainstem, and cerebellum, and the weight of each part was measured.

Abstract

The present invention addresses the problem of providing a new method for increasing the intracerebral histamine concentration. The present invention provides a compound represented by general formula (I) or a salt thereof. [In the formula, the structures of respective groups are as described in the description.]

Description

キノリン化合物、ＨＮＭＴ阻害剤、及びＡＤＨＤ、ナルコレプシー又はアルツハイマーの予防・治療剤Quinoline compound, HNMT inhibitor, and prophylactic/therapeutic agent for ADHD, narcolepsy or Alzheimer's disease
　［関連出願の相互参照］
　本出願は、２０２１年３月１２日に出願された、日本国特許出願第２０２１－０４０６５８号明細書（その開示全体が参照により本明細書中に援用される）に基づく優先権を主張する。本発明は、キノリン化合物、ＨＮＭＴ阻害剤、及びＡＤＨＤ、ナルコレプシー又はアルツハイマーを予防又は治療するための医薬に関する。 [Cross reference to related applications]
This application claims priority based on Japanese Patent Application No. 2021-040658 filed on March 12, 2021 (the entire disclosure of which is incorporated herein by reference). The present invention relates to quinoline compounds, HNMT inhibitors and medicaments for preventing or treating ADHD, Narcolepsy or Alzheimer's.
　アルツハイマー病(AD)は認知症の約６割を占めると言われており、その予防方法、治療方法の開発が行われている。例えば、アミロイドβやタウをターゲットとして1,000以上の化合物が開発候補となってきたが、現状では上市されていない。また、その他のメカニズムとして、カルシウム/カルモデュリン依存性プロテインキナーゼＩＩ(CaMKII)賦活化を標的とする研究開発も進められている。 Alzheimer's disease (AD) is said to account for about 60% of dementia, and its prevention and treatment methods are being developed. For example, more than 1,000 compounds targeting amyloid β and tau have been identified as candidates for development, but none have yet been marketed. As another mechanism, research and development targeting activation of calcium/calmodulin-dependent protein kinase II (CaMKII) is also underway.
　かかる状況の下、多岐にわたる神経疾患においてヒスタミン系の機能低下が見られることが明らかになり（非特許文献１１）、さらなるアプローチとして、神経伝達物質であるヒスタミンを標的とすることにも注目がされている。例えば、ヒスタミンH3受容体（H3R）拮抗薬の開発が試みられている（非特許文献１２）。しかし、H3受容体拮抗薬は脳のヒスタミン放出を誘発するが、その効果は一過性であり、時間経過に伴う脳内ヒスタミンの枯渇が問題であった。 Under these circumstances, it has become clear that the histamine system is impaired in a wide variety of neurological diseases (Non-Patent Document 11), and as a further approach, attention has also been focused on targeting the neurotransmitter histamine. ing. For example, attempts have been made to develop histamine H3 receptor (H3R) antagonists (Non-Patent Document 12). However, although H3-receptor antagonists induce cerebral histamine release, the effect is transient, and depletion of cerebral histamine over time has been a problem.
　本発明は、脳内ヒスタミン濃度を上昇させる新たな方法を提供することを課題とする。 An object of the present invention is to provide a new method for increasing the concentration of histamine in the brain.
　かかる状況の下、本発明者らは脳内ヒスタミン濃度を増加するための新規メカニズムについて鋭意検討した結果、ヒスタミン代謝酵素であるヒスタミンＮ－メチルトランスフェラーゼ (histamine N-methyltranferase、ＨＮＭＴ)に着目し、当該ＨＮＭＴを阻害することにより脳内ヒスタミン濃度を上昇させるというアプローチで研究を進めた（非特許文献１４）。そして、多種多様な化合物について多大なる試行錯誤を重ねた結果、後述の一般式（Ｉ）で表される化合物又はその塩がＨＮＭＴの阻害活性を有することを見出した。本発明はかかる新たな知見に基づくものである。従って、本発明は以下の項を提供する：　項１．下記一般式（Ｉ）で表される化合物又はその塩 Under such circumstances, the present inventors have made intensive studies on a novel mechanism for increasing the concentration of histamine in the brain. The research proceeded with an approach of increasing brain histamine concentration by inhibiting HNMT (Non-Patent Document 14). As a result of extensive trial and error with a wide variety of compounds, the inventors have found that the compound represented by general formula (I) or a salt thereof has HNMT inhibitory activity. The present invention is based on such new findings. Accordingly, the present invention provides the following items: Item 1. A compound represented by the following general formula (I) or a salt thereof
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
［式中、ｌは０～３の整数を示す。ｍは０～３の整数を示す。ｎは０～４の整数を示す。Ｘはハロゲン、アルキル基、ヒドロキシアルキル基、ヒドロキシル基、アルコキシ基、アルキルアミノ基又はアミノアルキル基を示す。Ｙはヒドロキシル基、置換基を有していてもよいアシルオキシ基、スルフェート基、チオール基又は置換基を有していてもよいアミノ基を示す。ｌが２以上の場合、複数存在するＸは同一でも異なっていてもよい。ｍが２以上の場合、複数存在するＹは同一でも異なっていてもよい。ｎが１以上の場合、炭素数ｎの二価飽和炭化水素基は、置換基として１個のオキソ基（＝Ｏ）を有してもよい。
基 [In the formula, l represents an integer of 0 to 3. m represents an integer of 0 to 3; n represents an integer of 0-4. X represents a halogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, an alkylamino group or an aminoalkyl group. Y represents a hydroxyl group, an optionally substituted acyloxy group, a sulfate group, a thiol group or an optionally substituted amino group. When l is 2 or more, multiple X's may be the same or different. When m is 2 or more, multiple Y's may be the same or different. When n is 1 or more, the divalent saturated hydrocarbon group having n carbon atoms may have one oxo group (=O) as a substituent.
group
Figure JPOXMLDOC01-appb-C000018
 は
Figure JPOXMLDOC01-appb-C000018
 teeth
Figure JPOXMLDOC01-appb-C000019
 を示す。
基
Figure JPOXMLDOC01-appb-C000019
 indicates
group
Figure JPOXMLDOC01-appb-C000020
 は
Figure JPOXMLDOC01-appb-C000020
 teeth
Figure JPOXMLDOC01-appb-C000021
 を示す。ただし、
Figure JPOXMLDOC01-appb-C000021
 indicates however,
Figure JPOXMLDOC01-appb-C000022
 は除く。］
Figure JPOXMLDOC01-appb-C000022
 except. ]
　項２．下記一般式（Ｉ）で表される化合物又はその塩を含む、ＨＮＭＴ阻害剤： Section 2. An HNMT inhibitor comprising a compound represented by the following general formula (I) or a salt thereof:
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
［式中、ｌは０～３の整数を示す。ｍは０～３の整数を示す。ｎの整数は０～４を示す。Ｘはハロゲン、アルキル基、ヒドロキシアルキル基、ヒドロキシル基、アルコキシ基、アルキルアミノ基又はアミノアルキル基を示す。Ｙはヒドロキシル基、置換基を有していてもよいアシルオキシ基、スルフェート基、カルバモイルオキシ基、チオール基又は置換基を有していてもよいアミノ基を示す。ｌが２以上の場合、複数存在するＸは同一でも異なっていてもよい。ｍが２以上の場合、複数存在するＹは同一でも異なっていてもよい。ｎが１以上の場合、炭素数ｎの二価飽和炭化水素基は、置換基として１個のオキソ基（＝Ｏ）を有してもよい。
基 [In the formula, l represents an integer of 0 to 3. m represents an integer of 0 to 3; The integer n represents 0-4. X represents a halogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, an alkylamino group or an aminoalkyl group. Y represents a hydroxyl group, an optionally substituted acyloxy group, a sulfate group, a carbamoyloxy group, a thiol group or an optionally substituted amino group. When l is 2 or more, multiple X's may be the same or different. When m is 2 or more, multiple Y's may be the same or different. When n is 1 or more, the divalent saturated hydrocarbon group having n carbon atoms may have one oxo group (=O) as a substituent.
group
Figure JPOXMLDOC01-appb-C000024
 は
Figure JPOXMLDOC01-appb-C000024
 teeth
Figure JPOXMLDOC01-appb-C000025
 を示す。
基
Figure JPOXMLDOC01-appb-C000025
 indicates
basis
Figure JPOXMLDOC01-appb-C000026
 は
Figure JPOXMLDOC01-appb-C000026
 teeth
Figure JPOXMLDOC01-appb-C000027
 を示す。］
Figure JPOXMLDOC01-appb-C000027
 indicates ]
　項３．下記一般式（Ｉ）で表される化合物又はその塩を含む、ＡＤＨＤ、ナルコレプシー又はアルツハイマーを予防又は治療するための医薬： Section 3. A medicament for preventing or treating ADHD, narcolepsy or Alzheimer's, comprising a compound represented by the following general formula (I) or a salt thereof:
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
［式中、ｌは０～３の整数を示す。ｍは０～３の整数を示す。ｎは０～４の整数を示す。Ｘはハロゲン、アルキル基、ヒドロキシアルキル基、ヒドロキシル基、アルコキシ基、アルキルアミノ基又はアミノアルキル基を示す。Ｙはヒドロキシル基、置換基を有していてもよいアシルオキシ基、スルフェート基、カルバモイルオキシ基、チオール基又は置換基を有していてもよいアミノ基を示す。ｌが２以上の場合、複数存在するＸは同一でも異なっていてもよい。ｍが２以上の場合、複数存在するＹは同一でも異なっていてもよい。ｎが１以上の場合、炭素数ｎの二価飽和炭化水素基は、置換基として１個のオキソ基（＝Ｏ）を有してもよい。
基 [In the formula, l represents an integer of 0 to 3. m represents an integer of 0 to 3; n represents an integer of 0-4. X represents a halogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, an alkylamino group or an aminoalkyl group. Y represents a hydroxyl group, an optionally substituted acyloxy group, a sulfate group, a carbamoyloxy group, a thiol group or an optionally substituted amino group. When l is 2 or more, multiple X's may be the same or different. When m is 2 or more, multiple Y's may be the same or different. When n is 1 or more, the divalent saturated hydrocarbon group having n carbon atoms may have one oxo group (=O) as a substituent.
group
Figure JPOXMLDOC01-appb-C000029
 は
Figure JPOXMLDOC01-appb-C000029
 teeth
Figure JPOXMLDOC01-appb-C000030
 を示す。
基
Figure JPOXMLDOC01-appb-C000030
 indicates
group
Figure JPOXMLDOC01-appb-C000031
 は
Figure JPOXMLDOC01-appb-C000031
 teeth
Figure JPOXMLDOC01-appb-C000032
 を示す。］
Figure JPOXMLDOC01-appb-C000032
 indicates ]
　項４．ｌが１以上の場合、少なくとも１つのＸがハロゲンであり、ｍが１以上の場合、少なくとも１つのＹがヒドロキシル基又は置換基を有していてもよいアシルオキシ基であり、ｎが０～２である、項１に記載の化合物もしくはその塩、項２に記載のＨＮＭＴ阻害剤又は項３に記載の医薬。 Section 4. when l is 1 or more, at least one X is a halogen, when m is 1 or more, at least one Y is a hydroxyl group or an optionally substituted acyloxy group, and n is 0 to 2 The compound or salt thereof according to Item 1, the HNMT inhibitor according to Item 2, or the medicament according to Item 3.
　本発明は、ＨＮＭＴを阻害するという新たなアプローチにより、脳内ヒスタミン濃度を上昇させる新たな方法を提供することができる。従って、本発明によれば、ＨＮＭＴ阻害により処置し得る種々の疾患、状態を改善し得る。 The present invention can provide a new method for increasing brain histamine levels through a new approach of inhibiting HNMT. Therefore, according to the present invention, various diseases and conditions that can be treated by HNMT inhibition can be ameliorated.
実験例１における各化合物のHNMT阻害活性の測定結果を示す。2 shows the measurement results of HNMT inhibitory activity of each compound in Experimental Example 1. FIG. 実験例２における、0.1 mmol（100 μmol）/kgのＨＡ９８投与1時間後の脳内（皮質、間脳、脳幹及び小脳の組織重量で補正）ヒスタミン濃度の測定結果を示す。1 shows the measurement results of intracerebral histamine concentration (corrected by tissue weight of cortex, diencephalon, brain stem and cerebellum) one hour after administration of 0.1 mmol (100 μmol)/kg of HA98 in Experimental Example 2. 実験例２における、0.1 mmol（100 μmol）/kgのＨＡ９８投与後の皮質、間脳、脳幹及び小脳のヒスタミン濃度の測定結果（経時的変化）を示す。2 shows the measurement results (change over time) of histamine concentrations in the cortex, diencephalon, brainstem, and cerebellum after administration of 0.1 mmol (100 μmol)/kg of HA98 in Experimental Example 2. FIG. 実験例２における、0.1 mmol（100 μmol）/kgのＨＡ９８投与後の皮質、間脳、脳幹及び小脳の１メチルヒスタミン濃度の測定結果（経時的変化）を示す。1 shows the measurement results (change over time) of 1-methylhistamine concentrations in the cortex, diencephalon, brainstem, and cerebellum after administration of 0.1 mmol (100 μmol)/kg of HA98 in Experimental Example 2. FIG. 実験例２における、DMSOあるいは3, 10, 30, 100 μmol/kgのＨＡ９８投与2時間後の皮質のヒスタミン濃度の測定結果を示す。2 shows the measurement results of cortical histamine concentration 2 hours after administration of DMSO or 3, 10, 30, 100 μmol/kg of HA98 in Experimental Example 2. FIG. 実験例２における、DMSOあるいは3, 10, 30, 100 μmol/kgのＨＡ９８投与2時間後の間脳のヒスタミン濃度の測定結果を示す。2 shows the measurement results of histamine concentration in the diencephalon 2 hours after administration of DMSO or 3, 10, 30, 100 μmol/kg of HA98 in Experimental Example 2. FIG. 実験例２における、DMSOあるいは3, 10, 30, 100 μmol/kgのＨＡ９８投与2時間後の脳幹のヒスタミン濃度の測定結果を示す。2 shows the measurement results of histamine concentration in the brainstem 2 hours after administration of DMSO or 3, 10, 30, 100 μmol/kg of HA98 in Experimental Example 2. FIG. 実験例２における、DMSOあるいは3, 10, 30, 100 μmol/kgのＨＡ９８投与2時間後の小脳のヒスタミン濃度の測定結果を示す。2 shows the measurement results of cerebellar histamine concentration 2 hours after administration of DMSO or 3, 10, 30, 100 μmol/kg of HA98 in Experimental Example 2. FIG. 実験例２における、0.1 mmol（100 μmol）/kgのＨＡ１０２投与2時間後の皮質、間脳、脳幹及び小脳のヒスタミン濃度の測定結果を示す。2 shows the measurement results of histamine concentrations in the cortex, diencephalon, brainstem, and cerebellum 2 hours after administration of 0.1 mmol (100 μmol)/kg of HA102 in Experimental Example 2. FIG. 実験例２における、0.1 mmol（100 μmol）/kgのＨＡ１０２投与2時間後の皮質、間脳、脳幹及び小脳の１Ｍのヒスタミン濃度の測定結果を示す。2 shows the measurement results of 1M histamine concentrations in cortex, diencephalon, brainstem and cerebellum 2 hours after administration of 0.1 mmol (100 μmol)/kg of HA102 in Experimental Example 2. FIG. 実験例２における、DMSOあるいは10μmol/kgのＨＡ104、HA105、HA106投与2時間後の皮質、間脳、脳幹及び小脳のヒスタミン濃度の測定結果を示す。2 shows the measurement results of histamine concentrations in the cortex, diencephalon, brainstem and cerebellum 2 hours after administration of DMSO or 10 μmol/kg of HA104, HA105 and HA106 in Experimental Example 2. FIG. 実験例２における、DMSOあるいは10μmol/kgのＨＡ104、HA105、HA106投与2時間後の皮質、間脳、脳幹及び小脳の１Ｍヒスタミン濃度の測定結果を示す。2 shows the measurement results of 1M histamine concentrations in cortex, diencephalon, brainstem and cerebellum 2 hours after administration of DMSO or 10 μmol/kg of HA104, HA105 and HA106 in Experimental Example 2. FIG.
　本発明化合物又はその塩
　本発明は、下記式（Ｉ）で表わされる化合物又はその塩を提供する： Compounds of the Present Invention or Salts Thereof The present invention provides compounds represented by the following formula (I) or salts thereof:
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
［式中、ｌは０～３の整数を示す。ｍは０～３の整数を示す。ｎは０～４の整数を示す。Ｘはハロゲン、アルキル基、ヒドロキシアルキル基、ヒドロキシル基、アルコキシ基、アルキルアミノ基又はアミノアルキル基を示す。Ｙはヒドロキシル基、置換基を有していてもよいアシルオキシ基、スルフェート基、カルバモイルオキシ基、チオール基又は置換基を有していてもよいアミノ基を示す。ｌが２以上の場合、複数存在するＸは同一でも異なっていてもよい。ｍが２以上の場合、複数存在するＹは同一でも異なっていてもよい。ｎが１以上の場合、炭素数ｎの二価飽和炭化水素基は、置換基として１個のオキソ基（＝Ｏ）を有してもよい。
基 [In the formula, l represents an integer of 0 to 3. m represents an integer of 0 to 3; n represents an integer of 0-4. X represents a halogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, an alkylamino group or an aminoalkyl group. Y represents a hydroxyl group, an optionally substituted acyloxy group, a sulfate group, a carbamoyloxy group, a thiol group or an optionally substituted amino group. When l is 2 or more, multiple X's may be the same or different. When m is 2 or more, multiple Y's may be the same or different. When n is 1 or more, the divalent saturated hydrocarbon group having n carbon atoms may have one oxo group (=O) as a substituent.
group
Figure JPOXMLDOC01-appb-C000034
 は
Figure JPOXMLDOC01-appb-C000034
 teeth
Figure JPOXMLDOC01-appb-C000035
 を示す。
基
Figure JPOXMLDOC01-appb-C000035
 indicates
group
Figure JPOXMLDOC01-appb-C000036
 は
Figure JPOXMLDOC01-appb-C000036
 teeth
Figure JPOXMLDOC01-appb-C000037
 を示す。］
Figure JPOXMLDOC01-appb-C000037
 indicates ]
本発明において、式（Ｉ）で表される化合物を単に化合物（Ｉ）と示すこともある。 In the present invention, the compound represented by formula (I) may be simply referred to as compound (I).
　本明細書中、一般式において、点線は結合が存在するか又は存在しないことを示す。例えば、
Figure JPOXMLDOC01-appb-C000038
 は、二重結合又は単結合を示す。 In general formulas herein, dotted lines indicate the presence or absence of a bond. for example,
Figure JPOXMLDOC01-appb-C000038
 represents a double bond or a single bond.
　本明細書において示される各基は、具体的には次の通りである。
本発明において「ハロゲン」としては、フッ素・塩素・臭素・ヨウ素等が挙げられ、塩素等が好ましい。 Each group shown in this specification is specifically as follows.
In the present invention, the "halogen" includes fluorine, chlorine, bromine, iodine and the like, preferably chlorine and the like.
　本発明において「アルキル基」とは、直鎖状又は分枝鎖状の飽和炭化水素基を示し、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、イソペンチル基、ｎ－ヘキシル基、ｎ－ヘプチル基、ｎ－オクチル基、ｎ－ノニル基、ｎ－デシル基等のＣ１－Ｃ１０アルキル基が挙げられ、好ましくはＣ１－Ｃ８アルキル基等が挙げられ、より好ましくはＣ１－Ｃ６アルキル基等が挙げられ、より好ましくはＣ１－Ｃ３アルキル基等が挙げられる。
　本発明において、「アルケニル基」とは、炭素－炭素二重結合を有する直鎖状又は分枝鎖状の炭化水素基を示す。アルケニル基１個当たりの炭素－炭素二重結合の数としては、例えば、１～３個、好ましくは１個等が挙げられる。アルケニル基としては、例えば、ビニル基、ビニル、１－プロペニル、２－プロペニル、１－メチル－１－プロペニル、２－メチル－１－プロペニル、２－メチル－２－プロペニル、２－プロペニル、２－ブテニル、１－ブテニル、３－ブテニル、２－ペンテニル、１－ペンテニル、３－ペンテニル、４－ペンテニル、１，３－ブタジエニル、１，３－ペンタジエニル、２－ペンテン－４－イル、２－ヘキセニル、１－ヘキセニル、５－へキセニル、３－ヘキセニル、４－へキセニル、１－へプセニル、１－オクテニル、１－ノネニル、１－デケニル、３，３－ジメチル－１－プロペニル、２－エチル－１－プロペニル、１，３，５－ヘキサトリエニル、１，３－ヘキサジエニル、１，４－ヘキサジエニル基等のＣ２－Ｃ１０アルケニル基が挙げられ、好ましくはＣ２－Ｃ８アルキル基等が挙げられ、より好ましくはＣ２－Ｃ６アルケニル基等が挙げられ、より好ましくはＣ２－Ｃ３アルキル基等が挙げられる。 In the present invention, the "alkyl group" refers to a linear or branched saturated hydrocarbon group, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, C1-C10 alkyl groups such as sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group and n-decyl group; C1-C8 alkyl groups are preferred, C1-C6 alkyl groups are more preferred, and C1-C3 alkyl groups are more preferred.
In the present invention, "alkenyl group" refers to a linear or branched hydrocarbon group having a carbon-carbon double bond. The number of carbon-carbon double bonds per alkenyl group is, for example, 1 to 3, preferably 1, and the like. Examples of alkenyl groups include vinyl, vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-propenyl, 2- butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl, 1-hexenyl, 1-octenyl, 1-nonenyl, 1-dekenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1 -C2-C10 alkenyl groups such as propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl and 1,4-hexadienyl groups, preferably C2-C8 alkyl groups and the like, more preferably includes a C2-C6 alkenyl group and the like, more preferably a C2-C3 alkyl group and the like.
　本発明において「ヒドロキシアルキル基」とは、少なくとも１個のヒドロキシル基を有するアルキル基を示し、例えば、ヒドロキシル基を１～３個（好ましくは１～２個、より好ましくは１個）有する、前記アルキル基が挙げられる。ヒドロキシアルキル基としては、例えば、ヒドロキシメチル基、２－ヒドロキシエチル基、１－ヒドロキシエチル基、、３－ヒドロキシ－ｎ－プロピル基、１－ヒドロキシプロパン－２－イル基、１－ヒドロキシ－ｎ－ブチル基、１，４－ジヒドロキシ－ｎ－ブチル基、５－ヒドロキシ－ｎ－ペンチル基、２，３，４－トリヒドロキシ－ｎ－ペンチル基、６－ヒドロキシ－ｎ－ヘキシル基、７－ヒドロキシ－ｎ－ヘプチル基、８－ヒドロキシ－ｎ－オクチル基、９－ヒドロキシ－ｎ－ノニル基、１０－ヒドロキシ－ｎ－デシル基等のヒドロキシル基を１～３個（好ましくは１～２個、より好ましくは１個）有するＣ１－Ｃ１０（好ましくはＣ１－Ｃ８、より好ましくはＣ１－Ｃ６、より好ましくはＣ１－Ｃ３）アルキル基が挙げられる。 In the present invention, the term "hydroxyalkyl group" refers to an alkyl group having at least one hydroxyl group, for example, having 1 to 3 (preferably 1 to 2, more preferably 1) hydroxyl group, An alkyl group is mentioned. Hydroxyalkyl groups include, for example, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxy-n-propyl group, 1-hydroxypropan-2-yl group, 1-hydroxy-n- butyl group, 1,4-dihydroxy-n-butyl group, 5-hydroxy-n-pentyl group, 2,3,4-trihydroxy-n-pentyl group, 6-hydroxy-n-hexyl group, 7-hydroxy- 1 to 3 (preferably 1 to 2, more preferably C1-C10 (preferably C1-C8, more preferably C1-C6, more preferably C1-C3) alkyl groups having 1).
　本発明において「アルコキシ基」としては、アルキル部分が前述のアルキル基であるアルコキシ基が挙げられる。より具体的には、アルコキシ基としては、例えば、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ｎ－ペンチルオキシ基、イソペンチルオキシ基、ｎ－ヘキシルオキシ基、ｎ－ヘプチルオキシ基、ｎ－オクチルオキシ基、ｎ－ノニルオキシ基、ｎ－デシルオキシ基等のＣ１－Ｃ１０アルコキシ基等が挙げられ、好ましくはＣ１－Ｃ８アルコキシ基等が挙げられ、より好ましくはＣ１－Ｃ６アルコキシ基等が挙げられ、より好ましくはＣ１－Ｃ３アルコキシ基等が挙げられる。 The "alkoxy group" in the present invention includes an alkoxy group in which the alkyl moiety is the aforementioned alkyl group. More specifically, alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and n-pentyloxy. group, isopentyloxy group, n-hexyloxy group, n-heptyloxy group, n-octyloxy group, n-nonyloxy group, n-decyloxy group and other C1-C10 alkoxy groups, preferably C1- C8 alkoxy group and the like, more preferably C1-C6 alkoxy group and the like, more preferably C1-C3 alkoxy group and the like.
　本発明において「アシルオキシ基」としては、ホルミルオキシ基及びアルキル部分が前述のアルキル基であるアルキルカルボニルオキシ基が挙げられる。より具体的には、アシルオキシ基としては、例えば、ホルミルオキシ基、アセチルオキシ基、プロピオニルオキシ基、ｎ－ブチリロイルオキシ基、イソブチリロイルオキシ基、ｎ－ペンタノイルオキシ基、３－メチルブタノイルオキシ基、２－メチルブタノイルオキシ基、ピバロイロキシ基、ｎ－ヘキサノイルオキシ基、４－メチルペンタノイルオキシ基、ｎ－へプタノイルオキシ基、ｎ－オクタノイルオキシ基、ｎ－ノナノイルオキシ基、ｎ－デカノイルオキシ基、ｎ－ウンデカノイルオキシ基等のホルミルオキシ基、アルキル部分がＣ１－Ｃ１０アルキル基であるアルキルカルボニルオキシ基等が挙げられ、好ましくはホルミルオキシ基、アルキル部分がＣ１－Ｃ８アルキル基であるアルキルカルボニルオキシ基等が挙げられ、より好ましくはホルミルオキシ基、アルキル部分がＣ１－Ｃ６アルキル基であるアルキルカルボニルオキシ基等が挙げられ、より好ましくはホルミルオキシ基、アルキル部分がＣ１－Ｃ３アルキル基であるアルキルカルボニルオキシ基等が挙げられ、さらに好ましくはホルミルオキシ基、アセチルオキシ基等が挙げられ、特に好ましくはアセチルオキシ基等が挙げられる。 In the present invention, the "acyloxy group" includes a formyloxy group and an alkylcarbonyloxy group in which the alkyl moiety is the aforementioned alkyl group. More specifically, acyloxy groups include, for example, formyloxy, acetyloxy, propionyloxy, n-butyroyloxy, isobutyroyloxy, n-pentanoyloxy, and 3-methylbutanoyl. oxy group, 2-methylbutanoyloxy group, pivaloyloxy group, n-hexanoyloxy group, 4-methylpentanoyloxy group, n-heptanoyloxy group, n-octanoyloxy group, n-nonanoyloxy group, n-deca noyloxy group, formyloxy group such as n-undecanoyloxy group, alkylcarbonyloxy group in which the alkyl moiety is a C1-C10 alkyl group, etc., preferably formyloxy group, alkyl moiety is a C1-C8 alkyl group An alkylcarbonyloxy group and the like, more preferably a formyloxy group, an alkylcarbonyloxy group in which the alkyl portion is a C1-C6 alkyl group, more preferably a formyloxy group, and an alkyl portion in which the C1-C3 Examples thereof include an alkylcarbonyloxy group which is an alkyl group, more preferably a formyloxy group and an acetyloxy group, and particularly preferably an acetyloxy group.
　本発明において「アルキルアミノ基」とは、アルキル基を１個又は２個有するアミノ基を示す。例えば、Ｎ－メチルアミノ基、Ｎ，Ｎ－ジメチルアミノ基、Ｎ－エチルアミノ基、Ｎ，Ｎ－ジエチルアミノ基、Ｎ－メチル－Ｎ－エチルアミノ基、Ｎ－ｎ－プロピルアミノ基、Ｎ－イソプロピルアミノ基、Ｎ－ｎ－ブチルアミノ基、Ｎ－イソブチルアミノ基、Ｎ－ｓｅｃ－ブチルアミノ基、Ｎ－ｔｅｒｔ－ブチルアミノ基、Ｎ－ｎ－ペンチルアミノ基、Ｎ－イソペンチルアミノ基、Ｎ－ｎ－ヘキシルアミノ基、Ｎ－ｎ－ヘプチルアミノ基、Ｎ－ｎ－オクチルアミノ基、Ｎ－ｎ－ノニルアミノ基、Ｎ－ｎ－デシルアミノ基等のＣ１－Ｃ１０アルキル基を１個又は２個（例えば、１個）有するアミノ基が挙げられ、好ましくはＣ１－Ｃ８アルキル基を１個又は２個（例えば、１個）有するアミノ基等が挙げられ、より好ましくはＣ１－Ｃ６アルキル基を１個又は２個（例えば、１個）有するアミノ基等が挙げられ、より好ましくはＣ１－Ｃ３アルキル基を１個又は２個（例えば、１個）有するアミノ基等が挙げられる。 "Alkylamino group" in the present invention means an amino group having one or two alkyl groups. For example, N-methylamino group, N,N-dimethylamino group, N-ethylamino group, N,N-diethylamino group, N-methyl-N-ethylamino group, Nn-propylamino group, N-isopropyl amino group, Nn-butylamino group, N-isobutylamino group, N-sec-butylamino group, N-tert-butylamino group, Nn-pentylamino group, N-isopentylamino group, N- 1 or 2 C1-C10 alkyl groups such as n-hexylamino group, Nn-heptylamino group, Nn-octylamino group, Nn-nonylamino group, Nn-decylamino group (e.g. , 1), preferably an amino group having 1 or 2 (e.g., 1) C1-C8 alkyl group, and the like, more preferably 1 or 1 C1-C6 alkyl group Examples thereof include amino groups having two (eg, one) groups, and more preferably amino groups having one or two (eg, one) C1-C3 alkyl groups.
　本発明において「アミノアルキル基」とは、少なくとも１個のアミノ基を有するアルキル基を示し、例えば、アミノ基を１～２個（好ましくは１個）有する、前記アルキル基が挙げられる。アミノアルキル基としては、例えば、アミノメチル基、２－アミノエチル基、１－アミノエチル基、、３－アミノ－ｎ－プロピル基、１－アミノプロパン－２－イル基、１－アミノ－ｎ－ブチル基、１，４－ジアミノ－ｎ－ブチル基、５－アミノ－ｎ－ペンチル基、６－アミノ－ｎ－ヘキシル基、７－アミノ－ｎ－ヘプチル基、８－アミノ－ｎ－オクチル基、９－アミノ－ｎ－ノニル基、１０－アミノ－ｎ－デシル基等のアミノ基を１～２個（好ましくは１個）有するＣ１－Ｃ１０（好ましくはＣ１－Ｃ８、より好ましくはＣ１－Ｃ６、より好ましくはＣ１－Ｃ３）アルキル基が挙げられる。
　本発明において、「アリール基」とは芳香族炭化水素環から水素原子を１個外してなる一価の基を意味する。アリール基としては、例えば、フェニル基、ビフェニル基、ナフチル基、アントラセニル基等のＣ６－Ｃ１４のアリール基等が挙げられ、好ましくはＣ６－Ｃ１０のアリール基等が挙げられ、より好ましくはフェニル基等が挙げられる。
　本発明において、「アリールアルキル基」とは少なくとも１個のアリール基を有するアルキル基を示し、例えば、アリール基を１～３個（好ましくは１個）有する、前記アルキル基が挙げられる。アリールアルキル基としては、例えば、ベンジル基、ナフチルメチル基、ビフェニルメチル基、アントラセニルメチル基、２－フェニルエチル基、１－フェニルエチル基、２－アントラセニルエチル基、３－フェニル－ｎ－プロピル基、１－フェニルプロパン－２－イル基、１－フェニル－ｎ－ブチル基、１，４－ジフェニル－ｎ－ブチル基、５－フェニル－ｎ－ペンチル基、２，３，４－トリフェニル－ｎ－ペンチル基、６－フェニル－ｎ－ヘキシル基、７－フェニル－ｎ－ヘプチル基、８－フェニル－ｎ－オクチル基、９－フェニル－ｎ－ノニル基、１０－フェニル－ｎ－デシル基等のフェニル基を１～３個（好ましくは１個）有するＣ１－Ｃ１０（好ましくはＣ１－Ｃ８、より好ましくはＣ１－Ｃ６、より好ましくはＣ１－Ｃ３）アルキル基が挙げられる。 In the present invention, the term "aminoalkyl group" refers to an alkyl group having at least one amino group, and includes, for example, the aforementioned alkyl groups having 1 to 2 (preferably 1) amino group. Examples of aminoalkyl groups include aminomethyl group, 2-aminoethyl group, 1-aminoethyl group, 3-amino-n-propyl group, 1-aminopropan-2-yl group, 1-amino-n- butyl group, 1,4-diamino-n-butyl group, 5-amino-n-pentyl group, 6-amino-n-hexyl group, 7-amino-n-heptyl group, 8-amino-n-octyl group, C1-C10 (preferably C1-C8, more preferably C1-C6, C1-C3) alkyl groups are more preferred.
In the present invention, "aryl group" means a monovalent group formed by removing one hydrogen atom from an aromatic hydrocarbon ring. The aryl group includes, for example, a C6-C14 aryl group such as a phenyl group, a biphenyl group, a naphthyl group, an anthracenyl group, etc., preferably a C6-C10 aryl group and the like, more preferably a phenyl group and the like. is mentioned.
In the present invention, the term "arylalkyl group" refers to an alkyl group having at least one aryl group, and includes, for example, the aforementioned alkyl groups having 1 to 3 (preferably 1) aryl group. Examples of arylalkyl groups include benzyl, naphthylmethyl, biphenylmethyl, anthracenylmethyl, 2-phenylethyl, 1-phenylethyl, 2-anthracenylethyl, and 3-phenyl-n. -propyl group, 1-phenylpropan-2-yl group, 1-phenyl-n-butyl group, 1,4-diphenyl-n-butyl group, 5-phenyl-n-pentyl group, 2,3,4-tri phenyl-n-pentyl group, 6-phenyl-n-hexyl group, 7-phenyl-n-heptyl group, 8-phenyl-n-octyl group, 9-phenyl-n-nonyl group, 10-phenyl-n-decyl C1-C10 (preferably C1-C8, more preferably C1-C6, more preferably C1-C3) alkyl groups having 1 to 3 (preferably 1) phenyl groups such as groups.
　本発明において、ｌは０～３の整数を示し、好ましくは０～２である。Ｘがハロゲンの場合、ｌは１が好ましい。本発明において、ｍは０～３を示し、好ましくは０～２であり、より好ましくは０又は１である。本発明において、ｎは０～４の整数を示し、好ましくは０～３を示し、より好ましくは０～２である。 In the present invention, l represents an integer of 0-3, preferably 0-2. l is preferably 1 when X is halogen. In the present invention, m represents 0-3, preferably 0-2, more preferably 0 or 1. In the present invention, n represents an integer of 0-4, preferably 0-3, more preferably 0-2.
　本発明において、ｌが１の場合、基Ｘは下記の基における＊又は＊＊の位置（好ましくは＊＊の位置）に存在することが好ましい。 In the present invention, when l is 1, the group X is preferably present at the * or ** position (preferably at the ** position) in the following groups.
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　また、本発明において、ｌが２～３（好ましくは１～２）の場合、基Ｘのうち少なくとも１個（もしくは少なくとも２個）は上記の基における＊又は＊＊の位置（好ましくは＊＊の位置）に存在することが好ましい。 Further, in the present invention, when l is 2 to 3 (preferably 1 to 2), at least one (or at least two) of the groups X is the position of * or ** (preferably ** position).
　本発明において、基 In the present invention, the base
Figure JPOXMLDOC01-appb-C000040
 が、基
Figure JPOXMLDOC01-appb-C000040
 but
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
であり、かつｍが１の場合、基Ｙは下記の基における＊又は＊＊の位置（好ましくは＊の位置）に存在することが好ましい。本発明において、ｎが１以上の場合、炭素数ｎの二価飽和炭化水素基は、置換基として１個のオキソ基（＝Ｏ）を有してもよい。かかる実施形態において、置換基として１個のオキソ基（＝Ｏ）を有する炭素数ｎの二価飽和炭化水素基の具体例としては、例えば、－Ｃ（＝Ｏ）－、－ＣＨ２－Ｃ（＝Ｏ）－、－ＣＨ２－ＣＨ２－Ｃ（＝Ｏ）－、－ＣＨ２－Ｃ（＝Ｏ）－ＣＨ２－、－ＣＨ２－ＣＨ２－Ｃ（＝Ｏ）－ＣＨ２－等が挙げられ、ｎ＝２の場合の－ＣＨ２－Ｃ（＝Ｏ）－が好ましい。本発明において、上記一般式Ａで示される基を単に基Ａと示すこともある。本発明において、上記一般式Ａ’で示される基を単に基Ａ’と示すこともある。また、本発明において、基Ａが、基Ａ’であり、かつｍが２～３（好ましくは１～２）の場合、基Ｙのうち少なくとも１個（もしくは少なくとも２個）は基Ａ’における＊又は＊＊の位置（好ましくは＊の位置）に存在することが好ましい。 and m is 1, the group Y is preferably present at the * or ** position (preferably the * position) in the following groups. In the present invention, when n is 1 or more, the divalent saturated hydrocarbon group having n carbon atoms may have one oxo group (=O) as a substituent. In such embodiments, specific examples of the divalent saturated hydrocarbon group having n carbon atoms and having one oxo group (=O) as a substituent include -C(=O)-, -CH 2 -C (=O)-, -CH 2 -CH 2 -C(=O)-, -CH 2 -C(=O)-CH 2 -, -CH 2 -CH 2 -C(=O)-CH 2 - and the like, and —CH 2 —C(═O)— when n=2 is preferred. In the present invention, the group represented by the general formula A may be simply referred to as group A. In the present invention, the group represented by the general formula A' may be simply referred to as group A'. Further, in the present invention, when the group A is a group A' and m is 2 to 3 (preferably 1 to 2), at least one (or at least two) of the groups Y is the group A' It is preferably present at the * or ** position (preferably at the * position).
　本発明において、基Ａが、基 In the present invention, group A is a group
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
であり、かつｍが１の場合、基Ｙは下記の基における＊の位置に存在することが好ましい。本発明において、上記一般式Ａ’’’で示される基を単に基Ａ’’’と示すこともある。また、本発明において、基Ａが、基Ａ’’’であり、かつｍが２～３（好ましくは１～２）の場合、基Ｙのうち１個は基Ａ’’’における＊の位置に存在することが好ましい。本発明において、基Ａが基Ａ’’’である場合、当該基Ａ’’’における
Figure JPOXMLDOC01-appb-C000043
 は二重結合であることが好ましい。 and m is 1, the group Y is preferably present at the * position in the following group. In the present invention, the group represented by the general formula A''' may be simply referred to as group A'''. Further, in the present invention, when the group A is a group A''' and m is 2 to 3 (preferably 1 to 2), one of the groups Y is the position of * in the group A''' preferably present in In the present invention, when the group A is a group A''', in the group A'''
Figure JPOXMLDOC01-appb-C000043
 is preferably a double bond.
　一般式（Ｉ）においてｌが１以上の場合、少なくとも１つのＸがハロゲンであることが好ましい。ｍが１以上の場合、少なくとも１つのＹがヒドロキシル基又は置換基を有していてもよいアシルオキシ基（より好ましくは置換基を有していてもよいアシルオキシ基）であることが好ましい。また、ｍが２以上の場合、全てのＹがヒドロキシル基若しくは置換基を有していてもよいアシルオキシ基であることが好ましいが、少なくとも１つのＹがヒドロキシル基若しくは置換基を有していてもよいアシルオキシ基であり、Ｙとしてヒドロキシル基及び置換基を有していてもよいアシルオキシ基以外の以外の基（例えば、アルキル基等）を有してもよい。これらの実施形態においてもｌが２以上の場合、複数存在するＸは同一でも異なっていてもよく、ｍが２以上の場合、複数存在するＹは同一でも異なっていてもよいことは前述の通りである。
また、本発明においては、基Ａが基Ａ’’’であることが好ましい。 When l is 1 or more in general formula (I), at least one X is preferably halogen. When m is 1 or more, at least one Y is preferably a hydroxyl group or an optionally substituted acyloxy group (more preferably an optionally substituted acyloxy group). Further, when m is 2 or more, it is preferable that all Y are hydroxyl groups or acyloxy groups which may have substituents, but at least one Y may have a hydroxyl group or a substituent. Y may have a group other than a hydroxyl group and an optionally substituted acyloxy group (for example, an alkyl group, etc.). Also in these embodiments, when l is 2 or more, the plurality of Xs may be the same or different, and when m is 2 or more, the plurality of Ys may be the same or different, as described above. is.
Moreover, in the present invention, it is preferred that the group A is a group A'''.
　一般式（Ｉ）においてＹが置換基を有するアシルオキシ基である場合、当該置換基の数は限定されないが、例えば、１～３個が挙げられ、１～２個が好ましく、１個がより好ましい。アシルオキシ基が置換基を有する場合、当該置換基としては特に限定されないが、例えば、置換基Ａを有していてもよい複素環基、置換基Ａを有してもよいアリール基等が挙げられる。複素環基又はアリール基が置換基Ａを有する場合、複素環基又はフェニル基１個当たりの置換基Ａの個数は限定されないが、好ましくは１～２個、より好ましく１個である。置換基Ａとしては、特に限定されないが、置換基Ａを有していてもよい複素環基又は置換基Ａを有してもよいフェニル基がシステイン残基と相互作用するような構造を有していることが好ましい。置換基Ａとしては、例えば、チオール基、α,β－不飽和カルボニル基、シアノ基、カルボキシル基、エステル基、アミノカルボキシル基等が挙げられる。アシルオキシ基が置換基を有する場合、当該アシルオキシ基としては、ホルミルオキシ基が好ましい。アシルオキシ基の置換基がシアノフェニル基である場合、シアノ基が置換する位置はオルト、パラ、メタのいずれでもよいが、パラ位が好ましい。本発明において、α,β－不飽和カルボニル基とは、
Figure JPOXMLDOC01-appb-C000044
 （式中、ＲＡは、同一又は異なって、水素又はアルキル基を示す。）
で表される基を示す。
　また、本発明において、エステル基とは、
－ＲＢ－ＲＣ
（式中、ＲＢは、－Ｃ（＝Ｏ）－Ｏ－又は－Ｏ－Ｃ（Ｏ）－を示す。ＲＣは、炭化水素基を示す。）
で表される基を示す。
　上記式中、基ＲＣで示される炭化水素基としては、例えば、アルキル基、アリール基、アリールアルキル基等が挙げられる。 When Y is an acyloxy group having a substituent in the general formula (I), the number of the substituents is not limited, but includes, for example, 1 to 3, preferably 1 to 2, more preferably 1. . When the acyloxy group has a substituent, the substituent is not particularly limited, and examples thereof include a heterocyclic group optionally having a substituent A, an aryl group optionally having a substituent A, and the like. . When the heterocyclic group or aryl group has a substituent A, the number of substituents A per heterocyclic group or phenyl group is not limited, but is preferably 1 to 2, more preferably 1. The substituent A is not particularly limited, but has a structure such that a heterocyclic group optionally having a substituent A or a phenyl group optionally having a substituent A interacts with a cysteine residue. preferably. Substituent A includes, for example, a thiol group, an α,β-unsaturated carbonyl group, a cyano group, a carboxyl group, an ester group, an aminocarboxyl group and the like. When the acyloxy group has a substituent, the acyloxy group is preferably a formyloxy group. When the substituent of the acyloxy group is a cyanophenyl group, the position where the cyano group is substituted may be ortho, para or meta, but the para position is preferred. In the present invention, the α,β-unsaturated carbonyl group is
Figure JPOXMLDOC01-appb-C000044
 (In the formula, R A is the same or different and represents hydrogen or an alkyl group.)
represents a group represented by
Further, in the present invention, the ester group is
-R B -R C
(In the formula, R B represents -C(=O)-O- or -O-C(O)-.R C represents a hydrocarbon group.)
represents a group represented by
Examples of the hydrocarbon group represented by the group R 1 C in the above formula include an alkyl group, an aryl group, an arylalkyl group, and the like.
　一般式（Ｉ）においてＹが置換基を有するアミノ基である場合、置換基としては、例えば、式　－Ｃ（＝Ｏ）－Ｏ－ＲＤ　（式中、基ＲＤは炭化水素基を示す。）で表される基等が挙げられる。上記式中、基ＲＤで示される炭化水素基としては、例えば、アルキル基、アルケニル基、アリール基、アリールアルキル基等が挙げられる。 In the general formula (I), when Y is an amino group having a substituent, the substituent may be, for example, the formula -C(=O)-OR D (wherein the group R D represents a hydrocarbon group ) and the like. Examples of the hydrocarbon group represented by the group RD in the above formula include an alkyl group, an alkenyl group, an aryl group, an arylalkyl group and the like.
　複素環基としては、例えば、窒素、酸素及び硫黄からなる群より選択される少なくとも一種のヘテロ原子を１～３個有する、単環式又は二環式の５～１０員環の飽和又は不飽和の環から水素原子を１個除去してなる一価の基が挙げられる。当該複素環基としてはヘテロ原子として窒素を有するものが好ましい。また、当該複素環基としては単環式の５～７員環が好ましく、６員環がより好ましい。当該複素環基としては不飽和複素環が好ましい。より具体的には、例えば、ピロリジニル基、テトラヒドロチオフェニル基、チオフェニル基、テトラヒドロフラニル基、フラニル基、ピリジニル基、ピラジニル基、ピぺリジニル基、ピペラジニル基、トリアジニル基、チアジニル基、インドリル基、キノリニル基、ナフチリジニル基、チエニル基等が挙げられる。 The heterocyclic group includes, for example, a monocyclic or bicyclic 5- to 10-membered saturated or unsaturated ring having 1 to 3 heteroatoms of at least one selected from the group consisting of nitrogen, oxygen and sulfur. and a monovalent group obtained by removing one hydrogen atom from the ring of . The heterocyclic group preferably has nitrogen as a heteroatom. The heterocyclic group is preferably a monocyclic 5- to 7-membered ring, more preferably a 6-membered ring. An unsaturated heterocyclic ring is preferable as the heterocyclic group. More specifically, for example, pyrrolidinyl group, tetrahydrothiophenyl group, thiophenyl group, tetrahydrofuranyl group, furanyl group, pyridinyl group, pyrazinyl group, piperidinyl group, piperazinyl group, triazinyl group, thiazinyl group, indolyl group, quinolinyl group, naphthyridinyl group, thienyl group, and the like.
　本発明の化合物（Ｉ）又はその塩は、ｉｎ　ｖｉｔｒｏだけでなく、ｉｎ　ｖｉｖｏでもＨＮＭＴの阻害活性を示すため有用である。具体的には、従来もＨＮＭＴを阻害することにより脳内ヒスタミン濃度を上昇させるというアプローチでの研究はなされていたが、従来のＨＮＭＴ阻害剤は非特異的であり、また脳移行性を有さない等の課題があった（非特許文献１１）。かかる状況の下、本発明の化合物（Ｉ）又はその塩、脳移行性を有し、ｉｎ　ｖｉｖｏでもＨＮＭＴを阻害することができるため有用である。 The compound (I) or a salt thereof of the present invention is useful because it exhibits HNMT inhibitory activity not only in vitro but also in vivo. Specifically, studies have been conducted in the past with an approach of increasing brain histamine concentration by inhibiting HNMT, but conventional HNMT inhibitors are nonspecific and do not transfer to the brain. There was a problem that there was no such problem (Non-Patent Document 11). Under such circumstances, the compound (I) or a salt thereof of the present invention is useful because it has brain-localizing properties and can inhibit HNMT even in vivo.
　好ましい実施形態において、化合物（Ｉ）としては、下記表１～２に表す化合物又はその塩を挙げることができる。本明細書において、下記化合物を、表中に示すコート番号（ＨＡ　Ｎｏ）にて表すことがある。 In a preferred embodiment, compound (I) includes the compounds or salts thereof shown in Tables 1 and 2 below. In this specification, the following compounds are sometimes represented by coat numbers (HA No) shown in the tables.
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
　化合物（Ｉ）は、種々の方法により製造され得るが、例えば下記反応式で示される方法により製造される。
［反応式－１］ Compound (I) can be produced by various methods, for example, by the method shown by the following reaction scheme.
[Reaction formula-1]
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
［式中、ｎ、ｍ、Ｘ9及びＹは前述の通り。ＺはＹで示される基が保護基で保護されてなる基を示す。Ａはハロゲンを示す。］
　上記反応式において、ＺはＹで示される基が保護基で保護されてなる基を示す。保護基としては、例えば、メトキシメチル基（ＭＯＭ）、シリル基（Ｒ３Ｓｉ）、アセチル基が挙げられる。従って、Ｙがヒドロキシル基である場合、基Ｚとしては、ＭＯＭＯ－、Ｒ３ＳｉＯ－、ＡｃＯ－等が挙げられる。 [In the formula, n, m, X9 and Y are as described above. Z represents a group obtained by protecting the group represented by Y with a protecting group. A represents halogen. ]
In the above reaction formula, Z represents a group obtained by protecting the group represented by Y with a protecting group. Protective groups include, for example, a methoxymethyl group (MOM), a silyl group (R3Si), and an acetyl group. Thus, when Y is a hydroxyl group, groups Z include MOMO-, R3SiO-, AcO-, and the like.
　反応式－１においては、まず、化合物１と化合物２とを反応させることにより、化合物３を得ることができる。化合物１及び化合物２は、後述する製造例に記載の方法に準じて製造することができる。化合物１と化合物２との使用割合は特に限定されないが、例えば、前者１モルに対し後者を約１～５モルで使用することができる。当該反応は、水素化ナトリウム、炭酸カリウム等の存在下で行うことができる。次に、化合物３を脱保護することにより、化合物（Ｉ）を得ることができる。当該反応は、塩酸、テトラブチルアンモニウムフルオリド、炭酸カリウム等の存在下で行うことができる。 In Reaction Formula-1, compound 3 can be obtained by reacting compound 1 and compound 2 first. Compound 1 and compound 2 can be produced according to the method described in Production Examples below. The ratio of compound 1 and compound 2 to be used is not particularly limited, but for example, about 1 to 5 mol of the latter can be used per 1 mol of the former. The reaction can be performed in the presence of sodium hydride, potassium carbonate, or the like. Compound (I) can then be obtained by deprotecting compound 3. The reaction can be carried out in the presence of hydrochloric acid, tetrabutylammonium fluoride, potassium carbonate, or the like.
　上記反応式の各反応は、通常、反応に悪影響を及ぼさない慣用の溶媒、例えば、水、トリエチルアミン、メタノール、エタノール、イソプロパノール、ｎ－ブタノール、トリフルオロエタノール、エチレングリコール、アセトン、メチルエチルケトン、テトラヒドロフラン、ジオキサン、ジエチルエーテルジグライム、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、酢酸等、これらの混合溶媒の中で行われる。また、各反応の反応温度は特に限定されず、通常、室温、冷却又は加熱下で反応が行われる。好ましくは、－７８～１５０℃等が挙げられる。核反応の反応時間も特に限定されないが、例えば、１～３０時間反応させることができる。 Each reaction of the above reaction scheme is usually carried out using a solvent that does not adversely affect the reaction, such as water, triethylamine, methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, ethylene glycol, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane. , diethyl ether diglyme, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, acetic acid, and the like, in a mixed solvent thereof. Moreover, the reaction temperature of each reaction is not particularly limited, and the reaction is usually carried out at room temperature, under cooling or heating. Preferably, it is -78 to 150°C. The reaction time of the nuclear reaction is also not particularly limited, but the reaction can be carried out, for example, for 1 to 30 hours.
　また、各反応式において示された原料及び目的化合物に溶媒和物（例えば、水和物、エタノレート等）が付加された形態の化合物も、各々の一般式に含まれる。好ましい溶媒和物としては水和物が挙げられる。 In addition, compounds in the form of solvates (eg, hydrates, ethanolates, etc.) added to the raw materials and target compounds shown in each reaction formula are also included in each general formula. Preferred solvates include hydrates.
　上記各反応式で得られる各々の目的化合物は、反応混合物を、例えば、冷却した後、濾過、濃縮、抽出等の単離操作によって粗反応生成物を分離し、カラムクロマトグラフィー、再結晶等の通常の精製操作によって、反応混合物から単離精製することができる。 Each target compound obtained in each of the above reaction schemes can be obtained by, for example, cooling the reaction mixture, and then separating the crude reaction product by an isolation operation such as filtration, concentration, or extraction, followed by column chromatography, recrystallization, or the like. It can be isolated and purified from the reaction mixture by ordinary purification procedures.
　ＨＮＭＴ阻害剤、及びＡＤＨＤ、ナルコレプシー又はアルツハイマーの予防・治療剤
　本発明化合物である化合物（Ｉ）又はその塩は、ＨＮＭＴ阻害作用を有する。従って、本発明によれば、ＨＮＭＴ阻害により処置し得る疾患を予防又は治療することができる。 HNMT Inhibitor and Preventive/Treatment Agent for ADHD, Narcolepsy or Alzheimer's The compound (I) or a salt thereof, which is the compound of the present invention, has an HNMT inhibitory action. Thus, according to the present invention, diseases treatable by HNMT inhibition can be prevented or treated.
　従って、本発明は、化合物（Ｉ）又はその塩を含む医薬を提供する。本発明の医薬の治療対象となる、ＨＮＭＴ阻害により処置し得る疾患としては、ＡＤＨＤ（注意欠陥・多動性障害）、ナルコレプシー又はアルツハイマー等が挙げられる（非特許文献６～８）。また、ヒスタミンは、記憶能向上効果（文献番号2）、抗てんかん効果（文献番号3）、食欲抑制効果（文献番号4）、鎮痛効果（文献番号5）等の報告もされている。従って、本発明の医薬は、記憶能向上、抗てんかん、食欲抑制、鎮痛等の用途に用いることもできる。 Accordingly, the present invention provides a medicament containing compound (I) or a salt thereof. Diseases that can be treated by HNMT inhibition, which are targeted for treatment by the pharmaceutical of the present invention, include ADHD (attention deficit/hyperactivity disorder), narcolepsy, Alzheimer's disease, and the like (Non-Patent Documents 6 to 8). Histamine has also been reported to have a memory-enhancing effect (Reference No. 2), an antiepileptic effect (Reference No. 3), an appetite suppressing effect (Reference No. 4), an analgesic effect (Reference No. 5), and the like. Therefore, the medicament of the present invention can also be used for memory enhancement, antiepileptic, appetite suppression, analgesia, and the like.
　本発明において、塩とは、薬学的に許容され得る塩を意図する。また、化合物（Ｉ）の塩は、酸付加塩と塩基との塩を包含する。酸付加塩の具体例として、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、過塩素酸塩、リン酸塩等の無機酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、安息香酸塩、トリフルオロ酢酸塩、酢酸塩、メタンスルホン酸塩、ｐ－トルエンスルホン酸塩、トリフルオロメタンスルホン酸塩等の有機酸塩、及びグルタミン酸塩、アスパラギン酸塩等の酸性アミノ酸塩が挙げられる。塩基との塩の具体例としては、ナトリウム塩、カリウム塩又はカルシウム塩のようなアルカリ金属又はアルカリ土類金属塩、ピリジン塩、トリエチルアミン塩のような有機塩基との塩、リジン、アルギニン等の塩基性アミノ酸との塩が挙げられる。 In the present invention, the term "salt" means a pharmaceutically acceptable salt. In addition, the salt of compound (I) includes acid addition salts and base salts. Specific examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, and phosphate, oxalate, malonate, and succinic acid. salt, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethane Examples include organic acid salts such as sulfonates, and acidic amino acid salts such as glutamate and aspartate. Specific examples of salts with bases include alkali metal or alkaline earth metal salts such as sodium salts, potassium salts or calcium salts, salts with organic bases such as pyridine salts and triethylamine salts, and bases such as lysine and arginine. and salts with synthetic amino acids.
　化合物（Ｉ）又はその塩は、水和物又は溶媒和物の形で存在することもあるので、これらの水和物及び溶媒和物もまた本発明の有効成分である化合物に包含される。また、化合物（Ｉ）には、幾何異性体、立体異性体、光学異性体等の異性体が存在する場合、特に明記しない限り、これらの異性体は化合物（Ｉ）に包含される。 Since compound (I) or a salt thereof may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds that are active ingredients of the present invention. In addition, when compound (I) has isomers such as geometric isomers, stereoisomers, and optical isomers, these isomers are included in compound (I) unless otherwise specified.
　溶媒和物を形成する溶媒としては、水、エタノール、プロパノール等のアルコール、酢酸等の有機酸、酢酸エチル等のエステル類、テトラヒドロフラン、ジエチルエーテル等のエーテル類、アセトン等のケトン類、ＤＭＳＯ等が例示される。 Solvents that form solvates include water, alcohols such as ethanol and propanol, organic acids such as acetic acid, esters such as ethyl acetate, ethers such as tetrahydrofuran and diethyl ether, ketones such as acetone, and DMSO. exemplified.
　本発明においては、化合物（Ｉ）又はその塩そのものを自己免疫疾患を治療するための医薬として用いても、薬学的に許容される各種担体（例えば、例えば等張化剤、キレート剤、安定化剤、ｐＨ調節剤、防腐剤、抗酸化剤、溶解補助剤、粘稠化剤等）と組み合わせた医薬組成物として用いてもよい。 In the present invention, even if compound (I) or a salt thereof itself is used as a medicament for treating an autoimmune disease, various pharmaceutically acceptable carriers (e.g., isotonic agents, chelating agents, stabilizing agents, agents, pH adjusters, preservatives, antioxidants, solubilizers, thickening agents, etc.).
　等張化剤としては、例えば、グルコース、トレハロース、ラクトース、フルクトース、マンニトール、キシリトール、ソルビトール等の糖類、グリセリン、ポリエチレングリコール、プロピレングリコール等の多価アルコール類、塩化ナトリウム、塩化カリウム、塩化カルシウム等の無機塩類等が挙げられる。 Examples of tonicity agents include sugars such as glucose, trehalose, lactose, fructose, mannitol, xylitol and sorbitol; polyhydric alcohols such as glycerin, polyethylene glycol and propylene glycol; sodium chloride, potassium chloride and calcium chloride; Inorganic salts etc. are mentioned.
　キレート剤としては、例えば、エデト酸二ナトリウム、エデト酸カルシウム二ナトリウム、エデト酸三ナトリウム、エデト酸四ナトリウム、エデト酸カルシウム等のエデト酸塩類、エチレンジアミン四酢酸塩、ニトリロ三酢酸又はその塩、ヘキサメタリン酸ソーダ、クエン酸等が挙げられる。 Examples of chelating agents include edetate salts such as disodium edetate, disodium calcium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or salts thereof, and hexamethalin. acid sodium, citric acid, and the like.
　安定化剤としては、例えば、亜硫酸水素ナトリウム等が挙げられる。 Examples of stabilizers include sodium hydrogen sulfite.
　ｐＨ調節剤としては、例えば、塩酸、炭酸、酢酸、クエン酸等の酸が挙げられ、さらに水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物、炭酸ナトリウム等のアルカリ金属炭酸塩又は炭酸水素塩、酢酸ナトリウム等のアルカリ金属酢酸塩、クエン酸ナトリウム等のアルカリ金属クエン酸塩、トロメタモール等の塩基等が挙げられる。 Examples of pH adjusters include acids such as hydrochloric acid, carbonic acid, acetic acid, and citric acid, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate, and hydrogen carbonate. salts, alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, and bases such as trometamol;
　防腐剤としては、例えば、ソルビン酸、ソルビン酸カリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル等のパラオキシ安息香酸エステル、グルコン酸クロルヘキシジン、塩化ベンザルコニウム、塩化ベンゼトニウム、塩化セチルピリジニウム等の第４級アンモニウム塩、アルキルポリアミノエチルグリシン、クロロブタノール、ポリクォード、ポリヘキサメチレンビグアニド、クロルヘキシジン等が挙げられる。 Examples of antiseptics include sorbic acid, potassium sorbate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, paraoxybenzoate such as butyl parahydroxybenzoate, chlorhexidine gluconate, benzalkonium chloride, chloride quaternary ammonium salts such as benzethonium and cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, chlorhexidine and the like.
　抗酸化剤としては、例えば、亜硫酸水素ナトリウム、乾燥亜硫酸ナトリウム、ピロ亜硫酸ナトリウム、濃縮混合トコフェロール等が挙げられる。 Examples of antioxidants include sodium hydrogen sulfite, dried sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherols, and the like.
　溶解補助剤としては、例えば、安息香酸ナトリウム、グリセリン、Ｄ－ソルビトール、ブドウ糖、プロピレングリコール、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、マクロゴール、Ｄ－マンニトール等が挙げられ、
　粘稠化剤としては、例えば、ポリエチレングリコール、メチルセルロース、エチルセルロース、カルメロースナトリウム、キサンタンガム、コンドロイチン硫酸ナトリウム、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコール等が挙げられる。 Examples of solubilizing agents include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, D-mannitol, etc.
Examples of thickening agents include polyethylene glycol, methylcellulose, ethylcellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like.
　また、上記医薬組成物は、化合物（Ｉ）又はその塩以外に、ＨＮＭＴ阻害により処置し得る疾患の治療効果が知られている化合物をさらに含んでいてもよい。ＡＤＨＤ（注意欠陥・多動性障害）の治療薬としては、例えば、メチルフェニデート、アトモキセチン、グアンファシン等が挙げられる。ナルコレプシーの治療薬としては、例えば、モダフィニル、メチルフェニデート、ペモリン等が挙げられる。アルツハイマーの治療薬としては、例えば、ドネペジル、メマンチン、ガランタミン等が挙げられる。 In addition, the pharmaceutical composition may further contain a compound known to have a therapeutic effect on diseases that can be treated by HNMT inhibition, in addition to compound (I) or a salt thereof. Examples of therapeutic agents for ADHD (attention deficit/hyperactivity disorder) include methylphenidate, atomoxetine, guanfacine and the like. Drugs for treating narcolepsy include, for example, modafinil, methylphenidate, pemoline and the like. Alzheimer's drugs include, for example, donepezil, memantine, galantamine and the like.
　医薬組成物の実施形態において、組成物中の化合物（Ｉ）又はその塩の含有量は特に限定されず、化合物（Ｉ）の含有量換算で、例えば、９０質量％以上、７０質量％以上、５０質量％以上、３０質量％以上、１０質量％以上、５質量％以上、１質量％以上等の条件から適宜設定できる。 In the embodiment of the pharmaceutical composition, the content of compound (I) or a salt thereof in the composition is not particularly limited, and in terms of the content of compound (I), for example, 90% by mass or more, 70% by mass or more, It can be appropriately set from conditions such as 50% by mass or more, 30% by mass or more, 10% by mass or more, 5% by mass or more, and 1% by mass or more.
　製剤形態は、特に限定されず、例えば錠剤、丸剤、カプセル剤、散剤、顆粒剤、シロップ剤、舌下剤等の経口投与剤； 注射剤（静脈注射、筋肉注射、局所注射等）、含嗽剤、点滴剤、外用剤（軟膏、クリーム、貼付薬、吸入薬）、座剤等の非経口投与剤等の各種製剤形態を挙げることができる。上記製剤形態のうち、好ましいものとしては、例えば、注射剤、経口投与剤、外用剤等が挙げられる。 The dosage form is not particularly limited, and for example, tablets, pills, capsules, powders, granules, syrups, sublingual preparations for oral administration; injections (intravenous injections, intramuscular injections, local injections, etc.), gargles , drops, external preparations (ointments, creams, patches, inhalants), and parenteral preparations such as suppositories. Among the above dosage forms, preferred are, for example, injections, orally administered drugs, external preparations, and the like.
　製剤中の本発明の化合物（Ｉ）の含有量は、投与経路、患者の年齢、体重、症状等によって異なり一概に規定できないが、化合物（Ｉ）の１日投与量が通常10～5000mg程度、より好ましくは100～1000mg程度になる量とすればよい。１日１回投与する場合は、1製剤中にこの量が含まれていればよく、１日３回投与する場合は、１製剤中にこの3分の１量が含まれていればよい。 The content of the compound (I) of the present invention in the formulation varies depending on the route of administration, patient age, body weight, symptoms, etc., and cannot be categorically defined. More preferably, the amount should be about 100 to 1000 mg. In the case of administration once a day, this amount should be contained in one preparation, and in the case of administration three times a day, one third of this amount should be contained in one preparation.
　本発明の医薬は、哺乳動物等の患者に投与される。哺乳動物としては、ヒト、サル、マウス、ラット、ウサギ、ネコ、イヌ、ブタ、ウシ、ウマ、ヒツジ等が挙げられる。 The pharmaceutical of the present invention is administered to patients such as mammals. Mammals include humans, monkeys, mice, rats, rabbits, cats, dogs, pigs, cows, horses, sheep and the like.
　前述のように、化合物（Ｉ）又はその塩は、ＨＮＭＴ阻害作用を有する。従って、本発明は、化合物（Ｉ）又はその塩を含むＨＮＭＴ阻害剤も提供する。ＨＮＭＴ阻害剤の有効成分、製剤形態、投与量等は、本発明の医薬と同様である。本発明においてＨＮＭＴ阻害とは、化合物（Ｉ）又はその塩を投与しなかった場合と比較して、ＨＮＭＴの活性、具体的には、ヒスタミンのメチル化が有意に抑制されることを意味する。ＨＮＭＴの活性測定は、実施例に記載の方法により行うことができる。 As described above, compound (I) or a salt thereof has an HNMT inhibitory effect. Accordingly, the present invention also provides HNMT inhibitors comprising compound (I) or salts thereof. The active ingredient, formulation form, dosage, etc. of the HNMT inhibitor are the same as those of the drug of the present invention. In the present invention, HNMT inhibition means significant suppression of HNMT activity, specifically methylation of histamine, as compared to when compound (I) or a salt thereof was not administered. HNMT activity can be measured by the method described in Examples.
　以下に実施例を用いて本発明の具体的な実施形態を例示的に説明するが、本発明は、かかる具体的な実施形態に限定されない。 Specific embodiments of the present invention will be exemplified below using examples, but the present invention is not limited to such specific embodiments.
　製造例１　HA-76の合成 Manufacturing example 1 Synthesis of HA-76
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　3β－ヒドロキシアンドロスト-5-エン-17-オン（1 mmol, 288.4 mg)、アリルアミン（4 mmol, 300.5μL）、酢酸（4 mmol, 228.5μL）およびナトリウムトリアセトキシボロヒドリド（2.5 mmol, 529.9 mg）のテトラヒドロフランとジクロロエタン混合溶液 (1:1, 10.0 mL) に溶解させた後、室温で 24 時間攪拌した。飽和炭酸水素ナトリウム水溶液（10 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 2 回抽出した後、有機層を水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 1:1）に付し、1 (266.1 mg, 81%) を白色結晶として得た。 3β-hydroxyandrost-5-en-17-one (1 mmol, 288.4 mg), allylamine (4 mmol, 300.5 μL), acetic acid (4 mmol, 228.5 μL) and sodium triacetoxyborohydride (2.5 mmol, 529.9 mg) ) in a mixed solution of tetrahydrofuran and dichloroethane (1:1, 10.0 mL), and then stirred at room temperature for 24 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added to stop the reaction, and after extraction with ethyl acetate (20 mL) twice, the organic layer was washed with water (30 mL) and saturated brine, and diluted with magnesium sulfate. It was dried and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give 1 (266.1 mg, 81%) as white crystals.
  1(200.0 mg, 0.6 mmol) 、テトラキストリフェニルホスフィンパラジウム（2 mol%, 13.9 mg）および 1,3-ジメチルバルビツル酸（1.8 mmol, 281.1 mg）をジクロロメタン（5 mL）中 35 度で 17 時間撹拌した。飽和炭酸ナトリウム（20 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 2 回抽出した後、有機層を水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール ＝ 10:1）に付し、2 (152.3 mg, 88%) を白色結晶として得た。 1 (200.0 mg, 0.6 mmol), tetrakistriphenylphosphine palladium (2 mol%, 13.9 mg) and 1,3-dimethylbarbituric acid (1.8 mmol, 281.1 mg) in dichloromethane (5 mL) at 35°C for 17 hours Stirred. After adding saturated sodium carbonate (20 mL) to stop the reaction, extract twice with ethyl acetate (20 mL), wash the organic layer with water (30 mL) and saturated brine, and dry over magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol = 10:1) to give 2 (152.3 mg, 88%) as white crystals.
  2(72.3 mg, 0.25 mmol) 、7-クロロ-4-(4-クロロフェノキシ)キノリン（72.3 mg, 0.25 mmol）、テトラキストリフェニルホスフィンヒドリドロジウム（10 mol%, 28.8 mg）および 1,2-ビス（ジフェニルホスフィノ）エタン（20 mol%, 19.9 mg）をジメチルスルホキシド（1.5 mL）中 150 度で 15 時間撹拌した。水（20 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 2 回抽出した後、有機層を水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:トルエン ＝ 1:1）に付し、HA-76 (58.6 mg, 0.13 mmol, 52%) を白色結晶として得た。 2 (72.3 mg, 0.25 mmol), 7-chloro-4-(4-chlorophenoxy)quinoline (72.3 mg, 0.25 mmol), tetrakistriphenylphosphine hydridrhodium (10 mol%, 28.8 mg) and 1,2-bis (Diphenylphosphino)ethane (20 mol%, 19.9 mg) was stirred in dimethylsulfoxide (1.5 mL) at 150 degrees for 15 hours. After adding water (20 mL) to stop the reaction, extract twice with ethyl acetate (20 mL), wash the organic layer with water (30 mL) and saturated brine, dry over magnesium sulfate, and vacuum. The solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:toluene = 1:1) to give HA-76 (58.6 mg, 0.13 mmol, 52%) as white crystals.
［HA-76化合物データ］
HA-76: Colorless solid; mp 187.0-187.5℃ (Hexane/Diethyl ether = 5); Rf = 0.22 (Toluene/Ethyl acetate = 1); 1H-NMR (400 MHz, CDCl3):δ0.89 (3H, s), 1.03 (3H, s), 1.01-1.13 (2H, m), 1.20-1.26 (1H, m), 1.31-1.43 (2H, m), 1.47-1.63 (6H, m), 1.79-1.84 (4H, m), 2.01-2.08 (1H, m), 2.23-2.36 (3H, m), 3.55 (1H, septet, J = 5.8 Hz), 3.64 (1H, q, J = 8.4 Hz), 4.99 (1H, d, J = 7.6 Hz), 5.38 (1H, d, J = 5.2 Hz), 6.53 (1H, d, J = 5.2 Hz), 7.36 (1H, dd, J = 9.2, 2.4 Hz), 7.64 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 2.0 Hz), 8.48 (1H, d, J = 5.6 Hz).; 13C-NMR (100 MHz, CDCl3):δ12.2, 19.4, 20.7, 23.8, 29.6, 31.5, 31.6, 32.1, 36.5, 37.2, 38.1, 42.2, 43.8, 50.1, 53.2, 62.6, 71.6, 99.7, 117.0, 120.6, 121.2, 125.2, 128.7, 134.9, 140.9, 149.0, 149.8, 151.8.; IR (KBr, cm-1): 3347, 2927, 1581, 1535, 1378, 1063.; LRMS (EI) m/z: 450 (M+, 100%), 272 (M+-178, 41%); HRMS (EI): 計算値C28H35ClN2O (M+): 450.2438, 実測値 450.2454. [HA-76 compound data]
HA-76: Colorless solid; mp 187.0-187.5℃ (Hexane/Diethyl ether = 5); Rf = 0.22 (Toluene/Ethyl acetate = 1); 1 H-NMR (400 MHz, CDCl 3 ): δ0.89 (3H , s), 1.03 (3H, s), 1.01-1.13 (2H, m), 1.20-1.26 (1H, m), 1.31-1.43 (2H, m), 1.47-1.63 (6H, m), 1.79-1.84 (4H, m), 2.01-2.08 (1H, m), 2.23-2.36 (3H, m), 3.55 (1H, septet, J = 5.8 Hz), 3.64 (1H, q, J = 8.4 Hz), 4.99 ( 1H, d, J = 7.6 Hz), 5.38 (1H, d, J = 5.2 Hz), 6.53 (1H, d, J = 5.2 Hz), 7.36 (1H, dd, J = 9.2, 2.4 Hz), 7.64 ( 1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 2.0 Hz), 8.48 (1H, d, J = 5.6 Hz).; 13 C-NMR (100 MHz, CDCl 3 ): δ12.2 , 19.4, 20.7, 23.8, 29.6, 31.5, 31.6, 31.1, 36.5, 37.2, 38.1, 43.2, 53.1, 62.6, 71.6, 99.6, 99.6, 120.0, 121.6, 125.2, 125.2, 128.9, 140.9, 140.9 , 149.8, 151.8.; IR (KBr, cm -1 ): 3347, 2927, 1581, 1535, 1378, 1063.; LRMS (EI) m/z: 450 (M + , 100%), 272 (M + - 178, 41%); HRMS ( EI): calculated C28H35ClN2O  (M + ): 450.2438, found 450.2454.
　製造例２　HA-84合成 Manufacturing example 2 Synthesis of HA-84
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　2 (72.3 mg, 0.25 mmol) 、8-フルオロキノリン（30 μL, 0.25 mmol）、テトラキストリフェニルホスフィンヒドリドロジウム（10 mol%, 28.8 mg）および 1,2-ビス（ジフェニルホスフィノ）エタン（20 mol%, 19.9 mg）をジメチルスルホキシド（0.5 mL）中 150 度で 15 時間撹拌した。水（20 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 2 回抽出した後、有機層を水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン: 酢酸エチル ＝ 4:1）に付し、HA-84 (27.0 mg, 0.065 mmol, 26%) を白色結晶として得た。 2 (72.3 mg, 0.25 mmol), 8-fluoroquinoline (30 μL, 0.25 mmol), tetrakistriphenylphosphine hydrrhodium (10 mol%, 28.8 mg) and 1,2-bis(diphenylphosphino)ethane (20 mol %, 19.9 mg) was stirred in dimethylsulfoxide (0.5 mL) at 150 degrees for 15 hours. After adding water (20 mL) to stop the reaction, extract twice with ethyl acetate (20 mL), wash the organic layer with water (30 mL) and saturated brine, dry over magnesium sulfate, and vacuum. The solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=4:1) to give HA-84 (27.0 mg, 0.065 mmol, 26%) as white crystals.
［HA-84化合物データ］
HA-84: Pale yellow solid; mp 96.5-97.0℃ (Hexane/Diethyl ether = 10); Rf = 0.20 (Hexane/Ethyl acetate = 4); 1H-NMR (400 MHz, CDCl3):δ0.91 (3H, s), 0.99-1.06 (1H, m), 1.02 (3H, s), 1.06-1.13 (1H, m), 1.21-1.25 (1H, m), 1.30-1.37 (1H, m), 1.40-1.52 (1H, m), 1.56-1.65 (5H, m), 1.71-1.76 (2H, m), 1.83-1.92 (3H, m), 2.03-2.08 (1H, m), 2.25-2.35 (3H, m), 3.54 (1H, septet, J = 6.8 Hz), 3.58-3.62 (1H, m), 5.38 (1H, bd, J = 5.2 Hz), 6.27 (1H, bs), 6.76 (1H, d, J = 7.2 Hz), 6.97 (1H, dd, J = 8.0, 1.2 Hz), 7.31 (1H, d, J = 8.0 Hz), 7.34 (1H, dd, J = 5.2, 4.0 Hz), 8.03 (1H, dd, J = 8.4, 1.6 Hz), 8.69 (1H, dd, J = 4.0, 1.6 Hz).; 13C-NMR (100 MHz, CDCl3):δ12.1, 19.4, 20.8, 23.8, 29.7, 31.57, 31.61, 32.1, 36.5, 37.2, 38.3, 42.2, 43.8, 50.2, 53.3, 63.0, 71.7, 105.0, 112.9, 121.2, 121.4, 127.7, 128.7, 136.0, 138.0, 140.8, 145.0, 146.6.; IR (KBr, cm-1): 3388, 2929, 1575, 1521, 1379, 1055, 788.; LRMS (EI) m/z: 416 (M+, 100%), 183 (M+-233, 44%); HRMS (EI): 計算値C28H36N2O (M+): 416.2828, 実測値 416.2815. [HA-84 compound data]
HA-84: Pale yellow solid; mp 96.5-97.0℃ (Hexane/Diethyl ether = 10); Rf = 0.20 (Hexane/Ethyl acetate = 4); 1 H-NMR (400 MHz, CDCl 3 ): δ0.91 ( 3H, s), 0.99-1.06 (1H, m), 1.02 (3H, s), 1.06-1.13 (1H, m), 1.21-1.25 (1H, m), 1.30-1.37 (1H, m), 1.40- 1.52 (1H, m), 1.56-1.65 (5H, m), 1.71-1.76 (2H, m), 1.83-1.92 (3H, m), 2.03-2.08 (1H, m), 2.25-2.35 (3H, m ), 3.54 (1H, septet, J = 6.8 Hz), 3.58-3.62 (1H, m), 5.38 (1H, bd, J = 5.2 Hz), 6.27 (1H, bs), 6.76 (1H, d, J = 7.2 Hz), 6.97 (1H, dd, J = 8.0, 1.2 Hz), 7.31 (1H, d, J = 8.0 Hz), 7.34 (1H, dd, J = 5.2, 4.0 Hz), 8.03 (1H, dd, J = 8.4, 1.6 Hz) , 8.69 ( 1H, dd, J = 4.0, 1.6 Hz). , 32.1, 36.5, 37.2, 38.3, 42.2, 43.8, 50.2, 53.3, 63.0, 71.7, 105.0, 112.9, 121.2, 121.4, 127.7, 128.7, 136.0, 138.0, 140.4 (IR.6, 140.4 ; 1 ): 3388, 2929, 1575, 1521, 1379, 1055, 788.; LRMS (EI) m/z: 416 (M + , 100%), 183 (M + -233, 44%); HRMS (EI) : Calculated value C28H36N2O  (M + ): 416.2828, found 416.2815.
　製造例３　HA-86合成 Manufacturing example 3 Synthesis of HA-86
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　2 (144.8 mg, 0.5 mmol) 、4-(4-クロロフェノキシ)キノリン（127.5 mg, 0.5 mmol）、テトラキストリフェニルホスフィンヒドリドロジウム（10 mol%, 28.8 mg）および 1,2-ビス（ジフェニルホスフィノ）エタン（20 mol%, 19.9 mg）をジメチルスルホキシド（0.7 mL）中 150 度で 15 時間撹拌した。水（20 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 2 回抽出した後、有機層を水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:トルエン ＝ 1:1）に付し、HA-86 (35.3 mg, 0.085 mmol, 17%) を白色結晶として得た。 2 (144.8 mg, 0.5 mmol), 4-(4-chlorophenoxy)quinoline (127.5 mg, 0.5 mmol), tetrakistriphenylphosphine hydridodium (10 mol%, 28.8 mg) and 1,2-bis(diphenylphosphino ) ethane (20 mol%, 19.9 mg) was stirred in dimethyl sulfoxide (0.7 mL) at 150 degrees for 15 hours. After adding water (20 mL) to stop the reaction, extract twice with ethyl acetate (20 mL), wash the organic layer with water (30 mL) and saturated brine, dry over magnesium sulfate, and vacuum. The solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:toluene = 1:1) to give HA-86 (35.3 mg, 0.085 mmol, 17%) as white crystals.
［HA-86化合物データ］
HA-86: Pale yellow solid; mp 152.0-152.5℃ (Chloroform); Rf = 0.23 (Toluene/Ethyl acetate = 1); 1H-NMR (400 MHz, CDCl3):δ0.84 (3H, s), 0.94-1.04 (1H, m), 0.98 (3H, s), 1.05-1.09 (1H, m), 1.16-1.22 (1H, m), 1.24-1.37 (2H, m), 1.40-1.60 (5H, m), 1.69-1.75 (1H, m), 1.77-1.81 (3H, m), 2.00 (1H, bd, J = 14.8 Hz), 2.20-2.34 (3H, m), 3.20 (1H, bs), 3.53 (1H, septet, J = 6.4 Hz), 3.59 (1H, q, J = 8.4 Hz), 5.01 (1H, d, J = 8.0 Hz), 5.32 (1H, d, J = 5.2 Hz), 6.49 (1H, d, J = 5.6 Hz), 7.38 (1H, td, J = 6.8, 0.8 Hz), 7.58 (1H, td, J = 7.2, 1.2 Hz), 7.69 (1H, d, J = 8.4 Hz), 7.94 (1H, dd, J = 8.0, 0.8 Hz), 8.45 (1H, d, J = 5.2 Hz).; 13C-NMR (100 MHz, CDCl3):δ12.1, 19.4, 20.6, 23.7, 29.5, 31.4, 31.5, 32.0, 36.5, 37.1, 38.0, 42.2, 43.7, 50.0, 53.0, 62.4, 71.2, 99.3, 118.5, 119.0, 120.9, 124.4, 128.9, 129.7, 141.1, 148.2, 149.7, 150.6.; IR (KBr, cm-1): 3358, 2930, 1581, 1533, 1347, 1062, 758.; LRMS (EI) m/z: 416 (M+, 62%), 398 (M+-18, 100%); HRMS (EI): 計算値C28H36N2O (M+): 416.2828, 実測値 416.2824. [HA-86 compound data]
HA-86: Pale yellow solid; mp 152.0-152.5°C (Chloroform); Rf = 0.23 (Toluene/Ethyl acetate = 1); 1 H-NMR (400 MHz, CDCl 3 ): δ0.84 (3H, s), 0.94-1.04 (1H, m), 0.98 (3H, s), 1.05-1.09 (1H, m), 1.16-1.22 (1H, m), 1.24-1.37 (2H, m), 1.40-1.60 (5H, m ), 1.69-1.75 (1H, m), 1.77-1.81 (3H, m), 2.00 (1H, bd, J = 14.8 Hz), 2.20-2.34 (3H, m), 3.20 (1H, bs), 3.53 ( 1H, septet, J = 6.4 Hz), 3.59 (1H, q, J = 8.4 Hz), 5.01 (1H, d, J = 8.0 Hz), 5.32 (1H, d, J = 5.2 Hz), 6.49 (1H, d, J = 5.6 Hz), 7.38 (1H, td, J = 6.8, 0.8 Hz), 7.58 (1H, td, J = 7.2, 1.2 Hz), 7.69 (1H, d, J = 8.4 Hz), 7.94 ( 1H, dd, J = 8.0, 0.8 Hz), 8.45 (1H, d, J = 5.2 Hz).; 13C -NMR (100 MHz, CDCl3 ): δ12.1, 19.4, 20.6, 23.7, 29.5, 31.4 , 31.5, 32.0, 36.5, 37.1, 38.0, 42.7, 43.0, 50.0, 62.0, 71.4, 99.3, 118.5, 119.0, 120.9, 124.9, 128.9, 129.9 cm -1 ): 3358, 2930, 1581, 1533, 1347, 1062, 758.; LRMS (EI) m/z: 416 (M + , 62%), 398 (M + -18, 100%); EI ): calculated C28H36N2O  (M + ): 416.2828, found 416.2824.
　製造例４　HA-90合成 Manufacturing Example 4 Synthesis of HA-90
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　3β－ヒドロキシアンドロスト-5-エン-17-オン（2.0 mmol, 576.9 mg）のテトラヒドロフラン溶液に、クロロメチルメチルエーテル（2.0 mmol, 150.0μL）と N,N-ジイソプロピルエチルアミン（2.4 mmol, 0.42 mL）を加えて、80 ℃ で 15 時間攪拌した。水（10 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 3 回抽出した。有機層を纏めて水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 5:1）に付し、3 (628.7 mg, 1.89 mmol, 95%) を白色結晶として得た。 Chloromethyl methyl ether (2.0 mmol, 150.0 μL) and N,N-diisopropylethylamine (2.4 mmol, 0.42 mL) were added to a tetrahydrofuran solution of 3β-hydroxyandrost-5-en-17-one (2.0 mmol, 576.9 mg). was added and stirred at 80°C for 15 hours. After adding water (10 mL) to stop the reaction, the mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined, washed with water (30 mL) and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=5:1) to give 3 (628.7 mg, 1.89 mmol, 95%) as white crystals.
  60% 水素化ナトリウム（6.24 mmol, 249.6 mg）のテトラヒドロフラン懸濁液に、0 ℃ でジエチル（シアノメチル）ホスホナート（6.24 mmol, 1.25 mL）を滴下した後 30 分間撹拌した。次いで、3 (628.7 mg, 1.89 mmol）を少しずつ加えた後、3 時間加熱還流下撹拌した。水（20 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 3 回抽出した。有機層を纏めて水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 6:1）に付し、4 (630.0 mg, 1.8 mmol, 95%) を白色結晶として得た。 To a suspension of 60% sodium hydride (6.24 mmol, 249.6 mg) in tetrahydrofuran, diethyl (cyanomethyl) phosphonate (6.24 mmol, 1.25 mL) was added dropwise at 0 °C and stirred for 30 minutes. Then, 3 (628.7 mg, 1.89 mmol) was added little by little, and the mixture was stirred under reflux for 3 hours. After adding water (20 mL) to stop the reaction, the mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined, washed with water (30 mL) and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=6:1) to give 4 (630.0 mg, 1.8 mmol, 95%) as white crystals.
  4(630.0 mg, 1.8 mmol) をエタノール（30 mL）に加えて、50 ℃ で溶解させた後、Pd/C（Pd 10%, 321.4 mg）を加えて水素雰囲気下50 ℃ で18 時間撹拌した。反応溶液をセライトを通して濾過した後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 5:1）に付し、5 (621.1 mg, 1.73 mmol, 96%) を白色結晶として得た。 4 (630.0 mg, 1.8 mmol) was added to ethanol (30 mL) and dissolved at 50 ℃, then Pd/C (Pd 10%, 321.4 mg) was added and stirred at 50 ℃ for 18 hours under a hydrogen atmosphere. . After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=5:1) to give 5 (621.1 mg, 1.73 mmol, 96%) as white crystals.
　5（610.3 mg, 1.7 mmol）をエタノール（20 mL）に 80 ℃ で溶解した後、4 M 水酸化カリウム水溶液（25 mL）を摘果して 15 時間撹拌した。室温まで放冷した後、酢酸エチル (30 mL) で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 2:1）に付し、6 (551.9 mg, 1.46 mmol, 86%) を白色結晶として得た。 After dissolving 5 (610.3 mg, 1.7 mmol) in ethanol (20 mL) at 80 °C, 4 M potassium hydroxide aqueous solution (25 mL) was added and stirred for 15 hours. After allowing to cool to room temperature, it was extracted three times with ethyl acetate (30 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1) to give 6 (551.9 mg, 1.46 mmol, 86%) as white crystals.
　リチウムアルミニウムヒドリド（48.2 mg, 1.27 mmol）をテトラヒドロフラン（6 mL）に懸濁させた後、6 (196.7 mg, 0.52 mmol) のテトラヒドロフラン（3 mL）溶液を 0 ℃で滴下した。次いで、反応混合液を昇温して 1 時間加熱還流下撹拌した。氷水に反応混合液を加えて反応を停止し、2 M 水酸化ナトリウム水溶液で液性を塩基性にした後、酢酸エチル (30 mL) で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 4:1）に付し、7 (191.3 mg, 0.52 mmol, 100%) を白色結晶として得た。 After suspending lithium aluminum hydride (48.2 mg, 1.27 mmol) in tetrahydrofuran (6 mL), a solution of 6 (196.7 mg, 0.52 mmol) in tetrahydrofuran (3 mL) was added dropwise at 0°C. Then, the reaction mixture was heated and stirred under reflux for 1 hour. The reaction mixture was added to ice water to stop the reaction, basified with 2 M aqueous sodium hydroxide solution, and then extracted three times with ethyl acetate (30 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=4:1) to give 7 (191.3 mg, 0.52 mmol, 100%) as white crystals.
  7(191.3 mg, 0.52 mmol) 、トリフェニルホスフィン（4.0 mmol, 1.05 g）、イミダゾール（4.0 mmol, 0.27 g）、ヨウ素（3.2 mmol, 0.81 g）のトルエン（20 mL）溶液を、80 ℃ で 2 時間撹拌した。飽和チオ硫酸ナトリウム水溶液を加えて反応を停止した後、ジクロロメタン（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（トルエン）に付し、 8 (196.5 mg, 0.41 mmol) を白色結晶として得た。 7 (191.3 mg, 0.52 mmol), triphenylphosphine (4.0 mmol, 1.05 g), imidazole (4.0 mmol, 0.27 g), and iodine (3.2 mmol, 0.81 g) in toluene (20 mL) at 80 °C. Stirred for an hour. A saturated aqueous sodium thiosulfate solution was added to stop the reaction, and the mixture was extracted three times with dichloromethane (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (toluene) to give 8 (196.5 mg, 0.41 mmol) as white crystals.
  8（61.6 mg, 0.13 mmol）と タクリン（77.3 mg, 0.39 mmol）のジメチルホルムアミド（1.5 mL）溶液に、水素化ナトリウム（31.2 mg, 0.78 mmol）を加えて 80℃で 1.5 時間撹拌した。水を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール：トリエチルアミン = 100:10:0.5）に付し、9 (63.0 mg, 0.13 mmol, 89%) を白色結晶として得た。 Sodium hydride (31.2 mg, 0.78 mmol) was added to a solution of 8 (61.6 mg, 0.13 mmol) and tacrine (77.3 mg, 0.39 mmol) in dimethylformamide (1.5 mL) and stirred at 80°C for 1.5 hours. After adding water to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol:triethylamine=100:10:0.5) to give 9 (63.0 mg, 0.13 mmol, 89%) as white crystals.
  9 (63.0 mg, 0.13 mmol) をメタノール（10 mL）とジクロロメタン（4 mL）に溶解した後、6M 塩酸（10 mL）を加えて、室温で 15 時間撹拌した。2M 水酸化ナトリウム水溶液を加えて塩基性にした後、ジクロロメタン（10 mL）で 3 回抽出した。有機層を纏めて、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール：トリエチルアミン = 90:10:1）に付し、HA-90 (53.6 mg, 0.11 mmol, 93%) を白色結晶として得た。 9 (63.0 mg, 0.13 mmol) was dissolved in methanol (10 mL) and dichloromethane (4 mL), 6M hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 15 hours. After adding 2M sodium hydroxide aqueous solution to make it basic, it was extracted three times with dichloromethane (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol:triethylamine=90:10:1) to give HA-90 (53.6 mg, 0.11 mmol, 93%) as white crystals.
［HA-90化合物データ］
HA-90: Pale yellow solid; mp 185.0-186.0℃ (Washed by hexane); Rf = 0.33 (Ethyl acetate:Methanol:Diethylamine = 100:10:0.5); 1H-NMR (400 MHz, CDCl3):δ0.59 (3H, s), 0.64 (1H, td, J = 14.8, 4.0 Hz), 0.81 (3H, s), 0.86-0.91 (1H, m), 0.96-1.07 (3H, m), 1.10-1.15 (2H, m), 1.20-1.32 (5H, m), 1.33-1.41 (2H, m), 1.42-1.47 (1H, m), 1.52-1.59 (2H, m), 1.61-1.72 (4H, m), 1.75-1.85 (4H, m), 1.92 (4H, quintet, J = 3.2 Hz), 2.71 (2H, bs), 3.06 (2H, bs), 3.39-3.44 (1H, m), 3.47-3.59 (1H, m), 3.59 (1H, septet, J = 6.0 Hz), 3.94 (1H, bs), 7.34 (1H, td, J = 7.2, 1.2 Hz), 7.55 (1H, td, J = 8.4, 1.2 Hz), 7.89 (1H, d, J = 8.4, 0.8 Hz), 7,95 (1H, d, J = 8.4, 0.4 Hz).; 13C-NMR (100 MHz, CDCl3):δ12.3, 12.7, 20.9, 22.8, 23.1, 24.7, 24.8, 28.4, 28.6, 31.5, 32.1, 32.8, 34.1, 35.46, 35.53, 37.0, 37.9, 38.1, 42.3, 44.9, 48.4, 49.0, 54.6, 55.7, 71.2, 115.6, 120.1, 122.8, 123.4, 128.2, 128.8, 147.5, 150.7, 158.4.; IR (KBr, cm-1): 3348, 2930, 2861, 1042, 755.; LRMS (EI) m/z: 500 (M+, 58%), 211 (M+-289, 100%); HRMS (EI): 計算値C34H48N2O(M+): 500.3767, 実測値 500.3764. [HA-90 compound data]
HA-90: Pale yellow solid; mp 185.0-186.0°C (Washed by hexane); Rf = 0.33 (Ethyl acetate:Methanol:Diethylamine = 100:10:0.5); 1 H-NMR (400 MHz, CDCl 3 ): δ0 .59 (3H, s), 0.64 (1H, td, J = 14.8, 4.0 Hz), 0.81 (3H, s), 0.86-0.91 (1H, m), 0.96-1.07 (3H, m), 1.10-1.15 (2H, m), 1.20-1.32 (5H, m), 1.33-1.41 (2H, m), 1.42-1.47 (1H, m), 1.52-1.59 (2H, m), 1.61-1.72 (4H, m) , 1.75-1.85 (4H, m), 1.92 (4H, quintet, J = 3.2 Hz), 2.71 (2H, bs), 3.06 (2H, bs), 3.39-3.44 (1H, m), 3.47-3.59 (1H , m), 3.59 (1H, septet, J = 6.0 Hz), 3.94 (1H, bs), 7.34 (1H, td, J = 7.2, 1.2 Hz), 7.55 (1H, td, J = 8.4, 1.2 Hz) , 7.89 (1H, d, J = 8.4, 0.8 Hz), 7,95 (1H, d, J = 8.4, 0.4 Hz).; 13 C-NMR (100 MHz, CDCl 3 ): δ12.3, 12.7, 20.9, 22.8, 24.1, 24.7, 24.8, 24.8, 28.6, 28.6, 31.5, 32.1, 34.1, 34.1, 35.53, 37.0, 37.0, 37.9, 38.1, 42.1, 44.9, 48.9 122.8, 123.4 , 128.2, 128.8, 147.5, 150.7, 158.4.; IR (KBr, cm -1 ): 3348, 2930, 2861, 1042, 755.; ), 211 (M + -289, 100 %); HRMS (EI): calculated C34H48N2O (M+ ) : 500.3767 , found 500.3764.
　製造例５　HA-93合成 Manufacturing example 5 Synthesis of HA-93
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　8（47.4 mg, 0.1 mmol）と 6-クロロ-1,2,3,4-テトラヒドロアクリジン-9-アミン（69.6 mg, 0.3 mmol）のジメチルホルムアミド（1.5 mL）溶液に、水素化ナトリウム（24.0 mg, 0.6 mmol）を加えて 80℃で 1.5 時間撹拌した。水を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール：トリエチルアミン = 100:10:0.5）に付し、10 (25.3 mg, 0.045 mmol, 47%) を白色結晶として得た。 Sodium hydride (24.0 mg , 0.6 mmol) was added and stirred at 80°C for 1.5 hours. After adding water to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol:triethylamine=100:10:0.5) to give 10 (25.3 mg, 0.045 mmol, 47%) as white crystals.
  10 (25.3 mg, 0.045 mmol) をメタノール（10 mL）とジクロロメタン（4 mL）に溶解した後、6M 塩酸（10 mL）を加えて、室温で 15 時間撹拌した。2M 水酸化ナトリウム水溶液を加えて塩基性にした後、ジクロロメタン（10 mL）で 3 回抽出した。有機層を纏めて、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール：トリエチルアミン = 50:10:1）に付し、HA-93 (10.9 mg, 0.04 mmol, 44%) を白色結晶として得た。 10 (25.3 mg, 0.045 mmol) was dissolved in methanol (10 mL) and dichloromethane (4 mL), 6M hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 15 hours. After adding 2M sodium hydroxide aqueous solution to make it basic, it was extracted three times with dichloromethane (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol:triethylamine=50:10:1) to give HA-93 (10.9 mg, 0.04 mmol, 44%) as white crystals.
［HA-93化合物データ］
HA-93: Colorless solid; mp 187.0-188.0℃ (Washed by hexane); Rf = 0.26 (Chloroform:Mthanol = 8:1); 1H-NMR (400 MHz, CDCl3):δ0.59 (3H, s), 0.65 (1H, ddd, J = 12.0, 10.8, 3.6 Hz), 0.81 (3H, s), 0.87-0.92 (1H, m), 0.94-1.01 (3H, m), 1.07-1.16 (2H, m), 1.20-1.30 (5H, m), 1.32-1.43 (3H, m), 1.50-1.60 (3H, m), 1.62-1.74 (6H, m), 1.75-1.85 (2H, m), 1.92 (4H, quintet, J = 3.6 Hz), 2.66 (2H, bs), 3.04 (2H, bs), 3.41-3.48 (1H, m), 3.50-3.55 (1H, m), 3.59 (1H, septet, J = 6.0 Hz), 7.27 (1H, dd, J = 9.2, 2.4 Hz), 7.90 (1H, d, J = 2.0 Hz), 7.90 (1H, d, J = 8.8 Hz).; 13C-NMR (100 MHz, CDCl3):δ12.3, 12.7, 20.9, 22.56, 22.64, 22.9, 24.5, 24.7, 28.4, 28.6, 31.5, 32.1, 32.8, 35.5, 35.6, 37.0, 37.9, 38.2, 42.3, 44.9, 48.4, 49.1, 44.6, 55.7, 71.3, 115.2, 118.1, 124.1, 124.7, 137.3, 134.1, 147.8, 151.0, 159.2; IR (KBr, cm-1): 3326, 2931, 1578, 1499, 1130, 1042, 755. ; LRMS (EI) m/z: 534 (M+, 72%), 245 (M+-289, 100%), 232 (M+-302, 80%).; HRMS (EI): 計算値C34H47ClN2O(M+): 534.3377, 実測値 534.3387. [HA-93 compound data]
HA-93: Colorless solid; mp 187.0-188.0°C (Washed by hexane); Rf = 0.26 (Chloroform:Mthanol = 8:1); 1 H-NMR (400 MHz, CDCl 3 ): δ0.59 (3H, s ), 0.65 (1H, ddd, J = 12.0, 10.8, 3.6 Hz), 0.81 (3H, s), 0.87-0.92 (1H, m), 0.94-1.01 (3H, m), 1.07-1.16 (2H, m ), 1.20-1.30 (5H, m), 1.32-1.43 (3H, m), 1.50-1.60 (3H, m), 1.62-1.74 (6H, m), 1.75-1.85 (2H, m), 1.92 (4H , quintet, J = 3.6 Hz), 2.66 (2H, bs), 3.04 (2H, bs), 3.41-3.48 (1H, m), 3.50-3.55 (1H, m), 3.59 (1H, septet, J = 6.0 Hz), 7.27 (1H, dd, J = 9.2, 2.4 Hz), 7.90 (1H, d, J = 2.0 Hz), 7.90 (1H, d, J = 8.8 Hz).; 13 C-NMR (100 MHz, CDCl3 ): δ12.3, 12.7, 20.9, 22.56, 22.64, 22.9, 24.5, 24.7, 28.4, 28.6, 31.5, 32.1, 32.8, 35.5, 35.6, 37.0, 37.9, 38.2, 42.3, 48.4, 44.4 44.6, 55.7, 71.3, 115.2, 118.1, 124.1, 124.7, 137.3, 134.1 , 147.8, 151.0, 159.2; EI) m/z: 534 (M + , 72%), 245 (M + -289, 100%), 232 (M + -302, 80%).; HRMS (EI): calculated C 34 H 47 ClN. 2 O(M + ): 534.3377, found 534. 3387.
　製造例６　HA-94合成 Manufacturing example 6 HA-94 synthesis
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　8（47.4 mg, 0.1 mmol）と 7-クロロ-1,2,3,4-テトラヒドロアクリジン-9-アミン（69.6 mg, 0.3 mmol）のジメチルホルムアミド（1.5 mL）溶液に、水素化ナトリウム（24.0 mg, 0.6 mmol）を加えて 80℃で 1.5 時間撹拌した。水を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール：トリエチルアミン = 100:10:0.5）に付し、11 (40.2 mg, 0.075 mmol, 75%) を白色結晶として得た。 Sodium hydride (24.0 mg , 0.6 mmol) was added and stirred at 80°C for 1.5 hours. After adding water to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol:triethylamine=100:10:0.5) to give 11 (40.2 mg, 0.075 mmol, 75%) as white crystals.
  11 (40.2 mg, 0.075 mmol) をメタノール（8 mL）に溶解した後、6M 塩酸（8 mL）を加えて、室温で 15 時間撹拌した。2M 水酸化ナトリウム水溶液を加えて塩基性にした後、ジクロロメタン（10 mL）で 3 回抽出した。有機層を纏めて、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール：トリエチルアミン = 100:10:1）に付し、HA-94 (15.3 mg, 0.028 mmol, 37%) を白色結晶として得た。 11 (40.2 mg, 0.075 mmol) was dissolved in methanol (8 mL), 6M hydrochloric acid (8 mL) was added, and the mixture was stirred at room temperature for 15 hours. After adding 2M sodium hydroxide aqueous solution to make it basic, it was extracted three times with dichloromethane (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol:triethylamine=100:10:1) to give HA-94 (15.3 mg, 0.028 mmol, 37%) as white crystals.
［HA-94化合物データ］
HA-94: Colorless solid; mp 240.0-242.0℃ (Washed by hexane); Rf = 0.35 (Ethyl acetate:Methanol:Diethyl amine = 100:10:1); 1H-NMR (400 MHz, CDCl3):δ0.60 (3H, s), 0.65 (1H, td, J = 13.4, 4.0 Hz), 0.81 (3H, s), 0.86-0.92 (1H, m), 0.94-1.03 (3H, m), 1.09-1.16 (2H, m), 1.22-1.30 (4H, m), 1.32-1.40 (3H, m), 1.41-1.48 (2H, m), 1.53-1.58 (2H, m), 1.63-1.74 (5H, m), 1.75-1.84 (2H, m), 1.92 (4H, quintet, J = 3.2 Hz), 2.68 (2H, bs), 3.03 (2H, bs), 3.38-3.50 (2H, bm), 3.59 (1H, septet, J = 5.2 Hz), 3.88 (1H, bs), 7.47 (1H, dd, J = 9.2, 2.4 Hz), 7.82 (1H, d, J = 8.8 Hz), 7.93 (1H, d, J = 2.0 Hz).; 13C-NMR (100 MHz, CDCl3): δ12.3, 12.7, 20.9, 22.8, 23.1, 24.7, 24.8, 28.4, 28.6, 31.5, 32.8, 34.1, 35.46, 35.53, 37.0, 37.9, 38.1, 42.3, 44.9, 48.4, 49.0, 54.6, 55.7, 71.2, 115.6, 120.1, 122.8, 123.4, 128.2, 128.8, 147.5, 150.7, 158.4; IR (KBr, cm-1): 3212, 2928, 2859, 1578, 1558, 1489, 1043, 752.; LRMS (EI) m/z: 534 (M+, 72%), 245 (M+-289, 100%), 232 (M+-302, 80%).; HRMS (EI): 計算値C34H47ClN2O(M+): 534.3377, 実測値 534.3387. [HA-94 compound data]
HA-94: Colorless solid; mp 240.0-242.0°C (Washed by hexane); Rf = 0.35 (Ethyl acetate:Methanol:Diethyl amine = 100:10:1); 1 H-NMR (400 MHz, CDCl 3 ): δ0 .60 (3H, s), 0.65 (1H, td, J = 13.4, 4.0 Hz), 0.81 (3H, s), 0.86-0.92 (1H, m), 0.94-1.03 (3H, m), 1.09-1.16 (2H, m), 1.22-1.30 (4H, m), 1.32-1.40 (3H, m), 1.41-1.48 (2H, m), 1.53-1.58 (2H, m), 1.63-1.74 (5H, m) , 1.75-1.84 (2H, m), 1.92 (4H, quintet, J = 3.2 Hz), 2.68 (2H, bs), 3.03 (2H, bs), 3.38-3.50 (2H, bm), 3.59 (1H, septet , J = 5.2 Hz), 3.88 (1H, bs), 7.47 (1H, dd, J = 9.2, 2.4 Hz), 7.82 (1H, d, J = 8.8 Hz), 7.93 (1H, d, J = 2.0 Hz ).; 13 C-NMR (100 MHz, CDCl 3 ): δ12.3, 12.7, 20.9, 22.8, 23.1, 24.7, 24.8, 28.4, 28.6, 31.5, 32.8, 34.1, 35.46, 35.53, 37.0, 37.9, 38.1 , 42.3, 44.9, 48.4, 49.0, 54.6, 55.7, 71.2, 115.6, 120.1, 122.8, 123.4 , 128.2, 128.8, 147.5, 150.7, 158.4; 1558, 1489, 1043, 752.; LRMS (EI) m/z: 534 (M + , 72%), 245 (M + -289, 100%), 232 (M + -302, 80%).; HRMS (EI): Calculated C34H47C lN 2 O(M + ): 534.3377, found 534.3387.
　製造例７　HA-88合成 Manufacturing example 7 HA-88 synthesis
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　6（56.7 mg, 0.15 mmol）のトルエン溶液に塩化チオニル（32..7μL, 0.45 mmol）を加えて 2 時間加熱還流した。塩化チオニルとトルエンを減圧下留去した後、トリエチルアミン（42.1μL, 0.3 mmol）および 7-クロロキノリン-4-アミン（32.1 mg, 0.18 mmol）のテトラヒドロフラン（2 mL）溶液を加えて 50℃で 2 時間撹拌した。水を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン: 酢酸エチル= 1:1）に付し、12 (60.0 mg, 0.11 mmol, 74%) を白色結晶として得た。 Thionyl chloride (32..7 μL, 0.45 mmol) was added to a toluene solution of 6 (56.7 mg, 0.15 mmol) and heated under reflux for 2 hours. After thionyl chloride and toluene were distilled off under reduced pressure, a solution of triethylamine (42.1 μL, 0.3 mmol) and 7-chloroquinolin-4-amine (32.1 mg, 0.18 mmol) in tetrahydrofuran (2 mL) was added and the mixture was stirred at 50°C for 2 hours. Stirred for an hour. After adding water to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give 12 (60.0 mg, 0.11 mmol, 74%) as white crystals.
  12 (27.0 mg, 0.05 mmol) をメタノール（5 mL）に溶解した後、6M 塩酸（5 mL）を加えて、室温で 15 時間撹拌した。2M 水酸化ナトリウム水溶液を加えて塩基性にした後、ジクロロメタン（5 mL）で 3 回抽出した。有機層を纏めて、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル = 2:1）に付し、HA-88 (13.9 mg, 0.028 mmol, 56%) を白色結晶として得た。 12 (27.0 mg, 0.05 mmol) was dissolved in methanol (5 mL), 6M hydrochloric acid (5 mL) was added, and the mixture was stirred at room temperature for 15 hours. After adding 2M sodium hydroxide aqueous solution to make it basic, it was extracted three times with dichloromethane (5 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1) to give HA-88 (13.9 mg, 0.028 mmol, 56%) as white crystals.
［HA-88化合物データ］
HA-88: Colorless solid; mp 152.0-153.0℃ (Washed by hexane); Rf = 0.38 (Hexane:Ethyl acetate = 1:1); 1H-NMR (400 MHz, CDCl3):δ0.65 (3H, s), 0.63-0.70 (1H, m), 0.81 (3H, s), 0.88-0.94 (1H, m), 0.97-1.19 (2H, m), 1.24-1.31 (5H, m), 1.34-1.43 (3H, m), 1.53-1.59 (2H, m), 1.65-1.70 (5H, m), 1.75-1.84 (1H, m), 1.92 (1H, qd, J = 9.6, 4.8 Hz), 1.98-2.14 (1H, m), 2.31 (1H, dd, J = 14.8, 10.0 Hz), 2.61 (1H, dd, J = 14.4, 4.4 Hz), 3.60 (1H, septet, J = 6.4 Hz), 7.50 (1H, dd, J = 9.2, 2.0 Hz), 7.77 (1H, d, J = 8.8 Hz), 7.99 (1H, s), 8.09 (1H, d, J = 2.4 Hz), 8.23 (1H, d, J = 4.8 Hz), 8.82 (1H, d, J = 4.8 Hz).; 13C-NMR (100 MHz, CDCl3):δ12.3, 12.8, 20.9, 24.5, 28.4, 28.6, 29.7, 31.4, 32.0, 35.5, 36.9, 37.4, 38.0, 39.0, 42.3, 44.8, 47.3, 54.4, 55.1, 71.2, 111.6, 118.6, 120.9, 127.2, 129.2, 135.3, 140.6, 149.1, 152.1, 172.3.; IR (KBr, cm-1): 3255, 2926, 1672, 1615, 1524, 1306, 1032, 754.; LRMS (EI) m/z: 494 (M+, 13%), 178 (M+-316, 100%); HRMS (EI): 計算値C30H39ClN2O2(M+): 494.2700, 実測値 494.2698. [HA-88 compound data]
HA-88: Colorless solid; mp 152.0-153.0°C (Washed by hexane); Rf = 0.38 (Hexane:Ethyl acetate = 1:1); 1 H-NMR (400 MHz, CDCl 3 ): δ0.65 (3H, s), 0.63-0.70 (1H, m), 0.81 (3H, s), 0.88-0.94 (1H, m), 0.97-1.19 (2H, m), 1.24-1.31 (5H, m), 1.34-1.43 ( 3H, m), 1.53-1.59 (2H, m), 1.65-1.70 (5H, m), 1.75-1.84 (1H, m), 1.92 (1H, qd, J = 9.6, 4.8 Hz), 1.98-2.14 ( 1H, m), 2.31 (1H, dd, J = 14.8, 10.0 Hz), 2.61 (1H, dd, J = 14.4, 4.4 Hz), 3.60 (1H, septet, J = 6.4 Hz), 7.50 (1H, dd , J = 9.2, 2.0 Hz), 7.77 (1H, d, J = 8.8 Hz), 7.99 (1H, s), 8.09 (1H, d, J = 2.4 Hz), 8.23 (1H, d, J = 4.8 Hz ), 8.82 (1H, d, J = 4.8 Hz).; 13 C-NMR (100 MHz, CDCl 3 ): δ12.3, 12.8, 20.9, 24.5, 28.4, 28.6, 29.7, 31.4, 32.0, 35.5, 36.9 , 37.4, 38.0, 39.0, 42.3, 44.8, 47.3, 54.4, 55.1, 71.2, 111.6, 118.6, 120.9, 127.2, 129.2, 135.3, 140.6, 149.1, 152.1, 129.2, 135.3 , 140.6, 149.1, 152.1, IR: -31, 172.3. , 2926, 1672, 1615, 1524, 1306, 1032, 754.; LRMS (EI) m/z: 494 (M + , 13%), 178 (M + -316, 100%); HRMS (EI): calculated Value C30H39ClN2O2 ( M + ) : 494.2700 , Measured value 494.2698.
　製造例８　HA-89合成 Production Example 8 Synthesis of HA-89
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　リチウムアルミニウムヒドリド（6.2 mg, 0.16 mmol）のテトラヒドロフラン（1.5 mL）懸濁液に12（42.6 mg, 0.08 mmol）のテトラヒドロフラン（1.5 mL）溶液を滴下した後、 2 時間加熱還流した。氷水に反応混合液を加えて反応を停止し、2 M 水酸化ナトリウム水溶液で液性を塩基性にした後、酢酸エチル (30 mL) で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 1:5）に付し、13 (34.2 mg, 0.13 mmol, 81%) を白色結晶として得た。 A solution of 12 (42.6 mg, 0.08 mmol) in tetrahydrofuran (1.5 mL) was added dropwise to a suspension of lithium aluminum hydride (6.2 mg, 0.16 mmol) in tetrahydrofuran (1.5 mL), and then heated under reflux for 2 hours. The reaction mixture was added to ice water to stop the reaction, basified with 2 M aqueous sodium hydroxide solution, and then extracted three times with ethyl acetate (30 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:5) to give 13 (34.2 mg, 0.13 mmol, 81%) as white crystals.
  13 (34.2 mg, 0.13 mmol) をメタノール（5 mL）に溶解した後、6M 塩酸（5 mL）を加えて、室温で 15 時間撹拌した。2M 水酸化ナトリウム水溶液を加えて塩基性にした後、ジクロロメタン（5 mL）で 3 回抽出した。有機層を纏めて、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール = 10:1）に付し、HA-89 (16.9 mg, 0.035 mmol, 54%) を白色結晶として得た。 13 (34.2 mg, 0.13 mmol) was dissolved in methanol (5 mL), 6M hydrochloric acid (5 mL) was added, and the mixture was stirred at room temperature for 15 hours. After adding 2M sodium hydroxide aqueous solution to make it basic, it was extracted three times with dichloromethane (5 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (chloroform:methanol = 10:1) to give HA-89 (16.9 mg, 0.035 mmol, 54%) as white crystals.
［HA-89化合物データ］
HA-89: Yellow solid; mp >210 ℃ (chloroform); Rf = 0.40 (Chloroform:Methanol = 8:1); 1H-NMR (400 MHz, CDCl3):δ0.63 (3H, s), 0.67 (1H, td, J = 12.8, 4.0 Hz), 0.82 (3H, s), 0.87-1.04 (3H, m), 1.11-1.21 (2H, m), 1.23-1.31 (4H, m), 1.34-1.46 (4H, m), 1.51-1.60 (3H, m), 1.65-1.78 (7H, m), 1.83-1.98 (2H, m), 3.23-3.35 (2H, m), 3.60 (1H, septet, J = 4.8 Hz), 4.94 (1H, bs), 6.40 (1H, d, J = 5.6 Hz), 7.37 (1H, dd, J = 8.8, 2.0 Hz), 7.64 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 2.0 Hz), 8.53 (1H, d, J = 5.6 Hz).; 13C-NMR (100 MHz, CDCl3):δ12.4, 12.7, 21.0, 24.7, 28.57, 28.65, 29.8, 31.5, 32.1, 35.5, 35.6, 37.0, 37.9, 38.2, 42.4, 42.8, 44.9, 48.7, 54.7, 55.7, 71.3, 99.0, 117.0, 120.7, 125.3, 128.9, 134.8, 149.1, 149.6, 152.1.; IR (KBr, cm-1): 3347, 2918, 1580, 1447, 1366, 1135, 798.; LRMS (EI) m/z: 480 (M+, 85%), 191 (M+-289, 100%); HRMS (EI): 計算値C30H41ClN2O(M+): 480.2907, 実測値 480.2884. [HA-89 compound data]
HA-89: Yellow solid; mp >210 °C (chloroform); Rf = 0.40 (Chloroform:Methanol = 8:1); 1 H-NMR (400 MHz, CDCl 3 ): δ0.63 (3H, s), 0.67 (1H, td, J = 12.8, 4.0 Hz), 0.82 (3H, s), 0.87-1.04 (3H, m), 1.11-1.21 (2H, m), 1.23-1.31 (4H, m), 1.34-1.46 (4H, m), 1.51-1.60 (3H, m), 1.65-1.78 (7H, m), 1.83-1.98 (2H, m), 3.23-3.35 (2H, m), 3.60 (1H, septet, J = 4.8 Hz), 4.94 (1H, bs), 6.40 (1H, d, J = 5.6 Hz), 7.37 (1H, dd, J = 8.8, 2.0 Hz), 7.64 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 2.0 Hz) , 8.53 ( 1H, d, J = 5.6 Hz). 29.8, 31.5, 32.1, 35.5, 37.0, 37.9, 37.9, 42.7, 44.9, 48.9, 54.7, 55.3, 99.0, 99.0, 120.0, 120.7, 125.9, 128.9 ,134.8, 149.6, 149.6, 152.1.; (KBr, cm -1 ): 3347, 2918, 1580, 1447, 1366, 1135, 798.; LRMS (EI) m/z: 480 (M + , 85%), 191 (M + -289, 100%) HRMS (EI): calculated C30H41ClN2O (M+ ) : 480.2907 , found 480.2884.
　製造例９　HA-91合成 Manufacturing example 9 HA-91 synthesis
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
　5（866.4 mg, 2.4 mmol）のテトラヒドロフラン（20 mL）溶液に水素化ジイソブチルアルミニウム（3.6 mmol）のテトラヒドロフラン（3.6 mL）溶液を－78 度で滴下して 1 時間攪拌した後、室温で 1 時間撹拌した。ロッシェル塩飽和水溶液を加えて反応を停止し、酢酸エチル (30 mL) で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 10:1）に付し、14 (246.1 mg, 0.68 mmol, 28%) を白色結晶として得た。 A solution of diisobutylaluminum hydride (3.6 mmol) in tetrahydrofuran (3.6 mL) was added dropwise to a solution of 5 (866.4 mg, 2.4 mmol) in tetrahydrofuran (20 mL) at -78°C, stirred for 1 hour, and then stirred at room temperature for 1 hour. did. A saturated aqueous solution of Rochelle's salt was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL) three times. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to give 14 (246.1 mg, 0.68 mmol, 28%) as white crystals.
　14（27.2 mg, 0.075 mmol）と 5-アミノキノリン（32.5 mg, 0.225 mmol）にジクロロエタン（3.0 mL）を加えて室温で 1 時間撹拌した。トリ酢酸水素化ホウ素ナトリウム（47.7 mg, 0.225 mmol）を加えて室温で 15 時間攪拌した。水を加えて反応を停止し、2M 水酸化ナトリウム水溶液で塩基性にした後、ジクロロメタン (10 mL) で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 1:1）に付し、15 (18.5 mg, 0.037 mmol, 49%) を白色結晶として得た。 Dichloroethane (3.0 mL) was added to 14 (27.2 mg, 0.075 mmol) and 5-aminoquinoline (32.5 mg, 0.225 mmol) and stirred at room temperature for 1 hour. Sodium triacetate borohydride (47.7 mg, 0.225 mmol) was added and stirred at room temperature for 15 hours. Water was added to stop the reaction, basified with 2M aqueous sodium hydroxide solution, and then extracted three times with dichloromethane (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give 15 (18.5 mg, 0.037 mmol, 49%) as white crystals.
  15 (18.5 mg, 0.037 mmol) をメタノール（20 mL）に溶解した後、6M 塩酸（20 mL）を加えて、室温で 15 時間撹拌した。2M 水酸化ナトリウム水溶液を加えて塩基性にした後、ジクロロメタン（10 mL）で 3 回抽出した。有機層を纏めて、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）に付し、HA-91 (11.1 mg, 0.025 mmol, 69%) を白色結晶として得た。 15 (18.5 mg, 0.037 mmol) was dissolved in methanol (20 mL), 6M hydrochloric acid (20 mL) was added, and the mixture was stirred at room temperature for 15 hours. After adding 2M sodium hydroxide aqueous solution to make it basic, it was extracted three times with dichloromethane (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate) to give HA-91 (11.1 mg, 0.025 mmol, 69%) as white crystals.
［HA-91化合物データ］
HA-91: Pale yellow solid; mp 256.0-257.5℃ (Washed by hexane and ethyl acetate); Rf = 0.50 (Hexane:Ethyl acetate = 2:1); 1H-NMR (400 MHz, CDCl3):δ0.64 (3H, s), 0.67 (1H, td, J = 12.4, 4.0 Hz), 0.82 (3H, s), 0.87-0.94 (1H, m), 0.95-1.04 (3H, m), 1.07-1.22 (2H, m), 1.24-1.32 (4H, m), 1.33-1.40 (2H, m), 1.43-1.50 (2H, m), 1.52-1.58 (3H, m), 1.61-1.84 (5H, m), 1.86-1.98 (2H, m), 3.20-3.28 (2H, m), 3.60 (1H, septet, J = 5.2 Hz), 4.31 (1H, bs), 6.62 (1H, d, J = 7.2 Hz), 7.33 (1H, dd, J = 8.4, 4.4 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.57 (1H, t, J = 8.4 Hz), 8.16 (1H, d, J = 8.0 Hz), 8.87 (1H, dd, J = 4.4, 1.6 Hz).; 13C-NMR (100 MHz, CDCl3):δ12.4, 12.7, 21.0, 24.7, 28.6, 28.7, 30.3, 31.5, 32.2, 35.5, 35.6, 37.0, 37.9, 38.2, 42.4, 43.8, 44.9, 48.9, 54.7, 55.7, 71.3, 104.5, 118.0, 118.3, 119.2, 128.7, 130.5, 143.8, 149.1, 149.8.; IR (KBr, cm-1): 3208, 2925, 1577, 1473, 1329, 1042, 793.; LRMS (EI) m/z: 446 (M+, 66%), 157 (M+-289, 100%); HRMS (EI): 計算値C30H42N2O (M+): 446.3297, 実測値 446.3302. [HA-91 compound data]
HA-91: Pale yellow solid; mp 256.0-257.5°C (Washed by hexane and ethyl acetate); Rf = 0.50 (Hexane:Ethyl acetate = 2:1); 1 H-NMR (400 MHz, CDCl 3 ): δ0. 64 (3H, s), 0.67 (1H, td, J = 12.4, 4.0 Hz), 0.82 (3H, s), 0.87-0.94 (1H, m), 0.95-1.04 (3H, m), 1.07-1.22 ( 2H, m), 1.24-1.32 (4H, m), 1.33-1.40 (2H, m), 1.43-1.50 (2H, m), 1.52-1.58 (3H, m), 1.61-1.84 (5H, m), 1.86-1.98 (2H, m), 3.20-3.28 (2H, m), 3.60 (1H, septet, J = 5.2 Hz), 4.31 (1H, bs), 6.62 (1H, d, J = 7.2 Hz), 7.33 (1H, dd, J = 8.4, 4.4 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.57 (1H, t, J = 8.4 Hz), 8.16 (1H, d, J = 8.0 Hz), 8.87 (1H, dd, J = 4.4, 1.6 Hz).; 13C -NMR (100 MHz, CDCl3 ): δ12.4, 12.7, 21.0, 24.7, 28.6, 28.7, 30.3, 31.5, 32.2, 35.5, 35.6, 37.0, 37.9, 38.2, 42.4, 43.8, 44.9, 48.9, 54.7, 55.7, 71.3, 104.5, 118.0, 118.3, 119.2, 128.7, 130.5, 143.8, 149.1, 149.8 ; 2925, 1577, 1473, 1329, 1042, 793.; LRMS (EI) m/z: 446 (M + , 66%), 157 (M + -289, 100%); HRMS (EI): calculated C 30 H42N2O _  (M + ): 446.3297, found 446.3302.
　製造例１０　HA-92合成 Production Example 10 Synthesis of HA-92
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
　8（30.0 mg, 0.06 mmol）と 7-クロロ-1,2,3,4-テトラヒドロアクリジン-9-アミン（33.9 mg, 0.19 mmol）のジメチルホルムアミド（1.0 mL）溶液に、水素化ナトリウム（16.0 mg, 0.4 mmol）を加えて 80℃で 1 時間撹拌した。水を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール= 10:1）に付し、16 (21.1 mg, 0.044 mmol, 73%) を白色結晶として得た。 Sodium hydride (16.0 mg , 0.4 mmol) was added and stirred at 80°C for 1 hour. After adding water to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol=10:1) to give 16 (21.1 mg, 0.044 mmol, 73%) as white crystals.
  16 (21.1 mg, 0.044 mmol) をメタノール（8 mL）とジクロロメタン（3 mL）に溶解した後、6M 塩酸（8 mL）を加えて、室温で 15 時間撹拌した。2M 水酸化ナトリウム水溶液を加えて塩基性にした後、ジクロロメタン（10 mL）で 3 回抽出した。有機層を纏めて、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣を酢酸エチルおよびヘキサンで洗浄して精製し、HA-92 (15.3 mg, 0.028 mmol, 37%) を白色結晶として得た。 16 (21.1 mg, 0.044 mmol) was dissolved in methanol (8 mL) and dichloromethane (3 mL), 6M hydrochloric acid (8 mL) was added, and the mixture was stirred at room temperature for 15 hours. After adding 2M sodium hydroxide aqueous solution to make it basic, it was extracted three times with dichloromethane (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was washed with ethyl acetate and hexane for purification to give HA-92 (15.3 mg, 0.028 mmol, 37%) as white crystals.
［HA-92化合物データ］
Yellow solid. Mp.> 210 ℃ (CDCl3); 1H-NMR (400 MHz, CDCl3):δ0.61-0.71 (4H, m), 0.83 (3H, s), 0.89-1.96 (24H, m), 3.21-3.36 (2H, m), 3.60 (1H, m), 4.84 (1H, bs), 6.43 (1H, d, J = 5.2 Hz), 7.56 (1H, dd, J = 8.8, 2.0 Hz), 7.68 (1H, d, J= 2.4 Hz), 7.92 (1H, d, J = 9.2 Hz), 8.54 (1H, d, J = 5.6 Hz).; 13C-NMR (100 MHz, CDCl3): δ12.4, 12.7, 21.0, 24.7, 28.5, 28.7, 29.8, 31.5, 32.1, 35.5, 35.6, 37.0, 37.9, 38.2, 42.4, 42.9, 44.9, 48.7, 54.7, 55.7, 71.3, 99.3, 118.7, 119.4, 129.7, 130.3, 131.6, 148.8, 151.2.; IR (KBr) 3325, 2926, 2859, 1583 cm-1.; MS (EI) 480 (M+, 77%), 191 (M+-C20H33O, 100%). HRMS Calcd for C30H41ClN2O: 480.2907. Found: 480.2928. [HA-92 compound data]
Yellow solid. Mp. > 210 ℃ ( CDCl 3 ); ), 3.21-3.36 (2H, m), 3.60 (1H, m), 4.84 (1H, bs), 6.43 (1H, d, J = 5.2 Hz), 7.56 (1H, dd, J = 8.8, 2.0 Hz) , 7.68 (1H, d, J= 2.4 Hz), 7.92 (1H, d, J = 9.2 Hz), 8.54 (1H, d, J = 5.6 Hz).; 13 C-NMR (100 MHz, CDCl 3 ): δ12.4, 12.7, 21.0, 24.7, 28.5, 28.7, 29.8, 31.5, 32.1, 35.5, 35.6, 37.0, 37.9, 38.2, 42.4, 42.9, 44.9, 48.7, 54.7, 55.7, 18.7, 19.3, 71.3 129.7, 130.3, 131.6, 148.8, 151.2.; IR (KBr) 3325, 2926, 2859, 1583 cm -1 .; MS (EI) 480 (M + , 77%), 191 (M + -C20H33O , 100%). HRMS Calcd for C30H41ClN2O : 480.2907 . Found: 480.2928.
　製造例１１　HA-99合成 Production Example 11 Synthesis of HA-99
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　6（129.8 mg, 0.35 mmol）のトルエン溶液に塩化チオニル（150μL, 1.05 mmol）を加えて 2 時間加熱還流した。塩化チオニルとトルエンを減圧下留去した後、トリエチルアミン（0.1 mL, 0.3 mmol）および 4-アミノキノリン（59.9 mg, 0.42 mmol）のテトラヒドロフラン（5 mL）溶液を加えて 50℃で 2 時間撹拌した。水を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン: 酢酸エチル= 1:1）に付し、17 (78.0 mg, 0.155 mmol, 45%) を白色結晶として得た。 Thionyl chloride (150 μL, 1.05 mmol) was added to a toluene solution of 6 (129.8 mg, 0.35 mmol) and heated under reflux for 2 hours. After removing thionyl chloride and toluene under reduced pressure, a solution of triethylamine (0.1 mL, 0.3 mmol) and 4-aminoquinoline (59.9 mg, 0.42 mmol) in tetrahydrofuran (5 mL) was added and stirred at 50°C for 2 hours. After adding water to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give 17 (78.0 mg, 0.155 mmol, 45%) as white crystals.
　リチウムアルミニウムヒドリド（7.6 mg, 0.2 mmol）のテトラヒドロフラン（3 mL）懸濁液に17 (57.9 mg, 0.115 mmol）のテトラヒドロフラン（5 mL）溶液を滴下した後、 2 時間加熱還流した。氷水に反応混合液を加えて反応を停止し、2 M 水酸化ナトリウム水溶液で液性を塩基性にした後、酢酸エチル (30 mL) で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール ＝ 6:1）に付し、18 (55.7 mg, 0.115 mmol, 100%) を白色結晶として得た。 A solution of 17 (57.9 mg, 0.115 mmol) in tetrahydrofuran (5 mL) was added dropwise to a suspension of lithium aluminum hydride (7.6 mg, 0.2 mmol) in tetrahydrofuran (3 mL), and then heated under reflux for 2 hours. The reaction mixture was added to ice water to stop the reaction, basified with 2 M aqueous sodium hydroxide solution, and then extracted three times with ethyl acetate (30 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol = 6:1) to give 18 (55.7 mg, 0.115 mmol, 100%) as white crystals.
   18 (55.7 mg, 0.115 mmol) をメタノール（10 mL）に溶解した後、6M 塩酸（10 mL）を加えて、室温で 15 時間撹拌した。2M 水酸化ナトリウム水溶液を加えて塩基性にした後、ジクロロメタン（5 mL）で 3 回抽出した。有機層を纏めて、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（トルエン：酢酸エチル：メタノール = 2:2:1）に付し、HA-99 (20.6 mg, 0.045 mmol, 39%) を白色結晶として得た。 18 (55.7 mg, 0.115 mmol) was dissolved in methanol (10 mL), 6M hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 15 hours. After adding 2M sodium hydroxide aqueous solution to make it basic, it was extracted three times with dichloromethane (5 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (toluene:ethyl acetate:methanol=2:2:1) to give HA-99 (20.6 mg, 0.045 mmol, 39%) as white crystals.
［HA-99化合物データ］
HA-99: Colorless solid. Mp.>210 ℃ (AcOEt/Hex = 1).; Rf = 0.48 (Toluene:Ethyl acetate:Methanol = 2:2:1).; 1H-NMR (400 MHz, CDCl3):δ0.64-0.71 (4H, m), 0.82 (3H, s), 0.87-1.98 (24H, m), 3.23-3.38 (2H, m), 3.57-3.64 (1H, m), 4.95 (1H, bs), 6.42 (1H, d, J = 5.2 Hz), 7.43 (1H, t, J = 7.2 Hz), 7.63 (1H, t, J = 7.2 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.98 (1H, d, J = 8.8 Hz), 8.56 (1H, d, J = 5.6 Hz). 13C-NMR (100 MHz, CDCl3):δ12.3, 12.7, 21.0, 24.7, 28.6, 28.7, 29.9, 31.5, 32.1, 35.5, 35.6, 37.0, 37.9, 38.2, 42.4, 42.8, 44.9, 48.7, 54.7, 55.7, 71.3, 98.7, 118.6, 119.1, 124.6, 129.0, 130.0, 148.4, 149.6, 151.1. IR (KBr) 3329, 2924, 2854, 1586, 760 cm-1. MS (EI) m/z 446 (M+, 47%), 157 (M+-C20H33O, 100%). HRMS Calcd for C30H42N2O: 446.3297. Found: 446.3284. [HA-99 compound data]
HA-99: Colorless solid. Mp.>210 ℃ (AcOEt/Hex = 1).; Rf = 0.48 (Toluene:Ethyl acetate:Methanol = 2:2:1).; 1 H-NMR (400 MHz, CDCl 3 ): δ0.64-0.71 (4H, m), 0.82 (3H, s), 0.87-1.98 (24H, m), 3.23-3.38 (2H, m), 3.57-3.64 (1H, m), 4.95 (1H , bs), 6.42 (1H, d, J = 5.2 Hz), 7.43 (1H, t, J = 7.2 Hz), 7.63 (1H, t, J = 7.2 Hz), 7.71 (1H, d, J = 8.0 Hz ), 7.98 ( 1H, d, J = 8.8 Hz), 8.56 ( 1H, d, J = 5.6 Hz). 28.7, 29.9, 31.5, 32.1, 35.5, 37.0, 37.9, 37.9, 38.7, 42.7, 44.9, 48.7, 54.7, 54.7, 71.3, 98.7, 98.7, 119.6, 129.6, 129.6, 129.0 IR (KBr) 3329, 2924, 2854, 1586, 760 cm -1 . MS (EI) m/z 446 (M + , 47%), 157 (M + -C 20 H 33 O, 100%). HRMS Calcd for C30H42N2O : 446.3297 . Found: 446.3284 .
　製造例１２　HA-95合成 Production Example 12 Synthesis of HA-95
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　3β－ヒドロキシアンドロスト-5-エン-17-オン（4 mmol, 1.15 g）とエチレングリコール（1.24 mL）のトルエン溶液に、p-トルエンスルホン酸（0.15 mmol, 28.9 mg）を加えて加熱還流下 3 時間撹拌した。飽和炭酸水素ナトリウム水溶液（10 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 2 回抽出した後、有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 2:1）に付し、19 (710.0 mg, 53%) を白色結晶として得た。 To a toluene solution of 3β-hydroxyandrost-5-en-17-one (4 mmol, 1.15 g) and ethylene glycol (1.24 mL), add p-toluenesulfonic acid (0.15 mmol, 28.9 mg) and heat under reflux. Stirred for 3 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added to stop the reaction, and after extraction with ethyl acetate (20 mL) twice, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. distilled off. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1) to give 19 (710.0 mg, 53%) as white crystals.
  19(700.0 mg, 2.11 mmol) のテトラヒドロフラン（10 mL）溶液にボラン-テトラヒドロフラン錯体溶液（1.0M テトラヒドロフラン溶液, 3.04 mL, 2.74 mmol）を 0℃ で滴下した後、室温で 3 時間撹拌した。過ホウ酸ナトリウム四水和物と水を加えて、室温で一昼夜撹拌した。飽和食塩水を加えてテトラヒドロフランで抽出した後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム:メタノール ＝ 20:1）に付し、20 (522.0 mg, 1.49 mmol, 71%) を白色結晶として得た。 A borane-tetrahydrofuran complex solution (1.0 M tetrahydrofuran solution, 3.04 mL, 2.74 mmol) was added dropwise to a solution of 19 (700.0 mg, 2.11 mmol) in tetrahydrofuran (10 mL) at 0°C, and the mixture was stirred at room temperature for 3 hours. Sodium perborate tetrahydrate and water were added, and the mixture was stirred at room temperature for a whole day and night. Saturated saline was added, and the mixture was extracted with tetrahydrofuran, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (chloroform:methanol = 20:1) to give 20 (522.0 mg, 1.49 mmol, 71%) as white crystals.
　20 (522.0 mg, 1.49 mmol) のメタノール（10 mL）溶液に 4M 塩酸（10 mL）を加えて、50℃ で 1 時間撹拌した。飽和炭酸水素ナトリウム水溶液（20 mL）を加えて　pH を 7 以上に調整して、酢酸エチル (20 mL) で 2 回抽出した。有機層を纏めて水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 1:2）に付し、21 (400.0 mg, 1.31 mmol, 88%) を白色結晶として得た。 4M hydrochloric acid (10 mL) was added to a solution of 20 (522.0 mg, 1.49 mmol) in methanol (10 mL), and the mixture was stirred at 50°C for 1 hour. A saturated aqueous sodium bicarbonate solution (20 mL) was added to adjust the pH to 7 or more, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:2) to give 21 (400.0 mg, 1.31 mmol, 88%) as white crystals.
　水素化ナトリウム（60%含有, 5.1 mmol, 203.5 mg）のテトラヒドロフラン懸濁液に、0 ℃ でジエチル（シアノメチル）ホスホナート（5.09 mmol, 824.2μL）を滴下した後 30 分間撹拌した。次いで、21 (390 mg, 1.27 mmol）を少しずつ加えた後、30 分間加熱還流下撹拌した。水（20 mL）を加えて反応を停止した後、酢酸エチル (10 mL) で 3 回抽出した。有機層を纏めて水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム:メタノール ＝ 100:3）に付し、22 (310.1 mg, 0.492 mmol, 74%) を白色液体として得た。 Diethyl (cyanomethyl) phosphonate (5.09 mmol, 824.2 μL) was added dropwise to a suspension of sodium hydride (containing 60%, 5.1 mmol, 203.5 mg) in tetrahydrofuran at 0 °C and stirred for 30 minutes. Then, 21 (390 mg, 1.27 mmol) was added little by little, and the mixture was heated under reflux with stirring for 30 minutes. After adding water (20 mL) to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with water (30 mL) and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (chloroform:methanol = 100:3) to give 22 (310.1 mg, 0.492 mmol, 74%) as a white liquid.
  22(50.0 mg, 0.152 mmol) のエタノール（20 mL）溶液に、Pd/C（0.152 mmol, 44 mg, 44 w/w%）を加えて水素雰囲気下室温で 2 時間撹拌した。反応溶液をセライトに通して濾過した後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）に付し、23 (44.5 mg, 0.134 mmol, 88%) を白色結晶として得た。 Pd/C (0.152 mmol, 44 mg, 44 w/w%) was added to an ethanol (20 mL) solution of 22 (50.0 mg, 0.152 mmol) and stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate) to give 23 (44.5 mg, 0.134 mmol, 88%) as white crystals.
　23 (33.2 mg, 0.10 mmol)のテトラヒドロフラン（1.0 mL）溶液に、クロロメチルメチルエーテル（0.54 mmol, 41.0μL）と N,N-ジイソプロピルエチルアミン（0.87 mmol, 151μL）を加えて、0 ℃ で 30 分間撹拌した後、15 時間加熱還流した。水（10 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 3 回抽出した。有機層を纏めて水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル:クロロホルム ＝ 4:1:1）に付し、24 (628.7 mg, 1.89 mmol, 95%) を無色液体として得た。 Chloromethyl methyl ether (0.54 mmol, 41.0 μL) and N,N-diisopropylethylamine (0.87 mmol, 151 μL) were added to a solution of 23 (33.2 mg, 0.10 mmol) in tetrahydrofuran (1.0 mL) and incubated at 0°C for 30 minutes. After stirring, the mixture was heated under reflux for 15 hours. After adding water (10 mL) to stop the reaction, the mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined, washed with water (30 mL) and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate:chloroform=4:1:1) to give 24 (628.7 mg, 1.89 mmol, 95%) as a colorless liquid.
　24（30.0 mg, 0.07 mmol）をエタノール（5 mL）に 80 ℃ で溶解した後、5M 水酸化カリウム水溶液（5 mL）を滴下して 18 時間撹拌した。室温まで放冷した後、飽和塩化アンモニウム水溶液を加えて反応を停止し、酢酸エチル (10 mL) で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 1:1）に付し、25 (29.0 mg, 0.066 mmol, 93%) を無色液体として得た。 After dissolving 24 (30.0 mg, 0.07 mmol) in ethanol (5 mL) at 80°C, 5M potassium hydroxide aqueous solution (5 mL) was added dropwise and stirred for 18 hours. After allowing to cool to room temperature, a saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate (10 mL) three times. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give 25 (29.0 mg, 0.066 mmol, 93%) as a colorless liquid.
　リチウムアルミニウムヒドリド（5.0 mg, 0.132 mmol）をテトラヒドロフラン（1 mL）に懸濁させた後、25 (29.0 mg, 0.066 mmol) のテトラヒドロフラン（1 mL）溶液を 0 ℃で滴下した。次いで、反応混合液を昇温して 30 分間加熱還流下撹拌した。飽和塩化アンモニウム水溶液を加えて反応を停止した後、酢酸エチル (20 mL) で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 1:1）に付し、26 (22.4 mg, 0.05 mmol, 80%) を無色液体として得た。 After suspending lithium aluminum hydride (5.0 mg, 0.132 mmol) in tetrahydrofuran (1 mL), a solution of 25 (29.0 mg, 0.066 mmol) in tetrahydrofuran (1 mL) was added dropwise at 0°C. Then, the reaction mixture was heated and stirred for 30 minutes while heating under reflux. A saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate (20 mL) three times. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give 26 (22.4 mg, 0.05 mmol, 80%) as a colorless liquid.
  26(133.0 mg, 0.33 mmol) 、トリフェニルホスフィン（3.3 mmol, 862.9 mg）、イミダゾール（3.3 mmol, 224.0 mg）、ヨウ素（2.64 mmol, 669.5 mg）のトルエン（5 mL）溶液を、80 ℃ で 1 時間撹拌した。飽和チオ硫酸ナトリウム水溶液を加えて反応を停止した後、ジクロロメタン（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（トルエン:酢酸エチル = 10:1）に付し、27 (145.0 mg, 0.27 mmol, 83%) を無色液体として得た。 26 (133.0 mg, 0.33 mmol), triphenylphosphine (3.3 mmol, 862.9 mg), imidazole (3.3 mmol, 224.0 mg), iodine (2.64 mmol, 669.5 mg) in toluene (5 mL) at 80 °C. Stirred for an hour. A saturated aqueous sodium thiosulfate solution was added to stop the reaction, and the mixture was extracted three times with dichloromethane (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (toluene:ethyl acetate = 10:1) to give 27 (145.0 mg, 0.27 mmol, 83%) as a colorless liquid.
  27（23.0 mg, 0.043 mmol）とタクリン（25.6 mg, 0.129 mmol）のジメチルホルムアミド（0.5 mL）溶液に、水素化ナトリウム（6.2 mg, 0.26 mmol）を加えて 80℃で 20 分間撹拌した。水を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール:トリエチルアミン = 100:30:0.2）に付し、28 (18.1 mg, 0.03 mmol, 69%) を白色結晶として得た。 Sodium hydride (6.2 mg, 0.26 mmol) was added to a solution of 27 (23.0 mg, 0.043 mmol) and tacrine (25.6 mg, 0.129 mmol) in dimethylformamide (0.5 mL) and stirred at 80°C for 20 minutes. After adding water to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol:triethylamine=100:30:0.2) to give 28 (18.1 mg, 0.03 mmol, 69%) as white crystals.
  28 (18.1 mg, 0.03 mmol) をメタノール（8 mL）に溶解した後、6M 塩酸（5 mL）とクロロホルム（数滴）を加えて、50℃で 30 分間撹拌した。飽和炭酸水素ナトリウム水溶液を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて、水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール:トリエチルアミン = 100:20:0.2）に付し、HA-95 (12.1 mg, 0.0234 mmol, 79%) を白色結晶として得た。 After dissolving 28 (18.1 mg, 0.03 mmol) in methanol (8 mL), 6M hydrochloric acid (5 mL) and chloroform (several drops) were added, and the mixture was stirred at 50°C for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to stop the reaction, and the mixture was extracted with ethyl acetate (10 mL) three times. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol:triethylamine=100:20:0.2) to give HA-95 (12.1 mg, 0.0234 mmol, 79%) as white crystals.
［HA-95化合物データ］
HA-95: Colorless solid; mp 138.5-140.0℃ (hexane:ethyl acetate = 3:1); Rf = 0.13 (Ethyl acetate:Methanol = 10:1); 1H-NMR (400 MHz, CDCl3):δ0.59 (3H, s), 0.68 (1H, t, J = 8.4 Hz), 0.81 (3H, s), 0.88 (1H, q, J = 11.6 Hz), 0.95-1.04 (4H, m), 1.13-1.31 (5H, m), 1.36-1.47 (4H, m), 1.55 (1H, bdd, J = 13.6, 2.8 Hz), 1.63-1.72 (3H, m), 1.76-1.86 (3H, m), 1.92 (4H, bs), 1.99 (1H, dt, J = 12.0, 4.0 Hz), 2.19 (1H, bd, J = 12.4 Hz), 2.70 (2H, bs), 3.07 (2H, bs), 3.38-3.45 (2H, m), 3.49-3.62 (2H, m), 7.34 (1H, t, J = 7.6 Hz), 7.55 (1H, t, J = 7.6 Hz), 7.92 (1H, d, J = 8.8 Hz), 7.95 (1H, d, J = 8.4 Hz).; 13C-NMR (100 MHz, CDCl3):δ12.6, 13.4, 20.8, 22.7, 23.0, 24.6, 28.4, 31.0, 31.6, 32.2, 32.7, 33.8, 34.2, 36.3, 37.3, 37.6, 41.6, 42.3, 48.3, 48.9, 51.6, 54.0, 55.3, 69.3, 71.1, 115.4, 120.0, 122.8, 123.5, 128.4, 128.5, 147.2, 150.8, 158.2.; IR (KBr, cm-1): 3346, 2933, 2864, 1579, 1500, 1044.; LRMS (EI) m/z: 516 (M+, 39%), 211 (M+-305, 100%); HRMS (EI): 計算値C34H48N2O2  (M+): 516.3716, 実測値 516.3705. [HA-95 compound data]
HA-95: Colorless solid; mp 138.5-140.0°C (hexane:ethyl acetate = 3:1); Rf = 0.13 (Ethyl acetate:Methanol = 10:1); 1 H-NMR (400 MHz, CDCl 3 ): δ0 .59 (3H, s), 0.68 (1H, t, J = 8.4 Hz), 0.81 (3H, s), 0.88 (1H, q, J = 11.6 Hz), 0.95-1.04 (4H, m), 1.13- 1.31 (5H, m), 1.36-1.47 (4H, m), 1.55 (1H, bdd, J = 13.6, 2.8 Hz), 1.63-1.72 (3H, m), 1.76-1.86 (3H, m), 1.92 ( 4H, bs), 1.99 (1H, dt, J = 12.0, 4.0 Hz), 2.19 (1H, bd, J = 12.4 Hz), 2.70 (2H, bs), 3.07 (2H, bs), 3.38-3.45 (2H , m), 3.49-3.62 (2H, m), 7.34 (1H, t, J = 7.6 Hz), 7.55 (1H, t, J = 7.6 Hz), 7.92 (1H, d, J = 8.8 Hz), 7.95 (1H, d, J = 8.4 Hz).; 13C -NMR (100 MHz, CDCl3 ): δ12.6, 13.4, 20.8, 22.7, 23.0, 24.6, 28.4, 31.0, 31.6, 32.2, 32.7, 33.8, 34.2, 36.3, 37.3, 37.6, 41.6, 42.3, 48.3, 48.9, 51.6, 54.0, 55.3, 69.3, 71.1, 115.4, 120.0, 122.8, 123.5, 128.4, 128.5, IR. -1 ): 3346, 2933, 2864, 1579, 1500, 1044.; LRMS (EI) m/z: 516 (M + , 39%), 211 (M + -305, 100%); HRMS (EI): Calculated C34H48N2O2 _ _  (M + ): 516.3716, found 516.3705.
　製造例１３　HA-96合成 Production Example 13 Synthesis of HA-96
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　27（40.0 mg, 0.075 mmol）と2-エチル-3-メチルキノリン-4-アミン（20.9 mg, 0.112 mmol）のジメチルホルムアミド（0.5 mL）溶液に、水素化ナトリウム（10.8 mg, 0.26 mmol）を加えて 80℃で 20 分間撹拌した。水を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール:トリエチルアミン = 100:20:3）に付し、29 (14.1 mg, 0.024 mmol, 32%) を無色液体として得た。 Sodium hydride (10.8 mg, 0.26 mmol) was added to a solution of 27 (40.0 mg, 0.075 mmol) and 2-ethyl-3-methylquinolin-4-amine (20.9 mg, 0.112 mmol) in dimethylformamide (0.5 mL). and stirred at 80°C for 20 minutes. After adding water to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol:triethylamine=100:20:3) to give 29 (14.1 mg, 0.024 mmol, 32%) as a colorless liquid.
  29 (14.1 mg, 0.024 mmol) をメタノール（8 mL）に溶解した後、6M 塩酸（8 mL）を加えて、50℃で 30 分間撹拌した。飽和炭酸水素ナトリウム水溶液を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて、水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール:トリエチルアミン = 20:4:1）に付し、HA-96 (10.2 mg, 0.020 mmol, 83%) を白色結晶として得た。 29 (14.1 mg, 0.024 mmol) was dissolved in methanol (8 mL), 6M hydrochloric acid (8 mL) was added, and the mixture was stirred at 50°C for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to stop the reaction, and the mixture was extracted with ethyl acetate (10 mL) three times. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol:triethylamine=20:4:1) to give HA-96 (10.2 mg, 0.020 mmol, 83%) as white crystals.
［HA-96化合物データ］
HA-96: Colorless solid; mp 125.5-126.0  ℃ (hexane:ethyl acetate = 1:1); Rf = 0.1 (Ethyl acetate:Methanol = 10:1); 1H-NMR (400 MHz, CDCl3):δ0.59 (3H, s), 0.69 (1H, td, J = 10.8, 2.8 Hz), 0.82 (3H, s), 0.88 (2H, q, J = 12.0 Hz), 0.99-1.06 (4H, m), 1.12-1.19 (2H, m), 1.24-1.28 (3H, m), 1.34 (3H, t, J = 7.6 Hz), 1.38-1.50 (3H, m), 1.55 (1H, dd, J = 13.6, 3.2 Hz), 1.64-1.73 (2H, m), 1.77-1.86 (2H, m), 1.77-1.86 (2H, m), 1.99 (1H, dt, J = 12.4, 4.0 Hz), 2.19 (1H, dquintet, J = 12.0, 2.4 Hz), 2.35 (3H, s), 3.01 (2H, q, J = 7.6 Hz), 3.32-3.47 (3H, m), 3.58 (1H, septet, J = 4.8 Hz), 7.39 (1H, td, J = 11.2, 1.2 Hz), 7.58 (1H, td, J = 7.2, 1.2 Hz), 7.92 (1H, d, J = 8.4 Hz), 8.00 (1H, d, J = 8.4 Hz).; 13C-NMR (100 MHz, CDCl3):δ12.6, 13.4, 13.45, 13.54, 20.8, 24.6, 28.4, 30.3, 31.0, 32.2, 32.5, 34.2, 36.3, 37.3, 37.7, 41.6, 42.3, 48.3, 49.1, 51.7, 54.1, 55.4, 69.3, 71.1, 114.7, 120.7, 122.2, 124.2, 128.3, 128.6, 146.7, 151.3, 162.9.; IR (KBr, cm-1): 3343, 2925, 2843, 1652, 1507, 1036.; LRMS (EI) m/z: 504 (M+, 59%), 199 (M+-305, 100%); HRMS (EI): 計算値C33H48N2O2  (M+): 504.3716, 実測値 504.3722. [HA-96 compound data]
HA-96: Colorless solid; mp 125.5-126.0 °C (hexane:ethyl acetate = 1:1); Rf = 0.1 (Ethyl acetate:Methanol = 10:1); 1 H-NMR (400 MHz, CDCl 3 ): δ0 .59 (3H, s), 0.69 (1H, td, J = 10.8, 2.8 Hz), 0.82 (3H, s), 0.88 (2H, q, J = 12.0 Hz), 0.99-1.06 (4H, m), 1.12-1.19 (2H, m), 1.24-1.28 (3H, m), 1.34 (3H, t, J = 7.6 Hz), 1.38-1.50 (3H, m), 1.55 (1H, dd, J = 13.6, 3.2 Hz), 1.64-1.73 (2H, m), 1.77-1.86 (2H, m), 1.77-1.86 (2H, m), 1.99 (1H, dt, J = 12.4, 4.0 Hz), 2.19 (1H, dquintet, J = 12.0, 2.4 Hz), 2.35 (3H, s), 3.01 (2H, q, J = 7.6 Hz), 3.32-3.47 (3H, m), 3.58 (1H, septet, J = 4.8 Hz), 7.39 ( 1H, td, J = 11.2, 1.2 Hz), 7.58 (1H, td, J = 7.2, 1.2 Hz), 7.92 (1H, d, J = 8.4 Hz), 8.00 (1H, d, J = 8.4 Hz). 13 C-NMR (100 MHz, CDCl 3 ): δ12.6, 13.4, 13.45, 13.54, 20.8, 24.6, 28.4, 30.3, 31.0, 32.2, 32.5, 34.2, 36.3, 37.3, 37.7, 41.6, 42.3, 4 , 49.1, 51.7, 54.1, 55.4, 69.3, 71.1, 114.7, 120.7, 122.2, 124.2, 128.3, 128.6, 146.7 , 151.3, 162.9; , 1036.; (EI) m/z: 504 (M + , 59%), 199 ( M + -305 , 100%); HRMS ( EI): calculated C33H48N2O2  (M + ): 504.3716, found 504.3722.
　製造例１４　HA-98合成 Production Example 14 Synthesis of HA-98
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　(S)-2,3,7,7-テトラヒドロ-7α－メチル-1H-インデン-1,5(6H)-ジオン (328.1 mg, 2.0 mmol) のメタノール (20 mL) 溶液に -78 度で水素化ホウ素ナトリウム (190 mg, 5.0 mmol) と塩化セリウム七水和物（1.78g, 4.8 mmol）を添加して 3 時間撹拌した後、水 (10 mL)を加えて反応を停止した。次いで、酢酸エチル (20 mL)で 6 回抽出した後、飽和食塩水で洗浄して硫酸マグネシウムで乾燥した。溶媒を減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 1:1）に付し、31 (95%, 1.9 mmol, 319.3 mg)を無色液体として得た。 (S)-2,3,7,7-Tetrahydro-7α-methyl-1H-indene-1,5(6H)-dione (328.1 mg, 2.0 mmol) in methanol (20 mL) was diluted with hydrogen at -78 degrees. After adding sodium borohydride (190 mg, 5.0 mmol) and cerium chloride heptahydrate (1.78 g, 4.8 mmol) and stirring for 3 hours, water (10 mL) was added to stop the reaction. After extraction with ethyl acetate (20 mL) six times, the extract was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give 31 (95%, 1.9 mmol, 319.3 mg) as a colorless liquid.
　31 (1.9 mmol, 319.3 mg)、t-ブチルジメチルシリルクロリド（1.9 mmol, mg）およびイミダゾール（2.85 mmol, mL）をジメチルホルムアミド（2.0 mL）中室温で 10 分間撹拌した後、水を加えて反応を停止した。酢酸エチル (10 mL) で 2 回抽出した後、有機層を飽和食塩水で洗浄して硫酸マグネシウムで乾燥した。溶媒を減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 4:1）に付し、32 (1.55 mmol, 437.2 mg, 82%)を白色結晶として得た。 31 (1.9 mmol, 319.3 mg), t-butyldimethylsilyl chloride (1.9 mmol, mg) and imidazole (2.85 mmol, mL) were stirred in dimethylformamide (2.0 mL) at room temperature for 10 minutes, then water was added to react. stopped. After extraction with ethyl acetate (10 mL) twice, the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=4:1) to give 32 (1.55 mmol, 437.2 mg, 82%) as white crystals.
  塩化オキサリル（1.86 mmol, 159.7 μL）のジクロロメタン溶液（2.0 mL）にジメチルスルホキシド（1.70 mmol, 120.7μL）のジクロロメタン溶液（1.0 mL）を -78 度で加えた後、5 分間撹拌した。次いで、32 (1.55 mmol, 437.2 mg)のジクロロメタン（3.0 mL）溶液を -78 度で加えて 15 分間撹拌した後、トリエチルアミン（7.75 mmol, 1.08 mL）を加えて 10 分間撹拌した。室温まで自然昇温した後、飽和塩化アンモニウム水溶液を加えて反応を停止した。ジクロロメタン (10 mL) で抽出した後、有機層を飽和食塩水で洗浄して硫酸マグネシウムで乾燥した。溶媒を減圧下溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 30:1）に付し、33 (91%, 1.41 mmol, 395.0 mg)を無色液体として得た。 A dichloromethane solution (1.0 mL) of dimethylsulfoxide (1.70 mmol, 120.7 μL) was added to a dichloromethane solution (2.0 mL) of oxalyl chloride (1.86 mmol, 159.7 μL) at -78 degrees, and the mixture was stirred for 5 minutes. Then, a solution of 32 (1.55 mmol, 437.2 mg) in dichloromethane (3.0 mL) was added at -78 degrees and stirred for 15 minutes, then triethylamine (7.75 mmol, 1.08 mL) was added and stirred for 10 minutes. After the temperature was naturally raised to room temperature, a saturated ammonium chloride aqueous solution was added to terminate the reaction. After extraction with dichloromethane (10 mL), the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=30:1) to give 33 (91%, 1.41 mmol, 395.0 mg) as a colorless liquid.
　33（1 mmol, 280.2 mg)、アリルアミン（4 mmol, 300.5μL）、酢酸（4 mmol, 228.5μL）およびナトリウムトリアセトキシボロヒドリド（2.5 mmol, 529.9 mg）のテトラヒドロフランとジクロロエタン混合溶液 (1:1, 10.0 mL) に溶解させた後、室温で 24 時間攪拌した。飽和炭酸水素ナトリウム水溶液（10 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 2 回抽出した後、有機層を水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 4:1）に付し、34 (273.0 mg, 0.85 mmol, 85%) を淡黄色液体として得た。 Tetrahydrofuran and dichloroethane solution (1:1, 10.0 mL), and then stirred at room temperature for 24 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added to stop the reaction, and after extraction with ethyl acetate (20 mL) twice, the organic layer was washed with water (30 mL) and saturated brine, and diluted with magnesium sulfate. It was dried and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=4:1) to give 34 (273.0 mg, 0.85 mmol, 85%) as a pale yellow liquid.
  34(273.0 mg, 0.85 mmol) 、テトラキストリフェニルホスフィンパラジウム（2 mol%, 19.7 mg）および 1,3-ジメチルバルビツル酸（2.55 mmol, 398.2 mg）をジクロロメタン（7 mL）中 35 度で 17 時間撹拌した。飽和炭酸ナトリウム（25 mL）を加えて反応を停止した後、酢酸エチル (25 mL) で 2 回抽出した後、有機層を水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール ＝ 10:1）に付し、35 (143.4 mg, 0.51 mmol, 60%) を淡黄色液体として得た。 34 (273.0 mg, 0.85 mmol), tetrakistriphenylphosphine palladium (2 mol%, 19.7 mg) and 1,3-dimethylbarbituric acid (2.55 mmol, 398.2 mg) in dichloromethane (7 mL) at 35°C for 17 hours Stirred. After adding saturated sodium carbonate (25 mL) to stop the reaction, extract twice with ethyl acetate (25 mL), wash the organic layer with water (30 mL) and saturated brine, and dry over magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol = 10:1) to give 35 (143.4 mg, 0.51 mmol, 60%) as a pale yellow liquid.
  35(70.3 mg, 0.25 mmol) と 4,7-ジクロロキノリン (0.375 mmol, 73.8 mg) および炭酸カリウム（0.5 mmol, 68.9 mg）をジメチルスルホキシド（2.0 mL）中 150 度で 15 時間撹拌した。水（20 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 2 回抽出した。次いで、有機層を水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン: 酢酸エチル ＝ 1:1）に付し、36 (44.3 mg, 0.10 mmol, 40%) を淡黄色結晶として得た。 35 (70.3 mg, 0.25 mmol), 4,7-dichloroquinoline (0.375 mmol, 73.8 mg) and potassium carbonate (0.5 mmol, 68.9 mg) were stirred in dimethylsulfoxide (2.0 mL) at 150 degrees for 15 hours. After adding water (20 mL) to stop the reaction, the mixture was extracted twice with ethyl acetate (20 mL). Then, the organic layer was washed with water (30 mL) and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give 36 (44.3 mg, 0.10 mmol, 40%) as pale yellow crystals.
　36 (44.3 mg, 0.10 mmol) をテトラヒドロフラン（0.5 mL）に溶解した後、テトラブチルアンモニウムフルオリドの 1.0 M テトラヒドロフラン溶液（0.25 mmol, 250μL）を加えて室温で 5 時間撹拌した。水（20 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 2 回抽出した。次いで、有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール：トリエチルアミン ＝ 100:100:0.5）に付し、HA-98 (18.3 mg, 0.056 mmol, 56%) を白色結晶として得た。 After dissolving 36 (44.3 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL), a 1.0 M tetrabutylammonium fluoride solution in tetrahydrofuran (0.25 mmol, 250 μL) was added and stirred at room temperature for 5 hours. After adding water (20 mL) to stop the reaction, the mixture was extracted twice with ethyl acetate (20 mL). Then, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol:triethylamine=100:100:0.5) to give HA-98 (18.3 mg, 0.056 mmol, 56%) as white crystals.
［HA-98化合物データ］
HA-98: Colorless solid; mp 159.5-160.0℃ (Hexane:Diethyl ether = 5:1); Rf = 0.20 (Chloroform：Methanol = 8：1); 1H-NMR (400 MHz, CDCl3):δ1.16 (3H, s), 1.56-1.62 (1H, m), 1.64-1.72 (1H, m), 1.80 (1H, dd, J = 9.6, 4.0 Hz), 2.05-2.09 (1H, m), 2.34 (2H, sixtet, J = 9.2 Hz), 2.58 (2H, bd, J = 14.0 Hz), 3.69 (1H, q, J = 8.0 Hz), 4.36 (1H, bs), 4.99 (1H, d, J = 8.4 Hz), 5.50 (1H, s), 6.52 (1H, d, J = 5.6 Hz), 7.37 (1H, dd, J = 8.8, 1.6 Hz), 7.67 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 1.6 Hz), 8.48 (1H, d, J = 5.2 Hz).; 13C-NMR (100 MHz, CDCl3):δ17.6, 26.0, 28.1, 29.5, 35.1, 44.3, 62.3, 68.1, 99.7, 117.0, 120.6, 123.6, 125.4, 128.7, 135.0, 148.1, 149.0, 149.5, 151.8.; IR (KBr, cm-1): 3327, 2934, 1577, 1540, 754.; No M+ion peak was detected. [HA-98 compound data]
HA-98: Colorless solid; mp 159.5-160.0℃ (Hexane:Diethyl ether = 5:1); Rf = 0.20 (Chloroform:Methanol = 8:1); 1 H-NMR (400 MHz, CDCl 3 ): δ1. 16 (3H, s), 1.56-1.62 (1H, m), 1.64-1.72 (1H, m), 1.80 (1H, dd, J = 9.6, 4.0 Hz), 2.05-2.09 (1H, m), 2.34 ( 2H, sixtet, J = 9.2 Hz), 2.58 (2H, bd, J = 14.0 Hz), 3.69 (1H, q, J = 8.0 Hz), 4.36 (1H, bs), 4.99 (1H, d, J = 8.4 Hz), 5.50 (1H, s), 6.52 (1H, d, J = 5.6 Hz), 7.37 (1H, dd, J = 8.8, 1.6 Hz), 7.67 (1H, d, J = 9.2 Hz), 7.96 ( 1H, d, J = 1.6 Hz) , 8.48 ( 1H, d, J = 5.2 Hz). , 68.1, 99.7, 117.0, 120.6, 123.6, 125.4, 128.7 , 135.0, 148.1, 149.0, 149.5, 151.8 ; peak was detected.
　製造例１５　HA-101合成 Production Example 15 Synthesis of HA-101
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　水素化ナトリウム（25.1 mmol, 1.0 g）のテトラヒドロフラン懸濁液に、0 ℃ でジエチル（シアノメチル）ホスホナート（25.1 mmol, 5.0 mL）を滴下した後 30 分間撹拌した。次いで、33 (1.76 g, 6.27 mmol）を少しずつ加えた後、3 時間加熱還流下撹拌した。水（20 mL）を加えて反応を停止した後、酢酸エチル (10 mL) で 3 回抽出した。有機層を纏めて水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:エーテル ＝ 10:1）に付し、37 (1.448 g, 4.74 mmol, 76%) を無色液体として得た。 Diethyl (cyanomethyl) phosphonate (25.1 mmol, 5.0 mL) was added dropwise to a suspension of sodium hydride (25.1 mmol, 1.0 g) in tetrahydrofuran at 0 °C and then stirred for 30 minutes. Then, 33 (1.76 g, 6.27 mmol) was added little by little, and the mixture was heated under reflux with stirring for 3 hours. After adding water (20 mL) to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with water (30 mL) and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ether=10:1) to give 37 (1.448 g, 4.74 mmol, 76%) as a colorless liquid.
　 37 (327.7 mg, 1.07 mmol) のエタノール（20 mL）溶液に、Pd/C（Pd 10%, 144 mg, 44 w/w%）を加えて水素雰囲気下室温で 9 時間撹拌した。反応溶液をセライトを通して濾過した後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:ジエチルエーテル ＝ 50:1）に付し、38 (200.1 mg, 0.65 mmol, 60.6%) を無色液体として得た。 Pd/C (Pd 10%, 144 mg, 44 w/w%) was added to an ethanol (20 mL) solution of 37 (327.7 mg, 1.07 mmol) and stirred at room temperature for 9 hours under a hydrogen atmosphere. After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:diethyl ether = 50:1) to give 38 (200.1 mg, 0.65 mmol, 60.6%) as a colorless liquid.
　38（200.1 mg, 0.65 mmol）をエタノール（2 mL）に 80 ℃ で溶解した後、5M 水酸化カリウム水溶液（2 mL）を滴下して 15 時間撹拌した。室温まで放冷した後、飽和塩化アンモニウム水溶液を加えて反応を停止し、酢酸エチル (10 mL) で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:ジエチルエーテル ＝ 4:1）に付し、39 (210.0 mg, 0.643 mmol, 99%) を無色液体として得た。 After dissolving 38 (200.1 mg, 0.65 mmol) in ethanol (2 mL) at 80 °C, 5M potassium hydroxide aqueous solution (2 mL) was added dropwise and stirred for 15 hours. After allowing to cool to room temperature, a saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate (10 mL) three times. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:diethyl ether = 4:1) to give 39 (210.0 mg, 0.643 mmol, 99%) as a colorless liquid.
　リチウムアルミニウムヒドリド（48.8 mg, 1.28 mmol）をテトラヒドロフラン（10 mL）に懸濁させた後、39 (210.0 mg, 0.643 mmol) のテトラヒドロフラン（5 mL）溶液を 0 ℃で滴下した。次いで、反応混合液を昇温して 2 時間加熱還流下撹拌した。飽和塩化アンモニウム水溶液を加えて反応を停止した後、酢酸エチル (20 mL) で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル ＝ 4:1）に付し、40 (175.0 mg, 0.56 mmol, 87%) を無色液体として得た。 After suspending lithium aluminum hydride (48.8 mg, 1.28 mmol) in tetrahydrofuran (10 mL), a solution of 39 (210.0 mg, 0.643 mmol) in tetrahydrofuran (5 mL) was added dropwise at 0°C. Then, the reaction mixture was heated and stirred under heating under reflux for 2 hours. A saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate (20 mL) three times. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=4:1) to give 40 (175.0 mg, 0.56 mmol, 87%) as a colorless liquid.
  40(175.0 mg, 0.56 mmol) 、トリフェニルホスフィン（5.6 mmol, 1.47 g）、イミダゾール（5.6 mmol, 0.38 g）、ヨウ素（4.5 mmol, 1.14 g）のトルエン（10 mL）溶液を、80 ℃ で 1 時間撹拌した。飽和チオ硫酸ナトリウム水溶液を加えて反応を停止した後、ジクロロメタン（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（トルエン）に付し、41 (190.0 mg, 0.45 mmol, 80%) を無色液体として得た。 40 (175.0 mg, 0.56 mmol), triphenylphosphine (5.6 mmol, 1.47 g), imidazole (5.6 mmol, 0.38 g), and iodine (4.5 mmol, 1.14 g) in toluene (10 mL) at 80 °C. Stirred for an hour. A saturated aqueous sodium thiosulfate solution was added to stop the reaction, and the mixture was extracted three times with dichloromethane (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (toluene) to give 41 (190.0 mg, 0.45 mmol, 80%) as a colorless liquid.
  41（30.0 mg, 0.071 mmol）と 2-アミノ-7-クロロキノリン（15.2 mg, 0.0852 mmol）のジメチルホルムアミド（0.5 mL）溶液に、水素化ナトリウム（10.2 mg, 0.42 mmol）を加えて 80℃で 20 分間撹拌した。水を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール = 10:1）に付し、42 (27.1 mg, 0.057 mmol, 80%) を無色液体として得た。 Sodium hydride (10.2 mg, 0.42 mmol) was added to a solution of 41 (30.0 mg, 0.071 mmol) and 2-amino-7-chloroquinoline (15.2 mg, 0.0852 mmol) in dimethylformamide (0.5 mL) at 80°C. Stirred for 20 minutes. After adding water to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol = 10:1) to give 42 (27.1 mg, 0.057 mmol, 80%) as a colorless liquid.
  42 (27.1 mg, 0.057 mmol) をメタノール（8 mL）に溶解した後、6M 塩酸（5 mL）を加えて、50℃で 30 分間撹拌した。飽和炭酸水素ナトリウム水溶液を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて、水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール = 10:3）に付し、HA-101 (18.2 mg, 0.051 mmol, 89%) を白色結晶として得た。 42 (27.1 mg, 0.057 mmol) was dissolved in methanol (8 mL), 6M hydrochloric acid (5 mL) was added, and the mixture was stirred at 50°C for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to stop the reaction, and the mixture was extracted with ethyl acetate (10 mL) three times. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol = 10:3) to give HA-101 (18.2 mg, 0.051 mmol, 89%) as white crystals.
［HA-101化合物データ］
HA-101: Pale yellow solid; mp 184.5-185.0℃ (Washed by hexane); Rf = 0.17 (Ethyl acetate:Methanol = 10:3); 1H-NMR (400 MHz, CDCl3):δ1.30-1.66 (10H, m), 1.81-1.96 (4H, m), 2.01-2.11 (2H, m), 3.20-3.28 (1H, m), 3.30-3.38 (1H, m), 3.98 (1H, septet, J = 2.8 Hz), 5.03 (1H, bs), 6.40 (1H, d, J = 5.6 Hz), 7,36 (1H, d, J = 11.2 Hz), 7.65 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 2.0 Hz), 8.53 (1H, d, J = 5.2 Hz).; 13C-NMR (100 MHz, CDCl3):δ22.8, 28.4, 28.7, 28.9, 29.1, 30.5, 35.5, 40.5, 41.9, 42.2, 43.1, 66.7, 99.0, 115.4, 117.0, 120.8, 125.3, 128.7, 134.9, 149.7, 151.8.; IR (KBr, cm-1): 3307, 2928, 1581.; LRMS (EI) m/z: 358 (M+, 58%), 191 (M+-167, 100%); HRMS (EI): 計算値C21H27ClN2O (M+): 358.1812, 実測値 358.1799. [HA-101 compound data]
HA-101: Pale yellow solid; mp 184.5-185.0°C (Washed by hexane); Rf = 0.17 (Ethyl acetate:Methanol = 10:3); 1 H-NMR (400 MHz, CDCl 3 ): δ1.30-1.66 (10H, m), 1.81-1.96 (4H, m), 2.01-2.11 (2H, m), 3.20-3.28 (1H, m), 3.30-3.38 (1H, m), 3.98 (1H, septet, J = 2.8 Hz), 5.03 (1H, bs), 6.40 (1H, d, J = 5.6 Hz), 7, 36 (1H, d, J = 11.2 Hz), 7.65 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 2.0 Hz) , 8.53 ( 1H, d, J = 5.2 Hz). 35.5, 40.5, 41.9, 42.2, 43.1, 66.7, 99.0, 115.4, 117.0, 120.8, 125.3 , 128.7, 134.9, 149.7, 151.8. ) m/z: 358 (M + , 58%), 191 (M + -167, 100%); HRMS ( EI): calculated C21H27ClN2O  (M + ): 358.1812, found 358.1799.
　製造例１６　HA-100合成 Manufacturing Example 16 Synthesis of HA-100
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
　41（30.0 mg, 0.071 mmol）とタクリン（16.0 mg, 0.0852 mmol）のジメチルホルムアミド（0.5 mL）溶液に、水素化ナトリウム（10.2 mg, 0.42 mmol）を加えて 80℃で 20 分間撹拌した。水を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール = 10:1）に付し、43 (24.7 mg, 0.050 mmol, 71%) を無色液体として得た。 Sodium hydride (10.2 mg, 0.42 mmol) was added to a solution of 41 (30.0 mg, 0.071 mmol) and tacrine (16.0 mg, 0.0852 mmol) in dimethylformamide (0.5 mL) and stirred at 80°C for 20 minutes. After adding water to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol = 10:1) to give 43 (24.7 mg, 0.050 mmol, 71%) as a colorless liquid.
  43 (24.7 mg, 0.050 mmol) をメタノール（8 mL）に溶解した後、6M 塩酸（5 mL）を加えて、50℃で 30 分間撹拌した。飽和炭酸水素ナトリウム水溶液を加えて反応を停止した後、酢酸エチル（10 mL）で 3 回抽出した。有機層を纏めて、水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール = 10:3）に付し、HA-100 (15.3 mg, 0.040 mmol, 81%) を白色結晶として得た。 43 (24.7 mg, 0.050 mmol) was dissolved in methanol (8 mL), 6M hydrochloric acid (5 mL) was added, and the mixture was stirred at 50°C for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to stop the reaction, and the mixture was extracted with ethyl acetate (10 mL) three times. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol = 10:3) to give HA-100 (15.3 mg, 0.040 mmol, 81%) as white crystals.
［HA-100化合物データ］
HA-100: Colorless solid; mp 60.0-61.0℃ (Washed by hexane); Rf = 0.24 (Ethyl acetate:Methanol = 10:3); 1H-NMR (400 MHz, CDCl3):δ0.85 (3H, s), 1.25-1.47 (6H, m), 1.49-1.58 (4H, m), 1.70-1.78 (1H, m), 1.83-1.88 (3H, m), 1.90-1.96 (5H, m), 2.71 (2H, bs), 3.06 (2H, bs), 3.40 (1H, ddd, J = 12.4, 9.2, 5.2 Hz), 3.94 (1H, septet, J = 2.8 Hz), 7.34 (1H, td, J = 7.2,1.6 Hz), 7.55 (1H, td, J = 7.2, 1.6 Hz), 7.90 (1H, d, J = 8.0 Hz), 7.95 (1H, dd, J = 7.6, 0.4 Hz).; 13C-NMR (100 MHz, CDCl3):δ22.8, 23.0, 24.8, 28.3, 28.5, 28.9, 29.1, 31.6, 33.2, 34.0, 35.4, 40.0, 41.9, 42.0, 49.1, 66.7, 115.7, 120.1, 122.7, 123.5, 128.2, 128.8, 147.5, 150.7, 158.4.; IR (KBr, cm-1): 3349, 2931, 2870, 1580, 1562, 1500, 756.; LRMS (EI) m/z: 378 (M+, 25%), 211 (M+-167, 100%); HRMS (EI): 計算値C25H34N2O (M+): 378.2671, 実測値 378.2681. [HA-100 compound data]
HA-100: Colorless solid; mp 60.0-61.0℃ (Washed by hexane); Rf = 0.24 (Ethyl acetate:Methanol = 10:3); 1 H-NMR (400 MHz, CDCl 3 ): δ0.85 (3H, s), 1.25-1.47 (6H, m), 1.49-1.58 (4H, m), 1.70-1.78 (1H, m), 1.83-1.88 (3H, m), 1.90-1.96 (5H, m), 2.71 ( 2H, bs), 3.06 (2H, bs), 3.40 (1H, ddd, J = 12.4, 9.2, 5.2 Hz), 3.94 (1H, septet, J = 2.8 Hz), 7.34 (1H, td, J = 7.2, 1.6 Hz), 7.55 (1H, td, J = 7.2, 1.6 Hz), 7.90 (1H, d, J = 8.0 Hz), 7.95 (1H, dd, J = 7.6, 0.4 Hz).; 13 C-NMR ( 100 MHz, CDCl3 ): δ22.8, 23.0, 24.8, 28.3, 28.5, 28.9, 29.1, 31.6, 33.2, 34.0, 35.4, 40.0, 41.9, 42.0, 49.1, 66.7, 115.7, 120.5, 122.8, 122.7 , 128.8, 147.5, 150.7, 158.4.; IR (KBr, cm -1 ): 3349, 2931, 2870, 1580, 1562, 1500, 756.; LRMS (EI) m/z: 378 (M + , 25%) , 211 (M + -167, 100%); HRMS ( EI): calculated C25H34N2O  (M + ): 378.2671, found 378.2681.
　製造例１７　HA-87合成 Production Example 17 Synthesis of HA-87
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　シクロペンチルアミン(0.25 mmol, 24.6 mL) と 4,7-ジクロロキノリン (0.25 mmol, 49.2 mg) および炭酸カリウム（0.5 mmol, 68.9 mg）をジメチルホルムアミド（1.0 mL）中 50 度で 15 時間撹拌した。水（20 mL）を加えて反応を停止した後、酢酸エチル (20 mL) で 2 回抽出した後、有機層を水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン: 酢酸エチル ＝ 1:1）に付し、HA-87 (22.7 mg, 37%) を淡黄色結晶として得た。 Cyclopentylamine (0.25 mmol, 24.6 mL), 4,7-dichloroquinoline (0.25 mmol, 49.2 mg) and potassium carbonate (0.5 mmol, 68.9 mg) were stirred in dimethylformamide (1.0 mL) at 50 degrees for 15 hours. After adding water (20 mL) to stop the reaction, extract twice with ethyl acetate (20 mL), wash the organic layer with water (30 mL) and saturated brine, dry over magnesium sulfate, and vacuum. The solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give HA-87 (22.7 mg, 37%) as pale yellow crystals.
［HA-87化合物データ］
HA-87: Colorless solid. Mp. = 154.0-155.0 ℃.; Rf = 0.4 (Hexane:Ethyl acetate = 1:1).; 1H-NMR (400 MHz, CDCl3):δ1.58-1.85 (6H, m), 2.12-2.22 (2H, m), 3.94-4.01 (1H, m), 4.97 (1H, d, J = 4.8 Hz), 6.44 (1H, d, J = 5.6 Hz), 7.34 (1H, dd, J = 8.8, 2.0 Hz), 7.63 (1H, d, J = 9.2 Hz), 7.94 (1H, d, J = 2.0 Hz), 8.52 (1H, d, J = 5.2 Hz). 13C-NMR (100 MHz, CDCl3):δ24.1, 33.3, 54.2, 99.9, 117.1, 120.8, 125.1, 128.8, 134.7, 149.1, 149.2, 152.0. IR (KBr) 3252, 2957, 2866, 1575 cm-1. MS (EI) 246 (M+, 91%), 217 (M+-CH3N, 100%), HRMS Calcd for C14H15ClN2: 246.0924. Found: 246.0940. [HA-87 compound data]
HA-87: Colorless solid. Mp. = 154.0-155.0 ℃.; Rf = 0.4 (Hexane:Ethyl acetate = 1:1).; 1 H-NMR (400 MHz, CDCl 3 ): δ1.58-1.85 (6H , m), 2.12-2.22 (2H, m), 3.94-4.01 (1H, m), 4.97 (1H, d, J = 4.8 Hz), 6.44 (1H, d, J = 5.6 Hz), 7.34 (1H, dd, J = 8.8, 2.0 Hz), 7.63 (1H, d, J = 9.2 Hz), 7.94 (1H, d, J = 2.0 Hz), 8.52 ( 1H, d, J = 5.2 Hz). (100 MHz, CDCl3 ): δ 24.1, 33.3, 54.2, 99.9, 117.1, 120.8, 125.1, 128.8, 134.7, 149.1, 149.2, 152.0. IR (KBr) 3252, 2957, 2866, 1575 cm -1 . (EI) 246 (M + , 91%), 217 (M + -CH3N , 100%), HRMS Calcd for C14H15ClN2 : 246.0924 . Found: 246.0940.
　製造例１８　HA102 合成
　33 (500 mg, 1.78 mmol) の酢酸エチル (18 mL) 溶液に、Pd/C (1.03 mmol, 297 mg, 44 w/w%) を加えて水素雰囲気下室温で1.5 時間攪拌した。反応溶液をセライトに通してろ過した後、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン = ９：１）に付し、44 (508.5 mg, 1.78 mmol, quant.) を無色液体として得た。
44 (500 mg, 1.77 mmol)、アリルアミン（7.08 mmol, 532 μL）、酢酸 (7.08 mmol, 405 μL)、ナトリウムトリアセトキシボロヒドリド (4.43 mmol, 938 mg) のテトラヒドロフラン/ジクロロメタン混合溶液 (1:1, 17.7 mL) を、室温で24時間攪拌した。飽和炭酸水素ナトリウム水溶液 (20 mL) を加えて反応を停止した後、酢酸エチル (20 mL) で 4 回抽出した。有機層を纏めて、水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル = 4 : 1）に付し、45 (151.5 mg, 0.49 mmol, 28%) を淡黄色液体として得た。
45 (151.5 mg, 0.49 mmol)、テトラキストリフェニルホスフィンパラジウム (2 mol%, 11.1 mg)、1, 3 －ジメチルバルビツル酸 (1.47 mmol, 219 mg) のジクロロメタン (3.5 mL) 溶液を、35 度で 17 時間攪拌した。飽和炭酸ナトリウム水溶液 (10 mL) を加えて反応を停止した後、酢酸エチル (15 mL) で3 回抽出した。有機層を纏めて、水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル：メタノール = 8 : 1) に付し、46 (113.9 mg, 0.4 mmol, 82%) を黄色液体として得た。
46 (113.9 mg, 0.4 mmol)、4, 7－ジクロロキノリン (0.61 mmol, 120 mg)、炭酸カリウム (0.8 mmol, 113.5 mg) のジメチルスルホキシド (3.0 mL) 溶液を、150 度で15 時間攪拌した。水 (25 mL) を加えて反応を停止した後、酢酸エチル (20 mL) で5 回抽出した。有機層を纏めて、水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン：酢酸エチル = 4 : 1) に付し、47 (82.4 mg, 0.185 mmol, 46%) を淡茶色結晶として得た。
47 (82.4 mg, 0.185 mmol) のテトラヒドロフラン (0.9 mL) 溶液に、テトラブチルアンモニウムフルオリドの 1.0 M テトラヒドロフラン溶液 (0.44 mmol, 0.44 ml) を加えて室温で 5 時間攪拌した。水 (5 mL) を加えて反応を停止した後、酢酸エチル (10 mL) で3 回抽出した。有機層を纏めて、水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン：酢酸エチル = 1 : 7) に付し、HA102 (21.7 mg, 0.07 mmol, 38%) を白色結晶として得た。
[HA-102 化合物データ]
HA-102: Colorless solid; mp 239.5-240.1 ℃ (Chloroform:Hexane = 10:1).; Rf = 0.21 (Methanol:Chloroform = 8:2); 1H-NMR (400 MHz, CDCl3): δ 1.15 (3H, s), 1.46-1.60 (4H, m), 1.70-2.00 (7H, m), 2.30-2.39 (1H, m), 3.78 (1H, q, J = 9.2 Hz), 3.85-3.93 (1H, m), 4.93 (1H, d, J = 8.4 Hz), 6.51 (1H, d, J = 5.6 Hz), 7.36 (1H, dd, J = 9.2, 1.6 Hz), 7.60 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 1.6 Hz), 8.50 (1H, d, J = 5.2 Hz).; 13C-NMR (100 MHz, CDCl3): δ 23.0, 25.1, 25.8, 28.4, 30.9, 33.9, 42.1, 44.2, 63.3, 66.8, 99.6, 117.2, 120.5, 125.3, 128.8, 134.9, 149.1, 149.8, 151.9.; IR (KBr, cm-1): 3437, 1636, 1577.; HRMS (EI): 計算値C19H23ClN2O (M+): 331.1572, 実測値 331.1570.  Preparation 18 HA102 Synthesis To a solution of 33 (500 mg, 1.78 mmol) in ethyl acetate (18 mL), Pd/C (1.03 mmol, 297 mg, 44 w/w%) was added and stirred at room temperature for 1.5 hours under hydrogen atmosphere. did. After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:hexane=9:1) to give 44 (508.5 mg, 1.78 mmol, quant.) as a colorless liquid.
A tetrahydrofuran/dichloromethane mixture solution (1:1, 17.7 mL) was stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogencarbonate solution (20 mL) was added to stop the reaction, and the mixture was extracted four times with ethyl acetate (20 mL). The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=4:1) to give 45 (151.5 mg, 0.49 mmol, 28%) as a pale yellow liquid.
A solution of 45 (151.5 mg, 0.49 mmol), tetrakistriphenylphosphine palladium (2 mol%, 11.1 mg), and 1, 3-dimethylbarbituric acid (1.47 mmol, 219 mg) in dichloromethane (3.5 mL) was heated at 35°C. Stirred for 17 hours. A saturated aqueous sodium carbonate solution (10 mL) was added to stop the reaction, and the mixture was extracted three times with ethyl acetate (15 mL). The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate:methanol=8:1) to give 46 (113.9 mg, 0.4 mmol, 82%) as a yellow liquid.
A solution of 46 (113.9 mg, 0.4 mmol), 4,7-dichloroquinoline (0.61 mmol, 120 mg) and potassium carbonate (0.8 mmol, 113.5 mg) in dimethylsulfoxide (3.0 mL) was stirred at 150 degrees for 15 hours. After adding water (25 mL) to stop the reaction, the mixture was extracted five times with ethyl acetate (20 mL). The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=4:1) to give 47 (82.4 mg, 0.185 mmol, 46%) as pale brown crystals.
To a solution of 47 (82.4 mg, 0.185 mmol) in tetrahydrofuran (0.9 mL) was added tetrabutylammonium fluoride in 1.0 M tetrahydrofuran solution (0.44 mmol, 0.44 ml), and the mixture was stirred at room temperature for 5 hours. After adding water (5 mL) to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:7) to give HA102 (21.7 mg, 0.07 mmol, 38%) as white crystals.
[HA-102 compound data]
HA-102: Colorless solid; mp 239.5-240.1 ℃ (Chloroform:Hexane = 10:1).; Rf = 0.21 (Methanol:Chloroform = 8:2); 1 H-NMR (400 MHz, CDCl 3 ): δ 1.15 (3H, s), 1.46-1.60 (4H, m), 1.70-2.00 (7H, m), 2.30-2.39 (1H, m), 3.78 (1H, q, J = 9.2 Hz), 3.85-3.93 (1H , m), 4.93 (1H, d, J = 8.4 Hz), 6.51 (1H, d, J = 5.6 Hz), 7.36 (1H, dd, J = 9.2, 1.6 Hz), 7.60 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 1.6 Hz), 8.50 (1H, d, J = 5.2 Hz).; 13 C-NMR (100 MHz, CDCl 3 ): δ 23.0, 25.1, 25.8, 28.4, 30.9, 33.9, 42.1, 44.2, 63.3, 66.8, 99.6, 117.2, 120.5, 125.3, 128.8, 134.9, 149.1, 149.8 , 151.9. ): calculated C19H23ClN2O (M+ ) : 331.1572 , found 331.1570.
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　製造例１９　HA103 合成　
36 (0.17 mmol, 75 mg) のテトラヒドロフラン溶液 (0.6 mL) に、1.0 M ボラン・テトラヒドロフラン溶液 (0.5 mL) を氷冷下ゆっくり滴下した後、室温まで昇温し2.5 時間攪拌した。その後反応液に 5 M 水酸化ナトリウム水溶液 (0.6 mL) および30% 過酸化水素溶液 (0.3 mL) をゆっくり滴下した後、室温まで昇温し 16 時間攪拌した。飽和食塩水 (10 mL) を加えて反応を停止した後、クロロホルム (20 mL) で3 回抽出した。有機層を纏めて、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン：酢酸エチル = 1 : 1) に付し、48 (21.0 mg, 0.046 mmol, 27%) を白色結晶として得た。
48 (21.0 mg, 0.046 mmol) をテトラヒドロフラン (0.22 mL) に溶解した後、1.0 M テトラブチルアンモニウムフルオリド・テトラヒドロフラン溶液 (0.11 mmol, 0.11 mL) を加えて、室温で 5 時間攪拌した。水 (3 mL) を加えて反応を停止した後、酢酸エチル (10 mL) で3 回抽出した。有機層を纏めて、水および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル) に付し、HA103 (9.2 mg, 0.026 mmol, 58%) を白色結晶として得た。
[HA-103 化合物データ]
HA-103: Colorless solid; Rf = 0.04 (Ethyl acetate); 1H-NMR (400 MHz, CDCl3): δ 0.98 (3H, s), 1.45 (1H, dt, J = 12.8, 4.0 Hz), 1.61-1.63 (2H, m), 1.73-1.87 (6H, m), 1.94-1.98 (1H, m), 2.42-2.51 (1H, m), 3.46-3.51 (1H, m), 3.54-3.57 (1H, m), 3.70-3.76 (1H, m), 4.89 (1H, d, J = 8.0 Hz), 6.52 (1H, d, J = 5.2 Hz), 7.37 (1H, dd, J = 8.8, 2.4 Hz), 7.62 (1H, d, J = 8.4 Hz), 7.97 (1H, d, J = 2.4 Hz), 8.50 (1H, d, J = 5.2 Hz).; IR (KBr, cm-1): 3320, 2926, 1577, 1260, 1019, 801.; HRMS (EI): 計算値C19H23ClN2O2(M++H): 347.1521, 実測値 347.1508.  Production Example 19 HA103 Synthesis
A 1.0 M borane/tetrahydrofuran solution (0.5 mL) was slowly added dropwise to a tetrahydrofuran solution (0.6 mL) of 36 (0.17 mmol, 75 mg) under ice cooling, and the mixture was warmed to room temperature and stirred for 2.5 hours. After that, 5 M aqueous sodium hydroxide solution (0.6 mL) and 30% hydrogen peroxide solution (0.3 mL) were slowly added dropwise to the reaction solution, and the mixture was warmed to room temperature and stirred for 16 hours. Saturated saline (10 mL) was added to stop the reaction, and the mixture was extracted with chloroform (20 mL) three times. The organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give 48 (21.0 mg, 0.046 mmol, 27%) as white crystals.
After dissolving 48 (21.0 mg, 0.046 mmol) in tetrahydrofuran (0.22 mL), 1.0 M tetrabutylammonium fluoride/tetrahydrofuran solution (0.11 mmol, 0.11 mL) was added, and the mixture was stirred at room temperature for 5 hours. After adding water (3 mL) to stop the reaction, the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate) to give HA103 (9.2 mg, 0.026 mmol, 58%) as white crystals.
[HA-103 compound data]
HA-103: Colorless solid; Rf = 0.04 (Ethyl acetate); 1 H-NMR (400 MHz, CDCl 3 ): δ 0.98 (3H, s), 1.45 (1H, dt, J = 12.8, 4.0 Hz), 1.61 -1.63 (2H, m), 1.73-1.87 (6H, m), 1.94-1.98 (1H, m), 2.42-2.51 (1H, m), 3.46-3.51 (1H, m), 3.54-3.57 (1H, m), 3.70-3.76 (1H, m), 4.89 (1H, d, J = 8.0 Hz), 6.52 (1H, d, J = 5.2 Hz), 7.37 (1H, dd, J = 8.8, 2.4 Hz), 7.62 (1H, d, J = 8.4 Hz), 7.97 (1H, d, J = 2.4 Hz), 8.50 (1H, d, J = 5.2 Hz).; 1577, 1260, 1019, 801.; HRMS (EI): calculated C19H23ClN2O2 (M + + H ): 347.1521 , found 347.1508.
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　製造例２０　HA104 合成
HA-98 (0.091 mmol, 30 mg) のテトラヒドロフラン溶液 (1.83 mL) に、ピリジン (0.27 mmol, 22.1 μL)、無水酢酸 (0.27 mmol, 25.8 μL) および 4 －ジメチルアミノピリジン (0.008 mmol, 1 mg) を氷冷下加えた後、室温で 12 時間攪拌した。酢酸エチル(10 mL) を加えて希釈し、0.1 M 塩酸水溶液 (10 mL) を加えて反応を停止した後、酢酸エチル (10 mL) で3 回抽出した。有機層を纏めて、飽和炭酸水素ナトリウム水溶液 (10 mL) および飽和食塩水 (10 mL) で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン：酢酸エチル = 1 : 1) に付し、HA104 (19.0 mg, 0.051 mmol, 57%) を白色結晶として得た。
[HA-104 化合物データ]
HA-104: Colorless solid; mp 174.6-175.2 ℃ (Hexane:Chloroform = 5:1).; Rf = 0.4 (Ethyl acetate); 1H-NMR (400 MHz, CDCl3): δ 1.20 (3H, s), 1.56-1.86 (4H, m), 2.07 (3H, s), 2.07-2.13 (1H, m), 2.31-2.40 (2H, m), 2.57-2.67 (1H, m), 3.69-3.76 (1H, m), 5.22 (1H, bs), 5.41-5.45 (1H, m), 5.45 (1H, s), 6.53 (1H, d, J = 6.0 Hz), 7.37 (1H, dd, J = 8.8, 2.4 Hz), 7.73 (1H, d, J = 8.8 Hz), 7.97 (1H, d, J = 2.4 Hz), 8.46 (1H, d, J = 6.0 Hz).; 13C-NMR (100 MHz, CDCl3): δ 17.6, 21.4, 25.1, 26.1, 28.0, 34.9, 44.3, 62.4, 70.9, 99.7, 116.9, 119.4, 120.9, 125.6, 128.1, 135.4, 148.2, 149.9, 150.5, 151.0, 171.0.; IR (KBr, cm-1): 3406, 1710, 1572, 1531, 1450, 1022, 853.; HRMS (EI): 計算値C21H24ClN2O2(M+): 371.1521, 実測値 371.1559.  Production Example 20 HA104 Synthesis
To a tetrahydrofuran solution (1.83 mL) of HA-98 (0.091 mmol, 30 mg) were added pyridine (0.27 mmol, 22.1 μL), acetic anhydride (0.27 mmol, 25.8 μL) and 4-dimethylaminopyridine (0.008 mmol, 1 mg). was added under ice-cooling, and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (10 mL) was added for dilution, 0.1 M hydrochloric acid aqueous solution (10 mL) was added to stop the reaction, and the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution (10 mL) and saturated brine (10 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give HA104 (19.0 mg, 0.051 mmol, 57%) as white crystals.
[HA-104 compound data]
HA-104: Colorless solid; mp 174.6-175.2 ℃ (Hexane:Chloroform = 5:1).; Rf = 0.4 (Ethyl acetate); 1 H-NMR (400 MHz, CDCl 3 ): δ 1.20 (3H, s) , 1.56-1.86 (4H, m), 2.07 (3H, s), 2.07-2.13 (1H, m), 2.31-2.40 (2H, m), 2.57-2.67 (1H, m), 3.69-3.76 (1H, m), 5.22 (1H, bs), 5.41-5.45 (1H, m), 5.45 (1H, s), 6.53 (1H, d, J = 6.0 Hz), 7.37 (1H, dd, J = 8.8, 2.4 Hz ), 7.73 (1H, d, J = 8.8 Hz), 7.97 (1H, d, J = 2.4 Hz), 8.46 (1H, d, J = 6.0 Hz).; 13 C-NMR (100 MHz, CDCl 3 ) : δ 17.6, 21.4, 25.1, 26.1, 28.0, 34.9, 44.3, 62.4, 70.9, 99.7, 116.9, 119.4, 120.9, 125.6, 128.1, 135.4, 148.2, 149.9, 150.5 cm; -1 ): 3406, 1710, 1572, 1531, 1450, 1022, 853.; HRMS (EI): calculated C21H24ClN2O2 ( M + ) : 371.1521 , found 371.1559.
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　製造例２１　HA105 合成
HA98 (0.1 mmol, 32.8 mg)、トリエチルアミン (0.1 mmol, 18 μL) のジクロロメタン溶液 (0.8 mL) に室温で 4-シアノベンゾイルクロライド (0.1 mmol, 17 mg)のジクロロメタン溶液 (0.5 mL) を滴下した後40 ℃で 6 時間攪拌した。水 (10 mL) を加えて反応を停止した後、酢酸エチル (20 mL) で3 回抽出した。有機層を纏めて水 (30 mL) および飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン：酢酸エチル = 1 : 3) に付し、HA105 (20.0 mg, 0.044 mmol, 44%)を淡黄色個体として得た。
[HA-105 化合物データ]
HA-105: Pale yellow solid; mp 115.3-116.4 ℃ (Hexane:Chloroform = 5:1).; Rf = 0.53 (Ethyl acetate); 1H-NMR (400 MHz, CDCl3): δ 1.26 (3H, s), 1.67- 1.94 (4H, m), 2.22 －2.29 (1H, m), 2.36 － 2.46 (2H, m), 2.61 － 2.70 (1H, m), 3.76 － 3.82 (1H, m), 5.57 (1H, s), 5.67 － 5.71 (1H, m), 6.56 (1H, d, J = 5.6 Hz), 7.38 (1H, dd, J = 2.0, 8.8 Hz), 7.75 (1H, dd, J = 3.2, 8.0 Hz), 7.75 (2H, d, J = 8.8 Hz), 7.99 (1H, d, J = 2.4 Hz), 8.16 (2H, d, J = 8.8 Hz), 8.49 (1H, d, J = 6.0 Hz).; IR (KBr, cm-1) ν 3413, 2957, 2230, 1717, 1575, 1272.; MS (ESI) m/z 458 (M++H, 100%) HRMS 計算値 C27H24ClN3O2(M++H): 458.1630, 実測値 458.1653.
Figure JPOXMLDOC01-appb-C000071
 Production Example 21 HA105 Synthesis
To a dichloromethane solution (0.8 mL) of HA98 (0.1 mmol, 32.8 mg) and triethylamine (0.1 mmol, 18 μL) was added dropwise a dichloromethane solution (0.5 mL) of 4-cyanobenzoyl chloride (0.1 mmol, 17 mg) at room temperature. Stirred at 40° C. for 6 hours. After adding water (10 mL) to stop the reaction, the mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined, washed with water (30 mL) and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:3) to give HA105 (20.0 mg, 0.044 mmol, 44%) as a pale yellow solid.
[HA-105 compound data]
HA-105: Pale yellow solid; mp 115.3-116.4 ℃ (Hexane:Chloroform = 5:1).; Rf = 0.53 (Ethyl acetate); 1 H-NMR (400 MHz, CDCl 3 ): δ 1.26 (3H, s ), 1.67 - 1.94 (4H, m), 2.22 - 2.29 (1H, m), 2.36 - 2.46 (2H, m), 2.61 - 2.70 (1H, m), 3.76 - 3.82 (1H, m), 5.57 (1H , s), 5.67 － 5.71 (1H, m), 6.56 (1H, d, J = 5.6 Hz), 7.38 (1H, dd, J = 2.0, 8.8 Hz), 7.75 (1H, dd, J = 3.2, 8.0 Hz), 7.75 (2H, d, J = 8.8 Hz), 7.99 (1H, d, J = 2.4 Hz), 8.16 (2H, d, J = 8.8 Hz), 8.49 (1H, d, J = 6.0 Hz) IR (KBr, cm -1 ) ν 3413, 2957, 2230, 1717, 1575, 1272.; MS (ESI) m/z 458 (M + +H, 100%) HRMS calculated C 27 H 24 ClN 3 O2 (M + +H): 458.1630, found 458.1653.
Figure JPOXMLDOC01-appb-C000071
　製造例２２　HA106 合成
ニコチン酸 (0.2 mmol, 24.6 mg) のトルエン (0.8 mL) 溶液に塩化チオニル (0.4 mmol, 30μL) を室温で滴下した後、加熱還流下2 時間攪拌した。減圧下溶媒と未反応の塩化チオニルを留去し、3-ピリジンカルボリルクロリドを得た。次いで、脱水テトラヒドロフラン (2 mL) を加えた後、HA98 (0.1 mmol, 32.8 mg) とトリエチルアミン (0.125 mmol, 52.5 μL) を加えて 80 ℃で 3 時間攪拌した。水 (10 mL) を加えて反応を停止した後、酢酸エチル (20 mL) で3 回抽出した。有機層を纏めて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル) に付し、HA106 (4.5 mg, 0.011 mmol, 11%) を淡黄色固体として得た。
[HA-106 化合物データ]
HA-106: Pale yellow solid; M.p. 82.2-83.8 ℃ (Hexane/Chloroform = 5).; Rf = 0.3 (Ethyl acetate); 1H-NMR (400 MHz, CDCl3) δ 1.27 (3H, s), 1.62-1.75 (2H, m), 1.85-1.94 (4H, m), 2.23-2.28 (1H, m), 2.37-2.44 (2H, m), 2.64-2.72 (1H, m), 3.74-3.84 (1H, m), 5.59 (1H, s), 5.66-5.74 (1H, m), 7.39-7.42 (2H, m), 7.76 (1H, d, J = 8.0 Hz), 8.01 (1H, d, J = 8.0 Hz), 8.32 (1H, td, J = 2.0, 8.0 Hz), 8.48 (1H, d, J = 5.2 Hz), 8.79 (1H, dd, J = 2.0, 5,2 Hz), 9.24 (1H, d, J = 1.2 Hz).; IR (KBr, cm-1) ν 3420, 1717, 1576, 1507, 1457, 743.; MS (ESI) m/z 434 (M++H, 100%) HRMS 計算値 C25H25ClN3O2 (M++H): 434.1630. 実測値 434.1652.
Figure JPOXMLDOC01-appb-C000072
 Production Example 22 To a solution of HA106 synthetic nicotinic acid (0.2 mmol, 24.6 mg) in toluene (0.8 mL) was added dropwise thionyl chloride (0.4 mmol, 30 µL) at room temperature, followed by stirring for 2 hours while heating under reflux. The solvent and unreacted thionyl chloride were distilled off under reduced pressure to obtain 3-pyridinecarboryl chloride. After adding dehydrated tetrahydrofuran (2 mL), HA98 (0.1 mmol, 32.8 mg) and triethylamine (0.125 mmol, 52.5 μL) were added, and the mixture was stirred at 80° C. for 3 hours. After adding water (10 mL) to stop the reaction, the mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate) to give HA106 (4.5 mg, 0.011 mmol, 11%) as a pale yellow solid.
[HA-106 compound data]
HA-106: Pale yellow solid; Mp 82.2-83.8 ℃ (Hexane/Chloroform = 5).; Rf = 0.3 (Ethyl acetate); 1 H-NMR (400 MHz, CDCl 3 ) δ 1.27 (3H, s), 1.62 -1.75 (2H, m), 1.85-1.94 (4H, m), 2.23-2.28 (1H, m), 2.37-2.44 (2H, m), 2.64-2.72 (1H, m), 3.74-3.84 (1H, m), 5.59 (1H, s), 5.66-5.74 (1H, m), 7.39-7.42 (2H, m), 7.76 (1H, d, J = 8.0 Hz), 8.01 (1H, d, J = 8.0 Hz ), 8.32 (1H, td, J = 2.0, 8.0 Hz), 8.48 (1H, d, J = 5.2 Hz), 8.79 (1H, dd, J = 2.0, 5,2 Hz), 9.24 (1H, d, J = 1.2 Hz).; IR (KBr, cm -1 ) ν 3420, 1717, 1576, 1507, 1457, 743.; MS (ESI) m/z 434 (M + +H, 100%) calculated HRMS C 25 H 25 ClN 3 O 2 (M + +H): 434.1630. Found 434.1652.
Figure JPOXMLDOC01-appb-C000072
　実験例１
候補化合物によるHNMT阻害活性の測定
ヒトHNMT蛋白質（50 nM）、ヒスタミン（10 μM、シグマアルドリッチ）、Sアデノシルメチオニン（10 μM、ニューイングランドバイオラボ）、1x MTase-glo Reagent（プロメガ）を緩衝液中（20 mM Tris、50 ｍM NaCl、1 mM EDTA、3 ｍM MgCl2、0.1 mg/mL BSA、1 mM DTT（全て富士フイルム和光純薬）、pH8.0）に溶解した。この溶液に対し、候補化合物を最終濃度が30 pM、100 pM、300 pM、1 nM、3 nM、10 nM、30 nM、100 nM、300 nM、1 μMとなるように加えて、全量で25 μLとなるようにし、96ウェルプレート（コーニング）に分注し、37℃で1時間反応させた。その後MTase-glo Detection Solution（プロメガ）を25 μLを加えて、更に25℃で30分間反応させた。その後、Luminoskan Ascent（ThermoFisher Scientific）を用いて発光量を測定し、阻害活性を求めた。IC50値はPrismソフトウェア（GraphPad）を用いて算出した。 Experimental example 1
Measurement of HNMT inhibitory activity by candidate compounds Human HNMT protein (50 nM), histamine (10 μM, Sigma-Aldrich), S-adenosylmethionine (10 μM, New England Biolabs), 1x MTase-glo Reagent (Promega) in buffer (20 mM Tris, 50 mM NaCl, 1 mM EDTA, 3 mM MgCl2, 0.1 mg/mL BSA, 1 mM DTT (all Fuji Film Wako Pure Chemical Industries), pH 8.0). To this solution, candidate compounds were added to final concentrations of 30 pM, 100 pM, 300 pM, 1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, and 1 μM for a total of 25 The mixture was made up to μL, dispensed into a 96-well plate (Corning), and reacted at 37°C for 1 hour. After that, 25 μL of MTase-glo Detection Solution (Promega) was added and reacted at 25° C. for 30 minutes. Then, the amount of luminescence was measured using Luminoskan Ascent (ThermoFisher Scientific) to determine the inhibitory activity. IC50 values were calculated using Prism software (GraphPad).
　結果を図１に示す。検討した4化合物はin vitroでHNMT阻害活性を有することが確認され、それぞれのIC50値はHA76 157 nM、HA87 464 nM、HA90 112 nM、HA95 88 nM、HA98 562 nM、HA102 1320 nM、HA104 17.5 nM、HA105 40.2 nM、HA106 403 nMと算出された。 The results are shown in Figure 1. The four compounds investigated were confirmed to have HNMT inhibitory activity in vitro, and their respective IC50 values were HA76 157 nM, HA87 464 nM, HA90 112 nM, HA95 88 nM, HA98 562 nM, HA102 1320 nM, HA104 17.5 nM. , HA105 40.2 nM and HA106 403 nM.
　実験例２
候補化合物による脳内ヒスタミン濃度増加作用
8週齢の雄性C57BL6/Jマウス（エスエルシー）を用いて実験を行った。まず候補化合物をDMSO（シグマアルドリッチ）に溶解し、3 μmol/kg, 10 μmol/kg, 30 μmol/kg, 100 μmol/kg の濃度でマウスの腹腔内に投与した。その後、マウスを頸椎脱臼にて安楽死処置し、脳を皮質、間脳、脳幹、小脳の4部位に分けて採取し、それぞれの重さを測定した。それぞれの脳部位に対して10倍量の0.4 M過塩素酸（富士フイルム和光純薬）を加えてポリトロンホモジェナイザーにてホモジェナイズし、その後20,000 x g、4℃、15分間の条件で遠心分離を行った。遠心上清に含まれるヒスタミンおよび1メチルヒスタミン量をHPLCシステム（エイコム）にて測定した。得られたヒスタミン量および1メチルヒスタミン量を組織重量で補正した。結果を図２～１２に示す。HA-98、HA102、HA104、HA105、HA106は脳内のヒスタミン濃度を増加させ、ヒスタミン代謝産物の1メチルヒスタミンの濃度を減少させた。 Experimental example 2
Effects of candidate compounds on increasing histamine levels in the brain
Experiments were performed using 8-week-old male C57BL6/J mice (SLC). First, candidate compounds were dissolved in DMSO (Sigma-Aldrich) and administered intraperitoneally to mice at concentrations of 3 μmol/kg, 10 μmol/kg, 30 μmol/kg and 100 μmol/kg. After that, the mice were euthanized by cervical dislocation, and the brain was divided into 4 parts, cortex, diencephalon, brainstem, and cerebellum, and the weight of each part was measured. Add 10 times the volume of 0.4 M perchloric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) to each brain region, homogenize with a Polytron homogenizer, and then centrifuge at 20,000 x g at 4°C for 15 minutes. gone. The amounts of histamine and 1-methylhistamine contained in the centrifugation supernatant were measured using an HPLC system (Acom). The histamine and 1-methylhistamine amounts obtained were corrected by tissue weight. The results are shown in Figures 2-12. HA-98, HA102, HA104, HA105, and HA106 increased histamine levels in the brain and decreased levels of histamine metabolite 1-methylhistamine.

Claims (4)

  1. 下記一般式（Ｉ）で表される化合物又はその塩
    Figure JPOXMLDOC01-appb-C000001
     ［式中、ｌは０～３の整数を示す。ｍは０～３の整数を示す。ｎは０～４の整数を示す。Ｘはハロゲン、アルキル基、ヒドロキシアルキル基、ヒドロキシル基、アルコキシ基、アルキルアミノ基又はアミノアルキル基を示す。Ｙはヒドロキシル基、置換基を有していてもよいアシルオキシ基、スルフェート基、カルバモイルオキシ基、チオール基又は置換基を有していてもよいアミノ基を示す。ｌが２以上の場合、複数存在するＸは同一でも異なっていてもよい。ｍが２以上の場合、複数存在するＹは同一でも異なっていてもよい。ｎが１以上の場合、炭素数ｎの二価飽和炭化水素基は、置換基として１個のオキソ基（＝Ｏ）を有してもよい。
    基
    Figure JPOXMLDOC01-appb-C000002
     は
    Figure JPOXMLDOC01-appb-C000003
     を示す。
    基
    Figure JPOXMLDOC01-appb-C000004
     は
    Figure JPOXMLDOC01-appb-C000005
     を示す。ただし、
    Figure JPOXMLDOC01-appb-C000006
     は除く。］     A compound represented by the following general formula (I) or a salt thereof
    Figure JPOXMLDOC01-appb-C000001
     [In the formula, l represents an integer of 0 to 3. m represents an integer of 0 to 3; n represents an integer of 0-4. X represents a halogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, an alkylamino group or an aminoalkyl group. Y represents a hydroxyl group, an optionally substituted acyloxy group, a sulfate group, a carbamoyloxy group, a thiol group or an optionally substituted amino group. When l is 2 or more, multiple X's may be the same or different. When m is 2 or more, multiple Y's may be the same or different. When n is 1 or more, the divalent saturated hydrocarbon group having n carbon atoms may have one oxo group (=O) as a substituent.
    basis
    Figure JPOXMLDOC01-appb-C000002
     teeth
    Figure JPOXMLDOC01-appb-C000003
     indicates
    basis
    Figure JPOXMLDOC01-appb-C000004
     teeth
    Figure JPOXMLDOC01-appb-C000005
     indicates however,
    Figure JPOXMLDOC01-appb-C000006
     except. ]
  2. 下記一般式（Ｉ）で表される化合物又はその塩を含む、ＨＮＭＴ阻害剤：
    Figure JPOXMLDOC01-appb-C000007
     ［式中、ｌは０～３の整数を示す。ｍは０～３の整数を示す。ｎの整数は０～４を示す。Ｘはハロゲン、アルキル基、ヒドロキシアルキル基、ヒドロキシル基、アルコキシ基、アルキルアミノ基又はアミノアルキル基を示す。Ｙはヒドロキシル基、置換基を有していてもよいアシルオキシ基、スルフェート基、カルバモイルオキシ基、チオール基又は置換基を有していてもよいアミノ基を示す。ｌが２以上の場合、複数存在するＸは同一でも異なっていてもよい。ｍが２以上の場合、複数存在するＹは同一でも異なっていてもよい。ｎが１以上の場合、炭素数ｎの二価飽和炭化水素基は、置換基として１個のオキソ基（＝Ｏ）を有してもよい。
    基
    Figure JPOXMLDOC01-appb-C000008
     は
    Figure JPOXMLDOC01-appb-C000009
     を示す。
    基
    Figure JPOXMLDOC01-appb-C000010
     は
    Figure JPOXMLDOC01-appb-C000011
     を示す。］     An HNMT inhibitor comprising a compound represented by the following general formula (I) or a salt thereof:
    Figure JPOXMLDOC01-appb-C000007
     [In the formula, l represents an integer of 0 to 3. m represents an integer of 0 to 3; The integer n represents 0-4. X represents a halogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, an alkylamino group or an aminoalkyl group. Y represents a hydroxyl group, an optionally substituted acyloxy group, a sulfate group, a carbamoyloxy group, a thiol group or an optionally substituted amino group. When l is 2 or more, multiple X's may be the same or different. When m is 2 or more, multiple Y's may be the same or different. When n is 1 or more, the divalent saturated hydrocarbon group having n carbon atoms may have one oxo group (=O) as a substituent.
    basis
    Figure JPOXMLDOC01-appb-C000008
     teeth
    Figure JPOXMLDOC01-appb-C000009
     indicates
    basis
    Figure JPOXMLDOC01-appb-C000010
     teeth
    Figure JPOXMLDOC01-appb-C000011
     indicates ]
  3. 下記一般式（Ｉ）で表される化合物又はその塩を含む、ＡＤＨＤ、ナルコレプシー又はアルツハイマーを予防又は治療するための医薬：
    Figure JPOXMLDOC01-appb-C000012
     ［式中、ｌは０～３の整数を示す。ｍは０～３の整数を示す。ｎは０～４の整数を示す。Ｘはハロゲン、アルキル基、ヒドロキシアルキル基、ヒドロキシル基、アルコキシ基、アルキルアミノ基又はアミノアルキル基を示す。Ｙはヒドロキシル基、置換基を有していてもよいアシルオキシ基、スルフェート基、チオール基又は置換基を有していてもよいアミノ基を示す。ｌが２以上の場合、複数存在するＸは同一でも異なっていてもよい。ｍが２以上の場合、複数存在するＹは同一でも異なっていてもよい。ｎが１以上の場合、炭素数ｎの二価飽和炭化水素基は、置換基として１個のオキソ基（＝Ｏ）を有してもよい。
    基
    Figure JPOXMLDOC01-appb-C000013
     は
    Figure JPOXMLDOC01-appb-C000014
     を示す。
    基
    Figure JPOXMLDOC01-appb-C000015
     は
    Figure JPOXMLDOC01-appb-C000016
     を示す。］     A medicament for preventing or treating ADHD, narcolepsy or Alzheimer's, comprising a compound represented by the following general formula (I) or a salt thereof:
    Figure JPOXMLDOC01-appb-C000012
     [In the formula, l represents an integer of 0 to 3. m represents an integer of 0 to 3; n represents an integer of 0-4. X represents a halogen, an alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, an alkylamino group or an aminoalkyl group. Y represents a hydroxyl group, an optionally substituted acyloxy group, a sulfate group, a thiol group or an optionally substituted amino group. When l is 2 or more, multiple X's may be the same or different. When m is 2 or more, multiple Y's may be the same or different. When n is 1 or more, the divalent saturated hydrocarbon group having n carbon atoms may have one oxo group (=O) as a substituent.
    basis
    Figure JPOXMLDOC01-appb-C000013
     teeth
    Figure JPOXMLDOC01-appb-C000014
     indicates
    basis
    Figure JPOXMLDOC01-appb-C000015
     teeth
    Figure JPOXMLDOC01-appb-C000016
     indicates ]
  4. ｌが１以上の場合、少なくとも１つのＸがハロゲンであり、ｍが１以上の場合、少なくとも１つのＹがヒドロキシル基又は置換基を有していてもよいアシルオキシ基であり、ｎが０～２である、請求項１に記載の化合物もしくはその塩、請求項２に記載のＨＮＭＴ阻害剤又は請求項３に記載の医薬。 when l is 1 or more, at least one X is a halogen, when m is 1 or more, at least one Y is a hydroxyl group or an optionally substituted acyloxy group, and n is 0 to 2 The compound or salt thereof according to claim 1, the HNMT inhibitor according to claim 2, or the medicament according to claim 3.
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